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.

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.

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...

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.

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.

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.

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.

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.

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.

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.

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/

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.

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.

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.

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.

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).

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.

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

A nucleolar targeting signal in PML-I addresses PML to nucleolar caps in stressed or senescent cells.

PubMed

Condemine, Wilfried; Takahashi, Yuki; Le Bras, Morgane; de Thé, Hugues

2007-09-15

The promyelocytic leukemia (PML) tumour suppressor is the organiser of PML nuclear bodies, which are domains the precise functions of which are still disputed. We show that upon several types of stress, endogenous PML proteins form nucleolar caps and eventually engulf nucleolar components. Only two specific PML splice variants (PML-I and PML-IV) are efficiently targeted to the nucleolus and the abundant PML-I isoform is required for the targeting of endogenous PML proteins to this organelle. We identified a nucleolar targeting domain within the evolutionarily conserved C-terminus of PML-I. This domain contains a predicted exonuclease III fold essential for the targeting of the PML-I C-terminus to nucleolar fibrillar centres. Furthermore, spontaneous or oncogene retrieval-induced senescence is associated with the formation of very large PML nuclear bodies that initially contain nucleolar components. Later, poly-ubiquitin conjugates are found on the outer shell or within most of these senescence-associated PML bodies. Thus, unexpectedly, the scarcely studied PML-I isoform links PML bodies, nucleolus, senescence and proteolysis.

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

PML tumor suppressor protein is required for HCV production

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

Kuroki, Misao; Research Fellow of the Japan Society for the Promotion of Science; Center for AIDS Research, Kumamoto University, Kumamoto 860-0811

2013-01-11

Highlights: Black-Right-Pointing-Pointer PML tumor suppressor protein is required for HCV production. Black-Right-Pointing-Pointer PML is dispensable for HCV RNA replication. Black-Right-Pointing-Pointer HCV could not alter formation of PML-NBs. Black-Right-Pointing-Pointer INI1 and DDX5, PML-related proteins, are involved in HCV life cycle. -- Abstract: PML tumor suppressor protein, which forms discrete nuclear structures termed PML-nuclear bodies, has been associated with several cellular functions, including cell proliferation, apoptosis and antiviral defense. Recently, it was reported that the HCV core protein colocalizes with PML in PML-NBs and abrogates the PML function through interaction with PML. However, role(s) of PML in HCV life cycle is unknown.more » To test whether or not PML affects HCV life cycle, we examined the level of secreted HCV core and the infectivity of HCV in the culture supernatants as well as the level of HCV RNA in HuH-7-derived RSc cells, in which HCV-JFH1 can infect and efficiently replicate, stably expressing short hairpin RNA targeted to PML. In this context, the level of secreted HCV core and the infectivity in the supernatants from PML knockdown cells was remarkably reduced, whereas the level of HCV RNA in the PML knockdown cells was not significantly affected in spite of very effective knockdown of PML. In fact, we showed that PML is unrelated to HCV RNA replication using the subgenomic HCV-JFH1 replicon RNA, JRN/3-5B. Furthermore, the infectivity of HCV-like particle in the culture supernatants was significantly reduced in PML knockdown JRN/3-5B cells expressing core to NS2 coding region of HCV-JFH1 genome using the trans-packaging system. Finally, we also demonstrated that INI1 and DDX5, the PML-related proteins, are involved in HCV production. Taken together, these findings suggest that PML is required for HCV production.« less

C-terminal motifs in promyelocytic leukemia protein isoforms critically regulate PML nuclear body formation.

PubMed

Li, Chuang; Peng, Qiongfang; Wan, Xiao; Sun, Haili; Tang, Jun

2017-10-15

Promyelocytic leukemia protein (PML) nuclear bodies (NBs), which are sub-nuclear protein structures, are involved in a variety of important cellular functions. PML-NBs are assembled by PML isoforms, and contact between small ubiquitin-like modifiers (SUMOs) with the SUMO interaction motif (SIM) are critically involved in this process. PML isoforms contain a common N-terminal region and a variable C-terminus. However, the contribution of the C-terminal regions to PML-NB formation remains poorly defined. Here, using high-resolution microscopy, we show that mutation of the SIM distinctively influences the structure of NBs formed by each individual PML isoform, with that of PML-III and PML-V minimally changed, and PML-I and PML-IV dramatically impaired. We further identify several C-terminal elements that are important in regulating NB structure and provide strong evidence to suggest that the 8b element in PML-IV possesses a strong ability to interact with SUMO-1 and SUMO-2, and critically participates in NB formation. Our findings highlight the importance of PML C-termini in NB assembly and function, and provide molecular insight into the PML-NB assembly of each distinctive isoform. © 2017. Published by The Company of Biologists Ltd.

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.

Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite

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

Hirano, Seishiro, E-mail: seishiro@nies.go.jp; Graduate School of Pharmaceutical Sciences, Chiba University; Watanabe, Takayuki

2013-12-15

Inorganic arsenite (iAs{sup 3+}) is a two-edged sword. iAs{sup 3+} is a well-known human carcinogen; nevertheless, it has been used as a therapeutic drug for acute promyelocytic leukemia (APL), which is caused by a fusion protein comprising retinoic acid receptor-α and promyelocytic leukemia (PML). PML, a nuclear transcription factor, has a RING finger domain with densely positioned cysteine residues. To examine PML-modulated cellular responses to iAs{sup 3+}, CHO-K1 and HEK293 cells were each used to establish cell lines that expressed ectopic human PML. Overexpression of PML increased susceptibility to iAs{sup 3+} in CHO-K1 cells, but not in HEK293 cells. Exposuremore » of PML-transfected cells to iAs{sup 3+} caused PML to change from a soluble form to less soluble forms, and this modification of PML was observable even with just 0.1 μM iAs{sup 3+} (7.5 ppb). Western blot and immunofluorescent microscopic analyses revealed that the biochemical changes of PML were caused at least in part by conjugation with small ubiquitin-like modifier proteins (SUMOylation). A luciferase reporter gene was used to investigate whether modification of PML was caused by oxidative stress or activation of antioxidant response element (ARE) in CHO-K1 cells. Modification of PML protein occurred faster than activation of the ARE in response to iAs{sup 3+}, suggesting that PML was not modified as a consequence of oxidative stress-induced ARE activation. - Highlights: • PML was found in nuclear microspecles in response to arsenite. • Arsenite triggers SUMOylation of PML. • Arsenite modifies PML at as low as 0.1 μM. • Modification of PML is not caused by ARE activation.« less

Solubility shift and SUMOylaltion of promyelocytic leukemia (PML) protein in response to arsenic(III) and fate of the SUMOylated PML

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

Hirano, Seishiro, E-mail: seishiro@nies.go.jp; Graduate School of Pharmaceutical Sciences, Chiba University; Tadano, Mihoko

2015-09-15

Promyelocytic leukemia (PML), which is a tumor suppressor protein that nevertheless plays an important role in the maintenance of leukemia initiating cells, is known to be biochemically modified by As{sup 3+}. We recently developed a simple method to evaluate the modification of PML by As{sup 3+} resulting in a change in solubility and the covalent binding of small ubiquitin-like modifier (SUMO). Here we semi-quantitatively investigated the SUMOylation of PML using HEK293 cells which were stably transfected with PML-VI (HEK-PML). Western blot analyses indicated that PML became insoluble in cold RadioImmunoPrecipitation Assay (RIPA) lysis buffer and was SUMOylated by both SUMO2/3more » and SUMO1 by As{sup 3+}. Surprisingly SUMO1 monomers were completely utilized for the SUMOylation of PML. Antimony (Sb{sup 3+}) but not bismuth (Bi{sup 3+}), Cu{sup 2+}, or Cd{sup 2+} biochemically modified PML similarly. SUMOylated PML decreased after removal of As{sup 3+} from the culture medium. However, unSUMOylated PML was still recovered in the RIPA-insoluble fraction, suggesting that SUMOylation is not requisite for changing the RIPA-soluble PML into the RIPA-insoluble form. Immunofluorescence staining of As{sup 3+}-exposed cells indicated that SUMO2/3 was co-localized with PML in the nuclear bodies. However, some PML protein was present in peri-nuclear regions without SUMO2/3. Functional Really Interesting New Gene (RING)-deleted mutant PML neither formed PML nuclear bodies nor was biochemically modified by As{sup 3+}. Conjugation with intracellular glutathione may explain the accessibility of As{sup 3+} and Sb{sup 3+} to PML in the nuclear region evading chelation and entrapping by cytoplasmic proteins such as metallothioneins. - Highlights: • As{sup 3+} is a carcinogen and also a therapeutic agent for leukemia. • PML becomes insoluble in RIPA and SUMOylated by As{sup 3+}. • Sb{sup 3+} modifies PML similar to As{sup 3+}. • Functional RING motif is necessary for As{sup 3+}-induced PML modification.« less

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

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.

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.

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.

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.

PML/RARA oxidation and arsenic binding initiate the antileukemia response of As2O3.

PubMed

Jeanne, Marion; Lallemand-Breitenbach, Valérie; Ferhi, Omar; Koken, Marcel; Le Bras, Morgane; Duffort, Stéphanie; Peres, Laurent; Berthier, Caroline; Soilihi, Hassane; Raught, Brian; de Thé, Hugues

2010-07-13

As(2)O(3) cures acute promyelocytic leukemia (APL) by initiating PML/RARA oncoprotein degradation, through sumoylation of its PML moiety. However, how As(2)O(3) initiates PML sumoylation has remained largely unexplained. As(2)O(3) binds vicinal cysteines and increases reactive oxygen species (ROS) production. We demonstrate that upon As(2)O(3) exposure, PML undergoes ROS-initiated intermolecular disulfide formation and binds arsenic directly. Disulfide-linked PML or PML/RARA multimers form nuclear matrix-associated nuclear bodies (NBs), become sumoylated and are degraded. Hematopoietic progenitors transformed by an As(2)O(3)-binding PML/RARA mutant exhibit defective As(2)O(3) response. Conversely, nonarsenical oxidants elicit PML/RARA multimerization, NB-association, degradation, and leukemia response in vivo, but do not affect PLZF/RARA-driven APLs. Thus, PML oxidation regulates NB-biogenesis, while oxidation-enforced PML/RARA multimerization and direct arsenic-binding cooperate to enforce APL's exquisite As(2)O(3) sensitivity. Copyright (c) 2010 Elsevier Inc. All rights reserved.

Pondering the puzzle of PML (promyelocytic leukemia) nuclear bodies: can we fit the pieces together using an RNA regulon?

PubMed

Borden, Katherine L B

2008-11-01

The promyelocytic leukemia protein PML and its associated nuclear bodies are hot topics of investigation. This interest arises for multiple reasons including the tight link between the integrity of PML nuclear bodies and several disease states and the impact of the PML protein and PML nuclear bodies on proliferation, apoptosis and viral infection. Unfortunately, an understanding of the molecular underpinnings of PML nuclear body function remains elusive. Here, a general overview of the PML field is provided and is extended to discuss whether some of the basic tenets of "PML-ology" are still valid. For instance, recent findings suggest that some components of PML nuclear bodies form bodies in the absence of the PML protein. Also, a new model for PML nuclear body function is proposed which provides a unifying framework for its effects on diverse biochemical pathways such as Akt signaling and the p53-Mdm2 axis. In this model, the PML protein acts as an inhibitor of gene expression post-transcriptionally via inhibiting a network node in the eIF4E RNA regulon. An example is given for how the PML RNA regulon model provided the basis for the development of a new anti-cancer strategy being tested in the clinic.

Distinct nuclear body components, PML and SMRT, regulate the trans-acting function of HTLV-1 Tax oncoprotein.

PubMed

Ariumi, Yasuo; Ego, Takeshi; Kaida, Atsushi; Matsumoto, Mikiko; Pandolfi, Pier Paolo; Shimotohno, Kunitada

2003-03-20

Several viruses target cellular promyelocytic leukemia (PML)-nuclear bodies (PML-NBs) to induce their disruption, marked morphological changes in these structures or the relocation to PML-NB components to the cytoplasm of infected cells. PML conversely interferes with viral replication. We demonstrate that PML acts as a coactivator for the human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein without direct binding. Tax was identified within interchromatin granule clusters (IGCs)/RNA splicing bodies (SBs), not PML-NBs; Tax expression did not affect PML-NB formation. Moreover, PML and CBP/p300 cooperatively activated Tax-mediated HTLV-1-LTR-dependent gene expression. Interestingly, two PML mutants, PML-RAR and PMLDelta216-331, which fail to form PML-NBs, could also coactivate Tax-mediated trans-acting function but had no effect on retinoic acid receptor (RAR)- or p53-dependent gene expression. In contrast, SMRT (silencing mediator for retinoic acid and thyroid hormone receptors), a nuclear corepressor found within the matrix-associated deacetylase (MAD) nuclear body, relocalized into Tax-associated nuclear bodies upon coexpression with Tax. SMRT coactivated the trans-acting function of Tax through direct binding. Coexpression of SMRT and PML resulted in an additive activation of Tax trans-acting function. Thus, crosstalk between distinct nuclear bodies may control Tax function.

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.

Localization and regulation of PML bodies in the adult mouse brain.

PubMed

Hall, Małgorzata H; Magalska, Adriana; Malinowska, Monika; Ruszczycki, Błażej; Czaban, Iwona; Patel, Satyam; Ambrożek-Latecka, Magdalena; Zołocińska, Ewa; Broszkiewicz, Hanna; Parobczak, Kamil; Nair, Rajeevkumar R; Rylski, Marcin; Pawlak, Robert; Bramham, Clive R; Wilczyński, Grzegorz M

2016-06-01

PML is a tumor suppressor protein involved in the pathogenesis of promyelocytic leukemia. In non-neuronal cells, PML is a principal component of characteristic nuclear bodies. In the brain, PML has been implicated in the control of embryonic neurogenesis, and in certain physiological and pathological phenomena in the adult brain. Yet, the cellular and subcellular localization of the PML protein in the brain, including its presence in the nuclear bodies, has not been investigated comprehensively. Because the formation of PML bodies appears to be a key aspect in the function of the PML protein, we investigated the presence of these structures and their anatomical distribution, throughout the adult mouse brain. We found that PML is broadly expressed across the gray matter, with the highest levels in the cerebral and cerebellar cortices. In the cerebral cortex PML is present exclusively in neurons, in which it forms well-defined nuclear inclusions containing SUMO-1, SUMO 2/3, but not Daxx. At the ultrastructural level, the appearance of neuronal PML bodies differs from the classic one, i.e., the solitary structure with more or less distinctive capsule. Rather, neuronal PML bodies have the form of small PML protein aggregates located in the close vicinity of chromatin threads. The number, size, and signal intensity of neuronal PML bodies are dynamically influenced by immobilization stress and seizures. Our study indicates that PML bodies are broadly involved in activity-dependent nuclear phenomena in adult neurons.

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

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.

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...

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.

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.

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.

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.

PML, SUMOylation, and Senescence

PubMed Central

Ivanschitz, Lisa; De Thé, Hugues; Le Bras, Morgane

2013-01-01

Since its discovery, 25 years ago, promyelocytic leukemia (PML) has been an enigma. Implicated in the oncogenic PML/RARA fusion, forming elusive intranuclear domains, triggering cell death or senescence, controlled by and perhaps controlling SUMOylation… there are multiple PML-related issues. Here we review the reciprocal interactions between PML, senescence, and SUMOylation, notably in the context of cellular transformation. PMID:23847762

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.

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 (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

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.

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.

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.

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.

Promyelocytic leukemia isoform IV confers resistance to encephalomyocarditis virus via the sequestration of 3D polymerase in nuclear bodies.

PubMed

Maroui, Mohamed Ali; Pampin, Mathieu; Chelbi-Alix, Mounira K

2011-12-01

Promyelocytic leukemia (PML) protein is the organizer of nuclear matrix-associated nuclear bodies (NBs), and its conjugation to the small ubiquitin-like modifier (SUMO) is required for the formation of these structures. Several alternatively spliced PML transcripts from a single PML gene lead to the production of seven PML isoforms (PML isoform I [PMLI] to VII [PMLVII]), which all share a N-terminal region that includes the RBCC (RING, B boxes, and a α-helical coiled-coil) motif but differ in the C-terminal region. This diversity of PML isoforms determines the specific functions of each isoform. There is increasing evidence implicating PML in host antiviral defense and suggesting various strategies involving PML to counteract viral production. We reported that mouse embryonic fibroblasts derived from PML knockout mice are more sensitive than wild-type cells to infection with encephalomyocarditis virus (EMCV). Here, we show that stable expression of PMLIV or PMLIVa inhibited viral replication and protein synthesis, leading to a substantial reduction of EMCV multiplication. This protective effect required PMLIV SUMOylation and was not observed with other nuclear PML isoforms (I, II, III, V, and VI) or with the cytoplasmic PMLVII. We demonstrated that only PMLIV interacted with EMCV 3D polymerase (3Dpol) and sequestered it within PML NBs. The C-terminal region specific to PMLIV was required for both interaction with 3Dpol and the antiviral properties. Also, depletion of PMLIV by RNA interference significantly boosted EMCV production in interferon-treated cells. These findings indicate the mechanism by which PML confers resistance to EMCV. They also reveal a new pathway mediating the antiviral activity of interferon against EMCV.

Promyelocytic Leukemia Isoform IV Confers Resistance to Encephalomyocarditis Virus via the Sequestration of 3D Polymerase in Nuclear Bodies ▿

PubMed Central

Maroui, Mohamed Ali; Pampin, Mathieu; Chelbi-Alix, Mounira K.

2011-01-01

Promyelocytic leukemia (PML) protein is the organizer of nuclear matrix-associated nuclear bodies (NBs), and its conjugation to the small ubiquitin-like modifier (SUMO) is required for the formation of these structures. Several alternatively spliced PML transcripts from a single PML gene lead to the production of seven PML isoforms (PML isoform I [PMLI] to VII [PMLVII]), which all share a N-terminal region that includes the RBCC (RING, B boxes, and a α-helical coiled-coil) motif but differ in the C-terminal region. This diversity of PML isoforms determines the specific functions of each isoform. There is increasing evidence implicating PML in host antiviral defense and suggesting various strategies involving PML to counteract viral production. We reported that mouse embryonic fibroblasts derived from PML knockout mice are more sensitive than wild-type cells to infection with encephalomyocarditis virus (EMCV). Here, we show that stable expression of PMLIV or PMLIVa inhibited viral replication and protein synthesis, leading to a substantial reduction of EMCV multiplication. This protective effect required PMLIV SUMOylation and was not observed with other nuclear PML isoforms (I, II, III, V, and VI) or with the cytoplasmic PMLVII. We demonstrated that only PMLIV interacted with EMCV 3D polymerase (3Dpol) and sequestered it within PML NBs. The C-terminal region specific to PMLIV was required for both interaction with 3Dpol and the antiviral properties. Also, depletion of PMLIV by RNA interference significantly boosted EMCV production in interferon-treated cells. These findings indicate the mechanism by which PML confers resistance to EMCV. They also reveal a new pathway mediating the antiviral activity of interferon against EMCV. PMID:21994459

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

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.

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

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

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.

Changes to anti-JCV antibody levels in a Swedish national MS cohort

PubMed Central

Warnke, Clemens; Ramanujam, Ryan; Plavina, Tatiana; Bergström, Tomas; Goelz, Susan; Subramanyam, Meena; Kockum, Ingrid; Rahbar, Afsar; Kieseier, Bernd C; Holmén, Carolina; Olsson, Tomas; Hillert, Jan; Fogdell-Hahn, Anna

2013-01-01

Background The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). Objective To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. Methods An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. Results Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. Conclusions Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted. PMID:23463870

Changes to anti-JCV antibody levels in a Swedish national MS cohort.

PubMed

Warnke, Clemens; Ramanujam, Ryan; Plavina, Tatiana; Bergström, Tomas; Goelz, Susan; Subramanyam, Meena; Kockum, Ingrid; Rahbar, Afsar; Kieseier, Bernd C; Holmén, Carolina; Olsson, Tomas; Hillert, Jan; Fogdell-Hahn, Anna

2013-11-01

The anti-JC virus (JCV) antibody status has been introduced to stratify patients with multiple sclerosis (MS) for higher or lower risk of progressive multifocal leukoencephalopathy (PML). To assess the potential utility of anti-JCV antibody levels for earlier diagnosis or prediction of PML. An analytically validated antibody assay was used to determine serological status, normalised optical density values, and dilution titres for anti-JCV antibodies. The method was applied to stored sera of 1157 patients with MS including five cases of PML, all enrolled in the Swedish pharmacovigilance study for natalizumab (NAT). Anticytomegalovirus (CMV) and antivaricella-zoster (VZV) antibody levels served as controls. Prior to treatment with NAT, anti-JCV antibody levels were stable in the anti-JCV positive patients. During therapy, a slight decrease in anti-JCV and anti-VZV antibody levels, but not anti-CMV antibody levels, was observed. All five patients who developed PML showed a mild to moderate increase in anti-JCV antibody levels at time of PML diagnosis; pre-PML samples suggested that this increase might start already prior to diagnosis of PML. Treatment initiation with NAT may lead to a slight decrease in anti-JCV and anti-VZV antibody levels, suggestive of a mild suppressive effect of NAT on antibody levels. Our findings in five cases of PML demonstrate that the onset of PML can be accompanied by increasing anti-JCV antibodies in serum. Monitoring of anti-JCV antibody levels could potentially be used as a tool for prediction or earlier diagnosis of PML during NAT treatment for MS. Further studies are warranted.

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.

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.

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.

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.

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

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.

Nuclear domain 10 components promyelocytic leukemia protein and hDaxx independently contribute to an intrinsic antiviral defense against human cytomegalovirus infection.

PubMed

Tavalai, Nina; Papior, Peer; Rechter, Sabine; Stamminger, Thomas

2008-01-01

Infection with DNA viruses commonly results in the association of viral genomes with a cellular subnuclear structure known as nuclear domain 10 (ND10). Recent studies demonstrated that individual ND10 components, like hDaxx or promyelocytic leukemia protein (PML), mediate an intrinsic immune response against human cytomegalovirus (HCMV) infection, strengthening the assumption that ND10 components are part of a cellular antiviral defense mechanism. In order to further define the role of hDaxx and PML for HCMV replication, we generated either primary human fibroblasts with a stable, individual knockdown of PML or hDaxx (PML-kd and hDaxx-kd, respectively) or cells exhibiting a double knockdown. Comparative analysis of HCMV replication in PML-kd or hDaxx-kd cells revealed that immediate-early (IE) gene expression increased to a similar extent, regardless of which ND10 constituent was depleted. Since a loss of PML, the defining component of ND10, results in a dispersal of the entire nuclear substructure, the increased replication efficacy of HCMV in PML-kd cells could be a consequence of the dissociation of the repressor protein hDaxx from its optimal subnuclear localization. However, experiments using three different recombinant HCMVs revealed a differential growth complementation in PML-kd versus hDaxx-kd cells, strongly arguing for an independent involvement in suppressing HCMV replication. Furthermore, infection experiments using double-knockdown cells devoid of both PML and hDaxx illustrated an additional enhancement in the replication efficacy of HCMV compared to the single-knockdown cells. Taken together, our data indicate that both proteins, PML and hDaxx, mediate an intrinsic immune response against HCMV infection by contributing independently to the silencing of HCMV IE gene expression.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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

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.

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

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.

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.

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

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.

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

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

A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study.

PubMed

Ishii, Junko; Shishido-Hara, Yukiko; Kawamoto, Michi; Fujiwara, Satoru; Imai, Yukihiro; Nakamichi, Kazuo; Kohara, Nobuo

2018-04-27

A 37-year-old woman with systemic lupus erythematosus (SLE) presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML.

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.

Nonreflective Conditions for Perfectly Matched Layer in Computational Aeroacoustics

NASA Astrophysics Data System (ADS)

Choung, Hanahchim; Jang, Seokjong; Lee, Soogab

2018-05-01

In computational aeroacoustics, boundary conditions such as radiation, outflow, or absorbing boundary conditions are critical issues in that they can affect the entire solution of the computation. Among these types of boundary conditions, the perfectly matched layer boundary condition, which has been widely used in computational fluid dynamics and computational aeroacoustics, is developed by augmenting the additional term in the original governing equations by an absorption function so as to stably absorb the outgoing waves. Even if the perfectly matched layer is analytically a perfectly nonreflective boundary condition, spurious waves occur at the interface, since the analysis is performed in discretized space. Hence, this study is focused on factors that affect numerical errors from perfectly matched layer to find the optimum conditions for nonreflective PML. Through a mathematical approach, a minimum width of perfectly matched layer and an optimum absorption coefficient are suggested. To validate the prediction of the analysis, numerical simulations are performed in a generalized coordinate system, as well as in a Cartesian coordinate system.

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.

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.

X-ray crystallographic and MD simulation studies on the mechanism of interfacial activation of a family I.3 lipase with two lids.

PubMed

Angkawidjaja, Clement; Matsumura, Hiroyoshi; Koga, Yuichi; Takano, Kazufumi; Kanaya, Shigenori

2010-07-02

The interfacial activation mechanism of family I.3 lipase from Pseudomonas sp. MIS38 (PML), which has two alpha-helical lids (lid1 and lid2), was investigated using a combination of X-ray crystallography and molecular dynamics (MD) simulation. The crystal structure of PML in an open conformation was determined at 2.1 A resolution in the presence of Ca(2+) and Triton X-100. Comparison of this structure with that in the closed conformation indicates that both lids greatly change their positions and lid1 is anchored by the calcium ion (Ca1) in the open conformation. This structure was not seriously changed even when the protein was dialyzed extensively against the Ca(2+)-free buffer containing Triton X-100 before crystallization, indicating that the open conformation is fairly stable unless a micellar substance is removed. The crystal structure of the PML derivative, in which the active site serine residue (Ser207) is diethylphosphorylated by soaking the crystal of PML in the open conformation in a solution containing diethyl p-nitrophenyl phosphate, was also determined. This structure greatly resembles that in the open conformation, indicating that PML structure in the open conformation represents that in the active form. MD simulation of PML in the open conformation in the absence of micelles showed that lid2 closes first, while lid1 maintains its open conformation. Likewise, MD simulation of PML in the closed conformation in the absence of Ca(2+) and in the presence of octane or trilaurin micelles showed that lid1 opens, while lid2 remains closed. These results suggest that Ca1 functions as a hook for stabilization of a fully opened conformation of lid1 and for initiation of subsequent opening of lid2. Copyright 2010 Elsevier Ltd. All rights reserved.

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.

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.

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.

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.

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.

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

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

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.

[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

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.

Promyelocytic leukemia bodies tether to early endosomes during mitosis.

PubMed

Palibrk, Vuk; Lång, Emma; Lång, Anna; Schink, Kay Oliver; Rowe, Alexander D; Bøe, Stig Ove

2014-01-01

During mitosis the nuclear envelope breaks down, leading to potential interactions between cytoplasmic and nuclear components. PML bodies are nuclear structures with tumor suppressor and antiviral functions. Early endosomes, on the other hand, are cytoplasmic vesicles involved in transport and growth factor signaling. Here we demonstrate that PML bodies form stable interactions with early endosomes immediately following entry into mitosis. The 2 compartments remain stably associated throughout mitosis and dissociate in the cytoplasm of newly divided daughter cells. We also show that a minor subset of PML bodies becomes anchored to the mitotic spindle poles during cell division. The study demonstrates a stable mitosis-specific interaction between a cytoplasmic and a nuclear compartment.

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

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.

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

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.

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.

The EarthServer Federation: State, Role, and Contribution to GEOSS

NASA Astrophysics Data System (ADS)

Merticariu, Vlad; Baumann, Peter

2016-04-01

The intercontinental EarthServer initiative has established a European datacube platform with proven scalability: known databases exceed 100 TB, and single queries have been split across more than 1,000 cloud nodes. Its service interface being rigorously based on the OGC "Big Geo Data" standards, Web Coverage Service (WCS) and Web Coverage Processing Service (WCPS), a series of clients can dock into the services, ranging from open-source OpenLayers and QGIS over open-source NASA WorldWind to proprietary ESRI ArcGIS. Datacube fusion in a "mix and match" style is supported by the platform technolgy, the rasdaman Array Database System, which transparently federates queries so that users simply approach any node of the federation to access any data item, internally optimized for minimal data transfer. Notably, rasdaman is part of GEOSS GCI. NASA is contributing its Web WorldWind virtual globe for user-friendly data extraction, navigation, and analysis. Integrated datacube / metadata queries are contributed by CITE. Current federation members include ESA (managed by MEEO sr.l.), Plymouth Marine Laboratory (PML), the European Centre for Medium-Range Weather Forecast (ECMWF), Australia's National Computational Infrastructure, and Jacobs University (adding in Planetary Science). Further data centers have expressed interest in joining. We present the EarthServer approach, discuss its underlying technology, and illustrate the contribution this datacube platform can make to GEOSS.

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.

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

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

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.

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.

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.

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.

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

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

[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.

Perfectly matched layers in a divergence preserving ADI scheme for electromagnetics

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

Kraus, C.; ETH Zurich, Chair of Computational Science, 8092 Zuerich; Adelmann, A., E-mail: andreas.adelmann@psi.ch

For numerical simulations of highly relativistic and transversely accelerated charged particles including radiation fast algorithms are needed. While the radiation in particle accelerators has wavelengths in the order of 100 {mu}m the computational domain has dimensions roughly five orders of magnitude larger resulting in very large mesh sizes. The particles are confined to a small area of this domain only. To resolve the smallest scales close to the particles subgrids are envisioned. For reasons of stability the alternating direction implicit (ADI) scheme by Smithe et al. [D.N. Smithe, J.R. Cary, J.A. Carlsson, Divergence preservation in the ADI algorithms for electromagnetics,more » J. Comput. Phys. 228 (2009) 7289-7299] for Maxwell equations has been adopted. At the boundary of the domain absorbing boundary conditions have to be employed to prevent reflection of the radiation. In this paper we show how the divergence preserving ADI scheme has to be formulated in perfectly matched layers (PML) and compare the performance in several scenarios.« less

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.

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.

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.

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

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.

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.

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.

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.

Lagrangian mixed layer modeling of the western equatorial Pacific

NASA Technical Reports Server (NTRS)

Shinoda, Toshiaki; Lukas, Roger

1995-01-01

Processes that control the upper ocean thermohaline structure in the western equatorial Pacific are examined using a Lagrangian mixed layer model. The one-dimensional bulk mixed layer model of Garwood (1977) is integrated along the trajectories derived from a nonlinear 1 1/2 layer reduced gravity model forced with actual wind fields. The Global Precipitation Climatology Project (GPCP) data are used to estimate surface freshwater fluxes for the mixed layer model. The wind stress data which forced the 1 1/2 layer model are used for the mixed layer model. The model was run for the period 1987-1988. This simple model is able to simulate the isothermal layer below the mixed layer in the western Pacific warm pool and its variation. The subduction mechanism hypothesized by Lukas and Lindstrom (1991) is evident in the model results. During periods of strong South Equatorial Current, the warm and salty mixed layer waters in the central Pacific are subducted below the fresh shallow mixed layer in the western Pacific. However, this subduction mechanism is not evident when upwelling Rossby waves reach the western equatorial Pacific or when a prominent deepening of the mixed layer occurs in the western equatorial Pacific or when a prominent deepening of the mixed layer occurs in the western equatorial Pacific due to episodes of strong wind and light precipitation associated with the El Nino-Southern Oscillation. Comparison of the results between the Lagrangian mixed layer model and a locally forced Eulerian mixed layer model indicated that horizontal advection of salty waters from the central Pacific strongly affects the upper ocean salinity variation in the western Pacific, and that this advection is necessary to maintain the upper ocean thermohaline structure in this region.

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.

Effects of Precipitation on Ocean Mixed-Layer Temperature and Salinity as Simulated in a 2-D Coupled Ocean-Cloud Resolving Atmosphere Model

NASA Technical Reports Server (NTRS)

Li, Xiaofan; Sui, C.-H.; Lau, K-M.; Adamec, D.

1999-01-01

A two-dimensional coupled ocean-cloud resolving atmosphere model is used to investigate possible roles of convective scale ocean disturbances induced by atmospheric precipitation on ocean mixed-layer heat and salt budgets. The model couples a cloud resolving model with an embedded mixed layer-ocean circulation model. Five experiment are performed under imposed large-scale atmospheric forcing in terms of vertical velocity derived from the TOGA COARE observations during a selected seven-day period. The dominant variability of mixed-layer temperature and salinity are simulated by the coupled model with imposed large-scale forcing. The mixed-layer temperatures in the coupled experiments with 1-D and 2-D ocean models show similar variations when salinity effects are not included. When salinity effects are included, however, differences in the domain-mean mixed-layer salinity and temperature between coupled experiments with 1-D and 2-D ocean models could be as large as 0.3 PSU and 0.4 C respectively. Without fresh water effects, the nocturnal heat loss over ocean surface causes deep mixed layers and weak cooling rates so that the nocturnal mixed-layer temperatures tend to be horizontally-uniform. The fresh water flux, however, causes shallow mixed layers over convective areas while the nocturnal heat loss causes deep mixed layer over convection-free areas so that the mixed-layer temperatures have large horizontal fluctuations. Furthermore, fresh water flux exhibits larger spatial fluctuations than surface heat flux because heavy rainfall occurs over convective areas embedded in broad non-convective or clear areas, whereas diurnal signals over whole model areas yield high spatial correlation of surface heat flux. As a result, mixed-layer salinities contribute more to the density differences than do mixed-layer temperatures.

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.

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.

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.

