40 CFR 721.10595 - Octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1).

Code of Federal Regulations, 2013 CFR

2013-07-01

...-dimethy-, ethyl sulfate (1:1). 721.10595 Section 721.10595 Protection of Environment ENVIRONMENTAL...-, ethyl sulfate (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1) (PMN P-11...

40 CFR 721.10595 - Octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1).

Code of Federal Regulations, 2014 CFR

2014-07-01

...-dimethy-, ethyl sulfate (1:1). 721.10595 Section 721.10595 Protection of Environment ENVIRONMENTAL...-, ethyl sulfate (1:1). (a) Chemical substance and significant new uses subject to reporting. (1) The chemical substance identified as octadecen-1-aminium, N-ethyl-N,N-dimethy-, ethyl sulfate (1:1) (PMN P-11...

Synergistic effects of N-ethyl-N-nitrosourea (an alkylating agent with a low Swain-Scott substrate constant) and X-rays in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Shima, N; Ichikawa, S

1997-01-01

The mutagenic interaction between N-ethyl-N-nitrosourea (ENU) and X-rays was tested in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. ENU, a monofunctional alkylating agent with a low Swain-Scott substrate constant (s) of 0.26, exhibited a strong cytotoxicity. ENU-induced somatic pink mutation frequency per 10(4) hair-cell divisions increased with increasing ENU dose, with a slope of 1.243 on a log-log graph, the slope value being similar to that for X-ray-induced mutation frequency. Three out of five combined treatments with ENU and X-rays produced mutation frequencies significantly higher than those expected from the additive effects of the two mutagens. Clear synergistic effects were detected when relatively higher X-ray doses were applied, resembling those confirmed earlier between methyl methanesulfonate (MMS) and X-rays, although the s value for ENU is very much smaller than that (0.88) for MMS. It is therefore concluded that mutagenic interactions between alkylating agents and X-rays do not have any clear relationship with the s values.

Reaction products from N-methyl-N-nitrosourea and deoxyribonucleic acid containing thymidine residues. Synthesis and identification of a new methylation product, O4-methyl-thymidine

PubMed Central

Lawley, P. D.; Orr, D. J.; Shah, S. A.; Farmer, P. B.; Jarman, M.

1973-01-01

1. DNA was treated with N-methyl-N-nitrosourea at pH7–8, 37°C, degraded to yield 3- and 7-methylpurines and deoxyribonucleosides and the reaction products were separated by chromatography on ion-exchange resins. The following methods for identification and determination of products were used: with unlabelled N-methyl-N-nitrosourea, u.v. absorption; use of methyl-14C-labelled N-methyl-N-nitrosourea and use of [14C]thymine-labelled DNA. 2. The synthesis of O4-methylthymidine and its identification by u.v. and mass spectroscopy are reported. 3. 3-Methylthymidine and O4-methylthymidine were found as methylation products from N-methyl-N-nitrosourea with thymidine and with DNA, in relatively small yields. Unidentified products containing thymine were found in enzymic digests of N-methyl-N-nitrosourea-treated DNA, which may be phosphotriesters. 4. The possible role of formation of methylthymines in mutagenesis by N-methyl-N-nitrosourea is discussed. PMID:4798180

Investigation of TRPV1 loss-of-function phenotypes in TRPV1 Leu206Stop mice generated by N-ethyl-N-nitrosourea mutagenesis.

PubMed

Christoph, Thomas; Kögel, Babette; Schiene, Klaus; Peters, Thomas; Schröder, Wolfgang

2018-06-02

N-ethyl-N-nitrosourea (ENU) random mutagenesis was used to generate a mouse model for the analysis of the transient receptor potential vanilloid 1 (TRPV1) cation channel. A transversion from T→A in exon 4 led to a Leu206Stop mutation generating a loss-of-function mutant. The TRPV1 agonist capsaicin was used to analyze functional and nociceptive parameters in vitro and in vivo in TRPV1 Leu206Stop mice and congenic C3HeB/FeJ controls. Capsaicin-induced [Ca 2+ ] i changes in small diameter DRG neurons were significantly diminished in TRPV1 Leu206Stop mice and administration of capsaicin induced neither hypothermia nor nocifensive behaviour in vivo. TRPV1 Leu206Stop mice were tested in the spinal nerve ligation of mononeuropathic pain and developed mechanical hypersensitivity two weeks after nerve injury. In the open field test, a significant increase in spontaneous locomotion was detected in TRPV1 Leu206Stop mice as compared to wildtype controls. TRPV1 knockout mice have been reported to carry a similar phenotype regarding capsaicin-evoked responses in vitro and in vivo. However, in contrast to TRPV1 Leu206Stop mice, TRPV1 knockout mice did not differ in spontaneous locomotion as compared to congenic C57BL/6 mice, suggesting subtle ENU-dependent or independent strain differences between TRPV1 Leu206Stop mice and their wildtype controls. In summary, these data revealed a target-related (i.e. capsaicin-evoked) phenotype of TRPV1 Leu206Stop mice closely resembling that of published TRPV1 knockout mice. However, since ENU-mutant mice are congenic with the mouse strain initially used in random mutagenesis, direct phenotypic comparison with the respective wildtype controls is possible, and the time-consuming backcrossing in lines with targeted mutations is avoided. Copyright © 2018 Elsevier Inc. All rights reserved.

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2013 CFR

2013-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2014 CFR

2014-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2012 CFR

2012-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

40 CFR 721.3152 - Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl...

Code of Federal Regulations, 2011 CFR

2011-07-01

...-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates (salts). 721.3152 Section 721... Ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates... ethanaminium, N-ethyl-2-hydroxy-N,N-bis(2-hydroxyethyl)-, diester with C12-18 fatty acids, ethyl sulfates...

The Enzymatic Release of O6-methylguanine and 3-methyladenine from DNA Reacted with the Carcinogen N-methyl-N-nitrosourea

PubMed Central

Kirtikar, D. M.; Goldthwait, D. A.

1974-01-01

Endonuclease II (deoxyribonucleate oligonucleotidohydrolase, EC 3.1.4.30) of Escherichia coli has been shown to break phosphodiester bonds in alkylated DNA and depurinated DNA. The hypothesis that depurination is a step in the mechanism of the reaction with alkylated DNA is supported by in vitro experiments with DNA reacted with N-methyl-N-nitrosourea. Endonuclease II releases O6-methylguanine and 3-methyladenine, but not 7-methylguanine, from DNA that has been methylated by the carcinogen N-methyl-N-nitrosourea. PMID:4600266

Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway.

PubMed

Esapa, Christopher T; Piret, Sian E; Nesbit, M Andrew; Loh, Nellie Y; Thomas, Gethin; Croucher, Peter I; Brown, Matthew A; Brown, Steve D M; Cox, Roger D; Thakker, Rajesh V

2016-01-01

Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in

Mice with an N-Ethyl-N-Nitrosourea (ENU) Induced Tyr209Asn Mutation in Natriuretic Peptide Receptor 3 (NPR3) Provide a Model for Kyphosis Associated with Activation of the MAPK Signaling Pathway

PubMed Central

Nesbit, M. Andrew; Loh, Nellie Y.; Thomas, Gethin; Croucher, Peter I.; Brown, Matthew A.; Brown, Steve D. M.; Cox, Roger D.; Thakker, Rajesh V.

2016-01-01

Non-syndromic kyphosis is a common disorder that is associated with significant morbidity and has a strong genetic involvement; however, the causative genes remain to be identified, as such studies are hampered by genetic heterogeneity, small families and various modes of inheritance. To overcome these limitations, we investigated 12 week old progeny of mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) using phenotypic assessments including dysmorphology, radiography, and dual-energy X-ray absorptiometry. This identified a mouse with autosomal recessive kyphosis (KYLB). KYLB mice, when compared to unaffected littermates, had: thoraco-lumbar kyphosis, larger vertebrae, and increased body length and increased bone area. In addition, female KYLB mice had increases in bone mineral content and plasma alkaline phosphatase activity. Recombination mapping localized the Kylb locus to a 5.5Mb region on chromosome 15A1, which contained 51 genes, including the natriuretic peptide receptor 3 (Npr3) gene. DNA sequence analysis of Npr3 identified a missense mutation, Tyr209Asn, which introduced an N-linked glycosylation consensus sequence. Expression of wild-type NPR3 and the KYLB-associated Tyr209Asn NPR3 mutant in COS-7 cells demonstrated the mutant to be associated with abnormal N-linked glycosylation and retention in the endoplasmic reticulum that resulted in its absence from the plasma membrane. NPR3 is a decoy receptor for C-type natriuretic peptide (CNP), which also binds to NPR2 and stimulates mitogen-activated protein kinase (MAPK) signaling, thereby increasing the number and size of hypertrophic chondrocytes. Histomorphometric analysis of KYLB vertebrae and tibiae showed delayed endochondral ossification and expansion of the hypertrophic zones of the growth plates, and immunohistochemistry revealed increased p38 MAPK phosphorylation throughout the growth plates of KYLB vertebrae. Thus, we established a model of kyphosis due to a novel NPR3 mutation, in

[The biochemical mechanisms of the action of N-alkyl-N-nitrosoureas. The possible reasons for drug resistance to these compounds].

