Development of a biochip-based assay integrated in a global strategy for identification of fusion transcripts in acute myeloid leukemia: a work flow for acute myeloid leukemia diagnosis.

PubMed

Giusiano, S; Formisano-Tréziny, C; Benziane, A; Maroc, N; Picard, C; Hermitte, F; Taranger-Charpin, C; Gabert, J

2010-08-01

Three major types of rearrangements are involved in acute myeloid leukemias (AML): t(8;21)(q22;q22), inv(16)(p13q22), and 11q23/MLL abnormalities. Their precise identification becomes essential for diagnosis, prognosis, and therapeutic choices. Resulting fusion transcripts (FT) are also powerful markers for monitoring the efficacy of treatment, the minimal residual disease (MRD) and could become therapeutic targets. Today, the challenge is to propose an individual follow-up for each patient even for those with a rare fusion event. In this study, we propose a biochip-based assay integrated in a global strategy for identification of rare FT in AML, after fluorescence in situ hybridization detection, as described by the World Health Organization classification. Using cell lines, we developed and validated a biochip-based assay called the AMLFusionChip that identifies every FT of AML1-ETO, CBFbeta-MYH11 as well as MLL-AF9, MLL-ENL, MLL-AF6, and MLL-AF10. The original design of our AMLFusionChip.v01 enables the identification of these FT wherever the breakpoint on the partner gene may be. In case of biochip negative result, our 3'RACE amplification strategy enables to clone and then sequence the new translocation partner. This AMLFusionChip strategy fits into the concept of personalized medicine for the largest number of patients.

WSi2/Si multilayer sectioning by reactive ion etching for multilayer Laue lens fabrication

NASA Astrophysics Data System (ADS)

Bouet, N.; Conley, R.; Biancarosa, J.; Divan, R.; Macrander, A. T.

2010-09-01

Reactive ion etching (RIE) has been employed in a wide range of fields such as semiconductor fabrication, MEMS (microelectromechanical systems), and refractive x-ray optics with a large investment put towards the development of deep RIE. Due to the intrinsic differing chemistries related to reactivity, ion bombardment, and passivation of materials, the development of recipes for new materials or material systems can require intense effort and resources. For silicon in particular, methods have been developed to provide reliable anisotropic profiles with good dimensional control and high aspect ratios1,2,3, high etch rates, and excellent material to mask etch selectivity. A multilayer Laue lens4 is an x-ray focusing optic, which is produced by depositing many layers of two materials with differing electron density in a particular stacking sequence where the each layer in the stack satisfies the Fresnel zone plate law. When this stack is sectioned to allow side-illumination with radiation, the diffracted exiting radiation will constructively interfere at the focal point. Since the first MLLs were developed at Argonne in the USA in 20064, there have been published reports of MLL development efforts in Japan5, and, very recently, also in Germany6. The traditional technique for sectioning multilayer Laue lens (MLL) involves mechanical sectioning and polishing7, which is labor intensive and can induce delamination or structure damage and thereby reduce yield. If a non-mechanical technique can be used to section MLL, it may be possible to greatly shorten the fabrication cycle, create more usable optics from the same amount of deposition substrate, and perhaps develop more advanced structures to provide greater stability or flexibility. Plasma etching of high aspect-ratio multilayer structures will also expand the scope for other types of optics fabrication (such as gratings, zone plates, and so-on). However, well-performing reactive ion etching recipes have been developed for only a small number of materials, and even less recipes exist for concurrent etching of more than one element so a fully material specific process needs to be developed. In this paper, sectioning of WSi2/Si multilayers for MLL fabrication using fluorinated gases is investigated. The main goals were to demonstrate the feasibility of this technique, achievement of high anisotropy, adequate sidewall roughness control and high etching rates. We note that this development for MLL sidewalls should be distinguished from work on improving aspect ratios in traditional Fresnel zone plates. Aspect ratios for MLL sidewalls are not similarly constrained.

A multicenter evaluation of comprehensive analysis of MLL translocations and fusion gene partners in acute leukemia using the MLL FusionChip device.

PubMed

Harrison, Christine J; Griffiths, Mike; Moorman, Fìona; Schnittger, Susanne; Cayuela, Jean-Michel; Shurtleff, Sheila; Gottardi, Enrico; Mitterbauer, Gerlinde; Colomer, Dolores; Delabesse, Eric; Castéras, Vincent; Maroc, Nicolas

2007-02-01

Rearrangements of the MLL gene are significant in acute leukemia. Among the most frequent translocations are t(4;11)(q21;q23) and t(9;11)(p22;q23), which give rise to the MLL-AFF1 and MLL-MLLT3 fusion genes (alias MLL-AF4 and MLL-AF9) in acute lymphoblastic and acute myeloid leukemia, respectively. Current evidence suggests that determining the MLL status of acute leukemia, including precise identification of the partner gene, is important in defining appropriate treatment. This underscores the need for accurate detection methods. A novel molecular diagnostic device, the MLL FusionChip, has been successfully used to identify MLL fusion gene translocations in acute leukemia, including the precise breakpoint location. This study evaluated the performance of the MLL FusionChip within a routine clinical environment, comprising nine centers worldwide, in the analysis of 21 control and 136 patient samples. It was shown that the assay allowed accurate detection of the MLL fusion gene, regardless of the breakpoint location, and confirmed that this multiplex approach was robust in a global multicenter trial. The MLL FusionChip was shown to be superior to other detection methods. The type of molecular information provided by MLL FusionChip gave an indication of the appropriate primers to design for disease monitoring of MLL patients following treatment.

Pharmacologic inhibition of the menin-MLL interaction blocks progression of MLL leukemia in vivo

DOE PAGES

Borkin, Dmitry; He, Shihan; Miao, Hongzhi; ...

2015-03-26

Chromosomal translocations affecting mixed lineage leukemia gene ( MLL) result in acute leukemias resistant to therapy. The leukemogenic activity of MLL fusion proteins is dependent on their interaction with menin, providing basis for therapeutic intervention. In this paper, we report the development of highly potent and orally bioavailable small-molecule inhibitors of the menin-MLL interaction, MI-463 and MI-503, and show their profound effects in MLL leukemia cells and substantial survival benefit in mouse models of MLL leukemia. Finally, we demonstrate the efficacy of these compounds in primary samples derived from MLL leukemia patients. In conclusion, overall, we demonstrate that pharmacologic inhibitionmore » of the menin-MLL interaction represents an effective treatment for MLL leukemias in vivo and provide advanced molecular scaffold for clinical lead identification.« less

Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia.

PubMed

Grembecka, Jolanta; He, Shihan; Shi, Aibin; Purohit, Trupta; Muntean, Andrew G; Sorenson, Roderick J; Showalter, Hollis D; Murai, Marcelo J; Belcher, Amalia M; Hartley, Thomas; Hess, Jay L; Cierpicki, Tomasz

2012-01-29

Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.

Bone marrow mesenchymal stem cells from infants with MLL-AF4+ acute leukemia harbor and express the MLL-AF4 fusion gene

PubMed Central

Catalina, Purificación; Rodríguez, René; Melen, Gustavo J.; Bueno, Clara; Arriero, Mar; García-Sánchez, Félix; Lassaletta, Alvaro; García-Sanz, Ramón

2009-01-01

MLL-AF4 fusion is a hallmark genetic abnormality in infant B-acute lymphoblastic leukemia (B-ALL) known to arise in utero. The cellular origin of leukemic fusion genes during human development is difficult to ascertain. The bone marrow (BM) microenvironment plays an important role in the pathogenesis of several hematological malignances. BM mesenchymal stem cells (BM-MSC) from 38 children diagnosed with cytogenetically different acute leukemias were screened for leukemic fusion genes. Fusion genes were absent in BM-MSCs of childhood leukemias carrying TEL-AML1, BCR-ABL, AML1-ETO, MLL-AF9, MLL-AF10, MLL-ENL or hyperdiploidy. However, MLL-AF4 was detected and expressed in BM-MSCs from all cases of MLL-AF4+ B-ALL. Unlike leukemic blasts, MLL-AF4+ BM-MSCs did not display monoclonal Ig gene rearrangements. Endogenous or ectopic expression of MLL-AF4 exerted no effect on MSC culture homeostasis. These findings suggest that MSCs may be in part tumor-related, highlighting an unrecognized role of the BM milieu on the pathogenesis of MLL-AF4+ B-ALL. MLL-AF4 itself is not sufficient for MSC transformation and the expression of MLL-AF4 in MSCs is compatible with a mesenchymal phenotype, suggesting a differential impact in the hematopoietic system and mesenchyme. The absence of monoclonal rearrangements in MLL-AF4+ BM-MSCs precludes the possibility of cellular plasticity or de-differentiation of B-ALL blasts and suggests that MLL-AF4 might arise in a population of prehematopoietic precursors. PMID:19995953

Acaricidal activity of petroleum ether extract of neem (Azadirachta indica) oil and its four fractions separated by column chromatography against Sarcoptes scabiei var. cuniculi larvae in vitro.

PubMed

Deng, Yunxia; Shi, Dongxia; Yin, Zhongqiong; Guo, Jianhong; Jia, Renyong; Xu, Jiao; Song, Xu; Lv, Cheng; Fan, Qiaojia; Liang, Xiaoxia; Shi, Fei; Ye, Gang; Zhang, Wei

2012-04-01

The petroleum ether extract of neem oil and its four fractions separated by column chromatography was diluted at different concentrations with liquid paraffin. The acaricidal bioassay was conducted using a dipping method. The results indicated that the median lethal concentration (LC50) of the petroleum ether extract (at the concentration of 500.0ml/l) was 70.9ml/l, 24h after treatment. At concentrations of 500.0, 250.0, 125.0, 62.5 and 31.2ml/l, the median lethal times (LT50) of the petroleum ether extract were 8.7, 8.8, 10.8, 11.5 and 13.1h, respectively. Thin-layer chromatography (TLC) showed that the petroleum ether extract of neem oil separated into four fractions (F1-F4). Acaricidal activity of 68.3% and 100.0% in the F2 and F4 was confirmed. These results suggest that petroleum ether extracts of neem oil and its four fractions possess useful acaricidal activity in vitro. Copyright © 2012 Elsevier Inc. All rights reserved.

Efficiency of a multilayer-Laue-lens with a 102 μm aperture

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

Macrander, Albert T., E-mail: atm@anl.gov; Wojcik, Michael; Maser, Jorg

2015-08-24

A multilayer-Laue-lens (MLL) comprised of WSi{sub 2}/Al layers stacked to a full thickness of 102 μm was characterized for its diffraction efficiency and dynamical diffraction properties by x-ray measurements made in the far field. The achieved aperture roughly doubles the previous maximum reported aperture for an MLL, thereby doubling the working distance. Negative and positive first orders were found to have 14.2% and 13.0% efficiencies, respectively. A section thickness of 9.6 μm was determined from Laue-case thickness fringes in the diffraction data. A background gas consisting of 90% Ar and 10% N{sub 2} was used for sputtering. This material system wasmore » chosen to reduce grown-in stress as the multilayer is deposited. Although some regions of the full MLL exhibited defects, the presently reported results were obtained for a region devoid of defects. The data compare well to dynamical diffraction calculations with Coupled Wave Theory (CWT) which provided confirmation of the optical constants and densities assumed for the CWT calculations.« less

Efficiency of a multilayer-Laue-lens with a 102 μm aperture

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

Macrander, Albert T.; Kubec, Adam; Conley, Raymond

2015-08-25

A multilayer-Laue-lens (MLL) comprised of WSi 2/Al layers stacked to a full thickness of 102 microns was characterized for its diffraction efficiency and dynamical diffraction properties by x-ray measurements made in the far field. The achieved aperture roughly doubles the previous maximum reported aperture for an MLL, thereby doubling the working distance. Negative and positive first orders were found to have 14.2 % and 13.0 % efficiencies, respectively. A section thickness of 9.6 μm was determined from Laue-case thickness fringes in the diffraction data. A background gas consisting of 90 % Ar and 10 % N 2 was used formore » sputtering. This material system was chosen to reduce grown-in stress as the multilayer is deposited. Although some regions of the full MLL exhibited defects, the presently reported results were obtained for a region devoid of defects. The data compare well to dynamical diffraction calculations with Coupled Wave Theory (CWT) which provided confirmation of the optical constants and densities assumed for the CWT calculations.« less

Targeting protein-protein interaction between MLL1 and reciprocal proteins for leukemia therapy.

PubMed

Wang, Zhi-Hui; Li, Dong-Dong; Chen, Wei-Lin; You, Qi-Dong; Guo, Xiao-Ke

2018-01-15

The mixed lineage leukemia protein-1 (MLL1), as a lysine methyltransferase, predominantly regulates the methylation of histone H3 lysine 4 (H3K4) and functions in hematopoietic stem cell (HSC) self-renewal. MLL1 gene fuses with partner genes that results in the generation of MLL1 fusion proteins (MLL1-FPs), which are frequently detected in acute leukemia. In the progress of leukemogenesis, a great deal of proteins cooperate with MLL1 to form multiprotein complexes serving for the dysregulation of H3K4 methylation, the overexpression of homeobox (HOX) cluster genes, and the consequent generation of leukemia. Hence, disrupting the interactions between MLL1 and the reciprocal proteins has been considered to be a new treatment strategy for leukemia. Here, we reviewed potential protein-protein interactions (PPIs) between MLL1 and its reciprocal proteins, and summarized the inhibitors to target MLL1 PPIs. The druggability of MLL1 PPIs for leukemia were also discussed. Copyright © 2017. Published by Elsevier Ltd.

Expression of HOXB genes is significantly different in acute myeloid leukemia with a partial tandem duplication of MLL vs. a MLL translocation: a cross-laboratory study.

PubMed

Liu, Hsi-Che; Shih, Lee-Yung; May Chen, Mei-Ju; Wang, Chien-Chih; Yeh, Ting-Chi; Lin, Tung-Huei; Chen, Chien-Yu; Lin, Chih-Jen; Liang, Der-Cherng

2011-05-01

In acute myeloid leukemia (AML), the mixed lineage leukemia (MLL) gene may be rearranged to generate a partial tandem duplication (PTD), or fused to partner genes through a chromosomal translocation (tMLL). In this study, we first explored the differentially expressed genes between MLL-PTD and tMLL using gene expression profiling of our cohort (15 MLL-PTD and 10 tMLL) and one published data set. The top 250 probes were chosen from each set, resulting in 29 common probes (21 unique genes) to both sets. The selected genes include four HOXB genes, HOXB2, B3, B5, and B6. The expression values of these HOXB genes significantly differ between MLL-PTD and tMLL cases. Clustering and classification analyses were thoroughly conducted to support our gene selection results. Second, as MLL-PTD, FLT3-ITD, and NPM1 mutations are identified in AML with normal karyotypes, we briefly studied their impact on the HOXB genes. Another contribution of this study is to demonstrate that using public data from other studies enriches samples for analysis and yields more conclusive results. 2011 Elsevier Inc. All rights reserved.

Two decades of leukemia oncoprotein epistasis: the MLL1 paradigm for epigenetic deregulation in leukemia

PubMed Central

Li, Bin E.; Ernst, Patricia

2015-01-01

MLL1, located on human chromosome 11, is disrupted in distinct recurrent chromosomal translocations in several leukemia subsets. Studying the MLL1 gene and its oncogenic variants has provided a paradigm for understanding cancer initiation and maintenance through aberrant epigenetic gene regulation. Here we review the historical development of model systems to recapitulate oncogenic MLL1-rearrangement (MLL-r) alleles encoding mixed-lineage leukemia fusion proteins (MLL-FPs) or internal gene rearrangement products. These largely mouse and human cell/xenograft systems have been generated and used to understand how MLL-r alleles affect diverse pathways to result in a highly penetrant, drug-resistant leukemia. The particular features of the animal models influenced the conclusions of mechanisms of transformation. We discuss significant downstream enablers, inhibitors, effectors, and collaborators of MLL-r leukemia, including molecules that directly interact with MLL-FPs and endogenous mixed-lineage leukemia protein, direct target genes of MLL-FPs, and other pathways that have proven to be influential in supporting or suppressing the leukemogenic activity of MLL-FPs. The use of animal models has been complemented with patient sample, genome-wide analyses to delineate the important genomic and epigenomic changes that occur in distinct subsets of MLL-r leukemia. Collectively, these studies have resulted in rapid progress toward developing new strategies for targeting MLL-r leukemia and general cell-biological principles that may broadly inform targeting aberrant epigenetic regulators in other cancers. PMID:25264566

Mll5 Is Required for Normal Spermatogenesis

PubMed Central

Yap, Damian B.; Walker, David C.; Prentice, Leah M.; McKinney, Steven; Turashvili, Gulisa; Mooslehner-Allen, Katrin; de Algara, Teresa Ruiz; Fee, John; de Tassigny, Xavier d'Anglemont; Colledge, William H.; Aparicio, Samuel

2011-01-01

Background Mll5 is currently a member of the Mll family of SET domain histone methyltransferase proteins but studies have also showed that it could be part of the SET3 branch of proteins. Recently, constitutive knock out animal studies have shown that Mll5 is required for proper haematopoietic stem cell differentiation, and loss of Mll5 results in synthetic lethality for genome de-methylation. Mll5 deficient male mice are infertile and here we analyse the consequences of Mll5 deficiency for spermatogenesis. Methodology/Principal Findings Mll5 deficient male mice, but not female mice, are infertile. Here we show using RNA in-situ hybridization that Mll5 is expressed in the germ cells of the testes of wild type mice. Consistent with the expression of Mll5, we demonstrate by electron microscopy, video microscopy and in vitro fertilisation techniques that Mll5 deficient mice have defects in terminal maturation and packaging of sperm. The defects seen include detachment of the acrosomal cap and impaired excess cytoplasm removal. Functional tests of sperm motility show a lack of progressive motility of spermatozoa from Mll5 deficient animals. None of these defects could be rescued by in vitro fertilization. Using microarray analysis we show that transcripts implicated in spermatogenesis are dysregulated. Conclusions/Significance Our data demonstrate a clear role of Mll5 in mammalian spermatogenesis at the level of terminal differentiation providing further support for its classification in the SET3 branch of proteins. Moreover, this study identifies Tlk2, Utx, Gpr64, Sult4a1, Rap2ip, Vstm2 and HoxA10 as possible Mll5 targets that together may account for the observed spermatozoa maturation defects. PMID:22069496

Developmentally induced Mll1 loss reveals defects in postnatal haematopoiesis.

PubMed

Gan, T; Jude, C D; Zaffuto, K; Ernst, P

2010-10-01

The mixed lineage leukemia (MLL) gene is disrupted by chromosomal translocations in acute leukemia, producing a fusion oncogene with altered properties relative to the wild-type gene. Murine loss-of-function studies have shown an essential role for Mll in developing the haematopoietic system, yet studies using different conditional knockout models have yielded conflicting results regarding the requirement for Mll during adult steady-state haematopoiesis. In this study, we used a loxP-flanked Mll allele (Mll(F)) and a developmentally regulated, haematopoietic-specific VavCre transgene to reassess the consequences of Mll loss in the haematopoietic lineage, without the need for inducers of Cre recombinase. We show that VavCre;Mll mutants exhibit phenotypically normal fetal haematopoiesis, but rarely survive past 3 weeks of age. Surviving animals are anemic, thrombocytopenic and exhibit a significant reduction in bone marrow haematopoietic stem/progenitor populations, consistent with our previous findings using the inducible Mx1Cre transgene. Furthermore, the analysis of VavCre mutants revealed additional defects in B-lymphopoiesis that could not be assessed using Mx1Cre-mediated Mll deletion. Collectively, these data support the conclusion that Mll has an essential role in sustaining postnatal haematopoiesis.

The MLL recombinome of acute leukemias in 2017.

PubMed

Meyer, C; Burmeister, T; Gröger, D; Tsaur, G; Fechina, L; Renneville, A; Sutton, R; Venn, N C; Emerenciano, M; Pombo-de-Oliveira, M S; Barbieri Blunck, C; Almeida Lopes, B; Zuna, J; Trka, J; Ballerini, P; Lapillonne, H; De Braekeleer, M; Cazzaniga, G; Corral Abascal, L; van der Velden, V H J; Delabesse, E; Park, T S; Oh, S H; Silva, M L M; Lund-Aho, T; Juvonen, V; Moore, A S; Heidenreich, O; Vormoor, J; Zerkalenkova, E; Olshanskaya, Y; Bueno, C; Menendez, P; Teigler-Schlegel, A; Zur Stadt, U; Lentes, J; Göhring, G; Kustanovich, A; Aleinikova, O; Schäfer, B W; Kubetzko, S; Madsen, H O; Gruhn, B; Duarte, X; Gameiro, P; Lippert, E; Bidet, A; Cayuela, J M; Clappier, E; Alonso, C N; Zwaan, C M; van den Heuvel-Eibrink, M M; Izraeli, S; Trakhtenbrot, L; Archer, P; Hancock, J; Möricke, A; Alten, J; Schrappe, M; Stanulla, M; Strehl, S; Attarbaschi, A; Dworzak, M; Haas, O A; Panzer-Grümayer, R; Sedék, L; Szczepański, T; Caye, A; Suarez, L; Cavé, H; Marschalek, R

2018-02-01

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients.

Effective Targeting of the P53/MDM2 Axis in Preclinical Models of Infant MLL-Rearranged Acute Lymphoblastic Leukemia

PubMed Central

Richmond, Jennifer; Carol, Hernan; Evans, Kathryn; High, Laura; Mendomo, Agnes; Robbins, Alissa; Meyer, Claus; Venn, Nicola C.; Marschalek, Rolf; Henderson, Michelle; Sutton, Rosemary; Kurmasheva, Raushan T.; Kees, Ursula R.; Houghton, Peter J.; Smith, Malcolm A.; Lock, Richard B.

2015-01-01

Purpose While the overall cure rate for pediatric acute lymphoblastic leukemia (ALL) approaches 90%, infants with ALL harboring translocations in the mixed-lineage leukemia (MLL) oncogene (infant MLL-ALL) experience shorter remission duration and lower survival rates (∼50%). Mutations in the p53 tumor suppressor gene are uncommon in infant MLL-ALL, and drugs that release p53 from inhibitory mechanisms may be beneficial. The purpose of this study was to assess the efficacy of the orally available nutlin, RG7112, against patient-derived MLL-ALL xenografts. Experimental Design Eight MLL-ALL patient-derived xenografts were established in immune-deficient mice, and their molecular features compared with B-lineage ALL and T-ALL xenografts. The sensitivity of MLL-ALL xenografts to RG7112 was assessed in vitro and in vivo, and the ability of RG7112 to induce p53, cell cycle arrest and apoptosis in vivo was evaluated. Results Gene expression analysis revealed that MLL-ALL, B-lineage ALL and T-ALL xenografts clustered according to subtype. Moreover, genes previously reported to be over-expressed in MLL-ALL, including MEIS1, CCNA1, and members of the HOXA family, were significantly up-regulated in MLL-ALL xenografts, confirming their ability to recapitulate the clinical disease. Exposure of MLL-ALL xenografts to RG7112 in vivo caused p53 up-regulation, cell cycle arrest and apoptosis. RG7112 as a single agent induced significant regressions in infant MLL-ALL xenografts. Therapeutic enhancement was observed when RG7112 was assessed using combination treatment with an induction-type regimen (vincristine/dexamethasone/L-asparaginase) against an MLL-ALL xenograft. Conclusion The utility of targeting the p53-MDM2 axis in combination with established drugs for the management of infant MLL-ALL warrants further investigation. PMID:25573381

Requirement for CDK6 in MLL-rearranged acute myeloid leukemia

PubMed Central

Placke, Theresa; Faber, Katrin; Nonami, Atsushi; Putwain, Sarah L.; Salih, Helmut R.; Heidel, Florian H.; Krämer, Alwin; Root, David E.; Barbie, David A.; Krivtsov, Andrei V.; Armstrong, Scott A.; Hahn, William C.; Huntly, Brian J.; Sykes, Stephen M.; Milsom, Michael D.; Scholl, Claudia

2014-01-01

Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9–driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts. PMID:24764564

Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4

PubMed Central

Dhar, Shilpa S.; Lee, Sung-Hun; Kan, Pu-Yeh; Voigt, Philipp; Ma, Li; Shi, Xiaobing; Reinberg, Danny; Lee, Min Gyu

2012-01-01

Mixed-lineage leukemia 4 (MLL4; also called MLL2 and ALR) enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3), a hallmark of gene activation. However, how MLL4-deposited H3K4me3 interplays with other histone marks in epigenetic processes remains largely unknown. Here, we show that MLL4 plays an essential role in differentiating NT2/D1 stem cells by activating differentiation-specific genes. A tandem plant homeodomain (PHD4–6) of MLL4 recognizes unmethylated or asymmetrically dimethylated histone H4 Arg 3 (H4R3me0 or H4R3me2a) and is required for MLL4's nucleosomal methyltransferase activity and MLL4-mediated differentiation. Kabuki syndrome mutations in PHD4–6 reduce PHD4–6's binding ability and MLL4's catalytic activity. PHD4–6's binding strength is inhibited by H4R3 symmetric dimethylation (H4R3me2s), a gene-repressive mark. The protein arginine methyltransferase 7 (PRMT7), but not PRMT5, represses MLL4 target genes by up-regulating H4R3me2s levels and antagonizes MLL4-mediated differentiation. Consistently, PRMT7 knockdown increases MLL4-catalyzed H3K4me3 levels. During differentiation, decreased H4R3me2s levels are associated with increased H3K4me3 levels at a cohort of genes, including many HOXA and HOXB genes. These findings indicate that the trans-tail inhibition of MLL4-generated H3K4me3 by PRMT7-regulated H4R3me2s may result from H4R3me2s's interference with PHD4–6's binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation. PMID:23249737

Trans-tail regulation of MLL4-catalyzed H3K4 methylation by H4R3 symmetric dimethylation is mediated by a tandem PHD of MLL4.

PubMed

Dhar, Shilpa S; Lee, Sung-Hun; Kan, Pu-Yeh; Voigt, Philipp; Ma, Li; Shi, Xiaobing; Reinberg, Danny; Lee, Min Gyu

2012-12-15

Mixed-lineage leukemia 4 (MLL4; also called MLL2 and ALR) enzymatically generates trimethylated histone H3 Lys 4 (H3K4me3), a hallmark of gene activation. However, how MLL4-deposited H3K4me3 interplays with other histone marks in epigenetic processes remains largely unknown. Here, we show that MLL4 plays an essential role in differentiating NT2/D1 stem cells by activating differentiation-specific genes. A tandem plant homeodomain (PHD(4-6)) of MLL4 recognizes unmethylated or asymmetrically dimethylated histone H4 Arg 3 (H4R3me0 or H4R3me2a) and is required for MLL4's nucleosomal methyltransferase activity and MLL4-mediated differentiation. Kabuki syndrome mutations in PHD(4-6) reduce PHD(4-6)'s binding ability and MLL4's catalytic activity. PHD(4-6)'s binding strength is inhibited by H4R3 symmetric dimethylation (H4R3me2s), a gene-repressive mark. The protein arginine methyltransferase 7 (PRMT7), but not PRMT5, represses MLL4 target genes by up-regulating H4R3me2s levels and antagonizes MLL4-mediated differentiation. Consistently, PRMT7 knockdown increases MLL4-catalyzed H3K4me3 levels. During differentiation, decreased H4R3me2s levels are associated with increased H3K4me3 levels at a cohort of genes, including many HOXA and HOXB genes. These findings indicate that the trans-tail inhibition of MLL4-generated H3K4me3 by PRMT7-regulated H4R3me2s may result from H4R3me2s's interference with PHD(4-6)'s binding activity and is a novel epigenetic mechanism that underlies opposing effects of MLL4 and PRMT7 on cellular differentiation.

HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development.

PubMed

Deng, Changwang; Li, Ying; Zhou, Lei; Cho, Joonseok; Patel, Bhavita; Terada, Naohiro; Li, Yangqiu; Bungert, Jörg; Qiu, Yi; Huang, Suming

2016-01-05

Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive. We report here that HoxBlinc RNA first specifies Flk1(+) mesoderm and then promotes hematopoietic differentiation through regulation of hoxb pathways. HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes. Depletion of HoxBlinc by shRNA-mediated knockdown or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxb genes and other factors regulating cardiac/hematopoietic differentiation. Reduced hoxb expression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2-b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1(+) precursors that undergo hematopoietic differentiation. Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1(+) precursors and differentiation of Flk1(+) cells into hematopoietic lineages. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

HoxBlinc RNA recruits Set1/MLL complexes to activate Hox gene expression patterns and mesoderm lineage development

PubMed Central

Deng, Changwang; Li, Ying; Zhou, Lei; Cho, Joonseok; Patel, Bhavita; Terada, Nao; Li, Yangqiu; Bungert, Jörg; Qiu, Yi; Huang, Suming

2015-01-01

Summary Trithorax proteins and long-intergenic noncoding RNAs are critical regulators of embryonic stem cell pluripotency; however, how they cooperatively regulate germ layer mesoderm specification remains elusive. We report here that HoxBlinc RNA first specifies Flk1+ mesoderm and then promotes hematopoietic differentiation through regulating hoxb gene pathways. HoxBlinc binds to the hoxb genes, recruits Setd1a/MLL1 complexes, and mediates long-range chromatin interactions to activate transcription of the hoxb genes. Depletion of HoxBlinc by shRNA-mediated KD or CRISPR-Cas9-mediated genetic deletion inhibits expression of hoxb genes and other factors regulating cardiac/hematopoietic differentiation. Reduced hoxb gene expression is accompanied by decreased recruitment of Set1/MLL1 and H3K4me3 modification, as well as by reduced chromatin loop formation. Re-expression of hoxb2-b4 genes in HoxBlinc-depleted embryoid bodies rescues Flk1+ precursors that undergo hematopoietic differentiation. Thus, HoxBlinc plays an important role in controlling hoxb transcription networks that mediate specification of mesoderm-derived Flk1+ precursors and differentiation of Flk1+ cells into hematopoietic lineages. PMID:26725110

The MLL recombinome of acute leukemias in 2017

PubMed Central

Meyer, C; Burmeister, T; Gröger, D; Tsaur, G; Fechina, L; Renneville, A; Sutton, R; Venn, N C; Emerenciano, M; Pombo-de-Oliveira, M S; Barbieri Blunck, C; Almeida Lopes, B; Zuna, J; Trka, J; Ballerini, P; Lapillonne, H; De Braekeleer, M; Cazzaniga, G; Corral Abascal, L; van der Velden, V H J; Delabesse, E; Park, T S; Oh, S H; Silva, M L M; Lund-Aho, T; Juvonen, V; Moore, A S; Heidenreich, O; Vormoor, J; Zerkalenkova, E; Olshanskaya, Y; Bueno, C; Menendez, P; Teigler-Schlegel, A; zur Stadt, U; Lentes, J; Göhring, G; Kustanovich, A; Aleinikova, O; Schäfer, B W; Kubetzko, S; Madsen, H O; Gruhn, B; Duarte, X; Gameiro, P; Lippert, E; Bidet, A; Cayuela, J M; Clappier, E; Alonso, C N; Zwaan, C M; van den Heuvel-Eibrink, M M; Izraeli, S; Trakhtenbrot, L; Archer, P; Hancock, J; Möricke, A; Alten, J; Schrappe, M; Stanulla, M; Strehl, S; Attarbaschi, A; Dworzak, M; Haas, O A; Panzer-Grümayer, R; Sedék, L; Szczepański, T; Caye, A; Suarez, L; Cavé, H; Marschalek, R

2018-01-01

Chromosomal rearrangements of the human MLL/KMT2A gene are associated with infant, pediatric, adult and therapy-induced acute leukemias. Here we present the data obtained from 2345 acute leukemia patients. Genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and 11 novel TPGs were identified. Thus, a total of 135 different MLL rearrangements have been identified so far, of which 94 TPGs are now characterized at the molecular level. In all, 35 out of these 94 TPGs occur recurrently, but only 9 specific gene fusions account for more than 90% of all illegitimate recombinations of the MLL gene. We observed an age-dependent breakpoint shift with breakpoints localizing within MLL intron 11 associated with acute lymphoblastic leukemia and younger patients, while breakpoints in MLL intron 9 predominate in AML or older patients. The molecular characterization of MLL breakpoints suggests different etiologies in the different age groups and allows the correlation of functional domains of the MLL gene with clinical outcome. This study provides a comprehensive analysis of the MLL recombinome in acute leukemia and demonstrates that the establishment of patient-specific chromosomal fusion sites allows the design of specific PCR primers for minimal residual disease analyses for all patients. PMID:28701730

Identification of CD34+ and CD34− leukemia-initiating cells in MLL-rearranged human acute lymphoblastic leukemia

PubMed Central

Aoki, Yuki; Watanabe, Takashi; Saito, Yoriko; Kuroki, Yoko; Hijikata, Atsushi; Takagi, Masatoshi; Tomizawa, Daisuke; Eguchi, Mariko; Eguchi-Ishimae, Minenori; Kaneko, Akiko; Ono, Rintaro; Sato, Kaori; Suzuki, Nahoko; Fujiki, Saera; Koh, Katsuyoshi; Ishii, Eiichi; Shultz, Leonard D.; Ohara, Osamu; Mizutani, Shuki

2015-01-01

Translocation of the mixed-lineage leukemia (MLL) gene with AF4, AF9, or ENL results in acute leukemia with both lymphoid and myeloid involvement. We characterized leukemia-initiating cells (LICs) in primary infant MLL-rearranged leukemia using a xenotransplantation model. In MLL-AF4 patients, CD34+CD38+CD19+ and CD34−CD19+ cells initiated leukemia, and in MLL-AF9 patients, CD34−CD19+ cells were LICs. In MLL-ENL patients, either CD34+ or CD34− cells were LICs, depending on the pattern of CD34 expression. In contrast, in patients with these MLL translocations, CD34+CD38−CD19−CD33− cells were enriched for normal hematopoietic stem cells (HSCs) with in vivo long-term multilineage hematopoietic repopulation capacity. Although LICs developed leukemic cells with clonal immunoglobulin heavy-chain (IGH) rearrangement in vivo, CD34+CD38−CD19−CD33− cells repopulated recipient bone marrow and spleen with B cells, showing broad polyclonal IGH rearrangement and recipient thymus with CD4+ single positive (SP), CD8+ SP, and CD4+CD8+ double-positive (DP) T cells. Global gene expression profiling revealed that CD9, CD32, and CD24 were over-represented in MLL-AF4, MLL-AF9, and MLL-ENL LICs compared with normal HSCs. In patient samples, these molecules were expressed in CD34+CD38+ and CD34− LICs but not in CD34+CD38−CD19−CD33− HSCs. Identification of LICs and LIC-specific molecules in primary human MLL-rearranged acute lymphoblastic leukemia may lead to improved therapeutic strategies for MLL-rearranged leukemia. PMID:25538041

MLL/WDR5 Complex Regulates Kif2A Localization to Ensure Chromosome Congression and Proper Spindle Assembly during Mitosis.

PubMed

Ali, Aamir; Veeranki, Sailaja Naga; Chinchole, Akash; Tyagi, Shweta

2017-06-19

Mixed-lineage leukemia (MLL), along with multisubunit (WDR5, RbBP5, ASH2L, and DPY30) complex catalyzes the trimethylation of H3K4, leading to gene activation. Here, we characterize a chromatin-independent role for MLL during mitosis. MLL and WDR5 localize to the mitotic spindle apparatus, and loss of function of MLL complex by RNAi results in defects in chromosome congression and compromised spindle formation. We report interaction of MLL complex with several kinesin and dynein motors. We further show that the MLL complex associates with Kif2A, a member of the Kinesin-13 family of microtubule depolymerase, and regulates the spindle localization of Kif2A during mitosis. We have identified a conserved WDR5 interaction (Win) motif, so far unique to the MLL family, in Kif2A. The Win motif of Kif2A engages in direct interactions with WDR5 for its spindle localization. Our findings highlight a non-canonical mitotic function of MLL complex, which may have a direct impact on chromosomal stability, frequently compromised in cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

Long-term disease-free survivors with cytogenetically normal acute myeloid leukemia and MLL partial tandem duplication: a Cancer and Leukemia Group B study

PubMed Central

Ruppert, Amy S.; Marcucci, Guido; Mrózek, Krzysztof; Paschka, Peter; Langer, Christian; Baldus, Claudia D.; Wen, Jing; Vukosavljevic, Tamara; Powell, Bayard L.; Carroll, Andrew J.; Kolitz, Jonathan E.; Larson, Richard A.; Caligiuri, Michael A.; Bloomfield, Clara D.

2007-01-01

The clinical impact of MLL partial tandem duplication (MLL-PTD) was evaluated in 238 adults aged 18 to 59 years with cytogenetically normal (CN) de novo acute myeloid leukemia (AML) who were treated intensively on similar Cancer and Leukemia Group B protocols 9621 and 19808. Twenty-four (10.1%) patients harbored an MLL-PTD. Of those, 92% achieved complete remission (CR) compared with 83% of patients without MLL-PTD (P = .39). Neither overall survival nor disease-free survival significantly differed between the 2 groups (P = .67 and P = .55, respectively). Thirteen MLL-PTD+ patients relapsed within 1.4 years of achieving CR. MLL-PTD+ patients who relapsed more often had other adverse CN-AML–associated molecular markers. In contrast with previously reported studies, 9 (41%) MLL-PTD+ patients continue in long-term first remission (CR1; range, 2.5-7.7 years). Intensive consolidation therapy that included autologous peripheral stem-cell transplantation during CR1 may have contributed to the better outcome of this historically poor-prognosis group of CN-AML patients with MLL-PTD. PMID:17341662

The distribution of MLL breakpoints correlates with outcome in infant acute leukaemia.

PubMed

Emerenciano, Mariana; Meyer, Claus; Mansur, Marcela B; Marschalek, Rolf; Pombo-de-Oliveira, Maria S

2013-04-01

Acute leukaemia in early childhood - and mainly infant leukaemia (IL) - is characterized by acquired genetic alterations, most commonly by the presence of distinct MLL rearrangements (MLL-r). The aim of this study was to investigate possible correlations between clinical features and molecular analyses of a series of 545 childhood leukaemia (≤24 months of age) cases: 385 acute lymphoblastic leukaemia (ALL) and 160 acute myeloid leukaemia (AML). The location of the genomic breakpoints was determined in a subset of 30 MLL-r cases. The overall survival of the investigated cohort was 60·5%, as determined by the Kaplan-Meier method. Worse outcomes were associated with age at diagnosis ≤6 months (P < 0·001), high white blood cell count (P = 0·001), and MLL-r (P = 0·002) in ALL, while children with AML displayed a poorer outcome (P = 0·009) regardless of their age strata. Moreover, we present first evidence that MLL-r patients with poor outcome preferentially displayed chromosomal breakpoints within MLL intron 11. Based on the literature, most MLL-r IL display a breakpoint localization towards intron 11, which in turn may explain their worse clinical course. In summary, the MLL breakpoint localization is of clinical importance and should be considered as a novel outcome predictor for MLL-r patients. © 2013 Blackwell Publishing Ltd.

Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.

PubMed

Wang, Lu; Zhao, Zibo; Ozark, Patrick A; Fantini, Damiano; Marshall, Stacy A; Rendleman, Emily J; Cozzolino, Kira A; Louis, Nundia; He, Xingyao; Morgan, Marc A; Takahashi, Yoh-Hei; Collings, Clayton K; Smith, Edwin R; Ntziachristos, Panagiotis; Savas, Jeffrey N; Zou, Lihua; Hashizume, Rintaro; Meeks, Joshua J; Shilatifard, Ali

2018-06-01

The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.

Transcription control by the ENL YEATS domain in acute leukaemia.

PubMed

Erb, Michael A; Scott, Thomas G; Li, Bin E; Xie, Huafeng; Paulk, Joshiawa; Seo, Hyuk-Soo; Souza, Amanda; Roberts, Justin M; Dastjerdi, Shiva; Buckley, Dennis L; Sanjana, Neville E; Shalem, Ophir; Nabet, Behnam; Zeid, Rhamy; Offei-Addo, Nana K; Dhe-Paganon, Sirano; Zhang, Feng; Orkin, Stuart H; Winter, Georg E; Bradner, James E

2017-03-09

Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo. To explain the mechanistic role of ENL in leukaemia pathogenesis and dynamic transcription control, a chemical genetic strategy was developed to achieve targeted protein degradation. Acute loss of ENL suppressed the initiation and elongation of RNA polymerase II at active genes genome-wide, with pronounced effects at genes featuring a disproportionate ENL load. Notably, an intact YEATS chromatin-reader domain was essential for ENL-dependent leukaemic growth. Overall, these findings identify a dependency factor in acute leukaemia and suggest a mechanistic rationale for disrupting the YEATS domain in disease.

The super elongation complex (SEC) and MLL in development and disease

PubMed Central

Smith, Edwin; Lin, Chengqi; Shilatifard, Ali

2011-01-01

Transcriptional regulation at the level of elongation is vital for the control of gene expression and metazoan development. The mixed lineage leukemia (MLL) protein and its Drosophila homolog, Trithorax, which exist within COMPASS (complex of proteins associated with Set1)-like complexes, are master regulators of development. They are required for proper homeotic gene expression, in part through methylation of histone H3 on Lys 4. In humans, the MLL gene is involved in a large number of chromosomal translocations that create chimeric proteins, fusing the N terminus of MLL to several proteins that share little sequence similarity. Several frequent translocation partners of MLL were found recently to coexist in a super elongation complex (SEC) that includes known transcription elongation factors such as eleven-nineteen lysine-rich leukemia (ELL) and P-TEFb. Importantly, the SEC is required for HOX gene expression in leukemic cells, suggesting that chromosomal translocations involving MLL could lead to the overexpression of HOX and other genes through the involvement of the SEC. Here, we review the normal developmental roles of MLL and the SEC, and how MLL fusion proteins can mediate leukemogenesis. PMID:21460034

MLL-ENL cooperates with SCF to transform primary avian multipotent cells.

PubMed

Schulte, Cathleen E; von Lindern, Marieke; Steinlein, Peter; Beug, Hartmut; Wiedemann, Leanne M

2002-08-15

The MLL gene is targeted by chromosomal translocations, which give rise to heterologous MLL fusion proteins and are associated with distinct types of acute lymphoid and myeloid leukaemia. To determine how MLL fusion proteins alter the proliferation and/or differentiation of primary haematopoietic progenitors, we introduced the MLL-AF9 and MLL-ENL fusion proteins into primary chicken bone marrow cells. Both fusion proteins caused the sustained outgrowth of immature haematopoietic cells, which was strictly dependent on stem cell factor (SCF). The renewing cells have a long in vitro lifespan exceeding the Hayflick limit of avian cells. Analysis of clonal cultures identified the renewing cells as immature, multipotent progenitors, expressing erythroid, myeloid, lymphoid and stem cell surface markers. Employing a two-step commitment/differentiation protocol involving the controlled withdrawal of SCF, the MLL-ENL-transformed progenitors could be induced to terminal erythroid or myeloid differentiation. Finally, in cooperation with the weakly leukaemogenic receptor tyrosine kinase v-Sea, the MLL-ENL fusion protein gave rise to multilineage leukaemia in chicks, suggesting that other activated, receptor tyrosine kinases can substitute for ligand-activated c-Kit in vivo.

High-Affinity Small-Molecule Inhibitors of the Menin-Mixed Lineage Leukemia (MLL) Interaction Closely Mimic a Natural Protein-Protein Interaction

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

He, Shihan; Senter, Timothy J.; Pollock, Jonathan

2014-10-02

The protein–protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin–MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ~288000 small molecules. We determined menin–inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin–MLL interactionmore » with IC 50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules.« less

The MLL recombinome of acute leukemias in 2013

PubMed Central

Meyer, C; Hofmann, J; Burmeister, T; Gröger, D; Park, T S; Emerenciano, M; Pombo de Oliveira, M; Renneville, A; Villarese, P; Macintyre, E; Cavé, H; Clappier, E; Mass-Malo, K; Zuna, J; Trka, J; De Braekeleer, E; De Braekeleer, M; Oh, S H; Tsaur, G; Fechina, L; van der Velden, V H J; van Dongen, J J M; Delabesse, E; Binato, R; Silva, M L M; Kustanovich, A; Aleinikova, O; Harris, M H; Lund-Aho, T; Juvonen, V; Heidenreich, O; Vormoor, J; Choi, W W L; Jarosova, M; Kolenova, A; Bueno, C; Menendez, P; Wehner, S; Eckert, C; Talmant, P; Tondeur, S; Lippert, E; Launay, E; Henry, C; Ballerini, P; Lapillone, H; Callanan, M B; Cayuela, J M; Herbaux, C; Cazzaniga, G; Kakadiya, P M; Bohlander, S; Ahlmann, M; Choi, J R; Gameiro, P; Lee, D S; Krauter, J; Cornillet-Lefebvre, P; Te Kronnie, G; Schäfer, B W; Kubetzko, S; Alonso, C N; zur Stadt, U; Sutton, R; Venn, N C; Izraeli, S; Trakhtenbrot, L; Madsen, H O; Archer, P; Hancock, J; Cerveira, N; Teixeira, M R; Lo Nigro, L; Möricke, A; Stanulla, M; Schrappe, M; Sedék, L; Szczepański, T; Zwaan, C M; Coenen, E A; van den Heuvel-Eibrink, M M; Strehl, S; Dworzak, M; Panzer-Grümayer, R; Dingermann, T; Klingebiel, T; Marschalek, R

2013-01-01

Chromosomal rearrangements of the human MLL (mixed lineage leukemia) gene are associated with high-risk infant, pediatric, adult and therapy-induced acute leukemias. We used long-distance inverse-polymerase chain reaction to characterize the chromosomal rearrangement of individual acute leukemia patients. We present data of the molecular characterization of 1590 MLL-rearranged biopsy samples obtained from acute leukemia patients. The precise localization of genomic breakpoints within the MLL gene and the involved translocation partner genes (TPGs) were determined and novel TPGs identified. All patients were classified according to their gender (852 females and 745 males), age at diagnosis (558 infant, 416 pediatric and 616 adult leukemia patients) and other clinical criteria. Combined data of our study and recently published data revealed a total of 121 different MLL rearrangements, of which 79 TPGs are now characterized at the molecular level. However, only seven rearrangements seem to be predominantly associated with illegitimate recombinations of the MLL gene (∼90%): AFF1/AF4, MLLT3/AF9, MLLT1/ENL, MLLT10/AF10, ELL, partial tandem duplications (MLL PTDs) and MLLT4/AF6, respectively. The MLL breakpoint distributions for all clinical relevant subtypes (gender, disease type, age at diagnosis, reciprocal, complex and therapy-induced translocations) are presented. Finally, we present the extending network of reciprocal MLL fusions deriving from complex rearrangements. PMID:23628958

Target genes discovery through copy number alteration analysis in human hepatocellular carcinoma.

PubMed

Gu, De-Leung; Chen, Yen-Hsieh; Shih, Jou-Ho; Lin, Chi-Hung; Jou, Yuh-Shan; Chen, Chian-Feng

2013-12-21

High-throughput short-read sequencing of exomes and whole cancer genomes in multiple human hepatocellular carcinoma (HCC) cohorts confirmed previously identified frequently mutated somatic genes, such as TP53, CTNNB1 and AXIN1, and identified several novel genes with moderate mutation frequencies, including ARID1A, ARID2, MLL, MLL2, MLL3, MLL4, IRF2, ATM, CDKN2A, FGF19, PIK3CA, RPS6KA3, JAK1, KEAP1, NFE2L2, C16orf62, LEPR, RAC2, and IL6ST. Functional classification of these mutated genes suggested that alterations in pathways participating in chromatin remodeling, Wnt/β-catenin signaling, JAK/STAT signaling, and oxidative stress play critical roles in HCC tumorigenesis. Nevertheless, because there are few druggable genes used in HCC therapy, the identification of new therapeutic targets through integrated genomic approaches remains an important task. Because a large amount of HCC genomic data genotyped by high density single nucleotide polymorphism arrays is deposited in the public domain, copy number alteration (CNA) analyses of these arrays is a cost-effective way to reveal target genes through profiling of recurrent and overlapping amplicons, homozygous deletions and potentially unbalanced chromosomal translocations accumulated during HCC progression. Moreover, integration of CNAs with other high-throughput genomic data, such as aberrantly coding transcriptomes and non-coding gene expression in human HCC tissues and rodent HCC models, provides lines of evidence that can be used to facilitate the identification of novel HCC target genes with the potential of improving the survival of HCC patients.

Phenotypic Analysis of ATM Protein Kinase in DNA Double-Strand Break Formation and Repair.

PubMed

Mian, Elisabeth; Wiesmüller, Lisa

2017-01-01

Ataxia telangiectasia mutated (ATM) encodes a serine/threonine protein kinase, which is involved in various regulatory processes in mammalian cells. Its best-known role is apical activation of the DNA damage response following generation of DNA double-strand breaks (DSBs). When DSBs appear, sensor and mediator proteins are recruited, activating transducers such as ATM, which in turn relay a widespread signal to a multitude of downstream effectors. ATM mutation causes Ataxia telangiectasia (AT), whereby the disease phenotype shows differing characteristics depending on the underlying ATM mutation. However, all phenotypes share progressive neurodegeneration and marked predisposition to malignancies at the organismal level and sensitivity to ionizing radiation and chromosome aberrations at the cellular level. Expression and localization of the ATM protein can be determined via western blotting and immunofluorescence microscopy; however, detection of subtle alterations such as resulting from amino acid exchanges rather than truncating mutations requires functional testing. Previous studies on the role of ATM in DSB repair, which connects with radiosensitivity and chromosomal stability, gave at first sight contradictory results. To systematically explore the effects of clinically relevant ATM mutations on DSB repair, we engaged a series of lymphoblastoid cell lines (LCLs) derived from AT patients and controls. To examine DSB repair both in a quantitative and qualitative manners, we used an EGFP-based assay comprising different substrates for distinct DSB repair mechanisms. In this way, we demonstrated that particular signaling defects caused by individual ATM mutations led to specific DSB repair phenotypes. To explore the impact of ATM on carcinogenic chromosomal aberrations, we monitored chromosomal breakage at a breakpoint cluster region hotspot within the MLL gene that has been associated with therapy-related leukemia. PCR-based MLL-breakage analysis of HeLa cells treated with and without pharmacological kinase inhibitors revealed ATM-dependent chromatin remodeling at the MLL break site giving access to DNA repair proteins but also nucleases triggering MLL rearrangements. This chapter summarizes these methods for functional characterization of ATM in patient LCLs and human cell lines.

[Diagnostic and Treatment Strategies in Morel-Lavallee Lesions in the Spinal Column and Pelvis].

PubMed

Becker, Christopher A; Kammerlander, Christian; Greiner, Axel; Sommer, Fabian; Linhart, Christoph; Böcker, Wolfgang; Rubenbauer, Bianka; Weidert, Simon

2018-04-12

The Morel-Lavallée lesion is one of the concomitant soft tissue lesions of pelvic fractures. Its role in spine fractures and its treatment in combination with osteosynthesis of pelvic or spine fractures have not yet been determined. The aim of this study was to analyse the best diagnostic and treatment options of both spine and pelvic fractures combined with Morel-Lavallée lesions (MLL). An analysis of the literature was performed via PubMed and Medline. This revealed a total of 197 studies and case reports. After analysing the literature, 19 studies/case reports met our inclusion criteria. There are several diagnostic options for MLL, including ultrasound, computed tomography or MRI. In spinal and pelvic lesions, ultrasound is capable of detecting MLL. Some authors tend to perform open debridement of the MLL, whereas others recommend percutanous treatment. Open debridement and vacuum-assisted closure are recommended in late diagnosed MLL, where primary suture of the soft tissue is impossible. Fracture fixation should be performed simultaneously to treatment of the MLL. Broad-spectrum cephalosporins combined with an aminoglycoside or piperacilline/tazobactam should be initiated. Radical debridement and drainage are recommended, especially when MLL is diagnosed late. Repeated ultrasound examinations should be performed of the surrounding soft tissue of the fracture. When MLL is diagnosed within 2 days, percutanous fracture and MLL treatment should be performed. After more than 2 days, both fracture and MLL should be treated with open debridement, open fracture fixation and primary suture if possible. Georg Thieme Verlag KG Stuttgart · New York.

MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study.

PubMed

Makrythanasis, P; van Bon, B W; Steehouwer, M; Rodríguez-Santiago, B; Simpson, M; Dias, P; Anderlid, B M; Arts, P; Bhat, M; Augello, B; Biamino, E; Bongers, E M H F; Del Campo, M; Cordeiro, I; Cueto-González, A M; Cuscó, I; Deshpande, C; Frysira, E; Izatt, L; Flores, R; Galán, E; Gener, B; Gilissen, C; Granneman, S M; Hoyer, J; Yntema, H G; Kets, C M; Koolen, D A; Marcelis, C l; Medeira, A; Micale, L; Mohammed, S; de Munnik, S A; Nordgren, A; Psoni, S; Reardon, W; Revencu, N; Roscioli, T; Ruiterkamp-Versteeg, M; Santos, H G; Schoumans, J; Schuurs-Hoeijmakers, J H M; Silengo, M C; Toledo, L; Vendrell, T; van der Burgt, I; van Lier, B; Zweier, C; Reymond, A; Trembath, R C; Perez-Jurado, L; Dupont, J; de Vries, B B A; Brunner, H G; Veltman, J A; Merla, G; Antonarakis, S E; Hoischen, A

2013-12-01

Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Birth characteristics, maternal reproductive history, and the risk of infant leukemia: a report from the Children's Oncology Group.

PubMed

Spector, Logan G; Davies, Stella M; Robison, Leslie L; Hilden, Joanne M; Roesler, Michelle; Ross, Julie A

2007-01-01

Leukemias with MLL gene rearrangements predominate in infants (<1 year of age), but not in older children, and may have a distinct etiology. High birth weight, higher birth order, and prior fetal loss have, with varying consistency, been associated with infant leukemia, but no studies have reported results with respect to MLL status. Here, we report for the first time such an analysis. During 1999 to 2003, mothers of 240 incident cases (113 MLL(+), 80 MLL(-), and 47 indeterminate) and 255 random digit dialed controls completed a telephone interview. Odds ratios and 95% confidence intervals for quartile of birth weight, birth order, gestational age, maternal age at delivery, prior fetal loss, pre-pregnancy body mass index, and weight gain during pregnancy were obtained using unconditional logistic regression; P for linear trend was obtained by modeling continuous variables. There was a borderline significant linear trend of increasing birth weight with MLL(+) (P = 0.06), but not MLL(-) (P = 0.93), infant leukemia. Increasing birth order showed a significant inverse linear trend, independent of birth weight, with MLL(+) (P = 0.01), but not MLL(-) (P = 0.18), infant leukemia. Other variables of interest were not notably associated with infant leukemia regardless of MLL status. This investigation further supports the contention that molecularly defined subtypes of infant leukemia have separate etiologies.

Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.

PubMed

Mouradov, Dmitri; Sloggett, Clare; Jorissen, Robert N; Love, Christopher G; Li, Shan; Burgess, Antony W; Arango, Diego; Strausberg, Robert L; Buchanan, Daniel; Wormald, Samuel; O'Connor, Liam; Wilding, Jennifer L; Bicknell, David; Tomlinson, Ian P M; Bodmer, Walter F; Mariadason, John M; Sieber, Oliver M

2014-06-15

Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ε proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses. ©2014 American Association for Cancer Research.

Cryopreservation and gel collagen culture of porcine hepatocytes

PubMed Central

Liu, Hong-Ling; Wang, Ying-Jie; Guo, Hai-Tao; Wang, Yu-Ming; Liu, Jun; Yu, Yue-Cheng

2004-01-01

AIM: To study the method of cryopreserving porcine hepatocytes and gel collagen culture measure after its cryopreservation. METHODS: Hepatocytes, isolated from Chinese experimental suckling mini-pigs by two-step perfusion with collagenase using an extra corporeal perfusion apparatus, were cryopreserved with 50 mL/L to 200 mL/L DMSO in liquid nitrogen for 4 mo, then thawed and seeded in 1 or between 2 layers of gel collagen. The expression of porcine albumin message RNA, cellular morphology and content of aspartate aminotransferase (AST) and urea nitrogen (UN) were examined during culture in gel. RESULTS: Viability of 150 mL/L DMSO group thawed hepatocytes was (83 ± 4)%, but after purification, its viability was (90 ± 5)%, attachment efficiency was (86 ± 7)%, the viability of thawed hepatocytes was near to fresh cells. When the thawed hepatocytes were cultivated in gel collagen with culture medium adding epidermal growth factor, the hepatocytes grew in various administrative levels in mixed collagen gel, and bunchy in the sandwich configuration cultures. For up to 10 days’ culture, the typical cellular morphological characteristics of cultivated hepatocytes could be observed. The leakage of AST was lower during culture in gel than that in common culture. At the same time, the UN synthesized by cells cultivated in mixed gel collagen was higher than that in other groups. CONCLUSION: Storage in liquid nitrogen can long keep hepatocytes’ activities, the concentration of 150 mL/L DMSO is fit for porcine hepatocytes’ cryopreservation. Thawed hepatocytes can be cultivated with collagenous matrix, which provides an environment that more closely resembles that in vivo and maintain the expression of certain liver-specific function of hepatocytes. PMID:15052684

Structure of the MLL CXXC domain – DNA complex and its functional role in MLL-AF9 leukemia

PubMed Central

Cierpicki, Tomasz; Risner, Laurie E.; Grembecka, Jolanta; Lukasik, Stephen M.; Popovic, Relja; Omonkowska, Monika; Shultis, David S.; Zeleznik-Le, Nancy J.; Bushweller, John H.

2010-01-01

MLL (Mixed Lineage Leukemia) is the target of chromosomal translocations which cause leukemias with poor prognosis. All leukemogenic MLL fusion proteins retain the CXXC domain which binds to nonmethylated CpG DNA. We present the solution structure of the MLL CXXC domain in complex with DNA, showing for the first time how the CXXC domain distinguishes nonmethylated from methylated CpG DNA. Based on the structure, we designed point mutations which disrupt DNA binding. Introduction of these mutations into MLL-AF9 results in increased DNA methylation of specific CpG nucleotides in Hoxa9, increased H3K9 methylation, decreased expression of Hoxa9 locus transcripts, loss of immortalization potential, and inability to induce leukemia in mice. These results establish that DNA binding by the CXXC domain and protection against DNA methylation is essential for MLL fusion leukemia. They also provide support for this interaction as a potential target for therapeutic intervention. PMID:20010842

Epigenetic regulation of planarian stem cells by the SET1/MLL family of histone methyltransferases

PubMed Central

Hubert, Amy; Henderson, Jordana M.; Ross, Kelly G.; Cowles, Martis W.; Torres, Jessica; Zayas, Ricardo M.

2013-01-01

Chromatin regulation is a fundamental mechanism underlying stem cell pluripotency, differentiation, and the establishment of cell type-specific gene expression profiles. To examine the role of chromatin regulation in stem cells in vivo, we study regeneration in the freshwater planarian Schmidtea mediterranea. These animals possess a high concentration of pluripotent stem cells, which are capable of restoring any damaged or lost tissues after injury or amputation. Here, we identify the S. mediterranea homologs of the SET1/MLL family of histone methyltransferases and COMPASS and COMPASS-like complex proteins and investigate their role in stem cell function during regeneration. We identified six S. mediterranea homologs of the SET1/MLL family (set1, mll1/2, trr-1, trr-2, mll5–1 and mll5–2), characterized their patterns of expression in the animal, and examined their function by RNAi. All members of this family are expressed in the stem cell population and differentiated tissues. We show that set1, mll1/2, trr-1, and mll5–2 are required for regeneration and that set1, trr-1 and mll5–2 play roles in the regulation of mitosis. Most notably, knockdown of the planarian set1 homolog leads to stem cell depletion. A subset of planarian homologs of COMPASS and COMPASS-like complex proteins are also expressed in stem cells and implicated in regeneration, but the knockdown phenotypes suggest that some complex members also function in other aspects of planarian biology. This work characterizes the function of the SET1/MLL family in the context of planarian regeneration and provides insight into the role of these enzymes in adult stem cell regulation in vivo. PMID:23235145

Epigenetic regulation of planarian stem cells by the SET1/MLL family of histone methyltransferases.

PubMed

Hubert, Amy; Henderson, Jordana M; Ross, Kelly G; Cowles, Martis W; Torres, Jessica; Zayas, Ricardo M

2013-01-01

Chromatin regulation is a fundamental mechanism underlying stem cell pluripotency, differentiation, and the establishment of cell type-specific gene expression profiles. To examine the role of chromatin regulation in stem cells in vivo, we study regeneration in the freshwater planarian Schmidtea mediterranea. These animals possess a high concentration of pluripotent stem cells, which are capable of restoring any damaged or lost tissues after injury or amputation. Here, we identify the S. mediterranea homologs of the SET1/MLL family of histone methyltransferases and COMPASS and COMPASS-like complex proteins and investigate their role in stem cell function during regeneration. We identified six S. mediterranea homologs of the SET1/MLL family (set1, mll1/2, trr-1, trr-2, mll5-1 and mll5-2), characterized their patterns of expression in the animal, and examined their function by RNAi. All members of this family are expressed in the stem cell population and differentiated tissues. We show that set1, mll1/2, trr-1, and mll5-2 are required for regeneration and that set1, trr-1 and mll5-2 play roles in the regulation of mitosis. Most notably, knockdown of the planarian set1 homolog leads to stem cell depletion. A subset of planarian homologs of COMPASS and COMPASS-like complex proteins are also expressed in stem cells and implicated in regeneration, but the knockdown phenotypes suggest that some complex members also function in other aspects of planarian biology. This work characterizes the function of the SET1/MLL family in the context of planarian regeneration and provides insight into the role of these enzymes in adult stem cell regulation in vivo.

MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells

PubMed Central

Maethner, Emanuel; Garcia-Cuellar, Maria-Paz; Breitinger, Constanze; Takacova, Sylvia; Divoky, Vladimir; Hess, Jay L.; Slany, Robert K.

2014-01-01

Summary Stimulation of transcriptional elongation is a key activity of leukemogenic MLL fusion proteins. Here we provide evidence that MLL-ENL also inhibits polycomb-mediated silencing as a prerequisite for efficient transformation. Biochemical studies identified ENL as scaffold that contacted the elongation machinery as well as the PRC1 (polycomb repressive complex 1) component CBX8. These interactions were mutually exclusive in vitro corresponding to an antagonistic behavior of MLL-ENL and CBX8 in vivo. CBX8 inhibited elongation in a specific reporter assay and this effect was neutralized by direct association with ENL. Correspondingly MLL-ENL defective in CBX8 binding could not fully activate gene loci necessary for transformation. Finally, we demonstrate dimerization of MLL-ENL as neomorphic activity that may augment polycomb inhibition and transformation. PMID:23623499

How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum.

PubMed

Banka, Siddharth; Veeramachaneni, Ratna; Reardon, William; Howard, Emma; Bunstone, Sancha; Ragge, Nicola; Parker, Michael J; Crow, Yanick J; Kerr, Bronwyn; Kingston, Helen; Metcalfe, Kay; Chandler, Kate; Magee, Alex; Stewart, Fiona; McConnell, Vivienne P M; Donnelly, Deirdre E; Berland, Siren; Houge, Gunnar; Morton, Jenny E; Oley, Christine; Revencu, Nicole; Park, Soo-Mi; Davies, Sally J; Fry, Andrew E; Lynch, Sally Ann; Gill, Harinder; Schweiger, Susann; Lam, Wayne W K; Tolmie, John; Mohammed, Shehla N; Hobson, Emma; Smith, Audrey; Blyth, Moira; Bennett, Christopher; Vasudevan, Pradeep C; García-Miñaúr, Sixto; Henderson, Alex; Goodship, Judith; Wright, Michael J; Fisher, Richard; Gibbons, Richard; Price, Susan M; C de Silva, Deepthi; Temple, I Karen; Collins, Amanda L; Lachlan, Katherine; Elmslie, Frances; McEntagart, Meriel; Castle, Bruce; Clayton-Smith, Jill; Black, Graeme C; Donnai, Dian

2012-04-01

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Striking a balance: regulation of transposable elements by Zfp281 and Mll2 in mouse embryonic stem cells

PubMed Central

Dai, Qian; Shen, Yang; Wang, Yan; Wang, Xin; Francisco, Joel Celio; Luo, Zhuojuan

2017-01-01

Abstract Transposable elements (TEs) compose about 40% of the murine genome. Retrotransposition of active TEs such as LINE-1 (L1) tremendously impacts genetic diversification and genome stability. Therefore, transcription and transposition activities of retrotransposons are tightly controlled. Here, we show that the Krüppel-like zinc finger protein Zfp281 directly binds and suppresses a subset of retrotransposons, including the active young L1 repeat elements, in mouse embryonic stem (ES) cells. In addition, we find that Zfp281-regulated L1s are highly enriched for 5-hydroxymethylcytosine (5hmC) and H3K4me3. The COMPASS-like H3K4 methyltransferase Mll2 is the major H3K4me3 methylase at the Zfp281-regulated L1s and required for their proper expression. Our studies also reveal that Zfp281 functions partially through recruiting the L1 regulators DNA hydroxymethylase Tet1 and Sin3A, and restricting Mll2 at these active L1s, leading to their balanced expression. In summary, our data indicate an instrumental role of Zfp281 in suppressing the young active L1s in mouse ES cells. PMID:29036642

Striking a balance: regulation of transposable elements by Zfp281 and Mll2 in mouse embryonic stem cells.

PubMed

Dai, Qian; Shen, Yang; Wang, Yan; Wang, Xin; Francisco, Joel Celio; Luo, Zhuojuan; Lin, Chengqi

2017-12-01

Transposable elements (TEs) compose about 40% of the murine genome. Retrotransposition of active TEs such as LINE-1 (L1) tremendously impacts genetic diversification and genome stability. Therefore, transcription and transposition activities of retrotransposons are tightly controlled. Here, we show that the Krüppel-like zinc finger protein Zfp281 directly binds and suppresses a subset of retrotransposons, including the active young L1 repeat elements, in mouse embryonic stem (ES) cells. In addition, we find that Zfp281-regulated L1s are highly enriched for 5-hydroxymethylcytosine (5hmC) and H3K4me3. The COMPASS-like H3K4 methyltransferase Mll2 is the major H3K4me3 methylase at the Zfp281-regulated L1s and required for their proper expression. Our studies also reveal that Zfp281 functions partially through recruiting the L1 regulators DNA hydroxymethylase Tet1 and Sin3A, and restricting Mll2 at these active L1s, leading to their balanced expression. In summary, our data indicate an instrumental role of Zfp281 in suppressing the young active L1s in mouse ES cells. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier.

PubMed

Santos, Margarida A; Faryabi, Robert B; Ergen, Aysegul V; Day, Amanda M; Malhowski, Amy; Canela, Andres; Onozawa, Masahiro; Lee, Ji-Eun; Callen, Elsa; Gutierrez-Martinez, Paula; Chen, Hua-Tang; Wong, Nancy; Finkel, Nadia; Deshpande, Aniruddha; Sharrow, Susan; Rossi, Derrick J; Ito, Keisuke; Ge, Kai; Aplan, Peter D; Armstrong, Scott A; Nussenzweig, André

2014-10-02

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL-AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4(-/-) MLL-AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL-AF9 blasts, which requires cyclin-dependent kinase inhibitor p21(Cip1) (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia.

Mutations in Mll2, an H3K4 Methyltransferase, Result in Insulin Resistance and Impaired Glucose Tolerance in Mice

PubMed Central

Schröter, David; Matthews, Helen C.; Bogani, Debora; Moir, Lee; Long, Anna; Church, Christopher; Hugill, Alison; Anstee, Quentin M.; Goldin, Rob; Thursz, Mark; Hollfelder, Florian; Cox, Roger D.

2013-01-01

We employed a random mutagenesis approach to identify novel monogenic determinants of type 2 diabetes. Here we show that haplo-insufficiency of the histone methyltransferase myeloid-lineage leukemia (Mll2/Wbp7) gene causes type 2 diabetes in the mouse. We have shown that mice heterozygous for two separate mutations in the SET domain of Mll2 or heterozygous Mll2 knockout mice were hyperglycaemic, hyperinsulinaemic and developed non-alcoholic fatty liver disease. Consistent with previous Mll2 knockout studies, mice homozygous for either ENU mutation (or compound heterozygotes) died during embryonic development at 9.5–14.5 days post coitum. Heterozygous deletion of Mll2 induced in the adult mouse results in a normal phenotype suggesting that changes in chromatin methylation during development result in the adult phenotype. Mll2 has been shown to regulate a small subset of genes, a number of which Neurod1, Enpp1, Slc27a2, and Plcxd1 are downregulated in adult mutant mice. Our results demonstrate that histone H3K4 methyltransferase Mll2 is a component of the genetic regulation necessary for glucose homeostasis, resulting in a specific disease pattern linking chromatin modification with causes and progression of type 2 diabetes, providing a basis for its further understanding at the molecular level. PMID:23826075

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription

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

Huang, Jing; Gurung, Buddha; Wan, Bingbing

2013-04-08

Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs. Menin interacts with many proteins and is involved in a variety of cellular processes. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity. Several MEN1 missense mutations disrupt the menin-JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription. Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions asmore » an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis. A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins. Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but that it can have opposite effects on transcription. The menin-JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.« less

Toxicity and physiological effects of neem pesticides applied to rice on the Nilaparvata lugens Stål, the brown planthopper.

PubMed

Senthil-Nathan, Sengottayan; Choi, Man-Young; Paik, Chae-Hoon; Seo, Hong-Yul; Kalaivani, Kandaswamy

2009-09-01

The effects of two different neem products (Parker Oil and Neema) on mortality, food consumption and survival of the brown planthopper, Nilaparvata lugens Stål (BPH) (Homoptera: Delphacidae) were investigated. The LC(50) (3.45 ml/L for nymph and 4.42 ml/L for adult in Parker Oil treatment; 4.18 ml/L for nymph and 5.63 ml/L for adult in Neema treatment) and LC(90) (8.72 ml/L for nymph and 11.1 ml/L for adult in Parker Oil treatment; 9.84 ml/L for nymph and 13.07 ml/L for adult in Neema treatment) were identified by probit analysis. The LC(90) (equal to recommended dose) was applied in the rice field. The effective concentration of both Parker Oil and Neema took more than 48 h to kill 80% of the N. lugens. Fourth instar nymph and adult female N. lugens were caged on rice plants and exposed to a series (both LC(50) and LC(90)) of neem concentrations. Nymph and adult female N. lugens that were chronically exposed to neem pesticides showed immediate mortality after application in laboratory experiment. The quantity of food ingested and assimilated by N. lugens on neem-treated rice plants was significantly less than on control rice plants. The results clearly indicate the neem-based pesticide (Parker Oil and Neema), containing low lethal concentration, can be used effectively to inhibit the growth and survival of N. lugens.

Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.

PubMed

Hannibal, Mark C; Buckingham, Kati J; Ng, Sarah B; Ming, Jeffrey E; Beck, Anita E; McMillin, Margaret J; Gildersleeve, Heidi I; Bigham, Abigail W; Tabor, Holly K; Mefford, Heather C; Cook, Joseph; Yoshiura, Koh-ichiro; Matsumoto, Tadashi; Matsumoto, Naomichi; Miyake, Noriko; Tonoki, Hidefumi; Naritomi, Kenji; Kaname, Tadashi; Nagai, Toshiro; Ohashi, Hirofumi; Kurosawa, Kenji; Hou, Jia-Woei; Ohta, Tohru; Liang, Deshung; Sudo, Akira; Morris, Colleen A; Banka, Siddharth; Black, Graeme C; Clayton-Smith, Jill; Nickerson, Deborah A; Zackai, Elaine H; Shaikh, Tamim H; Donnai, Dian; Niikawa, Norio; Shendure, Jay; Bamshad, Michael J

2011-07-01

Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome. Copyright © 2011 Wiley-Liss, Inc.

Crystal Structure of Menin Reveals Binding Site for Mixed Lineage Leukemia (MLL) Protein

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

Murai, Marcelo J.; Chruszcz, Maksymilian; Reddy, Gireesh

2014-10-02

Menin is a tumor suppressor protein that is encoded by the MEN1 (multiple endocrine neoplasia 1) gene and controls cell growth in endocrine tissues. Importantly, menin also serves as a critical oncogenic cofactor of MLL (mixed lineage leukemia) fusion proteins in acute leukemias. Direct association of menin with MLL fusion proteins is required for MLL fusion protein-mediated leukemogenesis in vivo, and this interaction has been validated as a new potential therapeutic target for development of novel anti-leukemia agents. Here, we report the first crystal structure of menin homolog from Nematostella vectensis. Due to a very high sequence similarity, the Nematostellamore » menin is a close homolog of human menin, and these two proteins likely have very similar structures. Menin is predominantly an {alpha}-helical protein with the protein core comprising three tetratricopeptide motifs that are flanked by two {alpha}-helical bundles and covered by a {beta}-sheet motif. A very interesting feature of menin structure is the presence of a large central cavity that is highly conserved between Nematostella and human menin. By employing site-directed mutagenesis, we have demonstrated that this cavity constitutes the binding site for MLL. Our data provide a structural basis for understanding the role of menin as a tumor suppressor protein and as an oncogenic co-factor of MLL fusion proteins. It also provides essential structural information for development of inhibitors targeting the menin-MLL interaction as a novel therapeutic strategy in MLL-related leukemias.« less

MicroRNA-106b~25 cluster is upregulated in relapsed MLL-rearranged pediatric acute myeloid leukemia

PubMed Central

Verboon, Lonneke J.; Obulkasim, Askar; de Rooij, Jasmijn D.E.; Katsman, Jenny E.; Sonneveld, Edwin; Baruchel, André; Trka, Jan; Reinhardt, Dirk; Pieters, Rob; Cloos, Jacqueline; Kaspers, Gertjan J.L.; Klusmann, Jan-Henning; Zwaan, Christian Michel; Fornerod, Maarten; van den Heuvel-Eibrink, Marry M.