A modified hexagonal photonic crystal fiber for terahertz applications

NASA Astrophysics Data System (ADS)

Islam, Md. Saiful; Sultana, Jakeya; Faisal, Mohammad; Islam, Mohammad Rakibul; Dinovitser, Alex; Ng, Brian W.-H.; Abbott, Derek

2018-05-01

We present a Zeonex based highly birefringent and dispersion flattened porous core photonic crystal fiber (PC-PCF) for polarization preserving applications in the terahertz region. In order to facilitate birefringence, an array of elliptical shaped air holes surrounded by porous cladding is introduced. The porous cladding comprises circular air-holes in a modified hexagonal arrangement. The transmission characteristics of the proposed PCF are investigated using a full-vector finite element method with perfectly matched layer (PML) absorbing boundary conditions. Simulation results show a high birefringence of 0.086 and an ultra-flattened dispersion variation of ± 0.03 ps/THz/cm at optimal design parameters. Besides, a number of other important wave-guiding properties including frequency dependence of the effective material loss (EML), confinement loss, and effective area are also investigated to assess the fiber's effectiveness as a terahertz waveguide.

Magneto-photonic crystal microcavities based on magnetic nanoparticles embedded in Silica matrix

NASA Astrophysics Data System (ADS)

Hocini, Abdesselam; Moukhtari, Riad; Khedrouche, Djamel; Kahlouche, Ahmed; Zamani, Mehdi

2017-02-01

Using the three-dimensional finite difference time domain method (3D FDTD) with perfectly matched layers (PML), optical and magneto-optical properties of two-dimensional magneto-photonic crystals micro-cavity is studied. This micro-cavity is fabricated by SiO2/ZrO2 or SiO2/TiO2 matrix doped with magnetic nanoparticles, in which the refractive index varied in the range of 1.51-1.58. We demonstrate that the Q factor for the designed cavity increases as the refractive index increases, and we find that the Q factor decreases as the volume fraction VF% due to off-diagonal elements increases. These magnetic microcavities may serve as a fundamental structure in a variety of ultra compact magneto photonic devices such as optical isolators, circulators and modulators in the future.

Investigation on flow and mixing characteristics of supersonic mixing layer induced by forced vibration of cantilever

NASA Astrophysics Data System (ADS)

Zhang, Dongdong; Tan, Jianguo; Lv, Liang

2015-12-01

The mixing process has been an important issue for the design of supersonic combustion ramjet engine, and the mixing efficiency plays a crucial role in the improvement of the combustion efficiency. In the present study, nanoparticle-based planar laser scattering (NPLS), particle image velocimetry (PIV) and large eddy simulation (LES) are employed to investigate the flow and mixing characteristics of supersonic mixing layer under different forced vibration conditions. The indexes of fractal dimension, mixing layer thickness, momentum thickness and scalar mixing level are applied to describe the mixing process. Results show that different from the development and evolution of supersonic mixing layer without vibration, the flow under forced vibration is more likely to present the characteristics of three-dimensionality. The laminar flow region of mixing layer under forced vibration is greatly shortened and the scales of rolled up Kelvin-Helmholtz vortices become larger, which promote the mixing process remarkably. The fractal dimension distribution reveals that comparing with the flow without vibration, the turbulent fluctuation of supersonic mixing layer under forced vibration is more intense. Besides, the distribution of mixing layer thickness, momentum thickness and scalar mixing level are strongly influenced by forced vibration. Especially, when the forcing frequency is 4000 Hz, the mixing layer thickness and momentum thickness are 0.0391 m and 0.0222 m at the far field of 0.16 m, 83% and 131% higher than that without vibration at the same position, respectively.

Analysis of Mixing Layer LES Data with Convective Mach Number 0.9 to 1.3

NASA Astrophysics Data System (ADS)

Helm, Clara M.; Martin, M. Pino

2017-11-01

The study of compressible mixing layers is essential to gaining a fundamental physical understanding of the global effects of compressibility on the development of turbulence in shear (Smits & Dussauge 2006). Research on compressible mixing layers is particularly difficult mainly because of the sensitivity of the mixing layer to initial conditions. A mixing layer occurs naturally in separated shock turbulent boundary layer interactions (STBLIs). We use our STBLI database to study the properties of mixing layers with convective Mach numbers of 0.9, 1.1, and 1.3. We report on the spreading rate, turbulence stress level, vortex shedding frequency, vortex convection velocity, and differences in the three-dimensional form of the vortices. The results are compared with mixing layer data available in literature and evaluated using the various scaling laws that have been proposed over the years. We discuss to what extent the mixing layer in the STBLI represents the canonical case and what additional insight into the is research area it provides. This work is supported by the Air Force Office of Scientific Research under Grant FA9550-17-1-0104.

Mixed Model Association with Family-Biased Case-Control Ascertainment.

PubMed

Hayeck, Tristan J; Loh, Po-Ru; Pollack, Samuela; Gusev, Alexander; Patterson, Nick; Zaitlen, Noah A; Price, Alkes L

2017-01-05

Mixed models have become the tool of choice for genetic association studies; however, standard mixed model methods may be poorly calibrated or underpowered under family sampling bias and/or case-control ascertainment. Previously, we introduced a liability threshold-based mixed model association statistic (LTMLM) to address case-control ascertainment in unrelated samples. Here, we consider family-biased case-control ascertainment, where case and control subjects are ascertained non-randomly with respect to family relatedness. Previous work has shown that this type of ascertainment can severely bias heritability estimates; we show here that it also impacts mixed model association statistics. We introduce a family-based association statistic (LT-Fam) that is robust to this problem. Similar to LTMLM, LT-Fam is computed from posterior mean liabilities (PML) under a liability threshold model; however, LT-Fam uses published narrow-sense heritability estimates to avoid the problem of biased heritability estimation, enabling correct calibration. In simulations with family-biased case-control ascertainment, LT-Fam was correctly calibrated (average χ 2 = 1.00-1.02 for null SNPs), whereas the Armitage trend test (ATT), standard mixed model association (MLM), and case-control retrospective association test (CARAT) were mis-calibrated (e.g., average χ 2 = 0.50-1.22 for MLM, 0.89-2.65 for CARAT). LT-Fam also attained higher power than other methods in some settings. In 1,259 type 2 diabetes-affected case subjects and 5,765 control subjects from the CARe cohort, downsampled to induce family-biased ascertainment, LT-Fam was correctly calibrated whereas ATT, MLM, and CARAT were again mis-calibrated. Our results highlight the importance of modeling family sampling bias in case-control datasets with related samples. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Scalar entrainment in the mixing layer

NASA Technical Reports Server (NTRS)

Sandham, N. D.; Mungal, M. G.; Broadwell, J. E.; Reynolds, W. C.

1988-01-01

New definitions of entrainment and mixing based on the passive scalar field in the plane mixing layer are proposed. The definitions distinguish clearly between three fluid states: (1) unmixed fluid, (2) fluid engulfed in the mixing layer, trapped between two scalar contours, and (3) mixed fluid. The difference betwen (2) and (3) is the amount of fluid which has been engulfed during the pairing process, but has not yet mixed. Trends are identified from direct numerical simulations and extensions to high Reynolds number mixing layers are made in terms of the Broadwell-Breidenthal mixing model. In the limit of high Peclet number (Pe = ReSc) it is speculated that engulfed fluid rises in steps associated with pairings, introducing unmixed fluid into the large scale structures, where it is eventually mixed at the Kolmogorov scale. From this viewpoint, pairing is a prerequisite for mixing in the turbulent plane mixing layer.

Direct numerical simulations of a reacting turbulent mixing layer by a pseudospectral-spectral element method

NASA Technical Reports Server (NTRS)

Mcmurtry, Patrick A.; Givi, Peyman

1992-01-01

An account is given of the implementation of the spectral-element technique for simulating a chemically reacting, spatially developing turbulent mixing layer. Attention is given to experimental and numerical studies that have investigated the development, evolution, and mixing characteristics of shear flows. A mathematical formulation is presented of the physical configuration of the spatially developing reacting mixing layer, in conjunction with a detailed representation of the spectral-element method's application to the numerical simulation of mixing layers. Results from 2D and 3D calculations of chemically reacting mixing layers are given.

Influences of Ocean Thermohaline Stratification on Arctic Sea Ice

NASA Astrophysics Data System (ADS)

Toole, J. M.; Timmermans, M.-L.; Perovich, D. K.; Krishfield, R. A.; Proshutinsky, A.; Richter-Menge, J. A.

2009-04-01

The Arctic Ocean's surface mixed layer constitutes the dynamical and thermodynamical link between the sea ice and the underlying waters. Wind stress, acting directly on the surface mixed layer or via wind-forced ice motion, produce surface currents that can in turn drive deep ocean flow. Mixed layer temperature is intimately related to basal sea ice growth and melting. Heat fluxes into or out of the surface mixed layer can occur at both its upper and lower interfaces: the former via air-sea exchange at leads and conduction through the ice, the latter via turbulent mixing and entrainment at the layer base. Variations in Arctic Ocean mixed layer properties are documented based on more than 16,000 temperature and salinity profiles acquired by Ice-Tethered Profilers since summer 2004 and analyzed in conjunction with sea ice observations from Ice Mass Balance Buoys and atmospheric heat flux estimates. Guidance interpreting the observations is provided by a one-dimensional ocean mixed layer model. The study focuses attention on the very strong density stratification about the mixed layer base in the Arctic that, in regions of sea ice melting, is increasing with time. The intense stratification greatly impedes mixed layer deepening by vertical convection and shear mixing, and thus limits the flux of deep ocean heat to the surface that could influence sea ice growth/decay. Consistent with previous work, this study demonstrates that the Arctic sea ice is most sensitive to changes in ocean mixed layer heat resulting from fluxes across its upper (air-sea and/or ice-water) interface.

High Operating Temperature Barrier Infrared Detector with Tailorable Cutoff Wavelength

NASA Technical Reports Server (NTRS)

Ting, David Z. (Inventor); Hill, Cory J. (Inventor); Seibel, Alexander (Inventor); Bandara, Sumith Y. (Inventor); Gunapala, Sarath D. (Inventor)

2015-01-01

A barrier infrared detector with absorber materials having selectable cutoff wavelengths and its method of manufacture is described. A GaInAsSb absorber layer may be grown on a GaSb substrate layer formed by mixing GaSb and InAsSb by an absorber mixing ratio. A GaAlAsSb barrier layer may then be grown on the barrier layer formed by mixing GaSb and AlSbAs by a barrier mixing ratio. The absorber mixing ratio may be selected to adjust a band gap of the absorber layer and thereby determine a cutoff wavelength for the barrier infrared detector. The absorber mixing ratio may vary along an absorber layer growth direction. Various contact layer architectures may be used. In addition, a top contact layer may be isolated into an array of elements electrically isolated as individual functional detectors that may be used in a detector array, imaging array, or focal plane array.

Revealing the timing of ocean stratification using remotely-sensed ocean fronts: links with marine predators

NASA Astrophysics Data System (ADS)

Miller, P. I.; Loveday, B. R.

2016-02-01

Stratification is of critical importance to the mixing and productivity of the ocean, though currently it can only be measured using in situ sampling, profiling buoys or underwater autonomous vehicles. Stratification is understood to affect the surface aggregation of pelagic fish and hence the foraging behaviour and distribution of their predators such as seabirds and cetaceans. Satellite Earth observation sensors cannot directly detect stratification, but can observe surface features related to the presence of stratification, for example shelf-sea fronts that separate tidally-mixed water from seasonally stratified water. This presentation describes a novel algorithm that accumulates evidence for stratification from a sequence of oceanic front maps, and in certain regions can reveal the timing of the seasonal onset and breakdown of stratification. Initial comparisons will be made with seabird locations acquired through GPS tagging. If successful, a remotely-sensed stratification timing index would augment the ocean front metrics already developed at PML, that have been applied in over 20 journal articles relating marine predators to ocean fronts. The figure below shows a preliminary remotely-sensed 'stratification' index, for 25-31 Jul. 2010, where red indicates water with stronger evidence for stratification.

Transverse ageostrophic circulations associated with elevated mixed layers

NASA Technical Reports Server (NTRS)

Keyser, D.; Carlson, T. N.

1984-01-01

The nature of the frontogenetically forced transverse ageostrophic circulations connected with elevated mixed layer structure is investigated as a first step toward diagnosing the complex vertical circulation patterns occurring in the vicinity of elevated mixed layers within a severe storm environment. The Sawyer-Eliassen ageostrophic circulation equation is reviewed and applied to the elevated mixed layer detected in the SESAME IV data set at 2100 GMT of May 9, 1979. The results of the ageostrophic circulation diagnosis are confirmed and refined by considering an analytic specification for the elevated mixed layer structure.

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.

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.

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

Late-Time Mixing Sensitivity to Initial Broadband Surface Roughness in High-Energy-Density Shear Layers

DOE PAGES

Flippo, K. A.; Doss, F. W.; Kline, J. L.; ...

2016-11-23

While using a large volume high-energy-density fluid shear experiment ( 8.5 cm 3 ) at the National Ignition Facility, we have demonstrated for the first time the ability to significantly alter the evolution of a supersonic sheared mixing layer by controlling the initial conditions of that layer. Furthermore, by altering the initial surface roughness of the tracer foil, we demonstrate the ability to transition the shear mixing layer from a highly ordered system of coherent structures to a randomly ordered system with a faster growing mix layer, indicative of strong mixing in the layer at a temperature of severalmore » tens of electron volts and at near solid density. Moreover, simulations using a turbulent-mix model show good agreement with the experimental results and poor agreement without turbulent mix.« 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.

The ocean mixed layer under Southern Ocean sea-ice: Seasonal cycle and forcing

NASA Astrophysics Data System (ADS)

Pellichero, Violaine; Sallée, Jean-Baptiste; Schmidtko, Sunke; Roquet, Fabien; Charrassin, Jean-Benoît

2017-02-01

The oceanic mixed layer is the gateway for the exchanges between the atmosphere and the ocean; in this layer, all hydrographic ocean properties are set for months to millennia. A vast area of the Southern Ocean is seasonally capped by sea-ice, which alters the characteristics of the ocean mixed layer. The interaction between the ocean mixed layer and sea-ice plays a key role for water mass transformation, the carbon cycle, sea-ice dynamics, and ultimately for the climate as a whole. However, the structure and characteristics of the under-ice mixed layer are poorly understood due to the sparseness of in situ observations and measurements. In this study, we combine distinct sources of observations to overcome this lack in our understanding of the polar regions. Working with elephant seal-derived, ship-based, and Argo float observations, we describe the seasonal cycle of the ocean mixed-layer characteristics and stability of the ocean mixed layer over the Southern Ocean and specifically under sea-ice. Mixed-layer heat and freshwater budgets are used to investigate the main forcing mechanisms of the mixed-layer seasonal cycle. The seasonal variability of sea surface salinity and temperature are primarily driven by surface processes, dominated by sea-ice freshwater flux for the salt budget and by air-sea flux for the heat budget. Ekman advection, vertical diffusivity, and vertical entrainment play only secondary roles. Our results suggest that changes in regional sea-ice distribution and annual duration, as currently observed, widely affect the buoyancy budget of the underlying mixed layer, and impact large-scale water mass formation and transformation with far reaching consequences for ocean ventilation.

Effect of shock interactions on mixing layer between co-flowing supersonic flows in a confined duct

NASA Astrophysics Data System (ADS)

Rao, S. M. V.; Asano, S.; Imani, I.; Saito, T.

2018-03-01

Experiments are conducted to observe the effect of shock interactions on a mixing layer generated between two supersonic streams of Mach number M _{1} = 1.76 and M _{2} = 1.36 in a confined duct. The development of this mixing layer within the duct is observed using high-speed schlieren and static pressure measurements. Two-dimensional, compressible Reynolds averaged Navier-Stokes equations are solved using the k-ω SST turbulence model in Fluent. Further, adverse pressure gradients are imposed by placing inserts of small (<7% of duct height) but finite (> boundary layer thickness) thickness on the walls of the test section. The unmatched pressures cause the mixing layer to bend and lead to the formation of shock structures that interact with the mixing layer. The mixing layer growth rate is found to increase after the shock interaction (nearly doubles). The strongest shock is observed when a wedge insert is placed in the M _{2} flow. This shock interacts with the mixing layer exciting flow modes that produce sinusoidal flapping structures which enhance the mixing layer growth rate to the maximum (by 1.75 times). Shock fluctuations are characterized, and it is observed that the maximum amplitude occurs when a wedge insert is placed in the M _{2} flow.

Zonally asymmetric response of the Southern Ocean mixed-layer depth to the Southern Annular Mode

NASA Astrophysics Data System (ADS)

Sallée, J. B.; Speer, K. G.; Rintoul, S. R.

2010-04-01

Interactions between the atmosphere and ocean are mediated by the mixed layer at the ocean surface. The depth of this layer is determined by wind forcing and heating from the atmosphere. Variations in mixed-layer depth affect the rate of exchange between the atmosphere and deeper ocean, the capacity of the ocean to store heat and carbon and the availability of light and nutrients to support the growth of phytoplankton. However, the response of the Southern Ocean mixed layer to changes in the atmosphere is not well known. Here we analyse temperature and salinity data from Argo profiling floats to show that the Southern Annular Mode (SAM), the dominant mode of atmospheric variability in the Southern Hemisphere, leads to large-scale anomalies in mixed-layer depth that are zonally asymmetric. From a simple heat budget of the mixed layer we conclude that meridional winds associated with departures of the SAM from zonal symmetry cause anomalies in heat flux that can, in turn, explain the observed changes of mixed-layer depth and sea surface temperature. Our results suggest that changes in the SAM, including recent and projected trends attributed to human activity, drive variations in Southern Ocean mixed-layer depth, with consequences for air-sea exchange, ocean sequestration of heat and carbon, and biological productivity.

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.

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.

Seasonal Mixed Layer Heat Budget in the Southeast Tropical Atlantic

NASA Astrophysics Data System (ADS)

Scannell, H. A.; McPhaden, M. J.

2016-12-01

We analyze a mixed layer heat budget at 6ºS, 8ºE from a moored buoy of the Prediction and Research Moored Array in the Atlantic (PIRATA) to better understand the causes of seasonal mixed layer temperature variability in the southeast tropical Atlantic. This region is of interest because it is susceptible to warm biases in coupled global climate models and has historically been poorly sampled. Previous work suggests that thermodynamic changes in both latent heat loss and absorbed solar radiation dominate mixed layer properties away from the equator in the tropical Atlantic, while advection and entrainment are more important near the equator. Changes in mixed layer salinity can also influence temperature through the formation of barrier layers and density gradients. Freshwater flux from the Congo River, migration of the Intertropical Convergence Zone and advection of water masses are considered important contributors to mixed layer salinity variability in our study region. We analyze ocean temperature, salinity and meteorological data beginning in 2013 using mooring, Argo, and satellite platforms to study how seasonal temperature variability in the mixed layer is influenced by air-sea interactions and ocean dynamics.

High Static Stability in the Mixed Layer Above the Extratropical Tropopause

NASA Astrophysics Data System (ADS)

Kunz, A.; Konopka, P.; Müller, R.; Pan, L. L.; Schiller, C.

2009-04-01

A strong relationship between the static stability N2 in the tropopause inversion layer (TIL) and the intensity of mixing is evident from in-situ observations during SPURT. With a new simple measure of mixing intensity based on O3/CO tracer correlations, a very high mixing intensity connected to a high N2 is found in the extratropical mixing layer. Using radiative transfer calculations we simulate the influence of trace gases such as O3 and H2O on the temperature gradient and thus on the static stability above the tropopause in an idealized (L-shaped) non-mixed and reference mixed atmosphere. N2 enhances due to an intensifying mixing in the LS. At the same time the temperature decreases together with a development of an inversion and the TIL. Hereby H2O plays the dominant role in maintenance the temperature inversion and the TIL structure. In case of non mixed profiles the TIL vanishes. The results motivate a link between the mixing layer and the TIL. The mixing layer contains on the one hand older air masses, with high values of N2 due to radiative adjustment. This part of the mixing layer is spatial identically to the TIL. On the other hand, there are younger air masses with somehow lower N2 values within the mixing layer, because of fast intrusion processes from the troposphere due to the permeability or so-called mid-latitude-breaks associated with the jet.

The effects of mixed layer dynamics on ice growth in the central Arctic

NASA Astrophysics Data System (ADS)

Kitchen, Bruce R.

1992-09-01

The thermodynamic model of Thorndike (1992) is coupled to a one dimensional, two layer ocean entrainment model to study the effect of mixed layer dynamics on ice growth and the variation in the ocean heat flux into the ice due to mixed layer entrainment. Model simulations show the existence of a negative feedback between the ice growth and the mixed layer entrainment, and that the underlying ocean salinity has a greater effect on the ocean beat flux than does variations in the underlying ocean temperature. Model simulations for a variety of surface forcings and initial conditions demonstrate the need to include mixed layer dynamics for realistic ice prediction in the arctic.

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

Parameterization of large-scale turbulent diffusion in the presence of both well-mixed and weakly mixed patchy layers

NASA Astrophysics Data System (ADS)

Osman, M. K.; Hocking, W. K.; Tarasick, D. W.

2016-06-01

Vertical diffusion and mixing of tracers in the upper troposphere and lower stratosphere (UTLS) are not uniform, but primarily occur due to patches of turbulence that are intermittent in time and space. The effective diffusivity of regions of patchy turbulence is related to statistical parameters describing the morphology of turbulent events, such as lifetime, number, width, depth and local diffusivity (i.e., diffusivity within the turbulent patch) of the patches. While this has been recognized in the literature, the primary focus has been on well-mixed layers, with few exceptions. In such cases the local diffusivity is irrelevant, but this is not true for weakly and partially mixed layers. Here, we use both theory and numerical simulations to consider the impact of intermediate and weakly mixed layers, in addition to well-mixed layers. Previous approaches have considered only one dimension (vertical), and only a small number of layers (often one at each time step), and have examined mixing of constituents. We consider a two-dimensional case, with multiple layers (10 and more, up to hundreds and even thousands), having well-defined, non-infinite, lengths and depths. We then provide new formulas to describe cases involving well-mixed layers which supersede earlier expressions. In addition, we look in detail at layers that are not well mixed, and, as an interesting variation on previous models, our procedure is based on tracking the dispersion of individual particles, which is quite different to the earlier approaches which looked at mixing of constituents. We develop an expression which allows determination of the degree of mixing, and show that layers used in some previous models were in fact not well mixed and so produced erroneous results. We then develop a generalized model based on two dimensional random-walk theory employing Rayleigh distributions which allows us to develop a universal formula for diffusion rates for multiple two-dimensional layers with general degrees of mixing. We show that it is the largest, most vigorous and less common turbulent layers that make the major contribution to global diffusion. Finally, we make estimates of global-scale diffusion coefficients in the lower stratosphere and upper troposphere. For the lower stratosphere, κeff ≈ 2x10-2 m2 s-1, assuming no other processes contribute to large-scale diffusion.

[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

Numerical Investigations of Wave-Induced Mixing in Upper Ocean Layer

NASA Astrophysics Data System (ADS)

Guan, Changlong

2017-04-01

The upper ocean layer is playing an important role in ocean-atmosphere interaction. The typical characteristics depicting the upper ocean layer are the sea surface temperature (SST) and the mixed layer depth (MLD). So far, the existing ocean models tend to over-estimate SST and to under-estimate MLD, due to the inadequate mixing in the mixing layer, which is owing to that several processes related mixing in physics are ignored in these ocean models. The mixing induced by surface gravity wave is expected to be able to enhance the mixing in the upper ocean layer, and therefore the over-estimation of SST and the under-estimate of MLD could be improved by including wave-induced mixing. The wave-induced mixing could be accomplished by the physical mechanisms, such as wave breaking (WB), wave-induced Reynolds stress (WR), and wave-turbulence interaction (WT). The General Ocean Turbulence Model (GOTM) is employed to investigate the effects of the three mechanisms concerning wave-induced mixing. The numerical investigation is carried out for three turbulence closure schemes, say, k-epsilon, k-omega and Mellor-Yamada (1982), with the observational data from OSC Papa station and wave data from ECMWF. The mixing enhancement by various waved-induced mixing mechanisms is investigated and verified.

Variability of the Mixed-Layer Height Over Mexico City

NASA Astrophysics Data System (ADS)

García-Franco, J. L.; Stremme, W.; Bezanilla, A.; Ruiz-Angulo, A.; Grutter, M.

2018-02-01

The diurnal and seasonal variability of the mixed-layer height in urban areas has implications for ground-level air pollution and the meteorological conditions. Measurements of the backscatter of light pulses with a commercial lidar system were performed for a continuous period of almost six years between 2011 and 2016 in the southern part of Mexico City. The profiles were temporally and vertically smoothed, clouds were filtered out, and the mixed-layer height was determined with an ad hoc treatment of both the filtered and unfiltered profiles. The results are in agreement when compared with values of mixed-layer height reconstructed from, (i) radiosonde data, and (ii) surface and vertical column densities of a trace gas. The daily maxima of the mean mixed-layer height reach values > 3 km above ground level in the months of March-April, and are clearly lower (< 2.7 km ) during the colder months from September-December. Mean daily minima are typically observed at 0700 local time (UTC - 6h), and are lowest during the winter months with values on average below 500 m. The data presented here show an anti-correlation between high-pollution episodes and the height of the mixed layer. The growth rate of the convective mixed-layer height has a seasonal behaviour, which is characterized together with the mixed-layer-height anomalies. A clear residual layer is evident from the backscattered signals recorded in days with specific atmospheric conditions, but also from the cloud-filtered mean diurnal profiles. The occasional presence of a residual layer results in an overestimation of the reported mixed-layer height during the night and early morning hours.

Problem of the thermodynamic status of the mixed-layer minerals

USGS Publications Warehouse

Zen, E.-A.

1962-01-01

Minerals that show mixed layering, particularly with the component layers in random sequence, pose problems because they may behave thermodynamically as single phases or as polyphase aggregates. Two operational criteria are proposed for their distinction. The first scheme requires two samples of mixed-layer material which differ only in the proportions of the layers. If each of these two samples are allowed to equilibrate with the same suitably chosen monitoring solution, then the intensive parameters of the solution will be invariant if the mixed-layer sample is a polyphase aggregate, but not otherwise. The second scheme makes use of the fact that portions of many titration curves of clay minerals show constancy of the chemical activities of the components in the equilibrating solutions, suggesting phase separation. If such phase separation occurs for a mixed-layer material, then, knowing the number of independent components in the system, it should be possible to decide on the number of phases the mixed-layer material represents. Knowledge of the phase status of mixed-layer material is essential to the study of the equilibrium relations of mineral assemblages involving such material, because a given mixed-layer mineral will be plotted and treated differently on a phase diagram, depending on whether it is a single phase or a polyphase aggregate. Extension of the titration technique to minerals other than the mixed-layer type is possible. In particular, this method may be used to determine if cryptoperthites and peristerites are polyphase aggregates. In general, for any high-order phase separation, the method may be used to decide just at what point in this continuous process the system must be regarded operationally as a polyphase aggregate. ?? 1962.

Variability of the Mixed-Layer Height Over Mexico City

NASA Astrophysics Data System (ADS)

García-Franco, J. L.; Stremme, W.; Bezanilla, A.; Ruiz-Angulo, A.; Grutter, M.

2018-06-01

The diurnal and seasonal variability of the mixed-layer height in urban areas has implications for ground-level air pollution and the meteorological conditions. Measurements of the backscatter of light pulses with a commercial lidar system were performed for a continuous period of almost six years between 2011 and 2016 in the southern part of Mexico City. The profiles were temporally and vertically smoothed, clouds were filtered out, and the mixed-layer height was determined with an ad hoc treatment of both the filtered and unfiltered profiles. The results are in agreement when compared with values of mixed-layer height reconstructed from, (i) radiosonde data, and (ii) surface and vertical column densities of a trace gas. The daily maxima of the mean mixed-layer height reach values > 3 km above ground level in the months of March-April, and are clearly lower (< 2.7 km) during the colder months from September-December. Mean daily minima are typically observed at 0700 local time (UTC - 6h), and are lowest during the winter months with values on average below 500 m. The data presented here show an anti-correlation between high-pollution episodes and the height of the mixed layer. The growth rate of the convective mixed-layer height has a seasonal behaviour, which is characterized together with the mixed-layer-height anomalies. A clear residual layer is evident from the backscattered signals recorded in days with specific atmospheric conditions, but also from the cloud-filtered mean diurnal profiles. The occasional presence of a residual layer results in an overestimation of the reported mixed-layer height during the night and early morning hours.

Laboratory simulations of the atmospheric mixed-layer in flow over complex topography

EPA Science Inventory

A laboratory study of the influence of complex terrain on the interface between a well-mixed boundary layer and an elevated stratified layer was conducted in the towing-tank facility of the U.S. Environmental Protection Agency. The height of the mixed layer in the daytime boundar...

DNSs of Multicomponent Gaseous and Drop-Laden Mixing Layers Achieving Transition to Turbulence

NASA Technical Reports Server (NTRS)

Bellan, Josette; Selle, Laurent

2007-01-01

A paper describes direct numerical simulations (DNSs) of three-dimensional mixing-layer flows undergoing transition to turbulence; the mixing layers may or may not be laden with evaporating liquid drops.

Planar ceramic membrane assembly and oxidation reactor system

DOEpatents

Carolan, Michael Francis; Dyer, legal representative, Kathryn Beverly; Wilson, Merrill Anderson; Ohm, Ted R.; Kneidel, Kurt E.; Peterson, David; Chen, Christopher M.; Rackers, Keith Gerard; Dyer, deceased, Paul Nigel

2007-10-09

Planar ceramic membrane assembly comprising a dense layer of mixed-conducting multi-component metal oxide material, wherein the dense layer has a first side and a second side, a porous layer of mixed-conducting multi-component metal oxide material in contact with the first side of the dense layer, and a ceramic channeled support layer in contact with the second side of the dense layer. The planar ceramic membrane assembly can be used in a ceramic wafer assembly comprising a planar ceramic channeled support layer having a first side and a second side; a first dense layer of mixed-conducting multi-component metal oxide material having an inner side and an outer side, wherein the inner side is in contact with the first side of the ceramic channeled support layer; a first outer support layer comprising porous mixed-conducting multi-component metal oxide material and having an inner side and an outer side, wherein the inner side is in contact with the outer side of the first dense layer; a second dense layer of mixed-conducting multi-component metal oxide material having an inner side and an outer side, wherein the inner side is in contact with the second side of the ceramic channeled layer; and a second outer support layer comprising porous mixed-conducting multi-component metal oxide material and having an inner side and an outer side, wherein the inner side is in contact with the outer side of the second dense layer.

Planar ceramic membrane assembly and oxidation reactor system

DOEpatents

Carolan, Michael Francis; Dyer, legal representative, Kathryn Beverly; Wilson, Merrill Anderson; Ohrn, Ted R.; Kneidel, Kurt E.; Peterson, David; Chen, Christopher M.; Rackers, Keith Gerard; Dyer, Paul Nigel

2009-04-07

Planar ceramic membrane assembly comprising a dense layer of mixed-conducting multi-component metal oxide material, wherein the dense layer has a first side and a second side, a porous layer of mixed-conducting multi-component metal oxide material in contact with the first side of the dense layer, and a ceramic channeled support layer in contact with the second side of the dense layer. The planar ceramic membrane assembly can be used in a ceramic wafer assembly comprising a planar ceramic channeled support layer having a first side and a second side; a first dense layer of mixed-conducting multi-component metal oxide material having an inner side and an outer side, wherein the inner side is in contact with the first side of the ceramic channeled support layer; a first outer support layer comprising porous mixed-conducting multi-component metal oxide material and having an inner side and an outer side, wherein the inner side is in contact with the outer side of the first dense layer; a second dense layer of mixed-conducting multi-component metal oxide material having an inner side and an outer side, wherein the inner side is in contact with the second side of the ceramic channeled layer; and a second outer support layer comprising porous mixed-conducting multi-component metal oxide material and having an inner side and an outer side, wherein the inner side is in contact with the outer side of the second dense layer.

Numerical simulation of the non-Newtonian mixing layer

NASA Technical Reports Server (NTRS)

Azaiez, Jalel; Homsy, G. M.

1993-01-01

This work is a continuing effort to advance our understanding of the effects of polymer additives on the structures of the mixing layer. In anticipation of full nonlinear simulations of the non-Newtonian mixing layer, we examined in a first stage the linear stability of the non-Newtonian mixing layer. The results of this study show that, for a fluid described by the Oldroyd-B model, viscoelasticity reduces the instability of the inviscid mixing layer in a special limit where the ratio (We/Re) is of order 1 where We is the Weissenberg number, a measure of the elasticity of the flow, and Re is the Reynolds number. In the present study, we pursue this project with numerical simulations of the non-Newtonian mixing layer. Our primary objective is to determine the effects of viscoelasticity on the roll-up structure. We also examine the origin of the numerical instabilities usually encountered in the simulations of non-Newtonian fluids.

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.

The salinity effect in a mixed layer ocean model

NASA Technical Reports Server (NTRS)

Miller, J. R.

1976-01-01

A model of the thermally mixed layer in the upper ocean as developed by Kraus and Turner and extended by Denman is further extended to investigate the effects of salinity. In the tropical and subtropical Atlantic Ocean rapid increases in salinity occur at the bottom of a uniformly mixed surface layer. The most significant effects produced by the inclusion of salinity are the reduction of the deepening rate and the corresponding change in the heating characteristics of the mixed layer. If the net surface heating is positive, but small, salinity effects must be included to determine whether the mixed layer temperature will increase or decrease. Precipitation over tropical oceans leads to the development of a shallow stable layer accompanied by a decrease in the temperature and salinity at the sea surface.

Ordered mixed-layer structures in the Mighei carbonaceous chondrite matrix

NASA Technical Reports Server (NTRS)

Mackinnon, I. D. R.