PubMed

Syrkin, A B; Gorbacheva, L B

1996-01-01

N-alkyl-N-nitrosoureas exhibit a wide spectrum of antitumor activity. They react as alkylating agents at nucleophilic sites in purine and pyrimidine moieties of DNA. The predominant site of this alkylation is N7 of guanine, which is followed by the site N3 of adenine and 06 of guanine. The formation and persistence of 0(6)-alkylguanine (0(6)-AG) may be of primary importance in cytotoxicity of the nitrosoureas. 0(6)-AG adducts of DNA of the tumor cells are repaired by protein 0(6)-alkylguanine-DNA transferase (0(6)-AGT) which transfers the alkyl group to internal cysteine residue being the acceptor protein for the alkyl group in an irreversible transfer reaction. 0(6)-AGT can protect the tumor cells against 0(6)-AG adducts by the way of inhibiting the formation of the DNA interstrand cross-links 0(6)-AGT plays an important role in the drug resistance because it repairs the DNA alkyl adducts at the 0(6) position of guanine. The 0(6)-AGT activity inversely correlates with the cytotoxic effect of the nitrosoureas. The agents like 0(6)-methylguanosine, 0(6)-methyl-2'-deoxyguanosine, and some 0(6)-benzylated guanine derivatives are effective inactivators of 0(6)-AGT, and thus can be used to enhance the cytotoxicity of N-nitrosoureas. The activation of 0(6)-AGT and other repairing enzymes such as alpha and beta DNA-polymerases as well as an increase in the level of reduced glutathione may be used in developing the resistance to the nitrosoureas.

Reevaluation of the effect of ellagic acid on N-methyl-N-nitrosourea DNA alkylation and mutagenicity

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

Lord, H.L.; Josephy, P.D.; Snieckus, V.A.

N-Methyl-N-nitrosourea (MNU) is a reactive, mutagenic methylating agent. MNU methylates DNA at various sites, including guanine N{sup 7}, guanine O{sup 6}, and adenine N{sup 3}. Dixit and Gold ((1986) Proc. Natl, Acad. Sci. U.S.A. 83, 8039-8043) reported that ellagic acid, a phenolic natural product, inhibited the mutagenicity of MNU in Salmonella typhimurium strain TA 100, inhibited salmon sperm DNA alkylation by ({sup 3}H)MNU, and also greatly reduced the ratio of guanine O{sup 6} to guanine N{sup 7} alkylation. We have examined the MNU-induced alkylation of calf thymus DNA and evaluated the effect of ellagic acid on this binding. Ellagic acidmore » had only a slight effect on total alkylation and did not alter the ratio of methylation at guanine-O{sup 6} and -N{sup 7} positions. In further experiments, ellagic acid did not significantly inhibit MNU mutagenicity. These findings do not support the potential use of ellagic acid as an inhibitor of biological damage induced by nitrosoureas.« less

Altered IFN-γ-mediated immunity and transcriptional expression patterns in N-Ethyl-N-nitrosourea-induced STAT4 mutants confer susceptibility to acute typhoid-like disease.

PubMed

Eva, Megan M; Yuki, Kyoko E; Dauphinee, Shauna M; Schwartzentruber, Jeremy A; Pyzik, Michal; Paquet, Marilène; Lathrop, Mark; Majewski, Jacek; Vidal, Silvia M; Malo, Danielle

2014-01-01

Salmonella enterica is a ubiquitous Gram-negative intracellular bacterium that continues to pose a global challenge to human health. The etiology of Salmonella pathogenesis is complex and controlled by pathogen, environmental, and host genetic factors. In fact, patients immunodeficient in genes in the IL-12, IL-23/IFN-γ pathway are predisposed to invasive nontyphoidal Salmonella infection. Using a forward genomics approach by N-ethyl-N-nitrosourea (ENU) germline mutagenesis in mice, we identified the Ity14 (Immunity to Typhimurium locus 14) pedigree exhibiting increased susceptibility following in vivo Salmonella challenge. A DNA-binding domain mutation (p.G418_E445) in Stat4 (Signal Transducer and Activator of Transcription Factor 4) was the causative mutation. STAT4 signals downstream of IL-12 to mediate transcriptional regulation of inflammatory immune responses. In mutant Ity14 mice, the increased splenic and hepatic bacterial load resulted from an intrinsic defect in innate cell function, IFN-γ-mediated immunity, and disorganized granuloma formation. We further show that NK and NKT cells play an important role in mediating control of Salmonella in Stat4(Ity14/Ity14) mice. Stat4(Ity14/Ity14) mice had increased expression of genes involved in cell-cell interactions and communication, as well as increased CD11b expression on a subset of splenic myeloid dendritic cells, resulting in compromised recruitment of inflammatory cells to the spleen during Salmonella infection. Stat4(Ity14/Ity14) presented upregulated compensatory mechanisms, although inefficient and ultimately Stat4(Ity14/Ity14) mice develop fatal bacteremia. The following study further elucidates the pathophysiological impact of STAT4 during Salmonella infection.

Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas.

PubMed

Ali-Osman, F; Giblin, J; Berger, M; Murphy, M J; Rosenblum, M L

1985-09-01

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for

Cell Fate of Müller Cells During Photoreceptor Regeneration in an N-Methyl-N-nitrosourea-Induced Retinal Degeneration Model of Zebrafish.

PubMed

Ogai, Kazuhiro; Hisano, Suguru; Sugitani, Kayo; Koriyama, Yoshiki; Kato, Satoru

2016-01-01

Zebrafish can regenerate several organs such as the tail fin, heart, central nervous system, and photoreceptors. Very recently, a study has demonstrated the photoreceptor regeneration in the alkylating agent N-methyl-N-nitrosourea (MNU)-induced retinal degeneration (RD) zebrafish model, in which whole photoreceptors are lost within a week after MNU treatment and then regenerated within a month. The research has also shown massive proliferation of Müller cells within a week. To address the question of whether proliferating Müller cells are the source of regenerating photoreceptors, which remains unknown in the MNU-induced zebrafish RD model, we employed a BrdU pulse-chase technique to label the proliferating cells within a week after MNU treatment. As a result of the BrdU pulse-chase technique, a number of BrdU(+) cells were observed in the outer nuclear layer as well as the inner nuclear layer. This implies that regenerating photoreceptors are derived from proliferating Müller cells in the zebrafish MNU-induced RD model.

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 40 Protection of Environment 31 2014-07-01 2014-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 40 Protection of Environment 32 2013-07-01 2013-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

40 CFR 721.8100 - Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 40 Protection of Environment 32 2012-07-01 2012-07-01 false Potassium N,N-bis (hydroxy-ethyl) cocoamine oxide phosphate, and potassium N,N-bis (hy-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. 721.8100...-droxy-ethyl) tal-lo-wa-mine oxide phos-phate. (a) Chemical substances and significant new use subject to...

Poly (N-ethyl aniline)/Ag Nanocomposite as Humidity Sensor

NASA Astrophysics Data System (ADS)

Pande, Nishigandh S.; Jaspal, Dipika; Ambekar, Jalindar

Poly (N-ethyl aniline)/Ag organic-inorganic composite has been synthesized by a single step in situ chemical oxidative polymerization method. The synthesis of Poly (N-ethyl aniline)/Ag nanocomposite has been confirmed by X-ray diffraction (XRD), Ultraviolet-Vis Spectroscopy (UV-visible), Fourier transform infrared analysis (FTIR) and FE-SEM investigations. XRD spectral study exhibited major diffraction in the range 20-80∘ (2θ) and indicated the semicrystalline nature of poly (N-ethyl aniline)/Ag nanocomposite. Characteristic peaks in UV-visible and FTIR spectra of poly (N-ethyl aniline) switched to higher wave numbers in poly (N-ethyl aniline)/Ag nanocomposite. Peaks at 1789cm-1, 1595cm-1, 667cm-1 and 501cm-1 in FTIR spectrum confirmed the formation of poly (N-ethyl aniline)/Ag nanocomposite. FE-SEM photographs reported agglomerated granular particulate nature of poly (N-ethyl aniline)/Ag nanocomposite. Synthesized poly (N-ethyl aniline)/Ag nanocomposite exhibited a high response to humidity, good reproducibility and stability at room temperature. An appreciable response was shown in the presence of 40% humid atmosphere for up to successive four cycles. Composite sensitivity has been found to increase with the increasing concentration of humidity, at room temperature.

40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

40 CFR 721.1085 - Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Benzenamine,4,4â²-methylenebis[N-ethyl-N-methyl-. 721.1085 Section 721.1085 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... Specific Chemical Substances § 721.1085 Benzenamine,4,4′-methylenebis[N-ethyl-N-methyl-. (a) Chemical...

Antimutagenic components in Glycyrrhiza against N-methyl-N-nitrosourea in the Ames assay.

PubMed

Inami, Keiko; Mine, Yusuke; Kojo, Yukiko; Tanaka, Satomi; Ishikawa, Satoko; Mochizuki, Masataka

2017-03-01

Antimutagenesis against N-nitroso compounds contribute to prevention of human cancer. We have found that Glycyrrhiza aspera ethanolic extract exhibits antimutagenic activity against N-methyl-N-nitrosourea (MNU) using the Ames assay with Salmonella typhimurium TA1535. In the present study, eight purified components from Glycyrrhiza, namely glabridin, glycyrrhetinic acid, glycyrrhizin, licochalcone A, licoricesaponin H2, licoricesaponin G2, liquiritigenin and liquiritin were evaluated for their antimutagenicity against MNU in the Ames assay with S. typhimurium TA1535. Glycyrrhetinic acid, glycyrrhizin, licoricesaponin G2, licoricesaponin H2 and liquiritin did not show the antimutagenicity against MNU in S. typhimurium TA1535. Glabridin, licochalcone A and liquiritigenin reduced revertant colonies derived from MNU in S. typhimurium TA1535 without showing cytotoxic effects, indicating that these compounds possess antimutagenic activity against MNU. The inhibitory activity of glabridin and licochalcone A was more effective than that of liquiritigenin. Thus, Glycyrrhiza contains antimutagenic components against DNA alkylating, direct-acting carcinogens.