2016-01-01

The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements. PMID:27351222

Microenvironment Determines Lineage Fate in a Human Model of MLL-AF9 Leukemia

PubMed Central

Wei, Junping; Wunderlich, Mark; Fox, Catherine; Alvarez, Sara; Cigudosa, Juan C.; Wilhelm, Jamie S.; Zheng, Yi; Cancelas, Jose A.; Gu, Yi; Jansen, Michael; DiMartino, Jorge F.; Mulloy, James C.

2008-01-01

Summary Faithful modeling of mixed lineage leukemia in murine cells has been difficult to achieve. We show that expression of MLL-AF9 in human CD34+ cells induces acute myeloid, lymphoid or mixed lineage leukemia in immunodeficient mice. Some leukemia stem cells (LSC) were multipotent and could be lineage directed by altering either the growth factors or the recipient strain of mouse, highlighting the importance of microenviromental cues. Other LSC were strictly lineage committed, demonstrating the heterogeneity of the stem cell compartment in MLL disease. Targeting the Rac signaling pathway by pharmacologic or genetic means resulted in rapid and specific apoptosis of MLL-AF9 cells, suggesting that the Rac signaling pathway may be a valid therapeutic target in MLL-rearranged AML. PMID:18538732

SON and its alternatively spliced isoforms control MLL complex-mediated H3K4me3 and transcription of leukemia-associated genes

PubMed Central

Kim, Jung-Hyun; Baddoo, Melody C.; Park, Eun Young; Stone, Joshua K.; Park, Hyeonsoo; Butler, Thomas W.; Huang, Gang; Yan, Xiaomei; Pauli-Behn, Florencia; Myers, Richard M.; Tan, Ming; Flemington, Erik K.; Lim, Ssang-Taek; Erin Ahn, Eun-Young

2016-01-01

SUMMARY Dysregulation of MLL complex-mediated histone methylation plays a pivotal role in gene expression associated with diseases, but little is known about cellular factors modulating MLL complex activity. Here, we report that SON, previously known as an RNA splicing factor, controls MLL complex-mediated transcriptional initiation. SON binds to DNA near transcription start sites, interacts with menin, and inhibits MLL complex assembly, resulting in decreased H3K4me3 and transcriptional repression. Importantly, alternatively spliced short isoforms of SON are markedly upregulated in acute myeloid leukemia. The short isoforms compete with full-length SON for chromatin occupancy, but lack the menin-binding ability, thereby antagonizing full-length SON function in transcriptional repression while not impairing full-length SON-mediated RNA splicing. Furthermore, overexpression of a short isoform of SON enhances replating potential of hematopoietic progenitors. Our findings define SON as a fine-tuner of the MLL-menin interaction and reveal short SON overexpression as a marker indicating aberrant transcriptional initiation in leukemia. PMID:26990989

MLL duplication in a pediatric patient with B-cell lymphoblastic lymphoma.

PubMed

Mater, David Van; Goodman, Barbara K; Wang, Endi; Gaca, Ana M; Wechsler, Daniel S

2012-04-01

Lymphoblastic lymphoma is the second most common type of non-Hodgkin lymphoma seen in children. Approximately, 90% of lymphoblastic lymphomas arise from T cells, with the remaining 10% being B-cell-lineage derived. Although T-cell lymphoblastic lymphoma most frequently occurs in the anterior mediastinum (thymus), B-cell lymphoblastic lymphoma (B-LBL) predominates in extranodal sites such as skin and bone. Here, we describe a pediatric B-LBL patient who presented with extensive abdominal involvement and whose lymphoma cells displayed segmental duplication of the mixed lineage leukemia (MLL) gene. MLL duplication/amplification has been described primarily in acute myeloid leukemia and myelodysplastic syndrome with no published reports of discrete MLL duplication/amplification events in B-LBL. The MLL gene duplication noted in this case may represent a novel mechanism for tumorigenesis in B-LBL.

MLL5, a trithorax homolog, indirectly regulates H3K4 methylation, represses cyclin A2 expression, and promotes myogenic differentiation

PubMed Central

Sebastian, Soji; Sreenivas, Prethish; Sambasivan, Ramkumar; Cheedipudi, Sirisha; Kandalla, Prashanth; Pavlath, Grace K.; Dhawan, Jyotsna

2009-01-01

Most cells in adult tissues are nondividing. In skeletal muscle, differentiated myofibers have exited the cell cycle permanently, whereas satellite stem cells withdraw transiently, returning to active proliferation to repair damaged myofibers. We have examined the epigenetic mechanisms operating in conditional quiescence by analyzing the function of a predicted chromatin regulator mixed lineage leukemia 5 (MLL5) in a culture model of reversible arrest. MLL5 is induced in quiescent myoblasts and regulates both the cell cycle and differentiation via a hierarchy of chromatin and transcriptional regulators. Knocking down MLL5 delays entry of quiescent myoblasts into S phase, but hastens S-phase completion. Cyclin A2 (CycA) mRNA is no longer restricted to S phase, but is induced throughout G0/G1, with activation of the cell cycle regulated element (CCRE) in the CycA promoter. Overexpressed MLL5 physically associates with the CCRE and impairs its activity. MLL5 also regulates CycA indirectly: Cux, an activator of CycA promoter and S phase is induced in RNAi cells, and Brm/Brg1, CCRE-binding repressors that promote differentiation are repressed. In knockdown cells, H3K4 methylation at the CCRE is reduced, reflecting quantitative global changes in methylation. MLL5 appears to lack intrinsic histone methyl transferase activity, but regulates expression of histone-modifying enzymes LSD1 and SET7/9, suggesting an indirect mechanism. Finally, expression of muscle regulators Pax7, Myf5, and myogenin is impaired in MLL5 knockdown cells, which are profoundly differentiation defective. Collectively, our results suggest that MLL5 plays an integral role in novel chromatin regulatory mechanisms that suppress inappropriate expression of S-phase-promoting genes and maintain expression of determination genes in quiescent cells. PMID:19264965

Effects of Petrol Exposure on Glucose, Liver and Muscle glycogen levels in the Common African toad Bufo regularis.

PubMed

Isehunwa, G O; Yusuf, I O; Alada, A Ar

2017-03-06

This study investigated the effects of exposure to petrol on blood glucose, liver and muscle glycogen levels in the common African toad Bufo regularis. A total of 126 adult toads of either sex weighing between 70-100g were used for this study. The experiment was divided into three phases. The phase 1 experiment the acute toxicity test consisted of animals divided into six groups of 10 toads per group and were exposed to water (H2O), H2O + Tween 80, 2ml/l, 3ml/l, 5ml/l, and 10ml/l of petrol respectively for 96 hours using the static renewal bioassay system. In the Phase 2 experiment, the animals were exposed to H2O, H2O + Tween 80, 0.14ml/l, 0.3ml/l, 0.6ml/l, and 1.13ml/l of petrol respectively for 3 days; while in phase 3 experiment they were exposed to petrol solutions for 14 days. After the various exposures, the blood glucose, liver and muscle glycogen contents were determined using standard methods. The results of the study showed that the median lethal concentration of petrol (96 hours LC50) was 4.5ml/l and sub-lethal concentration of petrol caused mortality of animals. Exposure to petrol solutions for 3 days had no significant effect on blood glucose level of the animals but caused significant decrease in the liver and muscle glycogen levels at high concentrations. In the animals exposed to petrol solutions for 14 days, there was a significant increase in glucose levels and significant reduction in liver and muscle glycogen levels at high concentrations when compared with the control. The results show that sub-lethal concentrations of petrol can cause mortality of animals, hyperglycemia and reduction in liver and muscle glycogen levels. The effects of petrol exposure on carbohydrate metabolism depend on the concentration and duration of exposure.

[Application of multiplex rt-PCR assay for screening rare or cryptic chromosome translocations in de novo patients with acute myeloid leukemia].

PubMed

Chen, Hai-Min; Yuan, Hai-Yang; Fan, Xing; He, Hai-Yan; Chen, Bing; Shi, Jing-Yi; Zhu, Yong-Mei

2010-10-01

This study was aimed to investigate the clinical feasibility of using multiplex PT-PCR assay for screening rare/cryptic chromosome translocations in patients with de novo acute myeloid leukemia. For 126 patients with de novo AML-M4/M5 without common chromosome translocations including t(15;17), t(8;21) and t(16;16), 3 parallel multiplex RT-PCR assays were set up to detect 6 mll-related gene rearrangements (mll/af10, mll/af17, mll/ell, mll/af9, mll/af6 and mll/enl) with low detection rate and 4 rare fusion genes (dek/can, tls/erg, aml1/mds (evi1) and npm/mlf1). The results showed that 11 patients with positive result from 126 patients were detected which involved in 5 molecular abnormalities. Among them, 10 cases were AML-M5 (16.67%), 1 cases AML-M4 (1.51%). The marker chromosomes were observed in 2 cases out of 11 cases through conventional karyotyping analysis, the karyotyping analysis in 1 case was not performed because this case had 1 mitotic figure only, no any cytogenetic aberrations were found in other 8 cases through R-band karyotyping analysis. It is concluded that multiplex RT-PCR designed in this study can quickly, effectively and accurately identify the rare/cryptic chromosome translocations and can be used in clinical detection.

[Establishment of the retrovirus-mediated murine model with MLL-AF9 leukemia].

PubMed

Xu, Si-Miao; Yang, Yang; Zhou, Mi; Zhao, Xue-Jiao; Qin, Yu; Zhang, Pei-Ling; Yuan, Rui-Feng; Zhou, Jian-Feng; Fang, Yong

2013-10-01

This study was purposed to establish a retrovirus-mediated murine model with MLL-AF9 leukemia, so as to provide a basis for further investigation of the pathogenesis and therapeutic strategy of MLL associated leukemia. Murine (CD45.2) primary hematopoietic precursor positively selected for expression of the progenitor marker c-Kit by means of MACS were transduced with a retrovirus carrying MLL-AF9 fusion gene. After cultured in vitro, the transduced cells were injected intravenously through the tail vein into the lethally irradiated mice (CD45.1). PCR, flow cytometry and morphological observation were employed to evaluate the murine leukemia model system. The results showed that MLL-AF9 fusion gene was expressed in the infected cells, and the cells had a dramatically enhanced potential to generate myeloid colonies with primitive and immature morphology. Flow cytometric analysis revealed that the immortalized cells highly expressed myeloid lineage surface markers Gr-1 and Mac-1. Moreover, the expression levels of Hoxa9 and Meis1 mRNA were significantly higher in the MLL-AF9 cells than that in control. The mice transplanted with MLL-AF9 cells displayed typical signs of leukemia within 6-12 weeks. Extensive infiltration leukemic cells was observed in the Wright-Giemsa stained peripheral blood smear and bone marrow, and also in the histology of liver and spleen. Flow cytometric analysis of the bone marrow and spleen cells demonstrated that the CD45.2 populations expressed highly myeloid markers Gr-1 and Mac-1. The leukemic mice died within 12 weeks. It is concluded that the retrovirus-mediated murine model with MLL-AF9 leukemia is successfully established, which can be applied in the subsequent researches.

Conformational Control of the Binding of the Transactivation Domain of the MLL Protein and c-Myb to the KIX Domain of CREB

PubMed Central

Korkmaz, Elif Nihal; Nussinov, Ruth; Haliloğlu, Türkan

2012-01-01

The KIX domain of CBP is a transcriptional coactivator. Concomitant binding to the activation domain of proto-oncogene protein c-Myb and the transactivation domain of the trithorax group protein mixed lineage leukemia (MLL) transcription factor lead to the biologically active ternary MLL∶KIX∶c-Myb complex which plays a role in Pol II-mediated transcription. The binding of the activation domain of MLL to KIX enhances c-Myb binding. Here we carried out molecular dynamics (MD) simulations for the MLL∶KIX∶c-Myb ternary complex, its binary components and KIX with the goal of providing a mechanistic explanation for the experimental observations. The dynamic behavior revealed that the MLL binding site is allosterically coupled to the c-Myb binding site. MLL binding redistributes the conformational ensemble of KIX, leading to higher populations of states which favor c-Myb binding. The key element in the allosteric communication pathways is the KIX loop, which acts as a control mechanism to enhance subsequent binding events. We tested this conclusion by in silico mutations of loop residues in the KIX∶MLL complex and by comparing wild type and mutant dynamics through MD simulations. The loop assumed MLL binding conformation similar to that observed in the KIX∶c-Myb state which disfavors the allosteric network. The coupling with c-Myb binding site faded, abolishing the positive cooperativity observed in the presence of MLL. Our major conclusion is that by eliciting a loop-mediated allosteric switch between the different states following the binding events, transcriptional activation can be regulated. The KIX system presents an example how nature makes use of conformational control in higher level regulation of transcriptional activity and thus cellular events. PMID:22438798

Complete molecular remission in relapsed and refractory acute myeloid leukaemia with MLL-AF9 treated with chidamide-based chemotherapy.

PubMed

Lun, Y; Yang, J-J; Wu, Y

2017-12-01

The mixed lineage leukaemia (MLL) gene translocations are found in approximately 10% of adults with acute myeloid leukaemia (AML) and are markers of poor prognosis. As the best reported response in relapsed and refractory MLL-rearranged AML is around 40%, reinduction treatment is very challenging for those patients. We report a case of relapsed and refractory AML with MLL-AF9, who did not respond to FLAG (fludarabine, cytarabine, granulocyte colony stimulating factor) regimen reinduction treatment, but achieved complete response and molecular remission after chidamide-based chemotherapy. Chidamide (CS055/HBI-8000) is a new histone deacetylase (HDAC) inhibitor that is clinically active in relapsed and refractory peripheral T-cell lymphomas. To the best of our knowledge, successful reinduction treatment on relapsed MLL-AF9 by chidamide-based regimen has not been previously reported. © 2017 John Wiley & Sons Ltd.

High resolution tip-tilt positioning system for a next generation MLL-based x-ray microscope

DOE PAGES

Xu, Weihe; Schlossberger, Noah; Xu, Wei; ...

2017-11-15

Multilayer Laue lenses (MLLs) are x-ray focusing optics with the potential to focus hard x-rays down to a single nanometer level. In order to achieve point focus, an MLL microscope needs to have the capability to perform tip-tilt motion of MLL optics and to hold the angular position for an extended period of time. Here, we present a 2D tip-tilt system that can achieve an angular resolution of over 100 microdegree with a working range of 4°, by utilizing a combination of laser interferometer and mini retroreflector. The linear dimensions of the developed system are about 30 mm in allmore » directions, and the thermal dissipation of the system during operation is negligible. Compact design and high angular resolution make the developed system suitable for MLL optics alignment in the next generation of MLL-based x-ray microscopes.« less

High resolution tip-tilt positioning system for a next generation MLL-based x-ray microscope

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

Xu, Weihe; Schlossberger, Noah; Xu, Wei

Multilayer Laue lenses (MLLs) are x-ray focusing optics with the potential to focus hard x-rays down to a single nanometer level. In order to achieve point focus, an MLL microscope needs to have the capability to perform tip-tilt motion of MLL optics and to hold the angular position for an extended period of time. Here, we present a 2D tip-tilt system that can achieve an angular resolution of over 100 microdegree with a working range of 4°, by utilizing a combination of laser interferometer and mini retroreflector. The linear dimensions of the developed system are about 30 mm in allmore » directions, and the thermal dissipation of the system during operation is negligible. Compact design and high angular resolution make the developed system suitable for MLL optics alignment in the next generation of MLL-based x-ray microscopes.« less

Favorable outcome in non-infant children with MLL-AF4-positive acute lymphoblastic leukemia: a report from the Tokyo Children's Cancer Study Group.

PubMed

Tomizawa, Daisuke; Kato, Motohiro; Takahashi, Hiroyuki; Fujimura, Junya; Inukai, Takeshi; Fukushima, Takashi; Kiyokawa, Nobutaka; Koh, Katsuyoshi; Manabe, Atsushi; Ohara, Akira

2015-11-01

Unlike acute lymphoblastic leukemia (ALL) in infants, MLL gene rearrangement (MLL-r) is rare in ALL children (≥1 year old). The outcome and optimal treatment options for MLL-r ALL remain controversial. Among the 1827 children enrolled in the Tokyo Children's Cancer Study Group ALL studies L95-14, L99-15, L99-1502, L04-16, and L07-1602 (1995-2009), 25 MLL-r ALL patients (1.3 %) were identified. Their median age and leukocyte count at diagnosis was 2 years old (range 1-15 years) and 27,690/μL (range 1800-1,113,000/μL), respectively. All but one patient achieved complete remission (CR) after induction therapy, and 19 underwent allogeneic hematopoietic stem cell transplantation (HSCT) in first CR according to the protocol. The 5-year event-free survival (EFS) and overall survival (OS) rate were 60.0 % [standard error (SE), 9.7 %] and 64.0 % (SE 9.6 %), respectively. Notably, 9/12 cases with MLL-AF4-positive ALL are alive in continuous CR with a 75.0 % (SE 12.5 %) EFS rate. The causes of treatment failure were as follows: one induction failure, five relapses, and five transplant-related deaths. With intensive chemotherapy and allogeneic HSCT, favorable outcome of children (≥1 year old) with MLL-AF4-positive ALL was observed. However, considering the risk of acute and late toxicities associated with HSCT, its indication should be restricted.

ARID5B polymorphism confers an increased risk to acquire specific MLL rearrangements in early childhood leukemia

PubMed Central

2014-01-01

Background Acute leukemia in early age (EAL) is characterized by acquired genetic alterations such as MLL rearrangements (MLL-r). The aim of this case-controlled study was to investigate whether single nucleotide polymorphisms (SNPs) of IKZF1, ARID5B, and CEBPE could be related to the onset of EAL cases (<24 months-old at diagnosis). Methods The SNPs (IKZF1 rs11978267, ARID5B rs10821936 and rs10994982, CEBPE rs2239633) were genotyped in 265 cases [169 acute lymphoblastic leukemia (ALL) and 96 acute myeloid leukaemia (AML)] and 505 controls by Taqman allelic discrimination assay. Logistic regression was used to evaluate the association between SNPs of cases and controls, adjusted on skin color and/or age. The risk was determined by calculating odds ratios (ORs) with 95% confidence interval (CI). Results Children with the IKZF1 SNP had an increased risk of developing MLL-germline ALL in white children. The heterozygous/mutant genotype in ARID5B rs10994982 significantly increased the risk for MLL-germline leukemia in white and non-white children (OR 2.60, 95% CI: 1.09-6.18 and OR 3.55, 95% CI: 1.57-8.68, respectively). The heterozygous genotype in ARID5B rs10821936 increased the risk for MLL-r leukemia in both white and non-white (OR 2.06, 95% CI: 1.12-3.79 and OR 2.36, 95% CI: 1.09-5.10, respectively). Furthermore, ARID5B rs10821936 conferred increased risk for MLL-MLLT3 positive cases (OR 7.10, 95% CI:1.54-32.68). Our data do not show evidence that CEBPE rs2239633 confers increased genetic susceptibility to EAL. Conclusions IKZF1 and CEBPE variants seem to play a minor role in genetic susceptibility to EAL, while ARID5B rs10821936 increased the risk of MLL-MLLT3. This result shows that genetic susceptibility could be associated with the differences regarding MLL breakpoints and partner genes. PMID:24564228

Acute leukaemia and myelodysplastic syndromes with chromosomal rearrangement involving 11q23 locus, but not MLL gene.

PubMed

Zuo, Wenli; Wang, Sa A; DiNardo, Courtney; Yabe, Mariko; Li, Shaoying; Medeiros, L Jeffrey; Tang, Guilin

2017-03-01

Chromosome 11q23 translocations, resulting in MLL (KMT2A ) rearrangement, have been well characterised in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). However, little is known of haematopoietic neoplasms associated with 11q23 translocation but without MLL rearrangement (11q23+/ MLL -). The aim of this study is to characterise such cases with 11q23+/ MLL -. We retrospectively searched our database for cases with haematopoietic malignancies with 11q23+/ MLL -. We identified nine patients, two with AML, two with B-lymphoblastic leukaemia (B-ALL); two with T-lymphoblastic leukaemia (T-ALL), two with myelodysplastic syndrome (MDS) and one with chronic myelomonocytic leukaemia (CMML). The translocations included t(X;11)(p11.2;q23), t(2;11)(p21;q23), t(6;11)(q27;q23), t(8;9;11)(q13;q13;q23), t(11;11)(p15;q23), t(11;14)(q23;q24) and t(11;15)(q23;q14). Five of six patients with acute leukaemia had received chemotherapy and detection of 11q23 translocation occurred at time of disease relapse. Both patients with MDS and the patient with CMML had 11q23 translocation detected at time of initial diagnosis, all three patients progressed to AML after >1 year on hypomethylating agent therapy. All patients received risk-adapted therapies, including stem cell transplant in five patients. At the last follow-up, eight patients died with a median overall survival of 14 months. 11q23+/ MLL - occurs rarely, involving different partner chromosomes and showing clinical and pathological features and disease subtypes different from those cases with MLL rearrangement. 11q23+/ MLL - appears to be associated with clonal evolution/disease progression in acute leukaemia, a high risk for AML progression in MDS/CMML and a high incidence of disease relapse. 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/.

FLT3 is implicated in cytarabine transport by human equilibrative nucleoside transporter 1 in pediatric acute leukemia.

PubMed

Català, Albert; Pastor-Anglada, Marçal; Caviedes-Cárdenas, Liska; Malatesta, Roberta; Rives, Susana; Vega-García, Nerea; Camós, Mireia; Fernández-Calotti, Paula

2016-08-02

FLT3 abnormalities are negative prognostic markers in acute leukemia. Infant leukemias are a subgroup with frequent MLL (KMT2A) rearrangements, FLT3 overexpression and high sensitivity to cytarabine, but dismal prognosis. Cytarabine is transported into cells by Human Equilibrative Nucleoside Transporter-1 (hENT1, SLC29A1), but the mechanisms that regulate hENT1 in acute leukemia have been scarcely studied.We explored the expression and functional link between FLT3 and main cytarabine transporters in 50 pediatric patients diagnosed with acute lymphoblastic leukemia and MLL rearrangement (ALL-MLL+) and other subtypes of leukemia, and in leukemia cell lines.A significant positive correlation was found between FLT3 and hENT1 expression in patients. Cytarabine uptake into cells was mediated mainly by hENT1, hENT2 and hCNT1. hENT1-mediated uptake of cytarabine was transiently abolished by the FLT3 inhibitor PKC412, and this effect was associated with decreased hENT1 mRNA and protein levels. Noticeably, the cytotoxicity of cytarabine was lower when cells were first exposed to FLT3 inhibitors (PKC412 or AC220), probably due to decreased hENT1 activity, but we observed a higher cytotoxic effect if FLT3 inhibitors were administered after cytarabine.FLT3 regulates hENT1 activity and thereby affects cytarabine cytotoxicity. The sequence of administration of cytarabine and FLT3 inhibitors is important to maintain their efficacy.

Evolution of AF6-RAS association and its implications in mixed-lineage leukemia

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

Smith, Matthew J.; Ottoni, Elizabeth; Ishiyama, Noboru

Elucidation of activation mechanisms governing protein fusions is essential for therapeutic development. MLL undergoes rearrangement with numerous partners, including a recurrent translocation fusing the epigenetic regulator to a cytoplasmic RAS effector, AF6/afadin. We show here that AF6 employs a non-canonical, evolutionarily conserved α-helix to bind RAS, unique to AF6 and the classical RASSF effectors. Further, all patients with MLL-AF6 translocations express fusion proteins missing only this helix from AF6, resulting in exposure of hydrophobic residues that induce dimerization. We provide evidence that oligomerization is the dominant mechanism driving oncogenesis from rare MLL translocation partners and employ our mechanistic understanding ofmore » MLL-AF6 to examine how dimers induce leukemia. Proteomic data resolve association of dimerized MLL with gene expression modulators, and inhibiting dimerization disrupts formation of these complexes while completely abrogating leukemogenesis in mice. Oncogenic gene translocations are thus selected under pressure from protein structure/function, underscoring the complex nature of chromosomal rearrangements.« less

Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance)

PubMed Central

Augert, Arnaud; Zhang, Qing; Bates, Breanna; Cui, Min; Wang, Xiaofei; Wildey, Gary; Dowlati, Afshin; MacPherson, David

2017-01-01

Introduction SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis. There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available. SCLC is rarely resected, limiting the number of samples available for genomic analyses of somatic mutations. Methods To identify potential driver mutations in human SCLC we sequenced the whole exomes of 18 primary SCLCs and seven cell lines along with matched normal controls. We extended these data by resequencing a panel of genes across 40 primary SCLCs and 48 cell lines. Results We report frequent mutations in the lysine methyltransferase 2D gene (KMT2D) (also known as MLL2), a key regulator of transcriptional enhancer function. KMT2D exhibited truncating nonsense/frameshift/splice site mutations in 8% of SCLC tumors and 17% of SCLC cell lines. We found that KMT2D mutation in human SCLC cell lines was associated with reduced lysine methyltransferase 2D protein levels and reduced monomethylation of histone H3 lysine 4, a mark associated with transcriptional enhancers. We also found mutations in other genes associated with transcriptional enhancer control, including CREB binding protein gene (CREBBP), E1A binding protein p300 gene (EP300), and chromodomain helicase DNA binding protein 7 gene (CHD7), and we report mutations in additional chromatin remodeling genes such as polybromo 1 gene (PBRM1). Conclusions These data indicate that KMT2D is one of the major mutated genes in SCLC, and they point to perturbation of transcriptional enhancer control as potentially contributing to SCLC. PMID:28007623

[Study on the hypoglycemic activity of different extracts of wild Psidium guajava leaves in Panzhihua Area].

PubMed

Wang, Bo; Liu, Heng-Chuan; Ju, Chang-Yan

2005-11-01

To illuminate the role of water-soluble, 650 ml/L edible alcohol and 950 ml/L edible alcohol-soluble extracts of wild Psidium guajava leaves in Panzhihua Area in decreasing blood glucose. High-level blood glucose models were made by use of male Kunming mice given intraperitoneal injection of glucose, subcutaneous injection of adrenaline and intraperitoneal injection of streptozotocin (STZ), respectively. Blood glucose concentration was measured after oral administration (gastrogavage) of the soluble extracts of Psidium guajava leaves, respectively. Body weight and organ morphology were observed, and organ index was obtained. The All available indexes were statistically analyzed in comparing the study groups and control group. three extracts resisted the rise of blood glucose level induced by exogenous glucose and adrenaline to various degrees. The extracts of water, 650 ml/L alcohol and 950 ml/L alcohol significantly decreased the blood glucose level in STZ-induced diabetic mice by 36.3%, 33.5% and 31.3% respectively. Furthermore, among three extracts, water-soluble extract showed little influence on the growth of mice. The water-soluble, 650 ml/L edible alcohol and 950 ml/L edible alcohol-soluble extracts of wild Psidium guajava leaves in Panzhihua area may have different hypoglycemic potential.

MLL4 Is Required to Maintain Broad H3K4me3 Peaks and Super-Enhancers at Tumor Suppressor Genes.

PubMed

Dhar, Shilpa S; Zhao, Dongyu; Lin, Tao; Gu, Bingnan; Pal, Khusboo; Wu, Sarah J; Alam, Hunain; Lv, Jie; Yun, Kyuson; Gopalakrishnan, Vidya; Flores, Elsa R; Northcott, Paul A; Rajaram, Veena; Li, Wei; Shilatifard, Ali; Sillitoe, Roy V; Chen, Kaifu; Lee, Min Gyu

2018-06-07

Super-enhancers are large clusters of enhancers that activate gene expression. Broad trimethyl histone H3 lysine 4 (H3K4me3) often defines active tumor suppressor genes. However, how these epigenomic signatures are regulated for tumor suppression is little understood. Here we show that brain-specific knockout of the H3K4 methyltransferase MLL4 (a COMPASS-like enzyme, also known as KMT2D) in mice spontaneously induces medulloblastoma. Mll4 loss upregulates oncogenic Ras and Notch pathways while downregulating neuronal gene expression programs. MLL4 enhances DNMT3A-catalyzed DNA methylation and SIRT1/BCL6-mediated H4K16 deacetylation, which antagonize expression of Ras activators and Notch pathway components, respectively. Notably, Mll4 loss downregulates tumor suppressor genes (e.g., Dnmt3a and Bcl6) by diminishing broad H3K4me3 and super-enhancers and also causes widespread impairment of these epigenomic signatures during medulloblastoma genesis. These findings suggest an anti-tumor role for super-enhancers and provide a unique tumor-suppressive mechanism in which MLL4 is necessary to maintain broad H3K4me3 and super-enhancers at tumor suppressor genes. Copyright © 2018 Elsevier Inc. All rights reserved.

Cooperation of MLL/AF10(OM-LZ) with PTPN11 activating mutation induced monocytic leukemia with a shorter latency in a mouse bone marrow transplantation model.

PubMed

Fu, Jen-Fen; Liang, Sung-Tzu; Huang, Ying-Jung; Liang, Kung-Hao; Yen, Tzung-Hai; Liang, Der-Cherng; Shih, Lee-Yung

2017-03-01

PTPN11 mutation, a RAS signaling pathway mutation, is associated with MLL translocations in acute leukemia. A girl with MLL/AF10 AML was found to carry PTPN11 G503A . To study the impact of PTPN11 G503A cooperating with MLL/AF10 on leukemogenesis, we established a retroviral transduction/transplantation mouse model. Compared to the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 wt , the cells harboring PTPN11 G503A were hypersensitive to GM-CSF and IL3, and more resistant to death upon treatment with daunorubicin but sensitive to cytarabine. The cells harboring PTPN11 G503A autonomously differentiated into macrophages (1.8%) in the medium containing IL3. Further studies showed that the cells had an elevated (∼2.9-fold) Csf1 transcription level and secreted more (∼4.5-fold) M-CSF to the medium which can stimulate monocyte/macrophage differentiation of BM cells. Mice transplanted with the cells harboring PTPN11 G503A had a higher concentration of M-CSF in plasma. When mixed with the MLL/AF10(OM-LZ) leukemia cells harboring PTPN11 wt , the cells harboring PTPN11 G503A had an increased competitive engraftment and clonal expansion in the BM and spleen of recipient mice, although no competitive growth advantage was observed in the in vitro co-culturing assays. The mice transplanted with the MLL/AF10(OM-LZ) cells harboring PTPN11 wt developed myelomonocytic leukemia, while those transplanted with the cells harboring PTPN11 G503A -induced monocytic leukemia in a shorter latency. Our results demonstrated that addition of PTPN11 G503A to MLL/AF10 affected cell proliferation, chemo-resistance, differentiation, in vivo BM recruitment/clonal expansion and accelerated disease progression. © 2016 UICC.

Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4.

PubMed

Herz, Hans-Martin; Mohan, Man; Garruss, Alexander S; Liang, Kaiwei; Takahashi, Yoh-Hei; Mickey, Kristen; Voets, Olaf; Verrijzer, C Peter; Shilatifard, Ali

2012-12-01

Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are implemented by Set1/COMPASS (complex of proteins associated with Set1), there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays with the cut wing margin enhancer implied a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles the histone modification patterns described for enhancers. Furthermore, studies in the mammalian system suggested a role for the Trr homolog Mll3 in similar processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX cooperate to regulate the transition from inactive/poised to active enhancers.

Enhancer-associated H3K4 monomethylation by Trithorax-related, the Drosophila homolog of mammalian Mll3/Mll4

PubMed Central

Herz, Hans-Martin; Mohan, Man; Garruss, Alexander S.; Liang, Kaiwei; Takahashi, Yoh-hei; Mickey, Kristen; Voets, Olaf; Verrijzer, C. Peter; Shilatifard, Ali

2012-01-01

Monomethylation of histone H3 on Lys 4 (H3K4me1) and acetylation of histone H3 on Lys 27 (H3K27ac) are histone modifications that are highly enriched over the body of actively transcribed genes and on enhancers. Although in yeast all H3K4 methylation patterns, including H3K4me1, are implemented by Set1/COMPASS (complex of proteins associated with Set1), there are three classes of COMPASS-like complexes in Drosophila that could carry out H3K4me1 on enhancers: dSet1, Trithorax, and Trithorax-related (Trr). Here, we report that Trr, the Drosophila homolog of the mammalian Mll3/4 COMPASS-like complexes, can function as a major H3K4 monomethyltransferase on enhancers in vivo. Loss of Trr results in a global decrease of H3K4me1 and H3K27ac levels in various tissues. Assays with the cut wing margin enhancer implied a functional role for Trr in enhancer-mediated processes. A genome-wide analysis demonstrated that Trr is required to maintain the H3K4me1 and H3K27ac chromatin signature that resembles the histone modification patterns described for enhancers. Furthermore, studies in the mammalian system suggested a role for the Trr homolog Mll3 in similar processes. Since Trr and mammalian Mll3/4 complexes are distinguished by bearing a unique subunit, the H3K27 demethylase UTX, we propose a model in which the H3K4 monomethyltransferases Trr/Mll3/Mll4 and the H3K27 demethylase UTX cooperate to regulate the transition from inactive/poised to active enhancers. PMID:23166019

Morus alba Leaf Lectin (MLL) Sensitizes MCF-7 Cells to Anoikis by Inhibiting Fibronectin Mediated Integrin-FAK Signaling through Ras and Activation of P38 MAPK

PubMed Central

Saranya, Jayaram; Shilpa, Ganesan; Raghu, Kozhiparambil G.; Priya, Sulochana

2017-01-01

Lectins are a unique class of carbohydrate binding proteins/glycoproteins, and many of them possess anticancer properties. They can induce cell cycle arrest and apoptosis, inhibit protein synthesis, telomerase activity and angiogenesis in cancer cells. In the present study, we have demonstrated the effect of Morus alba leaf lectin (MLL) on anoikis induction in MCF-7 cells. Anoikis induction in cancer cells has a significant role in preventing early stage metastasis. MLL treatment in monolayers of MCF-7 cells caused significant detachment of cells in a time and concentration dependent manner. The detached cells failed to re-adhere and grew even to culture plates coated with different matrix proteins. DNA fragmentation, membrane integrity studies, annexin V staining, caspase 9 activation and upregulation of Bax/Bad confirmed that the detached cells underwent apoptosis. Upregulation of matrix metalloproteinase 9 (MMP-9) caused a decrease in fibronectin (FN) production which facilitated the cells to detach by blocking the FN mediated downstream signaling. On treatment with MLL, we have observed downregulation of integrin expression, decreased phosphorylation of focal adhesion kinase (FAK), loss in FAK-integrin interaction and active Ras. MLL treatment downregulated the levels of phosphorylated Akt and PI3K. Also, we have studied the effect of MLL on two stress activated protein kinases p38 MAPK and JNK. p38 MAPK activation was found to be elevated, but there was no change in the level of JNK. Thus our study substantiated the possible antimetastatic effect of MLL by inducing anoikis in MCF-7 cells by activation of caspase 9 and proapoptotic Bax/Bad by blockage of FN mediated integrin/FAK signaling and partly by activation of p38 MAPK. PMID:28223935

Glucocorticoid sensitisation in Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia by the pan-BCL-2 family inhibitors gossypol and AT-101.

PubMed

Spijkers-Hagelstein, Jill A P; Schneider, Pauline; Pinhanços, Sandra Mimoso; Garrido Castro, Patricia; Pieters, Rob; Stam, Ronald W

2014-06-01

Resistance to glucocorticoids (GCs) remains a major problem in the treatment of infants with acute lymphoblastic leukaemia (ALL) carrying Mixed Lineage Leukaemia (MLL) translocations. Despite intensive research, the mechanism(s) underlying GC resistance remain poorly understood. Recent studies suggested an important role for the pro-survival BCL-2 family member MCL1 in GC resistance in MLL-rearranged ALL. We exposed GC-resistant MLL-rearranged SEMK2 cells to potent MCL1-inhibiting agents, including gossypol, AT-101, rapamycin, SU9516 and obatoclax (GX15-070) and determined GC sensitisation using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays. Using Western blotting we analysed the protein expression of most BCL-2 family members in MLL-rearranged SEMK2 cells after treatment with potent MCL-1 inhibiting agents. Only gossypol and its synthetic analogue AT-101 induced GC sensitivity in MLL-rearranged ALL cells. Remarkably, the GC-sensitising effects of gossypol and AT-101 appeared not to be mediated by down-regulation MCL1 or other anti-apoptotic BCL-2 family members, but rather involved up-regulation of multiple pro-apoptotic BCL-2 family members, in particular that of BIM and BID. In conclusion, gossypol and AT-101 induce GC sensitivity in MLL-rearranged ALL cells, most likely mediated by the activation of BID and BIM without the necessity to down-regulate anti-apoptotic BCL-2 family members like MCL1. Hence, co-administration of either gossypol or AT-101 during GC treatment of GC-resistant MLL-rearranged ALL patients may overcome GC resistance and improve prognosis in this high-risk childhood leukaemia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Trithorax dependent changes in chromatin landscape at enhancer and promoter regions drive female puberty.

PubMed

Toro, Carlos A; Wright, Hollis; Aylwin, Carlos F; Ojeda, Sergio R; Lomniczi, Alejandro

2018-01-04

Polycomb group (PcG) proteins control the timing of puberty by repressing the Kiss1 gene in hypothalamic arcuate nucleus (ARC) neurons. Here we identify two members of the Trithorax group (TrxG) of modifiers, mixed-lineage leukemia 1 (MLL1), and 3 (MLL3), as central components of an activating epigenetic machinery that dynamically counteracts PcG repression. Preceding puberty, MLL1 changes the chromatin configuration at the promoters of Kiss1 and Tac3, two genes required for puberty to occur, from repressive to permissive. Concomitantly, MLL3 institutes a chromatin structure that changes the functional status of a Kiss1 enhancer from poised to active. RNAi-mediated, ARC-specific Mll1 knockdown reduced Kiss1 and Tac3 expression, whereas CRISPR-Cas9-directed epigenome silencing of the Kiss1 enhancer selectively reduced Kiss1 activity. Both interventions delay puberty and disrupt reproductive cyclicity. Our results demonstrate that an epigenetic switch from transcriptional repression to activation is crucial to the regulatory mechanism controlling the timing of mammalian puberty.

Compositions and methods for detecting gene rearrangements and translocations

DOEpatents

Rowley, Janet D.; Diaz, Manuel O.

2000-01-01

Disclosed is a series of nucleic acid probes for use in diagnosing and monitoring certain types of leukemia using, e.g., Southern and Northern blot analyses and fluorescence in situ hybridization (FISH). These probes detect rearrangements, such as translocations involving chromosome band 11q23 with other chromosomes bands, including 4q21, 6q27, 9p22, 19p13.3, in both dividing leukemic cells and interphase nuclei. The breakpoints in all such translocations are clustered within an 8.3 kb BamHI genomic region of the MLL gene. A novel 0.7 kb BamH1 cDNA fragment derived from this gene detects rearrangements on Southern blot analysis with a single BamHI restriction digest in all patients with the common 11q23 translocations and in patients with other 11q23 anomalies. Northern blot analyses are presented demonstrating that the MLL gene has multiple transcripts and that transcript size differentiates leukemic cells from normal cells. Also disclosed are MLL fusion proteins, MLL protein domains and anti-MLL antibodies.

B-cell acute lymphoblastic leukemia with mature phenotype and MLL rearrangement: report of five new cases and review of the literature.

PubMed

Sajaroff, Elisa Olga; Mansini, Adrian; Rubio, Patricia; Alonso, Cristina Noemí; Gallego, Marta S; Coccé, Mariela C; Eandi-Eberle, Silvia; Bernasconi, Andrea Raquel; Ampatzidou, Maria; Paterakis, George; Papadhimitriou, Stefanos I; Petrikkos, Loizos; Papadakis, Vassilios; Polychronopoulou, Sophia; Rossi, Jorge G; Felice, Maria Sara

2016-10-01

The association between mature-B phenotype and MLL abnormalities in acute lymphoblastic leukemia (ALL) is a very unusual finding; only 14 pediatric cases have been reported so far. We describe the clinical and biological characteristics and outcome of five pediatric cases of newly diagnosed B lineage ALL with MLL abnormalities and mature immunophenotype based on light chain restriction and surface Ig expression. Blasts showed variable expression of CD10/CD34/TdT. MLL abnormalities with no MYC involvement were detected in all patients by G-banding, FISH, and/or RT-PCR. Three patients were treated according to Interfant protocol, one to ALLIC-09, and one received B-NHL-BFM-2004. All patients achieved complete remission and three of them relapsed. Despite the small cohort size, it could be postulated that B lineage ALL with MLL abnormalities and mature phenotype is a distinct entity that differs both from the typical Pro B ALL observed in infants and mature B-ALL with high MYC expression.

Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation

PubMed Central

Jo, Stephanie Y.; Granowicz, Eric M.; Maillard, Ivan; Thomas, Dafydd

2011-01-01

Disruptor of telomeric silencing 1-like (Dot1l) is a histone 3 lysine 79 methyltransferase. Studies of constitutive Dot1l knockout mice show that Dot1l is essential for embryonic development and prenatal hematopoiesis. DOT1L also interacts with translocation partners of Mixed Lineage Leukemia (MLL) gene, which is commonly translocated in human leukemia. However, the requirement of Dot1l in postnatal hematopoiesis and leukemogenesis of MLL translocation proteins has not been conclusively shown. With a conditional Dot1l knockout mouse model, we examined the consequences of Dot1l loss in postnatal hematopoiesis and MLL translocation leukemia. Deletion of Dot1l led to pancytopenia and failure of hematopoietic homeostasis, and Dot1l-deficient cells minimally reconstituted recipient bone marrow in competitive transplantation experiments. In addition, MLL-AF9 cells required Dot1l for oncogenic transformation, whereas cells with other leukemic oncogenes, such as Hoxa9/Meis1 and E2A-HLF, did not. These findings illustrate a crucial role of Dot1l in normal hematopoiesis and leukemogenesis of specific oncogenes. PMID:21398221

Can a Morel-Lavallée lesion be misdiagnosed as a mass like lesion?

PubMed

Lee, Yoon Jae; Kim, Jun Hyeok; Kim, Ji Young; Han, Hyun Ho

2017-12-01

The Morel-Lavallée lesion (MLL) is a post-traumatic closed soft tissue degloving injury. Common complaints of MLL patients are a haematoma or fluid collection on the trunk or the lower extremity. However, the authors introduce unique cases of MLL that present an atypical appearance. The fluid collection was not apparent, and the capsule formation was not detected on preoperative image study. The main complaint of patients was the uncomfortable mass-like lesion that was regarded as a simple benign lump. The purpose of this case study is to introduce the atypical cases of MLL and to help other physicians make accurate diagnosis based on trial and error of our cases. © 2017 Medicalhelplines.com Inc and John Wiley & Sons Ltd.

Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human

PubMed Central

Takahashi, Yoh-hei; Westfield, Gerwin H.; Oleskie, Austin N.; Trievel, Raymond C.; Shilatifard, Ali; Skiniotis, Georgios

2011-01-01

Histone H3 lysine 4 (H3K4) methylation is catalyzed by the highly evolutionarily conserved multiprotein complex known as Set1/COMPASS or MLL/COMPASS-like complexes from yeast to human, respectively. Here we have reconstituted fully functional yeast Set1/COMPASS and human MLL/COMPASS-like complex in vitro and have identified the minimum subunit composition required for histone H3K4 methylation. These subunits include the methyltransferase C-terminal SET domain of Set1/MLL, Cps60/Ash2L, Cps50/RbBP5, Cps30/WDR5, and Cps25/Dpy30, which are all common components of the COMPASS family from yeast to human. Three-dimensional (3D) cryo-EM reconstructions of the core yeast complex, combined with immunolabeling and two-dimensional (2D) EM analysis of the individual subcomplexes reveal a Y-shaped architecture with Cps50 and Cps30 localizing on the top two adjacent lobes and Cps60-Cps25 forming the base at the bottom. EM analysis of the human complex reveals a striking similarity to its yeast counterpart, suggesting a common subunit organization. The SET domain of Set1 is located at the juncture of Cps50, Cps30, and the Cps60-Cps25 module, lining the walls of a central channel that may act as the platform for catalysis and regulative processing of various degrees of H3K4 methylation. This structural arrangement suggested that COMPASS family members function as exo-methylases, which we have confirmed by in vitro and in vivo studies. PMID:22158900

Structural analysis of the core COMPASS family of histone H3K4 methylases from yeast to human.

PubMed

Takahashi, Yoh-hei; Westfield, Gerwin H; Oleskie, Austin N; Trievel, Raymond C; Shilatifard, Ali; Skiniotis, Georgios

2011-12-20

Histone H3 lysine 4 (H3K4) methylation is catalyzed by the highly evolutionarily conserved multiprotein complex known as Set1/COMPASS or MLL/COMPASS-like complexes from yeast to human, respectively. Here we have reconstituted fully functional yeast Set1/COMPASS and human MLL/COMPASS-like complex in vitro and have identified the minimum subunit composition required for histone H3K4 methylation. These subunits include the methyltransferase C-terminal SET domain of Set1/MLL, Cps60/Ash2L, Cps50/RbBP5, Cps30/WDR5, and Cps25/Dpy30, which are all common components of the COMPASS family from yeast to human. Three-dimensional (3D) cryo-EM reconstructions of the core yeast complex, combined with immunolabeling and two-dimensional (2D) EM analysis of the individual subcomplexes reveal a Y-shaped architecture with Cps50 and Cps30 localizing on the top two adjacent lobes and Cps60-Cps25 forming the base at the bottom. EM analysis of the human complex reveals a striking similarity to its yeast counterpart, suggesting a common subunit organization. The SET domain of Set1 is located at the juncture of Cps50, Cps30, and the Cps60-Cps25 module, lining the walls of a central channel that may act as the platform for catalysis and regulative processing of various degrees of H3K4 methylation. This structural arrangement suggested that COMPASS family members function as exo-methylases, which we have confirmed by in vitro and in vivo studies.

A case of pediatric B-Lymphoblastic leukemia presenting with a t(9;12)(p24;q11.2) involving JAK2 and concomitant MLL rearrangement with apparent insertion at 6q27

PubMed Central

2013-01-01

Background B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in pediatric patients and the leading cause of cancer-related death in children and young adults. Translocations of 9p24 involving JAK2 (9p24) and gain-of-function mutations of JAK2 with subsequent activation of the JAK2 kinase have been described in several hematological malignancies including B-ALL. However, rearrangements involving JAK2 are rare in B-ALL as only few cases have been described in the literature. Findings Herein, we present a case of pediatric B-ALL whose conventional cytogenetics revealed an abnormal karyotype with a reciprocal translocation involving 9p24 (JAK2) and 12p11.2. Fluorescence in situ hybridization (FISH) studies using the RP11-927H16 Spectrum Green JAK2 probe on previously G-banded metaphases confirmed the involvement of JAK2 in this rearrangement. Further FISH studies on the same previously G-banded metaphases using the LSI MLL probe helped to characterize an insertion of MLL into 6q27 as an additional abnormality in this karyotype. FISH studies performed on interphase nuclei also revealed an abnormal clone with MLL rearrangements in 23.6% of the nuclei examined as well as an abnormal clonal population with a deletion of the 5'IGH@ region in 88.3% of the nuclei examined. Conclusions Rearrangements of 9p24 can result in constitutive activation of JAK2, and have been observed in B-ALL. Rearrangements of the MLL gene have also been described extensively in B-ALL. However, rearrangements of MLL with a partner at 6q27 and in conjunction with a translocation involving JAK2 have not been previously described. This case pinpoints the importance of FISH and conventional cytogenetics to characterize complex rearrangements in which JAK2 and MLL are involved. The therapeutic targeting of JAK2 and MLL in cases like this may be prognostically beneficial. PMID:24274401

Selection, proliferation and differentiation of bone marrow-derived liver stem cells with a culture system containing cholestatic serum in vitro.

PubMed

Cai, Yun-Feng; Zhen, Zuo-Jun; Min, Jun; Fang, Tian-Ling; Chu, Zhong-Hua; Chen, Ji-Sheng

2004-11-15

To explore the feasibility of direct separation, selective proliferation and differentiation of the bone marrow-derived liver stem cells (BDLSC) from bone marrow cells with a culture system containing cholestatic serum in vitro. Whole bone marrow cells of rats cultured in routine medium were replaced with conditioning selection media containing 20 mL/L, 50 mL/L, 70 mL/L, and 100 mL/L cholestatic sera, respectively, after they attached to the plates. The optimal concentration of cholestatic serum was determined according to the outcome of the selected cultures. Then the selected BDLSC were induced to proliferate and differentiate with the addition of hepatocyte growth factor (HGF). The morphology and phenotypic markers of BDLSC were characterized using immunohistochemistry, RT-PCR and electron microscopy. The metabolic functions of differentiated cells were also determined by glycogen staining and urea assay. Bone marrow cells formed fibroblast-like but not hepatocyte-like colonies in the presence of 20 mL/L cholestatic serum. In 70 mL/L cholestatic serum, BDLSC colonies could be selected but could not maintain good growth status. In 100 mL/L cholestatic serum, all of the bone marrow cells were unable to survive. A 50 mL/L cholestatic serum was the optimal concentration for the selection of BDLSC at which BDLSC could survive while the other populations of the bone marrow cells could not. The selected BDLSC proliferated and differentiated after HGF was added. Hepatocyte-like colony-forming units (H-CFU) then were formed. H-CFU expressed markers of embryonic hepatocytes (AFP, albumin and cytokeratin 8/18), biliary cells (cytokeratin 19), hepatocyte functional proteins (transthyretin and cytochrome P450-2b1), and hepatocyte nuclear factors (HNF-1alpha and HNF-3beta). They also had glycogen storage and urea synthesis functions, two of the critical features of hepatocytes. The selected medium containing cholestatic serum can select BDLSC from whole bone marrow cells. It will be a new way to provide a readily available alternate source of cells for clinical hepatocyte therapy.

Transient spontaneous remission in congenital MLL-AF10 rearranged acute myeloid leukemia presenting with cardiorespiratory failure and meconium ileus.

PubMed

Gyárfás, Tobias; Wintgens, Juergen; Biskup, Wolfgang; Oschlies, Ilske; Klapper, Wolfram; Siebert, Reiner; Bens, Susanne; Haferlach, Claudia; Meisel, Roland; Kuhlen, Michaela; Borkhardt, Arndt

2016-12-01

Neonatal leukemia is a rare disease with an estimated prevalence of about one to five in a million neonates. The majority being acute myeloid leukemia (AML), neonatal leukemia can present with a variety of symptoms including hyperleucocytosis, cytopenia, hepatosplenomegaly, and skin infiltrates. Chromosomal rearrangements including mixed lineage leukemia (MLL) translocations are common in neonatal AML. A female neonate born at 34 weeks gestation presented with cardiorespiratory failure, hepatosplenomegaly, pancytopenia, and coagulopathy. She required intensive care treatment including mechanical ventilation, high-dose catecholamine therapy, and multiple transfusions. Small intestinal biopsy obtained during laparotomy for meconium ileus revealed an infiltrate by an undifferentiated monoblastic, MLL-rearranged leukemia. No other manifestations of leukemia could be detected. After spontaneous clinical remission, lasting 5 months without any specific treatment, the patient presented with leukemia cutis and full-blown monoblastic leukemia. MLL-AF10-rearranged AML could be re-diagnosed and successfully treated with chemotherapy and hematopoietic stem cell transplantation. Our patient exhibited a unique manifestation of neonatal MLL-AF10 rearranged AML with cardiorespiratory failure and intestinal infiltration. It highlights the importance of leukemia in the differential diagnosis of neonatal distress, congenital hematological abnormalities, and skin lesions.

Deciphering KRAS and NRAS mutated clone dynamics in MLL-AF4 paediatric leukaemia by ultra deep sequencing analysis.

PubMed

Trentin, Luca; Bresolin, Silvia; Giarin, Emanuela; Bardini, Michela; Serafin, Valentina; Accordi, Benedetta; Fais, Franco; Tenca, Claudya; De Lorenzo, Paola; Valsecchi, Maria Grazia; Cazzaniga, Giovanni; Kronnie, Geertruy Te; Basso, Giuseppe

2016-10-04

To induce and sustain the leukaemogenic process, MLL-AF4+ leukaemia seems to require very few genetic alterations in addition to the fusion gene itself. Studies of infant and paediatric patients with MLL-AF4+ B cell precursor acute lymphoblastic leukaemia (BCP-ALL) have reported mutations in KRAS and NRAS with incidences ranging from 25 to 50%. Whereas previous studies employed Sanger sequencing, here we used next generation amplicon deep sequencing for in depth evaluation of RAS mutations in 36 paediatric patients at diagnosis of MLL-AF4+ leukaemia. RAS mutations including those in small sub-clones were detected in 63.9% of patients. Furthermore, the mutational analysis of 17 paired samples at diagnosis and relapse revealed complex RAS clone dynamics and showed that the mutated clones present at relapse were almost all originated from clones that were already detectable at diagnosis and survived to the initial therapy. Finally, we showed that mutated patients were indeed characterized by a RAS related signature at both transcriptional and protein levels and that the targeting of the RAS pathway could be of beneficial for treatment of MLL-AF4+ BCP-ALL clones carrying somatic RAS mutations.

Utilization of Liposuction for Delayed Morel-Lavallée Lesion: A Case Report and Review.

PubMed

Gardner, Preston; Flis, Diana; Chaiyasate, Kongkrit

2017-01-01

Morel-Lavallée lesions are irregularly occurring and often overlooked results of traumatic injuries, resulting in potential long-term encapsulation of fluid between soft-tissue layers. The objective in this review was to discuss the delayed presentation of a Morel-Lavallée lesion and operative utility of liposuction in the patient's treatment and review literature with particular focus on diagnosis and therapeutic interventions. The reviewed case demonstrates the presentation and successful therapy of a young female presenting with a MLL and contour deformity.

Alteration of gene expression in human hepatocellular carcinoma with integrated hepatitis B virus DNA.

PubMed

Tamori, Akihiro; Yamanishi, Yoshihiro; Kawashima, Shuichi; Kanehisa, Minoru; Enomoto, Masaru; Tanaka, Hiromu; Kubo, Shoji; Shiomi, Susumu; Nishiguchi, Shuhei

2005-08-15

Integration of hepatitis B virus (HBV) DNA into the human genome is one of the most important steps in HBV-related carcinogenesis. This study attempted to find the link between HBV DNA, the adjoining cellular sequence, and altered gene expression in hepatocellular carcinoma (HCC) with integrated HBV DNA. We examined 15 cases of HCC infected with HBV by cassette ligation-mediated PCR. The human DNA adjacent to the integrated HBV DNA was sequenced. Protein coding sequences were searched for in the human sequence. In five cases with HBV DNA integration, from which good quality RNA was extracted, gene expression was examined by cDNA microarray analysis. The human DNA sequence successive to integrated HBV DNA was determined in the 15 HCCs. Eight protein-coding regions were involved: ras-responsive element binding protein 1, calmodulin 1, mixed lineage leukemia 2 (MLL2), FLJ333655, LOC220272, LOC255345, LOC220220, and LOC168991. The MLL2 gene was expressed in three cases with HBV DNA integrated into exon 3 of MLL2 and in one case with HBV DNA integrated into intron 3 of MLL2. Gene expression analysis suggested that two HCCs with HBV integrated into MLL2 had similar patterns of gene expression compared with three HCCs with HBV integrated into other loci of human chromosomes. HBV DNA was integrated at random sites of human DNA, and the MLL2 gene was one of the targets for integration. Our results suggest that HBV DNA might modulate human genes near integration sites, followed by integration site-specific expression of such genes during hepatocarcinogenesis.

Jumping translocations in hematological malignancies: a cytogenetic study of five cases.

PubMed

Manola, Kalliopi N; Georgakakos, Vasileios N; Stavropoulou, Chryssa; Spyridonidis, Alexandros; Angelopoulou, Maria K; Vlachadami, Ioanna; Katsigiannis, Andreas; Roussou, Paraskevi; Pantelias, Gabriel E; Sambani, Constantina

2008-12-01

Jumping translocations (JT) are rare cytogenetic aberrations in hematological malignancies that include unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to two or more different recipient chromosomes in different cell lines. We report five cases associated with different hematologic disorders and JT to contribute to the investigation of the origin, pathogenesis, and clinical significance of JT. These cases involve JT of 1q in a case of acute myeloblastic leukemia (AML)-M1, a case of Burkitt lymphoma, and a case of BCR/ABL-positive acute lymphoblastic leukemia, as well as a JT of 13q in a case of AML-M5, and a JT of 11q segment in a case of undifferentiated leukemia. To our knowledge, with regard to hematologic malignancies, this study presents the first case of JT associated with AML-M1, the first case of JT involving 13q as a donor chromosome, and the first report of JT involving a segment of 11q containing two copies of the MLL gene, jumping on to two recipient chromosomes in each cell line and resulting in six copies of the MLL gene. Our investigation suggests that JT may not contribute to the pathogenesis but rather to the progression of the disease, and it demonstrates that chromosome band 1q10 as a breakpoint of the donor chromosome 1q is also implicated in AML, not only in multiple myeloma as it has been known until now.

APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response

PubMed Central

Glaser, Alexander P.; Fantini, Damiano; Wang, Yiduo; Yu, Yanni; Rimar, Kalen J.; Podojil, Joseph R.; Miller, Stephen D.; Meeks, Joshua J.

2018-01-01

APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas (n = 395), Beijing Genomics Institute (n = 99), and Cancer Cell Line Encyclopedia. Tumors were split into “APOBEC-high” and “APOBEC-low” based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months, p = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes (TP53, ATR, BRCA2) and chromatin regulatory genes (ARID1A, MLL, MLL3), while APOBEC-low tumors are more likely to have mutations in FGFR3 and KRAS. APOBEC3A and APOBEC3B expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of APOBEC3B is increased after stimulation of APOBEC-high bladder cancer cell lines with IFNγ. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response. PMID:29435122

Nm-scale spatial resolution x-ray imaging with MLL nanofocusing optics: instrumentational requirements and challenges

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

Nazaretski, E.; Yan, H.; Lauer, K.

2016-08-30

The Hard X-ray Nanoprobe (HXN) beamline at NSLS-II has been designed and constructed to enable imaging experiments with unprecedented spatial resolution and detection sensitivity. The HXN X-ray Microscope is a key instrument for the beamline, providing a suite of experimental capabilities which includes scanning fluorescence, diffraction, differential phase contrast and ptychography utilizing Multilayer Laue Lenses (MLL) and zoneplate (ZP) as nanofocusing optics. In this paper, we present technical requirements for the MLL-based scanning microscope, outline the development concept and present first ~15 x 15 nm 2 spatial resolution x-ray fluorescence images.

Paralarvae of the complex Sthenoteuthis oualaniensis - Dosidicus gigas (Cephalopoda: Ommastrephidae) in the northern limit of the shallow oxygen minimum zone of the Eastern Tropical Pacific Ocean.

NASA Astrophysics Data System (ADS)

Sanchez Velasco, L.; Ruvalcaba-Aroche, E. D.; Beier, E.; Godinez, V. M.; Barton, E. D.; Diaz-Viloria, N.; Pacheco, M.

2016-02-01

The three-dimensional distribution of the paralarvae of the complex Sthenoteuthis oualaniensis - Dosidicus gigas (Cephalopoda: Ommastrephidae) was analyzed in the northern limit of the shallow oxygen minimum zone in the Eastern Tropical Pacific (April, 2012). The hypoxic water ( 1 mL/L) rises from 100 m depth in the entrance of the Gulf of California to 20 m depth off Cabo Corrientes. Most of the paralarvae of this complex, dominated by D. gigas, were concentrated in the Gulf entrance, between the thermocline ( 20 to 50 m depth) and the sea surface, in the warmest (> 19oC) and oxygenated (> 4 mL/L) layer. The highest abundance of paralarvae was detected in an anticyclonic eddy ( 120 km diameter and > 500 m deep), which contained lower salinity water (< 35 g/kg), consistent with formation in the California Current. Lower paralarvae abundance was recorded further south off Cabo Corrientes, where hypoxic layers were elevated as water shoaled near shore. No paralarvae were found in the north of the study area beyond the strong salinity front ( 34.8 - 35.4 g/kg) that bounded the anticyclone. These results showed an affinity of the paralarvae for lower salinity, oxygenated water, illustrated by the influence of the mesoescale anticyclonic eddy and the salinity front in their distribution. Based on this study, it can be hypothesized that the expansion of the depth range of hypoxic water observed in the Eastern Tropical Pacific is vertically restricting the paralarvae habitat and likely causing a northward expansion of its range.

Morel-Lavallee lesion.

PubMed

Li, Hui; Zhang, Fangjie; Lei, Guanghua

2014-01-01

To review current knowledge of the Morel-Lavallee lesion (MLL) to help clinicians become familiar with this entity. Familiarization may decrease missed diagnoses and misdiagnoses. It could also help steer the clinician to the proper treatment choice. A search was performed via PubMed and EMBASE from 1966 to July 2013 using the following keywords: Morel-Lavallee lesion, closed degloving injury, concealed degloving injury, Morel-Lavallee effusion, Morel-Lavallee hematoma, posttraumatic pseudocyst, posttraumatic soft tissue cyst. Chinese and English language literatures relevant to the subject were collected. Their references were also reviewed. Morel-Lavallee lesion is a relatively rare condition involving a closed degloving injury. It is characterized by a filled cystic cavity created by separation of the subcutaneous tissue from the underlying fascia. Apart from the classic location over the region of the greater trochanter, MLLs have been described in other parts of the body. The natural history of MLL has not yet been established. The lesion may decrease in volume, remain stable, enlarge progressively or show a recurrent pattern. Diagnosis of MLL was often missed or delayed. Ultrasonography, computed tomography, and magnetic resonance imaging have great value in the diagnosis of MLL. Treatment of MLL has included compression, local aspiration, open debridement, and sclerodesis. No standard treatment has been established. A diagnosis of MLL should be suspected when a soft, fluctuant area of skin or chronic recurrent fluid collection is found in a region exposed to a previous shear injury. Clinicians and radiologists should be aware of both the acute and chronic appearances to make the correct diagnosis. Treatment decisions should base on association with fractures, the condition of the lesion, symptom and desire of the patient.

Revisiting the biology of infant t(4;11)/MLL-AF4+ B-cell acute lymphoblastic leukemia

PubMed Central

Bueno, Clara; Prieto, Cristina; Acha, Pamela; Stam, Ronald W.; Marschalek, Rolf; Menéndez, Pablo

2015-01-01

Infant B-cell acute lymphoblastic leukemia (B-ALL) accounts for 10% of childhood ALL. The genetic hallmark of most infant B-ALL is chromosomal rearrangements of the mixed-lineage leukemia (MLL) gene. Despite improvement in the clinical management and survival (∼85-90%) of childhood B-ALL, the outcome of infants with MLL-rearranged (MLL-r) B-ALL remains dismal, with overall survival <35%. Among MLL-r infant B-ALL, t(4;11)+ patients harboring the fusion MLL-AF4 (MA4) display a particularly poor prognosis and a pro-B/mixed phenotype. Studies in monozygotic twins and archived blood spots have provided compelling evidence of a single cell of prenatal origin as the target for MA4 fusion, explaining the brief leukemia latency. Despite its aggressiveness and short latency, current progress on its etiology, pathogenesis, and cellular origin is limited as evidenced by the lack of mouse/human models recapitulating the disease phenotype/latency. We propose this is because infant cancer is from an etiologic and pathogenesis standpoint distinct from adult cancer and should be seen as a developmental disease. This is supported by whole-genome sequencing studies suggesting that opposite to the view of cancer as a “multiple-and-sequential-hit” model, t(4;11) alone might be sufficient to spawn leukemia. The stable genome of these patients suggests that, in infant developmental cancer, one “big-hit” might be sufficient for overt disease and supports a key contribution of epigenetics and a prenatal cell of origin during a critical developmental window of stem cell vulnerability in the leukemia pathogenesis. Here, we revisit the biology of t(4;11)+ infant B-ALL with an emphasis on its origin, genetics, and disease models. PMID:26463423

Surfactant-enhanced anaerobic acidogenesis of Canna indica L. by rumen cultures.

PubMed

Yue, Zheng-Bo; Yu, Han-Qing; Hu, Zhen-Hu; Harada, Hideki; Li, Yu-You

2008-06-01

Polyoxyethylene sorbitan monoolate (Tween 80) was used to enhance the anaerobic acidogenesis of Canna indica L. (canna) by rumen culture in this study. Dose of Tween 80 at 1 ml/l enhanced the volatile fatty acids (VFA) production from the acidogenesis of canna compared to the control. However, Tween 80 at higher dosages than 5 ml/l inhibited the rumen microbial activity and reduced the VFA yield. Response surface methodology was successfully used to optimize the VFA yield. A maximum of VFA yield of 0.147 g/g total solids (TS) added was obtained at canna and Tween 80 concentrations of 6.3g TS/l and 2.0 ml/l, respectively. Dosage of Tween 80 at 1-3.75 ml/l reduced the unproductive adsorption of microbes or enzymes on the lignin part in canna and increased microbial activity. A high VFA production was achieved from canna presoaked with Tween 80, suggesting that the structure of canna was disrupted by Tween 80.

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.

PubMed

Cheng, Yating; Jutooru, Indira; Chadalapaka, Gayathri; Corton, J Christopher; Safe, Stephen

2015-05-10

HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors.

Decontamination of a municipal landfill leachate from endocrine disruptors using a combined sorption/bioremoval approach.

PubMed

Loffredo, Elisabetta; Castellana, Giancarlo; Senesi, Nicola

2014-02-01

Sorption and biodegradation are the main mechanisms for the removal of endocrine disruptor compounds (EDs) from both solid and liquid matrices. There are recent evidences about the capacity of white-rot fungi to decontaminate water systems from phenolic EDs by means of their ligninolytic enzymes. Most of the available studies report the removal of EDs by biodegradation or adsorption separately. This study assessed the simultaneous removal of five EDs—the xenoestrogens bisphenol A (BPA), ethynilestradiol (EE2), and 4-n-nonylphenol (NP), and the herbicide linuron and the insecticide dimethoate—from a municipal landfill leachate (MLL) using a combined sorption/bioremoval approach. The adsorption matrices used were potato dextrose agar alone or added with each of the following adsorbent materials: ground almond shells, a coffee compost, a coconut fiber, and a river sediment. These matrices were either not inoculated or inoculated with the fungus Pleurotus ostreatus and superimposed on the MLL. The residual amount of each ED in the MLL was quantified after 4, 7, 12, and 20 days by HPLC analysis and UV detection. Preliminary experiments showed that (1) all EDs did not degrade significantly in the untreatedMLL for at least 28 days, (2) the mycelial growth of P. ostreatus was largely stimulated by components of the MLL, and (3) the enrichment of potato dextrose agar with any adsorbent material favored the fungal growth for 8 days after inoculation. A prompt relevant disappearance of EDs in the MLL occurred both without and, especially, with fungal activity, with the only exception of the very water soluble dimethoate that was poorly adsorbed and possibly degraded only during the first few days of experiments. An almost complete removal of phenolic EDs, especially EE2 and NP, occurred after 20 days or much earlier and was generally enhanced by the adsorbent materials used. Data obtained indicated that both adsorption and biodegradation mechanisms contribute significantly to MLL decontamination from the EDs studied and that the efficacy of the methodology adopted is directly related to the hydrophobicity of the contaminant.

Mode-locked laser with pulse interleavers in a monolithic photonic integrated circuit for millimeter wave and terahertz carrier generation.

PubMed

Lo, Mu-Chieh; Guzmán, Robinson; Gordón, Carlos; Carpintero, Guillermo

2017-04-15

This Letter presents a photonics-based millimeter wave and terahertz frequency synthesizer using a monolithic InP photonic integrated circuit composed of a mode-locked laser (MLL) and two pulse interleaver stages to multiply the repetition rate frequency. The MLL is a multiple colliding pulse MLL producing an 80 GHz repetition rate pulse train. Through two consecutive monolithic pulse interleaver structures, each doubling the repetition rate, we demonstrate the achievement of 160 and 320 GHz. The fabrication was done on a multi-project wafer run of a generic InP photonic technology platform.

Growing Cutting-edge X-ray Optics

ScienceCinema

Conley, Ray

2018-03-02

Ever imagined that an Xbox controller could help open a window into a world spanning just one billionth of a meter? Brookhaven Lab's Ray Conley grows cutting-edge optics called multilayer Laue lenses (MLL) one atomic layer at a time to focus high-energy x-rays to within a single nanometer. To achieve this focusing feat, Ray uses a massive, custom-built atomic deposition device, an array of computers, and a trusty Xbox controller. These lenses will be deployed at the Lab's National Synchrotron Light Source II, due to begin shining super-bright light on pressing scientific puzzles in 2015.

An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.

PubMed

Rickels, Ryan; Hu, Deqing; Collings, Clayton K; Woodfin, Ashley R; Piunti, Andrea; Mohan, Man; Herz, Hans-Martin; Kvon, Evgeny; Shilatifard, Ali

2016-07-21

Polycomb response elements (PREs) are specific DNA sequences that stably maintain the developmental pattern of gene expression. Drosophila PREs are well characterized, whereas the existence of PREs in mammals remains debated. Accumulating evidence supports a model in which CpG islands recruit Polycomb group (PcG) complexes; however, which subset of CGIs is selected to serve as PREs is unclear. Trithorax (Trx) positively regulates gene expression in Drosophila and co-occupies PREs to antagonize Polycomb-dependent silencing. Here we demonstrate that Trx-dependent H3K4 dimethylation (H3K4me2) marks Drosophila PREs and maintains the developmental expression pattern of nearby genes. Similarly, the mammalian Trx homolog, MLL1, deposits H3K4me2 at CpG-dense regions that could serve as PREs. In the absence of MLL1 and H3K4me2, H3K27me3 levels, a mark of Polycomb repressive complex 2 (PRC2), increase at these loci. By inhibiting PRC2-dependent H3K27me3 in the absence of MLL1, we can rescue expression of these loci, demonstrating a functional balance between MLL1 and PRC2 activities at these sites. Thus, our study provides rules for identifying cell-type-specific functional mammalian PREs within the human genome. Copyright © 2016 Elsevier Inc. All rights reserved.

Pediatric acute myeloid leukemia with NPM1 mutations is characterized by a gene expression profile with dysregulated HOX gene expression distinct from MLL-rearranged leukemias.

PubMed

Mullighan, C G; Kennedy, A; Zhou, X; Radtke, I; Phillips, L A; Shurtleff, S A; Downing, J R

2007-09-01

Somatic mutations in nucleophosmin (NPM1) occur in approximately 35% of adult acute myeloid leukemia (AML). To assess the frequency of NPM1 mutations in pediatric AML, we sequenced NPM1 in the diagnostic blasts from 93 pediatric AML patients. Six cases harbored NPM1 mutations, with each case lacking common cytogenetic abnormalities. To explore the phenotype of the AMLs with NPM1 mutations, gene expression profiles were obtained using Affymetrix U133A microarrays. NPM1 mutations were associated with increased expression of multiple homeobox genes including HOXA9, A10, B2, B6 and MEIS1. As dysregulated homeobox gene expression is also a feature of MLL-rearranged leukemia, the gene expression signatures of NPM1-mutated and MLL-rearranged leukemias were compared. Significant differences were identified between these leukemia subtypes including the expression of different HOX genes, with NPM1-mutated AML showing higher levels of expression of HOXB2, B3, B6 and D4. These results confirm recent reports of perturbed HOX expression in NPM1-mutated adult AML, and provide the first evidence that the NPM1-mutated signature is distinct from MLL-rearranged AML. These findings suggest that mutated NPM1 leads to dysregulated HOX expression via a different mechanism than MLL rearrangement.

Morel-Lavallee Lesion in the Upper Extremity.

PubMed

Cochran, Grant K; Hanna, Kathryn H

2017-01-01

Background: The Morel-Lavallee lesion (MLL) is a closed internal degloving injury that results from shearing of the skin and subcutaneous tissue from the underlying fascia. Disruption of the perforating blood vessels and lymphatics results in a lesion filled with serosanguinous fluid and necrotized fat. MLLs are most commonly described in association with pelvic and lower extremity trauma, and there are limited reports of these lesions in other locations. Methods: This case report describes a 58-year-old male referred from his primary care physician with a soft tissue mass in the upper arm. Careful history discovered prior trauma with extensive bruising and MRI revealed a large encapsulated mass consistent with MLL. Results: An open debridement with excision of pseudocapsule was performed. Meticulous closure over a drain was performed and the patient healed without complication or recurrence. Intra-operative cultures were negative and pathology was consistent with MLL. Conclusion: MLL should always be considered in the setting of previous trauma regardless the location. In the chronic setting an open approach with excision of pseudocapsule can have an acceptable result.

An Lnc RNA (GAS5)/SnoRNA-derived piRNA induces activation of TRAIL gene by site-specifically recruiting MLL/COMPASS-like complexes

PubMed Central

He, Xin; Chen, Xinxin; Zhang, Xue; Duan, Xiaobing; Pan, Ting; Hu, Qifei; Zhang, Yijun; Zhong, Fudi; Liu, Jun; Zhang, Hong; Luo, Juan; Wu, Kang; Peng, Gao; Luo, Haihua; Zhang, Lehong; Li, Xiaoxi; Zhang, Hui

2015-01-01

PIWI-interacting RNA (piRNA) silences the transposons in germlines or induces epigenetic modifications in the invertebrates. However, its function in the mammalian somatic cells remains unknown. Here we demonstrate that a piRNA derived from Growth Arrest Specific 5, a tumor-suppressive long non-coding RNA, potently upregulates the transcription of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a proapoptotic protein, by inducing H3K4 methylation/H3K27 demethylation. Interestingly, the PIWIL1/4 proteins, which bind with this piRNA, directly interact with WDR5, resulting in a site-specific recruitment of the hCOMPASS-like complexes containing at least MLL3 and UTX (KDM6A). We have indicated a novel pathway for piRNAs to specially activate gene expression. Given that MLL3 or UTX are frequently mutated in various tumors, the piRNA/MLL3/UTX complex mediates the induction of TRAIL, and consequently leads to the inhibition of tumor growth. PMID:25779046

A rare case of severe third degree friction burns and large Morel-Lavallee lesion of the abdominal wall.

