Arsenic-induced PML targeting onto nuclear bodies: Implications for the treatment of acute promyelocytic leukemia

PubMed Central

Zhu, Jun; Koken, Marcel H. M.; Quignon, Frédérique; Chelbi-Alix, Mounira K.; Degos, Laurent; Wang, Zhen Yi; Chen, Zhu; de Thé, Hugues

1997-01-01

Acute promyelocytic leukemia (APL) is associated with the t(15;17) translocation, which generates a PML/RARα fusion protein between PML, a growth suppressor localized on nuclear matrix-associated bodies, and RARα, a nuclear receptor for retinoic acid (RA). PML/RARα was proposed to block myeloid differentiation through inhibition of nuclear receptor response, as does a dominant negative RARα mutant. In addition, in APL cells, PML/RARα displaces PML and other nuclear body (NB) antigens onto nuclear microspeckles, likely resulting in the loss of PML and/or NB functions. RA leads to clinical remissions through induction of terminal differentiation, for which the respective contributions of RARα (or PML/RARα) activation, PML/RARα degradation, and restoration of NB antigens localization are poorly determined. Arsenic trioxide also leads to remissions in APL patients, presumably through induction of apoptosis. We demonstrate that in non-APL cells, arsenic recruits the nucleoplasmic form of several NB antigens onto NB, but induces the degradation of PML only, identifying a powerful tool to approach NB function. In APL cells, arsenic targets PML and PML/RARα onto NB and induces their degradation. Thus, RA and arsenic target RARα and PML, respectively, but both induce the degradation of the PML/RARα fusion protein, which should contribute to their therapeutic effects. The difference in the cellular events triggered by these two agents likely stems from RA-induced transcriptional activation and arsenic effects on NB proteins. PMID:9108090

Promyelocytic Leukemia Protein (PML) Controls Listeria monocytogenes Infection

PubMed Central

Ribet, David; Lallemand-Breitenbach, Valérie; Ferhi, Omar; Nahori, Marie-Anne; Varet, Hugo

2017-01-01

ABSTRACT The promyelocytic leukemia protein (PML) is the main organizer of stress-responsive subnuclear structures called PML nuclear bodies. These structures recruit multiple interactors and modulate their abundance or their posttranslational modifications, notably by the SUMO ubiquitin-like modifiers. The involvement of PML in antiviral responses is well established. In contrast, the role of PML in bacterial infection remains poorly characterized. Here, we show that PML restricts infection by the pathogenic bacterium Listeria monocytogenes but not by Salmonella enterica serovar Typhimurium. During infection, PML undergoes oxidation-mediated multimerization, associates with the nuclear matrix, and becomes de-SUMOylated due to the pore-forming activity of the Listeria toxin listeriolysin O (LLO). These events trigger an antibacterial response that is not observed during in vitro infection by an LLO-defective Listeria mutant, but which can be phenocopied by specific induction of PML de-SUMOylation. Using transcriptomic and proteomic microarrays, we also characterized a network of immunity genes and cytokines, which are regulated by PML in response to Listeria infection but independently from the listeriolysin O toxin. Our study thus highlights two mechanistically distinct complementary roles of PML in host responses against bacterial infection. PMID:28074026

The translation initiation factor 3 subunit eIF3K interacts with PML and associates with PML nuclear bodies

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

Salsman, Jayme; Pinder, Jordan; Tse, Brenda

2013-10-15

The promyelocytic leukemia protein (PML) is a tumor suppressor protein that regulates a variety of important cellular processes, including gene expression, DNA repair and cell fate decisions. Integral to its function is the ability of PML to form nuclear bodies (NBs) that serve as hubs for the interaction and modification of over 90 cellular proteins. There are seven canonical isoforms of PML, which encode diverse C-termini generated by alternative pre-mRNA splicing. Recruitment of specific cellular proteins to PML NBs is mediated by protein–protein interactions with individual PML isoforms. Using a yeast two-hybrid screen employing peptide sequences unique to PML isoformmore » I (PML-I), we identified an interaction with the eukaryotic initiation factor 3 subunit K (eIF3K), and in the process identified a novel eIF3K isoform, which we term eIF3K-2. We further demonstrate that eIF3K and PML interact both in vitro via pull-down assays, as well as in vivo within human cells by co-immunoprecipitation and co-immunofluorescence. In addition, eIF3K isoform 2 (eIF3K-2) colocalizes to PML bodies, particularly those enriched in PML-I, while eIF3K isoform 1 associates poorly with PML NBs. Thus, we report eIF3K as the first known subunit of the eIF3 translation pre-initiation complex to interact directly with the PML protein, and provide data implicating alternative splicing of both PML and eIF3K as a possible regulatory mechanism for eIF3K localization at PML NBs. - Highlights: • The PML-I C-terminus, encoded by exon 9, interacts with translation factor eIF3K. • We identify a novel eIF3K isoform that excludes exon 2 (eIF3K-2). • eIF3K-2 preferentially associates with PML bodies enriched in PML-I vs. PML-IV. • Alternative splicing of eIF3K regulates association with PML bodies.« less

Entrapment of viral capsids in nuclear PML cages is an intrinsic antiviral host defense against varicella-zoster virus.

PubMed

Reichelt, Mike; Wang, Li; Sommer, Marvin; Perrino, John; Nour, Adel M; Sen, Nandini; Baiker, Armin; Zerboni, Leigh; Arvin, Ann M

2011-02-03

The herpesviruses, like most other DNA viruses, replicate in the host cell nucleus. Subnuclear domains known as promyelocytic leukemia protein nuclear bodies (PML-NBs), or ND10 bodies, have been implicated in restricting early herpesviral gene expression. These viruses have evolved countermeasures to disperse PML-NBs, as shown in cells infected in vitro, but information about the fate of PML-NBs and their functions in herpesvirus infected cells in vivo is limited. Varicella-zoster virus (VZV) is an alphaherpesvirus with tropism for skin, lymphocytes and sensory ganglia, where it establishes latency. Here, we identify large PML-NBs that sequester newly assembled nucleocapsids (NC) in neurons and satellite cells of human dorsal root ganglia (DRG) and skin cells infected with VZV in vivo. Quantitative immuno-electron microscopy revealed that these distinctive nuclear bodies consisted of PML fibers forming spherical cages that enclosed mature and immature VZV NCs. Of six PML isoforms, only PML IV promoted the sequestration of NCs. PML IV significantly inhibited viral infection and interacted with the ORF23 capsid surface protein, which was identified as a target for PML-mediated NC sequestration. The unique PML IV C-terminal domain was required for both capsid entrapment and antiviral activity. Similar large PML-NBs, termed clastosomes, sequester aberrant polyglutamine (polyQ) proteins, such as Huntingtin (Htt), in several neurodegenerative disorders. We found that PML IV cages co-sequester HttQ72 and ORF23 protein in VZV infected cells. Our data show that PML cages contribute to the intrinsic antiviral defense by sensing and entrapping VZV nucleocapsids, thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The efficient sequestration of virion capsids in PML cages appears to be the outcome of a basic cytoprotective function of this distinctive category of PML-NBs in sensing and safely containing nuclear aggregates of aberrant proteins.

PMLRARα binds to Fas and suppresses Fas-mediated apoptosis through recruiting c-FLIP in vivo

PubMed Central

Tao, Rong-Hua; Berkova, Zuzana; Wise, Jillian F.; Rezaeian, Abdol-Hossein; Daniluk, Urszula; Ao, Xue; Hawke, David H.; Karp, Judith E.; Lin, Hui-Kuan; Molldrem, Jeffrey J.

2011-01-01

Defective Fas signaling leads to resistance to various anticancer therapies. Presence of potential inhibitors of Fas which could block Fas signaling can explain cancer cells resistance to apoptosis. We identified promyelocytic leukemia protein (PML) as a Fas-interacting protein using mass spectrometry analysis. The function of PML is blocked by its dominant-negative form PML–retinoic acid receptor α (PMLRARα). We found PMLRARα interaction with Fas in acute promyelocytic leukemia (APL)–derived cells and APL primary cells, and PML-Fas complexes in normal tissues. Binding of PMLRARα to Fas was mapped to the B-box domain of PML moiety and death domain of Fas. PMLRARα blockage of Fas apoptosis was demonstrated in U937/PR9 cells, human APL cells and transgenic mouse APL cells, in which PMLRARα recruited c-FLIPL/S and excluded procaspase 8 from Fas death signaling complex. PMLRARα expression in mice protected the mice against a lethal dose of agonistic anti-Fas antibody (P < .001) and the protected tissues contained Fas-PMLRARα-cFLIP complexes. Taken together, PMLRARα binds to Fas and blocks Fas-mediated apoptosis in APL by forming an apoptotic inhibitory complex with c-FLIP. The presence of PML-Fas complexes across different tissues implicates that PML functions in apoptosis regulation and tumor suppression are mediated by direct interaction with Fas. PMID:21803845

Sp100 isoform-specific regulation of human adenovirus 5 gene expression.

PubMed

Berscheminski, Julia; Wimmer, Peter; Brun, Juliane; Ip, Wing Hang; Groitl, Peter; Horlacher, Tim; Jaffray, Ellis; Hay, Ron T; Dobner, Thomas; Schreiner, Sabrina

2014-06-01

Promyelocytic leukemia nuclear bodies (PML-NBs) are nuclear structures that accumulate intrinsic host factors to restrict viral infections. To ensure viral replication, these must be limited by expression of viral early regulatory proteins that functionally inhibit PML-NB-associated antiviral effects. To benefit from the activating capabilities of Sp100A and simultaneously limit repression by Sp100B, -C, and -HMG, adenoviruses (Ads) employ several features to selectively and individually target these isoforms. Ads induce relocalization of Sp100B, -C, and -HMG from PML-NBs prior to association with viral replication centers. In contrast, Sp100A is kept at the PML tracks that surround the newly formed viral replication centers as designated sites of active transcription. We concluded that the host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression. Ad-dependent loss of Sp100 SUMOylation is another crucial part of the virus repertoire to counteract intrinsic immunity by circumventing Sp100 association with HP1, therefore limiting chromatin condensation. We provide evidence that Ad selectively counteracts antiviral responses and, at the same time, benefits from PML-NB-associated components which support viral gene expression by actively recruiting them to PML track-like structures. Our findings provide insights into novel strategies for manipulating transcriptional regulation to either inactivate or amplify viral gene expression. We describe an adenoviral evasion strategy that involves isoform-specific and active manipulation of the PML-associated restriction factor Sp100. Recently, we reported that the adenoviral transactivator E1A targets PML-II to efficiently activate viral transcription. In contrast, the PML-associated proteins Daxx and ATRX are inhibited by early viral factors. We show that this concept is more intricate and significant than originally believed, since adenoviruses apparently take advantage of specific PML-NB-associated proteins and simultaneously inhibit antiviral measures to maintain the viral infectious program. Specifically, we observed Ad-induced relocalization of the Sp100 isoforms B, C, and HMG from PML-NBs juxtaposed with viral replication centers. In contrast, Sp100A is retained at Ad-induced PML tracks that surround the newly formed viral replication centers, acting as designated sites of active transcription. The host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression.

Case definition for progressive multifocal leukoencephalopathy following treatment with monoclonal antibodies.

PubMed

Mentzer, Dirk; Prestel, Jürgen; Adams, Ortwin; Gold, Ralf; Hartung, Hans-Peter; Hengel, Hartmut; Kieseier, Bernd C; Ludwig, Wolf-Dieter; Keller-Stanislawski, Brigitte

2012-09-01

Novel immunosuppressive/modulating therapies with monoclonal antibodies (MABs) have been associated with progressive multifocal leukoencephalopathy (PML), a potentially fatal disease of the brain caused by the JC virus. Taking the complex diagnostic testing and heterogeneous clinical presentation of PML into account, an agreed case definition for PML is a prerequisite for a thorough assessment of PML. A working group was established to develop a standardised case definition for PML which permits data comparability across clinical trials, postauthorisation safety studies and passive postmarketing surveillance. The case definition is designed to define levels of diagnostic certainty of reported PML cases following treatment with MABs. It was subsequently used to categorise retrospectively suspected PML cases from Germany reported to the Paul-Ehrlich-Institute as the responsible national competent authority. The algorithm of the case definition is based on clinical symptoms, PCR for JC virus DNA in cerebrospinal fluid, brain MRI, and brain biopsy/autopsy. The case definition was applied to 119 suspected cases of PML following treatment with MABs and is considered to be helpful for case ascertainment of suspected PML cases for various MABs covering a broad spectrum of indications. Even if the available information is not yet complete, the case definition provides a level of diagnostic certainty. The proposed case definition permits data comparability among different medicinal products and among active as well as passive surveillance settings. It may form a basis for meaningful risk analysis and communication for regulators and healthcare professionals.

Interplay between Herpesvirus Infection and Host Defense by PML Nuclear Bodies.

PubMed

Tavalai, Nina; Stamminger, Thomas

2009-12-01

In recent studies we and others have identified the cellular proteins PML, hDaxx, and Sp100, which form a subnuclear structure known as nuclear domain 10 (ND10) or PML nuclear bodies (PML-NBs), as host restriction factors that counteract herpesviral infections by inhibiting viral replication at different stages. The antiviral function of ND10, however, is antagonized by viral regulatory proteins (e.g., ICP0 of herpes simplex virus; IE1 of human cytomegalovirus) which induce either a modification or disruption of ND10. This review will summarize the current knowledge on how viral replication is inhibited by ND10 proteins. Furthermore, herpesviral strategies to defeat this host defense mechanism are discussed.

Distinct temporal roles for the promyelocytic leukaemia (PML) protein in the sequential regulation of intracellular host immunity to HSV-1 infection

PubMed Central

Alandijany, Thamir; Conn, Kristen L.; McFarlane, Steven; Orr, Anne

2018-01-01

Detection of viral nucleic acids plays a critical role in the induction of intracellular host immune defences. However, the temporal recruitment of immune regulators to infecting viral genomes remains poorly defined due to the technical difficulties associated with low genome copy-number detection. Here we utilize 5-Ethynyl-2’-deoxyuridine (EdU) labelling of herpes simplex virus 1 (HSV-1) DNA in combination with click chemistry to examine the sequential recruitment of host immune regulators to infecting viral genomes under low multiplicity of infection conditions. Following viral genome entry into the nucleus, PML-nuclear bodies (PML-NBs) rapidly entrapped viral DNA (vDNA) leading to a block in viral replication in the absence of the viral PML-NB antagonist ICP0. This pre-existing intrinsic host defence to infection occurred independently of the vDNA pathogen sensor IFI16 (Interferon Gamma Inducible Protein 16) and the induction of interferon stimulated gene (ISG) expression, demonstrating that vDNA entry into the nucleus alone is not sufficient to induce a robust innate immune response. Saturation of this pre-existing intrinsic host defence during HSV-1 ICP0-null mutant infection led to the stable recruitment of PML and IFI16 into vDNA complexes associated with ICP4, and led to the induction of ISG expression. This induced innate immune response occurred in a PML-, IFI16-, and Janus-Associated Kinase (JAK)-dependent manner and was restricted by phosphonoacetic acid, demonstrating that vDNA polymerase activity is required for the robust induction of ISG expression during HSV-1 infection. Our data identifies dual roles for PML in the sequential regulation of intrinsic and innate immunity to HSV-1 infection that are dependent on viral genome delivery to the nucleus and the onset of vDNA replication, respectively. These intracellular host defences are counteracted by ICP0, which targets PML for degradation from the outset of nuclear infection to promote vDNA release from PML-NBs and the onset of HSV-1 lytic replication. PMID:29309427

HIV-associated progressive multifocal leukoencephalopathy: longitudinal study of JC virus non-coding control region rearrangements and host immunity.

PubMed

Iannetta, Marco; Bellizzi, Anna; Lo Menzo, Sara; Anzivino, Elena; D'Abramo, Alessandra; Oliva, Alessandra; D'Agostino, Claudia; d'Ettorre, Gabriella; Pietropaolo, Valeria; Vullo, Vincenzo; Ciardi, Maria Rosa

2013-06-01

John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), contains a hyper-variable non-coding control region usually detected in urine of healthy individuals as archetype form and in the brain and cerebrospinal fluid (CSF) of PML patients as rearranged form. We report a case of HIV-related PML with clinical, immunological and virological data longitudinally collected. On admission (t0), after 8-week treatment with a rescue highly active antiretroviral therapy (HAART), the patient showed a CSF-JCV load of 16,732 gEq/ml, undetectable HIV-RNA and an increase of CD4+ cell count. Brain magnetic resonance imaging (MRI) showed PML-compatible lesions without contrast enhancement. We considered PML-immune reconstitution inflammatory syndrome as plausible because of the sudden onset of neurological symptoms after the effective HAART. An experimental JCV treatment with mefloquine and mirtazapine was added to steroid boli. Two weeks later (t1), motor function worsened and MRI showed expanded lesions with cytotoxic oedema. CSF JCV-DNA increased (26,263 gEq/ml) and JCV viremia was detected. After 4 weeks (t2), JCV was detected only in CSF (37,719 gEq/ml), and 8 weeks after admission (t3), JC viral load decreased in CSF and JCV viremia reappeared. The patient showed high level of immune activation both in peripheral blood and CSF. He died 4 weeks later. Considering disease progression, combined therapy failure and immune hyper-activation, we finally classified the case as classical PML. The archetype variant found in CSF at t0/t3 and a rearranged sequence detected at t1/t2 suggest that PML can develop from an archetype virus and that the appearance of rearranged genotypes contribute to faster disease progression.

Overexpression of Promyelocytic Leukemia Protein Precludes the Dispersal of ND10 Structures and Has No Effect on Accumulation of Infectious Herpes Simplex Virus 1 or Its Proteins

PubMed Central

Lopez, Pascal; Jacob, Robert J.; Roizman, Bernard

2002-01-01

A key early event in the replication of herpes simplex virus 1 (HSV-1) is the localization of infected-cell protein no. 0 (ICP0) in nuclear structures knows as ND10 or promyelocytic leukemia oncogenic domains (PODs). This is followed by dispersal of ND10 constituents such as the promyelocytic leukemia protein (PML), CREB-binding protein (CBP), and Daxx. Numerous experiments have shown that this dispersal is mediated by ICP0. PML is thought to be the organizing structural component of ND10. To determine whether the virus targets PML because it is inimical to viral replication, telomerase-immortalized human foreskin fibroblasts and HEp-2 cells were transduced with wild-type baculovirus or a baculovirus expressing the Mr 69,000 form of PML. The transduced cultures were examined for expression and localization of PML in mock-infected and HSV-1-infected cells. The results obtained from studies of cells overexpressing PML were as follows. (i) Transduced cells accumulate large amounts of unmodified and SUMO-I-modified PML. (ii) Mock-infected cells exhibited enlarged ND10 structures containing CBP and Daxx in addition to PML. (iii) In infected cells, ICP0 colocalized with PML in ND10 early in infection, but the two proteins did not overlap or were juxtaposed in orderly structures. (iv) The enlarged ND10 structures remained intact at least until 12 h after infection and retained CBP and Daxx in addition to PML. (v) Overexpression of PML had no effect on the accumulation of viral proteins representative of α, β, or γ groups and had no effect on the accumulation of infectious virus in cells infected with wild-type virus or a mutant (R7910) from which the α0 genes had been deleted. These results indicate the following: (i) PML overexpressed in transduced cells cannot be differentiated from endogenous PML with respect to sumoylation and localization in ND10 structures. (ii) PML does not affect viral replication or the changes in the localization of ICP0 through infection. (iii) Disaggregation of ND10 structures is not an obligatory event essential for viral replication. PMID:12186918

HSV-1 Genome Subnuclear Positioning and Associations with Host-Cell PML-NBs and Centromeres Regulate LAT Locus Transcription during Latency in Neurons

PubMed Central

Catez, Frédéric; Picard, Christel; Held, Kathrin; Gross, Sylvain; Rousseau, Antoine; Theil, Diethilde; Sawtell, Nancy; Labetoulle, Marc; Lomonte, Patrick

2012-01-01

Major human pathologies are caused by nuclear replicative viruses establishing life-long latent infection in their host. During latency the genomes of these viruses are intimately interacting with the cell nucleus environment. A hallmark of herpes simplex virus type 1 (HSV-1) latency establishment is the shutdown of lytic genes expression and the concomitant induction of the latency associated (LAT) transcripts. Although the setting up and the maintenance of the latent genetic program is most likely dependent on a subtle interplay between viral and nuclear factors, this remains uninvestigated. Combining the use of in situ fluorescent-based approaches and high-resolution microscopic analysis, we show that HSV-1 genomes adopt specific nuclear patterns in sensory neurons of latently infected mice (28 days post-inoculation, d.p.i.). Latent HSV-1 genomes display two major patterns, called “Single” and “Multiple”, which associate with centromeres, and with promyelocytic leukemia nuclear bodies (PML-NBs) as viral DNA-containing PML-NBs (DCP-NBs). 3D-image reconstruction of DCP-NBs shows that PML forms a shell around viral genomes and associated Daxx and ATRX, two PML partners within PML-NBs. During latency establishment (6 d.p.i.), infected mouse TGs display, at the level of the whole TG and in individual cells, a substantial increase of PML amount consistent with the interferon-mediated antiviral role of PML. “Single” and “Multiple” patterns are reminiscent of low and high-viral genome copy-containing neurons. We show that LAT expression is significantly favored within the “Multiple” pattern, which underlines a heterogeneity of LAT expression dependent on the viral genome copy number, pattern acquisition, and association with nuclear domains. Infection of PML-knockout mice demonstrates that PML/PML-NBs are involved in virus nuclear pattern acquisition, and negatively regulate the expression of the LAT. This study demonstrates that nuclear domains including PML-NBs and centromeres are functionally involved in the control of HSV-1 latency, and represent a key level of host/virus interaction. PMID:22912575

Understanding the molecular pathogenesis of acute promyelocytic leukemia.

PubMed

Lo-Coco, Francesco; Hasan, Syed Khizer

2014-03-01

Acute promyelocytic leukemia (APL) is a distinct subset of acute myeloid leukemia (AML) associated with peculiar biologic and clinical features and requiring specific management. At the genetic level, APL is featured by a unique chromosome translocation t(15;17) which results in the PML-RARα gene fusion and chimeric protein. APL is the first example of differentiation therapy targeted to a defined genetic target i.e. PML-RARα. PML-RARα behaves as an altered retinoic acid receptor with an ability of transmitting oncogenic signaling leading to accumulation of undifferentiated promyelocytes. All-trans-retinoic acid (ATRA) induces disease remission in APL patients by triggering terminal differentiation of leukemic promyelocytes. More recently, arsenic trioxide (ATO) has been shown to contribute degradation of the PML-RARα oncoprotein through bonding the PML moiety and has shown excellent synergism with ATRA in clinical trials. Elucidating the oncogenic signaling of PML-RARα through various transcription factors and the study of APL mouse models have greatly helped to understand the molecular pathogenesis of APL. However, the precise molecular mechanism by which t(15;17) is formed and initiates leukemia remains unknown. While transforming oncogenic potential of PML-RARα has been described extensively, the mechanistic events important for the formation of t(15;17) have been taken from the model of Therapy-related APL (t-APL). Copyright © 2014 Elsevier Ltd. All rights reserved.

SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1

PubMed Central

Brown, James R.; Conn, Kristen L.; Wasson, Peter; Charman, Matthew; Tong, Lily; Grant, Kyle; McFarlane, Steven

2016-01-01

ABSTRACT Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukemia nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signaling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase protein inhibitor of activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation-competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well-characterized PML-NB proteins. In contrast to that of Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation. IMPORTANCE Adaptive, innate, and intrinsic immunity cooperatively and efficiently restrict the propagation of viral pathogens. Intrinsic immunity mediated by constitutively expressed cellular proteins represents the first line of intracellular defense against infection. PML-NB constituent proteins mediate aspects of intrinsic immunity to restrict herpes simplex virus 1 (HSV-1) as well as other viruses. These proteins repress viral replication through mechanisms that rely on SUMO signaling. However, the participating SUMOylation enzymes are not known. We identify the SUMO ligase PIAS1 as a constituent PML-NB antiviral protein. This finding distinguishes a SUMO ligase that may mediate signaling events important in PML-NB-mediated intrinsic immunity. Moreover, this research complements the recent identification of PIAS4 as an intrinsic antiviral factor, supporting a role for PIAS proteins as both positive and negative regulators of host immunity to virus infection. PMID:27099310

SUMO Ligase Protein Inhibitor of Activated STAT1 (PIAS1) Is a Constituent Promyelocytic Leukemia Nuclear Body Protein That Contributes to the Intrinsic Antiviral Immune Response to Herpes Simplex Virus 1.

PubMed

Brown, James R; Conn, Kristen L; Wasson, Peter; Charman, Matthew; Tong, Lily; Grant, Kyle; McFarlane, Steven; Boutell, Chris

2016-07-01

Aspects of intrinsic antiviral immunity are mediated by promyelocytic leukemia nuclear body (PML-NB) constituent proteins. During herpesvirus infection, these antiviral proteins are independently recruited to nuclear domains that contain infecting viral genomes to cooperatively promote viral genome silencing. Central to the execution of this particular antiviral response is the small ubiquitin-like modifier (SUMO) signaling pathway. However, the participating SUMOylation enzymes are not fully characterized. We identify the SUMO ligase protein inhibitor of activated STAT1 (PIAS1) as a constituent PML-NB protein. We show that PIAS1 localizes at PML-NBs in a SUMO interaction motif (SIM)-dependent manner that requires SUMOylated or SUMOylation-competent PML. Following infection with herpes simplex virus 1 (HSV-1), PIAS1 is recruited to nuclear sites associated with viral genome entry in a SIM-dependent manner, consistent with the SIM-dependent recruitment mechanisms of other well-characterized PML-NB proteins. In contrast to that of Daxx and Sp100, however, the recruitment of PIAS1 is enhanced by PML. PIAS1 promotes the stable accumulation of SUMO1 at nuclear sites associated with HSV-1 genome entry, whereas the accumulation of other evaluated PML-NB proteins occurs independently of PIAS1. We show that PIAS1 cooperatively contributes to HSV-1 restriction through mechanisms that are additive to those of PML and cooperative with those of PIAS4. The antiviral mechanisms of PIAS1 are counteracted by ICP0, the HSV-1 SUMO-targeted ubiquitin ligase, which disrupts the recruitment of PIAS1 to nuclear domains that contain infecting HSV-1 genomes through mechanisms that do not directly result in PIAS1 degradation. Adaptive, innate, and intrinsic immunity cooperatively and efficiently restrict the propagation of viral pathogens. Intrinsic immunity mediated by constitutively expressed cellular proteins represents the first line of intracellular defense against infection. PML-NB constituent proteins mediate aspects of intrinsic immunity to restrict herpes simplex virus 1 (HSV-1) as well as other viruses. These proteins repress viral replication through mechanisms that rely on SUMO signaling. However, the participating SUMOylation enzymes are not known. We identify the SUMO ligase PIAS1 as a constituent PML-NB antiviral protein. This finding distinguishes a SUMO ligase that may mediate signaling events important in PML-NB-mediated intrinsic immunity. Moreover, this research complements the recent identification of PIAS4 as an intrinsic antiviral factor, supporting a role for PIAS proteins as both positive and negative regulators of host immunity to virus infection. Copyright © 2016 Brown et al.

An enzyme-free and label-free surface plasmon resonance biosensor for ultrasensitive detection of fusion gene based on DNA self-assembly hydrogel with streptavidin encapsulation.

PubMed

Guo, Bin; Wen, Bo; Cheng, Wei; Zhou, Xiaoyan; Duan, Xiaolei; Zhao, Min; Xia, Qianfeng; Ding, Shijia

2018-07-30

In this research, an enzyme-free and label-free surface plasmon resonance (SPR) biosensing strategy has been developed for ultrasensitive detection of fusion gene based on the heterogeneous target-triggered DNA self-assembly aptamer-based hydrogel with streptavidin (SA) encapsulation. In the presence of target, the capture probes (Cp) immobilized on the chip surface can capture the PML/RARα, forming a Cp-PML/RARα duplex. After that, the aptamer-based network hydrogel nanostructure is formed on the gold surface via target-triggered self-assembly of X shaped polymers. Subsequently, the SA can be encapsulated into hydrogel by the specific binding of SA aptamer, forming the complex with super molecular weight. Thus, the developed strategy achieves dramatic enhancement of the SPR signal. Using PML/RARα "S" subtype as model analyte, the developed biosensing method can detect target down to 45.22 fM with a wide linear range from 100 fM to 10 nM. Moreover, the high efficiency biosensing method shows excellent practical ability to identify the clinical PCR products of PML/RARα. Thus, this proposed strategy presents a powerful platform for ultrasensitive detection of fusion gene and early diagnosis and monitoring of disease. Copyright © 2018 Elsevier B.V. All rights reserved.

SUMO5, a Novel Poly-SUMO Isoform, Regulates PML Nuclear Bodies

PubMed Central

Liang, Ya-Chen; Lee, Chia-Chin; Yao, Ya-Li; Lai, Chien-Chen; Schmitz, M. Lienhard; Yang, Wen-Ming

2016-01-01

Promyelocytic leukemia nuclear bodies (PML-NBs) are PML-based nuclear structures that regulate various cellular processes. SUMOylation, the process of covalently conjugating small ubiquitin-like modifiers (SUMOs), is required for both the formation and the disruption of PML-NBs. However, detailed mechanisms of how SUMOylation regulates these processes remain unknown. Here we report that SUMO5, a novel SUMO variant, mediates the growth and disruption of PML-NBs. PolySUMO5 conjugation of PML at lysine 160 facilitates recruitment of PML-NB components, which enlarges PML-NBs. SUMO5 also increases polySUMO2/3 conjugation of PML, resulting in RNF4-mediated disruption of PML-NBs. The acute promyelocytic leukemia oncoprotein PML-RARα blocks SUMO5 conjugation of PML, causing cytoplasmic displacement of PML and disruption of PML-NBs. Our work not only identifies a new member of the SUMO family but also reveals the mechanistic basis of the PML-NB life cycle in human cells. PMID:27211601

SUMOylation Promotes PML Degradation during Encephalomyocarditis Virus Infection▿

PubMed Central

El Mchichi, Bouchra; Regad, Tarik; Maroui, Mohamed-Ali; Rodriguez, Manuel S.; Aminev, Aleksey; Gerbaud, Sylvie; Escriou, Nicolas; Dianoux, Laurent; Chelbi-Alix, Mounira K.

2010-01-01

The promyelocytic leukemia (PML) protein is expressed in the diffuse nuclear fraction of the nucleoplasm and in matrix-associated structures, known as nuclear bodies (NBs). PML NB formation requires the covalent modification of PML to SUMO. The noncovalent interactions of SUMO with PML based on the identification of a SUMO-interacting motif within PML seem to be required for further recruitment within PML NBs of SUMOylated proteins. RNA viruses whose replication takes place in the cytoplasm and is inhibited by PML have developed various strategies to counteract the antiviral defense mediated by PML NBs. We show here that primary fibroblasts derived from PML knockout mice are more sensitive to infection with encephalomyocarditis virus (EMCV), suggesting that the absence of PML results in an increase in EMCV replication. Also, we found that EMCV induces a decrease in PML protein levels both in interferon-treated cells and in PMLIII-expressing cells. Reduction of PML was carried out by the EMCV 3C protease. Indeed, at early times postinfection, EMCV induced PML transfer from the nucleoplasm to the nuclear matrix and PML conjugation to SUMO-1, SUMO-2, and SUMO-3, leading to an increase in PML body size where the viral protease 3C and the proteasome component were found colocalizing with PML within the NBs. This process was followed by PML degradation occurring in a proteasome- and SUMO-dependent manner and did not involve the SUMO-interacting motif of PML. Together, these findings reveal a new mechanism evolved by EMCV to antagonize the PML pathway in the interferon-induced antiviral defense. PMID:20826694

Changing Nuclear Landscape and Unique PML Structures During Early Epigenetic Transitions of Human Embryonic Stem Cells

PubMed Central

Butler, John T.; Hall, Lisa L.; Smith, Kelly P.; Lawrence, Jeanne B.

2010-01-01

The complex nuclear structure of somatic cells is important to epigenomic regulation, yet little is known about nuclear organization of human embryonic stem cells (hESC). Here we surveyed several nuclear structures in pluripotent and transitioning hESC. Observations of centromeres, telomeres, SC35 speckles, Cajal Bodies, lamin A/C and emerin, nuclear shape and size demonstrate a very different “nuclear landscape” in hESC. This landscape is remodeled during a brief transitional window, concomitant with or just prior to differentiation onset. Notably, hESC initially contain abundant signal for spliceosome assembly factor, SC35, but lack discrete SC35 domains; these form as cells begin to specialize, likely reflecting cell-type specific genomic organization. Concomitantly, nuclear size increases and shape changes as lamin A/C and emerin incorporate into the lamina. During this brief window, hESC exhibit dramatically different PML-defined structures, which in somatic cells are linked to gene regulation and cancer. Unlike the numerous, spherical somatic PML bodies, hES cells often display ~1–3 large PML structures of two morphological types: long linear “rods” or elaborate “rosettes”, which lack substantial SUMO-1, Daxx, and Sp100.These occur primarily between Day 0–2 of differentiation and become rare thereafter. PML rods may be “taut” between other structures, such as centromeres, but clearly show some relationship with the lamina, where PML often abuts or fills a “gap” in early lamin A/C staining. Findings demonstrate that pluripotent hES cells have a markedly different overall nuclear architecture, remodeling of which is linked to early epigenomic programming and involves formation of unique PML-defined structures. PMID:19449340

Three years of experience: the Italian registry and safety data update.

PubMed

Mancardi, G L; Tedeschi, G; Amato, M P; D'Alessandro, R; Drago, F; Milanese, C; Popoli, P; Rossi, P; Savettieri, G; Tola, M R; Comi, G; Pozzilli, C; Bertolotto, A; Marrosu, M G; Grimaldi, L M E; Laroni, A; Vanacore, N; Covezzoli, A; De Rosa, M; Piccinni, C; Montanaro, N; Periotto, L; Iommelli, R; Tomino, C; Provinciali, L

2011-01-01

At the end of 2006, a pharmacovigilance program on natalizumab was settled by the Italian Pharmaceutical Agency, and on January 2007, multiple sclerosis patients poorly responding to the immunomodulating therapies or with an aggressive clinical form of disease from onset initiated to be registered and to receive the medication. On February 2010, almost 3,000 cases have been treated with natalizumab. The drop-out rate is 10%. Almost 800 cases received cycles of natalizumab for more than 18 months. One case of PML was reported and other adverse events are similar to those described in phase III studies. The majority of cases remained stable, while in 25% of cases, an improvement of disability was documented.

Android-assisted physics mobile learning to improve senior high school students' divergent thinking skills and physics HOTS

NASA Astrophysics Data System (ADS)

Mardiana, Nana; Kuswanto, Heru

2017-08-01

The aims of the research concerned here were to reveal (1) the characteristics of Android-assisted PML (physics mobile learning) to improve SMA (sekolah menengah atas, Indonesian senior high school) students' divergent thinking skills and physics HOTS (higher order thinking skills); (2) the feasibility of the Android-assisted PML; and (3) the influence of using the Android-assisted PML on improvement in SMA students' divergent thinking skills and physics HOTS. The7 research was of the R&D (research and development) type, adapted from theBorg-&-Gall development model. The research data were analyzed by means of MANOVA with the significance level of 5%. The results are as follows. (1) The product of the development, a learning media in software form with the android package(apk) format, is named PML (to refer to Physics Mobile Learning), which has such characterictics as being operable with use of Android devicesand being very good in quality in the aspect oflearning, material, software technology, and audiovisual appearance. 2) The developed learning media referred to as PML is appropriate for learning activity according to evaluation by a material expert, a media expert, peer reviewers, and physics teachers as well as according to results of students' tryouts. (3) The use of the Android-assisted PML media product could improve SMA students' divergent thinking skillsand physics HOTS with the respective high-category gain scores of 0.701 and 0.759.

PML is a ROS sensor activating p53 upon oxidative stress.

PubMed

Niwa-Kawakita, Michiko; Ferhi, Omar; Soilihi, Hassane; Le Bras, Morgane; Lallemand-Breitenbach, Valérie; de Thé, Hugues

2017-11-06

Promyelocytic leukemia (PML) nuclear bodies (NBs) recruit partner proteins, including p53 and its regulators, thereby controlling their abundance or function. Investigating arsenic sensitivity of acute promyelocytic leukemia, we proposed that PML oxidation promotes NB biogenesis. However, physiological links between PML and oxidative stress response in vivo remain unexplored. Here, we identify PML as a reactive oxygen species (ROS) sensor. Pml -/- cells accumulate ROS, whereas PML expression decreases ROS levels. Unexpectedly, Pml -/- embryos survive acute glutathione depletion. Moreover, Pml -/- animals are resistant to acetaminophen hepatotoxicity or fasting-induced steatosis. Molecularly, Pml -/- animals fail to properly activate oxidative stress-responsive p53 targets, whereas the NRF2 response is amplified and accelerated. Finally, in an oxidative stress-prone background, Pml -/- animals display a longevity phenotype, likely reflecting decreased basal p53 activation. Thus, similar to p53, PML exerts basal antioxidant properties but also drives oxidative stress-induced changes in cell survival/proliferation or metabolism in vivo. Through NB biogenesis, PML therefore couples ROS sensing to p53 responses, shedding a new light on the role of PML in senescence or stem cell biology. © 2017 Niwa-Kawakita et al.

Spatial and Temporal Resolution of Global Protein Synthesis during HSV Infection Using Bioorthogonal Precursors and Click Chemistry

PubMed Central

Serwa, Remigiusz A.; O’Hare, Peter

2016-01-01

We used pulse-labeling with the methionine analogue homopropargylglycine (HPG) to investigate spatiotemporal aspects of protein synthesis during herpes simplex virus (HSV) infection. In vivo incorporation of HPG enables subsequent selective coupling of fluorochrome-capture reagents to newly synthesised proteins. We demonstrate that HPG labeling had no effect on cell viability, on accumulation of test early or late viral proteins, or on overall virus yields. HPG pulse-labeling followed by SDS-PAGE analysis confirmed incorporation into newly synthesised proteins, while parallel processing by in situ cycloaddition revealed new insight into spatiotemporal aspects of protein localisation during infection. A striking feature was the rapid accumulation of newly synthesised proteins not only in a general nuclear pattern but additionally in newly forming sub-compartments represented by small discrete foci. These newly synthesised protein domains (NPDs) were similar in size and morphology to PML domains but were more numerous, and whereas PML domains were progressively disrupted, NPDs were progressively induced and persisted. Immediate-early proteins ICP4 and ICP0 were excluded from NPDs, but using an ICP0 mutant defective in PML disruption, we show a clear spatial relationship between NPDs and PML domains with NPDs frequently forming immediately adjacent and co-joining persisting PML domains. Further analysis of location of the chaperone Hsc70 demonstrated that while NPDs formed early in infection without overt Hsc70 recruitment, later in infection Hsc70 showed pronounced recruitment frequently in a coat-like fashion around NPDs. Moreover, while ICP4 and ICP0 were excluded from NPDs, ICP22 showed selective recruitment. Our data indicate that NPDs represent early recruitment of host and viral de novo translated protein to distinct structural entities which are precursors to the previously described VICE domains involved in protein quality control in the nucleus, and reveal new features from which we propose spatially linked platforms of newly synthesised protein processing after nuclear import. PMID:27706239

Mitosis-specific phosphorylation of PML at T409 regulates spindle checkpoint.

PubMed

Jin, J; Liu, J

2016-08-31

During mitosis, Promyelocytic leukemia nuclear bodies (PML NBs) change dramatically in morphology and composition, but little is known about function of PML in mitosis. Here, we show that PML is phosphorylated at T409 (PML p409) in a mitosis-specific manner. More importantly, PML p409 contributes to maintain the duration of pro-metaphase and regulates spindle checkpoint. Deficient PML p409 caused a shortening of pro-metaphase and challenged the nocodazole-triggered mitotic arrest. T409A mutation led to a higher frequency of misaligned chromosomes on metaphase plate, and subsequently death in late mitosis. In addition, inhibition of PML p409 repressed growth of tumor cells, suggesting that PML p409 is a potential target for cancer therapy. Collectively, our study demonstrated an important phosphorylated site of PML, which contributed to explore the role of PML in mitosis.

Comparative ultrastructure of CRM1-Nucleolar bodies (CNoBs), Intranucleolar bodies (INBs) and hybrid PML/p62 bodies uncovers new facets of nuclear body dynamic and diversity

PubMed Central

Souquere, Sylvie; Weil, Dominique; Pierron, Gérard

2015-01-01

In order to gain insights on the nuclear organization in mammalian cells, we characterized ultrastructurally nuclear bodies (NBs) previously described as fluorescent foci. Using high resolution immunoelectron microscopy (I-EM), we provide evidence that CNoBs (CRM1-Nucleolar bodies) and INBs (Intranucleolar bodies) are distinct genuine nucleolar structures in untreated HeLa cells. INBs are fibrillar and concentrate the post-translational modifiers SUMO1 and SUMO-2/3 as strongly as PML bodies. In contrast, the smallest CRM1-labeled CNoBs are vitreous, preferentially located at the periphery of the nucleolus and, intricately linked to the chromatin network. Upon blockage of the CRM1-dependent nuclear export by leptomycin B (LMB), CNoBs disappear while p62/SQSTM1-containing fibrillar nuclear bodies are induced. These p62 bodies are enriched in ubiquitinated proteins. They progressively associate with PML bodies to form hybrid bodies of which PML decorates the periphery while p62/SQSTM1 is centrally-located. Our study is expanding the repertoire of nuclear bodies; revealing a previously unrecognized composite nucleolar landscape and a new mode of interactions between ubiquitous (PML) and stress-induced (p62) nuclear bodies, resulting in the formation of hybrid bodies. PMID:26275159

RXR is an essential component of the oncogenic PML/RARA complex in vivo.

PubMed

Zhu, Jun; Nasr, Rihab; Pérès, Laurent; Riaucoux-Lormière, Florence; Honoré, Nicole; Berthier, Caroline; Kamashev, Dmitrii; Zhou, Jun; Vitoux, Dominique; Lavau, Catherine; de Thé, Hugues

2007-07-01

Although PML-enforced RARA homodimerization allows PML/RARA to bind DNA independently of its coreceptor RXR, the latter was identified within the PML/RARA complex. We demonstrate that a PML/RARA mutant defective for RXR binding fails to trigger APL development in transgenic mice, although it still transforms primary hematopoietic progenitors ex vivo. RXR enhances PML/RARA binding to DNA and is required for rexinoid-induced APL differentiation. In RA-treated PML/RARA-transformed cells, the absence of RXR binding results in monocytic, rather than granulocytic, differentiation. PML/RARA enhances posttranslational modifications of RXRA, including its sumoylation, suggesting that PML-bound sumoylation enzymes target RXRA and possibly other PML/RARA-bound chromatin proteins, further contributing to deregulated transcription. Thus, unexpectedly, RXR contributes to several critical aspects of in vivo transformation.

Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway.

PubMed

Lallemand-Breitenbach, Valérie; Jeanne, Marion; Benhenda, Shirine; Nasr, Rihab; Lei, Ming; Peres, Laurent; Zhou, Jun; Zhu, Jun; Raught, Brian; de Thé, Hugues

2008-05-01

In acute promyelocytic leukaemia (APL), arsenic trioxide induces degradation of the fusion protein encoded by the PML-RARA oncogene, differentiation of leukaemic cells and produces clinical remissions. SUMOylation of its PML moiety was previously implicated, but the nature of the degradation pathway involved and the role of PML-RARalpha catabolism in the response to therapy have both remained elusive. Here, we demonstrate that arsenic-induced PML SUMOylation triggers its Lys 48-linked polyubiquitination and proteasome-dependent degradation. When exposed to arsenic, SUMOylated PML recruits RNF4, the human orthologue of the yeast SUMO-dependent E3 ubiquitin-ligase, as well as ubiquitin and proteasomes onto PML nuclear bodies. Arsenic-induced differentiation is impaired in cells transformed by a non-degradable PML-RARalpha SUMOylation mutant or in APL cells transduced with a dominant-negative RNF4, directly implicating PML-RARalpha catabolism in the therapeutic response. We thus identify PML as the first protein degraded by SUMO-dependent polyubiquitination. As PML SUMOylation recruits not only RNF4, ubiquitin and proteasomes, but also many SUMOylated proteins onto PML nuclear bodies, these domains could physically integrate the SUMOylation, ubiquitination and degradation pathways.

Requirement of lid2 for interfacial activation of a family I.3 lipase with unique two lid structures.

PubMed

Cheng, Maria; Angkawidjaja, Clement; Koga, Yuichi; Kanaya, Shigenori

2012-10-01

A family I.3 lipase from Pseudomonas sp. MIS38 (PML) is characterized by the presence of two lids (lid1 and lid2) that greatly change conformation upon substrate binding. While lid1 represents the commonly known lid in lipases, lid2 is unique to PML and other family I.3 lipases. To clarify the role of lid2 in PML, a lid2 deletion mutant (ΔL2-PML) was constructed by deleting residues 35-64 of PML. ΔL2-PML requires calcium ions for both lipase and esterase activities as does PML, suggesting that it exhibits activity only when lid1 is fully open and anchored by the catalytically essential calcium ion, as does PML. However, when the enzymatic activity was determined using triacetin, the activity of PML exponentially increased as the substrate concentration reached and increased beyond the critical micellar concentration, while that of ΔL2-PML did not. These results indicate that PML undergoes interfacial activation, while ΔL2-PML does not. The activities of ΔL2-PML for long-chain triglycerides significantly decreased while its activity for fatty acid ethyl esters increased, compared with those of PML. Comparison of the tertiary models of ΔL2-PML in a closed and open conformation, which are optimized by molecular dynamics simulation, with the crystal structures of PML suggests that the hydrophobic surface area provided by lid1 and lid2 in an open conformation is considerably decreased by the deletion of lid2. We propose that the hydrophobic surface area provided by these lids is necessary to hold the micellar substrates firmly to the active site and therefore lid2 is required for interfacial activation of PML. © 2012 The Authors Journal compilation © 2012 FEBS.

The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion.

PubMed

Masroori, Nasser; Merindol, Natacha; Berthoux, Lionel

2016-03-22

The promyelocytic leukemia (PML) protein, a type I interferon (IFN-I)-induced gene product and a member of the tripartite motif (TRIM) family, modulates the transcriptional activity of viruses belonging to various families. Whether PML has an impact on the replication of HIV-1 has not been fully addressed, but recent studies point to its possible involvement in the restriction of HIV-1 in human cells and in the maintenance of transcriptional latency in human cell lines in which HIV-1 is constitutively repressed. We investigated further the restriction of HIV-1 and a related lentivirus, SIVmac, by PML in murine cells and in a lymphocytic human cell line. In particular, we studied the relevance of PML to IFN-I-mediated inhibition and the role of individual human isoforms. We demonstrate that both human PML (hPML) and murine PML (mPML) inhibit the early post-entry stages of the replication of HIV-1 and a related lentivirus, SIVmac. In addition, HIV-1 was transcriptionally silenced by mPML and by hPML isoforms I, II, IV and VI in MEFs. This PML-mediated transcriptional repression was attenuated in presence of the histone deacetylase inhibitor SAHA. In contrast, depletion of PML had no effect on HIV-1 gene expression in a human T cell line. PML was found to contribute to the inhibition of HIV-1 by IFN-I. Specifically, IFN-α and IFN-β treatments of MEFs enhanced the PML-dependent inhibition of HIV-1 early replication stages. We show that PML can inhibit HIV-1 and other lentiviruses as part of the IFN-I-mediated response. The restriction takes place at two distinct steps, i.e. reverse transcription and transcription, and in an isoform-specific, cellular context-specific fashion. Our results support a model in which PML activates innate immune antilentiviral effectors. These data are relevant to the development of latency reversal-inducing pharmacological agents, since PML was previously proposed as a pharmacological target for such inhibitors. This study also has implications for the development of murine models of HIV-1.

Stability of finite difference numerical simulations of acoustic logging-while-drilling with different perfectly matched layer schemes

NASA Astrophysics Data System (ADS)

Wang, Hua; Tao, Guo; Shang, Xue-Feng; Fang, Xin-Ding; Burns, Daniel R.

2013-12-01

In acoustic logging-while-drilling (ALWD) finite difference in time domain (FDTD) simulations, large drill collar occupies, most of the fluid-filled borehole and divides the borehole fluid into two thin fluid columns (radius ˜27 mm). Fine grids and large computational models are required to model the thin fluid region between the tool and the formation. As a result, small time step and more iterations are needed, which increases the cumulative numerical error. Furthermore, due to high impedance contrast between the drill collar and fluid in the borehole (the difference is >30 times), the stability and efficiency of the perfectly matched layer (PML) scheme is critical to simulate complicated wave modes accurately. In this paper, we compared four different PML implementations in a staggered grid finite difference in time domain (FDTD) in the ALWD simulation, including field-splitting PML (SPML), multiaxial PML(MPML), non-splitting PML (NPML), and complex frequency-shifted PML (CFS-PML). The comparison indicated that NPML and CFS-PML can absorb the guided wave reflection from the computational boundaries more efficiently than SPML and M-PML. For large simulation time, SPML, M-PML, and NPML are numerically unstable. However, the stability of M-PML can be improved further to some extent. Based on the analysis, we proposed that the CFS-PML method is used in FDTD to eliminate the numerical instability and to improve the efficiency of absorption in the PML layers for LWD modeling. The optimal values of CFS-PML parameters in the LWD simulation were investigated based on thousands of 3D simulations. For typical LWD cases, the best maximum value of the quadratic damping profile was obtained using one d 0. The optimal parameter space for the maximum value of the linear frequency-shifted factor ( α 0) and the scaling factor ( β 0) depended on the thickness of the PML layer. For typical formations, if the PML thickness is 10 grid points, the global error can be reduced to <1% using the optimal PML parameters, and the error will decrease as the PML thickness increases.

Efficiency of perfectly matched layers for seismic wave modeling in second-order viscoelastic equations

NASA Astrophysics Data System (ADS)

Ping, Ping; Zhang, Yu; Xu, Yixian; Chu, Risheng

2016-12-01

In order to improve the perfectly matched layer (PML) efficiency in viscoelastic media, we first propose a split multi-axial PML (M-PML) and an unsplit convolutional PML (C-PML) in the second-order viscoelastic wave equations with the displacement as the only unknown. The advantage of these formulations is that it is easy and efficient to revise the existing codes of the second-order spectral element method (SEM) or finite-element method (FEM) with absorbing boundaries in a uniform equation, as well as more economical than the auxiliary differential equations PML. Three models which are easily suffered from late time instabilities are considered to validate our approaches. Through comparison the M-PML with C-PML efficiency of absorption and stability for long time simulation, it can be concluded that: (1) for an isotropic viscoelastic medium with high Poisson's ratio, the C-PML will be a sufficient choice for long time simulation because of its weak reflections and superior stability; (2) unlike the M-PML with high-order damping profile, the M-PML with second-order damping profile loses its stability in long time simulation for an isotropic viscoelastic medium; (3) in an anisotropic viscoelastic medium, the C-PML suffers from instabilities, while the M-PML with second-order damping profile can be a better choice for its superior stability and more acceptable weak reflections than the M-PML with high-order damping profile. The comparative analysis of the developed methods offers meaningful significance for long time seismic wave modeling in second-order viscoelastic wave equations.

PML Nuclear Bodies

PubMed Central

Lallemand-Breitenbach, Valérie; de Thé, Hugues

2010-01-01

PML nuclear bodies are matrix-associated domains that recruit an astonishing variety of seemingly unrelated proteins. Since their discovery in the early 1960s, PML bodies have fascinated cell biologists because of their beauty and their tight association with cellular disorders. The identification of PML, a gene involved in an oncogenic chromosomal translocation, as the key organizer of these domains drew instant interest onto them. The multiple levels of PML body regulation by a specific posttranslational modification, sumoylation, have raised several unsolved issues. Functionally, PML bodies may sequester, modify or degrade partner proteins, but in many ways, PML bodies still constitute an enigma. PMID:20452955

PML nuclear bodies.

PubMed

Lallemand-Breitenbach, Valérie; de Thé, Hugues

2010-05-01

PML nuclear bodies are matrix-associated domains that recruit an astonishing variety of seemingly unrelated proteins. Since their discovery in the early 1960s, PML bodies have fascinated cell biologists because of their beauty and their tight association with cellular disorders. The identification of PML, a gene involved in an oncogenic chromosomal translocation, as the key organizer of these domains drew instant interest onto them. The multiple levels of PML body regulation by a specific posttranslational modification, sumoylation, have raised several unsolved issues. Functionally, PML bodies may sequester, modify or degrade partner proteins, but in many ways, PML bodies still constitute an enigma.

Implementation of perfectly matched layers in an arbitrary geometrical boundary for elastic wave modelling

NASA Astrophysics Data System (ADS)

Gao, Hongwei; Zhang, Jianfeng

2008-09-01

The perfectly matched layer (PML) absorbing boundary condition is incorporated into an irregular-grid elastic-wave modelling scheme, thus resulting in an irregular-grid PML method. We develop the irregular-grid PML method using the local coordinate system based PML splitting equations and integral formulation of the PML equations. The irregular-grid PML method is implemented under a discretization of triangular grid cells, which has the ability to absorb incident waves in arbitrary directions. This allows the PML absorbing layer to be imposed along arbitrary geometrical boundaries. As a result, the computational domain can be constructed with smaller nodes, for instance, to represent the 2-D half-space by a semi-circle rather than a rectangle. By using a smooth artificial boundary, the irregular-grid PML method can also avoid the special treatments to the corners, which lead to complex computer implementations in the conventional PML method. We implement the irregular-grid PML method in both 2-D elastic isotropic and anisotropic media. The numerical simulations of a VTI lamb's problem, wave propagation in an isotropic elastic medium with curved surface and in a TTI medium demonstrate the good behaviour of the irregular-grid PML method.

PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral transactivator

PubMed Central

Regad, Tarik; Saib, Ali; Lallemand-Breitenbach, Valérie; Pandolfi, Pier Paolo; de Thé, Hugues; Chelbi-Alix, Mounira K.

2001-01-01

The promyelocytic leukaemia (PML) protein localizes in the nucleus both in the nucleoplasm and in matrix-associated multiprotein complexes known as nuclear bodies (NBs). The number and the intensity of PML NBs increase in response to interferon (IFN). Overexpression of PML affects the replication of vesicular stomatitis virus and influenza virus. However, PML has a less powerful antiviral activity against these viruses than the IFN mediator MxA. Here, we show that overexpression of PML, but not that of Mx1 or MxA, leads to a drastic decrease of a complex retrovirus, the human foamy virus (HFV), gene expression. PML represses HFV transcription by complexing the HFV transactivator, Tas, preventing its direct binding to viral DNA. This physical interaction requires the N-terminal region of Tas and the RING finger of PML, but does not necessitate PML localization in NBs. Finally, we show that IFN treatment inhibits HFV replication in wild-type but not in PML–/– cells. These findings point to a role for PML in transcriptional repression and suggest that PML could play a key role in mediating an IFN-induced antiviral state against a complex retrovirus. PMID:11432836

Activation of a promyelocytic leukemia-tumor protein 53 axis underlies acute promyelocytic leukemia cure.

PubMed

Ablain, Julien; Rice, Kim; Soilihi, Hassane; de Reynies, Aurélien; Minucci, Saverio; de Thé, Hugues

2014-02-01

Acute promyelocytic leukemia (APL) is driven by the promyelocytic leukemia (PML)-retinoic acid receptor-α (PML-RARA) fusion protein, which interferes with nuclear receptor signaling and PML nuclear body (NB) assembly. APL is the only malignancy definitively cured by targeted therapies: retinoic acid (RA) and/or arsenic trioxide, which both trigger PML-RARA degradation through nonoverlapping pathways. Yet, the cellular and molecular determinants of treatment efficacy remain disputed. We demonstrate that a functional Pml-transformation-related protein 53 (Trp53) axis is required to eradicate leukemia-initiating cells in a mouse model of APL. Upon RA-induced PML-RARA degradation, normal Pml elicits NB reformation and induces a Trp53 response exhibiting features of senescence but not apoptosis, ultimately abrogating APL-initiating activity. Apart from triggering PML-RARA degradation, arsenic trioxide also targets normal PML to enhance NB reformation, which may explain its clinical potency, alone or with RA. This Pml-Trp53 checkpoint initiated by therapy-triggered NB restoration is specific for PML-RARA-driven APL, but not the RA-resistant promyelocytic leukemia zinc finger (PLZF)-RARA variant. Yet, as NB biogenesis is druggable, it could be therapeutically exploited in non-APL malignancies.

PML nuclear bodies in the pathogenesis of acute promyelocytic leukemia: active players or innocent bystanders?

PubMed

Brown, Nicola J M; Ramalho, Michal; Pedersen, Eva W; Moravcsik, Eva; Solomon, Ellen; Grimwade, David

2009-01-01

The promyelocytic leukemia gene (PML) encodes a protein which localizes to PML-nuclear bodies (NBs), sub-nuclear multi-protein structures, which have been implicated in diverse biological functions such as apoptosis, cell proliferation and senescence. However, the exact biochemical and molecular basis of PML function up until now has not been defined. Strikingly, over a decade ago, PML-NBs were found to be disrupted in acute promyelocytic leukemia (APL) in which PML is fused to the gene encoding retinoic acid receptor alpha (RARA) due to the t(15;17) chromosomal translocation, generating the PML-RARA chimeric protein. The treatment of APL patients with all-transretinoic acid (ATRA) and arsenic trioxide which target the PML-RARA oncoprotein results in clinical remission, associated with blast cell differentiation and reformation of the PML NBs, thus linking NB integrity with disease status. This review focuses on the current theories for molecular and biochemical functions of the PML-NBs, which would imply a role in the pathogenesis of APL, whilst also discussing the intriguing possibility that their disruption may not be in itself a significant oncogenic event.

Arsenic trioxide controls the fate of the PML-RARalpha oncoprotein by directly binding PML.

PubMed

Zhang, Xiao-Wei; Yan, Xiao-Jing; Zhou, Zi-Ren; Yang, Fei-Fei; Wu, Zi-Yu; Sun, Hong-Bin; Liang, Wen-Xue; Song, Ai-Xin; Lallemand-Breitenbach, Valérie; Jeanne, Marion; Zhang, Qun-Ye; Yang, Huai-Yu; Huang, Qiu-Hua; Zhou, Guang-Biao; Tong, Jian-Hua; Zhang, Yan; Wu, Ji-Hui; Hu, Hong-Yu; de Thé, Hugues; Chen, Sai-Juan; Chen, Zhu

2010-04-09

Arsenic, an ancient drug used in traditional Chinese medicine, has attracted worldwide interest because it shows substantial anticancer activity in patients with acute promyelocytic leukemia (APL). Arsenic trioxide (As2O3) exerts its therapeutic effect by promoting degradation of an oncogenic protein that drives the growth of APL cells, PML-RARalpha (a fusion protein containing sequences from the PML zinc finger protein and retinoic acid receptor alpha). PML and PML-RARalpha degradation is triggered by their SUMOylation, but the mechanism by which As2O3 induces this posttranslational modification is unclear. Here we show that arsenic binds directly to cysteine residues in zinc fingers located within the RBCC domain of PML-RARalpha and PML. Arsenic binding induces PML oligomerization, which increases its interaction with the small ubiquitin-like protein modifier (SUMO)-conjugating enzyme UBC9, resulting in enhanced SUMOylation and degradation. The identification of PML as a direct target of As2O3 provides new insights into the drug's mechanism of action and its specificity for APL.

Acute promyelocytic leukemia, arsenic, and PML bodies

PubMed Central

Le Bras, Morgane; Lallemand-Breitenbach, Valérie

2012-01-01

Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation. PMID:22778276

The cell biology of disease: Acute promyelocytic leukemia, arsenic, and PML bodies.

PubMed

de Thé, Hugues; Le Bras, Morgane; Lallemand-Breitenbach, Valérie

2012-07-09

Acute promyelocytic leukemia (APL) is driven by a chromosomal translocation whose product, the PML/retinoic acid (RA) receptor α (RARA) fusion protein, affects both nuclear receptor signaling and PML body assembly. Dissection of APL pathogenesis has led to the rediscovery of PML bodies and revealed their role in cell senescence, disease pathogenesis, and responsiveness to treatment. APL is remarkable because of the fortuitous identification of two clinically effective therapies, RA and arsenic, both of which degrade PML/RARA oncoprotein and, together, cure APL. Analysis of arsenic-induced PML or PML/RARA degradation has implicated oxidative stress in the biogenesis of nuclear bodies and SUMO in their degradation.

PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells.

PubMed

Zhu, Bo; Wang, Jia-Yu; Zhou, Jun-Jie; Zhou, Feng; Cheng, Wei; Liu, Ying-Ting; Wang, Jie; Chen, Xiao; Chen, Dian-Hua; Luo, Lan; Hua, Zi-Chun

2017-10-01

Acute promyelocytic leukemia (APL) is characterized and driven by the promyelocytic leukemia protein-retinoic acid receptor alpha (PML-RARα) fusion gene. Previous studies have highlighted the importance of PML-RARα degradation in the treatment against APL. Considering the presence of two zinc fingers in the PML-RARα fusion protein, we explored the function of zinc homeostasis in maintaining PML-RARα stability. We demonstrated for the first time that zinc depletion by its chelator N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) triggered PML-RARα degradation in NB4 APL cells via the proteasome pathway rather than the autophagy-lysosomal pathway. In contrast, autophagy protected TPEN-mediated PML-RARα degradation in NB4 APL cells. We further demonstrated that crosstalk between zinc homeostasis and nitric oxide pathway played a key role in maintaining PML-RARα stability in NB4 APL cells. These results demonstrate that zinc homeostasis is vital for maintaining PML-RARα stability, and zinc depletion by TPEN may be useful as a potential strategy to trigger PML-RARα degradation in APL cells. We also found that TPEN triggered apoptosis of NB4 APL cells in a time-dependent manner. The relationship between PML-RARα degradation and apoptosis triggered by TPEN deserves further study. Copyright © 2017 Elsevier Inc. All rights reserved.

CK2 and PML: regulating the regulator.

PubMed

Lallemand-Breitenbach, Valérie; de Thé, Hugues

2006-07-28

The PML protein induces senescence, and, upon oncogenic stress, its absence promotes cellular transformation. In this issue of Cell, Scaglioni et al. (2006) show that phosphorylation of PML by CK2, a kinase frequently activated in human cancers, promotes PML degradation. Therefore, pharmacological inhibition of CK2-induced PML loss could be used to offset tumor establishment.

A Role for PML in Innate Immunity

PubMed Central

Lunardi, Andrea; Gaboli, Mirella; Giorgio, Marco; Rivi, Roberta; Bygrave, Anne; Antoniou, Michael; Drabek, Dubravka; Dzierzak, Elaine; Fagioli, Marta; Salmena, Leonardo; Botto, Marina; Cordon-Cardo, Carlos; Luzzatto, Lucio; Pelicci, Pier Giuseppe; Grosveld, Frank; Pandolfi, Pier Paolo

2011-01-01

The promyelocytic leukemia gene (PML) of acute promyelocytic leukemia is an established tumor suppressor gene with critical functions in growth suppression, induction of apoptosis, and cellular senescence. Interestingly, although less studied, PML seems to play a key role also in immune response to viral infection. Herein, we report that Pml −/− mice spontaneously develop an atypical invasive and lethal granulomatous lesion known as botryomycosis (BTM). In Pml −/− mice, BTM is the result of impaired function of macrophages, whereby they fail to become activated and are thus unable to clear pathogenic microorganisms. Accordingly, Pml −/− mice are resistant to lipopolysaccharide (LPS)–induced septic shock as a result of an ineffective production of cytokines and chemokines, suggesting a role for PML in the innate immune Toll-like receptor (TLR)/NF-κB prosurvival pathway. These results not only shed light on a new fundamental function of PML in innate immunity, but they also point to a proto-oncogenic role for PML in certain cellular and pathological contexts. PMID:21779477

Differential Roles of PML Isoforms

PubMed Central

Nisole, Sébastien; Maroui, Mohamed Ali; Mascle, Xavier H.; Aubry, Muriel; Chelbi-Alix, Mounira K.

2013-01-01

The tumor suppressor promyelocytic leukemia (PML) protein is fused to the retinoic acid receptor alpha in patients suffering from acute promyelocytic leukemia (APL). Treatment of APL patients with arsenic trioxide (As2O3) reverses the disease phenotype by a process involving the degradation of the fusion protein via its PML moiety. Several PML isoforms are generated from a single PML gene by alternative splicing. They share the same N-terminal region containing the RBCC/tripartite motif but differ in their C-terminal sequences. Recent studies of all the PML isoforms reveal the specific functions of each. Here, we review the nomenclature and structural organization of the PML isoforms in order to clarify the various designations and classifications found in different databases. The functions of the PML isoforms and their differential roles in antiviral defense also are reviewed. Finally, the key players involved in the degradation of the PML isoforms in response to As2O3 or other inducers are discussed. PMID:23734343

Resistance to Virus Infection Conferred by the Interferon-Induced Promyelocytic Leukemia Protein

PubMed Central

Chelbi-Alix, Mounira K.; Quignon, Frédérique; Pelicano, Luis; Koken, Marcel H. M.; de Thé, Hugues

1998-01-01

The interferon (IFN)-induced promyelocytic leukemia (PML) protein is specifically associated with nuclear bodies (NBs) whose functions are yet unknown. Two of the NB-associated proteins, PML and Sp100, are induced by IFN. Here we show that overexpression of PML and not Sp100 induces resistance to infections by vesicular stomatitis virus (VSV) (a rhabdovirus) and influenza A virus (an orthomyxovirus) but not by encephalomyocarditis virus (a picornavirus). Inhibition of viral multiplication was dependent on both the level of PML expression and the multiplicity of infection and reached 100-fold. PML was shown to interfere with VSV mRNA and protein synthesis. Compared to the IFN mediator MxA protein, PML had less powerful antiviral activity. While nuclear body localization of PML did not seem to be required for the antiviral effect, deletion of the PML coiled-coil domain completely abolished it. Taken together, these results suggest that PML can contribute to the antiviral state induced in IFN-treated cells. PMID:9444998

Clearance of PML/RARA-bound promoters suffice to initiate APL differentiation.

PubMed

Vitaliano-Prunier, Adeline; Halftermeyer, Juliane; Ablain, Julien; de Reynies, Aurélien; Peres, Laurent; Le Bras, Morgane; Metzger, Daniel; de Thé, Hugues

2014-12-11

PML/RARA, a potent transcriptional inhibitor of nuclear receptor signaling, represses myeloid differentiation genes and drives acute promyelocytic leukemia (APL). Association of the retinoid X receptor-α (RXRA) coreceptor to PML/RARA is required for transformation, with RXRA promoting its efficient DNA binding. APL is exquisitely sensitive to retinoic acid (RA) and arsenic trioxide (arsenic), which both trigger cell differentiation in vivo. Whereas RA elicits transcriptional activation of PML/RARA targets, how arsenic triggers differentiation remains unclear. Here we demonstrate that extinction of PML/RARA triggers terminal differentiation in vivo. Similarly, ablation of retinoid X receptors loosens PML/RARA DNA binding, inducing terminal differentiation of APL cells ex vivo or in vivo. RXRA sumoylation directly contributes to PML/RARA-dependent transformation ex vivo, presumably by enhancing transcriptional repression. Thus, APL differentiation is a default program triggered by clearance of PML/RARA-bound promoters, rather than obligatory active transcriptional activation, explaining how arsenic elicits APL maturation through PML/RARA degradation. © 2014 by The American Society of Hematology.

An Adenovirus DNA Replication Factor, but Not Incoming Genome Complexes, Targets PML Nuclear Bodies.

PubMed

Komatsu, Tetsuro; Nagata, Kyosuke; Wodrich, Harald

2016-02-01

Promyelocytic leukemia protein nuclear bodies (PML-NBs) are subnuclear domains implicated in cellular antiviral responses. Despite the antiviral activity, several nuclear replicating DNA viruses use the domains as deposition sites for the incoming viral genomes and/or as sites for viral DNA replication, suggesting that PML-NBs are functionally relevant during early viral infection to establish productive replication. Although PML-NBs and their components have also been implicated in the adenoviral life cycle, it remains unclear whether incoming adenoviral genome complexes target PML-NBs. Here we show using immunofluorescence and live-cell imaging analyses that incoming adenovirus genome complexes neither localize at nor recruit components of PML-NBs during early phases of infection. We further show that the viral DNA binding protein (DBP), an early expressed viral gene and essential DNA replication factor, independently targets PML-NBs. We show that DBP oligomerization is required to selectively recruit the PML-NB components Sp100 and USP7. Depletion experiments suggest that the absence of one PML-NB component might not affect the recruitment of other components toward DBP oligomers. Thus, our findings suggest a model in which an adenoviral DNA replication factor, but not incoming viral genome complexes, targets and modulates PML-NBs to support a conducive state for viral DNA replication and argue against a generalized concept that PML-NBs target incoming viral genomes. The immediate fate upon nuclear delivery of genomes of incoming DNA viruses is largely unclear. Early reports suggested that incoming genomes of herpesviruses are targeted and repressed by PML-NBs immediately upon nuclear import. Genome localization and/or viral DNA replication has also been observed at PML-NBs for other DNA viruses. Thus, it was suggested that PML-NBs may immediately sense and target nuclear viral genomes and hence serve as sites for deposition of incoming viral genomes and/or subsequent viral DNA replication. Here we performed a detailed analyses of the spatiotemporal distribution of incoming adenoviral genome complexes and found, in contrast to the expectation, that an adenoviral DNA replication factor, but not incoming genomes, targets PML-NBs. Thus, our findings may explain why adenoviral genomes could be observed at PML-NBs in earlier reports but argue against a generalized role for PML-NBs in targeting invading viral genomes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis.

PubMed

Wijburg, Martijn T; Kleerekooper, Iris; Lissenberg-Witte, Birgit I; de Vos, Marlieke; Warnke, Clemens; Uitdehaag, Bernard M J; Barkhof, Frederik; Killestein, Joep; Wattjes, Mike P

2018-03-12

The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF. To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML. This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample. Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated. Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman ρ, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms. Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance.

Unsplit complex frequency shifted perfectly matched layer for second-order wave equation using auxiliary differential equations.

PubMed

Gao, Yingjie; Zhang, Jinhai; Yao, Zhenxing

2015-12-01

The complex frequency shifted perfectly matched layer (CFS-PML) can improve the absorbing performance of PML for nearly grazing incident waves. However, traditional PML and CFS-PML are based on first-order wave equations; thus, they are not suitable for second-order wave equation. In this paper, an implementation of CFS-PML for second-order wave equation is presented using auxiliary differential equations. This method is free of both convolution calculations and third-order temporal derivatives. As an unsplit CFS-PML, it can reduce the nearly grazing incidence. Numerical experiments show that it has better absorption than typical PML implementations based on second-order wave equation.

PML nuclear bodies: from architecture to function.

PubMed

Lallemand-Breitenbach, Valérie; de Thé, Hugues

2018-06-01

PML nuclear bodies are nucleated by the PML protein, which polymerizes into spherical shells where it concentrates many unrelated partner proteins. Emerging data has connected PML bodies to post-translational control, notably conjugation by SUMOs. High concentrations of SUMO-bound proteins were proposed to condense into liquid-like droplets and such phase transition may occur within NBs. Many stress pathways modulate NB formation and recent findings have directly implicated PML in oxidative stress response in vivo. PML may also undergo SUMO-dependent ubiquitination/degradation. We highlight recent advances linking PML to partner degradation and other adaptative post-translational modifications in the context of chromatin remodeling, telomere biology, senescence or viral infections. Copyright © 2018. Published by Elsevier Ltd.

Promyelocytic Leukemia Protein Is a Cell-Intrinsic Factor Inhibiting Parvovirus DNA Replication

PubMed Central

Mitchell, Angela M.; Hirsch, Matthew L.; Li, Chengwen

2014-01-01

Tripartite motif proteins are important viral restriction factors and affect processes ranging from uncoating to transcription to immune signaling. Specifically, the promyelocytic leukemia protein (TRIM19; also called PML) is a viral restriction factor inhibiting processes from uncoating to transcription to cell survival. Here we investigated PML's effect on adeno-associated virus (AAV), a parvovirus used for gene delivery. Although dependovirus (AAV) and autonomous parvovirus (minute virus of mice) replication centers can colocalize with PML, PML's functional effect on parvoviruses is unknown. Using PML knockout mice, we determined that PML knockout enhances recombinant AAV2 (rAAV2) transduction at a range of vector doses in both male and female mice. In fact, male and female PML knockout mice exhibited up to 56-fold and 28-fold increases in transduction, respectively. PML inhibited several rAAV serotypes, suggesting a conserved mechanism, and organ specificity correlated with PML expression. Mechanistically, PML inhibited rAAV second-strand DNA synthesis, precluding inhibition of self-complementary rAAV, and did not affect the prior steps in transduction. Furthermore, we confirmed the effect of human PML on rAAV transduction through small interfering RNA (siRNA)-mediated knockdown in HuH7 cells and determined that the highest level of inhibition was due to effects of PML isoform II (PMLII). Overexpression of PMLII resulted in inhibition of second-strand synthesis, vector production, and genome replication. Moreover, wild-type AAV2 production and infectivity were also inhibited by PMLII, demonstrating a PML interaction with wild-type AAV. These data have important implications for AAV-mediated gene therapy. Additionally, PMLII inhibition of AAV second-strand synthesis and replication, which are processes necessary for all parvoviruses, suggests implications for replication of other parvoviruses. PMID:24198403

Promyelocytic leukemia protein is a cell-intrinsic factor inhibiting parvovirus DNA replication.

PubMed

Mitchell, Angela M; Hirsch, Matthew L; Li, Chengwen; Samulski, R Jude

2014-01-01

Tripartite motif proteins are important viral restriction factors and affect processes ranging from uncoating to transcription to immune signaling. Specifically, the promyelocytic leukemia protein (TRIM19; also called PML) is a viral restriction factor inhibiting processes from uncoating to transcription to cell survival. Here we investigated PML's effect on adeno-associated virus (AAV), a parvovirus used for gene delivery. Although dependovirus (AAV) and autonomous parvovirus (minute virus of mice) replication centers can colocalize with PML, PML's functional effect on parvoviruses is unknown. Using PML knockout mice, we determined that PML knockout enhances recombinant AAV2 (rAAV2) transduction at a range of vector doses in both male and female mice. In fact, male and female PML knockout mice exhibited up to 56-fold and 28-fold increases in transduction, respectively. PML inhibited several rAAV serotypes, suggesting a conserved mechanism, and organ specificity correlated with PML expression. Mechanistically, PML inhibited rAAV second-strand DNA synthesis, precluding inhibition of self-complementary rAAV, and did not affect the prior steps in transduction. Furthermore, we confirmed the effect of human PML on rAAV transduction through small interfering RNA (siRNA)-mediated knockdown in HuH7 cells and determined that the highest level of inhibition was due to effects of PML isoform II (PMLII). Overexpression of PMLII resulted in inhibition of second-strand synthesis, vector production, and genome replication. Moreover, wild-type AAV2 production and infectivity were also inhibited by PMLII, demonstrating a PML interaction with wild-type AAV. These data have important implications for AAV-mediated gene therapy. Additionally, PMLII inhibition of AAV second-strand synthesis and replication, which are processes necessary for all parvoviruses, suggests implications for replication of other parvoviruses.

Importance of double-pole CFS-PML for broad-band seismic wave simulation and optimal parameters selection

NASA Astrophysics Data System (ADS)

Feng, Haike; Zhang, Wei; Zhang, Jie; Chen, Xiaofei

2017-05-01

The perfectly matched layer (PML) is an efficient absorbing technique for numerical wave simulation. The complex frequency-shifted PML (CFS-PML) introduces two additional parameters in the stretching function to make the absorption frequency dependent. This can help to suppress converted evanescent waves from near grazing incident waves, but does not efficiently absorb low-frequency waves below the cut-off frequency. To absorb both the evanescent wave and the low-frequency wave, the double-pole CFS-PML having two poles in the coordinate stretching function was developed in computational electromagnetism. Several studies have investigated the performance of the double-pole CFS-PML for seismic wave simulations in the case of a narrowband seismic wavelet and did not find significant difference comparing to the CFS-PML. Another difficulty to apply the double-pole CFS-PML for real problems is that a practical strategy to set optimal parameter values has not been established. In this work, we study the performance of the double-pole CFS-PML for broad-band seismic wave simulation. We find that when the maximum to minimum frequency ratio is larger than 16, the CFS-PML will either fail to suppress the converted evanescent waves for grazing incident waves, or produce visible low-frequency reflection, depending on the value of α. In contrast, the double-pole CFS-PML can simultaneously suppress the converted evanescent waves and avoid low-frequency reflections with proper parameter values. We analyse the different roles of the double-pole CFS-PML parameters and propose optimal selections of these parameters. Numerical tests show that the double-pole CFS-PML with the optimal parameters can generate satisfactory results for broad-band seismic wave simulations.

Progressive multifocal leukoencephalopathy: current treatment options and future perspectives

PubMed Central

Pavlovic, Dejan; Patera, Andriani C.; Nyberg, Fredrik; Gerber, Marianne; Liu, Maggie

2015-01-01

Progressive multifocal leukoencephalopathy (PML) is a rare but debilitating and frequently fatal viral disease of the central nervous system, primarily affecting individuals with chronically and severely suppressed immune systems. The disease was relatively obscure until the outbreak of HIV/AIDS, when it presented as one of the more frequent opportunistic infections in this immune deficiency syndrome. It attracted additional attention from the medical and scientific community following the discovery of significant PML risk associated with natalizumab, a monoclonal antibody used for treatment of relapsing–remitting multiple sclerosis. This was followed by association of PML with other immunosuppressive or immunomodulating drugs. PML is currently untreatable disease with poor outcomes, so it is a significant concern when developing new immunotherapies. Current prophylaxis and treatment of PML are focused on immune reconstitution, restoration of immune responses to JC virus infection, and eventual suppression of immune reconstitution inflammatory syndrome. This approach was successful in reducing the incidence of PML and improved survival of PML patients with HIV infection. However, the outcome for the majority of PML patients, regardless of their medical history, is still relatively poor. There is a high unmet need for both prophylaxis and treatment of PML. The aim of this review is to discuss potential drug candidates for prophylaxis and treatment of PML with a critical review of previously conducted and completed PML treatment studies as well as to provide perspectives for future therapies. PMID:26600871

Advances in the management of PML: focus on natalizumab.