1982-01-01

High resolution transmission electron microscopy of the Mighei carbonaceous chondrite matrix has revealed the presence of a new mixed layer structure material. This mixed-layer material consists of an ordered arrangement of serpentine-type (S) and brucite-type (B) layers in the sequence SBBSBB. Electron diffraction and imaging techniques show that the basal periodicity is approximately 17 A. Discrete crystals of SBB-type material are typically curved, of small size (less than 1 micron) and show structural variations similar to the serpentine group minerals. Mixed-layer material also occurs in association with planar serpentine. Characteristics of SBB-type material are not consistent with known terrestrial mixed-layer clay minerals. Evidence for formation by a condensation event or by subsequent alteration of pre-existing material is not yet apparent.

Near-inertial kinetic energy budget of the mixed layer and shear evolution in the transition layer in the Arabian Sea during the monsoons

NASA Astrophysics Data System (ADS)

Majumder, Sudip; Tandon, Amit; Rudnick, Daniel L.; Thomas Farrar, J.

2015-09-01

We present the horizontal kinetic energy (KE) balance of near-inertial currents in the mixed layer and explain shear evolution in the transition layer using observations from a mooring at 15.26° N in the Arabian Sea during the southwest monsoon. The highly sheared and stratified transition layer at the mixed-layer base varies between 5 m and 35 m and correlates negatively with the wind stress. Results from the mixed layer near-inertial KE (NIKE) balance suggest that wind energy at times can energize the transition layer and at other times is fully utilized within the mixed layer. A simple two layer model is utilized to study the shear evolution in the transition layer and shown to match well with observations. The shear production in this model arises from alignment of wind stress and shear. Although the winds are unidirectional during the monsoon, the shear in the transition layer is predominantly near-inertial. The near-inertial shear bursts in the observations show the same phasing and magnitude at near-inertial frequencies as the wind-shear alignment term.

Estimation of the mixing layer height over a high altitude site in Central Himalayan region by using Doppler lidar

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

Shukla, K. K.; Phanikumar, D. V.; Newsom, Rob K.

2014-03-01

A Doppler lidar was installed at Manora Peak, Nainital (29.4 N; 79.2 E, 1958 amsl) to estimate mixing layer height for the first time by using vertical velocity variance as basic measurement parameter for the period September-November 2011. Mixing layer height is found to be located ~0.57 +/- 0.1and 0.45 +/- 0.05km AGL during day and nighttime, respectively. The estimation of mixing layer height shows good correlation (R>0.8) between different instruments and with different methods. Our results show that wavelet co-variance transform is a robust method for mixing layer height estimation.

Rayleigh-Taylor and Richtmyer-Meshkov instability induced flow, turbulence, and mixing. II

NASA Astrophysics Data System (ADS)

Zhou, Ye

2017-12-01

Rayleigh-Taylor (RT) and Richtmyer-Meshkov(RM) instabilities are well-known pathways towards turbulent mixing layers, in many cases characterized by significant mass and species exchange across the mixing layers (Zhou, 2017. Physics Reports, 720-722, 1-136). Mathematically, the pathway to turbulent mixing requires that the initial interface be multimodal, to permit cross-mode coupling leading to turbulence. Practically speaking, it is difficult to experimentally produce a non-multi-mode initial interface. Numerous methods and approaches have been developed to describe the late, multimodal, turbulent stages of RT and RM mixing layers. This paper first presents the initial condition dependence of RT mixing layers, and introduces parameters that are used to evaluate the level of "mixedness" and "mixed mass" within the layers, as well as the dependence on density differences, as well as the characteristic anisotropy of this acceleration-driven flow, emphasizing some of the key differences between the two-dimensional and three-dimensional RT mixing layers. Next, the RM mixing layers are discussed, and differences with the RT mixing layer are elucidated, including the RM mixing layers dependence on the Mach number of the initiating shock. Another key feature of the RM induced flows is its response to a reshock event, as frequently seen in shock-tube experiments as well as inertial confinement events. A number of approaches to modeling the evolution of these mixing layers are then described, in order of increasing complexity. These include simple buoyancy-drag models, Reynolds-averaged Navier-Stokes models of increased complexity, including K- ε, K-L, and K- L- a models, up to full Reynolds-stress models with more than one length-scale. Multifield models and multiphase models have also been implemented. Additional complexities to these flows are examined as well as modifications to the models to understand the effects of these complexities. These complexities include the presence of magnetic fields, compressibility, rotation, stratification and additional instabilities. The complications induced by the presence of converging geometries are also considered. Finally, the unique problems of astrophysical and high-energy-density applications, and efforts to model these are discussed.

Hybrid plasmonic electro-optical absorption modulator based on epsilon-near-zero characteristics of ITO

NASA Astrophysics Data System (ADS)

Abdelatty, M. Y.; Badr, M. M.; Swillam, M. A.

2018-03-01

Using transparent conducting oxides (TCOs), like indium-tin-oxide (ITO), for optical modulation attracted research interest because of their epsilon-near-zero (ENZ) characteristics at telecom wavelengths. Utilizing indium-tin-oxide (ITO) in multilayer structure modulators, optical absorption of the active ITO layer can be electrically modulated over a large spectrum range. Although they show advances over common silicon electro-optical modulators (EOMs), they suffer from high insertion losses. To reduce insertion losses and device footprints without sacrificing bandwidth and modulation strength, slot waveguides are promising options because of their high optical confinement. In this paper, we present the study and the design of an electro-optical absorption modulator based on electrically tuning ITO carrier density inside a MOS structure. The device structure is based on dielectric slot waveguide with an ITO plasmonic waveguide modulation section. By changing the dimensions, the effective refractive indices for the slot mode and the off-sate mode of the plasmonic section can be matched. When applying electric field to the plasmonic section (on-state), carriers are generated at the ITO-dielectric interface that result in changing the layer where the electric field is confined from a transparent layer into a lossy layer. A finite difference time domain method with perfect matching layer (PML) absorbing boundary conditions is taken up to simulate and analyze this design. An extinction ratio of 2.3 dB is achieved for a 1-μm-short modulation section, at the telecommunications wavelength (1.55 μm). This EOM has advantages of simple design, easy fabrication, compact size, compatibility with existing silicon photonics platforms, as well as broadband performance.

The ocean mixed layer under Southern Ocean sea-ice: seasonal cycle and forcing.

NASA Astrophysics Data System (ADS)

Violaine, P.; Sallee, J. B.; Schmidtko, S.; Roquet, F.; Charrassin, J. B.

2016-02-01

The mixed-layer at the surface of the ocean is the gateway for all exchanges between air and sea. A vast area of the Southern Ocean is however seasonally capped by sea-ice, which alters this gateway and the characteristic the ocean mixed-layer. The interaction between the ocean mixed-layer and sea-ice plays a key role for water-mass formation and circulation, carbon cycle, sea-ice dynamics, and ultimately for the climate as a whole. However, the structure and characteristics of the mixed layer, as well as the processes responsible for its evolution, are poorly understood due to the lack of in-situ observations and measurements. We urgently need to better understand the forcing and the characteristics of the ocean mixed-layer under sea-ice if we are to understand and predict the world's climate. In this study, we combine a range of distinct sources of observation to overcome this lack in our understanding of the Polar Regions. Working on Elephant Seal-derived data as well as ship-based observations and Argo float data, we describe the seasonal cycle of the characteristics and stability of the ocean mixed layer over the entire Southern Ocean (South of 40°S), and specifically under sea-ice. Mixed-layer budgets of heat and freshwater are used to investigate the main forcings of the mixed-layer seasonal cycle. The seasonal variability of sea surface salinity and temperature are primarily driven by surface processes, dominated by sea-ice freshwater flux for the salt budget, and by air-sea flux for the heat budget. Ekman advection, vertical diffusivity and vertical entrainment play only secondary role.Our results suggest that changes in regional sea-ice distribution or sea-ice seasonal cycle duration, as currently observed, would widely affect the buoyancy budget of the underlying mixed-layer, and impacts large-scale water-mass formation and transformation.

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.

The Role of Late Summer Melt Pond Water Layers in the Ocean Mixed Layer on Enhancing Ice/Ocean Albedo Feedbacks in the Arctic

NASA Astrophysics Data System (ADS)

Stanton, T. P.; Shaw, W. J.

2016-02-01

Drainage of surface melt pond water into the top of the ocean mixed layer is seen widely in the Arctic ice pack in later summer (for example Gallaher et al 2015). Under calm conditions, this fresh water forms a thin, stratified layer immediately below the ice which is dynamically decoupled from the thicker, underlying seasonal mixed layer by the density difference between the two layers. The ephemeral surface layer is significantly warmer than the underlying ocean water owing to the higher freezing temperature of the fresh melt water. How the presence of this warm ephemeral layer enhances basal melt rate and speeds the destruction of the floes is investigated. High resolution timeseries measurements of T/S profiles in the 2m of the ocean immediately below the ice, and eddy-correlation fluxes of heat, salt and momentum 2.5m below the ice were made from an Autonomous Ocean Flux Buoy over a 2 month interval in later summer of 2015 as a component of the ONR Marginal Ice Zone project. The stratification and turbulent forcing observations are used with a 1 D turbulence closure model to understand how momentum and incoming radiative energy are stored and redistributed within the ephemeral layer. Under low wind forcing conditions both turbulent mixing energy and the water with high departure from freezing are trapped in the ephemeral layer by the strong density gradient at the base of the layer, resulting in rapid basal melting. This case is contrasted with model runs where the ephemeral layer heat is allowed to mix across the seasonal mixed layer, which results in slower basal melt rates. Consequently, the salinity-trapped warm ephemeral layer results in the formation of more open water earlier in the summer season, in turn resulting in increased cumulative heating of the ocean mixed layer, enhancing ice/ocean albedo feedbacks.

Modeling the diurnal cycle of carbon monoxide: Sensitivity to physics, chemistry, biology, and optics

NASA Astrophysics Data System (ADS)

Gnanadesikan, Anand

1996-05-01

As carbon monoxide within the oceanic surface layer is produced by solar radiation, diluted by mixing, consumed by biota, and outgassed to the atmosphere, it exhibits a diurnal cycle. The effect of dilution and mixing on this cycle is examined using a simple model for production and consumption, coupled to three different mixed layer models. The magnitude and timing of the peak concentration, the magnitude of the average concentration, and the air-sea flux are considered. The models are run through a range of heating and wind stress and compared to experimental data reported by Kettle [1994]. The key to the dynamics is the relative size of four length scales; Dmix, the depth to which mixing occurs over the consumption time; L, the length scale over which production occurs; Lout, the depth to which the mixed layer is ventilated over the consumption time; and Lcomp, the depth to which the diurnal production can maintain a concentration in equilibrium with the atmosphere. If Dmix ≫ L, the actual model parameterization can be important. If the mixed layer is maintained by turbulent diffusion, Dmix can be substantially less than the mixed layer depth. If the mixed layer is parameterized as a homogeneous slab, Dmix is equivalent to the mixed layer depth. If Dmix > Lout, production is balanced by consumption rather than outgassing. The ratio between Dmix and Lcomp determines whether the ocean is a source or a sink for CO. The main thermocline depth H sets an upper limit for Dmix and hence Dmix/L, Dmix/Lout, and Dmix/Lcomp. The models are run to simulate a single day of observations. The mixing parameterization is shown to be very important, with a model which mixes using small-scale diffusion, producing markedly larger surface concentrations than models which homogenize the mixed layer completely and instantaneously.

Observing the seasonal cycle of the upper ocean in the Ross Sea, Antarctica, with autonomous profiling floats

NASA Astrophysics Data System (ADS)

Porter, D. F.; Springer, S. R.; Padman, L.; Fricker, H. A.; Bell, R. E.

2017-12-01

The upper layers of the Southern Ocean where it meets the Antarctic ice sheet undergoes a large seasonal cycle controlled by surface radiation and by freshwater fluxes, both of which are strongly influenced by sea ice. In regions where seasonal sea ice and icebergs limit use of ice-tethered profilers and conventional moorings, autonomous profiling floats can sample the upper ocean. The deployment of seven Apex floats (by sea) and six ALAMO floats (by air) provides unique upper ocean hydrographic data in the Ross Sea close to the Ross Ice Shelf front. A novel choice of mission parameters - setting parking depth deeper than the seabed - limits their drift, allowing us to deploy the floats close to the ice shelf front, while sea ice avoidance algorithms allow the floats to to sample through winter under sea ice. Hydrographic profiles show the detailed development of the seasonal mixed layer close to the Ross front, and interannual variability of the seasonal mixed layer and deeper water masses on the central Ross Sea continental shelf. After the sea ice breakup in spring, a warm and fresh surface mixed layer develops, further warming and deepening throughout the summer. The mixed layer deepens, with maximum temperatures exceeding 0ºC in mid-February. By March, the surface energy budget becomes negative and sea ice begins to form, creating a cold, saline and dense surface layer. Once these processes overcome the stable summer stratification, convection erodes the surface mixed layer, mixing some heat downwards to deeper layers. There is considerable interannual variability in the evolution and strength of the surface mixed layer: summers with shorter ice-free periods result in a cooler and shallower surface mixed layer, which accumulates less heat than the summers with longer ice-free periods. Early ice breakup occurred in all floats in 2016/17 summer, enhancing the absorbed solar flux leading to a warmer surface mixed layer. Together, these unique measurements from autonomous profilers provide insight into the hydrographic state of the Ross Sea at the start of the spring period of sea-ice breakup, and how ocean mixing and sea ice interact to initiate the summer open-water season.

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

Experiments on the enhancement of compressible mixing via streamwise vorticity. II - Vortex strength assessment and seed particle dynamics

NASA Technical Reports Server (NTRS)

Naughton, J. W.; Cattafesta, L. N.; Settles, G. S.

1993-01-01

The effect of streamwise vorticity on compressible axisymmetric mixing layers is examined using vortex strength assessment and seed particle dynamics analysis. Experimental results indicate that the particles faithfully represent the dynamics of the turbulent swirling flow. A comparison of the previously determined mixing layer growth rates with the present vortex strength data reveals that the increase of turbulent mixing up to 60 percent scales with the degree of swirl. The mixing enhancement appears to be independent of the compressibility level of the mixing layer.

Numerical study of terrain-induced mesoscale motions and hydrostatic form drag in a heated, growing mixed layer

NASA Technical Reports Server (NTRS)

Deardorff, J. W.; Ueyoshi, K.; Han, Y.-J.

1984-01-01

Han et al. (1982) have found in a previous numerical study of terrain-induced mesoscale motions that the orography caused a steady-state flow pattern to occur. The study was concerned with a simplified case in which no surface heating occurred. The present investigation considers an extension of this study to the more realistic case of a heated, growing daytime mixed layer containing horizontal variations of potential temperature as well as velocity. The model is also extended to include three layers above the mixed layer. It is found for a heated, growing mixed layer, that the mesoscale form drag is a thermal-anomaly or buoyancy effect associated with horizontal variations of potential temperature within the layer.

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

An ocean large-eddy simulation of Langmuir circulations and convection in the surface mixed layer

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

Skyllingstad, E.D.; Denbo, D.W.

Numerical experiments were performed using a three-dimensional large-eddy simulation model of the ocean surface mixed layer that includes the Craik-Leibovich vortex force to parameterize the interaction of surface waves with mean currents. Results from the experiments show that the vortex force generates Langmuir circulations that can dominate vertical mixing. The simulated vertical velocity fields show linear, small-scale, coherent structures near the surface that extend downwind across the model domain. In the interior of the mixed layer, scales of motion increase to eddy sizes that are roughly equivalent to the mixed-layer depth. Cases with the vortex force have stronger circulations nearmore » the surface in contrast to cases with only heat flux and wind stress, particularly when the heat flux is positive. Calculations of the velocity variance and turbulence dissipation rates for cases with and without the vortex force, surface cooling, and wind stress indicate that wave-current interactions are a dominant mixing process in the upper mixed layer. Heat flux calculations show that the entrainment rate at the mixed-layer base can be up to two times greater when the vortex force is included. In a case with reduced wind stress, turbulence dissipation rates remained high near the surface because of the vortex force interaction with preexisting inertial currents. In deep mixed layers ({approximately}250 m) the simulations show that Langmuir circulations can vertically transport water 145 m during conditions of surface heating. Observations of turbulence dissipation rates and the vertical temperature structure support the model results. 42 refs., 20 figs., 21 tabs.« less

Upper Ocean Response to Hurricanes Katrina and Rita (2005) from Multi-sensor Satellites

NASA Astrophysics Data System (ADS)

Gierach, M. M.; Bulusu, S.

2006-12-01

Analysis of satellite observations and model simulations of the mixed layer provided an opportunity to assess the biological and physical effects of hurricanes Katrina and Rita (2005) in the Gulf of Mexico. Oceanic cyclonic circulation was intensified by the hurricanes' wind field, maximizing upwelling, surface cooling, and deepening the mixed layer. Two areas of maximum surface chlorophyll-a concentration and sea surface cooling were detected with peak intensities ranging from 2-3 mg m-3 and 4-6°C, along the tracks of Katrina and Rita. The temperature of the mixed layer cooled approximately 2°C and the depth of the mixed layer deepened by approximately 33-52 m. The forced deepening of the mixed layer injected nutrients into the euphotic zone, generating phytoplankton blooms 3-5 days after the passage of Katrina and Rita (2005).

Processes that generate and deplete liquid water and snow in thin midlevel mixed-phase clouds

NASA Astrophysics Data System (ADS)

Smith, Adam J.; Larson, Vincent E.; Niu, Jianguo; Kankiewicz, J. Adam; Carey, Lawrence D.

2009-06-01

This paper uses a numerical model to investigate microphysical, radiative, and dynamical processes in mixed-phase altostratocumulus clouds. Three cloud cases are chosen for study, each of which was observed by aircraft during the fifth or ninth Complex Layered Cloud Experiment (CLEX). These three clouds are numerically modeled using large-eddy simulation (LES). The observed and modeled clouds consist of a mixed-phase layer with a quasi-adiabatic profile of liquid, and a virga layer below that consists of snow. A budget of cloud (liquid) water mixing ratio is constructed from the simulations. It shows that large-scale ascent/descent, radiative cooling/heating, turbulent transport, and microphysical processes are all significant. Liquid is depleted indirectly via depositional growth of snow (the Bergeron-Findeisen process). This process is more influential than depletion of liquid via accretional growth of snow. Also constructed is a budget of snow mixing ratio, which turns out to be somewhat simpler. It shows that snow grows by deposition in and below the liquid (mixed-phase) layer, and sublimates in the remainder of the virga region below. The deposition and sublimation are balanced primarily by sedimentation, which transports the snow from the growth region to the sublimation region below. In our three clouds, the vertical extent of the virga layer is influenced more by the profile of saturation ratio below the liquid (mixed-phase) layer than by the mixing ratio of snow at the top of the virga layer.

Tropical warm pool rainfall variability and impact on upper ocean variability throughout the Madden-Julian oscillation

NASA Astrophysics Data System (ADS)

Thompson, Elizabeth J.

Heating and rain freshening often stabilize the upper tropical ocean, bringing the ocean mixed layer depth to the sea surface. Thin mixed layer depths concentrate subsequent fluxes of heat, momentum, and freshwater in a thin layer. Rapid heating and cooling of the tropical sea surface is important for controlling or triggering atmospheric convection. Ocean mixed layer depth and SST variability due to rainfall events have not been as comprehensively explored as the ocean's response to heating or momentum fluxes, but are very important to understand in the tropical warm pool where precipitation exceeds evaporation and many climate phenomena such as ENSO and the MJO (Madden Julian Oscillation) originate. The first part of the dissertation investigates tropical, oceanic convective and stratiform rainfall variability and determines how to most accurately estimate rainfall accumulation with radar from each rain type. The second, main part of the dissertation uses central Indian Ocean salinity and temperature microstructure measurements and surrounding radar-derived rainfall maps throughout two DYNAMO MJO events to determine the impact of precipitating systems on upper-ocean mixed layer depth and resulting SST variability. The ocean mixed layer was as shallow as 0-5 m during 528/1071 observation hours throughout 2 MJOs (54% of the data record). Out of 43 observation days, thirty-eight near-surface mixed layer depth events were attributed to freshwater stabilization, called rain-formed mixed layers (RFLs). Thirty other mixed layer stratification events were classified as diurnal warm layers (DWLs) due to stable temperature stratification by daytime heating. RFLs and DWLs were observed to interact in two ways: 1) RFLs fill preexisting DWLs and add to total near-surface mixed layer stratification, which occurred ten times; 2) RFLs last long enough to heat, creating a new DWL on top of the RFL, which happened nine times. These combination stratification events were responsible for the highest SST warming rates and some of the highest SSTs leading up to the most active precipitation and wind stage of the each MJO. DWLs without RFL interaction helped produce the highest SSTs in suppressed MJO conditions. As storm intensity, frequency, duration, and the ability of storms to maintain stratiform rain areas increased, RFLS became more common in the disturbed and active MJO phases. Along with the barrier layer, DWL and RFL stratification events helped suppress wind-mixing, cooling, and mixed layer deepening throughout the MJO. We hypothesize that both salinity and temperature stratification events, and their interactions, are important for controlling SST variability and therefore MJO initiation in the Indian Ocean. Most RFLs were caused by submesoscale and mesoscale convective systems with stratiform rain components and local rain accumulations above 10 mm but with winds mostly below 8 m s-1. We hypothesize that the stratiform rain components of storms helped stratify the ocean by providing weak but widespread, steady, long-lived freshwater fluxes. Although generally limited to rain rates ≤ 10 mm hr-1, it is demonstrated that stratiform rain can exert a strong buoyancy flux into the ocean, i.e. as high as maximum daytime solar heating. Storm morphology and the preexisting vertical structure of ocean stability were critical in determining ocean mixed layer depth variability in the presence of rain. Therefore, we suggest that high spatial and temporal resolution coupled ocean-atmosphere models that can parameterize or resolve storm morphology as well as ocean mixed layer and barrier layer evolution are needed to reproduce the diurnal and intraseasonal SST variability documented throughout the MJO.

An experimental study of secondary vortex structure in mixing layers

NASA Technical Reports Server (NTRS)

Bell, J. H.; Mehta, Rabindra D.

1990-01-01

This report covers the first eight months of an experimental research project on the secondary vortex structure in plane mixing layers. The aim of the project is to obtain quantitative data on the behavior of the secondary structure in a turbulent mixing layer at reasonable reynolds numbers (Re(sub delta(sub w)) approx. 50,000). In particular, we hope to resolve the questions of how the scale of the secondary vortex structure changes with the scale of the mixing layer, and whether the structures are fixed in space, or whether they 'meander' in the spanwise direction.

Nonlinear Stability and Structure of Compressible Reacting Mixing Layers

NASA Technical Reports Server (NTRS)

Day, M. J.; Mansour, N. N.; Reynolds, W. C.

2000-01-01

The parabolized stability equations (PSE) are used to investigate issues of nonlinear flow development and mixing in compressible reacting shear layers. Particular interest is placed on investigating the change in flow structure that occurs when compressibility and heat release are added to the flow. These conditions allow the 'outer' instability modes- one associated with each of the fast and slow streams-to dominate over the 'central', Kelvin-Helmholtz mode that unaccompanied in incompressible nonreacting mixing layers. Analysis of scalar probability density functions in flows with dominant outer modes demonstrates the ineffective, one-sided nature of mixing that accompany these flow structures. Colayer conditions, where two modes have equal growth rate and the mixing layer is formed by two sets of vortices, offer some opportunity for mixing enhancement. Their extent, however, is found to be limited in the mixing layer's parameter space. Extensive validation of the PSE technique also provides a unique perspective on central- mode vortex pairing, further supporting the view that pairing is primarily governed perspective sheds insight on how linear stability theory is able to provide such an accurate prediction of experimentally-observed, fully nonlinear flow phenomenon.

Coupling with ocean mixed layer leads to intraseasonal variability in tropical deep convection: Evidence from cloud-resolving simulations

NASA Astrophysics Data System (ADS)

Anber, Usama; Wang, Shuguang; Sobel, Adam

2017-03-01

The effect of coupling a slab ocean mixed layer to atmospheric convection is examined in cloud-resolving model (CRM) simulations in vertically sheared and unsheared environments without Coriolis force, with the large-scale circulation parameterized using the Weak Temperature Gradient (WTG) approximation. Surface fluxes of heat and moisture as well as radiative fluxes are fully interactive, and the vertical profile of domain-averaged horizontal wind is strongly relaxed toward specified profiles with vertical shear that varies from one simulation to the next. Vertical wind shear is found to play a critical role in the simulated behavior. There exists a threshold value of the shear strength above which the coupled system develops regular oscillations between deep convection and dry nonprecipitating states, similar to those found earlier in a much more idealized model which did not consider wind shear. The threshold value of the vertical shear found here varies with the depth of the ocean mixed layer. The time scale of the spontaneously generated oscillations also varies with mixed layer depth, from 10 days with a 1 m deep mixed layer to 50 days with a 10 m deep mixed layer. The results suggest the importance of the interplay between convection organized by vertical wind shear, radiative feedbacks, large-scale dynamics, and ocean mixed layer heat storage in real intraseasonal oscillations.

Southern Ocean Mixed-Layer Seasonal and Interannual Variations From Combined Satellite and In Situ Data

NASA Astrophysics Data System (ADS)

Buongiorno Nardelli, B.; Guinehut, S.; Verbrugge, N.; Cotroneo, Y.; Zambianchi, E.; Iudicone, D.

2017-12-01

The depth of the upper ocean mixed layer provides fundamental information on the amount of seawater that directly interacts with the atmosphere. Its space-time variability modulates water mass formation and carbon sequestration processes related to both the physical and biological pumps. These processes are particularly relevant in the Southern Ocean, where surface mixed-layer depth estimates are generally obtained either as climatological fields derived from in situ observations or through numerical simulations. Here we demonstrate that weekly observation-based reconstructions can be used to describe the variations of the mixed-layer depth in the upper ocean over a range of space and time scales. We compare and validate four different products obtained by combining satellite measurements of the sea surface temperature, salinity, and dynamic topography and in situ Argo profiles. We also compute an ensemble mean and use the corresponding spread to estimate mixed-layer depth uncertainties and to identify the more reliable products. The analysis points out the advantage of synergistic approaches that include in input the sea surface salinity observations obtained through a multivariate optimal interpolation. Corresponding data allow to assess mixed-layer depth seasonal and interannual variability. Specifically, the maximum correlations between mixed-layer anomalies and the Southern Annular Mode are found at different time lags, related to distinct summer/winter responses in the Antarctic Intermediate Water and Sub-Antarctic Mode Waters main formation areas.

An enhanced effective mode area fluorine doped octagonal photonic crystal fiber with extremely low loss

NASA Astrophysics Data System (ADS)

Kabir, Sumaiya; Razzak, S. M. Abdur

2018-07-01

In our paper an enhanced effective mode area octagonal photonic crystal fiber (PCF) is presented. This PCF ensures large effective mode area along with ultra-low confinement loss and bending loss. Both the elimination of air-holes from the rings near the core region and inclusion of low index fluorine doped silica rods in an octagonal pattern are the vital design features. We have used full vectorial finite element method (FEM) based software with circularly perfectly matched layer (PML) to simulate the guiding properties of PCF. Our proposed fiber achieves effective mode area of 1110 μm2. Moreover, it offers ultra-low confinement loss of 1.14 × 10-15 dB/m and can be bent as small as 30 cm without any significant bending loss of 6.49 × 10-9 dB/m. The PCF also ensures low non-linearity with small amount of splice loss. However, our proposed PCF can be used in applications like fiber amplifiers and lasers.

A new design of photonic crystal fiber with ultra-flattened dispersion to simultaneously minimize the dispersion and confinement loss

NASA Astrophysics Data System (ADS)

Olyaee, Saeed; Taghipour, Fahimeh

2011-02-01

Photonic crystal fibers (PCFs) are highly suitable transmission media for wavelength-division-multiplexing (WDM) systems, in which low and ultra-flattened dispersion of PCFs is extremely desirable. It is also required to concurrently achieve both a low confinement loss as well as a large effective area in a wide range of wavelengths. Relatively low dispersion with negligible variation has become feasible in the wavelength range of 1.1 to 1.8μm through the proposed design in this paper. According to a new structure of PCF presented in this study, the dispersion slope is 6.8×10-4ps/km.nm2 and the confinement loss reaches below 10-6 dB/km in this range, while at the same time an effective area of more than 50μm2 has been attained. For the analysis of this PCF, finite-difference time-domain (FDTD) method with the perfectly matched layers (PML) boundary conditions has been used.

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.

High Performance Computing of Meshless Time Domain Method on Multi-GPU Cluster

NASA Astrophysics Data System (ADS)

Ikuno, Soichiro; Nakata, Susumu; Hirokawa, Yuta; Itoh, Taku

2015-01-01

High performance computing of Meshless Time Domain Method (MTDM) on multi-GPU using the supercomputer HA-PACS (Highly Accelerated Parallel Advanced system for Computational Sciences) at University of Tsukuba is investigated. Generally, the finite difference time domain (FDTD) method is adopted for the numerical simulation of the electromagnetic wave propagation phenomena. However, the numerical domain must be divided into rectangle meshes, and it is difficult to adopt the problem in a complexed domain to the method. On the other hand, MTDM can be easily adept to the problem because MTDM does not requires meshes. In the present study, we implement MTDM on multi-GPU cluster to speedup the method, and numerically investigate the performance of the method on multi-GPU cluster. To reduce the computation time, the communication time between the decomposed domain is hided below the perfect matched layer (PML) calculation procedure. The results of computation show that speedup of MTDM on 128 GPUs is 173 times faster than that of single CPU calculation.

Direct simulations of chemically reacting turbulent mixing layers, part 2

NASA Technical Reports Server (NTRS)

Metcalfe, Ralph W.; Mcmurtry, Patrick A.; Jou, Wen-Huei; Riley, James J.; Givi, Peyman

1988-01-01

The results of direct numerical simulations of chemically reacting turbulent mixing layers are presented. This is an extension of earlier work to a more detailed study of previous three dimensional simulations of cold reacting flows plus the development, validation, and use of codes to simulate chemically reacting shear layers with heat release. Additional analysis of earlier simulations showed good agreement with self similarity theory and laboratory data. Simulations with a two dimensional code including the effects of heat release showed that the rate of chemical product formation, the thickness of the mixing layer, and the amount of mass entrained into the layer all decrease with increasing rates of heat release. Subsequent three dimensional simulations showed similar behavior, in agreement with laboratory observations. Baroclinic torques and thermal expansion in the mixing layer were found to produce changes in the flame vortex structure that act to diffuse the pairing vortices, resulting in a net reduction in vorticity. Previously unexplained anomalies observed in the mean velocity profiles of reacting jets and mixing layers were shown to result from vorticity generation by baroclinic torques.

[Characteristics of Winter Atmospheric Mixing Layer Height in Beijing-Tianjin-Hebei Region and Their Relationship with the Atmospheric Pollution].

PubMed

Li, Meng; Tang, Gui-qian; Huang, Jun; Liu, Zi-rui; An, Jun-lin; Wang, Yue-si

2015-06-01

Atmospheric mixing layer height (MLH) is one of the main factors affecting the atmospheric diffusion and plays an important role in air quality assessment and distribution of the pollutants. Based on the ceilometers data, this paper has made synchronous observation on MLH in Beijing-Tianjin-Hebei region (Beijing, Tianjin, Shijiazhuang and Qinhuangdao) in heavy polluted February 2014 and analyzed the respective overall change and its regional features. Results show that in February 2014,the average of mixing layer height in Qinhuangdao is the highest, up to 865 +/- 268 m, and in Shijiazhuang is the lowest (568 +/- 207 m), Beijing's and Tianjin's are in between, 818 +/- 319 m and 834 +/- 334 m respectively; Combined with the meteorological data, we find that radiation and wind speed are main factors of the mixing layer height; The relationship between the particle concentration and mixing layer height in four sites suggests that mixing layer is less than 800 m, concentration of fine particulate matter in four sites will exceed the national standard (GB 3095-2012, 75 microg x m(-3)). During the period of observation, the proportion of days that mixing layer is less than 800 m in Beijing, Tianjin, Shijiazhuang and Qinhuangdao are 50%, 43%, 80% and 50% respectively. Shijiazhuang though nearly formation contaminant concentration is high, within the atmospheric mixed layer pollutant load is not high. Unfavorable atmospheric diffusion conditions are the main causes of heavy pollution in Shijiazhuang for a long time. The results of the study are of great significance for cognitive Beijing-Tianjin-Hebei area pollution distribution, and can provide a scientific reference for reasonable distribution of regional pollution sources.

The roll-up and merging of coherent structures in shallow mixing layers

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

Lam, M. Y., E-mail: celmy@connect.ust.hk; Ghidaoui, M. S.; Kolyshkin, A. A.

2016-09-15

The current study seeks a fundamental explanation to the development of two-dimensional coherent structures (2DCSs) in shallow mixing layers. A nonlinear numerical model based on the depth-averaged shallow water equations is used to investigate the temporal evolution of shallow mixing layers, where the mapping from temporal to spatial results is made using the velocity at the center of the mixing layers. The flow is periodic in the streamwise direction. Transmissive boundary conditions are used in the cross-stream boundaries to prevent reflections. Numerical results are compared to linear stability analysis, mean-field theory, and secondary stability analysis. Results suggest that the onsetmore » and development of 2DCS in shallow mixing layers are the result of a sequence of instabilities governed by linear theory, mean-field theory, and secondary stability theory. The linear instability of the shearing velocity gradient gives the onset of 2DCS. When the perturbations reach a certain amplitude, the flow field of the perturbations changes from a wavy shape to a vortical (2DCS) structure because of nonlinearity. The development of the vertical 2DCS does not appear to follow weakly nonlinear theory; instead, it follows mean-field theory. After the formation of 2DCS, separate 2DCSs merge to form larger 2DCS. In this way, 2DCSs grow and shallow mixing layers develop and grow in scale. The merging of 2DCS in shallow mixing layers is shown to be caused by the secondary instability of the 2DCS. Eventually 2DCSs are dissipated by bed friction. The sequence of instabilities can cause the upscaling of the turbulent kinetic energy in shallow mixing layers.« less

Cloud and boundary layer interactions over the Arctic sea-ice in late summer

NASA Astrophysics Data System (ADS)

Shupe, M. D.; Persson, P. O. G.; Brooks, I. M.; Tjernström, M.; Sedlar, J.; Mauritsen, T.; Sjogren, S.; Leck, C.