PubMed

Brown, Darnell J; Lu, Kuo Jung G; Chang, Kristina; Levin, Jennifer; Schulz, John T; Goverman, Jeremy

2018-01-01

Morel-Lavallee lesions (MLLs) are rare internal degloving injuries typically caused by blunt traumatic injuries and most commonly occur around the hips and in association with pelvic or acetabular fractures. MLL is often overlooked in the setting of poly-trauma; therefore, clinicians must maintain a high degree of suspicion and be familiar with the management of such injuries, especially in obese poly-trauma patients. We present a 30-year-old female pedestrian struck by a motor vehicle who sustained multiple long bone fractures, a mesenteric hematoma, and full-thickness abdominal skin friction burn which masked a significant underlying abdominal MLL. The internal degloving caused significant devascularization of the overlying soft tissue and skin which required surgical drainage of hematoma, abdominal wall reconstruction with tangential excision, allografting, negative pressure wound therapy, and ultimately autografting. MLL is a rare, often overlooked, internal degloving injury. Surgeons must maintain a high index of suspicion when dealing with third degree friction burns as they may mask underlying injuries such as MLL, and a delay in diagnosis can lead to increased morbidity.

Production of hydrogen and volatile fatty acid by Enterobacter sp. T4384 using organic waste materials.

PubMed

Kim, Byung-Chun; Deshpande, Tushar R; Chun, Jongsik; Yi, Sung Chul; Kim, Hyunook; Um, Youngsoon; Sang, Byoung-In

2013-02-01

In a study of hydrogen-producing bacteria, strain T4384 was isolated from rice field samples in the Republic of Korea. The isolate was identified as Enterobacter sp. T4384 by phylogenetic analysis of 16S rRNA and rpoB gene sequences. Enterobacter sp. T4384 grew at a temperature range of 10-45 degrees C and at an initial pH range of 4.5-9.5. Strain T4384 produced hydrogen at 0-6% NaCl by using glucose, fructose, and mannose. In serum bottle cultures using a complete medium, Enterobacter sp. T4384 produced 1,098 ml/l H2, 4.0 g/l ethanol, and 1.0 g/l acetic acid. In a pH-regulated jar fermenter culture with the biogas removed, 2,202 ml/l H2, 6.2 g/l ethanol, and 1.0 g/l acetic acid were produced, and the lag-phase time was 4.8 h. Strain T4384 metabolized the hydrolysate of organic waste for the production of hydrogen and volatile fatty acid. The strain T4384 produced 947 ml/l H2, 3.2 g/l ethanol, and 0.2 g/l acetic acid from 6% (w/v) food waste hydrolysate; 738 ml/l H2, 4.2 g/l ethanol, and 0.8 g/l acetic acid from Miscanthus sinensis hydrolysate; and 805 ml/l H2, 5.0 g/l ethanol, and 0.7 g/l acetic acid from Sorghum bicolor hydrolysate.

DNA-damage-induced differentiation of leukaemic cells as an anti-cancer barrier

PubMed Central

Santos, Margarida A.; Faryabi, Robert B.; Ergen, Aysegul V.; Day, Amanda M.; Malhowski, Amy; Canela, Andres; Onozawa, Masahiro; Lee, Ji-Eun; Callen, Elsa; Gutierrez-Martinez, Paula; Chen, Hua-Tang; Wong, Nancy; Finkel, Nadia; Deshpande, Aniruddha; Sharrow, Susan; Rossi, Derrick J.; Ito, Keisuke; Ge, Kai; Aplan, Peter D.; Armstrong, Scott A.; Nussenzweig, André

2015-01-01

Self-renewal is the hallmark feature both of normal stem cells and cancer stem cells1. Since the regenerative capacity of normal haematopoietic stem cells is limited by the accumulation of reactive oxygen species and DNA double-strand breaks2–4, we speculated that DNA damage might also constrain leukaemic self-renewal and malignant haematopoiesis. Here we show that the histone methyl-transferase MLL4, a suppressor of B-cell lymphoma5,6, is required for stem-cell activity and an aggressive form of acute myeloid leukaemia harbouring the MLL–AF9 oncogene. Deletion of MLL4 enhances myelopoiesis and myeloid differentiation of leukaemic blasts, which protects mice from death related to acute myeloid leukaemia. MLL4 exerts its function by regulating transcriptional programs associated with the antioxidant response. Addition of reactive oxygen species scavengers or ectopic expression of FOXO3 protects MLL4−/− MLL–AF9 cells from DNA damage and inhibits myeloid maturation. Similar to MLL4 deficiency, loss of ATM or BRCA1 sensitizes transformed cells to differentiation, suggesting that myeloid differentiation is promoted by loss of genome integrity. Indeed, we show that restriction-enzyme-induced double-strand breaks are sufficient to induce differentiation of MLL–AF9 blasts, which requires cyclin-dependent kinase inhibitor p21Cip1 (Cdkn1a) activity. In summary, we have uncovered an unexpected tumour-promoting role of genome guardians in enforcing the oncogene-induced differentiation blockade in acute myeloid leukaemia. PMID:25079327

Biochemical reconstitution and phylogenetic comparison of human SET1 family core complexes involved in histone methylation.

PubMed

Shinsky, Stephen A; Monteith, Kelsey E; Viggiano, Susan; Cosgrove, Michael S

2015-03-06

Mixed lineage leukemia protein-1 (MLL1) is a member of the SET1 family of histone H3 lysine 4 (H3K4) methyltransferases that are required for metazoan development. MLL1 is the best characterized human SET1 family member, which includes MLL1-4 and SETd1A/B. MLL1 assembles with WDR5, RBBP5, ASH2L, DPY-30 (WRAD) to form the MLL1 core complex, which is required for H3K4 dimethylation and transcriptional activation. Because all SET1 family proteins interact with WRAD in vivo, it is hypothesized they are regulated by similar mechanisms. However, recent evidence suggests differences among family members that may reflect unique regulatory inputs in the cell. Missing is an understanding of the intrinsic enzymatic activities of different SET1 family complexes under standard conditions. In this investigation, we reconstituted each human SET1 family core complex and compared subunit assembly and enzymatic activities. We found that in the absence of WRAD, all but one SET domain catalyzes at least weak H3K4 monomethylation. In the presence of WRAD, all SET1 family members showed stimulated monomethyltransferase activity but differed in their di- and trimethylation activities. We found that these differences are correlated with evolutionary lineage, suggesting these enzyme complexes have evolved to accomplish unique tasks within metazoan genomes. To understand the structural basis for these differences, we employed a "phylogenetic scanning mutagenesis" assay and identified a cluster of amino acid substitutions that confer a WRAD-dependent gain-of-function dimethylation activity on complexes assembled with the MLL3 or Drosophila trithorax proteins. These results form the basis for understanding how WRAD differentially regulates SET1 family complexes in vivo. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma | Office of Cancer Genomics

Cancer.gov

In a recent Nature article, Morin et al. uncovered a novel role for chromatin modification in driving the progression of two non-Hodgkin lymphomas (NHLs), follicular lymphoma and diffuse large B-cell lymphoma. Through DNA and RNA sequencing of 117 tumor samples and 10 assorted cell lines, the authors identified and validated 109 genes with multiple mutations in these B-cell NHLs. Of the 109 genes, several genes not previously linked to lymphoma demonstrated positive selection for mutation including two genes involved in histone modification, MLL2 and MEF2B.

The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration

PubMed Central

Cheng, Yating; Jutooru, Indira; Chadalapaka, Gayathri; Corton, J. Christopher; Safe, Stephen

2015-01-01

HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5′ tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors. PMID:25912306

Effects of washed platelets vs platelet-rich plasma on the proliferation and mineralization of rat dental pulp cells.

PubMed

Zhang, L; Xie, Y H; Lin, B R

2015-08-14

We examined the effects of washed platelets (WPLTs) and platelet-rich plasma (PRP) on the proliferation and mineralization of rat dental pulp cells. Rat dental pulp cells were separated, cultured, and identified. Medium containing 1, 10, 100, or 500 mL/L PRP or WPLTs was added to 4th generation cells. The MTS method was used to determine cell proliferation. Alizarin red staining was used to observe the formation of mineralized nodules after cell mineralization and induction for 10 and 20 days under different culture conditions, and the areas of the mineralized nodules formed 20 days after induction were computed. The addition of 1, 10, and 100 mL/L WPLTs or PRP significantly promoted rat dental pulp cell proliferation (P < 0.05) whereas 500 mL/L WPLTs or PRP had no significant effect (P > 0.05). Under the same concentrations, no significant differences on cell proliferation were observed between WPLT and PRP treatments (P > 0.05 in all groups). After 10 days mineralization and culture, the 100 and 500 mL/L WPLT and PRP group positive nodule rates were significantly higher than those of the low concentration and the control groups (P < 0.05). After 20 days, the areas of the mineralized nodules formed in the 100 and 500 mL/L WPLT and PRP groups were significantly larger than those in the control group (P < 0.05). These results demonstrate that both WPLTs and PRP are equally able to significantly promote the proliferation and calcification of rat dental pulp cells under a certain range of concentrations.

Augmenting in vitro shoot multiplication by vipul (triacontanol) and adventitious rhizogenesis by rice bran extract in Dendrocalamus strictus.

PubMed

Mishra, Y; Rana, P K; Shirin, F; Ansari, S A

2001-02-01

Like other bamboo species, Dendrocalamus strictus flowers gregariously after a prolonged intermast period of 48 years and constitutes an ideal material for in vitro clonal propagation. In this study, MS liquid medium containing 0.5, 1.0 and 2.0 mL/L vipul (Godrej Agrovet, Ltd., Sachin, India), a commercial formulation of triacontanol, with or without BA (3.0 mg/L) was tested for in vitro shoot multiplication and 1.0, 2.5 and 5.0 mL/L of 20% (w/v) alcoholic/aqueous rice bran extract (alone or in combination) with NAA (3 mg/L) used for in vitro adventitious rhizogenesis in single node culture derived shoots of Dendrocalamus strictus.. After a multiplication cycle for 4-5 week, vipul (0.5 mL/L) with BA (3.0 mg/L) in the culture medium induced 4.59 fold shoot multiplication rate whereas application of BA and vipul alone had corresponding values of 3.29 and 0.53 fold respectively. Maximum vipul concentration (2 mL/L) with BA (3 mg/L) exhibited shoot multiplication higher than (or equal to) that of BA alone. Maximum in vitro rooting percentage (55.66%) was obtained on half MS medium enriched with alcoholic rice bran extract (2.5 mL/L) and NAA (3 mg/L). This is the first investigation reporting amelioration of in vitro shoot multiplication rate by triacontanol and rooting percentage by rice bran extract in explants from mature bamboo culms. The protocol is economical and rapid for in vitro clonal propagation of Dendrocalamus strictus.

Complete pulse characterization of quantum dot mode-locked lasers suitable for optical communication up to 160 Gbit/s.

PubMed

Schmeckebier, H; Fiol, G; Meuer, C; Arsenijević, D; Bimberg, D

2010-02-15

A complete characterization of pulse shape and phase of a 1.3 microm, monolithic-two-section, quantum-dot mode-locked laser (QD-MLL) at a repetition rate of 40 GHz is presented, based on frequency resolved optical gating. We show that the pulse broadening of the QD-MLL is caused by linear chirp for all values of current and voltage investigated here. The chirp increases with the current at the gain section, whereas larger bias at the absorber section leads to less chirp and therefore to shorter pulses. Pulse broadening is observed at very high bias, likely due to the quantum confined stark effect. Passive- and hybrid-QD-MLL pulses are directly compared. Improved pulse intensity profiles are found for hybrid mode locking. Via linear chirp compensation pulse widths down to 700 fs can be achieved independent of current and bias, resulting in a significantly increased overall mode-locking range of 101 MHz. The suitability of QD-MLL chirp compensated pulse combs for optical communication up to 160 Gbit/s using optical-time-division multiplexing are demonstrated by eye diagrams and autocorrelation measurements.

Structural and Biochemical Insights into MLL1 Core Complex Assembly

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

Avdic, Vanja; Zhang, Pamela; Lanouette, Sylvain

2012-05-02

Histone H3 Lys-4 methylation is predominantly catalyzed by a family of methyltransferases whose enzymatic activity depends on their interaction with a three-subunit complex composed of WDR5, RbBP5, and Ash2L. Here, we report that a segment of 50 residues of RbBP5 bridges the Ash2L C-terminal domain to WDR5. The crystal structure of WDR5 in ternary complex with RbBP5 and MLL1 reveals that both proteins binds peptide-binding clefts located on opposite sides of WDR5s {beta}-propeller domain. RbBP5 engages in several hydrogen bonds and van der Waals contacts within a V-shaped cleft formed by the junction of two blades on WDR5. Mutational analysesmore » of both the WDR5 V-shaped cleft and RbBP5 residues reveal that the interactions between RbBP5 and WDR5 are important for the stimulation of MLL1 methyltransferase activity. Overall, this study provides the structural basis underlying the formation of the WDR5-RbBP5 subcomplex and further highlight the crucial role of WDR5 in scaffolding the MLL1 core complex.« less

Lumbar Morel-Lavallée lesion: Case report and review of the literature.

PubMed

Zairi, F; Wang, Z; Shedid, D; Boubez, G; Sunna, T

2016-06-01

The Morel-Lavallée lesion (MLL) is a rarely reported closed degloving injury, in which shearing forces have lead to break off subcutaneous tissues from the underlying fascia. Lumbar MLL have been rarely reported to date, explaining that patients are frequently misdiagnosed. While patients could be treated conservatively or with non-invasive procedures, delayed diagnosis may require open surgery for its cure. Indeed, untreated lesions can cause pain, infection or growing subcutaneous mass that can be confused with a soft tissue tumor. We report the clinical and radiological features of a 45-year old man with voluminous lumbar MLL initially misdiagnosed. We also reviewed the relevant English literature to summarize the diagnostic tools and the main therapeutic options. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

SET1A/COMPASS and shadow enhancers in the regulation of homeotic gene expression

PubMed Central

Cao, Kaixiang; Collings, Clayton K.; Marshall, Stacy A.; Morgan, Marc A.; Rendleman, Emily J.; Wang, Lu; Sze, Christie C.; Sun, Tianjiao; Bartom, Elizabeth T.; Shilatifard, Ali

2017-01-01

The homeotic (Hox) genes are highly conserved in metazoans, where they are required for various processes in development, and misregulation of their expression is associated with human cancer. In the developing embryo, Hox genes are activated sequentially in time and space according to their genomic position within Hox gene clusters. Accumulating evidence implicates both enhancer elements and noncoding RNAs in controlling this spatiotemporal expression of Hox genes, but disentangling their relative contributions is challenging. Here, we identify two cis-regulatory elements (E1 and E2) functioning as shadow enhancers to regulate the early expression of the HoxA genes. Simultaneous deletion of these shadow enhancers in embryonic stem cells leads to impaired activation of HoxA genes upon differentiation, while knockdown of a long noncoding RNA overlapping E1 has no detectable effect on their expression. Although MLL/COMPASS (complex of proteins associated with Set1) family of histone methyltransferases is known to activate transcription of Hox genes in other contexts, we found that individual inactivation of the MLL1-4/COMPASS family members has little effect on early Hox gene activation. Instead, we demonstrate that SET1A/COMPASS is required for full transcriptional activation of multiple Hox genes but functions independently of the E1 and E2 cis-regulatory elements. Our results reveal multiple regulatory layers for Hox genes to fine-tune transcriptional programs essential for development. PMID:28487406

A novel non-SET domain multi-subunit methyltransferase required for sequential nucleosomal histone H3 methylation by the mixed lineage leukemia protein-1 (MLL1) core complex.

PubMed

Patel, Anamika; Vought, Valarie E; Dharmarajan, Venkatasubramanian; Cosgrove, Michael S

2011-02-04

Gene expression within the context of eukaryotic chromatin is regulated by enzymes that catalyze histone lysine methylation. Histone lysine methyltransferases that have been identified to date possess the evolutionarily conserved SET or Dot1-like domains. We previously reported the identification of a new multi-subunit histone H3 lysine 4 methyltransferase lacking homology to the SET or Dot1 family of histone lysine methyltransferases. This enzymatic activity requires a complex that includes WRAD (WDR5, RbBP5, Ash2L, and DPY-30), a complex that is part of the MLL1 (mixed lineage leukemia protein-1) core complex but that also exists independently of MLL1 in the cell. Here, we report that the minimal complex required for WRAD enzymatic activity includes WDR5, RbBP5, and Ash2L and that DPY-30, although not required for enzymatic activity, increases the histone substrate specificity of the WRAD complex. We also show that WRAD requires zinc for catalytic activity, displays Michaelis-Menten kinetics, and is inhibited by S-adenosyl-homocysteine. In addition, we demonstrate that WRAD preferentially methylates lysine 4 of histone H3 within the context of the H3/H4 tetramer but does not methylate nucleosomal histone H3 on its own. In contrast, we find that MLL1 and WRAD are required for nucleosomal histone H3 methylation, and we provide evidence suggesting that each plays distinct structural and catalytic roles in the recognition and methylation of a nucleosome substrate. Our results indicate that WRAD is a new H3K4 methyltransferase with functions that include regulating the substrate and product specificities of the MLL1 core complex.

FLT3-ITD and MLL-PTD influence the expression of MDR-1, MRP-1, and BCRP mRNA but not LRP mRNA assessed with RQ-PCR method in adult acute myeloid leukemia.

PubMed

Nasilowska-Adamska, Barbara; Solarska, Iwona; Paluszewska, Monika; Malinowska, Iwona; Jedrzejczak, Wieslaw W; Warzocha, Krzysztof

2014-04-01

Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are aberrations associated with leukemia which indicate unsatisfactory prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. We have analyzed the expression of MDR-1, multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP), and lung resistance protein (LRP) messenger RNA (mRNA) in relation to the mutational status of FLT3-ITD and MLL-PTD in 185 acute myeloid leukemia (AML) adult patients. The real-time quantitative polymerase chain reaction method was performed to assess the expression of the MDR-1, MRP-1, BCRP, and LRP mRNA, and the results were presented as coefficients calculated using an intermediate method according to Pfaffl's rule. Significantly higher expressions of MDR-1 mRNA were found in patients who did not harbor FLT3-ITD (0.20 vs. 0.05; p = 0.0001) and MRP-1 mRNA in patients with this mutation (0.96 vs. 0.70; p = 0.002) and of BCRP mRNA in patients with MLL-PTD (0.61 vs. 0.38; p = 0.03). In univariate analysis, the high expression of MDR-1 mRNA (≥0.1317) negatively influenced the outcome of induction therapy (p = 0.05), whereas the high expression of BCRP mRNA (≥1.1487) was associated with a high relapse rate (RR) (p = 0.013). We found that the high expression of MDR-1 (≥0.1317), MRP-1 (≥0.8409), and BCRP mRNA (≥1.1487) significantly influenced disease-free survival (DFS; p = 0.059, 0.032, and 0.009, respectively) and overall survival (0.048, 0.014, and 0.059, respectively). Moreover, a high expression of BCRP mRNA (≥1.1487) proved to be an independent prognostic factor for RR (p = 0.01) and DFS (p = 0.002) in multivariate analysis. The significant correlation between the expression of MDR-1, MRP-1, and BCRP mRNA and FLT3-ITD or MLL-PTD in AML patients requires further investigation.

[Hyperoxia induces reactive oxygen species production and promotes SIRT1 nucleocytoplasmic shuttling of peripheral blood mononuclear cells in premature infants in vitro].

PubMed

Yang, Xi; Dong, Wenbin; Li, Qingping; Kang, Lan; Lei, Xiaoping; Zhang, Lianyu; Lu, Youying; Zhai, Xuesong

2015-12-01

To explore the relationship between deacetylase sirtuin 1 (SIRT1) and reactive oxygen species (ROS) after oxygen therapy in the peripheral blood mononuclear cells (PBMCs) of the premature infants. According to the fraction of inspired O2 (FiO2), premature infants diagnosed with respiratory distress syndrome (RDS) (gestational age <32 weeks), were divided into three groups: low dosage oxygen group (FiO2 <300 mL/L), moderate dosage oxygen group (FiO2; 300 mL/L-400 mL/L), high dosage oxygen group (FiO2 >400 mL/L). After 48 hours of oxygen treatment, PBMCs and serum were collected from the peripheral blood. Then the intracellular ROS level was detected by MitoSOX(TM) Red labeling combined with confocal laser scanning microscopy; the malondialdehyde (MDA) content in the serum was determined by the whole spectrum spectrophotometer; the SIRT1 localization was observed by immunofluorescence staining; and the SIRT1 levels in PBMCs were examined by Western blotting. With the increase of FiO2, the ROS, MDA content and the rate of SIRT1 nucleocytoplasmic shuttling of PBMCs gradually increased and SIRT1 protein expression was significantly lowered. Hyperoxia induces ROS production in premature infants, promotes SIRT1 to cross from nucleus to cytoplasm, inhibits the resistant ability of SIRT1 to oxidative stress.

Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish

PubMed Central

Savoldi, Robson; Polari, Daniel; Pinheiro-da-Silva, Jaquelinne; Silva, Priscila F.; Lobao-Soares, Bruno; Yonamine, Mauricio; Freire, Fulvio A. M.; Luchiari, Ana C.

2017-01-01

The combined infusion of Banisteriopsis caapi stem and Psychotria viridis leaves, known as ayahuasca, has been used for centuries by indigenous tribes. The infusion is rich in N, N-dimethyltryptamine (DMT) and monoamine oxidase inhibitors, with properties similar to those of serotonin. Despite substantial progress in the development of new drugs to treat anxiety and depression, current treatments have several limitations. Alternative drugs, such as ayahuasca, may shed light on these disorders. Here, we present time-course behavioral changes induced by ayahuasca in zebrafish, as first step toward establishing an ideal concentration for pre-clinical evaluations. We exposed adult zebrafish to five concentrations of the ayahuasca infusion: 0 (control), 0.1, 0.5, 1, and 3 ml/L (n = 14 each group), and behavior was recorded for 60 min. We evaluated swimming speed, distance traveled, freezing and bottom dwelling every min for 60 min. Swimming speed and distance traveled decreased with an increase in ayahuasca concentration while freezing increased with 1 and 3 ml/L. Bottom dwelling increased with 1 and 3 ml/L, but declined with 0.1 ml/L. Our data suggest that small amounts of ayahuasca do not affect locomotion and reduce anxiety-like behavior in zebrafish, while increased doses of the drug lead to crescent anxiogenic effects. We conclude that the temporal analysis of zebrafish behavior is a sensitive method for the study of ayahuasca-induced functional changes in the vertebrate brain. PMID:28804451

Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish.

PubMed

Savoldi, Robson; Polari, Daniel; Pinheiro-da-Silva, Jaquelinne; Silva, Priscila F; Lobao-Soares, Bruno; Yonamine, Mauricio; Freire, Fulvio A M; Luchiari, Ana C

2017-01-01

The combined infusion of Banisteriopsis caapi stem and Psychotria viridis leaves, known as ayahuasca, has been used for centuries by indigenous tribes. The infusion is rich in N , N -dimethyltryptamine (DMT) and monoamine oxidase inhibitors, with properties similar to those of serotonin. Despite substantial progress in the development of new drugs to treat anxiety and depression, current treatments have several limitations. Alternative drugs, such as ayahuasca, may shed light on these disorders. Here, we present time-course behavioral changes induced by ayahuasca in zebrafish, as first step toward establishing an ideal concentration for pre-clinical evaluations. We exposed adult zebrafish to five concentrations of the ayahuasca infusion: 0 (control), 0.1, 0.5, 1, and 3 ml/L ( n = 14 each group), and behavior was recorded for 60 min. We evaluated swimming speed, distance traveled, freezing and bottom dwelling every min for 60 min. Swimming speed and distance traveled decreased with an increase in ayahuasca concentration while freezing increased with 1 and 3 ml/L. Bottom dwelling increased with 1 and 3 ml/L, but declined with 0.1 ml/L. Our data suggest that small amounts of ayahuasca do not affect locomotion and reduce anxiety-like behavior in zebrafish, while increased doses of the drug lead to crescent anxiogenic effects. We conclude that the temporal analysis of zebrafish behavior is a sensitive method for the study of ayahuasca-induced functional changes in the vertebrate brain.

Enhancers of Polycomb EPC1 and EPC2 sustain the oncogenic potential of MLL leukemia stem cells

PubMed Central

Huang, Xu; Spencer, Gary J; Lynch, James T; Ciceri, Filippo; Somerville, Tim D D; Somervaille, Tim C P

2013-01-01

Through a targeted knockdown (KD) screen of chromatin regulatory genes we identified the EP400 complex components EPC1 and EPC2 as critical oncogenic co-factors in acute myeloid leukemia (AML). EPC1 and EPC2 were required for the clonogenic potential of human AML cells of multiple molecular subtypes. Focusing on MLL-mutated AML as an exemplar, Epc1 or Epc2 KD induced apoptosis of murine MLL-AF9 AML cells and abolished leukemia stem cell potential. By contrast, normal hematopoietic stem and progenitor cells (HSPC) were spared. Similar selectivity was observed for human primary AML cells versus normal CD34+ HSPC. In keeping with these distinct functional consequences, Epc1 or Epc2 KD induced divergent transcriptional consequences in murine MLL-AF9 granulocyte-macrophage progenitor-like (GMP) cells versus normal GMP, with a signature of increased MYC activity in leukemic but not normal cells. This was caused by accumulation of MYC protein and was also observed following KD of other EP400 complex genes. Pharmacological inhibition of MYC:MAX dimerization, or concomitant MYC KD, reduced apoptosis following EPC1 KD, linking the accumulation of MYC to cell death. Therefore EPC1 and EPC2 are components of a complex which directly or indirectly serves to prevent MYC accumulation and AML cell apoptosis, thus sustaining oncogenic potential. PMID:24166297

Genetic variation of naturally growing olive trees in Israel: from abandoned groves to feral and wild?

PubMed

Barazani, Oz; Keren-Keiserman, Alexandra; Westberg, Erik; Hanin, Nir; Dag, Arnon; Ben-Ari, Giora; Fragman-Sapir, Ori; Tugendhaft, Yizhar; Kerem, Zohar; Kadereit, Joachim W

2016-12-13

Naturally growing populations of olive trees are found in the Mediterranean garrigue and maquis in Israel. Here, we used the Simple Sequence Repeat (SSR) genetic marker technique to investigate whether these represent wild var. sylvestris. Leaf samples were collected from a total of 205 trees at six sites of naturally growing olive populations in Israel. The genetic analysis included a multi-locus lineage (MLL) analysis, Rousset's genetic distances, Fst values, private alleles, other diversity values and a Structure analysis. The analyses also included scions and suckers of old cultivated olive trees, for which the dominance of one clone in scions (MLL1) and a second in suckers (MLL7) had been shown earlier. The majority of trees from a Judean Mts. population and from one population from the Galilee showed close genetic similarity to scions of old cultivated trees. Different from that, site-specific and a high number of single occurrence MLLs were found in four olive populations from the Galilee and Carmel which also were genetically more distant from old cultivated trees, had relatively high genetic diversity values and higher numbers of private alleles. Whereas in two of these populations MLL7 (and partly MLL1) were found in low frequency, the two other populations did not contain these MLLs and were very similar in their genetic structure to suckers of old cultivated olive trees that originated from sexual reproduction. The genetic distinctness from old cultivated olive trees, particularly of one population from Galilee and one from Carmel, suggests that trees at these sites might represent wild var. sylvestris. The similarity in genetic structure of these two populations with the suckers of old cultivated trees implies that wild trees were used as rootstocks. Alternatively, trees at these two sites may be remnants of old cultivated trees in which the scion-derived trunk died and was replaced by suckers. However, considering landscape and topographic environment at the two sites this second interpretation is less likely.

[Benign proliferative breast disease with and without atypia].

PubMed

Coutant, C; Canlorbe, G; Bendifallah, S; Beltjens, F

2015-12-01

In the last few years, diagnostics of high-risk breast lesions (atypical ductal hyperplasia [ADH], flat epithelial atypia [FEA], lobular neoplasia: atypical lobular hyperplasia [ALH], lobular carcinoma in situ [LCIS], radial scar [RS], usual ductal hyperplasia [UDH], adenosis, sclerosing adenosis [SA], papillary breast lesions, mucocele-like lesion [MLL]) have increased with the growing number of breast percutaneous biopsies. The management of these lesions is highly conditioned by the enlarged risk of breast cancer combined with either an increased probability of finding cancer after surgery, either a possible malignant transformation (in situ or invasive cancer), or an increased probability of developing cancer on the long range. An overview of the literature reports grade C recommendations concerning the management and follow-up of these lesions: in case of ADH, FEA, ALH, LCIS, RS, MLL with atypia, diagnosed on percutaneous biopsies: surgical excision is recommended; in case of a diagnostic based on vacuum-assisted core biopsy with complete disappearance of radiological signal for FEA or RS without atypia: surgical abstention is a valid alternative approved by multidisciplinary meeting. In case of ALH (incidental finding) associated with benign lesion responsible of radiological signal: abstention may be proposed; in case of UDH, adenosis, MLL without atypia, diagnosed on percutaneous biopsies: the concordance of radiology and histopathology findings must be ensured. No data is available to recommend surgery; in case of non-in sano resection for ADH, FEA, ALH, LCIS (except pleomorphic type), RS, MLL: surgery does not seem to be necessary; in case of previous ADH, ALH, LCIS: a specific follow-up is recommended in accordance with HAS's recommendations. In case of FEA and RS or MLL combined with atypia, little data are yet available to differ the management from others lesions with atypia; in case of UDH, usual sclerosing adenosis, RS without atypia, fibro cystic disease: no specific follow-up is recommended in agreement with HAS's recommendations. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

miR-125b promotes MLL-AF9–driven murine acute myeloid leukemia involving a VEGFA-mediated non–cell-intrinsic mechanism

PubMed Central

Liu, Jun; Guo, Bo; Chen, Zhuo; Wang, Nayi; Iacovino, Michelina; Cheng, Jijun; Roden, Christine; Pan, Wen; Khan, Sajid; Chen, Suning; Kyba, Michael; Fan, Rong; Guo, Shangqin

2017-01-01

The hematopoietic stem cell–enriched miR-125 family microRNAs (miRNAs) are critical regulators of hematopoiesis. Overexpression of miR-125a or miR-125b is frequent in human acute myeloid leukemia (AML), and the overexpression of these miRNAs in mice leads to expansion of hematopoietic stem cells accompanied by perturbed hematopoiesis with mostly myeloproliferative phenotypes. However, whether and how miR-125 family miRNAs cooperate with known AML oncogenes in vivo, and how the resultant leukemia is dependent on miR-125 overexpression, are not well understood. We modeled the frequent co-occurrence of miR-125b overexpression and MLL translocations by examining functional cooperation between miR-125b and MLL-AF9. By generating a knock-in mouse model in which miR-125b overexpression is controlled by doxycycline induction, we demonstrated that miR-125b significantly enhances MLL-AF9–driven AML in vivo, and the resultant leukemia is partially dependent on continued overexpression of miR-125b. Surprisingly, miR-125b promotes AML cell expansion and suppresses apoptosis involving a non–cell-intrinsic mechanism. MiR-125b expression enhances VEGFA expression and production from leukemia cells, in part by suppressing TET2. Recombinant VEGFA recapitulates the leukemia-promoting effects of miR-125b, whereas knockdown of VEGFA or inhibition of VEGF receptor 2 abolishes the effects of miR-125b. In addition, significant correlation between miR-125b and VEGFA expression is observed in human AMLs. Our data reveal cooperative and dependent relationships between miR-125b and the MLL oncogene in AML leukemogenesis, and demonstrate a miR-125b-TET2-VEGFA pathway in mediating non–cell-intrinsic leukemia-promoting effects by an oncogenic miRNA. PMID:28053194

Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells

PubMed Central

Somervaille, Tim C. P.; Matheny, Christina J.; Spencer, Gary J.; Iwasaki, Masayuki; Rinn, John L.; Witten, Daniela M.; Chang, Howard Y.; Shurtleff, Sheila A.; Downing, James R.; Cleary, Michael L.

2009-01-01

Summary The genetic programs that promote retention of self-renewing leukemia stem cells (LSCs) at the apex of cellular hierarchies in acute myeloid leukemia (AML) are not known. In a mouse model of human AML, LSCs exhibit variable frequencies that correlate with the initiating MLL oncogene and are maintained in a self-renewing state by a transcriptional sub-program more akin to that of embryonic stem cells (ESCs) than adult stem cells. The transcription/chromatin regulatory factors Myb, Hmgb3 and Cbx5 are critical components of the program and suffice for Hoxa/Meis-independent immortalization of myeloid progenitors when co-expressed, establishing the cooperative and essential role of an ESC-like LSC maintenance program ancillary to the leukemia initiating MLL/Hox/Meis program. Enriched expression of LSC maintenance and ESC-like program genes in normal myeloid progenitors and poor prognosis human malignancies links the frequency of aberrantly self-renewing progenitor-like cancer stem cells to prognosis in human cancer. PMID:19200802

Essential role of lncRNA binding for WDR5 maintenance of active chromatin and embryonic stem cell pluripotency

PubMed Central

Yang, Yul W; Flynn, Ryan A; Chen, Yong; Qu, Kun; Wan, Bingbing; Wang, Kevin C; Lei, Ming; Chang, Howard Y

2014-01-01

The WDR5 subunit of the MLL complex enforces active chromatin and can bind RNA; the relationship between these two activities is unclear. Here we identify a RNA binding pocket on WDR5, and discover a WDR5 mutant (F266A) that selectively abrogates RNA binding without affecting MLL complex assembly or catalytic activity. Complementation in ESCs shows that WDR5 F266A mutant is unable to accumulate on chromatin, and is defective in gene activation, maintenance of histone H3 lysine 4 trimethylation, and ESC self renewal. We identify a family of ESC messenger and lncRNAs that interact with wild type WDR5 but not F266A mutant, including several lncRNAs known to be important for ESC gene expression. These results suggest that specific RNAs are integral inputs into the WDR5-MLL complex for maintenance of the active chromatin state and embryonic stem cell fates. DOI: http://dx.doi.org/10.7554/eLife.02046.001 PMID:24521543

Slip events propagating along a ductile mid-crustal strike-slip shear zone (Malpica-Lamego line, Variscan Orogen, NW Iberia)

NASA Astrophysics Data System (ADS)

Llana-Fúnez, Sergio; de Paola, Nicola; Pozzi, Giacomo; Lopez-Sanchez, Marco Antonio

2017-04-01

The current level of erosion in NW Iberian peninsula exposes Variscan mid-crustal depths, where widespread deformation during orogenesis produced dominantly ductile structures. It constitutes an adequate window for the observation of structures close to the brittle-plastic transition in the continental crust. The shear zone object of this work is the Malpica-Lamego line (MLL), a major Variscan structure formed in the late stages of the Variscan collision. The MLL is a mostly strike-slip major structure that offsets laterally by several kilometres the assembly of allochthonous complexes, that contain a sub-horizontal suture zone, which are the remnants of the plate duplication during the Variscan convergence. The shear zone is exposed along the northern coast of Galicia (NW Spain). It is characterized by phyllonites and quartz-mylonites in a zone which is tens of meters in thickness. Within the phyllonites, a few seams of cataclastic rocks have been found in bands along the main fabric. Their cohesive character, the parallelism between the different bands, the fact that host rocks maintain mineral assemblage and that no cross-cutting relations in the field were identified, are considered indicative of these brittle structures forming coetaneously with the ductile shearing producing the phyllonites. Samples from the phyllonites, also from quartz-mylonites, were prepared and powdered to characterize friction properties in a rotary shear apparatus at high, seismic velocities (m/s). Preliminary experiments run at room temperature and effective normal stresses between 10 to 25 MPa, show that friction coefficients µ are relatively high and a limited drop in friction coefficient occurs after 10-20 cm of slip, with µ decreasing from 0.7 to 0.5. Fracturing seems coetaneous with dominant ductile shearing within the shear zone, however, given the frictional properties of the phyllonites, it is unlikely that brittle deformation nucleates within these fault rocks. Instead, it seems that faulting originated in other sectors of the fault zone, and then propagated through the studied section.

Development and characterization of monolithic multilayer Laue lens nanofocusing optics

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

Nazaretski, E.; Xu, W.; Bouet, N.

2016-06-27

We have developed an experimental approach to bond two independent linear Multilayer Laue Lenses (MLLs) together. A monolithic MLL structure was characterized using ptychography at 12 keV photon energy, and we demonstrated 12 nm and 24 nm focusing in horizontal and vertical directions, respectively. Fabrication of 2D MLL optics allows installation of these focusing elements in more conventional microscopes suitable for x-ray imaging using zone plates, and opens easier access to 2D imaging with high spatial resolution in the hard x-ray regime.

Development and characterization of monolithic multilayer Laue lens nanofocusing optics

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

Nazaretski, E.; Xu, W., E-mail: weihexu@bnl.gov; Bouet, N.

2016-06-27

We have developed an experimental approach to bond two independent linear Multilayer Laue Lenses (MLLs) together. A monolithic MLL structure was characterized using ptychography at 12 keV photon energy, and we demonstrated 12 nm and 24 nm focusing in horizontal and vertical directions, respectively. Fabrication of 2D MLL optics allows installation of these focusing elements in more conventional microscopes suitable for x-ray imaging using zone plates, and opens easier access to 2D imaging with high spatial resolution in the hard x-ray regime.

Development and characterization of monolithic multilayer Laue lens nanofocusing optics

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

Nazaretski, E.; Xu, W.; Bouet, N.

In this study, we have developed an experimental approach to bond two independent linear Multilayer Laue Lenses (MLLs) together. A monolithic MLL structure was characterized using ptychography at 12 keV photon energy, and we demonstrated 12 nm and 24 nm focusing in horizontal and vertical directions, respectively. Fabrication of 2D MLL optics allows installation of these focusing elements in more conventional microscopes suitable for x-ray imaging using zone plates, and opens easier access to 2D imaging with high spatial resolution in the hard x-ray regime.

Development and characterization of monolithic multilayer Laue lens nanofocusing optics

DOE PAGES

Nazaretski, E.; Xu, W.; Bouet, N.; ...

2016-06-27

In this study, we have developed an experimental approach to bond two independent linear Multilayer Laue Lenses (MLLs) together. A monolithic MLL structure was characterized using ptychography at 12 keV photon energy, and we demonstrated 12 nm and 24 nm focusing in horizontal and vertical directions, respectively. Fabrication of 2D MLL optics allows installation of these focusing elements in more conventional microscopes suitable for x-ray imaging using zone plates, and opens easier access to 2D imaging with high spatial resolution in the hard x-ray regime.

Processes influencing seasonal hypoxia in the northern California Current System

PubMed Central

Connolly, T. P.; Hickey, B. M.; Geier, S. L.; Cochlan, W. P.

2010-01-01

This paper delineates the role of physical and biological processes contributing to hypoxia, dissolved oxygen (DO) < 1.4 mL/L, over the continental shelf of Washington State in the northern portion of the California Current System (CCS). In the historical record (1950–1986) during the summer upwelling season, hypoxia is more prevalent and severe off Washington than further south off northern Oregon. Recent data (2003–2005) show that hypoxia over the Washington shelf occurred at levels previously observed in the historical data. 2006 was an exception, with hypoxia covering ~5000 km2 of the Washington continental shelf and DO concentrations below 0.5 mL/L at the inner shelf, lower than any known previous observations at that location. In the four years studied, upwelling of low DO water and changes in source water contribute to interannual variability, but cannot account for seasonal decreases below hypoxic concentrations. Deficits of DO along salinity surfaces, indicating biochemical consumption of DO, vary significantly between surveys, accounting for additional decreases of 0.5–2.5 mL/L by late summer. DO consumption is associated with denitrification, an indicator of biochemical sediment processes. Mass balances of DO and nitrate show that biochemical processes in the water column and sediments each contribute ~50% to the total consumption of DO in near-bottom water. At shorter than seasonal time scales on the inner shelf, along-shelf advection of hypoxic patches and cross-shelf advection of seasonal gradients are both shown to be important, changing DO concentrations by 1.5 mL/L or more over five days. PMID:20463844

Discovery of potent DOT1L inhibitors by AlphaLISA based High Throughput Screening assay.

PubMed

Song, Yakai; Li, Linjuan; Chen, Yantao; Liu, Jingqiu; Xiao, Senhao; Lian, Fulin; Zhang, Naixia; Ding, Hong; Zhang, Yuanyuan; Chen, Kaixian; Jiang, Hualiang; Zhang, Chenhua; Liu, Yu-Chih; Chen, Shijie; Luo, Cheng

2018-05-01

DOT1L (the disruptor of telomeric silencing 1-like), through its methyltransferase activity of H3K79, plays essential roles in transcriptional regulation, cell cycle regulation, and DNA damage response. In addition, DOT1L is believed to be involved in the development of MLL-rearranged leukemia driven by the MLL (mixed-lineage leukemia) fusion proteins, which thus to be a crucial target for leukemia therapy. Hence, discovering of novel DOT1L inhibitors has been in a great demand. In this study, we initiated the discovering process from setting up the AlphaLISA based High Throughput Screening (HTS) assay of DOT1L. Combining with radioactive inhibition assay and Surface Plasmon Resonance (SPR) binding assay, we identified compound 3 and its active analogues as novel DOT1L inhibitors with IC 50 values range from 7 μM to 20 μM in vitro. Together with the analysis of structure activity relationships (SAR) and binding modes of these compounds, we provided clues to assist in the future development of more potent DOT1L inhibitors. Moreover, compounds 3 and 9 effectively inhibited the proliferation of MLL-rearranged leukemia cells MV4-11, which could induce cell cycle arrest and apoptosis. In conclusion, we developed a HTS platform based on AlphaLISA method for screening and discovery of DOT1L novel inhibitor, through which we discovered compound 3 and its analogues as potent DOT1L inhibitors with promising MLL-rearranged leukemia therapeutic application. Copyright © 2018 Elsevier Ltd. All rights reserved.

MicroRNA-196b promotes cell proliferation and suppress cell differentiation in vitro

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

Cao, Donglin, E-mail: caodlgz@sina.com; Hu, Liangshan; Lei, Da

Highlights: • miRNA-196b increases proliferation and blocks differentiation of progenitor cell. • miRNA-196b inhibits apoptosis and increases viability of cells lines. • Forced expression of miR-196b blocks the differentiation of THP1 induced by PMA. - Abstract: MicroRNA-196b (miR-196b) is frequently amplified and aberrantly overexpressed in acute leukemias. To investigate the role of miR-196b in acute leukemias, it has been observed that forced expression of this miRNA increases proliferation and inhibits apoptosis in human cell lines. More importantly, we show that this miRNA can significantly increase the colony-forming capacity of mouse normal bone marrow progenitor cells alone, as well as partiallymore » blocking the cells from differentiation. Taken together, our studies suggest that miRNA-196b may play an essential role in the development of MLL-associated leukemias through inhibiting cell differentiation and apoptosis, while promoting cell proliferation.« less

Nucleoporin Nup98 associates with Trx/MLL and NSL histone-modifying complexes and regulates Hox gene expression.

PubMed

Pascual-Garcia, Pau; Jeong, Jieun; Capelson, Maya

2014-10-23

The nuclear pore complex is a transport channel embedded in the nuclear envelope and made up of 30 different components termed nucleoporins (Nups). In addition to their classical role in transport, a subset of Nups has a conserved role in the regulation of transcription via direct binding to chromatin. The molecular details of this function remain obscure, and it is unknown how metazoan Nups are recruited to their chromatin locations or what transcription steps they regulate. Here, we demonstrate genome-wide and physical association between Nup98 and histone-modifying complexes MBD-R2/NSL [corrected] and Trx/MLL. Importantly, we identify a requirement for MBD-R2 in recruitment of Nup98 to many of its genomic target sites. Consistent with its interaction with the Trx/MLL complex, Nup98 is shown to be necessary for Hox gene expression in developing fly tissues. These findings introduce roles of Nup98 in epigenetic regulation that may underlie the basis of oncogenicity of Nup98 fusions in leukemia.

Toxicity of water and sediment from stormwater retarding basins to Hydra hexactinella.

PubMed

Rosenkrantz, Rikke T; Pollino, Carmel A; Nugegoda, Dayanthi; Baun, Anders

2008-12-01

Hydra hexactinella was used to assess the toxicity of stormwater and sediment samples from three retarding basins in Melbourne, Australia, using an acute test, a sublethal test, and a pulse test. Stormwater from the Avoca St retarding basins resulted in a LC50 of 613 ml/L, NOEC and LOEC values of 50 ml/L and 100 ml/L, while the 7h pulse exposure caused a significant increase in the mean population growth rate compared to the control. Water samples from the two other retarding basins were found non-toxic to H. hexactinella. This is the first study to employ sediment tests with Hydra spp. on stormwater sediments and a lower population growth rate was observed for organisms exposed to sediment from the Avoca St retarding basins. The behavioral study showed that H. hexactinella tended to avoid the sediment-water interface when exposed to sediment from all retarding basins, compared to the reference sediment. Further work is needed to determine the long-term effects of stormwater polluted sediments and acute effects due to organism exposure to short-term high concentrations during rain events.

Expansion of oxygen minimum zones may reduce available habitat for tropical pelagic fishes

NASA Astrophysics Data System (ADS)

Stramma, Lothar; Prince, Eric D.; Schmidtko, Sunke; Luo, Jiangang; Hoolihan, John P.; Visbeck, Martin; Wallace, Douglas W. R.; Brandt, Peter; Körtzinger, Arne

2012-01-01

Climate model predictions and observations reveal regional declines in oceanic dissolved oxygen, which are probably influenced by global warming. Studies indicate ongoing dissolved oxygen depletion and vertical expansion of the oxygen minimum zone (OMZ) in the tropical northeast Atlantic Ocean. OMZ shoaling may restrict the usable habitat of billfishes and tunas to a narrow surface layer. We report a decrease in the upper ocean layer exceeding 3.5mll-1 dissolved oxygen at a rate of <=1myr-1 in the tropical northeast Atlantic (0-25°N, 12-30°W), amounting to an annual habitat loss of ~5.95×1013m3, or 15% for the period 1960-2010. Habitat compression and associated potential habitat loss was validated using electronic tagging data from 47 blue marlin. This phenomenon increases vulnerability to surface fishing gear for billfishes and tunas, and may be associated with a 10-50% worldwide decline of pelagic predator diversity. Further expansion of the Atlantic OMZ along with overfishing may threaten the sustainability of these valuable pelagic fisheries and marine ecosystems.

Ectopic expression of homeobox gene NKX2-1 in diffuse large B-cell lymphoma is mediated by aberrant chromatin modifications.

PubMed

Nagel, Stefan; Ehrentraut, Stefan; Tomasch, Jürgen; Quentmeier, Hilmar; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G; MacLeod, Roderick A F

2013-01-01

Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies.

A gene-trap strategy identifies quiescence-induced genes in synchronized myoblasts.

PubMed

Sambasivan, Ramkumar; Pavlath, Grace K; Dhawan, Jyotsna

2008-03-01

Cellular quiescence is characterized not only by reduced mitotic and metabolic activity but also by altered gene expression. Growing evidence suggests that quiescence is not merely a basal state but is regulated by active mechanisms. To understand the molecular programme that governs reversible cell cycle exit, we focused on quiescence-related gene expression in a culture model of myogenic cell arrest and activation. Here we report the identification of quiescence-induced genes using a gene-trap strategy. Using a retroviral vector, we generated a library of gene traps in C2C12 myoblasts that were screened for arrest-induced insertions by live cell sorting (FACS-gal). Several independent gene- trap lines revealed arrest-dependent induction of betagal activity, confirming the efficacy of the FACS screen. The locus of integration was identified in 15 lines. In three lines,insertion occurred in genes previously implicated in the control of quiescence, i.e. EMSY - a BRCA2--interacting protein, p8/com1 - a p300HAT -- binding protein and MLL5 - a SET domain protein. Our results demonstrate that expression of chromatin modulatory genes is induced in G0, providing support to the notion that this reversibly arrested state is actively regulated.

RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures

PubMed Central

2014-01-01

Background Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Methods Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Results Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Conclusions Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T). PMID:24571676

Biostimulant action of a plant-derived protein hydrolysate produced through enzymatic hydrolysis

PubMed Central

Colla, Giuseppe; Rouphael, Youssef; Canaguier, Renaud; Svecova, Eva; Cardarelli, Mariateresa

2014-01-01

The aim of this study was to evaluate the biostimulant action (hormone like activity, nitrogen uptake, and growth stimulation) of a plant-derived protein hydrolysate by means of two laboratory bioassays: a corn (Zea mays L.) coleoptile elongation rate test (Experiment 1), a rooting test on tomato cuttings (Experiment 2); and two greenhouse experiments: a dwarf pea (Pisum sativum L.) growth test (Experiment 3), and a tomato (Solanum lycopersicum L.) nitrogen uptake trial (Experiment 4). Protein hydrolysate treatments of corn caused an increase in coleoptile elongation rate when compared to the control, in a dose-dependent fashion, with no significant differences between the concentrations 0.75, 1.5, and 3.0 ml/L, and inodole-3-acetic acid treatment. The auxin-like effect of the protein hydrolysate on corn has been also observed in the rooting experiment of tomato cuttings. The shoot, root dry weight, root length, and root area were significantly higher by 21, 35, 24, and 26%, respectively, in tomato treated plants with the protein hydrolysate at 6 ml/L than untreated plants. In Experiment 3, the application of the protein hydrolysate at all doses (0.375, 0.75, 1.5, and 3.0 ml/L) significantly increased the shoot length of the gibberellin-deficient dwarf pea plants by an average value of 33% in comparison with the control treatment. Increasing the concentration of the protein hydrolysate from 0 to 10 ml/L increased the total dry biomass, SPAD index, and leaf nitrogen content by 20.5, 15, and 21.5%, respectively. Thus the application of plant-derived protein hydrolysate containing amino acids and small peptides elicited a hormone-like activity, enhanced nitrogen uptake and consequently crop performances. PMID:25250039

Quercetin alters the DNA damage response in human hematopoietic stem and progenitor cells via TopoII- and PI3K-dependent mechanisms synergizing in leukemogenic rearrangements.

PubMed

Biechonski, Shahar; Gourevich, Dana; Rall, Melanie; Aqaqe, Nasma; Yassin, Muhammad; Zipin-Roitman, Adi; Trakhtenbrot, Luba; Olender, Leonid; Raz, Yael; Jaffa, Ariel J; Grisaru, Dan; Wiesmuller, Lisa; Elad, David; Milyavsky, Michael

2017-02-15

Quercetin (Que) is an abundant flavonoid in the human diet and high-concentration food supplement with reported pro- and anti-carcinogenic activities. Topoisomerase II (TopoII) inhibition and subsequent DNA damage induction by Que was implicated in the mixed lineage leukemia gene (MLL) rearrangements that can induce infant and adult leukemias. This notion raised concerns regarding possible genotoxicities of Que in hematopoietic stem and progenitor cells (HSPCs). However, molecular targets mediating Que effects on DNA repair relevant to MLL translocations have not been defined. In this study we describe novel and potentially genotoxic Que activities in suppressing non-homologous end joining and homologous recombination pathways downstream of MLL cleavage. Using pharmacological dissection of DNA-PK, ATM and PI3K signalling we defined PI3K inhibition by Que with a concomitant decrease in the abundance of key DNA repair genes to be responsible for DNA repair inhibition. Evidence for the downstream TopoII-independent mutagenic potential of Que was obtained by documenting further increased frequencies of MLL rearrangements in human HSPCs concomitantly treated with Etoposide and Que versus single treatments. Importantly, by engaging a tissue engineered placental barrier, we have established the extent of Que transplacental transfer and hence provided the evidence for Que reaching fetal HSPCs. Thus, Que exhibits genotoxic effects in human HSPCs via different mechanisms when applied continuously and at high concentrations. In light of the demonstrated Que transfer to the fetal compartment our findings are key to understanding the mechanisms underlying infant leukemia and provide molecular markers for the development of safety values. © 2016 UICC.

RAS mutations in early age leukaemia modulated by NQO1 rs1800566 (C609T) are associated with second-hand smoking exposures.

PubMed

Andrade, Francianne Gomes; Furtado-Silva, Juliana Montibeller; Gonçalves, Bruno Alves de Aguiar; Thuler, Luiz Claudio Santos; Barbosa, Thayana Conceição; Emerenciano, Mariana; Siqueira, André; Pombo-de-Oliveira, Maria S

2014-02-26

Deregulation of the MAPK genes signalling caused by somatic mutations have been implied in leukaemia pathogenesis, including RAS mutation (RASmut) in acute myeloid leukaemia (AML), which has been associated with intra-uterine chemical exposures. A case-case study was conducted in order to explore maternal and child exposures to tobacco smoking associations with early age leukaemia (EAL). Covariables of reference were MLL rearrangements (MLL-r), RASmut and NQO1 rs1800566 (C609T). Samples from 150 acute lymphoblastic leukaemia (ALL) and 85 AML were included. Maternal exposures were assessed using a structured questionnaire with demographic, personal habits and residence history information. Restriction fragment length polymorphism and denaturing high performance liquid chromatography were used to screen FLT3, KRAS, and NRAS mutations; direct sequencing was performed to validate the results. NQO1 polymorphism was detected by real-time allelic discrimination technique. Overall, RASmut were detected in 28.7% of EAL cases; BRAFmut was found only in one AML patient. Higher rate of KRASmut was found in ALL (30.3%) compared to AML (20.8%) with MLL-r; RASmut showed an association with second-hand tobacco smoking exposures (OR, 3.06, 95% CI, 1.03-9.07). A considerable increased risk for EAL with the combination of RASmut and NQO1 609CT (OR, 4.24, 95% CI, 1.24-14.50) was observed. Our data demonstrated the increased risk association between maternal smoking and EAL with MLL-r. Additionally, suggests that children second-hand tobacco exposures are associated with increased risk of EAL with RASmut modulated by NQO1 rs1800566 (C609T).

The DOT1L inhibitor pinometostat reduces H3K79 methylation and has modest clinical activity in adult acute leukemia.

PubMed

Stein, Eytan M; Garcia-Manero, Guillermo; Rizzieri, David A; Tibes, Raoul; Berdeja, Jesus G; Savona, Michael R; Jongen-Lavrenic, Mojca; Altman, Jessica K; Thomson, Blythe; Blakemore, Stephen J; Daigle, Scott R; Waters, Nigel J; Suttle, A Benjamin; Clawson, Alicia; Pollock, Roy; Krivtsov, Andrei; Armstrong, Scott A; DiMartino, Jorge; Hedrick, Eric; Löwenberg, Bob; Tallman, Martin S

2018-05-03

Pinometostat (EPZ-5676) is a first-in-class, small-molecule inhibitor of the histone methyltransferase DOT1L. In this phase 1 study, pinometostat was evaluated for safety and efficacy in adult patients with advanced acute leukemias, particularly those involving MLL rearrangements ( MLL-r ) resulting from 11q23 translocations. Fifty-one patients were enrolled into 6 dose escalation cohorts (n=26) and 2 expansion cohorts (n=25) at pinometostat doses of 54 and 90 mg/m 2 /day by continuous intravenous infusion in 28-day cycles. As a maximum tolerated dose was not established in the dose escalation phase, the expansion doses were selected based upon safety and clinical response data combined with pharmacodynamic evidence of reduction in H3K79 methylation during dose escalation. Across all dose levels, plasma pinometostat concentrations increased in an approximately dose-proportional fashion, reaching an apparent steady state by 4-8 hours after infusion, and rapidly decreased following treatment cessation. The most common adverse events, of any cause, were fatigue (39%), nausea (39%), constipation (35%), and febrile neutropenia (35%). Overall, 2 patients, both with t(11;19), experienced complete remissions at 54 mg/m 2 /day by continuous intravenous infusion, demonstrating proof of concept for delivering clinically meaningful responses through targeting DOT1L using single agent pinometostat in MLL-r leukemia patients. Administration of pinometostat was generally safe with the maximum tolerated dose not being reached, although efficacy as a single agent was modest. This study demonstrates the therapeutic potential for targeting DOT1L in MLL-r leukemia and lays the groundwork for future combination approaches in this patient population. This clinical trial is registered at www.clinicaltrials.gov as no. NCT01684150. Copyright © 2018 American Society of Hematology.

The effect of cutting origin and organic plant growth regulator on the growth of Daun Ungu (Graptophyllum pictum) through stem cutting method

NASA Astrophysics Data System (ADS)

Pratama, S. P.; Yunus, A.; Purwanto, E.; Widyastuti, Y.

2018-03-01

Graptophyllum pictum is one of medical plants which has important chemical content to treat diseases. Leaf, bark and flower can be used to facilitate menstruation, treat hemorrhoid, constipation, ulcers, ulcers, swelling, and earache. G. pictum is difficult to propagated by seedling due to the long duration of seed formation, thusvegetative propagation is done by stem cutting. The aims of this study are to obtain optimum combination of cutting origin and organic plant growth regulator in various consentration for the growth of Daun Ungu through stem cutting method. This research was conducted at Research center for Medicinal Plant and Traditional DrugTanjungsari, Tegal Gede, Karanganyar in June to August 2016. Origin of cuttings and organic plant growth regulator were used as treatments factor. A completely randomized design (RAL) is used and data were analyzed by F test (ANOVA) with a confidence level of 95%. Any significant differences among treatment followed with Duncan test at a = 5%. The research indicates that longest root was resulted from the treatment of 0,5 ml/l of organic plant growth regulator. The treatment of 1 ml/l is able to increase the fresh and dry weight of root, treatment of 1,5 ml/l of organic plant growth regulator was able to increase the percentage of growing shoots. Treatment of base part as origin of cuttings increases the length, fresh weight and and dry weight of shoot, increase the number of leaves. Interaction treatment between 1 ml/l consentration of organic plant growth regulator and central part origin of cuttings is capable of increasing the leaf area, whereas treatment without organic plant growth regulator and base part as planting material affects the smallest leaf area.

Genotoxic potential and heart rate disorders in the Mediterranean mussel Mytilus galloprovincialis exposed to Superdispersant-25 and dispersed diesel oil.

PubMed

Martinović, Rajko; Kolarević, Stoimir; Kračun-Kolarević, Margareta; Kostić, Jovana; Marković, Sandra; Gačić, Zoran; Kljajić, Zoran; Vuković-Gačić, Branka

2015-07-01

The effects of ex situ exposure of Mytilus galloprovincialis to Superdispersant-25 (S-25), diesel oil and dispersed diesel oil mixtures were studied by the impact on level of DNA damage in haemocytes (comet assay) and the cardiac activity patterns of mussels. Specimens were exposed for 72 h in a static system to diesel oil (100 μL/L and 1 mL/L), S-25 (5 and 50 μL/L), and dispersed diesel oil mixtures M1 (diesel oil 100 μL/L + S-25 5 μL/L) and M2 (diesel oil 1 mL/L + S-25 50 μL/L). For positive control 40 μM CdCl2 was used. The comet assay results indicated genotoxic potential of S-25 while the effects of diesel oil alone were not observed. The highest response was detected for M1 while the effects of M2 were not detected. The heart rate disorders were recorded for the diesel oil (1 mL/L), S-25 (50 μL/L) and both dispersed diesel oil mixtures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Morel-Lavallee Lesion (MLL) Mimicking A Soft Tissue Neoplasm.

PubMed

Kumar, Sandeep; Hasan, Roumina; Kadavigere, Rajagopal; Maddukuri, Satish Babu; Puppala, Radha

2015-04-01

Morel-lavallee lesion (MLL) represents post traumatic subcutaneous cyst generally overlying bony prominences like greater trochanter, lower back, knee and scapula. A 51-year-old man presented with a swelling in left thigh since six years which was insidious in onset, gradually progressive in size and not associated with pain, fever or discharge. There was no history of trauma or any associated constitutional symptoms. Since there was no history of trauma recalled by the patient the clinical dilemma was between soft tissue sarcoma and cold abscess. We report a case of slow growing painless mass lesion of thigh, diagnosed on Magnetic Resonance Imaging (MRI) as morel lavallee lesion and describe its salient imaging features with treatment options.

The t(10;11)(p13;q14) in the U937 cell line results in the fusion of the AF10 gene and CALM, encoding a new member of the AP-3 clathrin assembly protein family.

PubMed Central

Dreyling, M H; Martinez-Climent, J A; Zheng, M; Mao, J; Rowley, J D; Bohlander, S K

1996-01-01

The translocation t(10;11)(p13;q14) is a recurring chromosomal abnormality that has been observed in patients with acute lymphoblastic leukemia as well as acute myeloid leukemia. We have recently reported that the monocytic cell line U937 has a t(10;11)(p13;q14) translocation. Using a combination of positional cloning and candidate gene approach, we cloned the breakpoint and were able to show that AF10 is fused to a novel gene that we named CALM (Clathrin Assembly Lymphoid Myeloid leukemia gene) located at 11q14. AF10, a putative transcription factor, had recently been cloned as one of the fusion partners of MLL. CALM has a very high homology in its N-terminal third to the murine ap-3 gene which is one of the clathrin assembly proteins. The N-terminal region of ap-3 has been shown to bind to clathrin and to have a high-affinity binding site for phosphoinositols. The identification of the CALM/AF10 fusion gene in the widely used U937 cell line will contribute to our understanding of the malignant phenotype of this line. Images Fig. 1 Fig. 3 PMID:8643484

Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies

PubMed Central

Zweidler-McKay, Patrick A.; He, Yiping; Xu, Lanwei; Rodriguez, Carlos G.; Karnell, Fredrick G.; Carpenter, Andrea C.; Aster, Jon C.; Allman, David; Pear, Warren S.

2005-01-01

Although Notch receptor expression on malignant B cells is widespread, the effect of Notch signaling in these cells is poorly understood. To investigate Notch signaling in B-cell malignancy, we assayed the effect of Notch activation in multiple murine and human B-cell tumors, representing both immature and mature subtypes. Expression of constitutively active, truncated forms of the 4 mammalian Notch receptors (ICN1-4) inhibited growth and induced apoptosis in both murine and human B-cell lines but not T-cell lines. Similar results were obtained in human precursor B-cell acute lymphoblastic leukemia lines when Notch activation was achieved by coculture with fibroblasts expressing the Notch ligands Jagged1 or Jagged2. All 4 truncated Notch receptors, as well as the Jagged ligands, induced Hes1 transcription. Retroviral expression of Hairy/Enhancer of Split-1 (Hes1) recapitulated the Notch effects, suggesting that Hes1 is an important mediator of Notch-induced growth arrest and apoptosis in B cells. Among the B-cell malignancies that were susceptible to Notch-mediated growth inhibition/apoptosis were mature B-cell and therapy-resistant B-cell malignancies, including Hodgkin, myeloma, and mixed-lineage leukemia (MLL)–translocated cell lines. These results suggest that therapies capable of activating Notch/Hes1 signaling may have therapeutic potential in a wide range of human B-cell malignancies. PMID:16118316

Ectopic Expression of Homeobox Gene NKX2-1 in Diffuse Large B-Cell Lymphoma Is Mediated by Aberrant Chromatin Modifications

PubMed Central

Nagel, Stefan; Ehrentraut, Stefan; Tomasch, Jürgen; Quentmeier, Hilmar; Meyer, Corinna; Kaufmann, Maren; Drexler, Hans G.; MacLeod, Roderick A. F.

2013-01-01

Homeobox genes encode transcription factors ubiquitously involved in basic developmental processes, deregulation of which promotes cell transformation in multiple cancers including hematopoietic malignancies. In particular, NKL-family homeobox genes TLX1, TLX3 and NKX2-5 are ectopically activated by chromosomal rearrangements in T-cell neoplasias. Here, using transcriptional microarray profiling and RQ-PCR we identified ectopic expression of NKL-family member NKX2-1, in a diffuse large B-cell lymphoma (DLBCL) cell line SU-DHL-5. Moreover, in silico analysis demonstrated NKX2-1 overexpression in 5% of examined DLBCL patient samples. NKX2-1 is physiologically expressed in lung and thyroid tissues where it regulates differentiation. Chromosomal and genomic analyses excluded rearrangements at the NKX2-1 locus in SU-DHL-5, implying alternative activation. Comparative expression profiling implicated several candidate genes in NKX2-1 regulation, variously encoding transcription factors, chromatin modifiers and signaling components. Accordingly, siRNA-mediated knockdown and overexpression studies confirmed involvement of transcription factor HEY1, histone methyltransferase MLL and ubiquitinated histone H2B in NKX2-1 deregulation. Chromosomal aberrations targeting MLL at 11q23 and the histone gene cluster HIST1 at 6p22 which we observed in SU-DHL-5 may, therefore, represent fundamental mutations mediating an aberrant chromatin structure at NKX2-1. Taken together, we identified ectopic expression of NKX2-1 in DLBCL cells, representing the central player in an oncogenic regulative network compromising B-cell differentiation. Thus, our data extend the paradigm of NKL homeobox gene deregulation in lymphoid malignancies. PMID:23637834

Impact of wines and wine constituents on cyclooxygenase-1, cyclooxygenase-2, and 5-lipoxygenase catalytic activity.

PubMed

Kutil, Zsofia; Temml, Veronika; Maghradze, David; Pribylova, Marie; Dvorakova, Marcela; Schuster, Daniela; Vanek, Tomas; Landa, Premysl

2014-01-01

Cyclooxygenases and lipoxygenases are proinflammatory enzymes; the former affects platelet aggregation, vasoconstriction, vasodilatation and later the development of atherosclerosis. Red wines from Georgia and central and western Europe inhibited cyclooxygenase-1 (COX-1) activity in the range of 63-94%, cyclooxygenase-2 (COX-2) activity in the range of 20-44% (tested at a concentration of 5 mL/L), and 5-lipoxygenase (5-LOX) activity in the range of 72-84% (at a concentration of 18.87 mL/L). White wines inhibited 5-LOX in the range of 41-68% at a concentration of 18.87 mL/L and did not inhibit COX-1 and COX-2. Piceatannol (IC50 = 0.76 μM) was identified as a strong inhibitor of 5-LOX followed by luteolin (IC50 = 2.25 μM), quercetin (IC50 = 3.29 μM), and myricetin (IC50 = 4.02 μM). trans-Resveratrol was identified as an inhibitor of COX-1 (IC50 = 2.27 μM) and COX-2 (IC50 = 3.40 μM). Red wine as a complex mixture is a powerful inhibitor of COX-1, COX-2, and 5-LOX, the enzymes involved in eicosanoid biosynthetic pathway.

Excess congenital non-synonymous variation in leukemia-associated genes in MLL− infant leukemia: a Children's Oncology Group report

PubMed Central

Valentine, M C; Linabery, A M; Chasnoff, S; Hughes, A E O; Mallaney, C; Sanchez, N; Giacalone, J; Heerema, N A; Hilden, J M; Spector, L G; Ross, J A; Druley, T E

2014-01-01

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins. PMID:24301523

Hyperdiploid karyotypes in acute myeloid leukemia define a novel entity: a study of 38 patients from the Groupe Francophone de Cytogenetique Hematologique (GFCH).

PubMed

Luquet, I; Laï, J L; Barin, C; Baranger, L; Bilhou-Nabera, C; Lippert, E; Gervais, C; Talmant, P; Cornillet-Lefebvre, P; Perot, C; Nadal, N; Mozziconacci, M J; Lafage-Pochitaloff, M; Eclache, V; Mugneret, F; Lefebvre, C; Herens, C; Speleman, F; Poirel, H; Tigaud, I; Cabrol, C; Rousselot, P; Daliphard, S; Imbert, M; Garand, R; Geneviève, F; Berger, R; Terre, C

2008-01-01

A series of 38 patients with acute myeloblastic leukemia (AML) with 49 or more chromosomes and without structural abnormalities was selected within the Groupe Francophone de Cytogénétique Hématologique (GFCH) to better define their characteristics. The median age of the patients was 65 years, and all FAB subtypes were represented. Although all chromosomes were gained, some seems to prevail: chromosome 8 (68%), 21 (47%), 19 (37%), and 13 and 14 (34% each). Since MLL rearrangement leads patients in a group with an unfavorable prognosis, search for cryptic rearrangements of MLL was performed in 34 patients and showed abnormalities in 5 (15%). When we applied the most frequent definition of complex karyotypes (three or more abnormalities), all patients with high hyperdiploid AML fall in the unfavorable category. Among the 18 patients without MLL rearrangement receiving an induction therapy, 16 (89%) reached CR and 6 (33%) were still alive after a 31-month median follow-up (14-61 months). Although this study was retrospective, these results suggest that high hyperdiploid AML without chromosome rearrangement seems to be a subgroup of uncommon AML (less than 1%), and may be better classified in the intermediate prognostic group.

EphA2 Is a Therapy Target in EphA2-Positive Leukemias but Is Not Essential for Normal Hematopoiesis or Leukemia

PubMed Central

Charmsaz, Sara; Beckett, Kirrilee; Smith, Fiona M.; Bruedigam, Claudia; Moore, Andrew S.; Al-Ejeh, Fares; Lane, Steven W.; Boyd, Andrew W.

2015-01-01

Members of the Eph family of receptor tyrosine kinases and their membrane bound ephrin ligands have been shown to play critical roles in many developmental processes and more recently have been implicated in both normal and pathological processes in post-embryonic tissues. In particular, expression studies of Eph receptors and limited functional studies have demonstrated a role for the Eph/ephrin system in hematopoiesis and leukemogenesis. In particular, EphA2 was reported on hematopoietic stem cells and stromal cells. There are also reports of EphA2 expression in many different types of malignancies including leukemia, however there is a lack of knowledge in understanding the role of EphA2 in hematopoiesis and leukemogenesis. We explored the role of EphA2 in hematopoiesis by analyzing wild type and EphA2 knockout mice. Mature, differentiated cells, progenitors and hematopoietic stem cells derived from knockout and control mice were analyzed and no significant abnormality was detected. These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis. Comparative studies using EphA2-negative MLL-AF9 leukemias derived from EphA2-knockout animals showed that there was no detectable functional role for EphA2 in the initiation or progression of the leukemic process. However, expression of EphA2 in leukemias initiated by MLL-AF9 suggested that this protein might be a possible therapy target in this type of leukemia. We showed that treatment with EphA2 monoclonal antibody IF7 alone had no effect on tumorigenicity and latency of the MLL-AF9 leukemias, while targeting of EphA2 using EphA2 monoclonal antibody with a radioactive payload significantly impaired the leukemic process. Altogether, these results identify EphA2 as a potential radio-therapeutic target in leukemias with MLL translocation. PMID:26083390

EphA2 Is a Therapy Target in EphA2-Positive Leukemias but Is Not Essential for Normal Hematopoiesis or Leukemia.

PubMed

Charmsaz, Sara; Beckett, Kirrilee; Smith, Fiona M; Bruedigam, Claudia; Moore, Andrew S; Al-Ejeh, Fares; Lane, Steven W; Boyd, Andrew W

2015-01-01

Members of the Eph family of receptor tyrosine kinases and their membrane bound ephrin ligands have been shown to play critical roles in many developmental processes and more recently have been implicated in both normal and pathological processes in post-embryonic tissues. In particular, expression studies of Eph receptors and limited functional studies have demonstrated a role for the Eph/ephrin system in hematopoiesis and leukemogenesis. In particular, EphA2 was reported on hematopoietic stem cells and stromal cells. There are also reports of EphA2 expression in many different types of malignancies including leukemia, however there is a lack of knowledge in understanding the role of EphA2 in hematopoiesis and leukemogenesis. We explored the role of EphA2 in hematopoiesis by analyzing wild type and EphA2 knockout mice. Mature, differentiated cells, progenitors and hematopoietic stem cells derived from knockout and control mice were analyzed and no significant abnormality was detected. These studies showed that EphA2 does not have an obligatory role in normal hematopoiesis. Comparative studies using EphA2-negative MLL-AF9 leukemias derived from EphA2-knockout animals showed that there was no detectable functional role for EphA2 in the initiation or progression of the leukemic process. However, expression of EphA2 in leukemias initiated by MLL-AF9 suggested that this protein might be a possible therapy target in this type of leukemia. We showed that treatment with EphA2 monoclonal antibody IF7 alone had no effect on tumorigenicity and latency of the MLL-AF9 leukemias, while targeting of EphA2 using EphA2 monoclonal antibody with a radioactive payload significantly impaired the leukemic process. Altogether, these results identify EphA2 as a potential radio-therapeutic target in leukemias with MLL translocation.

An Fc-engineered CD19 antibody eradicates MRD in patient-derived MLL-rearranged acute lymphoblastic leukemia xenografts.