PubMed

Fox, Robert

2011-11-01

Progressive multifocal leukoencephalopathy (PML), a rare opportunistic infection of the central nervous system, occurs mainly in the setting of broad-based and selective immunosuppression. The immunomodulatory agent most often implicated in the development of PML is the monoclonal antibody natalizumab. Management of PML begins with risk stratification. Factors that predict the risk of PML are JC virus (JCV) antibody status, history of chemotherapy use, and cumulative exposure to natalizumab. The risk of natalizumab-related PML increases up to a duration of 36 months of therapy, after which the risk appears to level off. If suspicious for PML, the use of a sensitive JCV polymerase chain reaction assay permits early diagnosis. Immune reconstitution represents the mainstay of treatment for PML. With rapid reversal of immunosuppression followed by immunologic recovery, almost all patients suffer clinical deterioration termed immune reconstitution inflammatory syndrome (IRIS). High-dose corticosteroids are often recommended if a clinical and imaging syndrome resembling IRIS develops after immune restoration.

Optimal damping profile ratios for stabilization of perfectly matched layers in general anisotropic media

DOE PAGES

Gao, Kai; Huang, Lianjie

2017-11-13

Conventional perfectly matched layers (PML) can be unstable for certain kinds of anisotropic media. Multi-axial PML removes such instability using nonzero damping coe cients in the directions tangential with the PML interface. While using non-zero damping pro le ratios can stabilize PML, it is important to obtain the smallest possible damping pro le ratios to minimize arti cial re ections caused by these non-zero ratios, particularly for 3D general anisotropic media. Using the eigenvectors of the PML system matrix, we develop a straightforward and e cient numerical algorithm to determine the optimal damping pro le ratios to stabilize PML inmore » 2D and 3D general anisotropic media. Numerical examples show that our algorithm provides optimal damping pro le ratios to ensure the stability of PML and complex-frequency-shifted PML for elastic-wave modeling in 2D and 3D general anisotropic media.« less

Optimal damping profile ratios for stabilization of perfectly matched layers in general anisotropic media

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

Gao, Kai; Huang, Lianjie

Conventional perfectly matched layers (PML) can be unstable for certain kinds of anisotropic media. Multi-axial PML removes such instability using nonzero damping coe cients in the directions tangential with the PML interface. While using non-zero damping pro le ratios can stabilize PML, it is important to obtain the smallest possible damping pro le ratios to minimize arti cial re ections caused by these non-zero ratios, particularly for 3D general anisotropic media. Using the eigenvectors of the PML system matrix, we develop a straightforward and e cient numerical algorithm to determine the optimal damping pro le ratios to stabilize PML inmore » 2D and 3D general anisotropic media. Numerical examples show that our algorithm provides optimal damping pro le ratios to ensure the stability of PML and complex-frequency-shifted PML for elastic-wave modeling in 2D and 3D general anisotropic media.« less

Functional Reorganization of Promyelocytic Leukemia Nuclear Bodies during BK Virus Infection

PubMed Central

Jiang, Mengxi; Entezami, Pouya; Gamez, Monica; Stamminger, Thomas; Imperiale, Michael J.

2011-01-01

BK virus (BKV) is the causative agent for polyomavirus-associated nephropathy, a severe disease found in renal transplant patients due to reactivation of a persistent BKV infection. BKV replication relies on the interactions of BKV with many nuclear components, and subnuclear structures such as promyelocytic leukemia nuclear bodies (PML-NBs) are known to play regulatory roles during a number of DNA virus infections. In this study, we investigated the relationship between PML-NBs and BKV during infection of primary human renal proximal tubule epithelial (RPTE) cells. While the levels of the major PML-NB protein components remained unchanged, BKV infection of RPTE cells resulted in dramatic alterations in both the number and the size of PML-NBs. Furthermore, two normally constitutive components of PML-NBs, Sp100 and hDaxx, became dispersed from PML-NBs. To define the viral factors responsible for this reorganization, we examined the cellular localization of the BKV large tumor antigen (TAg) and viral DNA. TAg colocalized with PML-NBs during early infection, while a number of BKV chromosomes were adjacent to PML-NBs during late infection. We demonstrated that TAg alone was not sufficient to reorganize PML-NBs and that active viral DNA replication is required. Knockdown of PML protein did not dramatically affect BKV growth in culture. BKV infection, however, was able to rescue the growth of an ICP0-null herpes simplex virus 1 mutant whose growth defect was partially due to its inability to disrupt PML-NBs. We hypothesize that the antiviral functions of PML-NBs are inactivated through reorganization during normal BKV infection. PMID:21304169

A High Content Screening (HCS) Assay for the Identification of Chemical Inducers of PML Oncogenic Domains (PODs)

PubMed Central

Yip, Kenneth W.; Cuddy, Michael; Pinilla, Clemencia; Giulanotti, Marc; Heynen-Genel, Susanne; Matsuzawa, Shu-ichi; Reed, John C.

2014-01-01

PML is a tumor suppressor that promotes apoptosis through both p53-dependent and - independent mechanisms, participates in Rb-mediated cell cycle arrest, inhibits neoangiogenesis, and contributes to maintenance of genomic stability. PML also plays a role in host defense against viruses, conferring antiviral activity. When active, PML localizes to subnuclear structures named PML oncogenic domains (PODs) or PML nuclear bodies (PML-NBs), whereas inactive PML is located diffusely throughout the nucleus of cells, thus providing a morphological indicator. Known activators of PML include arsenicals and interferons, however, these agents induce a plethora of toxic effects, limiting their effectiveness. The objective of the current study was to develop a high content screening (HCS) assay for the identification of chemical activators of PML. We describe methods for automated analysis of POD formation using high throughput microscopy (HTM) to localize PML immunofluorescence in conjunction with image analysis software for POD quantification. Using this HCS assay in 384 well format, we performed pilot screens of a small synthetic chemical library and mixture-based combinatorial libraries, demonstrating the robust performance of the assay. HCS counter-screening assays were also developed for hit characterization, based on immunofluorescence analyses of the subcellular location of phosphorylated H2AX or phosphorylated CHK1, which increase in a punctate nuclear pattern in response to DNA damage. Thus, the HCS assay devised here represents a high throughput screen that can be utilized to discover POD-inducing compounds that may restore the tumor suppressor activity of PML in cancers or possibly promote anti-viral states. PMID:21233309

Incoming human papillomavirus 16 genome is lost in PML protein-deficient HaCaT keratinocytes.

PubMed

Bienkowska-Haba, Malgorzata; Luszczek, Wioleta; Keiffer, Timothy R; Guion, Lucile G M; DiGiuseppe, Stephen; Scott, Rona S; Sapp, Martin

2017-05-01

Human papillomaviruses (HPVs) target promyelocytic leukemia (PML) nuclear bodies (NBs) during infectious entry and PML protein is important for efficient transcription of incoming viral genome. However, the transcriptional down regulation was shown to be promoter-independent in that heterologous promoters delivered by papillomavirus particles were also affected. To further investigate the role of PML protein in HPV entry, we used small hairpin RNA to knockdown PML protein in HaCaT keratinocytes. Confirming previous findings, PML knockdown in HaCaT cells reduced HPV16 transcript levels significantly following infectious entry without impairing binding and trafficking. However, when we quantified steady-state levels of pseudogenomes in interphase cells, we found strongly reduced genome levels compared with parental HaCaT cells. Because nuclear delivery was comparable in both cell lines, we conclude that viral pseudogenome must be removed after successful nuclear delivery. Transcriptome analysis by gene array revealed that PML knockdown in clonal HaCaT cells was associated with a constitutive interferon response. Abrogation of JAK1/2 signaling prevented genome loss, however, did not restore viral transcription. In contrast, knockdown of PML protein in HeLa cells did not affect HPV genome delivery and transcription. HeLa cells are transformed by HPV18 oncogenes E6 and E7, which have been shown to interfere with the JAK/Stat signaling pathway. Our data imply that PML NBs protect incoming HPV genomes. Furthermore, they provide evidence that PML NBs are key regulators of the innate immune response in keratinocytes. Promyelocytic leukemia nuclear bodies (PML NBs) are important for antiviral defense. Many DNA viruses target these subnuclear structures and reorganize them. Reorganization of PML NBs by viral proteins is important for establishment of infection. In contrast, HPVs require the presence of PML protein for efficient transcription of incoming viral genome. Our finding that PML protein prevents the loss of HPV genome following infection implies that the host cell may be able to recognize chromatinized HPV genome or the associated capsid proteins. A constitutively active interferon response in absence of PML protein suggests that PML NBs are key regulators of the innate immune response in keratinocytes. © 2016 John Wiley & Sons Ltd.

Therapy-induced PML/RARA proteolysis and acute promyelocytic leukemia cure.

PubMed

Nasr, Rihab; Lallemand-Breitenbach, Valérie; Zhu, Jun; Guillemin, Marie-Claude; de Thé, Hugues

2009-10-15

Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosomal translocation that yields the PML/RARA fusion gene. Clinically, besides chemotherapy, two drugs induce clinical remissions: retinoic acid (RA) and arsenic trioxide (As). Both agents directly target PML/RARA-mediated transcriptional repression and protein stability, inducing to various extent promyelocyte differentiation and clinical remission of APL patients. RA targets the RARA moiety of the fusion, whereas arsenic targets its PML part. PML/RARA expression in the mouse is sufficient to initiate APL. The RA-As association, which synergizes for PML/RARA degradation but not for differentiation, rapidly clears leukemia initiating cells (LIC), resulting in APL eradication in murine APL models, but also in several APL clinical trials. Cyclic AMP triggered PML/RARA phosphorylation also enhances RA-induced APL regression, PML/RARA degradation, and LIC clearance, raising new options for therapy-resistant patients. Although differentiation has a major role in debulking of the tumor, PML/RARA degradation seems to be the primary basis for APL eradication by the RA-As association. Oncoprotein degradation could be a general therapeutic strategy that may be extended beyond APL.

Unconditionally stable WLP-FDTD method for the modeling of electromagnetic wave propagation in gyrotropic materials.

PubMed

Li, Zheng-Wei; Xi, Xiao-Li; Zhang, Jin-Sheng; Liu, Jiang-fan

2015-12-14

The unconditional stable finite-difference time-domain (FDTD) method based on field expansion with weighted Laguerre polynomials (WLPs) is applied to model electromagnetic wave propagation in gyrotropic materials. The conventional Yee cell is modified to have the tightly coupled current density components located at the same spatial position. The perfectly matched layer (PML) is formulated in a stretched-coordinate (SC) system with the complex-frequency-shifted (CFS) factor to achieve good absorption performance. Numerical examples are shown to validate the accuracy and efficiency of the proposed method.

Progressive multifocal leukoencephalopathy in patients treated with fumaric acid esters: a review of 19 cases.

PubMed

Gieselbach, Robbert-Jan; Muller-Hansma, Annemarie H; Wijburg, Martijn T; de Bruin-Weller, Marjolein S; van Oosten, Bob W; Nieuwkamp, Dennis J; Coenjaerts, Frank E; Wattjes, Mike P; Murk, Jean-Luc

2017-06-01

Progressive multifocal leukoencephalopathy (PML) is a rare and potentially fatal condition caused by a brain infection with JC polyomavirus (JCV). PML develops almost exclusively in immunocompromised patients and has recently been associated with use of fumaric acid esters (FAEs), or fumarates. We reviewed the literature and the Dutch and European pharmacovigilance databases in order to identify all available FAE-associated PML cases and distinguish possible common features among these patients. A total of 19 PML cases associated with FAE use were identified. Five cases were associated with FAE use for multiple sclerosis and 14 for psoriasis. Ten patients were male and nine were female. The median age at PML diagnosis was 59 years. The median duration of FAE therapy to PML symptom onset or appearance of first PML lesion on brain imaging was 31 months (range 6-110). In all cases a certain degree of lymphocytopenia was reported. The median duration of lymphocytopenia to PML symptom onset was 23 months (range 6-72). The median lymphocyte count at PML diagnosis was 414 cells/µL. CD4 and CD8 counts were reported in ten cases, with median cell count of 137 and 39 cells/µL, respectively. Three patients died (16% mortality). The association between occurrence of PML in patients with low CD4 and CD8 counts is reminiscent of PML cases in the HIV population and suggests that loss of T cells is the most important risk factor.

Transient analysis of spectrally asymmetric magnetic photonic crystals with ferromagnetic losses

NASA Astrophysics Data System (ADS)

Jung, K.-Y.; Donderici, B.; Teixeira, F. L.

2006-10-01

We analyze transient electromagnetic pulse propagation in spectrally asymmetric magnetic photonic crystals (MPCs) with ferromagnetic losses. MPCs are dispersion-engineered materials consisting of a periodic arrangement of misaligned anisotropic dielectric and ferromagnetic layers that exhibit a stationary inflection point in the (asymmetric) dispersion diagram and unidirectional frozen modes. The analysis is performed via a late-time stable finite-difference time-domain method (FDTD) implemented with perfectly matched layer (PML) absorbing boundary conditions, and extended to handle (simultaneously) dispersive and anisotropic media. The proposed PML-FDTD algorithm is based on a D - H and B - E combined field approach that naturally decouples the FDTD update into two steps, one involving the (anisotropic and dispersive) constitutive material tensors and the other involving Maxwell’s equations in a complex coordinate space (to incorporate the PML). For ferromagnetic layers, a fully dispersive modeling of the permeability tensor is implemented to include magnetic losses in a consistent fashion. The numerical results illustrate some striking properties of MPCs, such as wave slowdown (frozen modes), amplitude increase (pulse compression), and unidirectional characteristics. The numerical model is also used to investigate the sensitivity of the MPC response against excitation (frequency and bandwidth), material (ferromagnetic losses), and geometric (layer misalignment and thickness) parameter variations.

Arsenic mediated disruption of promyelocytic leukemia protein nuclear bodies induces ganciclovir susceptibility in Epstein-Barr positive epithelial cells

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

Sides, Mark D.; Block, Gregory J.; Shan, Bin

Promyelocytic leukemia protein nuclear bodies (PML NBs) have been implicated in host immune response to viral infection. PML NBs are targeted for degradation during reactivation of herpes viruses, suggesting that disruption of PML NB function supports this aspect of the viral life cycle. The Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1) has been shown to suppress EBV reactivation. Our finding that LMP1 induces PML NB immunofluorescence intensity led to the hypothesis that LMP1 may modulate PML NBs as a means of maintaining EBV latency. Increased PML protein and morphometric changes in PML NBs were observed in EBV infected alveolarmore » epithelial cells and nasopharyngeal carcinoma cells. Treatment with low dose arsenic trioxide disrupted PML NBs, induced expression of EBV lytic proteins, and conferred ganciclovir susceptibility. This study introduces an effective modality to induce susceptibility to ganciclovir in epithelial cells with implications for the treatment of EBV associated pathologies.« less

Oxidative stress–induced assembly of PML nuclear bodies controls sumoylation of partner proteins

PubMed Central

Sahin, Umut; Ferhi, Omar; Jeanne, Marion; Benhenda, Shirine; Berthier, Caroline; Jollivet, Florence; Niwa-Kawakita, Michiko; Faklaris, Orestis; Setterblad, Niclas; Lallemand-Breitenbach, Valérie

2014-01-01

The promyelocytic leukemia (PML) protein organizes PML nuclear bodies (NBs), which are stress-responsive domains where many partner proteins accumulate. Here, we clarify the basis for NB formation and identify stress-induced partner sumoylation as the primary NB function. NB nucleation does not rely primarily on intermolecular interactions between the PML SUMO-interacting motif (SIM) and SUMO, but instead results from oxidation-mediated PML multimerization. Oxidized PML spherical meshes recruit UBC9, which enhances PML sumoylation, allow partner recruitment through SIM interactions, and ultimately enhance partner sumoylation. Intermolecular SUMO–SIM interactions then enforce partner sequestration within the NB inner core. Accordingly, oxidative stress enhances NB formation and global sumoylation in vivo. Some NB-associated sumoylated partners also become polyubiquitinated by RNF4, precipitating their proteasomal degradation. As several partners are protein-modifying enzymes, NBs could act as sensors that facilitate and confer oxidative stress sensitivity not only to sumoylation but also to other post-translational modifications, thereby explaining alterations of stress response upon PML or NB loss. PMID:24637324

JC virus chromogenic in situ hybridization in brain biopsies from patients with and without PML.

PubMed

Procop, Gary W; Beck, Rose C; Pettay, James D; Kohn, Debra J; Tuohy, Marion J; Yen-Lieberman, Belinda; Prayson, Richard A; Tubbs, Raymond R

2006-06-01

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by the JC polyoma virus. Electron microscopy and immunohistochemistry are the traditional methods of confirming the presence of the virus in brain biopsies from these patients. We studied the brain biopsies from 7 patients with PML and 6 patients without PML with chromogenic in situ hybridization (CISH) for the JC polyoma virus using a commercially available probe. The biopsies from the patients with the PML cases were proven to contain the JC polyoma virus by traditional and molecular methods. The CISH findings were compared with the known state of infection. All (7/7) of the biopsies from patients with PML were positive for the presence of polyoma virus by CISH, whereas the biopsies from patients without PML were uniformly negative. CISH seems to be a useful tool for the detection of the JC virus in brain biopsies from patients with PML, and is more accessible because a commercial probe is available.

PML is a ROS sensor activating p53 upon oxidative stress

PubMed Central

Soilihi, Hassane

2017-01-01

Promyelocytic leukemia (PML) nuclear bodies (NBs) recruit partner proteins, including p53 and its regulators, thereby controlling their abundance or function. Investigating arsenic sensitivity of acute promyelocytic leukemia, we proposed that PML oxidation promotes NB biogenesis. However, physiological links between PML and oxidative stress response in vivo remain unexplored. Here, we identify PML as a reactive oxygen species (ROS) sensor. Pml−/− cells accumulate ROS, whereas PML expression decreases ROS levels. Unexpectedly, Pml−/− embryos survive acute glutathione depletion. Moreover, Pml−/− animals are resistant to acetaminophen hepatotoxicity or fasting-induced steatosis. Molecularly, Pml−/− animals fail to properly activate oxidative stress–responsive p53 targets, whereas the NRF2 response is amplified and accelerated. Finally, in an oxidative stress–prone background, Pml−/− animals display a longevity phenotype, likely reflecting decreased basal p53 activation. Thus, similar to p53, PML exerts basal antioxidant properties but also drives oxidative stress–induced changes in cell survival/proliferation or metabolism in vivo. Through NB biogenesis, PML therefore couples ROS sensing to p53 responses, shedding a new light on the role of PML in senescence or stem cell biology. PMID:28931625

Cross Talk between PML and p53 during Poliovirus Infection: Implications for Antiviral Defense

PubMed Central

Pampin, Mathieu; Simonin, Yannick; Blondel, Bruno; Percherancier, Yann; Chelbi-Alix, Mounira K.

2006-01-01

PML nuclear bodies (NBs) are dynamic intranuclear structures harboring numerous transiently or permanently localized proteins. PML, the NBs' organizer, is directly induced by interferon, and its expression is critical for antiviral host defense. We describe herein the molecular events following poliovirus infection that lead to PML-dependent p53 activation and protection against virus infection. Poliovirus infection induces PML phosphorylation through the extracellular signal-regulated kinase pathway, increases PML SUMOylation, and induces its transfer from the nucleoplasm to the nuclear matrix. These events result in the recruitment of p53 to PML NBs, p53 phosphorylation on Ser15, and activation of p53 target genes leading to the induction of apoptosis. Moreover, the knock-down of p53 by small interfering RNA results in higher poliovirus replication, suggesting that p53 participates in antiviral defense. This effect, which requires the presence of PML, is transient since poliovirus targets p53 by inducing its degradation in a proteasome- and MDM2-dependent manner. Our results provide evidence of how poliovirus counteracts p53 antiviral activity by regulating PML and NBs, thus leading to p53 degradation. PMID:16912307

Cross talk between PML and p53 during poliovirus infection: implications for antiviral defense.

PubMed

Pampin, Mathieu; Simonin, Yannick; Blondel, Bruno; Percherancier, Yann; Chelbi-Alix, Mounira K

2006-09-01

PML nuclear bodies (NBs) are dynamic intranuclear structures harboring numerous transiently or permanently localized proteins. PML, the NBs' organizer, is directly induced by interferon, and its expression is critical for antiviral host defense. We describe herein the molecular events following poliovirus infection that lead to PML-dependent p53 activation and protection against virus infection. Poliovirus infection induces PML phosphorylation through the extracellular signal-regulated kinase pathway, increases PML SUMOylation, and induces its transfer from the nucleoplasm to the nuclear matrix. These events result in the recruitment of p53 to PML NBs, p53 phosphorylation on Ser15, and activation of p53 target genes leading to the induction of apoptosis. Moreover, the knock-down of p53 by small interfering RNA results in higher poliovirus replication, suggesting that p53 participates in antiviral defense. This effect, which requires the presence of PML, is transient since poliovirus targets p53 by inducing its degradation in a proteasome- and MDM2-dependent manner. Our results provide evidence of how poliovirus counteracts p53 antiviral activity by regulating PML and NBs, thus leading to p53 degradation.

Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies

PubMed Central

Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie

2013-01-01

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid–treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients. PMID:23509325

Uncoupling RARA transcriptional activation and degradation clarifies the bases for APL response to therapies.

PubMed

Ablain, Julien; Leiva, Magdalena; Peres, Laurent; Fonsart, Julien; Anthony, Elodie; de Thé, Hugues

2013-04-08

In PML/RARA-driven acute promyelocytic leukemia (APL), retinoic acid (RA) induces leukemia cell differentiation and transiently clears the disease. Molecularly, RA activates PML/RARA-dependent transcription and also initiates its proteasome-mediated degradation. In contrast, arsenic, the other potent anti-APL therapy, only induces PML/RARA degradation by specifically targeting its PML moiety. The respective contributions of RA-triggered transcriptional activation and proteolysis to clinical response remain disputed. Here, we identify synthetic retinoids that potently activate RARA- or PML/RARA-dependent transcription, but fail to down-regulate RARA or PML/RARA protein levels. Similar to RA, these uncoupled retinoids elicit terminal differentiation, but unexpectedly fail to impair leukemia-initiating activity of PML/RARA-transformed cells ex vivo or in vivo. Accordingly, the survival benefit conferred by uncoupled retinoids in APL mice is dramatically lower than the one provided by RA. Differentiated APL blasts sorted from uncoupled retinoid-treated mice retain PML/RARA expression and reinitiate APL in secondary transplants. Thus, differentiation is insufficient for APL eradication, whereas PML/RARA loss is essential. These observations unify the modes of action of RA and arsenic and shed light on the potency of their combination in mice or patients.

Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review.

PubMed

Fournier, Anna; Martin-Blondel, Guillaume; Lechapt-Zalcman, Emmanuèle; Dina, Julia; Kazemi, Apolline; Verdon, Renaud; Mortier, Emmanuel; de La Blanchardière, Arnaud

2017-01-01

Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12-66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0-301) and 101/μl (20-610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18-120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV-infected patients with worsening neurological symptoms after initiation or resumption of effective cART, independently of CD4 cell count prior to cART. If PCR for JCV is negative in CSF, brain biopsy should be discussed. Only large multicentric randomized trials could potentially demonstrate the possible efficacy of corticosteroids and/or CCR5 antagonists in the management of PML-IRIS.

Immune Reconstitution Inflammatory Syndrome Unmasking or Worsening AIDS-Related Progressive Multifocal Leukoencephalopathy: A Literature Review

PubMed Central

Fournier, Anna; Martin-Blondel, Guillaume; Lechapt-Zalcman, Emmanuèle; Dina, Julia; Kazemi, Apolline; Verdon, Renaud; Mortier, Emmanuel; de La Blanchardière, Arnaud

2017-01-01

Incidence of progressive multifocal leukoencephalopathy (PML) in HIV-infected patients has declined in the combined antiretroviral therapy (cART) era although a growing number of acquired immunodeficiency syndrome (AIDS)-related PML-immune reconstitution inflammatory syndromes (PML-IRIS) have been published during the same period. Therapeutic management of PML-IRIS is not consensual and mainly relies on corticosteroids. Our main aim was, in addition to provide a thoughtful analysis of published PML-IRIS cases, to assess the benefit of corticosteroids in the management of PML-IRIS, focusing on confirmed cases. We performed a literature review of the 46 confirmed cases of PML-IRIS cases occurring in HIV-infected patients from 1998 to September 2016 (21 unmasking and 25 paradoxical PML-IRIS). AIDS-related PML-IRIS patients were mostly men (sex ratio 4/1) with a median age of 40.5 years (range 12–66). Median CD4 T cell count before cART and at PML-IRIS onset was 45/μl (0–301) and 101/μl (20–610), respectively. After cART initiation, PML-IRIS occurred within a median timescale of 38 days (18–120). Clinical signs were motor deficits (69%), speech disorders (36%), cognitive disorders (33%), cerebellar ataxia (28%), and visual disturbances (23%). Brain MRI revealed hyperintense areas on T2-weighted sequences and FLAIR images (76%) and suggestive contrast enhancement (87%). PCR for John Cunningham virus (JCV) in cerebrospinal fluid (CSF) was positive in only 84% of cases; however, when performed, brain biopsy confirmed diagnosis of PML in 90% of cases and demonstrated histological signs of IRIS in 95% of cases. Clinical worsening related to PML-IRIS and leading to death was observed in 28% of cases. Corticosteroids were prescribed in 63% of cases and maraviroc in one case. Statistical analysis failed to demonstrate significant benefit from steroid treatment, despite spectacular improvement in certain cases. Diagnosis of PML-IRIS should be considered in HIV-infected patients with worsening neurological symptoms after initiation or resumption of effective cART, independently of CD4 cell count prior to cART. If PCR for JCV is negative in CSF, brain biopsy should be discussed. Only large multicentric randomized trials could potentially demonstrate the possible efficacy of corticosteroids and/or CCR5 antagonists in the management of PML-IRIS. PMID:28588577

Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy.

PubMed

Malhotra, Uma; Aboulafia, David M

2016-01-01

Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes. We describe the case of a man with a long history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who developed AHA while on stable antiretroviral therapy and then presented with new onset bleeding and hypotension. We treated our patient with incrementally increasing doses of cyclophosphamide resulting in resolution of coagulopathy. We review the medical literature for additional cases of HIV-associated AHA and discuss the challenges in the care of our patient, since the immunosuppression needed to eradicate the FVIII inhibitor had the potential to cause recrudescence of his PML. © The Author(s) 2015.

Acute Promyelocytic Leukemia: A Paradigm for Oncoprotein-Targeted Cure.

PubMed

de Thé, Hugues; Pandolfi, Pier Paolo; Chen, Zhu

2017-11-13

Recent clinical trials have demonstrated that the immense majority of acute promyelocytic leukemia (APL) patients can be definitively cured by the combination of two targeted therapies: retinoic acid (RA) and arsenic. Mouse models have provided unexpected insights into the mechanisms involved. Restoration of PML nuclear bodies upon RA- and/or arsenic-initiated PML/RARA degradation is essential, while RA-triggered transcriptional activation is dispensable for APL eradication. Mutations of the arsenic-binding site of PML/RARA, but also PML, have been detected in therapy-resistant patients, demonstrating the key role of PML in APL cure. PML nuclear bodies are druggable and could be harnessed in other conditions. Copyright © 2017 Elsevier Inc. All rights reserved.

PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence

PubMed Central

Ivanschitz, Lisa; Takahashi, Yuki; Jollivet, Florence; Ayrault, Olivier; Le Bras, Morgane; de Thé, Hugues

2015-01-01

Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction. PMID:26578773

Curing APL through PML/RARA degradation by As2O3.

PubMed

Lallemand-Breitenbach, Valerie; Zhu, Jun; Chen, Zhu; de Thé, Hugues

2012-01-01

Acute promyelocytic leukemia (APL) is a hematological malignancy driven by the PML/RARA oncogene. The prognosis for patients with APL was revolutionized by two treatments: retinoic acid (RA) and As(2)O(3) (arsenic trioxide). These were both shown a posteriori to target PML/RARA, explaining their exquisite specificity for APL. Arsenic, as a single agent, cures up to 70% of patients, whereas APL patients treated with the combination of RA and As(2)O(3) reach a stunning 90% cure rate. Recent physiopathological models highlight the key role of RA- and As(2)O(3)-triggered PML/RARA degradation, and the molecular mechanisms underlying As(2)O(3)-induced PML/RARA degradation have been recently clarified. As discussed below, arsenic binding, oxidation, sumoylation on PML nuclear bodies, and RNF4-mediated ubiquitination all contribute to the As(2)O(3)-triggered catabolism of PML/RARA. Copyright © 2011 Elsevier Ltd. All rights reserved.

PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence.

PubMed

Ivanschitz, Lisa; Takahashi, Yuki; Jollivet, Florence; Ayrault, Olivier; Le Bras, Morgane; de Thé, Hugues

2015-11-17

Promyelocytic leukemia protein (PML) nuclear bodies (NBs) recruit multiple partners, including p53 and many of its regulators. NBs are believed to facilitate several posttranslational modifications and are key regulators of senescence. PML, the organizer of NBs, is expressed as a number of splice variants that all efficiently recruit p53 partners. However, overexpression of only one of them, PML IV, triggers p53-driven senescence. Here, we show that PML IV specifically binds ARF, a key p53 regulator. Similar to ARF, PML IV enhances global SUMO-1 conjugation, particularly that of p53, resulting in p53 stabilization and activation. ARF interacts with and stabilizes the NB-associated UBC9 SUMO-conjugating enzyme, possibly explaining PML IV-enhanced SUMOylation. These results unexpectedly link two key tumor suppressors, highlighting their convergence for global control of SUMO conjugation, p53 activation, and senescence induction.

Role of nuclear bodies in apoptosis signalling.

PubMed

Krieghoff-Henning, Eva; Hofmann, Thomas G

2008-11-01

Promyelocytic leukemia nuclear bodies (PML NBs) are dynamic macromolecular multiprotein complexes that recruit and release a plethora of proteins. A considerable number of PML NB components play vital roles in apoptosis, senescence regulation and tumour suppression. The molecular basis by which PML NBs control these cellular responses is still just beginning to be understood. In addition to PML itself, numerous further tumour suppressors including transcriptional regulator p53, acetyl transferase CBP (CREB binding protein) and protein kinase HIPK2 (homeodomain interacting protein kinase 2) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity. Moreover, in response to death-receptor activation, PML NBs may act as nuclear depots that release apoptotic factors, such as the FLASH (FLICE-associated huge) protein, to amplify the death signal. PML NBs are also associated with other nuclear domains including Cajal bodies and nucleoli and share apoptotic regulators with these domains, implying crosstalk between NBs in apoptosis regulation. In conclusion, PML NBs appear to regulate cell death decisions through different, pathway-specific molecular mechanisms.

Promyelocytic Leukemia (Pml) Nuclear Bodies Are Protein Structures That Do Not Accumulate RNA

PubMed Central

Boisvert, François-Michel; Hendzel, Michael J.; Bazett-Jones, David P.

2000-01-01

The promyelocytic leukemia (PML) nuclear body (also referred to as ND10, POD, and Kr body) is involved in oncogenesis and viral infection. This subnuclear domain has been reported to be rich in RNA and a site of nascent RNA synthesis, implicating its direct involvement in the regulation of gene expression. We used an analytical transmission electron microscopic method to determine the structure and composition of PML nuclear bodies and the surrounding nucleoplasm. Electron spectroscopic imaging (ESI) demonstrates that the core of the PML nuclear body is a dense, protein-based structure, 250 nm in diameter, which does not contain detectable nucleic acid. Although PML nuclear bodies contain neither chromatin nor nascent RNA, newly synthesized RNA is associated with the periphery of the PML nuclear body, and is found within the chromatin-depleted region of the nucleoplasm immediately surrounding the core of the PML nuclear body. We further show that the RNA does not accumulate in the protein core of the structure. Our results dismiss the hypothesis that the PML nuclear body is a site of transcription, but support the model in which the PML nuclear body may contribute to the formation of a favorable nuclear environment for the expression of specific genes. PMID:10648561

[Neuropathology of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy].

PubMed

Kanda, Takashi

2015-07-01

The pathological findings of natalizumab-associated progressive multifocal leukoencephalopathy (PML) are reviewed. In addition to the classical pathology of PML including the presence of enlarged abnormal astrocytes, intranuclear inclusions mainly found within large swollen oligodendrocytes and abundant myelin-laden macrophages/microglia, massive perivascular and parenchymal mononuclear cell infiltration was observed. The latter pathologic picture is that of immune reconstitution inflammatory syndrome (IRIS), and most of these infiltrating cells are CD8-positive T cells. Because IRIS inevitably occurs after the cessation of natalizumab therapy due to the development of PML and subsequent plasma exchange, most of the published pathologic pictures of natalizumab-associated PML patients were a mixture of PML and PML-IRIS. PML-IRIS is also characterized by fewer oligodendroglial viral inclusions and fewer cells that are immunoreactive against anti-JCV antibodies. These findings suggest the effective removal of JCV after the return of normal immune-surveillance in the central nervous system, but clinicians should be aware that JCV elimination is not complete under the IRIS condition, and the immunosuppressive therapy against IRIS should be carefully performed. Mononuclear cell infiltration in natalizumab-associated PML-IRIS patients was much more prominent than that in HIV-associated PML-IRIS patients, reflecting the retained, even enhanced, systemic immunities in patients treated by natalizumab.

Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS

PubMed Central

Gheuens, S.; Smith, D.R.; Wang, X.; Alsop, D.C.; Lenkinski, R.E.

2012-01-01

Objective: Progressive multifocal leukoencephalopathy (PML) is a severe complication of natalizumab therapy in patients with multiple sclerosis (MS), which is often accompanied by an immune reconstitution inflammatory syndrome (IRIS) after removal of the drug. We describe a patient with MS who presented with simultaneous PML-IRIS 2 months after stopping natalizumab for other reasons. Case Report and Results: The patient had widespread PML and severe IRIS. He received corticosteroids and displayed a vigorous JC virus–specific cellular immune response. Elevated myoinositol and lipid/creatine peaks measured in PML lesions by proton magnetic resonance spectroscopy (1H-MRS) corresponded to episodes of contrast enhancement on MRI scans and persisted after the enhancement subsided. He demonstrated steady clinical improvement, but developed marked residual atrophy in areas affected by PML and inflammation, as well as seizures. Conclusions: New enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. Elevated myoinositol and lipid/creatine peaks appear to be more sensitive markers of inflammation in PML lesions than contrast enhancement. 1H-MRS may become useful as a biomarker for PML-IRIS by helping clinicians determine the need for corticosteroid administration and anticipate continuing clinical recovery. PMID:22517104

Multimodal Light Microscopy Approaches to Reveal Structural and Functional Properties of Promyelocytic Leukemia Nuclear Bodies.

PubMed

Hoischen, Christian; Monajembashi, Shamci; Weisshart, Klaus; Hemmerich, Peter

2018-01-01

The promyelocytic leukemia ( pml ) gene product PML is a tumor suppressor localized mainly in the nucleus of mammalian cells. In the cell nucleus, PML seeds the formation of macromolecular multiprotein complexes, known as PML nuclear bodies (PML NBs). While PML NBs have been implicated in many cellular functions including cell cycle regulation, survival and apoptosis their role as signaling hubs along major genome maintenance pathways emerged more clearly. However, despite extensive research over the past decades, the precise biochemical function of PML in these pathways is still elusive. It remains a big challenge to unify all the different previously suggested cellular functions of PML NBs into one mechanistic model. With the advent of genetically encoded fluorescent proteins it became possible to trace protein function in living specimens. In parallel, a variety of fluorescence fluctuation microscopy (FFM) approaches have been developed which allow precise determination of the biophysical and interaction properties of cellular factors at the single molecule level in living cells. In this report, we summarize the current knowledge on PML nuclear bodies and describe several fluorescence imaging, manipulation, FFM, and super-resolution techniques suitable to analyze PML body assembly and function. These include fluorescence redistribution after photobleaching, fluorescence resonance energy transfer, fluorescence correlation spectroscopy, raster image correlation spectroscopy, ultraviolet laser microbeam-induced DNA damage, erythrocyte-mediated force application, and super-resolution microscopy approaches. Since most if not all of the microscopic equipment to perform these techniques may be available in an institutional or nearby facility, we hope to encourage more researches to exploit sophisticated imaging tools for their research in cancer biology.

A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials.

PubMed

Parikh, Asit; Stephens, Kristin; Major, Eugene; Fox, Irving; Milch, Catherine; Sankoh, Serap; Lev, Michael H; Provenzale, James M; Shick, Jesse; Patti, Mark; McAuliffe, Megan; Berger, Joseph R; Clifford, David B

2018-05-08

Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs.

Diagnostic performance of brain MRI in pharmacovigilance of natalizumab-treated MS patients.

PubMed

Wattjes, Mike P; Wijburg, Martijn T; Vennegoor, Anke; Witte, Birgit I; Roosendaal, Stefan D; Sanchez, Esther; Liu, Yaou; Martins Jarnalo, Carine O; Richert, Nancy D; Uitdehaag, Bernard Mj; Barkhof, Frederik; Killestein, Joep

2016-08-01

In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML). To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability. In this retrospective diagnostic study, four blinded neuroradiologists assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with new asymptomatic PML lesions (n = 21) or new MS lesions (n = 20) or no new lesions (n = 7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation, and PML detection were determined. Interrater agreement was calculated. Overall sensitivity and specificity for the detection of new lesions, regardless of the nature of the lesions, were 77.4% and 89.3%, respectively; for PML-MS lesion differentiation, 74.2% and 84.7%, respectively; and for asymptomatic PML lesion detection, 59.5% and 91.7%, respectively. Interrater agreement for the tested categories was fair to moderate. The diagnostic performance of trained neuroradiologists using brain MRI in pharmacovigilance of natalizumab-treated MS patients is moderately good. Interrater agreement among trained readers is fair to moderate. © The Author(s), 2015.

Sumoylation of the Tumor Suppressor Promyelocytic Leukemia Protein Regulates Arsenic Trioxide-Induced Collagen Synthesis in Osteoblasts.

PubMed

Xu, Wen-Xiao; Liu, Sheng-Zhi; Wu, Di; Qiao, Guo-Fen; Yan, Jinglong

2015-01-01

Promyelocytic leukemia (PML) protein is a tumor suppressor that fuses with retinoic acid receptor-α (PML-RARα) to contribute to the initiation of acute promyelocytic leukemia (APL). Arsenic trioxide (ATO) upregulates expression of TGF-β1, promoting collagen synthesis in osteoblasts, and ATO binds directly to PML to induce oligomerization, sumoylation, and ubiquitination. However, how ATO upregulates TGF-β1 expression is uncertain. Thus, we suggested that PML sumoylation is responsible for regulation of TGF-β1 protein expression. Kunming mice were treated with ATO, and osteoblasts were counted under scanning electron microscopy. Masson's staining was used to quantify collagen content. hFOB1.19 cells were transfected with siRNA against UBC9 or RNF4, and then treated with ATO or FBS. TGF-β1, PML expression, and sumoylation were quantified with Western blot, and collagen quantified via immunocytochemistry. ATO enhanced osteoblast accumulation, collagen synthesis, and PML-NB formation in vivo. Knocking down UBC9 in hFOB1.19 cells inhibited ATO- and FBS-induced PML sumoylation, TGF-β1 expression, and collagen synthesis. Conversely, knocking down RNF4 enhanced ATO- and FBS-induced PML sumoylation, TGF-β1 expression, and collagen synthesis. These data suggest that PML sumoylation is required for ATO-induced collagen synthesis in osteoblasts. © 2015 S. Karger AG, Basel.

Restoration of promyelocytic leukemia protein-nuclear bodies in neuroblastoma cells enhances retinoic acid responsiveness.

PubMed

Yu, Jiang Hong; Nakajima, Ayako; Nakajima, Hiroshi; Diller, Lisa R; Bloch, Kenneth D; Bloch, Donald B

2004-02-01

Neuroblastoma is the most common solid tumor of infancy and is believed to result from impaired differentiation of neuronal crest embryonal cells. The promyelocytic leukemia protein (PML)-nuclear body is a cellular structure that is disrupted during the pathogenesis of acute promyelocytic leukemia, a disease characterized by impaired myeloid cell differentiation. During the course of studies to examine the composition and function of PML-nuclear bodies, we observed that the human neuroblastoma cell line SH-SY5Y lacked these structures and that the absence of PML-nuclear bodies was a feature of N- and I-type, but not S-type, neuroblastoma cell lines. Induction of neuroblastoma cell differentiation with 5-bromo-2'deoxyuridine, all-trans-retinoic acid, or IFN-gamma induced PML-nuclear body formation. PML-nuclear bodies were not detected in tissue sections prepared from undifferentiated neuroblastomas but were present in neuroblasts in differentiating tumors. Expression of PML in neuroblastoma cells restored PML-nuclear bodies, enhanced responsiveness to all-trans-retinoic acid, and induced cellular differentiation. Pharmacological therapies that increase PML expression may prove to be important components of combined modalities for the treatment of neuroblastoma.

Progressive Multifocal Leukoencephalopathy: Recent Advances and a Neuro-Ophthalmological Review.

PubMed

Sudhakar, Padmaja; Bachman, David M; Mark, Alexander S; Berger, Joseph R; Kedar, Sachin

2015-09-01

Progressive multifocal leukoencephalopathy (PML) is a severe often fatal opportunistic infection of the central nervous system caused by reactivation of a ubiquitous polyoma virus, JC virus. Although typically characterized by multifocal asymmetric subcortical white matter lesions, it may be monofocal and affect the cortical gray matter. Among the broad spectrum of clinical manifestations that occurs with PML, visual complaints are common. Combination of representative personally observed cases of PML and comprehensive review of case series of PML from 1958 through 2014. Neuro-ophthalmic signs and symptoms were reported in approximately 20%-50% of patients with PML and can be the presenting manifestation in half of these. A majority of these presentations occur from damage to cerebral visual pathways resulting in visual field defects, cortical blindness, and other disorders of visual association. Given the decreased frequency of infratentorial and cerebellar involvement, ocular motility disorders are less common. Visual complaints occur in patients with PML and are often the presenting sign. Awareness of this condition is helpful in avoiding unnecessary delays in the diagnosis of PML and management of the underlying condition. Recent guidelines have established criteria for diagnosis of PML in the high-risk patient population and strategies to mitigate the risk in these populations.

The Risk of Progressive Multifocal Leukoencephalopathy in the Biologic Era: Prevention and Management.

PubMed

Molloy, Eamonn S; Calabrese, Cassandra M; Calabrese, Leonard H

2017-02-01

Progressive multifocal leukoencephalopathy (PML) is a rare, typically fatal, demyelinating central nervous system infection caused by reactivation of the John Cunningham virus that generally occurs in immunosuppressed patients. With an evolving understanding of a greater clinical heterogeneity of PML and significant implications for therapy, PML should be considered in the differential diagnosis of neurologic presentations of rheumatic diseases. Increased awareness of PML among rheumatologists is required, as earlier diagnosis and restoration of immune function may improve the otherwise grim prognosis associated with PML. Copyright © 2016 Elsevier Inc. All rights reserved.

PCGF2 negatively regulates arsenic trioxide-induced PML-RARA protein degradation via UBE2I inhibition in NB4 cells.

PubMed

Jo, Sungsin; Lee, Young Lim; Kim, Sojin; Lee, Hongki; Chung, Heekyoung

2016-07-01

Arsenic trioxide (ATO) is a therapeutic agent for acute promyelocytic leukemia (APL) which induces PML-RARA protein degradation via enhanced UBE2I-mediated sumoylation. PCGF2, a Polycomb group protein, has been suggested as an anti-SUMO E3 protein by inhibiting the sumoylation of UBE2I substrates, HSF2 and RANGAP1, via direct interaction. Thus, we hypothesized that PCGF2 might play a role in ATO-induced PML-RARA degradation by interacting with UBE2I. PCGF2 protein was down-regulated upon ATO treatment in human APL cell line, NB4. Knockdown of PCGF2 in NB4 cells, in the absence of ATO treatment, was sufficient to induce sumoylation-, ubiquitylation- and PML nuclear body-mediated degradation of PML-RARA protein. Moreover, overexpression of PCGF2 protected ATO-mediated degradation of ectopic and endogenous PML-RARA in 293T and NB4 cells, respectively. In 293T cells, UBE2I-mediated PML-RARA degradation was reduced upon PCGF2 co-expression. In addition, UBE2I-mediated sumoylation of PML-RARA was reduced upon PCGF2 co-expression and PCGF2-UBE2I interaction was confirmed by co-immunoprecipitation. Likewise, endogenous PCGF2-UBE2I interaction was detected by co-immunoprecipitation and immunofluorescence assays in NB4 cells. Intriguingly, upon ATO-treatment, such interaction was disrupted and UBE2I was co-immunoprecipitated or co-localized with its SUMO substrate, PML-RARA. Taken together, our results suggested a novel role of PCGF2 in ATO-mediated degradation of PML-RARA that PCGF2 might act as a negative regulator of UBE2I via direct interaction. Copyright © 2016 Elsevier B.V. All rights reserved.

Parallel Ellipsoidal Perfectly Matched Layers for Acoustic Helmholtz Problems on Exterior Domains

DOE PAGES

Bunting, Gregory; Prakash, Arun; Walsh, Timothy; ...

2018-01-26

Exterior acoustic problems occur in a wide range of applications, making the finite element analysis of such problems a common practice in the engineering community. Various methods for truncating infinite exterior domains have been developed, including absorbing boundary conditions, infinite elements, and more recently, perfectly matched layers (PML). PML are gaining popularity due to their generality, ease of implementation, and effectiveness as an absorbing boundary condition. PML formulations have been developed in Cartesian, cylindrical, and spherical geometries, but not ellipsoidal. In addition, the parallel solution of PML formulations with iterative solvers for the solution of the Helmholtz equation, and howmore » this compares with more traditional strategies such as infinite elements, has not been adequately investigated. In this study, we present a parallel, ellipsoidal PML formulation for acoustic Helmholtz problems. To faciliate the meshing process, the ellipsoidal PML layer is generated with an on-the-fly mesh extrusion. Though the complex stretching is defined along ellipsoidal contours, we modify the Jacobian to include an additional mapping back to Cartesian coordinates in the weak formulation of the finite element equations. This allows the equations to be solved in Cartesian coordinates, which is more compatible with existing finite element software, but without the necessity of dealing with corners in the PML formulation. Herein we also compare the conditioning and performance of the PML Helmholtz problem with infinite element approach that is based on high order basis functions. On a set of representative exterior acoustic examples, we show that high order infinite element basis functions lead to an increasing number of Helmholtz solver iterations, whereas for PML the number of iterations remains constant for the same level of accuracy. Finally, this provides an additional advantage of PML over the infinite element approach.« less

Parallel Ellipsoidal Perfectly Matched Layers for Acoustic Helmholtz Problems on Exterior Domains

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

Bunting, Gregory; Prakash, Arun; Walsh, Timothy

Exterior acoustic problems occur in a wide range of applications, making the finite element analysis of such problems a common practice in the engineering community. Various methods for truncating infinite exterior domains have been developed, including absorbing boundary conditions, infinite elements, and more recently, perfectly matched layers (PML). PML are gaining popularity due to their generality, ease of implementation, and effectiveness as an absorbing boundary condition. PML formulations have been developed in Cartesian, cylindrical, and spherical geometries, but not ellipsoidal. In addition, the parallel solution of PML formulations with iterative solvers for the solution of the Helmholtz equation, and howmore » this compares with more traditional strategies such as infinite elements, has not been adequately investigated. In this study, we present a parallel, ellipsoidal PML formulation for acoustic Helmholtz problems. To faciliate the meshing process, the ellipsoidal PML layer is generated with an on-the-fly mesh extrusion. Though the complex stretching is defined along ellipsoidal contours, we modify the Jacobian to include an additional mapping back to Cartesian coordinates in the weak formulation of the finite element equations. This allows the equations to be solved in Cartesian coordinates, which is more compatible with existing finite element software, but without the necessity of dealing with corners in the PML formulation. Herein we also compare the conditioning and performance of the PML Helmholtz problem with infinite element approach that is based on high order basis functions. On a set of representative exterior acoustic examples, we show that high order infinite element basis functions lead to an increasing number of Helmholtz solver iterations, whereas for PML the number of iterations remains constant for the same level of accuracy. Finally, this provides an additional advantage of PML over the infinite element approach.« less

Multimodal Light Microscopy Approaches to Reveal Structural and Functional Properties of Promyelocytic Leukemia Nuclear Bodies

PubMed Central

Hoischen, Christian; Monajembashi, Shamci; Weisshart, Klaus; Hemmerich, Peter

2018-01-01

The promyelocytic leukemia (pml) gene product PML is a tumor suppressor localized mainly in the nucleus of mammalian cells. In the cell nucleus, PML seeds the formation of macromolecular multiprotein complexes, known as PML nuclear bodies (PML NBs). While PML NBs have been implicated in many cellular functions including cell cycle regulation, survival and apoptosis their role as signaling hubs along major genome maintenance pathways emerged more clearly. However, despite extensive research over the past decades, the precise biochemical function of PML in these pathways is still elusive. It remains a big challenge to unify all the different previously suggested cellular functions of PML NBs into one mechanistic model. With the advent of genetically encoded fluorescent proteins it became possible to trace protein function in living specimens. In parallel, a variety of fluorescence fluctuation microscopy (FFM) approaches have been developed which allow precise determination of the biophysical and interaction properties of cellular factors at the single molecule level in living cells. In this report, we summarize the current knowledge on PML nuclear bodies and describe several fluorescence imaging, manipulation, FFM, and super-resolution techniques suitable to analyze PML body assembly and function. These include fluorescence redistribution after photobleaching, fluorescence resonance energy transfer, fluorescence correlation spectroscopy, raster image correlation spectroscopy, ultraviolet laser microbeam-induced DNA damage, erythrocyte-mediated force application, and super-resolution microscopy approaches. Since most if not all of the microscopic equipment to perform these techniques may be available in an institutional or nearby facility, we hope to encourage more researches to exploit sophisticated imaging tools for their research in cancer biology. PMID:29888200

Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project

PubMed Central

Carson, Kenneth R.; Evens, Andrew M.; Richey, Elizabeth A.; Habermann, Thomas M.; Focosi, Daniele; Seymour, John F.; Laubach, Jacob; Bawn, Susie D.; Gordon, Leo I.; Winter, Jane N.; Furman, Richard R.; Vose, Julie M.; Zelenetz, Andrew D.; Mamtani, Ronac; Raisch, Dennis W.; Dorshimer, Gary W.; Rosen, Steven T.; Muro, Kenji; Gottardi-Littell, Numa R.; Talley, Robert L.; Sartor, Oliver; Green, David; Major, Eugene O.

2009-01-01

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons. PMID:19264918

FY11 Report on Metagenome Analysis using Pathogen Marker Libraries

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

Gardner, Shea N.; Allen, Jonathan E.; McLoughlin, Kevin S.

2011-06-02

A method, sequence library, and software suite was invented to rapidly assess whether any member of a pre-specified list of threat organisms or their near neighbors is present in a metagenome. The system was designed to handle mega- to giga-bases of FASTA-formatted raw sequence reads from short or long read next generation sequencing platforms. The approach is to pre-calculate a viral and a bacterial "Pathogen Marker Library" (PML) containing sub-sequences specific to pathogens or their near neighbors. A list of expected matches comparing every bacterial or viral genome against the PML sequences is also pre-calculated. To analyze a metagenome, readsmore » are compared to the PML, and observed PML-metagenome matches are compared to the expected PML-genome matches, and the ratio of observed relative to expected matches is reported. In other words, a 3-way comparison among the PML, metagenome, and existing genome sequences is used to quickly assess which (if any) species included in the PML is likely to be present in the metagenome, based on available sequence data. Our tests showed that the species with the most PML matches correctly indicated the organism sequenced for empirical metagenomes consisting of a cultured, relatively pure isolate. These runs completed in 1 minute to 3 hours on 12 CPU (1 thread/CPU), depending on the metagenome and PML. Using more threads on the same number of CPU resulted in speed improvements roughly proportional to the number of threads. Simulations indicated that detection sensitivity depends on both sequencing coverage levels for a species and the size of the PML: species were correctly detected even at ~0.003x coverage by the large PMLs, and at ~0.03x coverage by the smaller PMLs. Matches to true positive species were 3-4 orders of magnitude higher than to false positives. Simulations with short reads (36 nt and ~260 nt) showed that species were usually detected for metagenome coverage above 0.005x and coverage in the PML above 0.05x, and detection probability appears to be a function of both coverages. Multiple species could be detected simultaneously in a simulated low-coverage, complex metagenome, and the largest PML gave no false negative species and no false positive genera. The presence of multiple species was predicted in a complex metagenome from a human gut microbiome with 1.9 GB of short reads (75 nt); the species predicted were reasonable gut flora and no biothreat agents were detected, showing the feasibility of PML analysis of empirical complex metagenomes.« less

Promyelocytic Leukemia Protein, a Protein at the Crossroad of Oxidative Stress and Metabolism.

PubMed

Tessier, Sarah; Martin-Martin, Natalia; de Thé, Hugues; Carracedo, Arkaitz; Lallemand-Breitenbach, Valérie

2017-03-20

Cellular metabolic activity impacts the production of reactive oxygen species (ROS), both positively through mitochondrial oxidative processes and negatively by promoting the production of reducing agents (including NADPH and reduced glutathione). A defined metabolic state in cancer cells is critical for cell growth and long-term self-renewal, and such state is intrinsically associated with redox balance. Promyelocytic leukemia protein (PML) regulates several biological processes, at least in part, through its ability to control the assembly of PML nuclear bodies (PML NBs). Recent Advances: PML is oxidation-prone, and oxidative stress promotes NB biogenesis. These nuclear subdomains recruit many nuclear proteins and regulate their SUMOylation and other post-translational modifications. Some of these cargos-such as p53, SIRT1, AKT, and mammalian target of rapamycin (mTOR)-are key regulators of cell fate. PML was also recently shown to regulate oxidation. While it was long considered primarily as a tumor suppressor protein, PML-regulated metabolic switch uncovered that this protein could promote survival and/or stemness of some normal or cancer cells. In this study, we review the recent findings on this multifunctional protein. Studying PML scaffolding functions as well as its fine role in the activation of p53 or fatty acid oxidation will bring new insights in how PML could bridge oxidative stress, senescence, cell death, and metabolism. Antioxid. Redox Signal. 26, 432-444.

PML solution of longitudinal wave propagation in heterogeneous media

NASA Astrophysics Data System (ADS)

Farzanian, M.; Arbabi, Freydoon; Pak, Ronald

2016-06-01

This paper describes the development of a model for unbounded heterogeneous domains with radiation damping produced by an unphysical wave absorbing layer. The Perfectly Matched Layer (PML) approach is used along with a displacement-based finite element. The heterogeneous model is validated using the closed-form solution of a benchmark problem: a free rod with two-part modulus subjected to a specified time history. Both elastically supported and unsupported semi-infinite rods with different degrees of inhomogeneity and loading are considered. Numerical results illustrate the effects of inhomogeneity on the response and are compared with those for equivalent homogeneous domains. The effects of characteristic features of the inhomogeneous problem, presence of local maxima and cut-off frequency are determined. A degenerate case of a homogeneous semi-infinite rod on elastic foundations is produced by tending the magnitude of the foundation stiffness to zero. The response of the latter is compared with that of a free rod. The importance of proper selection of the PML parameters to highly accurate and efficient results is demonstrated by example problems.

Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts

PubMed Central

Meinecke, Ingmar; Cinski, Antje; Baier, Anja; Peters, Marvin A.; Dankbar, Berno; Wille, Aline; Drynda, Andreas; Mendoza, Heidi; Gay, Renate E.; Hay, Ronald T.; Ink, Barbara; Gay, Steffen; Pap, Thomas

2007-01-01

The small ubiquitin-like modifier (SUMO)-1 is an important posttranslational regulator of different signaling pathways and involved in the formation of promyelocytic leukemia (PML) protein nuclear bodies (NBs). Overexpression of SUMO-1 has been associated with alterations in apoptosis, but the underlying mechanisms and their relevance for human diseases are not clear. Here, we show that the increased expression of SUMO-1 in rheumatoid arthritis (RA) synovial fibroblasts (SFs) contributes to the resistance of these cells against Fas-induced apoptosis through increased SUMOylation of nuclear PML protein and increased recruitment of the transcriptional repressor DAXX to PML NBs. We also show that the nuclear SUMO-protease SENP1, which is found at lower levels in RA SFs, can revert the apoptosis-inhibiting effects of SUMO-1 by releasing DAXX from PML NBs. Our findings indicate that in RA SFs overexpression of SENP1 can alter the SUMO-1-mediated recruitment of DAXX to PML NBs, thus influencing the proapoptotic effects of DAXX. Accumulation of DAXX in PML NBs by SUMO-1 may, therefore, contribute to the pathogenesis of inflammatory disorders. PMID:17360386

Eradication of acute promyelocytic leukemia-initiating cells through PML-RARA degradation.

PubMed

Nasr, Rihab; Guillemin, Marie-Claude; Ferhi, Omar; Soilihi, Hassan; Peres, Laurent; Berthier, Caroline; Rousselot, Philippe; Robledo-Sarmiento, Macarena; Lallemand-Breitenbach, Valérie; Gourmel, Bernard; Vitoux, Dominique; Pandolfi, Pier Paolo; Rochette-Egly, Cécile; Zhu, Jun; de Thé, Hugues

2008-12-01

Retinoic acid and arsenic trioxide target the protein stability and transcriptional repression activity of the fusion oncoprotein PML-RARA, resulting in regression of acute promyelocytic leukemia (APL). Phenotypically, retinoic acid induces differentiation of APL cells. Here we show that retinoic acid also triggers growth arrest of leukemia-initiating cells (LICs) ex vivo and their clearance in PML-RARA mouse APL in vivo. Retinoic acid treatment of mouse APLs expressing the fusion protein PLZF-RARA triggers full differentiation, but not LIC loss or disease remission, establishing that differentiation and LIC loss can be uncoupled. Although retinoic acid and arsenic synergize to clear LICs through cooperative PML-RARA degradation, this combination does not enhance differentiation. A cyclic AMP (cAMP)-dependent phosphorylation site in PML-RARA is crucial for retinoic acid-induced PML-RARA degradation and LIC clearance. Moreover, activation of cAMP signaling enhances LIC loss by retinoic acid, identifying cAMP as another potential APL therapy. Thus, whereas transcriptional activation of PML-RARA is likely to control differentiation, its catabolism triggers LIC eradication and long-term remission of mouse APL. Therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells.

Promyelocytic leukemia protein enhances apoptosis of gastric cancer cells through Yes-associated protein.

PubMed

Xu, Zhipeng; Chen, Jiamin; Shao, Liming; Ma, Wangqian; Xu, Dingting

2015-09-01

It has been shown that Yes-associated protein (YAP) acts as a transcriptional co-activator to regulate p73-dependent apoptosis in response to DNA damage in some cell types, and promyelocytic leukemia (PML) protein is involved in the regulation loop through stabilization of YAP through sumoylation. Although YAP has been shown to be significantly upregulated in gastric cancer, whether the YAP/PML/p73 regulation loop also functions in gastric cancer is unknown. Here, we show significantly higher levels of YAP and significantly lower levels of PML in the gastric cancer specimen. Overexpression of YAP in gastric cancer cells significantly increased cell growth, but did not affect apoptosis. However, overexpression of PML in gastric cancer cells significantly increased cell apoptosis, resulting in decreases in cell growth, which seemed to require the presence of YAP. The effect of PML on apoptosis appeared to be conducted through p73-mediated modulation of apoptosis-associated genes, Bcl-2, Bak, and caspase9. Thus, our study suggests the presence of a YAP/PML/p73 regulatory loop in gastric cancer, and highlights PML as a promising tumor suppressor in gastric cancer through YAP-coordinated cancer cell apoptosis.

A Cerebellar Tremor in a Patient with Human Immunodeficiency Virus-1 Associated with Progressive Multifocal Leukoencephalopathy

PubMed Central

Kim, Hee-Jin; Lee, Jae-Jung; Lee, Phil Hyu

2009-01-01

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by JC virus infection in oligodendrocytes, especially in patients with acquired immunodeficiency syndrome (AIDS). Movement disorders associated with PML are very rare. Here, we report a case of PML in an AIDS patient who presented with a cerebellar tremor, caused by lesions in the cerebellar outflow tract. A cerebellar tremor can be a rare clinical manifestation in patients with PML. PMID:24868366

Progressive multifocal leukoencephalopathy after fingolimod treatment.

PubMed

Berger, Joseph R; Cree, Bruce A; Greenberg, Benjamin; Hemmer, Bernhard; Ward, Brian J; Dong, Victor M; Merschhemke, Martin

2018-05-15

We describe the characteristics of the 15 patients with fingolimod-associated progressive multifocal leukoencephalopathy (PML) identified from the Novartis data safety base and provide risk estimates for the disorder. The Novartis safety database was searched for PML cases with a data lock point of August 31, 2017. PML classification was based on previously published criteria. The risk and incidence were estimated using the 15 patients with confirmed PML and the overall population of patients treated with fingolimod. As of August 31, 2017, 15 fingolimod-treated patients had developed PML in the absence of natalizumab treatment in the preceding 6 months. Eleven (73%) were women and the mean age was 53 years (median: 53 years). Fourteen of the 15 patients were treated with fingolimod for >2 years. Two patients had confounding medical conditions. Two patients had natalizumab treatment. This included one patient whose last dose of natalizumab was 3 years and 9 months before the diagnosis of PML. The second patient was receiving fingolimod for 4 years and 6 months, which was discontinued to start natalizumab and was diagnosed with PML 3 months after starting natalizumab. Absolute lymphocyte counts were available for 14 of the 15 patients and none exhibited a sustained grade 4 lymphopenia (≤200 cells/μL). The risk of PML with fingolimod in the absence of prior natalizumab treatment is low. The estimated risk was 0.069 per 1,000 patients (95% confidence interval: 0.039-0.114), and the estimated incidence rate was 3.12 per 100,000 patient-years (95% confidence interval: 1.75-5.15). Neither clinical manifestations nor radiographic features suggested any unique features of fingolimod-associated PML. Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

IgA-mediated inhibition of human leucocyte function by interference with Fc gamma and C3b receptors.

PubMed

Saito, K; Kato, C; Katsuragi, H; Komatsuzaki, A

1991-09-01

The inhibitory effects of IgA from human colostrum, and IgA1 and IgA2 from human serum on the chemiluminescence (CL) response and phagocytosis of polymorphonuclear leucocytes (PML) to Staphylococcus epidermidis and the CL response to formylmethionyl-leucyl-phenylalanine (FMLP) were studied. The dose-dependent inhibition of the luminol-mediated CL response of human PML to the bacteria was observed in the presence of more than 0.1 mg/ml IgA from both colostrum and serum. The preincubation of PML with a solution of IgA enhanced the suppressive effect of IgA on the cells. Removal of IgA from the reaction mixture after preincubation resulted in recovery, with time, of the response of PML to the bacteria. The bacteria treated with IgA did not give rise to any inhibition of the response. The CL response of PML to FMLP was not affected by the presence of IgA in the reaction mixture. The decrease of phagocytic activity of PML in the presence of IgA resulted in a decrease of NADPH oxidase activity of PML after stimulation with the bacteria as compared with the absence of IgA. The effect of IgA on the receptors of Fc and C3b (CR1) on the surface of PML was measured by monitoring erythrocyte-antibody (EA) or erythrocyte-antibody-complement (EAC) rosette formation and by direct and indirect immunofluorescence techniques using anti-CR1 antibody and Fc-specific antibodies. The presence of IgA in the reaction mixture led to a quantitative decrease in CR1 and the ability to bind IgG to the surface of PML.

IgA-mediated inhibition of human leucocyte function by interference with Fc gamma and C3b receptors.

PubMed Central

Saito, K; Kato, C; Katsuragi, H; Komatsuzaki, A

1991-01-01

The inhibitory effects of IgA from human colostrum, and IgA1 and IgA2 from human serum on the chemiluminescence (CL) response and phagocytosis of polymorphonuclear leucocytes (PML) to Staphylococcus epidermidis and the CL response to formylmethionyl-leucyl-phenylalanine (FMLP) were studied. The dose-dependent inhibition of the luminol-mediated CL response of human PML to the bacteria was observed in the presence of more than 0.1 mg/ml IgA from both colostrum and serum. The preincubation of PML with a solution of IgA enhanced the suppressive effect of IgA on the cells. Removal of IgA from the reaction mixture after preincubation resulted in recovery, with time, of the response of PML to the bacteria. The bacteria treated with IgA did not give rise to any inhibition of the response. The CL response of PML to FMLP was not affected by the presence of IgA in the reaction mixture. The decrease of phagocytic activity of PML in the presence of IgA resulted in a decrease of NADPH oxidase activity of PML after stimulation with the bacteria as compared with the absence of IgA. The effect of IgA on the receptors of Fc and C3b (CR1) on the surface of PML was measured by monitoring erythrocyte-antibody (EA) or erythrocyte-antibody-complement (EAC) rosette formation and by direct and indirect immunofluorescence techniques using anti-CR1 antibody and Fc-specific antibodies. The presence of IgA in the reaction mixture led to a quantitative decrease in CR1 and the ability to bind IgG to the surface of PML. PMID:1834550

Progressive multifocal leukoencephalopathy in patients with systemic lupus erythematosus: a systematic literature review.

PubMed

Henegar, C E; Eudy, A M; Kharat, V; Hill, D D; Bennett, D; Haight, B

2016-05-01

To determine risk factors for progressive multifocal leukoencephalopathy (PML) in systemic lupus erythematosus (SLE) patients, and understand how underlying disease or treatment for SLE may be associated with PML in this population. Studies published in English between January 1, 1984 and October 31, 2014 that reported PML in adult SLE patients were included. Immunosuppression was defined as exposure to ≥1 immunosuppressant drug of interest at PML diagnosis: belimumab, rituximab, mycophenolate mofetil, azathioprine, cyclophosphamide, methotrexate and high-dose corticosteroids (>15 mg/day). Minimal immunosuppression was defined as low-dose corticosteroids (≤15 mg/day) and/or anti-malarials. Thirty-five publications met our inclusion criteria: four observational studies, two large case series, and 29 case reports that described 35 cases. Reported PML incidence rates among SLE patients based on observational studies ranged from 1.0 to 2.4 cases/100,000 person-years. Of the 35 case reports, three cases were exposed to no immunosuppressant drugs at PML diagnosis, five cases had minimal immunosuppression, 23 cases had immunosuppression, and four cases were indeterminate. The evidence from this literature review suggests that, while PML is a very rare disease in SLE patients, there does appear to be an increased risk of PML associated with SLE compared to the general population, potentially due to immunosuppression, other contributing factors in their underlying disease, treatments prescribed to manage disease, or some combination of these factors. Additional large observational studies, designed to assess exposure to drugs of interest and complicated treatment histories, are needed to provide further evidence about potential mechanisms contributing to the onset of PML in SLE patients. © The Author(s) 2016.

A Comparison of Three PML Treatments for CAA (and CFD)

NASA Technical Reports Server (NTRS)

Goodrich, John W.

2008-01-01

In this paper we compare three Perfectly Matched Layer (PML) treatments by means of a series of numerical experiments, using common numerical algorithms, computational grids, and code implementations. These comparisons are with the Linearized Euler Equations, for base uniform base flow. We see that there are two very good PML candidates, and that can both control the introduced error. Furthermore, we also show that corners can be handled with essentially no increase in the introduced error, and that with a good PML, the outer boundary is the most significant source of err

A Gauss-Newton full-waveform inversion in PML-truncated domains using scalar probing waves

NASA Astrophysics Data System (ADS)

Pakravan, Alireza; Kang, Jun Won; Newtson, Craig M.

2017-12-01

This study considers the characterization of subsurface shear wave velocity profiles in semi-infinite media using scalar waves. Using surficial responses caused by probing waves, a reconstruction of the material profile is sought using a Gauss-Newton full-waveform inversion method in a two-dimensional domain truncated by perfectly matched layer (PML) wave-absorbing boundaries. The PML is introduced to limit the semi-infinite extent of the half-space and to prevent reflections from the truncated boundaries. A hybrid unsplit-field PML is formulated in the inversion framework to enable more efficient wave simulations than with a fully mixed PML. The full-waveform inversion method is based on a constrained optimization framework that is implemented using Karush-Kuhn-Tucker (KKT) optimality conditions to minimize the objective functional augmented by PML-endowed wave equations via Lagrange multipliers. The KKT conditions consist of state, adjoint, and control problems, and are solved iteratively to update the shear wave velocity profile of the PML-truncated domain. Numerical examples show that the developed Gauss-Newton inversion method is accurate enough and more efficient than another inversion method. The algorithm's performance is demonstrated by the numerical examples including the case of noisy measurement responses and the case of reduced number of sources and receivers.

Comparison of artificial absorbing boundaries for acoustic wave equation modelling

NASA Astrophysics Data System (ADS)

Gao, Yingjie; Song, Hanjie; Zhang, Jinhai; Yao, Zhenxing

2017-12-01

Absorbing boundary conditions are necessary in numerical simulation for reducing the artificial reflections from model boundaries. In this paper, we overview the most important and typical absorbing boundary conditions developed throughout history. We first derive the wave equations of similar methods in unified forms; then, we compare their absorbing performance via theoretical analyses and numerical experiments. The Higdon boundary condition is shown to be the best one among the three main absorbing boundary conditions that are based on a one-way wave equation. The Clayton and Engquist boundary is a special case of the Higdon boundary but has difficulty in dealing with the corner points in implementaion. The Reynolds boundary does not have this problem but its absorbing performance is the poorest among these three methods. The sponge boundary has difficulties in determining the optimal parameters in advance and too many layers are required to achieve a good enough absorbing performance. The hybrid absorbing boundary condition (hybrid ABC) has a better absorbing performance than the Higdon boundary does; however, it is still less efficient for absorbing nearly grazing waves since it is based on the one-way wave equation. In contrast, the perfectly matched layer (PML) can perform much better using a few layers. For example, the 10-layer PML would perform well for absorbing most reflected waves except the nearly grazing incident waves. The 20-layer PML is suggested for most practical applications. For nearly grazing incident waves, convolutional PML shows superiority over the PML when the source is close to the boundary for large-scale models. The Higdon boundary and hybrid ABC are preferred when the computational cost is high and high-level absorbing performance is not required, such as migration and migration velocity analyses, since they are not as sensitive to the amplitude errors as the full waveform inversion.

Progressive Multifocal Leukoencephalopathy in Primary Immune Deficiencies: Stat1 Gain of Function and Review of the Literature.

PubMed

Zerbe, Christa S; Marciano, Beatriz E; Katial, Rohit K; Santos, Carah B; Adamo, Nick; Hsu, Amy P; Hanks, Mary E; Darnell, Dirk N; Quezado, Martha M; Frein, Cathleen; Barnhart, Lisa A; Anderson, Victoria L; Uzel, Gulbu; Freeman, Alexandra F; Lisco, Andrea; Nath, Avindra; Major, Eugene O; Sampaio, Elizabeth P; Holland, Steven M

2016-04-15

Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs). STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed. We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only. The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system. Published by Oxford University Press for the Infectious Diseases Society of America 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

PubMed

Amodeo, Valeria; A, Deli; Betts, Joanne; Bartesaghi, Stefano; Zhang, Ying; Richard-Londt, Angela; Ellis, Matthew; Roshani, Rozita; Vouri, Mikaella; Galavotti, Sara; Oberndorfer, Sarah; Leite, Ana Paula; Mackay, Alan; Lampada, Aikaterini; Stratford, Eva Wessel; Li, Ningning; Dinsdale, David; Grimwade, David; Jones, Chris; Nicotera, Pierluigi; Michod, David; Brandner, Sebastian; Salomoni, Paolo

2017-07-11

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A modal approach based on perfectly matched layers for the forced response of elastic open waveguides

NASA Astrophysics Data System (ADS)

Gallezot, M.; Treyssède, F.; Laguerre, L.

2018-03-01

This paper investigates the computation of the forced response of elastic open waveguides with a numerical modal approach based on perfectly matched layers (PML). With a PML of infinite thickness, the solution can theoretically be expanded as a discrete sum of trapped modes, a discrete sum of leaky modes and a continuous sum of radiation modes related to the PML branch cuts. Yet with numerical methods (e.g. finite elements), the waveguide cross-section is discretized and the PML must be truncated to a finite thickness. This truncation transforms the continuous sum into a discrete set of PML modes. To guarantee the uniqueness of the numerical solution of the forced response problem, an orthogonality relationship is proposed. This relationship is applicable to any type of modes (trapped, leaky and PML modes) and hence allows the numerical solution to be expanded on a discrete sum in a convenient manner. This also leads to an expression for the modal excitability valid for leaky modes. The physical relevance of each type of mode for the solution is clarified through two numerical test cases, a homogeneous medium and a circular bar waveguide example, excited by a point source. The former is favourably compared to a transient analytical solution, showing that PML modes reassemble the bulk wave contribution in a homogeneous medium. The latter shows that the PML mode contribution yields the long-term diffraction phenomenon whereas the leaky mode contribution prevails closer to the source. The leaky mode contribution is shown to remain accurate even with a relatively small PML thickness, hence reducing the computational cost. This is of particular interest for solving three-dimensional waveguide problems, involving two-dimensional cross-sections of arbitrary shapes. Such a problem is handled in a third numerical example by considering a buried square bar.

PML expression in soft tissue sarcoma: prognostic and predictive value in alkylating agents/antracycline-based first line therapy.

PubMed

Vincenzi, Bruno; Santini, Daniele; Schiavon, Gaia; Frezza, Anna Maria; Silletta, Marianna; Crucitti, Pierfilippo; Casali, Paolo; Dei Tos, Angelo P; Rossi, Sabrina; Rizzo, Sergio; Badalamenti, Giuseppe; Tomasino, Rosa Maria; Russo, Antonio; Butrynski, James E; Tonini, Giuseppe

2012-04-01

Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our study was to evaluate promyelocytic leukemia gene expression value as prognostic factor and as a factor predicting response to alkylating agents/antracycline-based first line therapy. One hundred eleven patients affected by locally advanced and metastatic soft tissue sarcoma were selected. PML expression was evaluated by immunohistochemical analysis in pathological samples and in the corresponding normal tissue from each case. PML immunohistochemical results were correlated with prognosis and with radiological response to alkylating agents/antracycline-based first line therapy. PML expression was significantly reduced in synovial sarcomas (P < 0.0001), in myofibroblastic sarcomas (P < 0.0001), angiosarcomas (P < 0.0001), in leiomyosarcomas (P = 0.003), in mixoid liposarcomas (P < 0.0001), and in dedifferentiated liposarcomas (P < 0.0001). No significant difference was found for pleomorphic sarcoma [31.8 (95% CI: 16.7-41.0); P = 0.21]. and pleomorphic liposarcomas (P = 0.51). Loss of PML expression was found to be statistically correlated with TTP (P < 0.0001), median duration of response (P = 0.007), and OS (P = 0.02). No correlation was observed between PML expression and treatment efficacy. PML IHC expression is down-regulated in synovial sarcomas, myofibroblastic sarcomas, angiosarcomas, liposarcoma, and leiomyosarcomas and its expression correlated with prognosis. Copyright © 2011 Wiley Periodicals, Inc.

[Descriptive analysis of the e-mail list "Neurología-RedIRIS" (http://listserv.rediris.es/neurologia.html): an active, plural instrument having scientific quality at the reach of the Spanish speaking neurology sector].

PubMed

Serrano-Castro, P J; Arjona Padillo, A; Guardado Santervás, P

2004-10-01

In recent years, professional mailing-lists (PML) have experienced wide diffusion in the field of the medicine thanks to their educational and academic potential. In neurology and in Spanish, Neurología list belonging to RedIRIS has played the lead in the history of PML. Since the year 1997, it has maintained approximately 200 persons related with neurology in communication and has exceeded more of 7,300 messages. We analyzed retrospectively the activity recorded in the Neurología PML between January and December 2003, recording variables related to the activity and scientific quality of the PML and to the origin and content of the messages. 758 messages were registered (2.07 messages/day; 3.73 messages/subscriber). 93 of 203 subscribers (45.81 %) participated on at least one occasion. 83 % of the messages came from Spain, there being an inverse relationship between the neurologists relative endowment and degree of participation in the PML. The most frequent messages referred to clinical cases followed by debate of topics of management and scientific consultations. The scientific quality of Neurología PML is comparable to other English language based PML analyzed based on the number of publications in Index Medicus and of the impact factor of its subscribers. Neurología PML has reached a level of maturity and enjoys a critical mass and a number of subscribers of high scientific level that assures its immediate future. Besides its educational and consultation functions, it may become an opinion forum for the Spanish neurologists without their losing their independence or Latin-American vocation.

MRI criteria differentiating asymptomatic PML from new MS lesions during natalizumab pharmacovigilance.