Ex vivo culture of tumor cells from N-methyl-N-nitrosourea-induced bladder cancer in rats: Development of organoids and an immortalized cell line.

PubMed

Yoshida, Takahiro; Kates, Max; Sopko, Nikolai A; Liu, Xiaopu; Singh, Alok K; Bishai, William R; Joice, Gregory; McConkey, David J; Bivalacqua, Trinity J

2018-04-01

We ex vivo cultured primary tumor cells from N-methyl-N-nitrosourea (MNU)-induced bladder tumors in rats and established an immortalized cell line from them. Bladder tumors in rats were induced by instillation of MNU into the murine bladder. Primary tumor cells were prepared by the cancer-tissue originated spheroid method. An immortalized cell line was established by co-culture with fibroblasts. The cultured tumor cells were molecularly and functionally characterized by quantitative real-time polymerase chain reaction, Western blot, growth assay, and transwell migration assay. Primary tumor cells were successfully prepared as multicellular spheroids from MNU-induced bladder tumors. The differentiation marker expression patterns observed in the original tumors were largely retained in the spheroids. We succeeded in establishing a cell line from the spheroids and named it T-MNU-1. Although basal markers (CK14 and CK5) were enriched in T-MNU-1 compared to the spheroids, T-MNU-1 expressed both luminal and basal markers. T-MNU-1 was able to migrate through a transwell. Tumor cells in MNU-induced bladder tumors were successfully cultured ex vivo as organoids, and an immortalized cell line was also established from them. The ex vivo models offer a platform that enables analysis of intrinsic characteristics of tumor cells excluding influence of microenvironment in MNU-induced bladder tumors. Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical carcinogenesis in the nervous system. Preferential accumulation of O6-methylguanine in rat brain deoxyribonucleic acid during repetitive administration of N-methyl-N-nitrosourea.

PubMed Central

Margison, G P; Kleihues, P

1975-01-01

The alkylation of purine bases in DNA of several rat tissues was determined during weekly injections (10 mg/kg) of N-[3H]methyl-N-nitrosourea, a dose schedule known to selectively induce tumours of the nervous system. Each group of animals was killed 1 week after the final injection, and the DNA hydrolysates were analysed by chromatography on Sephadex G-10. After five weekly applications, O6-methylguanine had accumulated in brain DNA to an extent which greatly exceeded that in kidney, spleen and intestine. In the liver, the final O6-methylguanine concentration was less than 1% of that in brain. Between the first and the fifth injection, the O6-methylguanine/7-methylguanine ratio in cerebral DNA increased from 0.28 to 0.68. In addition, 3-methylguanine was found to accumulate in brain DNA whereas in the other organs no significant quantities of this base were detectable. The results are compatible with the hypothesis that O6-alkylation of guanine in DNA plays a major role in the induction of tumours by N-methyl-N-nitrosourea and related carcinogens. The kinetics of the increase of O6-methylguanine in cerebral DNA suggest that there is no major cell fraction in the brain which is capable of excising chemically methylated bases from DNA. This repair deficiency could be a determining factor in the selective induction of nervous-system tumours by N-methyl-N-nitrosourea and other neuro-oncogenic compounds. PMID:1200992

G2 accumulation and melanin overproduction in malignant melanocytes treated with a new nitrosourea.

PubMed

Buchdahl, C; Papon, J; Communal, Y; Bourges, M; Madelmont, J C

1998-12-01

Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea), a new anticancer chloroethylnitrosourea (CENU) is being tested in a phase II clinical trial of disseminated melanoma. The antitumour effect of this drug is mainly due to DNA damage in malignant melanocytes. Recently, we have shown that this damage can induce apoptosis in some melanoma cell lines. In others, apoptosis is not clearly observed, although there is a strong cytostatic effect. In this paper, we have characterized the cytological effect of cystemustine on murine malignant melanocytes (B16 cell line) which are resistant to apoptosis induced by this CENU. The results show that 3 days after cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle. There was then a strong morphological modification during a long cytostatic phase up to 30 days after treatment. During this cytostatic phase, there was uncontrolled DNA synthesis and marked swelling. Also, tyrosinase activity, melanin content and the number of mature melanosomes were greatly increased. These results suggest that when malignant melanocytes are not able to undergo apoptosis after treatment with CENU, they accumulate in G2 and this is followed by enhancement of melanogenesis.

40 CFR 721.4090 - Ethanaminium, N-[bis(diethylamino)-methylene]-N-ethyl-, bromide.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Ethanaminium, N-[bis(diethylamino)-methylene]-N-ethyl-, bromide. 721.4090 Section 721.4090 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.4090 Ethanaminium, N-[bis(diethylamino)-methylene]-N...

40 CFR 721.4090 - Ethanaminium, N-[bis(diethylamino)-methylene]-N-ethyl-, bromide.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Ethanaminium, N-[bis(diethylamino)-methylene]-N-ethyl-, bromide. 721.4090 Section 721.4090 Protection of Environment ENVIRONMENTAL PROTECTION... New Uses for Specific Chemical Substances § 721.4090 Ethanaminium, N-[bis(diethylamino)-methylene]-N...

Chloridobis(ethyl­enediamine-κ2 N,N′)(n-pentyl­amine-κN)cobalt(III) dichloride monhydrate

PubMed Central

Anbalagan, K.; Tamilselvan, M.; Nirmala, S.; Sudha, L.

2009-01-01

The title complex, [CoCl(C5H13N)(C2H8N2)2]Cl2·H2O, comprises one chloridobis(ethyl­enediamine)(n-pentyl­amine)cobalt(III) cation, two chloride counter-anions and a water mol­ecule. The CoIII atom of the complex is hexa­coordinated by five N and one Cl atoms. The five N atoms are from two chelating ethyl­enediamine and one n-pentyl­amine ligands. Neighbouring cations and anions are connected by N—H⋯Cl and N—H⋯O hydrogen bonds to each other and also to the water mol­ecule. PMID:21582753

Topographic Quantification of the Transcorneal Electrical Stimulation (TES)-Induced Protective Effects on N-Methyl-N-Nitrosourea-Treated Retinas.

PubMed

Tao, Ye; Chen, Tao; Liu, Zhong-Yu; Wang, Li-Qiang; Xu, Wei-Wei; Qin, Li-Min; Peng, Guang-Hua; Yi-Fei, Huang

2016-09-01

To quantify the transcorneal electrical stimulation (TES)-induced effects on regional photoreceptors and visual signal pathway of N-methyl-N-nitrosourea (MNU)-treated retinas via topographic measurements. N-methyl-N-nitrosourea-administered mice received TES or sham stimulations and were subsequently subjected to electroretinography (ERG), multielectrode array (MEA), and histologic and immunohistochemistry examinations. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analyses were also performed to determine the mRNA levels of Bax, Bcl-2, Calpain-2, Caspase-3, brain-derived neurotrophic factor (BDNF), and ciliary neurotrophic factor (CNTF). Amplitudes of ERG b-wave in the TES-treated mice were significantly larger than those in the sham controls (P < 0.01). Microelectrode array examination revealed that the photoreceptors in TES-treated retina were efficiently preserved (P < 0.01). Morphologic measurements showed that the central retina region was more consolidated than the other areas in the TES-treated mice. Together with the disproportionate distribution of immunostaining in retinal flat mounts, these findings indicated that different rescuing kinetics existed among regional photoreceptors. Compared with the sham controls, a significantly increased signal-to-noise ratio was also found in the TES-treated mice (TES100: 2.02 ± 1.12; TES200: 4.42 ± 1.51; sham: 0.25 ± 0.13; P < 0.01). Moreover, qRT-PCR measurements suggested that the altered expression of several apoptotic factors and neurotrophic cytokines was correlated with TES-induced protection. Regional photoreceptors in the MNU-administered retinas exhibit different sensitivities to TES. Transcorneal electrical stimulation is capable of ameliorating MNU-induced photoreceptor degeneration and rectifying abnormalities in the inner visual signal pathways.

Novel bifunctional anthracycline and nitrosourea chemotherapy for human bladder cancer: analysis in a preclinical survival model.

PubMed

Glaves, D; Murray, M K; Raghavan, D

1996-08-01

A hybrid drug [N-2-chloroethylnitrosoureidodaunorubicin (AD312)] that combines structural and functional features of both anthracyclines and nitrosoureas was evaluated in a preclinical survival model of human bladder cancer. To measure the therapeutic activity of AD312, UCRU-BL13 transitional cell carcinoma cells were grown as xenografts in nude mice, and tumor growth rates were compared after i.v. administration of the drug at three dose levels. AD312 treatment at 45 and 60 mg/kg achieved 7-10-fold inhibition of tumor growth and increased host survival by 156 and 249%, respectively. Doses of 60 mg/kg showed optimal therapeutic efficacy, with sustained tumor growth inhibition, an over 2-fold increase in life span, and 40% of mice tumor free ("cured") at 120 days. Tumors were unresponsive to maximum tolerated doses of doxorubicin, a standard anthracycline used as a single agent and in combination therapies for bladder cancer. 1,3-Bis-[2-chloroethyl]-1-nitrosourea was used as a control for the apparently enhanced response of human tumors in murine hosts to nitrosoureas. 1, 3-Bis-[2-chloroethyl]-1-nitrosourea administered in three injections of 20 mg/kg did not cure mice but temporarily inhibited tumor growth by 70% and prolonged survival by 55%; its activity in this model suggests that it may be included in the repertoire of alkylating agents currently used for treatment of bladder cancers. AD312 showed increased antitumor activity with less toxicity than doxorubicin, and its bifunctional properties provide the opportunity for simultaneous treatment of individual cancer cells with two cytotoxic modalities as well as treatment of heterogeneous populations typical of bladder cancers. This novel cytotoxic drug cured doxorubicin-refractory disease and should be investigated for the clinical management of bladder cancer.