2013-05-01

Observations from the Arctic Summer Cloud Ocean Study (ASCOS), in the central Arctic sea-ice pack in late summer 2008, provide a detailed view of cloud-atmosphere-surface interactions and vertical mixing processes over the sea-ice environment. Measurements from a suite of ground-based remote sensors, near surface meteorological and aerosol instruments, and profiles from radiosondes and a helicopter are combined to characterize a week-long period dominated by low-level, mixed-phase, stratocumulus clouds. Detailed case studies and statistical analyses are used to develop a conceptual model for the cloud and atmosphere structure and their interactions in this environment. Clouds were persistent during the period of study, having qualities that suggest they were sustained through a combination of advective influences and in-cloud processes, with little contribution from the surface. Radiative cooling near cloud top produced buoyancy-driven, turbulent eddies that contributed to cloud formation and created a cloud-driven mixed layer. The depth of this mixed layer was related to the amount of turbulence and condensed cloud water. Coupling of this cloud-driven mixed layer to the surface boundary layer was primarily determined by proximity. For 75% of the period of study, the primary stratocumulus cloud-driven mixed layer was decoupled from the surface and typically at a warmer potential temperature. Since the near-surface temperature was constrained by the ocean-ice mixture, warm temperatures aloft suggest that these air masses had not significantly interacted with the sea-ice surface. Instead, back trajectory analyses suggest that these warm airmasses advected into the central Arctic Basin from lower latitudes. Moisture and aerosol particles likely accompanied these airmasses, providing necessary support for cloud formation. On the occasions when cloud-surface coupling did occur, back trajectories indicated that these air masses advected at low levels, while mixing processes kept the mixed layer in equilibrium with the near-surface environment. Rather than contributing buoyancy forcing for the mixed-layer dynamics, the surface instead simply appeared to respond to the mixed-layer processes aloft. Clouds in these cases often contained slightly higher condensed water amounts, potentially due to additional moisture sources from below.

Cloud and boundary layer interactions over the Arctic sea ice in late summer

NASA Astrophysics Data System (ADS)

Shupe, M. D.; Persson, P. O. G.; Brooks, I. M.; Tjernström, M.; Sedlar, J.; Mauritsen, T.; Sjogren, S.; Leck, C.

2013-09-01

Observations from the Arctic Summer Cloud Ocean Study (ASCOS), in the central Arctic sea-ice pack in late summer 2008, provide a detailed view of cloud-atmosphere-surface interactions and vertical mixing processes over the sea-ice environment. Measurements from a suite of ground-based remote sensors, near-surface meteorological and aerosol instruments, and profiles from radiosondes and a helicopter are combined to characterize a week-long period dominated by low-level, mixed-phase, stratocumulus clouds. Detailed case studies and statistical analyses are used to develop a conceptual model for the cloud and atmosphere structure and their interactions in this environment. Clouds were persistent during the period of study, having qualities that suggest they were sustained through a combination of advective influences and in-cloud processes, with little contribution from the surface. Radiative cooling near cloud top produced buoyancy-driven, turbulent eddies that contributed to cloud formation and created a cloud-driven mixed layer. The depth of this mixed layer was related to the amount of turbulence and condensed cloud water. Coupling of this cloud-driven mixed layer to the surface boundary layer was primarily determined by proximity. For 75% of the period of study, the primary stratocumulus cloud-driven mixed layer was decoupled from the surface and typically at a warmer potential temperature. Since the near-surface temperature was constrained by the ocean-ice mixture, warm temperatures aloft suggest that these air masses had not significantly interacted with the sea-ice surface. Instead, back-trajectory analyses suggest that these warm air masses advected into the central Arctic Basin from lower latitudes. Moisture and aerosol particles likely accompanied these air masses, providing necessary support for cloud formation. On the occasions when cloud-surface coupling did occur, back trajectories indicated that these air masses advected at low levels, while mixing processes kept the mixed layer in equilibrium with the near-surface environment. Rather than contributing buoyancy forcing for the mixed-layer dynamics, the surface instead simply appeared to respond to the mixed-layer processes aloft. Clouds in these cases often contained slightly higher condensed water amounts, potentially due to additional moisture sources from below.

Laboratory simulations of the atmospheric mixed-layer in flow ...

EPA Pesticide Factsheets

A laboratory study of the influence of complex terrain on the interface between a well-mixed boundary layer and an elevated stratified layer was conducted in the towing-tank facility of the U.S. Environmental Protection Agency. The height of the mixed layer in the daytime boundary layer can have a strong influence on the concentration of pollutants within this layer. Deflections of streamlines at the height of the interface are primarily a function of hill Froude number (Fr), the ratio of mixed-layer height (zi) to terrain height (h), and the crosswind dimension of the terrain. The magnitude of the deflections increases as Fr increases and zi / h decreases. For mixing-height streamlines that are initially below the terrain top, the response is linear with Fr; for those initially above the terrain feature the response to Fr is more complex. Once Fr exceeds about 2, the terrain related response of the mixed layer interface decreases somewhat with increasing Fr (toward more neutral flow). Deflections are also shown to increase as the crosswind dimensions of the terrain increases. Comparisons with numerical modeling, limited field data and other laboratory measurements reported in the literature are favorable. Additionally, visual observations of dye streamers suggests that the flow structure exhibited for our elevated inversions passing over three dimensional hills is similar to that reported in the literature for continuously stratified flow over two-dimensional h

Receptivity of the compressible mixing layer

NASA Astrophysics Data System (ADS)

Barone, Matthew F.; Lele, Sanjiva K.

2005-09-01

Receptivity of compressible mixing layers to general source distributions is examined by a combined theoretical/computational approach. The properties of solutions to the adjoint Navier Stokes equations are exploited to derive expressions for receptivity in terms of the local value of the adjoint solution. The result is a description of receptivity for arbitrary small-amplitude mass, momentum, and heat sources in the vicinity of a mixing-layer flow, including the edge-scattering effects due to the presence of a splitter plate of finite width. The adjoint solutions are examined in detail for a Mach 1.2 mixing-layer flow. The near field of the adjoint solution reveals regions of relatively high receptivity to direct forcing within the mixing layer, with receptivity to nearby acoustic sources depending on the source type and position. Receptivity ‘nodes’ are present at certain locations near the splitter plate edge where the flow is not sensitive to forcing. The presence of the nodes is explained by interpretation of the adjoint solution as the superposition of incident and scattered fields. The adjoint solution within the boundary layer upstream of the splitter-plate trailing edge reveals a mechanism for transfer of energy from boundary-layer stability modes to Kelvin Helmholtz modes. Extension of the adjoint solution to the far field using a Kirchhoff surface gives the receptivity of the mixing layer to incident sound from distant sources.

Discrete element simulation of charging and mixed layer formation in the ironmaking blast furnace

NASA Astrophysics Data System (ADS)

Mitra, Tamoghna; Saxén, Henrik

2016-11-01

The burden distribution in the ironmaking blast furnace plays an important role for the operation as it affects the gas flow distribution, heat and mass transfer, and chemical reactions in the shaft. This work studies certain aspects of burden distribution by small-scale experiments and numerical simulation by the discrete element method (DEM). Particular attention is focused on the complex layer-formation process and the problems associated with estimating the burden layer distribution by burden profile measurements. The formation of mixed layers is studied, and a computational method for estimating the extent of the mixed layer, as well as its voidage, is proposed and applied on the results of the DEM simulations. In studying a charging program and its resulting burden distribution, the mixed layers of coke and pellets were found to show lower voidage than the individual burden layers. The dynamic evolution of the mixed layer during the charging process is also analyzed. The results of the study can be used to gain deeper insight into the complex charging process of the blast furnace, which is useful in the design of new charging programs and for mathematical models that do not consider the full behavior of the particles in the burden layers.

A three-dimensional simulation of transition and early turbulence in a time-developing mixing layer

NASA Technical Reports Server (NTRS)

Cain, A. B.; Reynolds, W. C.; Ferziger, J. H.

1981-01-01

The physics of the transition and early turbulence regimes in the time developing mixing layer was investigated. The sensitivity of the mixing layer to the disturbance field of the initial condition is considered. The growth of the momentum thickness, the mean velocity profile, the turbulence kinetic energy, the Reynolds stresses, the anisotropy tensor, and particle track pictures of computations are all examined in an effort to better understand the physics of these regimes. The amplitude, spectrum shape, and random phases of the initial disturbance field were varied. A scheme of generating discrete orthogonal function expansions on some nonuniform grids was developed. All cases address the early or near field of the mixing layer. The most significant result shows that the secondary instability of the mixing layer is produced by spanwise variations in the straining field of the primary vortex structures.

Method for fabricating solar cells having integrated collector grids

NASA Technical Reports Server (NTRS)

Evans, J. C., Jr. (Inventor)

1979-01-01

A heterojunction or Schottky barrier photovoltaic device comprising a conductive base metal layer compatible with and coating predominately the exposed surface of the p-type substrate of the device such that a back surface field region is formed at the interface between the device and the base metal layer, a transparent, conductive mixed metal oxide layer in integral contact with the n-type layer of the heterojunction or Schottky barrier device having a metal alloy grid network of the same metal elements of the oxide constituents of the mixed metal oxide layer embedded in the mixed metal oxide layer, an insulating layer which prevents electrical contact between the conductive metal base layer and the transparent, conductive metal oxide layer, and a metal contact means covering the insulating layer and in intimate contact with the metal grid network embedded in the transparent, conductive oxide layer for conducting electrons generated by the photovoltaic process from the device.

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

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.

Lagrangian pathways of upwelling in the Southern Ocean

NASA Astrophysics Data System (ADS)

Viglione, Giuliana A.; Thompson, Andrew F.

2016-08-01

The spatial and temporal variability of upwelling into the mixed layer in the Southern Ocean is studied using a 1/10° ocean general circulation model. Virtual drifters are released in a regularly spaced pattern across the Southern Ocean at depths of 250, 500, and 1000 m during both summer and winter months. The drifters are advected along isopycnals for a period of 4 years, unless they outcrop into the mixed layer, where lateral advection and a parameterization of vertical mixing are applied. The focus of this study is on the discrete exchange between the model mixed layer and the interior. Localization of interior-mixed layer exchange occurs downstream of major topographic features across the Indian and Pacific basins, creating "hotspots" of outcropping. Minimal outcropping occurs in the Atlantic basin, while 59% of drifters outcrop in the Pacific sector and in Drake Passage (the region from 140° W to 40° W), a disproportionately large amount even when considering the relative basin sizes. Due to spatial and temporal variations in mixed layer depth, the Lagrangian trajectories provide a statistical measure of mixed layer residence times. For each exchange into the mixed layer, the residence time has a Rayleigh distribution with a mean of 30 days; the cumulative residence time of the drifters is 261 ± 194 days, over a period of 4 years. These results suggest that certain oceanic gas concentrations, such as CO2 and 14C, will likely not reach equilibrium with the atmosphere before being resubducted.

Hydrogen trapping under the effect of W-C mixed layers

NASA Astrophysics Data System (ADS)

Liu, N.; Huang, J.; Sato, K.; Xu, Q.; Shi, L. Q.; Wang, Y. X.

2014-03-01

The retention of hydrogen (H) isotope in plasma-facing materials (PFMs) is an important issue for next step fusion device. We used density functional theory (DFT) to study the chemical bonds of H in tungsten-carbon (W-C) mixed layers of tungsten surface, aiming to explore the retention behaviour of H in PFMs. The solubility of C in W was first calculated for revealing the phase components in W-C mixed layers. It was found that C has low solubility in W, which prefers to be segregated on the W surface. Vacancies can enhance the solution of C in W. This makes C appear somewhat carbide feature. Thus, W-C mixed layers should contain multiple phase components. H retention strongly depends on the phase components in the W-C mixed layers. The solution of C will suppress the retention of H in W no matter whether neighbouring vacancies are present, or not. Hydrocarbon precursors, which were observed in desorption experiments, prefer to form by means of H binding to C atoms in C amorphous, or in precipitators in the W-C mixed layers, while not in tungsten carbide phase or in W bulk. Our investigation reasonably explains the experimental results.

High Static Stability in the Mixed Layer Above the Extratropical Tropopause

NASA Astrophysics Data System (ADS)

Kunz, A.; Konopka, P.; Müller, R.; Schiller, C.

2008-12-01

A strong relationship between the static stability N2 and the strength of mixing in the mixed layer above the extratropical tropopause is evident from in-situ data observed during the SPURT aircraft campaigns. We present a method for quantifying the strength of mixing from O3/CO tracer correlations and we find that N2 is positively correlated with the strength of mixing. Age of air simulations with the CLaMS model reveal two different types of mixed regions. One type consisting of older airmasses with higher values of N2 which are created by radiative adjustment after a mixing event. These airmasses are within the TIL (Tropopause Inversion Layer), considering the TIL as part of the mixing layer. The second type comprises younger airmasses with somehow lower stratospheric N2 values within the mixing layer, because of recent intrusion processes due to the permeability or so-called mid-latitude-breaks associated with the jet stream. With the help of radiative transfer calculations we simulate the influence of trace gases such as O3 and H2O on the temperature gradient and thus on the static stability above the tropopause in the idealized case of non-mixing (L-shape) O3 and H2O profiles and in the reference case of mixed profiles. Within the altitude range of the SPURT campaigns the mean vertical SPURT profiles are used as reference, which are fitted to the HALOE climatological profiles above the UT/LS.

Temperature Versus Salinity Gradients Below the Ocean Mixed Layer

DTIC Science & Technology

2012-05-03

where salinity controls the depth of the mixed layer are understood to have “barrier” layers [Lukas and Lindstrom , 1991], where the depth of vertically...the horizontal. For example, Rudnick and Martin [2002] have shown that the ocean mixed layer at sub-mesoscales is horizontally well density compensated...Res., 102, 23,063–23,078, doi:10.1029/97JC01443. Barron, C. N., A. B. Kara, P. J. Martin , R. C. Rhodes, and L. F. Smedstad (2006), Formulation

Development of a Hybrid RANS/LES Method for Compressible Mixing Layer Simulations

NASA Technical Reports Server (NTRS)

Georgiadis, Nicholas J.; Alexander, J. Iwan D.; Reshotko, Eli

2001-01-01

A hybrid method has been developed for simulations of compressible turbulent mixing layers. Such mixing layers dominate the flows in exhaust systems of modem day aircraft and also those of hypersonic vehicles currently under development. The hybrid method uses a Reynolds-averaged Navier-Stokes (RANS) procedure to calculate wall bounded regions entering a mixing section, and a Large Eddy Simulation (LES) procedure to calculate the mixing dominated regions. A numerical technique was developed to enable the use of the hybrid RANS/LES method on stretched, non-Cartesian grids. The hybrid RANS/LES method is applied to a benchmark compressible mixing layer experiment. Preliminary two-dimensional calculations are used to investigate the effects of axial grid density and boundary conditions. Actual LES calculations, performed in three spatial directions, indicated an initial vortex shedding followed by rapid transition to turbulence, which is in agreement with experimental observations.

Investigation of mixed-host organic light emitting diodes

NASA Astrophysics Data System (ADS)

Yeh Yee, Kee

One of the limiting factors to the OLED stability or lifetime is the charge buildup at the bilayer heterojunction (HJ) between the hole transport layer (HTL) and electron transport layer (ETL). In recent years, this abrupt interface has been moderated by mixing HTL and ETL to form a single mixed-host, light emitting layer. For uniformly mixed-host (UM) OLED, the device lifetime and also the efficiency were improved due to the spatial broadening of the recombination zone. Similar device architectures, such as the step-wise graded mixed-host (SGM-OLED) and the continuously graded mixed-host (CGM-OLED) have also been implemented by a number of researchers. In this work, a premix of hole transport material (HTM) and electron transport material (ETM), namely TPD and Alq, is prepared for one-step thermal evaporation of the mixed-host light emitting layer (EML). Depending on the evaporation rate, the CGM-OLEDs with different concentration profiles of HTM and ETM in the EML are obtained, which are inversely proportional to each other.

Lidar observation of marine mixed layer

NASA Technical Reports Server (NTRS)

Yamagishi, Susumu; Yamanouchi, Hiroshi; Tsuchiya, Masayuki

1992-01-01

Marine mixed layer is known to play an important role in the transportation of pollution exiting ship funnels. The application of a diffusion model is critically dependent upon a reliable estimate of a lid. However, the processes that form lids are not well understood, though considerable progress toward marine boundary layer has been achieved. This report describes observations of the marine mixed layer from the course Ise-wan to Nii-jima with the intention of gaining a better understanding of their structure by a shipboard lidar. These observations were made in the summer of 1991. One interesting feature of the observations was that the multiple layers of aerosols, which is rarely numerically modeled, was encountered. No attempt is yet made to present a systematic analysis of all the data collected. Instead we focus on observations that seem to be directly relevant to the structure of the mixed layer.

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.

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

Development of a nonlocal convective mixing scheme with varying upward mixing rates for use in air quality and chemical transport models.

PubMed

Mihailović, Dragutin T; Alapaty, Kiran; Sakradzija, Mirjana

2008-06-01

Asymmetrical convective non-local scheme (CON) with varying upward mixing rates is developed for simulation of vertical turbulent mixing in the convective boundary layer in air quality and chemical transport models. The upward mixing rate form the surface layer is parameterized using the sensible heat flux and the friction and convective velocities. Upward mixing rates varying with height are scaled with an amount of turbulent kinetic energy in layer, while the downward mixing rates are derived from mass conservation. This scheme provides a less rapid mass transport out of surface layer into other layers than other asymmetrical convective mixing schemes. In this paper, we studied the performance of a nonlocal convective mixing scheme with varying upward mixing in the atmospheric boundary layer and its impact on the concentration of pollutants calculated with chemical and air-quality models. This scheme was additionally compared versus a local eddy-diffusivity scheme (KSC). Simulated concentrations of NO(2) and the nitrate wet deposition by the CON scheme are closer to the observations when compared to those obtained from using the KSC scheme. Concentrations calculated with the CON scheme are in general higher and closer to the observations than those obtained by the KSC scheme (of the order of 15-20%). Nitrate wet deposition calculated with the CON scheme are in general higher and closer to the observations than those obtained by the KSC scheme. To examine the performance of the scheme, simulated and measured concentrations of a pollutant (NO(2)) and nitrate wet deposition was compared for the year 2002. The comparison was made for the whole domain used in simulations performed by the chemical European Monitoring and Evaluation Programme Unified model (version UNI-ACID, rv2.0) where schemes were incorporated.

Quasi-Geostrophic Diagnosis of Mixed-Layer Dynamics Embedded in a Mesoscale Turbulent Field

NASA Astrophysics Data System (ADS)

Chavanne, C. P.; Klein, P.

2016-02-01

A new quasi-geostrophic model has been developed to diagnose the three-dimensional circulation, including the vertical velocity, in the upper ocean from high-resolution observations of sea surface height and buoyancy. The formulation for the adiabatic component departs from the classical surface quasi-geostrophic framework considered before since it takes into account the stratification within the surface mixed-layer that is usually much weaker than that in the ocean interior. To achieve this, the model approximates the ocean with two constant-stratification layers : a finite-thickness surface layer (or the mixed-layer) and an infinitely-deep interior layer. It is shown that the leading-order adiabatic circulation is entirely determined if both the surface streamfunction and buoyancy anomalies are considered. The surface layer further includes a diabatic dynamical contribution. Parameterization of diabatic vertical velocities is based on their restoring impacts of the thermal-wind balance that is perturbed by turbulent vertical mixing of momentum and buoyancy. The model skill in reproducing the three-dimensional circulation in the upper ocean from surface data is checked against the output of a high-resolution primitive-equation numerical simulation. Correlation between simulated and diagnosed vertical velocities are significantly improved in the mixed-layer for the new model compared to the classical surface quasi-geostrophic model, reaching 0.9 near the surface.

Mixed mosaic membranes prepared by layer-by-layer assembly for ionic separations.

PubMed

Rajesh, Sahadevan; Yan, Yu; Chang, Hsueh-Chia; Gao, Haifeng; Phillip, William A

2014-12-23

Charge mosaic membranes, which possess distinct cationic and anionic domains that traverse the membrane thickness, are capable of selectively separating dissolved salts from similarly sized neutral solutes. Here, the generation of charge mosaic membranes using facile layer-by-layer assembly methodologies is reported. Polymeric nanotubes with pore walls lined by positively charged polyethylenimine moieties or negatively charged poly(styrenesulfonate) moieties were prepared via layer-by-layer assembly using track-etched membranes as sacrificial templates. Subsequently, both types of nanotubes were deposited on a porous support in order to produce mixed mosaic membranes. Scanning electron microscopy demonstrates that the facile deposition techniques implemented result in nanotubes that are vertically aligned without overlap between adjacent elements. Furthermore, the nanotubes span the thickness of the mixed mosaic membranes. The effects of this unique nanostructure are reflected in the transport characteristics of the mixed mosaic membranes. The hydraulic permeability of the mixed mosaic membranes in piezodialysis operations was 8 L m(-2) h(-1) bar(-1). Importantly, solute rejection experiments demonstrate that the mixed mosaic membranes are more permeable to ionic solutes than similarly sized neutral molecules. In particular, negative rejection of sodium chloride is observed (i.e., the concentration of NaCl in the solution that permeates through a mixed mosaic membrane is higher than in the initial feed solution). These properties illustrate the ability of mixed mosaic membranes to permeate dissolved ions selectively without violating electroneutrality and suggest their utility in ionic separations.

Modeling the interplay between sea ice formation and the oceanic mixed layer: Limitations of simple brine rejection parameterizations

NASA Astrophysics Data System (ADS)

Barthélemy, Antoine; Fichefet, Thierry; Goosse, Hugues; Madec, Gurvan

2015-02-01

The subtle interplay between sea ice formation and ocean vertical mixing is hardly represented in current large-scale models designed for climate studies. Convective mixing caused by the brine release when ice forms is likely to prevail in leads and thin ice areas, while it occurs in models at the much larger horizontal grid cell scale. Subgrid-scale parameterizations have hence been developed to mimic the effects of small-scale convection using a vertical distribution of the salt rejected by sea ice within the mixed layer, instead of releasing it in the top ocean layer. Such a brine rejection parameterization is included in the global ocean-sea ice model NEMO-LIM3. Impacts on the simulated mixed layers and ocean temperature and salinity profiles, along with feedbacks on the sea ice cover, are then investigated in both hemispheres. The changes are overall relatively weak, except for mixed layer depths, which are in general excessively reduced compared to observation-based estimates. While potential model biases prevent a definitive attribution of this vertical mixing underestimation to the brine rejection parameterization, it is unlikely that the latter can be applied in all conditions. In that case, salt rejections do not play any role in mixed layer deepening, which is unrealistic. Applying the parameterization only for low ice-ocean relative velocities improves model results, but introduces additional parameters that are not well constrained by observations.

Modelling the interplay between sea ice formation and the oceanic mixed layer: limitations of simple brine rejection parameterizations

NASA Astrophysics Data System (ADS)

Barthélemy, Antoine; Fichefet, Thierry; Goosse, Hugues; Madec, Gurvan

2015-04-01

The subtle interplay between sea ice formation and ocean vertical mixing is hardly represented in current large-scale models designed for climate studies. Convective mixing caused by the brine release when ice forms is likely to prevail in leads and thin ice areas, while it occurs in models at the much larger horizontal grid cell scale. Subgrid-scale parameterizations have hence been developed to mimic the effects of small-scale convection using a vertical distribution of the salt rejected by sea ice within the mixed layer, instead of releasing it in the top ocean layer. Such a brine rejection parameterization is included in the global ocean--sea ice model NEMO-LIM3. Impacts on the simulated mixed layers and ocean temperature and salinity profiles, along with feedbacks on the sea ice cover, are then investigated in both hemispheres. The changes are overall relatively weak, except for mixed layer depths, which are in general excessively reduced compared to observation-based estimates. While potential model biases prevent a definitive attribution of this vertical mixing underestimation to the brine rejection parameterization, it is unlikely that the latter can be applied in all conditions. In that case, salt rejections do not play any role in mixed layer deepening, which is unrealistic. Applying the parameterization only for low ice--ocean relative velocities improves model results, but introduces additional parameters that are not well constrained by observations.

Prediction of dynamic and mixing characteristics of drop-laden mixing layers using DNS and LES

NASA Technical Reports Server (NTRS)

Okong'o, N.; Leboissetier, A.; Bellan, J.

2004-01-01

Direct Numerical Simulation (DNS) and Large Eddy Simulation (LES) have been conducted of a temporal mixing layer laden with evaporating drops, in order to assess the ability of LES to reproduce dynamic and mixing aspects of the DNS which affect combustion, independently of combustion models.

The seasonal cycle of the mixing layer height and its impact on black carbon concentrations in the Kathmandu Valley (Nepal)

NASA Astrophysics Data System (ADS)

Mues, Andrea; Rupakheti, Maheswar; Hoor, Peter; Bozem, Heiko; Münkel, Christoph; Lauer, Axel; Butler, Tim

2016-04-01

The properties and the vertical structure of the mixing layer as part of the planetary boundary layer are of key importance for local air quality. They have a substantial impact on the vertical dispersion of pollutants in the lower atmosphere and thus on their concentrations near the surface. In this study, ceilometer measurements taken within the framework of the SusKat project (Sustainable Atmosphere for the Kathmandu Valley) are used to investigate the mixing layer height in the Kathmandu Valley, Nepal. The applied method is based on the assumption that the aerosol concentration is nearly constant in the vertical and distinctly higher within the mixing layer than in the air above. Thus, the height with the steepest gradient within the ceilometer backscatter profile marks the top of the mixing layer. Ceilometer and black carbon (BC) measurements conducted from March 2013 through February 2014 provide a unique and important dataset for the analysis of the meteorological and air quality conditions in the Kathmandu Valley. In this study the mean diurnal cycle of the mixing layer height in the Kathmandu Valley for each season (pre-monsoon, monsoon, post-monsoon and winter season) and its dependency on the meteorological situation is investigated. In addition, the impact of the mixing layer height on the BC concentration is analyzed and compared to the relevance of other important processes such as emissions, horizontal advection and deposition. In all seasons the diurnal cycle is typically characterized by low mixing heights during the night, gradually increasing after sun rise reaching to maximum values in the afternoon before decreasing again. Seasonal differences can be seen particularly in the height of the mixing layer, e.g. from on average 153/1200 m (pre-monsoon) to 241/755 m (monsoon season) during the night/day, and the duration of enhanced mixing layer heights during daytime (around 12 hours (pre-monsoon season) to 8 hours (winter)). During the monsoon season, the observed diurnal cycle typically shows the lowest amplitude and the lowest mixing height during the day and the highest in the night and morning hours of all seasons. These characteristics can mainly be explained with frequently present clouds and the associated lack of incoming solar radiation and outgoing longwave radiation. In general there is a clear anti-correlation of the BC concentration and the mixing layer height although this relation is less pronounced in the monsoon season. The shape and magnitude of the BC diurnal cycle differs between the seasons (e.g., daily maximum concentration from around 6 to 50 μg/m3 depending on the season). This is partly due to the different meteorological conditions including the mixing layer height but also caused by the different (seasonal and diurnal) time profiles of the main emission sources. From late December to April, for instance, brick kilns are major emitters of black carbon. The brick kilns emit continuously throughout the day whereas in the other months sources with more pronounced diurnal cycles, such as traffic and cooking activities, are dominating the total emissions.

Mid-depth temperature maximum in an estuarine lake

NASA Astrophysics Data System (ADS)

Stepanenko, V. M.; Repina, I. A.; Artamonov, A. Yu; Gorin, S. L.; Lykossov, V. N.; Kulyamin, D. V.

2018-03-01

The mid-depth temperature maximum (TeM) was measured in an estuarine Bol’shoi Vilyui Lake (Kamchatka peninsula, Russia) in summer 2015. We applied 1D k-ɛ model LAKE to the case, and found it successfully simulating the phenomenon. We argue that the main prerequisite for mid-depth TeM development is a salinity increase below the freshwater mixed layer, sharp enough in order to increase the temperature with depth not to cause convective mixing and double diffusion there. Given that this condition is satisfied, the TeM magnitude is controlled by physical factors which we identified as: radiation absorption below the mixed layer, mixed-layer temperature dynamics, vertical heat conduction and water-sediments heat exchange. In addition to these, we formulate the mechanism of temperature maximum ‘pumping’, resulting from the phase shift between diurnal cycles of mixed-layer depth and temperature maximum magnitude. Based on the LAKE model results we quantify the contribution of the above listed mechanisms and find their individual significance highly sensitive to water turbidity. Relying on physical mechanisms identified we define environmental conditions favouring the summertime TeM development in salinity-stratified lakes as: small-mixed layer depth (roughly, ~< 2 m), transparent water, daytime maximum of wind and cloudless weather. We exemplify the effect of mixed-layer depth on TeM by a set of selected lakes.

Corrosion of low alloy steel containing 0.5% chromium in supercritical CO2-saturated brine and water-saturated supercritical CO2 environments

NASA Astrophysics Data System (ADS)

Wei, Liang; Gao, Kewei; Li, Qian

2018-05-01

The corrosion behavior of P110 low-Cr alloy steel in supercritical CO2-saturated brine (aqueous phase) and water-saturated supercritical CO2 (SC CO2 phase) was investigated. The results show that P110 steel primarily suffered general corrosion in the aqueous phase, while severe localized corrosion occurred in the SC CO2 phase. The formation of corrosion product scale on P110 steel in the aqueous phase divided into three stages: formation of the initial corrosion layer containing amorphous Cr(OH)3, FeCO3 and a small amount of Fe3C; transformation of initial corrosion layer to mixed layer, which consisted of FeCO3 and a small amount of Cr(OH)3 and Fe3C; growth and dissolution of the mixed layer. Finally, only a single mixed layer covered on the steel in the aqueous phase. However, the scale formed in SC CO2 phase consisted of two layers: the inner mixed layer and the dense outer FeCO3 crystalline layer.

Anomalies of the upper water column in the Mediterranean Sea

NASA Astrophysics Data System (ADS)

Rivetti, Irene; Boero, Ferdinando; Fraschetti, Simonetta; Zambianchi, Enrico; Lionello, Piero

2017-04-01

The evolution of the upper water column in the Mediterranean Sea during more than 60 years is reconstructed in terms of few parameters describing the mixed layer and the seasonal thermocline. The analysis covers the period 1945-2011 using data from three public sources: MEDAR-MEDATLAS, World Ocean Database, MFS-VOS program. Five procedures for estimating the mixed layer depth are described, discussed and compared using the 20-year long time series of temperature profiles of the DYFAMED station in the Ligurian Sea. On this basis the so-called three segments profile model (which approximates the upper water column with three segments representing mixed layer, thermocline and deep layer) has been selected for a systematic analysis at Mediterranean scale. A widespread increase of the thickness and temperature of the mixed layer, increase of the depth and decrease of the temperature of the thermocline base have been observed in summer and autumn during the recent decades. It is shown that positive temperature extremes of the mixed layer and of its thickness are potential drivers of the mass mortalities of benthic invertebrates documented since 1983. Hotspots of mixed layer anomalies have been also identified. These results refine previous analyses showing that ongoing and future warming of upper Mediterranean is likely to increase mass mortalities by producing environmental conditions beyond the limit of tolerance of some benthic species.

A Water Model Study on Mixing Behavior of the Two-Layered Bath in Bottom Blown Copper Smelting Furnace

NASA Astrophysics Data System (ADS)

Shui, Lang; Cui, Zhixiang; Ma, Xiaodong; Jiang, Xu; Chen, Mao; Xiang, Yong; Zhao, Baojun

2018-05-01

The bottom-blown copper smelting furnace is a novel copper smelter developed in recent years. Many advantages of this furnace have been found, related to bath mixing behavior under its specific gas injection scheme. This study aims to use an oil-water double-phased laboratory-scale model to investigate the impact of industry-adjustable variables on bath mixing time, including lower layer thickness, gas flow rate, upper layer thickness and upper layer viscosity. Based on experimental results, an overall empirical relationship of mixing time in terms of these variables has been correlated, which provides the methodology for industry to optimize mass transfer in the furnace.

Surface boundary layer turbulence in the Southern ocean

NASA Astrophysics Data System (ADS)

Merrifield, Sophia; St. Laurent, Louis; Owens, Breck; Naveira Garabato, Alberto

2015-04-01

Due to the remote location and harsh conditions, few direct measurements of turbulence have been collected in the Southern Ocean. This region experiences some of the strongest wind forcing of the global ocean, leading to large inertial energy input. While mixed layers are known to have a strong seasonality and reach 500m depth, the depth structure of near-surface turbulent dissipation and diffusivity have not been examined using direct measurements. We present data collected during the Diapycnal and Isopycnal Mixing Experiment in the Southern Ocean (DIMES) field program. In a range of wind conditions, the wave affected surface layer (WASL), where surface wave physics are actively forcing turbulence, is contained to the upper 15-20m. The lag-correlation between wind stress and turbulence shows a strong relationship up to 6 hours (˜1/2 inertial period), with the winds leading the oceanic turbulent response, in the depth range between 20-50m. We find the following characterize the data: i) Profiles that have a well-defined hydrographic mixed layer show that dissipation decays in the mixed layer inversely with depth, ii) WASLs are typically 15 meters deep and 30% of mixed layer depth, iii) Subject to strong winds, the value of dissipation as a function of depth is significantly lower than predicted by theory. Many dynamical processes are known to be missing from upper-ocean parameterizations of mixing in global models. These include surface-wave driven processes such as Langmuir turbulence, submesocale frontal processes, and nonlocal representations of mixing. Using velocity, hydrographic, and turbulence measurements, the existence of coherent structures in the boundary layer are investigated.