PubMed

Wijburg, Martijn T; Witte, Birgit I; Vennegoor, Anke; Roosendaal, Stefan D; Sanchez, Esther; Liu, Yaou; Martins Jarnalo, Carine O; Uitdehaag, Bernard Mj; Barkhof, Frederik; Killestein, Joep; Wattjes, Mike P

2016-10-01

Differentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation. Reference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters. We tested the association with PML for each characteristic and constructed a multivariable prediction model which we analysed using a receiver operating characteristic (ROC) curve. Presence of punctate T2 lesions, cortical grey matter involvement, juxtacortical white matter involvement, ill-defined and mixed lesion borders towards both grey and white matter, lesion size of >3 cm, and contrast enhancement were all associated with PML. Focal lesion appearance and periventricular localisation were associated with new MS lesions. In the multivariable model, punctate T2 lesions and cortical grey matter involvement predict for PML, while focal lesion appearance and periventricular localisation predict for new MS lesions (area under the curve: 0.988, 95% CI 0.977 to 1.0, sensitivity: 100%, specificity: 80.6%). The MRI characteristics of asymptomatic natalizumab-associated PML lesions proved to differ from new MS lesions. This led to a prediction model with a high discriminating power. Careful assessment of the presence of punctate T2 lesions, cortical grey matter involvement, focal lesion appearance and periventricular localisation allows for an early diagnosis of PML. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

The CFS-PML in numerical simulation of ATEM

NASA Astrophysics Data System (ADS)

Zhao, Xuejiao; Ji, Yanju; Qiu, Shuo; Guan, Shanshan; Wu, Yanqi

2017-01-01

In the simulation of airborne transient electromagnetic method (ATEM) in time-domain, the truncated boundary reflection can bring a big error to the results. The complex frequency shifted perfectly matched layer (CFS-PML) absorbing boundary condition has been proved to have a better absorption of low frequency incident wave and can reduce the late reflection greatly. In this paper, we apply the CFS-PML to three-dimensional numerical simulation of ATEM in time-domain to achieve a high precision .The expression of divergence equation in CFS-PML is confirmed and its explicit iteration format based on the finite difference method and the recursive convolution technique is deduced. Finally, we use the uniformity half space model and the anomalous model to test the validity of this method. Results show that the CFS-PML can reduce the average relative error to 2.87% and increase the accuracy of the anomaly recognition.

Quantitative SUMO proteomics reveals the modulation of several PML nuclear body associated proteins and an anti-senescence function of UBC9.

PubMed

McManus, Francis P; Bourdeau, Véronique; Acevedo, Mariana; Lopes-Paciencia, Stéphane; Mignacca, Lian; Lamoliatte, Frédéric; Rojas Pino, John W; Ferbeyre, Gerardo; Thibault, Pierre

2018-05-17

Several regulators of SUMOylation have been previously linked to senescence but most targets of this modification in senescent cells remain unidentified. Using a two-step purification of a modified SUMO3, we profiled the SUMO proteome of senescent cells in a site-specific manner. We identified 25 SUMO sites on 23 proteins that were significantly regulated during senescence. Of note, most of these proteins were PML nuclear body (PML-NB) associated, which correlates with the increased number and size of PML-NBs observed in senescent cells. Interestingly, the sole SUMO E2 enzyme, UBC9, was more SUMOylated during senescence on its Lys-49. Functional studies of a UBC9 mutant at Lys-49 showed a decreased association to PML-NBs and the loss of UBC9's ability to delay senescence. We thus propose both pro- and anti-senescence functions of protein SUMOylation.

Spinal cord lesions of progressive multifocal leukoencephalopathy in an acquired immunodeficiency syndrome patient.

PubMed

Bernal-Cano, F; Joseph, J T; Koralnik, I J

2007-10-01

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease of the central nervous system, which occurs in immunosuppressed individuals. This disease is caused by a reactivation of the polyomavirus JC (JCV). Clinical presentation can be variable from patient to patient as lesions can occur anywhere in the CNS white matter; however, they appear to spare the optic nerves and the spinal cord. The authors present a case of PML in the setting of acquired immunodeficiency syndrome (AIDS) who developed PML lesions in the spinal cord, discovered during the postmortem examination. This finding is significant because PML has recently been diagnosed in patients with multiple sclerosis (MS) treated with the novel immunomodulatory medication natalizumab. Indeed, spinal cord lesions are frequent in MS. Therefore clinicians should be aware that in addition to the brain, PML may also affect the spinal cord white matter.

Contribution of the Major ND10 Proteins PML, hDaxx and Sp100 to the Regulation of Human Cytomegalovirus Latency and Lytic Replication in the Monocytic Cell Line THP-1

PubMed Central

Wagenknecht, Nadine; Reuter, Nina; Scherer, Myriam; Reichel, Anna; Müller, Regina; Stamminger, Thomas

2015-01-01

Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we utilized the monocytic cell line THP-1 as an in vitro latency model for human cytomegalovirus infection (HCMV). Characterization of THP-1 cells by immunofluorescence and Western blot analysis confirmed the expression of all major ND10 components. THP-1 cells with a stable, individual knockdown of PML, hDaxx or Sp100 were generated. Importantly, depletion of the major ND10 proteins did not prevent the terminal cellular differentiation of THP-1 monocytes. After construction of a recombinant, endotheliotropic human cytomegalovirus expressing IE2-EYFP, we investigated whether the depletion of ND10 proteins affects the onset of viral IE gene expression. While after infection of differentiated, THP-1-derived macrophages as well as during differentiation-induced reactivation from latency an increase in the number of IE-expressing cells was readily detectable in the absence of the major ND10 proteins, no effect was observed in non-differentiated monocytes. We conclude that PML, hDaxx and Sp100 primarily act as cellular restriction factors during lytic HCMV replication and during the dynamic process of reactivation but do not serve as key determinants for the establishment of HCMV latency. PMID:26057166

Eradication of acute promyelocytic leukemia-initiating cells by PML/RARA-targeting.

PubMed

Nasr, Rihab; de Thé, Hugues

2010-06-01

Acute promyelocytic leukemia (APL) is characterized by a t(15;17) translocation that yields a PML/RARA fusion protein. Expression of PML/RARA, a potent transcriptional repressor, induces APL in mice. Both retinoic acid (RA) and arsenic trioxide directly target PML/RARA-mediated transcriptional repression and protein stability, inducing rapid differentiation of the promyelocytes and clinical remission in most APL patients. RA also triggers growth arrest and progressive clearance of leukemia initiating cells (LIC), both ex vivo and in vivo. Suboptimal RA concentrations or expression of the PLZF/RARA variant allows complete RA-induced differentiation, but neither LIC clearance nor disease remission. Thus, RA-induced differentiation and LIC clearance may be uncoupled. The RA/arsenic trioxide association, which dramatically synergizes for PML/RARA degradation but not for differentiation, rapidly clears LIC in a proteasome-dependent manner, resulting in APL eradication in murine models and patients. Collectively, these results demonstrate that LIC clearance, which mirrors PML/RARA degradation, is the primary basis for APL cure by the RA/arsenic trioxide association, rather than differentiation. Oncogene degradation could be a generally applicable therapeutic strategy to clear LICs in several types of tumors.

Constitutive expression of the promyelocytic leukemia-associated oncogene PML-RARalpha in TF1 cells: isoform-specific and retinoic acid-dependent effects on growth, bcl-2 expression, and apoptosis.

PubMed

Slack, J L; Yu, M

1998-05-01

Two major isoforms of PML-RARalpha are associated with (15;17)-positive acute promyelocytic leukemia (APL); however, functional differences between these isoforms have been difficult to define, and the molecular mechanism by which each isoform contributes to the pathogenesis of APL is not fully understood. To address these issues, the 'short' (S) and 'long' (L) isoforms of PML-RARalpha were constitutively expressed in the factor-dependent human erythroleukemia cell line, TF1. Expression of the L, but not the S, isoform inhibited growth of these cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). In the absence of GM-CSF, the S isoform partially protected against apoptosis, while the L isoform accelerated cell death. Treatment with all-trans retinoic acid (ATRA) inhibited cell growth and caused apoptosis only in PML-RARalpha-expressing cells, and these effects of ATRA were more marked in cells expressing the L isoform. ATRA treatment also led to downregulation of bcl-2 and endogenous RARalpha in PML-RARalpha-expressing cells, but had little effect on the level of exogenously expressed PML-RARalpha. We conclude that (1) subtle differences exist in the biologic activities of the L and S isoforms of PML-RARalpha, and (2) both isoforms are capable of transducing an ATRA-mediated signal that leads to downregulation of bcl-2 and induction of programmed cell death.

[Effect of topical application of a recombinant adenovirus carrying promyelocytic leukemia gene in a psoriasis-like mouse model].

PubMed

Wang, Qiongyu; Zhang, Aijun; Ma, Huiqun; Wang, Shijie; Ma, Yunyun; Zou, Xingwei; Li, Ruilian

2013-03-01

To investigate the effects of topical treatment with adenovirus-mediated promyelocytic leukemia gene (PML) gene in a psoriasis-like mouse model. The effect of adenovirus-mediated PML gene on the granular layer of mouse tail scale epidermis and epithelial mitosis were observed on longitudinal histological sections prepared from the tail skin and vaginal epithelium of the mice. Adenovirus-mediated PML gene significantly inhibited mitosis of mouse vaginal epithelial cells and promoted the formation of granular layer in mouse tail scale epidermis. The therapeutic effect of PML gene in the psoriasis-like mouse model may be associated with increased granular cells and suppressed epidemic cell proliferation.

A novel unsplit perfectly matched layer for the second-order acoustic wave equation.

PubMed

Ma, Youneng; Yu, Jinhua; Wang, Yuanyuan

2014-08-01

When solving acoustic field equations by using numerical approximation technique, absorbing boundary conditions (ABCs) are widely used to truncate the simulation to a finite space. The perfectly matched layer (PML) technique has exhibited excellent absorbing efficiency as an ABC for the acoustic wave equation formulated as a first-order system. However, as the PML was originally designed for the first-order equation system, it cannot be applied to the second-order equation system directly. In this article, we aim to extend the unsplit PML to the second-order equation system. We developed an efficient unsplit implementation of PML for the second-order acoustic wave equation based on an auxiliary-differential-equation (ADE) scheme. The proposed method can benefit to the use of PML in simulations based on second-order equations. Compared with the existing PMLs, it has simpler implementation and requires less extra storage. Numerical results from finite-difference time-domain models are provided to illustrate the validity of the approach. Copyright © 2014 Elsevier B.V. All rights reserved.

Pontomedullary lacerations in falls from a height--a retrospective autopsy study.

PubMed

Zivković, Vladimir; Nikolić, Slobodan; Babić, Dragan; Djonić, Danijela; Atanasijević, Tatjana; Djurić, Marija

2012-05-01

Brainstem pontomedullary laceration (PML) in falls from a height appears as isolated cases and usually in feet-first impacts with a ring fracture. The aim of this study was to determine the frequency of PML in falls from a height, as well as the frequency of concomitant head and neck injuries. Out of 261 cases, PML was present in 40. An impact to the chin, as well as a feet- or buttocks-first impact, most often led to PML owing to transmission of the impact force. Also, a lateral, frontal, or posterior head impact, with subsequent hinge fracture, as well as the frontoposterior hyperextension of the head associated with an upper spine fracture, could be possible mechanisms of PML in falls from a height. The jawbone and other facial bones act as shock absorbers, and their fracture diminishes energy transfer toward the skull and protects the brain and brainstem from injury. © 2011 American Academy of Forensic Sciences.

Progressive Multifocal Leukoencephalopathy Complicating HIV-1 Infection

PubMed Central

Cinque, Paola; Koralnik, Igor J.; Gerevini, Simonetta; Miro, Jose M.; Price, Richard W.

2010-01-01

Progressive multifocal leukoencephalopathy (PML) caused by the polyomavirus, JC virus (JCV), is one of the most dreaded complications of HIV-1 infection. Unlike other opportunistic infections, PML may present while blood CD4+ T cells remain above AIDS-defining levels and while patients receive combined antiretroviral therapy (cART), either shortly after starting or, more rarely, during chronic successful treatment. PML can be suspected by typical presentation with focal neurological deficits and corresponding demyelinating lesions at magnetic resonance imaging (MRI), while definitive diagnosis requires identification of JCV in cerebrospinal fluid (CSF) or brain tissue. While there is no specific treatment, reversal of immunosuppression by cART leads to clinical and MRI stabilization in 50-60% of PML patients and JCV clearance from CSF. A proportion of cART-treated patients develop inflammatory lesions, which may either accompany a favorable outcome or associate with clinical worsening. The reasons for variability in PML natural history and treatment responses are largely undefined, and more specific and rational approaches to management are sorely needed. PMID:19778765

Latency Entry of Herpes Simplex Virus 1 Is Determined by the Interaction of Its Genome with the Nuclear Environment

PubMed Central

Cohen, Camille; Streichenberger, Nathalie; Texier, Pascale; Takissian, Julie; Rousseau, Antoine; Poccardi, Nolwenn; Welsch, Jérémy; Corpet, Armelle; Schaeffer, Laurent; Labetoulle, Marc; Lomonte, Patrick

2016-01-01

Herpes simplex virus 1 (HSV-1) establishes latency in trigeminal ganglia (TG) sensory neurons of infected individuals. The commitment of infected neurons toward the viral lytic or latent transcriptional program is likely to depend on both viral and cellular factors, and to differ among individual neurons. In this study, we used a mouse model of HSV-1 infection to investigate the relationship between viral genomes and the nuclear environment in terms of the establishment of latency. During acute infection, viral genomes show two major patterns: replication compartments or multiple spots distributed in the nucleoplasm (namely “multiple-acute”). Viral genomes in the “multiple-acute” pattern are systematically associated with the promyelocytic leukemia (PML) protein in structures designated viral DNA-containing PML nuclear bodies (vDCP-NBs). To investigate the viral and cellular features that favor the acquisition of the latency-associated viral genome patterns, we infected mouse primary TG neurons from wild type (wt) mice or knock-out mice for type 1 interferon (IFN) receptor with wt or a mutant HSV-1, which is unable to replicate due to the synthesis of a non-functional ICP4, the major virus transactivator. We found that the inability of the virus to initiate the lytic program combined to its inability to synthesize a functional ICP0, are the two viral features leading to the formation of vDCP-NBs. The formation of the “multiple-latency” pattern is favored by the type 1 IFN signaling pathway in the context of neurons infected by a virus able to replicate through the expression of a functional ICP4 but unable to express functional VP16 and ICP0. Analyses of TGs harvested from HSV-1 latently infected humans showed that viral genomes and PML occupy similar nuclear areas in infected neurons, eventually forming vDCP-NB-like structures. Overall our study designates PML protein and PML-NBs to be major cellular components involved in the control of HSV-1 latency, probably during the entire life of an individual. PMID:27618691

Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

PubMed Central

Ferenczy, Michael W.; Marshall, Leslie J.; Nelson, Christian D. S.; Atwood, Walter J.; Nath, Avindra; Khalili, Kamel

2012-01-01

Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. PMID:22763635

A Promyelocytic Leukemia Protein-Thrombospondin-2 Axis and the Risk of Relapse in Neuroblastoma.

PubMed

Dvorkina, Maria; Nieddu, Valentina; Chakelam, Shalini; Pezzolo, Annalisa; Cantilena, Sandra; Leite, Ana Paula; Chayka, Olesya; Regad, Tarik; Pistorio, Angela; Sementa, Angela Rita; Virasami, Alex; Barton, Jack; Montano, Ximena; Lechertier, Tanguy; Brindle, Nicola; Morgenstern, Daniel; Lebras, Morgane; Burns, Alan J; Saunders, Nigel J; Hodivala-Dilke, Kairbaan; Bagella, Luigi; De The, Hugues; Anderson, John; Sebire, Neil; Pistoia, Vito; Sala, Arturo; Salomoni, Paolo

2016-07-01

Neuroblastoma is a childhood malignancy originating from the sympathetic nervous system with a complex biology, prone to metastasize and relapse. High-risk, metastatic cases are explained in part by amplification or mutation of oncogenes, such as MYCN and ALK, and loss of tumor suppressor genes in chromosome band 1p. However, it is fundamental to identify other pathways responsible for the large portion of neuroblastomas with no obvious molecular alterations. Neuroblastoma cell lines were used for the assessment of tumor growth in vivo and in vitro Protein expression in tissues and cells was assessed using immunofluorescence and IHC. The association of promyelocytic leukemia (PML) expression with neuroblastoma outcome and relapse was calculated using log-rank and Mann-Whitney tests, respectively. Gene expression was assessed using chip microarrays. PML is detected in the developing and adult sympathetic nervous system, whereas it is not expressed or is low in metastatic neuroblastoma tumors. Reduced PML expression in patients with low-risk cancers, that is, localized and negative for the MYCN proto-oncogene, is strongly associated with tumor recurrence. PML-I, but not PML-IV, isoform suppresses angiogenesis via upregulation of thrombospondin-2 (TSP2), a key inhibitor of angiogenesis. Finally, PML-I and TSP2 expression inversely correlates with tumor angiogenesis and recurrence in localized neuroblastomas. Our work reveals a novel PML-I-TSP2 axis for the regulation of angiogenesis and cancer relapse, which could be used to identify patients with low-risk, localized tumors that might benefit from chemotherapy. Clin Cancer Res; 22(13); 3398-409. ©2016 AACR. ©2016 American Association for Cancer Research.

Transcription and methylation analyses of preleukemic promyelocytes indicate a dual role for PML/RARA in leukemia initiation

PubMed Central

Gaillard, Coline; Tokuyasu, Taku A.; Rosen, Galit; Sotzen, Jason; Vitaliano-Prunier, Adeline; Roy, Ritu; Passegué, Emmanuelle; de Thé, Hugues; Figueroa, Maria E.; Kogan, Scott C.

2015-01-01

Acute promyelocytic leukemia is an aggressive malignancy characterized by the accumulation of promyelocytes in the bone marrow. PML/RARA is the primary abnormality implicated in this pathology, but the mechanisms by which this chimeric fusion protein initiates disease are incompletely understood. Identifying PML/RARA targets in vivo is critical for comprehending the road to pathogenesis. Utilizing a novel sorting strategy, we isolated highly purified promyelocyte populations from normal and young preleukemic animals, carried out microarray and methylation profiling analyses, and compared the results from the two groups of animals. Surprisingly, in the absence of secondary lesions, PML/RARA had an overall limited impact on both the transcriptome and methylome. Of interest, we did identify down-regulation of secondary and tertiary granule genes as the first step engaging the myeloid maturation block. Although initially not sufficient to arrest terminal granulopoiesis in vivo, such alterations set the stage for the later, complete differentiation block seen in leukemia. Further, gene set enrichment analysis revealed that PML/RARA promyelocytes exhibit a subtle increase in expression of cell cycle genes, and we show that this leads to both increased proliferation of these cells and expansion of the promyelocyte compartment. Importantly, this proliferation signature was absent from the poorly leukemogenic p50/RARA fusion model, implying a critical role for PML in the altered cell-cycle kinetics and ability to initiate leukemia. Thus, our findings challenge the predominant model in the field and we propose that PML/RARA initiates leukemia by subtly shifting cell fate decisions within the promyelocyte compartment. PMID:26088929

Selection of first-line therapy in multiple sclerosis using risk-benefit decision analysis.

PubMed

Bargiela, David; Bianchi, Matthew T; Westover, M Brandon; Chibnik, Lori B; Healy, Brian C; De Jager, Philip L; Xia, Zongqi

2017-02-14

To integrate long-term measures of disease-modifying drug efficacy and risk to guide selection of first-line treatment of multiple sclerosis. We created a Markov decision model to evaluate disability worsening and progressive multifocal leukoencephalopathy (PML) risk in patients receiving natalizumab (NTZ), fingolimod (FGL), or glatiramer acetate (GA) over 30 years. Leveraging publicly available data, we integrated treatment utility, disability worsening, and risk of PML into quality-adjusted life-years (QALYs). We performed sensitivity analyses varying PML risk, mortality and morbidity, and relative risk of disease worsening across clinically relevant ranges. Over the entire reported range of NTZ-associated PML risk, NTZ as first-line therapy is predicted to provide a greater net benefit (15.06 QALYs) than FGL (13.99 QALYs) or GA (12.71 QALYs) treatment over 30 years, after accounting for loss of QALYs due to PML or death (resulting from all causes). NTZ treatment is associated with delayed worsening to an Expanded Disability Status Scale score ≥6.0 vs FGL or GA (22.7, 17.0, and 12.4 years, respectively). Compared to untreated patients, NTZ-treated patients have a greater relative risk of death in the early years of treatment that varies according to PML risk profile. NTZ as a first-line treatment is associated with the highest net benefit across full ranges of PML risk, mortality, and morbidity compared to FGL or GA. Integrated modeling of long-term treatment risks and benefits informs stratified clinical decision-making and can support patient counseling on selection of first-line treatment options. © 2017 American Academy of Neurology.

Histone deacetylases: a common molecular target for differentiation treatment of acute myeloid leukemias?

PubMed

Minucci, S; Nervi, C; Lo Coco, F; Pelicci, P G

2001-05-28

Recent discoveries have identified key molecular events in the pathogenesis of acute promyelocytic leukemia (APL), caused by chromosomal rearrangements of the transcription factor RAR (resulting in a fusion protein with the product of other cellular genes, such as PML). Oligomerization of RAR, through a self-association domain present in PML, imposes an altered interaction with transcriptional co-regulators (NCoR/SMRT). NCoR/SMRT are responsible for recruitment of histone deacetylases (HDACs), which is required for transcriptional repression of PML-RAR target genes, and for the transforming potential of the fusion protein. Oligomerization and altered recruitment of HDACs are also responsible for transformation by the fusion protein AML1-ETO, extending these mechanisms to other forms of acute myeloid leukemias (AMLs) and suggesting that HDAC is a common target for myeloid leukemias. Strikingly, AML1-ETO expression blocks retinoic acid (RA) signaling in hematopoietic cells, suggesting that interference with the RA pathway (genetically altered in APL) by HDAC recruitment may be a common theme in AMLs. Treatment of APLs with RA, and of other AMLs with RA plus HDAC inhibitors (HDACi), results in myeloid differentiation. Thus, activation of the RA signaling pathway and inhibition of HDAC activity might represent a general strategy for the differentiation treatment of myeloid leukemias.

Design and fabrication of a hybrid maglev model employing PML and SML

NASA Astrophysics Data System (ADS)

Sun, R. X.; Zheng, J.; Zhan, L. J.; Huang, S. Y.; Li, H. T.; Deng, Z. G.

2017-10-01

A hybrid maglev model combining permanent magnet levitation (PML) and superconducting magnetic levitation (SML) was designed and fabricated to explore a heavy-load levitation system advancing in passive stability and simple structure. In this system, the PML was designed to levitate the load, and the SML was introduced to guarantee the stability. In order to realize different working gaps of the two maglev components, linear bearings were applied to connect the PML layer (for load) and the SML layer (for stability) of the hybrid maglev model. Experimental results indicate that the hybrid maglev model possesses excellent advantages of heavy-load ability and passive stability at the same time. This work presents a possible way to realize a heavy-load passive maglev concept.

PML-IRIS during Fingolimod Diagnosed after Natalizumab Discontinuation.

PubMed

Killestein, J; Vennegoor, A; van Golde, A E L; Bourez, R L J H; Wijlens, M L B; Wattjes, M P

2014-01-01

Background. Natalizumab treatment is frequently discontinued and replaced by alternative medication in multiple sclerosis (MS) patients having a high risk of progressive multifocal leukoencephalopathy (PML). Case Presentation. We report a PML case that was missed on magnetic resonance imaging (MRI) at the time Natalizumab treatment was discontinued. The patient subsequently developed a PML-immune reconstitution inflammatory syndrome after the initiation of Fingolimod treatment, suggesting that immune reconstitution may occur even during Fingolimod induced lymphopenia. Conclusion. This report highlights the need for strict drug surveillance using MRI of Natalizumab-associated MS patients at the time of drug discontinuation and beyond. This is important with respect to pharmacovigilance purposes not only for Natalizumab, but also for alternative drugs used after Natalizumab discontinuation.

Application of the perfectly matched layer in 3-D marine controlled-source electromagnetic modelling

NASA Astrophysics Data System (ADS)

Li, Gang; Li, Yuguo; Han, Bo; Liu, Zhan

2018-01-01

In this study, the complex frequency-shifted perfectly matched layer (CFS-PML) in stretching Cartesian coordinates is successfully applied to 3-D frequency-domain marine controlled-source electromagnetic (CSEM) field modelling. The Dirichlet boundary, which is usually used within the traditional framework of EM modelling algorithms, assumes that the electric or magnetic field values are zero at the boundaries. This requires the boundaries to be sufficiently far away from the area of interest. To mitigate the boundary artefacts, a large modelling area may be necessary even though cell sizes are allowed to grow toward the boundaries due to the diffusion of the electromagnetic wave propagation. Compared with the conventional Dirichlet boundary, the PML boundary is preferred as the modelling area of interest could be restricted to the target region and only a few absorbing layers surrounding can effectively depress the artificial boundary effect without losing the numerical accuracy. Furthermore, for joint inversion of seismic and marine CSEM data, if we use the PML for CSEM field simulation instead of the conventional Dirichlet, the modelling area for these two different geophysical data collected from the same survey area could be the same, which is convenient for joint inversion grid matching. We apply the CFS-PML boundary to 3-D marine CSEM modelling by using the staggered finite-difference discretization. Numerical test indicates that the modelling algorithm using the CFS-PML also shows good accuracy compared to the Dirichlet. Furthermore, the modelling algorithm using the CFS-PML shows advantages in computational time and memory saving than that using the Dirichlet boundary. For the 3-D example in this study, the memory saving using the PML is nearly 42 per cent and the time saving is around 48 per cent compared to using the Dirichlet.

Axonal ramification of neurons in the nucleus reticularis tegmenti pontis projecting to the paramedian lobule in the rabbit cerebellum.

PubMed

Bukowska, Dorota; Mierzejewska-Krzyzowska, Barbara; Zguczyński, Leszek

2005-01-01

Projections of the nucleus reticularis tegmenti pontis (NRTP) to the cerebellar paramedian lobule were examined in the rabbit by means of the double fluorescent retrograde tract-tracing method. The rabbit NRTP is composed of a medial, large part comprising zones A (dorsomedial), B (central) and C (lateral), and of a lateral, small part (the processus tegmentosus lateralis; PTL). Following unilateral injections of Fast Blue (FB) into the rostral part of the paramedian lobule (rPML) and of Diamidino Yellow (DY) into the caudal part (cPML), known to receive spinal inputs from forelimb and hindlimb, respectively, substantial numbers of single labeled neurons were found in all bilateral NRTP divisions, apart from the zone C. Most projection neurons to the PML were located in the medial and medioventral regions of the zone B. Smaller numbers of projection neurons were located in the PTL, zone A and outside the zone B among fibers of the medial lemniscus. The pattern of FB and DY labeling suggested that neurons projecting to the rPML and cPML originated in common rather than separate regions within the NRTP. In addition, a small percentage (mean 1.3%) of double FB+DY labeled neurons were detected with a clear contralateral preponderance, among single labeled FB or DY cells. In spite of the rarity, all the NRTP neurons giving rise to intralobular collateral projections can be regarded as potential sources of simultaneous modulating influences upon two functional different forelimb (rPML) and hindlimb (cPML) regions. The findings have been discussed in relation to earlier studies in other species and commented on with respect to the possible functional meaning of these projections.

From an old remedy to a magic bullet: molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia

PubMed Central

Zhou, Guang-Biao; Zhang, Xiao-Wei; Mao, Jian-Hua; de Thé, Hugues

2011-01-01

Arsenic had been used in treating malignancies from the 18th to mid-20th century. In the past 3 decades, arsenic was revived and shown to be able to induce complete remission and to achieve, when combined with all-trans retinoic acid and chemotherapy, a 5-year overall survival of 90% in patients with acute promyelocytic leukemia driven by the t(15;17) translocation-generated promyelocytic leukemia–retinoic acid receptor α (PML-RARα) fusion. Molecularly, arsenic binds thiol residues and induces the formation of reactive oxygen species, thus affecting numerous signaling pathways. Interestingly, arsenic directly binds the C3HC4 zinc finger motif in the RBCC domain of PML and PML-RARα, induces their homodimerization and multimerization, and enhances their interaction with the SUMO E2 conjugase Ubc9, facilitating subsequent sumoylation/ubiquitination and proteasomal degradation. Arsenic-caused intermolecular disulfide formation in PML also contributes to PML-multimerization. All-trans retinoic acid, which targets PML-RARα for degradation through its RARα moiety, synergizes with arsenic in eliminating leukemia-initiating cells. Arsenic perturbs a number of proteins involved in other hematologic malignancies, including chronic myeloid leukemia and adult T-cell leukemia/lymphoma, whereby it may bring new therapeutic benefits. The successful revival of arsenic in acute promyelocytic leukemia, together with modern mechanistic studies, has thus allowed a new paradigm to emerge in translational medicine. PMID:21422471

Performance advantages of CPML over UPML absorbing boundary conditions in FDTD algorithm

NASA Astrophysics Data System (ADS)

Gvozdic, Branko D.; Djurdjevic, Dusan Z.

2017-01-01

Implementation of absorbing boundary condition (ABC) has a very important role in simulation performance and accuracy in finite difference time domain (FDTD) method. The perfectly matched layer (PML) is the most efficient type of ABC. The aim of this paper is to give detailed insight in and discussion of boundary conditions and hence to simplify the choice of PML used for termination of computational domain in FDTD method. In particular, we demonstrate that using the convolutional PML (CPML) has significant advantages in terms of implementation in FDTD method and reducing computer resources than using uniaxial PML (UPML). An extensive number of numerical experiments has been performed and results have shown that CPML is more efficient in electromagnetic waves absorption. Numerical code is prepared, several problems are analyzed and relative error is calculated and presented.

Risk perception in natalizumab-treated multiple sclerosis patients and their neurologists.

PubMed

Heesen, Christoph; Kleiter, Ingo; Nguyen, Franziska; Schäffler, Nina; Kasper, Jürgen; Köpke, Sascha; Gaissmaier, Wolfgang

2010-12-01

Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients' and physicians' risk estimates and attitudes towards natalizumab treatment. Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet. After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects. Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.

The Perfectly Matched Layer absorbing boundary for fluid-structure interactions using the Immersed Finite Element Method.

PubMed

Yang, Jubiao; Yu, Feimi; Krane, Michael; Zhang, Lucy T

2018-01-01

In this work, a non-reflective boundary condition, the Perfectly Matched Layer (PML) technique, is adapted and implemented in a fluid-structure interaction numerical framework to demonstrate that proper boundary conditions are not only necessary to capture correct wave propagations in a flow field, but also its interacted solid behavior and responses. While most research on the topics of the non-reflective boundary conditions are focused on fluids, little effort has been done in a fluid-structure interaction setting. In this study, the effectiveness of the PML is closely examined in both pure fluid and fluid-structure interaction settings upon incorporating the PML algorithm in a fully-coupled fluid-structure interaction framework, the Immersed Finite Element Method. The performance of the PML boundary condition is evaluated and compared to reference solutions with a variety of benchmark test cases including known and expected solutions of aeroacoustic wave propagation as well as vortex shedding and advection. The application of the PML in numerical simulations of fluid-structure interaction is then investigated to demonstrate the efficacy and necessity of such boundary treatment in order to capture the correct solid deformation and flow field without the requirement of a significantly large computational domain.

High Temperature DC Bus Capacitor Cost Reduction & Performance Improvements

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

Yializis, Angelo; Taylor, Ralph S.

The goal of this DOE program is to develop high temperature, high energy density, lower cost DC- Link capacitors, for inverters used in electric drive vehicles. Most electric motors in Hybrid Electric Vehicles (“HEVs”), Plug-in Hybrid Vehicles (“PHVs”) and Electric Vehicles (“EVs”) are driven with variable AC voltage supplied by an inverter/converter power module that converts the DC battery voltage to three-phase AC voltage. A key component of the inverter circuit is the DC- Link capacitor used to minimize ripple current, voltage fluctuation, and transient suppression. The DC-Link capacitor is one of the largest, costliest, and most failure-prone components inmore » today’s electric drive invertersystems. The principal weakness of present day DC- Link capacitors is their reliance on a low temperature thermoplastic polypropylene (“PP”) film dielectric. PP is the dielectric of choice for inverter capacitor applications due to its high breakdown strength and low dissipation factor. Major limitations of metallized PP film capacitors include volumetric efficiency, performance under high thermal loads and cost. The latter is especially effectual at lower voltage applications (400V) where PP films with a thickness of about 2.5 m are required that are costly to process. Metallized PP capacitors also do not meet the traditional “under-the-hood” requirements for automotive electronics. The standard temperature requirement for most passive components in the automotive industry has been 125ºC and it is evolving to 140°C. The industry has addressed this problem by reducing the ambient temperature specification for PP capacitors from 125ºC to 105ºC, and also by placing the capacitors on a water-cooled bus bar to extend their life and reliably. The supply chain for the production of PP capacitors is, for the most part, horizontally integrated. It includes the producer of the PP film, the toll metallizer, that deposits a patterned aluminum conductor onto the PP film, and the capacitor producer that winds the metallized film, forms electrical connections, and packages the capacitor (some large capacitor OEMs also metallize their films). The horizontal nature of the supply chain is principally due to the very high capital costs required to integrate the film production process as well as the corresponding depreciation costs. The result is that hundreds of capacitor OEMs use the same base films and capacitor products vary mainly in the way they are wound, formed and packaged, with little or no ability to innovate. Sigma Technologies (“Sigma”) has developed a disruptive process for producing polymer dielectric capacitors that overcome the limitations of PP film capacitors. Metallized self-supported films are replaced with deposited polymer dielectrics, metallized in-line with the polymer deposition process. Highly cross linked, high temperature polymers are formed, that have a thickness as low as 0.1μm, a wide range of dielectric constants and breakdown strength higher than that of PP. The supply chain for producing such capacitors is reduced to a single step performed by the capacitor OEM, in which aluminum wire and a liquid monomer are introduced into a machine to create a large area bulk capacitor material. Polymer Multi-Layer (PML) capacitors are produced by depositing 1000s of dielectric and aluminum electrode on a rotating process drum, forming a nanolaminate “mother capacitor” material, that is segmented and processed into individual capacitor elements. The PML process combines the conventional stepsof a) polymer dielectric formation, b) electrode deposition, and c) winding the capacitor, into a single continuous process performed in a single machine. This allows for complete vertical integration of the capacitor production process, where the capacitor OEM has complete control the dielectric chemistry, the polymer thickness and the electrode metallization process. Sigma partnered with Delphi Automotive Systems (“Delphi”) and Oak Ridge National Labs (“ORNL”) to respond to a DOE Vehicle Technologies Office solicitation to develop a DC-Link capacitor with reduced cost, lower volume and superior thermal properties. The major objectives of the development program included: • Optimization of the polymer dielectric to meet an 140ºC operating environment • Improvements to Sigma’s PML capacitor pilot line to allow the production of sample quantities of DC-Link capacitors • Evaluation of the thermal properties of the PML capacitors • Development of a thermal model to predict capacitor performance under various operating conditions • Electrical and environmental evaluation of PML capacitors based on AEC Q200 standard • Development of a package for PML capacitors • Development of a business plan to transition the PML capacitor technology into production.« less

PML nuclear bodies: regulation, function and therapeutic perspectives.

PubMed

Sahin, Umut; Lallemand-Breitenbach, Valérie; de Thé, Hugues

2014-11-01

PML nuclear bodies (NBs) were first described by electron microscopy and rediscovered through their treatment-reversible disruption in a rare leukaemia. They recruit multiple partner proteins and now emerge as interferon- and oxidative stress-responsive sumoylation factories. NBs mediate interferon-induced viral restriction, enhance proteolysis, finely tune metabolism and enforce stress-induced senescence. Apart from being markers of cellular stress, PML NBs could be harnessed pharmacologically in a number of conditions, including cancer, viral infection or neurodegenerative diseases. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Host transcription factor Speckled 110 kDa (Sp110), a nuclear body protein, is hijacked by hepatitis B virus protein X for viral persistence.

PubMed

Sengupta, Isha; Das, Dipanwita; Singh, Shivaram Prasad; Chakravarty, Runu; Das, Chandrima

2017-12-15

Promyelocytic leukemia nuclear bodies (PML-NB) are sub-nuclear organelles that are the hub of numerous proteins. DNA/RNA viruses often hijack the cellular factors resident in PML-NBs to promote their proliferation in host cells. Hepatitis B virus (HBV), belonging to Hepadnaviridae family, remains undetected in early infection as it does not induce the innate immune response and is known to be the cause of several hepatic diseases leading to cirrhosis and hepatocellular carcinoma. The association of PML-NB proteins and HBV is being addressed in a number of recent studies. Here, we report that the PML-NB protein Speckled 110 kDa (Sp110) is SUMO1-modified and undergoes a deSUMOylation-driven release from the PML-NB in the presence of HBV. Intriguingly, Sp110 knockdown significantly reduced viral DNA load in the culture supernatant by activation of the type I interferon-response pathway. Furthermore, we found that Sp110 differentially regulates several direct target genes of hepatitis B virus protein X (HBx), a viral co-factor. Subsequently, we identified Sp110 as a novel interactor of HBx and found this association to be essential for the exit of Sp110 from the PML-NB during HBV infection and HBx recruitment on the promoter of these genes. HBx, in turn, modulates the recruitment of its associated transcription cofactors p300/HDAC1 to these co-regulated genes, thereby altering the host gene expression program in favor of viral persistence. Thus, we report a mechanism by which HBV can evade host immune response by hijacking the PML-NB protein Sp110, and therefore, we propose it to be a novel target for antiviral therapy. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Good outcome of brain stem progressive multifocal leukoencephalopathy in an immunosuppressed renal transplant patient: Importance of early detection and rapid immune reconstitution.

PubMed

Sauer, Roland; Gölitz, Philipp; Jacobi, Johannes; Schwab, Stefan; Linker, Ralf A; Lee, De-Hyung

2017-04-15

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic and often fatal disease of the CNS which may occur under immunosuppression in transplant patients. Brain stem PML is associated with a particularly bad prognosis. Here, we present a case of a renal transplant patient treated with mycophenolate mofetil (MMF) and tacrolimus who developed brain stem PML with limb ataxia, dysarthria and dysphagia. Diagnosis was established by typical MRI features and detection of JCV-DNA in the CSF. Immune reconstitution after stopping MMF and tacrolimus led to a complete and sustained remission of symptoms with improvement of the brain stem lesion over a follow-up over 20months. In summary, early detection of PML and consequent treatment may improve neurological outcomes even in brain stem disease with a notorious bad prognosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner.

PubMed

Dubuisson, Louise; Lormières, Florence; Fochi, Stefania; Turpin, Jocelyn; Pasquier, Amandine; Douceron, Estelle; Oliva, Anaïs; Bazarbachi, Ali; Lallemand-Breitenbach, Valérie; De Thé, Hugues; Journo, Chloé; Mahieux, Renaud

2018-05-01

Since the identification of the antisense protein of HTLV-2 (APH-2) and the demonstration that APH-2 mRNA is expressed in vivo in most HTLV-2 carriers, much effort has been dedicated to the elucidation of similarities and/or differences between APH-2 and HBZ, the antisense protein of HTLV-1. Similar to HBZ, APH-2 negatively regulates HTLV-2 transcription. However, it does not promote cell proliferation. In contrast to HBZ, APH-2 half-life is very short. Here, we show that APH-2 is addressed to PML nuclear bodies in T-cells, as well as in different cell types. Covalent SUMOylation of APH-2 is readily detected, indicating that APH-2 might be addressed to the PML nuclear bodies in a SUMO-dependent manner. We further show that silencing of PML increases expression of APH-2, while expression of HBZ is unaffected. On the other hand, SUMO-1 overexpression leads to a specific loss of APH-2 expression that is restored upon proteasome inhibition. Furthermore, the carboxy-terminal LAGLL motif of APH-2 is responsible for both the targeting of the protein to PML nuclear bodies and its short half-life. Taken together, these observations indicate that natural APH-2 targeting to PML nuclear bodies induces proteasomal degradation of the viral protein in a SUMO-dependent manner. Hence, this study deciphers the molecular and cellular bases of APH-2 short half-life in comparison to HBZ and highlights key differences in the post-translational mechanisms that control the expression of both proteins.

"Lack of knowledge is no excuse" HIV positive patient with progressive multifocal leukoencephalopathy. Case report from Kenya.

PubMed

Kafkova, Jirina; Silharova, Barbora

2017-11-01

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease that affects the central nervous system, which has high morbidity and mortality and no effective, targeted therapies are available. According to the data from developing countries, it affects about 3 to 5% patients who are HIV positive. We present a case of a 27-year-old patient, who got infected with the HIV virus from his mother. The patient had poor compliance to the therapy since its initiation. Due to poor compliance and immunological and virological failure of the first line ARVs, the patient developed PML. Despite confirmed diagnosis of PML and change of the regimen to the second line ARVs, due to progression of the condition, he sought care of an unknown physician, who prescribed therapy with azathioprine 150 mg twice daily, which the patient used for more than 2 weeks. Despite immediate virological suppression, the condition significantly worsened, until the patient developed paraparesis, postural tremor, head tremor, severe dysarthria; he was not able to walk, eat or express himself. The major roadblocks to diagnosis of PML include poor access to health care in general, as well as poor knowledge of the rare condition among the health care professionals. Therapy with azathioprine has been proved to be associated with the development of PML. Thus, in resource limited settings, there is an urgent need for improved access to health care and imaging and laboratory diagnostic means, which would decrease the economic and social burden of severe conditions, such as PML.

Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia

ClinicalTrials.gov

2017-07-18

Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Childhood Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Untreated Adult Acute Myeloid Leukemia; Untreated Childhood Myeloid Neoplasm

Chemical Markup, XML and the World-Wide Web. 8. Polymer Markup Language.

PubMed

Adams, Nico; Winter, Jerry; Murray-Rust, Peter; Rzepa, Henry S

2008-11-01

Polymers are among the most important classes of materials but are only inadequately supported by modern informatics. The paper discusses the reasons why polymer informatics is considerably more challenging than small molecule informatics and develops a vision for the computer-aided design of polymers, based on modern semantic web technologies. The paper then discusses the development of Polymer Markup Language (PML). PML is an extensible language, designed to support the (structural) representation of polymers and polymer-related information. PML closely interoperates with Chemical Markup Language (CML) and overcomes a number of the previously identified challenges.

Use of electrical impedance spectroscopy to detect malignant and potentially malignant oral lesions

PubMed Central

Murdoch, Craig; Brown, Brian H; Hearnden, Vanessa; Speight, Paul M; D’Apice, Katy; Hegarty, Anne M; Tidy, John A; Healey, T Jamie; Highfield, Peter E; Thornhill, Martin H

2014-01-01

The electrical properties of tissues depend on their architecture and cellular composition. We have previously shown that changes in electrical impedance can be used to differentiate between different degrees of cervical dysplasia and cancer of the cervix. In this proof-of-concept study, we aimed to determine whether electrical impedance spectroscopy (EIS) could distinguish between normal oral mucosa; benign, potentially malignant lesions (PML); and oral cancer. EIS data were collected from oral cancer (n=10), PML (n=27), and benign (n=10) lesions. EIS from lesions was compared with the EIS reading from the normal mucosa on the contralateral side of the mouth or with reference spectra from mucosal sites of control subjects (n=51). Healthy controls displayed significant differences in the EIS obtained from different oral sites. In addition, there were significant differences in the EIS of cancer and high-risk PML versus low-risk PML and controls. There was no significant difference between benign lesions and normal controls. Study subjects also deemed the EIS procedure considerably less painful and more convenient than the scalpel biopsy procedure. EIS shows promise at distinguishing among malignant, PML, and normal oral mucosa and has the potential to be developed into a clinical diagnostic tool. PMID:25285005

Replication of Merkel cell polyomavirus induces reorganization of promyelocytic leukemia nuclear bodies.

PubMed

Neumann, Friederike; Czech-Sioli, Manja; Dobner, Thomas; Grundhoff, Adam; Schreiner, Sabrina; Fischer, Nicole

2016-11-01

Merkel cell polyomavirus (MCPyV) is associated with Merkel cell carcinoma (MCC), a rare but aggressive skin cancer. The virus is highly prevalent: 60-80 % of adults are seropositive; however, cells permissive for MCPyV infection are unknown. Consequently, very little information about the MCPyV life cycle is available. Until recently, MCPyV replication could only be studied using a semi-permissive in vitro replication system (Neumann et al., 2011; Feng et al., 2011, Schowalter et al., 2011). MCPyV replication most likely depends on subnuclear structures such as promyelocytic leukemia protein nuclear bodies (PML-NBs), which are known to play regulatory roles in the infection of many DNA viruses. Here, we investigated PML-NB components as candidate host factors to control MCPyV DNA replication. We showed that PML-NBs change in number and size in cells actively replicating MCPyV proviral DNA. We observed a significant increase in PML-NBs in cells positive for MCPyV viral DNA replication. Interestingly, a significant amount of cells actively replicating MCPyV did not show any Sp100 expression. While PML and Daxx had no effect on MCPyV DNA replication, MCPyV replication was increased in cells depleted for Sp100, strongly suggesting that Sp100 is a negative regulator of MCPyV DNA replication.

Investigation of statistical iterative reconstruction for dedicated breast CT

PubMed Central

Makeev, Andrey; Glick, Stephen J.

2013-01-01

Purpose: Dedicated breast CT has great potential for improving the detection and diagnosis of breast cancer. Statistical iterative reconstruction (SIR) in dedicated breast CT is a promising alternative to traditional filtered backprojection (FBP). One of the difficulties in using SIR is the presence of free parameters in the algorithm that control the appearance of the resulting image. These parameters require tuning in order to achieve high quality reconstructions. In this study, the authors investigated the penalized maximum likelihood (PML) method with two commonly used types of roughness penalty functions: hyperbolic potential and anisotropic total variation (TV) norm. Reconstructed images were compared with images obtained using standard FBP. Optimal parameters for PML with the hyperbolic prior are reported for the task of detecting microcalcifications embedded in breast tissue. Methods: Computer simulations were used to acquire projections in a half-cone beam geometry. The modeled setup describes a realistic breast CT benchtop system, with an x-ray spectra produced by a point source and an a-Si, CsI:Tl flat-panel detector. A voxelized anthropomorphic breast phantom with 280 μm microcalcification spheres embedded in it was used to model attenuation properties of the uncompressed woman's breast in a pendant position. The reconstruction of 3D images was performed using the separable paraboloidal surrogates algorithm with ordered subsets. Task performance was assessed with the ideal observer detectability index to determine optimal PML parameters. Results: The authors' findings suggest that there is a preferred range of values of the roughness penalty weight and the edge preservation threshold in the penalized objective function with the hyperbolic potential, which resulted in low noise images with high contrast microcalcifications preserved. In terms of numerical observer detectability index, the PML method with optimal parameters yielded substantially improved performance (by a factor of greater than 10) compared to FBP. The hyperbolic prior was also observed to be superior to the TV norm. A few of the best-performing parameter pairs for the PML method also demonstrated superior performance for various radiation doses. In fact, using PML with certain parameter values results in better images, acquired using 2 mGy dose, than FBP-reconstructed images acquired using 6 mGy dose. Conclusions: A range of optimal free parameters for the PML algorithm with hyperbolic and TV norm-based potentials is presented for the microcalcification detection task, in dedicated breast CT. The reported values can be used as starting values of the free parameters, when SIR techniques are used for image reconstruction. Significant improvement in image quality can be achieved by using PML with optimal combination of parameters, as compared to FBP. Importantly, these results suggest improved detection of microcalcifications can be obtained by using PML with lower radiation dose to the patient, than using FBP with higher dose. PMID:23927318

QUASI-PML FOR WAVES IN CYLINDRICAL COORDINATES. (R825225)

EPA Science Inventory

We prove that the straightforward extension of Berenger's original perfectly matched layer (PML) is not reflectionless at a cylindrical interface in the continuum limit. A quasi-PLM is developed as an absorbing boundary condition (ABC) for the finite-difference time-domain method...

Qualitative Treatment-Subgroup Interactions in a Randomized Clinical Trial of Treatments for Adolescents with ADHD: Exploring What Cognitive-Behavioral Treatment Works for Whom

PubMed Central

Geurts, Hilde M.; Prins, Pier J. M.; Van Mechelen, Iven; Van der Oord, Saskia

2016-01-01

Objective This study explored qualitative treatment-subgroup interactions within data of a RCT with two cognitive behavioral treatments (CBT) for adolescents with ADHD: a planning-focused (PML) and a solution-focused CBT (SFT). Qualitative interactions imply that which treatment is best differs across subgroups of patients, and are therefore most relevant for personalized medicine. Methods Adolescents with ADHD (N = 159) received either PML or SFT. Pre-, post- and three-month follow-up data were gathered on parent-rated ADHD symptoms and planning problems. Pretreatment characteristics were explored as potential qualitative moderators of pretest to follow-up treatment effects, using an innovative analyses technique (QUINT; Dusseldorp & Van Mechelen, 2014). In addition, qualitative treatment-subgroup interactions for the therapeutic changes from pre- to posttest and from post- to follow-up test were investigated. Results For the entire time span from pretest to follow-up only a quantitative interaction was found, while from posttest to follow-up qualitative interactions were found: Adolescents with less depressive symptoms but more anxiety symptoms showed more improvement when receiving PML than SFT, while for other adolescents the effects of PML and SFT were comparable. Discussion Whereas subgroups in both treatments followed different trajectories, no subgroup was found for which SFT outperformed PML in terms of the global change in symptoms from pretest to three months after treatment. This implies that, based on this exploratory study, there is no need for personalized treatment allocation with regard to the CBTs under study for adolescents with ADHD. However, for a subgroup with comorbid anxiety symptoms but low depression PML clearly appears the treatment of preference. Trial Registration Nederlands Trial Register NTR2142 PMID:26977602

Risk of Progressive Multifocal Leukoencephalopathy in the Combination Antiretroviral Therapy Era in the French Hospital Database on Human Immunodeficiency Virus (ANRS-C4).

PubMed

Melliez, Hugues; Mary-Krause, Murielle; Bocket, Laurence; Guiguet, Marguerite; Abgrall, Sophie; De Truchis, Pierre; Katlama, Christine; Martin-Blondel, Guillaume; Henn, Aurelia; Revest, Matthieu; Robineau, Olivier; Khuong-Josses, Marie-Aude; Canestri, Anna; De Castro, Nathalie; Joly, Véronique; Mokhtari, Saadia; Risso, Karine; Gasnault, Jacques; Costagliola, Dominique

2018-04-04

Risk factors for progressive multifocal leukoencephalopathy (PML) in individuals with human immunodeficiency virus (HIV) infection are poorly documented in the era of combination antiretroviral therapy (cART). We studied HIV-1-infected individuals aged ≥15 years who had no history of PML and were prospectively followed up between 1997 and 2011 in the French Hospital Database on HIV (FHDH-ANRS CO4) cohort. Cox models were used to calculate adjusted hazard ratios (HRs), focusing on sub-Saharan origin, suggested to be protective, and recent cART initiation, potentially associated with an increased risk of PML. PML developed in 555 individuals, in 57 during the first 6 months of cART. From 1997-2000 to 2009-2011, the incidence fell from 1.15 (95% confidence interval [CI], .98-1.31) to 0.49 (.37-.61) per 1000 person-years. Sub-Saharan African origin had no clear influence (HR, 0.80; 95% CI, .58-1.11). Compared with men who have sex with men, injection drug users (IDUs) were at higher risk (HR, 1.80 [95% CI, 1.32-2.45] for male and 1.68 [1.13-2.48] for female IDUs). When IDUs were excluded, hepatitis C virus seropositivity was associated with an increased risk (HR, 1.40; 95% CI, 1.02-1.93). Compared with no cART initiation, initiation <6 months previously was associated with PML onset (HR, 4.91; 95% CI, 2.42-9.95). Recent cART initiation is associated with an increased risk of PML, as are injection drug use and hepatitis C virus seropositivity. Sub-Saharan African origin had no protective effect.

FOLLICULAR CELL CARCINOMA OF THE THYROID GLAND IN THREE CAPTIVE AGED RACCOON DOGS (NYCTEREUTES PROCYONOIDES).

PubMed

Kido, Nobuhide; Itagaki, Iori; Ono, Kaori; Omiya, Tomoko; Matsumoto, Rei

2015-12-01

The clinical and histologic features of thyroid carcinoma in raccoon dogs have not been previously reported. Three of four raccoon dogs (Nyctereutes procyonoides) over 8 yr of age at the Nogeyama Zoological Gardens developed thyroid follicular cell carcinomas that were detected at necropsy. The affected raccoon dogs were rescued from the wild and were housed at the Nogeyama Zoological Gardens for 8 yr 8 mo, 8 yr 10 mo, and 10 yr 3 mo, respectively. Although all of them appeared lethargic and developed partial alopecia or desquamation of their skin, they did not display any other specific clinical signs associated with a thyroid lesion. Serum thyroid hormone values were examined in two of the affected raccoon dogs and the average and standard deviation values (free-thyroxin [FT4]: 0.078 ± 0.077 pM/L and 0.062 ± 0.0039 pM/L; free-triiodothyronine [FT3]: 3.261 ± 0.765 pM/L and 3.407 ± 0.919 pM/L) were lower than the reference range (FT4: 0.141 ± 0.117 pM/L; FT3: 5.139 ± 2.412 pM/L) derived from a clinically normal raccoon dog. On necropsy, the thyroid lobes were markedly enlarged bilaterally. Histopathologically, the neoplastic cells in the thyroid gland appeared round or oval and columnar or cuboidal with minimal heteromorphism. Moreover, mostly small (but occasionally large) follicles were identified, and the neoplastic cells had infiltrated into the surrounding capsule and blood vessels. The histopathologic features of the thyroid tumors in the raccoon dogs revealed that the tumors were derived from follicular cells.

Pontomedullary lacerations and concomitant head and neck injuries: their underlying mechanism. A prospective autopsy study.

PubMed

Živković, Vladimir; Nikolić, Slobodan; Strajina, Veljko; Babić, Dragan; Djonić, Danijela; Djurić, Marija

2012-09-01

It is a well-documented fact that pontomedullary lacerations (PML) occur as a result of severe craniocervical injury, but their underlying mechanism has yet to be fully clarified. The aim of this prospective study has been to give greater insight into the underlying mechanism of PML through determining the site of blunt head-impact, as well as the presence of concomitant head and neck injuries in cases of brainstem PML. A total of 56 cases with partial PML have been analysed for this study. The case group was composed of 40 men and 16 women, averaging in age 44.2 ± 19.2 years and consisting of 7 motorcyclists, 4 bicyclists, 18 car occupants, 16 pedestrians, and 10 victims of falls from a height, as well as 1 victim of a fall from standing height. The presented study has shown that there are several possible mechanisms of PML. Impact to the chin, with or without a skull base fracture, most often leads to this fatal injury, due to the impact force transmission either through the jawbone or vertebral column; most likely in combination with a fronto-posterior hyperextension of the head. Additionally, lateral head-impacts with subsequent hinge fractures and PML may also be a possible mechanism. The jawbone and other facial bones are able to act as shock absorbers, and their fracture may diminish the energy transfer towards the skull and protect the brain and brainstem from injury. The upper cervical spine can act as damper and energy absorber as well, and may prevent any occurrence of fracture to the base of the skull.

Qualitative Treatment-Subgroup Interactions in a Randomized Clinical Trial of Treatments for Adolescents with ADHD: Exploring What Cognitive-Behavioral Treatment Works for Whom.

PubMed

Boyer, Bianca E; Doove, Lisa L; Geurts, Hilde M; Prins, Pier J M; Van Mechelen, Iven; Van der Oord, Saskia

2016-01-01

This study explored qualitative treatment-subgroup interactions within data of a RCT with two cognitive behavioral treatments (CBT) for adolescents with ADHD: a planning-focused (PML) and a solution-focused CBT (SFT). Qualitative interactions imply that which treatment is best differs across subgroups of patients, and are therefore most relevant for personalized medicine. Adolescents with ADHD (N = 159) received either PML or SFT. Pre-, post- and three-month follow-up data were gathered on parent-rated ADHD symptoms and planning problems. Pretreatment characteristics were explored as potential qualitative moderators of pretest to follow-up treatment effects, using an innovative analyses technique (QUINT; Dusseldorp & Van Mechelen, 2014). In addition, qualitative treatment-subgroup interactions for the therapeutic changes from pre- to posttest and from post- to follow-up test were investigated. For the entire time span from pretest to follow-up only a quantitative interaction was found, while from posttest to follow-up qualitative interactions were found: Adolescents with less depressive symptoms but more anxiety symptoms showed more improvement when receiving PML than SFT, while for other adolescents the effects of PML and SFT were comparable. Whereas subgroups in both treatments followed different trajectories, no subgroup was found for which SFT outperformed PML in terms of the global change in symptoms from pretest to three months after treatment. This implies that, based on this exploratory study, there is no need for personalized treatment allocation with regard to the CBTs under study for adolescents with ADHD. However, for a subgroup with comorbid anxiety symptoms but low depression PML clearly appears the treatment of preference. Nederlands Trial Register NTR2142.

AN FDTD ALGORITHM WITH PERFECTLY MATCHED LAYERS FOR CONDUCTIVE MEDIA. (R825225)

EPA Science Inventory

We extend Berenger's perfectly matched layers (PML) to conductive media. A finite-difference-time-domain (FDTD) algorithm with PML as an absorbing boundary condition is developed for solutions of Maxwell's equations in inhomogeneous, conductive media. For a perfectly matched laye...

A PML-FDTD ALGORITHM FOR SIMULATING PLASMA-COVERED CAVITY-BACKED SLOT ANTENNAS. (R825225)

EPA Science Inventory

A three-dimensional frequency-dependent finite-difference time-domain (FDTD) algorithm with perfectly matched layer (PML) absorbing boundary condition (ABC) and recursive convolution approaches is developed to model plasma-covered open-ended waveguide or cavity-backed slot antenn...

[PML-RARα and p21 are key factors for maintaining acute promyelocytic leukemia stem cells survival].

PubMed

Ding, Fei; Li, Jun-Min

2011-10-01

Tumor stem/progenitor cells are the cells with the characteristics of self-renewal, differentiating to all the other cell populations within tumor, which are also regarded as the source of tumor relapse, drug-resistance and metastasis. As a subtype of acute myeloid leukemia, acute promyelocytic leukemia (APL) represents the target of therapy due to the good response of the oncogenic protein PML-RARα to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). This review summarizes the latest research results of APL as follows: (1) there probably are two APL stem/progenitor cell populations within APL, and self-renewal and survival of APL stem/progenitor cells highly depend on PML-RARα expression, cell cycle inhibitor p21, self-renewal associated molecules and chemokines; and (2) ATRA and ATO eradicate APL stem/progenitor cells mainly by PML-RARα degradation, FOXO3A activation and the inhibition of self-renewal-associated signaling pathway of sonic hedgehog. These findings are helpful to improve other tumor therapy.

Dimerization-induced corepressor binding and relaxed DNA-binding specificity are critical for PML/RARA-induced immortalization

PubMed Central

Zhou, Jun; Pérès, Laurent; Honoré, Nicole; Nasr, Rihab; Zhu, Jun; de Thé, Hugues

2006-01-01

The pathogenesis of acute promyelocytic leukemia involves the transcriptional repression of master genes of myeloid differentiation by the promyelocytic leukemia–retinoic acid receptor α (PML/RARA) oncogene. PML-enforced RARA homodimerization allows the tighter binding of corepressors, silencing RARA target genes. In addition, homodimerization dramatically extends the spectrum of DNA-binding sites of the fusion protein compared with those of normal RARA. Yet, any contribution of these two properties of PML/RARA to differentiation arrest and immortalization of primary mouse hematopoietic progenitors was unknown. We demonstrate that dimerization-induced silencing mediator of retinoid and thyroid receptors (SMRT)-enhanced binding and relaxed DNA-binding site specificity are both required for efficient immortalization. Thus, enforced RARA dimerization is critical not only for triggering transcriptional repression but also for extending the repertoire of target genes. Our studies exemplify how dimerization-induced gain of functions converts an unessential transcription factor into a dominant oncogenic protein. PMID:16757557

PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins

PubMed Central

Janer, Alexandre; Martin, Elodie; Muriel, Marie-Paule; Latouche, Morwena; Fujigasaki, Hiroto; Ruberg, Merle; Brice, Alexis; Trottier, Yvon; Sittler, Annie

2006-01-01

The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant ataxin-7, demonstrating their role in ataxin-7 turnover. Interestingly, β-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders. PMID:16818720

SUMO regulates proteasome-dependent degradation of FLASH/Casp8AP2

PubMed Central

Vennemann, Astrid; Hofmann, Thomas G.

2013-01-01

FLASH/Casp8AP2 is a huge multifunctional protein involved in multiple cellular processes, reaching from death receptor signaling to regulation of histone gene transcription and histone mRNA processing. Previous work has shown that FLASH localizes to Cajal bodies and promyelocytic leukemia (PML) bodies. However, the function of its nuclear body association remains unclear. Here we demonstrate that murine FLASH is covalently modified by SUMO at Lys residue 1792. Interestingly, ectopic expression of SUMO results in proteasome-dependent degradation of FLASH. A point mutant of FLASH with a mutated SUMO acceptor lysine residue, FLASHK1792R, is resistant to SUMO-induced degradation. Finally, we show that arsenic trioxide, a drug known to potentiate SUMO modification and degradation of PML, triggers recruitment of FLASH to PML bodies and concomitant loss of FLASH protein. Our data suggest that SUMO targets FLASH for proteasome-dependent degradation, which is associated with recruitment of FLASH to PML bodies. PMID:23673342

Epstein-Barr virus origin of lytic replication mediates association of replicating episomes with promyelocytic leukaemia protein nuclear bodies and replication compartments.

PubMed

Amon, Wolfgang; White, Robert E; Farrell, Paul J

2006-05-01

Epstein-Barr virus (EBV) establishes a latent persistence from which it can be reactivated to undergo lytic replication. Late lytic-cycle gene expression is linked to lytic DNA replication, as it is sensitive to the same inhibitors that block lytic replication, and it has recently been shown that the viral origin of lytic replication (ori lyt) is required in cis for late-gene expression. During the lytic cycle, the viral genome forms replication compartments, which are usually adjacent to promyelocytic leukaemia protein (PML) nuclear bodies. A tetracycline repressor DNA-binding domain-enhanced green fluorescent protein fusion was used to visualize replicating plasmids carrying a tetracycline operator sequence array. ori lyt mediated the production of plasmid replication compartments that were associated with PML nuclear bodies. Plasmids carrying ori lyt and EBV itself were visualized in the same cells and replicated in similar regions of the nucleus, further supporting the validity of the plasmids for studying late-gene regulation.

A NONUNIFORM CYLINDRICAL FDTD ALGORITHM WITH IMPROVED PML AND QUASI-PML ABSORBING BOUNDARY CONDITIONS. (R825225)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Benefit-risk perception of natalizumab therapy in neurologists and a large cohort of multiple sclerosis patients.

PubMed

Heesen, Christoph; Kleiter, Ingo; Meuth, Sven G; Krämer, Julia; Kasper, Jürgen; Köpke, Sascha; Gaissmaier, Wolfgang

2017-05-15

Natalizumab (NAT) is associated with the risk of progressive multifocal leukoencephalopathy (PML). Risk stratification algorithms have been developed, however, without detectable reduction of PML incidence. To evaluate to which extent patients and physicians understand and accept risks associated with NAT treatment. Prospective observational cohort study in German MS centers (n=73) among NAT-treated MS patients (n=801) and their neurologists (n=99). Patients included in this study had mean disease duration of 10.2years and a mean NAT treatment duration of 24months. More than 90% of patients and physicians voted for shared decision making or an informed choice decision making approach. Patients and physicians perceived a similar threat from MS as serious disease and both overestimated treatment benefits from NAT based on trial data. Men perceived MS more severe than women and perception of seriousness increased with age in both groups and in patients as well with increasing disability. Although patients evaluated their PML risk higher, their risk acceptance was significantly higher than of their neurologists. Risk stratification knowledge was good among neurologists and significantly lower among patients. While patients and physicians seem to have realistic risk perception of PML and knowledge of risk stratification concepts, the threat of MS and the perception of treatment benefits may explain the ongoing high acceptance of PML risk. Copyright © 2017 Elsevier B.V. All rights reserved.

Investigation of statistical iterative reconstruction for dedicated breast CT

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

Makeev, Andrey; Glick, Stephen J.

2013-08-15

Purpose: Dedicated breast CT has great potential for improving the detection and diagnosis of breast cancer. Statistical iterative reconstruction (SIR) in dedicated breast CT is a promising alternative to traditional filtered backprojection (FBP). One of the difficulties in using SIR is the presence of free parameters in the algorithm that control the appearance of the resulting image. These parameters require tuning in order to achieve high quality reconstructions. In this study, the authors investigated the penalized maximum likelihood (PML) method with two commonly used types of roughness penalty functions: hyperbolic potential and anisotropic total variation (TV) norm. Reconstructed images weremore » compared with images obtained using standard FBP. Optimal parameters for PML with the hyperbolic prior are reported for the task of detecting microcalcifications embedded in breast tissue.Methods: Computer simulations were used to acquire projections in a half-cone beam geometry. The modeled setup describes a realistic breast CT benchtop system, with an x-ray spectra produced by a point source and an a-Si, CsI:Tl flat-panel detector. A voxelized anthropomorphic breast phantom with 280 μm microcalcification spheres embedded in it was used to model attenuation properties of the uncompressed woman's breast in a pendant position. The reconstruction of 3D images was performed using the separable paraboloidal surrogates algorithm with ordered subsets. Task performance was assessed with the ideal observer detectability index to determine optimal PML parameters.Results: The authors' findings suggest that there is a preferred range of values of the roughness penalty weight and the edge preservation threshold in the penalized objective function with the hyperbolic potential, which resulted in low noise images with high contrast microcalcifications preserved. In terms of numerical observer detectability index, the PML method with optimal parameters yielded substantially improved performance (by a factor of greater than 10) compared to FBP. The hyperbolic prior was also observed to be superior to the TV norm. A few of the best-performing parameter pairs for the PML method also demonstrated superior performance for various radiation doses. In fact, using PML with certain parameter values results in better images, acquired using 2 mGy dose, than FBP-reconstructed images acquired using 6 mGy dose.Conclusions: A range of optimal free parameters for the PML algorithm with hyperbolic and TV norm-based potentials is presented for the microcalcification detection task, in dedicated breast CT. The reported values can be used as starting values of the free parameters, when SIR techniques are used for image reconstruction. Significant improvement in image quality can be achieved by using PML with optimal combination of parameters, as compared to FBP. Importantly, these results suggest improved detection of microcalcifications can be obtained by using PML with lower radiation dose to the patient, than using FBP with higher dose.« less

Penalized maximum likelihood simultaneous longitudinal PET image reconstruction with difference-image priors.

PubMed

Ellis, Sam; Reader, Andrew J

2018-04-26

Many clinical contexts require the acquisition of multiple positron emission tomography (PET) scans of a single subject, for example, to observe and quantitate changes in functional behaviour in tumors after treatment in oncology. Typically, the datasets from each of these scans are reconstructed individually, without exploiting the similarities between them. We have recently shown that sharing information between longitudinal PET datasets by penalizing voxel-wise differences during image reconstruction can improve reconstructed images by reducing background noise and increasing the contrast-to-noise ratio of high-activity lesions. Here, we present two additional novel longitudinal difference-image priors and evaluate their performance using two-dimesional (2D) simulation studies and a three-dimensional (3D) real dataset case study. We have previously proposed a simultaneous difference-image-based penalized maximum likelihood (PML) longitudinal image reconstruction method that encourages sparse difference images (DS-PML), and in this work we propose two further novel prior terms. The priors are designed to encourage longitudinal images with corresponding differences which have (a) low entropy (DE-PML), and (b) high sparsity in their spatial gradients (DTV-PML). These two new priors and the originally proposed longitudinal prior were applied to 2D-simulated treatment response [ 18 F]fluorodeoxyglucose (FDG) brain tumor datasets and compared to standard maximum likelihood expectation-maximization (MLEM) reconstructions. These 2D simulation studies explored the effects of penalty strengths, tumor behaviour, and interscan coupling on reconstructed images. Finally, a real two-scan longitudinal data series acquired from a head and neck cancer patient was reconstructed with the proposed methods and the results compared to standard reconstruction methods. Using any of the three priors with an appropriate penalty strength produced images with noise levels equivalent to those seen when using standard reconstructions with increased counts levels. In tumor regions, each method produces subtly different results in terms of preservation of tumor quantitation and reconstruction root mean-squared error (RMSE). In particular, in the two-scan simulations, the DE-PML method produced tumor means in close agreement with MLEM reconstructions, while the DTV-PML method produced the lowest errors due to noise reduction within the tumor. Across a range of tumor responses and different numbers of scans, similar results were observed, with DTV-PML producing the lowest errors of the three priors and DE-PML producing the lowest bias. Similar improvements were observed in the reconstructions of the real longitudinal datasets, although imperfect alignment of the two PET images resulted in additional changes in the difference image that affected the performance of the proposed methods. Reconstruction of longitudinal datasets by penalizing difference images between pairs of scans from a data series allows for noise reduction in all reconstructed images. An appropriate choice of penalty term and penalty strength allows for this noise reduction to be achieved while maintaining reconstruction performance in regions of change, either in terms of quantitation of mean intensity via DE-PML, or in terms of tumor RMSE via DTV-PML. Overall, improving the image quality of longitudinal datasets via simultaneous reconstruction has the potential to improve upon currently used methods, allow dose reduction, or reduce scan time while maintaining image quality at current levels. © 2018 The Authors. Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.

Developing a Markup Language for Encoding Graphic Content in Plan Documents

ERIC Educational Resources Information Center

Li, Jinghuan

2009-01-01

While deliberating and making decisions, participants in urban development processes need easy access to the pertinent content scattered among different plans. A Planning Markup Language (PML) has been proposed to represent the underlying structure of plans in an XML-compliant way. However, PML currently covers only textual information and lacks…

High-resolution altitude profiles of the atmospheric turbulence with PML at the Sutherland Observatory

NASA Astrophysics Data System (ADS)

Catala, L.; Ziad, A.; Fanteï-Caujolle, Y.; Crawford, S. M.; Buckley, D. A. H.; Borgnino, J.; Blary, F.; Nickola, M.; Pickering, T.

2017-05-01

With the prospect of the next generation of ground-based telescopes, the extremely large telescopes, increasingly complex and demanding adaptive optics systems are needed. This is to compensate for image distortion caused by atmospheric turbulence and fully take advantage of mirrors with diameters of 30-40 m. This requires a more precise characterization of the turbulence. The Profiler of Moon Limb (PML) was developed within this context. The PML aims to provide high-resolution altitude profiles of the turbulence using differential measurements of the Moon limb position to calculate the transverse spatio-angular covariance of the angle of arrival fluctuations. The covariance of differential image motion for different separation angles is sensitive to the altitude distribution of the seeing. The use of the continuous Moon limb provides a large number of separation angles allowing for the high-resolution altitude of the profiles. The method is presented and tested with simulated data. Moreover, a PML instrument was deployed at the Sutherland Observatory in South Africa in 2011 August. We present here the results of this measurement campaign.

Interstitial insertion of RARα gene into PML gene in a patient with acute promyelocytic leukemia (APL) lacking the classic t(15;17).

PubMed

Goldschmidt, Neta; Yehuda-Gafni, Orly; Abeliovich, Deborah; Slyusarevsky, Elena; Rund, Deborah

2010-10-01

The diagnosis of APL is based on clinical and morphological tests though the final diagnosis is at the molecular level. An accurate diagnosis is important as it mandates targeted therapy to improve survival. We report a case of APL without t(15;17) in conventional cytogenetic study and with initially negative fluorescence in situ hybridization (FISH) study on cells in interphase. Reverse transcription polymerase chain reaction (RT-PCR) for the promyelocytic/retinoic acid receptor alpha gene (PML/RARα) fusion oncogene proved the clinical diagnosis as well as FISH study on cells in metaphase. The cause was a cryptic translocation of the RARα gene into PML. We reviewed 36 additional cases of APL diagnosed in our hospital since 1992. This was the only case that failed to show t(15;17) in cytogenetics. However, three cases with t(15;17) in cytogenetics had negative RT-PCR for PML/RARα. Our case emphasizes that cytogenetics, FISH and RT-PCR studies are complementary studies for the molecular diagnosis of APL.

Annexin A2-S100A10 heterotetramer is upregulated by PML/RARα fusion protein and promotes plasminogen-dependent fibrinolysis and matrix invasion in acute promyelocytic leukemia.

PubMed

Huang, Dan; Yang, Yan; Sun, Jian; Dong, Xiaorong; Wang, Jiao; Liu, Hongchen; Lu, Chengquan; Chen, Xueyu; Shao, Jing; Yan, Jinsong

2017-09-01

Aberrant expression of annexin A2-S100A10 heterotetramer (AIIt) associated with PML/RARα fusion protein causes lethal hyperfibrinolysis in acute promyelocytic leukemia (APL), but the mechanism is unclear. To facilitate the investigation of regulatory association between ANXA2 and promyelocytic leukemia/retinoic acid receptor a (PML/RARα) fusion protein, this work was performed to determine the transcription start site of ANXA2 promoter with rapid amplification of 5'-cDNA ends analysis. Zinc-induced U937/PR9 cells expressed PML/RARα fusion protein, and resultant increases in ANXA2 transcripts and translational expressions of both ANXA2 and S100A10, while S100A10 transcripts remained constitutive. The transactivation of ANXA2 promoter by PML/RARα fusion protein was 3.29 ± 0.13 fold higher than that by control pSG5 vector or wild-type RARα. The overexpression of ANXA2 in U937 transfected with full-length ANXA2 cDNA was associated with increased S100A10 subunit, although S100A10 transcripts remained constitutive. The tPA-dependent initial rate of plasmin generation (IRPG) in zinc-treated U937/PR9 increased by 2.13-fold, and cell invasiveness increased by 27.6%. Antibodies against ANXA2, S100A10, or combination of both all remarkably inhibited the IRPG and invasiveness in U937/PR9 and NB4. Treatment of zinc-induced U937/PR9 or circulating APL blasts with all-trans retinoic acid (ATRA) significantly reduced cell surface ANXA2 and S100A10 and associated reductions in IRPG and invasiveness. Thus, PML/RARα fusion protein transactivated the ANXA2 promoter to upregulate ANXA2 and accumulate S100A10. Increased AIIt promoted IRPG and invasiveness, both of which were partly abolished by antibodies against ANXA2 and S100A10 or by ATRA.

Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies.

PubMed

García-Suárez, Julio; de Miguel, Dunia; Krsnik, Isabel; Bañas, Helena; Arribas, Ignacio; Burgaleta, Carmen

2005-12-01

The aims of this study were to evaluate the clinical characteristics of HIV-negative patients affected by lymphoproliferative disorders (LPD) who developed progressive multifocal leukoencephalopathy (PML), to delineate the risk factors, and to analyze whether the new antineoplastic therapies are changing the natural history of this infectious disease. We retrospectively analyzed 46 cases with confirmed LPD-associated PML published from 1958 to 2004. Patients were stratified according to two different time periods: group A included patients diagnosed before 1989, and group B included patients diagnosed since 1990, after introduction of purine analogues. Group A patients (n = 22) had received alkylating agents and/or radiotherapy, and the majority (63.6%) had advanced Hodgkin disease. At univariate analysis, uncontrolled Hodgkin disease was the only risk factor for PML. In group B patients (n = 24), the most frequent treatments received were purine analogues (58.3%) and high-dose therapy with hematopoietic stem cell transplantation (33.3%; HDT/HSCT). B-cell chronic lymphocytic leukemia (45.8%) and aggressive non-Hodgkin lymphoma (24.9%) were the most frequent underlying LPDs. Patients treated with purine analogues were more likely to have active LPD, lower CD4 cell counts, and to be older and male than were HSCT recipients. The median interval from purine analogues or HDT/HSCT to PML was 11 months. In HDT/HSCT recipients, this interval was delayed for 10 months when peri-transplantation rituximab was used. Univariate analysis identified age >55 years, male sex, and CD4 cell counts

Viral FGARAT Homolog ORF75 of Rhesus Monkey Rhadinovirus Effects Proteasomal Degradation of the ND10 Components SP100 and PML.