Reduced DNA repair in mouse satellite DNA after treatment with methylmethanesulfonate, and N-methyl-N-nitrosourea.

PubMed Central

Bodell, W J; Banerjee, M R

1976-01-01

We have measured DNA repair in mouse satellite and main band DNA as resolved by Ag+-Cs2SO4 centrifugation in response to treatment with the alkylating agents, methyl methanesulfonate, and N-methyl-N-nitrosourea. We find that there is a statistically significant lower incorporation of 3H-Tdr into the satellite DNA as compared to the main band at varying periods after treatment with the alkylating agents. This suggests a reduced repair activity in the satellite DNA. We have measured the extent of binding of 14C-methyl methanesulfonate to the satellite, and main band DNA, and no difference in binding was observed, indicating that the reduced repair activity of satellite DNA is not due to a difference in binding of alkylating agents. We believe that the reduced incorporation of 3H-Tdr into satellite DNA may be due to its location in the condensed chromatin fraction. PMID:184436

Spin-labeled 1-alkyl-1-nitrosourea synergists of antitumor antibiotics.

PubMed

Gadjeva, V; Koldamova, R

2001-01-01

A new method for synthesis of four spin-labeled structural analogues of the antitumor drug 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), using ethyl nitrite for nitrosation of the intermediate spin-labeled ureas has been described. In vitro synergistic effects of 1-ethyl-3-[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)]-1-nitrosourea (3b) on the cytotoxicity of bleomycin and farmorubicin were found in human lymphoid leukemia tumor cells. We measured the tissue distribution of 3b in organ homogenates of C57BL mice by an electron paramagnetic resonance method. The spin-labeled nitrosourea was mainly localized in the lungs. Our results strongly support the development and validation of a new approach for synthesis of less toxic nitrosourea derivatives as potential synergists of antitumor drugs.

Optimisation of Croton gratissimus Oil Extraction by n-Hexane and Ethyl Acetate Using Response Surface Methodology.

PubMed

Jiyane, Phiwe Charles; Tumba, Kaniki; Musonge, Paul

2018-04-01

The extraction of oil from Croton gratissimus seeds was studied using the three-factor five-level full-factorial central composite rotatable design (CCRD) of the response surface methodology (RSM). The effect of the three factors selected, viz., extraction time, extraction temperature and solvent-to-feed ratio on the extraction oil yield was investigated when n-hexane and ethyl acetate were used as extraction solvents. The coefficients of determination (R 2 ) of the models developed were 0.98 for n-hexane extraction and 0.97 for ethyl acetate extraction. These results demonstrated that the models developed adequately represented the processes they described. From the optimized model, maximum extraction yield obtained from n-hexane and ethyl acetate extraction were 23.88% and 23.25%, respectively. In both cases the extraction temperature and solvent-to-feed ratio were 35°C and 5 mL/g, respectively. In n-hexane extraction the maximum conditions were reached only after 6 min whereas in ethyl acetate extraction it took 20 min to get the maximum extraction oil yield. Oil extraction of Croton gratissimus seeds, in this work, favoured the use of n-hexane as an extraction solvent as it offered higher oil yields at low temperatures and reduced residence times.

Induction of glandular stomach cancers in Helicobacter pylori-sensitive Mongolian gerbils treated with N-methyl-N-nitrosourea and N-methyl-N'-nitro-N-nitrosoguanidine in drinking water.

PubMed

Tatematsu, M; Yamamoto, M; Shimizu, N; Yoshikawa, A; Fukami, H; Kaminishi, M; Oohara, T; Sugiyama, A; Ikeno, T

1998-02-01

An animal model of stomach carcinogenesis was established using Mongolian gerbils with N-methyl-N-nitrosourea (MNU) and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as the carcinogens. In addition, the sensitivity of these gerbils to Helicobacter pylori (H. pylori) was confirmed. One hundred and sixty specific pathogen-free male MGS/Sea animals, 7 weeks old, were treated with MNU in the drinking water (30 ppm for alternate weeks to give 10 weeks exposure, or 10 ppm or 3 ppm for 20 weeks continuous exposure), or given MNNG in the drinking water at 400 ppm or 200 ppm for 20 weeks, or orally inoculated with ATCC43504 H. pylori (1.7 x 10(8) CFUs/animal). Adenocarcinomas in the glandular stomach were found in 2 out of 12 effective animals (2/ 12) treated with 30 ppm MNU at week 20, although all were dead or moribund by week 30 due to MNU toxicity. At week 50, the incidences of gastric adenocarcinomas in groups treated with 10 ppm MNU, 3 ppm MNU, 400 ppm MNNG, and 200 ppm MNNG were 2/21 (9.5%), 1/23 (4.3%), 7/ 11 (63.6%), and 1/10 (10.0%). The lesions were generally well differentiated, although poorly differentiated adenocarcinoma was also found in a single gerbil in each of the 10 ppm MNU and 400 ppm MNNG groups. In control animals no tumors were found. In the infection study, the animals were killed at week 20, and H. pylori was detected in all cases, causing multiple erosions with marked inflammatory cell infiltration in the lamina propria and submucosa, and frequent formation of lymphoid follicles. Thus, MNU and MNNG in the drinking water induced neoplastic lesions in the glandular stomach epithelium of H. pylori-sensitive gerbils.

Mutagenic synergism detected between dimethyl sulfate and X-rays but not found between N-methyl-N-nitrosourea and X-rays in the stamen hairs of Tradescantia clone BNL 4430.

PubMed

Shima, N; Ichikawa, S

1995-09-01

Mutagenic interactions with X-rays of two monofunctional alkylating agents, dimethyl sulfate (DMS) and N-methyl-N-nitrosourea (MNU), were studied in the stamen hairs of Tradescantia clone BNL 4430, a blue/pink heterozygote. The young inflorescence-bearing shoots with roots cultivated in the nutrient solution circulating growth chamber were used as tester plants. Synergism between two different mutagens was judged to have occurred when the mutation frequency observed after applying the two mutagens concurrently was statistically significantly higher than the mutation frequency expected from the additive effects of the two mutagens. Clear synergistic effects in inducing somatic pink mutations were detected with all combinations of doses of DMS and X-rays examined, even in a relatively low X-ray dose range (down to 299 mGy), resembling those confirmed earlier between ethyl methanesulfonate (EMS) and X-rays, but somewhat differing from the synergisms observed earlier between methyl methanesulfonate (MMS) and X-rays. On the other hand, no mutagenic synergism was detected between MNU and X-rays, even in a relatively high X-ray dose range (up to 862 mGy). The presence or absence of mutagenic synergisms of these alkylating agents with X-rays could be related to the action mechanism of each alkylating agent.

[(S)-1-Carbamoylethyl]bis(dimethylglyoximato-kappa2N,N')[(S)-1-phenylethylamine]cobalt(III) and bis(dimethylglyoximato-kappa2N,N')[(R)-1-(N-methylcarbamoyl)ethyl][(R)-1-phenylethylamine]cobalt(III) monohydrate.

PubMed

Orisaku, Keiko Komori; Hagiwara, Mieko; Ohgo, Yoshiki; Arai, Yoshifusa; Ohgo, Yoshiaki

2005-04-01

The title complexes, [Co(C3H6NO)(C4H7N2O2)2(C8H11N)] and [Co(C4H8NO)(C4H7N2O2)2(C8H11N)].H2O, were resolved from [(RS)-1-carbamoylethyl]bis(dimethylglyoximato)[(S)-1-phenylethylamine]cobalt(III) and bis(dimethylglyoximato)[(RS)-1-(N-methylcarbamoyl)ethyl][(R)-1-phenylethylamine]cobalt(III), respectively, and their crystal structures were determined in order to reveal the absolute configuration of the major enantiomer produced in the photoisomerization of each series of 2-carbamoylethyl and 2-(N-methylcarbamoyl)ethyl cobaloxime complexes.

Structure-based design of nitrosoureas containing tyrosine derivatives as potential antimelanoma agents.

PubMed

Gadjeva, Vesselina

2002-04-01

Two new nitrosoureas (TNUs), containing tyrosine derivatives as carriers of nitrosourea cytotoxic group have been synthesised. The physicochemical properties such as half-life time (tau(0.5)), alkylating and carbamoylating activities were determined. The nitrosoureas showed a higher inhibiting effect on the DOPA-oxidase activity of mushroom tyrosinase than that of the antitumour drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). In vitro cytotoxic effects of newly synthesised tyrosine containing nitrosoureas have been studied and compared to those of CCNU. A higher cytotoxicity to B16 melanoma cells than to YAC-1 and to lymphocytes was demonstrated for the tyrosine containing nitrosoureas in comparison with CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea derivatives as potential antimelanomic drugs might be developed.

Garlic and associated allyl sulfur components inhibit N-methyl-N-nitrosourea induced rat mammary carcinogenesis.