Frontolysis by surface heat flux in the Agulhas Return Current region with a focus on mixed layer processes: observation and a high-resolution CGCM

NASA Astrophysics Data System (ADS)

Ohishi, Shun; Tozuka, Tomoki; Komori, Nobumasa

2016-12-01

Detailed mechanisms for frontogenesis/frontolysis of the Agulhas Return Current (ARC) Front, defined as the maximum of the meridional sea surface temperature (SST) gradient at each longitude within the ARC region (40°-50°E, 55°-35°S), are investigated using observational datasets. Due to larger (smaller) latent heat release to the atmosphere on the northern (southern) side of the front, the meridional gradient of surface net heat flux (NHF) is found throughout the year. In austral summer, surface warming is weaker (stronger) on the northern (southern) side, and thus the NHF tends to relax the SST front. The weaker (stronger) surface warming, at the same time, leads to the deeper (shallower) mixed layer on the northern (southern) side. This enhances the frontolysis, because deeper (shallower) mixed layer is less (more) sensitive to surface warming. In austral winter, stronger (weaker) surface cooling on the northern (southern) side contributes to the frontolysis. However, deeper (shallower) mixed layer is induced by stronger (weaker) surface cooling on the northern (southern) side and suppresses the frontolysis, because the deeper (shallower) mixed layer is less (more) sensitive to surface cooling. Therefore, the frontolysis by the NHF becomes stronger (weaker) through the mixed layer processes in austral summer (winter). The cause of the meridional gradient of mixed layer depth is estimated using diagnostic entrainment velocity and the Monin-Obukhov depth. Furthermore, the above mechanisms obtained from the observation are confirmed using outputs from a high-resolution coupled general circulation model. Causes of model biases are also discussed.

Elastic modelling in tilted transversely isotropic media with convolutional perfectly matched layer boundary conditions

NASA Astrophysics Data System (ADS)

Han, Byeongho; Seol, Soon Jee; Byun, Joongmoo

2012-04-01

To simulate wave propagation in a tilted transversely isotropic (TTI) medium with a tilting symmetry-axis of anisotropy, we develop a 2D elastic forward modelling algorithm. In this algorithm, we use the staggered-grid finite-difference method which has fourth-order accuracy in space and second-order accuracy in time. Since velocity-stress formulations are defined for staggered grids, we include auxiliary grid points in the z-direction to meet the free surface boundary conditions for shear stress. Through comparisons of displacements obtained from our algorithm, not only with analytical solutions but also with finite element solutions, we are able to validate that the free surface conditions operate appropriately and elastic waves propagate correctly. In order to handle the artificial boundary reflections efficiently, we also implement convolutional perfectly matched layer (CPML) absorbing boundaries in our algorithm. The CPML sufficiently attenuates energy at the grazing incidence by modifying the damping profile of the PML boundary. Numerical experiments indicate that the algorithm accurately expresses elastic wave propagation in the TTI medium. At the free surface, the numerical results show good agreement with analytical solutions not only for body waves but also for the Rayleigh wave which has strong amplitude along the surface. In addition, we demonstrate the efficiency of CPML for a homogeneous TI medium and a dipping layered model. Only using 10 grid points to the CPML regions, the artificial reflections are successfully suppressed and the energy of the boundary reflection back into the effective modelling area is significantly decayed.

Synoptic-to-planetary scale wind variability enhances phytoplankton biomass at ocean fronts

NASA Astrophysics Data System (ADS)

Whitt, D. B.; Taylor, J. R.; Lévy, M.

2017-06-01

In nutrient-limited conditions, phytoplankton growth at fronts is enhanced by winds, which drive upward nutrient fluxes via enhanced turbulent mixing and upwelling. Hence, depth-integrated phytoplankton biomass can be 10 times greater at isolated fronts. Using theory and two-dimensional simulations with a coupled physical-biogeochemical ocean model, this paper builds conceptual understanding of the physical processes driving upward nutrient fluxes at fronts forced by unsteady winds with timescales of 4-16 days. The largest vertical nutrient fluxes occur when the surface mixing layer penetrates the nutricline, which fuels phytoplankton in the mixed layer. At a front, mixed layer deepening depends on the magnitude and direction of the wind stress, cross-front variations in buoyancy and velocity at the surface, and potential vorticity at the base of the mixed layer, which itself depends on past wind events. Consequently, mixing layers are deeper and more intermittent in time at fronts than outside fronts. Moreover, mixing can decouple in time from the wind stress, even without other sources of physical variability. Wind-driven upwelling also enhances depth-integrated phytoplankton biomass at fronts; when the mixed layer remains shallower than the nutricline, this results in enhanced subsurface phytoplankton. Oscillatory along-front winds induce both oscillatory and mean upwelling. The mean effect of oscillatory vertical motion is to transiently increase subsurface phytoplankton over days to weeks, whereas slower mean upwelling sustains this increase over weeks to months. Taken together, these results emphasize that wind-driven phytoplankton growth is both spatially and temporally intermittent and depends on a diverse combination of physical processes.

Observations of the Evolution of Turbulent Dissipation within the Ocean Surface Boundary Layer: an OSMOSIS study

NASA Astrophysics Data System (ADS)

Lucas, N. S.; Allen, J.; Belcher, S. E.; Boyd, T.; Brannigan, L.; Inall, M.; Palmer, M.; Polton, J.; Rippeth, T. P.

2016-02-01

This study presents a new 9.5 day dataset showing the evolution of the Ocean Surface Boundary Layer (OSBL) and dissipation of turbulence kinetic energy (TKE), carried out as part of OSMOSIS[i], at a location in the North East Atlantic Ocean in September 2012. The TKE dissipation measurements were made using three methods; (i) repeated profiling between 100m and the surface by an Ocean Microstructure glider, (ii) three series of profiles made using a loosely tethered velocity microstructure glider and (iii) a moored pulse-pulse coherent high frequency ADCP. Supporting measurements show the evolution of the water column structure, including surface wave measurements from a TRIAXYS wave buoy. This data shows two distinct regimes; the first, spanning 4 days with relatively low winds, displays a distinct diurnal cycle with the deepening of the active mixing layer during the night which shoaled during the day. The second spanned a significant storm, (with maximum winds speeds reaching 20 m s-1 and significant wave heights reaching 6 m), during which, rather than a deepening of the mixed layer as predicted by classical theory, the primary effect was a broadening of the transition layer, similar to that found by Dohan and Davies (2011). During the storm, significant dissipation was observed throughout the surface mixed layer and into the transition layer, driving fluxes of heat downwards through the base of the surface mixed layer. [i] Ocean Surface Mixing and Submesoscale Interaction Study Dohan, K. & Davis, R.E., 2011. Mixing in the Transition Layer during Two Storm Events. Journal of Physical Oceanography. 41 (1). pp. 42-66.

Mixed layers of sodium caseinate + dextran sulfate: influence of order of addition to oil-water interface.

PubMed

Jourdain, Laureline S; Schmitt, Christophe; Leser, Martin E; Murray, Brent S; Dickinson, Eric

2009-09-01

We report on the interfacial properties of electrostatic complexes of protein (sodium caseinate) with a highly sulfated polysaccharide (dextran sulfate). Two routes were investigated for preparation of adsorbed layers at the n-tetradecane-water interface at pH = 6. Bilayers were made by the layer-by-layer deposition technique whereby polysaccharide was added to a previously established protein-stabilized interface. Mixed layers were made by the conventional one-step method in which soluble protein-polysaccharide complexes were adsorbed directly at the interface. Protein + polysaccharide systems gave a slower decay of interfacial tension and stronger dilatational viscoelastic properties than the protein alone, but there was no significant difference in dilatational properties between mixed layers and bilayers. Conversely, shear rheology experiments exhibited significant differences between the two kinds of interfacial layers, with the mixed system giving much stronger interfacial films than the bilayer system, i.e., shear viscosities and moduli at least an order of magnitude higher. The film shear viscoelasticity was further enhanced by acidification of the biopolymer mixture to pH = 2 prior to interface formation. Taken together, these measurements provide insight into the origin of previously reported differences in stability properties of oil-in-water emulsions made by the bilayer and mixed layer approaches. Addition of a proteolytic enzyme (trypsin) to both types of interfaces led to a significant increase in the elastic modulus of the film, suggesting that the enzyme was adsorbed at the interface via complexation with dextran sulfate. Overall, this study has confirmed the potential of shear rheology as a highly sensitive probe of associative electrostatic interactions and interfacial structure in mixed biopolymer layers.

Computation of turbulent high speed mixing layers using a two-equation turbulence model

NASA Technical Reports Server (NTRS)

Narayan, J. R.; Sekar, B.

1991-01-01

A two-equation turbulence model was extended to be applicable for compressible flows. A compressibility correction based on modelling the dilational terms in the Reynolds stress equations were included in the model. The model is used in conjunction with the SPARK code for the computation of high speed mixing layers. The observed trend of decreasing growth rate with increasing convective Mach number in compressible mixing layers is well predicted by the model. The predictions agree well with the experimental data and the results from a compressible Reynolds stress model. The present model appears to be well suited for the study of compressible free shear flows. Preliminary results obtained for the reacting mixing layers are included.

Forced free-shear layer measurements

NASA Technical Reports Server (NTRS)

Leboeuf, Richard L.

1994-01-01

Detailed three-dimensional three-component phase averaged measurements of the spanwise and streamwise vorticity formation and evolution in acoustically forced plane free-shear flows have been obtained. For the first time, phase-averaged measurements of all three velocity components have been obtained in both a mixing layer and a wake on three-dimensional grids, yielding the spanwise and streamwise vorticity distributions without invoking Taylor's hypothesis. Initially, two-frequency forcing was used to phase-lock the roll-up and first pairing of the spanwise vortical structures in a plane mixing layer. The objective of this study was to measure the near-field vortical structure morphology in a mixing layer with 'natural' laminar initial boundary layers. For the second experiment the second and third subharmonics of the fundamental roll-up frequency were added to the previous two-frequency forcing in order to phase-lock the roll-up and first three pairings of the spanwise rollers in the mixing layer. The objective of this study was to determine the details of spanwise scale changes observed in previous time-averaged measurements and flow visualization of unforced mixing layers. For the final experiment, single-frequency forcing was used to phase-lock the Karman vortex street in a plane wake developing from nominally two-dimensional laminar initial boundary layers. The objective of this study was to compare measurements of the three-dimensional structure in a wake developing from 'natural' initial boundary layers to existing models of wake vortical structure.

Seasonal cycle of oceanic mixed layer and upper-ocean heat fluxes in the Mediterranean Sea from in-situ observations.

NASA Astrophysics Data System (ADS)

Houpert, Loïc; Testor, Pierre; Durrieu de Madron, Xavier; Estournel, Claude; D'Ortenzio, Fabrizio

2013-04-01

Heat fluxes across the ocean-atmosphere interface play a crucial role in the upper turbulent mixing. The depth reached by this turbulent mixing is indicated by an homogenization of seawater properties in the surface layer, and is defined as the Mixed Layer Depth (MLD). The thickness of the mixed layer determines also the heat content of the layer that directly interacts with the atmosphere. The seasonal variability of these air-sea fluxes is crucial in the calculation of heat budget. An improvement in the estimate of these fluxes is needed for a better understanding of the Mediterranean ocean circulation and climate, in particular in Regional Climate Models. There are few estimations of surface heat fluxes based on oceanic observations in the Mediterranean, and none of them are based on mixed layer observations. So, we proposed here new estimations of these upper-ocean heat fluxes based on mixed layer. We present high resolution Mediterranean climatology (0.5°) of the mean MLD based on a comprehensive collection of temperature profiles of last 43 years (1969-2012). The database includes more than 150,000 profiles, merging CTD, XBT, ARGO Profiling floats, and gliders observations. This dataset is first used to describe the seasonal cycle of the mixed layer depth on the whole Mediterranean on a monthly climatological basis. Our analysis discriminates several regions with coherent behaviors, in particular the deep water formation sites, characterized by significant differences in the winter mixing intensity. Heat storage rates (HSR) were calculated as the time rate of change of the heat content integrated from the surface down to a specific depth that is defined as the MLD plus an integration constant. Monthly climatology of net heat flux (NHF) from ERA-Interim reanalysis was balanced by the 1°x1° resolution heat storage rate climatology. Local heat budget balance and seasonal variability in the horizontal heat flux are then discussed by taking into account uncertainties, due to errors in monthly value estimation and to intra-annual and inter-annual variability.

Mixed layer warming-deepening in the Mediterranean Sea and its effect on the marine environment

NASA Astrophysics Data System (ADS)

Rivetti, Irene; Boero, Ferdinando; Fraschetti, Simonetta; Zambianchi, Enrico; Lionello, Piero

2015-04-01

This work aims at investigating the evolution of the ocean mixed layer in the Mediterranean Sea and linking it to the occurrence of mass mortalities of benthic invertebrates. The temporal evolution of selected parameters describing the mixed layer and the seasonal thermocline is provided for the whole Mediterranean Sea for spring, summer and autumn and for the period 1945-2011. For this analysis all temperature profiles collected in the basin with bottles, Mechanical Bathy-Thermographs (MBT), eXpendable Bathy-Thermographs (XBT), and Conductivity-Temperature-Depth (CTD) have been used (166,990). These data have been extracted from three public sources: the MEDAR-MEDATLAS, the World Ocean Database 2013 and the MFS-VOS program. Five different methods for estimating the mixed layer depth are compared using temperature profiles collected at the DYFAMED station in the Ligurian Sea and one method, the so-called three-segment method, has been selected for a systematic analysis of the evolution of the uppermost part of the whole Mediterranean Sea. This method approximates the upper water column with three segments representing mixed layer, thermocline and deep layer and has shown to be the most suitable method for capturing the mixed layer depth for most shapes of temperature profiles. Mass mortalities events of benthic invertebrates have been identified by an extensive search of all data bases in ISI Web of Knowledge considering studies published from 1945 to 2011. Studies reporting the geographical coordinates, the timing of the events, the species involved and the depth at which signs of stress occurred have been considered. Results show a general increase of thickness and temperature of the mixed layer, deepening and cooling of the thermocline base in summer and autumn. Possible impacts of these changes are mass mortalities events of benthic invertebrates that have been documented since 1983 mainly in summer and autumn. It is also shown that most mass mortalities occurred in months with anomalously high mixed layer depth temperature leading to the conclusion that warming of upper Mediterranean Sea has allowed interannual temperature variability to reach environmental conditions beyond the thermal tolerance of some species.

A New Theory of Mix in Omega Capsule Implosions

NASA Astrophysics Data System (ADS)

Knoll, Dana; Chacon, Luis; Rauenzahn, Rick; Simakov, Andrei; Taitano, William; Welser-Sherrill, Leslie

2014-10-01

We put forth a new mix model that relies on the development of a charge-separation electrostatic double-layer at the fuel-pusher interface early in the implosion of an Omega plastic ablator capsule. The model predicts a sizable pusher mix (several atom %) into the fuel. The expected magnitude of the double-layer field is consistent with recent radial electric field measurements in Omega plastic ablator implosions. Our theory relies on two distinct physics mechanisms. First, and prior to shock breakout, the formation of a double layer at the fuel-pusher interface due to fast preheat-driven ionization. The double-layer electric field structure accelerates pusher ions fairly deep into the fuel. Second, after the double-layer mix has occurred, the inward-directed fuel velocity and temperature gradients behind the converging shock transports these pusher ions inward. We first discuss the foundations of this new mix theory. Next, we discuss our interpretation of the radial electric field measurements on Omega implosions. Then we discuss the second mechanism that is responsible for transporting the pusher material, already mixed via the double-layer deep into the fuel, on the shock convergence time scale. Finally we make a connection to recent mix motivated experimental data on. This work conducted under the auspices of the National Nuclear Security Administration of the U.S. Department of Energy at Los Alamos National Laboratory, managed by LANS, LLC under Contract DE-AC52-06NA25396.

Functioning of microbial complexes in aerated layers of a highmoor peat bog

NASA Astrophysics Data System (ADS)

Golovchenko, A. V.; Bogdanova, O. Yu.; Stepanov, A. L.; Polyanskaya, L. M.; Zvyagintsev, D. G.

2010-09-01

Monitoring was carried out using the luminescent-microscopic method of the abundance parameters of different groups of microorganisms in a monolith and in the mixed layers of a highmoor peat bog (oligotrophic residual-eutrophic peat soil) in a year-long model experiment. The increase of the aeration as a result of mixing of the layers enhanced the activity of the soil fungi. This was attested to by the following changes: the increase of the fungal mycelium length by 6 times and of the fungal biomass by 4 times and the double decrease of the fraction of spores in the fungal complex. The response of the fungal complex to mixing was different in the different layers of the peat bog. The maximal effect was observed in the T1 layer and the minimal one in the T2 layer. The emission of CO2 in the mixed samples was 1.5-2 times higher than that from the undisturbed peat samples. In contrast with the fungi, the bacteria and actinomycetes were not affected by the aeration of the highmoor layers.

Estimating diffusivity from the mixed layer heat and salt balances in the North Pacific

NASA Astrophysics Data System (ADS)

Cronin, M. F.; Pelland, N.; Emerson, S. R.; Crawford, W. R.

2015-12-01

Data from two National Oceanographic and Atmospheric Administration (NOAA) surface moorings in the North Pacific, in combination with data from satellite, Argo floats and glider (when available), are used to evaluate the residual diffusive flux of heat across the base of the mixed layer from the surface mixed layer heat budget. The diffusion coefficient (i.e., diffusivity) is then computed by dividing the diffusive flux by the temperature gradient in the 20-m transition layer just below the base of the mixed layer. At Station Papa in the NE Pacific subpolar gyre, this diffusivity is 1×10-4 m2/s during summer, increasing to ~3×10-4 m2/s during fall. During late winter and early spring, diffusivity has large errors. At other times, diffusivity computed from the mixed layer salt budget at Papa correlate with those from the heat budget, giving confidence that the results are robust for all seasons except late winter-early spring and can be used for other tracers. In comparison, at the Kuroshio Extension Observatory (KEO) in the NW Pacific subtropical recirculation gyre, somewhat larger diffusivity are found based upon the mixed layer heat budget: ~ 3×10-4 m2/s during the warm season and more than an order of magnitude larger during the winter, although again, wintertime errors are large. These larger values at KEO appear to be due to the increased turbulence associated with the summertime typhoons, and weaker wintertime stratification.

Estimating diffusivity from the mixed layer heat and salt balances in the North Pacific

NASA Astrophysics Data System (ADS)

Cronin, Meghan F.; Pelland, Noel A.; Emerson, Steven R.; Crawford, William R.

2015-11-01

Data from two National Oceanographic and Atmospheric Administration (NOAA) surface moorings in the North Pacific, in combination with data from satellite, Argo floats and glider (when available), are used to evaluate the residual diffusive flux of heat across the base of the mixed layer from the surface mixed layer heat budget. The diffusion coefficient (i.e., diffusivity) is then computed by dividing the diffusive flux by the temperature gradient in the 20 m transition layer just below the base of the mixed layer. At Station Papa in the NE Pacific subpolar gyre, this diffusivity is 1 × 10-4 m2/s during summer, increasing to ˜3 × 10-4 m2/s during fall. During late winter and early spring, diffusivity has large errors. At other times, diffusivity computed from the mixed layer salt budget at Papa correlate with those from the heat budget, giving confidence that the results are robust for all seasons except late winter-early spring and can be used for other tracers. In comparison, at the Kuroshio Extension Observatory (KEO) in the NW Pacific subtropical recirculation gyre, somewhat larger diffusivities are found based upon the mixed layer heat budget: ˜ 3 × 10-4 m2/s during the warm season and more than an order of magnitude larger during the winter, although again, wintertime errors are large. These larger values at KEO appear to be due to the increased turbulence associated with the summertime typhoons, and weaker wintertime stratification.

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...

Boundary layer ozone - An airborne survey above the Amazon Basin

NASA Technical Reports Server (NTRS)

Gregory, Gerald L.; Browell, Edward V.; Warren, Linda S.

1988-01-01

Ozone data obtained over the forest canopy of the Amazon Basin during July and August 1985 in the course of NASA's Amazon Boundary Layer Experiment 2A are discussed, and ozone profiles obtained during flights from Belem to Tabatinga, Brazil, are analyzed to determine any cross-basin effects. The analyses of ozone data indicate that the mixed layer of the Amazon Basin, for the conditions of undisturbed meteorology and in the absence of biomass burning, is a significant sink for tropospheric ozone. As the coast is approached, marine influences are noted at about 300 km inland, and a transition from a forest-controlled mixed layer to a marine-controlled mixed layer is noted.

Characterization of porcine eyes based on autofluorescence lifetime imaging

NASA Astrophysics Data System (ADS)

Batista, Ana; Breunig, Hans Georg; Uchugonova, Aisada; Morgado, António Miguel; König, Karsten

2015-03-01

Multiphoton microscopy is a non-invasive imaging technique with ideal characteristics for biological applications. In this study, we propose to characterize three major structures of the porcine eye, the cornea, crystalline lens, and retina using two-photon excitation fluorescence lifetime imaging microscopy (2PE-FLIM). Samples were imaged using a laser-scanning microscope, consisting of a broadband sub-15 femtosecond (fs) near-infrared laser. Signal detection was performed using a 16-channel photomultiplier tube (PMT) detector (PML-16PMT). Therefore, spectral analysis of the fluorescence lifetime data was possible. To ensure a correct spectral analysis of the autofluorescence lifetime data, the spectra of the individual endogenous fluorophores were acquired with the 16-channel PMT and with a spectrometer. All experiments were performed within 12h of the porcine eye enucleation. We were able to image the cornea, crystalline lens, and retina at multiple depths. Discrimination of each structure based on their autofluorescence intensity and lifetimes was possible. Furthermore, discrimination between different layers of the same structure was also possible. To the best of our knowledge, this was the first time that 2PE-FLIM was used for porcine lens imaging and layer discrimination. With this study we further demonstrated the feasibility of 2PE-FLIM to image and differentiate three of the main components of the eye and its potential as an ophthalmologic technique.

Using a hybrid model to predict solute transfer from initially saturated soil into surface runoff with controlled drainage water.

PubMed

Tong, Juxiu; Hu, Bill X; Yang, Jinzhong; Zhu, Yan

2016-06-01

The mixing layer theory is not suitable for predicting solute transfer from initially saturated soil to surface runoff water under controlled drainage conditions. By coupling the mixing layer theory model with the numerical model Hydrus-1D, a hybrid solute transfer model has been proposed to predict soil solute transfer from an initially saturated soil into surface water, under controlled drainage water conditions. The model can also consider the increasing ponding water conditions on soil surface before surface runoff. The data of solute concentration in surface runoff and drainage water from a sand experiment is used as the reference experiment. The parameters for the water flow and solute transfer model and mixing layer depth under controlled drainage water condition are identified. Based on these identified parameters, the model is applied to another initially saturated sand experiment with constant and time-increasing mixing layer depth after surface runoff, under the controlled drainage water condition with lower drainage height at the bottom. The simulation results agree well with the observed data. Study results suggest that the hybrid model can accurately simulate the solute transfer from initially saturated soil into surface runoff under controlled drainage water condition. And it has been found that the prediction with increasing mixing layer depth is better than that with the constant one in the experiment with lower drainage condition. Since lower drainage condition and deeper ponded water depth result in later runoff start time, more solute sources in the mixing layer are needed for the surface water, and larger change rate results in the increasing mixing layer depth.

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.

LIF measurements of scalar mixing in turbulent shear layers

NASA Technical Reports Server (NTRS)

Karasso, Paris S.; Mungal, M. G.

1993-01-01

The structure of shear layer flows at high Reynolds numbers remains a very interesting problem. Straight mixing layers have been studied and yielded information on the probability density function (pdf) of a passive scalar across the layer. Konrad and Koochesfahani & Dimotakis measured the pdf of the mixture fraction for mixing layers of moderate Reynolds numbers, each about 25,000 (Re based on velocity difference and visual thickness). Their measurements showed a 'non-marching' pdf (central hump which is invariant from edge to edge across the layer), a result which is linked to the visualizations of the spanwise Kelvin-Helmholtz (K-H) instability mode, which is the primary instability for plane shear layer flows. A secondary instability mode, the Taylor-Gortler (T-G) instability, which is associated with streamwise vortical structures, has also been observed in shear layers. Image reconstruction by Jimenez et al. and volume renderings by Karasso & Mungal at low Re numbers have demonstrated that the K-H and the T-G instability modes occur simultaneously in a non-mutually destructive way, evidence that supports the quasi two-dimensional aspect of these flows and the non-marching character of the pdf at low Reynolds numbers. At higher Re numbers though, the interaction of these two instability modes is still unclear and may affect the mixing process. In this study, we perform measurements of the concentration pdf of plane mixing layers for different operating conditions. At a speed ratio of r = U(sub 1)/U(sub 2) = 4:1, we examine three Reynolds number cases: Re = 14,000, Re = 31,000, and Re = 62,000. Some other Re number cases' results, not presented in detail, are invoked to explain the behavior of the pdf of the concentration field. A case of r = 2.6:1 at Re = 20,000 is also considered. The planar laser-induced fluorescence technique is used to yield quantitative measurements. The different Re are obtained by changing the velocity magnitudes of the two streams. The question of resolution of these measurements is addressed. In order to investigate the effects of the initial conditions on the development and the structure of the mixing layer, the boundary layer on the high-speed side of the splitter plate is tripped. The average concentration and the average mixed fluid concentration are also calculated to further understand the changes in the shear layer for the different cases examined.

Lidar Characterization of Boundary Layer Transport and Mixing for Estimating Urban-Scale Greenhouse Gas Emissions

NASA Astrophysics Data System (ADS)

Hardesty, R. Michael; Brewer, W. Alan; Sandberg, Scott P.; Weickmann, Ann M.; Shepson, Paul B.; Cambaliza, Maria; Heimburger, Alexie; Davis, Kenneth J.; Lauvaux, Thomas; Miles, Natasha L.; Sarmiento, Daniel P.; Deng, A. J.; Gaudet, Brian; Karion, Anna; Sweeney, Colm; Whetstone, James

2016-06-01

A compact commercial Doppler lidar has been deployed in Indianapolis for two years to measure wind profiles and mixing layer properties as part of project to improve greenhouse measurements from large area sources. The lidar uses vertical velocity variance and aerosol structure to measure mixing layer depth. Comparisons with aircraft and the NOAA HRDL lidar generally indicate good performance, although sensitivity might be an issue under low aerosol conditions.

Characteristics of the nocturnal boundary layer inferred from ozone measurements onboard a Zeppelin airship

NASA Astrophysics Data System (ADS)

Rohrer, Franz; Li, Xin; Hofzumahaus, Andreas; Ehlers, Christian; Holland, Frank; Klemp, Dieter; Lu, Keding; Mentel, Thomas F.; Kiendler-Scharr, Astrid; Wahner, Andreas

2014-05-01

The nocturnal boundary layer (NBL) is a sublayer within the planetary boundary layer (PBL) which evolves above solid land each day in the late afternoon due to radiation cooling of the surface. It is a region of several hundred meters thickness which inhibits vertical mixing. A residual and a surface layer remain above and below the NBL. Inside the surface layer, almost all direct emissions of atmospheric constituents take place during this time. This stratification lasts until the next morning after sunrise. Then, the heating of the surface generates a new convectionally mixed layer which successively eats up the NBL from below. This process lasts until shortly before noon when the NBL disappears completely and the PBL is mixed convectionally. Ozone measurements onboard a Zeppelin airship in The Netherlands, in Italy, and in Finland are used to analyse this behaviour with respect to atmospheric constituents and consequences for the diurnal cycles observed in the surface layer, the nocturnal boundary layer, and the residual layer are discussed.

Turbulent mixing layers in the interstellar medium of galaxies

NASA Technical Reports Server (NTRS)

Slavin, J. D.; Shull, J. M.; Begelman, M. C.

1993-01-01

We propose that turbulent mixing layers are common in the interstellar medium (ISM). Injection of kinetic energy into the ISM by supernovae and stellar winds, in combination with density and temperature inhomogeneities, results in shear flows. Such flows will become turbulent due to the high Reynolds number (low viscosity) of the ISM plasma. These turbulent boundary layers will be particularly interesting where the shear flow occurs at boundaries of hot (approximately 10(exp 6) K) and cold or warm (10(exp 2) - 10(exp 4) K) gas. Mixing will occur in such layers producing intermediate-temperature gas at T is approximately equal to 10(exp 5.0) - 10(exp 5.5) that radiates strongly in the optical, ultraviolet, and EUV. We have modeled these layers under the assumptions of rapid mixing down to the atomic level and steady flow. By including the effects of non-equilibrium ionization and self-photoionization of the gas as it cools after mixing, we predict the intensities of numerous optical, infrared, and ultraviolet emission lines, as well as absorption column densities of C 4, N 5, Si 4, and O 6.

The use of Argo for validation and tuning of mixed layer models

NASA Astrophysics Data System (ADS)

Acreman, D. M.; Jeffery, C. D.

We present results from validation and tuning of 1-D ocean mixed layer models using data from Argo floats and data from Ocean Weather Station Papa (145°W, 50°N). Model tests at Ocean Weather Station Papa showed that a bulk model could perform well provided it was tuned correctly. The Large et al. [Large, W.G., McWilliams, J.C., Doney, S.C., 1994. Oceanic vertical mixing: a review and a model with a nonlocal boundary layer parameterisation. Rev. Geophys. 32 (Novermber), 363-403] K-profile parameterisation (KPP) model also gave a good representation of mixed layer depth provided the vertical resolution was sufficiently high. Model tests using data from a single Argo float indicated a tendency for the KPP model to deepen insufficiently over an annual cycle, whereas the tuned bulk model and general ocean turbulence model (GOTM) gave a better representation of mixed layer depth. The bulk model was then tuned using data from a sample of Argo floats and a set of optimum parameters was found; these optimum parameters were consistent with the tuning at OWS Papa.

Tropical Cyclone Induced Air-Sea Interactions Over Oceanic Fronts

NASA Astrophysics Data System (ADS)

Shay, L. K.

2012-12-01

Recent severe tropical cyclones underscore the inherent importance of warm background ocean fronts and their interactions with the atmospheric boundary layer. Central to the question of heat and moisture fluxes, the amount of heat available to the tropical cyclone is predicated by the initial mixed layer depth and strength of the stratification that essentially set the level of entrainment mixing at the base of the mixed layer. In oceanic regimes where the ocean mixed layers are thin, shear-induced mixing tends to cool the upper ocean to form cold wakes which reduces the air-sea fluxes. This is an example of negative feedback. By contrast, in regimes where the ocean mixed layers are deep (usually along the western part of the gyres), warm water advection by the nearly steady currents reduces the levels of turbulent mixing by shear instabilities. As these strong near-inertial shears are arrested, more heat and moisture transfers are available through the enthalpy fluxes (typically 1 to 1.5 kW m-2) into the hurricane boundary layer. When tropical cyclones move into favorable or neutral atmospheric conditions, tropical cyclones have a tendency to rapidly intensify as observed over the Gulf of Mexico during Isidore and Lili in 2002, Katrina, Rita and Wilma in 2005, Dean and Felix in 2007 in the Caribbean Sea, and Earl in 2010 just north of the Caribbean Islands. To predict these tropical cyclone deepening (as well as weakening) cycles, coupled models must have ocean models with realistic ocean conditions and accurate air-sea and vertical mixing parameterizations. Thus, to constrain these models, having complete 3-D ocean profiles juxtaposed with atmospheric profiler measurements prior, during and subsequent to passage is an absolute necessity framed within regional scale satellite derived fields.

Airborne lidar observations of long-range transport in the free troposphere

NASA Technical Reports Server (NTRS)

Shipley, S. T.; Browell, E. V.; Mcdougal, D. S.; Orndorff, B. L.; Haagenson, P.

1984-01-01

Airborne lidar measurements of ozone and aerosols in the lower troposphere show the presence of pollutant layers above the mixed layer. Two case studies are analyzed to identify probable source regions and mechanisms for material injection into the free troposphere above local mixed layers. An elevated haze/oxidant layer observed over South Carolina on Aug. 2, 1980, was found to originate in cumulus convection over Georgia on Aug. 1, 1980. An extensive haze/oxidant layer observed over southeastern Virginia on July 31, 1981, is shown to have been in contact with the New England mixed layer on July 30, 1981. This transported air mass is estimated to contribute approximately 30 percent of the ozone maximum measured at the surface in the Norfolk, VA, area on July 31, 1981. Such elevated 'reservoir' layers are transported over long ranges and are not detected by sensors which are confined to the surface.

Comparing Production and Placement of Warm-Mix Asphalt to Traditional Hot-Mix Asphalt for Constructing Airfield Pavements

DTIC Science & Technology

2013-08-01

Sasobit® STA 0+35 cross-section layer thicknesses as constructed............................... 36  Figure 50. Evotherm ™ center-line layer thicknesses...as constructed. ................................................ 37  Figure 51. Evotherm ™ STA 0+15 cross-section layer thicknesses as constructed...37  Figure 52. Evotherm ™ STA 0+25 cross-section layer thicknesses as constructed. .......................... 38  Figure 53

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

A numerical study of mixing enhancement in supersonic reacting flow fields. [in scramjets

NASA Technical Reports Server (NTRS)

Drummond, J. Philip; Mukunda, H. S.