PubMed

Hahn, Alexander S; Großkopf, Anna K; Jungnickl, Doris; Scholz, Brigitte; Ensser, Armin

2016-09-01

Nuclear domain 10 (ND10) components restrict herpesviral infection, and herpesviruses antagonize this restriction by a variety of strategies, including degradation or relocalization of ND10 proteins. The rhesus monkey rhadinovirus (RRV) shares many key biological features with the closely related Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) and readily infects cells of both human and rhesus monkey origin. We used the clustered regularly interspaced short palindromic repeat-Cas9 (CRISPR-Cas9) technique to generate knockout (ko) cells for each of the four ND10 components, PML, SP100, DAXX, and ATRX. These ko cells were analyzed with regard to permissiveness for RRV infection. In addition, we analyzed the fate of the individual ND10 components in infected cells by immunofluorescence and Western blotting. Knockout of the ND10 component DAXX markedly increased RRV infection, while knockout of PML or SP100 had a less pronounced effect. In line with these observations, RRV infection resulted in rapid degradation of SP100, followed by degradation of PML and the loss of ND10 structures, whereas the protein levels of ATRX and DAXX remained constant. Notably, inhibition of the proteasome but not inhibition of de novo gene expression prevented the loss of SP100 and PML in cells that did not support lytic replication, compatible with proteasomal degradation of these ND10 components through the action of a viral tegument protein. Expression of the RRV FGARAT homolog ORF75 was sufficient to effect the loss of SP100 and PML in transfected or transduced cells, implicating ORF75 as the viral effector protein. Our findings highlight the antiviral role of ND10 and its individual components and further establish the viral FGARAT homologs of the gammaherpesviruses to be important viral effectors that counteract ND10-instituted intrinsic immunity. Surprisingly, even closely related viruses like KSHV and RRV evolved to use different strategies to evade ND10-mediated restriction. RRV first targets SP100 for degradation and then targets PML with a delayed kinetic, a strategy which clearly differs from that of other gammaherpesviruses. Despite efficient degradation of these two major ND10 components, RRV is still restricted by DAXX, another abundant ND10 component, as evidenced by a marked increase in RRV infection and replication upon knockout of DAXX. Taken together, our findings substantiate PML, SP100, and DAXX as key antiviral proteins, in that the first two are targeted for degradation by RRV and the last one still potently restricts replication of RRV. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Computer Simulation of the Effect of Pretreatment with Reversible Acetylcholinesterase Inhibitors on the Protection Against Soman Poisoning

DTIC Science & Technology

1993-12-01

dr. U.A. Th. Brinkmnan 31* Directeur van het Medisch Biologisch Laboratorium TNO Prof. dr. W.R.F. Notten 32 PML-TNO, Directeur; daarna reserve 33 PML...Generaal Personeel Ministerie van Defensie 8* Adviseur van het Prins Maurits Laboratorium TNO Chemnische Research Prof. dr. G. Dijkstra 9* lid van de

Company Decontamination Systems (Compagnieontsmettingssystemen)

DTIC Science & Technology

1998-06-01

TNO-rapport Compagnieontsmettingssystemen PML 1998-AI08 TNO Prins Maurits Laboratorium Lange Kleiweg 137 Datum Postbus 45 2280 AA Rijswijk juni 1999...I8ECTED 4 TNO Prins Maurits Laboratorium is onderdeel _____ van de hoofdgroep TNO Defensieonderzoek waartoe verder behoren: TNO Fysisch en...Elektronisch Laboratorium Nederlandse Organisatie voor toegepast- TNO Technische Menskunde natuurwetenschappelijk onderzoek TNO TNO-rapport PML 1998-A108 2

In situ SUMOylation analysis reveals a modulatory role of RanBP2 in the nuclear rim and PML bodies

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

Saitoh, Noriko; Uchimura, Yasuhiro; The 21st Century Center of Excellence, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811

2006-05-01

SUMO modification plays a critical role in a number of cellular functions including nucleocytoplasmic transport, gene expression, cell cycle and formation of subnuclear structures such as promyelocytic leukemia (PML) bodies. In order to identify the sites where SUMOylation takes place in the cell, we developed an in situ SUMOylation assay using a semi-intact cell system and subsequently combined it with siRNA-based knockdown of nucleoporin RanBP2, also known as Nup358, which is one of the known SUMO E3 proteins. With the in situ SUMOylation assay, we found that both nuclear rim and PML bodies, besides mitotic apparatuses, are major targets formore » active SUMOylation. The ability to analyze possible SUMO conjugation sites would be a valuable tool to investigate where SUMO E3-like activities and/or SUMO substrates exist in the cell. Specific knockdown of RanBP2 completely abolished SUMOylation along the nuclear rim and dislocated RanGAP1 from the nuclear pore complexes. Interestingly, the loss of RanBP2 markedly reduced the number of PML bodies, in contrast to other, normal-appearing nuclear compartments including the nuclear lamina, nucleolus and chromatin, suggesting a novel link between RanBP2 and PML bodies. SUMOylation facilitated by RanBP2 at the nuclear rim may be a key step for the formation of a particular subnuclear organization. Our data imply that SUMO E3 proteins like RanBP2 facilitate spatio-temporal SUMOylation for certain nuclear structure and function.« less

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

Uozumi, Naoki; Matsumoto, Hotaru; Saitoh, Hisato, E-mail: hisa@kumamoto-u.ac.jp

The amino-nucleoside antibiotic, puromycin, acts by covalently linking to elongating polypeptide chains on ribosomes to generate prematurely terminated immature polypeptides. The trafficking of puromycin-conjugated (puromycylated) immature polypeptides within cell has, however, remained elusive. In this study, using O-propargyl-puromycin (OP-Puro), the distribution of puromycylated polypeptides was assessed in HeLa cells by click chemistry. Under standard culture conditions, OP-Puro signals were detected in the cytoplasm and nucleus with the highest concentrations in the nucleolus. Intriguingly, when proteasome activities were aborted using MG132, OP-Puro signals began to accumulate at promyelocytic leukemia nuclear bodies (PML-NBs) in addition to the nucleolus. We also found promiscuousmore » association of OP-Puro signals with SUMO-2/3 and ubiquitin at PML-NBs, but not at the nucleolus, during abortive proteasome activities. This study reveals a previously unknown distribution of OP-Puro that argues for a nuclear function in regulating immature protein homeostasis. -- Highlights: •Click chemistry detects O-propargyl-puromycin (OP-Puro) signals in the nucleus. •OP-Puro accumulates at PML-NBs during abortive proteasome activities. •SUMO and ubiquitin are promiscuously associated with OP-Puro at PML-NBs. •The nucleus may function in immature protein homeostasis.« less

A fraction of neurofibromin interacts with PML bodies in the nucleus of the CCF astrocytoma cell line

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

Godin, Fabienne; Villette, Sandrine; Vallee, Beatrice

Highlights: Black-Right-Pointing-Pointer We validate the use of specific anti-Nf1 antibodies for immunofluorescence studies. Black-Right-Pointing-Pointer We detect Nf1 in the cytoplasm and nucleus of CCF cells. Black-Right-Pointing-Pointer We demonstrate that Nf1 partially colocalizes with PML nuclear bodies. Black-Right-Pointing-Pointer We demonstrate that there is a direct interaction between a fraction of Nf1 and the PML bodies. -- Abstract: Neurofibromatosis type 1 is a common genetic disease that causes nervous system tumors, and cognitive deficits. It is due to mutations within the NF1 gene, which encodes the Nf1 protein. Nf1 has been shown to be involved in the regulation of Ras, cAMP andmore » actin cytoskeleton dynamics. In this study, using immunofluorescence experiments, we have shown a partial nuclear localization of Nf1 in the astrocytoma cell line: CCF and we have demonstrated that Nf1 partially colocalizes with PML (promyelocytic leukemia) nuclear bodies. A direct interaction between Nf1 and the multiprotein complex has further been demonstrated using 'in situ' proximity ligation assay (PLA).« less

Application of the perfectly matched layer in 2.5D marine controlled-source electromagnetic modeling

NASA Astrophysics Data System (ADS)

Li, Gang; Han, Bo

2017-09-01

For the traditional framework of EM modeling algorithms, the Dirichlet boundary is usually used which assumes the field values are zero at the boundaries. This crude condition requires that the boundaries should be sufficiently far away from the area of interest. Although cell sizes could become larger toward the boundaries as electromagnetic wave is propagated diffusively, a large modeling area may still be necessary to mitigate the boundary artifacts. In this paper, the complex frequency-shifted perfectly matched layer (CFS-PML) in stretching Cartesian coordinates is successfully applied to 2.5D frequency-domain marine controlled-source electromagnetic (CSEM) field modeling. By using this PML boundary, one can restrict the modeling area of interest to the target region. Only a few absorbing layers surrounding the computational area can effectively depress the artificial boundary effect without losing the numerical accuracy. A 2.5D marine CSEM modeling scheme with the CFS-PML is developed by using the staggered finite-difference discretization. This modeling algorithm using the CFS-PML is of high accuracy, and shows advantages in computational time and memory saving than that using the Dirichlet boundary. For 3D problem, this computation time and memory saving should be more significant.

Dual noise-like pulse and soliton operation of a fiber ring cavity

NASA Astrophysics Data System (ADS)

Bracamontes Rodríguez, Y. E.; Pottiez, O.; García Sanchez, E.; Lauterio Cruz, J. P.; Ibarra-Villalón, H.; Hernandez-Garcia, J. C.; Bello-Jimenez, M.; Beltrán-Pérez, G.; Ibarra-Escamilla, B.; Kuzin, E. A.

2017-03-01

Passively mode-locked fiber lasers (PML-FLs) are versatile sources that are capable of generating a broad variety of short and ultrashort optical pulses. Besides conservative solitons, PML-FLs allow the generation of different kinds of dissipative structures, usually called dissipative solitons, a concept that also encompasses more complex structures and collective behaviors such as soliton molecules, gas, rain of solitons, etc. In addition to this, PML-FLs are also able to generate even more complex objects, the so-called noise-like pulses (NLPs). A few recent research results revealed a connection between NLPs and solitons, a sign that deterministic ingredients enter into the composition of NLPs, whose nature is traditionally assumed to be random. Although it is usual that a fiber laser is able to generate either solitons or noise-like pulses, depending on pump power and adjustments in the cavity, these two regimes are rarely observed simultaneously. In this paper, a PML-FL in a ring configuration is presented, in which it is possible to observe and verify experimentally the simultaneous presence of NLPs and solitons. Interestingly, these two components are found in different spectral regions, which greatly facilitates their separation and individual study and characterization.

Role of the histone deacetylase complex in acute promyelocytic leukaemia.

PubMed

Lin, R J; Nagy, L; Inoue, S; Shao, W; Miller, W H; Evans, R M

1998-02-19

Non-liganded retinoic acid receptors (RARs) repress transcription of target genes by recruiting the histone deacetylase complex through a class of silencing mediators termed SMRT or N-CoR. Mutant forms of RARalpha, created by chromosomal translocations with either the PML (for promyelocytic leukaemia) or the PLZF (for promyelocytic leukaemia zinc finger) locus, are oncogenic and result in human acute promyelocytic leukaemia (APL). PML-RARalpha APL patients achieve complete remission following treatments with pharmacological doses of retinoic acids (RA); in contrast, PLZF-RARalpha patients respond very poorly, if at all. Here we report that the association of these two chimaeric receptors with the histone deacetylase (HDAC) complex helps to determine both the development of APL and the ability of patients to respond to retinoids. Consistent with these observations, inhibitors of histone deacetylase dramatically potentiate retinoid-induced differentiation of RA-sensitive, and restore retinoid responses of RA-resistant, APL cell lines. Our findings suggest that oncogenic RARs mediate leukaemogenesis through aberrant chromatin acetylation, and that pharmacological manipulation of nuclear receptor co-factors may be a useful approach in the treatment of human disease.

ΔNp73 overexpression promotes resistance to apoptosis but does not cooperate with PML/RARA in the induction of an APL-leukemic phenotype

PubMed Central

Lucena-Araujo, Antonio R.; Coelho-Silva, Juan L.; Pereira-Martins, Diego A.; Thomé, Carolina; Scheucher, Priscila S.; Lange, Ana P.; Paiva, Helder H.; Hemmelgarn, Benjamin T.; Morais-Sobral, Mariana C.; Azevedo, Elisa A.; Franca-Neto, Pedro L.; Franca, Rafael F.; Silva, Cleide L.; Krause, Alexandre; Rego, Eduardo M.

2017-01-01

Here, we evaluated whether the overexpression of transcriptionally inactive ΔNp73 cooperates with PML/RARA fusion protein in the induction of an APL-leukemic phenotype, as well as its role in vitro in proliferation, myeloid differentiation, and drug-induced apoptosis. Using lentiviral gene transfer, we showed in vitro that ΔNp73 overexpression resulted in increased proliferation in murine bone marrow (BM) cells from hCG-PML/RARA transgenic mice and their wild-type (WT) counterpart, with no accumulation of cells at G2/M or S phases; instead, ΔNp73-expressing cells had a lower rate of induced apoptosis. Next, we evaluated the effect of ΔNp73 on stem-cell self-renewal and myeloid differentiation. Primary BM cells lentivirally infected with human ΔNp73 were not immortalized in culture and did not present significant changes in the percentage of CD11b. Finally, we assessed the impact of ΔNp73 on leukemogenesis or its possible cooperation with PML/RARA fusion protein in the induction of an APL-leukemic phenotype. After 120 days of follow-up, all transplanted mice were clinically healthy and, no evidence of leukemia/myelodysplasia was apparent. Taken together, our data suggest that ΔNp73 had no leukemic transformation capacity by itself and apparently did not cooperate with the PML/RARA fusion protein to induce a leukemic phenotype in a murine BM transplantation model. In addition, the forced expression of ΔNp73 in murine BM progenitors did not alter the ATRA-induced differentiation rate in vitro or induce aberrant cell proliferation, but exerted an important role in cell survival, providing resistance to drug-induced apoptosis. PMID:28035072

Leukocyte Anti-Trafficking Strategies: Current Status and Future Directions.

PubMed

Sands, Bruce E

2017-01-01

In inflammatory bowel diseases (IBD), a pivotal step in the initiation and perpetuation of mucosal inflammation entails the recruitment of inflammatory leukocytes to the gut. Understanding the carefully coordinated series of molecular events that culminate in the recruitment of leukocytes to the gut has resulted in novel interventions with new capabilities in treating both Crohn's disease and ulcerative colitis. Key Messages: Natalizumab, an anti-α4 integrin antibody, was the first agent to demonstrate the efficacy of this approach for the induction and maintenance of response and remission in Crohn's disease. Widespread adoption was mitigated by the previously unknown risk of progressive multifocal leukoencephalopathy (PML) with this approach. Current approaches employ a more selective inhibition of adhesion molecules targeting the gut to avoid broad suppression of surveillance for JC virus, the causal pathogen of PML. Subsequently, vedolizumab, a humanized anti-α4β7 integrin antibody, has demonstrated efficacy in patients with IBD and has an excellent safety profile. To date, there have been no cases of PML in patients treated with vedolizumab, suggesting that this more selective agent does not have the same risk for PML as natalizumab. Other agents target β7 integrin (etrolizumab) and mucosal addressin cellular adhesion molecule-1, the endothelial ligand of α4β7 integrin. Efforts to inhibit the chemokine receptor CCR9 using the agent CCX282-B in Crohn's disease were not successful. An orally administered anti-α4 integrin compound showed some promise in a phase 2 trial but raises concern for PML. Finally, the S1P1 receptor agonist ozanimod showed promise in early trials in ulcerative colitis. In summary, anti-trafficking agents have the potential to provide safe and effective therapy for IBD, and are a burgeoning class of novel agents. © 2017 S. Karger AG, Basel.

Trafficking of the transcription factor Nrf2 to promyelocytic leukemia-nuclear bodies: implications for degradation of NRF2 in the nucleus.

PubMed

Malloy, Melanie Theodore; McIntosh, Deneshia J; Walters, Treniqka S; Flores, Andrea; Goodwin, J Shawn; Arinze, Ifeanyi J

2013-05-17

Ubiquitylation of Nrf2 by the Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase complex targets Nrf2 for proteasomal degradation in the cytoplasm and is an extensively studied mechanism for regulating the cellular level of Nrf2. Although mechanistic details are lacking, reports abound that Nrf2 can also be degraded in the nucleus. Here, we demonstrate that Nrf2 is a target for sumoylation by both SUMO-1 and SUMO-2. HepG2 cells treated with As2O3, which enhances attachment of SUMO-2/3 to target proteins, increased SUMO-2/3-modification (polysumoylation) of Nrf2. We show that Nrf2 traffics, in part, to promyelocytic leukemia-nuclear bodies (PML-NBs). Cell fractions harboring key components of PML-NBs did not contain biologically active Keap1 but contained modified Nrf2 as well as RING finger protein 4 (RNF4), a poly-SUMO-specific E3 ubiquitin ligase. Overexpression of wild-type RNF4, but not the catalytically inactive mutant, decreased the steady-state levels of Nrf2, measured in the PML-NB-enriched cell fraction. The proteasome inhibitor MG-132 interfered with this decrease, resulting in elevated levels of polysumoylated Nrf2 that was also ubiquitylated. Wild-type RNF4 accelerated the half-life (t½) of Nrf2, measured in PML-NB-enriched cell fractions. These results suggest that RNF4 mediates polyubiquitylation of polysumoylated Nrf2, leading to its subsequent degradation in PML-NBs. Overall, this work identifies Nrf2 as a target for sumoylation and provides a novel mechanism for its degradation in the nucleus, independent of Keap1.

Axon collaterals projection from nucleus reticularis tegmenti pontis onto the cerebellar paramedian lobule in the rabbit: a fluorescent double labelling study.

PubMed

Mierzejewska-Krzyzowska, B

1999-01-01

Double labelling method with retrograde transport of fluorescent tracers (Fast Blue; FB and Diamidino Yellow; DY) was employed in the rabbit to investigate whether neurones of the nucleus reticularis tegmenti pontis (NRTP) give off axon collaterals to the cerebellar paramedian lobule (PML) of both sides. Following injections to various regions of the homotopic or heterotopic sublobules of the left (FB) and right (DY) PML cortex, distribution of double labelled neurones within NRTP was analyzed. NRTP of the rabbit consists of a medial principal part (the nucleus papillioformis: PLF) and smaller lateral part (the processus tegmentosus lateralis: PTL). Within PLF three subdivisions are to be distinguished: the dorsomedial part -- zone A, the main part -- zone B and the ventrolateral part -- zone C. The present study in the rabbit indicated collateral projections from neurones in some NRTP regions to the both PML. The cells of origin of these projections were located prominently through the rostrocaudal extent of zone B. Projections from zone A were sparse and those from zone C were absent. Moreover, a weak projection arose mainly from the caudal aspect of PTL. It is concluded that the rostral (e and f) and middle (c and d) sublobules are the main targets for the NRTP-PML branching projections.

Wave propagation in anisotropic elastic materials and curvilinear coordinates using a summation-by-parts finite difference method

DOE PAGES

Petersson, N. Anders; Sjogreen, Bjorn

2015-07-20

We develop a fourth order accurate finite difference method for solving the three-dimensional elastic wave equation in general heterogeneous anisotropic materials on curvilinear grids. The proposed method is an extension of the method for isotropic materials, previously described in the paper by Sjögreen and Petersson (2012) [11]. The method we proposed discretizes the anisotropic elastic wave equation in second order formulation, using a node centered finite difference method that satisfies the principle of summation by parts. The summation by parts technique results in a provably stable numerical method that is energy conserving. Also, we generalize and evaluate the super-grid far-fieldmore » technique for truncating unbounded domains. Unlike the commonly used perfectly matched layers (PML), the super-grid technique is stable for general anisotropic material, because it is based on a coordinate stretching combined with an artificial dissipation. Moreover, the discretization satisfies an energy estimate, proving that the numerical approximation is stable. We demonstrate by numerical experiments that sufficiently wide super-grid layers result in very small artificial reflections. Applications of the proposed method are demonstrated by three-dimensional simulations of anisotropic wave propagation in crystals.« less

Retinoic acid induces proteasome-dependent degradation of retinoic acid receptor α (RARα) and oncogenic RARα fusion proteins

PubMed Central

Zhu, Jun; Gianni, Maurizio; Kopf, Eliezer; Honoré, Nicole; Chelbi-Alix, Mounira; Koken, Marcel; Quignon, Frédérique; Rochette-Egly, Cécile; de Thé, Hugues

1999-01-01

Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia/retinoic acid receptor α (PML/RARα) catabolism in acute promyelocytic leukemia (APL), we found that, in addition to caspase-mediated PML/RARα cleavage, RA triggers degradation of both PML/RARα and RARα. Similarly, in non-APL cells, RA directly targeted RARα and RARα fusions to the proteasome degradation pathway. Activation of either RARα or RXRα by specific agonists induced degradation of both proteins. Conversely, a mutation in RARα that abolishes heterodimer formation and DNA binding, blocked both RARα and RXRα degradation. Mutations in the RARα DNA-binding domain or AF-2 transcriptional activation region also impaired RARα catabolism. Hence, our results link transcriptional activation to receptor catabolism and suggest that transcriptional up-regulation of nuclear receptors by their ligands may be a feedback mechanism allowing sustained target-gene activation. PMID:10611294

Efficient finite element simulation of slot spirals, slot radomes and microwave structures

NASA Technical Reports Server (NTRS)

Gong, J.; Volakis, J. L.

1995-01-01

This progress report contains the following two documents: (1) 'Efficient Finite Element Simulation of Slot Antennas using Prismatic Elements' - A hybrid finite element-boundary integral (FE-BI) simulation technique is discussed to treat narrow slot antennas etched on a planar platform. Specifically, the prismatic elements are used to reduce the redundant sampling rates and ease the mesh generation process. Numerical results for an antenna slot and frequency selective surfaces are presented to demonstrate the validity and capability of the technique; and (2) 'Application and Design Guidelines of the PML Absorber for Finite Element Simulations of Microwave Packages' - The recently introduced perfectly matched layer (PML) uniaxial absorber for frequency domain finite element simulations has several advantages. In this paper we present the application of PML for microwave circuit simulations along with design guidelines to obtain a desired level of absorption. Different feeding techniques are also investigated for improved accuracy.

Regulation of Epidermal Growth Factor Receptor Expression by PML in Human Breast Cancer.

DTIC Science & Technology

1996-08-01

Characterization of a zinc finger gene disrupted by the t(15; 17) in acute promyelocytic leukemia. Science, 254:1371-1374. (32) Fagioli , M., Alcalay, M...DISTRIBUTION CODE Approved for public release; distribution unlimited 13. ABSTRACT (Maximum 200 We have determined that PML is a novel growth suppressor that...was found to be translocated from chromosome 15 and fused with the retinoic acid receptor- a gene on chromosome 17 (t(15; 17) in acute promyelogenous

Kwalificate/Classificatie van Explosieve Stoffen en Munitie. Rapport 2. Testontwikkeling (Qualification/Classification Explosive Materials and Munition. 2. Test Development)

DTIC Science & Technology

1992-11-01

beschermkap van het apparaat af te halen , waardoor bij een eventuele ontsteking het energetisch materiaal (al dan niet brandend) weg kan springen. Tevens...TNO-DefensieonderzoekPr TN TNO-rapport Kwalificatielclassificatie van explosieve stoffen ~ PML 1992-68 en munitief Rapport ]I: Testontwikkeling...rapport Kwalificatielclassificatie van explosieve stoffen PML 1992-68 en munitie Rapport f1: Testontwikkeling november 1992 ~~- ExorrIaar no:- 1ýMI

Detection of polyoma virus in brain tissue of patients with progressive multifocal leukoencephalopathy by real-time PCR and pyrosequencing.

PubMed

Beck, Rose C; Kohn, Debra J; Tuohy, Marion J; Prayson, Richard A; Yen-Lieberman, Belinda; Procop, Gary W

2004-03-01

We evaluated 2 methods, a LightCycler PCR assay and pyrosequencing for the detection of the JC polyoma virus (JCV) in fixed brain tissue of 10 patients with and 3 control patients without progressive multifocal leukoencephalopathy (PML). Nucleic acid extraction was performed after deparaffinization and proteinase K digestion. The LightCycler assay differentiates the BK virus (BKV), JCV, and SV40 using melt curve analysis. Conventional PCR was used with the same primers to generate products for pyrosequencing. Two sequencing primers were used that differentiate the polyoma viruses. Seven of 11 biopsies (1 patient had 2 biopsies) with PML were positive for JCV by real-time PCR and/or PCR/pyrosequencing. Three of 4 remaining biopsies were positive by real-time PCR but had melting points between JCV and SV40. The 4 specimens that were negative or atypical by LightCycler PCR were positive by traditional PCR, but 1 had an amplicon of lower molecular weight by gel electrophoresis. These were shown to represent JCV by at least 1 of the 2 pyrosequencing primers. The biopsies from patients without PML were PCR negative. Both the LightCycler and pyrosequencing assays are useful for confirming JCV in brain biopsies from patients with PML, but variant JCVs may require supplementary methods to confirm JCV infection.

Interferon β induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.

PubMed

Chort, Alice; Alves, Sandro; Marinello, Martina; Dufresnois, Béatrice; Dornbierer, Jean-Gabriel; Tesson, Christelle; Latouche, Morwena; Baker, Darren P; Barkats, Martine; El Hachimi, Khalid H; Ruberg, Merle; Janer, Alexandre; Stevanin, Giovanni; Brice, Alexis; Sittler, Annie

2013-06-01

We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.

Drug-associated progressive multifocal leukoencephalopathy: a clinical, radiological, and cerebrospinal fluid analysis of 326 cases.

PubMed

Maas, Roderick P P W M; Muller-Hansma, Annemarie H G; Esselink, Rianne A J; Murk, Jean-Luc; Warnke, Clemens; Killestein, Joep; Wattjes, Mike P

2016-10-01

The implementation of a variety of immunosuppressive therapies has made drug-associated progressive multifocal leukoencephalopathy (PML) an increasingly prevalent clinical entity. The purpose of this study was to investigate its diagnostic characteristics and to determine whether differences herein exist between the multiple sclerosis (MS), neoplasm, post-transplantation, and autoimmune disease subgroups. Reports of possible, probable, and definite PML according to the current diagnostic criteria were obtained by a systematic search of PubMed and the Dutch pharmacovigilance database. Demographic, epidemiologic, clinical, radiological, cerebrospinal fluid (CSF), and histopathological features were extracted from each report and differences were compared between the disease categories. In the 326 identified reports, PML onset occurred on average 29.5 months after drug introduction, varying from 14.2 to 37.8 months in the neoplasm and MS subgroups, respectively. The most common overall symptoms were motor weakness (48.6 %), cognitive deficits (43.2 %), dysarthria (26.3 %), and ataxia (24.1 %). The former two also constituted the most prevalent manifestations in each subgroup. Lesions were more often localized supratentorially (87.7 %) than infratentorially (27.4 %), especially in the frontal (64.1 %) and parietal lobes (46.6 %), and revealed enhancement in 27.6 % of cases, particularly in the MS (42.9 %) subgroup. Positive JC virus results in the first CSF sample were obtained in 63.5 %, while conversion after one or more negative outcomes occurred in 13.7 % of cases. 52.2 % of patients died, ranging from 12.0 to 83.3 % in the MS and neoplasm subgroups, respectively. In conclusion, despite the heterogeneous nature of the underlying diseases, motor weakness and cognitive changes were the two most common manifestations of drug-associated PML in all subgroups. The frontal and parietal lobes invariably constituted the predilection sites of drug-related PML lesions.

PML-Nuclear Bodies Regulate the Stability of the Fusion Protein Dendra2-Nrf2 in the Nucleus.

PubMed

Burroughs, Andrea Flores; Eluhu, Sylvia; Whalen, Diva; Goodwin, J Shawn; Sakwe, Amos M; Arinze, Ifeanyi J

2018-05-22

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a basic leucine-zipper transcription factor essential for cellular responses to oxidative stress. Degradation of Nrf2 in the cytoplasm, mediated by Keap1-Cullin3/RING box1 (Cul3-Rbx1) E3 ubiquitin ligase and the proteasome, is considered the primary pathway controlling the cellular abundance of Nrf2. Although the nucleus has been implicated in the degradation of Nrf2, little information is available on how this compartment participates in degrading Nrf2. Here, we fused the photoconvertible fluorescent protein Dendra2 to Nrf2 and capitalized on the irreversible change in color (green to red) that occurs when Dendra2 undergoes photoconversion to study degradation of Dendra2-Nrf2 in single live cells. Using this approach, we show that the half-life (t1/2) of Dendra2-Nrf2 in the whole cell, under homeostatic conditions, is 35 min. Inhibition of the proteasome with MG-132 or induction of oxidative stress with tert-butylhydroquinone (tBHQ) extended the half-life of Dendra2-Nrf2 by 6- and 28-fold, respectively. By inhibiting nuclear export using Leptomycin B, we provide direct evidence that degradation of Nrf2 also occurs in the nucleus and involves PML-NBs (Promyelocytic Leukemia-nuclear bodies). We further demonstrate that co-expression of Dendra2-Nrf2 and Crimson-PML-I lacking two PML-I sumoylation sites (K65R and K490R) changed the decay rate of Dendra2-Nrf2 in the nucleus and stabilized the nuclear derived Nrf2 levels in whole cells. Altogether, our findings provide direct evidence for degradation of Nrf2 in the nucleus and suggest that modification of Nrf2 in PML nuclear bodies contributes to its degradation in intact cells. © 2018 The Author(s). Published by S. Karger AG, Basel.

[Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial].

PubMed

Chen, Sai-Juan; Chen, Li-Juan; Zhou, Guang-Biao

2005-02-01

In the last twenty years, using all-trans retinoic acid (ATRA) as a differentiation inducer, Shanghai Institute of Hematology has achieved an important breakthrough in the treatment of acute promyelocytic leukemia (APL), which realized the theory of reversing phenotype of cells and provided a successful model of differentiation therapy in cancers. Our group first discovered in the world the variant chromosome translocation t(11;17)(q23;q21) of APL, and cloned the PML-RAR alpha, PLZF-RAR alpha and NPM-RAR alpha fusion genes corresponding to the characterized chromosome translocations t(15;17); t(11;17) and t(5;17) in APL. Moreover, establishment of transgenic mice model of APL proved their effects on leukemogenesis. The ability of ATRA to modify the recruitment of nuclear receptor co-repressor with PML-RAR alpha but not PLZF-RAR alpha caused by the variant chromosome translocation elucidated the therapeutic mechanism of ATRA from the molecular level and provides new insight into transcription-modulating therapy. Since 1994, our group has successfully applied arsenic trioxide (As(2)O(3)) in treating relapsed APL patients, with the complete remission rate of 70% - 80%. The molecular mechanism study revealed that As(2)O(3) exerts a dose-dependent dual effect on APL. Low-dose As(2)O(3) induced partial differentiation of APL cells, while the higher dose induced apoptosis. As(2)O(3) binds ubiquitin like SUMO-1 through the lysine 160 of PML, resulting in the degradation of PML-RAR alpha. Taken together, ATRA and As(2)O(3) target the transcription factor PML-RAR alpha, the former by retinoic acid receptor and the latter by PML sumolization, both induce PML-RAR alpha degradation and APL cells differentiation and apoptosis. Because of the different acting pathways, ATRA and As(2)O(3) have no cross-resistance and can be used as combination therapy. Clinical trial in newly diagnosed APL patients showed that ATRA/As(2)O(3) in combination yields a longer disease-free survival time. With the median survival of 18 months, none of the 20 cases in combination treatment relapsed, whereas 7 relapsed in 37 cases in mono-treatment. This is the best clinical effect achieved in treating adult acute leukemia to this day, possibly making APL the first adult curable leukemia. Based on the great success of the pathogenetic gene target therapy in APL, this strategy may extend to other leukemias. Combination of Gleevec and arsenic agents in treating chronic myeloid leukemia has already make a figure both in clinical and laboratory research, aiming at counteracting the abnormal tyrosine kinase activity of ABL and the degradating BCR-ABL fusion protein. In acute myeloid leukemia M(2b), using new target therapy degradating AML1-ETO fusion protein and reducing the abnormal tyrosine kinase activity of c-kit will also lead to new therapeutic management in acute leukemias.

Development of a Perfectly Matched Layer Technique for a Discontinuous-Galerkin Spectral-Element Method

NASA Technical Reports Server (NTRS)

Garai, Anirban; Murman, Scott M.; Madavan, Nateri K.

2016-01-01

The numerical simulation of many aerodynamic non-periodic flows of practical interest involves discretized computational domains that often must be artificially truncated. Appropriate boundary conditions are required at these truncated domain boundaries, and ideally, these boundary conditions should be perfectly "absorbing" or "nonreflecting" so that they do not contaminate the flow field in the interior of the domain. The proper specification of these boundaries is critical to the stability, accuracy, convergence, and quality of the numerical solution, and has been the topic of considerable research. The need for accurate boundary specification has been underscored in recent years with efforts to apply higher-fidelity methods (DNS, LES) in conjunction with high-order low-dissipation numerical schemes to realistic flow configurations. One of the most popular choices for specifying these boundaries is the characteristics-based boundary condition where the linearized flow field at the boundaries are decomposed into characteristic waves using either one-dimensional Riemann or other multi-dimensional Riemann approximations. The values of incoming characteristics are then suitably modified. The incoming characteristics are specified at the in flow boundaries, and at the out flow boundaries the variation of the incoming characteristic is zeroed out to ensure no reflection. This, however, makes the problem ill-posed requiring the use of an ad-hoc parameter to allow small reflections that make the solution stable. Generally speaking, such boundary conditions work reasonably well when the characteristic flow direction is normal to the boundary, but reflects spurious energy otherwise. An alternative to the characteristic-based boundary condition is to add additional "buffer" regions to the main computational domain near the artificial boundaries, and solve a different set of equations in the buffer region in order to minimize acoustic reflections. One approach that has been used involves modeling the pressure fluctuations as acoustic waves propagating in the far-field relative to a single noise-source inside the buffer region. This approach treats vorticity-induced pressure fluctuations the same as acoustic waves. Another popular approach, often referred to as the "sponge layer," attempts to dampen the flow perturbations by introducing artificial dissipation in the buffer region. Although the artificial dissipation removes all perturbations inside the sponge layer, incoming waves are still reflected from the interface boundary between the computational domain and the sponge layer. The effect of these refkections can be somewhat mitigated by appropriately selecting the artificial dissipation strength and the extent of the sponge layer. One of the most promising variants on the buffer region approach is the Perfectly Matched Layer (PML) technique. The PML technique mitigates spurious reflections from boundaries and interfaces by dampening the perturbation modes inside the buffer region such that their eigenfunctions remain unchanged. The technique was first developed by Berenger for application to problems involving electromagnetic wave propagation. It was later extended to the linearized Euler, Euler and Navier-Stokes equations by Hu and his coauthors. The PML technique ensures the no-reflection property for all waves, irrespective of incidence angle, wavelength, and propagation direction. Although the technique requires the solution of a set of auxiliary equations, the computational overhead is easily justified since it allows smaller domain sizes and can provide better accuracy, stability, and convergence of the numerical solution. In this paper, the PML technique is developed in the context of a high-order spectral-element Discontinuous Galerkin (DG) method. The technique is compared to other approaches to treating the in flow and out flow boundary, such as those based on using characteristic boundary conditions and sponge layers. The superiority of the current PML technique over other approaches is demonstrated for a range of test cases, viz., acoustic pulse propagation, convective vortex, shear layer flow, and low-pressure turbine cascade flow. The paper is structured as follows. We first derive the PML equations from the non{linear Euler equations. A short description of the higher-order DG method used is then described. Preliminary results for the four test cases considered are then presented and discussed. Details regarding current work that will be included in the final paper are also provided.

Death-domain associated protein-6 (DAXX) mediated apoptosis in hantavirus infection is counter-balanced by activation of interferon-stimulated nuclear transcription factors

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

Khaiboullina, Svetlana F., E-mail: sv.khaiboullina@gmail.com; Morzunov, Sergey P.; Boichuk, Sergei V.

2013-09-01

Hantaviruses are negative strand RNA species that replicate predominantly in the cytoplasm. They also activate numerous cellular responses, but their involvement in nuclear processes is yet to be established. Using human umbilical vein endothelial cells (HUVECs), this study investigates the molecular finger-print of nuclear transcription factors during hantavirus infection. The viral-replication-dependent activation of pro-myelocytic leukemia protein (PML) was followed by subsequent localization in nuclear bodies (NBs). PML was also found in close proximity to activated Sp100 nuclear antigen and interferon-stimulated gene 20 kDa protein (ISG-20), but co-localization with death-domain associated protein-6 (DAXX) was not observed. These data demonstrate that hantavirusmore » triggers PML activation and localization in NBs in the absence of DAXX-PLM-NB co-localization. The results suggest that viral infection interferes with DAXX-mediated apoptosis, and expression of interferon-activated Sp100 and ISG-20 proteins may indicate intracellular intrinsic antiviral attempts.« less

Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia.

PubMed

Pandolfi, P P

2001-04-01

Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARalpha fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and Stat5b genes, respectively, leading to the generation of RARalpha-X: and X:-RARalpha fusion genes. Both fusion proteins can exert oncogenic functions through their ability to interfere with the activities of X and RARalpha proteins. Here, it will be discussed in detail how an extensive biochemical analysis as well as a systematic in vivo genetic approach in the mouse has allowed the definition of the multiple oncogenic activities of PML-RARalpha, and how it has become apparent that this oncoprotein is able to impair RARalpha at the transcription level and the tumor suppressive function of the PML protein.

Implementation of personalized music listening for assisted living residents with dementia.

PubMed

Murphy, Kelly; Liu, Winston W; Goltz, Daniel; Fixsen, Emma; Kirchner, Stephen; Hu, Janice; White, Heidi

2018-05-03

Personalized music listening (PML) has been touted as a safe and inexpensive means of improving the quality of life, mood, and behavior of persons with dementia. A PML program was implemented in an assisted living facility and evaluated across the five dimensions of the RE-AIM framework: reach, effectiveness, adoption, implementation, and maintenance. The first 17 residents invited to participate were enrolled and followed over eight months. Effectiveness was evident in staff-reported mood improvement in 62% of encounters. Adoption was evident in qualitative feedback collected from medication technicians. Implementation was facilitated by low costs, engagement of external volunteers, highlighting outcomes that are relevant to staff, and attention to playlists over time. Maintenance required continued engagement of volunteers, ongoing fundraising, attention to facility staff engagement, and iterative adjustments to the program framework as staffing changes occurred. PML was found to be a meaningful intervention that is possible at a reasonable cost. Copyright © 2018 Elsevier Inc. All rights reserved.

Pontomedullary lacerations in unhelmeted motorcyclists and bicyclists: a retrospective autopsy study.

PubMed

Živković, Vladimir; Nikolić, Slobodan; Strajina, Veljko; Babić, Dragan; Djonić, Danijela; Djurić, Marija

2012-12-01

Pontomedullary lacerations (PMLs) have often been reported in car occupants and pedestrians, are less frequently described in motorcyclists, and are very rarely described in bicyclists. The aim of this study was to determine the frequency of brainstem PMLs among fatally injured motorcyclists and bicyclists as well as the frequency of concomitant cranial, facial, and cervical spine injuries in such cases. A possible underlying mechanism of PML in fatally injured motorcyclists and bicyclists might thus be established. Of 443 cases of fatally injured motorcyclists and bicyclists, a sample of 381 cases of fatally injured motorcyclists and bicyclists with head injury of Abbreviated Injury Scale score of 3 or greater was formed and further analyzed. This group was composed of 345 men and 36 women. The average age was 48.8 ± 20.8 years (range, 15-99 years). In the analyzed sample group, there were 158 motorcyclists and 223 bicyclists. Partial PMLs were present in 44 cases (12%) within the sample of 381 head injuries, which breaks down to 40 men and 4 women. In our study, the impact area on the head and the specific skull base fracture type were good predictors of either PML occurrence or absence (B = -2.036, Wald = 161.312, P < 0.01, for the whole model). Impact to the chin, with or without a skull base fracture, most often led to this fatal injury due to impact force transmission, either through jawbone or vertebral column. Also, lateral head impact, the most frequent in bicyclists, with subsequent hinge fracture, PML, and frontoposterior hyperextension of the head that is associated with upper spine fracture, could be possible mechanisms of brainstem injury in fatally injured motorcyclists or bicyclists. Our study showed that the jawbone, as well as other facial bones, could act as shock absorbers, and their fracture could diminish energy transfer toward the skull and protect the brain and brainstem from injury.

Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells.

PubMed

Hennig, D; Müller, S; Wichmann, C; Drube, S; Pietschmann, K; Pelzl, L; Grez, M; Bug, G; Heinzel, T; Krämer, O H

2015-01-20

Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα. Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis. A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells. Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.

Strategy in Regulatory Decision-Making for Management of Progressive Multifocal Leukoencephalopathy.

PubMed

Segec, A; Keller-Stanislawski, B; Vermeer, N S; Macchiarulo, C; Straus, S M; Hidalgo-Simon, A; De Bruin, M L

2015-11-01

Progressive multifocal leukoencephalopathy (PML) has been observed after the use of several medicines, including monoclonal antibodies. As these drugs play important roles in the therapeutic armamentarium, it is important to address the challenges that this severe adverse reaction poses to the safe use of medicines. Considering the need for consistent outcomes of regulatory decisions, the European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) used PML as an example to develop a systematic approach to labeling and risk minimization. © 2015 American Society for Clinical Pharmacology and Therapeutics.

Applications of non-standard maximum likelihood techniques in energy and resource economics

NASA Astrophysics Data System (ADS)

Moeltner, Klaus

Two important types of non-standard maximum likelihood techniques, Simulated Maximum Likelihood (SML) and Pseudo-Maximum Likelihood (PML), have only recently found consideration in the applied economic literature. The objective of this thesis is to demonstrate how these methods can be successfully employed in the analysis of energy and resource models. Chapter I focuses on SML. It constitutes the first application of this technique in the field of energy economics. The framework is as follows: Surveys on the cost of power outages to commercial and industrial customers usually capture multiple observations on the dependent variable for a given firm. The resulting pooled data set is censored and exhibits cross-sectional heterogeneity. We propose a model that addresses these issues by allowing regression coefficients to vary randomly across respondents and by using the Geweke-Hajivassiliou-Keane simulator and Halton sequences to estimate high-order cumulative distribution terms. This adjustment requires the use of SML in the estimation process. Our framework allows for a more comprehensive analysis of outage costs than existing models, which rely on the assumptions of parameter constancy and cross-sectional homogeneity. Our results strongly reject both of these restrictions. The central topic of the second Chapter is the use of PML, a robust estimation technique, in count data analysis of visitor demand for a system of recreation sites. PML has been popular with researchers in this context, since it guards against many types of mis-specification errors. We demonstrate, however, that estimation results will generally be biased even if derived through PML if the recreation model is based on aggregate, or zonal data. To countervail this problem, we propose a zonal model of recreation that captures some of the underlying heterogeneity of individual visitors by incorporating distributional information on per-capita income into the aggregate demand function. This adjustment eliminates the unrealistic constraint of constant income across zonal residents, and thus reduces the risk of aggregation bias in estimated macro-parameters. The corrected aggregate specification reinstates the applicability of PML. It also increases model efficiency, and allows-for the generation of welfare estimates for population subgroups.

PML-RARα kinetics and impact of FLT3-ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy.

PubMed

Cicconi, L; Divona, M; Ciardi, C; Ottone, T; Ferrantini, A; Lavorgna, S; Alfonso, V; Paoloni, F; Piciocchi, A; Avvisati, G; Ferrara, F; Di Bona, E; Albano, F; Breccia, M; Cerqui, E; Sborgia, M; Kropp, M G; Santoro, A; Levis, A; Sica, S; Amadori, S; Voso, M T; Mandelli, F; Lo-Coco, F

2016-10-01

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Frequency domain finite-element and spectral-element acoustic wave modeling using absorbing boundaries and perfectly matched layer

NASA Astrophysics Data System (ADS)

Rahimi Dalkhani, Amin; Javaherian, Abdolrahim; Mahdavi Basir, Hadi

2018-04-01

Wave propagation modeling as a vital tool in seismology can be done via several different numerical methods among them are finite-difference, finite-element, and spectral-element methods (FDM, FEM and SEM). Some advanced applications in seismic exploration benefit the frequency domain modeling. Regarding flexibility in complex geological models and dealing with the free surface boundary condition, we studied the frequency domain acoustic wave equation using FEM and SEM. The results demonstrated that the frequency domain FEM and SEM have a good accuracy and numerical efficiency with the second order interpolation polynomials. Furthermore, we developed the second order Clayton and Engquist absorbing boundary condition (CE-ABC2) and compared it with the perfectly matched layer (PML) for the frequency domain FEM and SEM. In spite of PML method, CE-ABC2 does not add any additional computational cost to the modeling except assembling boundary matrices. As a result, considering CE-ABC2 is more efficient than PML for the frequency domain acoustic wave propagation modeling especially when computational cost is high and high-level absorbing performance is unnecessary.

Polyoma virus JC DNA detection by polymerase chain reaction in CSF of HIV infected patients with suspected progressive multifocal leukoencephalopathy.

PubMed

Giri, J A; Gregoresky, J; Silguero, P; García Messina, O; Planes, N

2001-01-01

Several studies had previously demonstrated the high sensitivity and specificity of JCV DNA detection in CSF by PCR. This paper reported the implementation of a simple PCR procedure to detect JCV in the CSF in a cohort of HIV-1 infected patients from Argentina. Years ago, the confirmatory diagnosis of this disease was made by in-situ hybridization or immunohistochemistry techniques on brain biopsies. The PCR procedure described here improves the diagnosis of PML because it is simple and noninvasive, and allows the differential diagnosis of PML from other neurological syndromes associated with AIDS. Many recent studies report a significant benefit of combined antiretroviral therapy on the survival of HIV patients without clear neurological improvements. A negative correlation has been described between the concentration of JCV in the CSF and survival time in HIV-1 infected patients, and the level of immune depression may influence JCV replication. This suggests that a single CSF JCV viral load determination during the course of PML disease progression may be of prognostic value for managing HIV patients.

Polarization compensation at low p-GaN doping density in InGaN/GaN p-i-n solar cells: Effect of InGaN interlayers

NASA Astrophysics Data System (ADS)

Saini, Basant; Adhikari, Sonachand; Pal, Suchandan; Kapoor, Avinsahi

2017-07-01

The effectiveness of polarization matching layer (PML) between i-InGaN/p-GaN is studied numerically for Ga-face InGaN/GaN p-i-n solar cell at low p-GaN doping (∼5e17 cm-3). The simulations are performed for four InxGa1-xN/GaN heterostructures (x = 10%, 15%, 20% and 25%), thus investigating the impact of PML for low as well as high indium containing absorber regions. Use of PML presents a suitable alternative to counter the effects of polarization-induced electric fields arising at low p-GaN doping density especially for absorber regions with high indium (>10%). It is seen that it not only mitigates the negative effects of polarization-induced electric fields but also reduces the high potential barriers existing at i-InGaN/p-GaN heterojunction. The improvement in photovoltaic properties of the heterostructures even at low p-GaN doping validates this claim.

Dual origin of relapses in retinoic-acid resistant acute promyelocytic leukemia.

PubMed

Lehmann-Che, Jacqueline; Bally, Cécile; Letouzé, Eric; Berthier, Caroline; Yuan, Hao; Jollivet, Florence; Ades, Lionel; Cassinat, Bruno; Hirsch, Pierre; Pigneux, Arnaud; Mozziconacci, Marie-Joelle; Kogan, Scott; Fenaux, Pierre; de Thé, Hugues

2018-05-24

Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.

Investigation of Molecular Mechanism of JC virus Viroporin Activity.

PubMed

Suzuki, Tadaki

2015-01-01

Viroporins are small and hydrophobic viral proteins that form pores on host cell membranes, and their expression can increase the permeability of cellular membranes and the production of progeny virus particles. JC virus (JCV) is the causative agent of progressive multifocal leukoenchephalopathy (PML). We demonstrate that JCV Agno, which is the small and hydrophobic protein, andincreases the plasma membrane permeability and virion release, acts as a viroporin. We also demonstrate that an interaction of Agno with a host cellular protein regulates the viroporin activity of Agno. These findings indicate a new paradigm in virus-host interactions regulating viroporin activity and viral replication.

Acute promyelocytic leukaemia: novel insights into the mechanisms of cure.

PubMed

de Thé, Hugues; Chen, Zhu

2010-11-01

The fusion oncogene, promyelocytic leukaemia (PML)-retinoic acid receptor-α (RARA), initiates acute promyelocytic leukaemia (APL) through both a block to differentiation and increased self-renewal of leukaemic progenitor cells. The current standard of care is retinoic acid (RA) and chemotherapy, but arsenic trioxide also cures many patients with APL, and an RA plus arsenic trioxide combination cures most patients. This Review discusses the recent evidence that reveals surprising new insights into how RA and arsenic trioxide cure this leukaemia, by targeting PML-RARα for degradation. Drug-triggered oncoprotein degradation may be a strategy that is applicable to many cancers.

Investigation of dust particles with future Russian lunar missions: achievements of further development of PmL instrument.

NASA Astrophysics Data System (ADS)

Kuznetsov, Ilya; Zakharov, Alexander; Afonin, Valeri; Seran, Elena; Godefroy, Michel; Shashkova, Inna; Lyash, Andrey; Dolnikov, Gennady; Popel, Sergey; Lisin, Evgeny

2016-07-01

One of the complicating factors of the future robotic and human lunar landing missions is the influence of the dust. Meteorites bombardment has accompanied by shock-explosive phenomena, disintegration and mix of the lunar soil in depth and on area simultaneously. As a consequence, the lunar soil has undergone melting, physical and chemical transformations. Recently we have the some reemergence for interest of Moon investigation. The prospects in current century declare USA, China, India, and European Union. In Russia also prepare two missions: Luna-Glob and Luna-Resource. Not last part of investigation of Moon surface is reviewing the dust condition near the ground of landers. Studying the properties of lunar dust is important both for scientific purposes to investigation the lunar exosphere component and for the technical safety of lunar robotic and manned missions. The absence of an atmosphere on the Moon's surface is leading to greater compaction and sintering. Properties of regolith and dust particles (density, temperature, composition, etc.) as well as near-surface lunar exosphere depend on solar activity, lunar local time and position of the Moon relative to the Earth's magneto tail. Upper layers of regolith are an insulator, which is charging as a result of solar UV radiation and the constant bombardment of charged particles, creates a charge distribution on the surface of the moon: positive on the illuminated side and negative on the night side. Charge distribution depends on the local lunar time, latitude and the electrical properties of the regolith (the presence of water in the regolith can influence the local distribution of charge). On the day side of Moon near surface layer there exists possibility formation dusty plasma system. Altitude of levitation is depending from size of dust particle and Moon latitude. The distribution of dust particles by size and altitude has estimated with taking into account photoelectrons, electrons and ions of solar wind, solar emission. Dust analyzer instrument PmL for future Russian lander missions intends for investigation the dynamics of dusty plasma near lunar surface. PmL consists of three parts in the case of Luna-Glob: Impact Sensor and two Electric Field Sensors (EFC). There are 9 parts of PmL instrument for Luna-Resource mission: two Impact Sensors, 5 EFC (three on the Boom and two on the lander) and 2 Solar Wind and Dust Analyzers. These days the engineering model of PmL for LG-mission is finished. We obtained first practical results from the simulating chambers with dust particles injectors and plasma inside. All the important achievements are presented in this report as well as the roadmap for further development of PmL instruments in both of Russian lunar missions.

Single-cell analysis of Daxx and ATRX-dependent transcriptional repression

PubMed Central

Newhart, Alyshia; Rafalska-Metcalf, Ilona U.; Yang, Tian; Negorev, Dmitri G.; Janicki, Susan M.

2012-01-01

Summary Histone H3.3 is a constitutively expressed H3 variant implicated in the epigenetic inheritance of chromatin structures. Recently, the PML-nuclear body (PML-NB)/Nuclear Domain 10 (ND10) proteins, Daxx and ATRX, were found to regulate replication-independent histone H3.3 chromatin assembly at telomeres and pericentric heterochromatin. As it is not completely understood how PML-NBs/ND10s regulate transcription and resistance to viral infection, we have used a CMV-promoter-regulated inducible transgene array, at which Daxx and ATRX are enriched, to delineate the mechanisms through which they regulate transcription. When integrated into HeLa cells, which express both Daxx and ATRX, the array is refractory to activation. However, transcription can be induced when ICP0, the HSV-1 E3 ubiquitin ligase required to reverse latency, is expressed. As ATRX and Daxx are depleted from the activated array in ICP0-expressing HeLa cells, this suggests that they are required to maintain a repressed chromatin environment. As histone H3.3 is strongly recruited to the ICP0-activated array but does not co-localize with the DNA, this also suggests that chromatin assembly is blocked during activation. The conclusion that the Daxx and ATRX pathway is required for transcriptional repression and chromatin assembly at this site is further supported by the finding that an array integrated into the ATRX-negative U2OS cell line can be robustly activated and that histone H3.3 is similarly recruited and unincorporated into the chromatin. Therefore, this study has important implications for understanding gene silencing, viral latency and PML-NB/ND10 function. PMID:22976303

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes

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

Komatsu, Tetsuro; Department of Infection Biology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575; Will, Hans

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions asmore » well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. - Highlights: • Host nuclear antiviral factors were analyzed upon adenovirus genome delivery. • Interferon treatments fail to permit PML nuclear bodies to target adenoviral genomes. • Neither Sp100A nor B targets adenoviral genomes despite potentially opposite roles. • The nuclear DNA sensor IFI16 does not target incoming adenoviral genomes. • PHF13/SPOC1 targets neither incoming adenoviral genomes nor genome-bound protein VII.« less

Cloning of the first human anti-JCPyV/VP1 neutralizing monoclonal antibody: epitope definition and implications in risk stratification of patients under natalizumab therapy.

PubMed

Diotti, Roberta Antonia; Mancini, Nicasio; Clementi, Nicola; Sautto, Giuseppe; Moreno, Guisella Janett; Criscuolo, Elena; Cappelletti, Francesca; Man, Petr; Forest, Eric; Remy, Louise; Giannecchini, Simone; Clementi, Massimo; Burioni, Roberto

2014-08-01

JC virus (JCPyV) has gained novel clinical importance as cause of progressive multifocal leukoencephalopathy (PML), a rare demyelinating disease recently associated to immunomodulatory drugs, such as natalizumab used in multiple sclerosis (MS) cases. Little is known about the mechanisms leading to PML, and this makes the need of PML risk stratification among natalizumab-treated patients very compelling. Clinical and laboratory-based risk-stratification markers have been proposed, one of these is represented by the JCPyV-seropositive status, which includes about 54% of MS patients. We recently proposed to investigate the possible protective role of neutralizing humoral immune response in preventing JCPyV reactivation. In this proof-of-concept study, by cloning the first human monoclonal antibody (GRE1) directed against a neutralizing epitope on JCPyV/VP1, we optimized a robust anti-JCPyV neutralization assay. This allowed us to evaluate the neutralizing activity in JCPyV-positive sera from MS patients, demonstrating the lack of correlation between the level of anti-JCPyV antibody and anti-JCPyV neutralizing activity. Relevant consequences may derive from future clinical studies induced by these findings; indeed the study of the serum anti-JCPyV neutralizing activity could allow not only a better risk stratification of the patients during natalizumab treatment, but also a better understanding of the pathophysiological mechanisms leading to PML, highlighting the contribution of peripheral versus central nervous system JCPyV reactivation. Noteworthy, the availability of GRE1 could allow the design of novel immunoprophylactic strategies during the immunomodulatory treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

3-D frequency-domain seismic wave modelling in heterogeneous, anisotropic media using a Gaussian quadrature grid approach

NASA Astrophysics Data System (ADS)

Zhou, Bing; Greenhalgh, S. A.

2011-01-01

We present an extension of the 3-D spectral element method (SEM), called the Gaussian quadrature grid (GQG) approach, to simulate in the frequency-domain seismic waves in 3-D heterogeneous anisotropic media involving a complex free-surface topography and/or sub-surface geometry. It differs from the conventional SEM in two ways. The first is the replacement of the hexahedral element mesh with 3-D Gaussian quadrature abscissae to directly sample the physical properties or model parameters. This gives a point-gridded model which more exactly and easily matches the free-surface topography and/or any sub-surface interfaces. It does not require that the topography be highly smooth, a condition required in the curved finite difference method and the spectral method. The second is the derivation of a complex-valued elastic tensor expression for the perfectly matched layer (PML) model parameters for a general anisotropic medium, whose imaginary parts are determined by the PML formulation rather than having to choose a specific class of viscoelastic material. Furthermore, the new formulation is much simpler than the time-domain-oriented PML implementation. The specified imaginary parts of the density and elastic moduli are valid for arbitrary anisotropic media. We give two numerical solutions in full-space homogeneous, isotropic and anisotropic media, respectively, and compare them with the analytical solutions, as well as show the excellent effectiveness of the PML model parameters. In addition, we perform numerical simulations for 3-D seismic waves in a heterogeneous, anisotropic model incorporating a free-surface ridge topography and validate the results against the 2.5-D modelling solution, and demonstrate the capability of the approach to handle realistic situations.

Newmark-Beta-FDTD method for super-resolution analysis of time reversal waves

NASA Astrophysics Data System (ADS)

Shi, Sheng-Bing; Shao, Wei; Ma, Jing; Jin, Congjun; Wang, Xiao-Hua

2017-09-01

In this work, a new unconditionally stable finite-difference time-domain (FDTD) method with the split-field perfectly matched layer (PML) is proposed for the analysis of time reversal (TR) waves. The proposed method is very suitable for multiscale problems involving microstructures. The spatial and temporal derivatives in this method are discretized by the central difference technique and Newmark-Beta algorithm, respectively, and the derivation results in the calculation of a banded-sparse matrix equation. Since the coefficient matrix keeps unchanged during the whole simulation process, the lower-upper (LU) decomposition of the matrix needs to be performed only once at the beginning of the calculation. Moreover, the reverse Cuthill-Mckee (RCM) technique, an effective preprocessing technique in bandwidth compression of sparse matrices, is used to improve computational efficiency. The super-resolution focusing of TR wave propagation in two- and three-dimensional spaces is included to validate the accuracy and efficiency of the proposed method.

The human CTC1/STN1/TEN1 complex regulates telomere maintenance in ALT cancer cells

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

Huang, Chenhui; Jia, Pingping; Chastain, Megan

Maintaining functional telomeres is important for long-term proliferation of cells. About 15% of cancer cells are telomerase-negative and activate the alternative-lengthening of telomeres (ALT) pathway to maintain their telomeres. Recent studies have shown that the human CTC1/STN1/TEN1 complex (CST) plays a multi-faceted role in telomere maintenance in telomerase-expressing cancer cells. However, the role of CST in telomere maintenance in ALT cells is unclear. Here, we report that human CST forms a functional complex localizing in the ALT-associated PML bodies (APBs) in ALT cells throughout the cell cycle. Suppression of CST induces telomere instabilities including telomere fragility and elevates telomeric DNAmore » recombination, leading to telomere dysfunction. In addition, CST deficiency significantly diminishes the abundance of extrachromosomal circular telomere DNA known as C-circles and t-circles. Suppression of CST also results in multinucleation in ALT cells and impairs cell proliferation. Our findings imply that the CST complex plays an important role in regulating telomere maintenance in ALT cells. - Highlights: • CST localizes at telomeres and ALT-associated PML bodies in ALT cells throughout the cell cycle. • CST is important for promoting telomeric DNA replication in ALT cells. • CST deficiency decreases ECTR formation and increases T-SCE. • CST deficiency impairs ALT cell proliferation and results in multinucleation.« less

CI-Miner: A Semantic Methodology to Integrate Scientists, Data and Documents through the Use of Cyber-Infrastructure

NASA Astrophysics Data System (ADS)

Pinheiro da Silva, P.; CyberShARE Center of Excellence

2011-12-01

Scientists today face the challenge of rethinking the manner in which they document and make available their processes and data in an international cyber-infrastructure of shared resources. Some relevant examples of new scientific practices in the realm of computational and data extraction sciences include: large scale data discovery; data integration; data sharing across distinct scientific domains, systematic management of trust and uncertainty; and comprehensive support for explaining processes and results. This talk introduces CI-Miner - an innovative hands-on, open-source, community-driven methodology to integrate these new scientific practices. It has been developed in collaboration with scientists, with the purpose of capturing, storing and retrieving knowledge about scientific processes and their products, thereby further supporting a new generation of science techniques based on data exploration. CI-Miner uses semantic annotations in the form of W3C Ontology Web Language-based ontologies and Proof Markup Language (PML)-based provenance to represent knowledge. This methodology specializes in general-purpose ontologies, projected into workflow-driven ontologies(WDOs) and into semantic abstract workflows (SAWs). Provenance in PML is CI-Miner's integrative component, which allows scientists to retrieve and reason with the knowledge represented in these new semantic documents. It serves additionally as a platform to share such collected knowledge with the scientific community participating in the international cyber-infrastructure. The integrated semantic documents that are tailored for the use of human epistemic agents may also be utilized by machine epistemic agents, since the documents are based on W3C Resource Description Framework (RDF) notation. This talk is grounded upon interdisciplinary lessons learned through the use of CI-Miner in support of government-funded national and international cyber-infrastructure initiatives in the areas of geo-sciences (NSF-GEON and NSF-EarthScope), environmental sciences (CEON, NSF NEON, NSF-LTER and DOE-Ameri-Flux), and solar physics (VSTO and NSF-SPCDIS). The discussion on provenance is based on the use of PML in support of projects in collaboration with government organizations (DARPA, ARDA, NSF, DHS and DOE), research organizations (NCAR and PNNL), and industries (IBM and SRI International).

Mefloquine improved progressive multifocal leukoencephalopathy in a patient with systemic lupus erythematosus.

PubMed

Beppu, Minako; Kawamoto, Michi; Nukuzuma, Souichi; Kohara, Nobuo

2012-01-01

We describe a case of a 67-year-old man with systemic lupus erythematosus who presented with progressive left hemiplegia. Although the cerebral spinal fluid (CSF) polymerase chain reaction (PCR) for the JC virus was negative, a brain biopsy confirmed the diagnosis of progressive multifocal leukoencephalopathy (PML). The tapering of prednisone and the use of cidofovir could not arrest the disease progression. Administration of mefloquine stopped the extension of the lesion, and resulted in obvious clinical improvement. The CSF nested PCR for the JC virus also became negative. This widely used drug should be tried for the treatment of non-HIV PML.

Development of a Perfectly Matched Layer Technique for a Discontinuous-Galerkin Spectral-Element Method

NASA Technical Reports Server (NTRS)

Garai, Anirban; Diosady, Laslo T.; Murman, Scott M.; Madavan, Nateri K.

2016-01-01

The perfectly matched layer (PML) technique is developed in the context of a high- order spectral-element Discontinuous-Galerkin (DG) method. The technique is applied to a range of test cases and is shown to be superior compared to other approaches, such as those based on using characteristic boundary conditions and sponge layers, for treating the inflow and outflow boundaries of computational domains. In general, the PML technique improves the quality of the numerical results for simulations of practical flow configurations, but it also exhibits some instabilities for large perturbations. A preliminary analysis that attempts to understand the source of these instabilities is discussed.

ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation.

PubMed

Dassouki, Zeina; Sahin, Umut; El Hajj, Hiba; Jollivet, Florence; Kfoury, Youmna; Lallemand-Breitenbach, Valérie; Hermine, Olivier; de Thé, Hugues; Bazarbachi, Ali

2015-01-15

The human T-cell lymphotropic virus type I (HTLV-1) Tax transactivator initiates transformation in adult T-cell leukemia/lymphoma (ATL), a highly aggressive chemotherapy-resistant malignancy. The arsenic/interferon combination, which triggers degradation of the Tax oncoprotein, selectively induces apoptosis of ATL cell lines and has significant clinical activity in Tax-driven murine ATL or human patients. However, the role of Tax loss in ATL response is disputed, and the molecular mechanisms driving degradation remain elusive. Here we demonstrate that ATL-derived or HTLV-1-transformed cells are dependent on continuous Tax expression, suggesting that Tax degradation underlies clinical responses to the arsenic/interferon combination. The latter enforces promyelocytic leukemia protein (PML) nuclear body (NB) formation and partner protein recruitment. In arsenic/interferon-treated HTLV-1 transformed or ATL cells, Tax is recruited onto NBs and undergoes PML-dependent hyper-sumoylation by small ubiquitin-like modifier (SUMO)2/3 but not SUMO1, ubiquitination by RNF4, and proteasome-dependent degradation. Thus, the arsenic/interferon combination clears ATL through degradation of its Tax driver, and this regimen could have broader therapeutic value by promoting degradation of other pathogenic sumoylated proteins. © 2015 by The American Society of Hematology.

A novel CFS-PML boundary condition for transient electromagnetic simulation using a fictitious wave domain method

NASA Astrophysics Data System (ADS)

Hu, Yanpu; Egbert, Gary; Ji, Yanju; Fang, Guangyou

2017-01-01

In this study, we apply fictitious wave domain (FWD) methods, based on the correspondence principle for the wave and diffusion fields, to finite difference (FD) modeling of transient electromagnetic (TEM) diffusion problems for geophysical applications. A novel complex frequency shifted perfectly matched layer (PML) boundary condition is adapted to the FWD to truncate the computational domain, with the maximum electromagnetic wave propagation velocity in the FWD used to set the absorbing parameters for the boundary layers. Using domains of varying spatial extent we demonstrate that these boundary conditions offer significant improvements over simpler PML approaches, which can result in spurious reflections and large errors in the FWD solutions, especially for low frequencies and late times. In our development, resistive air layers are directly included in the FWD, allowing simulation of TEM responses in the presence of topography, as is commonly encountered in geophysical applications. We compare responses obtained by our new FD-FWD approach and with the spectral Lanczos decomposition method on 3-D resistivity models of varying complexity. The comparisons demonstrate that our absorbing boundary condition in FWD for the TEM diffusion problems works well even in complex high-contrast conductivity models.

Identification of a novel fusion gene, IRF2BP2-RARA, in acute promyelocytic leukemia.

PubMed

Yin, C Cameron; Jain, Nitin; Mehrotra, Meenakshi; Zhagn, Jianhua; Protopopov, Alexei; Zuo, Zhuang; Pemmaraju, Naveen; DiNardo, Courtney; Hirsch-Ginsberg, Cheryl; Wang, Sa A; Medeiros, L Jeffrey; Chin, Lynda; Patel, Keyur P; Ravandi, Farhad; Futreal, Andrew; Bueso-Ramos, Carlos E

2015-01-01

Acute promyelocytic leukemia (APL) is characterized by the fusion of retinoic acid receptor alpha (RARA) with promyelocytic leukemia (PML) or, rarely, other gene partners. This report presents a patient with APL with a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes. A bone marrow examination in a 19-year-old woman who presented with ecchymoses and epistaxis showed morphologic and immunophenotypic features consistent with APL. PML oncogenic domain antibody was positive. Results of fluorescence in situ hybridization, conventional cytogenetics, reverse transcription-polymerase chain reaction (RT-PCR), and oligonucleotide microarray for PML-RARA and common APL variant translocations were negative. Next-generation RNA-sequencing analysis followed by RT-PCR and direct sequencing revealed distinct breakpoints within IRF2BP2 exon 2 and RARA intron 2. The patient received all-trans retinoic acid, arsenic, and gemtuzumab ozogamicin, and achieved complete remission. However, the disease relapsed 10 months later, 2 months after consolidation therapy. This is the first report showing involvement of IRF2BP2 in APL, and it expands the list of novel RARA partners identified in APL. Copyright © 2015 by the National Comprehensive Cancer Network.

Althaea rosea Cavanil and Plantago major L. suppress neoplastic cell transformation through the inhibition of epidermal growth factor receptor kinase.

PubMed

Choi, Eun-Sun; Cho, Sung-Dae; Shin, Ji-Ae; Kwon, Ki Han; Cho, Nam-Pyo; Shim, Jung-Hyun

2012-10-01

For thousands of years in Asia, Althaea rosea Cavanil (ARC) and Plantago major L. (PML) have been used as powerful non-toxic therapeutic agents that inhibit inflammation. However, the anticancer mechanisms and molecular targets of ARC and PML are poorly understood, particularly in epidermal growth factor (EGF)-induced neoplastic cell transformation. The aim of this study was to evaluate the chemopreventive effects and mechanisms of the methanol extracts from ARC (MARC) and PML (MPML) in EGF-induced neoplastic cell transformation of JB6 P+ mouse epidermal cells using an MTS assay, anchorage-independent cell transformation assay and western blotting. Our results showed that MARC and MPML significantly suppressed neoplastic cell transformation by inhibiting the kinase activity of the EGF receptor (EGFR). The activation of EGFR by EGF was suppressed by MARC and MPML treatment in EGFR(+/+) cells, but not in EGFR(-/-) cells. In addition, MARC and MPML inhibited EGF-induced cell proliferation in EGFR-expressing murine embryonic fibroblasts (EGFR(+/+)). These results strongly indicate that EGFR targeting by MARC and MPML may be a good strategy for chemopreventive or chemotherapeutic applications.

Imaging analysis of nuclear antiviral factors through direct detection of incoming adenovirus genome complexes.

PubMed

Komatsu, Tetsuro; Will, Hans; Nagata, Kyosuke; Wodrich, Harald

2016-04-22

Recent studies involving several viral systems have highlighted the importance of cellular intrinsic defense mechanisms through nuclear antiviral proteins that restrict viral propagation. These factors include among others components of PML nuclear bodies, the nuclear DNA sensor IFI16, and a potential restriction factor PHF13/SPOC1. For several nuclear replicating DNA viruses, it was shown that these factors sense and target viral genomes immediately upon nuclear import. In contrast to the anticipated view, we recently found that incoming adenoviral genomes are not targeted by PML nuclear bodies. Here we further explored cellular responses against adenoviral infection by focusing on specific conditions as well as additional nuclear antiviral factors. In line with our previous findings, we show that neither interferon treatment nor the use of specific isoforms of PML nuclear body components results in co-localization between incoming adenoviral genomes and the subnuclear domains. Furthermore, our imaging analyses indicated that neither IFI16 nor PHF13/SPOC1 are likely to target incoming adenoviral genomes. Thus our findings suggest that incoming adenoviral genomes may be able to escape from a large repertoire of nuclear antiviral mechanisms, providing a rationale for the efficient initiation of lytic replication cycle. Copyright © 2016 Elsevier Inc. All rights reserved.

Evaluation of support loss in micro-beam resonators: A revisit

NASA Astrophysics Data System (ADS)

Chen, S. Y.; Liu, J. Z.; Guo, F. L.

2017-12-01

This paper presents an analytical study on evaluation of support loss in micromechanical resonators undergoing in-plane flexural vibrations. Two-dimensional elastic wave theory is used to determine the energy transmission from the vibrating resonator to the support. Fourier transform and Green's function technique are adopted to solve the problem of wave motions on the surface of the support excited by the forces transmitted by the resonator onto the support. Analytical expressions of support loss in terms of quality factor, taking into account distributed normal stress and shear stress in the attachment region, and coupling between the normal stress and shear stress as well as material disparity between the support and the resonator, have been derived. Effects of geometry of micro-beam resonators, and material dissimilarity between support and resonator on support loss are examined. Numerical results show that 'harder resonator' and 'softer support' combination leads to larger support loss. In addition, the Perfectly Matched Layer (PML) numerical simulation technique is employed for validation of the proposed analytical model. Comparing with results of quality factor obtained by PML technique, we find that the present model agrees well with the results of PML technique and the pure-shear model overestimates support loss noticeably, especially for resonators with small aspect ratio and large material dissimilarity between the support and resonator.

COS-7-based model: methodological approach to study John Cunningham virus replication cycle.

PubMed

Prezioso, C; Scribano, D; Rodio, D M; Ambrosi, C; Trancassini, M; Palamara, A T; Pietropaolo, V

2018-02-05

John Cunningham virus (JCV) is a human neurotropic polyomavirus whose replication in the Central Nervous System (SNC) induces the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV propagation and PML investigation have been severely hampered by the lack of an animal model and cell culture systems to propagate JCV have been very limited in their availability and robustness. We previously confirmed that JCV CY strain efficiently replicated in COS-7 cells as demonstrated by the progressive increase of viral load by quantitative PCR (Q-PCR) during the time of transfection and that archetypal regulatory structure was maintained, although two characteristic point mutations were detected during the viral cycle. This short report is an important extension of our previous efforts in defining our reliable model culture system able to support a productive JCV infection.Supernatants collected from transfected cells have been used to infect freshly seeded COS-7 cell line. An infectious viral progeny was obtained as confirmed by Western blot and immunofluorescence assay. During infection, the archetype regulatory region was conserved.Importantly, in this study we developed an improved culture system to obtain a large scale production of JC virus in order to study the genetic features, the biology and the pathogenic mechanisms of JC virus that induce PML.

HIPK2 restricts SIRT1 activity upon severe DNA damage by a phosphorylation-controlled mechanism

PubMed Central

Conrad, E; Polonio-Vallon, T; Meister, M; Matt, S; Bitomsky, N; Herbel, C; Liebl, M; Greiner, V; Kriznik, B; Schumacher, S; Krieghoff-Henning, E; Hofmann, T G

2016-01-01

Upon severe DNA damage a cellular signalling network initiates a cell death response through activating tumour suppressor p53 in association with promyelocytic leukaemia (PML) nuclear bodies. The deacetylase Sirtuin 1 (SIRT1) suppresses cell death after DNA damage by antagonizing p53 acetylation. To facilitate efficient p53 acetylation, SIRT1 function needs to be restricted. How SIRT1 activity is regulated under these conditions remains largely unclear. Here we provide evidence that SIRT1 activity is limited upon severe DNA damage through phosphorylation by the DNA damage-responsive kinase HIPK2. We found that DNA damage provokes interaction of SIRT1 and HIPK2, which phosphorylates SIRT1 at Serine 682 upon lethal damage. Furthermore, upon DNA damage SIRT1 and HIPK2 colocalize at PML nuclear bodies, and PML depletion abrogates DNA damage-induced SIRT1 Ser682 phosphorylation. We show that Ser682 phosphorylation inhibits SIRT1 activity and impacts on p53 acetylation, apoptotic p53 target gene expression and cell death. Mechanistically, we found that DNA damage-induced SIRT1 Ser682 phosphorylation provokes disruption of the complex between SIRT1 and its activator AROS. Our findings indicate that phosphorylation-dependent restriction of SIRT1 activity by HIPK2 shapes the p53 response. PMID:26113041

Puromycin induces SUMO and ubiquitin redistribution upon proteasome inhibition

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

Matsumoto, Hotaru; Saitoh, Hisato, E-mail: hisa@kumamoto-u.ac.jp; Department of Biological Sciences, Graduate School of Science and Technology, Kumamoto University, Kumamoto

2016-07-29

We have previously reported the co-localization of O-propargyl-puromycin (OP-Puro) with SUMO-2/3 and ubiquitin at promyelocytic leukemia-nuclear bodies (PML-NBs) in the presence of the proteasome inhibitor MG132, implying a role for the ubiquitin family in sequestering OP-puromycylated immature polypeptides to the nucleus during impaired proteasome activity. Here, we found that as expected puromycin induced SUMO-1/2/3 accumulation with ubiquitin at multiple nuclear foci in HeLa cells when co-exposed to MG132. Co-administration of puromycin and MG132 also facilitated redistribution of PML and the SUMO-targeted ubiquitin ligase RNF4 concurrently with SUMO-2/3. As removal of the drugs from the medium led to disappearance of themore » SUMO-2/3-ubiquitin nuclear foci, our findings indicated that nuclear assembly/disassembly of SUMO-2/3 and ubiquitin was pharmacologically manipulable, supporting our previous observation on OP-Puro, which predicted the ubiquitin family function in sequestrating aberrant proteins to the nucleus. -- Highlights: •Puromycin exhibits the O-propargyl-puromycin effect. •Puromycin induces SUMO redistribution upon proteasome inhibition. •Ubiquitin and RNF4 accumulate at PML-nuclear bodies with SUMO-2/3. •The ubiquitin family may function in nuclear sequestration of immature proteins.« less

Effect of facial massage on static balance in individuals with temporomandibular disorder - a pilot study.

PubMed

El Hage, Yasmin; Politti, Fabiano; Herpich, Carolina Marciela; de Souza, Dowglas Fernando Magalhães; de Paula Gomes, Cid André Fidelis; Amorim, Cesar Ferreira; de Oliveira Gonzalez, Tabajara; Biasotto-Gonzalez, Daniela Aparecida

2013-01-01

The influence of the neuromuscular system on the cervical region and mastication is directly associated with mandibular movements and neck posture. Normal occlusal homeostasis depends on complex sensory feedback mechanisms of the periodontal ligament, temporomandibular joint and other structures of the stomatognathic system. This feedback serves as a regulatory mechanism that helps determine the force and nature of muscle contractions. Alterations in the muscles of mastication, neck muscles, and occlusal characteristics constitute causal factors of imbalances in the postural muscle chains, leading to alterations in the center of pressure (CoP) of the feet. Thus, therapies that seek occlusal reestablishment, such as muscle relaxation techniques, may lead to a restructuring of the global equilibrium of the neuromuscular system and an improvement in body posture. The aim of the present pilot study was to investigate the immediate effect of facial massage on the CoP in the anteroposterior (CoPAP) and mediolateral (CoPML) directions in individuals with temporomandibular disorder (TMD). Twenty individuals with a diagnosis of TMD based on the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) were submitted to a facial massage technique. CoPAP and CoPML were evaluated using a force plate. Evaluations were performed under two visual conditions (eyes open and eyes closed) prior to resting in dorsal decubitus (baseline), after 10 minutes of rest (premassage) and after the administration of the massage technique (postmassage). No significant differences were found regarding CoPAP velocity with eyes open or the following aspects under either visual condition (eyes open or closed): CoPML velocity, RMS of CoPAP, RMS of CoPML, and sway area. The only significant difference was found for mean CoPAP velocity with eyes closed. While the results of the present study demonstrate the reliability of the reproduction of the data, facial massage had no immediate influence on postural control in individuals with TMD.

[Progressive multifocal leukoencephalitis complicating polymyositis].

PubMed

Elloumi, Mohamed; Ayadi, Nada; Mhiri, Chokri; Jlidi, Rachid; Baklouti, Soufiène

2003-02-01

Progressive multifocal leukoencephalitis (PML) must be evoked in patients presenting with a systemic disease during which multiple neurological deficiencies rapidly worsen. A 17 year-old girl suffering from histologically confirmed polymyositis was treated with corticosteroids. Two years after the diagnosis she exhibited global signs of cerebral damage with fever and magnetic resonance imaging evoked leukoencephalitis. An affection of the central nervous system, PML is characterised by the existence of multiple areas of demyelination in the hemispheric white substance of the cerebral trunk and sometimes the cerebellum, whereas the grey substance is usually spared. This entity occurs more frequently in HIV-infected patients, but also in patients in whom the immunodeficiency may have other causes, such as the treatment for a systemic disease for example.

Mutations Allow JC Polyomaviruses to Elude Antibody Recognition | Center for Cancer Research

Cancer.gov

JC polyomavirus (JCV) infects the urinary tract of most adults. In healthy individuals, JCV infection does not cause noticeable symptoms. However, in those with compromised immune systems, JCV can cause a lethal brain disease called progressive multifocal leukoencephalopathy (PML). Data from a recently approved assay to detect serum antibodies specific for the JCV protein VP1 revealed that patients with antibodies are at increased risk of developing PML. At the same time, sequencing studies of JCV in cerebrospinal fluid (CSF) identified a number of mutations in VP1. Christopher Buck, Ph.D., and Diana Pastrana, Ph.D., of CCR’s Laboratory of Cellular Oncology, and their colleagues hypothesized that the VP1 mutations could allow the virus to evade antibody-mediated elimination.