PubMed

Schaffer, E M; Liu, J Z; Green, J; Dangler, C A; Milner, J A

1996-04-19

Our previous studies demonstrated that dietary garlic powder supplementation inhibits N-nitrosamine induced DNA alkylation in liver and mammary tissue. The present studies compared the impact of dietary supplementation with garlic powder or two garlic constituents, water-soluble S-allyl cysteine (SAC) and oil-soluble diallyl disulfide (DADS), on the incidence of mammary tumorigenesis induced by N-methyl-N-nitrosourea (MNU). Female Sprague-Dawley rats were fed semi-purified casein based diets with or without supplements of garlic powder(20g/kg), SAC (57 micromol/kg) or DADS (57 micromol/kg) for 2 weeks prior to treatment with MNU (15 mg/kg body wt). Garlic powder, SAC and DADS supplementation significantly delayed the onset of mammary tumors compared to rats receiving the unsupplemented diet. Tumor incidence 23 weeks after MNU treatment was reduced by 76, 41 and 53% in rats fed garlic, SAC and DADS, respectively, compared to controls (P<0.05). Total tumor number was reduced 81, 35 and 65% by these supplements, respectively (P<0.05). In a separate study the quantity of mammary DNA alkylation occurring 3 h after MNU treatment was reduced in rats fed garlic, SAC or DADS (P<0.05). Specifically, O(6)-methylguanine adducts were reduced by 27, 18 and 23% in rats fed supplemental garlic, SAC and DADS, respectively, compared to controls. N(7)-Methylguanine adducts decreased by 48, 22 and 21% respectively, compared to rats fed the control diet. These studies demonstrate that garlic and associated allyl sulfur components, SAC and DADS, are effective inhibitors of MNU-induced mammary carcinogenesis.

40 CFR 721.5625 - Oxiranemethanamine, N,N′-[methylenebis(2-ethyl-4,1-phenylene)]bis[N-(oxiranylmethyl)]-.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 40 Protection of Environment 31 2011-07-01 2011-07-01 false Oxiranemethanamine, N,Nâ²-[methylenebis(2-ethyl-4,1-phenylene)]bis[N-(oxiranylmethyl)]-. 721.5625 Section 721.5625 Protection of... CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.5625 Oxiranemethanamine, N...

40 CFR 721.5625 - Oxiranemethanamine, N,N′-[methylenebis(2-ethyl-4,1-phenylene)]bis[N-(oxiranylmethyl)]-.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Oxiranemethanamine, N,Nâ²-[methylenebis(2-ethyl-4,1-phenylene)]bis[N-(oxiranylmethyl)]-. 721.5625 Section 721.5625 Protection of... CHEMICAL SUBSTANCES Significant New Uses for Specific Chemical Substances § 721.5625 Oxiranemethanamine, N...

Multiple programmed cell death pathways are involved in N-methyl-N-nitrosourea-induced photoreceptor degeneration.

PubMed

Reisenhofer, Miriam; Balmer, Jasmin; Zulliger, Rahel; Enzmann, Volker

2015-05-01

To identify programmed cell death (PCD) pathways involved in N-methyl-N-nitrosourea (MNU)-induced photoreceptor (PR) degeneration. Adult C57BL/6 mice received a single MNU i.p. injection (60 mg/kg bodyweight), and were observed over a period of 7 days. Degeneration was visualized by H&E overview staining and electron microscopy. PR cell death was measured by quantifying TUNEL-positive cells in the outer nuclear layer (ONL). Activity measurements of key PCD enzymes (calpain, caspases) were used to identify the involved cell death pathways. Furthermore, the expression level of C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), key players in endoplasmic reticulum (ER) stress-induced apoptosis, was analyzed using quantitative real-time PCR. A decrease in ONL thickness and the appearance of apoptotic PR nuclei could be detected beginning 3 days post-injection (PI). This was accompanied by an increase of TUNEL-positive cells. Significant upregulation of activated caspases (3, 9, 12) was found at different time periods after MNU injection. Additionally, several other players of nonconventional PCD pathways were also upregulated. Consequently, calpain activity increased in the ONL, with a maximum on day 7 PI and an upregulation of CHOP and GRP78 expression beginning on day 1 PI was found. The data indicate that regular apoptosis is the major cause of MNU-induced PR cell death. However, alternative PCD pathways, including ER stress and calpain activation, are also involved. Knowledge about the mechanisms involved in this mouse model of PR degeneration could facilitate the design of putative combinatory therapeutic approaches.

An Ethyl-Nitrosourea-Induced Point Mutation in Phex Causes Exon Skipping, X-Linked Hypophosphatemia, and Rickets

PubMed Central

Carpinelli, Marina R.; Wicks, Ian P.; Sims, Natalie A.; O’Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J.; Bahlo, Melanie; Alexander, Warren S.; Hilton, Douglas J.

2002-01-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G1) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease. PMID:12414538

An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets.

PubMed

Carpinelli, Marina R; Wicks, Ian P; Sims, Natalie A; O'Donnell, Kristy; Hanzinikolas, Katherine; Burt, Rachel; Foote, Simon J; Bahlo, Melanie; Alexander, Warren S; Hilton, Douglas J

2002-11-01

We describe the clinical, genetic, biochemical, and molecular characterization of a mouse that arose in the first generation (G(1)) of a random mutagenesis screen with the chemical mutagen ethyl-nitrosourea. The mouse was observed to have skeletal abnormalities inherited with an X-linked dominant pattern of inheritance. The causative mutation, named Skeletal abnormality 1 (Ska1), was shown to be a single base pair mutation in a splice donor site immediately following exon 8 of the Phex (phosphate-regulating gene with homologies to endopeptidases located on the X-chromosome) gene. This point mutation caused skipping of exon 8 from Phex mRNA, hypophosphatemia, and features of rickets. This experimentally induced phenotype mirrors the human condition X-linked hypophosphatemia; directly confirms the role of Phex in phosphate homeostasis, normal skeletal development, and rickets; and illustrates the power of mutagenesis in exploring animal models of human disease.

Synthesis and molecular docking against dihydrofolate reductase of novel pyridin-N-ethyl-N-methylbenzenesulfonamides as efficient anticancer and antimicrobial agents

NASA Astrophysics Data System (ADS)

Debbabi, Khaled F.; Bashandy, Mahmoud S.; Al-Harbi, Sami A.; Aljuhani, Enas H.; Al-Saidi, Hamed M.

2017-03-01

This article describes the synthesis of some novel sulfonamides having biologically active pyridine 21-28. Starting with 4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-N-ethyl-N-methylbenzenesulfonamide (2), which was prepared from condensation of acetophenone derivative 1 with 2-cyanoacetohydrazide. Interaction of compound 2 with different aldehydes namely 4-fluorobenzaldehyde, 4-hydroxybenzaldehyde and 4-N,N-dimethylbenzaldehyde afforded the corresponding hydrazono-ethyl-N-ethyl-N-methylbenzene sulfonamides 18-20 respectively, which when reacted with malononitrile and ethyl cyanoacetate afforded compounds 21-26 respectively. These compounds 21-26 can be prepared by another reaction route by interaction of compounds 2 with arylidine malononitrile and arylidine ethyl cyanoacetate in refluxing dioxane in the presence of trimethylamine as catalyst. Interaction of compound 2 with malononitrile and ethyl cyanoacetate afforded oxopyridine derivatives 27 and 28 respectively. All the new prepared compounds were evaluated for their antitumor activities against the cell lines MCF-7 in comparison with the reference drug Doxorubicin using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay. Compounds 25, 21, 23 with SI values of 9.72, 9.71, 8.81 respectively, exhibited better activity than doxorubicin (Dox) as a reference drug with SI value of 8.49. In addition, compounds 25, 27 and 22 exhibited anti-bacterial activity against gram-negative bacteria (Klebsiella pneumoniae) with inhibition zones 22.6, 20.3 and 19.3 mm respectively, which were more active than gentamicin as a reference drug with inhibition zone 17.3 mm. Molecular Operating Environment (MOE) performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some synthesized compounds suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDB SD: 4DFR) with further modification.

Molecular dynamics simulation of the ionic liquid N-ethyl-N,N-dimethyl-N-(2-methoxyethyl)ammonium bis(trifluoromethanesulfonyl)imide.

PubMed

Siqueira, Leonardo J A; Ribeiro, Mauro C C

2007-10-11

Thermodynamics, structure, and dynamics of an ionic liquid based on a quaternary ammonium salt with ether side chain, namely, N-ethyl-N,N-dimethyl-N-(2-methoxyethyl)ammonium bis(trifluoromethanesulfonyl)imide, MOENM2E TFSI, are investigated by molecular dynamics (MD) simulations. Average density and configurational energy of simulated MOENM2E TFSI are interpreted with models that take into account empirical ionic volumes. A throughout comparison of the equilibrium structure of MOENM2E TFSI with previous results for the more common ionic liquids based on imidazolium cations is provided. Several time correlation functions are used to reveal the microscopic dynamics of MOENM2E TFSI. Structural relaxation is discussed by the calculation of simultaneous space-time correlation functions. Temperature effects on transport coefficients (diffusion, conductivity, and viscosity) are investigated. The ratio between the actual conductivity and the estimate from ionic diffusion by the Nernst-Einstein equation indicates that correlated motion of neighboring ions in MOENM2E TFSI is similar to imidazolium ionic liquids. In line with experiment, Walden plot of conductivity and viscosity indicates that simulated MOENM2E TFSI should be classified as a poor ionic liquid.

Effects of Dietary Xanthophylls, Canthaxanthin and Astaxanthin on N-Methyl-N-nitrosourea-induced Rat Mammary Carcinogenesis.