PubMed

Schewe, Denis M; Alsadeq, Ameera; Sattler, Cornelia; Lenk, Lennart; Vogiatzi, Fotini; Cario, Gunnar; Vieth, Simon; Valerius, Thomas; Rosskopf, Sophia; Meyersieck, Fabian; Alten, Julia; Schrappe, Martin; Gramatzki, Martin; Peipp, Matthias; Kellner, Christian

2017-09-28

Antibody therapy constitutes a major advance in the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). To evaluate the efficacy and the mechanisms of action of CD19 monoclonal antibody therapy in pediatric BCP-ALL, we tested an Fc-engineered CD19 antibody carrying the S239D/I332E mutation for improved effector cell recruitment (CD19-DE). Patient-derived xenografts (PDX) of pediatric mixed-lineage leukemia gene ( MLL )-rearranged ALL were established in NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice. Antibody CD19-DE was efficient in prolonging the survival of NSG mice in a minimal residual disease (MRD) model. The majority of surviving mice remained polymerase chain reaction (PCR)-MRD negative after treatment. When antibody therapy was initiated in overt leukemia, antibody CD19-DE was still efficient in prolonging survival of xenografted mice in comparison with nontreated control animals, but the effects were less pronounced than in the MRD setting. Importantly, the combination of antibody CD19-DE and cytoreduction by chemotherapy (dexamethasone, vincristine, PEG-asparaginase) resulted in significantly improved survival rates in xenografted mice. Antibody CD19-DE treatment was also efficient in a randomized phase 2-like PDX trial using 13 MLL -rearranged BCP-ALL samples. Macrophage depletion by liposomal clodronate resulted in a reversal of the beneficial effects of CD19-DE, suggesting an important role for macrophages as effector cells. In support of this finding, CD19-DE was found to enhance phagocytosis of patient-derived ALL blasts by human macrophages in vitro. Thus, Fc-engineered CD19 antibodies may represent a promising treatment option for infants and children with MLL -rearranged BCP-ALL who have a poor outcome when treated with chemotherapy only. © 2017 by The American Society of Hematology.

Hydrogen peroxide bleaching of cotton in ultrasonic energy.

PubMed

Mistik, S Ilker; Yükseloglu, S Müge

2005-12-01

It is well known that, conventional hydrogen peroxide bleaching process is an important and a specific step for wet processors; however it has some problems such as long time, high energy consumption. On the other hand, using ultrasonic energy in bleaching is an alternative method for the conventional processes. In this work, 100% cotton materials of different forms such as raw fibre, ring-spun yarns and knitted fabrics produced from these cottons, were treated with hydrogen peroxide in two different concentrations (5 mL/L and 10 mL/L), at three different temperatures (20 degrees C, 30 degrees C, 40 degrees C) and times (20 min, 30 min, 60 min). Whiteness Index of the samples were then measured spectrophotometrically and the overall results were compared.

Development and validation of a comprehensive genomic diagnostic tool for myeloid malignancies

PubMed Central

McKerrell, Thomas; Moreno, Thaidy; Ponstingl, Hannes; Bolli, Niccolo; Dias, João M. L.; Tischler, German; Colonna, Vincenza; Manasse, Bridget; Bench, Anthony; Bloxham, David; Herman, Bram; Fletcher, Danielle; Park, Naomi; Quail, Michael A.; Manes, Nicla; Hodkinson, Clare; Baxter, Joanna; Sierra, Jorge; Foukaneli, Theodora; Warren, Alan J.; Chi, Jianxiang; Costeas, Paul; Rad, Roland; Huntly, Brian; Grove, Carolyn; Ning, Zemin; Tyler-Smith, Chris; Varela, Ignacio; Scott, Mike; Nomdedeu, Josep; Mustonen, Ville

2016-01-01

The diagnosis of hematologic malignancies relies on multidisciplinary workflows involving morphology, flow cytometry, cytogenetic, and molecular genetic analyses. Advances in cancer genomics have identified numerous recurrent mutations with clear prognostic and/or therapeutic significance to different cancers. In myeloid malignancies, there is a clinical imperative to test for such mutations in mainstream diagnosis; however, progress toward this has been slow and piecemeal. Here we describe Karyogene, an integrated targeted resequencing/analytical platform that detects nucleotide substitutions, insertions/deletions, chromosomal translocations, copy number abnormalities, and zygosity changes in a single assay. We validate the approach against 62 acute myeloid leukemia, 50 myelodysplastic syndrome, and 40 blood DNA samples from individuals without evidence of clonal blood disorders. We demonstrate robust detection of sequence changes in 49 genes, including difficult-to-detect mutations such as FLT3 internal-tandem and mixed-lineage leukemia (MLL) partial-tandem duplications, and clinically significant chromosomal rearrangements including MLL translocations to known and unknown partners, identifying the novel fusion gene MLL-DIAPH2 in the process. Additionally, we identify most significant chromosomal gains and losses, and several copy neutral loss-of-heterozygosity mutations at a genome-wide level, including previously unreported changes such as homozygosity for DNMT3A R882 mutations. Karyogene represents a dependable genomic diagnosis platform for translational research and for the clinical management of myeloid malignancies, which can be readily adapted for use in other cancers. PMID:27121471

The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies

PubMed Central

Martin, Daniel; Abba, Martin C.; Molinolo, Alfredo A.; Vitale-Cross, Lynn; Wang, Zhiyong; Zaida, Moraima; Delic, Naomi C.; Samuels, Yardena; Lyons, J. Guy; Gutkind, J. Silvio

2014-01-01

The recent elucidation of the genomic landscape of head and neck squamous cell carcinoma (HNSCC) has provided a unique opportunity to develop selective cancer treatment options. These efforts will require the establishment of relevant HNSCC models for preclinical testing. Here, we performed full exome and transcriptome sequencing of a large panel of HNSCC-derived cells from different anatomical locations and human papillomavirus (HPV) infection status. These cells exhibit typical mutations in TP53, FAT1, CDK2NA, CASP8, and NOTCH1, and copy number variations (CNVs) and mutations in PIK3CA, HRAS, and PTEN that reflect the widespread activation of the PI3K-mTOR pathway. SMAD4 alterations were observed that may explain the decreased tumor suppressive effect of TGF-β in HNSCC. Surprisingly, we identified HPV+ HNSCC cells harboring TP53 mutations, and documented aberrant TP53 expression in a subset of HPV+ HNSCC cases. This analysis also revealed that most HNSCC cells harbor multiple mutations and CNVs in epigenetic modifiers (e.g., EP300, CREBP, MLL1, MLL2, MLL3, KDM6A, and KDM6B) that may contribute to HNSCC initiation and progression. These genetically-defined experimental HNSCC cellular systems, together with the identification of novel actionable molecular targets, may now facilitate the pre-clinical evaluation of emerging therapeutic agents in tumors exhibiting each precise genomic alteration. PMID:25275298

Hydrogen and electricity production from a food processing wastewater using fermentation and microbial fuel cell technologies.

PubMed

Oh, Sang Eun; Logan, Bruce E

2005-11-01

Hydrogen can be produced from fermentation of sugars in wastewaters, but much of the organic matter remains in solution. We demonstrate here that hydrogen production from a food processing wastewater high in sugar can be linked to electricity generation using a microbial fuel cell (MFC) to achieve more effective wastewater treatment. Grab samples were taken from: plant effluent at two different times during the day (Effluents 1 and 2; 735+/-15 and 3250+/-90 mg-COD/L), an equalization tank (Lagoon; 1670+/-50mg-COD/L), and waste stream containing a high concentration of organic matter (Cereal; 8920+/-150 mg-COD/L). Hydrogen production from the Lagoon and effluent samples was low, with 64+/-16 mL of hydrogen per liter of wastewater (mL/L) for Effluent 1, 21+/-18 mL/L for Effluent 2, and 16+/-2 mL/L for the Lagoon sample. There was substantially greater hydrogen production using the Cereal wastewater (210+/-56 mL/L). Assuming a theoretical maximum yield of 4 mol of hydrogen per mol of glucose, hydrogen yields were 0.61-0.79 mol/mol for the Cereal wastewater, and ranged from 1 to 2.52 mol/mol for the other samples. This suggests a strategy for hydrogen recovery from wastewater based on targeting high-COD and high-sugar wastewaters, recognizing that sugar content alone is an insufficient predictor of hydrogen yields. Preliminary tests with the Cereal wastewater (diluted to 595 mg-COD/L) in a two-chambered MFC demonstrated a maximum of 81+/-7 mW/m(2) (normalized to the anode surface area), or 25+/-2 mA per liter of wastewater, and a final COD of <30 mg/L (95% removal). Using a one-chambered MFC and pre-fermented wastewater, the maximum power density was 371+/-10 mW/m(2) (53.5+/-1.4 mA per liter of wastewater). These results suggest that it is feasible to link biological hydrogen production and electricity producing using MFCs in order to achieve both wastewater treatment and bioenergy production.

Frequencies and prognostic impact of RAS mutations in MLL-rearranged acute lymphoblastic leukemia in infants

PubMed Central

Driessen, Emma M.C.; van Roon, Eddy H.J.; Spijkers-Hagelstein, Jill A.P.; Schneider, Pauline; de Lorenzo, Paola; Valsecchi, Maria Grazia; Pieters, Rob; Stam, Ronald W.

2013-01-01

Acute lymphoblastic leukemia in infants represents an aggressive malignancy associated with a high incidence (approx. 80%) of translocations involving the Mixed Lineage Leukemia (MLL) gene. Attempts to mimic Mixed Lineage Leukemia fusion driven leukemogenesis in mice raised the question whether these fusion proteins require secondary hits. RAS mutations are suggested as candidates. Earlier results on the incidence of RAS mutations in Mixed Lineage Leukemia-rearranged acute lymphoblastic leukemia are inconclusive. Therefore, we studied frequencies and relation with clinical parameters of RAS mutations in a large cohort of infant acute lymphoblastic leukemia patients. Using conventional sequencing analysis, we screened neuroblastoma RAS viral (v-ras) oncogene homolog gene (NRAS), v-Ki-ras Kirsten rat sarcoma viral oncogene homolog gene (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 gene (BRAF) for mutations in a large cohort (n=109) of infant acute lymphoblastic leukemia patients and studied the mutations in relation to several clinical parameters, and in relation to Homeobox gene A9 expression and the presence of ALL1 fused gene 4-Mixed Lineage Leukemia (AF4-MLL). Mutations were detected in approximately 14% of all cases, with a higher frequency of approximately 24% in t(4;11)-positive patients (P=0.04). Furthermore, we identified RAS mutations as an independent predictor (P=0.019) for poor outcome in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia, with a hazard ratio of 3.194 (95% confidence interval (CI):1.211–8.429). Also, RAS-mutated infants have higher white blood cell counts at diagnosis (P=0.013), and are more resistant to glucocorticoids in vitro (P<0.05). Finally, we demonstrate that RAS mutations, and not the lack of Homeobox gene A9 expression nor the expression of AF4-MLL are associated with poor outcome in t(4;11)-rearranged infants. We conclude that the presence of RAS mutations in Mixed Lineage Leukemia-rearranged infant acute lymphoblastic leukemia is an independent predictor for a poor outcome. Therefore, future risk-stratification based on abnormal RAS-pathway activation and RAS-pathway inhibition could be beneficial in RAS-mutated infant acute lymphoblastic leukemia patients. PMID:23403319

Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response.

PubMed

Nickerson, M L; Witte, N; Im, K M; Turan, S; Owens, C; Misner, K; Tsang, S X; Cai, Z; Wu, S; Dean, M; Costello, J C; Theodorescu, D

2017-01-05

The utility of tumor-derived cell lines is dependent on their ability to recapitulate underlying genomic aberrations and primary tumor biology. Here, we sequenced the exomes of 25 bladder cancer (BCa) cell lines and compared mutations, copy number alterations (CNAs), gene expression and drug response to BCa patient profiles in The Cancer Genome Atlas (TCGA). We observed a mutation pattern associated with altered CpGs and APOBEC-family cytosine deaminases similar to mutation signatures derived from somatic alterations in muscle-invasive (MI) primary tumors, highlighting a major mechanism(s) contributing to cancer-associated alterations in the BCa cell line exomes. Non-silent sequence alterations were confirmed in 76 cancer-associated genes, including mutations that likely activate oncogenes TERT and PIK3CA, and alter chromatin-associated proteins (MLL3, ARID1A, CHD6 and KDM6A) and established BCa genes (TP53, RB1, CDKN2A and TSC1). We identified alterations in signaling pathways and proteins with related functions, including the PI3K/mTOR pathway, altered in 60% of lines; BRCA DNA repair, 44%; and SYNE1-SYNE2, 60%. Homozygous deletions of chromosome 9p21 are known to target the cell cycle regulators CDKN2A and CDKN2B. This loci was commonly lost in BCa cell lines and we show the deletions extended to the polyamine enzyme methylthioadenosine (MTA) phosphorylase (MTAP) in 36% of lines, transcription factor DMRTA1 (27%) and antiviral interferon epsilon (IFNE, 19%). Overall, the BCa cell line genomic aberrations were concordant with those found in BCa patient tumors. We used gene expression and copy number data to infer pathway activities for cell lines, then used the inferred pathway activities to build a predictive model of cisplatin response. When applied to platinum-treated patients gathered from TCGA, the model predicted treatment-specific response. Together, these data and analysis represent a valuable community resource to model basic tumor biology and to study the pharmacogenomics of BCa.

Genetics Home Reference: CHOPS syndrome

MedlinePlus

... complex (SEC) and MLL in development and disease. Genes Dev. 2011 Apr 1;25(7):661-72. doi: 10.1101/gad.2015411. Review. Citation ... are genome editing and CRISPR-Cas9? What is precision medicine? What ...

Recovery of Copper from Cyanidation Tailing by Flotation

NASA Astrophysics Data System (ADS)

Qiu, Tingsheng; Huang, Xiong; Yang, Xiuli

2016-02-01

In this work, sodium hypochlorite, hydrogen peroxide, sodium metabisulfite and copper sulfate as activators were investigated to lessen the depression effect of cyanide for deep-depressing chalcopyrite. The experimental results indicate that the copper recovery exceeded 94%, 84% and 97% at the dosage: sodium hypochlorite 3 mL/L, hydrogen peroxide 2 mL/L, sodium metabisulfite 2 × 10-3 mol/L and copper sulfate 1.67 × 10-4 mol/L, respectively. According to the results of zeta potential and Fourier transform infrared spectrum, it is suggested that chalcopyrite was depressed because of the chemical adsorption of cyanide on the chalcopyrite surfaces. Sodium hypochlorite, hydrogen peroxide and sodium metabisulfite can destroy Cu-C bond on the deep-depressing chalcopyrite surface by chemical reaction. Copper sulfate can activate deep-depressing chalcopyrite by copper ion adsorption.

MOLECULAR CHARACTERIZATION OF HTLV-1 TAX INTERACTION WITH THE KIX DOMAIN OF CBP/p300

PubMed Central

Ramírez, Julita A.; Nyborg, Jennifer K.

2007-01-01

Summary The viral oncoprotein Tax mediates transcriptional activation of human T-cell leukemia virus type 1 (HTLV-1). Both Tax and the cellular transcription factor CREB bind to viral cyclic AMP response elements (vCREs) located in the viral promoter. Tax and serine 133 phosphorylated CREB (pCREB) bound to the HTLV-1 promoter facilitate viral transcription via the recruitment of the large cellular coactivators CBP/p300. While the interaction between the phosphorylated kinase inducible domain (pKID) of pCREB and the KIX domain of CBP/p300 has been well-characterized, the molecular interactions between KIX, full-length Tax, and pCREB have not been examined. In this study we biochemically characterized the interaction between Tax and KIX in a physiologically relevant complex containing pCREB and vCRE DNA. Our data show that Tax and pCREB simultaneously and independently bind two distinct surfaces on the KIX domain: Tax binds KIX at the previously-characterized mixed-lineage leukemia (MLL) protein interaction surface while pCREB binds KIX at the pKID-KIX interface. These results provide evidence for a model in which Tax and pCREB bind distinct surfaces of KIX for effective CBP/p300 recruitment to the HTLV-1 promoter. We also show that MLL competes with Tax for KIX binding, suggesting a novel mechanism of Tax oncogenesis in which normal MLL function is disrupted by Tax. PMID:17707401

Study of the reuse of treated wastewater on waste container washing vehicles.

PubMed

Vaccari, Mentore; Gialdini, Francesca; Collivignarelli, Carlo

2013-02-01

The wheelie bins for the collection of municipal solid waste (MSW) shall be periodically washed. This operation is usually carried out by specific vehicles which consume about 5000 L of water per day. Wastewater derived from bins washing is usually stored on the same vehicle and then discharged and treated in a municipal WWTP. This paper presents a study performed to evaluate the reuse of the wastewater collected from bins washing after it has been treated in a small plant mounted on the vehicle; the advantage of such a system would be the reduction of both vehicle dimension and water consumption. The main results obtained by coagulation-flocculation tests performed on two wastewater samples are presented. The addition of 2 mL/L of an aqueous solution of aluminum polychloride (18% w/w), about 35 mL/L of an aqueous solution of CaO (4% w/w) and 25 mL/L of an aqueous solution of an anionic polyelectrolyte (1 ‰ w/w) can significantly reduce turbidity and COD in treated water (to about 99% and 42%, respectively); the concomitant increase of UV transmittance at 254 nm (up to 15%) enables UV disinfection application by a series of two ordinary UV lamps. Much higher UV transmittance values (even higher than 80%) can be obtained by dosing powdered activated carbon, which also results in a greater removal of COD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Biohydrogen production by dark fermentation of glycerol using Enterobacter and Citrobacter Sp.

PubMed

Maru, Biniam T; Constanti, Magda; Stchigel, Alberto M; Medina, Francesc; Sueiras, Jesus E

2013-01-01

Glycerol is an attractive substrate for biohydrogen production because, in theory, it can produce 3 mol of hydrogen per mol of glycerol. Moreover, glycerol is produced in substantial amounts as a byproduct of producing biodiesel, the demand for which has increased in recent years. Therefore, hydrogen production from glycerol was studied by dark fermentation using three strains of bacteria: namely, Enterobacter spH1, Enterobacter spH2, and Citrobacter freundii H3 and a mixture thereof (1:1:1). It was found that, when an initial concentration of 20 g/L of glycerol was used, all three strains and their mixture produced substantial amounts of hydrogen ranging from 2400 to 3500 mL/L, being highest for C. freundii H3 (3547 mL/L) and Enterobacter spH1 (3506 mL/L). The main nongaseous fermentation products were ethanol and acetate, albeit in different ratios. For Enterobacter spH1, Enterobacter spH2, C. freundii H3, and the mixture (1:1:1), the ethanol yields (in mol EtOH/mol glycerol consumed) were 0.96, 0.67, 0.31, and 0.66, respectively. Compared to the individual strains, the mixture (1:1:1) did not show a significantly higher hydrogen level, indicating that there was no synergistic effect. Enterobacter spH1 was selected for further investigation because of its higher yield of hydrogen and ethanol. Copyright © 2012 American Institute of Chemical Engineers (AIChE).

GPR84 sustains aberrant β-catenin signaling in leukemic stem cells for maintenance of MLL leukemogenesis.

PubMed

Dietrich, Philipp A; Yang, Chen; Leung, Halina H L; Lynch, Jennifer R; Gonzales, Estrella; Liu, Bing; Haber, Michelle; Norris, Murray D; Wang, Jianlong; Wang, Jenny Yingzi

2014-11-20

β-catenin is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML). Targeted inhibition of β-catenin signaling has been hampered by the lack of pathway components amenable to pharmacologic manipulation. Here we identified a novel β-catenin regulator, GPR84, a member of the G protein-coupled receptor family that represents a highly tractable class of drug targets. High GPR84 expression levels were confirmed in human and mouse AML LSCs compared with hematopoietic stem cells (HSCs). Suppression of GPR84 significantly inhibited cell growth by inducing G1-phase cell-cycle arrest in pre-LSCs, reduced LSC frequency, and impaired reconstitution of stem cell-derived mixed-lineage leukemia (MLL) AML, which represents an aggressive and drug-resistant subtype of AML. The GPR84-deficient phenotype in established AML could be rescued by expression of constitutively active β-catenin. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a-transduced stem cells. Microarray analysis demonstrated that GPR84 significantly upregulated a small set of MLL-fusion targets and β-catenin coeffectors, and downregulated a hematopoietic cell-cycle inhibitor. Altogether, our data reveal a previously unrecognized role of GPR84 in maintaining fully developed AML by sustaining aberrant β-catenin signaling in LSCs, and suggest that targeting the oncogenic GPR84/β-catenin signaling axis may represent a novel therapeutic strategy for AML. © 2014 by The American Society of Hematology.

Prevalence of gene rearrangements in Mexican children with acute lymphoblastic leukemia: a population study-report from the Mexican Interinstitutional Group for the identification of the causes of childhood leukemia.

PubMed

Bekker-Méndez, Vilma Carolina; Miranda-Peralta, Enrique; Núñez-Enríquez, Juan Carlos; Olarte-Carrillo, Irma; Guerra-Castillo, Francisco Xavier; Pompa-Mera, Ericka Nelly; Ocaña-Mondragón, Alicia; Rangel-López, Angélica; Bernáldez-Ríos, Roberto; Medina-Sanson, Aurora; Jiménez-Hernández, Elva; Amador-Sánchez, Raquel; Peñaloza-González, José Gabriel; de Diego Flores-Chapa, José; Fajardo-Gutiérrez, Arturo; Flores-Lujano, Janet; Rodríguez-Zepeda, María Del Carmen; Dorantes-Acosta, Elisa María; Bolea-Murga, Victoria; Núñez-Villegas, Nancy; Velázquez-Aviña, Martha Margarita; Torres-Nava, José Refugio; Reyes-Zepeda, Nancy Carolina; González-Bonilla, Cesar; Mejía-Aranguré, Juan Manuel

2014-01-01

Mexico has one of the highest incidences of childhood leukemia worldwide and significantly higher mortality rates for this disease compared with other countries. One possible cause is the high prevalence of gene rearrangements associated with the etiology or with a poor prognosis of childhood acute lymphoblastic leukemia (ALL). The aims of this multicenter study were to determine the prevalence of the four most common gene rearrangements [ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL rearrangements] and to explore their relationship with mortality rates during the first year of treatment in ALL children from Mexico City. Patients were recruited from eight public hospitals during 2010-2012. A total of 282 bone marrow samples were obtained at each child's diagnosis for screening by conventional and multiplex reverse transcription polymerase chain reaction to determine the gene rearrangements. Gene rearrangements were detected in 50 (17.7%) patients. ETV6-RUNX1 was detected in 21 (7.4%) patients, TCF3-PBX1 in 20 (7.1%) patients, BCR-ABL1 in 5 (1.8%) patients, and MLL rearrangements in 4 (1.4%) patients. The earliest deaths occurred at months 1, 2, and 3 after diagnosis in patients with MLL, ETV6-RUNX1, and BCR-ABL1 gene rearrangements, respectively. Gene rearrangements could be related to the aggressiveness of leukemia observed in Mexican children.

Prevalence of Gene Rearrangements in Mexican Children with Acute Lymphoblastic Leukemia: A Population Study—Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

PubMed Central

Bekker-Méndez, Vilma Carolina; Miranda-Peralta, Enrique; Núñez-Enríquez, Juan Carlos; Olarte-Carrillo, Irma; Guerra-Castillo, Francisco Xavier; Pompa-Mera, Ericka Nelly; Ocaña-Mondragón, Alicia; Bernáldez-Ríos, Roberto; Medina-Sanson, Aurora; Jiménez-Hernández, Elva; Amador-Sánchez, Raquel; Peñaloza-González, José Gabriel; de Diego Flores-Chapa, José; Fajardo-Gutiérrez, Arturo; Flores-Lujano, Janet; Rodríguez-Zepeda, María del Carmen; Dorantes-Acosta, Elisa María; Bolea-Murga, Victoria; Núñez-Villegas, Nancy; Velázquez-Aviña, Martha Margarita; Torres-Nava, José Refugio; Reyes-Zepeda, Nancy Carolina; González-Bonilla, Cesar; Mejía-Aranguré, Juan Manuel

2014-01-01

Mexico has one of the highest incidences of childhood leukemia worldwide and significantly higher mortality rates for this disease compared with other countries. One possible cause is the high prevalence of gene rearrangements associated with the etiology or with a poor prognosis of childhood acute lymphoblastic leukemia (ALL). The aims of this multicenter study were to determine the prevalence of the four most common gene rearrangements [ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL rearrangements] and to explore their relationship with mortality rates during the first year of treatment in ALL children from Mexico City. Patients were recruited from eight public hospitals during 2010–2012. A total of 282 bone marrow samples were obtained at each child's diagnosis for screening by conventional and multiplex reverse transcription polymerase chain reaction to determine the gene rearrangements. Gene rearrangements were detected in 50 (17.7%) patients. ETV6-RUNX1 was detected in 21 (7.4%) patients, TCF3-PBX1 in 20 (7.1%) patients, BCR-ABL1 in 5 (1.8%) patients, and MLL rearrangements in 4 (1.4%) patients. The earliest deaths occurred at months 1, 2, and 3 after diagnosis in patients with MLL, ETV6-RUNX1, and BCR-ABL1 gene rearrangements, respectively. Gene rearrangements could be related to the aggressiveness of leukemia observed in Mexican children. PMID:25692130

Invasion of sorghum in the Americas by a new sugarcane aphid (Melanaphis sacchari) superclone.

PubMed

Nibouche, Samuel; Costet, Laurent; Holt, Jocelyn R; Jacobson, Alana; Pekarcik, Adrian; Sadeyen, Joëlle; Armstrong, J Scott; Peterson, Gary C; McLaren, Neal; Medina, Raul F

2018-01-01

In the United States (US), the sugarcane aphid (SCA) Melanaphis sacchari (Zehnter) (Hemiptera: Aphididae) was introduced in the 1970s, however at that time it was only considered a pest of sugarcane. In 2013, a massive outbreak of M. sacchari occured on sorghum, resulting in significant economic damage to sorghum grown in North America including the US, Mexico, and Puerto Rico. The aim of the present study was to determine if the SCA pest emergence in American sorghum resulted from the introduction of new genotypes. To this end we used microsatellite markers and COI sequencing to compare the genetic diversity of SCA populations collected in the Americas after the 2013 SCA outbreak on sorghum (during 2013-2017) to older samples collected before the pest outbreak (during 2007-2009). Our results show that the SCA outbreak in the Americas and the Caribbean observed since 2013 belong to populations exhibiting low genetic diversity and consisting of a dominant clonal lineage, MLL-F, which colonizes Sorghum spp. and sugarcane. The comparison of MLL-F specimens collected post-2013 with specimens collected in Louisiana in 2007 revealed that both populations are genetically distinct, according to COI sequencing and microsatellite data analyses. Our result suggest that MLL-F is a new invasive genotype introduced into the Americas that has spread rapidly across sorghum growing regions in the US, Mexico, Honduras and the Caribbean. The origin of this introduction is either Africa or Asia, with Asia being the most probable source.

Underground waste barrier structure

DOEpatents

Saha, Anuj J.; Grant, David C.

1988-01-01

Disclosed is an underground waste barrier structure that consists of waste material, a first container formed of activated carbonaceous material enclosing the waste material, a second container formed of zeolite enclosing the first container, and clay covering the second container. The underground waste barrier structure is constructed by forming a recessed area within the earth, lining the recessed area with a layer of clay, lining the clay with a layer of zeolite, lining the zeolite with a layer of activated carbonaceous material, placing the waste material within the lined recessed area, forming a ceiling over the waste material of a layer of activated carbonaceous material, a layer of zeolite, and a layer of clay, the layers in the ceiling cojoining with the respective layers forming the walls of the structure, and finally, covering the ceiling with earth.

High EVI1 expression is associated with MLL rearrangements and predicts decreased survival in paediatric acute myeloid leukaemia: a report from the children's oncology group.

PubMed

Ho, Phoenix A; Alonzo, Todd A; Gerbing, Robert B; Pollard, Jessica A; Hirsch, Betsy; Raimondi, Susana C; Cooper, Todd; Gamis, Alan S; Meshinchi, Soheil

2013-09-01

Ectopic viral integration site-1 (EVI1) is highly expressed in certain cytogenetic subsets of adult acute myeloid leukaemia (AML), and has been associated with inferior survival. We sought to examine the clinical and biological associations of EVI1(high) , defined as expression in excess of normal controls, in paediatric AML. EVI1 mRNA expression was measured via quantitative real-time polymerase chain reaction in diagnostic specimens obtained from 206 patients. Expression levels were correlated with clinical features and outcome. EVI1(high) was present in 58/206 (28%) patients. MLL rearrangements occurred in 40% of EVI1(high) patients as opposed to 12% of the EVI1(low/absent) patients (P < 0·001). No abnormalities of 3q26 were found in EVI1(high) patients by conventional cytogenetic analysis, nor were cryptic 3q26 abnormalities detected in a subset of patients screened by next-generation sequencing. French-American-British class M7 was enriched in the EVI1(high) group, accounting for 24% of these patients. EVI1(high) patients had significantly lower 5-year overall survival from study entry (51% vs. 68%, P = 0·015). However, in multivariate analysis including other established prognostic markers, EVI1 expression did not retain independent prognostic significance. EVI1 expression is currently being studied in a larger cohort of patients enrolled on subsequent Children's Oncology Group trials, to determine if EVI1(high) has prognostic value in MLL-rearranged or intermediate-risk subsets. © 2013 John Wiley & Sons Ltd.

[Diphenylene iodonium and apocynin reduce the translocation and level of p47phox in PBMCs of premature infants to inhibit reactive oxygen species production].

PubMed

Zhang, Lingping; Dong, Wenbin; Li, Qingping; Kang, Lan; Zhang, Lianyu; Lu, Youying; Zhai, Xuesong

2016-01-01

To observe the effects of NADPH oxidase inhibitor diphenylene iodonium (DPI) and apocynin on the generation of reactive oxygen species (ROS) induced by p47phox and the mechanism of p47phox-induced ROS production under hyperoxic conditions. Peripheral blood mononuclear cells (PBMCs) were isolated from the peripheral blood (2 mL) of premature infants of less than 32 weeks without oxygen uptake. The isolated cells were divided into four groups, control group, hyperoxia group, hyperoxia and DPI group, hyperoxia and apocynin group. The control group was cultured in incubator with 50 mL/L CO(2) at 37°, and the other groups were cultured in 950 mL/L O(2) and 50 mL/L CO(2) mixed gas. After 48 hours, ROS was detected by Mitosox Red staining under a confocal laser scanning microscope; malondialdehyde (MDA) was measured by thiobarbituric acid colorimetry; the location and translocation rate of p47phox was observed by immunofluorescence staining; the level of p47phox protein was tested by Western blotting. Compared with the hyperoxia group, the remaining three groups showed significantly decreased ROS and MDA levels and reduced translocation rate and level of p47phox. Compared with the control group, both the hyperoxia and DPI group and the hyperoxia and apocynin group were not significantly different in the above indexes. DPI and apocynin can reduce hyperoxia-induced ROS production by decreasing the translocation and level of p47phox.

Chemical Composition of the Essential Oil of Nigeria Grown Hoslundia opposita Vahl (Lamiaceae) Dried Leaves and Its Bioactivity against Cowpea Seed Bruchid.

PubMed

Babarinde, Samuel Adelani; Pitan, Olufemi Olutoyin Richard; Olatunde, Ganiyu Olatunji; Ajala, Michael Oluwole

2017-06-01

Due to several ecological and human hazards of synthetic pesticides in postharvest crop protection, there is the need to search for eco-friendly alternatives. In this study, chemical composition and insecticidal activities of essential oil (EO) obtained from Hoslundia opposita dried leaves were evaluated against cowpea seed bruchid. Eight constituents, predominated by oxygenated monoterpenes (78.86%), were identified using Gas Chromatography (GC)/MS. The constituents were 1,8-cineole (1; 61.15%), followed by α-terpineol (2; 16.81%), β-phellandrene (3; 13.24%), β-farnesene (4; 3.55%), α-pinene (5; 1.89%), Germacrene D (6; 1.83%), cis-sabinene hydrate (7; 0.90%) and caryophyllene (8; 0.63%). In fumigation bioassay, at 6 h after exposure (HAE), 0.78 ml EO/l air caused 35.33% mortality which was significantly lower than 60.90% and 63.6% observed at 3.15 and 6.25 ml/l air, respectively. Mortality reached 90.0% at 24 HAE regardless of the applied concentration. Lethal time for 50% of the bruchids (LT 50 ) at concentration of 0.78 ml/l air (6.89 h) was higher than the LT 50 at 3.15 and 6.25 ml/l air (4.72 and 4.44 h, respectively). H. opposita EO reduced Callosobruchus maculatus oviposition, while progeny emergence observed in EO-treated seeds (2.42 - 25.73) was significantly (P < 0.05) lower than 51.56 observed in control. The results confirm H. opposita EO's potentials for control of cowpea bruchids. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

Do observed levels of exploitation from consumption-oriented and trophy-oriented fisheries reduce relative stock densities of Muskellunge below target levels in northern Wisconsin?

USGS Publications Warehouse

Faust, Matthew D.; Hansen, Michael J.

2017-01-01

Muskellunge anglers desire to catch large fish, and release rates by recreational anglers often approach 100% (Isermann et al. 2011). Muskellunge are also a culturally significant fish for Chippewa tribes and support a subsistence spearing fishery in Wisconsin’s Ceded Territory (Erickson 2007). Although Muskellunge populations within the state’s Ceded Territory are exposed to both angling and spearing fishery exploitation, Faust and Hansen (2016) suggested that under certain conditions (e.g., high minimum length limits (MLL) and low spearing exploitation) Muskellunge fisheries with disparate motivations could coexist (i.e., sufficient numbers of large individuals remained despite harvest from consumptive fishery), but noted that larger declines in trophy Muskellunge abundance were predicted at lower MLLs (e.g., 102-cm). Fisheries managers with the Wisconsin Department of Natural Resources (WDNR) wished to further understand how specific relative stock densities (RSD), used by the WDNR to define and monitor trophy Muskellunge fisheries, are reduced at exploitation rates commonly experienced by populations in northern Wisconsin. Similarly, understanding how trophy Muskellunge abundance may have declined under the previous statewide MLL (i.e., 86-cm) at these levels of exploitation was also desired. Thus, our objectives were to 1) determine if observed levels of angling and spearing exploitation reduced predicted RSD indices below thresholds used by the WDNR to define trophy Muskellunge fisheries for three typical Muskellunge growth potentials in northern Wisconsin across a variety of MLLs; and 2) quantify how numbers of trophy Muskellunge declined under an 86-cm MLL at observed levels of exploitation.

Single-cell Sequencing Reveals Variants in ARID1A, GPRC5A and MLL2 Driving Self-renewal of Human Bladder Cancer Stem Cells.

PubMed

Yang, Zhao; Li, Chong; Fan, Zusen; Liu, Hongjie; Zhang, Xiaolong; Cai, Zhiming; Xu, Liqin; Luo, Jian; Huang, Yi; He, Luyun; Liu, Chunxiao; Wu, Song

2017-01-01

Cancer stem cells are considered responsible for many important aspects of tumors such as their self-renewal, tumor-initiating, drug-resistance and metastasis. However, the genetic basis and origination of human bladder cancer stem cells (BCSCs) remains unknown. Here, we conducted single-cell sequencing on 59 cells including BCSCs, bladder cancer non-stem cells (BCNSCs), bladder epithelial stem cells (BESCs) and bladder epithelial non-stem cells (BENSCs) from three bladder cancer (BC) specimens. Specifically, BCSCs demonstrate clonal homogeneity and suggest their origin from BESCs or BCNSCs through phylogenetic analysis. Moreover, 21 key altered genes were identified in BCSCs including six genes not previously described in BC (ETS1, GPRC5A, MKL1, PAWR, PITX2 and RGS9BP). Co-mutations of ARID1A, GPRC5A and MLL2 introduced by CRISPR/Cas9 significantly enhance the capabilities of self-renewal and tumor-initiating of BCNSCs. To our knowledge, our study first provides an overview of the genetic basis of human BCSCs with single-cell sequencing and demonstrates the biclonal origin of human BCSCs via evolution analysis. Human bladder cancer stem cells show the high level of consistency and may derived from bladder epithelial stem cells or bladder cancer non-stem cells. Mutations of ARID1A, GPRC5A and MLL2 grant bladder cancer non-stem cells the capability of self-renewal. Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations.

PubMed

Wu, Chenglin; de Miranda, Noel Fcc; Chen, Longyun; Wasik, Agata M; Mansouri, Larry; Jurczak, Wojciech; Galazka, Krystyna; Dlugosz-Danecka, Monika; Machaczka, Maciej; Zhang, Huilai; Peng, Roujun; Morin, Ryan D; Rosenquist, Richard; Sander, Birgitta; Pan-Hammarström, Qiang

2016-06-21

The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-κB activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-κB-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-κB activation in a subset of MCL.

Sintered Lining for Heat-Pipe Evaporator

NASA Technical Reports Server (NTRS)

Ernst, D. M.; Eastman, G. Y.

1985-01-01

Hotspots eliminated by lining inner wall. Distribution of heat transfer liquid in heat-pipe evaporator improved by lining inner wall with layer of sintered metal. Sintered layer takes place of layer of screen wick formerly sintered or bonded to wall. Since sintered layer always full of liquid, no hotspot of type that previously arose where former screen wick did not fit properly against wall.

Suppression of dilution in Ni-Cr-Si-B alloy cladding layer by controlling diode laser beam profile

NASA Astrophysics Data System (ADS)

Tanigawa, Daichi; Funada, Yoshinori; Abe, Nobuyuki; Tsukamoto, Masahiro; Hayashi, Yoshihiko; Yamazaki, Hiroyuki; Tatsumi, Yoshihiro; Yoneyama, Mikio

2018-02-01

A Ni-Cr-Si-B alloy layer was produced on a type 304 stainless steel plate by laser cladding. In order to produce cladding layer with smooth surface and low dilution, influence of laser beam profile on cladding layer was investigated. A laser beam with a constant spatial intensity at the focus spot was used to suppress droplet formation during the cladding layer formation. This line spot, formed with a focussing unit designed by our group, suppressed droplet generation. The layer formed using this line spot with a constant spatial intensity had a much smoother surface compared to a layer formed using a line spot with a Gaussian-like beam. In addition, the dilution of the former layer was much smaller. These results indicated that a line spot with a constant spatial intensity was more effective in producing a cladding layer with smooth surface and low dilution because it suppressed droplet generation.

Comprehensive mutation profiling of mucinous gastric carcinoma.

PubMed

Rokutan, Hirofumi; Hosoda, Fumie; Hama, Natsuko; Nakamura, Hiromi; Totoki, Yasushi; Furukawa, Eisaku; Arakawa, Erika; Ohashi, Shoko; Urushidate, Tomoko; Satoh, Hironori; Shimizu, Hiroko; Igarashi, Keiko; Yachida, Shinichi; Katai, Hitoshi; Taniguchi, Hirokazu; Fukayama, Masashi; Shibata, Tatsuhiro

2016-10-01

Mucinous gastric carcinoma (MGC) is a unique subtype of gastric cancer with a poor survival outcome. Comprehensive molecular profiles and putative therapeutic targets of MGC remain undetermined. We subjected 16 tumour-normal tissue pairs to whole-exome sequencing (WES) and an expanded set of 52 tumour-normal tissue pairs to subsequent targeted sequencing. The latter focused on 114 genes identified by WES. Twenty-two histologically differentiated MGCs (D-MGCs) and 46 undifferentiated MGCs (U-MGCs) were analysed. Chromatin modifier genes, including ARID1A (21%), MLL2 (19%), MLL3 (15%), and KDM6A (7%), were frequently mutated (47%) in MGC. We also identified mutations in potential therapeutic target genes, including MTOR (9%), BRCA2 (9%), BRCA1 (7%), and ERBB3 (6%). RHOA mutation was detected only in 4% of U-MGCs and in no D-MGCs. MYH9 was recurrently (13%) mutated in MGC, with all these being of the U-MGC subtype (p = 0.023). Three U-MGCs harboured MYH9 nonsense mutations. MYH9 knockdown enhanced cell migration and induced intracytoplasmic mucin and cellular elongation. BCOR mutation was associated with improved survival. In U-MGCs, the MLH1 expression status and combined mutation status (TP53/BCL11B or TP53/MLL2) were prognostic factors. A comparative analysis of driver genes revealed that the mutation profile of D-MGC was similar to that of intestinal-type gastric cancer, whereas U-MGC was a distinct entity, harbouring a different mutational profile to intestinal- and diffuse-type gastric cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

A novel forward osmosis system in landfill leachate treatment for removing polycyclic aromatic hydrocarbons and for direct fertigation.

PubMed

Li, Jing; Niu, Aping; Lu, Chun-Jiao; Zhang, Jing-Hui; Junaid, Muhammad; Strauss, Phyllis R; Xiao, Ping; Wang, Xiao; Ren, Yi-Wei; Pei, De-Sheng

2017-02-01

Landfill leachate (LL) is harmful to aquatic environment because it contains high concentrations of dissolved organic matter, inorganic components, heavy metals, and other xenobiotics. Thus, the remediation of LL is crucial for environmental conservation. Here, a potential application of the forward osmosis (FO) filtration process with ammonium bicarbonate (NH 4 HCO 3 ) as a draw solution (DS) was investigated to remediate membrane bioreactor-treated LL (M-LL). After the leachate treatment, the toxicity and removal efficiencies of polycyclic aromatic hydrocarbons (PAHs) were evaluated using zebrafish and cultured human cells. The water recovery rate was improved using the current protocol up to 86.6% and 91.6% by both the pressure retarded osmosis (PRO) mode and the forward osmosis (FO) mode. Water flux increased with the increasing DS concentrations, but solution velocities decreased with the operation time. Toxicity tests revealed that the M-LL treated by NH 4 HCO 3 had no toxic effect on zebrafish and human cells. Moreover, green fluorescent protein (GFP) expression in the transgenic zebrafish Tg(cyp1a:gfp) induced by PAHs was very weak compared to the effects induced by untreated M-LL. Since the diluted DS met local safety requirements of liquid fertilizer, it could be directly applied as the liquid fertilizer for fertigation. In conclusion, this novel FO system using NH 4 HCO 3 as the DS provides a cheap and efficient protocol to effectively remove PAHs and other pollutants in LL, and the diluted DS can be directly applied to crops as a liquid fertilizer, indicating that this technique is effective and eco-friendly for the treatment of different types of LL. Copyright © 2016 Elsevier Ltd. All rights reserved.

Rational Design of Orthogonal Multipolar Interactions with Fluorine in Protein–Ligand Complexes

DOE PAGES

Pollock, Jonathan; Borkin, Dmitry; Lund, George; ...

2015-08-19

Multipolar interactions involving fluorine and the protein backbone have been frequently observed in protein–ligand complexes. Such fluorine–backbone interactions may substantially contribute to the high affinity of small molecule inhibitors. Here we found that introduction of trifluoromethyl groups into two different sites in the thienopyrimidine class of menin–MLL inhibitors considerably improved their inhibitory activity. In both cases, trifluoromethyl groups are engaged in short interactions with the backbone of menin. In order to understand the effect of fluorine, we synthesized a series of analogues by systematically changing the number of fluorine atoms, and we determined high-resolution crystal structures of the complexes withmore » menin. Here, we found that introduction of fluorine at favorable geometry for interactions with backbone carbonyls may improve the activity of menin–MLL inhibitors as much as 5- to 10-fold. In order to facilitate the design of multipolar fluorine–backbone interactions in protein–ligand complexes, we developed a computational algorithm named FMAP, which calculates fluorophilic sites in proximity to the protein backbone. We demonstrated that FMAP could be used to rationalize improvement in the activity of known protein inhibitors upon introduction of fluorine. Furthermore, FMAP may also represent a valuable tool for designing new fluorine substitutions and support ligand optimization in drug discovery projects. Analysis of the menin–MLL inhibitor complexes revealed that the backbone in secondary structures is particularly accessible to the interactions with fluorine. Lastly, considering that secondary structure elements are frequently exposed at protein interfaces, we postulate that multipolar fluorine–backbone interactions may represent a particularly attractive approach to improve inhibitors of protein–protein interactions.« less

Stand-off transmission lines and method for making same

DOEpatents

Tuckerman, David B.

1991-01-01

Standoff transmission lines in an integrated circuit structure are formed by etching away or removing the portion of the dielectric layer separating the microstrip metal lines and the ground plane from the regions that are not under the lines. The microstrip lines can be fabricated by a subtractive process of etching a metal layer, an additive process of direct laser writing fine lines followed by plating up the lines or a subtractive/additive process in which a trench is etched over a nucleation layer and the wire is electrolytically deposited. Microstrip lines supported on freestanding posts of dielectric material surrounded by air gaps are produced. The average dielectric constant between the lines and ground plane is reduced, resulting in higher characteristic impedance, less crosstalk between lines, increased signal propagation velocities, and reduced wafer stress.

ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia

PubMed Central

Weisberg, Stuart P.; Smith-Raska, Matthew R.; Esquilin, Jose M.; Zhang, Ji; Arenzana, Teresita L.; Lau, Colleen M.; Churchill, Michael; Pan, Haiyan; Klinakis, Apostolos; Dixon, Jack E.; Mirny, Leonid A.; Mukherjee, Siddhartha; Reizis, Boris

2014-01-01

Summary Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem cell-related genetic regulator. PMID:24485662

Characterization of Photofrin photobleaching for singlet oxygen dose estimation during photodynamic therapy of MLL cells in vitro

NASA Astrophysics Data System (ADS)

Dysart, Jonathan S.; Patterson, Michael S.

2005-06-01

A singlet oxygen dose model is developed for PDT with Photofrin. The model is based on photosensitizer photobleaching kinetics, and incorporates both singlet oxygen and non-singlet oxygen mediated bleaching mechanisms. To test our model, in vitro experiments were performed in which MatLyLu (MLL) cells were incubated in Photofrin and then irradiated with 532 nm light. Photofrin fluorescence was monitored during treatment and, at selected fluence levels, cell viability was determined using a colony formation assay. Cell survival correlated well to calculated singlet oxygen dose, independent of initial Photofrin concentration or oxygenation. About 2 × 108 molecules of singlet oxygen per cell were required to reduce the surviving fraction by 1/e. Analysis of the photobleaching kinetics suggests that the lifetime of singlet oxygen in cells is 0.048 ± 0.005 µs. The generation of fluorescent photoproducts was not a result of singlet oxygen reactions exclusively, and therefore did not yield additional information to aid in quantifying singlet oxygen dose.

Validation of recent geopotential models in Tierra Del Fuego

NASA Astrophysics Data System (ADS)

Gomez, Maria Eugenia; Perdomo, Raul; Del Cogliano, Daniel

2017-10-01

This work presents a validation study of global geopotential models (GGM) in the region of Fagnano Lake, located in the southern Andes. This is an excellent area for this type of validation because it is surrounded by the Andes Mountains, and there is no terrestrial gravity or GNSS/levelling data. However, there are mean lake level (MLL) observations, and its surface is assumed to be almost equipotential. Furthermore, in this article, we propose improved geoid solutions through the Residual Terrain Modelling (RTM) approach. Using a global geopotential model, the results achieved allow us to conclude that it is possible to use this technique to extend an existing geoid model to those regions that lack any information (neither gravimetric nor GNSS/levelling observations). As GGMs have evolved, our results have improved progressively. While the validation of EGM2008 with MLL data shows a standard deviation of 35 cm, GOCO05C shows a deviation of 13 cm, similar to the results obtained on land.

Reducing sugar loss in enzymatic hydrolysis of ethylenediamine pretreated corn stover.

PubMed

Li, Wen-Chao; Li, Xia; Qin, Lei; Zhu, Jia-Qing; Han, Xiao; Li, Bing-Zhi; Yuan, Ying-Jin

2017-01-01

In this study, the effect of ethylenediamine (EDA) on enzymatic hydrolysis with different cellulosic substrates and the approaches to reduce sugar loss in enzymatic hydrolysis were investigated. During enzymatic hydrolysis, xylose yield reduced 21.2%, 18.1% and 13.0% with 7.5mL/L EDA for AFEX pretreated corn stover (CS), washed EDA pretreated CS and CS cellulose. FTIR and GPC analysis demonstrated EDA reacted with sugar and produced high molecular weight (MW) compounds. EDA was prone to react with xylose other than glucose. H 2 O 2 and Na 2 SO 3 cannot prevent sugar loss in glucose/xylose-EDA mixture, although they inhibited the browning and high MW compounds formation. By decreasing temperature to 30°C, the loss of xylose yield reduced to only 3.8%, 3.6% and 4.2% with 7.5mL/L EDA in the enzymatic hydrolysis of AFEX pretreated CS, washed EDA pretreated CS and CS cellulose. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stand-off transmission lines and method for making same

DOEpatents

Tuckerman, D.B.

1991-05-21

Standoff transmission lines in an integrated circuit structure are formed by etching away or removing the portion of the dielectric layer separating the microstrip metal lines and the ground plane from the regions that are not under the lines. The microstrip lines can be fabricated by a subtractive process of etching a metal layer, an additive process of direct laser writing fine lines followed by plating up the lines or a subtractive/additive process in which a trench is etched over a nucleation layer and the wire is electrolytically deposited. Microstrip lines supported on freestanding posts of dielectric material surrounded by air gaps are produced. The average dielectric constant between the lines and ground plane is reduced, resulting in higher characteristic impedance, less crosstalk between lines, increased signal propagation velocities, and reduced wafer stress. 16 figures.

New Observations of the Gulf of Aden Intermediate Water Intrusion into the Red Sea.

NASA Astrophysics Data System (ADS)

Bower, A.; Abualnaja, Y.

2012-04-01

The three-layer exchange flow between the Red Sea and the Indian Ocean during summer is characterized by a thick, northward intrusion of relatively cold, low-salinity and low in dissolved oxygen (< 0.5 ml/l); Gulf of Aden Intermediate Water (GAIW), sandwiched between two thin layers of outflow water. The flux of GAIW into the Red Sea is important in the heat, freshwater and nutrient budgets of the Red Sea, but the structure and pathways of the intrusion are not well-known due to a paucity of hydrographic and direct velocity observations. A research cruise was executed at the eastern side of the Red Sea during September-October 2011 to conduct the first large-scale survey of the intrusion. This mission is part of a series of expeditions in the Red Sea designed to investigate the seasonal Red Sea circulation. Surprisingly, the GAIW intrusion was observed to stretch nearly the entire length of the Red Sea (~1500 km) as a narrow eastern boundary current with subsurface velocity maximum of 0.1-0.3 m/s in the depth range 50-100 m. The intruding layer is weakly stratified compared to the background, possibly an indication of strong vertical mixing as it flows through the strait. Some GAIW was observed to enter deep channels in a coral reef bank (Farasan Banks) located in the southeastern Red Sea, and to enter the Red Sea interior, the latter possibly due to interactions between the boundary current and mesoscale eddies. The pathways and erosion of the GAIW intrusion will likely have major implications for the spatial distribution of biological productivity.

On the stability of an infinite swept attachment line boundary layer

NASA Technical Reports Server (NTRS)

Hall, P.; Mallik, M. R.; Poll, D. I. A.

1984-01-01

The instability of an infinite swept attachment line boundary layer is considered in the linear regime. The basic three dimensional flow is shown to be susceptible to travelling wave disturbances which propagate along the attachment line. The effect of suction on the instability is discussed and the results suggest that the attachment line boundary layer on a swept wing can be significantly stabilized by extremely small amounts of suction. The results obtained are in excellent agreement with the available experimental observations.

Development of corrosion resistant heat exchangers for flue gas desulfurization

NASA Astrophysics Data System (ADS)

Ernst, E.; Lorentz, R.

1984-12-01

A glass lining as protection against corrosion in flue gas desulfurization plants was developed. Glasses were evaluated under corrosive attack of fluoride-containing acids. The corrosion properties of one-layer and two-layer glass enamels are optimized. Two-layer systems always show better resistance and longer life. The optimized glass linings were tested in a power plant. Manufacturing principles for glass-lined heat exchanger elements are derived. The optimized glasses may be used as protective lining design for heat exchangers or parts of them.

RF Transmission Lines on Silicon Substrates

NASA Technical Reports Server (NTRS)

Ponchak, George E.

1999-01-01

A review of RF transmission lines on silicon substrates is presented. Through measurements and calculated results, it is shown that attenuation is dominated by conductor loss if silicon substrates with a resistivity greater than 2500 Ohm-cm are used. Si passivation layers affect the transmission line attenuation; however, measured results demonstrate that passivation layers do not necessarily increase attenuation. If standard, low resistivity Si wafers must be used, alternative transmission lines such as thin film microstrip and Co-Planar Waveguide (CPW) on thick polyimide layers must be used. Measured results presented here show that low loss per unit length is achievable with these transmission lines.

The recurrent SET-NUP214 fusion as a new HOXA activation mechanism in pediatric T-cell acute lymphoblastic leukemia

PubMed Central

Van Vlierberghe, Pieter; van Grotel, Martine; Tchinda, Joëlle; Lee, Charles; Beverloo, H. Berna; van der Spek, Peter J.; Stubbs, Andrew; Cools, Jan; Nagata, Kyosuke; Fornerod, Maarten; Buijs-Gladdines, Jessica; Horstmann, Martin; van Wering, Elisabeth R.; Soulier, Jean; Pieters, Rob

2008-01-01

T-cell acute lymphoblastic leukemia (T-ALL) is mostly characterized by specific chromosomal abnormalities, some occurring in a mutually exclusive manner that possibly delineate specific T-ALL subgroups. One subgroup, including MLL-rearranged, CALM-AF10 or inv (7)(p15q34) patients, is characterized by elevated expression of HOXA genes. Using a gene expression–based clustering analysis of 67 T-ALL cases with recurrent molecular genetic abnormalities and 25 samples lacking apparent aberrations, we identified 5 new patients with elevated HOXA levels. Using microarray-based comparative genomic hybridization (array-CGH), a cryptic and recurrent deletion, del (9)(q34.11q34.13), was exclusively identified in 3 of these 5 patients. This deletion results in a conserved SET-NUP214 fusion product, which was also identified in the T-ALL cell line LOUCY. SET-NUP214 binds in the promoter regions of specific HOXA genes, where it interacts with CRM1 and DOT1L, which may transcriptionally activate specific members of the HOXA cluster. Targeted inhibition of SET-NUP214 by siRNA abolished expression of HOXA genes, inhibited proliferation, and induced differentiation in LOUCY but not in other T-ALL lines. We conclude that SET-NUP214 may contribute to the pathogenesis of T-ALL by enforcing T-cell differentiation arrest. PMID:18299449

MEASUREMENT OF WASTE LOADING IN SALTSTONE

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

Harbour, J; Vickie Williams, V

2008-07-18

One of the goals of the Saltstone variability study is to identify the operational and compositional variables that control or influence the important processing and performance properties of Saltstone grout mixtures. One of those properties of importance is the Waste Loading (WL) of the decontaminated salt solution (DSS) in the Saltstone waste form. Waste loading is a measure of the amount of waste that can be incorporated within a waste form. The value of the Saltstone waste loading ultimately determines the number of vaults that will be required to disposition all of the DSS. In this report, the waste loadingmore » is defined as the volume in milliliters of DSS per liter of Saltstone waste form. The two most important parameters that determine waste loading for Saltstone are water to cementitious material (w/cm) ratio and the cured grout density. Data are provided that show the dependence of waste loading on the w/cm ratio for a fixed DSS composition using the current premix material (45% Blast Furnace Slag (BFS), 45% Fly Ash (FA) and 10% Ordinary Portland Cement (OPC)). The impact of cured grout density on waste loading was also demonstrated. Mixes (at 0.60 w/cm) made with a Modular Caustic side extraction Unit (MCU) simulant and either OPC or BFS have higher cured grout densities than mixes made with premix and increase the WL to 709 mL/L for the OPC mix and 689 mL/L for the BFS mix versus the value of 653 mL/L for MCU in premix at 0.60 w/cm ratio. Bleed liquid reduces the waste loading and lowers the effective w/cm ratio of Saltstone. A method is presented (and will be used in future tasks) for correcting the waste loading and the w/cm ratio of the as-batched mixes in those cases where bleed liquid is present. For example, the Deliquification, Dissolution and Adjustment (DDA) mix at an as-batched 0.60 w/cm ratio, when corrected for % bleed, gives a mix with a 0.55 w/cm ratio and a WL that has been reduced from 662 to 625 mL/L. An example is provided that demonstrated the quantitative impact of WL on the number of cells (each Saltstone vault contains two cells) required to disposition all of the {approx}100 million gallons of DSS available in the tanks. This calculation revealed that the number of cells required over the range of 0.48 to 0.62 w/cm ratio (equivalent to a WL range of 591 to 666 mL/L) varies from 65 to 57 cells (33 to 29 vaults). The intent of this oversimplified example was to show the range of variation in vaults expected due to w/cm ratio rather than to estimate the actual number of vaults required. There is a tradeoff between the waste loading and the processing and performance properties of Saltstone. The performance properties improve in general as the w/cm ratio decreases whereas the waste loading is reduced at lower w/cm ratios resulting in a larger number of Saltstone vaults. The final performance and processing requirements of Saltstone will determine the maximum waste loading achievable.« less

Active Layer and Moisture Measurements for Intensive Site 0 and 1, Barrow, Alaska

DOE Data Explorer

John Peterson

2015-04-17

These are measurements of Active Layer Thickness collected along several lines beginning in September, 2011 to the present. The data were collected at several time periods along the Site0 L2 Line, the Site1 AB Line, and an ERT Monitoring Line near Area A in Site1.

Ultra-high density diffraction grating

DOEpatents

Padmore, Howard A.; Voronov, Dmytro L.; Cambie, Rossana; Yashchuk, Valeriy V.; Gullikson, Eric M.

2012-12-11

A diffraction grating structure having ultra-high density of grooves comprises an echellette substrate having periodically repeating recessed features, and a multi-layer stack of materials disposed on the echellette substrate. The surface of the diffraction grating is planarized, such that layers of the multi-layer stack form a plurality of lines disposed on the planarized surface of the structure in a periodical fashion, wherein lines having a first property alternate with lines having a dissimilar property on the surface of the substrate. For example, in one embodiment, lines comprising high-Z and low-Z materials alternate on the planarized surface providing a structure that is suitable as a diffraction grating for EUV and soft X-rays. In some embodiments, line density of between about 10,000 lines/mm to about 100,000 lines/mm is provided.

Demonstration and Validation of a Fractured Rock Passive Flux Meter

DTIC Science & Technology

2015-04-01

Thick continuous lines are stream lines and thin dashed lines are potential lines. Green lines are isochrones, i.e., dye , tracer or contaminant...layer of cloth material impregnated with a visible dye . The core inflates separately from the two end packers to provide a mechanism for holding the one...leaches visible dyes and tracers from the internal and external sorbent layers and produces residual dye and tracer distributions. Visual

What Is Happening at Spectral Type F5 in Hyades F Stars?

NASA Technical Reports Server (NTRS)

Boehm-Vitense, Erika; Robinson, Richard; Carpenter, Kenneth; Mena-Werth, Jose

2002-01-01

Aiming at a better understanding of the mechanisms heating the chromospheres, transition regions, and coronae of cool stars, we study ultraviolet, low-resolution Hubble Space Telescope/Space Telescope Imaging Spectrograph spectra of Hyades main-sequence F stars. We study the B-V dependence(s) of the chromospheric and transition layer emission line fluxes and their dependences on rotational velocities. We find that the transition layer emission line fluxes and also those of strong chromospheric lines decrease steeply between B-V = 0.42 and 0.45, i.e., at spectral type F5, for which the rotational velocities also decrease steeply. The magnitude of the line-flux decrease increases for lines of ions with increasing degree of ionization. This shows that the line-flux decrease is not due to a change in the surface filling factor but rather due to a change of the relative importance of different heating mechanisms. For early F stars with B-V < 0.42 we find for the transition layer emission lines increasing fluxes for increasing v sin i, indicating magnetohydrodynamic heating. The v sin i dependence is strongest for the high-ionization lines. On the other hand, the low chromospheric lines show no dependence on v sin i, indicating acoustic shock heating for these layers. This also contributes to the heating of the transition layers. The Mg II and Ca II lines show decreasing fluxes for increasing v sin i, as long as v sin i is less than approx. 40 km/s. The coronal X-ray emission also decreases for increasing v sin i, except for v sin i larger than approx. 100 km/s. We have at present no explanation for this behavior. For late F stars the chromospheric lines show v sin i dependences similar to those observed for early F stars, again indicating acoustic heating for these layers. We were unable to determine the v sin i dependence of the transition layer lines because of too few single star targets. The decrease of emission line fluxes at the spectral type F5, with steeply decreasing v sin i, indicates, however, a decreasing contribution of magnetohydrodynamic heating for the late F stars. The X-ray emission for the late F stars increases for increasing v sin i, indicating magnetohydrodynamic heating for the coronae of the late F stars, different from the early F stars.

A Novel, Diazonium-Phenolic Resin Two-Layer Resist System Utilizing Photoinduced Interfacial Insolubilization

NASA Astrophysics Data System (ADS)

Uchino, Shou-ichi; Iwayanagi, Takao; Ueno, Takumi; Hashimoto, Michiaki; Nonogaki, Saburo

1987-08-01

This paper deals with a negative two-layer photoresist system utilizing a photoinduced insolubilization process at the interface. The bottom layer is a phenolic resin either with or without aromatic azide and the top layer is a photosensitive layer comprised of an aromatic diazonium compound and a water soluble polymer. Upon exposure to light, the diazo compound decomposes to cause insolubilization at the interface between the two layers. The system exhibits high contrast due to the combination of interfacial insolubilization and contrast enhancement by photobleaching of the diazonium compound. Patterns of 0.5 um lines and spaces are obtained using an i-line stepper and a resist system containing 4-diazo-N,N-dimethylaniline chloride zinc chloride in the top layer and 3-(4-azidostyry1)- 5,5-dimethyl- 2-cyclohexen-1-one in the bottom layer. Resists with varying spectral responses from mid-UV to g-line can be designed by selecting the kind of diazo compound used in the top layer.

Heating mechanism(s) for transition layers in giants

NASA Technical Reports Server (NTRS)

Bohm-Vitense, Erika; Mena-Werth, Jose

1991-01-01

The emission-line fluxes of lines originating in the lower parts of the transition layers between stellar chromospheres and coronas are studied. Simon and Drake (1989) suspect different heating mechanisms for 'hot' and cool stars. Changes in the flux ratios for the C IV to C II emission lines support this suspicion. Large C IV/C II line flux ratios appear to be indicative of magnetically controlled heating. A correlation between excess continuum flux around 1950 A and C II emission-line fluxes are confirmed for the cooler giants (late F and cooler). Excess continuum flux correlates positively with large C IV/C II line flux ratio. The excess continuum flux corresponds to an increase in temperature by several hundred degrees in layers with a mean optical depth of about 0.03. For chromospherically active stars these layers experience a mechanical flux deposition of the order of 1 percent of the total radiative flux. This flux is tentatively identified as an MHD wave flux similar to Alfven waves.

Site Inspection Report for Former Nansemond Ordnance Depot, Suffolk, VA

DTIC Science & Technology

2012-01-01

previously addressed, or there is no reason to suspect contamination was ever present at an MRS. Note: HHE MODULE RATING No Longer Required A D HHH HML...Required A D HHH HML MMM Combination Rating E HLL MML MLL F GLLL Evaluation Pending No Longer Required Alternative Module Ratings No Known or

The Long Non-coding RNA HOTTIP Enhances Pancreatic Cancer Cell Proliferation, Survival and Migration

EPA Science Inventory

ABSTRACTHOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expres...

Multilevel Leadership and Organizational Effectiveness in Indian Technical Education: The Mediating Role of Communication, Power and Culture

ERIC Educational Resources Information Center

Gochhayat, Jyotiranjan; Giri, Vijai N.; Suar, Damodar

2017-01-01

This study provides a new conceptualization of educational leadership with a multilevel and integrative approach. It examines the impact of multilevel leadership (MLL) on the effectiveness of technical educational institutes through the mediating effects of organizational communication, bases of power and organizational culture. Data were…

Effect of the culture media optimization, pH and temperature on the biohydrogen production and the hydrogenase activities by Klebsiella pneumoniae ECU-15.

PubMed

Xiao, Yan; Zhang, Xu; Zhu, Minglong; Tan, Wensong

2013-06-01

The low yield of the biohydrogen production is the main constraint for its industrialization process. In order to improve its production, medium compositions of the hydrogen fermentation by Klebsiella pneumoniae ECU-15 were optimized through the response surface methodology (RSM). Experimental results showed that the optimum hydrogen production of 5363.8 ml/L was obtained when the concentration of glucose, the ammonium sulfate and the trace elements were 35.62 g/L, 2.78 g/L and 23.15 ml/L at temperature 37.0°C, pH 6.0. H2 evolving hydrogenase was greatly enhanced by the optimization of the medium compositions. The activity of H2 evolving hydrogenase increased with the temperature, and decreased with the pH, while the activity of the uptake hydrogenase increased with the temperature and the pH. So the biohydrogen production process of the K. pneumoniae ECU-15 was the comprehensive results of the evolution hydrogen process and the uptake hydrogen process. Copyright © 2013 Elsevier Ltd. All rights reserved.

Integrated analysis of germline and somatic variants in ovarian cancer.

PubMed

Kanchi, Krishna L; Johnson, Kimberly J; Lu, Charles; McLellan, Michael D; Leiserson, Mark D M; Wendl, Michael C; Zhang, Qunyuan; Koboldt, Daniel C; Xie, Mingchao; Kandoth, Cyriac; McMichael, Joshua F; Wyczalkowski, Matthew A; Larson, David E; Schmidt, Heather K; Miller, Christopher A; Fulton, Robert S; Spellman, Paul T; Mardis, Elaine R; Druley, Todd E; Graubert, Timothy A; Goodfellow, Paul J; Raphael, Benjamin J; Wilson, Richard K; Ding, Li

2014-01-01

We report the first large-scale exome-wide analysis of the combined germline-somatic landscape in ovarian cancer. Here we analyse germline and somatic alterations in 429 ovarian carcinoma cases and 557 controls. We identify 3,635 high confidence, rare truncation and 22,953 missense variants with predicted functional impact. We find germline truncation variants and large deletions across Fanconi pathway genes in 20% of cases. Enrichment of rare truncations is shown in BRCA1, BRCA2 and PALB2. In addition, we observe germline truncation variants in genes not previously associated with ovarian cancer susceptibility (NF1, MAP3K4, CDKN2B and MLL3). Evidence for loss of heterozygosity was found in 100 and 76% of cases with germline BRCA1 and BRCA2 truncations, respectively. Germline-somatic interaction analysis combined with extensive bioinformatics annotation identifies 222 candidate functional germline truncation and missense variants, including two pathogenic BRCA1 and 1 TP53 deleterious variants. Finally, integrated analyses of germline and somatic variants identify significantly altered pathways, including the Fanconi, MAPK and MLL pathways.

ACK1/TNK2 Regulates Histone H4 Tyr88-phosphorylation and AR Gene Expression in Castration-Resistant Prostate Cancer.

PubMed

Mahajan, Kiran; Malla, Pavani; Lawrence, Harshani R; Chen, Zhihua; Kumar-Sinha, Chandan; Malik, Rohit; Shukla, Sudhanshu; Kim, Jongphil; Coppola, Domenico; Lawrence, Nicholas J; Mahajan, Nupam P

2017-06-12

The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state. Copyright © 2017 Elsevier Inc. All rights reserved.

Menin regulates the function of hematopoietic stem cells and lymphoid progenitors

PubMed Central

Chen, Ya-Xiong; Friedman, Ann; Yang, Yuqing; Tubbs, Anthony T.; Shestova, Olga; Pear, Warren S.

2009-01-01

Men1 is a tumor suppressor gene mutated in endocrine neoplasms. Besides its endocrine role, the Men1 gene product menin interacts with the mixed lineage leukemia (MLL) protein, a histone H3 lysine 4 methyltransferase. Although menin and MLL fusion proteins cooperate to activate Homeobox (Hox) gene expression during transformation, little is known about the normal hematopoietic functions of menin. Here, we studied hematopoiesis after Men1 ablation. Menin loss modestly impaired blood neutrophil, lymphocyte, and platelet counts. Without hematopoietic stress, multilineage and myelo-erythroid bone marrow progenitor numbers were preserved, while B lymphoid progenitors were decreased. In contrast, competitive transplantation revealed a marked functional defect of long-term hematopoietic stem cells (HSC) in the absence of menin, despite normal initial homing of progenitors to the bone marrow. HoxA9 gene expression was only modestly decreased in menin-deficient HSCs. These observations reveal a novel and essential role for menin in HSC homeostasis that was most apparent during situations of hematopoietic recovery, suggesting that menin regulates molecular pathways that are essential during the adaptive HSC response to stress. PMID:19228930

Improving the Slepton Reach through Cascade Decay at the LHC

NASA Astrophysics Data System (ADS)

Eckel, Jonathan; Su, Shufang; Shepherd, William

2011-10-01

LHC studies on the slepton sector have mostly been focused on direct slepton Drell-Yan pair production. We analyzed the case when the left-handed sleptons are lighter than winos and can appear in the on-shell decay of those particles. The invariant mass of the lepton pairs, Mll, from the neutralino decay has a distinctive triangle shape with a sharp cutoff. We discuss the utilization of the triangle shape in the Mll distribution to identify the slepton signal. We studied the trilepton signal and obtained the σxBR xacceptance that is needed for a 5 σ discovery as a function of the cutoff mass for the LHC with center of mass energy 14 TeV and 100 fb-1 integrated luminosity. Our results are model independent such that they could be applied to other models with similar decay topology. When applied to the MSSM case, it is found that with 30 (100) fb-1, the left-handed slepton mass of about 500 (600) GeV could be reached, which extends far beyond the slepton mass reach in the usual Drell-Yan study.

An assessment of sauger population characteristics on two Tennessee River reservoirs

USGS Publications Warehouse

Graham, Christy L.; Bettoli, Phillip William; Churchill, Timothy N.

2015-01-01

In 1992, a 356-mm minimum length limit (MLL) was enacted on Kentucky Lake and a 381-mm MLL was enacted on Watts Bar Lake, two mainstem reservoirs on the Tennessee River, in an attempt to reduce exploitation and improve the size structure of the sauger (Sander canadensis) populations. The objectives of this study were to compare sauger population characteristics immediately following (1993–1994) and 15 years after (2008–2009) the regulations took effect, examine spatial and temporal patterns in growth, examine recruitment patterns in each reservoir using a recruitment variability index (RVI), and assess the current likelihood of overfishing. Saugers were collected with experimental gill nets in each reservoir and aged using otoliths. A Beverton-Holt yield-per-recruit model was used to simulate angler yields and estimate the likelihood of growth overfishing. Recruitment overfishing was assessed by examining spawning potential ratios under various MLL and exploitation rate scenarios. The sauger population in Kentucky Lake experienced modest improvements in size and age structure over the 15 years following enactment of more restrictive harvest regulations, whereas the population in Watts Bar Lake changed very little, if at all, in terms of size and age structure. Mean lengths of age-3 sauger were significantly greater in Watts Bar Lake than in Kentucky Lake in both time periods. The RVI values indicated that between 1993 and 2009 the sauger in Kentucky Lake displayed more stable recruitment than the Watts Bar Lake population. Neither population exhibited signs of growth overfishing in 2008–09 under the current length limits; however, the Watts Bar Lake population would be susceptible to recruitment overfishing at high (>40%) exploitation rates if natural mortality was as low as 20%. These analyses have demonstrated that the Watts Bar Lake and Kentucky Lake populations, in terms of size and age structure, have remained relatively stable over 15+ years and the MLLs appear to be conserving the stocks.

Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia

PubMed Central

Geng, Huimin; Brennan, Sarah; Milne, Thomas A.; Chen, Wei-Yi; Li, Yushan; Hurtz, Christian; Kweon, Soo-Mi; Zickl, Lynette; Shojaee, Seyedmehdi; Neuberg, Donna; Huang, Chuanxin; Biswas, Debabrata; Xin, Yuan; Racevskis, Janis; Ketterling, Rhett P.; Luger, Selina M.; Lazarus, Hillard; Tallman, Martin S.; Rowe, Jacob M.; Litzow, Mark R.; Guzman, Monica L.; Allis, C. David; Roeder, Robert G.; Müschen, Markus; Paietta, Elisabeth; Elemento, Olivier; Melnick, Ari M.

2012-01-01

Genetic lesions such as BCR-ABL1, E2A-PBX1 and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point towards disease mechanisms and useful biomarkers and therapeutic targets. We therefore performed DNA methylation and gene expression profiling on a cohort of 215 adult B-ALL patients enrolled in a single phase III clinical trial (ECOG E2993) and normal control B-cells. In BCR-ABL1-positive B-ALL, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in ALL patients regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALL. In E2A-PBX1-positive B-ALL, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 ChIP sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6 targeted therapy as a new therapeutic strategy for MLLr B-ALL. PMID:23107779

Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia

PubMed Central

Wiemels, Joseph L.; Smith, Rosalyn N.; Taylor, G. Malcolm; Eden, Osborn B.; Alexander, Freda E.; Greaves, Mel F.

2001-01-01

Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C→T) and 1,298 (A→C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15–0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07–0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20–1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia. PMID:11274424

Simple prediction method of lumbar lordosis for planning of lumbar corrective surgery: radiological analysis in a Korean population.

PubMed

Lee, Chong Suh; Chung, Sung Soo; Park, Se Jun; Kim, Dong Min; Shin, Seong Kee

2014-01-01

This study aimed at deriving a lordosis predictive equation using the pelvic incidence and to establish a simple prediction method of lumbar lordosis for planning lumbar corrective surgery in Asians. Eighty-six asymptomatic volunteers were enrolled in the study. The maximal lumbar lordosis (MLL), lower lumbar lordosis (LLL), pelvic incidence (PI), and sacral slope (SS) were measured. The correlations between the parameters were analyzed using Pearson correlation analysis. Predictive equations of lumbar lordosis through simple regression analysis of the parameters and simple predictive values of lumbar lordosis using PI were derived. The PI strongly correlated with the SS (r = 0.78), and a strong correlation was found between the SS and LLL (r = 0.89), and between the SS and MLL (r = 0.83). Based on these correlations, the predictive equations of lumbar lordosis were found (SS = 0.80 + 0.74 PI (r = 0.78, R (2) = 0.61), LLL = 5.20 + 0.87 SS (r = 0.89, R (2) = 0.80), MLL = 17.41 + 0.96 SS (r = 0.83, R (2) = 0.68). When PI was between 30° to 35°, 40° to 50° and 55° to 60°, the equations predicted that MLL would be PI + 10°, PI + 5° and PI, and LLL would be PI - 5°, PI - 10° and PI - 15°, respectively. This simple calculation method can provide a more appropriate and simpler prediction of lumbar lordosis for Asian populations. The prediction of lumbar lordosis should be used as a reference for surgeons planning to restore the lumbar lordosis in lumbar corrective surgery.