The Construction of the Small Scale Cook-off Bomb (SCB) op het PML-TNO (De constructie vande Small scale Cook-off Bomb (SCB) op het PML-TNO)

DTIC Science & Technology

1993-03-01

cervV epa Addm Ing. J.A. van (3ooI - 12-02-1993 It7T- PAPOTNCNTAE g,: Accesion For Frederikkaze~rne, gebouw 140 OGRBIER TS CAI T v/ d Burchlaafl 31 HPC...16A r~l D TIC -;S TEL. 070-3166394/6395 ONGERUBRICEERD) !’ ,ro’ ;Cc FAX. (31) 070-.3166202 Srevtil:JSl--to ElostbUs 90701 Saiqwag ......zto I...Tabel I geeft d onderdelen van de TNO~~~~-SC e e fiknemattnozc a ei etU rnebe[I] becrvnSB Tae I ljtvnodreediqu atvscinvnd I-C TaeD ef e onder d n o

TSOS and TSOS-FK hybrid methods for modelling the propagation of seismic waves

NASA Astrophysics Data System (ADS)

Ma, Jian; Yang, Dinghui; Tong, Ping; Ma, Xiao

2018-05-01

We develop a new time-space optimized symplectic (TSOS) method for numerically solving elastic wave equations in heterogeneous isotropic media. We use the phase-preserving symplectic partitioned Runge-Kutta method to evaluate the time derivatives and optimized explicit finite-difference (FD) schemes to discretize the space derivatives. We introduce the averaged medium scheme into the TSOS method to further increase its capability of dealing with heterogeneous media and match the boundary-modified scheme for implementing free-surface boundary conditions and the auxiliary differential equation complex frequency-shifted perfectly matched layer (ADE CFS-PML) non-reflecting boundaries with the TSOS method. A comparison of the TSOS method with analytical solutions and standard FD schemes indicates that the waveform generated by the TSOS method is more similar to the analytic solution and has a smaller error than other FD methods, which illustrates the efficiency and accuracy of the TSOS method. Subsequently, we focus on the calculation of synthetic seismograms for teleseismic P- or S-waves entering and propagating in the local heterogeneous region of interest. To improve the computational efficiency, we successfully combine the TSOS method with the frequency-wavenumber (FK) method and apply the ADE CFS-PML to absorb the scattered waves caused by the regional heterogeneity. The TSOS-FK hybrid method is benchmarked against semi-analytical solutions provided by the FK method for a 1-D layered model. Several numerical experiments, including a vertical cross-section of the Chinese capital area crustal model, illustrate that the TSOS-FK hybrid method works well for modelling waves propagating in complex heterogeneous media and remains stable for long-time computation. These numerical examples also show that the TSOS-FK method can tackle the converted and scattered waves of the teleseismic plane waves caused by local heterogeneity. Thus, the TSOS and TSOS-FK methods proposed in this study present an essential tool for the joint inversion of local, regional, and teleseismic waveform data.

Can Feulgen Stain be a Reliable Biomarker over PAP Stain for Estimation of Micronuclei Score?

PubMed Central

Prasad, Umesh Chandra; Chandolia, Betina; Manjunath, S M; Basu, Shiva; Verma, Silvie

2016-01-01

Introduction Malignant transformation of the Potentially Malignant Lesions (PML) in the oral cavity is associated with elevated mortality rate because of its aggressive and exceedingly invasive nature. Meticulous diagnosis and prompt therapy of PML may help prevent malignant conversion in oral lesions. Carcinogenic insult to oral cells results in chromosomal damage and formation of Micronuclei (Mn), before the development of clinical symptoms. Aim To determine the genotoxic effect of smoking and chewing tobacco on target tissue using Mn assay and to evaluate the prevalence of other nuclear anomalies associated with it and to determine the reliability of feulgen stain for Mn assay over Papaincolau (PAP) stain. Materials and Methods PAP and feulgen staining was done to study Mn in individuals who were having tobacco habits (smoking and chewing) without lesion (n=30), individuals who were having tobacco habit (smoking and chewing) with PML (n=30) and apparently healthy subjects (n=30). Data was analysed for statistical significance using SPSS 17.0 by Kruskal - Wallis Test and Bonferronii test. Results Tobacco habits in the form of smoking and chewing have mutagenic effects on human chromosomes which is indicated by increased frequency of Mn in oral exfoliative cells. The mean Mn frequency using feulgen stain was found to be 12.27 with lesion, 10.23 with without lesion and 3.87 in controls. Whereas, metanucleated analysis revealed no significant correlation with the formation of Mn. Non-specific DNA stain (PAP) showed high numbers of Mn cells in all the groups compared to feulgen. Statistically significant difference (p<0.0001) was observed when both the stains were compared for Mn numbers. Conclusion These findings indicate that the individuals having tobacco habits (smoking and chewing) with lesion have high number of Mn cells, thus supporting the assay to be used as a reliable biomarker to assess the genotoxic effect of tobacco in the oral mucosa. The reason for almost twice as high Mn in PAP stained smears is suggestive of cell injury which is collimated by formation of keratin bodies, resulting in its misinterpretation as Mn, leading to false positive results. Hence, it was concluded that PAP stain can be used to identify abnormal cytological changes resulting from mutagenic agent but not to interpret Mn. PMID:27891448

Statistical process control analysis for patient quality assurance of intensity modulated radiation therapy

NASA Astrophysics Data System (ADS)

Lee, Rena; Kim, Kyubo; Cho, Samju; Lim, Sangwook; Lee, Suk; Shim, Jang Bo; Huh, Hyun Do; Lee, Sang Hoon; Ahn, Sohyun

2017-11-01

This study applied statistical process control to set and verify the quality assurances (QA) tolerance standard for our hospital's characteristics with the criteria standards that are applied to all the treatment sites with this analysis. Gamma test factor of delivery quality assurances (DQA) was based on 3%/3 mm. Head and neck, breast, prostate cases of intensity modulated radiation therapy (IMRT) or volumetric arc radiation therapy (VMAT) were selected for the analysis of the QA treatment sites. The numbers of data used in the analysis were 73 and 68 for head and neck patients. Prostate and breast were 49 and 152 by MapCHECK and ArcCHECK respectively. C p value of head and neck and prostate QA were above 1.0, C pml is 1.53 and 1.71 respectively, which is close to the target value of 100%. C pml value of breast (IMRT) was 1.67, data values are close to the target value of 95%. But value of was 0.90, which means that the data values are widely distributed. C p and C pml of breast VMAT QA were respectively 1.07 and 2.10. This suggests that the VMAT QA has better process capability than the IMRT QA. Consequently, we should pay more attention to planning and QA before treatment for breast Radiotherapy.

Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives.

PubMed

McCulloch, Derek; Brown, Christina; Iland, Harry

2017-01-01

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) with a unique morphological appearance, associated coagulopathy and canonical balanced translocation of genetic material between chromosomes 15 and 17. APL was first described as a distinct subtype of AML in 1957 by Dr Leif Hillestad who recognized the pattern of an acute leukemia associated with fibrinolysis, hypofibrinogenemia and catastrophic hemorrhage. In the intervening years, the characteristic morphology of APL has been described fully with both classical hypergranular and variant microgranular forms. Both are characterized by a balanced translocation between the long arms of chromosomes 15 and 17, [t(15;17)(q24;q21)], giving rise to a unique fusion gene PML-RARA and an abnormal chimeric transcription factor (PML-RARA), which disrupts normal myeloid differentiation programs. The success of current treatments for APL is in marked contrast to the vast majority of patients with non-promyelocytic AML. The overall prognosis in non-promyelocytic AML is poor, and although there has been an improvement in overall survival in patients aged <60 years, only 30%-40% of younger patients are still alive 5 years after diagnosis. APL therapy has diverged from standard AML therapy through the empirical discovery of two agents that directly target the molecular basis of the disease. The evolution of treatment over the last 4 decades to include all- trans retinoic acid and arsenic trioxide, with chemotherapy limited to patients with high-risk disease, has led to complete remission in 90%-100% of patients in trials and rates of overall survival between 86% and 97%.

Spanish consensus on the use of natalizumab (Tysabri®)-2013.

PubMed

Fernández, O; García-Merino, J A; Arroyo, R; Álvarez-Cermeño, J C; Izquierdo, G; Saiz, A; Olascoaga, J; Rodríguez-Antigüedad, A; Prieto, J M; Oreja-Guevara, C; Hernández, M A; Moral, E; Meca, J; Montalbán, X

2015-06-01

Natalizumab treatment has been shown to be very efficacious in clinical trials and very effective in clinical practice in patients with relapsing-remitting multiple sclerosis, by reducing relapses, slowing disease progression, and improving magnetic resonance imaging patterns. However, the drug has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The first consensus statement on natalizumab use, published in 2011, has been updated to include new data on diagnostic procedures, monitoring for patients undergoing treatment, PML management, and other topics of interest including the management of patients discontinuing natalizumab. This updated version followed the method used in the first consensus. A group of Spanish experts in multiple sclerosis (the authors of the present document) reviewed all currently available literature on natalizumab and identified the relevant topics would need updating based on their clinical experience. The initial draft passed through review cycles until the final version was completed. Studies in clinical practice have demonstrated that changing to natalizumab is more effective than switching between immunomodulators. They favour early treatment with natalizumab rather than using natalizumab in a later stage as a rescue therapy. Although the drug is very effective, its potential adverse effects need to be considered, with particular attention to the patient's likelihood of developing PML. The neurologist should carefully explain the risks and benefits of the treatment, comparing them to the risks of multiple sclerosis in terms the patient can understand. Before treatment is started, laboratory tests and magnetic resonance images should be available to permit proper follow-up. The risk of PML should be stratified as high, medium, or low according to presence or absence of anti-JC virus antibodies, history of immunosuppressive therapy, and treatment duration. Although the presence of anti-JC virus antibodies is a significant finding, it should not be considered an absolute contraindication for natalizumab. This update provides general recommendations, but neurologists must use their clinical expertise to provide personalised follow-up for each patient. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

Improved Survival of HIV-1-Infected Patients with Progressive Multifocal Leukoencephalopathy Receiving Early 5-Drug Combination Antiretroviral Therapy

PubMed Central

Hendel-Chavez, Houria; Dulioust, Anne; Pakianather, Sophie; Mazet, Anne-Aurélie; de Goer de Herve, Marie-Ghislaine; Lancar, Rémi; Lascaux, Anne-Sophie; Porte, Lydie; Delfraissy, Jean-François; Taoufik, Yassine

2011-01-01

Background Progressive multifocal leukoencephalopathy (PML), a rare devastating demyelinating disease caused by the polyomavirus JC (JCV), occurs in severely immunocompromised patients, most of whom have advanced-stage HIV infection. Despite combination antiretroviral therapy (cART), 50% of patients die within 6 months of PML onset. We conducted a multicenter, open-label pilot trial evaluating the survival benefit of a five-drug cART designed to accelerate HIV replication decay and JCV-specific immune recovery. Methods and Findings All the patients received an optimized cART with three or more drugs for 12 months, plus the fusion inhibitor enfuvirtide during the first 6 months. The main endpoint was the one-year survival rate. A total of 28 patients were enrolled. At entry, median CD4+ T-cell count was 53 per microliter and 86% of patients had detectable plasma HIV RNA and CSF JCV DNA levels. Seven patients died, all before month 4. The one-year survival estimate was 0.75 (95% confidence interval, 0.61 to 0.93). At month 6, JCV DNA was undetectable in the CSF of 81% of survivors. At month 12, 81% of patients had undetectable plasma HIV RNA, and the median CD4+ T-cell increment was 105 per microliter. In univariate analysis, higher total and naive CD4+ T-cell counts and lower CSF JCV DNA level at baseline were associated with better survival. JCV-specific functional memory CD4+ T-cell responses, based on a proliferation assay, were detected in 4% of patients at baseline and 43% at M12 (P = 0.008). Conclusions The early use of five-drug cART after PML diagnosis appears to improve survival. This is associated with recovery of anti-JCV T-cell responses and JCV clearance from CSF. A low CD4+ T-cell count (particularly naive subset) and high JCV DNA copies in CSF at PML diagnosis appear to be risk factors for death. Trial Registration ClinicalTrials.gov NCT00120367 PMID:21738597

Acute promyelocytic leukemia in children and adolescents.

PubMed

Stein, Eytan M; Tallman, Martin S

2014-01-01

Acute promyelocytic leukemia (APL) is a rare subtype of AML characterized by a reciprocal balanced translocation between chromosomes 15 and 17 that fuses the PML gene with the RARα gene and leads to the leukemic phenotype. Although best described in large clinical trials of adults, APL, like other forms of AML, also occurs in children. The positive outcome of children with APL mirrors the dramatic increase in survival seen in adults since the introduction of all-trans retinoic acid (ATRA). In this paper, we review the diagnosis of APL in children as well as large, retrospective, clinical trial data collected on pediatric APL. We also raise management issues and toxicities that are unique to children. © 2014 S. Karger AG, Basel.

Mycophenolate

MedlinePlus

... cured and that usually causes death or severe disability). Tell your doctor if you have or have ever had PML, or another condition that affects your immune system such as human immunodeficiency virus (HIV); acquired immunodeficiency syndrome (AIDS); sarcoidosis ( ...

Research Results

NASA Astrophysics Data System (ADS)

2010-10-01

Relations found between human memories and similar neural patterns Double Star Program Received the IAA Laurels for Team Achievement Award Prof. Piao's Review Paper Published in Nature Arsenic Trioxide Controls the Fate of the PML-RARα Oncoprotein by Directly Binding PML Setdb2 restricts dorsal organizer territory and regulates left-right asymmetry through suppressing fgf8 activity Short-range scattering in quantum dots Single-molecule magnets may find their use in microelectronics β-Arrestin1 Regulates Zebrafish Hematopoiesis through Binding to YY1 and Relieving Polycomb Group Repression Studies shown gene present and absent complementation may contribute to the heterosis of maize Low frequency genetic variation may determine complex diseases Cation-π interaction playing vital roles in the regulation of integrin affinity, signaling, and biological functions Soybean diversity map may provide important basis for breeding Mutations related to Alzheimer's and rare skin disease

Regulation of the p73 protein stability and degradation

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

Oberst, Andrew; Rossi, Mario; Salomoni, Paolo

2005-06-10

p73, a homologue to the tumor suppressor gene p53, is involved in tumorigenesis, though its specific role remains unclear. The gene has two distinct promoters which allow the formation of two protein isoforms with opposite effects: full-length transactivating (TA) p73 shows pro-apoptotic effects, while the shorter {delta}Np73, which lacks the N-terminal transactivating domain, has an evident anti-apoptotic function. Unlike p53, the p73 gene is rarely mutated in human cancers. However, alterations in the relative levels of TA and {delta}Np73 have been shown to correlate with prognosis in several human cancers, suggesting that the fine regulation of these two isoforms ismore » of pivotal importance in controlling proliferation and cell death. Much effort is currently focused on the elucidation of the mechanisms that differentially control TA and {delta}Np73 activity and protein stability, a process complicated by the finding that both proteins are regulated by a similar suite of complex post-translational modifications that include ubiquitination, sequential phosphorylation, prolyl-isomerization, recruitment into the PML-nuclear body (PML-NB), and acetylation. Here we shall consider the main regulatory partners of p73, with particular attention to the recently discovered Itch- and Nedd8-mediated degradation pathways, along with the emerging roles of PML, p38 MAP kinase, Pin1, and p300 in p73 transcriptional activation, and possible mechanisms for the differential regulation of the TAp73 and {delta}Np73 isoforms.« less

Late relapse of progressive multifocal leucoencephalopathy postallogenic transplant in a young patient with CLL.

PubMed

Sanchez-Quintana, Ana; Breña-Atienza, Joaquín; Marrero-Santos, Carmen; Alvarez-Acosta, Luis

2013-08-05

We describe a case of progressive multifocal leucoencephalopathy (PML) in a 39-year-old patient diagnosed with chronic lymphocytic leukaemia (CLL) who underwent two allogenic matched-sibling stem cell transplantations. PML was confirmed just after the first transplantation with cerebral MRI and by PCR in the cerebrospinal fluid. After immunosuppression withdrawal and cidofovir treatment, he achieved a reversal of clinical symptoms, John Cunningham (JC) virus positivity and MRI lesions regression. He remained asymptomatic for 5 years with no signs of infection activity, even though he received three new chemotherapy regimens due to a CLL relapse. However, after the second stem cell transplantation, new neurological symptoms began and a reactivation of the JC virus infection was detected. This time, treatment with mefloquine was started, but he experienced a progressive neurological deterioration and died 1 month after the symptoms began.

On the Huygens absorbing boundary conditions for electromagnetics

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

Berenger, Jean-Pierre

A new absorbing boundary condition (ABC) is presented for the solution of Maxwell equations in unbounded spaces. Called the Huygens ABC, this condition is a generalization of two previously published ABCs, namely the multiple absorbing surfaces (MAS) and the re-radiating boundary condition (rRBC). The properties of the Huygens ABC are derived theoretically in continuous spaces and in the finite-difference (FDTD) discretized space. A solution is proposed to render the Huygens ABC effective for the absorption of evanescent waves. Numerical experiments with the FDTD method show that the effectiveness of the Huygens ABC is close to that of the PML ABCmore » in some realistic problems of numerical electromagnetics. It is also shown in the paper that a combination of the Huygens ABC with the PML ABC is very well suited to the solution of some particular problems.« less

Innate responses to gene knockouts impact overlapping gene networks and vary with respect to resistance to viral infection.

PubMed

Liu, Yonghong; Liu, Yuanyuan; Wu, Jiaming; Roizman, Bernard; Zhou, Grace Guoying

2018-04-03

Analyses of the levels of mRNAs encoding IFIT1, IFI16, RIG-1, MDA5, CXCL10, LGP2, PUM1, LSD1, STING, and IFNβ in cell lines from which the gene encoding LGP2, LSD1, PML, HDAC4, IFI16, PUM1, STING, MDA5, IRF3, or HDAC 1 had been knocked out, as well as the ability of these cell lines to support the replication of HSV-1, revealed the following: ( i ) Cell lines lacking the gene encoding LGP2, PML, or HDAC4 (cluster 1) exhibited increased levels of expression of partially overlapping gene networks. Concurrently, these cell lines produced from 5 fold to 12 fold lower yields of HSV-1 than the parental cells. ( ii ) Cell lines lacking the genes encoding STING, LSD1, MDA5, IRF3, or HDAC 1 (cluster 2) exhibited decreased levels of mRNAs of partially overlapping gene networks. Concurrently, these cell lines produced virus yields that did not differ from those produced by the parental cell line. The genes up-regulated in cell lines forming cluster 1, overlapped in part with genes down-regulated in cluster 2. The key conclusions are that gene knockouts and subsequent selection for growth causes changes in expression of multiple genes, and hence the phenotype of the cell lines cannot be ascribed to a single gene; the patterns of gene expression may be shared by multiple knockouts; and the enhanced immunity to viral replication by cluster 1 knockout cell lines but not by cluster 2 cell lines suggests that in parental cells, the expression of innate resistance to infection is specifically repressed.

Domain retention in transcription factor fusion genes and its biological and clinical implications: a pan-cancer study

PubMed Central

Kim, Pora; Ballester, Leomar Y.; Zhao, Zhongming

2017-01-01

Genomic rearrangements involving transcription factors (TFs) can form fusion proteins resulting in either enhanced, weakened, or even loss of TF activity. Functional domain (FD) retention is a critical factor in the activity of transcription factor fusion genes (TFFGs). A systematic investigation of FD retention in TFFGs and their outcome (e.g. expression changes) in a pan-cancer study has not yet been completed. Here, we examined the FD retention status in 386 TFFGs across 13 major cancer types and identified 83 TFFGs involving 67 TFs that retained FDs. To measure the potential biological relevance of TFs in TFFGs, we introduced a Major Active Isofusion Index (MAII) and built a prioritized TFFG network using MAII scores and the observed frequency of fusion positive samples. Interestingly, the four TFFGs (PML-RARA, RUNX1-RUNX1T1, TMPRSS2-ERG, and SFPQ-TFE3) with the highest MAII scores showed 50 differentially expressed target genes (DETGs) in fusion-positive versus fusion-negative cancer samples. DETG analysis revealed that they were involved in tumorigenesis-related processes in each cancer type. PLAU, which encodes plasminogen activator urokinase and serves as a biomarker for tumor invasion, was found to be consistently activated in the samples with the highest MAII scores. Among the 50 DETGs, 21 were drug targetable genes. Fourteen of these 21 DETGs were expressed in acute myeloid leukemia (AML) samples. Accordingly, we constructed an AML-specific TFFG network, which included 38 DETGs in RUNX1-RUNX1T1 or PML-RARA positive samples. In summary, this study revealed several TFFGs and their potential target genes, and provided insights into the clinical implications of TFFGs. PMID:29299133

Autofluorescence guided diagnostic evaluation of suspicious oral mucosal lesions: opportunities, limitations, and pitfalls

NASA Astrophysics Data System (ADS)

Vigneswaran, Nadarajah

2011-03-01

Wide-filed autofluorescence examination is currently considered as a standard of care for screening and diagnostic evaluation of early neoplastic changes of the skin, cervix, lung, bladder, gastrointestinal tract and oral cavity. Naturally occurring fluorophores within the tissue absorb UV and visible light and can re-emit some of this light at longer wavelengths in the form of fluorescence. This non-invasive tissue autofluorescence imaging is used in optical diagnostics, especially in the early detection of cancer. Usually, malignant transformation is associated with thickening of the epithelium, enhanced cellular density due to increased nuclear cytoplasmic ratio which may attenuate the excitation leading to a decrease in collagen autofluorescence. Hence, dysplastic and cancerous tissues often exhibit decreased blue-green autofluorescence and appear darker compared to uninvolved mucosa. Currently, there are three commercially available devices to examine tissue autofluorescence in the oral cavity. In this study we used the oral cancer screening device IdentafiTM 3000 to examine the tissue reflectance and autofluorescence of PML and confounding lesions of the oral cavity. Wide-field autofluorescence imaging enables rapid inspection of large mucosal surfaces, to aid in recognition of suspicious lesions and may also help in discriminate the PML (class 1) from some of the confounding lesions (class II). However, the presence of inflammation or pigments is also associated with loss of stromal autofluorescence, and may give rise to false-positive results with widefield fluorescence imaging. Clinicians who use these autofluorescence based oral cancer screening devices should be aware about the benign oral mucosal lesions that may give false positivity so that unnecessary patient's anxiety and the need for scalpel biopsy can be eliminated.

Deficit of heat shock transcription factor 1-heat shock 70 kDa protein 1A axis determines the cell death vulnerability in a model of spinocerebellar ataxia type 6.

PubMed

Li, Li; Saegusa, Hironao; Tanabe, Tsutomu

2009-11-01

Spinocerebellar ataxia type 6 (SCA6) is caused by a small expansion of polyglutamine (polyQ)-encoding CAG repeat in Ca(v)2.1 calcium channel gene. To gain insights into pathogenic mechanism of SCA6, we used HEK293 cells expressing fusion protein of enhanced green fluorescent protein and Ca(v)2.1 carboxyl terminal fragment (EGFP-Ca(v)2.1CT) [L24 and S13 cells containing 24 polyQ (disease range) and 13 polyQ (normal range), respectively] and examined their responses to some stressors. When exposed to CdCl(2), L24 cells showed lower viability than the control S13 cells and caspase-dependent apoptosis was enhanced more in L24 cells. Localization of EGFP-Ca(v)2.1CT was almost confined to the nucleus, where it existed as speckle-like structures. Interestingly, CdCl(2) treatment resulted in disruption of more promyelocytic leukemia nuclear bodies (PML-NBs) in L24 cells than in S13 cells and in cells where PML-NBs were disrupted, aggregates of EGFP-Ca(v)2.1CT became larger. Furthermore, a large number of aggregates were formed in L24 cells than in S13 cells. Results of RNAi experiments indicated that HSPA1A determined the difference against CdCl(2) toxicity. Furthermore, protein expression of heat shock transcription factor 1 (HSF1), which activates HSPA1A expression, was down-regulated in L24 cells. Therefore, HSF1-HSPA1A axis is critical for the vulnerability in L24 cells.

Evaluating statistical approaches to leverage large clinical datasets for uncovering therapeutic and adverse medication effects.

PubMed

Choi, Leena; Carroll, Robert J; Beck, Cole; Mosley, Jonathan D; Roden, Dan M; Denny, Joshua C; Van Driest, Sara L

2018-04-18

Phenome-wide association studies (PheWAS) have been used to discover many genotype-phenotype relationships and have the potential to identify therapeutic and adverse drug outcomes using longitudinal data within electronic health records (EHRs). However, the statistical methods for PheWAS applied to longitudinal EHR medication data have not been established. In this study, we developed methods to address two challenges faced with reuse of EHR for this purpose: confounding by indication, and low exposure and event rates. We used Monte Carlo simulation to assess propensity score (PS) methods, focusing on two of the most commonly used methods, PS matching and PS adjustment, to address confounding by indication. We also compared two logistic regression approaches (the default of Wald vs. Firth's penalized maximum likelihood, PML) to address complete separation due to sparse data with low exposure and event rates. PS adjustment resulted in greater power than propensity score matching, while controlling Type I error at 0.05. The PML method provided reasonable p-values, even in cases with complete separation, with well controlled Type I error rates. Using PS adjustment and the PML method, we identify novel latent drug effects in pediatric patients exposed to two common antibiotic drugs, ampicillin and gentamicin. R packages PheWAS and EHR are available at https://github.com/PheWAS/PheWAS and at CRAN (https://www.r-project.org/), respectively. The R script for data processing and the main analysis is available at https://github.com/choileena/EHR. leena.choi@vanderbilt.edu. Supplementary data are available at Bioinformatics online.

Inhibition of the NAD-Dependent Protein Deacetylase SIRT2 Induces Granulocytic Differentiation in Human Leukemia Cells

PubMed Central

Sunami, Yoshitaka; Araki, Marito; Hironaka, Yumi; Morishita, Soji; Kobayashi, Masaki; Liew, Ei Leen; Edahiro, Yoko; Tsutsui, Miyuki; Ohsaka, Akimichi; Komatsu, Norio

2013-01-01

Sirtuins, NAD-dependent protein deacetylases, play important roles in cellular functions such as metabolism and differentiation. Whether sirtuins function in tumorigenesis is still controversial, but sirtuins are aberrantly expressed in tumors, which may keep cancerous cells undifferentiated. Therefore, we investigated whether the inhibition of sirtuin family proteins induces cellular differentiation in leukemic cells. The sirtuin inhibitors tenovin-6 and BML-266 induce granulocytic differentiation in the acute promyelocytic leukemia (APL) cell line NB4. This differentiation is likely caused by an inhibition of SIRT2 deacetylase activity, judging from the accumulation of acetylated α-tubulin, a major SIRT2 substrate. Unlike the clinically used differentiation inducer all-trans retinoic acid, tenovin-6 shows limited effects on promyelocytic leukemia–retinoic acid receptor α (PML-RAR-α) stability and promyelocytic leukemia nuclear body formation in NB4 cells, suggesting that tenovin-6 does not directly target PML-RAR-α activity. In agreement with this, tenovin-6 induces cellular differentiation in the non-APL cell line HL-60, where PML-RAR-α does not exist. Knocking down SIRT2 by shRNA induces granulocytic differentiation in NB4 cells, which demonstrates that the inhibition of SIRT2 activity is sufficient to induce cell differentiation in NB4 cells. The overexpression of SIRT2 in NB4 cells decreases the level of granulocytic differentiation induced by tenovin-6, which indicates that tenovin-6 induces granulocytic differentiation by inhibiting SIRT2 activity. Taken together, our data suggest that targeting SIRT2 is a viable strategy to induce leukemic cell differentiation. PMID:23460888

[Association between ambient PM(l0)/PM(2.5) concentration and outpatient department visits due to respiratory disease in a hospital in Jinan, 2013-2015: a time series analysis].

PubMed

Zhao, M J; Geng, X Y; Cui, L L; Zhou, J W; Zhang, J

2017-03-10

Objective: To estimate the influence of the ambient PM(l0) and PM(2.5) pollution on the hospital outpatient department visit due to respiratory diseases in local residents in Jinan quantitatively. Methods: Time serial analysis using generalized addictive model (GAM) was conducted. After controlling the confounding factors, such as long term trend, weekly pattern and meteorological factors, considering lag effect and the influence of other air pollutants, the excess relative risks of daily hospital visits associated with increased ambient PM(10) and PM(2.5) levels were estimated by fitting a Poisson regression model. Results: A 10 μg/m(3) increase of PM(10) and PM(2.5) levels was associated with an increase of 0.36%(95 %CI : 0.30%-0.43%) and 0.50%(95 %CI : 0.30%-0.70%) respectively for hospital visits due to respiratory diseases. Lag effect of 6 days was strongest, the excess relative risks were 0.65% (95 % CI : 0.58% -0.71% ) and 0.54% (95 % CI : 0.42%-0.67%) respectively. When NO(2) concentration was introduced, the daily hospital visits due to respiratory disease increased by 0.83% as a 10 μg/m(3) increase of PM(10) concentration (95 % CI : 0.76%-0.91%). Conclusion: The ambient PM(l0) and PM(2.5) pollution was positively associated with daily hospital visits due to respiratory disease in Jinan, and ambient NO(2) concentration would have the synergistic effect.

Activities of various compounds against murine and primate polyomaviruses.

PubMed Central

Andrei, G; Snoeck, R; Vandeputte, M; De Clercq, E

1997-01-01

Polyomavirus infections in humans are due to BK virus (BKV) and JC virus (JCV). Diseases associated with human polyomaviruses occur mostly in immunocompromised adults, e.g., progressive multifocal leukoencephalopathy (PML), caused by JCV, in AIDS patients and hemorrhagic cystitis and uretral stenosis, caused by BKV, in transplant recipients. No therapy is available for these diseases, which necessitates the development of chemical entities that are active against polyomaviruses. Several antiviral compounds were evaluated to determine their effects on the in vitro replication of mouse polyomavirus and the primate viruses simian virus 40 (SV40), SV40 PML-1, and SV40 PML-2. The activity of the different compounds was assessed by a cytopathic effect reduction assay and confirmed in a virus yield assay. Cidofovir [HPMPC; (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] and its cyclic counterpart emerged as the most selective antipolyomavirus agents. The 50% inhibitory concentrations for HPMPC were in the range of 4 to 7 micrograms/ml, and its selectivity index varied from 11 to 20 for mouse polyomavirus and from 23 to 33 for SV40 strains in confluent cell monolayers. Cell cytotoxicity was up to 15-fold greater in growing cells. Other acyclic nucleoside phosphonates (i.e., HPMPA; [(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine] and PMEG [9-(2-phosphonylmethoxyethyl)-guanine]) also showed some activity but had low selectivity. None of the other drugs tested against these animal viruses (i.e., acyclovir, ganciclovir, brivudine, ribavirin, foscarnet, and cytarabine) showed significant activity. Thus, HPMPC deserves further evaluation as a candidate drug for polyomavirus infections in the immunocompromised host. PMID:9055998

Angiogenesis-related gene expression analysis in celiac disease.

PubMed

Castellanos-Rubio, Ainara; Caja, Sergio; Irastorza, Iñaki; Fernandez-Jimenez, Nora; Plaza-Izurieta, Leticia; Vitoria, Juan Carlos; Maki, Markku; Lindfors, Katri; Bilbao, Jose Ramon

2012-05-01

Celiac disease (CD) involves disturbance of the small-bowel mucosal vascular network, and transglutaminase autoantibodies (TGA) have been related to angiogenesis disturbance, a complex phenomenon probably also influenced by common genetic variants in angiogenesis-related genes. A set of genes with "angiogenesis" GO term identified in a previous expression microarray experiment (SCG2, STAB1, TGFA, ANG, ERBB2, GNA13, PML, CASP8, ECGF1, JAG1, HIF1A, TNFSF13 and TGM2) was selected for genetic and functional studies. SNPs that showed a trend for association with CD in the first GWAS were genotyped in 555 patients and 541 controls. Gene expression of all genes was quantified in 15 pairs of intestinal biopsies (diagnosis vs. GFD) and in three-dimensional HUVEC and T84 cell cultures incubated with TGA-positive and negative serum. A regulatory SNP in TNFSF13 (rs11552708) is associated with CD (p = 0.01, OR = 0.7). Expression changes in biopsies pointed to TGM2 and PML as up-regulated antiangiogenic genes and to GNA13, TGFA, ERBB2 and SCG2 as down-regulated proangiogenic factors in CD. TGA seem to enhance TGM2 expression in both cell models, but PML expression was induced only in T84 enterocytes while GNA13 and ERBB2 were repressed in HUVEC endothelial cells, with several genes showing discordant effects in each model, highlighting the complexity of gene interactions in the pathogenesis of CD. Finally, cell culture models are useful tools to help dissect complex responses observed in human explants.

PML AND PSTD ALGORITHM FOR ARBITRARY LOSSY ANISOTROPIC MEDIA. (R825225)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

AN FDTD ALGORITHM WITH PML FOR DISPERSIVE, CONDUCTIVE MEDIA. (R825225)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Evidence for a Dual Antiviral Role of the Major Nuclear Domain 10 Component Sp100 during the Immediate-Early and Late Phases of the Human Cytomegalovirus Replication Cycle ▿

PubMed Central

Tavalai, Nina; Adler, Martina; Scherer, Myriam; Riedl, Yvonne; Stamminger, Thomas

2011-01-01

In recent studies, the nuclear domain 10 (ND10) components PML and hDaxx were identified as cellular restriction factors that inhibit the initiation of human cytomegalovirus (HCMV) replication. The antiviral function of ND10, however, is antagonized by the IE1 protein, which induces ND10 disruption. Here we show that IE1 not only de-SUMOylates PML immediately upon infection but also directly targets Sp100. IE1 expression alone was sufficient to downregulate endogenous Sp100 independently of the presence of PML. Moreover, cotransfection experiments revealed that IE1 negatively interferes with the SUMOylation of all Sp100 isoforms. The modulation of Sp100 at immediate-early (IE) times of infection, indeed, seemed to have an in vivo relevance for HCMV replication, since knockdown of Sp100 resulted in more cells initiating the viral gene expression program. In addition, we observed that Sp100 was degraded in a proteasome-dependent manner at late times postinfection, suggesting that Sp100 may play an additional antiviral role during the late phase. Infection experiments conducted with Sp100 knockdown human foreskin fibroblasts (HFFs) confirmed this hypothesis: depletion of Sp100 resulted in augmented release of progeny virus particles compared to that from control cells. Consistent with this observation, we noted increased amounts of viral late gene products in the absence of Sp100. Importantly, this elevated late gene expression was not dependent on enhanced viral IE gene expression. Taken together, our data provide evidence that Sp100 is the first ND10-related factor identified that not only possesses the potential to restrict the initial stage of infection but also inhibits HCMV replication during the late phase. PMID:21734036

Predictors of Response to Multiple Sclerosis Therapeutics in Individual Patients.

PubMed

Hegen, Harald; Auer, Michael; Deisenhammer, Florian

2016-10-01

Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Several disease-modifying therapies have been shown to ameliorate the disease course; however, the individual treatment response and the occurrence of adverse events remain highly unpredictable. In the last 2 decades, a multitude of studies have aimed to identify biomarkers that enable treatment allocation in the individual patient or subgroup of patients with regard to treatment efficacy and safety profile. Following a PubMed database search, we provide an overview on what is presently known about body fluid markers for the prediction of response to the currently approved MS therapeutics. We also discuss the potential use of biomarkers with regard to drug-induced adverse events. To date, only a few molecules have been introduced in clinical routine: anti-drug antibodies against interferon (IFN)-β and natalizumab that are associated with abolished drug levels and treatment failure; anti-JC virus (JCV) antibody index that allows risk stratification for the development of progressive multifocal leukoencephalopathy (PML), a rare but severe adverse event during natalizumab treatment; and serostatus of varicella zoster virus as screening examination prior to fingolimod therapy to prevent the infection. A few candidate biomarkers still need closer examination, such as type I IFN signature and T-helper cell (Th)-17 reactivity for prediction of IFN-β treatment response, L-selectin expression for prediction of natalizumab-associated PML, interleukin (IL)-21 levels for prediction of secondary autoimmunity after exposure to alemtuzumab, lymphocyte count with regard to PML risk while receiving dimethyl fumarate or N-terminal-pro-B-type natriuretic peptide (NT-proBNP) for monitoring of cardiac side effects during mitoxantrone therapy.

Learning to live on a Mars day: fatigue countermeasures during the Phoenix Mars Lander mission.

PubMed

Barger, Laura K; Sullivan, Jason P; Vincent, Andrea S; Fiedler, Edna R; McKenna, Laurence M; Flynn-Evans, Erin E; Gilliland, Kirby; Sipes, Walter E; Smith, Peter H; Brainard, George C; Lockley, Steven W

2012-10-01

To interact with the robotic Phoenix Mars Lander (PML) spacecraft, mission personnel were required to work on a Mars day (24.65 h) for 78 days. This alien schedule presents a challenge to Earth-bound circadian physiology and a potential risk to workplace performance and safety. We evaluated the acceptability, feasibility, and effectiveness of a fatigue management program to facilitate synchronization with the Mars day and alleviate circadian misalignment, sleep loss, and fatigue. Operational field study. PML Science Operations Center. Scientific and technical personnel supporting PML mission. Sleep and fatigue education was offered to all support personnel. A subset (n = 19) were offered a short-wavelength (blue) light panel to aid alertness and mitigate/reduce circadian desynchrony. They were assessed using a daily sleep/work diary, continuous wrist actigraphy, and regular performance tests. Subjects also completed 48-h urine collections biweekly for assessment of the circadian 6-sulphatoxymelatonin rhythm. Most participants (87%) exhibited a circadian period consistent with adaptation to a Mars day. When synchronized, main sleep duration was 5.98 ± 0.94 h, but fell to 4.91 ± 1.22 h when misaligned (P < 0.001). Self-reported levels of fatigue and sleepiness also significantly increased when work was scheduled at an inappropriate circadian phase (P < 0.001). Prolonged wakefulness (≥ 21 h) was associated with a decline in performance and alertness (P < 0.03 and P < 0.0001, respectively). The ability of the participants to adapt successfully to the Mars day suggests that future missions should utilize a similar circadian rhythm and fatigue management program to reduce the risk of sleepiness-related errors that jeopardize personnel safety and health during critical missions.

THE PERFECTLY MATCHED LAYER (PML) FOR ACOUSTIC WAVES IN ABSORPTIVE MEDIA. (R825225)

EPA Science Inventory

The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Concl...

Region 9: Nevada Adequate Letter (1/26/2002), Response to Comments, and Adequacy Review Table

EPA Pesticide Factsheets

A letter from Jack Broadbent, Director, to Allen Biaggi Regarding Nevada's PMlO State Implementation Plan for Clark County; EPA's response regarding the adequacy of the PM10 Transportation Conformity budgets Contained in Clark County's PM10 Attainment

NPM and BRG1 mediate transcriptional resistance to retinoic acid in Acute Promyelocytic Leukemia

PubMed Central

Nichol, Jessica N.; Galbraith, Matthew D.; Kleinman, Claudia L.; Espinosa, Joaquín M.; Miller, Wilson H.

2016-01-01

Summary Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA) sensitive Acute Promyelocytic Leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction between PML/RARA, Nucleophosmin (NPM) and Topoisomerase II Beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA-differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML) therefore, our model may be applicable to other more common leukemias driven by NPM. PMID:26997274

An Endogenous Accelerator for Viral Gene Expression Confers a Fitness Advantage

PubMed Central

Teng, Melissa W.; Bolovan-Fritts, Cynthia; Dar, Roy D.; Womack, Andrew; Simpson, Michael L.; Shenk, Thomas; Weinberger, Leor S.

2012-01-01

Many signaling circuits face a fundamental tradeoff between accelerating their response speed while maintaining final levels below a cytotoxic threshold. Here, we describe a transcriptional circuitry that dynamically converts signaling inputs into faster rates without amplifying final equilibrium levels. Using time-lapse microscopy, we find that transcriptional activators accelerate human cytomegalovirus (CMV) gene expression in single cells without amplifying steady-state expression levels, and this acceleration generates a significant replication advantage. We map the accelerator to a highly self-cooperative transcriptional negative-feedback loop (Hill coefficient ~ 7) generated by homo-multimerization of the virus’s essential transactivator protein IE2 at nuclear PML bodies. Eliminating the IE2-accelerator circuit reduces transcriptional strength through mislocalization of incoming viral genomes away from PML bodies and carries a heavy fitness cost. In general, accelerators may provide a mechanism for signal-transduction circuits to respond quickly to external signals without increasing steady-state levels of potentially cytotoxic molecules. PMID:23260143

JC Virus Leuko-Encephalopathy in Reduced Intensity Conditioning Cord Blood Transplant Recipient with a Review of the Literature.

PubMed

El-Cheikh, Jean; Fürst, Sabine; Casalonga, Francois; Crocchiolo, Roberto; Castagna, Luca; Granata, Angela; Oudin, Claire; Faucher, Catherine; Berger, Pierre; Sarran, Anthony; Blaise, Didier

2012-01-01

We report here the case of progressive multifocal leukoencephalopathy (PML) related to human polyomavirus JC (JCV) infection after an allogeneic transplantation with umbilical cord blood cells in 59-year-old woman with follicular Non Hodgkin lymphoma. She presented with dysphagia and weakness; magnetic resonance imaging demonstrated marked signal abnormality in the sub-cortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was positive for John Cunningham (JC) virus. JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Brain biopsy was not done. Extensive investigations for other viral infections seen in immuno-compromised patients were negative. The patient's neurologic deficits rapidly increased throughout her hospital stay, and she died one month after the diagnosis. These findings could have practical implications and demonstrate that in patients presenting neurological symptoms and radiological signs after UCBT, the JCV encephalitis must be early suspected.

JC Virus Leuko-Encephalopathy in Reduced Intensity Conditioning Cord Blood Transplant Recipient with a Review of the Literature

PubMed Central

El-Cheikh, Jean; Fürst, Sabine; Casalonga, Francois; Crocchiolo, Roberto; Castagna, Luca; Granata, Angela; Oudin, Claire; Faucher, Catherine; Berger, Pierre; Sarran, Anthony; Blaise, Didier

2012-01-01

We report here the case of progressive multifocal leukoencephalopathy (PML) related to human polyomavirus JC (JCV) infection after an allogeneic transplantation with umbilical cord blood cells in 59-year-old woman with follicular Non Hodgkin lymphoma. She presented with dysphagia and weakness; magnetic resonance imaging demonstrated marked signal abnormality in the sub-cortical white matter of the left frontal lobe and in the posterior limb of the right internal capsule. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) was positive for John Cunningham (JC) virus. JC viral DNA in the CSF was positive, establishing the diagnosis of PML. Brain biopsy was not done. Extensive investigations for other viral infections seen in immuno-compromised patients were negative. The patient’s neurologic deficits rapidly increased throughout her hospital stay, and she died one month after the diagnosis. These findings could have practical implications and demonstrate that in patients presenting neurological symptoms and radiological signs after UCBT, the JCV encephalitis must be early suspected. PMID:22811792

An Acetylation Switch Regulates SUMO-Dependent Protein Interaction Networks

PubMed Central

Ullmann, Rebecca; Chien, Christopher D.; Avantaggiati, Maria Laura; Muller, Stefan

2013-01-01

SUMMARY The attachment of the SUMO modifier to proteins controls cellular signaling pathways through noncovalent binding to SUMO-interaction motifs (SIMs). Canonical SIMs contain a core of hydrophobic residues that bind to a hydrophobic pocket on SUMO. Negatively charged residues of SIMs frequently contribute to binding by interacting with a basic surface on SUMO. Here we define acetylation within this basic interface as a central mechanism for the control of SUMO-mediated interactions. The acetyl-mediated neutralization of basic charges on SUMO prevents binding to SIMs in PML, Daxx, and PIAS family members but does not affect the interaction between RanBP2 and SUMO. Acetylation is controlled by HDACs and attenuates SUMO- and PIAS-mediated gene silencing. Moreover, it affects the assembly of PML nuclear bodies and restrains the recruitment of the corepressor Daxx to these structures. This acetyl-dependent switch thus expands the regulatory repertoire of SUMO signaling and determines the selectivity and dynamics of SUMO-SIM interactions. PMID:22578841

The Analysis and Construction of Perfectly Matched Layers for the Linearized Euler Equations

NASA Technical Reports Server (NTRS)

Hesthaven, J. S.

1997-01-01

We present a detailed analysis of a recently proposed perfectly matched layer (PML) method for the absorption of acoustic waves. The split set of equations is shown to be only weakly well-posed, and ill-posed under small low order perturbations. This analysis provides the explanation for the stability problems associated with the split field formulation and illustrates why applying a filter has a stabilizing effect. Utilizing recent results obtained within the context of electromagnetics, we develop strongly well-posed absorbing layers for the linearized Euler equations. The schemes are shown to be perfectly absorbing independent of frequency and angle of incidence of the wave in the case of a non-convecting mean flow. In the general case of a convecting mean flow, a number of techniques is combined to obtain a absorbing layers exhibiting PML-like behavior. The efficacy of the proposed absorbing layers is illustrated though computation of benchmark problems in aero-acoustics.

Puromycin induces SUMO and ubiquitin redistribution upon proteasome inhibition.

PubMed

Matsumoto, Hotaru; Saitoh, Hisato

2016-07-29

We have previously reported the co-localization of O-propargyl-puromycin (OP-Puro) with SUMO-2/3 and ubiquitin at promyelocytic leukemia-nuclear bodies (PML-NBs) in the presence of the proteasome inhibitor MG132, implying a role for the ubiquitin family in sequestering OP-puromycylated immature polypeptides to the nucleus during impaired proteasome activity. Here, we found that as expected puromycin induced SUMO-1/2/3 accumulation with ubiquitin at multiple nuclear foci in HeLa cells when co-exposed to MG132. Co-administration of puromycin and MG132 also facilitated redistribution of PML and the SUMO-targeted ubiquitin ligase RNF4 concurrently with SUMO-2/3. As removal of the drugs from the medium led to disappearance of the SUMO-2/3-ubiquitin nuclear foci, our findings indicated that nuclear assembly/disassembly of SUMO-2/3 and ubiquitin was pharmacologically manipulable, supporting our previous observation on OP-Puro, which predicted the ubiquitin family function in sequestrating aberrant proteins to the nucleus. Copyright © 2016 Elsevier Inc. All rights reserved.

[RXR, a key member of the oncogenic complex in acute promyelocytic leukemia].

PubMed

Halftermeyer, Juliane; Le Bras, Morgane; De Thé, Hugues

2011-11-01

Acute promyelocytic leukaemia (APL) is induced by fusion proteins always implying the retinoic acid receptor RARa. Although PML-RARa and other fusion oncoproteins are able to bind DNA as homodimers, in vivo they are always found in association with the nuclear receptor RXRa (Retinoid X Receptor). Thus, RXRa is an essential cofactor of the fusion protein for the transformation. Actually, RXRa contributes to several aspects of in vivo -transformation: RARa fusion:RXRa hetero-oligomeric complexes bind DNA with a much greater affinity than RARa fusion homodimers. Besides, PML-RARa:RXRa recognizes an enlarged repertoire of DNA binding sites. Thus the association between fusion proteins and RXRa regulates more genes than the homodimer alone. Titration of RXRa by the fusion protein may also play a role in the transformation process, as well as post-translational modifications of RXRa in the complex. Finally, RXRa is required for rexinoid-induced APL differentiation. Thus, RXRa is a key member of the oncogenic complex. © 2011 médecine/sciences – Inserm / SRMS.

Generation and Characterization of JCV Permissive Hybrid Cell Lines

PubMed Central

Sariyer, Ilker K.; Safak, Mahmut; Gordon, Jennifer; Khalili, Kamel

2009-01-01

JC virus (JCV) is a human neurotropic polyomavirus whose replication in the central nervous system induces the fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). JCV particles have been detected primarily in oligodendrocytes and astrocytes of the brains of patients with PML and in the laboratory its propagation is limited to primary cultures of human fetal glial cells. In this short communication, the development of a new cell culture system is described through the fusion of primary human fetal astrocytes with the human glioblastoma cell line, U-87MG. The new hybrid cell line obtained from this fusion has the capacity to support efficiently expression of JCV and replication of viral DNA in vitro up to 16 passages. This cell line can serve as a reliable culture system to study the biology of JCV host cell interaction, determine the mechanisms involved in cell type specific replication of JCV, and provide a convenient cell culture system for high throughput screening of anti-viral agents. PMID:19442856

Increase of apatite dissolution rate by Scots pine roots associated or not with Burkholderia glathei PML1(12)Rp in open-system flow microcosms

NASA Astrophysics Data System (ADS)

Calvaruso, Christophe; Turpault, Marie-Pierre; Frey-Klett, Pascale; Uroz, Stéphane; Pierret, Marie-Claire; Tosheva, Zornitza; Kies, Antoine

2013-04-01

The release of nutritive elements through apatite dissolution represents the main source of phosphorus, calcium, and several micronutrients (e.g., Zn, Cu) for organisms in non-fertilized forest ecosystems. The aim of this study was to quantify, for the first time, the dissolution rate of apatite grains by tree roots that were or were not associated with a mineral weathering bacterial strain, and by various acids known to be produced by tree roots and soil bacterial strains in open-system flow microcosms. In addition, we explored whether the mobilization of trace elements (including rare earth elements) upon apatite dissolution was affected by the presence of trees and associated microorganisms. The dissolution rate of apatite by Scots pine plants that were or were not inoculated with the strain Burkholderia glathei PML1(12)Rp, and by inorganic (nitric) and organic (citric, oxalic and gluconic) acids at pH 5.5, 4.8, 3.8, 3.5, 3.0, and 2.0 was monitored in two controlled experiments: "plant-bacteria interaction" and "inorganic and organic acids". Analyses of the outlet solutions in the "plant-bacteria interaction" experiment showed that Scots pine roots and B. glathei PML1(12)Rp produced protons and organic acids such as gluconate, oxalate, acetate, and lactate. The weathering budget calculation revealed that Scots pines (with or without PML1(12)Rp) significantly increased (factor > 10) the release of Ca, P, As, Sr, Zn, U, Y, and rare earth elements such as Ce, La, Nd from apatite, compared to control abiotic treatment. Scanning electron microscopy observation confirmed traces of apatite dissolution in contact of roots. Most dissolved elements were taken up by Scots pine roots, i.e., approximately 50% of Ca, 70% of P, 30% of As, 70% of Sr, 90% of Zn, and 100% of U, Y, and rare earth elements. Interestingly, no significant additional effect due to the bacterial strain PML1(12)Rp on apatite dissolution and Scots pine nutrition and growth was observed. The "inorganic and organic acids" experiment demonstrated that the apatite dissolution efficacy of organic acids was higher than for the inorganic acid and varied in function of the acids: oxalic acid > citric acid > gluconic acid > nitric acid for pH ⩽3.5. In addition, apatite dissolution increased with increasing acidity for each acid. Only oxalic acid generated non-stoichiometric release of calcium and phosphorus from apatite in the solution at pH ⩽3.5, due to the precipitation of Ca-oxalate crystals at apatite surfaces. Comparison of the experiments revealed that the apatite dissolution rate by Scots pines supplied with nutritive solution at pH 5.5 reached 2.0 × 10-13 mol cm-2 s-1 and was equivalent to rates with nitric acid at pH 3.2, gluconic acid at pH 3.5, citric acid at pH 3.7, and oxalic acid at pH 3.8. Altogether our results highlight that, through the production of weathering agents, notably protons and organic acids, tree roots and root-associated microorganisms are able to significantly increase the release of macro- and micro-nutrients from apatite, thus maintaining high-nutrient conditions to support their growth.

Pure quasi-P wave equation and numerical solution in 3D TTI media

NASA Astrophysics Data System (ADS)

Zhang, Jian-Min; He, Bing-Shou; Tang, Huai-Gu

2017-03-01

Based on the pure quasi-P wave equation in transverse isotropic media with a vertical symmetry axis (VTI media), a quasi-P wave equation is obtained in transverse isotropic media with a tilted symmetry axis (TTI media). This is achieved using projection transformation, which rotates the direction vector in the coordinate system of observation toward the direction vector for the coordinate system in which the z-component is parallel to the symmetry axis of the TTI media. The equation has a simple form, is easily calculated, is not influenced by the pseudo-shear wave, and can be calculated reliably when δ is greater than ɛ. The finite difference method is used to solve the equation. In addition, a perfectly matched layer (PML) absorbing boundary condition is obtained for the equation. Theoretical analysis and numerical simulation results with forward modeling prove that the equation can accurately simulate a quasi-P wave in TTI medium.

Alphaherpesvirus Proteins Related to Herpes Simplex Virus Type 1 ICP0 Affect Cellular Structures and Proteins

PubMed Central

Parkinson, Jane; Everett, Roger D.

2000-01-01

The herpes simplex virus type 1 (HSV-1) immediate-early protein ICP0 interacts with several cellular proteins and induces the proteasome-dependent degradation of others during infection. In this study we show that ICP0 is required for the proteasome-dependent degradation of the ND10 protein Sp100 and, as with the other target proteins, the ICP0 RING finger domain is essential. Further, comparison of the kinetics and ICP0 domain requirements for the degradation of PMI and Sp100 suggests that a common mechanism is involved. Homologues of ICP0 are encoded by other members of the alphaherpesvirus family. These proteins show strong sequence homology to ICP0 within the RING finger domain but limited similarity elsewhere. Using transfection assays, we have shown that all the ICP0 homologues that we tested have significant effects on the immunofluorescence staining character of at least one of the proteins destabilized by ICP0, and by using a recombinant virus, we found that the equine herpesvirus ICP0 homologue induced the proteasome-dependent degradation of endogenous CENP-C and modified forms of PML and Sp100. However, in contrast to ICP0, the homologue proteins had no effect on the distribution of the ubiquitin-specific protease USP7 within the cell, consistent with their lack of a USP7 binding domain. We also found that ICP0 by itself could induce the abrogation of SUMO-1 conjugation and then the proteasome-dependent degradation of unmodified exogenous PML in transfected cells, thus demonstrating that other HSV-1 proteins are not required. Surprisingly, the ICP0 homologues were unable to cause these effects. Overall, these data suggest that the members of the ICP0 family of proteins may act via a similar mechanism or pathway involving their RING finger domain but that their intrinsic activities and effects on endogenous and exogenous proteins differ in detail. PMID:11024129

The replication defect of ICP0-null mutant herpes simplex virus 1 can be largely complemented by the combined activities of human cytomegalovirus proteins IE1 and pp71.

PubMed

Everett, Roger D; Bell, Adam J; Lu, Yongxu; Orr, Anne

2013-01-01

Herpes simplex virus 1 (HSV-1) immediate-early protein ICP0 is required for efficient lytic infection and productive reactivation from latency and induces derepression of quiescent viral genomes. Despite being unrelated at the sequence level, ICP0 and human cytomegalovirus proteins IE1 and pp71 share some functional similarities in their abilities to counteract antiviral restriction mediated by components of cellular nuclear structures known as ND10. To investigate the extent to which IE1 and pp71 might substitute for ICP0, cell lines were developed that express either IE1 or pp71, or both together, in an inducible manner. We found that pp71 dissociated the hDaxx-ATRX complex and inhibited accumulation of these proteins at sites juxtaposed to HSV-1 genomes but had no effect on the promyelocytic leukemia protein (PML) or Sp100. IE1 caused loss of the small ubiquitin-like modifier (SUMO)-conjugated forms of PML and Sp100 and inhibited the recruitment of these proteins to HSV-1 genome foci but had little effect on hDaxx or ATRX in these assays. Both IE1 and pp71 stimulated ICP0-null mutant plaque formation, but neither to the extent achieved by ICP0. The combination of IE1 and pp71, however, inhibited recruitment of all ND10 proteins to viral genome foci, stimulated ICP0-null mutant HSV-1 plaque formation to near wild-type levels, and efficiently induced derepression of quiescent HSV-1 genomes. These results suggest that ND10-related intrinsic resistance results from the additive effects of several ND10 components and that the effects of IE1 and pp71 on subsets of these components combine to mirror the overall activities of ICP0.

The Replication Defect of ICP0-Null Mutant Herpes Simplex Virus 1 Can Be Largely Complemented by the Combined Activities of Human Cytomegalovirus Proteins IE1 and pp71

PubMed Central

Bell, Adam J.; Lu, Yongxu; Orr, Anne

2013-01-01

Herpes simplex virus 1 (HSV-1) immediate-early protein ICP0 is required for efficient lytic infection and productive reactivation from latency and induces derepression of quiescent viral genomes. Despite being unrelated at the sequence level, ICP0 and human cytomegalovirus proteins IE1 and pp71 share some functional similarities in their abilities to counteract antiviral restriction mediated by components of cellular nuclear structures known as ND10. To investigate the extent to which IE1 and pp71 might substitute for ICP0, cell lines were developed that express either IE1 or pp71, or both together, in an inducible manner. We found that pp71 dissociated the hDaxx-ATRX complex and inhibited accumulation of these proteins at sites juxtaposed to HSV-1 genomes but had no effect on the promyelocytic leukemia protein (PML) or Sp100. IE1 caused loss of the small ubiquitin-like modifier (SUMO)-conjugated forms of PML and Sp100 and inhibited the recruitment of these proteins to HSV-1 genome foci but had little effect on hDaxx or ATRX in these assays. Both IE1 and pp71 stimulated ICP0-null mutant plaque formation, but neither to the extent achieved by ICP0. The combination of IE1 and pp71, however, inhibited recruitment of all ND10 proteins to viral genome foci, stimulated ICP0-null mutant HSV-1 plaque formation to near wild-type levels, and efficiently induced derepression of quiescent HSV-1 genomes. These results suggest that ND10-related intrinsic resistance results from the additive effects of several ND10 components and that the effects of IE1 and pp71 on subsets of these components combine to mirror the overall activities of ICP0. PMID:23135716

Methods for Characterizing the Distribution of Exhaust Emissions from Light-Duty, Gasoline-Powered Motor Vehicles in the U.S. Fleet

EPA Science Inventory

Mobile sources significantly contribute to ambient concentrations of airborne particulate matter. Source apportionment studies for PMlO and PM2.5 indicate that mobile sources can be responsible for over half of the ambient PM measured in an urban area. Recent source apportionment...

NPM and BRG1 Mediate Transcriptional Resistance to Retinoic Acid in Acute Promyelocytic Leukemia.

PubMed

Nichol, Jessica N; Galbraith, Matthew D; Kleinman, Claudia L; Espinosa, Joaquín M; Miller, Wilson H

2016-03-29

Perturbation in the transcriptional control of genes driving differentiation is an established paradigm whereby oncogenic fusion proteins promote leukemia. From a retinoic acid (RA)-sensitive acute promyelocytic leukemia (APL) cell line, we derived an RA-resistant clone characterized by a block in transcription initiation, despite maintaining wild-type PML/RARA expression. We uncovered an aberrant interaction among PML/RARA, nucleophosmin (NPM), and topoisomerase II beta (TOP2B). Surprisingly, RA stimulation in these cells results in enhanced chromatin association of the nucleosome remodeler BRG1. Inhibition of NPM or TOP2B abrogated BRG1 recruitment. Furthermore, NPM inhibition and targeting BRG1 restored differentiation when combined with RA. Here, we demonstrate a role for NPM and BRG1 in obstructing RA differentiation and implicate chromatin remodeling in mediating therapeutic resistance in malignancies. NPM mutations are the most common genetic change in patients with acute leukemia (AML); therefore, our model may be applicable to other more common leukemias driven by NPM. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

SeaShark and Starfish opertional data processing schemes for AVHRR and SeaWiFs

NASA Astrophysics Data System (ADS)

Flowerdew, R. J.; Corlyon, Anaa M.; Greer, W. A. D.; Newby, Steve J.; Winder, C. P.

1997-02-01

SeaShark is an operational software package for processing, archiving and cataloguing AVHRR and SeaWiFS data using an operator friendly GUI. Upon receipt of a customer order, it produces standard AVHRR data products, including Sea Surface Temperature (SST) and it has recently been modified to include SeaWiFS level 2 data processing. This uses an atmospheric correction scheme developed by the Plymouth Marine Laboratory, UK (PML) that builds upon the standard Gordon and Wang approach to be applicable over both case 1 and case 2 waters. Higher level products are then generated using PML algorithms, including chlorophyll a, a CZCS-type pigment, Kd, and suspended particulate matter. Outputs are in CEOS-compatible format. The software also produces fast delivery products (FDPs) of chlorophyll a and SST. These FDPs are combined in the StarFish software package to provide maps indicating potential location of phytoplankton and the preferred thermal environment of certain pelagic fish species. Fishing vessels may obtain these maps over Inmarsat, allowing them to achieve a greater efficiency hence lower cost.

Immunohistochemical detection of Ym1/Ym2 chitinase-like lectins associated with hyalinosis and polypoid adenomas of the transitional epithelium in a mouse with acute myeloid leukemia.

PubMed

Marchesi, F; Minucci, S; Pelicci, P G; Gobbi, A; Scanziani, E

2006-09-01

An 8-month-old PML/RARalpha knock-in female mouse developed a promyelocytic-like myeloid leukemia with an expected latency. At necropsy, besides the typical findings associated with myeloid leukemia, a severe unilateral hydronephrosis was observed. By histopathologic examination, 2 polypoid adenomas arising from the transitional epithelium of the renal pelvis and ureter were detected. The epithelial cells of the polypoid adenomas showed accumulation of hyaline eosinophilic material within the cytoplasm. Large amounts of extracellular eosinophilic crystals were also associated with the transitional cell adenomas. Immunohistochemical analysis revealed that the eosinophilic intracytoplasmic material and the extracellular eosinophilic crystals were composed of Ym proteins. A unilateral hyaline droplet tubular nephropathy was associated with the myeloid leukemia. Expression of Ym proteins characterized both the neoplastic myeloid infiltrates and the tubular hyaline droplets. In the present PML/RARalpha knock-in female mouse, the accumulation of Ym proteins associated with the myeloid leukemia and with the polypoid adenomas of the transitional epithelium underlies 2 distinct pathogenetic mechanisms.

Partial Least Squares Based Gene Expression Analysis in EBV- Positive and EBV-Negative Posttransplant Lymphoproliferative Disorders.

PubMed

Wu, Sa; Zhang, Xin; Li, Zhi-Ming; Shi, Yan-Xia; Huang, Jia-Jia; Xia, Yi; Yang, Hang; Jiang, Wen-Qi

2013-01-01

Post-transplant lymphoproliferative disorder (PTLD) is a common complication of therapeutic immunosuppression after organ transplantation. Gene expression profile facilitates the identification of biological difference between Epstein-Barr virus (EBV) positive and negative PTLDs. Previous studies mainly implemented variance/regression analysis without considering unaccounted array specific factors. The aim of this study is to investigate the gene expression difference between EBV positive and negative PTLDs through partial least squares (PLS) based analysis. With a microarray data set from the Gene Expression Omnibus database, we performed PLS based analysis. We acquired 1188 differentially expressed genes. Pathway and Gene Ontology enrichment analysis identified significantly over-representation of dysregulated genes in immune response and cancer related biological processes. Network analysis identified three hub genes with degrees higher than 15, including CREBBP, ATXN1, and PML. Proteins encoded by CREBBP and PML have been reported to be interact with EBV before. Our findings shed light on expression distinction of EBV positive and negative PTLDs with the hope to offer theoretical support for future therapeutic study.

Redistribution of cell cycle by arsenic trioxide is associated with demethylation and expression changes of cell cycle related genes in acute promyelocytic leukemia cell line (NB4).

PubMed

Hassani, Saeed; Khaleghian, Ali; Ahmadian, Shahin; Alizadeh, Shaban; Alimoghaddam, Kamran; Ghavamzadeh, Ardeshir; Ghaffari, Seyed H

2018-01-01

PML-RARα perturbs the normal epigenetic setting, which is essential to oncogenic transformation in acute promyelocytic leukemia (APL). Transcription induction and recruitment of DNA methyltransferases (DNMTs) by PML-RARα and subsequent hypermethylation are components of this perturbation. Arsenic trioxide (ATO), an important drug in APL therapy, concurrent with degradation of PML-RARα induces cell cycle change and apoptosis. How ATO causes cell cycle alteration has remained largely unexplained. Here, we investigated DNA methylation patterns of cell cycle regulatory genes promoters, the effects of ATO on the methylated genes and cell cycle distribution in an APL cell line, NB4. Analysis of promoter methylation status of 22 cell cycle related genes in NB4 revealed that CCND1, CCNE1, CCNF, CDKN1A, GADD45α, and RBL1 genes were methylated 60.7, 84.6, 58.6, 8.7, 33.4, and 73.7%, respectively, that after treatment with 2 μM ATO for 48 h, turn into 0.6, 13.8, 0.1, 6.6, 10.7, and 54.5% methylated. ATO significantly reduced the expression of DNMT1, 3A, and 3B. ATO induced the expression of CCND1, CCNE1, and GADD45α genes, suppressed the expression of CCNF and CDKN1A genes, which were consistent with decreased number of cells in G1 and S phases and increased number of cells in G2/M phase. In conclusion, demethylation and alteration in the expression level of the cell cycle related genes may be possible mechanisms in ATO-induced cell cycle arrest in APL cells. It may suggest that ATO by demethylation of CCND1 and CCNE1 and their transcriptional activation accelerates G1 and S transition into the G2/M cell cycle arrest.

High WT1 expression is an early predictor for relapse in patients with acute promyelocytic leukemia in first remission with negative PML-RARa after anthracycline-based chemotherapy: a single-center cohort study.

PubMed

Yoon, Jae-Ho; Kim, Hee-Je; Kwak, Dae-Hun; Park, Sung-Soo; Jeon, Young-Woo; Lee, Sung-Eun; Cho, Byung-Sik; Eom, Ki-Seong; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Cho, Seok-Goo; Kim, Dong-Wook; Lee, Jong Wook; Min, Woo-Sung

2017-01-23

Wilms' tumor gene 1 (WT1) expression is a well-known predictor for relapse in acute myeloid leukemia. We monitored WT1 decrement along the treatment course to identify its significant role as a marker for residual disease in acute promyelocytic leukemia (APL) and tried to suggest its significance for relapse prediction. In this single center retrospective study, we serially measured PML-RARa and WT1 expression from 117 APL patients at diagnosis, at post-induction and post-consolidation chemotherapies, and at every 3 months after starting maintenance therapy. All 117 patients were in molecular remission after treatment of at least 2 consolidation chemotherapies. We used WT1 ProfileQuant™ kit (Ipsogen) for WT1 monitoring. High WT1 expression (>120 copies/10 4 ABL1) after consolidation and at early period (3 months) after maintenance therapy significantly predicted subsequent relapse. All paired PML-RARa RQ-PCR were not detected except for one sample with early relapse. Patients with high WT1 expression at 3 months after maintenance therapy (n = 40) showed a significantly higher relapse rate (30.5 vs. 6.9%, P < 0.001) and inferior disease free survival (62.8 vs. 91.4%, P < 0.001). Multivariate analysis revealed that high peak leukocyte counts at diagnosis (HR = 6.4, P < 0.001) and high WT1 expression at 3 months after maintenance therapy (HR = 7.1, P < 0.001) were significant factors for prediction of relapse. Our data showed high post-remission WT1 expression was a reliable marker for prediction of subsequent molecular relapse in APL. In this high-risk group, early intervention with ATRA ± ATO, anti-CD33 antibody therapy, and WT1-specific therapy may be used for relapse prevention. Clinical Research Information Service (CRIS), KCT0002079.

A one dimensional numerical approach for computing the eigenmodes of elastic waves in buried pipelines

NASA Astrophysics Data System (ADS)

Duan, Wenbo; Kirby, Ray; Mudge, Peter; Gan, Tat-Hean

2016-12-01

Ultrasonic guided waves are often used in the detection of defects in oil and gas pipelines. It is common for these pipelines to be buried underground and this may restrict the length of the pipe that can be successfully tested. This is because acoustic energy travelling along the pipe walls may radiate out into the surrounding medium. Accordingly, it is important to develop a better understanding of the way in which elastic waves propagate along the walls of buried pipes, and so in this article a numerical model is developed that is suitable for computing the eigenmodes for uncoated and coated buried pipes. This is achieved by combining a one dimensional eigensolution based on the semi-analytic finite element (SAFE) method, with a perfectly matched layer (PML) for the infinite medium surrounding the pipe. This article also explores an alternative exponential complex coordinate stretching function for the PML in order to improve solution convergence. It is shown for buried pipelines that accurate solutions may be obtained over the entire frequency range typically used in long range ultrasonic testing (LRUT) using a PML layer with a thickness equal to the pipe wall thickness. This delivers a fast and computationally efficient method and it is shown for pipes buried in sand or soil that relevant eigenmodes can be computed and sorted in less than one second using relatively modest computer hardware. The method is also used to find eigenmodes for a buried pipe coated with the viscoelastic material bitumen. It was recently observed in the literature that a viscoelastic coating may effectively isolate particular eigenmodes so that energy does not radiate from these modes into the surrounding [elastic] medium. A similar effect is also observed in this article and it is shown that this occurs even for a relatively thin layer of bitumen, and when the shear impedance of the coating material is larger than that of the surrounding medium.

Augmented telomerase activity, reduced telomere length and the presence of alternative lengthening of telomere in renal cell carcinoma: plausible predictive and diagnostic markers.

PubMed

Pal, Deeksha; Sharma, Ujjawal; Khajuria, Ragini; Singh, Shrawan Kumar; Kakkar, Nandita; Prasad, Rajendra

2015-05-15

In this study, we analyzed 100 cases of renal cell carcinoma (RCC) for telomerase activity, telomere length and alternative lengthening of telomeres (ALT) using the TRAP assay, TeloTTAGGG assay kit and immunohistochemical analysis of ALT associated promyelocytic leukemia (PML) bodies respectively. A significantly higher (P=0.000) telomerase activity was observed in 81 cases of RCC which was correlated with clinicopathological features of tumor for instance, stage (P=0.008) and grades (P=0.000) but not with the subtypes of RCC (P = 0.355). Notwithstanding, no correlation was found between telomerase activity and subtypes of RCC. Strikingly, the telomere length was found to be significantly shorter in RCC (P=0.000) to that of corresponding normal renal tissues and it is well correlated with grades (P=0.016) but not with stages (P=0.202) and subtypes (P=0.669) of RCC. In this study, telomere length was also negatively correlated with the age of patients (r(2)=0.528; P=0.000) which supports the notion that it could be used as a marker for biological aging. ALT associated PML bodies containing PML protein was found in telomerase negative cases of RCC. It suggests the presence of an ALT pathway mechanism to maintain the telomere length in telomerase negative RCC tissues which was associated with high stages of RCC, suggesting a prevalent mechanism for telomere maintenance in high stages. In conclusion, the telomerase activity and telomere length can be used as a diagnostic as well as a predictive marker in RCC. The prevalence of ALT mechanism in high stages of RCC is warranted for the development of anti-ALT inhibitors along with telomerase inhibitor against RCC as a therapeutic approach. Copyright © 2015 Elsevier B.V. All rights reserved.

Oil and fatty acids in eggplant (Solanum melongena L.) and some related and unrelated Solanum Spp.

USDA-ARS?s Scientific Manuscript database

The seed oil content of 305 genebank accessions of eggplant (Solanum melongena L. ), six related specied (S. aethiopicum L., S. incanum L., S. anaguivi Lam., S linnaeanum Hepper & P.M.L. Jaeger, S. litchensteinii L., and S. macrocarpon L.) and 25 additional Solanum species, was determined by NMR. Eg...

Hematopoietic stem cells burn fat to prevent exhaustion.

PubMed

Lallemand-Breitenbach, Valerie; de Thé, Hugues

2012-10-05

Ito et al. (2012) recently report in Nature Medicine that fatty acid oxidation (FAO) regulated by PPARδ controls asymmetric division in hematopoietic stem cells (HSCs). This metabolic mechanism prevents HSC exhaustion and is downstream of the promyelocytic leukemia protein PML, suggesting therapeutic implications for HSC function and disease. Copyright © 2012 Elsevier Inc. All rights reserved.

The Human Cytomegalovirus IE2 and UL112-113 Proteins Accumulate in Viral DNA Replication Compartments That Initiate from the Periphery of Promyelocytic Leukemia Protein-Associated Nuclear Bodies (PODs or ND10)

PubMed Central

Ahn, Jin-Hyun; Jang, Won-Jong; Hayward, Gary S.

1999-01-01

During human cytomegalovirus (HCMV) infection, the periphery of promyelocytic leukemia protein (PML)-associated nuclear bodies (also known as PML oncogenic domains [PODs] or ND10) are sites for both input viral genome deposition and immediate-early (IE) gene transcription. At very early times after infection, the IE1 protein localizes to and subsequently disrupts PODs, whereas the IE2 protein localizes within or adjacent to PODs. This process appears to be required for efficient viral gene expression and DNA replication. We have investigated the initiation of viral DNA replication compartment formation by studying the localization of viral IE proteins, DNA replication proteins, and the PML protein during productive infection. Localization of IE2 adjacent to PODs between 2 and 6 h after infection was confirmed by confocal microscopy of human fibroblasts (HF cells) infected with both wild-type HCMV(Towne) and with an IE1-deletion mutant HCMV(CR208) that fails to disrupt PODs. In HCMV(Towne)-infected HF cells at 24 to 48 h, IE2 also accumulated in newly formed viral DNA replication compartments containing the polymerase processivity factor (UL44), the single-stranded DNA binding protein (SSB; UL57), the UL112-113 accessory protein, and newly incorporated bromodeoxyuridine (BrdU). Double labeling of the HCMV(CR208)-infected HF cells demonstrated that formation of viral DNA replication compartments initiates within granular structures that bud from the periphery of some of the PODs and subsequently coalesce into larger structures that are flanked by PODs. In transient DNA transfection assays, both the N terminus (codons 136 to 290) and the C terminus (codons 379 to 579) of IE2 exon 5, but not the central region between them, were found to be necessary for both the punctate distribution of IE2 and its association with PODs. Like IE2, the UL112-113 accessory replication protein was also distributed in a POD-associated pattern in both DNA-transfected and virus-infected cells beginning at 6 h. Furthermore, when all six replication core machinery proteins (polymerase complex, SSB, and helicase-primase complex) were expressed together in the presence of UL112-113, they also accumulated at POD-associated sites, suggesting that the UL112-113 protein (but not IE2) may play a role in recruitment of viral replication fork proteins into the periphery of PODs. These results show that (i) subsequent to accumulating at the periphery of PODs, IE2 is incorporated together with the core proteins into viral DNA replication compartments that initiate from the periphery of PODs and then grow to fill the space between groups of PODs, and (ii) the UL112-113 protein appears to have a key role in assembling and recruiting the core replication machinery proteins in the initial stages of viral replication compartment formation. PMID:10559364

The Explosion of the Display Fireworks Assembly Plant MS Vuurwerk on February 14, Culemborg, The Netherlands

DTIC Science & Technology

1992-08-01

explosion. This was demonstrated during trials performed Xn 1989 by TNO-PML as a mass explosion occurred during a bonfire test [5J. - Knfitter vulcano ...They had a height of about 25 cm and a ground diameter of 8 cm. They have all functioned properly. No- vulcano was found in its original state

Mutations Allow JC Polyomaviruses to Elude Antibody Recognition | Center for Cancer Research

Cancer.gov

JC polyomavirus (JCV) infects the urinary tract of most adults. In healthy individuals, JCV infection does not cause noticeable symptoms. However, in those with compromised immune systems, JCV can cause a lethal brain disease called progressive multifocal leukoencephalopathy (PML). Data from a recently approved assay to detect serum antibodies specific for the JCV protein VP1

Microgranular variant of acute promyelocytic leukemia with der(17) ins(17;15): A case report and review of the literature

PubMed Central

GUAN, HONGZAI; LIU, JING; GUO, XIAOFANG; WU, CHUNMEI; YU, HUAWEI

2015-01-01

Acute promyelocytic leukemia (APL) with variant translocations is rare. The patient of the present case report, a 2-year-old male with a microgranular variant of APL carrying der(17) ins(17;15) translocation, exhibited fever and epistaxis. The complete blood count showed marked leukocytosis with 72% atypical promyelocytes, anemia and thrombocytopenia. Conventional cytogenetic analysis of the bone marrow cells revealed a karyotype of 47, XY, add(3)(q29), −7, ins(17;15)(q12;q14q22),+21,+mar. The promyelocytic leukemia/retinoic acid receptor α (PML/RARα) rearrangement and insertion were confirmed by fluorescence in situ hybridization. The PML/RARα transcripts were not detected by the reverse transcription polymerase chain reaction, and the patient was diagnosed with microgranular variant M3 APL. The patient achieved remission after a 30-day treatment and was still in remission during a recent follow-up. The present findings suggest that the ins(17;15) variant in APL may not be associated with an unfavorable prognosis. In summary, we reported an extremely rare case of APL with der(17) ins(17;15) abnormality in a pediatric patient and reviewed the literature. PMID:26622430

ATRX induction by mutant huntingtin via Cdx2 modulates heterochromatin condensation and pathology in Huntington's disease

PubMed Central

Lee, J; Hong, Y K; Jeon, G S; Hwang, Y J; Kim, K Y; Seong, K H; Jung, M-K; Picketts, D J; Kowall, N W; Cho, K S; Ryu, H

2012-01-01

Aberrant chromatin remodeling is involved in the pathogenesis of Huntington's disease (HD) but the mechanism is not known. Herein, we report that mutant huntingtin (mtHtt) induces the transcription of alpha thalassemia/mental retardation X linked (ATRX), an ATPase/helicase and SWI/SNF-like chromatin remodeling protein via Cdx-2 activation. ATRX expression was elevated in both a cell line model and transgenic model of HD, and Cdx-2 occupancy of the ATRX promoter was increased in HD. Induction of ATRX expanded the size of promyelocytic leukemia nuclear body (PML-NB) and increased trimethylation of H3K9 (H3K9me3) and condensation of pericentromeric heterochromatin, while knockdown of ATRX decreased PML-NB and H3K9me3 levels. Knockdown of ATRX/dXNP improved the hatch rate of fly embryos expressing mtHtt (Q127). ATRX/dXNP overexpression exacerbated eye degeneration of eye-specific mtHtt (Q127) expressing flies. Our findings suggest that transcriptional alteration of ATRX by mtHtt is involved in pericentromeric heterochromatin condensation and contributes to the pathogenesis of HD. PMID:22240898

Vedolizumab: A New Opponent in the Battle Against Crohn's Disease and Ulcerative Colitis.