1988-01-01

NASA Langley has intensively investigated the components of ramjet and scramjet systems for endoatmospheric, airbreathing hypersonic propulsion; attention is presently given to the optimization of scramjet combustor fuel-air mixing and reaction characteristics. A supersonic, spatially developing and reacting mixing layer has been found to serve as an excellent physical model for the mixing and reaction process. Attention is presently given to techniques that have been applied to the enhancement of the mixing processes and the overall combustion efficiency of the mixing layer. A fuel injector configuration has been computationally designed which significantly increases mixing and reaction rates.

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

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.

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

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

Large Eddy Simulation of Heat Entrainment Under Arctic Sea Ice

NASA Astrophysics Data System (ADS)

Ramudu, Eshwan; Gelderloos, Renske; Yang, Di; Meneveau, Charles; Gnanadesikan, Anand

2018-01-01

Arctic sea ice has declined rapidly in recent decades. The faster than projected retreat suggests that free-running large-scale climate models may not be accurately representing some key processes. The small-scale turbulent entrainment of heat from the mixed layer could be one such process. To better understand this mechanism, we model the Arctic Ocean's Canada Basin, which is characterized by a perennial anomalously warm Pacific Summer Water (PSW) layer residing at the base of the mixed layer and a summertime Near-Surface Temperature Maximum (NSTM) within the mixed layer trapping heat from solar radiation. We use large eddy simulation (LES) to investigate heat entrainment for different ice-drift velocities and different initial temperature profiles. The value of LES is that the resolved turbulent fluxes are greater than the subgrid-scale fluxes for most of our parameter space. The results show that the presence of the NSTM enhances heat entrainment from the mixed layer. Additionally there is no PSW heat entrained under the parameter space considered. We propose a scaling law for the ocean-to-ice heat flux which depends on the initial temperature anomaly in the NSTM layer and the ice-drift velocity. A case study of "The Great Arctic Cyclone of 2012" gives a turbulent heat flux from the mixed layer that is approximately 70% of the total ocean-to-ice heat flux estimated from the PIOMAS model often used for short-term predictions. Present results highlight the need for large-scale climate models to account for the NSTM layer.

Mixing Layer Formation near the Tropopause Due to Gravity Wave Critical Level Interactions in a Cloud-Resolving Model.

NASA Astrophysics Data System (ADS)

Moustaoui, Mohamed; Joseph, Binson; Teitelbaum, Hector

2004-12-01

A plausible mechanism for the formation of mixing layers in the lower stratosphere above regions of tropical convection is demonstrated numerically using high-resolution, two-dimensional (2D), anelastic, nonlinear, cloud-resolving simulations. One noteworthy point is that the mixing layer simulated in this study is free of anvil clouds and well above the cloud anvil top located in the upper troposphere. Hence, the present mechanism is complementary to the well-known process by which overshooting cloud turrets causes mixing within stratospheric anvil clouds. The paper is organized as a case study verifying the proposed mechanism using atmospheric soundings obtained during the Central Equatorial Pacific Experiment (CEPEX), when several such mixing layers, devoid of anvil clouds, had been observed. The basic dynamical ingredient of the present mechanism is (quasi stationary) gravity wave critical level interactions, occurring in association with a reversal of stratospheric westerlies to easterlies below the tropopause region. The robustness of the results is shown through simulations at different resolutions. The insensitivity of the qualitative results to the details of the subgrid scheme is also evinced through further simulations with and without subgrid mixing terms. From Lagrangian reconstruction of (passive) ozone fields, it is shown that the mixing layer is formed kinematically through advection by the resolved-scale (nonlinear) velocity field.

Receptivity to Unsteady Disturbances at the Trailing Edge in a Finite-Width Mixing Layer Flow.

NASA Astrophysics Data System (ADS)

Rabchuk, James Allen

1995-01-01

A theoretical study of the receptivity to harmonic disturbances at the trailing edge of a finite-width mixing layer has been carried out. The unsteady Kutta condition at the trailing edge has been reexamined at the vorticity scale of the steady mixing layer profile, and the underlying physical mechanism of this condition explained. The receptivity problem of harmonic forcing at the trailing edge is shown to reduce to an initial-value problem for the downstream mixing layer or wake. A linear coupling term for the response field amplitude is derived which is proportional to the square root of the Strouhal number and the difference in the gradient of the forcing pressure field tangential to the plate near the trailing edge. An initial-value problem is then solved for an inviscid, incompressible mixing layer with a piecewise linear velocity profile leaving the trailing edge of a flat plate, subject to harmonic forcing. The Wiener-Hopf technique is used to solve for the stream function of the response field over a range of forcing frequencies and mean flow velocities. The solutions are shown to agree with previous solutions for infinitesimally thin shear layers from Bechert, 1988 and Orszag and Crow, 1970, in the limit that the Strouhal number relative to the mixing layer thickness, S, is small. In addition, solutions are obtained for moderate values of S, for which the mixing layer is most unstable. It is shown that for increasing S, the initial amplitudes of the discrete modes of instability decrease like 1 over S and then level off, while the neutrally stable mode of response is increasingly amplified. It is also shown that the overall phase of the response is nearly independent of S, except at a cross-stream position where the phase shifts by 180 degrees and the amplitude of the response goes to zero, which moves from the low to the high speed flow as S increases.

The role of ice nuclei recycling in the maintenance of cloud ice in Arctic mixed-phase stratocumulus

DOE PAGES

Solomon, Amy; Feingold, G.; Shupe, M. D.

2015-09-25

This study investigates the maintenance of cloud ice production in Arctic mixed-phase stratocumulus in large eddy simulations that include a prognostic ice nuclei (IN) formulation and a diurnal cycle. Balances derived from a mixed-layer model and phase analyses are used to provide insight into buffering mechanisms that maintain ice in these cloud systems. We find that, for the case under investigation, IN recycling through subcloud sublimation considerably prolongs ice production over a multi-day integration. This effective source of IN to the cloud dominates over mixing sources from above or below the cloud-driven mixed layer. Competing feedbacks between dynamical mixing andmore » recycling are found to slow the rate of ice lost from the mixed layer when a diurnal cycle is simulated. Furthermore, the results of this study have important implications for maintaining phase partitioning of cloud ice and liquid that determine the radiative forcing of Arctic mixed-phase clouds.« less

The role of ice nuclei recycling in the maintenance of cloud ice in Arctic mixed-phase stratocumulus

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

Solomon, Amy; Feingold, G.; Shupe, M. D.

This study investigates the maintenance of cloud ice production in Arctic mixed-phase stratocumulus in large eddy simulations that include a prognostic ice nuclei (IN) formulation and a diurnal cycle. Balances derived from a mixed-layer model and phase analyses are used to provide insight into buffering mechanisms that maintain ice in these cloud systems. We find that, for the case under investigation, IN recycling through subcloud sublimation considerably prolongs ice production over a multi-day integration. This effective source of IN to the cloud dominates over mixing sources from above or below the cloud-driven mixed layer. Competing feedbacks between dynamical mixing andmore » recycling are found to slow the rate of ice lost from the mixed layer when a diurnal cycle is simulated. Furthermore, the results of this study have important implications for maintaining phase partitioning of cloud ice and liquid that determine the radiative forcing of Arctic mixed-phase clouds.« less

A new method for estimating the turbulent heat flux at the bottom of the daily mixed layer

NASA Technical Reports Server (NTRS)

Imawaki, Shiro; Niiler, Pearn P.; Gautier, Catherine H.; Knox, Robert A.; Halpern, David

1988-01-01

Temperature data in the mixed layer and net solar irradiance data at the sea surface are used to estimate the vertical turbulent heat flux at the bottom of the daily mixed layer. The method is applied to data obtained in the eastern tropical Pacific, where the daily cycle in the temperature field is confined to the upper 10-25 m. Equatorial turbulence measurements indicate that the turbulent heat flux is much greater during nighttime than daytime.

The turblent mixing layer - Geometry of large vortices

NASA Astrophysics Data System (ADS)

Browand, F. K.; Troutt, T. R.

1985-09-01

Large spanwide vortices in a mixing layer have been studied in numerous investigations. The present study represents an attempt to define the geometry of the large vortices. In the conducted experiments, the flow develops from a laminar boundary layer, or from an intentionally tripped turbulent boundary layer. However, no other forcing is provided. It is pointed out that in both cases the downstream structure becomes indistinguishable. The experimental apparatus and the employed techniques are discussed, taking into account details regarding the wind tunnel, the detection of the structure, and aspects of digitization. Attention is given to the mean growth of the mixing layer, the mean vortex spacing, the spanwise correlation of vortex structure, velocity-field visualizations, the transition criterion, and the permanence of structure.

Radon Measurements of Atmospheric Mixing (RAMIX) 2006–2014 Final Campaign Summary

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

Fischer, ML; Biraud, SC

2015-05-01

Uncertainty in vertical mixing between the surface layer, boundary layer, and free troposphere leads to large uncertainty in “top-down” estimates of regional land-atmosphere carbon exchange (i.e., estimates based on measurements of atmospheric CO2 mixing ratios. Radon-222 (222Rn) is a valuable tracer for measuring atmospheric mixing because it is emitted from the land surface and has a short enough half-life (3.8 days) to allow characterization of mixing processes based on vertical profile measurements.

Radon Measurements of Atmospheric Mixing (RAMIX) 2006–2014 Final Campaign Summary

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

Fischer, ML; Biraud, SC; Hirsch, A

2015-05-01

Uncertainty in vertical mixing between the surface layer, boundary layer, and free troposphere leads to large uncertainty in “top-down” estimates of regional land-atmosphere carbon exchange (i.e., estimates based on measurements of atmospheric CO 2 mixing ratios). The radioisotope radon-222 ( 222Rn) is a valuable tracer for measuring atmospheric mixing because it is emitted from the land surface and has a short enough half-life (3.8 days) to allow characterization of mixing processes based on vertical profile measurements.

A perspective view of the plane mixing layer

NASA Technical Reports Server (NTRS)

Jimenez, J.; Cogollos, M.; Bernal, L. P.

1984-01-01

A three-dimensional model of the plane mixing layer is constructed by applying digital image processing and computer graphic techniques to laser fluorescent motion pictures of its transversal sections. A system of streamwise vortex pairs is shown to exist on top of the classical spanwise eddies. Its influence on mixing is examined.

Temperature-Dependent Helium Ion-Beam Mixing in an Amorphous SiOC/Crystalline Fe Composite

DOE PAGES

Su, Qing; Price, Lloyd; Shao, Lin; ...

2016-10-31

Temperature dependent He-irradiation-induced ion-beam mixing between amorphous silicon oxycarbide (SiOC) and crystalline Fe was examined with a transmission electron microscope (TEM) and via Rutherford backscattering spectrometry (RBS). The Fe marker layer (7.2 ± 0.8 nm) was placed in between two amorphous SiOC layers (200 nm). The amount of ion-beam mixing after 298, 473, 673, 873, and 1073 K irradiation was investigated. Both TEM and RBS results showed no ion-beam mixing between Fe and SiOC after 473 and 673 K irradiation and a very trivial amount of ion-beam mixing (~2 nm) after 298 K irradiation. At irradiation temperatures higher than 873more » K, the Fe marker layer broke down and RBS could no longer be used to quantitatively examine the amount of ion mixing. The results indicate that the Fe/SiOC nanocomposite is thermally stable and tends to demix in the temperature range from 473 to 673 K. For application of this composite structure at temperatures of 873 K or higher, layer stability is a key consideration.« less

Numerical Investigation of a Cavitating Mixing Layer of Liquefied Natural Gas (LNG) Behind a Flat Plate Splitter

NASA Astrophysics Data System (ADS)

Rahbarimanesh, Saeed; Brinkerhoff, Joshua

2017-11-01

The mutual interaction of shear layer instabilities and phase change in a two-dimensional cryogenic cavitating mixing layer is investigated using a numerical model. The developed model employs the homogeneous equilibrium mixture (HEM) approach in a density-based framework to compute the temperature-dependent cavitation field for liquefied natural gas (LNG). Thermal and baroclinic effects are captured via iterative coupled solution of the governing equations with dynamic thermophysical models that accurately capture the properties of LNG. The mixing layer is simulated for vorticity-thickness Reynolds numbers of 44 to 215 and cavitation numbers of 0.1 to 1.1. Attached cavity structures develop on the splitter plate followed by roll-up of the separated shear layer via the well-known Kelvin-Helmholtz mode, leading to streamwise accumulation of vorticity and eventual shedding of discrete vortices. Cavitation occurs as vapor cavities nucleate and grow from the low-pressure cores in the rolled-up vortices. Thermal effects and baroclinic vorticity production are found to have significant impacts on the mixing layer instability and cavitation processes.

Vacuum-deposited polymer/silver reflector material

NASA Astrophysics Data System (ADS)

Affinito, John D.; Martin, Peter M.; Gross, Mark E.; Bennett, Wendy D.

1994-09-01

Weatherable, low cost, front surface, solar reflectors on flexible substrates would be highly desirable for lamination to solar concentrator panels. The method to be described in this paper may permit such reflector material to be fabricated for less the 50$CNT per square foot. Vacuum deposited Polymer/Silver/Polymer reflectors and Fabry-Perot interference filters were fabricated in a vacuum web coating operation on polyester substrates. Reflectivities were measured in the wavelength range from .4 micrometers to .8 micrometers . It is hoped that a low cost substrate can be used with the substrate laminated to the concentrator and the weatherable acrylic polymer coating facing the sun. This technique should be capable of deposition line speeds approaching 1500 linear feet/minute2. Central to this technique is a new vacuum deposition process for the high rate deposition of polymer films. This polymer process involves the flash evaporation of an acrylic monomer onto a moving substrate. The monomer is subsequently cured by an electron beam or ultraviolet light. This high speed polymer film deposition process has been named the PML process- for Polymer Multi- Layer.

The use of 2D and 3D WA-BPM models to analyze total-internal-reflection-based integrated optical switches

NASA Astrophysics Data System (ADS)

Wang, Pengfei; Brambilla, Gilberto; Semenova, Yuliya; Wu, Qiang; Zheng, Jie; Farrell, Gerald

2011-08-01

The well known beam propagation method (BPM) has become one of the most useful, robust and effective numerical simulation tools for the investigation of guided-wave optics, for example integrated optical waveguides and fiber optic devices. In this paper we examine the use of the 2D and 3D wide angle-beam propagation method (WA-BPM) combined with the well known perfectly matched layer (PML) boundary conditions as a tool to analyze TIR based optical switches, in particular the relationship between light propagation and the geometrical parameters of a TIR based optical switch. To analyze the influence of the length and the width of the region in which the refractive index can be externally controlled, the 3D structure of a 2x2 TIR optical switch is firstly considered in 2D using the effective index method (EIM). Then the influence of the etching depth and the tilt angle of the reflection facet on the switch performance are investigated with a 3D model.

Research on radiation characteristic of plasma antenna through FDTD method.

PubMed

Zhou, Jianming; Fang, Jingjing; Lu, Qiuyuan; Liu, Fan

2014-01-01

The radiation characteristic of plasma antenna is investigated by using the finite-difference time-domain (FDTD) approach in this paper. Through using FDTD method, we study the propagation of electromagnetic wave in free space in stretched coordinate. And the iterative equations of Maxwell equation are derived. In order to validate the correctness of this method, we simulate the process of electromagnetic wave propagating in free space. Results show that electromagnetic wave spreads out around the signal source and can be absorbed by the perfectly matched layer (PML). Otherwise, we study the propagation of electromagnetic wave in plasma by using the Boltzmann-Maxwell theory. In order to verify this theory, the whole process of electromagnetic wave propagating in plasma under one-dimension case is simulated. Results show that Boltzmann-Maxwell theory can be used to explain the phenomenon of electromagnetic wave propagating in plasma. Finally, the two-dimensional simulation model of plasma antenna is established under the cylindrical coordinate. And the near-field and far-field radiation pattern of plasma antenna are obtained. The experiments show that the variation of electron density can introduce the change of radiation characteristic.

The effects of the laminar/turbulent boundary layer states on the development of a plane mixing layer

NASA Technical Reports Server (NTRS)

Foss, J. F.

1977-01-01

The effect of the laminar/turbulent boundary layer state on the mean and rms velocities of a developing plane mixing layer was investigated. The use of commonly accepted nondimensional representations of the data confirm (at least) an approximately self-preserving condition. It is suggested that the effects of the laminar/turbulent initial condition persist in the self-preserving region.

Tradeoffs in Chemical and Thermal Variations in the Post-perovskite Phase Transition: Mixed Phase Regions in the Deep Lower Mantle?

NASA Astrophysics Data System (ADS)

Giles, G. F.; Spera, F. J.; Yuen, D. A.

2005-12-01

The recent discovery of a phase-transition in Mg-rich perovskite (Pv) to a post-perovskite (pPv) phase at lower mantle depths and its relationship to D", lower mantle heterogeneity and iron content prompted an investigation of the relative importance of lower mantle (LM) compositional and temperature fluctuations in creating topographic undulations on mixed phase regions. Above the transition, Mg-rich Pv makes up ~70 percent by mass of the LM. Using results from experimental phase equilibria, first-principles computations and thermodynamic relations for Fe2+-Mg mixing in silicates, a preliminary thermodynamic model for the perovskite to post-perovskite phase transition in the divariant system MgSiO3-FeSiO3 is developed. Complexities associated with components Fe2O3 and Al2O3 and other phases (Ca-Pv, magnesiowustite) are neglected. The model predicts phase transition pressures are sensitive to the FeSiO3 content of perovskite (~-1.5 GPa per one mole percent FeSiO3). This leads to considerable topography along the top boundary of the mixed phase region. The Clapeyron slope for the Pv to pPv transition at XFeSiO3=0.1 is +11 MPa/K about 20% higher than for pure Mg-Pv. Increasing bulk concentration of iron elevates the mixed (two-phase) layer above the core-mantle boundary (CMB); increasing temperature acts to push the mixed layer deeper into the LM into the D" thermal boundary layer resting upon the (CMB). For various LM geotherms and CMB temperatures, a single mixed layer of thickness ~300 km lies within the bottom 40% of the lower mantle. For low iron contents (XFeSiO3 ~5 mole percent or less), two perched layers are found. This is the divariant analog to the univariant double-crosser. The hotter the mantle, the deeper the mixed phase layer; the more iron-rich the LM, the higher the mixed phase layer. In a hotter Hadean Earth with interior temperatures everywhere 200-500 K warmer pPv is not stable unless the LM bulk composition is Fe-enriched compared to the present upper mantle.

Modulating surface rheology by electrostatic protein/polysaccharide interactions.

PubMed

Ganzevles, Renate A; Zinoviadou, Kyriaki; van Vliet, Ton; Cohen, Martien A; de Jongh, Harmen H

2006-11-21

There is a large interest in mixed protein/polysaccharide layers at air-water and oil-water interfaces because of their ability to stabilize foams and emulsions. Mixed protein/polysaccharide adsorbed layers at air-water interfaces can be prepared either by adsorption of soluble protein/polysaccharide complexes or by sequential adsorption of complexes or polysaccharides to a previously formed protein layer. Even though the final protein and polysaccharide bulk concentrations are the same, the behavior of the adsorbed layers can be very different, depending on the method of preparation. The surface shear modulus of a sequentially formed beta-lactoglobulin/pectin layer can be up to a factor of 6 higher than that of a layer made by simultaneous adsorption. Furthermore, the surface dilatational modulus and surface shear modulus strongly (up to factors of 2 and 7, respectively) depend on the bulk -lactoglobulin/pectin mixing ratio. On the basis of the surface rheological behavior, a mechanistic understanding of how the structure of the adsorbed layers depends on the protein/polysaccharide interaction in bulk solution, mixing ratio, ionic strength, and order of adsorption to the interface (simultaneous or sequential) is derived. Insight into the effect of protein/polysaccharide interactions on the properties of adsorbed layers provides a solid basis to modulate surface rheological behavior.

The Vertical Dust Profile over Gale Crater

NASA Astrophysics Data System (ADS)

Guzewich, S.; Newman, C. E.; Smith, M. D.; Moores, J.; Smith, C. L.; Moore, C.; Richardson, M. I.; Kass, D. M.; Kleinboehl, A.; Martin-Torres, F. J.; Zorzano, M. P.; Battalio, J. M.

2017-12-01

Regular joint observations of the atmosphere over Gale Crater from the orbiting Mars Reconnaissance Orbiter/Mars Climate Sounder (MCS) and Mars Science Laboratory (MSL) Curiosity rover allow us to create a coarse, but complete, vertical profile of dust mixing ratio from the surface to the upper atmosphere. We split the atmospheric column into three regions: the planetary boundary layer (PBL) within Gale Crater that is directly sampled by MSL (typically extending from the surface to 2-6 km in height), the region of atmosphere sampled by MCS profiles (typically 25-80 km above the surface), and the region of atmosphere between these two layers. Using atmospheric optical depth measurements from the Rover Environmental Monitoring System (REMS) ultraviolet photodiodes (in conjunction with MSL Mast Camera solar imaging), line-of-sight opacity measurements with the MSL Navigation Cameras (NavCam), and an estimate of the PBL depth from the MarsWRF general circulation model, we can directly calculate the dust mixing ratio within the Gale Crater PBL and then solve for the dust mixing ratio in the middle layer above Gale Crater but below the atmosphere sampled by MCS. Each atmospheric layer has a unique seasonal cycle of dust opacity, with Gale Crater's PBL reaching a maximum in dust mixing ratio near Ls = 270° and a minimum near Ls = 90°. The layer above Gale Crater, however, has a seasonal cycle that closely follows the global opacity cycle and reaches a maximum near Ls = 240° and exhibits a local minimum (associated with the "solsticial pauses") near Ls = 270°. Knowing the complete vertical profile also allows us to determine the frequency of high-altitude dust layers above Gale, and whether such layers truly exhibit the maximum dust mixing ratio within the entire vertical column. We find that 20% of MCS profiles contain an "absolute" high-altitude dust layer, i.e., one in which the dust mixing ratio within the high-altitude dust layer is the maximum dust mixing ratio in the vertical column of atmosphere over Gale Crater.

A random distribution reacting mixing layer model

NASA Technical Reports Server (NTRS)

Jones, Richard A.; Marek, C. John; Myrabo, Leik N.; Nagamatsu, Henry T.

1994-01-01

A methodology for simulation of molecular mixing, and the resulting velocity and temperature fields has been developed. The ideas are applied to the flow conditions present in the NASA Lewis Research Center Planar Reacting Shear Layer (PRSL) facility, and results compared to experimental data. A gaussian transverse turbulent velocity distribution is used in conjunction with a linearly increasing time scale to describe the mixing of different regions of the flow. Equilibrium reaction calculations are then performed on the mix to arrive at a new species composition and temperature. Velocities are determined through summation of momentum contributions. The analysis indicates a combustion efficiency of the order of 80 percent for the reacting mixing layer, and a turbulent Schmidt number of 2/3. The success of the model is attributed to the simulation of large-scale transport of fluid. The favorable comparison shows that a relatively quick and simple PC calculation is capable of simulating the basic flow structure in the reacting and nonreacting shear layer present in the facility given basic assumptions about turbulence properties.

Implementation of a diffusion convection surface evolution model in WallDYN

NASA Astrophysics Data System (ADS)

Schmid, K.

2013-07-01

In thermonuclear fusion experiments with multiple plasma facing materials the formation of mixed materials is inevitable. The formation of these mixed material layers is a dynamic process driven the tight interaction between transport in the plasma scrape off layer and erosion/(re-) deposition at the surface. To track this global material erosion/deposition balance and the resulting formation of mixed material layers the WallDYN code has been developed which couples surface processes and plasma transport. The current surface model in WallDYN cannot fully handle the growth of layers nor does it include diffusion. However at elevated temperatures diffusion is a key process in the formation of mixed materials. To remedy this shortcoming a new surface model has been developed which, for the first time, describes both layer growth/recession and diffusion in a single continuous diffusion/convection equation. The paper will detail the derivation of the new surface model and compare it to TRIDYN calculations.

High static stability in the mixing layer above the extratropical tropopause

NASA Astrophysics Data System (ADS)

Kunz, A.; Konopka, P.; Müller, R.; Pan, L. L.; Schiller, C.; Rohrer, F.

2009-08-01

The relationship between the static stability N2 and the mixing in the tropopause inversion layer (TIL) is investigated using in situ aircraft observations during SPURT (trace gas transport in the tropopause region). With a new simple measure of mixing degree based on O3-CO tracer correlations, high N2 related to an enhanced mixing in the extratropical mixing layer is found. This relation becomes even more pronounced if fresh mixing events are excluded, indicating that mixing within the TIL occurs on a larger than synoptic timescale. A temporal variance analysis of N2 suggests that processes responsible for the composition of the TIL take place on seasonal timescales. Using radiative transfer calculations, we simulate the influence of a change in O3 and H2O vertical gradients on the temperature gradient and thus on the static stability above the tropopause, which are contrasted in an idealized nonmixed atmosphere and in a reference mixed atmosphere. The results show that N2 increases with enhanced mixing degree near the tropopause. At the same time, the temperature above the tropopause decreases together with the development of an inversion and the TIL. In the idealized case of nonmixed profiles the TIL vanishes. Furthermore, the results suggest that H2O plays a major role in maintaining the temperature inversion and the TIL structure compared to O3. The results substantiate the link between the extratropical mixing layer and the TIL.

A molecular dynamics study of the role of pressure on the response of reactive materials to thermal initiation

NASA Astrophysics Data System (ADS)

Weingarten, N. Scott; Mattson, William D.; Yau, Anthony D.; Weihs, Timothy P.; Rice, Betsy M.

2010-05-01

To elucidate the mechanisms of energy release in a reacting nickel/aluminum bilayer, we simulate the exothermic alloying reactions using both microcanonical and isoenthalpic-isobaric molecular dynamics simulations and an embedded-atom method type potential. The mechanism of the mixing consists of a sequence of steps in which mixing and reaction first occurs at the interface; the resulting heat generated from the mixing then melts the Al layer; subsequent mixing leads to further heat generation after which the Ni layer melts. The mixing continues until the alloying reactions are completed. The results indicate that pressure has a significant influence on the rates of atomic mixing and alloying reactions. Local pressures and temperatures within the individual layers at the time of melting are calculated, and these results are compared with the pressure-dependent melting curves determined for pure Al and pure Ni using this interaction potential.

Simulation of the planetary boundary layer with the UCLA general circulation model

NASA Technical Reports Server (NTRS)

Suarez, M. J.; Arakawa, A.; Randall, D. A.

1981-01-01

A planetary boundary layer (PBL) model is presented which employs a mixed layer entrainment formulation to describe the mass exchange between the mixed layer with the upper, laminar atmosphere. A modified coordinate system couples the mixed layer model with large scale and sub-grid scale processes of a general circulation model. The vertical coordinate is configured as a sigma coordinate with the lower boundary, the top of the PBL, and the prescribed pressure level near the tropopause expressed as coordinate surfaces. The entrainment mass flux is parameterized by assuming the dissipation rate of turbulent kinetic energy to be proportional to the positive part of the generation by convection or mechanical production. The results of a simulation of July are presented for the entire globe.

Black carbon solar absorption suppresses turbulence in the atmospheric boundary layer.

PubMed

Wilcox, Eric M; Thomas, Rick M; Praveen, Puppala S; Pistone, Kristina; Bender, Frida A-M; Ramanathan, Veerabhadran

2016-10-18

The introduction of cloud condensation nuclei and radiative heating by sunlight-absorbing aerosols can modify the thickness and coverage of low clouds, yielding significant radiative forcing of climate. The magnitude and sign of changes in cloud coverage and depth in response to changing aerosols are impacted by turbulent dynamics of the cloudy atmosphere, but integrated measurements of aerosol solar absorption and turbulent fluxes have not been reported thus far. Here we report such integrated measurements made from unmanned aerial vehicles (UAVs) during the CARDEX (Cloud Aerosol Radiative Forcing and Dynamics Experiment) investigation conducted over the northern Indian Ocean. The UAV and surface data reveal a reduction in turbulent kinetic energy in the surface mixed layer at the base of the atmosphere concurrent with an increase in absorbing black carbon aerosols. Polluted conditions coincide with a warmer and shallower surface mixed layer because of aerosol radiative heating and reduced turbulence. The polluted surface mixed layer was also observed to be more humid with higher relative humidity. Greater humidity enhances cloud development, as evidenced by polluted clouds that penetrate higher above the top of the surface mixed layer. Reduced entrainment of dry air into the surface layer from above the inversion capping the surface mixed layer, due to weaker turbulence, may contribute to higher relative humidity in the surface layer during polluted conditions. Measurements of turbulence are important for studies of aerosol effects on clouds. Moreover, reduced turbulence can exacerbate both the human health impacts of high concentrations of fine particles and conditions favorable for low-visibility fog events.

Black carbon solar absorption suppresses turbulence in the atmospheric boundary layer

PubMed Central

Wilcox, Eric M.; Thomas, Rick M.; Praveen, Puppala S.; Pistone, Kristina; Bender, Frida A.-M.; Ramanathan, Veerabhadran

2016-01-01

The introduction of cloud condensation nuclei and radiative heating by sunlight-absorbing aerosols can modify the thickness and coverage of low clouds, yielding significant radiative forcing of climate. The magnitude and sign of changes in cloud coverage and depth in response to changing aerosols are impacted by turbulent dynamics of the cloudy atmosphere, but integrated measurements of aerosol solar absorption and turbulent fluxes have not been reported thus far. Here we report such integrated measurements made from unmanned aerial vehicles (UAVs) during the CARDEX (Cloud Aerosol Radiative Forcing and Dynamics Experiment) investigation conducted over the northern Indian Ocean. The UAV and surface data reveal a reduction in turbulent kinetic energy in the surface mixed layer at the base of the atmosphere concurrent with an increase in absorbing black carbon aerosols. Polluted conditions coincide with a warmer and shallower surface mixed layer because of aerosol radiative heating and reduced turbulence. The polluted surface mixed layer was also observed to be more humid with higher relative humidity. Greater humidity enhances cloud development, as evidenced by polluted clouds that penetrate higher above the top of the surface mixed layer. Reduced entrainment of dry air into the surface layer from above the inversion capping the surface mixed layer, due to weaker turbulence, may contribute to higher relative humidity in the surface layer during polluted conditions. Measurements of turbulence are important for studies of aerosol effects on clouds. Moreover, reduced turbulence can exacerbate both the human health impacts of high concentrations of fine particles and conditions favorable for low-visibility fog events. PMID:27702889

Helicity in supercritical temporal mixing layers

NASA Technical Reports Server (NTRS)

Bellan, J.; Okong'o, N.

2003-01-01

Databases of transitional states obtained from Direct Numerical Simulations (DNS) of temporal, supercritical mixing layers for two species systems, 02/H2 and C7Hle/N2, are analyzed to elucidate species-specific turbulence aspects.

Heat and salt budgets over the Gulf Stream North Wall during LatMix survey in winter 2012.

NASA Astrophysics Data System (ADS)

Sanchez-Rios, A.; Shearman, R. K.; D'Asaro, E. A.; Lee, C.; Gula, J.; Klymak, J. M.

2016-02-01

As part of the ONR-sponsored LatMix Experiment, ship-based and glider-based observations following a Lagrangian float are used to examine the evolution of temperature, salinity and density along the Gulf Stream north wall in wintertime. Satellite observations during the survey and the in-situ measurements showed the presence of submesoscale (<10 km) features along the front. Models have successfully reproduced similar features, but observations are lacking, particularly at the small scales needed to understand their role in the transport of heat and salt across the front and out of the mixed layer. Calculating the trend in time at each depth and cross-front location we found an increase of heat and salinity in regions where the strongest cross-front gradients of velocity were observed at the mixed layer and around 150m depth, these changes are density compensated and suggest isopycnal mixing and a connection between the mixed layer and subsurface layers. The large Rossby number (Ro>1) calculated for this regions corroborates the possibility of submesoscale dynamics. Using a heat and salinity budget, we show that surface forcing, entrainment from below and advection by the mean flow velocities are not sufficient to explain the observed rate of change of heat and salinity in the mixed layer. Although confidence estimates prevent an accurate flux divergence calculation, Reynold flux estimates are consistent with a cross-frontal exchange that can reproduce the observed temporal trends.

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.

Tests of Parameterized Langmuir Circulation Mixing in the Oceans Surface Mixed Layer II

DTIC Science & Technology

2017-08-11

inertial oscillations in the ocean are governed by three-dimensional processes that are not accounted for in a one-dimensional simulation , and it was...Unlimited 52 Paul Martin (228) 688-5447 Recent large-eddy simulations (LES) of Langmuir circulation (LC) within the surface mixed layer (SML) of...used in the Navy Coastal Ocean Model (NCOM) and tested for (a) a simple wind-mixing case, (b) simulations of the upper ocean thermal structure at Ocean

Development of the CD symcap platform to study gas-shell mix in implosions at the National Ignition Facility

DOE PAGES

Casey, D. T.; Smalyuk, V. A.; Tipton, R. E.; ...

2014-09-09

Surrogate implosions play an important role at the National Ignition Facility (NIF) for isolating aspects of the complex physical processes associated with fully integrated ignition experiments. The newly developed CD Symcap platform has been designed to study gas-shell mix in indirectly driven, pure T₂-gas filled CH-shell implosions equipped with 4 μm thick CD layers. This configuration provides a direct nuclear signature of mix as the DT yield (above a characterized D contamination background) is produced by D from the CD layer in the shell, mixing into the T-gas core. The CD layer can be placed at different locations within themore » CH shell to probe the depth and extent of mix. CD layers placed flush with the gas-shell interface and recessed up to 8 μm have shown that most of the mix occurs at the inner-shell surface. In addition, time-gated x-ray images of the hotspot show large brightly-radiating objects traversing through the hotspot around bang-time, which are likely chunks of CH/CD plastic. This platform is a powerful new capability at the NIF for understanding mix, one of the key performance issues for ignition experiments.« less

Use of screenings to produce HMA mixtures

DOT National Transportation Integrated Search

2002-10-01

Thin-lift hot mix asphalt (HMA) layers are utilized in almost every maintenance and rehabilitation application. These mix types require smaller maximum particle sizes than most conventional HMA surface layers. Although the primary functions of thin-l...