Fabrication of Crack-Free Barium Titanate Thin Film with High Dielectric Constant Using Sub-Micrometric Scale Layer-by-Layer E-Jet Deposition.

PubMed

Liang, Junsheng; Li, Pengfei; Wang, Dazhi; Fang, Xu; Ding, Jiahong; Wu, Junxiong; Tang, Chang

2016-01-19

Dense and crack-free barium titanate (BaTiO₃, BTO) thin films with a thickness of less than 4 μm were prepared by using sub-micrometric scale, layer-by-layer electrohydrodynamic jet (E-jet) deposition of the suspension ink which is composed of BTO nanopowder and BTO sol. Impacts of the jet height and line-to-line pitch of the deposition on the micro-structure of BTO thin films were investigated. Results show that crack-free BTO thin films can be prepared with 4 mm jet height and 300 μm line-to-line pitch in this work. Dielectric constant of the prepared BTO thin film was recorded as high as 2940 at 1 kHz at room temperature. Meanwhile, low dissipation factor of the BTO thin film of about 8.6% at 1 kHz was also obtained. The layer-by-layer E-jet deposition technique developed in this work has been proved to be a cost-effective, flexible and easy to control approach for the preparation of high-quality solid thin film.

Boundary Layer Transition in the Leading Edge Region of a Swept Cylinder in High Speed Flow

NASA Technical Reports Server (NTRS)

Coleman, Colin P.

1998-01-01

Experiments were conducted on a 76 degree swept cylinder to establish the behavior of the attachment line transition process in a low-disturbance level, Mach number 1.6 flow. For a near adiabatic wall condition, the attachment-line boundary layer remained laminar up to the highest attainable Reynolds number. The attachment-line boundary layer transition under the influence of trip wires depended on wind tunnel disturbance level, and a transition onset condition for this flow is established. Internal heating raised the surface temperature of the attachment line to induce boundary layer instabilities. This was demonstrated experimentally for the first time and the frequencies of the most amplified disturbances were determined over a range of temperature settings. Results were in excellent agreement to those predicted by a linear stability code, and provide the first experimental verification of theory. Transition onset along the heated attachment line at an R-bar of 800 under quiet tunnel conditions was found to correlate with an N factor of 13.2. Increased tunnel disturbance levels caused the transition onset to occur at lower cylinder surface temperatures and was found to correlate with an approximate N factor of 1 1.9, so demonstrating that the attachment-line boundary layer is receptive to increases in the tunnel disturbance level.

Direct Simulation of Evolution and Control of Three-Dimensional Instabilities in Attachment-Line Boundary Layers

NASA Technical Reports Server (NTRS)

Joslin, Ronald D.

1995-01-01

The spatial evolution of three-dimensional disturbances in an attachment-line boundary layer is computed by direct numerical simulation of the unsteady, incompressible Navier-Stokes equations. Disturbances are introduced into the boundary layer by harmonic sources that involve unsteady suction and blowing through the wall. Various harmonic- source generators are implemented on or near the attachment line, and the disturbance evolutions are compared. Previous two-dimensional simulation results and nonparallel theory are compared with the present results. The three-dimensional simulation results for disturbances with quasi-two-dimensional features indicate growth rates of only a few percent larger than pure two-dimensional results; however, the results are close enough to enable the use of the more computationally efficient, two-dimensional approach. However, true three-dimensional disturbances are more likely in practice and are more stable than two-dimensional disturbances. Disturbances generated off (but near) the attachment line spread both away from and toward the attachment line as they evolve. The evolution pattern is comparable to wave packets in at-plate boundary-layer flows. Suction stabilizes the quasi-two-dimensional attachment-line instabilities, and blowing destabilizes these instabilities; these results qualitatively agree with the theory. Furthermore, suction stabilizes the disturbances that develop off the attachment line. Clearly, disturbances that are generated near the attachment line can supply energy to attachment-line instabilities, but suction can be used to stabilize these instabilities.

Looking Into and Through the Ross Ice Shelf - ROSETTA-ICE

NASA Astrophysics Data System (ADS)

Bell, R. E.

2015-12-01

Our current understanding of the structure and stability of the Ross Ice Shelf is based on satellite studies of the ice surface and the 1970's RIGGS program. The study of the flowlines evident in the MODIS imagery combined with surface geophysics has revealed a complex history with ice streams Mercer, Whillans and Kamb changing velocity over the past 1000 years. Here, we present preliminary IcePod and IceBridge radar data acquired in December 2014 and November 2013 across the Ross Ice Shelf that show clearly, for the first time, the structure of the ice shelf and provide insights into ice-ocean interaction. The three major layers of the ice shelf are (1) the continental meteoric ice layer), ice formed on the grounded ice sheet that entered the ice shelf where ice streams and outlet glaciers crossed the grounding line (2) the locally accumulating meteoric ice layer, ice and snow that forms from snowfall on the floating ice shelf and (3) a basal marine ice layer. The locally accumulating meteoric ice layer contains well-defined internal layers that are generally parallel to the ice surface and thickens away from the grounding line and reaches a maximum thickness of 220m along the line crossing Roosevelt Island. The continental meteoric layer is located below a broad irregular internal reflector, and is characterized by irregular internal layers. These internal layers are often folded, likely a result of deformation as the ice flowed across the grounding line. The basal marine ice layer, up to 50m thick, is best resolved in locations where basal crevasses are present, and appears to thicken along the flow at rates of decimeters per year. Each individual flowband of the ice shelf contains layers that are distinct in their structure. For example, the thickness of the locally accumulated layer is a function of both the time since crossing the grounding line and the thickness of the incoming ice. Features in the meteoric ice, such as distinct folds, can be traced between the two IceBridge lines located 47 km apart. The ROSETTA-ICE program will begin a systematic mapping of the Ross Ice Shelf and sub-ice topography using the IcePod system beginning in 2015. Together the new gravity-derived bathymetry and the mapping of the ice shelf structure will provide key insights into the stability of the ice shelf.

Molecular characterization and expression profiling of BMP 3 gene in broiler and layer chicken.

PubMed

Divya, Devara; Bhattacharya, Tarun Kumar; Gnana Prakash, Manthani; Chatterjee, R N; Shukla, Renu; Guru Vishnu, Pothana Boyina; Vinoth, Amirthalingam; Dushyanth, Kotha

2018-04-10

A study was carried out to characterize and explore the expression profile of BMP 3 gene in control broiler and control layer chicken. The total open reading frame of BMP 3 (1389 bp) was cloned and sequenced. The control broiler and control layer chicken showed variation at nucleotide and amino acid level with reference gene (Gallus gallus, NCBI Acc. No. NM_001034819). When compared to reference gene, the control broiler showed four nucleotide differences (c.192A>G, c.519C>T, 903G>A and 960C>G), while, control layer showed variation at c.33G>C, 192A>G, 858G>A, 904G>A, 960C>G and 1257C>T making six differences in total. However, between control broiler and control layer lines, nucleotide differences was observed at c.33G>C, 519T>C, 858G>A, 903A>G, 904G>A and 1257C>T. The change at amino acid level between reference and control broiler was p.D320N and with control layer chicken, it was p.D302N and p.D320N. On the other hand, a single amino acid difference (p.D302N) was observed between the control broiler and control layer chicken lines. The phylogenetic study displayed a close relationship between broiler and layer lines and reference gene and also with other avian species resulting in a cluster formation. These cluster in turn displayed a distant link with the mammalian species. The expression profile of BMP 3 gene exhibited a variation at different stages of embryonic development and also at post embryonic period among the lines with control layer showing higher expression than that of broiler chicken. The protein was also detected in bone marrow tissue of broiler and layer lines by western blotting. It is concluded that the BMP 3 gene sequence differed at nucleotide and amino acid level among the lines and the gene expressed differentially at different periods of embryonic development and also at post hatch period.

Chicken line-dependent mortality after experimental infection with three type IIxIII recombinant Toxoplasma gondii clones.

PubMed

Schares, G; Herrmann, D C; Maksimov, P; Matzkeit, B; Conraths, F J; Moré, G; Preisinger, R; Weigend, S

2017-09-01

Three genetically different clones of Toxoplasma gondii, also different in mouse virulence, were studied by experimental infection in chickens. For the experiments, four chicken lines were used, which differed in phylogenetic origin and performance level: two white egg layer lines, one with high laying performance (WLA), one with low (R11) and two brown layer lines, also displaying high (BLA) and low (L68) egg number. Chickens were intraperitoneally infected with three different T. gondii isolates representing type IIxIII recombinant clones, i.e. showing both, type II- and type III-specific alleles. These clones (K119/2 2C10, B136/1 B6H6, K119/2 A7) had exhibited virulence differences in a mouse model. In chickens, a significantly higher mortality was observed in white layer lines, but not in brown layer lines, suggesting that differences in the phylogenetic background may influence the susceptibility of chickens for toxoplasmosis. In addition, antibody (IgY) levels varied in surviving chickens at 31 days post infection. While low to intermediate antibody levels were observed in white layers, intermediate to high levels were measured in brown layers. Infection with a T. gondii clone showing low chicken virulence resulted in higher antibody levels in all chicken lines compared to infection with T. gondii clones of intermediate or high chicken virulence. This was in agreement with the parasite load as determined by real-time PCR. Overall, results show that progeny resulting from natural sexual recombination of T. gondii clonal lineages, may differ in their virulence for mice and chickens. Copyright © 2016 Elsevier Inc. All rights reserved.

Rolled-up transmission line structure for a radiofrequency integrated circuit (RFIC)

DOEpatents

Li, Xiuling; Huang, Wen

2015-04-28

A rolled-up transmission line structure for a radiofrequency integrated circuit (RFIC) comprises a multilayer sheet in a rolled configuration comprising multiple turns about a longitudinal axis, where the multilayer sheet comprises a conductive pattern layer on a strain-relieved layer. The conductive pattern layer comprises a first conductive film and a second conductive film separated from the first conductive film in a rolling direction. In the rolled configuration, the first conductive film surrounds the longitudinal axis, and the second conductive film surrounds the first conductive film. The first conductive film serves as a signal line and the second conductive film serves as a conductive shield for the rolled-up transmission line structure.

Fabrication of Crack-Free Barium Titanate Thin Film with High Dielectric Constant Using Sub-Micrometric Scale Layer-by-Layer E-Jet Deposition

PubMed Central

Liang, Junsheng; Li, Pengfei; Wang, Dazhi; Fang, Xu; Ding, Jiahong; Wu, Junxiong; Tang, Chang

2016-01-01

Dense and crack-free barium titanate (BaTiO3, BTO) thin films with a thickness of less than 4 μm were prepared by using sub-micrometric scale, layer-by-layer electrohydrodynamic jet (E-jet) deposition of the suspension ink which is composed of BTO nanopowder and BTO sol. Impacts of the jet height and line-to-line pitch of the deposition on the micro-structure of BTO thin films were investigated. Results show that crack-free BTO thin films can be prepared with 4 mm jet height and 300 μm line-to-line pitch in this work. Dielectric constant of the prepared BTO thin film was recorded as high as 2940 at 1 kHz at room temperature. Meanwhile, low dissipation factor of the BTO thin film of about 8.6% at 1 kHz was also obtained. The layer-by-layer E-jet deposition technique developed in this work has been proved to be a cost-effective, flexible and easy to control approach for the preparation of high-quality solid thin film. PMID:28787860

DUV mask writer for BEOL 90-nm technology layers

NASA Astrophysics Data System (ADS)

Hong, Dongsung; Krishnan, Prakash; Coburn, Dianna; Jeewakhan, Nazneen; Xie, Shengqi; Broussard, Joshua; Ferguson, Bradley; Green, Kent G.; Buck, Peter; Jackson, Curt A.; Martinez, Larry

2003-12-01

Mask CD resolution and uniformity requirements for back end of line (BEOL) layers for the 90nm Technology Node push the capability of I-line mask writers; yet, do not require the capability offered by more expensive 50KeV ebeam mask writers. This suite of mask layers seems to be a perfect match for the capabilities of the DUV mask writing tools, which offer a lower cost option to the 50KeV platforms. This paper will evaluate both the mask and wafer results from all three platforms of mask writers (50KeV VSB,ETEC Alta 4300TM DUV laser and ETEC Alta 3500TM I-line laser) for a Cypress 90nm node Metal 1 layer, and demonstrate the benefits of the DUV platform with no change to OPC for this layer.

Monolithic high voltage nonlinear transmission line fabrication process

DOEpatents

Cooper, Gregory A.

1994-01-01

A process for fabricating sequential inductors and varactor diodes of a monolithic, high voltage, nonlinear, transmission line in GaAs is disclosed. An epitaxially grown laminate is produced by applying a low doped active n-type GaAs layer to an n-plus type GaAs substrate. A heavily doped p-type GaAs layer is applied to the active n-type layer and a heavily doped n-type GaAs layer is applied to the p-type layer. Ohmic contacts are applied to the heavily doped n-type layer where diodes are desired. Multiple layers are then either etched away or Oxygen ion implanted to isolate individual varactor diodes. An insulator is applied between the diodes and a conductive/inductive layer is thereafter applied on top of the insulator layer to complete the process.

Lithology and characteristic of landslide in Gombel Hill by 2D geoelectric resistivity method using dipole-dipole configuration

NASA Astrophysics Data System (ADS)

Setyawan, Agus; Satria Fikri, Muhammad; Endro Suseno, Jatmiko; Fuad, Muhamad

2018-05-01

Gombel hill locates at Semarang, Central Java, Indonesia. Base on Semarang’s susceptiblity map zone, Gombel hill is belong to high susceptibility and instability zone. Instability may cause faults to Gombel hill area, unfortunately the geosciences research in Gombel is still lack. The geophysical survey has been conducted using 2D geoelectric resistivity method with dipole – dipole configuration to identify the lithology of landslide at Gombel hill. The data have been collected from three lines. The first and third line have 100 m length, and the second line have 80 m length with 5 m space in each lines. The data were processed and modelled using Res2Dinv software. From the first line, suspected there are two layers which formed the structure of the subsurface. The second line suspected there are three layers which formed the structure of the subsurface. And the last line suspected there are two layers which formed the structure of the subsurface. Overall, the landslide of Gombel hill area can be found with depth 5 m – 6 m and found at contact between clay and clay rock layer. We expect the results can be used for mitigation hazard and planning the developing infrastructure in Gombel area.

2-Phenoxyethanol as anaesthetic in removing relocating 102 species of fishes representing from Sea World to uShaka Marine World, South Africa.

PubMed

Vaughan, D B; Penning, M R; Christison, K W

2008-09-01

2-Phenoxyethanol was used as an anaesthetic to translocate 102 species of fishes representing 30 families from the Sea World aquarium on Durban's beachfront to uShaka Marine World. Most fishes responded well to a final anaesthetic concentration of 0.150 ml/l and there were no mortalities.

CTD and Bottle Data from Leg 1: 20 December 1986 - 18 January 1987. Leg 2: 17 July - 15 August 1987

DTIC Science & Technology

1989-06-01

tabular data includes pressure, temperature, salinity, oxygen in ml/l and in micro -moles per kilogram, oxygen percent saturation, potential...I f T I T 7 1 1- - -1[ 1 1 1 1 I I IO- -r- Distribution List ARGENTINA FRANCE Alberto Piola Dr. Michele Fieux Armada Argentina, Servicio de

Antigen Loss Variants: Catching Hold of Escaping Foes.

PubMed

Vyas, Maulik; Müller, Rolf; Pogge von Strandmann, Elke

2017-01-01

Since mid-1990s, the field of cancer immunotherapy has seen steady growth and selected immunotherapies are now a routine and preferred therapeutic option of certain malignancies. Both active and passive cancer immunotherapies exploit the fact that tumor cells express specific antigens on the cell surface, thereby mounting an immune response specifically against malignant cells. It is well established that cancer cells typically lose surface antigens following natural or therapy-induced selective pressure and these antigen-loss variants are often the population that causes therapy-resistant relapse. CD19 and CD20 antigen loss in acute lymphocytic leukemia and chronic lymphocytic leukemia, respectively, and lineage switching in leukemia associated with mixed lineage leukemia (MLL) gene rearrangements are well-documented evidences in this regard. Although increasing number of novel immunotherapies are being developed, majority of these do not address the control of antigen loss variants. Here, we review the occurrence of antigen loss variants in leukemia and discuss the therapeutic strategies to tackle the same. We also present an approach of dual-targeting immunoligand effectively retargeting NK cells against antigen loss variants in MLL-associated leukemia. Novel immunotherapies simultaneously targeting more than one tumor antigen certainly hold promise to completely eradicate tumor and prevent therapy-resistant relapses.

Dysregulation of haematopoietic stem cell regulatory programs in acute myeloid leukaemia.

PubMed

Basilico, Silvia; Göttgens, Berthold

2017-07-01

Haematopoietic stem cells (HSC) are situated at the apex of the haematopoietic differentiation hierarchy, ensuring the life-long supply of mature haematopoietic cells and forming a reservoir to replenish the haematopoietic system in case of emergency such as acute blood loss. To maintain a balanced production of all mature lineages and at the same time secure a stem cell reservoir, intricate regulatory programs have evolved to control multi-lineage differentiation and self-renewal in haematopoietic stem and progenitor cells (HSPCs). Leukaemogenic mutations commonly disrupt these regulatory programs causing a block in differentiation with simultaneous enhancement of proliferation. Here, we briefly summarize key aspects of HSPC regulatory programs, and then focus on their disruption by leukaemogenic fusion genes containing the mixed lineage leukaemia (MLL) gene. Using MLL as an example, we explore important questions of wider significance that are still under debate, including the importance of cell of origin, to what extent leukaemia oncogenes impose specific regulatory programs and the relevance of leukaemia stem cells for disease development and prognosis. Finally, we suggest that disruption of stem cell regulatory programs is likely to play an important role in many other pathologies including ageing-associated regenerative failure.

Radionuclide Concentrations in Soils and Vegetation at Low-Level Radioactive Waste Disposal Area G during the 1997 Growing Season

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

L. Naranjo, Jr.; P. R. Fresquez; R. J. Wechsler

1998-08-01

Soil and overstory and understory vegetation (washed and unwashed) collected at eight locations within and around Area G-a low-level radioactive solid-waste disposal facility at Los Alamos National Laboratory-were analyzed for 3H, 238Pu, 239Pu, 137CS, 234U, 235U, 228AC, Be, 214Bi, 60Co, 40& 54Mn, 22Na, 214Pb and 208Tl. In general, most radionuclide concentrations, with the exception of 3Ef and ~9Pu, in soils and overstory and understory vegetation collected from within and around Area G were within upper (95'%) level background concentrations. Although 3H concentrations in vegetation from most sites were significantly higher than background (>2 pCi mL-l), concentrations decreased markedly in comparisonmore » to last year's results. The highest `H concentration in vegetation was detected from a juniper tree that was growing over tritium shaft /+150; it contained 530,000 pCi 3H mL-l. Also, as in the pas~ the transuranic waste pad area contained the highest levels of 239Pu in soils and in understory vegetation as compared to other areas at Area G.« less

SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance.

PubMed

Cruickshank, V Adam; Sroczynska, Patrycja; Sankar, Aditya; Miyagi, Satoru; Rundsten, Carsten Friis; Johansen, Jens Vilstrup; Helin, Kristian

2015-01-01

Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes.

Effects of different feeder layers on culture of bovine embryonic stem cell-like cells in vitro.

PubMed

Cong, Shan; Cao, Guifang; Liu, Dongjun

2014-12-01

To find a suitable feeder layer is important for successful culture conditions of bovine embryonic stem cell-like cells. In this study, expression of pluripotency-related genes OCT4, SOX2 and NANOG in bovine embryonic stem cell-like cells on mouse embryonic fibroblast feeder layers at 1-5 passages were monitored in order to identify the possible reason that bovine embryonic stem cell-like cells could not continue growth and passage. Here, we developed two novel feeder layers, mixed embryonic fibroblast feeder layers of mouse and bovine embryonic fibroblast at different ratios and sources including mouse fibroblast cell lines. The bovine embryonic stem cell-like cells generated in our study displayed typical stem cell morphology and expressed specific markers such as OCT4, stage-specific embryonic antigen 1 and 4, alkaline phosphatase, SOX2, and NANOG mRNA levels. When feeder layers and cell growth factors were removed, the bovine embryonic stem cell-like cells formed embryoid bodies in a suspension culture. Furthermore, we compared the expression of the pluripotent markers during bovine embryonic stem cell-like cell in culture on mixed embryonic fibroblast feeder layers, including mouse fibroblast cell lines feeder layers and mouse embryonic fibroblast feeder layers by real-time quantitative polymerase chain reaction. Results suggested that mixed embryonic fibroblast and sources including mouse fibroblast cell lines feeder layers were more suitable for long-term culture and growth of bovine embryonic stem cell-like cells than mouse embryonic fibroblast feeder layers. The findings may provide useful experimental data for the establishment of an appropriate culture system for bovine embryonic stem cell lines.

Development, Characterization, and Pluripotency Analysis of Buffalo (Bubalus bubalis) Embryonic Stem Cell Lines Derived from In Vitro–Fertilized, Hand-Guided Cloned, and Parthenogenetic Embryos

PubMed Central

Shah, Syed Mohmad; Saini, Neha; Ashraf, Syma; Zandi, Mohammad; Manik, Radhey Sham; Singla, Suresh Kumar; Palta, Prabhat

2015-01-01

Abstract We present the derivation, characterization, and pluripotency analysis of three buffalo embryonic stem cell (buESC) lines, from in vitro–fertilized, somatic cell nuclear–transferred, and parthenogenetic blastocysts. These cell lines were developed for later differentiation into germ lineage cells and elucidation of the signaling pathways involved. The cell lines were established from inner cell masses (ICMs) that were isolated manually from the in vitro–produced blastocysts. Most of the ICMs (45–55%) resulted in formation of primary colonies that were subcultured after 8–10 days, leading subsequently to the formation of three buESC lines, one from each blastocyst type. All the cell lines expressed stem cell markers, such as Alkaline Phosphatase, OCT4, NANOG, SSEA1, SSEA4, TRA-1-60, TRA-1-81, SOX2, REX1, CD-90, STAT3, and TELOMERASE. They differentiated into all three germ layers as determined by ectodermal, mesodermal, and endodermal RNA and protein markers. All of the cell lines showed equal expression of pluripotency markers as well as equivalent differentiation potential into all the three germ layers. The static suspension culture–derived embryoid bodies (EBs) showed greater expression of all the three germ layer markers as compared to hanging drop culture–derived EBs. When analyzed for germ layer marker expression, EBs derived from 15% fetal bovine serum (FBS)-based spontaneous differentiation medium showed greater differentiation across all the three germ layers as compared to those derived from Knock-Out Serum Replacement (KoSR)-based differentiation medium. PMID:26168169

Pomegranate polyphenols and extract inhibit nuclear factor of activated T-cell activity and microglial activation in vitro and in a transgenic mouse model of Alzheimer disease.

PubMed

Rojanathammanee, Lalida; Puig, Kendra L; Combs, Colin K

2013-05-01

Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 mo followed by repeat Barnes maze testing for both groups. Three months of pomegranate feeding decreased the path length to escape of mice compared with their initial 12-mo values (P < 0.05) and their control-fed counterparts (P < 0.05). Brains of the 3-mo study pomegranate-fed mice had lower tumor necrosis factor α (TNF-α) concentrations (P < 0.05) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity (P < 0.05) compared with controls. Brains of the 3-mo pomegranate or control mice were also compared with an additional control group of 12-mo-old mice for histologic analysis. Immunocytochemistry showed that pomegranate- but not control-fed mice had attenuated microgliosis (P < 0.05) and Aβ plaque deposition (P < 0.05) compared with 12-mo-old mice. An additional behavioral study again used 12-mo-old male APP/PS1 mice tested by T-maze followed by division into a control group provided with free access to normal chow and sugar supplemented drinking water or a treatment group provided with normal chow and pomegranate extract-supplemented drinking water (6.25 mL/L) for 1 mo followed by repeat T-maze testing in both groups. One month of pomegranate feeding increased spontaneous alternations versus control-fed mice (P < 0.05). Cell culture experiments verified that 2 polyphenol components of pomegranate extract, punicalagin and ellagic acid, attenuated NFAT activity in a reporter cell line (P < 0.05) and decreased Aβ-stimulated TNF-α secretion by murine microglia (P < 0.05). These data indicate that dietary pomegranate produces brain antiinflammatory effects that may attenuate AD progression.

Pomegranate Polyphenols and Extract Inhibit Nuclear Factor of Activated T-Cell Activity and Microglial Activation In Vitro and in a Transgenic Mouse Model of Alzheimer Disease123

PubMed Central

Rojanathammanee, Lalida; Puig, Kendra L.; Combs, Colin K.

2013-01-01

Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 mo followed by repeat Barnes maze testing for both groups. Three months of pomegranate feeding decreased the path length to escape of mice compared with their initial 12-mo values (P < 0.05) and their control-fed counterparts (P < 0.05). Brains of the 3-mo study pomegranate-fed mice had lower tumor necrosis factor α (TNF-α) concentrations (P < 0.05) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity (P < 0.05) compared with controls. Brains of the 3-mo pomegranate or control mice were also compared with an additional control group of 12-mo-old mice for histologic analysis. Immunocytochemistry showed that pomegranate- but not control-fed mice had attenuated microgliosis (P < 0.05) and Aβ plaque deposition (P < 0.05) compared with 12-mo-old mice. An additional behavioral study again used 12-mo-old male APP/PS1 mice tested by T-maze followed by division into a control group provided with free access to normal chow and sugar supplemented drinking water or a treatment group provided with normal chow and pomegranate extract–supplemented drinking water (6.25 mL/L) for 1 mo followed by repeat T-maze testing in both groups. One month of pomegranate feeding increased spontaneous alternations versus control-fed mice (P < 0.05). Cell culture experiments verified that 2 polyphenol components of pomegranate extract, punicalagin and ellagic acid, attenuated NFAT activity in a reporter cell line (P < 0.05) and decreased Aβ-stimulated TNF-α secretion by murine microglia (P < 0.05). These data indicate that dietary pomegranate produces brain antiinflammatory effects that may attenuate AD progression. PMID:23468550

Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy.

PubMed

Picaud, Sarah; Fedorov, Oleg; Thanasopoulou, Angeliki; Leonards, Katharina; Jones, Katherine; Meier, Julia; Olzscha, Heidi; Monteiro, Octovia; Martin, Sarah; Philpott, Martin; Tumber, Anthony; Filippakopoulos, Panagis; Yapp, Clarence; Wells, Christopher; Che, Ka Hing; Bannister, Andrew; Robson, Samuel; Kumar, Umesh; Parr, Nigel; Lee, Kevin; Lugo, Dave; Jeffrey, Philip; Taylor, Simon; Vecellio, Matteo L; Bountra, Chas; Brennan, Paul E; O'Mahony, Alison; Velichko, Sharlene; Müller, Susanne; Hay, Duncan; Daniels, Danette L; Urh, Marjeta; La Thangue, Nicholas B; Kouzarides, Tony; Prinjha, Rab; Schwaller, Jürg; Knapp, Stefan

2015-12-01

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9(+) acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. ©2015 American Association for Cancer Research.

Generation of a selective small molecule inhibitor of the CBP/p300 bromodomain for leukemia therapy

PubMed Central

Jones, Katherine; Meier, Julia; Olzscha, Heidi; Monteiro, Octovia; Martin, Sarah; Philpott, Martin; Tumber, Anthony; Filippakopoulos, Panagis; Yapp, Clarence; Wells, Christopher; Che, Ka Hing; Bannister, Andrew; Robson, Samuel; Kumar, Umesh; Parr, Nigel; Lee, Kevin; Lugo, Dave; Jeffrey, Philip; Taylor, Simon; Vecellio, Matteo L.; Bountra, Chas; Brennan, Paul E.; O’Mahony, Alison; Velichko, Sharlene; Müller, Susanne; Hay, Duncan; Daniels, Danette L.; Urh, Marjeta; La Thangue, Nicholas B.; Kouzarides, Tony; Prinjha, Rab; Schwaller, Jürg; Knapp, Stefan

2016-01-01

The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein-protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ AML cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. PMID:26552700

Monolithic high voltage nonlinear transmission line fabrication process

DOEpatents

Cooper, G.A.

1994-10-04

A process for fabricating sequential inductors and varistor diodes of a monolithic, high voltage, nonlinear, transmission line in GaAs is disclosed. An epitaxially grown laminate is produced by applying a low doped active n-type GaAs layer to an n-plus type GaAs substrate. A heavily doped p-type GaAs layer is applied to the active n-type layer and a heavily doped n-type GaAs layer is applied to the p-type layer. Ohmic contacts are applied to the heavily doped n-type layer where diodes are desired. Multiple layers are then either etched away or Oxygen ion implanted to isolate individual varistor diodes. An insulator is applied between the diodes and a conductive/inductive layer is thereafter applied on top of the insulator layer to complete the process. 6 figs.

Deep ventilation process in Patagonian fjord, Chile

NASA Astrophysics Data System (ADS)

Pérez-Santos, Iván; Silvan, Nelson; Castillo, Manuel; Mayorga, Nicolas; Schneider, Wolfgang; Montero, Paulina; Daneri, Giovanni; Valle-Levinson, Arnoldo; Pizarro, Oscar; Ramirez, Nadín; Igor, Gabriela; Navarro, Eduardo

2017-04-01

The Puyuhuapi Fjord (44.6° S) has previously been reported as one of the hypoxic fjords in Chilean Patagonia (dissolved oxygen -DO below 2 mL L-1). Hydrographic sampling between 1995-2016 confirmed hypoxia below 100 m depth, down to the bottom (250 m). A line of sensors at an oceanographic mooring in Puyuhuapi were deployed to continuously record the temporal-vertical behaviour of water column temperature and salinity from the surface down to 120 m, from February to July 2015. A multi-Parameter water quality sonde was deployed at the bottom of the line, with a DO optical sensor. From February to mid-May, hypoxia was sustained (1.4-1.6 mL L-1). However, from May until the end of June, DO values increased (2.8 mL L-1), exceeding the hypoxia threshold. This was the first event of deep ventilation reported in a Chilean Patagonian Fjord. During this time period, deep water temperatures increased by 1.3 °C, coinciding with the decreased in salinity from 33.6 to 32.8. The main cause of this event was attributed to the arrival of a new volume of mixed oceanic water into the fjord, transported by Modified Subantartic Water, with warm temperatures, lower salinities and slightly higher DO values, given its origin in the surface layer of the outer oceanic region. A new experiment was carried out during January-November, 2016 in order to corroborate the ventilation process and its connection with the adjacent ocean. Temperature, salinity and DO sensors were deployed in the outside fjords region close to the ocean (Melinka Channel) and in Puyuhuapi Fjord, to record the data at very high temporal resolution. The distance between both stations was 150 km. In the oceanic mooring the DO time series collected at 150 m depth showed hypoxia in summer related to the position of the Equatorial Sub-surface water, but from fall DO started to increase registering high values in August and September (4-5 mL/L) when the Subantartic Water arrive. The DO records in Puyuhuapi at 120 m showed a similar behaviour but with lower magnitude, confirmed the 2015 results. Winds and internal wave, registered with acoustic current profilers, contributed to this connection. The deep ventilation recorded in Patagonian Fjords would be helping to maintain their environmental health avoiding dead zones due to the increasing input of organic matter from salmon aquaculture.

Investigation of the Influence of Heat Balance Shifts on the Freeze Microstructure and Composition in Aluminum Smelting Bath System: Cryolite-CaF2-AlF3-Al2O3

NASA Astrophysics Data System (ADS)

Liu, Jingjing; Fallah-Mehrjardi, Ata; Shishin, Denis; Jak, Evgueni; Dorreen, Mark; Taylor, Mark

2017-12-01

In an aluminum electrolysis cell, the side ledge forms on side walls to protect it from the corrosive cryolitic bath. In this study, a series of laboratory analogue experiments have been carried out to investigate the microstructure and composition of side ledge (freeze linings) at different heat balance steady states. Three distinct layers are found in the freeze linings formed in the designed Cryolite-CaF2-AlF3-Al2O3 electrolyte system: a closed (columnar) crystalline layer, an open crystalline layer, and a sealing layer. This layered structure changes when the heat balance is shifted between different steady states, by melting or freezing the open crystalline layer. Phase chemistry of the freeze lining is studied in this paper to understand the side ledge formation process upon heat balance shifts. Electron probe X-ray microanalysis (EPMA) is used to characterize the microstructure and compositions of distinct phases existing in the freeze linings, which are identified as cryolite, chiolite, Ca-cryolite, and alumina. A freeze formation mechanism is further developed based on these microstructural/compositional investigations and also thermodynamic calculations through the software—FactSage. It is found that entrapped liquid channels exist in the open crystalline layer, assisting with the mass transfer between solidified crystals and bulk molten bath.

Carbon and nitrogen abundances determined from transition layer lines

NASA Technical Reports Server (NTRS)

Boehm-Vitense, Erika; Mena-Werth, Jose

1992-01-01

The possibility of determining relative carbon, nitrogen, and silicon abundances from the emission-line fluxes in the lower transition layers between stellar chromospheres and coronae is explored. Observations for main-sequence and luminosity class IV stars with presumably solar element abundances show that for the lower transition layers Em = BT sup -gamma. For a given carbon abundance the constants gamma and B in this relation can be determined from the C II and C IV emission-line fluxes. From the N V and S IV lines, the abundances of these elements relative to carbon can be determined from their surface emission-line fluxes. Ratios of N/C abundances determined in this way for some giants and supergiants agree within the limits of errors with those determined from molecular bands. For giants, an increase in the ratio of N/C at B-V of about 0.8 is found, as expected theoretically.

Modeling of Ice Flow and Internal Layers Along a Flow Line Through Swiss Camp in West Greenland

NASA Technical Reports Server (NTRS)

Wang, W. L.; Zwally, H. Jay; Abdalati, W.; Luo, S.; Koblinsky, Chester J. (Technical Monitor)

2001-01-01

An anisotropic ice flow line model is applied to a flow line through Swiss Camp (69.57 N, 49.28 W) in West Greenland to estimate the dates of internal layers detected by Radio-Echo Sounding measurements. The effect of an anisotropic ice fabric on ice flow is incorporated into the steady state flow line model. The stress-strain rate relationship for anisotropic ice is characterized by an enhancement factor based on the laboratory observations of ice deformation under combined compression and shear stresses. By using present-day data of accumulation rate, surface temperature, surface elevation and ice thickness along the flow line as model inputs, a very close agreement is found between the isochrones generated from the model and the observed internal layers with confirmed dates. The results indicate that this part of Greenland ice sheet is primarily in steady state.

Response of the solar atmosphere to a simple flare burst: UV emission from the flare transition layer.

NASA Astrophysics Data System (ADS)

Shmeleva, O. P.

The flare transition layer exists as a relatively steady formation even during impulsive heating. It is maintained by a heat flow from the high-temperature plasma, where the major part of the electron beam energy is absorbed. The lifetime of this plasma is much greater than the impulsive heating time. Intensities of resonance UV lines are calculated using both the model of impulsive nonthermal heating by energetic electrons and the model of continuous thermal heating. The calculated line intensity is almost constant during a long time. The line Doppler shifts predicted by the former model match observations. This suggests that the model represents sufficiently well the actual dynamics of the flare plasma. The flare transition layer is a thin formation, its thickness being Δξ = 1021m-2. It is therefore described adequately within the p = const approximation though the picture of hydrodynamic response of the solar atmosphere to the impulsive heating by energy flows is rather complicated and nonsteady, of course. The intensities of the C IV λλ154.8, 155.1 nm and O VI λλ103.2, 103.8 nm lines are calculated within the scope of the model of continuous thermal heating, in which the conductive heating of the flare transition layer is balanced by radiative cooling. The line intensities are proportional to the pressure in the layer, which permits the pressure to be found from the observed line intensities. The analysis reveals that both heating models adequately represent the actual structure and dynamics of plasma in a flare. In the flare transition layer, the classical heat conduction always does work.

A User’s Manual for Fiber Diffraction: The Automated Picker and Huber Diffractometers

DTIC Science & Technology

1990-07-01

17 3. Layer line scan of degummed silk ( Bombyx mori ) ................................. 18...index (arbitrary units) Figure 3. Layer line scan of degummed silk ( Bombyx mori ) showing layers 0 through 6. If the fit is rejected, new values for... originally made at intervals larger than 0.010. The smoothing and interpolation is done by a least-squares polynomial fit to segments of the data. The number

Frequency Characteristics of the MAGLEV Double-layered Propulsion Coil

NASA Astrophysics Data System (ADS)

Ema, Satoshi

The MAGLEV (magnetically levitated vehicle) is now well along in development testing at Yamanashi Test Line. The MAGLEV power source needs to supply a variable voltage and variable frequency to propulsion coils, which installed on outdoor guideway. The output voltage of the electric power converter contains many higher harmonics, which causes many troubles such as inductive interference. Accordingly, it is necessary to clarify the frequency characteristics of the propulsion coils and the power feeding circuit. In view of this situation, experiments and the theoretical analysis concerning the frequency characteristics of the propulsion coils with single-layer arrangement and the power feeding circuit at Miyazaki Test Line had been performed by the author. But the arrangement of the propulsion coils had been changed in Yamanashi Test Line from the single-layered coils to the double-layered coils for the stability of the super-conducting magnet on board. Thus, experiments and investigations concerning the frequency characteristics(resonance characteristics)of the propulsion coils with double-layer arrangement at Yamanashi Test Line have been performed but a theoretical analysis had not been done enough. A theoretical analysis was therefore done in this paper by applying the inverted L equivalent circuit with mutual inductance and capacitance to the propulsion coil, from which the positive and zero phase characteristics of the double-layered propulsion coils were analyzed.

On the Formation of Planetesimals: Radial Contraction of the Dust Layer Interacting with the Protoplanetary Disk Gas

NASA Astrophysics Data System (ADS)

Makalkin, A. B.; Artyushkova, M. E.

2017-11-01

Radial contraction of the dust layer in the midplane of a gas-dust protoplanetary disk that consists of large dust aggregates is modeled. Sizes of aggregates vary from centimeters to meters assuming the monodispersion of the layer. The highly nonlinear continuity equation for the solid phase of the dust layer is solved numerically. The purpose of the study is to identify the conditions under which the solid matter is accumulated in the layer, which contributes to the formation of planetesimals as a result of gravitational instability of the dust phase of the layer. We consider the collective interaction of the layer with the surrounding gas of the protoplanetary disk: shear stresses act on the gas in the dust layer that has a higher orbital velocity than the gas outside the layer, this leads to a loss of angular momentum and a radial drift of the layer. The stress magnitude is determined by the turbulent viscosity, which is represented as the sum of the α-viscosity associated with global turbulence in the disk and the viscosity associated with turbulence that is localized in a thin equatorial region comprising the dust layer and is caused by the Kelvin-Helmholtz instability. The evaporation of water ice and the continuity of the mass flux of the nonvolatile component on the ice line is also taken into account. It is shown that the accumulation of solid matter on either side of the ice line and in other regions of the disk is determined primarily by the ratio of the radii of dust aggregates on either side of the ice line. If after the ice evaporation the sizes (or density) of dust aggregates decrease by an order of magnitude or more, the density of the solid phase of the layer's matter in the annular zone adjacent to the ice line from the inside increases sharply. If, however, the sizes of the aggregates on the inner side of the ice line are only a few times smaller than behind the ice line, then in the same zone there is a deficit of mass at the place of the modern asteroid belt. We have obtained constraints on the parameters at which the layer compaction is possible: the global turbulence viscosity parameter (α < 10-5), the initial radial distribution of the surface density of the dust layer, and the distribution of the gas surface density in the disk. Restrictions on the surface density depend on the size of dust aggregates. It is shown that the timescale of radial contraction of a dust layer consisting of meter-sized bodies is two orders of magnitude and that of decimeter ones, an order of magnitude greater than the timescale of the radial drift of individual particles if there is no dust layer.

Improvements of mechanical fatigue reliability of Cu interconnects on flexible substrates through MoTi alloy under-layer

NASA Astrophysics Data System (ADS)

Lee, Young-Joo; Shin, Hae-A.-Seul; Nam, Dae-Hyun; Yeon, Han-Wool; Nam, Boae; Woo, Kyoohee; Joo, Young-Chang

2015-01-01

The mechanical fatigue of Cu films and lines on flexible substrates was investigated, and an improvement in the structures through the use of a MoTi alloy under-layer was proposed. Fatigue reliability was decreased by 3-fold in lines compared with films in the tensile condition and by 6-fold in the compressive condition. Crack formation was observed to be more detrimental for lines than for films. With a MoTi under-layer, the fatigue limit was increased by 2 times that of a structure without MoTi in the tensile condition and by 15 times in the compressive bending condition. The suppression of delamination through the use of a MoTi under-layer improved the fatigue reliability under compressive bending.

Optical emission spectroscopy of point-plane corona and back-corona discharges in air

NASA Astrophysics Data System (ADS)

Czech, T.; Sobczyk, A. T.; Jaworek, A.

2011-12-01

Results of spectroscopic investigations and current-voltage characteristics of corona discharge and back discharge on fly-ash layer, generated in point-plane electrode geometry in air at atmospheric pressure are presented in the paper. The characteristics of both discharges are similar but differ in the current and voltage ranges of all the discharge forms distinguished during the experiments. Three forms of back discharge, for positive and negative polarity, were investigated: glow, streamer and low-current back-arc. In order to characterize ionisation and excitation processes in back discharge, the emission spectra were measured and compared with those obtained for normal corona discharge generated in the same electrode configuration but with fly ash layer removed. The emission spectra were measured in two discharge zones: near the tip of needle electrode and near the plate. Visual forms of the discharge were recorded with digital camera and referred to current-voltage characteristics and emission spectra. The measurements have shown that spectral lines emitted by back discharge depend on the form of discharge and the discharge current. From the comparison of the spectral lines of back and normal discharges an effect of fly ash layer on the discharge morphology can be determined. The recorded emission spectra formed by ionised gas and plasma near the needle electrode and fly ash layer are different. It should be noted that in back arc emission, spectral lines of fly ash layer components can be distinguished. On the other hand, in needle zone, the emission of high intensity N2 second positive system and NO γ lines can be noticed. Regardless of these gaseous lines, also atomic lines of dust layer were present in the spectrum. The differences in spectra of back discharge for positive and negative polarities of the needle electrode have been explained by considering the kind of ions generated in the crater in fly ash layer. The aim of these studies is to better understand the discharge processes encountered in electrostatic precipitators.

The Few and the Proud: Veterans in Congress on Defense Issues

DTIC Science & Technology

2013-04-15

defense spending cuts and increased support for the war in Afghanistan among veterans in Congress. 15. SUBJECT TERMS civil-military gap; veterans in...Mll..ITARY STUDIES TITLE: The Few and the Proud: Veterans in Congress on Defense Issues SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR ... the civil-military gap, leading to less backing for legislation supporting defense and veterans’ issues due to ignorance

Nearshore Sea Clutter Measurements from a Fixed Platform

DTIC Science & Technology

2012-04-01

Water (MLL W) datum. 7. GPS Two differential GPS units, Magellan ProMark 3.0, were utilized to determine precise differences in position between the...8 Figure 8. (a) Trihedral configuration on the small boat and position of the GPS and IMU sensors. (b) Profile view of...SIO Miniature Directional Wave Buoys The Scripps Institution of Oceanography designs and manufactures GPS -based miniature directional wave buoys

DNA Damage Repair Factors have a Tumor Promoting Role in MLL-fusion Leukemia | Center for Cancer Research

Cancer.gov

Cancers develop when cells accumulate DNA mutations that allow them to grow and divide inappropriately. Thus, proteins involved in repairing DNA damage are generally suppressors of cancer formation, and their expression is often lost in the early stages of cancer initiation. In contrast, cancer stem cells, like their normal counterparts, must retain their ability to

U.S. EPA, Pesticide Product Label, HILO FLEA AND TICK SPRAY II, 09/12/1991

EPA Pesticide Factsheets

2011-04-14

... "r mit" wlll'lI 1l1'I'Ivlnll pI"I"h • .-I. AI"w 1"·lIlr.1 "1111,,,"' I" Ih"'''"llhlv .h·V 101'1".1' "" I "R. R"mllVl' .1t'1" 11111' hi ... ". ... ll\\lllt hi,' iU, lIIH"'n~l iO\\l~ 'lf~1 ~nn. ...

Distribution of the deep-sea genus Bathypterois (Pisces: Ipnopidae) in the Eastern Central Pacific.

PubMed

Cruz-Acevedo, Edgar; Betancourt-Lozano, Miguel; Aguirre-Villaseñor, Hugo

2017-03-01

The genus Bathypterois (tripod fish) comprises 19 species of deep-sea fishes distributed worldwide. The biology and distribution of the species of this genus are relatively poorly known throughout the Eastern Central Pacific (ECP). This work aims to update the geographic and bathymetric distribution of species of Bathypterois throughout the ECP. To describe the influence of depth, temperature and dissolved oxygen concentrations (DO) on latitudinal and depth distribution of members of the genus throughout the Mexican Pacific, 51 specimens of B. atricolor (12 trawls) and 112 of B. ventralis (18 trawls), collected during TALUD project, were analyzed. Bathypterois atricolor had broader environmental niches (depth: 0.47, temperature: 0.46, DO: 0.39), and inhabits deeper and colder sites (Electivity positives: > 1 000 m, < 3.2 °C, 1.0-1.62 mL/L) than B. ventralis, which had narrow environmental niches (depth: 0.34, temperature: 0.32, DO: 0.28), with high affinity to warmer sites and lower DO concentrations (Electivity positives: 778-1 400 m, 3.3-5.8 °C, < 1.0 mL/L). Both species used different environmental strata (niche overlap; depth: 0.34, temperature: 0.32, DO: 0.28). The adaptation of B. atricolor to live in a broad range of DO concentrations explains its almost circumglobal distribution, while B. ventralis lives almost permanently in the Oxygen Minimum Zone (< 0.05 mL/L), so the DO could be a limiting factor, reducing its potential geographic and bathymetric distributions. None of these species had been previously recorded in the central Gulf of California, and B. ventralis had not been recorded along the West coast of Baja California. This study confirms that both species have a continuous distribution within the ECP, our new records extended the known northernmost range for B. atricolor by 886 km (from 22°46' N to 30°45’ N) and for B. ventralis by 645 km (from 21°18’ N to 27°07’ N).

Mutational landscape of goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix is distinct from typical carcinoids and colorectal adenocarcinomas.

PubMed

Johncilla, Melanie; Stachler, Matthew; Misdraji, Joseph; Lisovsky, Mikhail; Yozu, Masato; Lindeman, Neal; Lauwers, Gregory Y; Odze, Robert D; Srivastava, Amitabh

2018-02-08

There is limited data on the spectrum of molecular alterations in goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids of the appendix. We used next generation sequencing to determine mutations of potential pathogenetic and therapeutic significance in this rare group of tumors. Adequate DNA was successfully extracted in 34/46 cases and the final group included 18 goblet cell carcinoids and 16 adenocarcinoma ex goblet cell carcinoids. Illumina TruSeq™ was used for sequencing exons of a custom 282 gene panel using an Illumina HiSeq 2000. All cases had a minimum coverage depth of at least 50 reads. After filtering through the Exome Sequencing Project, the number of mutations per case ranged from 0-9 (mean:3). The mutational burden in adenocarcinoma ex goblet cell carcinoids was significantly higher than goblet cell carcinoids (mean 5 vs. 3; p < 0.05) but the spectrum of alterations overlapped between the two groups. The most frequent mutations included ARID1A (4/34), ARID2 (4/34), CDH1 (4/34), RHPN2 (4/34), and MLL2 (3/34). Some mutations typically seen in conventional colorectal adenocarcinomas were also identified but with much lower frequency (APC :4/34; KRAS :2/34). MLL2 and KRAS mutations were only seen in adenocarcinoma ex goblet cell carcinoids and TP53 mutations were limited to poorly differentiated adenocarcinoma ex goblet cell carcinoids (2/34). Copy number changes could be evaluated in 15/34 cases and showed low copy number gains in CDKN1B (6/15) and NFKBIA (6/15), among others. The overlapping molecular alterations suggest that goblet cell carcinoids and adenocarcinoma ex goblet cell carcinoids are best considered two grades of differentiation of the same tumor rather than two distinct histological types. Mutations in TP53, CDH1 and MLL2 mutations were predominantly present in the adenocarcinoma ex goblet cell carcinoid group consistent with transformation to a higher grade lesion. The unique mutational profile also offers an explanation for the poor chemosensitivity in these tumors and highlights the need for developing new targeted therapies.

[THE COMPARISON OF RESULTS OF DETECTION OF MINIMAL RESIDUAL DISEASE IN PERIPHERAL BLOOD AND MARROW IN CHILDREN OF THE FIRST YEAR OF LIFE WITH ACUTE LYMPHOBLASTIC LEUCOSIS].

PubMed

Tsaur, G A; Riger, T O; Popov, A M; Nasedkina, T V; Kustanovich, A M; Solodovnikov, A G; Streneva, O V; Shorikov, E V; Tsvirenko, S V; Saveliev, L I; Fechina, L G

2015-04-01

The occurrence of minimal residual disease is an important prognostic factor under acute lymphoblastic leucosis in children and adults. In overwhelming majority of research studies bone marrow is used to detect minimal residual disease. The comparative characteristic of detection of minimal residual disease in peripheral blood and bone marrow was carried out. The prognostic role of occurrence of minimal residual disease in peripheral blood and bone marrow under therapy according protocol MLL-Baby was evaluated. The analysis embraced 142 pair samples from 53 patients with acute lymphoblastic leucosis and various displacements of gene MLL younger than 365 days. The minimal residual disease was detected by force of identification of chimeric transcripts using polymerase chain reaction in real-time mode in 7 sequential points of observation established by protocol of therapy. The comparability of results of qualitative detection of minimal residual disease in bone marrow and peripheral blood amounted to 84.5%. At that, in all 22 (15.5%) discordant samples minimal residual disease was detected only in bone marrow. Despite of high level of comparability of results of detection of minimal residual disease in peripheral blood and bone marrow the occurrence of minimal residual disease in peripheral blood at various stages of therapy demonstrated no independent prognostic significance. The established differences had no relationship with sensitivity of method determined by value of absolute expression of gene ABL. Most likely, these differences reflected real distribution of tumor cells. The results of study demonstrated that application of peripheral blood instead of bone marrow for monitoring of minimal residual disease under acute lymphoblastic leucosis in children of first year of life is inappropriate. At the same time, retention of minimal residual disease in TH4 in bone marrow was an independent and prognostic unfavorable factor under therapy of acute lymphoblastic leucosis of children of first year of life according protocol MLL-Baby (OO=7.326, confidence interval 2.378-22.565).

Si III OV Bright Line of Scattering Polarized Light That Has Been Observed in the CLASP and Its Center-to-Limb Variation

NASA Technical Reports Server (NTRS)

Katsukawa, Yukio; Ishikawa, Ryoko; Kano, Ryohei; Kubo, Masahito; Noriyuki, Narukage; Kisei, Bando; Hara, Hirohisa; Yoshiho, Suematsu; Goto, Motouji; Ishikawa, Shinnosuke;

Emission lines in the long period Cepheid l Carinae

NASA Technical Reports Server (NTRS)

Boehm-Vitense, Erika; Love, Stanley G.

1991-01-01

For the Cepheid (l) Carinae with a pulsation period of 35.5 days we have studied the emission line fluxes as a function of pulsational phase in order to find out whether we see chromosphere and transition layer emission or whether we see emission due to an outward moving shock. All emission lines show a steep increase in flux shortly before maximum light suggestive of a shock moving through the surface layers. The large ratio of the C IV to C II line fluxes shows that these are not transition layer lines. During maximum light the large ratio of the C IV to C II line fluxes also suggests that we see emission from a shock with velocities greater than 100 km/sec such that C IV emission can be excited. With such velocities mass outflow appears possible. The variations seen in the Mg II line profiles show that there is an internal absorption over a broad velocity band independent of the pulsational phase. We attribute this absorption to a circumstellar 'shell'. This 'shell' appears to be seen also as spatially extended emission in the O I line at 1300 angstrom, which is probably excited by resonance with Ly beta.

ISO ammonia line absorption reveals a layer of hot gas veiling Sgr B2

NASA Astrophysics Data System (ADS)

Ceccarelli, C.; Baluteau, J.-P.; Walmsley, M.; Swinyard, B. M.; Caux, E.; Sidher, S. D.; Cox, P.; Gry, C.; Kessler, M.; Prusti, T.

2002-02-01

We report the first results of the unbiased spectral high resolution survey obtained towards Sgr B2 with the Long Wavelength Spectrometer on board ISO. The survey detected more than one hundreds lines from several molecules. Ammonia is the molecule with the largest number (21) of detected lines in the survey. We detected NH3 transitions from levels with energies from 45 to 500 cm-1. The detected transitions are from both para and ortho ammonia and metastable and non-metastable levels. All the ammonia lines are in absortion against the FIR continuum of Sgr B2. With such a large number of detected lines in such a large range of energy levels, we could very efficiently constrain the main parameters of the absorbing gas layer. The gas is at (700 +/- 100) K and has a density lower than 104 cm-3. The total NH3 column density in the layer is (3+/- 1) x 1016 cm-2, equally shared between ortho and para ammonia. Given the derived relatively high gas temperature and ammonia column density, our observations support the hypothesis previously proposed of a layer of shocked gas between us and Sgr B2. We also discuss previous observations of far infrared line absorption from other molecules, like H2O and HF, in the light of this hot absorbing layer. If the absorption is done by the hot absorbing layer rather than by the warm envelope surrounding Sgr B2, as was previously supposed in order to interpret the mentioned observations, the derived H2O and HF abundances are one order of magitude larger than previously estimated. Yet, the present H2O and HF observations do not allow one to disentangle the absorption from the hot layer against the warm envelope. Our conclusions are hence that care should be applied when interpreting the absorption observations in Sgr B2, as the hot layer clearly seen in the ammonia transitions may substantially contribute to the absorption. ISO is an ESA project with instruments funded by ESA Member States (especially the PI countries: France, Germany, The Netherlands and the United Kingdom) and with the participation of ISAS and NASA.

Free and bound excitons in thin wurtzite GaN layers on sapphire

NASA Astrophysics Data System (ADS)

Merz, C.; Kunzer, M.; Kaufmann, U.; Akasaki, I.; Amano, H.

1996-05-01

Free and bound excitons have been studied by photoluminescence in thin (0268-1242/11/5/010/img8) wurtzite-undoped GaN, n-type GaN:Si as well as p-type GaN:Mg and GaN:Zn layers grown by metal-organic chemical vapour phase deposition (MOCVD). An accurate value for the free A exciton binding energy and an estimate for the isotropically averaged hole mass of the uppermost 0268-1242/11/5/010/img9 valence band are deduced from the data on undoped samples. The acceptor-doped samples reveal recombination lines which are attributed to excitons bound to 0268-1242/11/5/010/img10 and 0268-1242/11/5/010/img11 respectively. These lines are spectrally clearly separated and the exciton localization energies are in line with Haynes' rule. Whenever a comparison is possible, it is found that the exciton lines in these thin MOCVD layers are ultraviolet-shifted by 20 to 25 meV as compared to quasi-bulk (0268-1242/11/5/010/img12) samples. This effect is interpreted in terms of the compressive hydrostatic stress component which thin GaN layers experience when grown on sapphire with an AlN buffer layer.

RF tuning element

NASA Technical Reports Server (NTRS)

McGrath, William R. (Inventor); Lubecke, Victor M. (Inventor)

1992-01-01

A device for tuning a circuit includes a substrate, a transmission line on the substrate that includes first and second conductors coupled to a circuit to be tuned, and a movable short-circuit for varying the impedance the transmission line presents to the circuit to be tuned. The movable short-circuit includes a dielectric layer disposed atop the transmission line and a distributed shorting element in the form of a conductive member that is configured to be slid along at least a portion of the transmission line atop the dielectric layer. The conductive member is configured to span the first and second conductors of the transmission line and to define at least a first opening that spans the two conductors so that the conductive member includes first and second sections separated by the first opening. The first and second sections of the conductive member combine with the first and second conductors of the transmission line to form first and second low impedance sections of transmission line, and the opening combines with the first and second conductors of the transmission line and the dielectric layer to form a first high impedance section of transmission line intermediate the first and second low impedance sections. Each of the first low impedance section and the first high impedance section have a length along the transmission line of approximately one-quarter wavelength, thus providing a periodic variation of transmission line impedance. That enhances reflection of rf power.

Choroidal Haller's and Sattler's Layers Thickness in Normal Indian Eyes.

PubMed

Roy, Rupak; Saurabh, Kumar; Vyas, Chinmayi; Deshmukh, Kaustubh; Sharma, Preeti; Chandrasekharan, Dhileesh P; Bansal, Aditya

2018-01-01

This study aims to study normative choroidal thickness (CT) and Haller's and Sattler's layers thickness in normal Indian eyes. The choroidal imaging of 73 eyes of 43 healthy Indian individuals was done using enhanced depth imaging feature of spectralis optical coherence tomography. Rraster scan protocol centered at fovea was used for imaging separately by two observers. CT was defined as the length of the perpendicular line drown from the outer border of hypereflective RPE-Bruch's complex to inner margin of choroidoscleral junction. Choroidal vessel layer thickness was measured after defining a largest choroidal vessel lumen within 750 μ on either side of the subfoveal CT vector. A perpendicular line was drawn to the innermost border of this lumen, and the distance between the perpendicular line and innermost border of choroidoscleral junction gave large choroidal vessel layer thickness (LCVLT, Haller's layer). Medium choroidal vessel layer thickness (MCVLT, Sattler's layer) was measured as the distance between same perpendicular line and outer border of hypereflective RPE-Bruch's complex. The mean age of individuals was 28.23 ± 15.29 years (range 14-59 years). Overall, the mean subfoveal CT was 331.6 ± 63.9 μ. Mean LCVLT was 227.08 ± 51.24 μ and the mean MCVLT was 95.65 ± 23.62 μ. CT was maximum subfoveally with gradual reduction in the thickness as the distance from the fovea increased. This is the first study describing the choroidal sublayer thickness, i.e., Haller's and Sattler's layer thickness along with CT in healthy Indian population.

Choroidal Haller's and Sattler's Layers Thickness in Normal Indian Eyes

PubMed Central

Roy, Rupak; Saurabh, Kumar; Vyas, Chinmayi; Deshmukh, Kaustubh; Sharma, Preeti; Chandrasekharan, Dhileesh P.; Bansal, Aditya

2018-01-01

AIM: This study aims to study normative choroidal thickness (CT) and Haller's and Sattler's layers thickness in normal Indian eyes. MATERIALS AND METHODS: The choroidal imaging of 73 eyes of 43 healthy Indian individuals was done using enhanced depth imaging feature of spectralis optical coherence tomography. Rraster scan protocol centered at fovea was used for imaging separately by two observers. CT was defined as the length of the perpendicular line drown from the outer border of hypereflective RPE-Bruch's complex to inner margin of choroidoscleral junction. Choroidal vessel layer thickness was measured after defining a largest choroidal vessel lumen within 750 μ on either side of the subfoveal CT vector. A perpendicular line was drawn to the innermost border of this lumen, and the distance between the perpendicular line and innermost border of choroidoscleral junction gave large choroidal vessel layer thickness (LCVLT, Haller's layer). Medium choroidal vessel layer thickness (MCVLT, Sattler's layer) was measured as the distance between same perpendicular line and outer border of hypereflective RPE-Bruch's complex. RESULTS: The mean age of individuals was 28.23 ± 15.29 years (range 14–59 years). Overall, the mean subfoveal CT was 331.6 ± 63.9 μ. Mean LCVLT was 227.08 ± 51.24 μ and the mean MCVLT was 95.65 ± 23.62 μ. CT was maximum subfoveally with gradual reduction in the thickness as the distance from the fovea increased. CONCLUSION: This is the first study describing the choroidal sublayer thickness, i.e., Haller's and Sattler's layer thickness along with CT in healthy Indian population. PMID:29899646

Long-Distance Translocation of Protein during Morphogenesis of the Fruiting Body in the Filamentous Fungus, Agaricus bisporus

PubMed Central

Woolston, Benjamin M.; Schlagnhaufer, Carl; Wilkinson, Jack; Larsen, Jeffrey; Shi, Zhixin; Mayer, Kimberly M.; Walters, Donald S.; Curtis, Wayne R.; Romaine, C. Peter

2011-01-01

Commercial cultivation of the mushroom fungus, Agaricus bisporus, utilizes a substrate consisting of a lower layer of compost and upper layer of peat. Typically, the two layers are seeded with individual mycelial inoculants representing a single genotype of A. bisporus. Studies aimed at examining the potential of this fungal species as a heterologous protein expression system have revealed unexpected contributions of the mycelial inoculants in the morphogenesis of the fruiting body. These contributions were elucidated using a dual-inoculant method whereby the two layers were differientially inoculated with transgenic β-glucuronidase (GUS) and wild-type (WT) lines. Surprisingly, use of a transgenic GUS line in the lower substrate and a WT line in the upper substrate yielded fruiting bodies expressing GUS activity while lacking the GUS transgene. Results of PCR and RT-PCR analyses for the GUS transgene and RNA transcript, respectively, suggested translocation of the GUS protein from the transgenic mycelium colonizing the lower layer into the fruiting body that developed exclusively from WT mycelium colonizing the upper layer. Effective translocation of the GUS protein depended on the use of a transgenic line in the lower layer in which the GUS gene was controlled by a vegetative mycelium-active promoter (laccase 2 and β-actin), rather than a fruiting body-active promoter (hydrophobin A). GUS-expressing fruiting bodies lacking the GUS gene had a bonafide WT genotype, confirmed by the absence of stably inherited GUS and hygromycin phosphotransferase selectable marker activities in their derived basidiospores and mycelial tissue cultures. Differientially inoculating the two substrate layers with individual lines carrying the GUS gene controlled by different tissue-preferred promoters resulted in up to a ∼3.5-fold increase in GUS activity over that obtained with a single inoculant. Our findings support the existence of a previously undescribed phenomenon of long-distance protein translocation in A. bisporus that has potential application in recombinant protein expression and biotechnological approaches for crop improvement. PMID:22163014

Series interconnected photovoltaic cells and method for making same

DOEpatents

Albright, S.P.; Chamberlin, R.R.; Thompson, R.A.

1995-01-31

A novel photovoltaic module and method for constructing the same are disclosed. The module includes a plurality of photovoltaic cells formed on a substrate and laterally separated by interconnection regions. Each cell includes a bottom electrode, a photoactive layer and a top electrode layer. Adjacent cells are connected in electrical series by way of a conductive-buffer line. The buffer line is also useful in protecting the bottom electrode against severing during downstream layer cutting processes. 11 figs.

Conditions for double layers in the earth's magnetosphere and perhaps in other astrophysical objects

NASA Technical Reports Server (NTRS)

Lyons, L. R.

1987-01-01

It is suggested that the features which govern the formation of the double layers are: (1) the divergence of the magnetospheric electric field, (2) the ionospheric conductivity, and (3) the current-voltage characteristics of auroral magnetic field lines. Also considered are conditions in other astrophysical objects that could lead to the formation of DLs in a manner analogous to what occurs in the earth's auroral zones. It is noted that two processes can drive divergent Pedersen currents within a collisional conducting layer: (1) sheared plasma flow applied anywhere along the magnetic field lines connected to the conducting layer and (2) a neutral flow with shear within the conducting layer.

Paralarvae of the complex Sthenoteuthis oualaniensis-Dosidicus gigas (Cephalopoda: Ommastrephidae) in the northern limit of the shallow oxygen minimum zone of the Eastern Tropical Pacific Ocean (April 2012)

NASA Astrophysics Data System (ADS)

Sánchez-Velasco, Laura; Ruvalcaba-Aroche, Erick D.; Beier, Emilio; Godínez, Victor M.; Barton, Eric D.; Díaz-Viloria, Noe; Pacheco, María. R.

2016-03-01

The three-dimensional distribution of the paralarvae of the complex Sthenoteuthis oualaniensis-Dosidicus gigas (Cephalopoda: Ommastrephidae) was analyzed at the northern limit of the shallow oxygen minimum zone in the Eastern Tropical Pacific in April 2012. The upper limit of the oxygen minimum water (˜44 µmol/kg or 1 mL/L) rises from ˜100 m depth in the entrance of the Gulf of California to ˜20 m depth off Cabo Corrientes. Most of the paralarvae of this complex, dominated by D. gigas, were concentrated in the Gulf entrance, between the thermocline (˜20 to ˜50 m depth) and the sea surface, in the warmest (>19°C) oxygenated (>176 µmol/kg) layer. The highest abundance of paralarvae was detected in an anticyclonic eddy (˜120 km diameter and >500 m deep), which contained lower-salinity water (<35 g/kg), consistent with formation in the California Current. Lower paralarvae abundance was recorded further south off Cabo Corrientes, where hypoxic layers were elevated as water shoaled nearshore. Almost no paralarvae were found in the north of the study area beyond the strong salinity front (˜34.8-35.4 g/kg) that bounded the anticyclone. These results showed an affinity of the paralarvae for lower-salinity, oxygenated water, illustrated by the influence of the mesoscale anticyclonic eddy and the salinity front in their distribution. Based on this study, it can be concluded that the expansion of the depth range of hypoxic water observed in the Eastern Tropical Pacific may be increasing environmental stress on the paralarvae by vertically restricting their habitat, and so affecting their survival.

Simulation and experimental research of heat leakage of cryogenic transfer lines

NASA Astrophysics Data System (ADS)

Deng, B. C.; Xie, X. J.; Pan, W.; Jiang, R. X.; Li, J.; Yang, S. Q.; Li, Q.

2017-12-01

The heat leakage of cryogenic transfer lines directly influences the performance of large-scale helium refrigerator. In this paper, a thermal model of cryogenic transfer line considering numerical simulation of support coupled with MLI was established. To validate the model, test platform of cryogenic transfer lines with the merits of disassembly outer pipe and changeable easily multi-layer insulation has been built. The experimental results of heat leakage through overall length of cryogenic transfer lines, support and multi-layer insulation were obtained. The heat leakages of multi-layer insulation, a support and the overall leakage are 1.02 W/m, 0.44 W and 1.46 W/m from experimental data, respectively. The difference of heat leakage of MLI between experiment and simulation were less than 5%. The temperature distribution of support and MLI obtained in presented model in good agreement with experimental data. It is expected to reduce the overall heat leakage of cryogenic transfer lines further by optimizing structure of support based on the above thermal model and test platform in this paper.

CT incidence of Morel-Lavallee lesions in patients with pelvic fractures: a 4-year experience at a level 1 trauma center.

PubMed

Beckmann, Nicholas M; Cai, Chunyan

2016-12-01

The aim of this study is to determine the incidence and location of Morel-Lavallee lesions (MLLs) on pelvic CTs performed in evaluation of pelvic fractures and determine if correlation exists between MLLs and mechanism of injury or pelvic ring injury pattern. A retrospective review was performed of pelvic CTs on 1493 consecutive patients presenting with pelvic fractures at our level 1 trauma center. MLLs occurred in 182 of 1493 patients presenting with pelvic fractures. Statistical significance in MLL incidence was found across mechanism of injuries with MLLs being seen most frequently in MCC/ATV accidents and crush injuries. A little over half of MLLs occurred over the lateral thigh with almost all other MLLs occurring over the posterior (flank or lumbar) region. MLLs were much more common in vertical shear and spinopelvic dissociation pelvic ring fracture patterns compared to lateral compression and AP compression patterns. In lateral compression injuries, MLLs most commonly occurred over the thigh. In all other pelvic ring injury patterns, MLLs were predominately posterior. MLL's are not as rare as previously believed. The lateral thigh and lumbar/flank regions should be closely inspected on pelvic trauma patients to identify MLLs, particularly in patients with a spinopelvic dissociation injury pattern.

The Comparative Experimental Study of Multilabel Classification for Diagnosis Assistant Based on Chinese Obstetric EMRs

PubMed Central

Zhang, Kunli; Zhao, Yueshu; Zan, Hongying; Zhuang, Lei

2018-01-01

Obstetric electronic medical records (EMRs) contain massive amounts of medical data and health information. The information extraction and diagnosis assistants of obstetric EMRs are of great significance in improving the fertility level of the population. The admitting diagnosis in the first course record of the EMR is reasoned from various sources, such as chief complaints, auxiliary examinations, and physical examinations. This paper treats the diagnosis assistant as a multilabel classification task based on the analyses of obstetric EMRs. The latent Dirichlet allocation (LDA) topic and the word vector are used as features and the four multilabel classification methods, BP-MLL (backpropagation multilabel learning), RAkEL (RAndom k labELsets), MLkNN (multilabel k-nearest neighbor), and CC (chain classifier), are utilized to build the diagnosis assistant models. Experimental results conducted on real cases show that the BP-MLL achieves the best performance with an average precision up to 0.7413 ± 0.0100 when the number of label sets and the word dimensions are 71 and 100, respectively. The result of the diagnosis assistant can be introduced as a supplementary learning method for medical students. Additionally, the method can be used not only for obstetric EMRs but also for other medical records. PMID:29666671

CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 gene variants and risk of childhood medulloblastoma.

PubMed

Dahlin, Anna M; Hollegaard, Mads V; Wibom, Carl; Andersson, Ulrika; Hougaard, David M; Deltour, Isabelle; Hjalmars, Ulf; Melin, Beatrice

2015-10-01

Recent studies have described a number of genes that are frequently altered in medulloblastoma tumors and that have putative key roles in the development of the disease. We hypothesized that common germline genetic variations in these genes may be associated with medulloblastoma development. Based on recent publications, we selected 10 genes that were frequently altered in medulloblastoma: CCND2, CTNNB1, DDX3X, GLI2, SMARCA4, MYC, MYCN, PTCH1, TP53, and MLL2 (now renamed as KMT2D). Common genetic variants (single nucleotide polymorphisms) annotating these genes (n = 221) were genotyped in germline DNA (neonatal dried blood spot samples) from 243 childhood medulloblastoma cases and 247 control subjects from Sweden and Denmark. Eight genetic variants annotating three genes in the sonic hedgehog signaling pathway; CCND2, PTCH1, and GLI2, were found to be associated with the risk of medulloblastoma (P(combined) < 0.05). The findings were however not statistically significant following correction for multiple testing by the very stringent Bonferroni method. The results do not support our hypothesis that common germline genetic variants in the ten studied genes are associated with the risk of developing medulloblastoma.

A Role for the Nucleosome Assembly Proteins TAF-Iβ and NAP1 in the Activation of BZLF1 Expression and Epstein-Barr Virus Reactivation

PubMed Central

Frappier, Lori

2013-01-01

The reactivation of Epstein-Barr virus (EBV) from latent to lytic infection begins with the expression of the viral BZLF1 gene, leading to a subsequent cascade of viral gene expression and amplification of the EBV genome. Using RNA interference, we show that nucleosome assembly proteins NAP1 and TAF-I positively contribute to EBV reactivation in epithelial cells through the induction of BZLF1 expression. In addition, overexpression of NAP1 or the β isoform of TAF-I (TAF-Iβ) in AGS cells latently infected with EBV was sufficient to induce BZLF1 expression. Chromatin immunoprecipitation experiments performed in AGS-EBV cells showed that TAF-I associated with the BZLF1 promoter upon lytic induction and affected local histone modifications by increasing H3K4 dimethylation and H4K8 acetylation. MLL1, the host protein known to dimethylate H3K4, was found to associate with the BZLF1 promoter upon lytic induction in a TAF-I-dependent manner, and MLL1 depletion decreased BZLF1 expression, confirming its contribution to lytic reactivation. The results indicate that TAF-Iβ promotes BZLF1 expression and subsequent lytic infection by affecting chromatin at the BZLF1 promoter. PMID:23691099

A role for the nucleosome assembly proteins TAF-Iβ and NAP1 in the activation of BZLF1 expression and Epstein-Barr virus reactivation.

PubMed

Mansouri, Sheila; Wang, Shan; Frappier, Lori

2013-01-01

The reactivation of Epstein-Barr virus (EBV) from latent to lytic infection begins with the expression of the viral BZLF1 gene, leading to a subsequent cascade of viral gene expression and amplification of the EBV genome. Using RNA interference, we show that nucleosome assembly proteins NAP1 and TAF-I positively contribute to EBV reactivation in epithelial cells through the induction of BZLF1 expression. In addition, overexpression of NAP1 or the β isoform of TAF-I (TAF-Iβ) in AGS cells latently infected with EBV was sufficient to induce BZLF1 expression. Chromatin immunoprecipitation experiments performed in AGS-EBV cells showed that TAF-I associated with the BZLF1 promoter upon lytic induction and affected local histone modifications by increasing H3K4 dimethylation and H4K8 acetylation. MLL1, the host protein known to dimethylate H3K4, was found to associate with the BZLF1 promoter upon lytic induction in a TAF-I-dependent manner, and MLL1 depletion decreased BZLF1 expression, confirming its contribution to lytic reactivation. The results indicate that TAF-Iβ promotes BZLF1 expression and subsequent lytic infection by affecting chromatin at the BZLF1 promoter.

Measurement of isoprene solubility in water, human blood and plasma by multiple headspace extraction gas chromatography coupled with solid phase microextraction.