PubMed

Poulakos, Mara; Machin, Jade D; Pauly, Julienne; Grace, Yasmin

2016-10-01

Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders affecting the gastrointestinal (GI) tract that encompass Crohn's disease (CD) and ulcerative colitis (UC). In these disease states, epithelial damage of the intestinal mucosa is evident due to increased lymphocyte trafficking to the area, which affects the normal intestinal barrier function. Currently available pharmacotherapy can be limited in terms of efficacy and associated toxicities. Newer agents have emerged, including the monoclonal antibody natalizumab, which antagonizes integrin, an important component within the inflammation cascade. Natalizumab works by modulating both the GI and brain biologic responses and as a result there is risk of the opportunistic infection known as progressive multifocal leukoencephalopathy (PML), putting patients at risk for severe disability and death. Vedolizumab, another integrin inhibitor, is selective for modulating the gut biologic response but not the brain, consequently decreasing the risk for PML. To generate information regarding the role of vedolizumab in the treatment of IBD, a literature search was conducted, yielding 7 phase I to III clinical trials. This article serves as a summary of efficacy, safety, and other relevant information from clinical studies to explore the role of vedolizumab in the treatment of CD and UC. © The Author(s) 2015.

Inhibition of HSV-1 Replication by Gene Editing Strategy

PubMed Central

Roehm, Pamela C.; Shekarabi, Masoud; Wollebo, Hassen S.; Bellizzi, Anna; He, Lifan; Salkind, Julian; Khalili, Kamel

2016-01-01

HSV-1 induced illness affects greater than 85% of adults worldwide with no permanent curative therapy. We used RNA-guided CRISPR/Cas9 gene editing to specifically target for deletion of DNA sequences of the HSV-1 genome that span the region directing expression of ICP0, a key viral protein that stimulates HSV-1 gene expression and replication. We found that CRISPR/Cas9 introduced InDel mutations into exon 2 of the ICP0 gene profoundly reduced HSV-1 infectivity in permissive human cell culture models and protected permissive cells against HSV-1 infection. CRISPR/Cas9 mediated targeting ICP0 prevented HSV-1-induced disintegration of promonocytic leukemia (PML) nuclear bodies, an intracellular event critical to productive HSV-1 infection that is initiated by interaction of the ICP0 N-terminus with PML. Combined treatment of cells with CRISPR targeting ICP0 plus the immediate early viral proteins, ICP4 or ICP27, completely abrogated HSV-1 infection. We conclude that RNA-guided CRISPR/Cas9 can be used to develop a novel, specific and efficacious therapeutic and prophylactic platform for targeted viral genomic ablation to treat HSV-1 diseases. PMID:27064617

Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia

PubMed Central

Lallemand-Breitenbach, Valérie; Guillemin, Marie-Claude; Janin, Anne; Daniel, Marie-Thérèse; Degos, Laurent; Kogan, Scott C.; Michael Bishop, J.; de Thé, Hugues

1999-01-01

In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARα fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARα transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies. PMID:10190895

The essential role of guinea pig cytomegalovirus (GPCMV) IE1 and IE2 homologs in viral replication and IE1-mediated ND10 targeting

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

Hornig, Julia; Choi, K. Yeon; McGregor, Alistair,

Guinea pig cytomegalovirus (GPCMV) immediate early proteins, IE1 and IE2, demonstrated structural and functional homologies with human cytomegalovirus (HCMV). GPCMV IE1 and IE2 co-localized in the nucleus with each other, the viral polymerase and guinea pig ND10 components (gpPML, gpDaxx, gpSp100, gpATRX). IE1 showed direct interaction with ND10 components by immunoprecipitation unlike IE2. Additionally, IE1 protein disrupted ND10 bodies. IE1 mutagenesis mapped the nuclear localization signal to the C-terminus and identified the core domain for gpPML interaction. Individual knockout of GPCMV GP122 or GP123 (IE2 and IE1 unique exons respectively) was lethal to the virus. However, an IE1 mutant (codonsmore » 234–474 deleted), was viable with attenuated viral growth kinetics and increased susceptibility to type I interferon (IFN-I). In HCMV, the IE proteins are important T cell target antigens. Consequently, characterization of the homologs in GPCMV provides a basis for their evaluation in candidate vaccines against congenital infection.« less

Simulations of acoustic waves in channels and phonation in glottal ducts

NASA Astrophysics Data System (ADS)

Yang, Jubiao; Krane, Michael; Zhang, Lucy

2014-11-01

Numerical simulations of acoustic wave propagation were performed by solving compressible Navier-Stokes equations using finite element method. To avoid numerical contamination of acoustic field induced by non-physical reflections at computational boundaries, a Perfectly Matched Layer (PML) scheme was implemented to attenuate the acoustic waves and their reflections near these boundaries. The acoustic simulation was further combined with the simulation of interaction of vocal fold vibration and glottal flow, using our fully-coupled Immersed Finite Element Method (IFEM) approach, to study phonation in the glottal channel. In order to decouple the aeroelastic and aeroacoustic aspects of phonation, the airway duct used has a uniform cross section with PML properly applied. The dynamics of phonation were then studied by computing the terms of the equations of motion for a control volume comprised of the fluid in the vicinity of the vocal folds. It is shown that the principal dynamics is comprised of the near cancellation of the pressure force driving the flow through the glottis, and the aerodynamic drag on the vocal folds. Aeroacoustic source strengths are also presented, estimated from integral quantities computed in the source region, as well as from the radiated acoustic field.

The essential role of guinea pig cytomegalovirus (GPCMV) IE1 and IE2 homologs in viral replication and IE1-mediated ND10 targeting

PubMed Central

Hornig, Julia; Choi, K. Yeon; McGregor, Alistair

2017-01-01

Guinea pig cytomegalovirus (GPCMV) immediate early proteins, IE1 and IE2, demonstrated structural and functional homologies with human cytomegalovirus (HCMV). GPCMV IE1 and IE2 co-localized in the nucleus with each other, the viral polymerase and guinea pig ND10 components (gpPML, gpDaxx, gpSp100, gpATRX). IE1 showed direct interaction with ND10 components by immunoprecipitation unlike IE2. Additionally, IE1 protein disrupted ND10 bodies. IE1 mutagenesis mapped the nuclear localization signal to the C-terminus and identified the core domain for gpPML interaction. Individual knockout of GPCMV GP122 or GP123 (IE2 and IE1 unique exons respectively) was lethal to the virus. However, an IE1 mutant (codons 234–474 deleted), was viable with attenuated viral growth kinetics and increased susceptibility to type I interferon (IFN-I). In HCMV, the IE proteins are important T cell target antigens. Consequently, characterization of the homologs in GPCMV provides a basis for their evaluation in candidate vaccines against congenital infection. PMID:28189970

Finite-element analysis of scattering parameters of surface acoustic wave bandpass filter formed on barium titanate thin film

NASA Astrophysics Data System (ADS)

Timoshenko; Kalinchuk; Shirokov

2018-04-01

The frequency dependence of scattering parameters of interdigital surface acoustic wave transducers placed on ferroelectric barium titanate (BaTiO3) epitaxial film in c-phase coated over magnesium oxide has been studied using the finite-element method (FEM) approach along with the perfectly matched layer (PML) technique. The interdigital transducer which has a comb-like structure with aluminum electrodes excites the mechanical wave. The distance between the fingers allows tuning the frequency properties of the wave propagation. The magnesium oxide is taken as the substrate. The two-dimensional model of two-port surface acoustic wave filter is created to calculate scattering parameters and to show how to design the fixture in COMSOLTM. Some practical computational challenges of finite element modeling of SAW devices in COMSOLTM are shown. The effect of lattice misfit strain on acoustic properties of heterostructures of BaTiO3 epitaxial film in c-phase at room temperature is discussed in present article for two low-frequency surface acoustic resonances.

[Compartmentalization of the cell nucleus and spatial organization of the genome].

PubMed

Gavrilov, A A; Razin, S V

2015-01-01

The eukaryotic cell nucleus is one of the most complex cell organelles. Despite the absence of membranes, the nuclear space is divided into numerous compartments where different processes in- volved in the genome activity take place. The most important nuclear compartments include nucleoli, nuclear speckles, PML bodies, Cajal bodies, histone locus bodies, Polycomb bodies, insulator bodies, transcription and replication factories. The structural basis for the nuclear compartmentalization is provided by genomic DNA that occupies most of the nuclear volume. Nuclear compartments, in turn, guide the chromosome folding by providing a platform for the spatial interaction of individual genomic loci. In this review, we discuss fundamental principles of higher order genome organization with a focus on chromosome territories and chromosome domains, as well as consider the structure and function of the key nuclear compartments. We show that the func- tional compartmentalization of the cell nucleus and genome spatial organization are tightly interconnected, and that this form of organization is highly dynamic and is based on stochastic processes.

Microbial Degradation of RDX and HMX

DTIC Science & Technology

2004-02-01

can be performed on aqueous solutions and soil leachates . In this 0 100 200 300 400 500 0 1 2 3 4 5 6 4- N D A B (µ m ol .k g- 1 ) Days 4- N D A B (µ... Phytoremediation and Natural Attenuation, Ed A. Singh and O. Ward. Vol. 1, Springer-Verlag (Book chapter) 2. Bonin, P.M.L., D. Bejan, L. Schutt, J. Hawari

All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia

PubMed Central

Shen, Zhi-Xiang; Shi, Zhan-Zhong; Fang, Jing; Gu, Bai-Wei; Li, Jun-Min; Zhu, Yong-Mei; Shi, Jing-Yi; Zheng, Pei-Zheng; Yan, Hua; Liu, Yuan-Fang; Chen, Yu; Shen, Yang; Wu, Wen; Tang, Wei; Waxman, Samuel; de Thé, Hugues; Wang, Zhen-Yi; Chen, Sai-Juan; Chen, Zhu

2004-01-01

Both all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but they had not been used jointly in an integrated treatment protocol for remission induction or maintenance among newly diagnosed APL patients. In this study, 61 newly diagnosed APL subjects were randomized into three treatment groups, namely by ATRA, As2O3, and the combination of the two drugs. CR was determined by hematological analysis, tumor burden was examined with real-time quantitative RT-PCR of the PML-RARα (promyelocytic leukemia-retinoic acid receptor α) fusion transcripts, and side effects were evaluated by means of clinical examinations. Mechanisms possibly involved were also investigated with cellular and molecular biology methods. Although CR rates in three groups were all high (≥90%), the time to achieve CR differed significantly, with that of the combination group being the shortest one. Earlier recovery of platelet count was also found in this group. The disease burden as reflected by fold change of PML-RARα transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As2O3 mono-therapy (P < 0.01). This difference persisted after consolidation (P < 0.05). Importantly, all 20 cases in the combination group remained in CR whereas 7 of 37 cases treated with mono-therapy relapsed (P < 0.05) after a follow-up of 8–30 months (median: 18 months). Synergism of ATRA and As2O3 on apoptosis and degradation of PML-RARα oncoprotein might provide a plausible explanation for superior efficacy of combinative therapy in clinic. In conclusion, the ATRA/As2O3 combination for remission/maintenance therapy of APL brings much better results than either of the two drugs used alone in terms of the quality of CR and the status of the disease-free survival. PMID:15044693

Learning to Live on a Mars Day: Fatigue Countermeasures during the Phoenix Mars Lander Mission

PubMed Central

Barger, Laura K.; Sullivan, Jason P.; Vincent, Andrea S.; Fiedler, Edna R.; McKenna, Laurence M.; Flynn-Evans, Erin E.; Gilliland, Kirby; Sipes, Walter E.; Smith, Peter H.; Brainard, George C.; Lockley, Steven W.

2012-01-01

Study Objectives: To interact with the robotic Phoenix Mars Lander (PML) spacecraft, mission personnel were required to work on a Mars day (24.65 h) for 78 days. This alien schedule presents a challenge to Earth-bound circadian physiology and a potential risk to workplace performance and safety. We evaluated the acceptability, feasibility, and effectiveness of a fatigue management program to facilitate synchronization with the Mars day and alleviate circadian misalignment, sleep loss, and fatigue. Design: Operational field study. Setting: PML Science Operations Center. Participants: Scientific and technical personnel supporting PML mission. Interventions: Sleep and fatigue education was offered to all support personnel. A subset (n = 19) were offered a short-wavelength (blue) light panel to aid alertness and mitigate/reduce circadian desynchrony. They were assessed using a daily sleep/work diary, continuous wrist actigraphy, and regular performance tests. Subjects also completed 48-h urine collections biweekly for assessment of the circadian 6-sulphatoxymelatonin rhythm. Measurements and Results: Most participants (87%) exhibited a circadian period consistent with adaptation to a Mars day. When synchronized, main sleep duration was 5.98 ± 0.94 h, but fell to 4.91 ± 1.22 h when misaligned (P < 0.001). Self-reported levels of fatigue and sleepiness also significantly increased when work was scheduled at an inappropriate circadian phase (P < 0.001). Prolonged wakefulness (≥ 21 h) was associated with a decline in performance and alertness (P < 0.03 and P < 0.0001, respectively). Conclusions: The ability of the participants to adapt successfully to the Mars day suggests that future missions should utilize a similar circadian rhythm and fatigue management program to reduce the risk of sleepiness-related errors that jeopardize personnel safety and health during critical missions. Citation: Barger LK; Sullivan JP; Vincent AS; Fiedler ER; McKenna LM; Flynn-Evans EE; Gilliland K; Sipes WE; Smith PH; Brainard GC; Lockley SW. Learning to live on a Mars day: fatigue countermeasures during the Phoenix Mars Lander mission. SLEEP 2012;35(10):1423-1435. PMID:23024441

A stochastic risk assessment for Eastern Europe and Central Asian countries for earthquakes

NASA Astrophysics Data System (ADS)

Daniell, James; Schaefer, Andreas; Toro, Joaquin; Murnane, Rick; Tijssen, Annegien; Simpson, Alanna; Saito, Keiko; Winsemius, Hessel; Ward, Philip

2015-04-01

This systematic assessment of earthquake risk for 33 countries in the ECA region was motivated by the interest of the World Bank and the Global Facility for Disaster Reduction and Recovery (GFDRR) in supporting Disaster Risk Management (DRM) efforts. They envisaged an exposure-based analysis that looked at the potential economic and/or social exposure of the populations of various countries to earthquake risk. Using a stochastic earthquake hazard model and historical catalogues, a unified earthquake catalogue was created for the 33 countries. A combined fault and background source model was created using data from many authors. The maximum magnitude and seismotectonic source zone discretization was undertaken using logic tree approaches. Site effects were taken into account on the basis of local topography and tectonic regime. Two approaches were used to calculate local ground motion - intensity prediction equations for MMI and a combination of GMPEs for stable and active settings. A 1km grid was used for analysis with aggregations of exposure quantified in terms of GDP and capital stock using disaggregated provincial analysis from CATDAT, as well as population data from Deltares. Vulnerability functions were calculated using socio-economic empirical functions derived by Daniell (2014) for the countries taking into account historical losses, seismic resistant code implementation and building typologies in each country. PML curves were created for each province in the 33 nations, through 3 methods; the 1st using direct historical values via the CATDAT Damaging Earthquakes Database; the 2nd using normalization procedures in order to provide a quick estimate of the historical record quantified in today's terms filling in gaps; and the 3rd being a traditional stochastic modelling approach over a period of 10,000 years taking all uncertainties into account. SSP projections of growth from the OECD were used to quantify the risk in 2010, 2030 and 2080 in order to examine future loss potential. Four loss metrics were quantified as PML curves - (1) Population affected in damaged areas (I>6), (2) GDP affected in damaged areas (I>6), (3) Deaths, (4) Economic Losses. The approach taken has large uncertainties, as with any stochastic earthquake risk analysis, and more detailed and refined analysis can be undertaken in any one of the countries, but the approach showed a ballpark figure for planning and development as well as a view as to expected losses where existing detailed models do not exist.

Computer-Based Methods for Thermodynamic Analysis of Materials Processing.

DTIC Science & Technology

1983-11-30

metallic alloys (12,13), silicides (14),and oxynitride * . systems (15). - . 2. Thermochemical System Employed to Characterize Binary Ill-V Phase Diagrams The...reference to Figure I shows that the stable form of RbF is the sodium chloride S form. Table I shows that OGH -oS -RFRFLS-RFRFLM-12866-.381T J/g.at. (5...KF, BF=(I/3)8aF LF-(I/4)LaF3V PF-(113)PbF 2 S- Sodium Chloride Structures Stable form of NF, KE, RE and (;F L-Liquid, M-Stable form of ZF, KeStable form

A Comparison of Pseudo-Maximum Likelihood and Asymptotically Distribution-Free Dynamic Factor Analysis Parameter Estimation in Fitting Covariance Structure Models to Block-Toeplitz Matrices Representing Single-Subject Multivariate Time-Series.

ERIC Educational Resources Information Center

Molenaar, Peter C. M.; Nesselroade, John R.

1998-01-01

Pseudo-Maximum Likelihood (p-ML) and Asymptotically Distribution Free (ADF) estimation methods for estimating dynamic factor model parameters within a covariance structure framework were compared through a Monte Carlo simulation. Both methods appear to give consistent model parameter estimates, but only ADF gives standard errors and chi-square…

Evaporation from Sand

DTIC Science & Technology

1992-04-01

Instituuts Advies R2ad PML Prof. dr. U.A.Th. Brinkanl~ 36. Direactur van het Medisch Biologisch Laboratorium TNO Prof.Dr. W.R.F. Notten 37. Directeur...Grootsdialige Rampenbestrijdcing Ministerie van Binnenlandsc Zaken Drs. H. Evers 9. Adviseur van het Prins Maurits Laboratorium TWO Prot. Dr. J.M. van...Rossum, 10. Adyisew, van het Prins Maurits Laboratorium TWO Chernisdie Research Prof.Dr. G. Dijkstra 11. H~ur. NBC DMKIJOMAT/KIO Ir. AAM. Slagveer 12

First NATO/SIBCA Exercise in Sampling of Chemical Warfare Agents (Eerste NATO/SIBCA-oefening in monstername van chemische strijdmiddelen).

DTIC Science & Technology

1998-01-01

TNO-rapport PML1997-A81 Eerste NATO/SIBCA-oefening in monster- name van chemische strijdmiddelen TNO Prins Maurits Laboratorium Lange Kleiweg...27 Aantal pagina’s : 53 (incl. bijlagen, excl. RDP & distributielijst) Aantal bijlagen : 4 TNO Prins Maurits Laboratorium is onderdeel...van de hoofdgroep TNO Defensieonderzoek waartoe verder behoren: TNO Fysisch en Elektronisch Laboratorium TNO Technische Menskunde Nederlandse

Simpson's paradox - aggregating and partitioning populations in health disparities of lung cancer patients.

PubMed

Fu, P; Panneerselvam, A; Clifford, B; Dowlati, A; Ma, P C; Zeng, G; Halmos, B; Leidner, R S

2015-12-01

It is well known that non-small cell lung cancer (NSCLC) is a heterogeneous group of diseases. Previous studies have demonstrated genetic variation among different ethnic groups in the epidermal growth factor receptor (EGFR) in NSCLC. Research by our group and others has recently shown a lower frequency of EGFR mutations in African Americans with NSCLC, as compared to their White counterparts. In this study, we use our original study data of EGFR pathway genetics in African American NSCLC as an example to illustrate that univariate analyses based on aggregation versus partition of data leads to contradictory results, in order to emphasize the importance of controlling statistical confounding. We further investigate analytic approaches in logistic regression for data with separation, as is the case in our example data set, and apply appropriate methods to identify predictors of EGFR mutation. Our simulation shows that with separated or nearly separated data, penalized maximum likelihood (PML) produces estimates with smallest bias and approximately maintains the nominal value with statistical power equal to or better than that from maximum likelihood and exact conditional likelihood methods. Application of the PML method in our example data set shows that race and EGFR-FISH are independently significant predictors of EGFR mutation. © The Author(s) 2011.

Translocation (10;17)(p15;q21) is a recurrent anomaly in acute myeloblastic leukemia.

PubMed

Tempescul, Adrian; Guillerm, Gaëlle; Douet-Guilbert, Nathalie; Morel, Frédéric; Le Bris, Marie-Josée; De Braekeleer, Marc

2007-01-01

We report here two cases of patients with acute myeloblastic leukemia, type M1 (FAB classification), associated with a t(10;17)(p15;q21). Fluorescence in situ hybridization with the LSI PML/RARA dual-color probe showed the breakpoint to be distal to the RARA locus. Four other patients with this translocation have been reported, three of them having acute undifferentiated or poorly differentiated leukemia.

Next-Generation Sequencing in Neuropathologic Diagnosis of Infections of the Nervous System (Open Access)

DTIC Science & Technology

2016-06-13

syndrome ; JCV 5 JC polyomavirus; NGS 5 next- generation sequencing; PML 5 progressive multifocal leukoencephalopathy. Ascertainment of the etiology of...Hunt-like syndrome and focal pachymeningitis. A 69-year-old man developed left-sided ptosis and Figure 1 Heatmap shows the top microbial species in each...The symptoms were followed by decreased vision, diplopia, ophthalmoplegia, and facial numbness. He was diagnosed with Tolosa-Hunt syndrome and treated

Natalizumab for relapsing remitting multiple sclerosis.

PubMed

Pucci, Eugenio; Giuliani, Giorgio; Solari, Alessandra; Simi, Silvana; Minozzi, Silvia; Di Pietrantonj, Carlo; Galea, Ian

2011-10-05

Natalizumab (NTZ) (Tysabri(®)) is a monoclonal antibody that inhibits leukocyte migration across the blood-brain barrier, thus reducing inflammation in central nervous system, and has been approved worldwide for the treatment of relapsing-remitting multiple sclerosis (RRMS). To evaluate the efficacy, tolerability and safety of NTZ in the treatment of patients with RRMS. We searched the Cochrane Multiple Sclerosis Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 1), MEDLINE (PubMed) and EMBASE, all up to 19 February 2010, and bibliographies of papers. Handsearching was carried out. Trialists and pharmaceutical companies were contacted. Furthermore, the websites of US Food and Drug Administration (FDA), the European Medicines Evaluation Agency (EMA) and the National Institute for health and Clinical Excellence (NICE) were also checked. All double-blind, randomised, controlled trials analysing more than a single infusion of NTZ (dosage > 3 mg/kg intravenous infusion every 4 weeks), also including its use as add-on treatment, versus placebo or other drugs in patients with RRMS. No restrictions on the basis of duration of treatment or length of follow up. Three reviewers independently selected articles which met the inclusion criteria. Disagreements were solved by discussion. Two reviewers independently extracted the data and assessed the methodological quality of each trial. Missing data was sought by contacting principal authors and Biogen Idec, through Biogen-Dompé Italia. Three studies met the inclusion criteria. These included one placebo-controlled trial (942 patients) and two add-on placebo-controlled trials, i.e. one plus glatiramer acetate (110 patients) and the second plus interferon beta-1a (1171 patients).This review assessed the efficacy, tolerability and safety of NTZ in patients with RRMS. Data was conclusive with respect to efficacy and tolerability, but not safety. As far as efficacy is concerned, the results showed statistically significant evidence in favour of NTZ for all the primary outcomes and for the secondary ones where data was available. NTZ reduced the risk of experiencing at least one new exacerbation at 2 years by about 40% and of experiencing progression at 2 years by about 25% as compared to a control group. MRI parameters showed statistical evidence in favour of participants receiving NTZ. Infusion reactions, anxiety, sinus congestion, lower limb swelling, rigors, vaginitis and menstrual disorders were reported as adverse events (AEs) more frequently after NTZ treatment. In this review NTZ was found to be well tolerated over a follow-up period of two years: the number of patients experiencing at least one AE (including severe and serious AEs) during this period did not differ between NTZ-treated patients and controls. Safety concerns have been raised about Progressive Multifocal Leukoencephalopathy (PML). In the trials included in this review, two cases of PML were encountered: one in a patient who had received 29 doses of NTZ and a second fatal case of PML in another patient after 37 doses of NTZ. Our protocol was insufficient to evaluate PML risk as well as other rare and long-term adverse events such as cancers and other opportunistic infections, which are very important issues in considering the risk/benefit ratio of NTZ. Although one trial did not contribute to efficacy results due to its duration, we found robust evidence in favour of a reduction in relapses and disability at 2 years in RRMS patients treated with NTZ. The drug was well tolerated. There are current significant safety concerns due to reporting of an increasing number of PML cases in patients treated with NTZ. This review was unable to provide an up-to-date systematic assessment of the risk due to the maximum 2 year-duration of the trials included. An independent systematic review of the safety profile of NTZ is warranted. NTZ should be used only by skilled neurologists in MS centres under surveillance programs.All the data in this review came from trials supported by the Pharmaceutical Industry. In agreement with the Cochrane Collaboration policy, this may be considered a potential source of bias.

Dust particles investigation for future Russian lunar missions.

NASA Astrophysics Data System (ADS)

Dolnikov, Gennady; Horanyi, Mihaly; Esposito, Francesca; Zakharov, Alexander; Popel, Sergey; Afonin, Valeri; Borisov, Nikolay; Seran, Elena; Godefroy, Michel; Shashkova, Inna; Kuznetsov, Ilya; Lyash, Andrey; Vorobyova, Elena; Petrov, Oleg; Lisin, Evgeny

One of the complicating factors of the future robotic and human lunar landing missions is the influence of the dust. Meteorites bombardment has accompanied by shock-explosive phenomena, disintegration and mix of the lunar soil in depth and on area simultaneously. As a consequence, the lunar soil has undergone melting, physical and chemical transformations. Recently we have the some reemergence for interest of Moon investigation. The prospects in current century declare USA, China, India, and European Union. In Russia also prepare two missions: Luna-Glob and Luna-Resource. Not last part of investigation of Moon surface is reviewing the dust condition near the ground of landers. Studying the properties of lunar dust is important both for scientific purposes to investigation the lunar exosphere component and for the technical safety of lunar robotic and manned missions. The absence of an atmosphere on the Moon's surface is leading to greater compaction and sintering. Properties of regolith and dust particles (density, temperature, composition, etc.) as well as near-surface lunar exosphere depend on solar activity, lunar local time and position of the Moon relative to the Earth's magneto tail. Upper layers of regolith are an insulator, which is charging as a result of solar UV radiation and the constant bombardment of charged particles, creates a charge distribution on the surface of the moon: positive on the illuminated side and negative on the night side. Charge distribution depends on the local lunar time, latitude and the electrical properties of the regolith (the presence of water in the regolith can influence the local distribution of charge). On light side of Moon near surface layer there exists possibility formation dusty plasma system. Altitude of levitation is depending from size of dust particle and Moon latitude. The distribution dust particle by size and altitude has estimated with taking into account photoelectrons, electrons and ions of solar wind, solar emission. Dust analyzer instrument PmL for future Russian lender missons intends for investigation the dynamics of dusty plasma near lunar surface. PmL consist of three blocks: Impact Sensor and two Electric Field Sensors. Dust Experiment goals are: 1) Impact sensor to investigate the dynamics of dust particles near the lunar surface (speed, charge, mass, vectors of a fluxes) a) high speed micrometeorites b) secondary particles after micrometeorites soil bombardment c) levitating dust particles due to electrostatic fields PmL instrument will measure dust particle impulses. In laboratory tests we used - min impulse so as 7•10-11 N•c, by SiO2 dust particles, 20-40 µm with velocity about 0,5 -2,5 m/c, dispersion 0.3, and - max impulse was 10-6 N•c with possibility increased it by particles Pb-Sn 0,7 mm with velocity 1 m/c, dispersion ±0.3. Also Impact Sensor will measure the charge of dust particle as far as 10-15 C ( 1000 electrons). In case the charge and impulse of a dust particle are measured we can obtain velocity and mass of them. 2) Electric field Sensor will measure the value and dynamics of the electric fields the lunar surface. Two Electric Field Sensors both are measured the concentration and temperature of charged particles (electrons, ions, dust particles). Uncertainty of measurements is 10%. Electric Field Sensors contain of Lengmure probe. Using Lengmure probe to dark and light Moon surface we can obtain the energy spectra photoelectrons in different period of time. PmL instrument is developing, working out and manufacturing in IKI. Simultaneously with the PmL dust instrument to study lunar dust it would be very important to use an onboard TV system adjusted for imaging physical properties of dust on the lunar surface (adhesion, albedo, porosity, etc), and to collect dust particles samples from the lunar surface to return these samples to the Earth for measure a number of physic-chemical properties of the lunar dust, e.g. a quantum yield of photoemission, what is very important for modeling physical processes in the lunar exosphere.

The Subfascial Approach to Primary and Secondary Breast Augmentation with Autologous Fat Grafting and Form-Stable Implants.

PubMed

Sampaio Goes, João Carlos; Munhoz, Alexandre Mendonça; Gemperli, Rolf

2015-10-01

This article presents an overview of the subfascial approach to primary and secondary breast augmentation with form-stable implants associated with autologous fat grafting. Although breast augmentation is a well-studied procedure, there are few previous reports concerning the subfascial technique and, especially, this technique associated with lipofilling. Consequently, the authors present their experience with a form-stable, anatomically shaped silicone gel breast implant, which has recently been approved in the United States following FDA clinical trials. Primary and secondary breast augmentations using form-stable implants resulted in satisfactory outcomes. Copyright © 2015 Elsevier Inc. All rights reserved.

The human CTC1/STN1/TEN1 complex regulates telomere maintenance in ALT cancer cells.

PubMed

Huang, Chenhui; Jia, Pingping; Chastain, Megan; Shiva, Olga; Chai, Weihang

2017-06-15

Maintaining functional telomeres is important for long-term proliferation of cells. About 15% of cancer cells are telomerase-negative and activate the alternative-lengthening of telomeres (ALT) pathway to maintain their telomeres. Recent studies have shown that the human CTC1/STN1/TEN1 complex (CST) plays a multi-faceted role in telomere maintenance in telomerase-expressing cancer cells. However, the role of CST in telomere maintenance in ALT cells is unclear. Here, we report that human CST forms a functional complex localizing in the ALT-associated PML bodies (APBs) in ALT cells throughout the cell cycle. Suppression of CST induces telomere instabilities including telomere fragility and elevates telomeric DNA recombination, leading to telomere dysfunction. In addition, CST deficiency significantly diminishes the abundance of extrachromosomal circular telomere DNA known as C-circles and t-circles. Suppression of CST also results in multinucleation in ALT cells and impairs cell proliferation. Our findings imply that the CST complex plays an important role in regulating telomere maintenance in ALT cells. Copyright © 2017 Elsevier Inc. All rights reserved.

Preparation and Analysis of Samples for the Third Round Robin Verification Exercise

DTIC Science & Technology

1992-07-01

Hooge 34 Lid instituuts Advies Raad PML Prof. dr. U.A. Th. Brinkman 35 Directeur van het Medisch Biologisch Laboratorium TNO Proft dr. W.R.F. Notten 36...1991 werd uitgevoerd, heeft het Prins Maurits Laboratorium TNO de monsters aangemaakt die bestonden uit rubber, verf en beton. Deze materialen, die...Maurits Laboratorium TNO Chemische Research Prof. dr. G. Dijksrra 10 HBur. NBC-DMKIJOMATIKIO In. A.A.M. Slagveer 11 Lid van de Contact Cominissie NBC

Treatment of pseudobulbar affect with citalopram in a patient with progressive multifocal leukoencephalopthy.

PubMed

King, R R; Reiss, J P

2012-01-01

Pseudobulbar affect (PBA) manifests in a variety of neurologic illnesses suggesting a heterogeneous pathophysiology with common underpinnings. We report successful treatment of PBA with a selective serotonin reuptake inhibitor (SSRI) in a 54-year-old woman following progressive multifocal leukoencephalopathy (PML). In light of recent focus on dextromethorphan/quinidine (DM/Q) for the treatment of PBA, the clinician is reminded of the effectiveness of SSRIs. Copyright © 2011 Elsevier Ltd. All rights reserved.

Importance of ERK activation in As2O3-induced differentiation and promyelocytic leukemia nuclear bodies formation in neuroblastoma cells.

PubMed

Petit, A; Delaune, A; Falluel-Morel, A; Goullé, J-P; Vannier, J-P; Dubus, I; Vasse, M

2013-11-01

Neuroblastoma malignant cell growth is dependent on their undifferentiated status. Arsenic trioxide (As2O3) induces neuroblastoma cell differentiation in vitro, but its mechanisms still remains unknown. We used three human neuroblastoma cell lines (SH-SY5Y, IGR-N-91, LAN-1) that differ from their MYCN and p53 status to explore the intracellular events activated by As2O3 and involved in neurite outgrowth, a morphological marker of differentiation. As2O3 (2μM) induced neurite outgrowth in all cell lines, which was dependent on ERK activation but independent on MYCN status. This process was induced either by a sustained (3 days) or a transient (2h) incubation with As2O3, indicating that very early events trigger the induction of differentiation. In parallel, As2O3 induced a rapid assembly of promyelocytic leukemia nuclear bodies (PML-NB) in an ERK-dependent manner. In conclusion, mechanisms leading to neuroblastoma cell differentiation in response to As2O3 appear to involve the ERK pathway activation and PML-NB formation, which are observed in response to other differentiating molecules such as retinoic acid derivates. This open new perspectives based on the use of treatment combinations to potentiate the differentiating effects of each drug alone and reduce their adverse side effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting PML-RARα and Oncogenic Signaling Pathways by Chinese Herbal Mixture Tien-Hsien Liquid in Acute Promyelocytic Leukemia NB4 Cells

PubMed Central

Yao, Chih-Jung; Yang, Chia-Ming; Chuang, Shuang-En; Yan, Jiann-Long; Liu, Chun-Yen; Chen, Suz-Wen; Yan, Kun-Huang; Lai, Tung-Yuan; Lai, Gi-Ming

2011-01-01

Tien-Hsien Liquid (THL) is a Chinese herbal mixture that has been used worldwide as complementary treatment for cancer patients in the past decade. Recently, THL has been shown to induce apoptosis in various types of solid tumor cells in vitro. However, the underlying molecular mechanisms have not yet been well elucidated. In this study, we explored the effects of THL on acute promyelocytic leukemia (APL) NB4 cells, which could be effectively treated by some traditional Chinese remedies containing arsenic trioxide. The results showed THL could induce G2/M arrest and apoptosis in NB4 cells. Accordingly, the decrease of cyclin A and B1 were observed in THL-treated cells. The THL-induced apoptosis was accompanied with caspase-3 activation and decrease of PML-RARα fusion protein. Moreover, DNA methyltransferase 1 and oncogenic signaling pathways such as Akt/mTOR, Stat3 and ERK were also down-regulated by THL. By using ethyl acetate extraction and silica gel chromatography, an active fraction of THL named as EAS5 was isolated. At about 0.5–1% of the dose of THL, EAS5 appeared to have most of THL-induced multiple molecular targeting effects in NB4 cells. Based on the findings of these multi-targeting effects, THL might be regarding as a complementary and alternative therapeutic agent for refractory APL. PMID:19897545

Theoretical Analysis of Penalized Maximum-Likelihood Patlak Parametric Image Reconstruction in Dynamic PET for Lesion Detection.

PubMed

Yang, Li; Wang, Guobao; Qi, Jinyi

2016-04-01

Detecting cancerous lesions is a major clinical application of emission tomography. In a previous work, we studied penalized maximum-likelihood (PML) image reconstruction for lesion detection in static PET. Here we extend our theoretical analysis of static PET reconstruction to dynamic PET. We study both the conventional indirect reconstruction and direct reconstruction for Patlak parametric image estimation. In indirect reconstruction, Patlak parametric images are generated by first reconstructing a sequence of dynamic PET images, and then performing Patlak analysis on the time activity curves (TACs) pixel-by-pixel. In direct reconstruction, Patlak parametric images are estimated directly from raw sinogram data by incorporating the Patlak model into the image reconstruction procedure. PML reconstruction is used in both the indirect and direct reconstruction methods. We use a channelized Hotelling observer (CHO) to assess lesion detectability in Patlak parametric images. Simplified expressions for evaluating the lesion detectability have been derived and applied to the selection of the regularization parameter value to maximize detection performance. The proposed method is validated using computer-based Monte Carlo simulations. Good agreements between the theoretical predictions and the Monte Carlo results are observed. Both theoretical predictions and Monte Carlo simulation results show the benefit of the indirect and direct methods under optimized regularization parameters in dynamic PET reconstruction for lesion detection, when compared with the conventional static PET reconstruction.

Localization, trafficking, and temperature-dependence of the Aequorea green fluorescent protein in cultured vertebrate cells.

PubMed Central

Ogawa, H; Inouye, S; Tsuji, F I; Yasuda, K; Umesono, K

1995-01-01

The localization, trafficking, and fluorescence of Aequorea green fluorescent protein (GFP) in cultured vertebrate cells transiently transfected with GFP cDNA were studied. Fluorescence of GFP in UV light was found to be strongest when cells were incubated at 30 degrees C but was barely visible at an incubation temperature of 37 degrees C. COS-1 cells, primary chicken embryonic retina cells, and carp epithelial cells were fluorescently labeled under these conditions. GFP was distributed uniformly throughout the cytoplasm and nucleus independent of cell type examined. When GFP was fused to PML protooncogene product, fluorescence was detected in a unique nuclear organelle pattern indistinguishable from that of PML protein, showing the potential use of GFP as a fluorescent tag. To analyze both function and intracellular trafficking of proteins fused to GFP, a GFP-human glucocorticoid receptor fusion construct was prepared. The GFP-human glucocorticoid receptor efficiently transactivated the mouse mammary tumor virus promoter in response to dexamethasone at 30 degrees C but not at 37 degrees C, indicating that temperature is important, even for function of the GFP fusion protein. The dexamethasone-induced translocation of GFP-human glucocorticoid receptor from cytoplasm to nucleus was complete within 15 min; the translocation could be monitored in a single living cell in real time. Images Fig. 1 Fig. 2 Fig. 3 Fig. 5 PMID:8524871

Transcriptional activation of JC virus by human T-lymphotropic virus type I Tax protein in human neuronal cell lines.

PubMed

Okada, Y; Sawa, H; Tanaka, S; Takada, A; Suzuki, S; Hasegawa, H; Umemura, T; Fujisawa, J; Tanaka, Y; Hall, W W; Nagashima, K

2000-06-02

Polyomavirus JC (JCV) causes the human demyelinating disease, progressive multifocal leukoencephalopathy (PML). The recent demonstration of cases of PML in association with human T-lymphotropic virus type I (HTLV-I) infection prompted us to examine whether the HTLV-I-encoded regulatory protein Tax activates JCV transcription. By employing a dual luciferase assay, we initially found that the expression of Tax activated the transcriptional potential of both early and late promoters of JCV in human neuronal but not in non-neuronal cells. We subsequently analyzed the mechanism of Tax-induced activation of the JCV promoter in neuronal cells with the following results: 1) the JCV promoter that lacks the NF-kappaB-binding motif could not be activated by Tax; 2) the overexpression of IkappaBalpha abolished Tax-induced transcriptional activation of the JCV promoter; 3) a Tax mutant (M22) lacking the potential for activation via the NF-kappaB pathway did not activate the JCV promoter. Furthermore, Tax enhances the gene expression of JCV T antigen and VP1. We examined mechanisms of the cell-specific activation of the JCV promoter by Tax. Electrophoretic mobility shift assay demonstrated the presence of Tax-bound protein(s) that were specifically present in non-neuronal cells. This study is the first demonstration of the activation of JCV promoter by HTLV-I Tax in an NF-kappaB-dependent manner.

Elektrische Scheepsvoortstuwing en Supergeleiding: Een Literatuurstudie (Electric Ship Propulsion and Superconductivity: A Desk Study)

DTIC Science & Technology

1992-06-01

opdraCmlgoeVO en e; opdrachtnemer verweren naar doeha ’Algemen. Voorwearden voor Onderzoeks- ONGERTJBRICEERD opdrachlefl son TNO’, dan wel do belreflende...Opomp’kaneal NaK isolatielaag mom ankerstroomn NaK max. niveau van NaK -as Figuur 4.7 Seriewchakeling van de schijven met NaK TNO-rappert PML 2824880131Pgn De...suporgeleidend worden uitgovocrd kin de constructie aanmerkelijk worden vereenvoudigd. Voor generatoren onder de 100 MW wegen de kosten, verbonden son de grotere

Refinement of the CALIOP cloud mask algorithm

NASA Astrophysics Data System (ADS)

Katagiri, Shuichiro; Sato, Kaori; Ohta, Kohei; Okamoto, Hajime

2018-04-01

A modified cloud mask algorithm was applied to the CALIOP data to have more ability to detect the clouds in the lower atmosphere. In this algorithm, we also adopt the fully attenuation discrimination and the remain noise estimation using the data obtained at an altitude of 40 km to avoid contamination of stratospheric aerosols. The new cloud mask shows an increase in the lower cloud fraction. Comparison of the results to the data observed with a PML ground observation was also made.

Proceedings of the Workshop on Flight Testing to Identify Pilot Workload and Pilot Dynamics Held at the Edwards AFB, California on 19-21 January 1982

DTIC Science & Technology

1982-05-01

precognitive stages or, in other words, a *Adaptation changes strategy and performance in a new environment, whereas learning or skill development changes...expect the pursuit level of operation to have a lower PML than the compen- satory stage.. 3. Final stage ( precognitive control). At this level of skill...in degraded system performance, if not failure. The compensatory-pursuit- precognitive pathways structure is suitable to represent not only a pilot or

Progressive multifocal leukoence--phalopathy presenting as homonymous hemianopia in a patient with acquired immunodeficiency syndrome.

PubMed

Pandey, Amit; Bandivdekar, Karishma; Ramchandani, Suresh; Ramchandani, Sushama

2012-01-01

We present a case of a Human Immunodeficiency Virus (HIV) positive patient who was referred for retinal evaluation to rule out ophthalmic manifestations of Acquired Immunodeficiency Syndrome (AIDS). She complained of some disturbance in vision in both eyes. Fundus examination showed no abnormality. Perimetry, done to rule out optic nerve pathology, showed a left homonymous hemianopia. Magnetic Resonance Imaging (MRI) scan showed features of Progressive Multifocal Leukoencephalopathy (PML). She had no other neurological symptoms or signs.

Acoustic Microsensors III. Direct Detection of Staphylococcal Enterotoxin B Employing a Piezoelectric Crystal Immunosensor with a Flexible Carboxylated Dextran Matrix as the Biochemical Interface.

DTIC Science & Technology

1998-03-01

8217real time’ monitoring van biologische strijdmiddelen en aanverwante verbindingen. TNO- PML onderzoekt de mogelijkheden van een immunoreactie op een...toxine, dat voedselvergiftiging veroorzaakt, behoort tot de biologische strijdmid- delen. SEB werd door PG33 gekozen als teststof om de diverse...onderzoek zieh richten op de detectie van grote antigenen die tot de biologische strijdmiddelen behoren, zoals sommige virussen en bacteri- en. De

Chemical Agonists of the PML/Daxx Pathway for Prostate Cancer Therapy

DTIC Science & Technology

2011-04-01

positive nuclei. These data suggest that the assay is highly specific and will not suffer from promiscuous reactivity with NIH library compounds...Figure 16B). Strikingly, when we compared Daxx levels in PCa cell lines to a nontumorigenic human prostatic epithelial line, PWR -1E, they were...Lysates from six different cell types ( PWR -1E, ALVA-31 Daxx K/D, ALVA-31 WT, DU145, LNCaP, and PC3) were normalized for total protein content (60 μg

Energy/dissipation-preserving Birkhoffian multi-symplectic methods for Maxwell's equations with dissipation terms

DOE PAGES

Su, Hongling; Li, Shengtai

2016-02-03

In this study, we propose two new energy/dissipation-preserving Birkhoffian multi-symplectic methods (Birkhoffian and Birkhoffian box) for Maxwell's equations with dissipation terms. After investigating the non-autonomous and autonomous Birkhoffian formalism for Maxwell's equations with dissipation terms, we first apply a novel generating functional theory to the non-autonomous Birkhoffian formalism to propose our Birkhoffian scheme, and then implement a central box method to the autonomous Birkhoffian formalism to derive the Birkhoffian box scheme. We have obtained four formal local conservation laws and three formal energy global conservation laws. We have also proved that both of our derived schemes preserve the discrete versionmore » of the global/local conservation laws. Furthermore, the stability, dissipation and dispersion relations are also investigated for the schemes. Theoretical analysis shows that the schemes are unconditionally stable, dissipation-preserving for Maxwell's equations in a perfectly matched layer (PML) medium and have second order accuracy in both time and space. Numerical experiments for problems with exact theoretical results are given to demonstrate that the Birkhoffian multi-symplectic schemes are much more accurate in preserving energy than both the exponential finite-difference time-domain (FDTD) method and traditional Hamiltonian scheme. Finally, we also solve the electromagnetic pulse (EMP) propagation problem and the numerical results show that the Birkhoffian scheme recovers the magnitude of the current source and reaction history very well even after long time propagation.« less

Energy/dissipation-preserving Birkhoffian multi-symplectic methods for Maxwell's equations with dissipation terms

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

Su, Hongling; Li, Shengtai

In this study, we propose two new energy/dissipation-preserving Birkhoffian multi-symplectic methods (Birkhoffian and Birkhoffian box) for Maxwell's equations with dissipation terms. After investigating the non-autonomous and autonomous Birkhoffian formalism for Maxwell's equations with dissipation terms, we first apply a novel generating functional theory to the non-autonomous Birkhoffian formalism to propose our Birkhoffian scheme, and then implement a central box method to the autonomous Birkhoffian formalism to derive the Birkhoffian box scheme. We have obtained four formal local conservation laws and three formal energy global conservation laws. We have also proved that both of our derived schemes preserve the discrete versionmore » of the global/local conservation laws. Furthermore, the stability, dissipation and dispersion relations are also investigated for the schemes. Theoretical analysis shows that the schemes are unconditionally stable, dissipation-preserving for Maxwell's equations in a perfectly matched layer (PML) medium and have second order accuracy in both time and space. Numerical experiments for problems with exact theoretical results are given to demonstrate that the Birkhoffian multi-symplectic schemes are much more accurate in preserving energy than both the exponential finite-difference time-domain (FDTD) method and traditional Hamiltonian scheme. Finally, we also solve the electromagnetic pulse (EMP) propagation problem and the numerical results show that the Birkhoffian scheme recovers the magnitude of the current source and reaction history very well even after long time propagation.« less

Oxidation of selected organophosphate pesticides during chlorination of simulated drinking water.

PubMed

Kamel, Alaa; Byrne, Christian; Vigo, Craig; Ferrario, Joseph; Stafford, Charles; Verdin, Gregory; Siegelman, Frederic; Knizner, Steven; Hetrick, James

2009-02-01

Ten organophosphate (OP) pesticides: phorate, disulfoton, terbufos, methidathion, bensulide, chlorethoxyfos, phosmet, methyl parathion, phostebupirim, and temephos were evaluated for their potential to undergo oxidation to their respective oxons and/or other oxidation analogues in laboratory water. Samples were collected at time intervals up to 72h of chlorination and analyzed by both gas chromatography-mass selective detection (GC-MSD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that methidathion and methyl parathion were stable in unchlorinated water, while all other OP pesticides were not stable over the 72h exposure period. In chlorinated water, phorate and disulfoton formed stable sulfone oxons. Temephos formed stable dioxon sulfoxide and dioxon sulfone. Methidathion, bensulide, chlorethyoxyfos, methyl parathion, and phostebupirim formed stable oxons over the 72h exposure period. Terbufos, phorate, disulfoton and temephos oxon sulfoxides; temephos sulfoxide; and phosmet oxon were initially formed but were not detected after 24h. The data illustrate that organothiophosphate pesticides may form oxons and/or other oxidation analogues during chlorination in water treatment plants, which are persistent for at least 72h.

Berberine alkaloid: Quantum chemical study of different forms by the DFT and MP2 methods

NASA Astrophysics Data System (ADS)

Danilov, V. I.; Dailidonis, V. V.; Hovorun, D. M.; Kurita, N.; Murayama, Y.; Natsume, T.; Potopalsky, A. I.; Zaika, L. A.

2006-10-01

The stable structures and electronic properties for the berberine cation as well as possible ammonium, carbinol and amino-aldehyde forms of protoberberine salts in the presence of hydroxyl ions were investigated by the B3LYP/6-31G(d,p) and MP2/6-31++G(d,p) methods. The geometry optimizations by both methods lead to the nonplanar propeller-twisted and buckled structure for the all forms. The obtained bond lengths and bond angles agree with the experimental values. The comparison of total energies elucidates that the amino-aldehyde form is the most preferable tautomer in gas phase, while the carbinol form is less stable. The least stable tautomer is the ammonium form.

Crosslinked polyimides prepared from N-(3-ethynylphenyl)maleimide

NASA Technical Reports Server (NTRS)

Gerber, Margaret K. (Inventor); St.clair, Terry L. (Inventor)

1993-01-01

The compound N-(3-ethynylphenyl)maleimide (NEPMI) was used to prepare thermally stable, glassy polyimides which did not exhibit glass transition temperatures below 500 C. NEPMI was blended with the maleimide of methylene dianiline (BMI) and heated to form the polyimide. NEPMI was also mixed with Thermid 600 R, a commercially available bisethynyl oligomeric material, and heated to form a thermally stable, glassy polyimide. Lastly, NEPMI was blended with both BMI and Thermid 600 R to form thermally stable, glassy polyimides.

Natalizumab for induction of remission in Crohn's disease.

PubMed

Macdonald, J K; McDonald, J W D

2006-07-19

The pathogenesis of Crohn's disease involves migration of leukocytes into gut tissue and subsequent inflammation. Natalizumab (Tysabri, Elan Pharmaceuticals and Biogen Idec) a recombinant humanized IgG4 monoclonal antibody that blocks adhesion and subsequent migration of leukocytes into the gut by binding the alpha4 integrin is a member of a new class of molecules known as selective adhesion molecule (SAM) inhibitors. The results of animal studies suggest that alpha4 integrin blockade could be a useful therapy for inflammatory bowel disease. The results of randomized controlled trials suggest that natalizumab may be an effective therapy for active Crohn's disease. This systematic review summarizes the current evidence on the use of natalizumab for the induction of remission in Crohn's disease. To determine the efficacy and safety of natalizumab for induction of remission in Crohn's disease. A computer assisted search of the Cochrane Central Register of Controlled Trials, the Cochrane Inflammatory Bowel Disease and Functional Bowel Disorders Review Group Specialized Trials Register, MEDLINE and EMBASE was performed to identify relevant publications between 1966 and June 2005. The medical subject heading (MeSH) terms "Crohn disease" or "inflammatory bowel disease", "Natalizumab" or "Antegren" or "Tysabri" and "Antibodies, Monoclonal" were used to perform key word searches of each database. Manual searches of reference lists from potentially relevant papers were performed in order to identify additional studies that may have been missed using the computer-assisted search strategy. Abstracts from major gastroenterological meetings were searched to identify research submitted in abstract form only. Personal contacts, leaders in the field, and the manufacturers were contacted to identify other studies which may not be published. We included only randomized controlled trials comparing natalizumab to a placebo or control therapy for the induction of remission in Crohn's disease. Data were analyzed using Review Manager (RevMan 4.2.8). All data were analyzed on an intention-to-treat basis. For pooled data, summary test statistics were derived using the relative risk and 95% confidence intervals. Fixed and random effects models were used where appropriate. The definitions of treatment success, remission and clinical improvement were set by the authors of each paper, and the data were combined for analysis only if these definitions were sufficiently similar. Pooled data from the three included studies suggest that natalizumab (3 to 4 mg/kg) may be effective for induction of clinical response and remission in patients with moderately to severely active Crohn's disease. This benefit is statistically significant for one, two and three infusion treatments. There was a trend toward increased benefit with additional infusions of natalizumab. Natalizumab appears to provide greater benefit for patient subgroups characterized by objective confirmation of active inflammation or chronically active disease despite conventional therapies. These subgroup analyses demonstrated significantly greater clinical response and remission rates for natalizumab compared with placebo in patients with elevated C-reactive protein levels, active disease despite the use of immunosuppressants, or prior anti-tumor necrosis factor therapy. These benefits were apparent for both short term (one infusion) and longer term treatment (two or three infusions). Natalizumab was generally well tolerated and the safety profile observed in the three included studies was similar. Adverse events occurred infrequently and were experienced by a similar proportion of natalizumab and placebo treated patients. There were no statistically significant differences between natalizumab and placebo treated patients in the proportions of patients who withdrew due to adverse events or those who experienced serious adverse events. The included trials lacked adequate power to detect serious adverse events that occur infrequently. Recently, two patients with multiple sclerosis treated with natalizumab in combination with interferon beta-1a and one patient with Crohn's disease treated with natalizumab in combination with azathioprine developed progressive multifocal leukoencephalopathy (PML) resulting in two patient deaths. As a result all dosing in clinical trials and commercial use of natalizumab has been suspended. A retrospective investigation was conducted to assess the risk of PML in natalizumab treated patients and no new cases were identified. Pooled data and the results of an ongoing study suggest that natalizumab may be effective for induction of clinical response and remission in patients with moderately to severely active Crohn's disease. The clinical benefit of induction therapy with natalizumab in Crohn's disease should be weighed against the potential risk of serious adverse events. Currently natalizumab is not available on the market for routine clinical use as a consequence of the unexpected association with PML. However, preliminary data from the retrospective investigation of adverse events associated with natalizumab suggest that it may be possible to identify patients at risk for PML by testing for the appearance of JC virus in plasma.

Divergent Trends of Anti-JCPyV Serum Reactivity and Neutralizing Activity in Multiple Sclerosis (MS) Patients during Treatment with Natalizumab.

PubMed

Diotti, Roberta Antonia; Capra, Ruggero; Moiola, Lucia; Caputo, Valeria; De Rossi, Nicola; Sangalli, Francesca; Martinelli, Vittorio; Burioni, Roberto; Clementi, Massimo; Mancini, Nicasio

2016-05-07

The association between natalizumab and progressive multifocal leukoencephalopathy (PML) is established, but a reliable clinical risk stratification flow-chart is lacking. New risk factors are needed, such as the possible role of the anti-JC polyomavirus (JCPyV) neutralizing antibody. In this pilot study, we analyzed this parameter during natalizumab treatment. Sequential sera of 38 multiple sclerosis patients during their first year of natalizumab treatment were collected, and grouped according to the number of infusions. For 11 patients, samples were also available after 24 infusions (T24), when progressive multifocal leukoencephalopathy (PML) risk is higher. The reactivity against VP1, the main JCPyV surface protein, and the anti-JCPyV neutralizing activity were evaluated. During the first year, a lack of correlation between anti-JCPyV antibody response and its neutralizing activity was observed: a significant decrease in anti-JCPyV antibody response was observed (p = 0.0039), not paralleled by a similar trend in the total anti-JCPyV neutralizing activity (p = 0.2239). This lack of correlation was even more evident at T24 when, notwithstanding a significant increase in the anti-JCPyV response (p = 0.0097), a further decrease of the neutralizing activity was observed (p = 0.0062). This is the first study evidencing, prospectively, the lack of correlation between the anti-JCPyV antibody response and its neutralizing activity during natalizumab treatment.

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies.

PubMed

Ehm, Patrick; Nalaskowski, Marcus M; Wundenberg, Torsten; Jücker, Manfred

2015-01-01

The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in haematopoietic cells. By converting PI(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane, SHIP1 modifies PI3-kinase mediated signaling. We have recently demonstrated that SHIP1 is a nucleo-cytoplasmic shuttling protein and SHIP1 nuclear puncta partially colocalize with FLASH, a component of nuclear bodies. In this study, we demonstrate that endogenous SHIP1 localizes to intranucleolar regions of both normal and leukemic haematopoietic cells. In addition, we report that ectopically expressed SHIP1 accumulates in nucleolar cavities and colocalizes with the tumor suppressor protein p53 and components of PML nuclear bodies (e.g. SP100, SUMO-1 and CK2). Moreover, SHIP1 also colocalizes in nucleolar cavities with components of the ubiquitin-proteasome pathway. By using confocal microscopy data, we generated 3D-models revealing the enormous extent of the SHIP1 aggresomes in the nucleolus. Furthermore, treatment of cells with the proteasome inhibitor MG132 causes an enlargement of nucleolar SHIP1 containing structures. Unexpectedly, this accumulation can be partially prevented by treatment with the inhibitor of nuclear protein export Leptomycin B. In recent years, several proteins aggregating in nucleolar cavities were shown to be key factors of neurodegenerative diseases and cancerogenesis. Our findings support current relevance of nuclear localized SHIP1.

The tumor suppressor SHIP1 colocalizes in nucleolar cavities with p53 and components of PML nuclear bodies

PubMed Central

Ehm, Patrick; Nalaskowski, Marcus M; Wundenberg, Torsten; Jücker, Manfred

2015-01-01

The inositol 5-phosphatase SHIP1 is a negative regulator of signaling processes in haematopoietic cells. By converting PI(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane, SHIP1 modifies PI3-kinase mediated signaling. We have recently demonstrated that SHIP1 is a nucleo-cytoplasmic shuttling protein and SHIP1 nuclear puncta partially colocalize with FLASH, a component of nuclear bodies. In this study, we demonstrate that endogenous SHIP1 localizes to intranucleolar regions of both normal and leukemic haematopoietic cells. In addition, we report that ectopically expressed SHIP1 accumulates in nucleolar cavities and colocalizes with the tumor suppressor protein p53 and components of PML nuclear bodies (e.g. SP100, SUMO-1 and CK2). Moreover, SHIP1 also colocalizes in nucleolar cavities with components of the ubiquitin-proteasome pathway. By using confocal microscopy data, we generated 3D-models revealing the enormous extent of the SHIP1 aggresomes in the nucleolus. Furthermore, treatment of cells with the proteasome inhibitor MG132 causes an enlargement of nucleolar SHIP1 containing structures. Unexpectedly, this accumulation can be partially prevented by treatment with the inhibitor of nuclear protein export Leptomycin B. In recent years, several proteins aggregating in nucleolar cavities were shown to be key factors of neurodegenerative diseases and cancerogenesis. Our findings support current relevance of nuclear localized SHIP1. PMID:25723258

Best practice in the use of natalizumab in multiple sclerosis.

PubMed

Fernández, Oscar

2013-03-01

Natalizumab is approved for the treatment of patients with relapsing-remitting multiple sclerosis who have failed first-line treatment with traditional disease-modifying therapies or who have highly active disease. The drug has proved highly effective, both in a clinical trial setting and in clinical practice, with marked reductions in the rate of clinical relapses and slowed disease progression. These clinical outcomes are mirrored by a marked reduction in disease activity as evidenced by magnetic resonance imaging of the brain. However, natalizumab treatment has been associated with a risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal condition caused by JC virus (JCV) activation. When this condition was detected in a clinical trial shortly after approval, the drug was immediately and voluntarily withdrawn from the market. As a condition of its reinstatement, stringent pharmacovigilance measures and a risk management plan were enforced. The recent availability of a two-step enzyme-linked immunosorbent assay (ELISA) test for the presence of anti-JCV antibodies (free testing is available in a central laboratory for registered centers), along with an ever-improving understanding of other risk factors such as prior immunosuppressant use and duration of treatment, allow an increasingly refined stratification of the risk of PML. This improved stratification of risk can help guide decisions about treatment. This review will also deal with other topics of relevance to clinical practice such as the development of antinatalizumab antibodies and their negative implications in terms of hypersensitivity reactions and loss of efficacy, withdrawal of treatment, and compassionate pediatric use.

Effect of Grinding on the Solid-State Stability and Particle Dissolution of Acyclovir Polymorphs.

PubMed

Magnoni, Federico; Gigliobianco, Maria Rosa; Vargas Peregrina, Dolores; Censi, Roberta; Di Martino, Piera

2017-10-01

The present work investigated the solid state change of 4 acyclovir polymorphs when ground at room temperature (Method A) and under cryo-grinding in the presence of liquid nitrogen (Method B). Modifications in particle size and shape (evaluated by scanning electron microscopy) and in the water content (evaluated by thermal analysis) were related to transitions at the solid state, as confirmed by X-ray powder diffractometry. Anhydrous Form I was stable under grinding by both Methods A and B. The anhydrous Form II was stable during grinding under Method A, whereas it was progressively converted to the hydrate Form V during grinding under Method B. The hydrate Form V was stable under Method A, whereas it was converted to the anhydrous Form I after 15 min and then to the hydrate Form VI after 45 min of grinding. The hydrate Form VI proved to be stable under grinding by both Methods A and B. Thus, Form I and VI were the only forms that yielded a sizeable decrease in particle size under grinding, with a consequent increase in particle dissolution rate, while maintaining solid state physicochemical stability. Form I treated under Method B grinding gave the best dissolution rate. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

The Absence of a Mature Cell Wall Sacculus in Stable Listeria monocytogenes L-Form Cells Is Independent of Peptidoglycan Synthesis.

PubMed

Studer, Patrick; Borisova, Marina; Schneider, Alexander; Ayala, Juan A; Mayer, Christoph; Schuppler, Markus; Loessner, Martin J; Briers, Yves

2016-01-01

L-forms are cell wall-deficient variants of otherwise walled bacteria that maintain the ability to survive and proliferate in absence of the surrounding peptidoglycan sacculus. While transient or unstable L-forms can revert to the walled state and may still rely on residual peptidoglycan synthesis for multiplication, stable L-forms cannot revert to the walled form and are believed to propagate in the complete absence of peptidoglycan. L-forms are increasingly studied as a fundamental biological model system for cell wall synthesis. Here, we show that a stable L-form of the intracellular pathogen Listeria monocytogenes features a surprisingly intact peptidoglycan synthesis pathway including glycosyl transfer, in spite of the accumulation of multiple mutations during prolonged passage in the cell wall-deficient state. Microscopic and biochemical analysis revealed the presence of peptidoglycan precursors and functional glycosyl transferases, resulting in the formation of peptidoglycan polymers but without the synthesis of a mature cell wall sacculus. In conclusion, we found that stable, non-reverting L-forms, which do not require active PG synthesis for proliferation, may still continue to produce aberrant peptidoglycan.

NLS-RARα promotes proliferation and inhibits differentiation in HL-60 cells.

PubMed

Hu, Xiu-Xiu; Zhong, Liang; Zhang, Xi; Gao, Yuan-Mei; Liu, Bei-Zhong

2014-01-01

A unique mRNA produced in leukemic cells from a t(15;17) acute promyelocytic leukemia (APL) patient encodes a fusion protein between the retinoic acid receptor α (RARα) and a myeloid gene product called PML. Studies have reported that neutrophil elastase (NE) cleaves bcr-1-derived PML-RARα in early myeloid cells, leaving only the nuclear localization signal (NLS) of PML attached to RARα. The resultant NLS-RARα fusion protein mainly localizes to, and functions within, the cell nucleus. It is speculated that NLS-RARα may act in different ways from the wild-type RARα, but its biological characteristics have not been reported. This study takes two approaches. Firstly, the NLS-RARα was silenced with pNLS-RARα-shRNA. The mRNA and protein expression of NLS-RARα were detected by RT-PCR and Western blot respectively. Cell proliferation in vitro was assessed by MTT assay. Flow cytometry (FCM) was used to detect the differentiation of cells. Secondly, the NLS-RARα was over-expressed by preparation of recombinant adenovirus HL-60/pAd-NLS-RARα. The assays of mRNA and protein expression of NLS-RARα, and cell proliferation, were as above. By contrast, cell differentiation was stimulated by all trans retinoic acid (ATRA) (2.5µmol/L) at 24h after virus infection of pAd-NLS-RARα, and then detected by CD11b labeling two days later. The transcription and translation of C-MYC was detected in HL-60/pAd-NLS-RARα cells which treated by ATRA. Our results showed that compared to the control groups, the expression of NLS-RARα was significantly reduced in the HL-60/pNLS-RARα-shRNA cells, and increased dramatically in the HL-60/pAd-NLS-RARα cells. The proliferation was remarkably inhibited in the HL-60/pNLS-RARα-shRNA cells in a time-dependent manner, but markedly promoted in the HL-60/pAd-NLS-RARα cells. FCM outcome revealed the differentiation increased in HL-60/pNLS-RARα-shRNA cells, and decreased in the HL-60/pAd-NLS-RARα cells treated with 2.5µmol/L ATRA. The expression of C-MYC increased strikingly in HL-60/pAd-NLS-RARα cells treated with 2.5µmol/L ATRA. Down-regulation of NLS-RARα expression inhibited the proliferation and induced the differentiation of HL-60 cells. On the contrary, over-expression of NLS-RARα promoted proliferation and reduced the ATRA-induced differentiation of HL-60 cells.

Probing Toluene and Ethylbenzene Stable Glass Formation using Inert Gas Permeation

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

Smith, R. Scott; May, Robert A.; Kay, Bruce D.

Inert gas permeation is used to investigate the formation of stable glasses of toluene and ethylbenzene. The effect of deposition temperature (Tdep) on the kinetic stability of the vapor deposited glasses is determined using Kr desorption spectra from within sandwich layers of either toluene or ethylbenzene. The results for toluene show that the most stable glass is formed at Tdep = 0.92 Tg, although glasses with a kinetic stability within 50% of the most stable glass were found with deposition temperatures from 0.85 to 0.95 Tg. Similar results were found for ethylbenzene, which formed its most stable glass at 0.91more » Tg and formed stable glasses from 0.81 to 0.96 Tg. These results are consistent with recent calorimetric studies and demonstrate that the inert gas permeation technique provides a direct method to observe the onset of molecular translation motion that accompanies the glass to supercooled liquid transition.« less

Stabilization of Quinapril by Incorporating Hydrogen Bonding Interactions

PubMed Central

Roy, B. N.; Singh, G. P.; Godbole, H. M.; Nehate, S. P.

2009-01-01

In the present study stability of various known solvates of quinapril hydrochloride has been compared with nitromethane solvate. Nitromethane solvate was found to be more stable compared to other known solvates. Single crystal X-ray diffraction analysis of quinapril nitromethane solvate shows intermolecular hydrogen bonding between quinapril molecule and nitromethane. Stabilization of quinapril by forming strong hydrogen bonding network as in case of co-crystals was further studied by forming co-crystal with tris(hydroxymethyl)amino methane. Quinapril free base forms a stable salt with tris(hydroxymethyl)amino methane not reported earlier. Quinapril tris(hydroxymethyl)amino methane salt found to be stable even at 80° for 72 h i.e. hardly any formation of diketopiperazine and diacid impurity. As expected single crystal X-ray diffraction analysis reveals tris(hydroxymethyl)amino methane salt of quinapril shows complex hydrogen bonding network between the two entities along with ionic bond. The properties of this stable salt - stable in solid as well as solution phase, might lead to an alternate highly stable formulation. PMID:20502545

A conservative numerical scheme for modeling nonlinear acoustic propagation in thermoviscous homogeneous media

NASA Astrophysics Data System (ADS)

Diaz, Manuel A.; Solovchuk, Maxim A.; Sheu, Tony W. H.

2018-06-01

A nonlinear system of partial differential equations capable of describing the nonlinear propagation and attenuation of finite amplitude perturbations in thermoviscous media is presented. This system constitutes a full nonlinear wave model that has been formulated in the conservation form. Initially, this model is investigated analytically in the inviscid limit where it has been found that the resulting flux function fulfills the Lax-Wendroff theorem, and the scheme can match the solutions of the Westervelt and Burgers equations numerically. Here, high-order numerical descriptions of strongly nonlinear wave propagations become of great interest. For that matter we consider finite difference formulations of the weighted essentially non-oscillatory (WENO) schemes associated with explicit strong stability preserving Runge-Kutta (SSP-RK) time integration methods. Although this strategy is known to be computationally demanding, it is found to be effective when implemented to be solved in graphical processing units (GPUs). As we consider wave propagations in unbounded domains, perfectly matching layers (PML) have been also considered in this work. The proposed system model is validated and illustrated by using one- and two-dimensional benchmark test cases proposed in the literature for nonlinear acoustic propagation in homogeneous thermoviscous media.

3D Visualization for Phoenix Mars Lander Science Operations

NASA Technical Reports Server (NTRS)

Edwards, Laurence; Keely, Leslie; Lees, David; Stoker, Carol

2012-01-01

Planetary surface exploration missions present considerable operational challenges in the form of substantial communication delays, limited communication windows, and limited communication bandwidth. A 3D visualization software was developed and delivered to the 2008 Phoenix Mars Lander (PML) mission. The components of the system include an interactive 3D visualization environment called Mercator, terrain reconstruction software called the Ames Stereo Pipeline, and a server providing distributed access to terrain models. The software was successfully utilized during the mission for science analysis, site understanding, and science operations activity planning. A terrain server was implemented that provided distribution of terrain models from a central repository to clients running the Mercator software. The Ames Stereo Pipeline generates accurate, high-resolution, texture-mapped, 3D terrain models from stereo image pairs. These terrain models can then be visualized within the Mercator environment. The central cross-cutting goal for these tools is to provide an easy-to-use, high-quality, full-featured visualization environment that enhances the mission science team s ability to develop low-risk productive science activity plans. In addition, for the Mercator and Viz visualization environments, extensibility and adaptability to different missions and application areas are key design goals.

Word Frequency Analysis. MOS: 11C. Skill Levels 1 & 2.

DTIC Science & Technology

1981-05-01

EU .I~~k St.AAIWS6PPUTO.6 115 6 %CRRWi A SicURILY . ;u IPS ’.’’ 65pS - g* " ks - - (. S SIGAL 0S0LNT M Sirt STAKES * g1Pptl 6STRA ESIB S...a9. PMl 26 M0AY @,... oPC "N 409 6..TKING I C.LEgMSPTSP ..... ,,,.p5~IeM S.t MAS.,...AS.EI.....NUJOI So....~1.ap 1o MAY 10R.pClI AoS 0..7.T1, PI

The Crank Nicolson Time Integrator for EMPHASIS.

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

McGregor, Duncan Alisdair Odum; Love, Edward; Kramer, Richard Michael Jack

2018-03-01

We investigate the use of implicit time integrators for finite element time domain approxi- mations of Maxwell's equations in vacuum. We discretize Maxwell's equations in time using Crank-Nicolson and in 3D space using compatible finite elements. We solve the system by taking a single step of Newton's method and inverting the Eddy-Current Schur complement allowing for the use of standard preconditioning techniques. This approach also generalizes to more complex material models that can include the Unsplit PML. We present verification results and demonstrate performance at CFL numbers up to 1000.

Selective predation by feral cats on a native skink on Guam

USGS Publications Warehouse

Lardner, Björn; Reed, Robert N.; Adams, Amy A. Yackel; Mazurek, M.J.; Hinkle, Thomas J.; Levasseur, Patricia M.; Palmer, Meredith S.; Savidge, Julie A.

2013-01-01

Two species of skinks (Fig. 1) occur in a 5-ha plot on Guam where we have been conducting intensive research on Brown Treesnake (Boiga irregularis) population biology for nearly a decade (Rodda et al. 2007). The Pacific Blue-tailed Skink (Emoia caeruleocauda [de Vis 1892]) is native to Guam, whereas the Curious Skink (Carlia ailanpalai Zug 2004) is invasive. On the evening of 27 November 2012, PML and MSP discovered a pile of vomited skinks (Fig. 2) inside the plot (UTM 55P: 269125 m E, 1508930 m N).

Acute promyelocytic leukemia: new issues on pathogenesis and treatment response.

PubMed

Vitoux, Dominique; Nasr, Rihab; de The, Hugues

2007-01-01

Pathogenesis of acute promyelocytic leukemia appears to be one of the best understood among human malignancies. The ability of retinoic acid (RA) and arsenic trioxide to directly target the oncogenic promyelocytic leukemia-retinoic receptor A (PML-RARA) fusion protein also made this disease the first model for oncogene-targeted therapies. A set of recent data has significantly increased the complexity of our view of acute promyelocytic leukemia pathogenesis, as well as of therapeutic response. This review summarizes and discusses these findings, which yield novels questions and models.

Trajectory Simulation Model for a Side- Thruster Guided MLRS-Type Vehicle

DTIC Science & Technology

1999-05-01

km halen . Voor de toekomst heeft men behoefte aan een dracht van ongeveer 60 km. Het is de doelstelling van opdracht A95KL410 om kennis en inzicht...G.M.H.J.L. Gadiot Datum mei 1999 Opdrachtnr. A95KL410 Rapportnr. PML 1998-A80 Figuur M.I.- Lancering van een M26-raket vanaf een MLRS ’launcher’. De...Koninklijke Nederlandse Landmacht (KL) heeft het ’Multiple Launcher Rocket System’ (MLRS) in gebruik. Met de huidige uitrusting kan men een dracht van 30

Targeting of the N-terminal coiled coil oligomerization interface of BCR interferes with the transformation potential of BCR-ABL and increases sensitivity to STI571.

PubMed

Beissert, Tim; Puccetti, Elena; Bianchini, Andrea; Güller, Saskia; Boehrer, Simone; Hoelzer, Dieter; Ottmann, Oliver Gerhard; Nervi, Clara; Ruthardt, Martin

2003-10-15

Translocations involving the abl locus on chromosome 9 fuses the tyrosine kinase c-ABL to proteins harboring oligomerization interfaces such as BCR or TEL, enabling these ABL-fusion proteins (X-ABL) to transform cells and to induce leukemia. The ABL kinase activity is blocked by the ABL kinase inhibitor STI571 which abrogates transformation by X-ABL. To investigate the role of oligomerization for the transformation potential of X-ABL and for the sensitivity to STI571, we constructed ABL chimeras with oligomerization interfaces of proteins involved in leukemia-associated translocations such as BCR, TEL, PML, and PLZF. We assessed the capacity of these chimeras to form high molecular weight (HMW) complexes as compared with p185(BCR-ABL). There was a direct relationship between the size of HMW complexes formed by these chimeras and their capacity to induce factor independence in Ba/F3 cells, whereas there was an inverse relationship between the size of the HMW complexes and the sensitivity to STI571. The targeting of the oligomerization interface of p185(BCR-ABL) by a peptide representing the coiled coil region of BCR reduced its potential to transform fibroblasts and increased sensitivity to STI571. Our results indicate that targeting of the oligomerization interfaces of the X-ABL enhances the effects of STI571 in the treatment of leukemia caused by X-ABL.

Dynamics of glass-forming liquids. XV. Dynamical features of molecular liquids that form ultra-stable glasses by vapor deposition

NASA Astrophysics Data System (ADS)

Chen, Zhen; Richert, Ranko

2011-09-01

The dielectric relaxation behavior of ethylbenzene (EBZ) in its viscous regime is measured, and the glass transition temperature (Tg = 116 K) as well as fragility (m = 98) are determined. While the Tg of EBZ from this work is consistent with earlier results, the fragility is found much higher than what has been assumed previously. Literature data is supplemented by the present results on EBZ to compile the dynamic behavior of those glass formers that are known to form ultra-stable glasses by vapor deposition. These dynamics are contrasted with those of ethylcyclohexane, a glass former for which a comparable vapor deposition failed to produce an equally stable glassy state. In a graph that linearizes Vogel-Fulcher-Tammann behavior, i.e., the derivative of -logτ with respect to T/Tg raised to the power of -1/2 versus T/Tg, all ultra-stable glass formers fall onto one master curve in a wide temperature range, while ethylcyclohexane deviates for T ≫ Tg. This result suggests that ultra-stable glass formers share common behavior regarding the dynamics of their supercooled liquid state if scaled to their respective Tg values, and that fragility and related features are linked to the ability to form ultra-stable materials.

Temperature Dependent Characterization of Terahertz Vibrations of Explosives and Related Threat Materials

DTIC Science & Technology

2010-12-10

absorption spectra of 1,3,5,7- tetranitro-1,3,5,7-tetrazocane ( HMX ) polymorphs ,” Chem. Phys. Lett. 489(1-3), 48–53 (2010). 23. P. Main, R. E...The β polymorph is the most stable form of the four polymorphs (α,β,γ,δ) of HMX and the room temperature THz spectrum of β- HMX has been measured by...EXPRESS 27248 polymorph to be formed. The α- HMX and δ- HMX forms are described as stable above room temperature: α- HMX is stable from 377 K to 429 K [24

Characterization of a Stable L-Form of Bacillus subtilis 168

PubMed Central

Gilpin, Richard W.; Young, Frank E.; Chatterjee, Anadi N.

1973-01-01

A stable L-form of Bacillus subtilis 168 (sal-1) has been isolated which grows and divides logarithmically in liquid medium with a generation time of 60 min. This mutant does not synthesize cell wall as evidenced by chemical, biochemical, and morphological analyses. Antibiotics which specifically inhibit cell wall biosynthesis do not affect the growth of the L-form. Significant differences exist between the membrane proteins of the bacillary form and the L-form. The relative profile of membrane proteins varies with the salt concentration of the medium in both the L-form and the bacillary form. Images PMID:4631836

Survival and reversion of a stable L form in soil

NASA Technical Reports Server (NTRS)

Horwitz, A. H.; Casida, L. E., Jr.

1978-01-01

The stable L form of Agromyces ramosus reverted to a bacterial form when incubated in sterilized soil. The cellular and colonial morphology of this bacterial form resembled that of the original parent bacterial form. The two forms differed, however, in that the revertant maintained its bacterial form when transferred onto a low-salt (NaCl) medium but was virtually completely induced into the L-form state on a high-salt medium. The original parent bacterial form was not sensitive to salt. The possibility is discussed that an L-form - bacterial-form cycle for this bacterium might occur naturally in soil. This cycle would be mediated by fluctuations in local salt concentrations in the soil.