PubMed

Yuri, Takashi; Yoshizawa, Katsuhiko; Emoto, Yuko; Kinoshita, Yuichi; Yuki, Michiko; Tsubura, Airo

Natural xanthophylls, canthaxanthin and astaxanthin are known to exhibit anticancer activity. However, the dietary effects of canthaxanthin and astaxanthin on N-methyl-N-nitrosourea (MNU)-induced mammary cancer remain controversial, and their mechanisms of action have not been clearly identified. Three-week-old female Sprague-Dawley rats were fed a xanthophyll-free (basal diet) diet or experimental diets containing canthaxanthin or astaxanthin (0.04% and 0.4%) for 5 weeks (until 8 weeks of age), after which all rats were provided the basal diet (n=15 each). Rats were administered MNU at 6 weeks of age, and the incidence of mammary tumors at 20 weeks of age was compared. The expression of adiponectin in mammary adipose tissues taken at 7 weeks of age was also compared. Compared to the basal diet group, the 0.4% (but not the 0.04%) astaxanthin diet significantly reduced the incidence of palpable mammary carcinoma (92% vs. 42%; p<0.05), while the low and high canthaxanthin diets produced no significant inhibition. Adiponectin immunoblotting showed significantly higher expression in the 0.4% astaxanthin diet group, while the other groups were similar to the basal diet group. High concentrations of astaxanthin suppress MNU-induced mammary carcinoma. Changes in adiponectin may be involved in the mechanism of action. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

DNA precursor pool: a significant target for N-methyl-N-nitrosourea in C3H/10T1/2 clone 8 cells.

PubMed Central

Topal, M D; Baker, M S

1982-01-01

Synchronized C3H/10T1/2 clone 8 cells were treated in vitro with a nontoxic dose of N-methyl-N-nitrosourea during their S phase. Chromatographic isolation of the deoxyribonucleotide DNA precursor pool and measurement of the precursor content per cell showed that a nucleic acid residue in the precursor pool is 190-13,000 times more susceptible to methylation than a residue in the DNA duplex, depending on the site of methylation. This conclusion comes from measurements indicating that, for example, the N-1 position of adenine in dATP is 6.3 times more methylated than the same position in the DNA, even though the adenine content of the pool is only a fraction (0.0005) of the adenine content of the DNA helix. The comparative susceptibility between pool and DNA was found to vary with the site of methylation in the order the N-1 position of adenine greater than phosphate greater than the N-3 position of adenine greater than the O6 position of guanine greater than the N-7 position of guanine. The significance of these results for chemical mutagenesis and carcinogenesis is discussed. PMID:6954535

The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina.

PubMed

Tao, Ye; Chen, Tao; Liu, Bei; Yang, Guo Qing; Peng, Guanghua; Zhang, Hua; Huang, Yi Fei

2015-07-01

The neurotoxic effects of N-methyl-N-nitrosourea (MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptor (PR) degeneration. With the helping of MEA (multielectrode array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retina were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PR dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits have been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underlying mechanism of human RP. Copyright © 2015 Elsevier Inc. All rights reserved.

Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitrosoureas.

PubMed

Kohn, K W

1977-05-01

Bifunctional alkylating agents are known to cross-link DNA by simultaneously alkylating two guanine residues located on opposite strands. Despite this apparent requirement for bifunctionality, 1-(2-chloroethyl)-1-nitrosoureas bearing a single alkylating function were found to cross-link DNA in vitro. Cross-linking was demonstrated by showing inhibition of alkali-induced strand separation. Extensive cross-linking was observed in DNA treated with 1-(2-chloroethyl)-1-nitrosourea, 1,3-bis-(2-chloroethyl)-1-nitrosourea, and 1-(2-chloroethyl(-3-cyclohexyl-1-nitrosourea. The reaction occurs in two steps, an intital binding followed by a second step which can proceed after removal of unbound drug. It is suggested that the first step is chloroethylation of a nucleophilic site on one strand and that the second step involves displacement of Cl- by a nucleophilic site on the opposite strand, resulting in an ethyl bridge between the strands. Consistent with this possibility, 1-(2-fluoroethyl)-3-cyclohexyl-1-nitrosourea produced much less cross-linking, as expected from the known low activity of F-, compared with Cl-, as leaving group. 1-Methyl-1-nitrosourea, which is known to depurinate DNA, produced no detectable cross-linking.

21 CFR 176.160 - Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine. 176.160 Section 176.160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS...

21 CFR 176.160 - Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 3 2012-04-01 2012-04-01 false Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine. 176.160 Section 176.160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS...

21 CFR 176.160 - Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 3 2013-04-01 2013-04-01 false Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine. 176.160 Section 176.160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS...

21 CFR 176.160 - Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 3 2011-04-01 2011-04-01 false Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine. 176.160 Section 176.160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD FOR HUMAN CONSUMPTION (CONTINUED) INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS...

21 CFR 176.160 - Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false Chromium (Cr III) complex of N-ethyl-N-heptadecylfluoro-octane sulfonyl glycine. 176.160 Section 176.160 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) INDIRECT FOOD ADDITIVES: PAPER AND PAPERBOARD COMPONENTS Substances for Use Only as Components of...

Biomonitoring of N-ethyl-2-pyrrolidone in automobile varnishers.

PubMed

Koslitz, Stephan; Meier, Swetlana; Schindler, Birgit Karin; Weiss, Tobias; Koch, Holger Martin; Brüning, Thomas; Käfferlein, Heiko Udo

2014-12-01

N-alkyl-2-pyrrolidones are important organic solvents for varnishes in industry. This study investigates exposure to N-ethyl-2-pyrrolidone (NEP) in varnishing of hard plastic components in an automobile plant. Two specific biomarkers of exposure, 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI), were analyzed in urine samples of 14 workers. For this purpose, pre-shift, post-shift and next day pre-shift urine samples were collected midweek. Twelve workers performed regular work tasks (loading, wiping and packing), whereas two workers performed special work tasks including cleaning the sprayer system with organic solvents containing N-alkyl-2-pyrrolidones. Spot urine samples of nine non-exposed persons of the same plant served as controls. Median post-shift urinary levels of workers with regular work tasks (5-HNEP: 0.15 mg/L; 2-HESI: 0.19 mg/L) were ∼5-fold higher compared to the controls (0.03 mg/L each). Continuously increasing metabolite levels, from pre-shift via post-shift to pre-shift samples of the following day, were observed in particular for the two workers with the special working tasks. Maximum levels were 31.01 mg/L (5-HNEP) and 8.45 mg/L (2-HESI). No clear trend was evident for workers with regular working tasks. In summary, we were able to show that workers can be exposed to NEP during varnishing tasks in the automobile industry. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

PubMed

Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

2017-07-01

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

Acute administration of n-3 rich triglyceride emulsions provides cardioprotection in murine models after ischemia-reperfusion.

PubMed

Zirpoli, Hylde; Abdillahi, Mariane; Quadri, Nosirudeen; Ananthakrishnan, Radha; Wang, Lingjie; Rosario, Rosa; Zhu, Zhengbin; Deckelbaum, Richard J; Ramasamy, Ravichandran

2015-01-01

Dietary n-3 fatty acids (FAs) may reduce cardiovascular disease risk. We questioned whether acute administration of n-3 rich triglyceride (TG) emulsions could preserve cardiac function and decrease injury after ischemia/reperfusion (I/R) insult. We used two different experimental models: in vivo, C57BL/6 mice were exposed to acute occlusion of the left anterior descending coronary artery (LAD), and ex-vivo, C57BL/6 murine hearts were perfused using Langendorff technique (LT). In the LAD model, mice treated with n-3 TG emulsion (1.5 g/kg body weight), immediately after ischemia and 1 h later during reperfusion, significantly reduced infarct size and maintained cardiac function (p<0.05). In the LT model, administration of n-3 TG emulsion (300 mg TG/100 ml) during reperfusion significantly improved functional recovery (p<0.05). In both models, lactate dehydrogenase (LDH) levels, as a marker of injury, were significantly reduced by n-3 TG emulsion. To investigate the mechanisms by which n-3 FAs protects hearts from I/R injury, we investigated changes in key pathways linked to cardioprotection. In the ex-vivo model, we showed that n-3 FAs increased phosphorylation of AKT and GSK3β proteins (p<0.05). Acute n-3 TG emulsion treatment also increased Bcl-2 protein level and reduced an autophagy marker, Beclin-1 (p<0.05). Additionally, cardioprotection by n-3 TG emulsion was linked to changes in PPARγ protein expression (p<0.05). Rosiglitazone and p-AKT inhibitor counteracted the positive effect of n-3 TG; GSK3β inhibitor plus n-3 TG significantly inhibited LDH release. We conclude that acute n-3 TG injection during reperfusion provides cardioprotection. This may prove to be a novel acute adjunctive reperfusion therapy after treating patients with myocardial infarction.

Acute Administration of n-3 Rich Triglyceride Emulsions Provides Cardioprotection in Murine Models after Ischemia-Reperfusion

PubMed Central

Zirpoli, Hylde; Abdillahi, Mariane; Quadri, Nosirudeen; Ananthakrishnan, Radha; Wang, Lingjie; Rosario, Rosa; Zhu, Zhengbin; Deckelbaum, Richard J.; Ramasamy, Ravichandran

2015-01-01

Dietary n-3 fatty acids (FAs) may reduce cardiovascular disease risk. We questioned whether acute administration of n-3 rich triglyceride (TG) emulsions could preserve cardiac function and decrease injury after ischemia/reperfusion (I/R) insult. We used two different experimental models: in vivo, C57BL/6 mice were exposed to acute occlusion of the left anterior descending coronary artery (LAD), and ex-vivo, C57BL/6 murine hearts were perfused using Langendorff technique (LT). In the LAD model, mice treated with n-3 TG emulsion (1.5g/kg body weight), immediately after ischemia and 1h later during reperfusion, significantly reduced infarct size and maintained cardiac function (p<0.05). In the LT model, administration of n-3 TG emulsion (300mgTG/100ml) during reperfusion significantly improved functional recovery (p<0.05). In both models, lactate dehydrogenase (LDH) levels, as a marker of injury, were significantly reduced by n-3 TG emulsion. To investigate the mechanisms by which n-3 FAs protects hearts from I/R injury, we investigated changes in key pathways linked to cardioprotection. In the ex-vivo model, we showed that n-3 FAs increased phosphorylation of AKT and GSK3β proteins (p<0.05). Acute n-3 TG emulsion treatment also increased Bcl-2 protein level and reduced an autophagy marker, Beclin-1 (p<0.05). Additionally, cardioprotection by n-3 TG emulsion was linked to changes in PPARγ protein expression (p<0.05). Rosiglitazone and p-AKT inhibitor counteracted the positive effect of n-3 TG; GSK3β inhibitor plus n-3 TG significantly inhibited LDH release. We conclude that acute n-3 TG injection during reperfusion provides cardioprotection. This may prove to be a novel acute adjunctive reperfusion therapy after treating patients with myocardial infarction. PMID:25559887

ENU mutagenesis to generate genetically modified rat models.