PubMed

Mochalski, Paweł; King, Julian; Kupferthaler, Alexander; Unterkofler, Karl; Hinterhuber, Hartmann; Amann, Anton

2011-12-01

The aim of this study was to determine the solubility (liquid-to-air ratios) of isoprene in water, human blood and plasma. To this end, an experimental setup combining multiple headspace extraction, solid phase microextraction and gas chromatography-mass spectrometry was applied. The water:air partition coefficients of isoprene were determined for the temperature range 4.5-37 °C and amounted to 1.171-0.277 (g mL(l)(-1)) (g mL(a)(-1))(-1). On the basis of these data, the enthalpy of volatilization was calculated as 29.46 ± 2.83 kJ mol(-1). The blood:air partition coefficients at 37 °C were determined for ten normal healthy volunteers spread around a median value of 0.95 ± 0.09 (g mL(l)(-1)) (g mL(a)(-1))(-1) and were approximately 16% lower than the plasma:air partition coefficients (1.11 ± 0.2). The applied methodology can be particularly attractive for solubility studies targeting species at very low concentrations in the solution, i.e. when headspace sample enrichment is necessary to provide sufficient measurement sensitivity and reliability. This can be especially helpful if environmental or physiological solute levels have to be considered.

Musashi2 sustains the mixed-lineage leukemia–driven stem cell regulatory program

PubMed Central

Park, Sun-Mi; Gönen, Mithat; Vu, Ly; Minuesa, Gerard; Tivnan, Patrick; Barlowe, Trevor S.; Taggart, James; Lu, Yuheng; Deering, Raquel P.; Hacohen, Nir; Figueroa, Maria E.; Paietta, Elisabeth; Fernandez, Hugo F.; Tallman, Martin S.; Melnick, Ari; Levine, Ross; Leslie, Christina; Lengner, Christopher J.; Kharas, Michael G.

2015-01-01

Leukemia stem cells (LSCs) are found in most aggressive myeloid diseases and contribute to therapeutic resistance. Leukemia cells exhibit a dysregulated developmental program as the result of genetic and epigenetic alterations. Overexpression of the RNA-binding protein Musashi2 (MSI2) has been previously shown to predict poor survival in leukemia. Here, we demonstrated that conditional deletion of Msi2 in the hematopoietic compartment results in delayed leukemogenesis, reduced disease burden, and a loss of LSC function in a murine leukemia model. Gene expression profiling of these Msi2-deficient animals revealed a loss of the hematopoietic/leukemic stem cell self-renewal program and an increase in the differentiation program. In acute myeloid leukemia patients, the presence of a gene signature that was similar to that observed in Msi2-deficent murine LSCs correlated with improved survival. We determined that MSI2 directly maintains the mixed-lineage leukemia (MLL) self-renewal program by interacting with and retaining efficient translation of Hoxa9, Myc, and Ikzf2 mRNAs. Moreover, depletion of MLL target Ikzf2 in LSCs reduced colony formation, decreased proliferation, and increased apoptosis. Our data provide evidence that MSI2 controls efficient translation of the oncogenic LSC self-renewal program and suggest MSI2 as a potential therapeutic target for myeloid leukemia. PMID:25664853

Characterization of a highly efficient chevron-shaped anti-contamination device

NASA Astrophysics Data System (ADS)

Fiore, M.; Vermeersch, O.; Forte, M.; Casalis, G.; François, C.

2016-04-01

This paper is devoted to the characterization of an optimized chevron-shaped anti-contamination device (ACD). This device can prevent efficiently the propagation of turbulence from the fuselage along the attachment line (hypothetical streamline that spreads the flow going to suction side and the one going to pressure side) of swept wings and enables the development of a new laminar boundary layer downstream. More specifically, the aim is to prevent boundary-layer transition along the attachment line by a contamination process. This process is characterized by the typical Reynolds number overline{R} and the associated Poll's criterion. Thus, ACD efficiency will be expressed in terms of overline{R} values. Some experiments performed on a new numerically optimized ACD have shown its ability to prevent leading-edge contamination up to overline{R} values close to the natural transition process of the laminar boundary layer along the attachment line. The corresponding stability analysis of the laminar boundary layer is made using the Görtler-Hämmerlin stability approach. The study is completed with the different transition processes that can occur downstream the attachment line, around the airfoil, especially with crossflow analysis.

Parallel inhomogeneity and the Alfven resonance. 1: Open field lines

NASA Technical Reports Server (NTRS)

Hansen, P. J.; Harrold, B. G.

1994-01-01

In light of a recent demonstration of the general nonexistence of a singularity at the Alfven resonance in cold, ideal, linearized magnetohydrodynamics, we examine the effect of a small density gradient parallel to uniform, open ambient magnetic field lines. To lowest order, energy deposition is quantitatively unaffected but occurs continuously over a thickened layer. This effect is illustrated in a numerical analysis of a plasma sheet boundary layer model with perfectly absorbing boundary conditions. Consequences of the results are discussed, both for the open field line approximation and for the ensuing closed field line analysis.

The role of diffusion-controlled oscillatory nucleation in the formation of line rock in pegmatite-aplite dikes

USGS Publications Warehouse

Webber, K.L.; Falster, A.U.; Simmons, W.B.; Foord, E.E.

1997-01-01

The George Ashley Block (GAB), located in the Pala Pegmatite District, San Diego County, California, is a composite pegmatite-aplite dike of 8 m thickness displaying striking mineralogical layering in the aphte portion of the dike, referred to as line rock. Rhythmic layering is characterized by garnet-rich bands alternating with albite-quartz-muscovite-rich bands. Cumulus textures are notably absent from the layered portion of the dike. Elongated quartz, megacrysts are oriented perpendicular to the garnet-rich layers and poikilitically include garnet, albite, and muscovite. Calculated crystal-free magma viscosity with 3% H2O is 106.2 Pa s and the calculated settling velocity for garnet is 0??51 cm/year. Conductive cooling calculations based on emplacement of a 650??C dike into 150?? C fractured gabbroic country rock at 1??5 kbar, and accounting for latent heat of crystallization, demonstrate that the line rock portion of the dike cools to 550?? C in about 1 year. Crystal size distribution studies also suggest very rapid nucleation and crystallization. Diffusion-controlled gel crystallization experiments yield textures virtually identical to those observed in the layered aplite, including rhythmic banding, colloform layering, and band discontinuities. Thus, observed textures and calculated magmatic parameters suggest that mineralogical layering in the GAB results from an in situ diffusion-controlled process of oscillatory nucleation and crystallization. We propose that any event that promotes strong undercooling has the potential to initiate rapid heterogeneous nucleation and oscillatory crystal growth, leading to the development of a layer of excluded components in front of the crystallization front, and the formation of line rock.

Remote sensing of the boundary layer over the oceans. [by IRIS measurements

NASA Technical Reports Server (NTRS)

Prabhakara, C.; Dalu, G.; Nath, N. R.; Lo, R.

1978-01-01

The paper explores the possibility of remotely sensing the boundary layer structure over the oceans by means of the Nimbus 4 IR Interferometric Spectrometer (IRIS) measurements in the water vapor bands. It is found from theoretical considerations that the moderately strong spectral lines in the 9-micron water vapor window region contain useful information about the lowest layers in the atmosphere. The difference between the observed line strength and the theoretically predicted line strength provides information about the departure in the atmospheric temperature and water vapor profiles from standard conditions. The observations of METEOR oceanographic expedition over the North and South Atlantic, and the Indian Ocean expedition make it possible to model the inversion conditions. It is concluded that significant characteristics of the temperature and water vapor profiles in the boundary layer of the atmosphere can be remotely sensed using the water vapor spectral measurements over the oceans.

Megavolt parallel potentials arising from double-layer streams in the Earth's outer radiation belt.

PubMed

Mozer, F S; Bale, S D; Bonnell, J W; Chaston, C C; Roth, I; Wygant, J

2013-12-06

Huge numbers of double layers carrying electric fields parallel to the local magnetic field line have been observed on the Van Allen probes in connection with in situ relativistic electron acceleration in the Earth's outer radiation belt. For one case with adequate high time resolution data, 7000 double layers were observed in an interval of 1 min to produce a 230,000 V net parallel potential drop crossing the spacecraft. Lower resolution data show that this event lasted for 6 min and that more than 1,000,000 volts of net parallel potential crossed the spacecraft during this time. A double layer traverses the length of a magnetic field line in about 15 s and the orbital motion of the spacecraft perpendicular to the magnetic field was about 700 km during this 6 min interval. Thus, the instantaneous parallel potential along a single magnetic field line was the order of tens of kilovolts. Electrons on the field line might experience many such potential steps in their lifetimes to accelerate them to energies where they serve as the seed population for relativistic acceleration by coherent, large amplitude whistler mode waves. Because the double-layer speed of 3100  km/s is the order of the electron acoustic speed (and not the ion acoustic speed) of a 25 eV plasma, the double layers may result from a new electron acoustic mode. Acceleration mechanisms involving double layers may also be important in planetary radiation belts such as Jupiter, Saturn, Uranus, and Neptune, in the solar corona during flares, and in astrophysical objects.

Gastrointestinal cell lines form polarized epithelia with an adherent mucus layer when cultured in semi-wet interfaces with mechanical stimulation.

PubMed

Navabi, Nazanin; McGuckin, Michael A; Lindén, Sara K

2013-01-01

Mucin glycoproteins are secreted in large quantities by mucosal epithelia and cell surface mucins are a prominent feature of the glycocalyx of all mucosal epithelia. Currently, studies investigating the gastrointestinal mucosal barrier use either animal experiments or non-in vivo like cell cultures. Many pathogens cause different pathology in mice compared to humans and the in vitro cell cultures used are suboptimal because they are very different from an in vivo mucosal surface, are often not polarized, lack important components of the glycocalyx, and often lack the mucus layer. Although gastrointestinal cell lines exist that produce mucins or polarize, human cell line models that reproducibly create the combination of a polarized epithelial cell layer, functional tight junctions and an adherent mucus layer have been missing until now. We trialed a range of treatments to induce polarization, 3D-organization, tight junctions, mucin production, mucus secretion, and formation of an adherent mucus layer that can be carried out using standard equipment. These treatments were tested on cell lines of intestinal (Caco-2, LS513, HT29, T84, LS174T, HT29 MTX-P8 and HT29 MTX-E12) and gastric (MKN7, MKN45, AGS, NCI-N87 and its hTERT Clone5 and Clone6) origins using Ussing chamber methodology and (immuno)histology. Semi-wet interface culture in combination with mechanical stimulation and DAPT caused HT29 MTX-P8, HT29 MTX-E12 and LS513 cells to polarize, form functional tight junctions, a three-dimensional architecture resembling colonic crypts, and produce an adherent mucus layer. Caco-2 and T84 cells also polarized, formed functional tight junctions and produced a thin adherent mucus layer after this treatment, but with less consistency. In conclusion, culture methods affect cell lines differently, and testing a matrix of methods vs. cell lines may be important to develop better in vitro models. The methods developed herein create in vitro mucosal surfaces suitable for studies of host-pathogen interactions at the mucosal surface.

Gastrointestinal Cell Lines Form Polarized Epithelia with an Adherent Mucus Layer when Cultured in Semi-Wet Interfaces with Mechanical Stimulation

PubMed Central

Navabi, Nazanin; McGuckin, Michael A.; Lindén, Sara K.

2013-01-01

Mucin glycoproteins are secreted in large quantities by mucosal epithelia and cell surface mucins are a prominent feature of the glycocalyx of all mucosal epithelia. Currently, studies investigating the gastrointestinal mucosal barrier use either animal experiments or non-in vivo like cell cultures. Many pathogens cause different pathology in mice compared to humans and the in vitro cell cultures used are suboptimal because they are very different from an in vivo mucosal surface, are often not polarized, lack important components of the glycocalyx, and often lack the mucus layer. Although gastrointestinal cell lines exist that produce mucins or polarize, human cell line models that reproducibly create the combination of a polarized epithelial cell layer, functional tight junctions and an adherent mucus layer have been missing until now. We trialed a range of treatments to induce polarization, 3D-organization, tight junctions, mucin production, mucus secretion, and formation of an adherent mucus layer that can be carried out using standard equipment. These treatments were tested on cell lines of intestinal (Caco-2, LS513, HT29, T84, LS174T, HT29 MTX-P8 and HT29 MTX-E12) and gastric (MKN7, MKN45, AGS, NCI-N87 and its hTERT Clone5 and Clone6) origins using Ussing chamber methodology and (immuno)histology. Semi-wet interface culture in combination with mechanical stimulation and DAPT caused HT29 MTX-P8, HT29 MTX-E12 and LS513 cells to polarize, form functional tight junctions, a three-dimensional architecture resembling colonic crypts, and produce an adherent mucus layer. Caco-2 and T84 cells also polarized, formed functional tight junctions and produced a thin adherent mucus layer after this treatment, but with less consistency. In conclusion, culture methods affect cell lines differently, and testing a matrix of methods vs. cell lines may be important to develop better in vitro models. The methods developed herein create in vitro mucosal surfaces suitable for studies of host-pathogen interactions at the mucosal surface. PMID:23869232

Multilayer insulation blanket, fabricating apparatus and method

DOEpatents

Gonczy, John D.; Niemann, Ralph C.; Boroski, William N.

1992-01-01

An improved multilayer insulation blanket for insulating cryogenic structures operating at very low temperatures is disclosed. An apparatus and method for fabricating the improved blanket are also disclosed. In the improved blanket, each successive layer of insulating material is greater in length and width than the preceding layer so as to accommodate thermal contraction of the layers closest to the cryogenic structure. The fabricating apparatus has a rotatable cylindrical mandrel having an outer surface of fixed radius that is substantially arcuate, preferably convex, in cross-section. The method of fabricating the improved blanket comprises (a) winding a continuous sheet of thermally reflective material around the circumference of the mandrel to form multiple layers, (b) binding the layers along two lines substantially parallel to the edges of the circumference of the mandrel, (c) cutting the layers along a line parallel to the axle of the mandrel, and (d) removing the bound layers from the mandrel.

Method of fabricating a multilayer insulation blanket

DOEpatents

Gonczy, John D.; Niemann, Ralph C.; Boroski, William N.

1993-01-01

An improved multilayer insulation blanket for insulating cryogenic structures operating at very low temperatures is disclosed. An apparatus and method for fabricating the improved blanket are also disclosed. In the improved blanket, each successive layer of insulating material is greater in length and width than the preceding layer so as to accommodate thermal contraction of the layers closest to the cryogenic structure. The fabricating apparatus has a rotatable cylindrical mandrel having an outer surface of fixed radius that is substantially arcuate, preferably convex, in cross-section. The method of fabricating the improved blanket comprises (a) winding a continuous sheet of thermally reflective material around the circumference of the mandrel to form multiple layers, (b) binding the layers along two lines substantially parallel to the edges of the circumference of the mandrel, (c) cutting the layers along a line parallel to the axle of the mandrel, and (d) removing the bound layers from the mandrel.

Method of fabricating a multilayer insulation blanket

DOEpatents

Gonczy, J.D.; Niemann, R.C.; Boroski, W.N.

1993-07-06

An improved multilayer insulation blanket for insulating cryogenic structures operating at very low temperatures is disclosed. An apparatus and method for fabricating the improved blanket are also disclosed. In the improved blanket, each successive layer of insulating material is greater in length and width than the preceding layer so as to accommodate thermal contraction of the layers closest to the cryogenic structure. The fabricating apparatus has a rotatable cylindrical mandrel having an outer surface of fixed radius that is substantially arcuate, preferably convex, in cross-section. The method of fabricating the improved blanket comprises (a) winding a continuous sheet of thermally reflective material around the circumference of the mandrel to form multiple layers, (b) binding the layers along two lines substantially parallel to the edges of the circumference of the mandrel, (c) cutting the layers along a line parallel to the axle of the mandrel, and (d) removing the bound layers from the mandrel.

Multilayer insulation blanket, fabricating apparatus and method

DOEpatents

Gonczy, J.D.; Niemann, R.C.; Boroski, W.N.

1992-09-01

An improved multilayer insulation blanket for insulating cryogenic structures operating at very low temperatures is disclosed. An apparatus and method for fabricating the improved blanket are also disclosed. In the improved blanket, each successive layer of insulating material is greater in length and width than the preceding layer so as to accommodate thermal contraction of the layers closest to the cryogenic structure. The fabricating apparatus has a rotatable cylindrical mandrel having an outer surface of fixed radius that is substantially arcuate, preferably convex, in cross-section. The method of fabricating the improved blanket comprises (a) winding a continuous sheet of thermally reflective material around the circumference of the mandrel to form multiple layers, (b) binding the layers along two lines substantially parallel to the edges of the circumference of the mandrel, (c) cutting the layers along a line parallel to the axle of the mandrel, and (d) removing the bound layers from the mandrel. 7 figs.

Topology of magnetic flux ropes and formation of fossil flux transfer events and boundary layer plasmas

NASA Technical Reports Server (NTRS)

Lee, L. C.; Ma, Z. W.; Fu, Z. F.; Otto, A.

1993-01-01

A mechanism for the formation of fossil flux transfer events and the low-level boundary layer within the framework of multiple X-line reconnection is proposed. Attention is given to conditions for which the bulk of magnetic flux in a flux rope of finite extent has a simple magnetic topology, where the four possible connections of magnetic field lines are: IMF to MSP, MSP to IMF, IMF to IMF, and MSP to MSP. For a sufficient relative shift of the X lines, magnetic flux may enter a flux rope from the magnetosphere and exit into the magnetosphere. This process leads to the formation of magnetic flux ropes which contain a considerable amount of magnetosheath plasma on closed magnetospheric field lines. This process is discussed as a possible explanation for the formation of fossil flux transfer events in the magnetosphere and the formation of the low-latitude boundary layer.

On the instability of a three-dimensional attachment-line boundary layer - Weakly nonlinear theory and a numerical approach

NASA Technical Reports Server (NTRS)

Hall, P.; Malik, M. R.

1986-01-01

The instability of a three-dimensional attachment-line boundary layer is considered in the nonlinear regime. Using weakly nonlinear theory, it is found that, apart from a small interval near the (linear) critical Reynolds number, finite-amplitude solutions bifurcate subcritically from the upper branch of the neutral curve. The time-dependent Navier-Stokes equations for the attachment-line flow have been solved using a Fourier-Chebyshev spectral method and the subcritical instability is found at wavenumbers that correspond to the upper branch. Both the theory and the numerical calculations show the existence of supercritical finite-amplitude (equilibrium) states near the lower branch which explains why the observed flow exhibits a preference for the lower branch modes. The effect of blowing and suction on nonlinear stability of the attachment-line boundary layer is also investigated.

On the instability of a 3-dimensional attachment line boundary layer: Weakly nonlinear theory and a numerical approach

NASA Technical Reports Server (NTRS)

Hall, P.; Malik, M. R.

1984-01-01

The instability of a three dimensional attachment line boundary layer is considered in the nonlinear regime. Using weakly nonlinear theory, it is found that, apart from a small interval near the (linear) critical Reynolds number, finite amplitude solutions bifurcate subcritically from the upper branch of the neutral curve. The time dependent Navier-Stokes equations for the attachment line flow have been solved using a Fourier-Chebyshev spectral method and the subcritical instability is found at wavenumbers that correspond to the upper branch. Both the theory and the numerical calculations show the existence of supercritical finite amplitude (equilibrium) states near the lower branch which explains why the observed flow exhibits a preference for the lower branch modes. The effect of blowing and suction on nonlinear stability of the attachment line boundary layer is also investigated.

Refractory lining system for high wear area of high temperature reaction vessel

DOEpatents

Hubble, David H.; Ulrich, Klaus H.

1998-01-01

A refractory-lined high temperature reaction vessel comprises a refractory ring lining constructed of refractory brick, a cooler, and a heat transfer medium disposed between the refractory ring lining and the cooler. The refractory brick comprises magnesia (MgO) and graphite. The heat transfer medium contacts the refractory brick and a cooling surface of the cooler, and is composed of a material that accommodates relative movement between the refractory brick and the cooler. The brick is manufactured such that the graphite has an orientation providing a high thermal conductivity in the lengthwise direction through the brick that is higher than the thermal conductivity in directions perpendicular to the lengthwise direction. The graphite preferably is flake graphite, in the range of about 10 to 20 wt %, and has a size distribution selected to provide maximum brick density. The reaction vessel may be used for performing a reaction process including the steps of forming a layer of slag on a melt in the vessel, the slag having a softening point temperature range, and forming a protective frozen layer of slag on the interior-facing surface of the refractory lining in at least a portion of a zone where the surface contacts the layer of slag, the protective frozen layer being maintained at or about the softening point of the slag.

Consolidation of Soft Layers by Finite Strain Analysis.

DTIC Science & Technology

1982-03-01

compressible foundation or layer is divided into for computation purposes. NBL an integer denoting the following options: 1 = consolidation calculated for...i.e., NDATAI 1), the data file should be sequenced in the following manner: a. NST, NPROB, NDATA1, NDATA2 b. NST, NPT, NBL c. NST, GSBL, HBL, WLl, LBL...particular line types: Line type c: Q0 and DQ have nonzero values only if NBL = 3. If NBL = 2, all data values are set to zero except NST. Line type d: There

Separated flows receptivity for external disturbances

NASA Astrophysics Data System (ADS)

Zanin, B. Yu.

2017-10-01

Results of experimental investigations of the flow over a straight-wing model in a low-turbulence wind tunnel are reported. The influence of a turbulent wake due to a thin filament on the structure of boundary layer on the model surface was examined. Also the fishing line was installed in the test section of the wind tunnel and the effect of line on the boundary-layer flow structure is considered. Flow visualization in boundary layer and hot-wire measurements were performed. The wake and the grid substantially modified the boundary layer flow pattern: the separation disappeared from the wing surface, and the formation of longitudinal structures was observed.

Human amniotic epithelial cells as feeder layer to derive and maintain human embryonic stem cells from poor-quality embryos.

PubMed

Ávila-González, Daniela; Vega-Hernández, Eva; Regalado-Hernández, Juan Carlos; De la Jara-Díaz, Julio Francisco; García-Castro, Irma Lydia; Molina-Hernández, Anayansi; Moreno-Verduzco, Elsa Romelia; Razo-Aguilera, Guadalupe; Flores-Herrera, Héctor; Portillo, Wendy; Díaz-Martínez, Néstor Emmanuel; García-López, Guadalupe; Díaz, Néstor Fabián

2015-09-01

Data from the literature suggest that human embryonic stem cell (hESC) lines used in research do not genetically represent all human populations. The derivation of hESC through conventional methods involve the destruction of viable human embryos, as well the use of mouse embryonic fibroblasts as a feeder layer, which has several drawbacks. We obtained the hESC line (Amicqui-1) from poor-quality (PQ) embryos derived and maintained on human amniotic epithelial cells (hAEC). This line displays a battery of markers of pluripotency and we demonstrated the capacity of these cells to produce derivates of the three germ layers. Copyright © 2015. Published by Elsevier B.V.

Lenalidomide and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2018-06-18

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia

Decitabine and Bortezomib in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2014-11-06

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

(DCT) A Reconfigurable RF Photonics Unit Cell For Integrated Circuits

DTIC Science & Technology

2012-08-10

Public Release In this work, the integration of a Quantum Dot Mode Locked Laser , that acts as a microwave and millimeter wave source, with a wideband...antenna is presented. Two aspects of research are discussed. The first aspect deals with a Mode Locked Laser (MLL) based on quantum dot (QD...designed antennas were integrated with laser chips using the lithographic method. The challenges of designing this wideband antenna that can operate

From Looking at Our Schools (LAOS) to Whole School Evaluation--Management, Leadership and Learning (WSE-MLL): The Evolution of Inspection in Irish Schools over the Past Decade

ERIC Educational Resources Information Center

McNamara, Gerry; O'Hara, Joe

2012-01-01

This paper attempts to provide an overview of the key assumptions underpinning the "Whole School Evaluation" (WSE) inspection policy developed in Ireland since 2003. Beginning with a documentary analysis the paper argues that the capacity to generate useful self evaluative data in schools was seen as being at the heart of the model of…

D 2 and D-T Liquid-Layer Target Shots at the National Ignition Facility

DOE PAGES

Walters, Curtis; Alger, Ethan; Bhandarkar, Suhas; ...

2018-01-19

Experiments at the National Ignition Facility (NIF) using targets containing a deuterium-tritium (D-T) fuel layer have, until recently, required that a high-quality layer of solid D-T (herein referred to as an ice layer) be formed in the capsule. The development of a process to line the inner surface of a target capsule with a foam layer of a thickness that is typical of ice layers has resulted in the ability to field targets with liquid layers wetting the foam. Successful fielding of liquid-layer targets on NIF required not only a foam-lined capsule but also changes to the capsule filling processmore » and the manner with which the inventory is maintained in the capsule. Additionally, changes to target heater power and the temperature drops across target components were required in order to achieve the desired range of shot temperatures. Finally, these changes and the target’s performance during four target shots on NIF are discussed.« less

D 2 and D-T Liquid-Layer Target Shots at the National Ignition Facility

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

Walters, Curtis; Alger, Ethan; Bhandarkar, Suhas

Experiments at the National Ignition Facility (NIF) using targets containing a deuterium-tritium (D-T) fuel layer have, until recently, required that a high-quality layer of solid D-T (herein referred to as an ice layer) be formed in the capsule. The development of a process to line the inner surface of a target capsule with a foam layer of a thickness that is typical of ice layers has resulted in the ability to field targets with liquid layers wetting the foam. Successful fielding of liquid-layer targets on NIF required not only a foam-lined capsule but also changes to the capsule filling processmore » and the manner with which the inventory is maintained in the capsule. Additionally, changes to target heater power and the temperature drops across target components were required in order to achieve the desired range of shot temperatures. Finally, these changes and the target’s performance during four target shots on NIF are discussed.« less

Regional peculiarities in the inter-annual distribution of the red 630.0 nm line nightglow intensities over Abastumani

NASA Astrophysics Data System (ADS)

Toriashvili, L.; Didebulidze, G. G.; Todua, M.

2017-12-01

Peculiarities of the inter-annual distribution of atomic oxygen red OI 630.0 nm line nightglow intensity observed from Abastumani Astrophysical Observatory (41.75 N; 42.82 E) are considered, using the long-term dataset. This distribution demonstrates semi-annual and annual-like variations which occur during solar minimum, as well as maximum phases. The maximum values of the red line intensities are in Summer, however in June it is lower than in May and July, which may be due to regional effects. This phenomenon is considered as a the possible result of regional dynamical processes influencing the behavior of the ionosphere F2 layer which cause changes of electrons/ions densities in the 630.0 nm line luminous region (maximum luminous layer is at about 230-280 km). Using the red line intensities and ionosphere F2 layer electron density data of the IRI-12 model, the changes of meridional thermospheric wind velocities are estimated for this mid-latitude region. These meridional and vertical wind field changes causes of variations of the red line intensities in June can be caused by tidal wind and accompanied by atmospheric gravity waves activities.

Electromigration in epitaxial Cu(001) lines

NASA Astrophysics Data System (ADS)

Ramanath, G.; Kim, H.; Goindi, H. S.; Frederick, M. J.; Shin, C.-S.; Goswami, R.; Petrov, I.; Greene, J. E.

2002-04-01

We report the electromigration (EM) response of single-domain epitaxial Cu(001) lines on layers of Ta, TaN, and TiN. Epitaxial Cu(001) lines on nitride layers exhibit nearly two orders of magnitude higher mean-time-to-failure (MTTF) values than those on Ta, indicating the strong influence of the underlayer. The activation energy of EM for Cu on the nitrides is ˜0.8-1.2 eV, and that of Cu on Ta is ˜0.2 eV, for 200-300 °C. Our results also indicate that the MTTF values correlate inversely to the crystal quality of the Cu layers measured by X-ray diffraction. The EM resistance of epitaxial Cu lines with different crystal quality on TaN were measured to separate the effects of interface chemistry and crystal quality. While higher quality epitaxial films reveal a higher EM resistance, the magnitude of the change is smaller than that obtained by changing the interface chemistry. Epitaxial lines exhibit more than 3-4 orders of magnitude higher MTTF than polycrystalline lines on the same underlayer. Based upon our results, we propose that the Cu/underlayer interface chemistry and presence of grain boundary diffusion play important roles in unpassivated Cu films.

The energy input mechanism into the lower transition regions between stellar chromospheres and coronae

NASA Technical Reports Server (NTRS)

Boehm-Vitense, Erika

1988-01-01

The ratio of the emission line fluxes for the C II and C IV lines in the lower transition regions (T = 30,000 to 100,000 K) between stellar chromospheres and transition layers is shown to depend mainly on the temperature gradient in the line emitting regions which can therefore be determined from this line ratio. From the observed constant (within the limits of observational error) ratio of the emission line fluxes of the C II (1335 A) and C IV (1550 A) lines it is concluded that the temperature gradients in the lower transition layers are similar for the large majority of stars independently of T sub eff, L, and degree of activity. This means that the temperature dependence of the damping length for the mechanical flux must be the same for all these stars. Since for different kinds of mechanical fluxes the dependence of the damping length on gas pressure and temperature is quite different, it is concluded that the same heating mechanism must be responsible for the heating of all the lower transition layers of these stars, regardless of their chromospheric activity. Only the amount of mechanical flux changes. The T Tauri stars are exceptions: their emission lines are probably mainly due to circumstellar material.

Aberrant promoter hypermethylation of PBRM1, BAP1, SETD2, KDM6A and other chromatin-modifying genes is absent or rare in clear cell RCC

PubMed Central

Ibragimova, Ilsiya; Maradeo, Marie E.; Dulaimi, Essel; Cairns, Paul

2013-01-01

Recent sequencing studies of clear cell (conventional) renal cell carcinoma (ccRCC) have identified inactivating point mutations in the chromatin-modifying genes PBRM1, KDM6A/UTX, KDM5C/JARID1C, SETD2, MLL2 and BAP1. To investigate whether aberrant hypermethylation is a mechanism of inactivation of these tumor suppressor genes in ccRCC, we sequenced the promoter region within a bona fide CpG island of PBRM1, KDM6A, SETD2 and BAP1 in bisulfite-modified DNA of a representative series of 50 primary ccRCC, 4 normal renal parenchyma specimens and 5 RCC cell lines. We also interrogated the promoter methylation status of KDM5C and ARID1A in the Cancer Genome Atlas (TCGA) ccRCC Infinium data set. PBRM1, KDM6A, SETD2 and BAP1 were unmethylated in all tumor and normal specimens. KDM5C and ARID1A were unmethylated in the TCGA 219 ccRCC and 119 adjacent normal specimens. Aberrant promoter hypermethylation of PBRM1, BAP1 and the other chromatin-modifying genes examined here is therefore absent or rare in ccRCC. PMID:23644518

Glucose-induced expression of MIP-1 genes requires O-GlcNAc transferase in monocytes

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

Chikanishi, Toshihiro; ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi-shi, Saitama 332-0012; Fujiki, Ryoji

2010-04-16

O-glycosylation has emerged as an important modification of nuclear proteins, and it appears to be involved in gene regulation. Recently, we have shown that one of the histone methyl transferases (MLL5) is activated through O-glycosylation by O-GlcNAc transferase (OGT). Addition of this monosaccharide is essential for forming a functional complex. However, in spite of the abundance of OGT in the nucleus, the impact of nuclear O-glycosylation by OGT remains largely unclear. To address this issue, the present study was undertaken to test the impact of nuclear O-glycosylation in a monocytic cell line, THP-1. Using a cytokine array, MIP-1{alpha} and -1{beta}more » genes were found to be regulated by nuclear O-glycosylation. Biochemical purification of the OGT interactants from THP-1 revealed that OGT is an associating partner for distinct co-regulatory complexes. OGT recruitment and protein O-glycosylation were observed at the MIP-1{alpha} gene promoter; however, the known OGT partner (HCF-1) was absent when the MIP-1{alpha} gene promoter was not activated. From these findings, we suggest that OGT could be a co-regulatory subunit shared by functionally distinct complexes supporting epigenetic regulation.« less

Analytical Models of Exoplanetary Atmospheres. V. Non-gray Thermal Structure with Coherent Scattering

NASA Astrophysics Data System (ADS)

Mohandas, Gopakumar; Pessah, Martin E.; Heng, Kevin

2018-05-01

We apply the picket fence treatment to model the effects brought about by spectral lines on the thermal structure of irradiated atmospheres. The lines may be due to pure absorption processes, pure coherent scattering processes, or some combination of absorption and scattering. If the lines arise as a pure absorption process, the surface layers of the atmosphere are cooler, whereas this surface cooling is completely absent if the lines are due to pure coherent isotropic scattering. The lines also lead to a warming of the deeper atmosphere. The warming of the deeper layers is, however, independent of the nature of line formation. Accounting for coherent isotropic scattering in the shortwave and longwave continuum results in anti-greenhouse cooling and greenhouse warming on an atmosphere-wide scale. The effects of coherent isotropic scattering in the line and continuum operate in tandem to determine the resulting thermal structure of the irradiated atmosphere.

Precambrian crust and lithosphere beneath the Northern Canadian Cordillera discovered by LITHOPROBE seismic reflection profiling

NASA Astrophysics Data System (ADS)

Clowes, R. M.; Cook, F. A.; Snyder, D. B.; van der Velden, A. J.; Hall, K. W.; Erdmer, P.; Evenchick, C. A.

2003-04-01

The Cordillera in northern Canada is underlain by westward tapering layers that can be followed from outcrops of Proterozoic strata in the Foreland Belt to the lowermost crust of the orogenic interior, a distance of as much as 500 km across strike. The layering was discovered on two new deep seismic reflection profiles in the Yukon (Line 3; ~650 km) and northern British Columbia (Line 2; ~1245 km in two segments) that were acquired as part of the LITHOPROBE Slave - Northern Cordillera Lithospheric Evolution (SNORCLE) transect. Along Line 3, the layering is visible between 5.0 and 12.0 s (~15 to 36 km depth). It is followed southwestward for nearly 650 km (~500 km across strike) and thins to less than 1.0 s (~3.0-3.5 km thickness) near the Moho at the Yukon-Alaska international boundary. Farther south, along Line 2, the upper part of the layering correlates with outcrops of Proterozoic (1.76-1.0 Ga) strata on the east. Near the outcrop, the layering is >15 km thick. It projects westward into the middle and lower crust for ~700 km (~300 km across strike) where it disappears as a thin taper at the base of the crust. The layering is disrupted at the Tintina fault zone, a late to post-orogenic strike-slip fault with up to 800 km of displacement, which appears as a vertical zone of little reflectivity on both profiles (~300 km apart). The base of the layered reflection zone coincides with the Moho, which exhibits variable character and undulates in a series of broad (~150 km) arches. Although the mantle is generally non-reflective, an event dips eastward from ~14.0 s (~45 km) at the western end of Line 3 near the coast to ~21.0 s (73 km depth) beneath exposed Eocene magmatic rocks. It is interpreted as a relict subduction surface of the Kula plate. Some implications of the interpretation of Proterozoic layered rocks beneath most of the northern Cordillera are: (1) ancient North American crust and lithosphere project westward beneath most of the Northern Cordillera, (2) the detachments that carry deformed rocks the northern Canadian Cordillera are largely confined to the crust above the layering, and (3) rocks of most of the accreted terranes overlie the layering. Most of the accreted rocks thus appear to be thin (<10 km thick), far-traveled flakes. However, one major terrane, Stikinia, may thicken westward as the underlying layered zone thins such that the lower crustal layering disappears beneath the northeastern portion of Stikinia; the boundary between Stikinia and adjacent rocks to the east may be a crustal-scale tectonic wedge above the deep layering.

Series interconnected photovoltaic cells and method for making same

DOEpatents

Albright, Scot P.; Chamberlin, Rhodes R.; Thompson, Roger A.

1995-01-01

A novel photovoltaic module (10) and method for constructing the same are disclosed. The module (10) includes a plurality of photovoltaic cells (12) formed on a substrate (14) and laterally separated by interconnection regions (15). Each cell (12) includes a bottom electrode (16), a photoactive layer (18) and a top electrode layer (20). Adjacent cells (12) are connected in electrical series by way of a conductive-buffer line (22). The buffer line (22) is also useful in protecting the bottom electrode (16) against severing during downstream layer cutting processes.

Helium emission from model flare layers. [of outer solar atmosphere

NASA Technical Reports Server (NTRS)

Kulander, J. I.

1976-01-01

The emission of visible and UV He I and He II line radiation from a plane-parallel model flare layer characterized by electron temperatures of 10,000 to 50,000 K and electron densities of 10 to the 10th power to 10 to the 15th power per cu cm is analyzed by solving the statistical-equilibrium equations for a 30-level He I-II-III system, using parametric representations of the line and continuum radiation fields. The atomic model was chosen to provide accurate solutions for the first two resonance lines of He I and He II as well as for the D3 and 10,830-A lines of He I. Reaction rates are discussed, and sample solutions to the steady-state population equations are given for a generally optically thin gas assumed to be irradiated over 2pi sr by a blackbody spectrum at 6000 K. Specific results are examined for ionization equilibrium, level populations, approximate optical depths of a 1000-km-thick flare layer, line intensities, and upper-level population rates.

On-line Gibbs learning. II. Application to perceptron and multilayer networks

NASA Astrophysics Data System (ADS)

Kim, J. W.; Sompolinsky, H.

1998-08-01

In the preceding paper (``On-line Gibbs Learning. I. General Theory'') we have presented the on-line Gibbs algorithm (OLGA) and studied analytically its asymptotic convergence. In this paper we apply OLGA to on-line supervised learning in several network architectures: a single-layer perceptron, two-layer committee machine, and a winner-takes-all (WTA) classifier. The behavior of OLGA for a single-layer perceptron is studied both analytically and numerically for a variety of rules: a realizable perceptron rule, a perceptron rule corrupted by output and input noise, and a rule generated by a committee machine. The two-layer committee machine is studied numerically for the cases of learning a realizable rule as well as a rule that is corrupted by output noise. The WTA network is studied numerically for the case of a realizable rule. The asymptotic results reported in this paper agree with the predictions of the general theory of OLGA presented in paper I. In all the studied cases, OLGA converges to a set of weights that minimizes the generalization error. When the learning rate is chosen as a power law with an optimal power, OLGA converges with a power law that is the same as that of batch learning.

Numerical simulation for the coupled thermo-mechanical performance of a lined rock cavern for underground compressed air energy storage

NASA Astrophysics Data System (ADS)

Zhou, Shu-Wei; Xia, Cai-Chu; Zhao, Hai-Bin; Mei, Song-Hua; Zhou, Yu

2017-12-01

Compressed air energy storage (CAES) is a technology that uses compressed air to store surplus electricity generated from low power consumption time for use at peak times. This paper presents a thermo-mechanical modeling for the thermodynamic and mechanical responses of a lined rock cavern used for CAES. The simulation was accomplished in COMSOL Multiphysics and comparisons of the numerical simulation and some analytical solutions validated the thermo-mechanical modeling. Air pressure and temperatures in the sealing layer and concrete lining exhibited a similar trend of ‘up-down-down-up’ in one cycle. Significant temperature fluctuation occurred only in the concrete lining and sealing layer, and no strong fluctuation was observed in the host rock. In the case of steel sealing, principal stresses in the sealing layer were larger than those in the concrete and host rock. The maximum compressive stresses of the three layers and the displacement on the cavern surface increased with the increase of cycle number. However, the maximum tensile stresses exhibited the opposite trend. Polymer sealing achieved a relatively larger air temperature and pressure compared with steel and air-tight concrete sealing. For concrete layer thicknesses of 0 and 0.1 m and an initial air pressure of 4.5 MPa, the maximum rock temperature could reach 135 °C and 123 °C respectively in a 30 day simulation.

Photobleachable Diazonium Salt-Phenolic Resin Two-Layer Resist System

NASA Astrophysics Data System (ADS)

Uchino, Shou-ichi; Iwayanagi, Takao; Hashimoto, Michiaki

1988-01-01

This article describes a new negative two-layer photoresist system formed by a simple, successive spin-coating method. An aqueous acetic acid solution of diazonium salt and poly(N-vinylpyrrolidone) is deposited so as to contact a phenolic resin film spin-coated on a silicon wafer. The diazonium salt diffuses into the phenolic resin layer after standing for several minutes. The residual solution on the phenolic resin film doped with diazonium salt is spun to form the diazonium salt-poly(N-vinylpyrrolidone) top layer. This forms a uniform two-layer resist without phase separation or striation. Upon UV exposure, the diazonium salt in the top layer bleaches to act as a CEL dye, while the diazonium salt in the bottom layer decomposes to cause insolubilization. Half μm line-and-space patterns are obtained with an i-line stepper using 4-diazo-N,N-dimethylaniline chloride zinc chloride double salt as the diazonium salt and a cresol novolac resin for the bottom polymer layer. The resist formation processes, insolubilization mechanism, and the resolution capability of the new two-layer resist are discussed.

Surface-water hydrology of the Little Black River basin, Missouri and Arkansas, before water-land improvement practices

USGS Publications Warehouse

Berkas, W.R.; Femmer, Suzanne R.; Mesko, T.O.; Thompson, B.W.

1987-01-01

The U. S. Department of Agriculture, Soil Conservation Service, in accordance with Public Law 566, is implementing various types of water-land improvement practices in the Little Black River basin in southeastern Missouri. These practices are designed, in part, to decrease the suspended sediment (SS) transport in the basin, decrease flood damage in the basin, and improve drainage in the agricultural area. The general features of the basin, such as geology, groundwater hydrology, soils, land use, water use, and precipitation are described; surface water quantity, quality, and suspended sediment discharge are also described. The aquifers are the Mississippi River valley alluvial aquifer, which can yield about 3,500 gal/min to properly constructed wells, and the Ozark and St. Francois aquifers, which can yield from about 30 to 500 gal/min to properly constructed wells. Soils in the area have formed in loess and cherty residuum in the uplands or have formed in alluvial sediment in the lowlands. About 93% of the estimated 3 billion gal/year of water used in the basin is for crop irrigation. The average monthly precipitation varies slightly throughout the year, with an average annual precipitation of about 47 inches. Water quality data were collected at seven stations. Specific conductance values ranged from 50 to 400 microsiemens/cm at 25 C. Water temperatures ranged from 0.0 C in the winter to 33.5 C in summer. pH values ranged from 6.4 to 8.5 units. Dissolved oxygen concentrations ranged from 2.2 to 12.8 ml/l. Total nitrogen concentrations ranged from 0.13 to 2.20 ml/l as nitrogen, with organic nitrogen as the most abundant form. Phosphorus concentrations ranged from zero to 0.29 ml/l as phosphorus. Bacterial counts were largest during storm runoff in the basin with livestock waste as the significant contributor. For the period from October 1, 1980, to September 30, 1984, the average annual SS discharge ranged from 2,230 tons/yr in the headwater areas to 27,800 tons/yr at the most downstream station. The average annual SS yield ranged from 59.6 to 85.9 tons/sq mi. (Author 's abstract)

Propagation of sound waves through a linear shear layer: A closed form solution

NASA Technical Reports Server (NTRS)

Scott, J. N.

1978-01-01

Closed form solutions are presented for sound propagation from a line source in or near a shear layer. The analysis was exact for all frequencies and was developed assuming a linear velocity profile in the shear layer. This assumption allowed the solution to be expressed in terms of parabolic cyclinder functions. The solution is presented for a line monopole source first embedded in the uniform flow and then in the shear layer. Solutions are also discussed for certain types of dipole and quadrupole sources. Asymptotic expansions of the exact solutions for small and large values of Strouhal number gave expressions which correspond to solutions previously obtained for these limiting cases.

Epidermal cyst mimicking incision line metastasis.

PubMed

Gündoğdu, Ramazan; Ayhan, Erhan; Çolak, Tahsin

2017-01-01

Epidermal cysts are cystic tumors lined with keratinized squamous layer and filled with keratin debris. Epidermal cysts may develop by implantation of surface epidermal layer into the dermis or subcutaneous tissue after trauma or surgical procedures. Cervix cancer spreads either directly or via the vascular and lymphatic systems. Distant skin metastasis of endometrium or cervix cancer is very rare. In this case report, a patient who had a history of cervix cancer operation 11 years ago and presented with a mass that mimicked incision line metastasis and was histopathologically diagnosed with epidermal cyst is presented.

Epidermal cyst mimicking incision line metastasis

PubMed Central

Gündoğdu, Ramazan; Ayhan, Erhan; Çolak, Tahsin

2017-01-01

Epidermal cysts are cystic tumors lined with keratinized squamous layer and filled with keratin debris. Epidermal cysts may develop by implantation of surface epidermal layer into the dermis or subcutaneous tissue after trauma or surgical procedures. Cervix cancer spreads either directly or via the vascular and lymphatic systems. Distant skin metastasis of endometrium or cervix cancer is very rare. In this case report, a patient who had a history of cervix cancer operation 11 years ago and presented with a mass that mimicked incision line metastasis and was histopathologically diagnosed with epidermal cyst is presented. PMID:28740968

Refractory lining system for high wear area of high temperature reaction vessel

DOEpatents

Hubble, D.H.; Ulrich, K.H.

1998-04-21

A refractory-lined high temperature reaction vessel comprises a refractory ring lining constructed of refractory brick, a cooler, and a heat transfer medium disposed between the refractory ring lining and the cooler. The refractory brick comprises magnesia (MgO) and graphite. The heat transfer medium contacts the refractory brick and a cooling surface of the cooler, and is composed of a material that accommodates relative movement between the refractory brick and the cooler. The brick is manufactured such that the graphite has an orientation providing a high thermal conductivity in the lengthwise direction through the brick that is higher than the thermal conductivity in directions perpendicular to the lengthwise direction. The graphite preferably is flake graphite, in the range of about 10 to 20 wt %, and has a size distribution selected to provide maximum brick density. The reaction vessel may be used for performing a reaction process including the steps of forming a layer of slag on a melt in the vessel, the slag having a softening point temperature range, and forming a protective frozen layer of slag on the interior-facing surface of the refractory lining in at least a portion of a zone where the surface contacts the layer of slag, the protective frozen layer being maintained at or about the softening point of the slag. 10 figs.

Refractory lining system for high wear area of high temperature reaction vessel

DOEpatents

Hubble, D.H.; Ulrich, K.H.

1998-09-22

A refractory-lined high temperature reaction vessel comprises a refractory ring lining constructed of refractory brick, a cooler, and a heat transfer medium disposed between the refractory ring lining and the cooler. The refractory brick comprises magnesia (MgO) and graphite. The heat transfer medium contacts the refractory brick and a cooling surface of the cooler, and is composed of a material that accommodates relative movement between the refractory brick and the cooler. The brick is manufactured such that the graphite has an orientation providing a high thermal conductivity in the lengthwise direction through the brick that is higher than the thermal conductivity in directions perpendicular to the lengthwise direction. The graphite preferably is flake graphite, in the range of about 10 to 20 wt %, and has a size distribution selected to provide maximum brick density. The reaction vessel may be used for performing a reaction process including the steps of forming a layer of slag on a melt in the vessel, the slag having a softening point temperature range, and forming a protective frozen layer of slag on the interior-facing surface of the refractory lining in at least a portion of a zone where the surface contacts the layer of slag, the protective frozen layer being maintained at or about the softening point of the slag. 10 figs.

Absorption line studies of reflection from horizontally inhomogeneous layers. [in cloudy planetary atmospheres

NASA Technical Reports Server (NTRS)

Appleby, J. F.; Van Blerkom, D. J.

1975-01-01

The article details an inhomogeneous reflecting layer (IRFL) model designed to survey absorption line behavior from a Squires-like cloud cover (which is characterized by convection cell structure). Computational problems and procedures are discussed in detail. The results show trends usually opposite to those predicted by a simple reflecting layer model. Per cent equivalent width variations for the tower model are usually somewhat greater for weak than for relatively strong absorption lines, with differences of a factor of about two or three. IRFL equivalent width variations do not differ drastically as a function of geometry when the total volume of absorbing gas is held constant. The IRFL results are in many instances consistent with observed equivalent width variations of Jupiter, Saturn, and Venus.

Magnetic field line draping in the plasma depletion layer

NASA Technical Reports Server (NTRS)

Sibeck, D. G.; Lepping, R. P.; Lazarus, A. J.

1990-01-01

Simultaneous IMP 8 solar wind and ISEE 1/2 observations for a northern dawn ISEE 1/2 magnetopause crossing on November 6, 1977. During this crossing, ISEE 1/2 observed quasi-periodic pulses of magnetosheathlike plasma on northward magnetic field lines. The ISEE 1/2 observations were originally interpreted as evidence for strong diffusion of magnetosheath plasma across the magnetopause and the Kelvin-Helmholtz instability at the inner edge of the low-latitude boundary layer. An alternate explanation, in terms of magnetic field merging and flux transfer events, has also been advocated. In this paper, a third interpretation is proposed in terms of quasi-periodic magnetopause motion which causes the satellites to repeatedly exit the magnetosphere and observe draped northward magnetosheath magnetic field lines in the plasma depletion layer.

High-Si content BARC for dual-BARC systems such as trilayer patterning

NASA Astrophysics Data System (ADS)

Kennedy, Joseph; Xie, Song-Yuan; Wu, Ze-Yu; Katsanes, Ron; Flanigan, Kyle; Lee, Kevin; Slezak, Mark; Liu, Zhi; Lin, Shang-Ho

2009-03-01

This work discusses the requirements and performance of Honeywell's middle layer material, UVAS, for tri-layer patterning. UVAS is a high Si content polymer synthesized directly from Si containing starting monomer components. The monomers are selected to produce a film that meets the requirements as a middle layer for tri-layer patterning (TLP) and gives us a level of flexibility to adjust the properties of the film to meet the customer's specific photoresist and patterning requirements. Results of simulations of the substrate reflectance versus numerical aperture, UVAS thickness, and under layer film are presented. ArF photoresist line profiles and process latitude versus UVAS bake at temperatures as low as 150ºC are presented and discussed. Immersion lithographic patterning of ArF photoresist line space and contact hole features will be presented. A sequence of SEM images detailing the plasma etch transfer of line space photoresist features through the middle and under layer films comprising the TLP film stack will be presented. Excellent etch selectivity between the UVAS and the organic under layer film exists as no edge erosion or faceting is observed as a result of the etch process. A detailed study of the impact of a PGMEA solvent photoresist rework process on the lithographic process window of a TLP film stack was performed with the results indicating that no degradation to the UVAS film occurs.

PRESSURE SHIFT AND GRAVITATIONAL REDSHIFT OF BALMER LINES IN WHITE DWARFS: REDISCUSSION

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

Halenka, Jacek; Olchawa, Wieslaw; Madej, Jerzy

2015-08-01

The Stark-induced shift and asymmetry, the so-called pressure shift (PS) of H{sub α} and H{sub β} Balmer lines in spectra of DA white dwarfs (WDs), have been examined in detail as masking effects in measurements of the gravitational redshift in WDs. The results are compared with our earlier ones from a quarter of a century ago. In these earlier papers, the standard, symmetrical Stark line profiles, as a dominant constituent of the Balmer line profiles but shifted as a whole by the PS effect, were applied to all spectrally active layers of the WD atmosphere. At present, in each ofmore » the WD layers, the Stark line profiles (especially of H{sub β}) are inherently asymmetrical and shifted due to the effects of strong inhomogeneity of the perturbing fields in plasma. To calculate the Stark line profiles in successive layers of the WD atmosphere we used the modified Full Computer Simulation Method, able to take adequately into account the complexity of local elementary quantum processes in plasma. In the case of the H{sub α} line, the present value of Stark-induced shift of the synthetic H{sub α} line profile is about half the previous one and it is negligible in comparison with the gravitational redshift. In the case of the H{sub β} line, the present value of Stark-induced shift of the synthetic H{sub β} line profile is about twice the previous one. The source of this extra shift is the asymmetry of H{sub β} peaks.« less

Menin regulates Inhbb expression through an Akt/Ezh2-mediated H3K27 histone modification.

PubMed

Gherardi, Samuele; Ripoche, Doriane; Mikaelian, Ivan; Chanal, Marie; Teinturier, Romain; Goehrig, Delphine; Cordier-Bussat, Martine; Zhang, Chang X; Hennino, Ana; Bertolino, Philippe

2017-04-01

Although Men1 is a well-known tumour suppressor gene, little is known about the functions of Menin, the protein it encodes for. Since few years, numerous publications support a major role of Menin in the control of epigenetics gene regulation. While Menin interaction with MLL complex favours transcriptional activation of target genes through H3K4me3 marks, Menin also represses gene expression via mechanisms involving the Polycomb repressing complex (PRC). Interestingly, Ezh2, the PRC-methyltransferase that catalyses H3K27me3 repressive marks and Menin have been shown to co-occupy a large number of promoters. However, lack of binding between Menin and Ezh2 suggests that another member of the PRC complex is mediating this indirect interaction. Having found that ActivinB - a TGFβ superfamily member encoded by the Inhbb gene - is upregulated in insulinoma tumours caused by Men1 invalidation, we hypothesize that Menin could directly participate in the epigenetic-repression of Inhbb gene expression. Using Animal model and cell lines, we report that loss of Menin is directly associated with ActivinB-induced expression both in vivo and in vitro. Our work further reveals that ActivinB expression is mediated through a direct modulation of H3K27me3 marks on the Inhbb locus in Menin-KO cell lines. More importantly, we show that Menin binds on the promoter of Inhbb gene where it favours the recruitment of Ezh2 via an indirect mechanism involving Akt-phosphorylation. Our data suggests therefore that Menin could take an important part to the Ezh2-epigenetic repressive landscape in many cells and tissues through its capacity to modulate Akt phosphorylation. Copyright © 2017 Elsevier B.V. All rights reserved.

D 2 and DT Liquid-Layer Target Shots on NIF

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

Walters, Curtis; Alger, Ethan; Bhandarkar, Suhas

Experiments at the National Ignition Facility (NIF) using targets containing a Deuterium-Tritium (DT) fuel layer have, until recently, required that a high-quality layer of solid deuterium-tritium (herein referred to as an "ice-layer") be formed in the capsule. The development of a process to line the inner surface of a target capsule with a foam layer of a thickness that is typical of icelayers has resulted in the ability to field targets with liquid layers wetting the foam. Successful fielding of liquid-layer targets on NIF required not only a foam lined capsule, but also changes to the capsule filling process andmore » the manner with which the inventory is maintained in the capsule. Additionally, changes to target heater power and the temperature drops across target components were required in order to achieve the desired range of shot temperatures. These changes, and the target's performance during four target shots on NIF will be discussed.« less

Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2018-04-02

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Combustion Mechanisms of Wide Distribution Propellants

DTIC Science & Technology

1988-06-01

trimodal propellants were formulated. Each set contains an HTPB binder and duplicate formulations were made with either a IPDI or a DDI curative. The...Distinctive Mechanisms Previous studies [12,131 have shown that HTPB * propellants with wide AP distributions burn at rates much different than predictions...propellants. 17 .- = i.= i i i il =.. .l=limim mll ili= =.l i@ w. -’- 87% 400/20/ 3 MICRON,AP/ HTPB PROPELLANT 2.0 Z -1.0 --- 0--.-7- 0 CALCULATIONO0

Busulfan and Etoposide Followed by Peripheral Blood Stem Cell Transplant and Low-Dose Aldesleukin in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2017-05-03

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Childhood Acute Myeloid Leukemia in Remission; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia

Clofarabine, Cytarabine, and G-CSF in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2018-02-08

Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Promyelocytic Leukemia (M3); Recurrent Adult Acute Myeloid Leukemia

Decitabine in Treating Patients With Previously Untreated Acute Myeloid Leukemia

ClinicalTrials.gov

2016-05-18

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

CPI-613, Cytarabine, and Mitoxantrone Hydrochloride in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2017-07-31

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia

Performance Evaluation of a Radar by Computer

DTIC Science & Technology

1992-09-01

spatial-resolution map (0.25 nmi x 2.80 ) is employed to select the appropriate threshold values for the ground clutter; a doppler weighting that...seconds with approximately 16 mi’ x 3-Doppler-bin resolution. The second filter integrates over 5 seconds and covers within 20 miles of radar and within 3...also includes receiver matching loss , beamshape loss , and the signal processing loss. D, can be written as D,=D, (n) MLL,= -f- (3.2) where x

Development of Personalized Cancer Therapy for Men with AdvancedProstate Cancer

DTIC Science & Technology

2016-10-01

propose to study the mechanism of pharmacologic inhibition of the MLL complex in prostate cancer cells 3) we will assess the in vivo efficacy of the...Project Goals: 1) Enroll patients with known or suspicious for prostate cancer in the NIH MRI /metabolic imaging program, 2) Whole exome and...Henderson 02/11/2014-01/31/2017 Project Goals: 1) Enroll patients with known or suspicious for prostate cancer in the NIH MRI /metabolic imaging program

Allogeneic haematopoietic stem cell transplantation for infant acute lymphoblastic leukaemia with KMT2A (MLL) rearrangements: a retrospective study from the paediatric acute lymphoblastic leukaemia working group of the Japan Society for Haematopoietic Cell Transplantation.

PubMed

Kato, Motohiro; Hasegawa, Daiichiro; Koh, Katsuyoshi; Kato, Keisuke; Takita, Junko; Inagaki, Jiro; Yabe, Hiromasa; Goto, Hiroaki; Adachi, Souichi; Hayakawa, Akira; Takeshita, Yasufumi; Sawada, Akihisa; Atsuta, Yoshiko; Kato, Koji

2015-02-01

Allogeneic haematopoietic stem cell transplantation (HSCT) is still considered to play an important role as a consolidation therapy for high-risk infants with acute lymphoblastic leukaemia (ALL). Here, we retrospectively analysed outcomes of HSCT in infants with ALL based on nationwide registry data of the Japan Society for Haematopoietic Cell Transplantation. A total of 132 allogeneic HSCT for infant ALL with KMT2A (MLL) gene rearrangements, which were performed in first complete remission (CR1), were analysed. The 5-year overall survival rate after transplantation was 67·4 ± 4·5%). Although recent HSCT (after 2004) had a trend toward better survival, no statistical correlation was observed between outcomes and each factor, including age at diagnosis, initial leucocyte count, cytogenetics, donor types or conditioning of HSCT. Myeloablative conditioning with total body irradiation did not provide a better survival (60·7 ± 9·2%) over that with busulfan (BU; 67·8 ± 5·7%). Two of the 28 patients treated with irradiation, but none of the 90 BU-treated patients, developed a secondary malignant neoplasm. In conclusion, allogeneic HSCT using BU was a valuable option for infant ALL with KMT2A rearrangements in CR1. © 2014 John Wiley & Sons Ltd.

Extracellular matrix stiffness causes systematic variations in proliferation and chemosensitivity in myeloid leukemias.

PubMed

Shin, Jae-Won; Mooney, David J

2016-10-25

Extracellular matrix stiffness influences biological functions of some tumors. However, it remains unclear how cancer subtypes with different oncogenic mutations respond to matrix stiffness. In addition, the relevance of matrix stiffness to in vivo tumor growth kinetics and drug efficacy remains elusive. Here, we designed 3D hydrogels with physical parameters relevant to hematopoietic tissues and adapted them to a quantitative high-throughput screening format to facilitate mechanistic investigations into the role of matrix stiffness on myeloid leukemias. Matrix stiffness regulates proliferation of some acute myeloid leukemia types, including MLL-AF9 + MOLM-14 cells, in a biphasic manner by autocrine regulation, whereas it decreases that of chronic myeloid leukemia BCR-ABL + K-562 cells. Although Arg-Gly-Asp (RGD) integrin ligand and matrix softening confer resistance to a number of drugs, cells become sensitive to drugs against protein kinase B (PKB or AKT) and rapidly accelerated fibrosarcoma (RAF) proteins regardless of matrix stiffness when MLL-AF9 and BCR-ABL are overexpressed in K-562 and MOLM-14 cells, respectively. By adapting the same hydrogels to a xenograft model of extramedullary leukemias, we confirm the pathological relevance of matrix stiffness in growth kinetics and drug sensitivity against standard chemotherapy in vivo. The results thus demonstrate the importance of incorporating 3D mechanical cues into screening for anticancer drugs.

NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia

PubMed Central

LaRue, Rebecca S.; Nguyen, Hanh T.; Sachs, Karen; Noble, Klara E.; Mohd Hassan, Nurul Azyan; Diaz-Flores, Ernesto; Rathe, Susan K.; Sarver, Aaron L.; Bendall, Sean C.; Ha, Ngoc A.; Diers, Miechaleen D.; Nolan, Garry P.; Shannon, Kevin M.; Largaespada, David A.

2014-01-01

Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we used a murine model that harbors Mll-AF9 and a tetracycline-repressible, activated NRAS (NRASG12V). Using computational approaches to explore our gene-expression data sets, we found that NRASG12V enforced the leukemia self-renewal gene-expression signature and was required to maintain an MLL-AF9– and Myb-dependent leukemia self-renewal gene-expression program. NRASG12V was required for leukemia self-renewal independent of its effects on growth and survival. Analysis of the gene-expression patterns of leukemic subpopulations revealed that the NRASG12V-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell–enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1Low cells, which harbor leukemia stem cells, were preferentially sensitive to NRASG12V withdrawal. NRASG12V maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell–specific therapies. Together, these experimental results define a RAS oncogene–driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction. PMID:25316678

Calibrated Link Budget of a Silicon Photonics WDM Transceiver with SOA and Semiconductor Mode-Locked Laser.

PubMed

Moscoso-Mártir, Alvaro; Müller, Juliana; Islamova, Elmira; Merget, Florian; Witzens, Jeremy

2017-09-20

Based on the single channel characterization of a Silicon Photonics (SiP) transceiver with Semiconductor Optical Amplifier (SOA) and semiconductor Mode-Locked Laser (MLL), we evaluate the optical power budget of a corresponding Wavelength Division Multiplexed (WDM) link in which penalties associated to multi-channel operation and the management of polarization diversity are introduced. In particular, channel cross-talk as well as Cross Gain Modulation (XGM) and Four Wave Mixing (FWM) inside the SOA are taken into account. Based on these link budget models, the technology is expected to support up to 12 multiplexed channels without channel pre-emphasis or equalization. Forward Error Correction (FEC) does not appear to be required at 14 Gbps if the SOA is maintained at 25 °C and MLL-to-SiP as well as SiP-to-SOA interface losses can be maintained below 3 dB. In semi-cooled operation with an SOA temperature below 55 °C, multi-channel operation is expected to be compatible with standard 802.3bj Reed-Solomon FEC at 14 Gbps provided interface losses are maintained below 4.5 dB. With these interface losses and some improvements to the Transmitter (Tx) and Receiver (Rx) electronics, 25 Gbps multi-channel operation is expected to be compatible with 7% overhead hard decision FEC.

Brief Report: Human Acute Myeloid Leukemia Reprogramming to Pluripotency Is a Rare Event and Selects for Patient Hematopoietic Cells Devoid of Leukemic Mutations.

PubMed

Lee, Jong-Hee; Salci, Kyle R; Reid, Jennifer C; Orlando, Luca; Tanasijevic, Borko; Shapovalova, Zoya; Bhatia, Mickie

2017-09-01

Induced pluripotent stem cell reprogramming has provided critical insights into disease processes by modeling the genetics and related clinical pathophysiology. Human cancer represents highly diverse genetics, as well as inter- and intra-patient heterogeneity, where cellular model systems capable of capturing this disease complexity would be invaluable. Acute myeloid leukemia (AML) represents one of most heterogeneous cancers and has been divided into genetic subtypes correlated with unique risk stratification over the decades. Here, we report our efforts to induce pluripotency from the heterogeneous population of human patients that represents this disease in the clinic. Using robust optimized reprogramming methods, we demonstrate that reprogramming of AML cells harboring leukemic genomic aberrations is a rare event with the exception of those with de novo mixed-lineage leukemia (MLL) mutations that can be reprogrammed and model drug responses in vitro. Our findings indicate that unlike hematopoietic cells devoid of genomic aberrations, AML cells harboring driver mutations are refractory to reprogramming. Expression of MLL fusion proteins in AML cells did not contribute to induced reprogramming success, which continued to select for patient derived cells devoid of AML patient-specific aberrations. Our study reveals that unanticipated blockades to achieving pluripotency reside within the majority of transformed AML patient cells. Stem Cells 2017;35:2095-2102. © 2017 AlphaMed Press.

The comparison of heavy metals (Pb and Cd) in the water and sediment during spring and neap tide tidal periods in Popoh Bay, Indonesia

NASA Astrophysics Data System (ADS)

Yona, D.; Febriana, R.; Handayani, M.

2018-04-01

This study attempted to investigate different concentration of lead (Pb) dan cadmium (Cd) in the water and sediment during spring and neap tidal periods in the Popoh Bay, Indonesia. Water and sediment samples were taken during spring and neap tides from eight sampling stations in the study area. The result shows higher concentration of Pb than the concentration of Cd in both spring and neap tides due to higher input of Pb from the oil pollution by boat and fisheries activities. Pb concentrations were doubled during neap tide in both water and sediments with the value of 0.51 and 0.28 ml/L in the water during neap and spring tide, respectively; and 0.27 ppm and 0.16 mg/kg in the sediment during neap and spring tide, respectively. On the other hand, Cd concentrations in the water were found in almost similar values between spring and neap tide (0.159 and 0.165 ml/L in spring tide and neap tide, respectively), but in the sediment, the concentration was a little higher during spring tide (0.09 and 0.05 mg/kg during spring and neap tide, respectively). This study shows that water movement during spring and neap tides has significant effect on the distribution of heavy metals.

Effect of agomelatine on memory deficits and hippocampal gene expression induced by chronic social defeat stress in mice

PubMed Central

Martin, Vincent; Allaïli, Najib; Euvrard, Marine; Marday, Tevrasamy; Riffaud, Armance; Franc, Bernard; Mocaër, Elisabeth; Gabriel, Cecilia; Fossati, Philippe; Lehericy, Stéphane; Lanfumey, Laurence

2017-01-01

Chronic stress is known to induce not only anxiety and depressive-like phenotypes in mice but also cognitive impairments, for which the action of classical antidepressant compounds remains unsatisfactory. In this context, we investigated the effects of chronic social defeat stress (CSDS) on anxiety-, social- and cognitive-related behaviors, as well as hippocampal Bdnf, synaptic plasticity markers (PSD-95, Synaptophysin, Spinophilin, Synapsin I and MAP-2), and epigenetic modifying enzymes (MYST2, HDAC2, HDAC6, MLL3, KDM5B, DNMT3B, GADD45B) gene expression in C57BL/6J mice. CSDS for 10 days provoked long-lasting anxious-like phenotype in the open field and episodic memory deficits in the novel object recognition test. While total Bdnf mRNA level was unchanged, Bdnf exon IV, MAP-2, HDAC2, HDAC6 and MLL3 gene expression was significantly decreased in the CSDS mouse hippocampus. In CSDS mice treated 3 weeks with 50 mg/kg/d agomelatine, an antidepressant with melatonergic receptor agonist and 5-HT2C receptor antagonist properties, the anxious-like phenotype was not reversed, but the treatment successfully prevented the cognitive impairments and hippocampal gene expression modifications. Altogether, these data evidenced that, in mice, agomelatine was effective in alleviating stress-induced altered cognitive functions, possibly through a mechanism involving BDNF signaling, synaptic plasticity and epigenetic remodeling. PMID:28374847

Layering extraction from subsurface radargrams over Greenland and the Martian NPLD by combining wavelet analysis with Hough transforms

NASA Astrophysics Data System (ADS)

Xiong, Si-Ting; Muller, Jan-Peter

2017-04-01

Extracting lines from an imagery is a solved problem in the field of edge detection. Different to images taken by camera, radargrams are a set of radar echo profiles, which record wave energy reflected by subsurface reflectors, at each location of a radar footprint along the satellite's ground track. The radargrams record where there is a dielectric contrast caused by different deposits, and other subsurface features, such as facies, and internal distributions like porosity and fluids. Among the subsurface features, layering is an important one which reflect the sequence of seasonal or yearly deposits on the ground [1-2]. In the field of image processing, line detection methods, such as the Radon Transform or Hough Transform, are able to extract these subsurface layers from rasterised versions of the echograms. However, due to the attenuation of radar waves whilst propagating through geological media, radargrams sometimes suffer from gradient and high background noise. These attributes of radargrams cause errors in detection when conventional line detection methods are directly applied. In this study, we have developed a continuous wavelet analysis technique to be applied directly to the radar echo profiles in a radargram in order to detect segmented lines, and then a conventional line detection method, such as a Hough transform can be applied to connect these segmented lines. This processing chain is tested by using datasets from a radargram acquired by the Multi-channel Coherent Radar Depth Sounder (MCoRDS) on an airborne platform in Greenland and a radargram acquired by the SHAllow RADar (SHARAD) on board the Mars Reconnaissance Orbiter (MRO) [3] over Martian North Polar Layered Deposits (NPLD). Keywords: Subsurface mapping, Radargram, SHARAD, Greenland, Martian NPLD, Subsurface layering, line detection References: [1] Phillips, R. J., et al. "Mars north polar deposits: Stratigraphy, age, and geodynamical response." Science 320.5880 (2008): 1182-1185. [2] Cutts, James A., and Blake H. Lewis. "Models of climate cycles recorded in Martian polar layered deposits." Icarus 50.2 (1982): 216-244. [3] Plaut J J, Picardi G, Safaeinili A, et al. Subsurface radar sounding of the south polar layered deposits of Mars[J]. science, 2007, 316(5821): 92-95. Acknowledgements: Part of the research leading to these results has received funding from the STFC "MSSL Consolidated Grant" ST/K000977/1 and partial support from the European Union's Seventh Framework Programme (FP7/2007-2013) under iMars grant agreement No. 607379 as well as from the China Scholarship Council and the UCL Dean of MAPS fund.

The study of microstrip antenna arrays and related problems

NASA Technical Reports Server (NTRS)

Lo, Y. T.

1986-01-01

In February, an initial computer program to be used in analyzing the four-element array module was completed. This program performs the analysis of modules composed of four rectangular patches which are corporately fed by a microstrip line network terminated in four identical load impedances. Currently, a rigorous full-wave analysis of various types of microstrip line feed structures and patches is being performed. These tests include the microstrip line feed between layers of different electrical parameters. A method of moments was implemented for the case of a single dielectric layer and microstrip line fed rectangular patches in which the primary source is assumed to be a magnetic current ribbon across the line some distance from the patch. Measured values are compared with those computed by the program.

Instability and Transition of Flow at, and Near, an Attachment-Line: Including Control by Surface Suction

NASA Technical Reports Server (NTRS)

Smith, A.; Poll, D. I. A.

1998-01-01

Experiments have been performed on an untapered, swept cylinder model in the Cranfield College of Aeronautics 8 ft x 6 ft low-speed wind tunnel to investigate the effect of surface transpiration on the process of relaminarization in the attachment-line boundary layer. Suction coefficients for complete suppression of turbulence were determined as a function of Reynolds number and spanwise distance. The effect of attachment-line suction on the spanwise propagation of gross disturbances emanating from the fuselage-wing junction region was also studied. Finally, the effect of blowing on a laminar attachment-line boundary layer was also considered and excellent agreement was achieved with previous studies.

Expression of myostatin is not altered in lines of poultry exhibiting myofiber hyper- and hypoplasia.

PubMed

Mott, I; Ivarie, R

2002-06-01

Decades of selective breeding have yielded lines of poultry with substantial myofiber hyperplasia, vet little is known about what genes have been altered during the course of selection. Myostatin is a strong negative regulator of muscle mass in mice and cattle and could have been one of many genetic factors contributing to increased myofiber deposition in growth-selected lines of poultry. To test this hypothesis, the sequence and expression patterns of myostatin were analyzed in growth-selected lines of chickens and quail. The sequence of broiler myostatin cDNA, amplified via reverse transcription (RT)-PCR from embryonic muscle RNA, contained no missense mutations in the coding sequence when compared to that of White Leghorn layers, although two silent single nucleotide polymorphisms (SNP) were found. Northern analysis of myostatin transcripts from embryonic pectoralis and quadriceps showed no significant differences in expression levels between broiler and layer muscle RNA. However, levels of myostatin transcripts were greatly reduced in muscles of posthatch chicks compared to embryonic muscle. Myostatin protein was also present in broiler and layer embryonic muscle at similar levels. No significant polymorphisms or differences in RNA expression levels were found in embryonic muscles of divergently selected lines of Japanese quail. These results indicate that intense artificial selection in these growth-selected lines of poultry has neither silenced the expression of myostatin nor created null alleles via mutation in the lines analyzed.

Program scheme using common source lines in channel stacked NAND flash memory with layer selection by multilevel operation

NASA Astrophysics Data System (ADS)

Kim, Do-Bin; Kwon, Dae Woong; Kim, Seunghyun; Lee, Sang-Ho; Park, Byung-Gook

2018-02-01

To obtain high channel boosting potential and reduce a program disturbance in channel stacked NAND flash memory with layer selection by multilevel (LSM) operation, a new program scheme using boosted common source line (CSL) is proposed. The proposed scheme can be achieved by applying proper bias to each layer through its own CSL. Technology computer-aided design (TCAD) simulations are performed to verify the validity of the new method in LSM. Through TCAD simulation, it is revealed that the program disturbance characteristics is effectively improved by the proposed scheme.

Quantifying the effects of genetic selection and genetic variation for body size, carcass composition, and meat quality in the domestic fowl (Gallus domesticus).

PubMed

Sandercock, D A; Nute, G R; Hocking, P M

2009-05-01

A multistrain experiment was conducted to quantify the extent of genetic differences in carcass and muscle yields, muscle quality, support organs, and taste panel assessments of cooked breast muscle of 296 birds from 37 lines of commercial broiler, layer, and traditional chickens. The birds were reared as broilers and 4 males from each line were slaughtered at 6 and 10 wk of age. The extent of genetic variation was measured as the intraclass correlation. The intraclass correlation for live weight; carcass yields; breast, drum, and wing portions; and associated muscle yields were high, whereas those for the thigh portion and yield were low. Broilers had more breast and thigh muscle but similar drum muscle as a proportion of carcass weight compared with layer and traditional lines. Genetic variation for muscle quality (plasma creatine kinase activity) was high; that for muscle color (L, a, and b) and hemorrhage score were moderate in size and were greater at 10 than at 6 wk of age. Broiler lines had greater creatine kinase activity indicative of greater muscle pathology; breast muscle was lighter, less red and yellow in color, and had a greater hemorrhage score than muscle from layer and traditional lines, which were similar. Intraclass correlations for taste panel scores were low and generally not significant except for texture, chicken flavor intensity, flavor liking, and overall liking at 6 wk of age. Significantly greater scores from broiler compared with layer and traditional lines for texture, chicken flavor intensity, and overall liking were observed. At 10 wk of age, chicken flavor intensity did not differ between broiler or layer birds but was significantly greater in both groups than traditional birds. Genetic variation for relative weight of abdominal fat, spleen, and heart was moderately high and greater at 10 than at 6 wk of age. Broiler carcasses had a relatively high proportion of abdominal fat and smaller spleen and heart weights.