Defect-induced mix experiment for NIF

NASA Astrophysics Data System (ADS)

Schmitt, M. J.; Bradley, P. A.; Cobble, J. A.; Hsu, S. C.; Krasheninnikova, N. S.; Kyrala, G. A.; Magelssen, G. R.; Murphy, T. J.; Obrey, K. A.; Tregillis, I. L.; Wysocki, F. J.; Finnegan, S. M.

2013-11-01

The Defect Induced Mix Experiment (DIME-II) will measure the implosion and mix characteristics of CH capsules filled with 5 atmospheres of DT by incorporating mid-Z dopant layers of Ge and Ga. This polar direct drive (PDD) experiment also will demonstrate the filling of a CH capsule at target chamber center using a fill tube. Diagnostics for these experiments include areal x-ray backlighting to obtain early time images of the implosion trajectory and a multiple-monochromatic imager (MMI) to collect spectrally-resolved images of the capsule dopant line emission near bangtime. The inclusion of two (or more) thin dopant layers at separate depths within the capsule shell facilitates spatial correlation of mix between the layers and the hot gas core on a single shot. The dopant layers are typically 2 μm thick and contain dopant concentrations of 1.5%. Three dimensional Hydra simulations have been performed to assess the effects of PDD asymmetry on capsule performance.

Closing the Seasonal Ocean Surface Temperature Balance in the Eastern Tropical Oceans from Remote Sensing and Model Reanalyses

NASA Technical Reports Server (NTRS)

Roberts, J. Brent; Clayson, C. A.

2012-01-01

Residual forcing necessary to close the MLTB on seasonal time scales are largest in regions of strongest surface heat flux forcing. Identifying the dominant source of error - surface heat flux error, mixed layer depth estimation, ocean dynamical forcing - remains a challenge in the eastern tropical oceans where ocean processes are very active. Improved sub-surface observations are necessary to better constrain errors. 1. Mixed layer depth evolution is critical to the seasonal evolution of mixed layer temperatures. It determines the inertia of the mixed layer, and scales the sensitivity of the MLTB to errors in surface heat flux and ocean dynamical forcing. This role produces timing impacts for errors in SST prediction. 2. Errors in the MLTB are larger than the historical 10Wm-2 target accuracy. In some regions, a larger accuracy can be tolerated if the goal is to resolve the seasonal SST cycle.

LANL C10.2 Projects in FY13

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

Batha, Steven H.; Fincke, James R.; Schmitt, Mark J.

2012-06-07

LANL has two projects in C10.2: Defect-Induced Mix Experiment (DIME) (ongoing, several runs at Omega; NIF shots this summer); and Shock/Shear (tested at Omega for two years; NIF shots in second half of FY13). Each project is jointly funded by C10.2, other C10 MTEs, and Science Campaigns. DIME is investigating 4{pi} and feature-induced mix in spherically convergent ICF implosions by using imaging of the mix layer. DIME prepared for NIF by demonstrating its PDD mix platform on Omega including imaging mid-Z doped layers and defects. DIME in FY13 will focus on PDD symmetry-dependent mix and moving burn into the mixmore » region for validation of mix/burn models. Re-Shock and Shear are two laser-driven experiments designed to study the turbulent mixing of materials. In FY-2012 43 shear and re-shock experimental shots were executed on the OMEGA laser and a complete time history obtained for both. The FY-2013 goal is to transition the experiment to NIF where the larger scale will provide a longer time period for mix layer growth.« less

Similarity scaling of turbulence in small temperate lake: implication for gas flux: implication for gas flux

NASA Astrophysics Data System (ADS)

Tedford, E. W.; MacIntyre, S.; Miller, S. D.; Czikowsky, M. J.

2013-12-01

The actively mixing layer, or surface layer, is the region of the upper mixed layer of lakes, oceans and the atmosphere directly influenced by wind, heating and cooling. Turbulence within the surface mixing layer has a direct impact on important ecological processes. The Monin-Obukhov length scale (LMO) is a critical length scale used in predicting and understanding turbulence in the actively mixed layer. On the water side of the air-water interface, LMO is defined as: LMO=-u*^3/(0.4 JB0) where u*, the shear velocity, is defined as (τ/rho)^0.5 where τ is the shear stress and rho is the density of water and JBO is the buoyancy flux at the surface. Above the depth equal to the absolute value of the Monin-Obukhov length scale (zMO), wind shear is assumed to dominate the production of turbulent kinetic energy (TKE). Below zMO, the turbulence is assumed to be suppressed when JB0 is stabilizing (warming surface waters) and enhanced when the buoyancy flux is destabilizing (cooling surface waters). Our observed dissipations were well represented using the canonical similarity scaling equations. The Monin-Obukhov length scale was generally effective in separating the surface-mixing layer into two regions: an upper region, dominated by wind shear; and a lower region, dominated by buoyancy flux. During both heating and cooling and above a depth equal to |LMO|, turbulence was dominated by wind shear and dissipation followed law of the wall scaling although was slightly augmented by buoyancy flux during both heating and cooling. Below a depth equal to |LMO| during cooling, dissipation was nearly uniform with depth. Although distinguishing between an upper region of the actively mixing layer dominated by wind stress and a lower portion dominated by buoyancy flux is typically accurate the most accurate estimates of dissipation include the effects of both wind stress and buoyancy flux throughout the actively mixed layer. We demonstrate and discuss the impact of neglecting the non-dominant forcing (buoyancy flux above zMO and wind stress below zMO) above and below zMO.

Upper Ocean Mixing Processes and Circulation in the Arabian Sea during Monsoons using Remote Sensing, Hydrographic Observations and HYCOM Simulations

DTIC Science & Technology

2015-09-30

effecting the salinity of the upper layer and the formation of the barrier layer (BL) within the isothermal layer. The BL in turn controls vertical mixing...daily values over a month with a 1° horizontal resolution [Reynolds et al., 2002]. Daily data (from Coriolis project) and Monthly gridded Argo

Spatiotemporal Variability in Observations of Urban Mixed-Layer Heights from Surface-based Lidar Systems during DISCOVER-AQ 2011

NASA Astrophysics Data System (ADS)

Lewis, J. R.; Banks, R. F.; Berkoff, T.; Welton, E. J.; Joseph, E.; Thompson, A. M.; Decola, P.; Hegarty, J. D.

2015-12-01

Accurate characterization of the planetary boundary layer height is crucial for numerical weather prediction, estimating pollution emissions and modeling air quality. More so, given the increasing trend in global urban populations, there is a growing need to improve our understanding of the urban boundary layer structure and development. The Deriving Information on Surface conditions from COlumn and VERtically resolved observations relevant to Air Quality (DISCOVER-AQ) 2011 field campaign, which took place in the Baltimore-Washington DC region, offered a unique opportunity to study boundary layer processes in an urban area using a geographically dense collection of surface-based lidar systems (see figure). Lidars use aerosols as tracers for atmospheric boundary layer dynamics with high vertical and temporal resolutions. In this study, we use data from two permanent Micropulse Lidar Network (MPLNET) sites and five field deployed Micropulse lidar (MPL) systems in order to observe spatiotemporal variations in the daytime mixed layer height. We present and compare lidar-derived retrievals of the mixed layer height using two different methods. The first method uses the wavelet covariance transform and a "fuzzy logic" attribution scheme in order to determine the mixed layer height. The second method uses an objective approach utilizing a time-adaptive extended Kalman filter. Independent measurements of the boundary layer height are obtained using profiles from ozonesonde launches at the Beltsville and Edgewood sites for comparison with lidar observations.

Control of Evaporation Behavior of an Inkjet-Printed Dielectric Layer Using a Mixed-Solvent System

NASA Astrophysics Data System (ADS)

Yang, Hak Soon; Kang, Byung Ju; Oh, Je Hoon

2016-01-01

In this study, the evaporation behavior and the resulting morphology of inkjet-printed dielectric layers were controlled using a mixed-solvent system to fabricate uniform poly-4-vinylphenol (PVP) dielectric layers without any pinholes. The mixed-solvent system consisted of two different organic solvents: 1-hexanol and ethanol. The effects of inkjet-printing variables such as overlap condition, substrate temperature, and different printing sequences (continuous and interlacing printing methods) on the inkjet-printed dielectric layer were also investigated. Increasing volume fraction of ethanol (VFE) is likely to reduce the evaporation rate gradient and the drying time of the inkjet-printed dielectric layer; this diminishes the coffee stain effect and thereby improves the uniformity of the inkjet-printed dielectric layer. However, the coffee stain effect becomes more severe with an increase in the substrate temperature due to the enhanced outward convective flow. The overlap condition has little effect on the evaporation behavior of the printed dielectric layer. In addition, the interlacing printing method results in either a stronger coffee stain effect or wavy structures of the dielectric layers depending on the VFE of the PVP solution. All-inkjet-printed capacitors without electrical short circuiting can be successfully fabricated using the optimized PVP solution (VFE = 0.6); this indicates that the mixed-solvent system is expected to play an important role in the fabrication of high-quality inkjet-printed dielectric layers in various printed electronics applications.

Area production in supercritical, transitional mixing layers for reactive flow applications

NASA Technical Reports Server (NTRS)

Bellan, J.; Okong'o, N.

2002-01-01

An investigation of surface area production is conducted for supercritical mixing layers; the results are relevant to flame area evolution and fluid disintegration. In this study, the surface is chosen perpendicular to the mass fraction gradient.

Detailed characteristics of drop-laden mixing layers: LES predictions compared to DNS

NASA Technical Reports Server (NTRS)

Okong'o, N.; Leboissetier, A.; Bellan, J.

2004-01-01

Results have been compared from Direct Numerical Simulation (DNS) and Large Eddy Simulation (LES) of a temporal mixing layer laden with evaporating drops, to assess the ability of LES to reproduce detailed characteristics of DNS.

A Hybrid Numerical Method for Turbulent Mixing Layers. Degree awarded by Case Western Reserve Univ.

NASA Technical Reports Server (NTRS)

Georgiadis, Nicholas J.

2001-01-01

A hybrid method has been developed for simulations of compressible turbulent mixing layers. Such mixing layers dominate the flows in exhaust systems of modern day aircraft and also those of hypersonic vehicles currently under development. The method configurations in which a dominant structural feature provides an unsteady mechanism to drive the turbulent development in the mixing layer. The hybrid method uses a Reynolds-averaged Navier-Stokes (RANS) procedure to calculate wall bounded regions entering a mixing section, and a Large Eddy Simulation (LES) procedure to calculate the mixing dominated regions. A numerical technique was developed to enable the use of the hybrid RANS-LES method on stretched, non-Cartesian grids. Closure for the RANS equations was obtained using the Cebeci-Smith algebraic turbulence model in conjunction with the wall-function approach of Ota and Goldberg. The wall-function approach enabled a continuous computational grid from the RANS regions to the LES region. The LES equations were closed using the Smagorinsky subgrid scale model. The hybrid RANS-LES method is applied to a benchmark compressible mixing layer experiment. Preliminary two dimensional calculations are used to investigate the effects of axial grid density and boundary conditions. Vortex shedding from the base region of a splitter plate separating the upstream flows was observed to eventually transition to turbulence. The location of the transition, however, was much further downstream than indicated by experiments. Actual LES calculations, performed in three spatial directions, also indicated vortex shedding, but the transition to turbulence was found to occur much closer to the beginning of the mixing section. which is in agreement with experimental observations. These calculations demonstrated that LES simulations must be performed in three dimensions. Comparisons of time-averaged axial velocities and turbulence intensities indicated reasonable agreement with experimental data.

Validation of an ocean shelf model for the prediction of mixed-layer properties in the Mediterranean Sea west of Sardinia

NASA Astrophysics Data System (ADS)

Onken, Reiner

2017-04-01

The Regional Ocean Modeling System (ROMS) has been employed to explore the sensitivity of the forecast skill of mixed-layer properties to initial conditions, boundary conditions, and vertical mixing parameterisations. The initial and lateral boundary conditions were provided by the Mediterranean Forecasting System (MFS) or by the MERCATOR global ocean circulation model via one-way nesting; the initial conditions were additionally updated through the assimilation of observations. Nowcasts and forecasts from the weather forecast models COSMO-ME and COSMO-IT, partly melded with observations, served as surface boundary conditions. The vertical mixing was parameterised by the GLS (generic length scale) scheme Umlauf and Burchard (2003) in four different set-ups. All ROMS forecasts were validated against the observations which were taken during the REP14-MED survey to the west of Sardinia. Nesting ROMS in MERCATOR and updating the initial conditions through data assimilation provided the best agreement of the predicted mixed-layer properties with the time series from a moored thermistor chain. Further improvement was obtained by the usage of COSMO-ME atmospheric forcing, which was melded with real observations, and by the application of the k-ω vertical mixing scheme with increased vertical eddy diffusivity. The predicted temporal variability of the mixed-layer temperature was reasonably well correlated with the observed variability, while the modelled variability of the mixed-layer depth exhibited only agreement with the observations near the diurnal frequency peak. For the forecasted horizontal variability, reasonable agreement was found with observations from a ScanFish section, but only for the mesoscale wave number band; the observed sub-mesoscale variability was not reproduced by ROMS.

Mixed layer depths via Doppler lidar during low-level jet events

NASA Astrophysics Data System (ADS)

Carroll, Brian; Demoz, Belay; Bonin, Timothy; Delgado, Ruben

2018-04-01

A low-level jet (LLJ) is a prominent wind speed peak in the lower troposphere. Nocturnal LLJs have been shown to transport and mix atmospheric constituents from the residual layer down to the surface, breaching quiescent nocturnal conditions due to high wind shear. A new fuzzy logic algorithm combining turbulence and aerosol information from Doppler lidar scans can resolve the strength and depth of this mixing below the jet. Conclusions will be drawn about LLJ relations to turbulence and mixing.

Solid-state membrane module

DOEpatents

Gordon, John Howard [Salt Lake City, UT; Taylor, Dale M [Murray, UT

2011-06-07

Solid-state membrane modules comprising at least one membrane unit, where the membrane unit has a dense mixed conducting oxide layer, and at least one conduit or manifold wherein the conduit or manifold comprises a dense layer and at least one of a porous layer and a slotted layer contiguous with the dense layer. The solid-state membrane modules may be used to carry out a variety of processes including the separating of any ionizable component from a feedstream wherein such ionizable component is capable of being transported through a dense mixed conducting oxide layer of the membrane units making up the membrane modules. For ease of construction, the membrane units may be planar.

Relationship Between the Sonic Layer Depth and Mixed Layer Depth Identified from U.S. Navy Sea Glider Data

DTIC Science & Technology

2014-09-01

LAYER DEPTH AND MIXED LAYER DEPTH IDENTIFIED FROM U.S. NAVY SEA GLIDER DATA Vance A. Villarreal September 2014 Thesis Advisor: Peter C. Chu Second...searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments...DEPTH IDENTIFIED FROM U.S. NAVY SEA GLIDER DATA 5. FUNDING NUMBERS 6. AUTHOR(S) Vance A. Villarreal 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES

Numerical simulations of compressible mixing layers

NASA Technical Reports Server (NTRS)

Normand, Xavier

1990-01-01

Direct numerical simulations of two-dimensional temporally growing compressible mixing layers are presented. The Kelvin-Helmholtz instability is initially excited by a white-noise perturbation superimposed onto a hyperbolic tangent meanflow profile. The linear regime is studied at low resolution in the case of two flows of equal temperatures, for convective Mach numbers from 0.1 to 1 and for different values of the Reynolds number. At higher resolution, the complete evolution of a two-eddy mixing layer between two flows of different temperatures is simulated at moderate Reynolds number. Similarities and differences between flows of equal convective Mach numbers are discussed.

Photoionized Mixing Layer Models of the Diffuse Ionized Gas

NASA Astrophysics Data System (ADS)

Binette, Luc; Flores-Fajardo, Nahiely; Raga, Alejandro C.; Drissen, Laurent; Morisset, Christophe

2009-04-01

It is generally believed that O stars, confined near the galactic midplane, are somehow able to photoionize a significant fraction of what is termed the "diffuse ionized gas" (DIG) of spiral galaxies, which can extend up to 1-2 kpc above the galactic midplane. The heating of the DIG remains poorly understood, however, as simple photoionization models do not reproduce the observed line ratio correlations well or the DIG temperature. We present turbulent mixing layer (TML) models in which warm photoionized condensations are immersed in a hot supersonic wind. Turbulent dissipation and mixing generate an intermediate region where the gas is accelerated, heated, and mixed. The emission spectrum of such layers is compared with observations of Rand of the DIG in the edge-on spiral NGC 891. We generate two sequence of models that fit the line ratio correlations between [S II]/Hα, [O I]/Hα, [N II]/[S II], and [O III]/Hβ reasonably well. In one sequence of models, the hot wind velocity increases, while in the other, the ionization parameter and layer opacity increase. Despite the success of the mixing layer models, the overall efficiency in reprocessing the stellar UV is much too low, much less than 1%, which compels us to reject the TML model in its present form.

Effect of integrating straw into agricultural soils on soil infiltration and evaporation.

PubMed

Cao, Jiansheng; Liu, Changming; Zhang, Wanjun; Guo, Yunlong

2012-01-01

Soil water movement is a critical consideration for crop yield in straw-integrated fields. This study used an indoor soil column experiment to determine soil infiltration and evaporation characteristics in three forms of direct straw-integrated soils (straw mulching, straw mixing and straw inter-layering). Straw mulching is covering the land surface with straw. Straw mixing is mixing straw with the top 10 cm surface soil. Then straw inter-layering is placing straw at the 20 cm soil depth. There are generally good correlations among the mulch integration methods at p < 0.05, and with average errors/biases <10%. Straw mixing exhibited the best effect in terms of soil infiltration, followed by straw mulching. Due to over-burden weight-compaction effect, straw inter-layering somehow retarded soil infiltration. In terms of soil water evaporation, straw mulching exhibited the best effect. This was followed by straw mixing and then straw inter-layering. Straw inter-layering could have a long-lasting positive effect on soil evaporation as it limited the evaporative consumption of deep soil water. The responses of the direct straw integration modes to soil infiltration and evaporation could lay the basis for developing efficient water-conservation strategies. This is especially useful for water-scarce agricultural regions such as the arid/semi-arid regions of China.

Combustion Diagnostics and Flow Visualization of Hypergolic Combustion and Gelled Mixing Behavior

DTIC Science & Technology

1997-12-19

difference. Also, Exciplex Flourescence imaging has been implented to visualize diffusion layers which form at the contact interface of mixing...have been implemented and developed as a result of this effort. Among these techniques the most noteworthy involves a unique application of Exciplex ...fluorescence for visualization of diffusion layers formed between mixing liquids. Time resolved images of Exciplex fluorescence have been obtained

3D Orthorhombic Elastic Wave Propagation Pre-Test Simulation of SPE DAG-1 Test

NASA Astrophysics Data System (ADS)

Jensen, R. P.; Preston, L. A.

2017-12-01

A more realistic representation of many geologic media can be characterized as a dense system of vertically-aligned microfractures superimposed on a finely-layered horizontal geology found in shallow crustal rocks. This seismic anisotropy representation lends itself to being modeled as an orthorhombic elastic medium comprising three mutually orthogonal symmetry planes containing nine independent moduli. These moduli can be determined by observing (or prescribing) nine independent P-wave and S-wave phase speeds along different propagation directions. We have developed an explicit time-domain finite-difference (FD) algorithm for simulating 3D elastic wave propagation in a heterogeneous orthorhombic medium. The components of the particle velocity vector and the stress tensor are governed by a set of nine, coupled, first-order, linear, partial differential equations (PDEs) called the velocity-stress system. All time and space derivatives are discretized with centered and staggered FD operators possessing second- and fourth-order numerical accuracy, respectively. Additionally, we have implemented novel perfectly matched layer (PML) absorbing boundary conditions, specifically designed for orthorhombic media, to effectively suppress grid boundary reflections. In support of the Source Physics Experiment (SPE) Phase II, a series of underground chemical explosions at the Nevada National Security Site, the code has been used to perform pre-test estimates of the Dry Alluvium Geology - Experiment 1 (DAG-1). Based on literature searches, realistic geologic structure and values for orthorhombic P-wave and S-wave speeds have been estimated. Results and predictions from the simulations are presented.

Effect of initial conditions on constant pressure mixing between two turbulent streams

NASA Astrophysics Data System (ADS)

Kangovi, S.

1983-02-01

It is pointed out that a study of the process of mixing between two dissimilar streams has varied applications in different fields. The applications include the design of an after burner in a high by-pass ratio aircraft engine and the disposal of effluents in a stream. The mixing process determines important quantities related to the energy transfer from main stream to the secondary stream, the temperature and velocity profiles, and the local kinematic and dissipative structure within the mixing region, and the growth of the mixing layer. Hill and Page (1968) have proposed the employment of an 'assumed epsilon' method in which the eddy viscosity model of Goertler (1942) is modified to account for the initial boundary layer. The present investigation is concerned with the application of the assumed epsilon technique to the study of the effect of initial conditions on the development of the turbulent mixing layer between two compressible, nonisoenergetic streams at constant pressure.

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.

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.

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.

Mixing Acid Salts and Layered Double Hydroxides in Nanoscale under Solid Condition

PubMed Central

Nakayama, Hirokazu; Hayashi, Aki

2014-01-01

The immobilization of potassium sorbate, potassium aspartate and sorbic acid in layered double hydroxide under solid condition was examined. By simply mixing two solids, immobilization of sorbate and aspartate in the interlayer space of nitrate-type layered double hydroxide, so called intercalation reaction, was achieved, and the uptakes, that is, the amount of immobilized salts and the interlayer distances of intercalation compounds were almost the same as those obtained in aqueous solution. However, no intercalation was achieved for sorbic acid. Although intercalation of sorbate and aspartate into chloride-type layered double hydroxide was possible, the uptakes for these intercalation compounds were lower than those obtained using nitrate-type layered double hydroxide. The intercalation under solid condition could be achieved to the same extent as for ion-exchange reaction in aqueous solution, and the reactivity was similar to that observed in aqueous solution. This method will enable the encapsulation of acidic drug in layered double hydroxide as nano level simply by mixing both solids. PMID:25080007

Mixing Acid Salts and Layered Double Hydroxides in Nanoscale under Solid Condition.

PubMed

Nakayama, Hirokazu; Hayashi, Aki

2014-07-30

The immobilization of potassium sorbate, potassium aspartate and sorbic acid in layered double hydroxide under solid condition was examined. By simply mixing two solids, immobilization of sorbate and aspartate in the interlayer space of nitrate-type layered double hydroxide, so called intercalation reaction, was achieved, and the uptakes, that is, the amount of immobilized salts and the interlayer distances of intercalation compounds were almost the same as those obtained in aqueous solution. However, no intercalation was achieved for sorbic acid. Although intercalation of sorbate and aspartate into chloride-type layered double hydroxide was possible, the uptakes for these intercalation compounds were lower than those obtained using nitrate-type layered double hydroxide. The intercalation under solid condition could be achieved to the same extent as for ion-exchange reaction in aqueous solution, and the reactivity was similar to that observed in aqueous solution. This method will enable the encapsulation of acidic drug in layered double hydroxide as nano level simply by mixing both solids.

Aspects of Supercritical Turbulence: Direct Numerical Simulation of O2/H2 and C7H16/N2 Temporal Mixing Layers

NASA Technical Reports Server (NTRS)

Bellan, J.; Okongo, N. A.; Harstad, K. G.; Hutt, John (Technical Monitor)

2002-01-01

Results from Direct Numerical Simulations of temporal, supercritical mixing layers for two species systems are analyzed to elucidate species-specific turbulence aspects. The two species systems, O2/H2 and C7HG16/N2, have different thermodynamic characteristics; thus, although the simulations are performed at similar reduced pressure (ratio of the pressure to the critical pressure), the former system is dose to mixture ideality and has a relatively high solubility with respect to the latter, which exhibits strong departures from mixture ideality Due to the specified, smaller initial density stratification, the C7H16/N2 layers display higher growth and increased global molecular mixing as well as larger turbulence levels. However, smaller density gradients at the transitional state for the O2/H2 system indicate that on a local basis, the layer exhibits an enhanced mixing, this being attributed to the increased solubility and to mixture ideality. These thermodynamic features are shown to affect the irreversible entropy production (i.e. the dissipation), which is larger for the O2/H2 layer and is primarily concentrated in high density-gradient magnitude regions that are distortions of the initial density stratification boundary. In contrast, the regions of largest dissipation in the C7H16/N2 layer are located in high density-gradient magnitude regions resulting from the mixing of the two fluids.

The Vertical Dust Profile Over Gale Crater, Mars

NASA Astrophysics Data System (ADS)

Guzewich, Scott D.; Newman, C. E.; Smith, M. D.; Moores, J. E.; Smith, C. L.; Moore, C.; Richardson, M. I.; Kass, D.; Kleinböhl, A.; Mischna, M.; Martín-Torres, F. J.; Zorzano-Mier, M.-P.; Battalio, M.

2017-12-01

We create a vertically coarse, but complete, profile of dust mixing ratio from the surface to the upper atmosphere over Gale Crater, Mars, using the frequent joint atmospheric observations of the orbiting Mars Climate Sounder (MCS) and the Mars Science Laboratory Curiosity rover. Using these data and an estimate of planetary boundary layer (PBL) depth from the MarsWRF general circulation model, we divide the vertical column into three regions. The first region is the Gale Crater PBL, the second is the MCS-sampled region, and the third is between these first two. We solve for a well-mixed dust mixing ratio within this third (middle) layer of atmosphere to complete the profile. We identify a unique seasonal cycle of dust within each atmospheric layer. Within the Gale PBL, dust mixing ratio maximizes near southern hemisphere summer solstice (Ls = 270°) and minimizes near winter solstice (Ls = 90-100°) with a smooth sinusoidal transition between them. However, the layer above Gale Crater and below the MCS-sampled region more closely follows the global opacity cycle and has a maximum in opacity near Ls = 240° and exhibits a local minimum (associated with the "solsticial pause" in dust storm activity) near Ls = 270°. With knowledge of the complete vertical dust profile, we can also assess the frequency of high-altitude dust layers over Gale. We determine that 36% of MCS profiles near Gale Crater contain an "absolute" high-altitude dust layer wherein the dust mixing ratio is the maximum in the entire vertical column.

Estimation of oceanic subsurface mixing under a severe cyclonic storm using a coupled atmosphere-ocean-wave model

NASA Astrophysics Data System (ADS)

Prakash, Kumar Ravi; Nigam, Tanuja; Pant, Vimlesh

2018-04-01

A coupled atmosphere-ocean-wave model was used to examine mixing in the upper-oceanic layers under the influence of a very severe cyclonic storm Phailin over the Bay of Bengal (BoB) during 10-14 October 2013. The coupled model was found to improve the sea surface temperature over the uncoupled model. Model simulations highlight the prominent role of cyclone-induced near-inertial oscillations in subsurface mixing up to the thermocline depth. The inertial mixing introduced by the cyclone played a central role in the deepening of the thermocline and mixed layer depth by 40 and 15 m, respectively. For the first time over the BoB, a detailed analysis of inertial oscillation kinetic energy generation, propagation, and dissipation was carried out using an atmosphere-ocean-wave coupled model during a cyclone. A quantitative estimate of kinetic energy in the oceanic water column, its propagation, and its dissipation mechanisms were explained using the coupled atmosphere-ocean-wave model. The large shear generated by the inertial oscillations was found to overcome the stratification and initiate mixing at the base of the mixed layer. Greater mixing was found at the depths where the eddy kinetic diffusivity was large. The baroclinic current, holding a larger fraction of kinetic energy than the barotropic current, weakened rapidly after the passage of the cyclone. The shear induced by inertial oscillations was found to decrease rapidly with increasing depth below the thermocline. The dampening of the mixing process below the thermocline was explained through the enhanced dissipation rate of turbulent kinetic energy upon approaching the thermocline layer. The wave-current interaction and nonlinear wave-wave interaction were found to affect the process of downward mixing and cause the dissipation of inertial oscillations.

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.

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.

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.

Disintegration of fluids under supercritical conditions from mixing layer studies

NASA Technical Reports Server (NTRS)

Okong'o, N.; Bellan, J.

2003-01-01

Databases of transitional states obtained from Direct Numerical simulations (DNS) of temporal, supercritical mixing layers for two species systems, O2/H2 and C7H16/N2, are analyzed to elucidate species-specific turbulence aspects and features of fluid disintegration.

Determination of the in-place hot-mix asphalt layer modulus for rehabilitation projects using a mechanistic-empirical procedure.

DOT National Transportation Integrated Search

2006-01-01

This project evaluated the procedures proposed by the Mechanistic-Empirical Pavement Design Guide (MEPDG) to characterize existing hot-mix asphalt (HMA) layers for rehabilitation purposes. Thirty-three cores were extracted from nine sites in Virginia...

Assessment of mixed-layer height estimation from single-wavelength ceilometer profiles

EPA Science Inventory

Differing boundary/mixed-layer height measurement methods were assessed in moderately polluted and clean environments, with a focus on the Vaisala CL51 ceilometer. This intercomparison was performed as part of ongoing measurements at the Chemistry And Physics of the Atmospheric B...

Stability of mixing layers

NASA Technical Reports Server (NTRS)

Tam, Christopher; Krothapalli, A

1993-01-01

The research program for the first year of this project (see the original research proposal) consists of developing an explicit marching scheme for solving the parabolized stability equations (PSE). Performing mathematical analysis of the computational algorithm including numerical stability analysis and the determination of the proper boundary conditions needed at the boundary of the computation domain are implicit in the task. Before one can solve the parabolized stability equations for high-speed mixing layers, the mean flow must first be found. In the past, instability analysis of high-speed mixing layer has mostly been performed on mean flow profiles calculated by the boundary layer equations. In carrying out this project, it is believed that the boundary layer equations might not give an accurate enough nonparallel, nonlinear mean flow needed for parabolized stability analysis. A more accurate mean flow can, however, be found by solving the parabolized Navier-Stokes equations. The advantage of the parabolized Navier-Stokes equations is that its accuracy is consistent with the PSE method. Furthermore, the method of solution is similar. Hence, the major part of the effort of the work of this year has been devoted to the development of an explicit numerical marching scheme for the solution of the Parabolized Navier-Stokes equation as applied to the high-seed mixing layer problem.

Update on Area Production in Mixing of Supercritical Fluids

NASA Technical Reports Server (NTRS)

Okongo, Nora; Bellan, Josette

2003-01-01

The focus of this research is on supercritical C7H16/N2 and O2/H2 mixing layers undergoing transitions to turbulence. The C7H16/N2 system serves as a simplified model of hydrocarbon/air systems in gas-turbine and diesel engines; the O2/H2 system is representative of liquid rocket engines. One goal of this research is to identify ways of controlling area production to increase disintegration of fluids and enhance combustion in such engines. As used in this research, "area production" signifies the fractional rate of change of surface area oriented perpendicular to the mass-fraction gradient of a mixing layer. In the study, a database of transitional states obtained from direct numerical simulations of the aforementioned mixing layers was analyzed to investigate global layer characteristics, phenomena in regions of high density-gradient magnitude (HDGM), irreversible entropy production and its relationship to the HDGM regions, and mechanisms leading to area production.

Magnetic studies on Layered solid solution Lix(Ni0.4Mn0.6)2-xO2

NASA Astrophysics Data System (ADS)

Nakao, K.; Nakamura, T.; Yamada, Y.; Koshiba, N.

2011-05-01

Lix(Ni0.4Mn0.6)2-xO2 (1.09<=x<=1.23) were prepared by the solid-state reaction using LiOH and coprecipitated mixed hydroxide as raw materials. All the compounds have a layered rock-salt structure, and the cation mixing degree (Ni2+ occupancy in the Li-layer) decreases with an increase in x. From the low-temperature magnetic measurement, they all have negative Weiss temperature and spontaneous magnetization, that is, they are ferromagnetic materials. Both the Curie temperature and the spontaneous magnetization at 4.2K decrease with an increase in x. These magnetic variations are attributed to the lowering of the cation mixing degree: the magnetic interaction network turns to two-dimensional one with the loss of the inert-layer coupling. These situations may be considered semi-quantitatively using the ferromagnetic cluster model. Additionally, the cation mixing degree has an influence on their electrochemical properties such as cycle fading and rate capability.

Turbulent entrainment in a strongly stratified barrier layer

NASA Astrophysics Data System (ADS)

Pham, H. T.; Sarkar, S.

2017-06-01

Large-eddy simulation (LES) is used to investigate how turbulence in the wind-driven ocean mixed layer erodes the stratification of barrier layers. The model consists of a stratified Ekman layer that is driven by a surface wind. Simulations at a wide range of N0/f are performed to quantify the effect of turbulence and stratification on the entrainment rate. Here, N0 is the buoyancy frequency in the barrier layer and f is the Coriolis parameter. The evolution of the mixed layer follows two stages: a rapid initial deepening and a late-time growth at a considerably slower rate. During the first stage, the mixed layer thickens to the depth that is proportional to u∗/fN0 where u∗ is the frictional velocity. During the second stage, the turbulence in the mixed layer continues to deepen further into the barrier layer, and the turbulent length scale is shown to scale with u∗/N0, independent of f. The late-time entrainment rate E follows the law of E=0.035Ri∗-1/2 where Ri∗ is the Richardson number. The exponent of -1/2 is identical but the coefficient of 0.035 is much smaller relative to the value of 2-3/2 for the nonrotating boundary layer. Simulations using the KPP model (version applicable to this simple case without additional effects of Langmuir turbulence or surface buoyancy flux) also yield the entrainment scaling of E∝Ri∗-1/2; however, the proportionality coefficient varies with the stratification. The structure of the Ekman current is examined to illustrate the strong effect of stratification in the limit of large N0/f.