[Experimental study of IFN-alpha and IFN-gamma on reversing ATRA-resistance in MR2 cell line].

PubMed

He, Peng-Cheng; Zhang, Mei; Li, Jing; Cao, Yun-Xin; Cai, Rui-Bo; Liu, Ya-Lin

2007-03-01

To explore the possibility and the possible mechanism of reversing ATRA-resistance in MR2 cells by using IFN-alpha and IFN-gamma in combination with all-trans retinoic acid (ATRA). After MR2 cells(ATRA-resistance cell line) were treated with IFN-alpha, IFN-gamma and ATRA alone or IFN-alpha and IFN-gamma in combination with ATRA respectively, the cell proliferation was tested by MTT colorimetry, the cell differentiation was tested through light microscope, by NBT test and flow cytometry (FCM). The expression of promyelocytic leukemia (PML) protein was observed by indirect immunofluorescence staining. Both IFN-alpha and IFN-gamma could inhibit the proliferation of MR2 cells. The effects were more obviously in both IFN-alpha+ATRA group and IFN-gamma+ATRA group. But there were no significant difference between either IFN-alpha group and IFN-gamma group or IFN-alpha+ATRA group and IFN-gamma+ATRA group (P>0.05). Both IFN could also induce the differentiation of MR2 cells. The effects of IFN-alpha+ATRA group and IFN-gamma+ATRA group were more obvious. However, the differentiation of MR2 cells induced by IFN-gamma+ATRA group was more higher than that by IFN-alpha+ATRA group (P<0.05). Both IFN could induce the expression of PML protein. The reversing effcet of IFN-gamma+ATRA group on ATRA-resistence in MR2 cells are more powerful than that of IFN-alpha+ATRA group, which may be related to the different signal transduction pathway of IFN-alpha and IFN-gamma.

Long-term outcome of 31 cases of refractory acute promyelocytic leukemia treated with compound realgar natural indigo tablets administered alternately with chemotherapy

PubMed Central

LIU, YANFENG; HE, PENGCHENG; CHENG, XIAOYAN; ZHANG, MEI

2015-01-01

The aim of the present study was to investigate the long-term survival of patients with refractory acute promyelocytic leukemia (APL) that were administered alternately with compound realgar natural indigo tablet (CRNIT) treatment and chemotherapy. In total, 31 patients with refractory APL were administered with CRNIT treatment alternately with chemotherapy. The complete remission (CR) and relapse rates were estimated by bone marrow (BM) examination. The expression of the promyelocytic leukemia-retinoic acid receptor α (PML-RARα) fusion protein and the apoptosis rate in the retinoic acid (RA)-resistant NB4-R1 cell line administered with CRNIT treatment in vitro were measured by western blot analysis and flow cytometry, respectively. The patients were followed up for 12–60 months, with a median follow-up time of 43 months. The total continuous CR rate was 90.32% (28/31), and the duration of response was between 10.3 and 60 months (median, 42.4 months). The total relapse rate was 9.68% (3/31), and the median time of relapse was 13 months (range, 8–27 months). During the treatment with CRNITs, there was no evident BM depression and only limited side-effects were experienced. Additionally, in vitro cell molecular biology results revealed that CRNIT treatment resulted in a marked induction of apoptosis and degradation of the PML-RARα fusion protein. The present results revealed that CRNIT treatment in combination with chemotherapy is an effective and feasible therapy for the treatment of patients with refractory APL. PMID:26622649

Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia.

PubMed

Wang, Lan; Zhou, Guang-Biao; Liu, Ping; Song, Jun-Hong; Liang, Yang; Yan, Xiao-Jing; Xu, Fang; Wang, Bing-Shun; Mao, Jian-Hua; Shen, Zhi-Xiang; Chen, Sai-Juan; Chen, Zhu

2008-03-25

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARalpha) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G(1)/G(0) arrest in APL cells through hitting multiple targets compared with the effects of mono- or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RARalpha degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine.

Modelling evapotranspiration using the modified Penman-Monteith equation and MODIS data over the Albany Thicket in South Africa

NASA Astrophysics Data System (ADS)

Gwate, O.; Mantel, Sukhmani K.; Palmer, Anthony R.; Gibson, Lesley A.

2016-10-01

Evapotranspiration (ET) is one of the least understood components of the water cycle, particularly in data scarce areas. In a context of climate change, evaluating water vapour fluxes of a particular area is crucial to help understand dynamics in water balance. In data scarce areas, ET modelling becomes vital. The study modelled ET using the Penman-Monteith- Leuning (PML) equation forced by Moderate Resolution Imaging Spectroradiometer (MODIS) leaf area index (LAI) and MODIS albedo with ancillary meteorological data from an automatic weather station. The study area is located on the Albany Thicket (AT) biome of South Africa and the dominant plant species is Portulacaria afra. The biggest challenge to the implementation of the PML is the parameterisation of surface and stomatal conductance. We tested the use of volumetric soil water content (fswc), precipitation and equilibrium evaporation ratio (fzhang) and soil drying after precipitation (f) approaches to account for the fraction (f) of evaporation from the soil. ET from the model was validated using an eddy covariance system (EC). Post processing of eddy covariance data was implement using EddyPro software. The fdrying method performed better with a root mean square observations standard deviation ratio (RSR) of 0.97. The results suggest that modelling ET over the AT vegetation is delicate owing to strong vegetation phenological control of the ET process. The convergent evolution of the vegetation has resulted in high plant available water than the model can detect. It is vital to quantify plant available water in order to improve ET modelling in thicket vegetation.

Operational environmental assessment "Prestige" (a recent application of the MOCASSIM system).

NASA Astrophysics Data System (ADS)

Vitorino, J.; Rusu, E.; Almeida, S.; Monteiro, M.; Lermusiaux, P.; Haley, P.; Leslie, W.; Miller, P.; Coelho, E.; Signell, R.

2003-04-01

The sinking of tanker "Prestige", on the 19th November 2002, offshore the northwestern coasts of Spain and Portugal, has lead to a major environmental disaster. In this contribution we present several aspects of the operational environmental assessment "Prestige" conducted by Instituto Hidrografico (IH) in close colaboration with Instituto de Meteorologia (IM), the Harvard University, the Plymouth Marine Laboratory (PML) and the Saclancentre. The operational system MOCASSIM, which is presently being developed at IH, was used to provide forecasts of the evolution of oceanographic conditions offshore the NW Iberian coast. The system integrates a primitive equation model with data assimilation (the Harvard Ocean Prediction System - HOPS) and two wave models (the SWAN and WW3 models). The numerical domains used in both HOPS and SWAN models covered the area bewteen 40ºN and 46ºN and from 7ºW to 15ºW, and included the sinking area as well as the coastal regions more directly exposed to the oil spill. The models were run with atmospheric forcing conditions provided by the limited area model ALADIN, run operationally at IM, complemented with NOGAPS wind fields from the NATO METOC site of Rota. The HOPS simulations included assimilation of several data available for region. These data sets included CTD casts from the Northern Spanish shelf and slope (made available by University of Baleares) and SST data processed at the Remote Sensing Group of the PML. Results from both models were used in oil spill models and allowed an estimation of the impacts on the coastal areas.

Dentoskeletal features in individuals with ectopic eruption of the permanent maxillary first molar

PubMed Central

Rozzi, Matteo; Cardoni, Giulia; Ricchiuti, Maria Rosaria; Cozza, Paola

2015-01-01

Objective The aim of the study was to analyze the prevalence and distribution of ectopic eruption of the permanent maxillary first molar (EEM) in individuals scheduled for orthodontic treatment and to investigate the association of EEM with dental characteristics, maxillary skeletal features, crowding, and other dental anomalies. Methods A total of 1,317 individuals were included and randomly divided into two groups. The first 265 subjects were included as controls, while the remaining 1,052 subjects included the sample from which the final experimental EEM group was derived. The mesiodistal (M-D) crown width of the deciduous maxillary second molar and permanent maxillary first molar, maxillary arch length (A-PML), maxillomandibular transverse skeletal relationships (anterior and posterior transverse interarch discrepancies, ATID and PTID), maxillary and mandibular tooth crowding, and the presence of dental anomalies were recorded for each subject, and the statistical significance of differences in these parameters between the EEM and control groups was determined using independent sample t-tests. Chi-square tests were used to compare the prevalence of other dental anomalies between the two groups. Results The prevalence of maxillary EEM was 2.5%. The M-D crown widths, ATID and PTID, and tooth crowding were significantly greater, while A-PML was significantly smaller, in the EEM group than in the control group. Only two subjects showed an association between EEM and maxillary lateral incisor anomalies, which included agenesis in one and microdontia in the other. Conclusions EEM may be a risk factor for maxillary arch constriction and severe tooth crowding. PMID:26258065

Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease.

PubMed

Garvey, L; Winston, A; Walsh, J; Post, F; Porter, K; Gazzard, B; Fisher, M; Leen, C; Pillay, D; Hill, T; Johnson, M; Gilson, R; Anderson, J; Easterbrook, P; Bansi, L; Orkin, C; Ainsworth, J; Palfreeman, A; Gompels, M; Phillips, A N; Sabin, C A

2011-02-22

The impact of different antiretroviral agents on the risk of developing or surviving CNS disease remains unknown. The aim of this study was to investigate whether using antiretroviral regimens with higher CNS penetration effectiveness (CPE) scores was associated with reduced incidence of CNS disease and improved survival in the UK Collaborative HIV Cohort (CHIC) Study. Adults without previous CNS disease, who commenced combination antiretroviral therapy (cART) between 1996 and 2008, were included (n = 22,356). Initial and most recent cART CPE scores were calculated. CNS diseases were HIV encephalopathy (HIVe), progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis (TOXO), and cryptococcal meningitis (CRYPTO). Incidence rates and overall survival were stratified by CPE score. A multivariable Poisson regression model was used to identify independent associations. The median (interquartile range) CPE score for initial cART regimen increased from 7 (5-8) in 1996-1997 to 9 (8-10) in 2000-2001 and subsequently declined to 6 (7-8) in 2006-2008. Differences in gender, HIV acquisition risk group, and ethnicity existed between CPE score strata. A total of 251 subjects were diagnosed with a CNS disease (HIVe 80; TOXO 59; CRYPTO 56; PML 54). CNS diseases occurred more frequently in subjects prescribed regimens with CPE scores ≤ 4, and less frequently in those with scores ≥ 10; however, these differences were nonsignificant. Initial and most recent cART CPE scores ≤ 4 were independently associated with increased risk of death. Clinical status at time of commencing cART influences antiretroviral selection and CPE score. This information should be considered when utilizing CPE scores for retrospective analyses.

Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

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

Huai, Lei; Wang, Cuicui; Zhang, Cuiping

2012-06-08

Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acutemore » promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.« less

Best practice in the use of natalizumab in multiple sclerosis

PubMed Central

2013-01-01

Natalizumab is approved for the treatment of patients with relapsing–remitting multiple sclerosis who have failed first-line treatment with traditional disease-modifying therapies or who have highly active disease. The drug has proved highly effective, both in a clinical trial setting and in clinical practice, with marked reductions in the rate of clinical relapses and slowed disease progression. These clinical outcomes are mirrored by a marked reduction in disease activity as evidenced by magnetic resonance imaging of the brain. However, natalizumab treatment has been associated with a risk of progressive multifocal leukoencephalopathy (PML), a potentially fatal condition caused by JC virus (JCV) activation. When this condition was detected in a clinical trial shortly after approval, the drug was immediately and voluntarily withdrawn from the market. As a condition of its reinstatement, stringent pharmacovigilance measures and a risk management plan were enforced. The recent availability of a two-step enzyme-linked immunosorbent assay (ELISA) test for the presence of anti-JCV antibodies (free testing is available in a central laboratory for registered centers), along with an ever-improving understanding of other risk factors such as prior immunosuppressant use and duration of treatment, allow an increasingly refined stratification of the risk of PML. This improved stratification of risk can help guide decisions about treatment. This review will also deal with other topics of relevance to clinical practice such as the development of antinatalizumab antibodies and their negative implications in terms of hypersensitivity reactions and loss of efficacy, withdrawal of treatment, and compassionate pediatric use. PMID:23483450

JC Polyomavirus Attachment, Entry, and Trafficking: Unlocking the Keys to a Fatal Infection

PubMed Central

Maginnis, Melissa S.; Nelson, Christian D.S.; Atwood, Walter J.

2014-01-01

The human JC polyomavirus (JCPyV) causes a lifelong persistent infection in the reno-urinary tract in the majority of the adult population worldwide. In healthy individuals infection is asymptomatic, while in immunocompromised individuals the virus can spread to the central nervous system and cause a fatal demyelinating disease known as progressive multifocal leukoencephalopathy (PML). There are currently very few treatment options for this rapidly progressing and devastating disease. Understanding the basic biology of JCPyV-host cell interactions is critical for the development of therapeutic strategies to prevent or treat PML. Research in our laboratory has focused on gaining a detailed mechanistic understanding of the initial steps in the JCPyV life cycle in order to define how JCPyV selectively targets cells in the kidney and brain. JCPyV requires sialic acids to attach to host cells and initiate infection, and JCPyV demonstrates specificity for the oligosaccharide lactoseries tetrasaccharide c (LSTc) with an α2,6-linked sialic acid. Following viral attachment, JCPyV entry is facilitated by the 5-hydroxytryptamine (5-HT)2 family of serotonin receptors via clathrin-dependent endocytosis. JCPyV then undergoes retrograde transport to the endoplasmic reticulum (ER) where viral disassembly begins. A novel retrograde transport inhibitor termed Retro-2cycl prevents trafficking of JCPyV to the ER and inhibits both initial virus infection and infectious spread in cell culture. Understanding the molecular mechanisms by which JCPyV establishes infection will open up new avenues for the prevention or treatment of virus-induced disease. PMID:25078361

Systematic review of the published data on the worldwide prevalence of John Cunningham virus in patients with multiple sclerosis and neuromyelitis optica.

PubMed

Paz, Sonia Patricia Castedo; Branco, Luciana; Pereira, Marina Alves de Camargo; Spessotto, Caroline; Fragoso, Yara Dadalti

2018-01-01

John Cunningham virus (JCV) is a polyoma virus that infects humans, mainly in childhood or adolescence, and presents no symptomatic manifestations. JCV can cause progressive multifocal leukoencephalopathy (PML) in immunosuppressed individuals, including those undergoing treatment for multiple sclerosis (MS) and neuromyelitis optica (NMO). PML is a severe and potentially fatal disease of the brain. The prevalence of JCV antibodies in human serum has been reported to be between 50.0 and 90.0%. The aim of the present study was to review worldwide data on populations of patients with MS and NMO in order to establish the rates of JCV seropositivity in these individuals. The present review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines and used the following search terms: "JCV" OR "JC virus" AND "multiple sclerosis" OR "MS" OR "NMO" OR "neuromyelitis optica" AND "prevalence." These terms were searched for both in smaller and in larger clusters of words. The databases searched included PubMed, MEDLINE, SciELO, LILACS, Google Scholar, and Embase. After the initial selection, 18 papers were included in the review. These articles reported the prevalence of JCV antibodies in the serum of patients with MS or NMO living in 26 countries. The systematic review identified data on 29,319 patients with MS/NMO and found that 57.1% of them (16,730 individuals) were seropositive for the anti-JCV antibody (range, 40.0 to 69.0%). The median worldwide prevalence of JCV among adults with MS or NMO was found to be 57.1%.

Susceptibility of Primary Human Choroid Plexus Epithelial Cells and Meningeal Cells to Infection by JC Virus.

PubMed

O'Hara, Bethany A; Gee, Gretchen V; Atwood, Walter J; Haley, Sheila A

2018-04-15

JC polyomavirus (JCPyV) establishes a lifelong persistence in roughly half the human population worldwide. The cells and tissues that harbor persistent virus in vivo are not known, but renal tubules and other urogenital epithelial cells are likely candidates as virus is shed in the urine of healthy individuals. In an immunosuppressed host, JCPyV can become reactivated and cause progressive multifocal leukoencephalopathy (PML), a fatal demyelinating disease of the central nervous system. Recent observations indicate that JCPyV may productively interact with cells in the choroid plexus and leptomeninges. To further study JCPyV infection in these cells, primary human choroid plexus epithelial cells and meningeal cells were challenged with virus, and their susceptibility to infection was compared to the human glial cell line, SVG-A. We found that JCPyV productively infects both choroid plexus epithelial cells and meningeal cells in vitro Competition with the soluble receptor fragment LSTc reduced virus infection in these cells. Treatment of cells with neuraminidase also inhibited both viral infection and binding. Treatment with the serotonin receptor antagonist, ritanserin, reduced infection in SVG-A and meningeal cells. We also compared the ability of wild-type and sialic acid-binding mutant pseudoviruses to transduce these cells. Wild-type pseudovirus readily transduced all three cell types, but pseudoviruses harboring mutations in the sialic acid-binding pocket of the virus failed to transduce the cells. These data establish a novel role for choroid plexus and meninges in harboring virus that likely contributes not only to meningoencephalopathies but also to PML. IMPORTANCE JCPyV infects greater than half the human population worldwide and causes central nervous system disease in patients with weakened immune systems. Several recent reports have found JCPyV in the choroid plexus and leptomeninges of patients with encephalitis. Due to their role in forming the blood-cerebrospinal fluid barrier, the choroid plexus and leptomeninges are also poised to play roles in virus invasion of brain parenchyma, where infection of macroglial cells leads to the development of progressive multifocal leukoencephalopathy, a severely debilitating and often fatal infection. In this paper we show for the first time that primary choroid plexus epithelial cells and meningeal cells are infected by JCPyV, lending support to the association of JCPyV with meningoencephalopathies. These data also suggest that JCPyV could use these cells as reservoirs for the subsequent invasion of brain parenchyma. Copyright © 2018 American Society for Microbiology.

Preparation of highly oxidized RBa.sub.2 Cu.sub.4 O.sub.8 superconductors

DOEpatents

Morris, Donald E.

1991-01-01

Novel superconducting materials in the form of compounds, structures or phases are formed by performing otherwise known syntheses in a highly oxidizing atmosphere rather than that created by molecular oxygen at atmospheric pressure or below. This leads to the successful synthesis of novel superconducting compounds which are thermodynamically stable at the conditions under which they are formed. The compounds and structures thus formed are substantially nonsusceptible to variations in their oxygen content when subjected to changing temperatures, thereby forming a temperature-stable substantially single phase crystal.

The topological pressure-temperature phase diagram of fluoxetine nitrate: monotropy unexpectedly turning into enantiotropy

NASA Astrophysics Data System (ADS)

Céolin, René; Rietveld, Ivo B.

2017-04-01

The phase behavior of pharmaceuticals is important for regulatory requirements and dosage form development. Racemic fluoxetine nitrate possesses two crystalline forms for which initial measurements indicated that they have a monotropic relationship with form I the only stable form. By constructing the topological pressure-temperature phase diagram, it has been shown that unexpectedly form II has a stable domain in the phase diagram and can be easily obtained by heating and grinding. The pressure necessary to obtain form II is only 11 MPa, which is much lower than most pressure used for tableting in the pharmaceutical industry.

Form-Stable Phase Change Materials Based on Eutectic Mixture of Tetradecanol and Fatty Acids for Building Energy Storage: Preparation and Performance Analysis

PubMed Central

Huang, Jingyu; Lu, Shilei; Kong, Xiangfei; Liu, Shangbao; li, Yiran

2013-01-01

This paper is focused on preparation and performance analysis of a series of form-stable phase change materials (FSPCMs), based on eutectic mixtures as phase change materials (PCMs) for thermal energy storage and high-density polyethylene (HDPE)-ethylene-vinyl acetate (EVA) polymer as supporting materials. The PCMs were eutectic mixtures of tetradecanol (TD)–capric acid (CA), TD–lauric acid (LA), and TD–myristic acid (MA), which were rarely explored before. Thermal properties of eutectic mixtures and FSPCMs were measured by differential scanning calorimeter (DSC). The onset melting/solidification temperatures of form-stable PCMs were 19.13 °C/13.32 °C (FS TD–CA PCM), 24.53 °C/24.92 °C (FS TD–LA PCM), and 33.15 °C/30.72 °C (FS TD–MA PCM), respectively, and latent heats were almost greater than 90 J/g. The surface morphologies and chemical stability of form-stable PCM were surveyed by scanning electron microscopy (SEM) and Fourier-transform infrared (FT-IR) spectroscopy, respectively. The thermal cycling test revealed that the thermal reliability of these three form-stable PCMs was good. Thermal storage/release experiment indicated melting/solidification time was shortened by introducing 10 wt % aluminum powder (AP). It is concluded that these FSPCMs can act as potential building thermal storage materials in terms of their satisfactory thermal properties. PMID:28788358

Form-Stable Phase Change Materials Based on Eutectic Mixture of Tetradecanol and Fatty Acids for Building Energy Storage: Preparation and Performance Analysis.

PubMed

Huang, Jingyu; Lu, Shilei; Kong, Xiangfei; Liu, Shangbao; Li, Yiran

2013-10-22

This paper is focused on preparation and performance analysis of a series of form-stable phase change materials (FSPCMs), based on eutectic mixtures as phase change materials (PCMs) for thermal energy storage and high-density polyethylene (HDPE)-ethylene-vinyl acetate (EVA) polymer as supporting materials. The PCMs were eutectic mixtures of tetradecanol (TD)-capric acid (CA), TD-lauric acid (LA), and TD-myristic acid (MA), which were rarely explored before. Thermal properties of eutectic mixtures and FSPCMs were measured by differential scanning calorimeter (DSC). The onset melting/solidification temperatures of form-stable PCMs were 19.13 °C/13.32 °C (FS TD-CA PCM), 24.53 °C/24.92 °C (FS TD-LA PCM), and 33.15 °C/30.72 °C (FS TD-MA PCM), respectively, and latent heats were almost greater than 90 J/g. The surface morphologies and chemical stability of form-stable PCM were surveyed by scanning electron microscopy (SEM) and Fourier-transform infrared (FT-IR) spectroscopy, respectively. The thermal cycling test revealed that the thermal reliability of these three form-stable PCMs was good. Thermal storage/release experiment indicated melting/solidification time was shortened by introducing 10 wt % aluminum powder (AP). It is concluded that these FSPCMs can act as potential building thermal storage materials in terms of their satisfactory thermal properties.

Brine-in-crude-oil emulsions at the Strategic Petroleum Reserve

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

Nemer, Martin B.; Lord, David L.; MacDonald, Terry L.

2013-10-01

Metastable water-in-crude-oil emulsion formation could occur in a Strategic Petroleum Reserve (SPR) cavern if water were to flow into the crude-oil layer at a sufficient rate. Such a situation could arise during a drawdown from a cavern with a broken-hanging brine string. A high asphaltene content (> 1.5 wt %) of the crude oil provides the strongest predictor of whether a metastable water-in-crude-oil emulsion will form. However there are many crude oils with an asphaltene content > 1.5 wt % that don't form stable emulsions, but few with a low asphaltene content that do form stable emulsions. Most of themore » oils that form stable emulsions are "sour" by SPR standards indicating they contain total sulfur > 0.50 wt %.« less

Publisher Correction: RING tetramerization is required for nuclear body biogenesis and PML sumoylation.

PubMed

Wang, Pengran; Benhenda, Shirine; Wu, Haiyan; Lallemand-Breitenbach, Valérie; Zhen, Tao; Jollivet, Florence; Peres, Laurent; Li, Yuwen; Chen, Sai-Juan; Chen, Zhu; de Thé, Hugues; Meng, Guoyu

2018-05-04

In the originally published version of this Article, the authors Sai-Juan Chen and Zhu Chen were incorrectly listed as being affiliated with 'University Paris Diderot, Sorbonne Paris Cité, INSERM U944, CNRS UMR7212, Equipe labellisée LNCC, Hôpital St. Louis 1, Paris 75475, France', and the affiliation 'Institute of Health Sciences, Shanghai Institutes for Biological Sciences and Graduate School, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China' was inadvertently omitted. These errors have now been corrected in both the PDF and HTML versions of the Article.

Identification of three redundant segments responsible for herpes simplex virus 1 ICP0 to fuse with ND10 nuclear bodies.

PubMed

Zheng, Yi; Gu, Haidong

2015-04-01

Infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) is a key regulator in both lytic and latent infections. In lytic infection, an important early event is the colocalization of ICP0 to nuclear domain 10 (ND10), the discrete nuclear bodies that impose restrictions on viral expression. ICP0 contains an E3 ubiquitin ligase that degrades promyelocytic leukemia protein (PML) and Sp100, two major components of ND10, and disperses ND10 to alleviate repression. We previously reported that the association between ICP0 and ND10 is a dynamic process that includes three steps: adhesion, fusion, and retention. ICP0 residues 245 to 474, defined as ND10 entry signal (ND10-ES), is a region required for the fusion step. Without ND10-ES, ICP0 adheres at the ND10 surface but fails to enter. In the present study, we focus on characterizing ND10-ES. Here we report the following. (i) Fusion of ICP0 with ND10 relies on specific sequences located within ND10-ES. Replacement of ND10-ES by the corresponding region from ORF61 of varicella-zoster virus did not rescue ND10 fusion. (ii) Three tandem ND10 fusion segments (ND10-FS1, ND10-FS2, and ND10-FS3), encompassing 200 amino acids within ND10-ES, redundantly facilitate fusion. Each of the three segments is sufficient to independently drive the fusion process, but none of the segments by themselves are necessary for ND10 fusion. Only when all three segments are deleted is fusion blocked. (iii) The SUMO interaction motif located within ND10-FS2 is not required for ND10 fusion but is required for the complete degradation of PML, suggesting that PML degradation and ND10 fusion are regulated by different molecular mechanisms. ND10 nuclear bodies are part of the cell-intrinsic antiviral defenses that restrict viral gene expression upon virus infection. As a countermeasure, infected cell protein 0 (ICP0) of herpes simplex virus 1 (HSV-1) localizes to ND10s, degrades the ND10 organizer, and disperses ND10 components in order to alleviate repression. We studied the ICP0-ND10 association to delineate elements important for this dynamic interaction and to understand its role in viral replication and host defense. In this work, we show that ICP0 contains three redundant segments to ensure an effective mergence of ICP0 with ND10 nuclear bodies. This is the first study to systematically investigate ICP0 elements that are important for ICP0-ND10 fusion. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Comparative semiempirical and ab initio study of the structural and chemical properties of uric acid and its anions

NASA Astrophysics Data System (ADS)

Altarsha, Muhannad; Monard, Gérald; Castro, Bertrand

Semiempirical, density functional theory (DFT), and ab initio calculations have been performed to assess the relative stabilities of 15 possible tautomer forms of neutral uric acid, and of the different urate mono- and dianion forms. These methods have also been used to compute ionization potentials (IPs) for uric acid and its derived anions. Overall, we have found that semiempirical calculations, in particular PM3, perform well as compared with B3LYP or MP2 computations toward these different structural and chemical properties of uric acid: the triketo form of uric acid is the most stable tautomer form of neutral uric acid. Three other tautomer forms are relatively close in energy, within the range 2-6 kcal/mol above the triketo form, with a mean energy deviation of only 1.3 kcal/mol between PM3 and DFT or ab initio results; the monoanion form of uric acid obtained by abstracting one proton in position 3 (denoted UAN3-) is the most stable form among all four possible urate monoanions both in gas phase and in solution; the dianion form of uric acid obtained by abstracting two protons, respectively, in positions 3 and 9 of uric acid (denoted UAN3-N9-) is the most stable urate dianion form both in gas phase and in solution. However, these two most stable species do not have the lowest IPs in solution: among monoanions and dianions, respectively, the species with the lowest IPs are UAN7- and UAN7-N9-.

Polymorphs and polymorphic cocrystals of temozolomide.

PubMed

Babu, N Jagadeesh; Reddy, L Sreenivas; Aitipamula, Srinivasulu; Nangia, Ashwini

2008-07-07

Crystal polymorphism in the antitumor drug temozolomide (TMZ), cocrystals of TMZ with 4,4'-bipyridine-N,N'-dioxide (BPNO), and solid-state stability were studied. Apart from a known X-ray crystal structure of TMZ (form 1), two new crystalline modifications, forms 2 and 3, were obtained during attempted cocrystallization with carbamazepine and 3-hydroxypyridine-N-oxide. Conformers A and B of the drug molecule are stabilized by intramolecular amide N--HN(imidazole) and N--HN(tetrazine) interactions. The stable conformer A is present in forms 1 and 2, whereas both conformers crystallized in form 3. Preparation of polymorphic cocrystals I and II (TMZBPNO 1:0.5 and 2:1) were optimized by using solution crystallization and grinding methods. The metastable nature of polymorph 2 and cocrystal II is ascribed to unused hydrogen-bond donors/acceptors in the crystal structure. The intramolecularly bonded amide N-H donor in the less stable structure makes additional intermolecular bonds with the tetrazine C==O group and the imidazole N atom in stable polymorph 1 and cocrystal I, respectively. All available hydrogen-bond donors and acceptors are used to make intermolecular hydrogen bonds in the stable crystalline form. Synthon polymorphism and crystal stability are discussed in terms of hydrogen-bond reorganization.

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

Alred, Erik J.; Scheele, Emily G.; Berhanu, Workalemahu M.

Recent experiments indicate a connection between the structure of amyloid aggregates and their cytotoxicity as related to neurodegenerative diseases. Of particular interest is the Iowa Mutant, which causes early-onset of Alzheimer's disease. While wild-type Amyloid β-peptides form only parallel beta-sheet aggregates, the mutant also forms meta-stable antiparallel beta sheets. Since these structural variations may cause the difference in the pathological effects of the two Aβ-peptides, we have studied in silico the relative stability of the wild type and Iowa mutant in both parallel and antiparallel forms. We compare regular molecular dynamics simulations with such where the viscosity of the samplesmore » is reduced, which, we show, leads to higher sampling efficiency. By analyzing and comparing these four sets of all-atom molecular dynamics simulations, we probe the role of the various factors that could lead to the structural differences. Our analysis indicates that the parallel forms of both wild type and Iowa mutant aggregates are stable, while the antiparallel aggregates are meta-stable for the Iowa mutant and not stable for the wild type. The differences result from the direct alignment of hydrophobic interactions in the in-register parallel oligomers, making them more stable than the antiparallel aggregates. The slightly higher thermodynamic stability of the Iowa mutant fibril-like oligomers in its parallel organization over that in antiparallel form is supported by previous experimental measurements showing slow inter-conversion of antiparallel aggregates into parallel ones. Knowledge of the mechanism that selects between parallel and antiparallel conformations and determines their relative stability may open new avenues for the development of therapies targeting familial forms of early-onset Alzheimer's disease.« less

c-di-GMP can form remarkably stable G-quadruplexes at physiological conditions in the presence of some planar intercalators.

PubMed

Nakayama, Shizuka; Kelsey, Ilana; Wang, Jingxin; Sintim, Herman O

2011-04-28

The ubiquitous bacterial biofilm regulator, c-di-GMP can form G-quadruplexes at physiological conditions in the presence of some aromatic compounds, such as acriflavine and proflavine. The fluorescence of these compounds is quenched upon c-di-GMP binding and some of the formed c-di-GMP G-quadruplexes are stable even at 75 °C. © The Royal Society of Chemistry 2011

Using Finite Element and Eigenmode Expansion Methods to Investigate the Periodic and Spectral Characteristic of Superstructure Fiber Bragg Gratings

PubMed Central

He, Yue-Jing; Hung, Wei-Chih; Lai, Zhe-Ping

2016-01-01

In this study, a numerical simulation method was employed to investigate and analyze superstructure fiber Bragg gratings (SFBGs) with five duty cycles (50%, 33.33%, 14.28%, 12.5%, and 10%). This study focuses on demonstrating the relevance between design period and spectral characteristics of SFBGs (in the form of graphics) for SFBGs of all duty cycles. Compared with complicated and hard-to-learn conventional coupled-mode theory, the result of the present study may assist beginner and expert designers in understanding the basic application aspects, optical characteristics, and design techniques of SFBGs, thereby indirectly lowering the physical concepts and mathematical skills required for entering the design field. To effectively improve the accuracy of overall computational performance and numerical calculations and to shorten the gap between simulation results and actual production, this study integrated a perfectly matched layer (PML), perfectly reflecting boundary (PRB), object meshing method (OMM), and boundary meshing method (BMM) into the finite element method (FEM) and eigenmode expansion method (EEM). The integrated method enables designers to easily and flexibly design optical fiber communication systems that conform to the specific spectral characteristic by using the simulation data in this paper, which includes bandwidth, number of channels, and band gap size. PMID:26861322

Analysis of Spatial Point Patterns in Nuclear Biology

PubMed Central

Weston, David J.; Adams, Niall M.; Russell, Richard A.; Stephens, David A.; Freemont, Paul S.

2012-01-01

There is considerable interest in cell biology in determining whether, and to what extent, the spatial arrangement of nuclear objects affects nuclear function. A common approach to address this issue involves analyzing a collection of images produced using some form of fluorescence microscopy. We assume that these images have been successfully pre-processed and a spatial point pattern representation of the objects of interest within the nuclear boundary is available. Typically in these scenarios, the number of objects per nucleus is low, which has consequences on the ability of standard analysis procedures to demonstrate the existence of spatial preference in the pattern. There are broadly two common approaches to look for structure in these spatial point patterns. First a spatial point pattern for each image is analyzed individually, or second a simple normalization is performed and the patterns are aggregated. In this paper we demonstrate using synthetic spatial point patterns drawn from predefined point processes how difficult it is to distinguish a pattern from complete spatial randomness using these techniques and hence how easy it is to miss interesting spatial preferences in the arrangement of nuclear objects. The impact of this problem is also illustrated on data related to the configuration of PML nuclear bodies in mammalian fibroblast cells. PMID:22615822

Isolation, sequencing and expression of RED, a novel human gene encoding an acidic-basic dipeptide repeat.

PubMed

Assier, E; Bouzinba-Segard, H; Stolzenberg, M C; Stephens, R; Bardos, J; Freemont, P; Charron, D; Trowsdale, J; Rich, T

1999-04-16

A novel human gene RED, and the murine homologue, MuRED, were cloned. These genes were named after the extensive stretch of alternating arginine (R) and glutamic acid (E) or aspartic acid (D) residues that they contain. We term this the 'RED' repeat. The genes of both species were expressed in a wide range of tissues and we have mapped the human gene to chromosome 5q22-24. MuRED and RED shared 98% sequence identity at the amino acid level. The open reading frame of both genes encodes a 557 amino acid protein. RED fused to a fluorescent tag was expressed in nuclei of transfected cells and localised to nuclear dots. Co-localisation studies showed that these nuclear dots did not contain either PML or Coilin, which are commonly found in the POD or coiled body nuclear compartments. Deletion of the amino terminal 265 amino acids resulted in a failure to sort efficiently to the nucleus, though nuclear dots were formed. Deletion of a further 50 amino acids from the amino terminus generates a protein that can sort to the nucleus but is unable to generate nuclear dots. Neither construct localised to the nucleolus. The characteristics of RED and its nuclear localisation implicate it as a regulatory protein, possibly involved in transcription.

Effect of Si Content on Oxide Formation on Surface of Molten Fe-Cr-C Alloy Bath During Oxygen Top Blowing

NASA Astrophysics Data System (ADS)

Mihara, Ryosuke; Gao, Xu; Kim, Sun-joong; Ueda, Shigeru; Shibata, Hiroyuki; Seok, Min Oh; Kitamura, Shin-ya

2018-02-01

Using a direct observation experimental method, the oxide formation behavior on the surface of Fe-Cr-5 mass pct C-Si alloy baths during decarburization by a top-blown Ar-O2 mixture was studied. The effects of the initial Si and Cr content of the alloy, temperature, and oxygen feed ratio on oxide formation were investigated. The results showed that, for alloys without Si, oxide particles, unstable oxide films, and stable oxide films formed sequentially. The presence of Si in the alloy changed the formation behavior of stable oxide film, and increased the crucial C content when stable oxide film started to form. Increasing the temperature, decreasing the initial Cr content, and increasing the ratio of the diluting gas decreased the critical C content at which a stable oxide film started to form. In addition, the P CO and a_{{{Cr}2 {O}3 }} values at which oxides started to form were estimated using Hilty's equation and the equilibrium relation to understand the formation conditions and the role of each parameter in oxide formation.

Conformational analysis, tautomerization, IR, Raman, and NMR studies of benzyl acetoacetate

NASA Astrophysics Data System (ADS)

Tayyari, Sayyed Faramarz; Naghavi, Farnaz; Pojhan, Sahar; McClurg, Ryan W.; Sammelson, Robert E.

2011-02-01

A complete conformational analysis of the keto and enol forms of benzyl acetoacetate (BAA), a β-dicarbonyl compound, was carried out by ab initio calculations, at the density functional theory (DFT) level. By inspection of all possible conformers and tautomers, 22 stable cis-enol, 28 stable trans-enol, and five keto conformers were obtained. Among all stable cis-enol forms only six of them are engaged in intramolecular hydrogen bond. The hydrogen bond strength of the most stable conformer of BAA is compared with that of acetylacetone (AA) and dimethyl oxaloacetate (DMOA). Harmonic vibrational frequencies of the most stable enol and keto forms and their deuterated analogues were also calculated and compared with the experimental data. According to the theoretical calculations, the hydrogen bond strength of the most stable enol conformer of BAA is 56.7 kJ/mol (calculated at the B3LYP/6-311++G ∗∗ level), about 10 kJ/mol less than that of AA. This weakening of hydrogen bond is consistent with the spectroscopic results. NMR studies indicate that BAA exists mainly as a keto tautomer in all considered solutions. The Gibbs energies for keto/enol tautomerization were calculated at the B3LYP level, with several basis sets, in both gas phase and CH 3CN solution (using PCM model), for the most stable enol and keto conformers.

Photochemical isomerizations of thiosemicarbazide, a matrix isolation study.

PubMed

Rostkowska, Hanna; Lapinski, Leszek; Kozankiewicz, Boleslaw; Nowak, Maciej J

2012-10-11

Two thione conformers of monomeric thiosemicarbazide were trapped from the gas phase into a low-temperature Ar matrix. A phototransformation converting the less stable form of the compound into the most stable conformer was induced by irradiation with near-IR (λ = 1462 nm) or UV (λ > 320 nm) light. This photoeffect allowed separation of the IR spectra of the observed thione forms. The structures of both observed isomers were identified by comparison of the separated experimental IR spectra with the spectra theoretically predicted for two most stable forms of the compound. The population ratio of the two conformers in an Ar matrix, prior to any irradiation, was estimated to be equal ≈2:1. Irradiation of matrix-isolated thiosemicarbazide with shorter-wavelength UV (λ > 270 nm) light induced a phototautomeric reaction generating thiol forms of the compound.

Failure of in vitro-differentiated mesenchymal stem cells from the synovial membrane to form ectopic stable cartilage in vivo.

PubMed

De Bari, Cosimo; Dell'Accio, Francesco; Luyten, Frank P

2004-01-01

We previously reported the identification in a nude mouse assay of molecular markers predictive of the capacity of articular cartilage-derived cells (ACDCs) to form ectopic stable cartilage that is resistant to vascular invasion and endochondral ossification. In the present study, we investigated whether in vitro-differentiated mesenchymal stem cells (MSCs) from the synovial membrane (SM) express the stable-chondrocyte markers and form ectopic stable cartilage in vivo. Chondrogenesis was induced in micromass culture with the addition of transforming growth factor beta1 (TGFbeta1). After acquisition of the cartilage phenotype, micromasses were implanted subcutaneously into nude mice. Alternatively, cells were released enzymatically and either replated in monolayer or injected intramuscularly into nude mice. Marker analysis was performed by quantitative reverse transcription-polymerase chain reaction. Cell death was detected with TUNEL assay. Cartilage-like micromasses and released cells expressed the stable-chondrocyte markers at levels comparable with those expressed by stable ACDCs. The released cells lost chondrocyte marker expression by 24 hours in monolayer and failed to form cartilage when injected intramuscularly into nude mice. Instead, myogenic differentiation was detected. When intact TGFbeta1-treated micromasses were implanted subcutaneously, they partially lost their cartilage phenotype and underwent cell death and neoangiogenesis within 1 week. At later time points (15-40 days), we retrieved neither cartilage nor bone, and human cells were not detectable. The chondrocyte-like phenotype of human SM MSCs, induced in vitro under specific conditions, appears to be unstable and is not sufficient to obtain ectopic formation of stable cartilage in vivo. Studies in animal models of joint surface defect repair are necessary to evaluate the stability of the SM MSC chondrocyte-like phenotype within the joint environment.

Serum IgG antibodies from healthy subjects up to 100 years old react to JC polyomavirus.

PubMed

Bononi, Ilaria; Mazzoni, Elisa; Pietrobon, Silvia; Manfrini, Marco; Torreggiani, Elena; Rossini, Marika; Lotito, Francesca; Guerra, Giovanni; Rizzo, Paola; Martini, Fernanda; Tognon, Mauro

2018-08-01

JC polyomavirus (JCPyV) was identified in 1971 in the brain tissue of a patient (J.C.) affected by the progressive multifocal leukoencephalopathy (PML). JCPyV encodes for the oncoproteins large T antigen (Tag) and small t-antigen (tag). These oncoproteins are responsible of the cell transformation and tumorigenesis in experimental animals. JCPyV is ubiquitous in human populations. After the primary infection, which is usually asymptomatic, JCPyV remains lifelong in the host in a latent phase. Its reactivation may occur in heathy subjects and immunocompromised patients. Upon reactivation, JCPyV could reach (i) the CNS inducing the PML, (ii) the kidney of transplant patients causing the organ rejection. Association between JCPyV, which is a small DNA tumor virus, and gliomas and colorectal carcinomas has been published. In the present investigation, we report on a new indirect ELISA with two specific synthetic peptides mimicking JCPyV VP1 immunogenic epitopes to detect specific serum IgG antibodies against JCPyV. Serum samples of healthy subjects (n = 355) ranging 2-100 years old, were analyzed by this new indirect ELISA. The linear peptides VP1 K and VP1 N resemble the natural JCPyV VP1 capsidic epitopes constituting a docking site for serum antibodies. Data from this innovative immunologic assay indicate that the overall prevalence of JCPyV-VP1 antibodies in healthy subjects is at 39%. The innovative indirect ELISA with JCPyV VP1 mimotopes seems to be a useful method to detect specific IgG antibodies against this virus, without cross-reactivity with the closely related SV40 and BKPyV polyomaviruses. © 2018 Wiley Periodicals, Inc.

Coastal conduit in southwestern Hudson Bay (Canada) in summer: Rapid transit of freshwater and significant loss of colored dissolved organic matter

NASA Astrophysics Data System (ADS)

Granskog, Mats A.; MacDonald, Robie W.; Kuzyk, Zou Zou A.; Senneville, Simon; Mundy, Christopher-John; Barber, David G.; Stern, Gary A.; Saucier, Francois

2009-08-01

Distributions of freshwater (sea-ice melt and runoff) were investigated along inshore-offshore sections in southwestern Hudson Bay for fall conditions. Conductivity-temperature-density profiles and bottle samples collected for salinity, oxygen isotope (δ18O), and colored dissolved organic matter (CDOM) analyses were used to discriminate between contributions of river water (RW) and sea-ice melt (SIM). Stations had a fresh summer surface mixed layer 5-25 m thick overlying a cold subsurface layer indicative of the previous winter's polar mixed layer (PML). The fraction of RW decreased strongly with distance from shore, while the opposite was true for SIM. The majority of RW was constrained in a coastal domain within 100-150 km from shore, which, because of high alongshore velocities, accounts for the majority of freshwater and volume transports. On the basis of freshwater inventories and composition, brine and RW accumulate in the PML over winter because of ice formation and downward mixing. The summer surface circulation results in an annual net export of SIM from the region. Residence times for freshwater components in the southwestern sector of the bay, based on currents derived from a 3-D ocean model for Hudson Bay, are about 1-10 months, implying rapid transit of freshwater. Despite the short residence time for RW (1-3 months), CDOM is significantly photobleached and provides an unreliable tracer for RW. Photobleaching represents an important sink for dissolved organic carbon entering from rivers and could, in part, explain why Hudson Bay is only a minor sink for atmospheric CO2 in the open water season.

Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia

PubMed Central

Wang, Lan; Zhou, Guang-Biao; Liu, Ping; Song, Jun-Hong; Liang, Yang; Yan, Xiao-Jing; Xu, Fang; Wang, Bing-Shun; Mao, Jian-Hua; Shen, Zhi-Xiang; Chen, Sai-Juan; Chen, Zhu

2008-01-01

To enhance therapeutic efficacy and reduce adverse effects, practitioners of traditional Chinese medicine (TCM) prescribe a combination of plant species/minerals, called formulae, based on clinical experience. Nearly 100,000 formulae have been recorded, but the working mechanisms of most remain unknown. In trying to address the possible beneficial effects of formulae with current biomedical approaches, we use Realgar-Indigo naturalis formula (RIF), which has been proven to be very effective in treating human acute promyelocytic leukemia (APL) as a model. The main components of RIF are realgar, Indigo naturalis, and Salvia miltiorrhiza, with tetraarsenic tetrasulfide (A), indirubin (I), and tanshinone IIA (T) as major active ingredients, respectively. Here, we report that the ATI combination yields synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro. ATI causes intensified ubiquitination/degradation of promyelocytic leukemia (PML)-retinoic acid receptor α (RARα) oncoprotein, stronger reprogramming of myeloid differentiation regulators, and enhanced G1/G0 arrest in APL cells through hitting multiple targets compared with the effects of mono- or biagents. Furthermore, ATI intensifies the expression of Aquaglyceroporin 9 and facilitates the transportation of A into APL cells, which in turn enhances A-mediated PML-RARα degradation and therapeutic efficacy. Our data also indicate A as the principal component of the formula, whereas T and I serve as adjuvant ingredients. We therefore suggest that dissecting the mode of action of clinically effective formulae at the molecular, cellular, and organism levels may be a good strategy in exploring the value of traditional medicine. PMID:18344322

JC virus induces altered patterns of cellular gene expression: Interferon-inducible genes as major transcriptional targets

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

Verma, Saguna; Ziegler, Katja; Ananthula, Praveen

2006-02-20

Human polyomavirus JC (JCV) infects 80% of the population worldwide. Primary infection, typically occurring during childhood, is asymptomatic in immunocompetent individuals and results in lifelong latency and persistent infection. However, among the severely immunocompromised, JCV may cause a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). Virus-host interactions influencing persistence and pathogenicity are not well understood, although significant regulation of JCV activity is thought to occur at the level of transcription. Regulation of the JCV early and late promoters during the lytic cycle is a complex event that requires participation of both viral and cellular factors. We have used cDNA microarraymore » technology to analyze global alterations in gene expression in JCV-permissive primary human fetal glial cells (PHFG). Expression of more than 400 cellular genes was altered, including many that influence cell proliferation, cell communication and interferon (IFN)-mediated host defense responses. Genes in the latter category included signal transducer and activator of transcription 1 (STAT1), interferon stimulating gene 56 (ISG56), myxovirus resistance 1 (MxA), 2'5'-oligoadenylate synthetase (OAS), and cig5. The expression of these genes was further confirmed in JCV-infected PHFG cells and the human glioblastoma cell line U87MG to ensure the specificity of JCV in inducing this strong antiviral response. Results obtained by real-time RT-PCR and Western blot analyses supported the microarray data and provide temporal information related to virus-induced changes in the IFN response pathway. Our data indicate that the induction of an antiviral response may be one of the cellular factors regulating/controlling JCV replication in immunocompetent hosts and therefore constraining the development of PML.« less

Trimester specific reference intervals for thyroid function tests in normal Indian pregnant women.

PubMed

Sekhri, Tarun; Juhi, Juhi Agarwal; Wilfred, Reena; Kanwar, Ratnesh S; Sethi, Jyoti; Bhadra, Kuntal; Nair, Sirimavo; Singh, Satveer

2016-01-01

Accurate assessment of thyroid function during pregnancy is critical, for initiation of thyroid hormone therapy, as well as for adjustment of thyroid hormone dose in hypothyroid cases. We evaluated pregnant women who had no past history of thyroid disorders and studied their thyroid function in each trimester. 86 normal pregnant women in the first trimester of pregnancy were selected for setting reference intervals. All were healthy, euthyroid and negative for thyroid peroxidase antibody (TPOAb). These women were serially followed throughout pregnancy. 124 normal nonpregnant subjects were selected for comparison. Thyrotropin (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and anti-TPO were measured using Roche Elecsys 1010 analyzer. Urinary iodine content was determined by simple microplate method. The 2.5th and 97.5th percentiles were calculated as the reference intervals for thyroid hormone levels during each trimester. SPSS (version 14.0, SPSS Inc., Chicago, IL, USA) was used for data processing and analysis. The reference intervals for the first, second and third trimesters for the following parameters: TSH 0.09-6.65, 0.51-6.66, 0.91-4.86 µIU/mL, FT4 9.81-18.53, 8.52-19.43, 7.39-18.28 pM/L and FT3 3.1-6.35, 2.39-5.12, 2.57-5.68 pM/L respectively. Thyroid hormone concentrations significantly differed during pregnancy at different stages of gestation. The pregnant women in the study had median urinary iodine concentration of 150-200 µg/l during each trimester. The trimester-specific reference intervals for thyroid tests during pregnancy have been established for pregnant Indian women serially followed during pregnancy using 2.5th and 97.5th percentiles.

Brain magnetic resonance imaging screening is not useful for HIV-1-infected patients without neurological symptoms.

PubMed

Nishijima, Takeshi; Gatanaga, Hiroyuki; Teruya, Katsuji; Tajima, Tsuyoshi; Kikuchi, Yoshimi; Hasuo, Kanehiro; Oka, Shinichi

2014-10-01

We investigated the diagnostic usefulness of brain magnetic resonance imaging (MRI) screening in HIV-1-infected patients without neurological symptoms in detecting intracranial diseases at early stages. In this retrospective analysis, the study patients were HIV-1-infected patients who underwent brain MRI scan in clinical practice between 2001 and 2013. We excluded patients with MRI for (1) follow-up examination for prediagnosed intracranial diseases, (2) cancer staging, (3) screening mycobacterium/bacteria/fungi disease proliferation in the brain, and (4) evaluation for meningitis/encephalitis. The study patients (n=485) were classified into two groups: those who underwent brain MRI scan without any neurological symptoms/signs (asymptomatic patients, n=158) and those who underwent MRI due to such symptoms (symptomatic patients, n=327). Asymptomatic patients had lower CD4 counts than symptomatic patients (median 78 versus 241/μl). Intracranial diseases were detected in three (2%) of the asymptomatic patients [two toxoplasmosis and one progressive multifocal leukoencephalopathy (PML)] compared to 58 (19%) of the symptomatic patients (the χ(2) test, p<0.01). The latter included toxoplasmosis (n=10), PML (n=7), cytomegalovirus encephalitis (n=3), primary central nervous system lymphoma (n=3), cryptococcoma/meningitis (n=3), and HIV-associated dementia (n=17). Among symptomatic patients, intracranial diseases were common in those with slurred speech (3/6, 50%), seizure (4/10, 40%), eyesight/vision abnormality (5/16, 31%), altered mental status (8/31, 26%), and hemiplegia/numbness (13/50, 26%). For patients with CD4 count <200/μl, intracranial diseases were detected in only 3 (3%) of 144 asymptomatic patients, compared with 46 (32%) of 113 symptomatic patients (p<0.01). Brain MRI screening for HIV-1-infected patients without neurological symptoms is of little value.

Human Homolog of Drosophila Ariadne (HHARI) is a marker of cellular proliferation associated with nuclear bodies

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

Elmehdawi, Fatima; Wheway, Gabrielle; Szymanska, Katarzyna

2013-02-01

HHARI (also known as ARIH1) is an ubiquitin-protein ligase and is the cognate of the E2, UbcH7 (UBE2L3). To establish a functional role for HHARI in cellular proliferation processes, we performed a reverse genetics screen that identified n=86/522 (16.5%) ubiquitin conjugation components that have a statistically significant effect on cell proliferation, which included HHARI as a strong hit. We then produced and validated a panel of specific antibodies that establish HHARI as both a nuclear and cytoplasmic protein that is expressed in all cell types studied. HHARI was expressed at higher levels in nuclei, and co-localized with nuclear bodies includingmore » Cajal bodies (p80 coilin, NOPP140), PML and SC35 bodies. We confirmed reduced cellular proliferation after ARIH1 knockdown with individual siRNA duplexes, in addition to significantly increased levels of apoptosis, an increased proportion of cells in G2 phase of the cell cycle, and significant reductions in total cellular RNA levels. In head and neck squamous cell carcinoma biopsies, there are higher levels of HHARI expression associated with increased levels of proliferation, compared to healthy control tissues. We demonstrate that HHARI is associated with cellular proliferation, which may be mediated through its interaction with UbcH7 and modification of proteins in nuclear bodies. -- Highlights: ► We produce and validate new antibody reagents for the ubiquitin-protein ligase HHARI. ► HHARI colocalizes with nuclear bodies including Cajal, PML and SC35 bodies. ► We establish new functions in cell proliferation regulation for HHARI. ► Increased HHARI expression associates with squamous cell carcinoma and proliferation.« less

Vedolizumab: An integrin-receptor antagonist for treatment of Crohn's disease and ulcerative colitis.

PubMed

Hahn, Lindsay; Beggs, Ashton; Wahaib, Kristy; Kodali, Leela; Kirkwood, Vanessa

2015-08-01

The pharmacology, pharmacokinetics, safety, efficacy, and dosing recommendations of vedolizumab, an integrin-receptor antagonist for the treatment of Crohn's disease (CD) and ulcerative colitis (UC), are reviewed. Vedolizumab is an integrin-receptor antagonist for the treatment of CD and UC in adults with moderately to severely active disease who have had an inadequate response with, lost response to, or were intolerant to anti-tumor necrosis factor (TNF) agents or immunomodulators or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids. Phase III clinical trials have demonstrated efficacy in achieving remission as induction and maintenance therapy in CD and UC. Remission was also achieved at week 10 in patients with CD in whom previous treatment with anti-TNF agents had failed. Adverse effects of vedolizumab include nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in the extremities. To date, no cases of progressive multifocal leukoencephalopathy (PML) have been reported. The recommended dose of vedolizumab in adults with UC or CD is 300 mg administered via intravenous infusion at zero, two, and six weeks, followed by every eight weeks. The average wholesale unit price is $5782.80, but a patient assistance program is available. Vedolizumab is a new alternative for patients with moderate-to-severe UC or CD, as well as patients who have not responded to anti-TNF agents. The current safety profile and lack of reported PML make it a promising addition to the treatment of these conditions. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Antiretroviral therapy CNS penetration and HIV-1–associated CNS disease

PubMed Central

Winston, A.; Walsh, J.; Post, F.; Porter, K.; Gazzard, B.; Fisher, M.; Leen, C.; Pillay, D.; Hill, T.; Johnson, M.; Gilson, R.; Anderson, J.; Easterbrook, P.; Bansi, L.; Orkin, C.; Ainsworth, J.; Palfreeman, A.; Gompels, M.; Phillips, A.N.; Sabin, C.A.

2011-01-01

Objective: The impact of different antiretroviral agents on the risk of developing or surviving CNS disease remains unknown. The aim of this study was to investigate whether using antiretroviral regimens with higher CNS penetration effectiveness (CPE) scores was associated with reduced incidence of CNS disease and improved survival in the UK Collaborative HIV Cohort (CHIC) Study. Methods: Adults without previous CNS disease, who commenced combination antiretroviral therapy (cART) between 1996 and 2008, were included (n = 22,356). Initial and most recent cART CPE scores were calculated. CNS diseases were HIV encephalopathy (HIVe), progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis (TOXO), and cryptococcal meningitis (CRYPTO). Incidence rates and overall survival were stratified by CPE score. A multivariable Poisson regression model was used to identify independent associations. Results: The median (interquartile range) CPE score for initial cART regimen increased from 7 (5–8) in 1996–1997 to 9 (8–10) in 2000–2001 and subsequently declined to 6 (7–8) in 2006–2008. Differences in gender, HIV acquisition risk group, and ethnicity existed between CPE score strata. A total of 251 subjects were diagnosed with a CNS disease (HIVe 80; TOXO 59; CRYPTO 56; PML 54). CNS diseases occurred more frequently in subjects prescribed regimens with CPE scores ≤4, and less frequently in those with scores ≥10; however, these differences were nonsignificant. Initial and most recent cART CPE scores ≤4 were independently associated with increased risk of death. Conclusion: Clinical status at time of commencing cART influences antiretroviral selection and CPE score. This information should be considered when utilizing CPE scores for retrospective analyses. PMID:21339496

Comparison of Newly Diagnosed and Relapsed Patients with Acute Promyelocytic Leukemia Treated with Arsenic Trioxide: Insight into Mechanisms of Resistance

PubMed Central

Chendamarai, Ezhilarasi; Ganesan, Saravanan; Alex, Ansu Abu; Kamath, Vandana; Nair, Sukesh C.; Nellickal, Arun Jose; Janet, Nancy Beryl; Srivastava, Vivi; Lakshmi, Kavitha M.; Viswabandya, Auro; Abraham, Aby; Aiyaz, Mohammed; Mullapudi, Nandita; Mugasimangalam, Raja; Padua, Rose Ann; Chomienne, Christine; Chandy, Mammen; Srivastava, Alok; George, Biju; Balasubramanian, Poonkuzhali; Mathews, Vikram

2015-01-01

There is limited data on the clinical, cellular and molecular changes in relapsed acute promyeloytic leukemia (RAPL) in comparison with newly diagnosed cases (NAPL). We undertook a prospective study to compare NAPL and RAPL patients treated with arsenic trioxide (ATO) based regimens. 98 NAPL and 28 RAPL were enrolled in this study. RAPL patients had a significantly lower WBC count and higher platelet count at diagnosis. IC bleeds was significantly lower in RAPL cases (P=0.022). The ability of malignant promyelocytes to concentrate ATO intracellularly and their in-vitro IC50 to ATO was not significantly different between the two groups. Targeted NGS revealed PML B2 domain mutations in 4 (15.38%) of the RAPL subset and none were associated with secondary resistance to ATO. A microarray GEP revealed 1744 genes were 2 fold and above differentially expressed between the two groups. The most prominent differentially regulated pathways were cell adhesion (n=92), cell survival (n=50), immune regulation (n=74) and stem cell regulation (n=51). Consistent with the GEP data, immunophenotyping revealed significantly increased CD34 expression (P=0.001) in RAPL cases and there was in-vitro evidence of significant microenvironment mediated innate resistance (EM-DR) to ATO. Resistance and relapse following treatment with ATO is probably multi-factorial, mutations in PML B2 domain while seen only in RAPL may not be the major clinically relevant cause of subsequent relapses. In RAPL additional factors such as expansion of the leukemia initiating compartment along with EM-DR may contribute significantly to relapse following treatment with ATO based regimens. PMID:25822503

Evidence for alternative lengthening of telomeres in liposarcomas in the absence of ALT-associated PML bodies.

PubMed

Jeyapalan, Jennie N; Mendez-Bermudez, Aaron; Zaffaroni, Nadia; Dubrova, Yuri E; Royle, Nicola J

2008-06-01

Immortalized and cancer cells maintain their telomeres by activation of a telomere maintenance mechanism (TMM). In approximately 85% of cancers telomerase is activated (TA) but in some tumours, in particular sarcomas, an alternative lengthening of telomeres (ALT) pathway is used. Liposarcomas are the most common soft-tissue sarcoma in adults and they activate ALT or telomerase with equal frequency, however no TMM has been identified in approximately 50% of liposarcomas. In our study, we have shown that instability at the minisatellite MS32, usually associated with ALT activation, aids the identification of liposarcomas that have recombination-like activity at telomeres in absence of ALT associated PML-bodies (APBs). Furthermore, using single molecule telomere analysis, we have detected complex telomere mutations directly in ALT positive liposarcomas and interestingly in some liposarcomas with an unknown TMM but high MS32 instability. We have shown by sequence analysis that some of these complex telomere mutations must arise by an inter-molecular recombination-like process rather than by deletion caused by t-loop excision or by unequal telomere-sister-chromatid-exchange (T-SCE), which is known to be elevated in ALT cell lines. Preliminary evidence also suggests that inter-molecular recombination events may be processed differently in liposarcomas with APBs compared to those without. In conclusion, we have shown for the first time, that some telomerase negative liposarcomas without APBs have other features associated with ALT, indicating that the incidence of ALT in these tumours has previously been under-estimated. This has major implications for the use of cancer treatments targeted at TMMs. (c) 2008 Wiley-Liss, Inc.

Stability hierarchy between Piracetam forms I, II, and III from experimental pressure-temperature diagrams and topological inferences.

PubMed

Toscani, Siro; Céolin, René; Minassian, Léon Ter; Barrio, Maria; Veglio, Nestor; Tamarit, Josep-Lluis; Louër, Daniel; Rietveld, Ivo B

2016-01-30

The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II-III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid-solid and solid-liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements. Copyright © 2015 Elsevier B.V. All rights reserved.

DNA CTG triplet repeats involved in dynamic mutations of neurologically related gene sequences form stable duplexes

NASA Technical Reports Server (NTRS)

Smith, G. K.; Jie, J.; Fox, G. E.; Gao, X.

1995-01-01

DNA triplet repeats, 5'-d(CTG)n and 5'-d(CAG)n, are present in genes which have been implicated in several neurodegenerative disorders. To investigate possible stable structures formed by these repeating sequences, we have examined d(CTG)n, d(CAG)n and d(CTG).d(CAG)n (n = 2 and 3) using NMR and UV optical spectroscopy. These studies reveal that single stranded (CTG)n (n > 2) forms stable, antiparallel helical duplexes, while the single stranded (CAG)n requires at least three repeating units to form a duplex. NMR and UV melting experiments show that the Tm increases in the order of [(CAG)3]2 < [(CTG)3]2 << (CAG)3.(CTG)3. The (CTG)3 duplex is stable and exhibits similar NMR spectra in solutions containing 0.1-4 M NaCl and at a pH range from 4.6 to 8.8. The (CTG)3 duplex, which contains multiple-T.T mismatches, displays many NMR spectral characteristics similar to those of B-form DNA. However, unique NOE and 1H-31P coupling patterns associated with the repetitive T.T mismatches in the CTG repeats are discerned. These results, in conjunction with recent in vitro studies suggest that longer CTG repeats may form hairpin structures, which can potentially cause interruption in replication, leading to dynamic expansion or deletion of triplet repeats.

Stability of Iowa mutant and wild type Aβ-peptide aggregates

NASA Astrophysics Data System (ADS)

Alred, Erik J.; Scheele, Emily G.; Berhanu, Workalemahu M.; Hansmann, Ulrich H. E.

2014-11-01

Recent experiments indicate a connection between the structure of amyloid aggregates and their cytotoxicity as related to neurodegenerative diseases. Of particular interest is the Iowa Mutant, which causes early-onset of Alzheimer's disease. While wild-type Amyloid β-peptides form only parallel beta-sheet aggregates, the mutant also forms meta-stable antiparallel beta sheets. Since these structural variations may cause the difference in the pathological effects of the two Aβ-peptides, we have studied in silico the relative stability of the wild type and Iowa mutant in both parallel and antiparallel forms. We compare regular molecular dynamics simulations with such where the viscosity of the samples is reduced, which, we show, leads to higher sampling efficiency. By analyzing and comparing these four sets of all-atom molecular dynamics simulations, we probe the role of the various factors that could lead to the structural differences. Our analysis indicates that the parallel forms of both wild type and Iowa mutant aggregates are stable, while the antiparallel aggregates are meta-stable for the Iowa mutant and not stable for the wild type. The differences result from the direct alignment of hydrophobic interactions in the in-register parallel oligomers, making them more stable than the antiparallel aggregates. The slightly higher thermodynamic stability of the Iowa mutant fibril-like oligomers in its parallel organization over that in antiparallel form is supported by previous experimental measurements showing slow inter-conversion of antiparallel aggregates into parallel ones. Knowledge of the mechanism that selects between parallel and antiparallel conformations and determines their relative stability may open new avenues for the development of therapies targeting familial forms of early-onset Alzheimer's disease.

Solid-state properties and crystallization behavior of PHA-739521 polymorphs.

PubMed

Sun, Changquan Calvin

2006-08-17

PHA-739521 is an experimental compound that exhibits polymorphism. The two anhydrous crystal forms, I and II, are characterized using powder X-ray diffractometry, thermal analyses, moisture sorption gravimetry. Both Forms I and II are non-hygroscopic and are stable to compaction pressure. The melting temperature is about 152 degrees C for Form I and 168 degrees C for Form II. Forms I and II are enantiotropically related where Form I is more stable below a transition temperature of approximately 70 degrees C. Crystallization behavior of this compound from solutions and during heating is also studied. Information obtained is used to design an appropriate crystallization process to successfully manufacture desired polymorph at large scale.

Investigating the principles of recrystallization from glyceride melts.

PubMed

Windbergs, Maike; Strachan, Clare J; Kleinebudde, Peter

2009-01-01

Different lipids were melted and resolidified as model systems to gain deeper insight into the principles of recrystallization processes in lipid-based dosage forms. Solid-state characterization was performed on the samples with differential scanning calorimetry and X-ray powder diffraction. Several recrystallization processes could be identified during storage of the lipid layers. Pure triglycerides that generally crystallize to the metastable alpha-form from the melt followed by a recrystallization process to the stable beta-form with time showed a chain-length-dependent behavior during storage. With increasing chain length, the recrystallization to the stable beta-form was decelerated. Partial glycerides exhibited a more complex recrystallization behavior due to the fact that these substances are less homogenous. Mixtures of a long-chain triglyceride and a partial glyceride showed evidence of some interaction between the two components as the partial glyceride hindered the recrystallization of the triglyceride to the stable beta-form. In addition, the extent of this phenomenon depended on the amount of partial glyceride in the mixture. Based on these results, changes in solid dosage forms based on glycerides during processing and storage can be better understood.

Stable powders made from photosensitive polycrystalline complexes of heterocyclic monomers and their polymers

NASA Technical Reports Server (NTRS)

Murphy, Oliver J. (Inventor); Hitchens, G. Duncan (Inventor); Hodko, Dalibor (Inventor)

1999-01-01

The present invention relates to a low electronic conductivity polymer composition having well dispersed metal granules, a stable powder made from photosensitive polycrystalline complexes of pyrrole, or its substituted derivatives and silver cations for making the polymer composition, and methods of forming the stable powder and polymer composition, respectively. A polycrystalline complex of silver and a monomer, such as pyrrole, its substituted derivatives or combinations thereof, is precipitated in the form of a stable photosensitive powder upon addition of the monomer to a solvent solution, such as toluene containing an electron acceptor. The photosensitive powder can be stored in the dark until needed. The powder may be dissolved in a solvent, cast onto a substrate and photopolymerized.

A stable compound of helium and sodium at high pressure

DOE PAGES

Dong, Xiao; Oganov, Artem R.; Goncharov, Alexander F.; ...

2017-02-06

Helium is generally understood to be chemically inert and this is due to its extremely stable closed-shell electronic configuration, zero electron affinity and an unsurpassed ionization potential. It is not known to form thermodynamically stable compounds, except a few inclusion compounds. Here, using the ab initio evolutionary algorithm USPEX and subsequent high-pressure synthesis in a diamond anvil cell, we report the discovery of a thermodynamically stable compound of helium and sodium, Na 2He, which has a fluorite-type structure and is stable at pressures >113 GPa. We show that the presence of He atoms causes strong electron localization and makes thismore » material insulating. This phase is an electride, with electron pairs localized in interstices, forming eight-centre two-electron bonds within empty Na 8 cubes. As a result, we also predict the existence of Na 2HeO with a similar structure at pressures above 15 GPa.« less

A stable compound of helium and sodium at high pressure

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

Dong, Xiao; Oganov, Artem R.; Goncharov, Alexander F.

Helium is generally understood to be chemically inert and this is due to its extremely stable closed-shell electronic configuration, zero electron affinity and an unsurpassed ionization potential. It is not known to form thermodynamically stable compounds, except a few inclusion compounds. Here, using the ab initio evolutionary algorithm USPEX and subsequent high-pressure synthesis in a diamond anvil cell, we report the discovery of a thermodynamically stable compound of helium and sodium, Na 2He, which has a fluorite-type structure and is stable at pressures >113 GPa. We show that the presence of He atoms causes strong electron localization and makes thismore » material insulating. This phase is an electride, with electron pairs localized in interstices, forming eight-centre two-electron bonds within empty Na 8 cubes. We also predict the existence of Na 2HeO with a similar structure at pressures above 15 GPa.« less

A stable compound of helium and sodium at high pressure

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

Dong, Xiao; Oganov, Artem R.; Goncharov, Alexander F.

Helium is generally understood to be chemically inert and this is due to its extremely stable closed-shell electronic configuration, zero electron affinity and an unsurpassed ionization potential. It is not known to form thermodynamically stable compounds, except a few inclusion compounds. Here, using the ab initio evolutionary algorithm USPEX and subsequent high-pressure synthesis in a diamond anvil cell, we report the discovery of a thermodynamically stable compound of helium and sodium, Na 2He, which has a fluorite-type structure and is stable at pressures >113 GPa. We show that the presence of He atoms causes strong electron localization and makes thismore » material insulating. This phase is an electride, with electron pairs localized in interstices, forming eight-centre two-electron bonds within empty Na 8 cubes. As a result, we also predict the existence of Na 2HeO with a similar structure at pressures above 15 GPa.« less

Application of hierarchical cascading technique to finite element method simulation in bulk acoustic wave devices

NASA Astrophysics Data System (ADS)

Li, Xinyi; Bao, Jingfu; Huang, Yulin; Zhang, Benfeng; Omori, Tatsuya; Hashimoto, Ken-ya

2018-07-01

In this paper, we propose the use of the hierarchical cascading technique (HCT) for the finite element method (FEM) analysis of bulk acoustic wave (BAW) devices. First, the implementation of this technique is presented for the FEM analysis of BAW devices. It is shown that the traveling-wave excitation sources proposed by the authors are fully compatible with the HCT. Furthermore, a HCT-based absorbing mechanism is also proposed to replace the perfectly matched layer (PML). Finally, it is demonstrated how the technique is much more efficient in terms of memory consumption and execution time than the full FEM analysis.

Crystallization and transformation of polymorphic forms of trioleoyl glycerol and 1,2-dioleoyl-3-rac-linoleoyl glycerol.

PubMed

Bayés-García, Laura; Calvet, Teresa; Cuevas-Diarte, Miquel Àngel; Ueno, Satoru; Sato, Kiyotaka

2013-08-08

This study examined the influence of different thermal treatments on the crystallization and transformation of trioleoyl glycerol (OOO) and 1,2-dioleoyl-3-rac-linoleoyl glycerol (OOL). Two triacylglycerol (TAG) samples were cooled at 0.5-15 °C·min(-1) and heated at 2 and 15 °C·min(-1). The polymorphic characteristics of the two TAGs were analyzed in situ using differential scanning calorimetry, Raman spectroscopy, and synchrotron radiation X-ray diffraction. Multiple polymorphic forms were identified in OOO (α, β'2, β'1, β2, and β1) and OOL (α, β'2, and β'1). Larger quantities of more stable forms (e.g., β2 and β1 of OOO and β'1 of OOL) were obtained when the samples were slowly cooled and heated. In contrast, less stable polymorphs were obtained with increased cooling and heating rates. Polymorphic transformations occurred in either solid-state or melt-mediation and were influenced by heating rates. The results were analyzed by considering the activation energies for crystallization and transformation of stable and less stable polymorphic forms in comparison with previous studies on 1,3-dipalmitoyl-2-oleoyl-glycerol and 1, 3-dioleoyl-2-palmitoyl-glycerol.

METHOD OF COATING GRAPHITE WITH STABLE METAL CARBIDES AND NITRIDES

DOEpatents

Gurinsky, D.H.

1959-10-27

A method is presented for forming protective stable nitride and carbide compounds on the surface of graphite. This is accomplished by contacting the graphite surface with a fused heavy liquid metal such as bismuth or leadbismuth containing zirconium, titanium, and hafnium dissolved or finely dispersed therein to form a carbide and nitride of at least one of the dissolved metals on the graphite surface.

Polyfibroblast: A Self-Healing and Galvanic Protection Additive

DTIC Science & Technology

2011-07-25

3 Key Accomplishments 3.1 Silane Formulation Processability Silane coupling agents may be added to the existing microcapsules either in low...constrained by the need to form stable microcapsules . To this end, we explored a number of recipes in which the following silane coupling agents were...Isocyanatopropyltrimethoxy silane (ITS). • Glycidoxypropyltrimethoxy silane (GPS) As expected, the lowest concentrations most readily formed stable microcapsules . The

Synthesis and characterization of thermally stable and/or conductive polymers

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

Gajiwala, H.M.

1992-01-01

Eight new thermally stable polyimides were synthesized from two tricyclic heterocyclic diamines: thionine which has a phenothiazine moiety and proflavine which has an acridine unit. The polymerization reactions were optimized with respect to solvents, reaction time, reaction temperature, solid contents, etc., and their structure property relationships were studied. All these soluble polyimides have nice film forming properties. One of the polyimides containing the acridine moiety, appears to have a tendency to form a liquid crystalline state when its solution is passed through a fine capillary. All of these polyimides were thermally stable in air up to 500-550[degrees]C and up tomore » 600[degrees]C in a nitrogen atmosphere. They have refractive indices in the range of 1.65 to 1.85 and have relatively low value of permittivity. Two other thermally stable polymers, viz., polybenzimidazole and the ladder polymer having the phenazine moiety in the backbone were also synthesized. For these polymerization reactions, tetraamino derivative of phenazine was synthesized from the commercially available diamino, dinitro derivative of benzene. The polybenzimidazole was prepared via the azomethine pathway. This polymer had an intrinsic viscosity of 0.94 in methanesulfonic acid. The nice film forming polybenzimidazole polymer was found to be thermally stable up to 400[degrees]C. The ladder type of a polymer was synthesized by condensation polymerization between tetraaminophenazine and dihydroxybenzophenone in polyphosphoric acid at an elevated temperature. The completely conjugated ladder polymer was found to be semiconducting on doping with iodine. This polymer was highly crystalline as demonstrated by its X-ray diffraction pattern. A morphology study of the polymer indicated that the material has a tendency to form dendritic crystals. The polymer was thermally stable up to about 400[degrees]C in air.« less

E1B-55K mediated regulation of RNF4 STUbL promotes HAdV gene expression.

PubMed

Müncheberg, Sarah; Hay, Ron T; Ip, Wing H; Meyer, Tina; Weiß, Christina; Brenke, Jara; Masser, Sawinee; Hadian, Kamyar; Dobner, Thomas; Schreiner, Sabrina

2018-04-25

HAdV E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in non-permissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 Ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB-associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established.RNF4, a cellular SUMO-targeted Ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOylated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM, and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNAi resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies. IMPORTANCE Daxx is a PML-NB-associated transcription factor, which was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 Ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4 and E1B-55K targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor, which is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention. Copyright © 2018 American Society for Microbiology.

Aggresome formation by the adenoviral protein E1B55K is not conserved among adenovirus species and is not required for efficient degradation of nuclear substrates.

PubMed

Blanchette, Paola; Wimmer, Peter; Dallaire, Frédéric; Cheng, Chi Ying; Branton, Philip E

2013-05-01

Much of the work on the basic molecular biology of human adenoviruses has been carried out on a very limited number of the more than 60 serotypes, primarily the highly related species C viruses adenovirus type 5 (Ad5) and Ad2 and, to some extent, Ad12 of species A. Until recently, it has been widely assumed that insights obtained with these model viruses were representative of all human adenoviruses. Recent studies on the E3 ubiquitin ligase formed by the viral E1B55K and E4orf6 proteins with a cellular Cullin-based complex indicated that although all species form such a functional complex, significant variations exist in terms of complex composition and the substrates that are degraded. In the present report we conducted a comprehensive analysis of the localization of E1B55K products from representatives of six of the seven adenovirus species in the presence and the absence of the corresponding E4orf6 protein. We found that although in some species E1B55K localized in aggresomes, such was not always the case, suggesting that these structures are not necessary for the efficient degradation of substrates. In addition, differences were evident in the localization of E1B55K, although all forms readily associated with PML. Finally, Ad5 E1B55K was seen to localize in close proximity to Rab11, a marker for the endosomal recycling compartment, and both focused at the microtubule organizing center. These findings suggest that E1B55K from some species may employ the transport system utilized by the membrane recycling pathway to assemble aggresomes and the possibility that this structure might then affect recycling of cell surface components.

Cocrystal dissociation in the presence of water: a general approach for identifying stable cocrystal forms.