Optical Coatings With Graded Index Layers For High Power Laser Applications: Design

NASA Astrophysics Data System (ADS)

Zukic, Muamer; Guenther, Karl H.

1988-06-01

Graded index layers provide a greater flexibility for the design of optical coatings than "homogeneous" layers. A graded index layer can replace the whole or a part of a traditional multilayer stack of alternating thin films of high and low refractive index. This paper presents design examples for broadband antireflection coatings, narrowband high reflectors (also referred to as minus filters or rejection line filters), and non-polarizing beam splitters. Optimized refractive index profiles are derived for broadband antireflection coatings for various combinations of incident medium and substrate. The rejection line filter example uses a sinusoidal (rugate) index profile. The non-polarizing beamsplitter summarizes the topical contents of a paper presented in another conference at the same symposium.

Effect of Wall Temperature on Roughness Induced Attachment-Line Transition

NASA Technical Reports Server (NTRS)

Dietz, Anthony; Coleman, Colin; Laub, Jim; Poll, D. I. A.; Nixon, David (Technical Monitor)

1999-01-01

An experiment on a cooled swept cylinder in a low-disturbance Mach 1.6 wind tunnel is described. The flow attachment line is disturbed by trip wires of varying size and the laminar/turbulent state of the downstream boundary layer is determined with a hot wire. The results demonstrate that although cooling the wall increases the stability of the boundary layer, it promotes roughness induced transition. Analysis of the data suggests that the attachment- line Reynolds number can account for the effect of wall cooling if the viscosity is evaluated at a particular reference temperature.

Colliding Magnetic Flux Ropes and Quasi-Separatrix Layers in a Laboratory Plasma

NASA Astrophysics Data System (ADS)

Lawrence, Eric Eugene

An experimental study of the dynamics of colliding magnetic flux ropes and the magnetic reconnection that occurs during these collisions is presented. A magnetic flux rope is a bundle of twisted magnetic field lines that is ubiquitous in space and solar plasmas. The flux ropes are created in the Large Plasma Device (LAPD) using two heated lanthanum hexaboride (LaB6) cathodes that inject currents into the background plasma. The currents are initially parallel to the background magnetic field. The azimuthal field of each current together with the background axial field create helical twisted flux ropes. It is found that the flux ropes rotate in time (corkscrew) and collide with each other. During a collision, antiparallel magnetic fields can undergo magnetic reconnection. When these collisions occur, we observe current layers flowing in the opposite direction of the injected current, a signatuare of reconnection. Analysis of the three-dimensional magnetic field lines shows the existence of quasi-separatrix layers (QSLs). These are regions in the magnetic configuration where there are large spatial gradients in the connectivity of field line footpoints in the boundary surfaces. QSLs are thought to be favorable sites for magnetic reconnection. It is shown that the location and shape of the QSL is similar to what is seen in simulations of merging flux ropes. Furthermore, the field line structure of the QSL is similar to that of a twisted hyperbolic flux tube (HFT). An HFT is a type of QSL that has been shown to be a preferred site for current sheet formation in simulations of interacting coronal loops. The HFT in this experiment is found to be generally near the reverse current layers, although the agreement is not perfect. Looking at the time evolution of the QSL, we find that the QSL cross-sectional area grows and contracts at the same time that the flux ropes collide and that the reverse current layers appear. Analysis of the field line motion shows that, during reconnection, bundles of field lines rapidly flip across the QSLs. This is analagous to the way that field lines are pushed across a separatrix in 2D reconnection.

Impact of humidity on functionality of on-paper printed electronics.

PubMed

Bollström, Roger; Pettersson, Fredrik; Dolietis, Peter; Preston, Janet; Osterbacka, Ronald; Toivakka, Martti

2014-03-07

A multilayer coated paper substrate, combining barrier and printability properties was manufactured utilizing a pilot-scale slide curtain coating technique. The coating structure consists of a thin mineral pigment layer coated on top of a barrier layer. The surface properties, i.e. smoothness and surface porosity, were adjusted by the choice of calendering parameters. The influence of surface properties on the fine line printability and conductivity of inkjet-printed silver lines was studied. Surface roughness played a significant role when printing narrow lines, increasing the risk of defects and discontinuities, whereas for wider lines the influence of surface roughness was less critical. A smooth, calendered surface resulted in finer line definition, i.e. less edge raggedness. Dimensional stability and its influence on substrate surface properties as well as on the functionality of conductive tracks and transistors were studied by exposure to high/low humidity cycles. The barrier layer of the multilayer coated paper reduced the dimensional changes and surface roughness increase caused by humidity and helped maintain the conductivity of the printed tracks. Functionality of a printed transistor during a short, one hour humidity cycle was maintained, but a longer exposure to humidity destroyed the non-encapsulated transistor.

Possible effects of free convection on fire behavior - laminar and turbulent line and point sources of heat

Treesearch

S. Scesa; F. M. Sauer

1954-01-01

The transfer theory is applied to the problem of atmospheric diffusion of momentum and heat induced by line and point sources of heat on the surface of the earth. In order that the validity of the approximations of the boundary layer theory be realized, the thickness of the layer in which the temperatures and velocities differ appreciably from the values at...

Detailed line shape analysis of the C KVV Auger peak of two carbon allotropes measured using a time of flight positron annihilation induced Auger electron spectrometer

NASA Astrophysics Data System (ADS)

Fairchild, A. J.; Chirayath, V. A.; Chrysler, M. D.; Gladen, R. W.; Imam, S. K.; Koymen, A. R.; Weiss, A. H.

We report a detailed line shape analysis of the positron induced C KVV Auger line shape from highly oriented pyrolytic graphite (HOPG) and a single layer of graphene grown on polycrystalline Cu. A model consisting of the self-fold of the one-electron density of states including terms for hole-hole interactions, charge screening effects, and intrinsic loss mechanisms is compared to experimental C KVV line shapes measured using a positron induced Auger electron spectrometer (PAES). In traditional Auger spectroscopies which use an electron or photon to initiate the Auger process, extracting the relatively small Auger signal from the large secondary background can be quite difficult. Using a very low energy positron beam to create the core hole through an anti-matter matter annihilation entirely eliminates this background. Additionally, PAES has sensitivity to the top most atomic layer since the positron becomes trapped in an image potential well at the surface before annihilation. Therefore, the PAES signal from a single layer of graphene on polycrystalline Cu is primarily from the graphene overlayer with small contributions from the Cu substrate while the PAES signal from HOPG can be viewed as a single graphene layer with a graphite substrate. The influence of these two substrates on C KVV line shape is discussed. This work was supported by NSF Grant No. DMR 1508719 and DMR 1338130.

Vortical structures and development of laminar flow over convergent-divergent riblets

NASA Astrophysics Data System (ADS)

Xu, Fang; Zhong, Shan; Zhang, Shanying

2018-05-01

In this work, the development of a laminar boundary layer over a rectangular convergent-divergent riblet section with a finite streamwise length is studied experimentally using dye visualization and particle image velocimetry in a water flume. The flow topology over this highly directional spanwise roughness is established from this study. It is shown that convergent-divergent riblets generate a spanwise flow above the riblets from the diverging line toward the adjacent converging line. This consequently leads to the formation of a weak recirculating secondary flow in cross-stream planes across the boundary layer that creates a downwash motion over the diverging line and an upwash motion over the converging line. It is found that the fluid inside the riblet valley follows a helicoidal path and it also interacts with the crossflow boundary layer hence playing a key role in determining the structure of the secondary flow across the boundary layer. The impact of riblet wavelength on vortical structures is also revealed for the first time. A larger riblet wavelength is seen to produce a stronger upwash/downwash and hence a more intense secondary flow as well as a stronger deceleration effect on the crossflow. Furthermore, the streamwise development of the flow over the riblet section can be divided into a developing stage followed by a developed stage. In the developing stage, the magnitude of induced streamwise velocity and vorticity over the converging line continues to increase, whereas in the developed stage the values of these parameters remain essentially unchanged.

AR-42 and Decitabine in Treating Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2018-03-12

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Bendamustine and Idarubicin in Treating Older Patients With Previously Untreated AML or MDS

ClinicalTrials.gov

2017-07-20

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Untreated Adult Acute Myeloid Leukemia

Noise Hazard Evaluation Sound Level Data on Noise Sources

DTIC Science & Technology

1975-01-01

Saw, Root Woodworking 43-20-J 102 16. Construction Saw, DeWalt Industrial 2185A 96 17. Cross-Cut Sw, Automatic 1-H 94 18, Cross-Cut Saw, DeWalt 3561...Saw, GM Diehr 750 92 53. Rip Saw, Wabach Industrial 750 97 59. Rip Saw, Yates American B. 102 60. Router: Black & Decker 118 61. Ruuter, Rockwell 150B...13. Sander, Disk, National-Detroit Dual Action 100 14. Stapler , Senco Mll 94* 15. Stapling Gun, Bostich II 105* 16. Stapling Gun, Bostich III 104* 17

Dasatinib, Cytarabine, and Idarubicin in Treating Patients With High-Risk Acute Myeloid Leukemia

ClinicalTrials.gov

2018-05-04

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

A Methodology for Determining Land Value and Associated Benefits Created from Dredged Material Containment.

DTIC Science & Technology

1978-06-01

accessibility. 228. The diagram below represents the basic relationship among the physical criteria: n^^^o MLl»3 Geographic Location Setting ^ r-; 11 T>,r...value is the difference be- tween the raw site value and the development value. The diagram below illustrates the basic relationship among the...except for the effect of demand on market price and the length of time that a site would remain on the market. The diagram below illustrates the

Study of iron deposit using seismic refraction and resistivity in Carajás Mineral Province, Brazil

NASA Astrophysics Data System (ADS)

Nogueira, Pedro Vencovsky; Rocha, Marcelo Peres; Borges, Welitom Rodrigues; Silva, Adalene Moreira; Assis, Luciano Mozer de

2016-10-01

This work comprises the acquisition, processing and interpretation of 2D seismic shallow refraction (P-wave) and resistivity profiles located in the iron ore deposit of N4WS, Carajás Mineral Province (CMP), northern Brazil. The geophysical methods were used to identify the boundaries of the iron ore deposit. Another objective was to evaluate the potentiality of these geophysical methods in that geological context. In order to validate the results, the geophysical lines were located to match a geological borehole line. For the seismic refraction, we used 120 channels, spaced by 10 m, in a line of 1190 m, with seven shot points. The resistivity method used in the acquisition was the electrical resistivity imaging, with pole-pole array, in order to reach greater depths. The resistivity line had a length of 1430 m, with 10 m spacing between electrodes. The seismic results produced a model with two distinct layers. Based on the velocities values, the first layer was interpreted as altered rocks, and the second layer as more preserved rocks. It was not possible to discriminate different lithologies with the seismic method inside each layer. From the resistivity results, a zone of higher resistivity (> 3937 Ω·m) was interpreted as iron ore, and a region of intermediate resistivity (from 816 to 2330 Ω·m) as altered rocks. These two regions represent the first seismic layer. On the second seismic layer, an area with intermediated resistivity values (from 483 to 2330 Ω·m) was interpreted as mafic rocks, and the area with lower resistivity (< 483 Ω·m) as jaspilite. Our results were compared with geological boreholes and show reasonable correlation, suggesting that the geophysical anomalies correspond to the main variations in composition and physical properties of rocks.

Thermal Boundary Layer Effects on Line-of-Sight Tunable Diode Laser Absorption Spectroscopy (TDLAS) Gas Concentration Measurements.

PubMed

Qu, Zhechao; Werhahn, Olav; Ebert, Volker

2018-06-01

The effects of thermal boundary layers on tunable diode laser absorption spectroscopy (TDLAS) measurement results must be quantified when using the line-of-sight (LOS) TDLAS under conditions with spatial temperature gradient. In this paper, a new methodology based on spectral simulation is presented quantifying the LOS TDLAS measurement deviation under conditions with thermal boundary layers. The effects of different temperature gradients and thermal boundary layer thickness on spectral collisional widths and gas concentration measurements are quantified. A CO 2 TDLAS spectrometer, which has two gas cells to generate the spatial temperature gradients, was employed to validate the simulation results. The measured deviations and LOS averaged collisional widths are in very good agreement with the simulated results for conditions with different temperature gradients. We demonstrate quantification of thermal boundary layers' thickness with proposed method by exploitation of the LOS averaged the collisional width of the path-integrated spectrum.

Apparatus and method for the electrolytic production of metals

DOEpatents

Sadoway, Donald R.

1991-01-01

Improved electrolytic cells and methods for producing metals by electrolytic reduction of a compound dissolved in a molten electrolyte are disclosed. In the improved cells and methods, a protective surface layer is formed upon at least one electrode in the electrolytic reduction cell and, optionally, upon the lining of the cell. This protective surface layer comprises a material that, at the operating conditions of the cell: (a) is not substantially reduced by the metal product; (b) is not substantially reactive with the cell electrolyte to form materials that are reactive with the metal product; and, (c) has an electrochemical potential that is more electronegative than that of the compound undergoing electrolysis to produce the metal product of the cell. The protective surface layer can be formed upon an electrode metal layer comprising a material, the oxide of which also satisfies the protective layer selection criteria. The protective layer material can also be used on the surface of a cell lining.

User-guided segmentation for volumetric retinal optical coherence tomography images

PubMed Central

Yin, Xin; Chao, Jennifer R.; Wang, Ruikang K.

2014-01-01

Abstract. Despite the existence of automatic segmentation techniques, trained graders still rely on manual segmentation to provide retinal layers and features from clinical optical coherence tomography (OCT) images for accurate measurements. To bridge the gap between this time-consuming need of manual segmentation and currently available automatic segmentation techniques, this paper proposes a user-guided segmentation method to perform the segmentation of retinal layers and features in OCT images. With this method, by interactively navigating three-dimensional (3-D) OCT images, the user first manually defines user-defined (or sketched) lines at regions where the retinal layers appear very irregular for which the automatic segmentation method often fails to provide satisfactory results. The algorithm is then guided by these sketched lines to trace the entire 3-D retinal layer and anatomical features by the use of novel layer and edge detectors that are based on robust likelihood estimation. The layer and edge boundaries are finally obtained to achieve segmentation. Segmentation of retinal layers in mouse and human OCT images demonstrates the reliability and efficiency of the proposed user-guided segmentation method. PMID:25147962

User-guided segmentation for volumetric retinal optical coherence tomography images.

PubMed

Yin, Xin; Chao, Jennifer R; Wang, Ruikang K

2014-08-01

Despite the existence of automatic segmentation techniques, trained graders still rely on manual segmentation to provide retinal layers and features from clinical optical coherence tomography (OCT) images for accurate measurements. To bridge the gap between this time-consuming need of manual segmentation and currently available automatic segmentation techniques, this paper proposes a user-guided segmentation method to perform the segmentation of retinal layers and features in OCT images. With this method, by interactively navigating three-dimensional (3-D) OCT images, the user first manually defines user-defined (or sketched) lines at regions where the retinal layers appear very irregular for which the automatic segmentation method often fails to provide satisfactory results. The algorithm is then guided by these sketched lines to trace the entire 3-D retinal layer and anatomical features by the use of novel layer and edge detectors that are based on robust likelihood estimation. The layer and edge boundaries are finally obtained to achieve segmentation. Segmentation of retinal layers in mouse and human OCT images demonstrates the reliability and efficiency of the proposed user-guided segmentation method.

Linear Stability of Relativistic Space-Charge Flow in a Magnetically Insulated Transmission Line Oscillator

DTIC Science & Technology

1989-04-01

MILO Magnetica fy insulated transmission line Slow-wave structure Relativistic Brillouin flow Space-charge waves Slow electromagnetic waves (over) 19... resonant layer always see a decelerating axial electric field. Consequently, field energy increases at the expense of particle energy. 17 AFWL-TR-88-103...Ve). If ve is greater than the structure coupling velocity, a resonant layer of electrons will always be present, and oscillations will occur at any

Mode propagation in optical nanowaveguides with dielectric cores and surrounding metal layers.

PubMed

Lapchuk, Anatoly S; Shin, Dongho; Jeong, Ho-Seop; Kyong, Chun Su; Shin, Dong-Ik

2005-12-10

The mode spectrum in an optical nanowaveguide consisting of a dielectric-core layer surrounded by two identical metal layers is investigated. A simple model based on mode matching to predict the properties of mode propagation in such optical nanowaveguides is proposed. It is shown that quasi-TM00 and quasi-TM10 modes supported by an optical microstrip line do not have a cutoff frequency, regardless of the size of the metal strips, the thickness of the dielectric slab, and the cross-sectional shape. The transverse size of the TM00 mode supported by a nanosized microstrip line was found to be approximately equal to the transverse dimension of the microstrip line. In closed rectangular and elliptical nanowaveguides, i.e., in which all dielectric surfaces are covered with metal films, the cross-sectional shape of the waveguide should be stretched along one side to produce propagation conditions for the fundamental mode.

LH Power Losses In Front of the JET Launcher

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

Jacquet, P.; Arnoux, G.; Kirov, K.

2009-11-26

In recent JET experiments, Lower Hybrid (LH) power losses in the Scrape-Off Layer (SOL) were characterized using infra-red (IR) thermography. Hot spots were observed on objects intercepting the field lines passing in front of the LH launcher, i.e. on poloidal limiters and on dumplates located at the top of the tokamak; their locations being in good agreement with magnetic field line tracing using the EFIT equilibrium code. The dumplate temperature was monitored while scanning the launcher position so that the radial distance between field lines intercepting the hot spots and the launcher was increased up to 3.5 cm. The dissipationmore » layer in front of the launcher was estimated to be at least 3.5 cm wide, in agreement with recent measurements on Tore-Supra, but not with simple models that predict a dissipation layer in the mm range.« less

Experimental study of HgCdTe imaging sensor irradiated by pulse CO2 laser

NASA Astrophysics Data System (ADS)

Wang, Xi; Wang, Qingsheng; Hu, Hongtao; Fang, Xiaodong; Nie, Jinsong

2016-10-01

The damages of TEA-CO2 laser to HgCdTe imaging sensor are researched experimentally and theoretically. The shadows, cracks and dark line are observed. There is a gap between photosensitive layer and CdZnTe which decreases light transmittance, so that the shadows occur. It shows that the crack damages begin from photosensitive layer. The sensor is irradiated by pulse laser, the absorptivity of photosensitive layer is strong, sharp temperatures fluctuations inside the sensor, leading to stress. With the stress increased, the cracks are observed on the surface of the detector. Cracked the surface of the substrate, and effective transmission reduced, which caused gray pixel response decline. The dark line in image occurs several times because Hg atoms separate out from the detector and gather together at the Si-COMS which makes a short circuit between silicon substrate and signal choice line. The volatility of Hg makes the short circuit is unstable, resulting in the dark line repeated in the output image, but the short circuit occurs by chance.

The preparation method of terahertz monolithic integrated device

NASA Astrophysics Data System (ADS)

Zhang, Cong; Su, Bo; He, Jingsuo; Zhang, Hongfei; Wu, Yaxiong; Zhang, Shengbo; Zhang, Cunlin

2018-01-01

The terahertz monolithic integrated device is to integrate the pumping area of the terahertz generation, the detection area of the terahertz receiving and the metal waveguide of terahertz transmission on the same substrate. The terahertz generation and detection device use a photoconductive antenna structure the metal waveguide use a microstrip line structure. The evanescent terahertz-bandwidth electric field extending above the terahertz transmission line interacts with, and is modified by, overlaid dielectric samples, thus enabling the characteristic vibrational absorption resonances in the sample to be probed. In this device structure, since the semiconductor substrate of the photoconductive antenna is located between the strip conductor and the dielectric layer of the microstrip line, and the semiconductor substrate cannot grow on the dielectric layer directly. So how to prepare the semiconductor substrate of the photoconductive antenna and how to bond the semiconductor substrate to the dielectric layer of the microstrip line is a key step in the terahertz monolithic integrated device. In order to solve this critical problem, the epitaxial wafer structure of the two semiconductor substrates is given and transferred to the desired substrate by two methods, respectively.

Attachment-Line Heating in a Compressible Flow

NASA Astrophysics Data System (ADS)

Reed, Helen; Saric, William

2011-11-01

The attachment-line boundary layer on a swept wing can be subject to either an instability or contamination by wing-root turbulence. A model of the attachment-line boundary layer is first developed including compressibility and wall heating in a Falkner-Skan-Cooke class of 3-D boundary layers with Hartree parameter of 1.0. For cases otherwise subcritical to either contamination or instability, the destabilizing effect of leading-edge heating under a variety of sweep angles and flight conditions is demonstrated. The results correlate with the attachment-line Reynolds number. Because the required heating levels are reasonable and achievable to trip the flow over the wing to turbulent, one possible application of this work is in the establishing of a baseline turbulent flow (on demand) for the calibration of a laminar-flow-control health monitoring system. *Portion based on work under Framework Agreement between Airbus Americas and NIA, and opinions, findings, conclusions do not necessarily reflect views of Airbus or NIA. Support from AFOSR/NASA National Center for Hypersonic Research in Laminar-Turbulent Transition through Grant FA9550-09-1-0341 gratefully acknowledged.

Method and apparatus for an inflatable shell

NASA Technical Reports Server (NTRS)

Johnson, Christopher J. (Inventor)

2012-01-01

A method of assembling an inflatable shell of a structure comprises folding a plurality of shell sections about a set of fold lines and integrating the plurality of shell sections together with one another to form the shell. In another embodiment, an inflatable shell comprises a plurality of shell sections, each shell section having two pairs of fold lines for folding into stowage comprising a first gore section having a plurality of first gore panels layered and collectively folded about at a first set of fold lines. Each layer of the first gore panels and second gore panels are configured such that, once the first gore panel and second gore panel are attached to one another at the respective side edges of each panel, the lines of attachment forming a second set of fold lines for the shell section. A system and method for fabricating gore panels is also disclosed.

A spectroscopic study using line ratios of lithiumlike ions in a laser-produced plasma

NASA Astrophysics Data System (ADS)

Moreno, J. C.; Goldsmith, S.; Griem, H. R.

1989-02-01

Spectra of highly ionized titanium and calcium in the extreme ultraviolet region were observed in laser-produced plasmas using the OMEGA 24 beam (351 nm) laser system at the University of Rochester. The plasmas were produced using glass microballoon targets coated with a layer of a medium Z element and a layer of parylene (CH). Time-integrated electron temperatures and densities were obtained by comparing measured line intensity ratios of lithiumlike charge states of Ti and Ca to numerical calculations from a collisional-radiative model. The variation of line intensity ratios with electron density and temperature using the collisional-radiative model is discussed.

Frequency Domain Modelling of Electromagnetic Wave Propagation in Layered Media

NASA Astrophysics Data System (ADS)

Schmidt, Felix; Lünenschloss, Peter; Mai, Juliane; Wagner, Norman; Töpfer, Hannes; Bumberger, Jan

2016-04-01

The amount of water in porous media such as soils and rocks is a key parameter when water resources are under investigation. Especially the quantitative spatial distribution and temporal evolution of water contents in soil formations are needed. In high frequency electromagnetic applications soil water content is quantitatively derived from the propagation behavior of electromagnetic waves along waveguides embedded in soil formations. The spatial distribution of the dielectric material properties along the waveguide can be estimated by numerical solving of the inverse problem based on the full wave forward model in time or frequency domain. However, current approaches mostly neglect or approximate the frequency dependence of the electromagnetic material properties of transfer function of the waveguide. As a first prove of concept a full two port broadband frequency domain forward model for propagation of transverse electromagnetic (TEM) waves in coaxial waveguide has been implemented. It is based on the propagation matrix approach for layered transmission line sections. Depending on the complexity of the material different models for the frequency dependent complex permittivity were applied. For the validation of the model a broadband frequency domain measurement with network analyzer technique was used. The measurement is based on a 20 cm long 50 Ohm 20/46 coaxial transmission line cell considering inhomogeneous material distributions. This approach allows (i) an increase of the waveguide calibration accuracy in comparison to conventional TDR based technique and (ii) the consideration of the broadband permittivity spectrum of the porous material. In order to systematic analyze the model, theoretical results were compared with measurements as well as 3D broadband finite element modeling of homogeneous and layered media in the coaxial transmission line cell. Defined standards (Teflon, dry glass beads, de-ionized water) were placed inside the line as the dielectric layers in different configurations. With a Thru Reflect Line calibration (TRL) the influences of connectors and adapters at the coaxial line sample holder were removed. The combination of the full two port calibration procedure and broadband modeling approach turns out to achieve a good accordance of modeling and experimental results. The next step is the implementation of an inversion to calculate the material parameters of every layer out of the s-parameters of the layered sample.

Frequency Domain Modelling of Electromagnetic Wave Propagation in Layered Media

NASA Astrophysics Data System (ADS)

Schmidt, Felix; Wagner, Norman; Lünenschloß, Peter; Toepfer, Hannes; Dietrich, Peter; Kaliorias, Andreas; Bumberger, Jan

2015-04-01

The amount of water in porous media such as soils and rocks is a key parameter when water resources are under investigation. Especially the quantitative spatial distribution and temporal evolution of water contents in soil formations are needed. In high frequency electromagnetic applications soil water content is quantitatively derived from the propagation behavior of electromagnetic waves along waveguides embedded in soil formations. The spatial distribution of the dielectric material properties along the waveguide can be estimated by numerical solving of the inverse problem based on the full wave forward model in time or frequency domain. However, current approaches mostly neglect or approximate the frequency dependence of the electromagnetic material properties of transfer function of the waveguide. As a first prove of concept a full two port broadband frequency domain forward model for propagation of transverse electromagnetic (TEM) waves in coaxial waveguide has been implemented. It is based on the propagation matrix approach for layered transmission line sections Depending on the complexity of the material different models for the frequency dependent complex permittivity were applied. For the validation of the model a broadband frequency domain measurement with network analyzer technique was used. The measurement is based on a 20 cm long 50 Ohm 20/46 coaxial transmission line cell considering inhomogeneous material distributions. This approach allows (i) an increase of the waveguide calibration accuracy in comparison to conventional TDR based technique and (ii) the consideration of the broadband permittivity spectrum of the porous material. In order to systematic analyze the model, theoretical results were compared with measurements as well as 3D broadband finite element modeling of homogeneous and layered media in the coaxial transmission line cell. Defined standards (Teflon, dry glass beads, de-ionized water) were placed inside the line as the dielectric layers in different configurations. With a Thru Reflect Line calibration (TRL) the influences of connectors and adapters at the coaxial line sample holder were removed. The combination of the full two port calibration procedure and broadband modeling approach turns out to achieve a good accordance of modeling and experimental results. The next step is the implementation of an inversion to calculate the material parameters of every layer out of the s-parameters of the layered sample.

Shock-tube studies of atomic silicon emission in the spectral range 180 to 300 nm. [environment simulation for Jupiter probes

NASA Technical Reports Server (NTRS)

Prakash, S. G.; Park, C.

1978-01-01

Emission spectroscopy of shock-heated atomic silicon was performed in the spectral range 180 to 300 nm, in an environment simulating the ablation layer expected around a Jovian entry probe with a silica heat shield. From the spectra obtained at temperatures from 6000 to 10,000 K and electron number densities from 1 quadrillion to 100 quadrillion per cu cm, the Lorentzian line-widths were determined. The results showed that silicon lines are broadened significantly by both electrons (Stark broadening) and hydrogen atoms (Van der Waals broadening), and the combined line-widths are much larger than previously assumed. From the data, the Stark and the Van der Waals line-widths were determined for 34 silicon lines. Radiative transport through a typical shock layer was computed using the new line-width data. The computations showed that silicon emission in the hot region is large, but it is mostly absorbed in the colder region adjacent to the wall.

Transition from single to multiple double layers. [of plasma

NASA Technical Reports Server (NTRS)

Chan, C.; Hershkowitz, N.

1982-01-01

Laboratory results are presented to define parameters which allow the boundary conditions to control the characteristics of double layers of plasma. It is shown that multiple double layers arise when the ratio of Debye length to system length decreases, a result which is in line with boundary layer theory. The significance of inclusion of the system length is noted to render BGK treatments of double layers, wherein the length is neglected, invalid.

Evolutionary changes of Hox genes and relevant regulatory factors provide novel insights into mammalian morphological modifications.

PubMed

Li, Kui; Sun, Xiaohui; Chen, Meixiu; Sun, Yingying; Tian, Ran; Wang, Zhengfei; Xu, Shixia; Yang, Guang

2018-01-01

The diversity of body plans of mammals accelerates the innovation of lifestyles and the extensive adaptation to different habitats, including terrestrial, aerial and aquatic habitats. However, the genetic basis of those phenotypic modifications, which have occurred during mammalian evolution, remains poorly explored. In the present study, we synthetically surveyed the evolutionary pattern of Hox clusters that played a powerful role in the morphogenesis along the head-tail axis of animal embryos and the main regulatory factors (Mll, Bmi1 and E2f6) that control the expression of Hox genes. A deflected density of repetitive elements and lineage-specific radical mutations of Mll have been determined in marine mammals with morphological changes, suggesting that evolutionary changes may alter Hox gene expression in these lineages, leading to the morphological modification of these lineages. Although no positive selection was detected at certain ancestor nodes of lineages, the increased ω values of Hox genes implied the relaxation of functional constraints of these genes during the mammalian evolutionary process. More importantly, 49 positively-selected sites were identified in mammalian lineages with phenotypic modifications, indicating adaptive evolution acting on Hox genes and regulatory factors. In addition, 3 parallel amino acid substitutions in some Hox genes were examined in marine mammals, which might be responsible for their streamlined body. © 2017 The Authors. Integrative Zoology published by International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia.

PubMed

Chakrabarty, Sanjiban; Varghese, Vinay Koshy; Sahu, Pranoy; Jayaram, Pradyumna; Shivakumar, Bhadravathi M; Pai, Cannanore Ganesh; Satyamoorthy, Kapaettu

2017-06-27

Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma. Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma. Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects. Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.

[Inhibitory effect on Microcystis aeruginosa as well as separation and identification of the allelochemicals of welsh onion].

PubMed

Zhou, Yang; Li, Yuan; Li, Cheng; Liu, Lu; Zhang, Tingting

2013-11-01

To study the inhibition of welsh onion on Microcystis aeruginosa, and separat and identify of the allelochemicals from welsh onion. METHEDS: The inhibitory effect of different concentrations of fistular onion stalk and fistular onion leaf water extracts on M. aeruginosa were studied; besides, separation and identification of the allelochemicals of welsh onion were also studied. Both fistular onion stalk and fistular onion leaf water extracts had, to different degree, inhibitory effect on the growth of M. aeruginosat. Compared with the control group, the fluorescence intensity of fistular onion stalk and fistular onion leaf were lower than the control group in the same period, and the inhibitory effect were more obvious with the increase of the water extract concentrations, to the fifth day, M. aeruginosa almost completely dead of the highest concentration(50 ml/L) of fistular onion stalk water extract treated group, the EC50 of water extract from fistular onion stalk to M. aeruginosa was 12.7 ml/L, equivalent to fresh weight 1.27 g/L. Main allelochemicals in fistular onion stalk includes allyl mercaptan, cyclopentyl mercaptan, and so on. The inhibiting assay on M. aeruginosa showed that the EC50 of allyl mercaptan and cyclopentyl mercaptan respectively were 0.03 and 0.02 g/L. The fistular onion stalk water extracts has very good algicidal effect, allelopathic algal inhibiting substances primarily are sulfocompound, which have the potential to develop into biological algicide.

Characterization of CD22 Expression in Acute Lymphoblastic Leukemia

PubMed Central

Shah, Nirali N.; Stetler-Stevenson, Maryalice; Yuan, Constance M.; Richards, Kelly; Delbrook, Cindy; Kreitman, Robert J.; Pastan, Ira; Wayne, Alan S.

2015-01-01

Background CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). Procedure Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. Results CD22 expression was demonstrated in all subjects (n=163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349 – 19,653, n=160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349-3,624, n=20 versus 3,853 sites/cell, range 451-19,653, n=140; p=<0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22% – 82% CD22+). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. Conclusions These characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population. PMID:25728039

Heterogeneous effects of M-CSF isoforms on the progression of MLL-AF9 leukemia.

PubMed

Wang, Rong; Feng, Wenli; Yang, Feifei; Yang, Xiao; Wang, Lina; Chen, Chong; Hu, Yuting; Ren, Qian; Zheng, Guoguang

2018-02-01

Macrophage colony-stimulating factor (M-CSF) regulates both malignant cells and microenvironmental cells. Its splicing isoforms show functional heterogeneity. However, their roles on leukemia have not been well established. Here, the expression of total M-CSF in patients with hematopoietic malignancies was analyzed. The roles of M-CSF isoforms on the progression of acute myeloid leukemia (AML) were studied by establishing MLL-AF9-induced mouse AML models with high level membrane-bound M-CSF (mM-CSF) or soluble M-CSF (sM-CSF). Total M-CSF was highly expressed in myeloid leukemia patients. Furthermore, mM-CSF but not sM-CSF prolonged the survival of leukemia mice. While sM-CSF was more potent to promote proliferation and self-renew, mM-CSF was more potent to promote differentiation. Moreover, isoforms had different effects on leukemia-associated macrophages (LAMs) though they both increase monocytes/macrophages by growth-promoting and recruitment effects. In addition, mM-CSF promoted specific phagocytosis of leukemia cells by LAMs. RNA-seq analysis revealed that mM-CSF enhanced phagocytosis-associated genes and activated oxidative phosphorylation and metabolism pathway. These results highlight heterogeneous effects of M-CSF isoforms on AML progression and the mechanisms of mM-CSF, that is, intrinsically promoting AML cell differentiation and extrinsically enhancing infiltration of macrophages and phagocytosis by macrophages, which may provide potential clues for clinical diagnosis and therapy. © 2017 Australasian Society for Immunology Inc.

Enhancing the growth and yield of Ramie (Boehmeria nivea L.) by ramie biomass waste in liquid form and gibberellic acid

NASA Astrophysics Data System (ADS)

Suherman, C.; Nuraini, A.; Wulandari, A. P.; Kadapi, M.

2017-05-01

Ramie (Boehmeria nivea L.) is one of the most important sources of natural fibre, a sustainable biomass. The growth and yield of ramie are affected by mineral nutrients. In the present study, we usedfertilizers from waste of ramie biomass in liquid form (liquid organic fertilizer, LOF) and the other treatment is by gibberellic acid (GA3). This study was to obtain the effect of treatments on enhance the growth and yield of ramie. Hence, we measure the character that related to the important parameter for biomass product of ramie. Such plant height, stem diameter, dry plant weight, and ramie fresh stem weight of ramie clone Pujon 13. This research was conducted from January 2016 to March 2016 at Research Field Ciparanje, Faculty of Agriculture, Padjadjaran University, Jatinangor, Sumedang, West Java with an altitude of about ± 750 m above sea level. The type of Soil in this area is Inceptisolsoil order and thetype of rainfall according to Schmidt and Fergusson Classification is C type. The experiment used Randomized Block Design (RBD) which consisted of eight treatments (GA and LOF) and four replications. The concentration of GA from 0, 50, 100 and 150 ppm and for concentration of LOF is 40 mlL-1. We suggested the treatment of GA 150 ppm with 40 mlL-1 LOF was the best treatment on enhancing plant height and stem fresh weight of ramie clone Pujon 13.

Effect of pH on optimization of photofermentative hydrogen production by co-culture of Rhodobacter sphaeroides-NMBL-02 and Bacillus firmus-NMBL-03.

PubMed

Pandey, A; Dolly, S; Semwal, D; Pandey, A

2017-07-31

Rhodobacter sphaeroides NMBL-02, photosynthetic purple non sulfur (PNS) bacteria and associated Bacillus firmus NMBL-03 were isolated from water sample collected from 15-20 inches beneath the surface of ponds from Northern region of India in modified Sistrom's media (120 ml) containing 3 g/L malate and 1.2 g/L ammonium sulfate. The isolation was done in air tight serum bottles (120 ml) under tungsten bulb (1.8 kLux light intensity) at 30 oC ± 2 oC. The PNS and heterotrophic bacteria associated with the culture was purified by clonal selection method and characterized by 16S rDNA sequencing. The PNS isolate was identified as Rhodobacter sphaeroides NMBL-02 (ID: 1467407, Accession BANKIT: JN256030) and associated heterotroph as Bacillus firmus NMBL-03 (Gene Bank Accession no.: JN 256029). The effect of initial medium pH on optimization of hydrogen production was investigated in batch process. The maximum hydrogen potential and hydrogen production rate was 2310 ± 55 ml/L and 4.75 ml/L culture/h respectively using glutamate (1.7 mmol/L) as nitrogen source and malate (22.38 mmol/L) as carbon source with 76.39% malate conversion efficiency at initial medium pH 5.0. This co-culture has the ability to produce significant amount of hydrogen in the pH range of 5.0 to 10.0 with 76.39% to 35.71% malate conversion respectively.

Autophagy is dispensable for Kmt2a/Mll-Mllt3/Af9 AML maintenance and anti-leukemic effect of chloroquine.

PubMed

Chen, Xiaoyi; Clark, Jason; Wunderlich, Mark; Fan, Cuiqing; Davis, Ashley; Chen, Song; Guan, Jun-Lin; Mulloy, James C; Kumar, Ashish; Zheng, Yi

2017-05-04

Recently, macroautophagy/autophagy has emerged as a promising target in various types of solid tumor treatment. However, the impact of autophagy on acute myeloid leukemia (AML) maintenance and the validity of autophagy as a viable target in AML therapy remain unclear. Here we show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared with normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent phagophore (the autophagosome precursor) membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo. Mechanistically, neither Atg5 nor Rb1cc1 disruption impairs endolysosome formation or survival signaling pathways. The autophagy inhibitor chloroquine shows autophagy-independent anti-leukemic effects in vitro but has no efficacy in vivo likely due to limited achievable drug efficacy in blood. Further, vesicular exocytosis appears to mediate chloroquine resistance in AML cells, and exocytotic inhibition significantly enhances the anti-leukemic effect of chloroquine. Thus, chloroquine can induce leukemia cell death in vitro in an autophagy-independent manner but with inadequate efficacy in vivo, and vesicular exocytosis is a possible mechanism of chloroquine resistance in MA9-AML. This study also reveals that autophagy-specific targeting is unlikely to benefit MA9-AML therapy.

Length limits fail to restructure a Largemouth Bass population: A 28‐year case history

USGS Publications Warehouse

Miranda, Leandro E.; Colvin, M.E.; Shamaskin, A. C.; Bull, L. A.; Holman, T.; Jones, R.

2017-01-01

Length limits have been implemented by fisheries management agencies to achieve population density, size structure, and angler satisfaction objectives. By redirecting harvest towards or away from particular length‐ or age‐groups, length limits rely on harvest by anglers to maintain a population at or near a desired state. The fish population changes that follow the implementation of harvest regulations may take several years to manifest, so long‐term monitoring may be needed to adequately evaluate length limits. We used an innovative application of cluster analysis to facilitate evaluation of the effects of three consecutive length limits on a population of Largemouth Bass Micropterus salmoides over a 28‐year period in Ross Barnett Reservoir, Mississippi. A 13–16‐in protected slot length limit (10 years), followed by a 15‐in minimum length limit (MLL; 11 years), followed by a 12‐in MLL (7 years) failed to restructure the Largemouth Bass population due to what we suggest was the expansion of a voluntary catch‐and‐release attitude that started in the first decade of the study period. Various population metrics shifted towards values expected in an unharvested population, and the observed shifts can be attributed to a harvest deficit created by the prevailing catch‐and‐release attitude. Largemouth Bass harvest regulations may no longer be relevant in many waters. The utility of regulations for restructuring Largemouth Bass populations is largely dependent on harvesting attitudes that vary geographically, depending on cultural characteristics and demographics.

Recoveries of rat lymph FA after administration of specific structured 13C-TAG.

PubMed

Vistisen, Bodil; Mu, Huiling; Høy, Carl-Erik

2003-09-01

The potential of the specific structured TAG MLM [where M = caprylic acid (8:0) and L = linoleic acid (18:2n-6)] is the simultaneous delivery of energy and EFA. Compared with long-chain TAG (LLL), they may be more rapidly hydrolyzed and absorbed. This study examined the lymphatic recoveries of intragastrically administered L*L*L*, M*M*M*, ML*M, and ML*L* (where * = 13C-labeled FA) in rats. Lymph lipids were separated into lipid classes and analyzed by GC combustion isotope ratio MS. The recoveries of lymph TAG 18:2n-6 8 h after administration of L*L*L*, ML*M, and ML*L* were 38.6, 48.4, and 49.1%, respectively, whereas after 24 h the recoveries were approximately 50% in all experimental groups. The exogenous contribution to lymph TAG 18:2n-6 was approximately 80 and 60% at maximum absorption of the specific structured TAG and L*L*L*, respectively, 3-6 h after administration. The tendency toward more rapid recovery of exogenous long-chain FA following administration of specific structured TAG compared with long-chain TAG was probably due to fast hydrolysis. The lymphatic recovery of 8:0 was 2.2% 24 h after administration of M*M*M*. This minor lymphatic recovery of exogenous 8:0 was probably due to low stimulation of chylomicron formation. These results demonstrate tendencies toward faster lymphatic recovery of long-chain FA after administration of specific structured TAG compared with long-chain TAG.

A new application of PVDF line-focus transducers on measuring dispersion curves of a layered medium

NASA Astrophysics Data System (ADS)

Lee, Yung-Chun; Ko, Shin-Pin

2000-05-01

In the past few years, PVDF line-focus acoustic transducers have been proven to be a useful and convenient tool for accurately measuring surface wave velocity. The transducer is very easy to construct and the measurement system can be readily established with conventional ultrasonic instruments. In this investigation, however, the capability of PVDF line-focus transducers will be further extended to the measurement of dispersion relation of surface acoustic waves of a layered medium. To achieve this, a number of line-focus transducers are first fabricated with PVDF films of various thickness so that they can operate at different frequencies. Experimental testing on these transducers shows that surface acoustic waves of frequency ranging from 2 MHz to 20 MHz can be effectively generated and detected. For the determination of surface wave velocity as a function of frequency, a new method of processing the measured waveforms during a z-direction defocusing measurements is developed. A mathematical model is given to explain how this method works. With the transducers and the analyzing method, the surface wave dispersion relation of a layer/substrate configuration have been experimentally determined. Samples include thick polymeric films as well as metal films deposited on glass, aluminum, and silicon crystal. Possibility of determining material properties of the layers from the measured dispersion curves will be discussed.

STELLAR CONTRIBUTION FUNCTIONS IN THE AGE OF CHEMICAL STRATIFICATION

NASA Astrophysics Data System (ADS)

Cowley, Charles; Sheminova, Valya; Castelli, Fiorella; Monier, Richard

2018-01-01

Contribution functions (CF's) were important tools to probe formation depths of features in the early numerical calculations of analytical stellar spectroscopy. In more recent work, CF's have played a minor role. Gray's (2005) text briefly discusses CF's, but CF's are not in Hubeny and Mihalas (2015). Gurtovenko and Sheminova (2015) give an extensive review of contribution functions in a recent preprint (arXiv:1505.00975). The realization that the atmospheres of certain stars are chemically stratified (Ryabchikova, Wade \\& LeBlanc, 2003, in IAU Symp. 210), and much subsequent work makes CF's of current interest. We employ new as well as older methods to compute CF's to find important layers, either for specific intensity or line depth for various points on the line profile. The most important layer is the one that causes the biggest change in the magnitude of the feature when the line absorption coefficient is set equal to zero for successive layers. This is readily done for a stratified or unstratified model. For an equivalent width, W, we calculate $(W-W_i/W) $, where $W_i$ is the equivalent width without absorption from the $i^th$ layer. We concentrate on cases where stratification is most obvious, for example, the Ca II K-line profile in the roAp stars and HR 6000 (Castelli, et al. 2017, A\\&A, 601, A119).

Landscape of somatic mutations and clonal evolution in mantle cell lymphoma.

PubMed

Beà, Sílvia; Valdés-Mas, Rafael; Navarro, Alba; Salaverria, Itziar; Martín-Garcia, David; Jares, Pedro; Giné, Eva; Pinyol, Magda; Royo, Cristina; Nadeu, Ferran; Conde, Laura; Juan, Manel; Clot, Guillem; Vizán, Pedro; Di Croce, Luciano; Puente, Diana A; López-Guerra, Mónica; Moros, Alexandra; Roue, Gael; Aymerich, Marta; Villamor, Neus; Colomo, Lluís; Martínez, Antonio; Valera, Alexandra; Martín-Subero, José I; Amador, Virginia; Hernández, Luis; Rozman, Maria; Enjuanes, Anna; Forcada, Pilar; Muntañola, Ana; Hartmann, Elena M; Calasanz, María J; Rosenwald, Andreas; Ott, German; Hernández-Rivas, Jesús M; Klapper, Wolfram; Siebert, Reiner; Wiestner, Adrian; Wilson, Wyndham H; Colomer, Dolors; López-Guillermo, Armando; López-Otín, Carlos; Puente, Xose S; Campo, Elías

2013-11-05

Mantle cell lymphoma (MCL) is an aggressive tumor, but a subset of patients may follow an indolent clinical course. To understand the mechanisms underlying this biological heterogeneity, we performed whole-genome and/or whole-exome sequencing on 29 MCL cases and their respective matched normal DNA, as well as 6 MCL cell lines. Recurrently mutated genes were investigated by targeted sequencing in an independent cohort of 172 MCL patients. We identified 25 significantly mutated genes, including known drivers such as ataxia-telangectasia mutated (ATM), cyclin D1 (CCND1), and the tumor suppressor TP53; mutated genes encoding the anti-apoptotic protein BIRC3 and Toll-like receptor 2 (TLR2); and the chromatin modifiers WHSC1, MLL2, and MEF2B. We also found NOTCH2 mutations as an alternative phenomenon to NOTCH1 mutations in aggressive tumors with a dismal prognosis. Analysis of two simultaneous or subsequent MCL samples by whole-genome/whole-exome (n = 8) or targeted (n = 19) sequencing revealed subclonal heterogeneity at diagnosis in samples from different topographic sites and modulation of the initial mutational profile at the progression of the disease. Some mutations were predominantly clonal or subclonal, indicating an early or late event in tumor evolution, respectively. Our study identifies molecular mechanisms contributing to MCL pathogenesis and offers potential targets for therapeutic intervention.

Seismic Line Location Map Hot Pot Project, Humboldt County, Nevada 2010

DOE Data Explorer

Lane, Michael

2010-01-01

Seismic Line Location Map Hot Pot Project, Humboldt County, Nevada 2010. ArcGIS map package containing topographic base map, Township and Range layer, Oski BLM and private leases at time of survey, and locations, with selected shot points, of the five seismic lines.

Analysing intracellular deformation of polymer capsules using structured illumination microscopy

NASA Astrophysics Data System (ADS)

Chen, Xi; Cui, Jiwei; Sun, Huanli; Müllner, Markus; Yan, Yan; Noi, Ka Fung; Ping, Yuan; Caruso, Frank

2016-06-01

Understanding the behaviour of therapeutic carriers is important in elucidating their mechanism of action and how they are processed inside cells. Herein we examine the intracellular deformation of layer-by-layer assembled polymer capsules using super-resolution structured illumination microscopy (SIM). Spherical- and cylindrical-shaped capsules were studied in three different cell lines, namely HeLa (human epithelial cell line), RAW264.7 (mouse macrophage cell line) and differentiated THP-1 (human monocyte-derived macrophage cell line). We observed that the deformation of capsules was dependent on cell line, but independent of capsule shape. This suggests that the mechanical forces, which induce capsule deformation during cell uptake, vary between cell lines, indicating that the capsules are exposed to higher mechanical forces in HeLa cells, followed by RAW264.7 and then differentiated THP-1 cells. Our study demonstrates the use of super-resolution SIM in analysing intracellular capsule deformation, offering important insights into the cellular processing of drug carriers in cells and providing fundamental knowledge of intracellular mechanobiology. Furthermore, this study may aid in the design of novel drug carriers that are sensitive to deformation for enhanced drug release properties.Understanding the behaviour of therapeutic carriers is important in elucidating their mechanism of action and how they are processed inside cells. Herein we examine the intracellular deformation of layer-by-layer assembled polymer capsules using super-resolution structured illumination microscopy (SIM). Spherical- and cylindrical-shaped capsules were studied in three different cell lines, namely HeLa (human epithelial cell line), RAW264.7 (mouse macrophage cell line) and differentiated THP-1 (human monocyte-derived macrophage cell line). We observed that the deformation of capsules was dependent on cell line, but independent of capsule shape. This suggests that the mechanical forces, which induce capsule deformation during cell uptake, vary between cell lines, indicating that the capsules are exposed to higher mechanical forces in HeLa cells, followed by RAW264.7 and then differentiated THP-1 cells. Our study demonstrates the use of super-resolution SIM in analysing intracellular capsule deformation, offering important insights into the cellular processing of drug carriers in cells and providing fundamental knowledge of intracellular mechanobiology. Furthermore, this study may aid in the design of novel drug carriers that are sensitive to deformation for enhanced drug release properties. Electronic supplementary information (ESI) available: Additional figures. See DOI: 10.1039/c6nr02151d

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

Self-Irradiation Effects on 99Mo Reagents and Products

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

Carson, S.D.; Garcia, M.J.; McDonald, M.J.

1998-10-07

produced in 1996 and shipped to pharmaceutical houses for evaluation of compatibility with oxime solution used to precipitate `?vfo as the oxime complex is both air and light-sensitive, and containing a black precipitate that forms during shipment, presumably as a result of self- irradiation. Addition of sodium hypochlorite to the product solution prior to shipment prevents precipitate formation, indicating the precipitate is a reduced form of `%lo. to remove any precipitate. Duplicate aliquots of the filtered samples were titrated to a phenolphthalein irradiation and afler standing at room temperature for 86.4 hours. Precipitates were washed to a FTIR analysis ofmore » the white precipitate showed it to be alpha benzoin oxime. Since the basic After 86.4 hours, no precipitate had formed in bottles containing sodium hypochlorite. Black precipitate had formed in all bottles that did not contain sodium hypochlorite after 14.4 hours. The precipitate appeared to initially form on the surface of the HDPE sample bottles and Black precipitate was first noticed in sample set 1 after 28.8 hrs' irradiation. No visible sample containing precipitate was kept at room temperature in the original bottle. Precipitate in sample sets 2 and 3. Since no precipitate formed in these bottles, this was equivalent to duplicate samples. Once the precipitate in the 20-mL aliquots that had been set aside had returned to sample sets 1 through 3 and the samples with redissolved precipitate all experienced an average decrease in base strength of 0.013 meq mL-l. Sample 1-C had a decrease of 0.004 meq mL-l and sample 1-D had returned to the initial value of 0.198 meq mL-l. Raman spectra for the black precipitate from samples l-C, 1-D and supplemental sample set 1 Fig. 2. Raman spectra of the black precipitate formed in 9%40 product solutions after 28.8,43.2, 72 and 86.4 hours of `oCo irradiation in Sandia's Gamma Irradiation Facility. increase with time, as seen in the titration of 1-C and 1-D samples. The precipitate does not expect to see precipitate in the glass bottles. The fact that no precipitate is observed when the no precipitate is observed in a glass container is an indication that the rates of molybdenum that precipitate does not form when the solution is in a glass bottle. A hydrogen source other« less

A Fast Hyperspectral Vector Radiative Transfer Model in UV to IR spectral bands

NASA Astrophysics Data System (ADS)

Ding, J.; Yang, P.; Sun, B.; Kattawar, G. W.; Platnick, S. E.; Meyer, K.; Wang, C.

2016-12-01

We develop a fast hyperspectral vector radiative transfer model with a spectral range from UV to IR with 5 nm resolutions. This model can simulate top of the atmosphere (TOA) diffuse radiance and polarized reflectance by considering gas absorption, Rayleigh scattering, and aerosol and cloud scattering. The absorption component considers several major atmospheric absorbers such as water vapor, CO2, O3, and O2 including both line and continuum absorptions. A regression-based method is used to parameterize the layer effective optical thickness for each gas, which substantially increases the computation efficiency for absorption while maintaining high accuracy. This method is over 500 times faster than the existing line-by-line method. The scattering component uses the successive order of scattering (SOS) method. For Rayleigh scattering, convergence is fast due to the small optical thickness of atmospheric gases. For cloud and aerosol layers, a small-angle approximation method is used in SOS calculations. The scattering process is divided into two parts, a forward part and a diffuse part. The scattering in the small-angle range in the forward direction is approximated as forward scattering. A cloud or aerosol layer is divided into thin layers. As the ray propagates through each thin layer, a portion diverges as diffuse radiation, while the remainder continues propagating in forward direction. The computed diffuse radiance is the sum of all of the diffuse parts. The small-angle approximation makes the SOS calculation converge rapidly even in a thick cloud layer.

Deep-sea macroplankton distribution (at 400 to 2300 m) in the northwestern Mediterranean in relation to environmental factors

NASA Astrophysics Data System (ADS)

Cartes, J. E.; Fanelli, E.; López-Pérez, C.; Lebrato, M.

2013-03-01

Changes in the composition and biomass distribution of deep-living zooplankton over wide gradients of depth (400-2300 m) and longitude (~ 180 km) have been analyzed in the Balearic Basin (western Mediterranean), seeking the environmental variables responsible for these changes. Zooplankton tends to aggregate at different levels of the water column (forming Deep Scattering Layers, DSL) and in the Benthic Boundary Layer (BBL). Macrozooplankton biomass and composition were analyzed along a transect performed in July 2010 in midwater (between ~ 350 and 450 m) and near the bottom (at ~ 5-200 mab), over soundings of 450-2263 m, including the top of Valencia Seamount (at ~ 40° 25' N-02° 42' E, 1076 m). Zooplankton changed significantly in composition at the mesoscale (~ 180 km) in both the DSL and the BBL. Siphonophores and calanoid copepods were the most dominant deep zooplankton taxa, calanoids reaching higher abundance in the BBL (1761-5177 individuals/1000 m3) than in the DSL (1568-1743 individuals/1000 m3). There was a significant increase in near-bottom zooplankton biomass over the middle slope, at 1000-1300 m, linked to an increase in scyphozoans and siphonophores (Lensia spp. and Abylopsis tetragona) with peaks of 1.5-2.0 gWW/1000 m3. The peak of near-bottom zooplankton at 1000-1300 m coincided with the lowest temperatures (13.08 °C) and maximum O2 concentration (4.40 ml/l) near the bottom and below 1000 m with higher records in near-bottom turbidity. Gelatinous zooplankton are the main prey in the diet of the demersal fish Alepocephalus rostratus in the western Mediterranean, fish responsible for the peak of megafauna biomass reported at around 1200-1400 m in the deep Mediterranean and at similar depths in other oceanic areas (e.g. the NW Atlantic). We suggest that deep-sea environmental conditions can govern peaks of near-bottom zooplankton, as well as influence the structure of the demersal fish community.

Fine line structures of ceramic films formed by patterning of metalorganic precursors using photolithography and ion beams

NASA Astrophysics Data System (ADS)

Hung, L. S.; Zheng, L. R.

1992-05-01

Fine line structures of ceramic thin films were fabricated by patterning of metalorganic precursors using photolithography and ion beams. A trilevel structure was developed with an outer resist layer to transfer patterns, a silver delineated layer as an implantation mask, and a planar resist layer protecting the precursor film from chemical attacking and sputtering. Ion irradiation through the Ag stencil rendered metal carboxylates insoluble in 2-ethylhexanoic acid, permitting patterning of the precursor film with patterning features on micron scales. The potential of this technique was demonstrated in patterning of Bi2Sr2CaCu2O(8+x) and Pb(Zr(0.53)Ti(0.47) thin films.

Optical Metrology for CIGS Solar Cell Manufacturing and its Cost Implications

NASA Astrophysics Data System (ADS)

Sunkoju, Sravan Kumar

Solar energy is a promising source of renewable energy which can meet the demand for clean energy in near future with advances in research in the field of photovoltaics and cost reduction by commercialization. Availability of a non-contact, in-line, real time robust process control strategies can greatly aid in reducing the gap between cell and module efficiencies, thereby leading to cost-effective large-scale manufacturing of high efficiency CIGS solar cells. In order to achieve proper process monitoring and control for the deposition of the functional layers of CuIn1-xGaxSe 2 (CIGS) based thin film solar cell, optical techniques such as spectroscopic reflectometry and polarimetry are advantageous because they can be set up in an unobtrusive manner in the manufacturing line, and collect data in-line and in-situ. The use of these techniques requires accurate optical models that correctly represent the properties of the layers being deposited. In this study, Spectroscopic ellipsometry (SE) has been applied for the characterization of each individual stage of CIGS layers deposited using the 3-stage co-evaporation process along with the other functional layers. Dielectric functions have been determined for the energy range from 0.7 eV to 5.1 eV. Critical-point line-shape analysis was used in this study to determine the critical point energies of the CIGS based layers. To control the compositional and thickness uniformity of all the functional layers during the fabrication of CIGS solar cells over large areas, multilayer photovoltaics (PV) stack optical models were developed with the help of extracted dielectric functions. In this study, mapping capability of RC2 spectroscopic ellipsometer was used to map all the functional layer thicknesses of a CIGS solar cell in order to probe the spatial non-uniformities that can affect the performance of a cell. The optical functions for each of the stages of CIGS 3-stage deposition process along with buffer layer and transparent conducting oxide (TCO) bi-layer, thus derived were used in a fiber optic-based spectroscopic reflectometry optical monitoring system installed in the pilot line at the PVMC's Halfmoon facility. Results obtained from this study show that the use of regular fiber optics, instead of polarization-maintaining fiber optics, is sufficient for the purpose of process monitoring. Also, the technique does not need to be used "in-situ", but the measurements can be taken in-line, and are applicable to a variety of deposition techniques used for different functional layers deposited on rigid or flexible substrates. In addition, effect of Cu concentration on the CIGS optical properties has been studied. Mixed CIGS/Cu2-xSe phase was observed at the surface at the end of the second stage of 3-stage deposition process, under Cu-rich conditions. A significant change in optical behavior of CIGS due to Cu2-xSe at the surface was observed under Cu-rich conditions, which can be used as end-point detection method to move from 2nd stage to 3rd stage in the deposition process. Developed optical functions were applied to in-line reflectance measurements not only to identify the Cu2-xSe phase at the surface but also to measure the thickness of the mixed CIGS/Cu2-xSe layer. This spectroscopic reflectometry based in-line process control technique can be used for end-point detection as well as to control thickness during the preparation of large area CIGS films. These results can assist in the development of optical process-control tools for the manufacturing of high quality CIGS based photovoltaic cells, increasing the uptime and yield of the production line. Finally, to understand the cost implications, low cost potential of two different deposition technologies has been studied on both rigid and flexible substrates with the help of cost analysis. Cost advantages of employing a contactless optics based process control technique have been investigated in order to achieve a low cost of < 0.5 $/W for CIGS module production. Based on cost analysis, one of the best strategies for achieving the low cost targets would be increasing manufacturing throughput, using roll-to-roll thin-film module manufacturing, with co-evaporation and chemical bath deposition processes for absorber and buffer layer respectively, while applying a low-cost process control technique such as spectroscopic reflectometry to improve module efficiencies and maintain high yield.

Study of helium emissions from active solar regions

NASA Technical Reports Server (NTRS)

Kulander, J. L.

1973-01-01

A theoretical study is made of the visible and UV line radiation of He I atoms and He II ions from a plane-parallel model flare layer. Codes were developed for the solution of the statistically steady state equation for a 30 level He I - II - III model, and the line and continuum transport equations. These codes are described and documented in the report along with sample solutions. Optical depths and some line intensities are presented for a 1000 km thick layer. Solutions of the steady state equations are presented for electron temperatures 10,000 to 50,000 K and electron densities 10 to the 10th power to 10 to the 14th power/cu cm.

Establishment of rat embryonic stem-like cells from the morula using a combination of feeder layers.

PubMed

Sano, Chiaki; Matsumoto, Asako; Sato, Eimei; Fukui, Emiko; Yoshizawa, Midori; Matsumoto, Hiromichi

2009-08-01

Embryonic stem (ES) cells are characterized by pluripotency, in particular the ability to form a germline on injection into blastocysts. Despite numerous attempts, ES cell lines derived from rat embryos have not yet been established. The reason for this is unclear, although certain intrinsic biological differences among species and/or strains have been reported. Herein, using Wistar-Imamichi rats, specific characteristics of preimplantation embryos are described. At the blastocyst stage, Oct4 (also called Pou5f1) was expressed in both the inner cell mass (ICM) and the trophectoderm (TE), whereas expression of Cdx2 was localized to the TE. In contrast, at an earlier stage, expression of Oct4 was detected in all the nuclei in the morula. These stages were examined using a combination of feeder layers (rat embryonic fibroblast [REF] for primary outgrowth and SIM mouse embryo-derived thioguanine- and ouabain-resistant [STO] cells for passaging) to establish rat ES-like cell lines. The rat ES-like cell lines obtained from the morula maintained expression of Oct4 over long-term culture, whereas cell lines derived from blastocysts lost pluripotency during early passage. The morula-derived ES-like cell lines showed Oct4 expression in a long-term culture, even after cryogenic preservation, thawing and EGFP transfection. These results indicate that rat ES-like cell lines with long-term Oct4 expression can be established from the morula of Wistar-Imamichi rats using a combination of feeder layers.

Symptom-Adapted Physical Activity Intervention in Minimizing Physical Function Decline in Older Patients With Acute Myeloid Leukemia Undergoing Chemotherapy

ClinicalTrials.gov

2018-05-24

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

FGFR1 tyrosine kinase domain duplication in pilocytic astrocytoma with anaplasia

PubMed Central

Ballester, Leomar Y.; Penas-Prado, Marta; Leeds, Norman E.; Huse, Jason T.; Fuller, Gregory N.

2018-01-01

We report the case of a 27-yr-old male with visual field loss who had a 4.9-cm complex cystic mass in the right occipital lobe. Histologic examination showed pilocytic astrocytoma (PA) with anaplasia, and molecular characterization revealed FGFR1 duplication with additional variants of unknown significance in several genes (ARID1A, ARID1B, CHEK2, EPHA5, and MLL2). This is one of only a very few reported cases of anaplastic PA with characterization of molecular alterations. PMID:29610389

Bioelectrical Impedance Measurement for Predicting Treatment Outcome in Patients With Newly Diagnosed Acute Leukemia

ClinicalTrials.gov

2018-04-26

Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Mast Cell Leukemia; Myeloid/NK-cell Acute Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

Phase I Combination of Midostaurin, Bortezomib, and Chemo in Relapsed/Refractory Acute Myeloid Leukemia

ClinicalTrials.gov

2016-07-04

Acute Myeloid Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following; Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Cediranib Maleate in Treating Patients With Relapsed, Refractory, or Untreated Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

ClinicalTrials.gov

2016-12-28

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

The evolution of an unsteady translating nonlinear rossby-wave critical layer

NASA Astrophysics Data System (ADS)

Haynes, Peter H.; Cowley, Stephen J.

When a monochromatic Rossby wave is forced on a flow which is slowly varying in time, the location of the critical line, where the phase speed of the wave is equal to that of the flow, also slowly changes. It is shown that this translation can play an important role in the vorticity balance near the critical line. The behavior of the translating critical layer is analyzed for various values of y, a parameter which measures the relative importance of nonlinear advection and translation. First, the vorticity equation in the critical layer is solved numerically in an important special case, where the velocity field in the critical layer is independent of the vorticity distribution and constant in time. The solutions reveal a number of new aspects of the behavior which are introduced by the translation, including the formation of a wake behind the critical layer, and the possibility of "trapping" of fluid particles in the critical layer if y exceeds a threshold value. Viewed in a frame of reference moving with the critical line the vorticity distribution may tend to a steady state, except in a "vorticity front" far downstream in the wake. If streamlines in the critical layer are open this steady state may be a predominantly inviscid one; if they are closed a steady state is possible only with non-zero dissipation. For both the unsteady and steady flows the translation allows the "logarithmic phase jump" across the critical layer, 4, to be non-zero and negative. Hence, even when the viscosity is vanishingly small, the critical layer can act as a strong "absorber" of Eliassen-Palm wave activity. Second, steady-state solutions are obtained numerically for a case when the velocity field in the critical layer is not independent of the vorticity distribution there. The interaction restricts the formation of closed streamlines, and an asymptotic open-streamline solution for large y can be found. The critical layer again acts an absorber of wave activity, but with decreasing eNectiveness as y increases.

Quantifying near-wall coherent structures in turbulent convection

NASA Astrophysics Data System (ADS)

Gunasegarane, G. S.; A Puthenveettil, Baburaj; K Agrawal, Yogesh; Schmeling, Daniel; Bosbach, Johannes; Arakeri, Jaywant; IIT Madras-DLR-IISc Collaboration

2011-11-01

We present planforms of line plumes formed on horizontal surfaces in turbulent convection, along with the length of near- wall line plumes measured from these planforms, in a six decade range of Rayleigh numbers (105 < Ra <1011) and at three Prandtl numbers (Pr = 0 . 7 , 6 , 602). Using geometric constraints on the relations for the mean plume spacings, we obtain expressions for the total length of these near-wall plumes in turbulent convection. The plume length per unit area (Lp / A), made dimensionless by the near-wall length scale in turbulent convection (Zw) remains a constant for a given fluid. The Nusselt number is shown to be directly proportional to Lp H / A for a given fluid layer of height H. Increase in Pr has a weak influence in decreasing Lp / A . These expressions match the measurements, thereby showing that the assumption of laminar natural convection boundary layers in turbulent convection is consistent with the observed total length of line plumes. We then show that similar relationships are obtained based on the assumption that the line plumes are the outcome of the instability of laminar natural convection boundary layers on the horizontal surfaces.

Conductor backed and shielded multi-layer coplanar waveguide designs on LTCC for RF carrier boards for packaging PICs

NASA Astrophysics Data System (ADS)

Marraccini, Philip J.; Jezzini, Moises A.; Peters, Frank H.

2016-05-01

Designing photonic integrated circuits (PICs) with packaging in mind is important since this impacts the performance of the final product. In coherent optical communication applications there are a large number of DC and RF lines that need routed to connect the PIC to the outer packaging. These RF lines should be impedance matched to the devices, isolated from each other, low loss and protected against electromagnetic interference (EMI) over the frequency range of interest to achieve the performance required for the application. Multilevel low temperature co-fired ceramic (LTCC) boards can be used as a carrier board connecting the PIC to the packaging due to its good RF performance, machinability, compatibility with hermetic sealing, and ability to integrate drivers into the board. Flexibility with layer numbers enables additional layers for shielding against electromagnetic interference or increased space for routing electrical connections. In this paper the design, simulations, and measured results for a set of 4 phase matched transmission lines in LTCC that would be used with an IQ MZM are presented. The measured 3dB bandwidth for a set of four phase matched transmission lines for an IQ MZM was measured to be 19.8 GHz.

Radio frequency switching network: a technique for infrared sensing

NASA Astrophysics Data System (ADS)

Mechtel, Deborah M.; Jenkins, R. Brian; Joyce, Peter J.; Nelson, Charles L.

2016-10-01

This paper describes a unique technique that implements photoconductive sensors in a radio frequency (RF) switching network designed to locate in real-time the position and intensity of IR radiation incident on a composite structure. In the implementation described here, photoconductive sensors act as rapid response switches in a two-layer RF network embedded in an FR-4 laminate. To detect radiation, phosphorous-doped silicon photoconductive sensors are inserted in GHz range RF transmission lines. By permitting signal propagation only when a sensor is illuminated, the RF signals are selectively routed from lower layer transmission lines to upper layer lines, thereby pinpointing the location and strength of incident radiation. Simulations based on a high frequency three-dimensional planar electromagnetics model are presented and compared to the experimental results. The experimental results are described for GHz range RF signal control for 300- and 180-mW incident energy from 975- to 1060-nm wavelength lasers, respectively, where upon illumination, RF transmission line signal output power doubled when compared to nonilluminated results. The experimental results are also reported for 100-W incident energy from a 1060-nm laser. Test results illustrate real-time signal processing would permit a structure to be controlled in response to incident radiation.

Improved contact resistance stability in a MEMS separable electrical connector

NASA Astrophysics Data System (ADS)

Larsson, M. P.

2005-12-01

A MEMS in-line separable electrical connector with improved contact resistance stability to thermal fluctuations and mating cycles is described. The design allows sliding, in-line connection between separate halves, inducing vertical deflections on a set of flexible conductors to establish stable electrical contacts. Features are present on both halves to ensure precise lateral and vertical self-alignment; preventing shorts and maintaining consistent conductor deflections. Characterisation on early prototypes revealed significant variability in contact resistance with thermal fluctuations and mating cycle history. As flexible conductors are multi-layered structures of Au supported by a thick structural layer of Ni, they undergo differential thermal expansion, introducing variability in contact resistance with temperature. Sliding contact wear during repeated mating leads to removal of portions of the Au surface coating, and electrical contact between underlying (non-noble) Ni layers. By using a harder Co-Au alloy as the contact surface layer and modifying the arrangement of constituent conductor layers to balance thermal stresses, improvements to both wear and thermal tolerance of contact resistance can be obtained. Devices implementing the above design modifications show stable contact resistance over 100 mating cycles and an increase in contact resistance of between 3.5 and 7% over a temperature rise of 60°C. The electrical performance improvements increase the attractiveness of the MEMS in-line separable connector concept for applications in portable electronics and MEMS integration.

Silicon superlattices. 2: Si-Ge heterostructures and MOS systems

NASA Technical Reports Server (NTRS)

Moriarty, J. A.

1983-01-01

Five main areas were examined: (1) the valence-and conduction-band-edge electronic structure of the thin layer ( 11 A) silicon-superlattice systems; (2) extension of thin-layer calculations to layers of thickness 11 A, where most potential experimental interest lies; (3) the electronic structure of thicker-layer (11 to 110 A) silicon superlattices; (4) preliminary calculations of impurity-scattering-limited electron mobility in the thicker-layer superlattices; and (5) production of the fine metal lines that would be required to produce on MOS superlattice.

Skin-layer of the eruptive magnetic flux rope in large solar flares

NASA Astrophysics Data System (ADS)

Kichigin, G. N.; Miroshnichenko, L. I.; Sidorov, V. I.; Yazev, S. A.

2016-07-01

The analysis of observations of large solar flares made it possible to propose a hypothesis on existence of a skin-layer in magnetic flux ropes of coronal mass ejections. On the assumption that the Bohm coefficient determines the diffusion of magnetic field, an estimate of the skin-layer thickness of ~106 cm is obtained. According to the hypothesis, the electric field of ~0.01-0.1 V/cm, having the nonzero component along the magnetic field of flux rope, arises for ~5 min in the surface layer of the eruptive flux rope during its ejection into the upper corona. The particle acceleration by the electric field to the energies of ~100 MeV/nucleon in the skin-layer of the flux rope leads to their precipitation along field lines to footpoints of the flux rope. The skin-layer presence induces helical or oval chromospheric emission at the ends of flare ribbons. The emission may be accompanied by hard X-ray radiation and by the production of gamma-ray line at the energy of 2.223 MeV (neutron capture line in the photosphere). The magnetic reconnection in the corona leads to a shift of the skin-layer of flux rope across the magnetic field. The area of precipitation of accelerated particles at the flux-rope footpoints expands in this case from the inside outward. This effect is traced in the chromosphere and in the transient region as the expanding helical emission structures. If the emission extends to the spot, a certain fraction of accelerated particles may be reflected from the magnetic barrier (in the magnetic field of the spot). In the case of exit into the interplanetary space, these particles may be recorded in the Earth's orbit as solar proton events.

Improvement of Surface Layer Characteristics by Shot Lining

NASA Astrophysics Data System (ADS)

Harada, Yasunori

In the present study, lining of the metal with foils using shot peening was investigated to improve the surface layer characteristics. In the shot peening experiment, the foils set on the metal are pelted with hard particles traveling at a high velocity. The foils are bonded to the metal surface due to plastic deformation induced by the collision of the particles. The foils and the metal are heated to heighten the bondability because of the reduction of flow stress. Lining the metal with the hard powder sandwiched between two aluminum foil sheets was also attempted. In this experiment, a centrifugal shot peening machine wite an electrical heater was employed. The metals are commercially aluminium alloys and magnesium alloys, and the foils are commercially aluminum, titanium and nickel. The effects of shot speed and the heating temperature on the bondability were examined. Wear resistance was also evaluated by grinding. The foils were successfully bonded to the metal surface. It was found that the present method is effective in improving of surface layer characteristics.

A broadband permeability measurement of FeTaN lamination stack by the shorted microstrip line method

NASA Astrophysics Data System (ADS)

Chen, Xin; Ma, Yungui; Xu, Feng; Wang, Peng; Ong, C. K.

2009-01-01

In this paper, the microwave characteristics of a FeTaN lamination stack are studied with a shorted microstrip line method. The FeTaN lamination stack was fabricated by gluing 54 layers of FeTaN units with epoxy together. The FeTaN units were deposited on both sides of an 8 μm polyethylene terephthate (Mylar) film as the substrate by rf magnetron sputtering. On each side of the Mylar substrate, three 100-nm FeTaN layers are laminated with two 8 nm Al2O3 layers. The complex permeability of FeTaN lamination stack is calculated by the scattering parameters using the shorted load transmission line model based on the quasi-transverse-electromagnetic approximation. A full wave analysis combined with an optimization process is employed to determine the accurate effective permeability values. The optimized complex permeability data can be used for the microwave filter design.