Structural properties and diffusion processes of the Cu 3Au (0 0 1) surface

NASA Astrophysics Data System (ADS)

Wang, Fang; Zhang, Jian-Min; Zhang, Yan; Ji, Vincent

2010-09-01

The surface relaxation and surface energy of both the mixed AuCu and pure Cu terminated Cu 3Au (0 0 1) surfaces are simulated and calculated by using the modified analytical embedded-atom method. We find that the mixed AuCu termination is energetically preferred over the pure Cu termination thereby the mono-vacancy diffusion is also investigated in the topmost few layers of the mixed AuCu terminated Cu 3Au (0 0 1) surface. In the mixed AuCu terminated surface the relaxed Au atoms are raised above Cu atoms for 0.13 Å in the topmost layer. All the surface atoms displace outwards, this effect occurs in the first three layers and changes the first two inter-layer spacing. For mono-vacancy migration in the first layer, the migration energies of Au and Cu mono-vacancy via two-type in-plane displace: the nearest neighbor jump (NNJ) and the second nearest neighbor jump (2NNJ), are calculated and the results show that the NNJ requires a much lower energy than 2NNJ. For the evolution of the energy requirements for successive nearest neighbor jumps (SNNJ) along three different paths: circularity, zigzag and beeline, we find that the circularity path is preferred over the other two paths due to its minimum energy barriers and final energies. In the second layer, the NN jumps in intra- and inter-layer of the Cu mono-vacancy are investigated. The calculated energy barriers and final energies show that the vacancy prefer jump up to a proximate Cu site. This replacement between the Cu vacancy in the second layer and Cu atom in the first layer is remunerative for the Au atoms enrichment in the topmost layer.

Argo float observations of basin-scale deep convection in the Irminger Sea during winter 2011-2012

NASA Astrophysics Data System (ADS)

Thierry, V.; Piron, A.; Mercier, H.; Caniaux, G.

2016-02-01

An analysis of Argo data during the 2011-2012 winter revealed the presence of an exceptionally large number of profiles over the Irminger Basin with mixed layer depths (MLD) exceeding 700 m, which was deep enough to reach the pool of the intermediate Labrador Sea Water located in the Irminger Sea. Among them, 4 profiles exhibited an MLD of 1000 m, which was the maximum value observed this winter. Owing to the exceptional Argo sampling in the Irminger Sea during that winter the different phases of the mixed layer deepening down to 1000 m and their spatial extents were observed for the first time in the Irminger Sea. Two intense convective periods occurred in late January south of Cape Farewell and in late February-early March east of Greenland. A final deepening period was observed in mid-March during which the deepest mixed layers were observed. This long deepening period occurred in large regional areas and was followed by a rapid restratification phase. A mixed layer heat budget along the trajectories of the 4 floats that sampled the deepest mixed layers showed that heat loss at the air-sea interface was mainly responsible for heat content variations in the mixed layer. Greenland Tip Jets were of primary importance for the development of deep convection in the Irminger Sea in the 2011-2012 winter. They enhanced the winter heat loss and two long (more than 24 hours), intense and close in time late events boosted the mixed layer deepening down to 1000m. Net air-sea fluxes, the number of Greenland Tip Jets, the stratification of the water column, the NAO index and Ekman-induced heat flux are pertinent indicators to assess the favorable conditions for the development of deep convection in the Irminger Sea. When considering each of those indicators, we concluded that the 2011-2012 event was not significantly different compared to the three other documented occurrences of deep convection in the Irminger Sea.This work is a contribution to the NAOS project.

[Carbon storage of forest vegetation and allocation for main forest types in the east of Da-xing'an Mountains based on additive biomass model].

PubMed

Peng, Wei; Dong, Li Hu; Li, Feng Ri

2016-12-01

Based on the biomass investigation data of main forest types in the east of Daxing'an Mountains, the additive biomass models of 3 main tree species were developed and the changes of carbon storage and allocation of forest community of tree layer, shrub layer, herb layer and litter layer from different forest types were discussed. The results showed that the carbon storage of tree layer, shrub layer, herb layer and litter layer for Rhododendron dauricum-Larix gmelinii forest was 71.00, 0.34, 0.05 and 11.97 t·hm -2 , respectively. Similarly, the carbon storage of the four layers of Ledum palustre-L. gmelinii forest was 47.82, 0.88, 0, 5.04 t·hm -2 , 56.56, 0.44, 0.04, 8.72 t·hm -2 for R. dauricum-mixed forest of L. gmelinii-Betula platyphylla, 46.21, 0.66, 0.07, 6.16 t·hm -2 for L. palustre-mixed forest of L. gmelinii-B. platyphylla, 40.90, 1.37, 0.04, 3.67 t·hm -2 for R. dauricum-B. platyphylla forest, 36.28, 1.12, 0.18, 4.35 t·hm -2 for L. palustre-B. platyphylla forest. The carbon storage of forest community for the understory vegetation of R. dauricum was higher than that of the forest with L. palustre. In the condition of similar circumstances for the understory, the order of carbon storage for forest community was L. gmelinii forest > the mixed forest of L. gmelinii-B. platyphylla > B. platyphylla forest. The carbon storage of different forest types was different with the order of R. dauricum-L. gmelinii forest (83.36 t·hm -2 )> R. dauricum-mixed forest of L. gmelinii-B. platyphylla (65.76 t·hm -2 ) > L. palustre-L. gmelinii forest (53.74 t·hm -2 )> L. palustre-mixed forest of L. gmelinii-B. platyphylla (53.10 t·hm -2 )> R. dauricum-B. platyphylla forest (45.98 t·hm -2 ) > L. palustre-B. platyphylla forest (41.93 t·hm -2 ). The order of carbon storage for the vertical distribution in forest communities with diffe-rent forest types was the tree layer (85.2%-89.0%) > litter layer (8.0%-14.4%) > shrub layer (0.4%-2.7%) > herb layer (0-0.4%).

Estimation of evaporation from equilibrium diurnal boundary layer humidity

NASA Astrophysics Data System (ADS)

Salvucci, G.; Rigden, A. J.; Li, D.; Gentine, P.

2017-12-01

Simplified conceptual models of the convective boundary layer as a well mixed profile of potential temperature (theta) and specific humidity (q) impinging on an initially stably stratified linear potential temperature profile have a long history in atmospheric sciences. These one dimensional representations of complex mixing are useful for gaining insights into land-atmosphere interactions and for prediction when state of the art LES approaches are infeasible. As previously shown (e.g. Betts), if one neglects the role of q in bouyancy, the framework yields a unique relation between mixed layer Theta, mixed layer height (h), and cumulative sensible heat flux (SH) throughout the day. Similarly assuming an initially q profile yields a simple relation between q, h, and cumulative latent heat flux (LH). The diurnal dynamics of theta and q are strongly dependent on SH and the initial lapse rates of theta (gamma_thet) and q (gamma q). In the estimation method proposed here, we further constrain these relations with two more assumptions: 1) The specific humidity is the same at the start of the period of boundary layer growth and at the collapse; and 2) Once the mixed layer reaches the LCL, further drying occurs proportionally to the deardorff convective velocity scale (omega) multiplied by q. Assumption (1) is based on the idea that below the cloud layer, there are no sinks of moisture within the mixed layer (neglecting lateral humidity divergence). Thus the net mixing of dry air aloft with evaporation from the surface must balance. Inclusion of the simple model of moisture loss above the LCL into the bulk-CBL model allows definition of an equilibrium humidity (q) condition at which the diurnal cycle of q repeats (i.e. additions of q from surface balance entrainment of dry air from above). Surprisingly, this framework allows estimation of LH from q, theta, and estimated net radiation by solving for the value of Evaporative Fraction (EF) for which the diurnal cycle of q repeats. Three parameters need specification: cloud area fraction, entrainment factor, and morning lapse rate. Surprisingly, a single set of values for these parameters are adequate to estimate EF at over 70 tested Ameriflux sites to within about 20%, though improvements are gained using a single regression model for gamma_thet that has been fitted to radiosonde data.

Numerical experiments with a wind- and buoyancy-driven two-and-a-half-layer upper ocean model

NASA Astrophysics Data System (ADS)

Cherniawsky, J. Y.; Yuen, C. W.; Lin, C. A.; Mysak, L. A.

1990-09-01

We describe numerical experiments with a limited domain (15°-67°N, 65° west to east) coarse-resolution two-and-a-half-layer upper ocean model. The model consists of two active variable density layers: a Niiler and Kraus (1977) type mixed layer and a pycnocline layer, which overlays a semipassive deep ocean. The mixed layer is forced with a cosine wind stress and Haney type heat and precipitation-evaporation fluxes, which were derived from zonally averaged climatological (Levitus, 1982) surface temperatures and salinities for the North Atlantic. The second layer is forced from below with (1) Newtonian cooling to climatological temperatures and salinities at the lower boundary, (2) convective adjustment, which occurs whenever the density of the second layer is unstable with respect to climatology, and (3) mass entrainment in areas of strong upwelling, when the deep ocean ventilates through the bottom surface. The sensitivity of this model to changes in its internal (mixed layer) and external (e.g., a Newtonian coupling coefficient) parameters is investigated and compared to the results from a control experiment. We find that the model is not overly sensitive to changes in most of the parameters that were tested, albeit these results may depend to some extent on the choice of the control experiment.

Fabrication of selective-area growth InGaN LED by mixed-source hydride vapor-phase epitaxy

NASA Astrophysics Data System (ADS)

Bae, Sung Geun; Jeon, Injun; Jeon, Hunsoo; Kim, Kyoung Hwa; Yang, Min; Yi, Sam Nyung; Lee, Jae Hak; Ahn, Hyung Soo; Yu, Young Moon; Sawaki, Nobuhiko; Kim, Suck-Whan

2018-01-01

We prepared InGaN light-emitting diodes (LEDs) with the active layers grown from a mixed source of Ga-In-N materials on an n-type GaN substrate by a selective-area growth method and three fabrication steps: photolithography, epitaxial layer growth, and metallization. The preparation followed a previously developed experimental process using apparatus for mixed-source hydride vapor-phase epitaxy (HVPE), which consisted of a multi-graphite boat, for insulating against the high temperature and to control the growth rate of epilayers, filled with the mixed source on the inside and a radio-frequency (RF) heating coil for heating to a high temperature (T > 900 °C) and for easy control of temperature outside the source zone. Two types of LEDs were prepared, with In compositions of 11.0 and 6.0% in the InGaN active layer, and room-temperature electroluminescence measurements exhibited a main peak corresponding to the In composition at either 420 or 390 nm. The consecutive growth of InGaN LEDs by the mixed-source HVPE method provides a technique for the production of LEDs with a wide range of In compositions in the active layer.

Numerical simulation of a plane turbulent mixing layer, with applications to isothermal, rapid reactions

NASA Technical Reports Server (NTRS)

Lin, P.; Pratt, D. T.

1987-01-01

A hybrid method has been developed for the numerical prediction of turbulent mixing in a spatially-developing, free shear layer. Most significantly, the computation incorporates the effects of large-scale structures, Schmidt number and Reynolds number on mixing, which have been overlooked in the past. In flow field prediction, large-eddy simulation was conducted by a modified 2-D vortex method with subgrid-scale modeling. The predicted mean velocities, shear layer growth rates, Reynolds stresses, and the RMS of longitudinal velocity fluctuations were found to be in good agreement with experiments, although the lateral velocity fluctuations were overpredicted. In scalar transport, the Monte Carlo method was extended to the simulation of the time-dependent pdf transport equation. For the first time, the mixing frequency in Curl's coalescence/dispersion model was estimated by using Broadwell and Breidenthal's theory of micromixing, which involves Schmidt number, Reynolds number and the local vorticity. Numerical tests were performed for a gaseous case and an aqueous case. Evidence that pure freestream fluids are entrained into the layer by large-scale motions was found in the predicted pdf. Mean concentration profiles were found to be insensitive to Schmidt number, while the unmixedness was higher for higher Schmidt number. Applications were made to mixing layers with isothermal, fast reactions. The predicted difference in product thickness of the two cases was in reasonable quantitative agreement with experimental measurements.

Effectiveness of Three Different Irrigants - 17% Ethylenediaminetetraacetic Acid, Q-MIX, and Phytic Acid in Smear Layer Removal: A Comparative Scanning Electron Microscope Study.

PubMed

Jagzap, Janhavi Balasaheb; Patil, Sanjay S; Gade, Vandana Jaykumar; Chandhok, Deepika J; Upagade, Madhura A; Thakur, Deepa A

2017-01-01

Removal of smear layer from the root canal walls is important for long-standing endodontic success. The aim of this study is to evaluate and compare smear layer removing ability among 17% ethylenediaminetetraacetic acid (EDTA), Q-MIX, and phytic acid by scanning electron microscopy (SEM). This in-vitro experimental study assessed smear layer removal using three different irrigants. Thirty single-rooted freshly extracted human permanent premolars were collected, disinfected, and decoronated to a standardized root length of 13 mm. Root canals were cleaned and shaped till F2 universal rotary protaper at working length 1 mm short of the apex. They were randomly divided into three groups, and final irrigation was done accordingly. Group 1 ( n = 10): with 1 ml of 17% EDTA, Group 2 ( n = 10): with 1 ml of Q-MIX, Group 3 ( n = 10): with 1 ml of phytic acid. Samples were then longitudinally sectioned and evaluated under SEM at coronal, middle, and apical levels. Two-way analysis of variance and Tukey's post hoc test were performed. The level of significance was set at 0.05. Smear layer removing ability among irrigants and sections in descending order: 17 EDTA > Q-MIX > phytic acid; coronal > middle > apical. 17% EDTA showed better and promising results followed by Q-MIX and then phytic acid.

Substantial energy input to the mesopelagic ecosystem from the seasonal mixed-layer pump

PubMed Central

Dall’Olmo, Giorgio; Dingle, James; Polimene, Luca; Brewin, Robert J.W.; Claustre, Hervé

2016-01-01

The “mesopelagic” is the region of the ocean between about 100 and 1000 m that harbours one of the largest ecosystems and fish stocks on the planet1,2. This vastly unexplored ecosystem is believed to be mostly sustained by chemical energy, in the form of fast-sinking particulate organic carbon, supplied by the biological carbon pump3. Yet, this supply appears insufficient to match mesopelagic metabolic demands4–6. The mixed-layer pump is a physically-driven biogeochemical process7–11 that could further contribute to meet these energetic requirements. However, little is known about the magnitude and spatial distribution of this process at the global scale. Here we show that the mixed-layer pump supplies an important seasonal flux of organic carbon to the mesopelagic. By combining mixed-layer depths from Argo floats with satellite retrievals of particulate organic carbon, we estimate that this pump exports a global flux of about 0.3 Pg C yr−1 (range 0.1 – 0.5 Pg C yr−1). In high-latitude regions where mixed-layers are deep, this flux is on average 23%, but can be greater than 100% of the carbon supplied by fast sinking particles. Our results imply that a relatively large flux of organic carbon is missing from current energy budgets of the mesopelagic. PMID:27857779

Self-similarity of a Rayleigh–Taylor mixing layer at low Atwood number with a multimode initial perturbation

DOE PAGES

Morgan, B. E.; Olson, B. J.; White, J. E.; ...

2017-06-29

High-fidelity large eddy simulation (LES) of a low-Atwood number (A = 0.05) Rayleigh-Taylor mixing layer is performed using the tenth-order compact difference code Miranda. An initial multimode perturbation spectrum is specified in Fourier space as a function of mesh resolution such that a database of results is obtained in which each successive level of increased grid resolution corresponds approximately to one additional doubling of the mixing layer width, or generation. The database is then analyzed to determine approximate requirements for self-similarity, and a new metric is proposed to quantify how far a given simulation is from the limit of self-similarity.more » It is determined that mixing layer growth reaches a high degree of self-similarity after approximately 4.5 generations. Statistical convergence errors and boundary effects at late time, however, make it impossible to draw similar conclusions regarding the self-similar growth of more sensitive turbulence parameters. Finally, self-similar turbulence profiles from the LES database are compared with one-dimensional simulations using the k-L-a and BHR-2 Reynolds-averaged Navier-Stokes (RANS) models. The k-L-a model, which is calibrated to reproduce a quadratic turbulence kinetic energy profile for a self-similar mixing layer, is found to be in better agreement with the LES than BHR-2 results.« less

Did Irving Langmuir Observe Langmuir Circulations?

NASA Astrophysics Data System (ADS)

D'Asaro, E. A.; Harcourt, R. R.; Shcherbina, A.; Thomson, J. M.; Fox-Kemper, B.

2012-12-01

Although surface waves are known to play an important role in mixing the upper ocean, the current generation of upper ocean boundary layer parameterizations does not include the explicit effects of surface waves. Detailed simulations using LES models which include the Craik-Leibovich wave-current interactions, now provide quantitative predictions of the enhancement of boundary layer mixing by waves. Here, using parallel experiments in Lake Washington and at Ocean Station Papa, we show a clear enhancement of vertical kinetic energy across the entire upper ocean boundary layer which can be attributed to surface wave effects. The magnitude of this effect is close to that predicted by LES models, but is not large, less than a factor of 2 on average, and increased by large Stokes drift and shallow mixed layers. Global estimates show the largest wave enhancements occur on the equatorial side of the westerlies in late Spring, due to the combination of large waves, shallow mixed layers and weak winds. In Lakes, however, the waves and the Craik-Leibovich interactions are weak, making it likely that the counter-rotating vortices famously observed by Irving Langmuir in Lake George were not driven by wave-current interactions.

Convection and the seeding of the North Atlantic bloom

NASA Astrophysics Data System (ADS)

D'Asaro, Eric A.

Observations of vertical velocities in deep wintertime mixed layers using neutrally buoyant floats show that the convectively driven vertical velocities, roughly 1000 m per day, greatly exceed the sinking velocities of phytoplankton, 10 m or less per day. These velocities mix plankton effectively and uniformly across the convective layer and are therefore capable of returning those that have sunk to depth back into the euphotic zone. This mechanism cycles cells through the surface layer during the winter and provides a seed population for the spring bloom. A simple model of this mechanism applied to immortal phytoplankton in the subpolar Labrador Sea predicts that the seed population in early spring will be a few percent of the fall concentration if the plankton sink more slowly than the mean rate at which the surface well-mixed layer grows over the winter. Plankton that sink faster than this will mostly sink into the abyss with only a minute fraction remaining by spring. The shallower mixed layers of mid-latitudes are predicted to be much less effective at maintaining a seed population over the winter, limiting the ability of rapidly sinking cells to survive the winter.

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.

Release from or through a wax matrix system. IV. Generalized expression of the release process for a reservoir device tablet.

PubMed

Yonezawa, Yorinobu; Ishida, Sumio; Suzuki, Shinobu; Sunada, Hisakazu

2002-09-01

Generalization of the release process through the wax matrix layer was examined by use of a reservoir device tablet. The wax matrix layer of the reservoir device tablet was prepared from a physical mixture of lactose and hydrogenated castor oil to simplify the release properties. Release through the wax matrix layer showed zero-order kinetics in a steady state after a given lag time, and could be divided into two stages. The first stage was the formation process of water channel by dissolving the soluble component in the wax matrix layer. The lag time obtained by applying the square root law equation was well connected with the amount of the matrix layer and mixed weight ratio of components in this layer. The second stage was the zero-order release process of drug in the reservoir through the wax matrix layer, because the effective surface area was fixed. The release rate constants were connected with thickness of the matrix layer and permeability coefficient, and the permeability coefficients were connected with the diffusion coefficient of drug and porosity. Hence the release rate constant could be connected with the amount of matrix layer and the mixed weight ratio of components in the matrix layer. It was therefore suggested that the release process could be generalized using the amount of matrix layer and the mixed weight ratio of components in the matrix layer.

Revealing the Location of the Mixing Layer in a Hot Bubble

NASA Astrophysics Data System (ADS)

Guerrero, M. A.; Fang, X.; Chu, Y.-H.; Toalá, J. A.; Gruendl, R. A.

2017-10-01

The fast stellar winds can blow bubbles in the circumstellar material ejected from previous phases of stellar evolution. These are found at different scales, from planetary nebulae (PNe) around stars evolving to the white dwarf stage, to Wolf-Rayet (WR) bubbles and up to large-scale bubbles around massive star clusters. In all cases, the fast stellar wind is shock-heated and a hot bubble is produced. Processes of mass evaporation and mixing of nebular material and heat conduction occurring at the mixing layer between the hot bubble and the optical nebula are key to determine the thermal structure of these bubbles and their evolution. In this contribution we review our current understanding of the X-ray observations of hot bubbles in PNe and present the first spatially-resolved study of a mixing layer in a PN.

HST STIS Observations of the Mixing Layer in the Cat’s Eye Nebula

NASA Astrophysics Data System (ADS)

Fang, Xuan; Guerrero, Martín A.; Toalá, Jesús A.; Chu, You-Hua; Gruendl, Robert A.

2016-05-01

Planetary nebulae (PNe) are expected to have a ˜105 K interface layer between the ≥slant 106 K inner hot bubble and the ˜104 K optical nebular shell. The PN structure and evolution, and the X-ray emission, depend critically on the efficiency of the mixing of material at this interface layer. However, neither its location nor its spatial extent have ever been determined. Using high-spatial resolution HST STIS spectroscopic observations of the N v λ λ 1239,1243 lines in the Cat’s Eye Nebula (NGC 6543), we have detected this interface layer and determined its location, extent, and physical properties for the first time in a PN. We confirm that this interface layer, as revealed by the spatial distribution of the N v λ1239 line emission, is located between the hot bubble and the optical nebular shell. We estimate a thickness of 1.5× {10}16 cm and an electron density of ˜200 cm-3 for the mixing layer. With a thermal pressure of ˜2 × 10-8 dyn cm-2, the mixing layer is in pressure equilibrium with the hot bubble and ionized nebular rim of NGC 6543. Based on observations made with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. The observations are associated with program #12509.

Impact of the Loess Plateau on the atmospheric boundary layer structure and air quality in the North China Plain: a case study.

PubMed

Hu, Xiao-Ming; Ma, ZhiQiang; Lin, Weili; Zhang, Hongliang; Hu, Jianlin; Wang, Ying; Xu, Xiaobin; Fuentes, Jose D; Xue, Ming

2014-11-15

The North China Plain (NCP), to the east of the Loess Plateau, experiences severe regional air pollution. During the daytime in the summer, the Loess Plateau acts as an elevated heat source. The impacts of such a thermal effect on meteorological phenomena (e.g., waves, precipitation) in this region have been discussed. However, its impacts on the atmospheric boundary layer structure and air quality have not been reported. It is hypothesized that the thermal effect of the Plateau likely modulates the boundary layer structure and ambient concentrations of pollutants over the NCP under certain meteorological conditions. Thus, this study investigates such effect and its impacts using measurements and three-dimensional model simulations. It is found that in the presence of daytime westerly wind in the lower troposphere (~1 km above the NCP), warmer air above the Loess Plateau was transported over the NCP and imposed a thermal inversion above the mixed boundary layer, which acted as a lid and suppressed the mixed layer growth. As a result, pollutants accumulated in the shallow mixed layer and ozone was efficiently produced. The downward branch of the thermally-induced Mountain-Plains Solenoid circulation over the NCP contributed to enhancing the capping inversion and exacerbating air pollution. Previous studies have reported that low mixed layer, a factor for elevated pollution in the NCP, may be caused by aerosol scattering and absorption of solar radiation, frontal inversion, and large scale subsidence. The present study revealed a different mechanism (i.e., westerly warm advection) for the suppression of the mixed layer in summer NCP, which caused severe O3 pollution. This study has important implications for understanding the essential meteorological factors for pollution episodes in this region and forecasting these severe events. Copyright © 2014 Elsevier B.V. All rights reserved.

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.

Research on Radiation Characteristic of Plasma Antenna through FDTD Method

PubMed Central

Zhou, Jianming; Fang, Jingjing; Lu, Qiuyuan; Liu, Fan

2014-01-01

The radiation characteristic of plasma antenna is investigated by using the finite-difference time-domain (FDTD) approach in this paper. Through using FDTD method, we study the propagation of electromagnetic wave in free space in stretched coordinate. And the iterative equations of Maxwell equation are derived. In order to validate the correctness of this method, we simulate the process of electromagnetic wave propagating in free space. Results show that electromagnetic wave spreads out around the signal source and can be absorbed by the perfectly matched layer (PML). Otherwise, we study the propagation of electromagnetic wave in plasma by using the Boltzmann-Maxwell theory. In order to verify this theory, the whole process of electromagnetic wave propagating in plasma under one-dimension case is simulated. Results show that Boltzmann-Maxwell theory can be used to explain the phenomenon of electromagnetic wave propagating in plasma. Finally, the two-dimensional simulation model of plasma antenna is established under the cylindrical coordinate. And the near-field and far-field radiation pattern of plasma antenna are obtained. The experiments show that the variation of electron density can introduce the change of radiation characteristic. PMID:25114961

A first-order k-space model for elastic wave propagation in heterogeneous media.

PubMed

Firouzi, K; Cox, B T; Treeby, B E; Saffari, N

2012-09-01

A pseudospectral model of linear elastic wave propagation is described based on the first order stress-velocity equations of elastodynamics. k-space adjustments to the spectral gradient calculations are derived from the dyadic Green's function solution to the second-order elastic wave equation and used to (a) ensure the solution is exact for homogeneous wave propagation for timesteps of arbitrarily large size, and (b) also allows larger time steps without loss of accuracy in heterogeneous media. The formulation in k-space allows the wavefield to be split easily into compressional and shear parts. A perfectly matched layer (PML) absorbing boundary condition was developed to effectively impose a radiation condition on the wavefield. The staggered grid, which is essential for accurate simulations, is described, along with other practical details of the implementation. The model is verified through comparison with exact solutions for canonical examples and further examples are given to show the efficiency of the method for practical problems. The efficiency of the model is by virtue of the reduced point-per-wavelength requirement, the use of the fast Fourier transform (FFT) to calculate the gradients in k space, and larger time steps made possible by the k-space adjustments.

A Locally Modal B-Spline Based Full-Vector Finite-Element Method with PML for Nonlinear and Lossy Plasmonic Waveguide

NASA Astrophysics Data System (ADS)

Karimi, Hossein; Nikmehr, Saeid; Khodapanah, Ehsan

2016-09-01

In this paper, we develop a B-spline finite-element method (FEM) based on a locally modal wave propagation with anisotropic perfectly matched layers (PMLs), for the first time, to simulate nonlinear and lossy plasmonic waveguides. Conventional approaches like beam propagation method, inherently omit the wave spectrum and do not provide physical insight into nonlinear modes especially in the plasmonic applications, where nonlinear modes are constructed by linear modes with very close propagation constant quantities. Our locally modal B-spline finite element method (LMBS-FEM) does not suffer from the weakness of the conventional approaches. To validate our method, first, propagation of wave for various kinds of linear, nonlinear, lossless and lossy materials of metal-insulator plasmonic structures are simulated using LMBS-FEM in MATLAB and the comparisons are made with FEM-BPM module of COMSOL Multiphysics simulator and B-spline finite-element finite-difference wide angle beam propagation method (BSFEFD-WABPM). The comparisons show that not only our developed numerical approach is computationally more accurate and efficient than conventional approaches but also it provides physical insight into the nonlinear nature of the propagation modes.

A novel Zeonex based oligoporous-core photonic crystal fiber for polarization preserving terahertz applications

NASA Astrophysics Data System (ADS)

Islam, Md. Saiful; Sultana, Jakeya; Dinovitser, Alex; Ng, Brian W.-H.; Abbott, Derek

2018-04-01

A novel waveguide consisting of oligo-porous core photonic crystal fiber (PCF) with a kagome lattice cladding has been designed for highly birefringent and near zero dispersion flattened applications of terahertz waves. The wave guiding properties of the designed PCF including birefringence, dispersion, effective material loss (EML), core power fraction, confinement loss, and modal effective area are investigated using a full vector Finite Element Method (FEM) with Perfectly Matched Layer (PML) absorbing boundary condition. Simulation results demonstrate that an ultra-high birefringence of 0.079, low EML of 0.05 cm-1, higher core power fraction of 44% and negligible confinement loss of 7 . 24 × 10-7 cm-1 can be achieved at 1 THz. Furthermore, for the y-polarization mode a near zero flattened dispersion of 0 . 49 ± 0 . 05 ps/THz/cm is achieved within a broad frequency range of 0.8-1.7 THz. The fabrication of the proposed fiber is feasible using the existing fabrication technology. Due to favorable wave-guiding properties, the proposed fiber has potential for terahertz imaging, sensing and polarization maintaining applications in the terahertz frequency range.

Finite-difference modeling of the electroseismic logging in a fluid-saturated porous formation

NASA Astrophysics Data System (ADS)

Guan, Wei; Hu, Hengshan

2008-05-01

In a fluid-saturated porous medium, an electromagnetic (EM) wavefield induces an acoustic wavefield due to the electrokinetic effect. A potential geophysical application of this effect is electroseismic (ES) logging, in which the converted acoustic wavefield is received in a fluid-filled borehole to evaluate the parameters of the porous formation around the borehole. In this paper, a finite-difference scheme is proposed to model the ES logging responses to a vertical low frequency electric dipole along the borehole axis. The EM field excited by the electric dipole is calculated separately by finite-difference first, and is considered as a distributed exciting source term in a set of extended Biot's equations for the converted acoustic wavefield in the formation. This set of equations is solved by a modified finite-difference time-domain (FDTD) algorithm that allows for the calculation of dynamic permeability so that it is not restricted to low-frequency poroelastic wave problems. The perfectly matched layer (PML) technique without splitting the fields is applied to truncate the computational region. The simulated ES logging waveforms approximately agree with those obtained by the analytical method. The FDTD algorithm applies also to acoustic logging simulation in porous formations.

Mixed-layer kaolinite-montmorillonite from the Yucatan Peninsula, Mexico

USGS Publications Warehouse

Schultz, L.G.; Shepard, A.O.; Blackmon, P.D.; Starkey, H.C.

1971-01-01

Clay beds 1–2 m thick and interbedded with marine limestones probably of early Eocene age are composed of nearly pure mixed-layer kaolinite-montmorillonite. Particle size studies, electron micrographs, X-ray diffraction studies, chemical analyses, cation exchange experiments, DTA, and TGA indicate that clays from three different localities contain roughly equal proportions of randomly interlayered kaolinite and montmorillonite layers. The montmorillonite structural formulas average K0·2Na0·2Ca0·2Mg0·2(Al2·5Fe1·03+Mg0·5)(Al0·75Si7.25)O20+(OH)4−, with a deficiency of structural (OH) in either the montmorillonite or kaolinite layers. Nonexchangeable K+ indicates that a few layers are mica-like. Crystals are mostly round plates 1/10 to 1/20 µ across. The feature most diagnostic of the mixed-layer character is an X-ray reflection near 8 Å after heating at 300°C. The clays are inferred to have developed by weathering of volcanic ash and subsequent erosion and deposition in protected nearshore basins.

Fusion yield rate recovery by escaping hot-spot fast ions in the neighboring fuel layer

NASA Astrophysics Data System (ADS)

Tang, Xian-Zhu; McDevitt, C. J.; Guo, Zehua; Berk, H. L.

2014-02-01

Free-streaming loss by fast ions can deplete the tail population in the hot spot of an inertial confinement fusion (ICF) target. Escaping fast ions in the neighboring fuel layer of a cryogenic target can produce a surplus of fast ions locally. In contrast to the Knudsen layer effect that reduces hot-spot fusion reactivity due to tail ion depletion, the inverse Knudsen layer effect increases fusion reactivity in the neighboring fuel layer. In the case of a burning ICF target in the presence of significant hydrodynamic mix which aggravates the Knudsen layer effect, the yield recovery largely compensates for the yield reduction. For mix-dominated sub-ignition targets, the yield reduction is the dominant process.

MOFwich: Sandwiched Metal-Organic Framework-Containing Mixed Matrix Composites for Chemical Warfare Agent Removal.

PubMed

Peterson, Gregory W; Lu, Annie X; Hall, Morgan G; Browe, Matthew A; Tovar, Trenton; Epps, Thomas H

2018-02-28

This work describes a new strategy for fabricating mixed matrix composites containing layered metal-organic framework (MOF)/polymer films as functional barriers for chemical warfare agent protection. Through the use of mechanically robust polymers as the top and bottom encasing layers, a high-MOF-loading, high-performance-core layer can be sandwiched within. We term this multifunctional composite "MOFwich". We found that the use of elastomeric encasing layers enabled core layer reformation after breakage, an important feature for composites and membranes alike. The incorporation of MOFs into the core layer led to enhanced removal of chemical warfare agents while simultaneously promoting moisture vapor transport through the composite, showcasing the promise of these composites for protection applications.

A Non-Fickian Mixing Model for Stratified Turbulent Flows

DTIC Science & Technology

2013-09-30

lateral gradients in the mixed layer, indicative of surface fronts, and with the magnitude of mixed layer depth MLD. Direct testing with our results shows...both are induced by atmospheric forcing. In our case, atmospheric fluxes and wind forcing are still the cause of SM occurrence, but mostly through their...California upwelling simulations, where MLD did not change significantly between HR and LR simulations. As suggested by Capet et al. (2008b), this is likely