PubMed

Eddleston, Mark D; Madusanka, Nadeesh; Jones, William

2014-09-01

In previous studies, cocrystals have been shown to be susceptible to dissociation at high humidity because of differences in the solubilities of the two coformer molecules, especially when these molecules can form hydrates. Contrastingly, however, the propensity of the pharmaceutically active compound caffeine to hydrate formation is reduced by cocrystallization with oxalic acid. Here, the stability of the oxalic acid cocrystal of caffeine is investigated from a thermodynamic perspective through the use of aqueous slurries of caffeine hydrate and oxalic acid dihydrate. Conversion to the anhydrous caffeine-oxalic acid cocrystal occurred under these conditions confirming that this form is thermodynamically stable in an aqueous environment. The slurry methodology was further developed as a general approach to screening for cocrystals that are not susceptible to dissociation at high humidity. In this manner, cocrystals of the hydrate-forming molecules theophylline, carbamazepine, and piroxicam that are stable at high humidity, indefinitely avoiding hydrate formation, were identified. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Structures and functions in the crowded nucleus: new biophysical insights

NASA Astrophysics Data System (ADS)

Hancock, Ronald

2014-09-01

Concepts and methods from the physical sciences have catalysed remarkable progress in understanding the cell nucleus in recent years. To share this excitement with physicists and encourage their interest in this field, this review offers an overview of how the physics which underlies structures and functions in the nucleus is becoming more clear thanks to methods which have been developed to simulate and study macromolecules, polymers, and colloids. The environment in the nucleus is very crowded with macromolecules, making entropic (depletion) forces major determinants of interactions. Simulation and experiments are consistent with their key role in forming membraneless compartments such as nucleoli, PML and Cajal bodies, and discrete "territories" for chromosomes. The chromosomes, giant linear polyelectrolyte polymers, exist in vivo in a state like a polymer melt. Looped conformations are predicted in crowded conditions, and have been confirmed experimentally and are central to the regulation of gene expression. Polymer theory has revealed how the chromosomes are so highly compacted in the nucleus, forming a "crumpled globule" with fractal properties which avoids knots and entanglements in DNA while allowing facile accessibility for its replication and transcription. Entropic repulsion between looped polymers can explain the confinement of each chromosome to a discrete region of the nucleus. Crowding and looping are predicted to facilitate finding the specific targets of factors which modulate activities of DNA. Simulation shows that entropic effects contribute to finding and repairing potentially lethal double-strand breaks in DNA by increasing the mobility of the broken ends, favouring their juxtaposition for repair. Signaling pathways are strongly influenced by crowding, which favours a processive mode of response (consecutive reactions without releasing substrates). This new information contributes to understanding the sometimes counter-intuitive consequences.

Three-dimensional wideband electromagnetic modeling on massively parallel computers

NASA Astrophysics Data System (ADS)

Alumbaugh, David L.; Newman, Gregory A.; Prevost, Lydie; Shadid, John N.

1996-01-01

A method is presented for modeling the wideband, frequency domain electromagnetic (EM) response of a three-dimensional (3-D) earth to dipole sources operating at frequencies where EM diffusion dominates the response (less than 100 kHz) up into the range where propagation dominates (greater than 10 MHz). The scheme employs the modified form of the vector Helmholtz equation for the scattered electric fields to model variations in electrical conductivity, dielectric permitivity and magnetic permeability. The use of the modified form of the Helmholtz equation allows for perfectly matched layer ( PML) absorbing boundary conditions to be employed through the use of complex grid stretching. Applying the finite difference operator to the modified Helmholtz equation produces a linear system of equations for which the matrix is sparse and complex symmetrical. The solution is obtained using either the biconjugate gradient (BICG) or quasi-minimum residual (QMR) methods with preconditioning; in general we employ the QMR method with Jacobi scaling preconditioning due to stability. In order to simulate larger, more realistic models than has been previously possible, the scheme has been modified to run on massively parallel (MP) computer architectures. Execution on the 1840-processor Intel Paragon has indicated a maximum model size of 280 × 260 × 200 cells with a maximum flop rate of 14.7 Gflops. Three different geologic models are simulated to demonstrate the use of the code for frequencies ranging from 100 Hz to 30 MHz and for different source types and polarizations. The simulations show that the scheme is correctly able to model the air-earth interface and the jump in the electric and magnetic fields normal to discontinuities. For frequencies greater than 10 MHz, complex grid stretching must be employed to incorporate absorbing boundaries while below this normal (real) grid stretching can be employed.

From toothpaste to topological insulators and materials for valleytronics: The journeys of fluorinated tin

NASA Astrophysics Data System (ADS)

Barraza-Lopez, Salvador; Rivero, Pablo; Yan, Jia-An; Garcia-Suarez, Victor Manuel; Ferrer, Jaime

2015-03-01

Tin fluoride has a vast literature. This material is stable in bulk form at room temperature and has commercial applications that include fluorinated toothpaste. Bulk tin fluoride has a pair of fluorine atoms bridging two tin atoms. In the recent past the electronic properties of 2D tin with honeycomb structure have been discussed thus generating a wealth of literature that emphasizes its non-topologically-trivial electronic properties due to the combination of a Dirac-like dispersion and a strong spin-orbit coupling given its large atomic mass. Nevertheless the stability of such freestanding structures has been contested recently. As it turns out, the most stable form of fluorinated tin does not possess a graphane-like structure either. In the most stable phase to be discussed here, fluorine atoms tilt away from (graphane-like) positions over/below tin atoms; in an atomistic arrangement similar to the one seen on their parent bulk structure. Electronic properties depend on atomistic coordination, and the most stable form of fluorinated tin does not possess non-trivial topological properties. Nevertheless it represents a new paradigm for valleytronics in 2D.

A Manual for a Laboratory Information Management System (LIMS) For Light Stable Isotopes - Version 7.0

DTIC Science & Technology

1998-01-01

A MANUAL FOR A LABORATORY INFORMATION MANAGEMENT SYSTEM (LIMS) FOR LIGHT STABLE ISOTOPES— VERSION 7.0 U.S. GEOLOGICAL SURVEY Open-File Report 98-284...Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std Z39-18 A MANUAL FOR A LABORATORY INFORMATION MANAGEMENT SYSTEM (LIMS) FOR LIGHT STABLE...Europa Scientific ..................................................120 1 A MANUAL FOR A LABORATORY INFORMATION MANAGEMENT SYSTEM (LIMS) FOR LIGHT STABLE

Microbial stabilization and mass reduction of wastes containing radionuclides and toxic metals

DOEpatents

Francis, A.J.; Dodge, C.J.; Gillow, J.B.

1991-09-10

A process is provided to treat wastes containing radionuclides and toxic metals with Clostridium sp. BFGl to release a large fraction of the waste solids into solution and convert the radionuclides and toxic metals to a more concentrated and stable form with concurrent volume and mass reduction. The radionuclides and toxic metals being in a more stable form are available for recovery, recycling and disposal. 18 figures.

Microbial stabilization and mass reduction of wastes containing radionuclides and toxic metals

DOEpatents

Francis, Arokiasamy J.; Dodge, Cleveland J.; Gillow, Jeffrey B.

1991-01-01

A process is provided to treat wastes containing radionuclides and toxic metals with Clostridium sp. BFGl to release a large fraction of the waste solids into solutin and convert the radionuclides and toxic metals to a more concentrated and stable form with concurrent volume and mass reduction. The radionuclides and toxic metals being in a more stable form are available for recovery, recycling and disposal.

Precise side-chain conformation analysis of L-phenylalanine in α-helical polypeptide by quantum-chemical calculation and 13C CP-MAS NMR measurement

NASA Astrophysics Data System (ADS)

Niimura, Subaru; Suzuki, Junya; Kurosu, Hiromichi; Yamanobe, Takeshi; Shoji, Akira

2010-04-01

To clarify the positive role of side-chain conformation in the stability of protein secondary structure (main-chain conformation), we successfully calculated the optimization structure of a well-defined α-helical octadecapeptide composed of L-alanine (Ala) and L-phenylalanine (Phe) residues, H-(Ala) 8-Phe-(Ala) 9-OH, based on the molecular orbital calculation with density functional theory (DFT/B3LYP/6-31G(d)). From the total energy and the precise secondary structural parameters such as main-chain dihedral angles and hydrogen-bond parameters of the optimized structure, we confirmed that the conformational stability of an α-helix is affected dominantly by the side-chain conformation ( χ1) of the Phe residue in this system: model A ( T form: around 180° of χ1) is most stable in α-helix and model B ( G + form: around -60° of χ1) is next stable, but model C ( G - form: around 60° of χ1) is less stable. In addition, we demonstrate that the stable conformation of poly( L-phenylalanine) is an α-helix with the side-chain T form, by comparison of the carbonyl 13C chemical shift measured by 13C CP-MAS NMR and the calculated one.

Monolithic amplifier with stable, high resistance feedback element and method for fabricating the same

DOEpatents

O'Connor, Paul

1998-08-11

A monolithic amplifier includes a stable, high resistance feedback circuit and a dynamic bias circuit. The dynamic bias circuit is formed with active elements matched to those in the amplifier and feedback circuit to compensate for variations in the operating and threshold voltages thereby maintaining a stable resistance in the feedback circuit.

Conformational analysis of glutamic acid: a density functional approach using implicit continuum solvent model.

PubMed

Turan, Başak; Selçuki, Cenk

2014-09-01

Amino acids are constituents of proteins and enzymes which take part almost in all metabolic reactions. Glutamic acid, with an ability to form a negatively charged side chain, plays a major role in intra and intermolecular interactions of proteins, peptides, and enzymes. An exhaustive conformational analysis has been performed for all eight possible forms at B3LYP/cc-pVTZ level. All possible neutral, zwitterionic, protonated, and deprotonated forms of glutamic acid structures have been investigated in solution by using polarizable continuum model mimicking water as the solvent. Nine families based on the dihedral angles have been classified for eight glutamic acid forms. The electrostatic effects included in the solvent model usually stabilize the charged forms more. However, the stability of the zwitterionic form has been underestimated due to the lack of hydrogen bonding between the solute and solvent; therefore, it is observed that compact neutral glutamic acid structures are more stable in solution than they are in vacuum. Our calculations have shown that among all eight possible forms, some are not stable in solution and are immediately converted to other more stable forms. Comparison of isoelectronic glutamic acid forms indicated that one of the structures among possible zwitterionic and anionic forms may dominate over the other possible forms. Additional investigations using explicit solvent models are necessary to determine the stability of charged forms of glutamic acid in solution as our results clearly indicate that hydrogen bonding and its type have a major role in the structure and energy of conformers.

The drug-induced degradation of oncoproteins: an unexpected Achilles' heel of cancer cells?

PubMed

Ablain, Julien; Nasr, Rihab; Bazarbachi, Ali; de Thé, Hugues

2011-07-01

Many targeted therapies against cancer are aimed at inhibiting the enzymatic activity of kinases. Thus far, this approach has undoubtedly yielded significant clinical improvements, but has only rarely achieved cures. Other drugs, which selectively elicit proteasome-dependent degradation of oncoproteins, induce the loss of cancer cell self-renewal and promote cell differentiation and/or apoptosis. In acute promyelocytic leukemia, the cooperative degradation of PML/RARA by arsenic and retinoic acid cures most patients. In this condition and others, drug-induced proteolysis of oncoproteins is feasible and underlies improved clinical outcome. Several transcription factors, nuclear receptors, or fusion proteins driving cancer growth could be candidates for proteolysis-based drug-discovery programs.

Gas Testing at the NBC-Filter of the M-Frigates of the Royal Dutch Navy According to the NATO Standard (Gastesten aan het NBC-Filter voor het M-Fregat van de oninklijke Marine volgens NAVO-eisen)

DTIC Science & Technology

1992-06-01

man de eisen van bet NAVO.-document voldsan word.. Het AstroCarb-filter bleek voor alle geteste gassen gemakkelijk de vereiste doorbroaktijden te halen ...hill ?NO famwtyn J-3r d~mf tI~nq"M#-rI~ m t~w)-im TNO RCl1 U W2 AM " TNO-por PML1 32490333 Pagins 2 Samenvatting De gasbescherniende eigenschappen van ...De schoktest tastte de prestaties van bet filter niet man. Summary The gas protective properties of an AstroCarb 200 NBC filter which is usid in the

Calculation of the Internal and External Risk of Stored Ammunition and Explosives by Means of the Computer Model RISKANAL

DTIC Science & Technology

1998-07-01

950.0 140.0 HS8 HS 8 8 5 0 420.0 50.0 HS9 HS 9 9 2 0 190.0 -245.0 HS10 HS 10 10 1 0 10.0 -245.0 HS11 HS 11 11 1 0 -150.0 50.0 RD1 RD 12 13 1000 50...Ceelen 8 DM&P TNO-DO 9 * DM&P TNO-DQ, accountco6rdinator KL 10* TNO-FEL, Bibliotheek 11 /13 Bibliotheek KMA 14* Lid Instituuts Advies Raad PML Prof. B...Vastgesteld door Maj. Wt. Ceelen Vastgesteld d.d. 9 juni 1998 (deze rubricering wijzigt niet) Titel Ongerubriceerd Managementuittreksel Ongerubriceerd

(2+1) -dimensional stable spatial Raman solitons

NASA Astrophysics Data System (ADS)

Shverdin, M. Y.; Yavuz, D. D.; Walker, D. R.

2004-03-01

We analyze the formation, propagation, and interaction of stable two-frequency (2+1) -dimensional solitons, formed in a Raman media driven near maximum molecular coherence. The propagating light is trapped in the two transverse dimensions.

The a(4) Scheme-A High Order Neutrally Stable CESE Solver

NASA Technical Reports Server (NTRS)

Chang, Sin-Chung

2009-01-01

The CESE development is driven by a belief that a solver should (i) enforce conservation laws in both space and time, and (ii) be built from a nondissipative (i.e., neutrally stable) core scheme so that the numerical dissipation can be controlled effectively. To provide a solid foundation for a systematic CESE development of high order schemes, in this paper we describe a new high order (4-5th order) and neutrally stable CESE solver of a 1D advection equation with a constant advection speed a. The space-time stencil of this two-level explicit scheme is formed by one point at the upper time level and two points at the lower time level. Because it is associated with four independent mesh variables (the numerical analogues of the dependent variable and its first, second, and third-order spatial derivatives) and four equations per mesh point, the new scheme is referred to as the a(4) scheme. As in the case of other similar CESE neutrally stable solvers, the a(4) scheme enforces conservation laws in space-time locally and globally, and it has the basic, forward marching, and backward marching forms. Except for a singular case, these forms are equivalent and satisfy a space-time inversion (STI) invariant property which is shared by the advection equation. Based on the concept of STI invariance, a set of algebraic relations is developed and used to prove the a(4) scheme must be neutrally stable when it is stable. Numerically, it has been established that the scheme is stable if the value of the Courant number is less than 1/3

Experimental research in the phase change materials based on paraffin and expanded perlite

NASA Astrophysics Data System (ADS)

Jiesheng, Liu; Faping, Li; Xiaoqiang, Gong; Rongtang, Zhang

2018-06-01

In this study, paraffin (PA)/expanded perlite (EP) form-stable phase change material (PCM) was first fabricated using the direct impregnation method without vacuum treatment. Absorptive capacity results showed that the PA/EP composite can obtain good absorptive capacity with the temperature 80 °C and the time 2 h. Compared with the water absorption of EP, the decrease in the water absorption of PA/EP form-stable proved that the absorption of PA into porous EP has been carried out successfully. Scanning electron microscope (SEM) and Fourier transform infrared (FT-IR) results show that paraffin can be well impregnated into EP pores and has good compatibility with it. Differential scanning calorimetry (DSC) results reveal that paraffin/EP composite PCM has melting temperature and latent heat of 53.6 °C and 91.3 J/g, respectively. The durability cycles results suggest that form-stable PA/EP PCM shows good durability.

The topological pressure-temperature phase diagram and crystal structures of the dimorphic system spiperone.

PubMed

Robert, B; Perrin, M-A; Coquerel, G; Céolin, R; Rietveld, I B

2016-03-01

The topological pressure-temperature phase diagram for the dimorphism of spiperone, a potent neuroleptic drug, has been constructed using literature data and improved crystal structures obtained with new crystallographic data from single-crystal X-ray diffraction at various temperatures. It is inferred that form II, which is the more dense form and exhibits the lower melting temperature, becomes the more stable phase under pressure. Under ambient conditions, form I is more stable. Copyright © 2015 Académie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

Polymer compositions, polymer films and methods and precursors for forming same

DOEpatents

Klaehn, John R; Peterson, Eric S; Orme, Christopher J

2013-09-24

Stable, high performance polymer compositions including polybenzimidazole (PBI) and a melamine-formaldehyde polymer, such as methylated, poly(melamine-co-formaldehyde), for forming structures such as films, fibers and bulky structures. The polymer compositions may be formed by combining polybenzimidazole with the melamine-formaldehyde polymer to form a precursor. The polybenzimidazole may be reacted and/or intertwined with the melamine-formaldehyde polymer to form the polymer composition. For example, a stable, free-standing film having a thickness of, for example, between about 5 .mu.m and about 30 .mu.m may be formed from the polymer composition. Such films may be used as gas separation membranes and may be submerged into water for extended periods without crazing and cracking. The polymer composition may also be used as a coating on substrates, such as metal and ceramics, or may be used for spinning fibers. Precursors for forming such polymer compositions are also disclosed.

Influence of early diagenesis on the vertical distribution of metal forms in sediments of Bohai Bay, China.

PubMed

Lu, Xueqiang; Zhang, Yan; Liu, Honglei; Xing, Meinan; Shao, Xiaolong; Zhao, Feng; Li, Xiaojuan; Liu, Qiongqiong; Yu, Dan; Yuan, Xuezhu; Yuan, Min

2014-11-15

The influence of early diagenesis on the vertical distribution of metal forms in the sediments of Bohai Bay was discussed in this paper. The results showed that the concentrations were: Al > Fe ≈ Ca > Mn > Cr > Zn > Cu > Pb > Cd. In vertical distribution, the forms of Cr and Pb were stable from the top to the bottom. However, the exchangeable forms and acid-extracted forms of Cd, Cu and Zn presented an obvious declining trend. The metals would be transformed to more stable forms during the early-diagenesis process. Further analysis found that early diagenesis can change the sedimentary environment, affecting pH, oxidation-reduction potential (ORP), total dissolved solid (TDS) and the structure of organic matter (OM), all main factors influencing metal forms in the sediments of Bohai Bay. Copyright © 2014 Elsevier Ltd. All rights reserved.

Monolithic amplifier with stable, high resistance feedback element and method for fabricating the same

DOEpatents

O`Connor, P.

1998-08-11

A monolithic amplifier includes a stable, high resistance feedback circuit and a dynamic bias circuit. The dynamic bias circuit is formed with active elements matched to those in the amplifier and feedback circuit to compensate for variations in the operating and threshold voltages thereby maintaining a stable resistance in the feedback circuit. 11 figs.

Salmonella L-forms: formation in human bile in vitro and isolation culture from patients' gallbladder samples by a non-high osmotic isolation technique.

PubMed

Wang, D N; Wu, W J; Wang, T; Pan, Y Z; Tang, K L; She, X L; Ding, W J; Wang, H

2015-05-01

Bacterial L-forms have always been considered as osmotic-pressure-sensitive cell-wall-deficient bacteria and isolation culture of L-forms must use media with high osmotic pressure. However, isolation culture of stable L-forms formed in humans and animals is very difficult because they have adapted to the physiological osmotic pressure condition of the host. We use a non-high osmotic isolation technique to isolate stable L-forms of Salmonella Typhi and Salmonella Paratyphi A from bile-inducer cultures in vitro and from patients' gallbladder specimens. Multiplex PCR assay for Salmonella-specific genes and nucleotide sequencing are used to identify the Salmonella L-forms in stable L-form isolates. Using this method, we confirmed that Salmonella Paratyphi A and Salmonella Typhi cannot be isolated from bile-inducer cultures cultured for 6 h or 48 h, but the L-forms can be isolated from 1 h to 45 days. In the 524 gallbladder samples, the positive rate for bacterial forms was 19.7% and the positive rate for Salmonella spp. was 0.6% by routine bacteriological methods. The positive rate for bacterial L-forms was 75.4% using non-high osmotic isolation culture. In the L-form isolates, the positive rate of Salmonella invA gene was 3.1%. In these invA-positive L-form isolates, four were positive for the invA and flic-d genes of Salmonella Typhi, and ten were positive for the invA and flic-a genes of Salmonella Paratyphi A. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

A full genomic characterization of the development of a stable Small Colony Variant cell-type by a clinical Staphylococcus aureus strain.

PubMed

Bui, Long M G; Kidd, Stephen P

2015-12-01

A key to persistent and recurrent Staphylococcus aureus infections is its ability to adapt to diverse and toxic conditions. This ability includes a switch into a biofilm or to the quasi-dormant Small Colony Variant (SCV). The development and molecular attributes of SCVs have been difficult to study due to their rapid reversion to their parental cell-type. We recently described the unique induction of a matrix-embedded and stable SCV cell-type in a clinical S. aureus strain (WCH-SK2) by growing the cells with limiting conditions for a prolonged timeframe. Here we further study their characteristics. They possessed an increased viability in the presence of antibiotics compared to their non-SCV form. Their stability implied that there had been genetic changes; we therefore determined both the genome sequence of WCH-SK2 and its stable SCV form at a single base resolution, employing Single Molecular Real-Time (SMRT) sequencing that enabled the methylome to also be determined. The genetic features of WCH-SK2 have been identified; the SCCmec type, the pathogenicity and genetic islands and virulence factors. The genetic changes that had occurred in the stable SCV form were identified; most notably being in MgrA, a global regulator, and RsbU, a phosphoserine phosphatase within the regulatory pathway of the sigma factor SigB. There was a shift in the methylomes of the non-SCV and stable SCV forms. We have also shown a similar induction of this cell-type in other S. aureus strains and performed a genetic comparison to these and other S. aureus genomes. We additionally map RNAseq data to the WCH-SK2 genome in a transcriptomic analysis of the parental, SCV and stable SCV cells. The results from this study represent the unique identification of a suite of epigenetic, genetic and transcriptional factors that are implicated in the switch in S. aureus to its persistent SCV form. Copyright © 2015 Elsevier B.V. All rights reserved.

Molecular structure and vibrational assignment of dimethyl oxaloacetate

NASA Astrophysics Data System (ADS)

Tayyari, Sayyed Faramarz; Salemi, Sirous; Tabrizi, Mansoureh Zahedi; Behforouz, Mohammad

2004-06-01

A complete conformational analysis of the keto and chelated enol forms of dimethyl oxaloacetate (DMOA), a β-dicarbonyl compound, was carried out by ab initio calculations, at the density functional theory (DFT) level. In addition to nine stable enol conformers, which are stabilized by intramolecular hydrogen bonds, twelve stable keto conformers were also obtained. The considerably higher energy of the keto compared to that of the most stable enol conformer makes the presence of keto form, at least in the gas phase, unlikely. Theoretical calculations in the solution, using the Onsager Method, suggest two coexisting enol conformers in the solution. This finding is in agreement with the experimental data. The hydrogen bond strength of the most stable conformer of DMOA is compared with that of acetylacetone (AA). Harmonic vibrational frequencies of this stable enol form and its deuterated analog were also calculated and compared with the experimental data. According to the theoretical calculations, the enolated proton in dimethyl oxaloacetate moves in an asymmetric single minimum potential with a hydrogen bond strength of 31.1 kJ/mol, 35.3 kJ/mol less than that of AA. This weakening of hydrogen bond is consistent with the frequency shifts for OH/OD stretching, OH/OD out-of-plane bending and O⋯O stretching modes. The calculated O ⋯O distance is about 0.07-0.08 Å longer than that of its parent AA.

Stable carbon and sulfur isotopes as records of the early biosphere

NASA Technical Reports Server (NTRS)

Desmarais, David J.

1989-01-01

The abundance ratios of the stable isotopes of light elements such as carbon and sulfur can differ between various naturally-occurring chemical compounds. If coexisting compounds have achieved mutual chemical and isotopic equilibrium, then the relative isotopic composition can record the conditions at which equilibrium was last maintained. If coexisting chemical compounds indeed formed simultaneously but had not achieved mutual equilibrium, then their relative isotopic compositions often reflect the conditions and mechanisms associated with the kinetically controlled reactions responsible for their production. In the context of Mars, the stable isotopic compositions of various minerals might record not only the earlier environmental conditions of the planet, but also whether or not the chemistry of life ever occurred there. Two major geochemical reservoirs occur in Earth's crust, both for carbon and sulfur. In rocks formed in low temperature sedimentary environments, the oxidized forms of these elements tend to be enriched in the isotope having the larger mass, relative to the reduced forms. In sediments where the organics and sulfides were formed by biological processes, these isotopic contrasts were caused by the processes of biological CO2 fixation and dissimilatory sulfate reduction. Such isotopic contrasts between oxidized and reduced forms of carbon and sulfur are permitted by thermodynamics at ambient temperatures. However, nonbiological chemical reactions associated with the production of organic matter and the reduction of organics and sulfides are extremely slow at ambient temperatures. Thus the synthesis of organics and sulfides under ambient conditions illustrates life's profound role as a chemical catalyst that has altered the chemistry of Earth's crust. Because the stable isotopes of carbon and sulfur can reflect their chemistry, they are useful probes of the Martian surface.

Synthesis of Difluoroaminoxy-, Difluoroamino- or Fluorodiazonium-Containing Materials.

DTIC Science & Technology

1987-01-30

the olefin. The cyclic nitroso compounds underwent thermal decomposition at 165 OC in Pyrex glass to form colorless nitro derivatives. 1,2...absence of glass , (perfluorocvcloaikvl)difluoroamines, e.g., (DNF2 , formed. All of the new compounds are stable at 25 "C and are hvdrolvticallv stable...extended periods in Pyrex glass at 25 OC. Strong vibrational bands in the Raman spectra at 7󈧶 cm r were assigned to v__ H. Carbonvl fluoride as a

Stable monolayer honeycomb-like structures of RuX2 (X =S,Se)

NASA Astrophysics Data System (ADS)

Ersan, Fatih; Cahangirov, Seymur; Gökoǧlu, Gökhan; Rubio, Angel; Aktürk, Ethem

2016-10-01

Recent studies show that several metal oxides and dichalcogenides (M X2) , which exist in nature, can be stable in two-dimensional (2D) form and each year several new M X2 structures are explored. The unstable structures in H (hexagonal) or T (octahedral) forms can be stabilized through Peierls distortion. In this paper, we propose new 2D forms of RuS2 and RuSe2 materials. We investigate in detail the stability, electronic, magnetic, optical, and thermodynamic properties of 2D Ru X2 (X =S,Se) structures from first principles. While their H and T structures are unstable, the distorted T structures (T'-Ru X2) are stable and have a nonmagnetic semiconducting ground state. The molecular dynamic simulations also confirm that T'-Ru X2 systems are stable even at 500 K without any structural deformation. T'-RuS2 and T'-RuSe2 have indirect band gaps with 0.745 eV (1.694 eV with HSE) and 0.798 eV (1.675 eV with HSE) gap values, respectively. We also examine their bilayer and trilayer forms and find direct and smaller band gaps. We find that AA stacking is more favorable than the AB configuration. The new 2D materials obtained can be good candidates with striking properties for applications in semiconductor electronic, optoelectronic devices, and sensor technology.

Stable, non-dissipative, and conservative flux-reconstruction schemes in split forms

NASA Astrophysics Data System (ADS)

Abe, Yoshiaki; Morinaka, Issei; Haga, Takanori; Nonomura, Taku; Shibata, Hisaichi; Miyaji, Koji

2018-01-01

A stable, non-dissipative, and conservative flux-reconstruction (FR) scheme is constructed and demonstrated for the compressible Euler and Navier-Stokes equations. A proposed FR framework adopts a split form (also known as the skew-symmetric form) for convective terms. Sufficient conditions to satisfy both the primary conservation (PC) and kinetic energy preservation (KEP) properties are rigorously derived by polynomial-based analysis for a general FR framework. It is found that the split form needs to be expressed in the PC split form or KEP split form to satisfy each property in discrete sense. The PC split form is retrieved from existing general forms (Kennedy and Gruber [33]); in contrast, we have newly introduced the KEP split form as a comprehensive form constituting a KEP scheme in the FR framework. Furthermore, Gauss-Lobatto (GL) solution points and g2 correction function are required to satisfy the KEP property while any correction functions are available for the PC property. The split-form FR framework to satisfy the KEP property, eventually, is similar to the split-form DGSEM-GL method proposed by Gassner [23], but which, in this study, is derived solely by polynomial-based analysis without explicitly using the diagonal-norm SBP property. Based on a series of numerical tests (e.g., Sod shock tube), both the PC and KEP properties have been verified. We have also demonstrated that using a non-dissipative KEP flux, a sixteenth-order (p15) simulation of the viscous Taylor-Green vortex (Re = 1 , 600) is stable and its results are free of unphysical oscillations on relatively coarse mesh (total number of degrees of freedom (DoFs) is 1283).

Analysis of the characteristics of DC nozzle arcs in air and guidance for the search of SF6 replacement gas

NASA Astrophysics Data System (ADS)

Liu, J.; Zhang, Q.; Yan, J. D.; Zhong, J.; Fang, M. T. C.

2016-11-01

It is shown that the arc model based on laminar flow cannot predict satisfactorily the voltage of an air arc burning in a supersonic nozzle. The Prandtl mixing length model (PML) and a modified k-epsilon turbulence model (MKE) are used to introduce turbulence enhanced momentum and energy transport. Arc voltages predicted by these two turbulence models are in good agreement with experiments at the stagnation pressure (P 0) of 10 bar. The predicted arc voltages by MKE for P 0  =  13 bar and 7 bar are in better agreement with experiments than those predicted by PML. MKE is therefore a preferred turbulence model for an air nozzle arc. There are two peaks in ρC P of air at 4000 K and 7000 K due, respectively, to the dissociation of oxygen and that of nitrogen. These peaks produce corresponding peaks in turbulent thermal conductivity, which results in very broad radial temperature profile and a large arc radius. Thus, turbulence indirectly enhances axial enthalpy transport, which becomes the dominant energy transport process for the overall energy balance of the arc column at high currents. When the current reduces, turbulent thermal conduction gradually becomes dominant. The temperature dependence of ρC P has a decisive influence on the radial temperature profile of a turbulent arc, thus the thermal interruption capability of a gas. Comparison between ρC P for air and SF6 shows that ρC P for SF6 has peaks below 4000 K. This renders a distinctive arc core and a small arc radius for turbulent SF6, thus superior arc quenching capability. It is suggested, for the first time, that ρC P provides guidance for the search of a replacement switching gas for SF6.

A new method for estimating the probable maximum hail loss of a building portfolio based on hailfall intensity determined by radar measurements

NASA Astrophysics Data System (ADS)

Aller, D.; Hohl, R.; Mair, F.; Schiesser, H.-H.

2003-04-01

Extreme hailfall can cause massive damage to building structures. For the insurance and reinsurance industry it is essential to estimate the probable maximum hail loss of their portfolio. The probable maximum loss (PML) is usually defined with a return period of 1 in 250 years. Statistical extrapolation has a number of critical points, as historical hail loss data are usually only available from some events while insurance portfolios change over the years. At the moment, footprints are derived from historical hail damage data. These footprints (mean damage patterns) are then moved over a portfolio of interest to create scenario losses. However, damage patterns of past events are based on the specific portfolio that was damaged during that event and can be considerably different from the current spread of risks. A new method for estimating the probable maximum hail loss to a building portfolio is presented. It is shown that footprints derived from historical damages are different to footprints of hail kinetic energy calculated from radar reflectivity measurements. Based on the relationship between radar-derived hail kinetic energy and hail damage to buildings, scenario losses can be calculated. A systematic motion of the hail kinetic energy footprints over the underlying portfolio creates a loss set. It is difficult to estimate the return period of losses calculated with footprints derived from historical damages being moved around. To determine the return periods of the hail kinetic energy footprints over Switzerland, 15 years of radar measurements and 53 years of agricultural hail losses are available. Based on these data, return periods of several types of hailstorms were derived for different regions in Switzerland. The loss set is combined with the return periods of the event set to obtain an exceeding frequency curve, which can be used to derive the PML.

Characterization of flood and precipitation events in Southwestern Germany and stochastic simulation of extreme precipitation (Project FLORIS-SV)

NASA Astrophysics Data System (ADS)

Florian, Ehmele; Michael, Kunz

2016-04-01

Several major flood events occurred in Germany in the past 15-20 years especially in the eastern parts along the rivers Elbe and Danube. Examples include the major floods of 2002 and 2013 with an estimated loss of about 2 billion Euros each. The last major flood events in the State of Baden-Württemberg in southwest Germany occurred in the years 1978 and 1993/1994 along the rivers Rhine and Neckar with an estimated total loss of about 150 million Euros (converted) each. Flood hazard originates from a combination of different meteorological, hydrological and hydraulic processes. Currently there is no defined methodology available for evaluating and quantifying the flood hazard and related risk for larger areas or whole river catchments instead of single gauges. In order to estimate the probable maximum loss for higher return periods (e.g. 200 years, PML200), a stochastic model approach is designed since observational data are limited in time and space. In our approach, precipitation is linearly composed of three elements: background precipitation, orographically-induces precipitation, and a convectively-driven part. We use linear theory of orographic precipitation formation for the stochastic precipitation model (SPM), which is based on fundamental statistics of relevant atmospheric variables. For an adequate number of historic flood events, the corresponding atmospheric conditions and parameters are determined in order to calculate a probability density function (pdf) for each variable. This method involves all theoretically possible scenarios which may not have happened, yet. This work is part of the FLORIS-SV (FLOod RISk Sparkassen Versicherung) project and establishes the first step of a complete modelling chain of the flood risk. On the basis of the generated stochastic precipitation event set, hydrological and hydraulic simulations will be performed to estimate discharge and water level. The resulting stochastic flood event set will be used to quantify the flood risk and to estimate probable maximum loss (e.g. PML200) for a given property (buildings, industry) portfolio.

Biocontrol of the Sugarcane Borer Eldana saccharina by Expression of the Bacillus thuringiensis cry1Ac7 and Serratia marcescens chiA Genes in Sugarcane-Associated Bacteria

PubMed Central

Downing, Katrina J.; Leslie, Graeme; Thomson, Jennifer A.

2000-01-01

The cry1Ac7 gene of Bacillus thuringiensis strain 234, showing activity against the sugarcane borer Eldana saccharina, was cloned under the control of the tac promoter. The fusion was introduced into the broad-host-range plasmid pKT240 and the integration vector pJFF350 and without the tac promoter into the broad-host-range plasmids pML122 and pKmM0. These plasmids were introduced into a Pseudomonas fluorescens strain isolated from the phylloplane of sugarcane and the endophytic bacterium Herbaspirillum seropedicae found in sugarcane. The ptac-cry1Ac7 construct was introduced into the chromosome of P. fluorescens using the integration vector pJFF350 carrying the artificial interposon Omegon-Km. Western blot analysis showed that the expression levels of the integrated cry1Ac7 gene were much higher under the control of the tac promoter than under the control of its endogenous promoter. It was also determined that multicopy expression in P. fluorescens and H. seropedicae of ptac-cry1Ac7 carried on pKT240 caused plasmid instability with no detectable protein expression. In H. seropedicae, more Cry1Ac7 toxin was produced when the gene was cloned under the control of the Nmr promoter on pML122 than in the opposite orientation and bioassays showed that the former resulted in higher mortality of E. saccharina larvae than the latter. P. fluorescens 14::ptac-tox resulted in higher mortality of larvae than did P. fluorescens 14::tox. An increased toxic effect was observed when P. fluorescens 14::ptac-tox was combined with P. fluorescens carrying the Serratia marcescens chitinase gene chiA, under the control of the tac promoter, integrated into the chromosome. PMID:10877771

Safety and Effectiveness of Natalizumab: First Report of Interim Results of Post-Marketing Surveillance in Japan.

PubMed

Saida, Takahiko; Yokoyama, Kazumasa; Sato, Ryusuke; Makioka, Haruki; Iizuka, Yukihiko; Hase, Masakazu; Ling, Yan; Torii, Shinichi

2017-12-01

Natalizumab, a humanized anti-α4 integrin monoclonal antibody, received marketing approval in Japan in 2014 for the treatment of multiple sclerosis (MS). Because the previous large-scale clinical trials of natalizumab were mainly conducted in Europe and North American countries, and data in patients with MS from Japan were limited, we conducted an all-case post-marketing surveillance of natalizumab-treated MS patients from Japan to investigate the safety and effectiveness of natalizumab in a real-world clinical setting in Japan. Here, we report the results of an interim analysis. During the observation period of 2 years, all patients who were treated with natalizumab subsequent to its approval in Japan were followed. The effectiveness of natalizumab was assessed by examining the changes in expanded disability status scale (EDSS) score and annualized relapse rate (ARR) from baseline. Safety was assessed by analyzing the incidence of adverse drug reactions (ADRs). The safety analysis included 106 patients (mean age 39.3 years; women 62.3%) whose data were collected until the data lock point (February 7, 2016). The effectiveness analysis included 75 patients. The majority of patients had relapsing-remitting MS (93/106 patients; 87.7%). The mean length of treatment exposure in the present study was 6.6 months. During the 2-year observation period, no significant change in the EDSS was observed, while the ARR decreased significantly from baseline (72.9% reduction, p = 0.001). ADRs and serious ADRs were observed in 11.3% and 3.8% of patients, respectively; however, no new safety concerns were detected. No patient had progressive multifocal leukoencephalopathy (PML) during the present study period. The safety and effectiveness of natalizumab were confirmed in Japanese patients with MS in clinical practice. Nevertheless, potential risks including PML require continuous, careful observation. Biogen Japan Ltd (Tokyo, Japan).

Elastodynamic cloaking and field enhancement for soft spheres

NASA Astrophysics Data System (ADS)

Diatta, Andre; Guenneau, Sebastien

2016-11-01

We propose a spherical cloak described by a non-singular asymmetric elasticity tensor {C} depending upon a small parameter η, that defines the softness of a region one would like to conceal from elastodynamic waves. By varying η, we generate a class of soft spheres dressed by elastodynamic cloaks, which are shown to considerably reduce the scattering of the soft spheres. Importantly, such cloaks also provide some wave protection except for a countable set of frequencies, for which some large elastic field enhancement can be observed within the soft spheres. Through an investigation of trapped modes in elasticity, we supply a good approximation of such Mie-type resonances by some transcendental equation. Our results, unlike previous studies that focused merely on the invisibility aspects, shed light on potential pitfalls of elastodynamic cloaks for earthquake protection designed via geometric transforms: a seismic cloak needs to be designed in such a way that its inner resonances differ from eigenfrequencies of the building one wishes to protect. In order to circumvent this downfall of field enhancement inside the cloaked area, we introduce a novel generation of cloaks, named here, mixed cloaks. Such mixed cloaks consist of a shell that detours incoming waves, hence creating an invisibility region, and of a perfectly matched layer (PML, located at the inner boundary of the cloaks) that absorbs residual wave energy in such a way that aforementioned resonances in the soft sphere are strongly attenuated. The designs of mixed cloaks with a non-singular elasticity tensor combined with an inner PML and non-vanishing density bring seismic cloaks one step closer to a practical implementation. Note in passing that the concept of mixed cloaks also applies in the case of singular cloaks and can be translated in other wave areas for a similar purpose (i.e. to smear down inner resonances within the invisibility region).

Precursor polymer compositions comprising polybenzimidazole

DOEpatents

Klaehn, John R.; Peterson, Eric S.; Orme, Christopher J.

2015-07-14

Stable, high performance polymer compositions including polybenzimidazole (PBI) and a melamine-formaldehyde polymer, such as methylated, poly(melamine-co-formaldehyde), for forming structures such as films, fibers and bulky structures. The polymer compositions may be formed by combining polybenzimidazole with the melamine-formaldehyde polymer to form a precursor. The polybenzimidazole may be reacted and/or intertwined with the melamine-formaldehyde polymer to form the polymer composition. For example, a stable, free-standing film having a thickness of, for example, between about 5 .mu.m and about 30 .mu.m may be formed from the polymer composition. Such films may be used as gas separation membranes and may be submerged into water for extended periods without crazing and cracking. The polymer composition may also be used as a coating on substrates, such as metal and ceramics, or may be used for spinning fibers. Precursors for forming such polymer compositions are also disclosed.

Ultra-Stable Oscillators for Probe Radio Science Investigations

NASA Technical Reports Server (NTRS)

Asmar, Sami

2012-01-01

An Ultra-Stable Oscillator (USO) is: A frequency reference, and A clock It is stable, small, and sensitive. It is a science and an art form. It is flown on spacecraft/probes. It]is utilized at ground stations alone or as a cleanup loop. It eliminates lock-up time on uplink for occultation egress & effect of media on uplink signal. It has enabled significant planetary science investigations.

High strength, tough alloy steel

DOEpatents

Thomas, Gareth; Rao, Bangaru V. N.

1979-01-01

A high strength, tough alloy steel is formed by heating the steel to a temperature in the austenite range (1000.degree.-1100.degree. C.) to form a homogeneous austenite phase and then cooling the steel to form a microstructure of uniformly dispersed dislocated martensite separated by continuous thin boundary films of stabilized retained austenite. The steel includes 0.2-0.35 weight % carbon, at least 1% and preferably 3-4.5% chromium, and at least one other substitutional alloying element, preferably manganese or nickel. The austenite film is stable to subsequent heat treatment as by tempering (below 300.degree. C.) and reforms to a stable film after austenite grain refinement.

Earth observation image of Von Karman Vortices taken during STS-100

NASA Image and Video Library

2001-04-30

STS100-710-182 (19 April-1 May 2001) --- Easily recognizable in this STS-100 70mm frame are phenomena known as the von Karman vortices, which were forming in the stratocumulus field downwind from the volcanic island of Rishiri-to in the northern Sea of Japan off the northwest coast of Hokkaido, Japan. According to NASA scientists studying the STS-100 photo collection, these features form when a stable atmosphere with low clouds flows past a relatively small obstacle with a height greater than the depth of the cloud layer. Because the atmosphere is stable, a series of eddies form in the moving cloud field.

Effect of Annealing on the Passive Film Stability and Corrosion Resistance of New Families of Iron-Based Amorphous Metals

DTIC Science & Technology

2011-06-01

metallic glass easier to create and more stable once formed, thus improving the corrosion resistance. Adding titanium will enable the formation of...glass easier to create and more stable once formed, thus improving the corrosion resistance. Adding titanium will enable the formation of an extremely...research, it was hypothesized that additions of titanium could enable the formation of a protective titanium oxide film on the surface of the alloy

Personality, Study Methods and Academic Performance

ERIC Educational Resources Information Center

Entwistle, N. J.; Wilson, J. D.

1970-01-01

A questionnaire measuring four student personality types--stable introvert, unstable introvert, stable extrovert and unstable extrovert--along with the Eysenck Personality Inventory (Form A) were give to 72 graduate students at Aberdeen University and the results showed recognizable interaction between study methods, motivation and personality…

Highly birefringent large negative dispersion-flattened photonic crystal fibre for broadband residual dispersion compensation

NASA Astrophysics Data System (ADS)

Faisal, Mohammad; Bala, Animesh; Roy Chowdhury, Kanan; Mia, Md. Borhan

2018-07-01

A triangular lattice photonic crystal fibre is presented in this paper for residual dispersion compensation. The fibre exhibits a flattened negative dispersion of -992.01 ± 6.93 ps/(nm-km) over S+C+L wavelength bands and -995.83 ± 0.42 ps/(nm-km) over C-band. The birefringence is about 4.4 × 10-2 at the excitation wavelength of 1550 nm which is also very high. Full vector finite element method (FEM) with a perfectly matched absorbing layer (PML) boundary condition is applied to numerically investigate the guiding properties of this PCF. The fibre operates at fundamental mode only. All these properties endorse this fibre as a suitable candidate for compensating residual dispersion and polarization maintaining applications.

Jealousy Graphs: Structure and Complexity of Decentralized Stable Matching

DTIC Science & Technology

2013-01-01

REPORT Jealousy Graphs: Structure and Complexity of Decentralized Stable Matching 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: The stable matching...Franceschetti 858-822-2284 3. DATES COVERED (From - To) Standard Form 298 (Rev 8/98) Prescribed by ANSI Std. Z39.18 - Jealousy Graphs: Structure and...market. Using this structure, we are able to provide a ner analysis of the complexity of a subclass of decentralized matching markets. Jealousy

ATP-stabilized amorphous calcium carbonate nanospheres and their application in protein adsorption.

PubMed

Qi, Chao; Zhu, Ying-Jie; Lu, Bing-Qiang; Zhao, Xin-Yu; Zhao, Jing; Chen, Feng; Wu, Jin

2014-05-28

Calcium carbonate is a common substance found in rocks worldwide, and is the main biomineral formed in shells of marine organisms and snails, pearls and eggshells. Amorphous calcium carbonate (ACC) is the least stable polymorph of calcium carbonate, which is so unstable under normal conditions that it is difficult to be prepared in vitro because it rapidly crystallizes to form one of the more stable polymorphs in aqueous solution. Herein, we report the successful synthesis of highly stable ACC nanospheres in vitro using adenosine 5'-triphosphate disodium salt (ATP) as a stabilizer. The effect of ATP on the stability of ACC nanospheres is investigated. Our experiments show that ATP plays an unique role in the stabilization of ACC nanospheres in aqueous solution. Moreover, the as-prepared ACC nanospheres are highly stable in phosphate buffered saline for a relatively long period of time (12 days) even under relatively high concentrations of calcium and phosphate ions. The cytotoxicity tests show that the as-prepared highly stable ACC nanospheres have excellent biocompatibility. The highly stable ACC nanospheres have high protein adsorption capacity, implying that they are promising for applications in biomedical fields such as drug delivery and protein adsorption. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Demonstration of Thermodynamics and Kinetics Using FriXion Erasable Pens

ERIC Educational Resources Information Center

Campbell, Dean J.; Bosma, Wayne B.; Bannon, Stephen J.; Gunter, Molly M.; Hammar, Margaret K.

2012-01-01

FriXion erasable pens contain thermochromic inks that have colored low-temperature forms and colorless high-temperature forms. Liquid nitrogen can be used to kinetically trap the high-temperature forms of the ink at temperatures at which ordinarily the low-temperature forms are more thermodynamically stable. (Contains 2 figures.)

The role of metals in carcinogenesis: biochemistry and metabolism.

PubMed Central

Jennette, K W

1981-01-01

The oxyanions of vanadium, chromium, molybdenum, arsenic, and selenium are stable forms of these elements in high oxidation states which cross cell membranes using the normal phosphate and/or sulfate transport systems of the cell. Once inside the cell, these oxyanions may sulfuryl transfer reactions. Often the oxyanions serve as alternate enzyme substrates but form ester products which are hydrolytically unstable compared with the sulfate and phosphate esters and, therefore, decompose readily in aqueous solution. Arsenite and selenite are capable of reacting with sulfhydryl groups in proteins. Some cells are able to metabolize redox active oxyanions to forms of the elements in other stable oxidation states. Specific enzymes may be involved in the metabolic processes. The metabolites of these elements may form complexes with small molecules, proteins and nucleic acids which inhibit their ability to function properly. The divalent ions of beryllium, manganese, cobalt, nickel, cadmium, mercury, and lead are stable forms of these elements which may mimic essential divalent ions such as magnesium, calcium, iron, copper, or zinc. These ions may complex small molecules, enzymes, and nucleic acids in such a way that the normal activity of these species is altered. Free radicals may be produced in the presence of these metal ions which damage critical cellular molecules. PMID:7023933

Glasses of three alkyl phosphates show a range of kinetic stabilities when prepared by physical vapor deposition

NASA Astrophysics Data System (ADS)

Beasley, M. S.; Tylinski, M.; Chua, Y. Z.; Schick, C.; Ediger, M. D.

2018-05-01

In situ AC nanocalorimetry was used to characterize vapor-deposited glasses of three phosphates with increasing lengths of alkyl side chains: trimethyl phosphate, triethyl phosphate, and tributyl phosphate. The as-deposited glasses were assessed in terms of their reversing heat capacity, onset temperature, and isothermal transformation time. Glasses with a range of kinetic stabilities were prepared, including kinetically stable glasses, as indicated by high onset temperatures and long transformation times. Trimethyl phosphate forms kinetically stable glasses, similar to many other organic molecules, while triethyl phosphate and tributyl phosphate do not. Triethyl phosphate and tributyl phosphate present the first examples of non-hydrogen bonding systems that are unable to form stable glasses via vapor deposition at 0.2 nm/s. Based on experiments utilizing different deposition rates, we conclude that triethyl phosphate and tributyl phosphate lack the surface mobility required for stable glass formation. This may be related to their high enthalpies of vaporization and the internal structure of the liquid state.

Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status.

PubMed

Zhou, Jie; Coles, Lisa D; Kartha, Reena V; Nash, Nardina; Mishra, Usha; Lund, Troy C; Cloyd, James C

2015-08-01

There is an increasing interest in using N-acetylcysteine (NAC) as a treatment for neurodegenerative disorders to increase glutathione (GSH) levels and its redox status. The purpose of this study was to characterize the biosynthesis of NAC to GSH using a novel stable isotope-labeled technique, and investigate the pharmacodynamics of NAC in vivo. Female wild-type mice were given a single intravenous bolus dose of 150 mg kg(-1) stable-labeled NAC. Plasma, red blood cells (RBC), and brain tissues were collected at predesignated time points. Stable-labeled NAC and its metabolite GSH (both labeled and unlabeled forms) were quantified in blood and brain samples. Molar ratios of the reduced and oxidized forms of GSH (GSH divided by glutathione disulfide, redox ratio) were also determined. The elimination phase half-life of NAC was approximately 34 min. Both labeled and unlabeled GSH in RBC were found to increase; however, the area under the curve above baseline (AUCb0-280 ) of labeled GSH was only 1% of the unlabeled form. These data indicate that NAC is not a direct precursor of GSH. In addition, NAC has prolonged effects in brain even when the drug has been eliminated from systemic circulation. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Sequence-Selective Formation of Synthetic H-Bonded Duplexes

PubMed Central

2017-01-01

Oligomers equipped with a sequence of phenol and pyridine N-oxide groups form duplexes via H-bonding interactions between these recognition units. Reductive amination chemistry was used to synthesize all possible 3-mer sequences: AAA, AAD, ADA, DAA, ADD, DAD, DDA, and DDD. Pairwise interactions between the oligomers were investigated using NMR titration and dilution experiments in toluene. The measured association constants vary by 3 orders of magnitude (102 to 105 M–1). Antiparallel sequence-complementary oligomers generally form more stable complexes than mismatched duplexes. Mismatched duplexes that have an excess of H-bond donors are stabilized by the interaction of two phenol donors with one pyridine N-oxide acceptor. Oligomers that have a H-bond donor and acceptor on the ends of the chain can fold to form intramolecular H-bonds in the free state. The 1,3-folding equilibrium competes with duplex formation and lowers the stability of duplexes involving these sequences. As a result, some of the mismatch duplexes are more stable than some of the sequence-complementary duplexes. However, the most stable mismatch duplexes contain DDD and compete with the most stable sequence-complementary duplex, AAA·DDD, so in mixtures that contain all eight sequences, sequence-complementary duplexes dominate. Even higher fidelity sequence selectivity can be achieved if alternating donor–acceptor sequences are avoided. PMID:28857551

Microfluidic control of droplet formation from stable emulsions formed by aqueous two-phase systems

NASA Astrophysics Data System (ADS)

Teixeira, Alyne G.; Tsai, Meng-Chiao; Frampton, John P.

2018-02-01

Aqueous two-phase systems (ATPSs) form from the thermodynamic separation of two dissolved incompatible solutes, such as two polymers, a polymer and a salt, and a polymer and a surfactant. At most supercritical concentrations, ATPS emulsions can be formed by vigorous mixing. These emulsions typically settle into distinct layers in minutes to hours. However, it is also possible to choose ATPS compositions with extremely long settling times that resemble stable emulsions. Here, we generated stable emulsions from a polyethylene glycol (PEG)-dextran ATPS by selecting ATPS compositions at the extreme ends of the tie lines connecting the binodal curve delineating phase-separating compositions. Droplets of PEG in a continuous dextran phase did not coalesce appreciably over the course of several days when stored in a conical tube or syringe. However, upon exposure to laminar flow conditions in a microfluidic channel, droplets were observed to coalesce. Through microscopic characterization of droplet volume, an increase in droplet size and decrease in overall droplet number was observed as a function of channel distance, suggesting a progressive droplet merging phenomenon. This novel approach to control droplet size by encouraging coalescence of stable emulsions under laminar flow in a microfluidic channel enables the production of droplets ranging from fL to several pL, which may enable various future biotechnology applications.

Polymorphism of phosphoric oxide

USGS Publications Warehouse

Hill, W.L.; Faust, G.T.; Hendricks, S.B.

1943-01-01

The melting points and monotropic relationship of three crystalline forms of phosphoric oxide were determined by the method of quenching. Previous vapor pressure data are discussed and interpreted to establish a pressure-temperature diagram (70 to 600??) for the one-component system. The system involves three triple points, at which solid, liquid and vapor (P4O10) coexist in equilibrium, namely: 420?? and 360 cm., 562?? and 43.7 cm. and 580?? and 55.5 cm., corresponding to the hexagonal, orthorhombic and stable polymorphs, respectively, and at least two distinct liquids, one a stable polymer of the other, which are identified with the melting of the stable form and the hexagonal modification, respectively. Indices of refraction of the polymorphs and glasses were determined. The density and the thermal, hygroscopic and structural properties of the several phases are discussed.

Method of making high strength, tough alloy steel

DOEpatents

Thomas, Gareth; Rao, Bangaru V. N.

1979-01-01

A high strength, tough alloy steel, particularly suitable for the mining industry, is formed by heating the steel to a temperature in the austenite range (1000.degree.-1100.degree. C.) to form a homogeneous austenite phase and then cooling the steel to form a microstructure of uniformly dispersed dislocated martensite separated by continuous thin boundary films of stabilized retained austenite. The steel includes 0.2-0.35 weight % carbon, at least 1% and preferably 3-4.5% chromium, and at least one other subsitutional alloying element, preferably manganese or nickel. The austenite film is stable to subsequent heat treatment as by tempering (below 300.degree. C.) and reforms to a stable film after austenite grain refinement.

New rapid-curing, stable polyimide polymers with high-temperature strength and thermal stability

NASA Technical Reports Server (NTRS)

Burns, E. A.; Jones, J. F.; Kendrick, W. R.; Lubowitz, H. R.; Thorpe, R. S.; Wilson, E. R.

1969-01-01

Additive-type polymerization reaction forms thermally stable polyimide polymers, thereby eliminating the volatile matter attendant with the condensation reaction. It is based on the utilization of reactive alicyclic rings positioned on the ends of polyimide prepolymers having relatively low molecular weights.

Isolation and characterization of Keratinibaculum paraultunense gen. nov., sp. nov., a novel thermophilic, anaerobic bacterium with keratinolytic activity.

PubMed

Huang, Yan; Sun, Yingjie; Ma, Shichun; Chen, Lu; Zhang, Hui; Deng, Yu

2013-08-01

A novel thermophilic, anaerobic, keratinolytic bacterium designated KD-1 was isolated from grassy marshland. Strain KD-1 was a spore-forming rod with a Gram-positive type cell wall, but stained Gram-negative. The temperature, pH, and NaCl concentration range necessary for growth was 30-65 °C (optimum 55 °C), 6.0-10.5 (optimum 8.0-8.5), and 0-6% (optimum 0.2%) (w/v), respectively. Strain KD-1 possessed extracellular keratinase, and the optimum activity of the crude enzyme was pH 8.5 and 70 °C. The enzyme was identified as a thermostable serine-type protease. The strain was sensitive to rifampin, chloramphenicol, kanamycin, and tetracycline and was resistant to erythromycin, neomycin, penicillin, and streptomycin. The main cellular fatty acid was predominantly C15:0 iso (64%), and the G+C content was 28 mol%. Morphological and physiological characterization, together with phylogenetic analysis based on 16S rRNA gene sequencing identified KD-1 as a new species of a novel genus of Clostridiaceae with 95.3%, 93.8% 16S rRNA gene sequence similarity to Clostridium ultunense BS(T) (DSM 10521(T)) and Tepidimicrobium xylanilyticum PML14(T) (= JCM 15035(T)), respectively. We propose the name Keratinibaculum paraultunense gen. nov., sp. nov., with KD-1 (=JCM 18769(T) =DSM 26752(T)) as the type strain. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Quantum Chemical Study of Rare Gas/Halide Interactions as a Model for High Energy Density Material. 1. Transition Properties in HC1

DTIC Science & Technology

1994-11-01

separation of a stable, negatively charged exciplex such as (ClXe2)- and a self- trapped positive hole (STi) localized on a Xe+ (n = 2-3) molecule. The first...solid to form Xe + HO + 2hv -- Xe÷ (HCI)-, which quickly reacts with another Xe atom to form the more stable tri-atomic exciplex X407. This exciplex ...Transfer Reaction Dynamics in Rare Gas Solids. I. Photodynamics of Localized Xenon Chloride Exciplexes ." Journal of Chemical Physics. vol. 85, p. 5660

Structural, thermodynamic, and kinetic aspects of the trimorphism of hydrocortisone.

PubMed

Suitchmezian, Viktor; Jess, Inke; Näther, Christian

2008-10-01

Hydrocortisone was investigated for polymorphism and pseudopolymorphism and three different polymorphic modifications (I-III) and one 2-propanol solvate were found. Forms I and III crystallize in the orthorhombic space group P2(1)2(1)2(1), whereas form II and the 2-propanol solvate crystallize monoclinic in space group P2(1). In all the modifications the molecules are connected by intermolecular O--H...O hydrogen bonding. In the 2-propanol solvate, channels are formed in which the solvent molecules are embedded. Solvent-mediated conversion experiments reveal that the commercially available form I represents the thermodynamically most stable modification at room temperature, whereas forms II and III are metastable. On heating, form III transforms into form II in an endothermic reaction, which shows that an enantiotropic relationship exists between these forms. Form I exhibits the highest melting point and the highest heat of fusion and thus represents the thermodynamically most stable form over the whole temperature range. DSC measurements indicate that form I behaves monotropic to forms II and III. Desolvation of the 2-propanol solvate at higher temperatures results in a transformation into form II, whereas the removal of 2-propanol at room temperature and in vacuum reduced pressure leads to the formation of form III. (c) 2008 Wiley-Liss, Inc. and the American Pharmacists Association

Shelf-Stable Food Safety

MedlinePlus

... Forms Standard Forms FSIS United States Department of Agriculture Food Safety and Inspection Service About FSIS District ... plants by inspectors from the U.S. Department of Agriculture's Food Safety and Inspection Service. Products made into ...

What controls channel form in steep mountain streams?

NASA Astrophysics Data System (ADS)

Palucis, M. C.; Lamb, M. P.

2017-07-01

Steep mountain streams have channel morphologies that transition from alternate bar to step-pool to cascade with increasing bed slope, which affect stream habitat, flow resistance, and sediment transport. Experimental and theoretical studies suggest that alternate bars form under large channel width-to-depth ratios, step-pools form in near supercritical flow or when channel width is narrow compared to bed grain size, and cascade morphology is related to debris flows. However, the connection between these process variables and bed slope—the apparent dominant variable for natural stream types—is unclear. Combining field data and theory, we find that certain bed slopes have unique channel morphologies because the process variables covary systematically with bed slope. Multiple stable states are predicted for other ranges in bed slope, suggesting that a competition of underlying processes leads to the emergence of the most stable channel form.

Characterization of human glucocorticoid receptor complexes formed with DNA fragments containing or lacking glucocorticoid response elements

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

Tully, D.B.; Cidlowski, J.A.

1989-03-07

Sucrose density gradient shift assays were used to study the interactions of human glucocorticoid receptors (GR) with small DNA fragments either containing or lacking glucocorticoid response element (GRE) DNA consensus sequences. When crude cytoplasmic extracts containing ({sup 3}H)triamcinolone acetonide (({sup 3}H)TA) labeled GR were incubated with unlabeled DNA under conditions of DNA excess, a GRE-containing DNA fragment obtained from the 5' long terminal repeat of mouse mammary tumor virus (MMTV LTR) formed a stable 12-16S complex with activated, but not nonactivated, ({sup 3}H)TA receptor. By contrast, if the cytosols were treated with calf thymus DNA-cellulose to deplete non-GR-DNA-binding proteins priormore » to heat activation, a smaller 7-10S complex was formed with the MMTV LTR DNA fragment. Activated ({sup 3}H)TA receptor from DNA-cellulose pretreated cytosols also interacted with two similarly sized fragments from pBR322 DNA. Stability of the complexes formed between GR and these three DNA fragments was strongly affected by even moderate alterations in either the salt concentration or the pH of the gradient buffer. Under all conditions tested, the complex formed with the MMTV LTR DNA fragment was more stable than the complexes formed with either of the pBR322 DNA fragments. Together these observations indicate that the formation of stable complexes between activated GR and isolated DNA fragments requires the presence of GRE consensus sequences in the DNA.« less

Are gastroenterologists less tolerant of treatment risks than patients? Benefit-risk preferences in Crohn's disease management.

PubMed

Johnson, F Reed; Hauber, Brett; Özdemir, Semra; Siegel, Corey A; Hass, Steven; Sands, Bruce E

2010-10-01

Crohn's disease is a serious and debilitating gastrointestinal disorder with a high, unmet need for new treatments. Biologic agents have the potential to alter the natural course of Crohn's disease but present known risks of potential serious adverse events (SAEs). Previous studies have shown that patients are willing to accept elevated SAE risks in exchange for clinical efficacy. Gastroenterologists and patients may have similar goals of maximizing treatment benefit while minimizing risk; however, gastroenterologists may assess the relative importance of risk differently than patients. To (a) understand how gastroenterologists caring for patients with Crohn's disease balance benefits and risks in their treatment decisions and (b) compare their treatment preferences with those of adult patients with Crohn's disease. Both patient and gastroenterologist treatment preferences were elicited using a web-based, choice-format conjoint survey instrument. The conjoint questions required subjects to choose between 2 hypothetical treatment options with differing levels of treatment attributes. Patients evaluated the treatment options for themselves, and gastroenterologists evaluated the treatment options for each of 3 hypothetical patient types: (a) female aged 25 years with no history of Crohn's disease surgery (young), (b) male aged 45 years with 1 Crohn's disease surgery (middleaged), and (c) female older than 70 years with 4 Crohn's disease surgeries (older). Treatment attributes represented the expected outcomes of treatment: severity of daily symptoms, frequency of flare-ups, serious disease complications, oral steroid use, and the risks of 3 potentially fatal SAEs - lymphoma, serious or opportunistic infections, and progressive multifocal leukoencephalopathy (PML) - during 10 years of treatment. Maximum acceptable risk (MAR), defined as the highest level of SAE risk that subjects would accept in return for a given improvement in efficacy (i.e., the increase in treatment risk that exactly offsets the hypothetical increase in treatment benefit), was calculated using preference weights (parameter marginal log odds ratios) that were estimated with conjoint analysis (random parameters logit models). Gastroenterologists' and patients' mean MARs for 3 SAE risks were calculated for 6 improvements in Crohn's disease symptoms, and gastroenterologists' preference weights for each of the 3 patient profiles were compared. Gastroenterologists' MARs for a hypothetical middle-aged patient were then compared with predicted MARs derived using data from the patient study for male patients aged 40 to 50 years with 1 surgery. After exclusion of nonrespondents (n = 4,021 of 4,422 gastroenterologists; n = 681 of 1,285 patients) and nonevaluable respondents (n = 86 gastroenterologists; n = 24 patients), 315 gastroenterologists and 580 patients were included in the final analytic samples. There were no statistically significant differences in gastroenterologists' preference weights for the middle-aged versus young patient profiles. However, preference weights indicated that gastroenterologists are more concerned about 5% side-effect risks for the older patient profile than for the middle-aged patient profile. For symptomatic improvements from severe symptoms to remission, gastroenterologists' highest MARs were for lymphoma: 6.21%, 8.99%, and 25.00% for the young, middle-aged, and older patient types, respectively. In analyses of improvements from severe to moderate symptoms and from moderate symptoms to remission for hypothetical middle-aged patients, gastroenterologists' 10-year risk tolerance ranged between 1.96% lymphoma risk in return for an improvement from moderate symptoms to remission and 4.93% lymphoma risk for an improvement from severe to moderate symptoms; patients' 10-year risk tolerance for middle-aged patients ranged between 1.52% PML risk in return for an improvement from severe to moderate symptoms and 5.86% infection risk for an improvement from moderate symptoms to remission. On average, gastroenterologists and patients disagreed about how much risk is tolerable for improvements in efficacy. In exchange for improvements from severe to moderate symptoms for the middle-aged patient profile, gastroenterologists were significantly more tolerant than patients of treatment risks of PML (P < 0.001) and serious infection (P = 0.001) but not lymphoma (P = 0.230). In contrast, in exchange for improvements from moderate symptoms to remission for the same patient profile, patients were significantly more tolerant than gastroenterologists of treatment risks for serious infection (P < 0.001) and lymphoma (P < 0.001) but not PML (P = 0.158). Gastroenterologists and patients have well-defined preferences among treatment attributes and are willing to accept tradeoffs between efficacy and treatment risks. However, risk tolerance varies depending on the type of patient for whom gastroenterologists are being asked to consider treatment. In rating treatment preferences for patients with a middle-aged profile, gastroenterologists are less tolerant of SAE risks than patients in exchange for improvement from moderate symptoms to remission.

Generation of poleward moving auroral forms (PMAFs) during periods of dayside auroral oval expansions/contractions and periods when the dayside auroral oval is expanded and stable

NASA Astrophysics Data System (ADS)

Fasel, G. J.; Flicker, J.; Sibeck, D. G.; Alyami, M.; Angelo, A.; Aylward, R. J.; Bender, S.; Christensen, M.; Kim, J.; Kristensen, H.; Orellana, Y.; Sahin, O.; Yoon, J.; Green, D.; Sigernes, F.; Lorentzen, D. A.

2013-12-01

The latitude of the equatorial edge of the dayside auroral oval has been shown to vary with the direction of the IMF Bz-component. The equatorward/poleward edge of the dayside auroral oval shifts equatorward/poleward when the IMF Bz-component is negative/positive [Burch, 1973; Akasofu, 1977; Horwitz and Akasofu, 1977; Sandholt et al., 1986, 1988]. Past studies have shown that poleward-moving auroral forms (PMAFs) are a common feature during equatorward expansions of the dayside auroral oval. Horwitz and Akasofu [1977] noted a one-to-one correspondence of luminous PMAFs associated with an equatorward expansion of the dayside auroral oval. During the southward turning of the IMF Bz-component the merging rate on the dayside increases [Newell and Meng, 1987] leading to the erosion of the dayside magnetopause. The field line merging process is thought to be most efficient when the interplanetary magnetic field (IMF) Bz-component turns southward. Both Vorobjev et al. [1975] and Horwitz and Akasofu [1977] attributed these PMAFs to magnetic flux being eroded away from the dayside magnetopause and transported antisunward. Dayside poleward-moving auroral forms are also observed during periods of an expanded and stable dayside auroral oval for both northern and southern hemisphere observations [Sandholt et al., 1986, 1989, 1990; Rairden and Mende, 1989; Mende et al., 1990]. Poleward-moving auroral forms have also been observed during some dayside oval contractions but have not been discussed much in the literature. This study examines the dayside auroral oval during periods of expansion, contraction, and during periods of an expanded and stable dayside auroral oval. This statistical study will provide the following results: number of poleward-moving auroral forms that are generated during dayside auroral oval expansions/contractions and during periods of a stable and expanded dayside auroral oval, the average initial and final elevation angle of the dayside auroral oval, time for dayside auroral oval to expand or contract, and the solar wind parameters (IMF Bx, By, Bz, speed, and pressure) associated with each interval (expansion, contraction, or stable and expanded).

R-loops: targets for nuclease cleavage and repeat instability.

PubMed

Freudenreich, Catherine H

2018-01-11

R-loops form when transcribed RNA remains bound to its DNA template to form a stable RNA:DNA hybrid. Stable R-loops form when the RNA is purine-rich, and are further stabilized by DNA secondary structures on the non-template strand. Interestingly, many expandable and disease-causing repeat sequences form stable R-loops, and R-loops can contribute to repeat instability. Repeat expansions are responsible for multiple neurodegenerative diseases, including Huntington's disease, myotonic dystrophy, and several types of ataxias. Recently, it was found that R-loops at an expanded CAG/CTG repeat tract cause DNA breaks as well as repeat instability (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Two factors were identified as causing R-loop-dependent breaks at CAG/CTG tracts: deamination of cytosines and the MutLγ (Mlh1-Mlh3) endonuclease, defining two new mechanisms for how R-loops can generate DNA breaks (Su and Freudenreich, Proc Natl Acad Sci USA 114, E8392-E8401, 2017). Following R-loop-dependent nicking, base excision repair resulted in repeat instability. These results have implications for human repeat expansion diseases and provide a paradigm for how RNA:DNA hybrids can cause genome instability at structure-forming DNA sequences. This perspective summarizes mechanisms of R-loop-induced fragility at G-rich repeats and new links between DNA breaks and repeat instability.

Immobilization of actinides in stable mineral type and ceramic materials (high temperature synthesis)

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

Starkov, O.; Konovalov, E.

1996-05-01

Alternative vitrification technologies are being developed in the world for the immobilization of high radioactive waste in materials with improved thermodynamic stability, as well as improved chemical and thermal stability and stability to radiation. Oxides, synthesized in the form of analogs to rock-forming minerals and ceramics, are among those materials that have highly stable properties and are compatible with the environment. In choosing the appropriate material, we need to be guided by its geometric stability, the minimal number of cations in the structure of the material and the presence of structural elements in the mineral that are isomorphs of uraniummore » and thorium, actinoids found in nature. Rare earth elements, yttrium, zirconium and calcium are therefore suitable. The minerals listed in the table (with the exception of the zircon) are pegatites by origin, i.e. they are formed towards the end of the magma crystallization of silicates form the residual melt, enriched with Ta, Nb, Ti, Zr, Ce, Y, U and Th. Uranium and thorium in the form of isomorphic admixtures form part of the lattice of the mineral. These minerals, which are rather simple in composition and structure and are formed under high temperatures, may be viewed as natural physio-chemical systems that are stable and long-lived in natural environments. The similarity of the properties of actinoids and lanthanoids plays an important role in the geochemistry of uranium and thorium; however, uranium (IV) is closer to the {open_quotes}heavy{close_quotes} group of lanthanoids (the yttrium group) while thorium (IV) is closer to the {open_quotes}light{close_quotes} group (the cerium group). That is why rare earth minerals contain uranium and thorium in the form of isomorphic admixtures.« less

Stable DNA replication: interplay between DNA replication, homologous recombination, and transcription.

PubMed

Kogoma, T

1997-06-01

Chromosome replication in Escherichia coli is normally initiated at oriC, the origin of chromosome replication. E. coli cells possess at least three additional initiation systems for chromosome replication that are normally repressed but can be activated under certain specific conditions. These are termed the stable DNA replication systems. Inducible stable DNA replication (iSDR), which is activated by SOS induction, is proposed to be initiated from a D-loop, an early intermediate in homologous recombination. Thus, iSDR is a form of recombination-dependent DNA replication (RDR). Analysis of iSDR and RDR has led to the proposal that homologous recombination and double-strand break repair involve extensive semiconservative DNA replication. RDR is proposed to play crucial roles in homologous recombination, double-strand break repair, restoration of collapsed replication forks, and adaptive mutation. Constitutive stable DNA replication (cSDR) is activated in mhA mutants deficient in RNase HI or in recG mutants deficient in RecG helicase. cSDR is proposed to be initiated from an R-loop that can be formed by the invasion of duplex DNA by an RNA transcript, which most probably is catalyzed by RecA protein. The third form of SDR is nSDR, which can be transiently activated in wild-type cells when rapidly growing cells enter the stationary phase. This article describes the characteristics of these alternative DNA replication forms and reviews evidence that has led to the formulation of the proposed models for SDR initiation mechanisms. The possible interplay between DNA replication, homologous recombination, DNA repair, and transcription is explored.

Polyolefin composites containing a phase change material

DOEpatents

Salyer, Ival O.

1991-01-01

A composite useful in thermal energy storage, said composite being formed of a polyolefin matrix having a phase change material such as a crystalline alkyl hydrocarbon incorporated therein, said polyolefin being thermally form stable; the composite is useful in forming pellets, sheets or fibers having thermal energy storage characteristics; methods for forming the composite are also disclosed.

Amorphous Calcium Carbonate in Biomineralization: Stable and Precursor Phases

NASA Astrophysics Data System (ADS)

Weiner, S.

2003-12-01

The biological formation of the crystalline polymorphs of calcium carbonate, aragonite and calcite, is widespread. The less stable polymorphs, vaterite and monohydrocalcite are also formed by some organisms. Surprisingly, the highly unstable phase, amorphous calcium carbonate (ACC), is formed by a variety of organisms from different phyla. Most of these are stable at least within the lifetime of the organism. The stable forms all have a stoichiometry of CaCO3.H2O. Despite the fact that they do not diffract X-rays. Studies of their short range order by EXAFS, reveal species specific variations in the number and distances of atoms that surround the calcium ion. Proteins extracted from stable biogenic ACC are able to stabilize the phase in vitro. ACC has also been identified as a transient precursor phase during the formation of the calcitic larval spicule of the sea urchin and the formation of the larval shell of a bivalve. The transient form has little or no water associated with the CaCO3. Preliminary EXAFS data suggest that the short range order of the sea urchin spicule transient ACC resembles calcite. Proteins extracted from these spicules are able to stabilize ACC provided Mg is present in the solution. As the mollusks and the echinoderms are on two different branches of the animal phylogenetic tree, it is conceivable that the strategy of using ACC as a precursor phase at least for larval mineralization may be widespread. It has yet to be shown that it is used by adults of either phylum. The manner in which organisms precipitate, stabilize and destabilize if necessary, this highly metastable phase of calcium carbonate presents many fascinating and enigmatic questions, whose solutions could well contribute to a better understanding of basic processes in biomineralization. For more details and references, see Addadi, L., Raz, S. and Weiner, S. (2003). Taking advantage of disorder: Amorphous calcium carbonate and its roles in biomineralization. Adv. Mat.15, 959-970.

Metallic Thin-Film Bonding and Alloy Generation

NASA Technical Reports Server (NTRS)

Peotter, Brian S. (Inventor); Fryer, Jack Merrill (Inventor); Campbell, Geoff (Inventor); Droppers, Lloyd (Inventor)

2016-01-01

Diffusion bonding a stack of aluminum thin films is particularly challenging due to a stable aluminum oxide coating that rapidly forms on the aluminum thin films when they are exposed to atmosphere and the relatively low meting temperature of aluminum. By plating the individual aluminum thin films with a metal that does not rapidly form a stable oxide coating, the individual aluminum thin films may be readily diffusion bonded together using heat and pressure. The resulting diffusion bonded structure can be an alloy of choice through the use of a carefully selected base and plating metals. The aluminum thin films may also be etched with distinct patterns that form a microfluidic fluid flow path through the stack of aluminum thin films when diffusion bonded together.

Fabrication and thermal properties of tetradecanol/graphene aerogel form-stable composite phase change materials.

PubMed

Mu, Boyuan; Li, Min

2018-06-11

In this study, tetradecanol/graphene aerogel form-stable composite phase change materials were prepared by physical absorption. Two kinds of graphene aerogels were prepared using vitamin C and ethylenediamine to enhance the thermal conductivity of tetradecanol and prevent its leakage during phase transition. The form-stable composite phase change material exhibited excellent thermal energy storage capacity. The latent heat of the tetradecanol/graphene aerogel composite phase change materials with 5 wt.% graphene aerogel was similar to the theoretical latent heat of pure tetradecanol. The thermal conductivity of the tetradecanol/graphene aerogel composite phase change material improved gradually as the graphene aerogel content increased. The prepared tetradecanol/graphene aerogel composite phase change materials exhibited good thermal reliability and thermal stability, and no chemical reaction occurred between tetradecanol and the graphene aerogel. In addition, the latent heat and thermal conductivity of the tetradecanol/ethylenediamine-graphene aerogel composites were higher than those of tetradecanol/vitamin C-graphene aerogel composites, and the flexible shape of the ethylenediamine-graphene aerogel is suitable for application of the tetradecanol/ethylenediamine-graphene aerogel composite.

An Absorbing Boundary Condition for the Lattice Boltzmann Method Based on the Perfectly Matched Layer

PubMed Central

Najafi-Yazdi, A.; Mongeau, L.

2012-01-01

The Lattice Boltzmann Method (LBM) is a well established computational tool for fluid flow simulations. This method has been recently utilized for low Mach number computational aeroacoustics. Robust and nonreflective boundary conditions, similar to those used in Navier-Stokes solvers, are needed for LBM-based aeroacoustics simulations. The goal of the present study was to develop an absorbing boundary condition based on the perfectly matched layer (PML) concept for LBM. The derivation of formulations for both two and three dimensional problems are presented. The macroscopic behavior of the new formulation is discussed. The new formulation was tested using benchmark acoustic problems. The perfectly matched layer concept appears to be very well suited for LBM, and yielded very low acoustic reflection factor. PMID:23526050

The role of SUMOylation in ageing and senescent decline.

PubMed

Princz, Andrea; Tavernarakis, Nektarios

2017-03-01

Posttranslational protein modifications are playing crucial roles in essential cellular mechanisms. SUMOylation is a reversible posttranslational modification of specific target proteins by the attachment of a small ubiquitin-like protein. Although the mechanism of conjugation of SUMO to proteins is analogous to ubiquitination, it requires its own, specific set of enzymes. The consequences of SUMOylation are widely variable, depending on the physiological state of the cell and the attached SUMO isoform. Accumulating recent findings have revealed a prominent role of SUMOylation in molecular pathways that govern senescence and ageing. Here, we review the link between SUMO attachment events and cellular processes that influence senescence and ageing, including promyelocytic leukaemia (PML) nuclear body and telomere function, autophagy, reactive oxygen species (ROS) homeostasis and growth factor signalling. Copyright © 2017 Elsevier B.V. All rights reserved.

Microarray analysis of glial cells resistant to JCV infection suggests a correlation between viral infection and inflammatory cytokine gene expression

PubMed Central

Manley, Kate; Gee, Gretchen V; Simkevich, Carl P; Sedivy, John M; Atwood, Walter J

2007-01-01

The human polyomavirus, JCV, has a highly restricted tropism and primarily infects glial cells. The mechanisms restricting infection of cells by JCV are poorly understood. Previously we developed and described a glial cell line that was resistant to JCV infection with the aim of using these cells to identify factors that determine JCV tropism. Gene expression profiling of susceptible and resistant glial cells revealed a direct correlation between the expression of inflammatory cytokines and susceptibility to JCV infection. This correlation manifested at the level of viral gene transcription. Previous studies have suggested a link between an increase in cytokine gene expression in HIV patients and the development of PML and these data support this hypothesis. PMID:17555786