PubMed

van Boxtel, Ruben; Gould, Michael N; Cuppen, Edwin; Smits, Bart M G

2010-01-01

The rat is one of the most preferred model organisms in biomedical research and has been extremely useful for linking physiology and pathology to the genome. However, approaches to genetically modify specific genes in the rat germ line remain relatively scarce. To date, the most efficient approach for generating genetically modified rats has been the target-selected N-ethyl-N-nitrosourea (ENU) mutagenesis-based technology. Here, we describe the detailed protocols for ENU mutagenesis and mutant retrieval in the rat model organism.

The neurotoxic effects of N-methyl-N-nitrosourea on the electrophysiological property and visual signal transmission of rat's retina

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

Tao, Ye; Chen, Tao; Liu, Bei

The neurotoxic effects of N-methyl-N-nitrosourea (MNU) on the inner retinal neurons and related visual signal circuits have not been described in any animal models or human, despite ample morphological evidences about the MNU induced photoreceptor (PR) degeneration. With the helping of MEA (multielectrode array) recording system, we gained the opportunity to systemically explore the neural activities and visual signal pathways of MNU administrated rats. Our MEA research identified remarkable alterations in the electrophysiological properties and firstly provided instructive information about the neurotoxicity of MNU that affects the signal transmission in the inner retina. Moreover, the spatial electrophysiological functions of retinamore » were monitored and found that the focal PRs had different vulnerabilities to the MNU. The MNU-induced PR dysfunction exhibited a distinct spatial- and time-dependent progression. In contrast, the spiking activities of both central and peripheral RGCs altered synchronously in response to the MNU administration. Pharmacological tests suggested that gap junctions played a pivotal role in this homogeneous response of RGCs. SNR analysis of MNU treated retina suggested that the signaling efficiency and fidelity of inner retinal circuits have been ruined by this toxicant, although the microstructure of the inner retina seemed relatively consolidated. The present study provided an appropriate example of MEA investigations on the toxicant induced pathological models and the effects of the pharmacological compounds on neuron activities. The positional MEA information would enrich our knowledge about the pathology of MNU induced RP models, and eventually be instrumental for elucidating the underlying mechanism of human RP. - Highlights: • We systemically explored the neural activities and visual signal pathways of MNU administrated retinas. • The focal photoreceptors had different vulnerabilities to the MNU administration. �

Bromidotetra-kis-(1H-2-ethyl-5-methyl-imidazole-κN)copper(II) bromide.

PubMed

Godlewska, Sylwia; Baranowska, Katarzyna; Socha, Joanna; Dołęga, Anna

2011-12-01

The Cu(II) ion in the title compound, [CuBr(C(6)H(10)N(2))(4)]Br, is coordinated in a square-based-pyramidal geometry by the N atoms of four imidazole ligands and a bromide anion in the apical site. Both the Cu(II) and Br(-) atoms lie on a crystallographic fourfold axis. In the crystal, the [CuBr(C(6)H(10)N(2))(4)](+) complex cations are linked to the uncoordinated Br(-) anions (site symmetry [Formula: see text]) by N-H⋯Br hydrogen bonds, generating a three-dimensional network. The ethyl group of the imidazole ligand was modelled as disordered over two orientations with occupancies of 0.620 (8) and 0.380 (8).

Methylation of ribonucleic acid by the carcinogens dimethyl sulphate, N-methyl-N-nitrosourea and N-methyl-N′-nitro-N-nitrosoguanidine. Comparisons of chemical analyses at the nucleoside and base levels

PubMed Central

Lawley, P. D.; Shah, S. A.

1972-01-01

1. The following methods for hydrolysis of methyl-14C-labelled RNA, and for chromatographic isolation and determination of the products, were investigated: enzymic digestion to nucleosides at pH6 or 8; alkaline hydrolysis and conversion into nucleosides; hydrolysis by acid to pyrimidine nucleotides and purine bases, or completely to bases; chromatography on Dowex 50 (NH4+ form) at pH6 or 8.9, or on Dowex 50 (H+ form), or on Sephadex G-10. 2. The suitability of the various methods for determination of methylation products was assessed. The principal product, 7-methylguanosine, was unstable under the conditions used for determinations of nucleosides. 3- and 7-Methyladenine and 3- and 7-methylguanine are best determined as bases; 1-methyladenine and 3-methylcytosine can be isolated as either nucleosides or bases; O6-methylguanine is unstable under the acid hydrolysis conditions used and can be determined as the nucleoside; 3-methyluracil was detected, but may be derived from methylation of the ionized form of uracil. 3. Differences between the patterns of methylation of RNA and homopolyribonucleotides by the N-methyl-N-nitroso compounds and dimethyl sulphate were found: the nitroso compounds were able to methylate O-6 of guanine, were relatively more reactive at N-7 of adenine and probably at N-3 of guanine, but less reactive at N-1 of adenine, N-3 of cytosine and probably at N-3 of uridine. They probably reacted more with the ribose–phosphate chain, but no products from this were identified. 4. The possible influences of these differences on biological action of the methylating agents is discussed. Nitroso compounds may differ principally in their ability to induce miscoding in the Watson–Crick sense by reaction at O-6 of guanine. Both types of agent may induce miscoding to a lesser extent through methylation at N-3 of guanine; both can methylate N atoms, presumably preventing Watson–Crick hydrogen-bonding. N-Methyl-N-nitrosourea can degrade RNA, possibly

Sequence distribution of acetaldehyde-derived N2-ethyl-dG adducts along duplex DNA.

PubMed

Matter, Brock; Guza, Rebecca; Zhao, Jianwei; Li, Zhong-ze; Jones, Roger; Tretyakova, Natalia

2007-10-01

Acetaldehyde (AA) is the major metabolite of ethanol and may be responsible for an increased gastrointestinal cancer risk associated with alcohol beverage consumption. Furthermore, AA is one of the most abundant carcinogens in tobacco smoke and induces tumors of the respiratory tract in laboratory animals. AA binding to DNA induces Schiff base adducts at the exocyclic amino group of dG, N2-ethylidene-dG, which are reversible on the nucleoside level but can be stabilized by reduction to N2-ethyl-dG. Mutagenesis studies in the HPRT reporter gene and in the p53 tumor suppressor gene have revealed the ability of AA to induce G-->A transitions and A-->T transversions, as well as frameshift and splice mutations. AA-induced point mutations are most prominent at 5'-AGG-3' trinucleotides, possibly a result of sequence specific adduct formation, mispairing, and/or repair. However, DNA sequence preferences for the formation of acetaldehyde adducts have not been previously examined. In the present work, we employed a stable isotope labeling-HPLC-ESI+-MS/MS approach developed in our laboratory to analyze the distribution of acetaldehyde-derived N2-ethyl-dG adducts along double-stranded oligodeoxynucleotides representing two prominent lung cancer mutational "hotspots" and their surrounding DNA sequences. 1,7,NH 2-(15)N-2-(13)C-dG was placed at defined positions within DNA duplexes derived from the K-ras protooncogene and the p53 tumor suppressor gene, followed by AA treatment and NaBH 3CN reduction to convert N2-ethylidene-dG to N2-ethyl-dG. Capillary HPLC-ESI+-MS/MS was used to quantify N2-ethyl-dG adducts originating from the isotopically labeled and unlabeled guanine nucleobases and to map adduct formation along DNA duplexes. We found that the formation of N2-ethyl-dG adducts was only weakly affected by the local sequence context and was slightly increased in the presence of 5-methylcytosine within CG dinucleotides. These results are in contrast with sequence

Preventive effect of Oenothera rosea on N-methyl-N-nitrosourea-(NMU) induced gastric cancer in rats.

PubMed

Almora-Pinedo, Yuan; Arroyo-Acevedo, Jorge; Herrera-Calderon, Oscar; Chumpitaz-Cerrate, Víctor; Hañari-Quispe, Renán; Tinco-Jayo, Aldo; Franco-Quino, Cesar; Figueroa-Salvador, Linder

2017-01-01

Currently, gastric cancer (GC) is considered a public health problem worldwide. Using medicinal plants for the prevention of chronic diseases such as cancer constitutes new alternatives in traditional medicine. Oenothera rosea (OR) could be an option, but it needs to be evaluated. The main objective of this study was to evaluate the protective effect of OR extract on N-methyl-N-nitrosourea (NMU)-induced GC in rats. In total, 80 male Holtzman rats were randomized into five groups. Group A received the saline solution (5mL/kg), group B received NMU 500 μg/kg (cancer inductor) by oral administration for 16 weeks, and groups C, D, and E were treated with OR extract (100, 200, and 300 mg/kg, respectively) and NMU in order to evaluate the preventive effect on cancer induced by NMU for 16 weeks. Blood and histological samples of stomachs were collected to determine histopathological, biochemical, and hematological parameters between different experimental groups. Groups C, D, and E presented less histopathological changes such as anaplastic and hyperplastic cells, compared with group B. Hematological and biochemical parameters were recorded, and superoxide dismutase, malondialdehyde, and nitric oxide levels were statistically less than those of NMU group ( P <0.05, P <0.01, and P <0.01). Considering the histopathological signs and the antioxidant activity in vivo as well as hematological and biochemical parameters of ethanolic extract of OR, we concluded that its administration in rats has a protective effect on GC, which is induced experimentally. This species could be studied in clinical trials for patients with GC in the future.