Simulation of Nonlinear Instabilities in an Attachment-Line Boundary Layer

NASA Technical Reports Server (NTRS)

Joslin, Ronald D.

1996-01-01

The linear and the nonlinear stability of disturbances that propagate along the attachment line of a three-dimensional boundary layer is considered. The spatially evolving disturbances in the boundary layer are computed by direct numerical simulation (DNS) of the unsteady, incompressible Navier-Stokes equations. Disturbances are introduced either by forcing at the in ow or by applying suction and blowing at the wall. Quasi-parallel linear stability theory and a nonparallel theory yield notably different stability characteristics for disturbances near the critical Reynolds number; the DNS results con rm the latter theory. Previously, a weakly nonlinear theory and computations revealed a high wave-number region of subcritical disturbance growth. More recent computations have failed to achieve this subcritical growth. The present computational results indicate the presence of subcritically growing disturbances; the results support the weakly nonlinear theory. Furthermore, an explanation is provided for the previous theoretical and computational discrepancy. In addition, the present results demonstrate that steady suction can be used to stabilize disturbances that otherwise grow subcritically along the attachment line.

A terahertz in-line polarization converter based on through-via connected double layer slot structures

PubMed Central

Woo, Jeong Min; Hussain, Sajid; Jang, Jae-Hyung

2017-01-01

A terahertz (THz) in-line polarization converter that yields a polarization conversion ratio as high as 99.9% is demonstrated at 1 THz. It has double-layer slot structures oriented in orthogonal directions that are electrically connected by 1/8-wavelngth-long through-via holes beside the slot structures. The slots on the front metal-plane respond to the incident THz wave with polarization orthogonal to the slots and generates a circulating surface current around the slots. The surface current propagates along a pair of through-via holes that function as a two-wire transmission line. The propagating current generates a surface current around the backside slot structures oriented orthogonal to the slot structures on the front metal layer. The circulating current generates a terahertz wave polarized orthogonal to the backside slot structures and the 90° polarization conversion is completed. The re-radiating THz wave with 90° converted polarization propagates in the same direction as the incident THz wave. PMID:28211498

Defect tolerance in resistor-logic demultiplexers for nanoelectronics.

PubMed

Kuekes, Philip J; Robinett, Warren; Williams, R Stanley

2006-05-28

Since defect rates are expected to be high in nanocircuitry, we analyse the performance of resistor-based demultiplexers in the presence of defects. The defects observed to occur in fabricated nanoscale crossbars are stuck-open, stuck-closed, stuck-short, broken-wire, and adjacent-wire-short defects. We analyse the distribution of voltages on the nanowire output lines of a resistor-logic demultiplexer, based on an arbitrary constant-weight code, when defects occur. These analyses show that resistor-logic demultiplexers can tolerate small numbers of stuck-closed, stuck-open, and broken-wire defects on individual nanowires, at the cost of some degradation in the circuit's worst-case voltage margin. For stuck-short and adjacent-wire-short defects, and for nanowires with too many defects of the other types, the demultiplexer can still achieve error-free performance, but with a smaller set of output lines. This design thus has two layers of defect tolerance: the coding layer improves the yield of usable output lines, and an avoidance layer guarantees that error-free performance is achieved.

MODTRAN3: Suitability as a flux-divergence code

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

Anderson, G.P.; Chetwynd, J.H.; Wang, J.

1995-04-01

The Moderate Resolution Atmospheric Radiance and Transmittance Model (MODTRAN3) is the developmental version of MODTRAN and MODTRAN2. The Geophysics Directorate, Phillips Laboratory, released a beta version of this model in October 1994. It encompasses all the capabilities of LOWTRAN7, the historic 20 cm{sup -1} resolution (full width at half maximum, FWHM) radiance code, but incorporates a much more sensitive molecular band model with 2 cm{sup -1} resolution. The band model is based directly upon the HITRAN spectral parameters, including both temperature and pressure (line shape) dependencies. Validation against full Voigt line-by-line calculations (e.g., FASCODE) has shown excellent agreement. In addition,more » simple timing runs demonstrate potential improvement of more than a factor of 100 for a typical 500 cm{sup -1} spectral interval and comparable vertical layering. Not only is MODTRAN an excellent band model for {open_quotes}full path{close_quotes} calculations (that is, radiance and/or transmittance from point A to point B), but it replicates layer-specific quantities to a very high degree of accuracy. Such layer quantities, derived from ratios and differences of longer path MODTRAN calculations from point A to adjacent layer boundaries, can be used to provide inversion algorithm weighting functions or similarly formulated quantities. One of the most exciting new applications is the rapid calculation of reliable IR cooling rates, including species, altitude, and spectral distinctions, as well as the standard spectrally integrated quantities. Comparisons with prior line-by-line cooling rate calculations are excellent, and the techniques can be extended to incorporate global climatologies of both standard and trace atmospheric species.« less

The effect of finish line preparation and layer thickness on the failure load and fractography of ZrO2 copings.

PubMed

Reich, Sven; Petschelt, Anselm; Lohbauer, Ulrich

2008-05-01

To prevent tooth weakening or pulp irritation, there is a need for a minimally invasive method of preparing single anterior crowns. Restoration dimensions for reduced coping thicknesses or less invasive finish line preparations are required. The purposed of this in vitro was to study investigate the fracture performance of high-strength zirconia copings, compare knife-edge margins with chamfer finish lines, and examine the effect of reducing the layer thickness from 0.5 mm to 0.3 mm. Y-TZP zirconia copings were manufactured on brass dies of a maxillary central incisor. Forty copings, with 2 layer thicknesses (0.5 and 0.3 mm), and 2 finish line preparations (knife edge and chamfer; n=10) were cemented using a conventional glass ionomer cement and stored in distilled water at 37 degrees C for 24 hours. The copings were vertically loaded until fracture using a universal testing machine. Data were analyzed by 2-way ANOVA (alpha=.05). Fractographic examination was performed using scanning electron microscopy and confocal laser scanning microscopy. A significantly higher mean failure load was measured for knife-edge (0.5 mm, 1110 +/-175 N; 0.3 mm, 730 +/-160 N) versus chamfer (0.5 mm, 697 +/-126 N; 0.3 mm, 455 +/-79 N) preparations (P<.001), and for 0.5-mm versus 0.3-mm thickness layers (P<.001). Knife-edge preparations present a promising alternative to chamfer finish lines; the fracture load required for knife-edge preparations was 38% greater than that required for chamfer preparations, regardless of coping thickness. Reducing the thickness of a single crown coping from 0.5 to 0.3 mm resulted in a 35% reduction in fracture load required for either preparation type.

76 FR 67379 - Importation of Dracaena Plants From Costa Rica

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-01

... rooting zone for plants produced by air layering) to the farthest terminal growing point. Paragraph (y)(2... the soil line (or top of the rooting zone for plants produced by air layering) to the farthest...

Taking into Account Interelement Interference in X-Ray Fluorescence Analysis of Thin Two-Layer Ti/V Systems

NASA Astrophysics Data System (ADS)

Mashin, N. I.; Razuvaev, A. G.; Cherniaeva, E. A.; Gafarova, L. M.; Ershov, A. V.

2018-03-01

We propose a new method for determining the thickness of layers in x-ray fluorescence analysis of two-layer Ti/V systems, using easily fabricated standardized film layers obtained by sputter deposition of titanium on a polymer film substrate. We have calculated correction factors taking into account the level of attenuation for the intensity of the primary emission from the x-ray tube and the analytical line for the element of the bottom layer in the top layer, and the enhancement of the fluorescence intensity for the top layer by the emission of atoms in the bottom layer.

Solar cells and methods of fabrication thereof

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

Shumate, Seth Daniel; Hutchings, Douglas Arthur; Mohammed, Hafeezuddin

A passivation layer is deposited on a first portion of a region of the solar cell. A grid line is deposited on a second portion of the region. The passivation layer is annealed to drive chemical species from the passivation layer to deactivate an electrical activity of a dopant in the first portion of the region of the solar cell.

Background, Foreground and the Ground in Between: Layers of Depth!

ERIC Educational Resources Information Center

McGovern, Cynthia

2009-01-01

This article describes a lesson in picture depth. The lesson involves tracing paper layers, object size and raising the horizon line per page layer. Students learn to look at and scan a photograph or print, break down the picture's qualities, and design elements and principles. Students also gain an increased appreciation for design and artist…

A crab swarm at an ecological hotspot: patchiness and population density from AUV observations at a coastal, tropical seamount.

PubMed

Pineda, Jesús; Cho, Walter; Starczak, Victoria; Govindarajan, Annette F; Guzman, Héctor M; Girdhar, Yogesh; Holleman, Rusty C; Churchill, James; Singh, Hanumant; Ralston, David K

2016-01-01

A research cruise to Hannibal Bank, a seamount and an ecological hotspot in the coastal eastern tropical Pacific Ocean off Panama, explored the zonation, biodiversity, and the ecological processes that contribute to the seamount's elevated biomass. Here we describe the spatial structure of a benthic anomuran red crab population, using submarine video and autonomous underwater vehicle (AUV) photographs. High density aggregations and a swarm of red crabs were associated with a dense turbid layer 4-10 m above the bottom. The high density aggregations were constrained to 355-385 m water depth over the Northwest flank of the seamount, although the crabs also occurred at lower densities in shallower waters (∼280 m) and in another location of the seamount. The crab aggregations occurred in hypoxic water, with oxygen levels of 0.04 ml/l. Barcoding of Hannibal red crabs, and pelagic red crabs sampled in a mass stranding event in 2015 at a beach in San Diego, California, USA, revealed that the Panamanian and the Californian crabs are likely the same species, Pleuroncodes planipes, and these findings represent an extension of the southern endrange of this species. Measurements along a 1.6 km transect revealed three high density aggregations, with the highest density up to 78 crabs/m(2), and that the crabs were patchily distributed. Crab density peaked in the middle of the patch, a density structure similar to that of swarming insects.

A crab swarm at an ecological hotspot: patchiness and population density from AUV observations at a coastal, tropical seamount

PubMed Central

Cho, Walter; Starczak, Victoria; Govindarajan, Annette F.; Guzman, Héctor M.; Girdhar, Yogesh; Holleman, Rusty C.; Churchill, James; Singh, Hanumant; Ralston, David K.

2016-01-01

A research cruise to Hannibal Bank, a seamount and an ecological hotspot in the coastal eastern tropical Pacific Ocean off Panama, explored the zonation, biodiversity, and the ecological processes that contribute to the seamount’s elevated biomass. Here we describe the spatial structure of a benthic anomuran red crab population, using submarine video and autonomous underwater vehicle (AUV) photographs. High density aggregations and a swarm of red crabs were associated with a dense turbid layer 4–10 m above the bottom. The high density aggregations were constrained to 355–385 m water depth over the Northwest flank of the seamount, although the crabs also occurred at lower densities in shallower waters (∼280 m) and in another location of the seamount. The crab aggregations occurred in hypoxic water, with oxygen levels of 0.04 ml/l. Barcoding of Hannibal red crabs, and pelagic red crabs sampled in a mass stranding event in 2015 at a beach in San Diego, California, USA, revealed that the Panamanian and the Californian crabs are likely the same species, Pleuroncodes planipes, and these findings represent an extension of the southern endrange of this species. Measurements along a 1.6 km transect revealed three high density aggregations, with the highest density up to 78 crabs/m2, and that the crabs were patchily distributed. Crab density peaked in the middle of the patch, a density structure similar to that of swarming insects. PMID:27114859

Influence of shot peening on corrosion properties of biocompatible magnesium alloy AZ31 coated by dicalcium phosphate dihydrate (DCPD).

PubMed

Mhaede, Mansour; Pastorek, Filip; Hadzima, Branislav

2014-06-01

Magnesium alloys are promising materials for biomedical applications because of many outstanding properties like biodegradation, bioactivity and their specific density and Young's modulus are closer to bone than the commonly used metallic implant materials. Unfortunately their fatigue properties and low corrosion resistance negatively influenced their application possibilities in the field of biomedicine. These problems could be diminished through appropriate surface treatments. This study evaluates the influence of a surface pre-treatment by shot peening and shot peening+coating on the corrosion properties of magnesium alloy AZ31. The dicalcium phosphate dihydrate coating (DCPD) was electrochemically deposited in a solution containing 0.1M Ca(NO3)2, 0.06M NH4H2PO4 and 10mL/L of H2O2. The effect of shot peening on the surface properties of magnesium alloy was evaluated by microhardness and surface roughness measurements. The influence of the shot peening and dicalcium phosphate dihydrate layer on the electrochemical characteristics of AZ31 magnesium alloy was evaluated by potentiodynamic measurements and electrochemical impedance spectroscopy in 0.9% NaCl solution at a temperature of 22±1°C. The obtained results were analyzed by the Tafel-extrapolation method and equivalent circuit method. The results showed that the application of shot peening process followed by DCPD coating improves the properties of the AZ31 surface from corrosion and mechanical point of view. Copyright © 2014 Elsevier B.V. All rights reserved.

Isolation of ethyl acetic based AGF bio-nutrient and its application on the growth of Capsicum annum L. plants

NASA Astrophysics Data System (ADS)

Hendrawan, Sonjaya, Yaya; Khoerunnisa, Fitri; Musthapa, Iqbal; Nurmala, Astri Rizki

2015-12-01

The study aimed to obtain the bionutrient derived from extraction of AGF leafs in ethyl acetic solvents and to explore its application on the plant growth of capsicum annum L. (curly red chili). Particularly, the fraction of secondary metabolites groups composed bionutrient was intensively elucidated by liquid vacuum chromatography technique. The characterization of secondary metabolites groups was conducted through several methods, i.e. thin layer chromatography, phytochemical screening, and FTIR spectroscopy. The AGF extracts based bionutrient then was applied on capsicum annum L. plants with dosage of 2 and 10 mL/L. The ethyl acetic solvent and commercial nutrient of Phonska and pesticide of curacron (EC 500) were selected as a blank and a positive control to evaluate the growth pattern of capsicum annum L., respectively. The result showed that the CF 1 dan CF2 of AGF extract contained alkaloid and terpenoid of secondary metabolite group, the CF 3, and CF 4 of AGF extracts were dominated by alkaloid, flavonoid, and terpenoid, while the CF 5 of AGF extract contained alkaloid, tannin and terpenoid groups. The CF 2 of AGF extract has the highest growth rate constant of 0.1702 week-1 with the number and heaviest mass of the yield of 82 pieces and 186.60, respectively. It was also showed the significant bio-pesticide activity that should be useful to support plant growth, indicating that AGF extract can be applied as both bio-nutrient and bio-pesticide.

An alternate lining scheme for solar ponds - Results of a liner test rig

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

Raman, P.; Kishore, V.V.N.

1990-01-01

Solar pond lining schemes consisting of combinations of clays and Low Density Polyethylene (LDPE) films have been experimentally evaluated by means of a Solar Pond Liner Test Rig. Results indicate that LDPE film sandwiched between two layers of clay can be effectively used for lining solar ponds.

A High-resolution Multi-wavelength Simultaneous Imaging System with Solar Adaptive Optics

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

Rao, Changhui; Zhu, Lei; Gu, Naiting

A high-resolution multi-wavelength simultaneous imaging system from visible to near-infrared bands with a solar adaptive optics system, in which seven imaging channels, including the G band (430.5 nm), the Na i line (589 nm), the H α line (656.3 nm), the TiO band (705.7 nm), the Ca ii IR line (854.2 nm), the He i line (1083 nm), and the Fe i line (1565.3 nm), are chosen, is developed to image the solar atmosphere from the photosphere layer to the chromosphere layer. To our knowledge, this is the solar high-resolution imaging system with the widest spectral coverage. This system wasmore » demonstrated at the 1 m New Vaccum Solar Telescope and the on-sky high-resolution observational results were acquired. In this paper, we will illustrate the design and performance of the imaging system. The calibration and the data reduction of the system are also presented.« less

From the Nano- to the Macroscale - Bridging Scales for the Moving Contact Line Problem

NASA Astrophysics Data System (ADS)

Nold, Andreas; Sibley, David; Goddard, Benjamin; Kalliadasis, Serafim; Complex Multiscale Systems Team

2016-11-01

The moving contact line problem remains an unsolved fundamental problem in fluid mechanics. At the heart of the problem is its multiscale nature: a nanoscale region close to the solid boundary where the continuum hypothesis breaks down, must be resolved before effective macroscale parameters such as contact line friction and slip can be obtained. To capture nanoscale properties very close to the contact line and to establish a link to the macroscale behaviour, we employ classical density-functional theory (DFT), in combination with extended Navier-Stokes-like equations. Using simple models for viscosity and slip at the wall, we compare our computations with the Molecular Kinetic Theory, by extracting the contact line friction, depending on the imposed temperature of the fluid. A key fluid property captured by DFT is the fluid layering at the wall-fluid interface, which has a large effect on the shearing properties of a fluid. To capture this crucial property, we propose an anisotropic model for the viscosity, which also allows us to scrutinize the effect of fluid layering on contact line friction.

Research and embedded implementation of Layer 3 switch

NASA Astrophysics Data System (ADS)

Song, Jin; Cheng, Zijing

2009-12-01

In the internetworking world, switches and routers have been deployed for workgroup and enterprise connectivity. In the past, switches mainly operated at Layer 2 (they were extensions of bridges), while routers were clearly Layer3 devices. Recently, the line has blurred and switches operating at Layer 3 are becoming more popular. This paper explains the Linux Bridge, Layer 2 Switches, Virtual LAN (VLAN) and Layer 3 Switches. The flow chart of Layer 3 switches and working routine related to Layer 3 switch technology were investigated in detail. This paper presents a new method to implement layer 3 switching that is entirely accomplished in software and is embedded implemented by code transplanting based on PowerPC 460GT platform.

MEMS switches having non-metallic crossbeams

NASA Technical Reports Server (NTRS)

Scardelletti, Maximillian C (Inventor)

2009-01-01

A RF MEMS switch comprising a crossbeam of SiC, supported by at least one leg above a substrate and above a plurality of transmission lines forming a CPW. Bias is provided by at least one layer of metal disposed on a top surface of the SiC crossbeam, such as a layer of chromium followed by a layer of gold, and extending beyond the switch to a biasing pad on the substrate. The switch utilizes stress and conductivity-controlled non-metallic thin cantilevers or bridges, thereby improving the RF characteristics and operational reliability of the switch. The switch can be fabricated with conventional silicon integrated circuit (IC) processing techniques. The design of the switch is very versatile and can be implemented in many transmission line mediums.

First observations of SPEAR-induced topside and bottomside sporadic E layer heating observed using the EISCAT Svalbard and SuperDARN radars

NASA Astrophysics Data System (ADS)

Baddeley, L. J.; Haggstrøm, I.; Yeoman, T. K.; Rietveld, M.

2012-01-01

We present the first observations of heater-induced simultaneous topside and bottomside sporadic E layer enhancements at very high latitudes (78.15°N) using the Space Plasma Exploration by Active Radar (SPEAR) heating facility and the European Incoherent Scatter (EISCAT) Svalbard Radar. During the experiment the SPEAR heating facility was transmitting with O-mode polarization in a field-aligned direction with a constant effective radiated power of ˜16 MW. Results show distinct heater-induced enhancements in both the ion and plasma line spectra. The plasma line enhancements are observed at the SPEAR heater frequency of 4.45 MHz. The plasma line observations represent the highest spatial resolution data (100 m) obtained of such heater-induced enhancements and indicate simultaneous enhancements at both the topside and bottomside of the layer, respectively (located at ˜107.5 and 109 km altitude, respectively). It is postulated that the results represent evidence of O- to Z-mode conversion of the heater wave occurring at the bottom of the E layer, allowing propagation through the layer resulting in simultaneous topside enhancements. The Z-mode enhancements are observed outside the Spitze angle, which is thought to be a result of field-aligned irregularities causing an increase in angular extent of the observations. Additional data from the Super Dual Auroral Radar Network (SuperDARN) HF Finland radar are also shown, which indicate that upon a thinning of the sporadic E layer, the heater beam propagated into the F region, where it induced artificial field-aligned irregularities.

Turbulent boundary layers with secondary flow

NASA Technical Reports Server (NTRS)

Grushwitz, E.

1984-01-01

An experimental analysis of the boundary layer on a plane wall, along which the flow occurs, whose potential flow lines are curved in plane parallel to the wall is discussed. According to the equation frequently applied to boundary layers in a plane flow, which is usually obtained by using the pulse law, a generalization is derived which is valid for boundary layers with spatial flow. The wall shear stresses were calculated with this equation.

Three-dimensional boundary layers approaching separation

NASA Technical Reports Server (NTRS)

Williams, J. C., III

1976-01-01

The theory of semi-similar solutions of the laminar boundary layer equations is applied to several flows in which the boundary layer approaches a three-dimensional separation line. The solutions obtained are used to deduce the nature of three-dimensional separation. It is shown that in these cases separation is of the "ordinary" type. A solution is also presented for a case in which a vortex is embedded within the three-dimensional boundary layer.

Characterization of photoreceptor degeneration in the rhodopsin P23H transgenic rat line 2 using optical coherence tomography.

PubMed

Monai, Natsuki; Yamauchi, Kodai; Tanabu, Reiko; Gonome, Takayuki; Ishiguro, Sei-Ichi; Nakazawa, Mitsuru

2018-01-01

To characterize the optical coherence tomography (OCT) appearances of photoreceptor degeneration in the rhodopsin P23H transgenic rat (line 2) in relation to the histological, ultrastructural, and electroretinography (ERG) findings. Homozygous rhodopsin P23H transgenic albino rats (line 2, very-slow degeneration model) were employed. Using OCT (Micron IV®; Phoenix Research Labs, Pleasanton, CA, USA), the natural course of photoreceptor degeneration was recorded from postnatal day (P) 15 to P 287. The OCT images were qualitatively observed by comparing them to histological and ultrastructural findings at P 62 and P 169. In addition, each retinal layer was quantitatively analyzed longitudinally during degeneration, compared it to that observed in wild type Sprague-Dawley (SD) rats. The relationships between the ERG (full-field combined rod-cone response, 3.0 cds/m2 stimulation) findings and OCT images were also analyzed. In the qualitative study, the two layers presumably corresponding to the photoreceptor inner segment ellipsoid zone (EZ) and interdigitation zone (IZ) were identified in the P23H rat until PN day 32. However, the photoreceptor inner and outer segment (IS/OS) layer became diffusely hyperreflective on OCT after P 46, and the EZ and IZ zones could no longer be identified on OCT. In contrast, in the SD rats, the EZ and IZ were clearly distinguished until at least P 247. The ultrastructural study showed partial disarrangements of the photoreceptor outer segment discs in the P23H rats at P 62, although a light-microscopic histological study detected almost no abnormality in the outer segment. In the quantitative study, the outer retinal layer including the outer plexiform layer (OPL) and the outer nuclear layer (ONL) became significantly thinner in the P23H rats than in the SD rats after P 71. The thickness of the IS/OS layer was maintained in the P23H rats until P 130, and it became statistically thinner than in the SD rats at P 237. The longitudinal attenuation in the amplitude of the a- and b-waves of ERG was significantly correlated with the thickness of the combined OPL and ONL but not with that of the IS/OS layer. OCT showed the degenerated photoreceptor IS/OS layer in rhodopsin P23H transgenic rats (line 2) as a diffuse hyperreflective zone, even in the early stage, with the partially disarranged and destabilized OS discs recognizable by ultrastructural assessment but not by a histological study. The amplitude of the a- and b-waves mainly depends on the thickness of the OPL and ONL layer rather than the thickness of the photoreceptor IS/OS layer in P23H rats.

Derivation of Human Skin Fibroblast Lines for Feeder Cells of Human Embryonic Stem Cells.

PubMed

Unger, Christian; Felldin, Ulrika; Rodin, Sergey; Nordenskjöld, Agneta; Dilber, Sirac; Hovatta, Outi

2016-02-03

After the first derivations of human embryonic stem cell (hESC) lines on fetal mouse feeder cell layers, the idea of using human cells instead of mouse cells as feeder cells soon arose. Mouse cells bear a risk of microbial contamination, and nonhuman immunogenic proteins are absorbed from the feeders to hESCs. Human skin fibroblasts can be effectively used as feeder cells for hESCs. The same primary cell line, which can be safely used for up to 15 passages after stock preparations, can be expanded and used for large numbers of hESC derivations and cultures. These cells are relatively easy to handle and maintain. No animal facilities or animal work is needed. Here, we describe the derivation, culture, and cryopreservation procedures for research-grade human skin fibroblast lines. We also describe how to make feeder layers for hESCs using these fibroblasts. Copyright © 2016 John Wiley & Sons, Inc.

Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards.

PubMed

Al-Kzayer, Lika'a Fasih Y; Sakashita, Kazuo; Matsuda, Kazuyuki; Al-Hadad, Salma Abbas; Al-Jadiry, Mazin Faisal; Abed, Wisam Majeed; Abdulkadhim, Jaafar M H; Al-Shujairi, Tariq Abadi; Hasan, Janan Ghalib; Al-Abdullah, Hussam M Salih; Al-Ani, Mouroge H; Saber, Paiman Ali I; Inoshita, Toshi; Kamata, Minoru; Koike, Kenichi

2012-09-01

Genetic examination of childhood leukemia has not been available in Iraq. We here report the frequency of TEL-AML1, E2A-PBX1, MLL-AF4, and BCR-ABL chimeric transcripts in 264 Iraqi children newly diagnosed with acute lymphoblastic leukemia (ALL), using FTA cards impregnated with bone marrow aspirate or whole blood. The diagnosis of ALL was made according to standard French-American-British morphologic criteria. Based on the results of storage temperature and duration, most of the FTA samples were preserved at 4°C for up to 6 weeks in five Iraqi hospitals and then transferred to Japan for molecular analysis. Nested reverse transcription-polymerase chain reaction was adopted for the analysis. TEL-AML1 chimeric transcript product was found in 32 (12.1%) of 264 ALL patients. Eleven (4.2%) patients, 4 (1.5%) patients, and 11 (4.2%) patients had E2A-PBX1 mRNA, MLL-AF4 mRNA, and BCR-ABL mRNA, respectively. One patient had both TEL-AML1 and E2A-PBX1 fusion genes. The incidence of TEL-AML1 in Iraqi ALL children appears to be similar to or slightly higher than those of Jordan (12%) and Kuwait (7%). The prevalence and clinical findings of ALL patients with either E2A-PBX1 or BCR-ABL were comparable to the data reported elsewhere. International collaboration via FTA cards may be helpful to improve diagnosis and management of patients with hematological malignancies in low-income and underdeveloped countries. Copyright © 2012 Wiley Periodicals, Inc.

Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance.

PubMed

Vukovic, Milica; Guitart, Amelie V; Sepulveda, Catarina; Villacreces, Arnaud; O'Duibhir, Eoghan; Panagopoulou, Theano I; Ivens, Alasdair; Menendez-Gonzalez, Juan; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E M; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L; Wood, Andrew; O'Carroll, Dónal; Ratcliffe, Peter J; Kranc, Kamil R

2015-12-14

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance. © 2015 Vukovic et al.

Hif-1α and Hif-2α synergize to suppress AML development but are dispensable for disease maintenance

PubMed Central

Vukovic, Milica; Guitart, Amelie V.; Sepulveda, Catarina; Villacreces, Arnaud; O'Duibhir, Eoghan; Panagopoulou, Theano I.; Ivens, Alasdair; Menendez-Gonzalez, Juan; Iglesias, Juan Manuel; Allen, Lewis; Glykofrydis, Fokion; Subramani, Chithra; Armesilla-Diaz, Alejandro; Post, Annemarie E.M.; Schaak, Katrin; Gezer, Deniz; So, Chi Wai Eric; Holyoake, Tessa L.; Wood, Andrew; O'Carroll, Dónal; Ratcliffe, Peter J.

2015-01-01

Leukemogenesis occurs under hypoxic conditions within the bone marrow (BM). Knockdown of key mediators of cellular responses to hypoxia with shRNA, namely hypoxia-inducible factor-1α (HIF-1α) or HIF-2α, in human acute myeloid leukemia (AML) samples results in their apoptosis and inability to engraft, implicating HIF-1α or HIF-2α as therapeutic targets. However, genetic deletion of Hif-1α has no effect on mouse AML maintenance and may accelerate disease development. Here, we report the impact of conditional genetic deletion of Hif-2α or both Hif-1α and Hif-2α at different stages of leukemogenesis in mice. Deletion of Hif-2α accelerates development of leukemic stem cells (LSCs) and shortens AML latency initiated by Mll-AF9 and its downstream effectors Meis1 and Hoxa9. Notably, the accelerated initiation of AML caused by Hif-2α deletion is further potentiated by Hif-1α codeletion. However, established LSCs lacking Hif-2α or both Hif-1α and Hif-2α propagate AML with the same latency as wild-type LSCs. Furthermore, pharmacological inhibition of the HIF pathway or HIF-2α knockout using the lentiviral CRISPR-Cas9 system in human established leukemic cells with MLL-AF9 translocation have no impact on their functions. We therefore conclude that although Hif-1α and Hif-2α synergize to suppress the development of AML, they are not required for LSC maintenance. PMID:26642852

Biochemical responses in armored catfish (Pterygoplichthys anisitsi) after short-term exposure to diesel oil, pure biodiesel and biodiesel blends.

PubMed

Nogueira, Lílian; da Silva, Danilo Grünig Humberto; Oliveira, Thiago Yukio Kikuchi; da Rosa, Joel Maurício Correa; Felício, Andréia Arantes; de Almeida, Eduardo Alves

2013-09-01

Biodiesel fuel is gradually replacing petroleum-based diesel oil use. Despite the biodiesel being considered friendlier to the environment, little is known about its effects in aquatic organisms. In this work we evaluated whether biodiesel exposure can affect oxidative stress parameters and biotransformation enzymes in armored catfish (Pterygoplichthys anisitsi, Loricariidae), a South American endemic species. Thus, fish were exposed for 2 and 7d to 0.01mLL(-1) and 0.1mLL(-1) of pure diesel, pure biodiesel (B100) and blends of diesel with 5% (B5) and 20% (B20) biodiesel. Lipid peroxidation (malondialdehyde) levels and the activities of the enzymes glutathione S-transferase, superoxide dismutase, catalase and glutathione peroxidase were measured in liver and gills. Also, DNA damage (8-oxo-7, 8-dihydro-2'-deoxyguanosine) levels in gills and 7-ethoxyresorufin-O-deethylase activity in liver were assessed. Pure diesel, B5 and B20 blends changed most of the enzymes tested and in some cases, B5 and B20 induced a higher enzyme activity than pure diesel. Antioxidant system activation in P. anisitsi was effective to counteract reactive oxygen species effects, since DNA damage and lipid peroxidation levels were maintained at basal levels after all treatments. However, fish gills exposed to B20 and B100 presented increased lipid peroxidation. Despite biodiesel being more biodegradable fuel that emits less greenhouse gases, the increased lipid peroxidation showed that biofuel and its blends also represent hazards to aquatic biota. Copyright © 2013 Elsevier Ltd. All rights reserved.

The sperm motility pattern in ecotoxicological tests. The CRYO-Ecotest as a case study.

PubMed

Fabbrocini, Adele; D'Adamo, Raffaele; Del Prete, Francesco; Maurizio, Daniela; Specchiulli, Antonietta; Oliveira, Luis F J; Silvestri, Fausto; Sansone, Giovanni

2016-01-01

Changes in environmental stressors inevitably lead to an increasing need for innovative and more flexible monitoring tools. The aim of this work has been the characterization of the motility pattern of the cryopreserved sea bream semen after exposure to a dumpsite leachate sample, for the identification of the best representative parameters to be used as endpoints in an ecotoxicological bioassay. Sperm motility has been evaluated either by visual and by computer-assisted analysis; parameters concerning motility on activation and those describing it in the times after activation (duration parameters) have been assessed, discerning them in terms of sensitivity, reliability and methodology of assessment by means of multivariate analyses. The EC50 values of the evaluated endpoints ranged between 2.3 and 4.5ml/L, except for the total motile percentage (aTM, 7.0ml/L), which proved to be the less sensitive among all the tested parameters. According to the multivariate analyses, a difference in sensitivity among "activation" endpoints in respect of "duration" ones can be inferred; on the contrary, endpoints seem to be equally informative either describing total motile sperm or the rapid sub-population, as well as the assessment methodology seems to be not discriminating. In conclusion, the CRYO-Ecotest is a multi-endpoint bioassay that can be considered a promising innovative ecotoxicological tool, characterized by a high plasticity, as its endpoints can be easy tailored each time according to the different needs of the environmental quality assessment programs. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of utilization of tomato extract and foliar fertilizer as media on shoots multiplication of banana cv Ambon in vitro

NASA Astrophysics Data System (ADS)

Bidhari, L. A.; Purwanto, E.; Yunus, A.

2018-03-01

The good quality banana seeds are still difficult to obtain. There are two ways to provide seeds, namely conventional and tissue culture (in vitro). Tomato extract contains natural ZPT or phytohormone which can be utilized in modification of banana tissue culture media. The aim of this study was to determine the influence of media types and tomato extracts in various concentrations for multiplication of banana cv. Ambon in vitro. The study was conducted from October - December 2016 at the Tissue Culture Laboratory of Horticulture Seed Center, Salaman, Magelang. The experimental design used was completely randomized design with two treatment factors. The firs factor was media type with the addition of foliar fertilizer, the second factor was modification of tomato extract with 4 levels. The results showed that the different of the treated media treatment did not affect the emerge of leaf and leaf length, the number of roots and root length. The emerge of the leaves of all treatments occurred at 6 days after planting with the highest average length was obtained in MS treatment with a combination of tomato extract 50 ml/l (10.3 cm). The use of MS medium with a combination of tomato extract 50 ml/l generated the average root number 15.5 with a root lengths 7.5 cm. Substitution of MS medium with tomato extract and foliar fertilizer did not show better results compared to the use of MS media in the multiplication of banana shoots in tissue culture.

Toxicological characterization of a novel wastewater treatment process using EDTA-Na2Zn as draw solution (DS) for the efficient treatment of MBR-treated landfill leachate.

PubMed

Niu, Aping; Ren, Yi-Wei; Yang, Li; Xie, Shao-Lin; Jia, Pan-Pan; Zhang, Jing-Hui; Wang, Xiao; Li, Jing; Pei, De-Sheng

2016-07-01

Landfill leachate has become an important source of environmental pollution in past decades, due to the increase of waste volume. Acute toxic and genotoxic hazards to organisms can be caused by landfill leachate. Thus, how to efficiently recover water from landfill leachate and effectively eliminate combined toxicity of landfill leachate are the most pressing issues in waste management. In this study, EDTA-Na2Zn as draw solution (DS) was used to remove the toxicity of membrane bioreactor-treated landfill leachate (MBR-treated landfill leachate) in forward osmosis (FO) process, and nanofiltration (NF) was designed for recovering the diluted DS. Zebrafish and human cells were used for toxicity assay after the novel wastewater treatment process using EDTA-Na2Zn as DS. Results showed that the water recovery rate of MBR-treated landfill leachate (M-LL) in FO membrane system could achieve 66.5% and 71.2% in the PRO and FO mode respectively, and the diluted DS could be efficiently recovered by NF. Toxicity tests performed by using zebrafish and human cells showed that M-LL treated by EDTA-Na2Zn had no toxicity effect on zebrafish larvae and human cells, but it had very slight effect on zebrafish embryos. In conclusion, all results indicated that EDTA-Na2Zn as DS can effectively eliminate toxicity of landfill leachate and this method is economical and eco-friendly for treatment of different types of landfill leachate. Copyright © 2016 Elsevier Ltd. All rights reserved.

Unraveling the effect of structurally different classes of insecticide on germination and early plant growth of soybean [Glycine max (L.) Merr].

PubMed

Dhungana, Sanjeev Kumar; Kim, Il-Doo; Kwak, Hwa-Sook; Shin, Dong-Hyun

2016-06-01

Although a considerable number of studies about the effect of different insecticides on plant physiology and metabolism have been carried out, research work about the comparative action of structurally different classes of insecticide on physiological and biochemical properties of soybean seed germination and early growth has not been found. The objective of this study was to investigate the effect of different classes of insecticides on soybean seed germination and early plant growth. Soybean seeds of Bosuk cultivar were soaked for 24h in distilled water or recommended dose (2mLL(-1), 1mLL(-1), 0.5gL(-1), and 0.5gL(-1) water for insecticides Mepthion, Myungtaja, Actara, and Stonate, respectively) of pesticide solutions of four structurally different classes of insecticides - Mepthion (fenitrothion; organophosphate), Myungtaja (etofenprox; pyrethroid), Actara (thiamethoxam; neonicotinoid), and Stonate (lambda-cyhalothrin cum thiamethoxam; pyrethroid cum neonicotinoid) - which are used for controlling stink bugs in soybean crop. Insecticides containing thiamethoxam and lamda-cyhalothrin cum thiamethoxam showed positive effects on seedling biomass and content of polyphenol and flavonoid, however fenitrothion insecticide reduced the seed germination, seed and seedling vigor, and polyphenol and flavonoid contents in soybean. Results of this study reveal that different classes of insecticide have differential influence on physiologic and metabolic actions like germination, early growth, and antioxidant activities of soybean and this implies that yield and nutrient content also might be affected with the application of different types of insecticide. Copyright © 2015 Elsevier B.V. All rights reserved.

Characterization of CD22 expression in acute lymphoblastic leukemia.

PubMed

Shah, Nirali N; Stevenson, Maryalice Stetler; Yuan, Constance M; Richards, Kelly; Delbrook, Cindy; Kreitman, Robert J; Pastan, Ira; Wayne, Alan S

2015-06-01

CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. CD22 expression was demonstrated in all subjects (n = 163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349-19,653, n = 160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349-3,624, n = 20 versus 3,853 sites/cell, range 451-19,653, n = 140; P = <0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22%-82% CD22 +). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. These characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.

Interactions of 1,12-diamino-4,9-dioxadodecane (OSpm) and Cu(II) ions with pyrimidine and purine nucleotides: adenosine-5'-monophosphate (AMP) and cytidine-5'-monophosphate (CMP).

PubMed

Lomozik, L; Gasowska, A; Krzysko, G

2006-11-01

The interactions of Cu(II) ions with adenosine-5'-monophosphate (AMP), cytidine-5'-monophosphate (CMP) and 1,12-diamino-4,9-dioxadodecane (OSpm) were studied. A potentiometric method was applied to determine the composition and stability constants of complexes formed, while the mode of interactions was analysed by spectral methods (ultraviolet and visible spectroscopy (UV-Vis), electron paramagnetic resonance (EPR), (13)C NMR, (31)P NMR). In metal-free systems, molecular complexes nucleotide-polyamine (NMP)H(x)(OSpm) were formed. The endocyclic nitrogen atoms of the purine ring N(1), N(7), the nitrogen atom of the pyrimidine ring N(3), the oxygen atoms of the phosphate group of the nucleotide and the protonated nitrogen atoms of the polyamine were the reaction centres. The mode of interaction of the metal ion with OSpm and the nucleotides (AMP or CMP) in the coordination compounds was established. In the system Cu(II)/OSpm the dinuclear complex Cu(2)(OSpm) forms, while in the ternary systems Cu(II)/nucleotide/OSpm the species type MH(x)LL' and MLL' appear. In the MH(x)LL' type species, the main centres of copper (II) ion binding in the nucleotide are the phosphate groups. The protonated amino groups of OSpm are involved in non-covalent interaction with the nitrogen atoms N(1), N(7) or N(3) of the purine or pyrimidine ring, whereas at higher pH, deprotonated nitrogen atoms of polyamine are engaged in metallation in MLL' species.

Observation of Z decays to four leptons with the CMS detector at the LHC

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

Chatrchyan, S.; Khachatryan, V.; Sirunyan, A. M.

The first observation of the Z boson decaying to four leptons in proton-proton collisions is presented. The analyzed data set corresponds to an integrated luminosity of 5.02 inverse femtobarns at sqrt(s) = 7 TeV collected by the CMS detector at the Large Hadron Collider. A pronounced resonance peak, with a statistical significance of 9.7 sigma, is observed in the distribution of the invariant mass of four leptons (electrons and/or muons) with mass and width consistent with expectations for Z boson decays. The branching fraction and cross section reported here are defined by phase space restrictions on the leptons, namely, 80more » < m[4l] < 100 GeV, where m[4l] is the invariant mass of the four leptons, and m[ll] > 4 GeV for all pairs of leptons, where m[ll] is the two-lepton invariant mass. The measured branching fraction is B(Z to 4l) = (4.2 /+0.9/-0.8 (stat.) +/- 0.2 (syst.)) 10E-6 and agrees with the standard model prediction of 4.45 10E-6. The measured cross section times branching fraction is sigma(pp to Z) B(Z to 4 l) = 112 +23/-20 (stat.) +7/-5 (syst.) +3/-2 (lumi.) fb, also consistent with the standard model prediction of 120 fb. The four-lepton mass peak arising from Z to 4 l decays provides a calibration channel for the Higgs boson search in the H to ZZ to 4 l decay mode.« less

Detection of antibiotics in goat's milk: effect of detergents on the response of microbial inhibitor tests.

PubMed

Romero, Tamara; Beltrán, María Carmen; Althaus, Rafael Lisandro; Molina, María Pilar

2014-08-01

The aim of the study was to evaluate the interference of acid and alkaline detergents employed in the cleaning of milking equipment of caprine dairy farms on the performance of microbial tests used in antibiotic control (BRT MRL, Delvotest MCS, and Eclipse 100). Eight concentrations of commercial detergents, five acid (0-0.25%) and five alkaline (0-1%) were add to antimicrobial-free goat's milk to evaluate the detergent effect on the response of microbial inhibitor tests. To evaluate the effect of detergents on the detection capability of microbial tests two detergents at 0.5 ml/l (one acid and one basic) and eight concentrations of four β-lactam antibiotics (ampicillin, amoxicillin, cloxacillin and benzylpenicillin) were used. Milk without detergents was used as control. The spiked samples were analysed twelve times by three microbial tests. The results showed that the presence of acid detergents did not affect the response of microbial tests for any of the concentrations tested. However, at concentrations equal to or greater than 2 ml/l alkaline detergents positive results were found in microbial tests (16.7-100%). The detection limits of the screening tests for penicillins were not modified substantially by the presence of detergents. In general, the presence of acid and alkaline detergents in goat's milk did not produce a great interference in the microbial tests, only high concentrations of detergents could cause non-compliant results, but these concentrations are difficult to find in practice if proper cleaning procedures are applied in goat dairy farms.

Remote sensing of hydrologic variables in boreal areas, phase 1

NASA Technical Reports Server (NTRS)

Peck, Eugene L.; Carroll, Thomas R.

1994-01-01

The major effort by HYD-6 members has been to develop a network of flight lines to provide the maximum amount of information on the temporal and spatial variation in soil moisture for the Boreal Ecosystem Atmosphere Study (BOREAS) study areas. Field visits to the southern study area (SSA) were conducted during May 1993 to obtain first hand information on the flight lines that had been previously selected for BOREAS snow studies. In September 1993 airborne gamma radiation surveys were conducted over the SSA, the northern study area (NSA), and for five flight lines along the transect between the two study areas. In situ measurements of soil moisture and water content of the moss/humus layer were obtained for calibration of selected gamma radiation flights lines in the SSA and for two of the transit lines. The flight lines for which soil moisture will be measured during the three IFC's during the summer of 1994 is a subset of the total flight lines that have been flown for the snow surveys. During the WFC in February 1994, airborne gamma radiation surveys were flown over all of the flight lines. Members of HYD-4 collected in-situ measurements (soil moisture, water content of the moss/humus layer, and water equivalent of the snow cover).

Reactive composite compositions and mat barriers

DOEpatents

Langton, Christine A.; Narasimhan, Rajendran; Karraker, David G.

2001-01-01

A hazardous material storage area has a reactive multi-layer composite mat which lines an opening into which a reactive backfill and hazardous material are placed. A water-inhibiting cap may cover the hazardous material storage area. The reactive multi-layer composite mat has a backing onto which is placed an active layer which will neutralize or stabilize hazardous waste and a fronting layer so that the active layer is between the fronting and backing layers. The reactive backfill has a reactive agent which can stabilize or neutralize hazardous material and inhibit the movement of the hazardous material through the hazardous material storage area.

Implementation of atomic layer etching of silicon: Scaling parameters, feasibility, and profile control

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

Ranjan, Alok, E-mail: alok.ranjan@us.tel.com; Wang, Mingmei; Sherpa, Sonam D.

2016-05-15

Atomic or layer by layer etching of silicon exploits temporally segregated self-limiting adsorption and material removal steps to mitigate the problems associated with continuous or quasicontinuous (pulsed) plasma processes: selectivity loss, damage, and profile control. Successful implementation of atomic layer etching requires careful choice of the plasma parameters for adsorption and desorption steps. This paper illustrates how process parameters can be arrived at through basic scaling exercises, modeling and simulation, and fundamental experimental tests of their predictions. Using chlorine and argon plasma in a radial line slot antenna plasma source as a platform, the authors illustrate how cycle time, ionmore » energy, and radical to ion ratio can be manipulated to manage the deviation from ideality when cycle times are shortened or purges are incomplete. Cell based Monte Carlo feature scale modeling is used to illustrate profile outcomes. Experimental results of atomic layer etching processes are illustrated on silicon line and space structures such that iso-dense bias and aspect ratio dependent free profiles are produced. Experimental results also illustrate the profile control margin as processes move from atomic layer to multilayer by layer etching. The consequence of not controlling contamination (e.g., oxygen) is shown to result in deposition and roughness generation.« less

Rooster Semen Cryopreservation: Effect of Pedigree Line and Male Age on Post-Thaw Sperm Function

USDA-ARS?s Scientific Manuscript database

The fertility rates of cryopreserved poultry semen are highly variable and not reliable for use in preservation of commercial genetic stocks. Our objective was to evaluate the cryosurvival of semen from 8 pedigreed layer lines at the onset and end of production. Semen from 160 roosters (20/line) was...

Turbulent dusty boundary layer in an ANFO surface-burst explosion

NASA Astrophysics Data System (ADS)

Kuhl, A. L.; Ferguson, R. E.; Chien, K. Y.; Collins, J. P.

1992-01-01

This paper describes the results of numerical simulations of the dusty, turbulent boundary layer created by a surface burst explosion. The blast wave was generated by the detonation of a 600-T hemisphere of ANFO, similar to those used in large-scale field tests. The surface was assumed to be ideally noncratering but contained an initial loose layer of dust. The dust-air mixture in this fluidized bed was modeled as a dense gas (i.e., an equilibrium model, valid for very small-diameter dust particles). The evolution of the flow was calculated by a high-order Godunov code that solves the nonsteady conservation laws. Shock interactions with dense layer generated vorticity near the wall, a result that is similar to viscous, no-slip effects found in clean flows. The resulting wall shear layer was unstable, and rolled up into large-scale rotational structures. These structures entrained dense material from the wall layer and created a chaotically striated flow. The boundary layer grew due to merging of the large-scale structures and due to local entrainment of the dense material from the fluidized bed. The chaotic flow was averaged along similarity lines (i.e., lines of constant values of x = r/Rs and y = z/Rs where R(sub s) = ct(exp alpha)) to establish the mean-flow profiles and the r.m.s. fluctuating-flow profiles of the boundary layer.

Inner Plasma Structure of the Low-Latitude Reconnection Layer

NASA Technical Reports Server (NTRS)

Zhang, Q.-H.; Dunlop, M. W.; Lockwood, M.; Lavraud, B.; Bogdanova, Y. V.; Hasegawa, H.; Yang, H. -G.; Liu, R. -Y.; Hu, H. -Q.; Zhang, B. -C.;

Determination of the Mass Absorption Coefficient in Two-Layer Ti/V and V/Ti Thin Film Systems by the X-Ray Fluorescence Method

NASA Astrophysics Data System (ADS)

Mashin, N. I.; Chernyaeva, E. A.; Tumanova, A. N.; Gafarova, L. M.

2016-03-01

A new XRF procedure for the determination of the mass absorption coefficient in thin film Ti/V and V/Ti two-layer systems has been proposed. The procedure uses easy-to-make thin-film layers of sputtered titanium and vanadium on a polymer film substrate. Correction coefficients have been calculated that take into account attenuation of primary radiation of the X-ray tube, as well as attenuation of the spectral line of the bottom layer element in the top layer.

The Impact of Seed Layer Structure on the Recrystallization of ECD Cu and its Alloys

NASA Astrophysics Data System (ADS)

O'Brien, Brendan B.

Despite the significant improvements originally offered by the use of Cu over Al as the interconnect material for semiconductor devices, the continued down-scaling of interconnects has presented significant challenges for semiconductor engineers. As the metal line widths shrink, both the conductivity and reliability of lines decrease due to a stubbornly fine-grained microstructure in narrow lines. Understanding microstructural transformation of the ECD Cu in narrow features which leads to this polygranular microstructure is the first focus of this dissertation. As in the case of Cu films, the underlying seed layer strongly influences progress of transformation. Unlike films, however, the seed layer is not homogenous in patterned substrates, but differs according to the size of the trench and the location within the trench (field, bottom, and sidewall). Based on these findings, and the known influence of texture on the transformation of ECD Cu, a rapid trench initiated transformation process was posited for narrow interconnect lines. Time-resolved TEM observation of the ECD Cu in 48 nm lines during the transformation process confirmed the hypothesis. In fact, the TEM images revealed that the transformation was even faster than anticipated, and that the microstructure of the Cu inside the lines was stagnant after a mere 1.5 hours at room temperature. Studies of the transformation at elevated temperatures found that, despite anneals at 250°C for up to an hour, the grain size distribution for the Cu in narrow lines for all times converged, whether annealed at room temperature or 250°C. These data suggest that process was being driven by the 'consumable' internal energy stored in the as-plated microstructure. This is different than the transformation of the overburden, which is driven by a competition between surface energy and internal stress buildup due to film densification and relief due to the secondary growth of a 200 texture component. Based on these findings, two methods for manipulating the microstructure of the ECD Cu in the narrow lines were explored, including changes to the seed layer through ion implantation, and altering the as-plated Cu microstructure through co-ECD of alloys. The influence on the microstructure and applicability of both of these techniques to BEOL processing will also be discussed.

Uncertainty Analysis of Air Radiation for Lunar Return Shock Layers

NASA Technical Reports Server (NTRS)

Kleb, Bil; Johnston, Christopher O.

2008-01-01

By leveraging a new uncertainty markup technique, two risk analysis methods are used to compute the uncertainty of lunar-return shock layer radiation predicted by the High temperature Aerothermodynamic Radiation Algorithm (HARA). The effects of epistemic uncertainty, or uncertainty due to a lack of knowledge, is considered for the following modeling parameters: atomic line oscillator strengths, atomic line Stark broadening widths, atomic photoionization cross sections, negative ion photodetachment cross sections, molecular bands oscillator strengths, and electron impact excitation rates. First, a simplified shock layer problem consisting of two constant-property equilibrium layers is considered. The results of this simplified problem show that the atomic nitrogen oscillator strengths and Stark broadening widths in both the vacuum ultraviolet and infrared spectral regions, along with the negative ion continuum, are the dominant uncertainty contributors. Next, three variable property stagnation-line shock layer cases are analyzed: a typical lunar return case and two Fire II cases. For the near-equilibrium lunar return and Fire 1643-second cases, the resulting uncertainties are very similar to the simplified case. Conversely, the relatively nonequilibrium 1636-second case shows significantly larger influence from electron impact excitation rates of both atoms and molecules. For all cases, the total uncertainty in radiative heat flux to the wall due to epistemic uncertainty in modeling parameters is 30% as opposed to the erroneously-small uncertainty levels (plus or minus 6%) found when treating model parameter uncertainties as aleatory (due to chance) instead of epistemic (due to lack of knowledge).

Spatially resolving the outer atmosphere of the M giant BK Virginis in the CO first overtone lines with VLTI/AMBER

NASA Astrophysics Data System (ADS)

Ohnaka, K.; Hofmann, K.-H.; Schertl, D.; Weigelt, G.; Malbet, F.; Massi, F.; Meilland, A.; Stee, Ph.

2012-01-01

Context. The mass-loss mechanism in normal K-M giant stars with small variability amplitudes is not yet understood, although the majority among red giant stars are precisely of this type. Aims: We present high-spatial and high-spectral resolution observations of the M7 giant BK Vir with AMBER at the Very Large Telescope Interferometer (VLTI). Our aim is to probe the physical properties of the outer atmosphere by spatially resolving the star in the individual CO first overtone lines. Methods: BK Vir was observed between 2.26 and 2.31 μm using the 16-32-48 m telescope configuration with an angular resolution of 9.8 mas and a spectral resolution of 12 000. Results: The uniform-disk diameters observed in the CO first overtone lines are 12 - 31% larger than those measured in the continuum. We also detected asymmetry in the CO line-forming region, which manifests itself as non-zero/non-π differential and closure phases. The data taken 1.5 months apart show possible time variation on a spatial scale of 30 mas (corresponding to 3 × stellar diameter) at the CO band head. Comparison of the observed data with the MARCS photospheric model shows that whereas the observed CO line spectrum can be satisfactorily reproduced by the model, the angular sizes observed in the CO lines are much larger than predicted by the model. Our model with two additional CO layers above the MARCS photosphere reproduces the observed spectrum and interferometric data in the CO lines simultaneously. This model suggests that the inner CO layer at ~1.2 R⋆ is very dense and warm with a CO column density of ~1022 cm-2 and temperatures of 1900 - 2100 K, while the outer CO layer at 2.5-3.0 R⋆ is characterized by column densities of 1019-1020 cm-2 and temperatures of 1500 - 2100 K. Conclusions: Our AMBER observations of BK Vir have spatially resolved the extended molecular outer atmosphere of a normal M giant in the individual CO lines for the first time. The temperatures derived for the CO layers are higher than, or equal to, the uppermost layer of the MARCS photospheric model, implying the operation of some heating mechanism in the outer atmosphere. This study also illustrates that testing photospheric models only with the spectra of strong molecular or atomic features can be misleading. Based on AMBER observations made with the Very Large Telescope Interferometer of the European Southern Observatory. Program ID: 081.D-0233(A) (AMBER Guaranteed Time Observation).

A flash spectrum of Cl I, C I, N I, and Ni II absorption in 31 Cygni: A direct observation of the reversing layer

NASA Technical Reports Server (NTRS)

Ahmad, Imad A.

1987-01-01

In the process of surveying IUE observations of the zeta Aurigae binary system 31 Cygni for evidence of a shock, the presence of narrow low temperature lines Cl I, C I, N I, and Ni II has been discovered. These lines cannot be due to the local interstellar medium, since they appear only in one of the 16 high resolution, short wavelength observations made of this system. The phase of their appearance is theta = 0.017, approximately two months after egress of the blue dwarf component from eclipse behind the cool supergiant. Such lines might be produced by the shining of the hot dwarf companion's continuum through the edge of the supergiant's reversing layer or through a condensation in the supergiant atmosphere. If the former is the case, then the height of the reversing layer may be estimated from this observation. The radial velocities and equivalent widths of ten of these lines have been measured and the former is found to be -8.2 +/- 0.5 km/sec, precisely equal to the radial velocity of the system center of mass. This places a strict upper limit on the rotational velocity of the supergiant: V sub rot less than 2 km/s to better than 3 sigma.

Vertical bloch line memory

NASA Technical Reports Server (NTRS)

Katti, Romney R. (Inventor); Stadler, Henry L. (Inventor); Wu, Jiin-chuan (Inventor)

1995-01-01

A new read gate design for the vertical Bloch line (VBL) memory is disclosed which offers larger operating margin than the existing read gate designs. In the existing read gate designs, a current is applied to all the stripes. The stripes that contain a VBL pair are chopped, while the stripes that do not contain a VBL pair are not chopped. The information is then detected by inspecting the presence or absence of the bubble. The margin of the chopping current amplitude is very small, and sometimes non-existent. A new method of reading Vertical Bloch Line memory is also disclosed. Instead of using the wall chirality to separate the two binary states, the spatial deflection of the stripe head is used. Also disclosed herein is a compact memory which uses vertical Bloch line (VBL) memory technology for providing data storage. A three-dimensional arrangement in the form of stacks of VBL memory layers is used to achieve high volumetric storage density. High data transfer rate is achieved by operating all the layers in parallel. Using Hall effect sensing, and optical sensing via the Faraday effect to access the data from within the three-dimensional packages, an even higher data transfer rate can be achieved due to parallel operation within each layer.

Virtual Slice Through Icy Layered Deposits Near Mars South Pole

NASA Image and Video Library

2007-03-15

The upper image is a radargram showing data from the subsurface of Mars in the ice-rich layered deposits that surround the south pole. The lower image shows the position of the ground track white line on a topographic map

Neutron flux spectrum revealed by Nb-based current-biased kinetic inductance detector with a 10B conversion layer

NASA Astrophysics Data System (ADS)

Miyajima, Shigeyuki; Shishido, Hiroaki; Narukami, Yoshito; Yoshioka, Naohito; Fujimaki, Akira; Hidaka, Mutsuo; Oikawa, Kenichi; Harada, Masahide; Oku, Takayuki; Arai, Masatoshi; Ishida, Takekazu

2017-01-01

We successfully derived the time-dependent flux of pulsed neutrons using a superconducting Nb-based current-biased kinetic inductance detector (CB-KID) with a 10B conversion layer at Japan Proton Accelerator Research Complex. Our CB-KID is a meander line made of a 40-nm-thick Nb thin film with 1 - μm line width, which is covered with a 150-nm-thick 10B conversion layer. The detector works at a temperature below 4 K. The evaluated detection efficiency of the CB-KID in this experiment is 0.23 % at the neutron energy of 25.4 meV. The time-dependent flux spectra of pulsed neutrons thus obtained are in good agreement with the results obtained by the Monte Carlo simulations.

Experimental visualization of the cathode layer in AC surface dielectric barrier discharge

NASA Astrophysics Data System (ADS)

Kim, Sang-You; Lho, Taihyeop; Chung, Kyu-Sun

2018-06-01

A narrow etched polyimide line at the bottom edge of a biased electrode (BE) and a non-etched dielectric surface near the biased electrode were observed in an atmospheric AC flexible surface dielectric barrier discharge of polyimide dielectric. These findings are attributed to the bombardment of positive oxygen ions on the bottom edge of the BE and the electron breakdown trajectory not contacting the polyimide surface following the electric field lines formed between the BE edge and the surface charge layer on the dielectric. The length of the non-etched dielectric surface during the first micro-discharge was observed as 22 μm. This occurred, regardless of three different operating durations, which is in good agreement with the length of the cathode layer according to Paschen's law.

Wave interactions in a three-dimensional attachment line boundary layer

NASA Technical Reports Server (NTRS)

Hall, Philip; Mackerrell, Sharon O.

1988-01-01

The 3-D boundary layer on a swept wing can support different types of hydrodynamic instability. Attention is focused on the so-called spanwise contamination problem, which occurs when the attachment line boundary layer on the leading edge becomes unstable to Tollmien-Schlichting waves. In order to gain insight into the interactions important in that problem, a simplified basic state is considered. This simplified flow corresponds to the swept attachment line boundary layer on an infinite flat plate. The basic flow here is an exact solution of the Navier-Stokes equations and its stability to 2-D waves propagating along the attachment can be considered exactly at finite Reynolds number. This has been done in the linear and weakly nonlinear regimes. The corresponding problem is studied for oblique waves and their interaction with 2-D waves is investigated. In fact, oblique modes cannot be described exactly at finite Reynolds number so it is necessary to make a high Reynolds number approximation and use triple deck theory. It is shown that there are two types of oblique wave which, if excited, cause the destabilization of the 2-D mode and the breakdown of the disturbed flow at a finite distance from the leading edge. First, a low frequency mode related to the viscous stationary crossflow mode is a possible cause of breakdown. Second, a class of oblique wave with frequency comparable with that of the 2-D mode is another cause of breakdown. It is shown that the relative importance of the modes depends on the distance from the attachment line.

Aponeurosis of the levator palpebrae superioris in Chinese subjects

PubMed Central

Pan, Er; Nie, Yun-Fei; Wang, Zhen-Jun; Peng, Li-Xia; Wu, Yan-Hong; Li, Qin

2016-01-01

Abstract An accurate understanding of the anatomy of the levator palpebrae superioris aponeurosis (LPSA) is critical for successful blepharoplasty of aponeurotic ptosis. We investigated the macroscopic and microscopic anatomy of the LPSA. This prospective live gross anatomy study enrolled 200 adult Chinese patients with bilateral mild ptosis undergoing elective blepharoplasty. Full-thick eyelid tissues and sagittal sections from the eyelid skin to the conjunctiva were examined with Masson trichrome staining or antismooth muscle actin (SMA) immunohistochemistry. Gross anatomy showed that the space between the superficial and deep layers of the LPSA could be accessed after incising the overlying superficial fascia, by retracting the white line. Adipose layers were clearly observed in 195 out of 200 patients with bilateral mild ptosis, among which 180 cases had the superficial layer connected to the uncoated adipose. Fifteen cases had the superficial layer connected to the smoothly coated layer, and 5 cases had the superficial layer directly connected to the deep loose fiber, almost without adipose. In previously untreated patients, the LPSA space was located beneath the intact orbital septum. In those with previous surgeries, it was beneath the superficial layer of the LPSA, underlying the destructed orbital septum. Cadaveric histology showed that the deep layer of the LPSA extended into the anterior layer of the tarsal plate and the superficial layer reflexed upward in continuity with the vertical orbital septum. An occult space existed between the 2 layers of the LPSA, with a smooth lining on the deep layer. The superficial layer of the LPSA was SMA-immunonegative but the deep layer was slightly immunopositive for SMA. An occult anatomic space exists between the superficial and deep layers of the LPSA, in proximity to the superior tarsal plate margin. Recognition of the more anatomically significant LPSA deep layer may help improve the aesthetic outcome of blepharoplasty. PMID:27495084

Au/Ti resistors used for Nb/Pb-alloy Josephson junctions. II. Thermal stability

NASA Astrophysics Data System (ADS)

Murakami, Masanori; Kim, K. K.

1984-10-01

In the preceding paper bilayered Au/Ti resistors were found to have excellent electrical stability during storage at room temperature after preannealing at an elevated temperature, which is essential to design logic and memory circuits of Nb/Pb-alloy Josephson junction devices. The resistors could contact directly with the Pb-alloy control lines in which Pb and In atoms which are known to intermix easily with Au atoms are contained. Since Pb and In atoms in the control lines are separated from Au atoms of the resistors by thin Ti layers, thermal stability at the contacts is a major concern for use of the Au/Ti resistor material in the Josephson devices. In the present study, surface morphology change and diffusion mechanism at the resistor/control-line contacts were studied using x-ray diffraction and scanning electron microscopy for square-shaped Au/Ti resistors covered by Pb-In layers. The samples were isothermally annealed at temperatures ranging from 353 to 423 K. The diffusion did not occur immediately after annealing at these temperatures. After the incubation period, the interdiffusion was observed to initiate at the edges of the resistors facing to the center of the cathode. Significant amounts of the In atoms in the Pb-In layers were observed to diffuse into the Au layers of the resistors, forming AuIn2 compounds under the Ti layers. By measuring growth rates of the AuIn2 layers, the diffusion coefficients and the activation energy for the layer growth were determined. Also, by analyzing changes in the In concentration in the Pb-In layers during annealing, interdiffusion coefficients of In atoms in the Pb-In layers were determined using a computer simulation technique. The activation energy was about 1.1 eV. Since these diffusion coefficients were found to be very close to those determined previously in bulk materials, the diffusion kinetics is believed to be controlled by the lattice diffusion. Based on the present results, several methods to reduce the interdiffusion between Pb-alloy and Au/Ti resistors were proposed.

Boundary layer transition observations on a body of revolution with surface heating and cooling in water

NASA Astrophysics Data System (ADS)

Arakeri, V. H.

1980-04-01

Boundary layer flow visualization in water with surface heat transfer was carried out on a body of revolution which had the predicted possibility of laminar separation under isothermal conditions. Flow visualization was by in-line holographic technique. Boundary layer stabilization, including elimination of laminar separation, was observed to take place on surface heating. Conversely, boundary layer destabilization was observed on surface cooling. These findings are consistent with the theoretical predictions of Wazzan et al. (1970).

Pulsating Magnetic Reconnection Driven by Three-Dimensional Flux-Rope Interactions.

PubMed

Gekelman, W; De Haas, T; Daughton, W; Van Compernolle, B; Intrator, T; Vincena, S

2016-06-10

The dynamics of magnetic reconnection is investigated in a laboratory experiment consisting of two magnetic flux ropes, with currents slightly above the threshold for the kink instability. The evolution features periodic bursts of magnetic reconnection. To diagnose this complex evolution, volumetric three-dimensional data were acquired for both the magnetic and electric fields, allowing key field-line mapping quantities to be directly evaluated for the first time with experimental data. The ropes interact by rotating about each other and periodically bouncing at the kink frequency. During each reconnection event, the formation of a quasiseparatrix layer (QSL) is observed in the magnetic field between the flux ropes. Furthermore, a clear correlation is demonstrated between the quasiseparatrix layer and enhanced values of the quasipotential computed by integrating the parallel electric field along magnetic field lines. These results provide clear evidence that field lines passing through the quasiseparatrix layer are undergoing reconnection and give a direct measure of the nonlinear reconnection rate. The measurements suggest that the parallel electric field within the QSL is supported predominantly by electron pressure; however, resistivity may play a role.

Control of vortical separation on conical bodies

NASA Technical Reports Server (NTRS)

Mourtos, Nikos J.; Roberts, Leonard

1987-01-01

In a variety of aeronautical applications, the flow around conical bodies at incidence is of interest. Such applications include, but are not limited to, highly maneuverable aircraft with delta wings, the aerospace plane and nose portions of spike inlets. The theoretical model used has three parts. First, the single line vortex model is used within the framework of slender body theory, to compute the outer inviscid field for specified separation lines. Next, the three dimensional boundary layer is represented by a momentum equation for the cross flow, analogous to that for a plane boundary layer; a von Karman Pohlhausen approximation is applied to solve this equation. The cross flow separation for both laminar and turbulent layers is determined by matching the pressure at the upper and lower separation points. This iterative procedure yields a unique solution for the separation lines and consequently for the position of the vortices and the vortex lift on the body. Lastly, control of separation is achieved by blowing tangentially from a slot located along a cone generator. It is found that for very small blowing coefficients, the separation can be postponed or suppressedy completely.

Low-Dose Total-Body Irradiation and Fludarabine Phosphate Followed by Unrelated Donor Stem Cell Transplant in Treating Patients With Fanconi Anemia

ClinicalTrials.gov

2017-02-16

Adult Acute Myeloid Leukemia in Remission; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Childhood Acute Myeloid Leukemia in Remission; Childhood Myelodysplastic Syndromes; Fanconi Anemia; Previously Treated Myelodysplastic Syndromes

Sorafenib Tosylate and Chemotherapy in Treating Older Patients With Acute Myeloid Leukemia

ClinicalTrials.gov

2018-06-01

Acute Myeloid Leukemia; Acute Myeloid Leukemia (Megakaryoblastic) With t(1;22)(p13.3;q13.3); RBM15-MKL1; Acute Myeloid Leukemia With a Variant RARA Translocation; Acute Myeloid Leukemia With Inv(3) (q21.3;q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM; Acute Myeloid Leukemia With t(6;9) (p23;q34.1); DEK-NUP214; Acute Myeloid Leukemia With t(9;11)(p22.3;q23.3); MLLT3-KMT2A; Acute Myeloid Leukemia With Variant MLL Translocations; Untreated Adult Acute Myeloid Leukemia

Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy

ClinicalTrials.gov

2018-06-18

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); de Novo Myelodysplastic Syndromes; Myelodysplastic Syndrome With Isolated Del(5q); Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia

FGFR1 tyrosine kinase domain duplication in pilocytic astrocytoma with anaplasia.

PubMed

Ballester, Leomar Y; Penas-Prado, Marta; Leeds, Norman E; Huse, Jason T; Fuller, Gregory N

2018-04-01

We report the case of a 27-yr-old male with visual field loss who had a 4.9-cm complex cystic mass in the right occipital lobe. Histologic examination showed pilocytic astrocytoma (PA) with anaplasia, and molecular characterization revealed FGFR1 duplication with additional variants of unknown significance in several genes ( ARID1A, ARID1B, CHEK2, EPHA5, and MLL2 ). This is one of only a very few reported cases of anaplastic PA with characterization of molecular alterations. © 2018 Ballester et al.; Published by Cold Spring Harbor Laboratory Press.

Comparative Nozzle Study for Applying Aqueous Film Forming Foam on Large-Scale Fires

DTIC Science & Technology

1978-04-01

MATERIALS The AFFF concentrate used in all the tests was FC-206, Lot 60, and met Military Specification, MIL - F - 24385 (Reference 7). JP-4 was used as...1974. 7. Military Speciiication, MlL- F - 24385 (Navy), November 21, 1969 and Amendment-8, June 20, 1974, "Fire Extinguishing Agent, Aqueous Film Forming...cx.itairnd ca air- ) ’O A7473 IEDITION OF I NOV 6% IS OBSOLETE D$/1 0102-LF 014-6601 UN ASI F ]LD SEQAIY LA$IFCAIO O THIS PAGE ’Who% lie(& Cd St CUP!TY

Software Engineering Education.

DTIC Science & Technology

1987-05-01

A-D-AI82bN3 JO U4WR El 14N NWRC j MCA! CIo~~l-MN~J02Ua~ 1/1 NYSI/ EI- -TR- SWT -8 -L U NCLA SSI F IED PAYF/G L2/5 MI. 1.0I2 W 136 2’ UN,, - mll I m...tghteeight aurriuls . empae ta t i ohe An additional refinement of the curriculum content can bem aterial taught m ight also be taught in co urses w hose a...descriptions of possible courses. Bloo -. [Bioom56] has defined a taxonomy of educational Software System Clsae. Several different classes can obe

Clofarabine, Cytarabine, and Filgrastim in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia, Advanced Myelodysplastic Syndrome, and/or Advanced Myeloproliferative Neoplasm

ClinicalTrials.gov

2017-09-18

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Untreated Adult Acute Myeloid Leukemia; Myeloproliferative Neoplasm With 10% Blasts or Higher

Foundation Report on Stonewall Jackson Dam, West Fork River Basin, Weston, West Virginia. Volume 1.

DTIC Science & Technology

1987-12-21

zone , aid occasiOriIly , reremen-ta-t ioanr had a. cut r ed in the trocks adjicingr the fault. zone.- The -.ource_ o~f t h is waiter is app- arently ...hi Kibler- Project Eritnr---------------------------------------Emil Ito Men den ilIlla Partty CIhief...45) SIULGL - W, W - FUWTIM MllWNS 3 QM XWP To U" IU MMN MEN TiS M WMS MIW O STATID EV. OU ZME STIE IMMKi. M UM l O IwoD TIE FM l M M (ft) (ft) 4s) k4

Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia

ClinicalTrials.gov

2018-03-15

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia

Decitabine in Treating Patients With Myelodysplastic Syndromes or Acute Myeloid Leukemia

ClinicalTrials.gov

2013-09-27

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; de Novo Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Myeloid Leukemia

Organ printing: from bioprinter to organ biofabrication line.

PubMed

Mironov, Vladimir; Kasyanov, Vladimir; Markwald, Roger R

2011-10-01

Organ printing, or the layer by layer additive robotic biofabrication of functional three-dimensional tissue and organ constructs using self-assembling tissue spheroid building blocks, is a rapidly emerging technology that promises to transform tissue engineering into a commercially successful biomedical industry. It is increasingly obvious that similar well-established industries implement automated robotic systems on the path to commercial translation and economic success. The use of robotic bioprinters alone however is not sufficient for the development of large industrial scale organ biofabrication. The design and development of a fully integrated organ biofabrication line is imperative for the commercial translation of organ printing technology. This paper presents recent progress and challenges in the development of the essential components of an organ biofabrication line. Copyright © 2011 Elsevier Ltd. All rights reserved.

Measurement of crossflow vortices, attachment-line flow, and transition using microthin hot films

NASA Technical Reports Server (NTRS)

Mangalam, S. M.; Agarwal, N. K.; Maddalon, D. V.; Saric, W. S.

1990-01-01

A flow diagnostic experiment was conducted on a 45-deg swept-wing model using surface-mounted, multielement, microthin, hot-film sensors. The cross-flow vortex spacing, the attachment-line flow characteristics, and the transition region were all determined using an advanced data acquisition and instrumentation system. In addition to the frequencies of traveling waves predicted by linear stability theory, amplified disturbances at much higher frequencies were observed. Simultaneous measurements from sensors located at a number of chord and span locations highlighted the strong three-dimensionality of the boundary-layer flow in the presence of cross-flow vortices. The state of the attachment-line boundary layer was determined using a multielement sensor wrapped around the wing leading edge. The transition region flow characteristics were also identified.

Thick Escaping Magnetospheric Ion Layer in Magnetopause Reconnection with MMS Observations

NASA Technical Reports Server (NTRS)

Nagai, T.; Kitamura, N.; Hasagawa, H.; Shinohara, I.; Yokota, S.; Saito, Y.; Nakamura, R.; Giles, B. L.; Pollock, C.; Moore, T. E.;

Effects of Repeated Social Disruption on the Serotonergic and Dopaminergic Systems in two Genetic Lines of White Leghorn Layers

USDA-ARS?s Scientific Manuscript database

The study was designed to examine whether there are genetic differences in response to repeated social disruption (RSD). Two genetic strains of White Leghorn hens were used in the study; i.e., HGPS (the line selected for high group production and survivability), and DXL (DeKalb XL commercial line). ...