Cyanidin-3-glucoside extracted from mulberry fruit can reduce N-methyl-N-nitrosourea-induced retinal degeneration in rats.

PubMed

Lee, Seung Hee; Jeong, Eojin; Paik, Sun-Sook; Jeon, Ji Hyun; Jung, Sung Won; Kim, Hyun-Bok; Kim, Muyan; Chun, Myung-Hoon; Kim, In-Beom

2014-01-01

To investigate the effect of cyanidin-3-O-glucoside (C3G) on a rat retinal degeneration (RD) model. Experimental RD was induced in rats by the intraperitoneal injection of N-methyl-N-nitrosourea (MNU) at 50 mg/kg. C3G extracted from mulberry (Morus alba L.) fruit (50 mg/kg) was orally administered, daily for 1, 2 and 4 weeks after MNU injection. The effects of C3G administration on MNU-induced RD retinas were histologically and functionally assessed by hematoxylin and eosin staining and electroretinography (ERG), respectively. The degree of retinal injury in C3G-administered RD rats was evaluated by immunohistochemistry with an antibody against glial fibrillary acidic protein (GFAP). The preferential protective effect of C3G on scotopic vision was examined by western blot analysis. Marked loss of photoreceptors in the outer nuclear layer (ONL) was observed in RD rats at 2 and 4 weeks after MNU injection, while the ONL in the MNU-induced RD rats given C3G was relatively well preserved. Immunohistochemistry with anti-GFAP showed that retinal injury was also reduced in the retinas of the rats given C3G. Functional assessment by using ERG recordings showed that scotopic ERG responses were significantly increased in RD rats given C3G for 4 weeks (p < 0.01) compared with that of untreated RD rats. In the RD rats given short-term C3G (for 1 and 2 weeks), the increase in ERG responses was not significant. In addition, western blot analysis showed that rhodopsin level in the C3G-administered RD retinas significantly increased compared to that in the non-administered RD retinas (p < 0.05), whereas red/green opsin level did not show any significant difference. Long-term administration of C3G extracted from mulberry fruit could structurally reduce photoreceptor damage and functionally improve scotopic visual functions in the RD rat model induced by MNU.

Poly(DL-lactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate): synthesis, characterization, micellization behavior in aqueous solutions, and encapsulation of the hydrophobic drug dipyridamole.

PubMed

Karanikolopoulos, Nikos; Zamurovic, Miljana; Pitsikalis, Marinos; Hadjichristidis, Nikos

2010-02-08

We synthesized a series of well-defined poly(dl-lactide)-b-poly(N,N-dimethylamino-2-ethyl methacrylate) (PDLLA-b-PDMAEMA) amphiphilic diblock copolymers by employing a three-step procedure: (a) ring-opening polymerization (ROP) of dl-lactide using n-decanol and stannous octoate, Sn(Oct)(2), as the initiating system, (b) reaction of the PDLLA hydroxyl end groups with bromoisobutyryl bromide, and (c) atom transfer radical polymerization, ATRP, of DMAEMA with the newly created bromoisobutyryl initiating site. The aggregation behavior of the prepared block copolymers was investigated by dynamic light scattering and zeta potential measurements at 25 degrees C in aqueous solutions of different pH values. The hydrophobic drug dipyridamole was efficiently incorporated into the copolymer aggregates in aqueous solutions of pH 7.40. High partition coefficient values were determined by fluorescence spectroscopy.

Response of melanoma tumor phospholipid metabolism to chloroethyle nitrosourea: a high resolution proton NMR spectroscopy study.

PubMed

Morvan, Daniel; Demidem, Aïcha; Madelmont, Jean-Claude

2003-07-01

Phospholipid metabolism is tightly involved in tumor growth regulation and tumor cell survival. The response of phospholipid metabolism to chloroethyle nitrosourea treatment is investigated in a murine B16 melanoma model. Measurements of phospholipid derivatives are performed on intact tumor tissue samples using one- and two-dimensional proton NMR spectroscopy. During the tumor growth inhibition phase under treatment, tumors overexpress phosphocholine, phosphoethanolamine, glycerophosphocholine and glycerophosphoethanolamine, whereas phosphatidylcholine and phosphatidylethanolamine levels are maintained to control levels. During re-growth, which remained quantitatively much below control growth, chloroethyle nitrosourea-treated melanoma tumors overexpress phosphocholine and phosphoethanolamine only. In treated melanoma, phosphatidylcholine levels show an inverse relationship with tumor growth rates. In conclusion, chloroethyle nitrosourea-treated melanoma tumors maintain their phosphatidylcholine levels and exhibit transformed phospholipid metabolism phenotype, by mechanisms that could participate in tumor cell survival.

Evaluation of the immunological cellular response of Cebus apella exposed to the carcinogen N-methyl-N-nitrosourea and treated with CANOVA®.

PubMed

Feio, Danielle Cristinne Azevedo; Muniz, José Augusto Pereira Carneiro; Montenegro, Raquel Carvalho; Burbano, Rommel Rodriguez; De Brito Junior, Lacy Cardoso; De Lima, Patrícia Danielle Lima

2014-01-01

The immune response modifier Canova® is a homeopathic remedy indicated for patients with depressed immune system, since this drug appears to increase adaptive immunity and induce an immune response against multiple and severe pathological conditions, including cancer. We evaluated the pattern of immune cellular response in non-human primates of the species Cebus apella exposed to N-methyl-N-nitrosourea (MNU) with and without Canova®. Twelve animals were divided into four groups, with three animals each: negative control and three experimental groups, MNU-alone (35 days); MNU (35 days)-plus-Canova® (3 days) and Canova®-alone (3 days). The animals received MNU orally and Canova® by three intravenous injections. Evaluation of the cellular immune response was performed by immunophenotyping of T-lymphocytes (CD4(+), CD8(+)), B-lymphocytes and natural killer cells. Analysis was also performed of the cell cycle. Our results suggest an increase of T-lymphocytes (CD4(+)CD3(+)) only in the Canova® group, while in the MNU-plus-Canova® group only B-lymphocytes increased. Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Preventive effect of Oenothera rosea on N-methyl-N-nitrosourea-(NMU) induced gastric cancer in rats

PubMed Central

Almora-Pinedo, Yuan; Arroyo-Acevedo, Jorge; Herrera-Calderon, Oscar; Chumpitaz-Cerrate, Víctor; Hañari-Quispe, Renán; Tinco-Jayo, Aldo; Franco-Quino, Cesar; Figueroa-Salvador, Linder

2017-01-01

Background Currently, gastric cancer (GC) is considered a public health problem worldwide. Using medicinal plants for the prevention of chronic diseases such as cancer constitutes new alternatives in traditional medicine. Oenothera rosea (OR) could be an option, but it needs to be evaluated. Aim The main objective of this study was to evaluate the protective effect of OR extract on N-methyl-N-nitrosourea (NMU)-induced GC in rats. Methods In total, 80 male Holtzman rats were randomized into five groups. Group A received the saline solution (5mL/kg), group B received NMU 500 μg/kg (cancer inductor) by oral administration for 16 weeks, and groups C, D, and E were treated with OR extract (100, 200, and 300 mg/kg, respectively) and NMU in order to evaluate the preventive effect on cancer induced by NMU for 16 weeks. Blood and histological samples of stomachs were collected to determine histopathological, biochemical, and hematological parameters between different experimental groups. Results Groups C, D, and E presented less histopathological changes such as anaplastic and hyperplastic cells, compared with group B. Hematological and biochemical parameters were recorded, and superoxide dismutase, malondialdehyde, and nitric oxide levels were statistically less than those of NMU group (P<0.05, P<0.01, and P<0.01). Conclusion Considering the histopathological signs and the antioxidant activity in vivo as well as hematological and biochemical parameters of ethanolic extract of OR, we concluded that its administration in rats has a protective effect on GC, which is induced experimentally. This species could be studied in clinical trials for patients with GC in the future. PMID:29270029

Thermochromic Excited - State Dipole Moment Measurements of p-Cyano-N,N-diethylaniline in Ethyl Acetate

NASA Astrophysics Data System (ADS)

Kawski, A.; Kuklinski, B.; Bojarski, P.

2003-03-01

The effect of temperature on absorption and fluorescence spectra of p-cyano-N,N-diethylaniline (CDEA) in ethyl acetate has been studied for temperatures ranging from 293 K to 418 K. At T = 293 K two fluorescence bands are observed: long wavelength emission (LE) and short wavelength emission (SE) of much lower intensity compared to the first one.With temperature increase (which leads to the decrease of dielectric constant ɛ of the solvent) the intensity of SE band strongly increases, however its hypsochromic shift compared to the shift of LE band is rather slight. The electric dipole moments for CDEA determined based on this thermochromic method are: μLEe = 13.4 D and μSEe = 7.5 D for μg = 5.5 D, and μLE e = 13.9 D and μSEe = 8.3 D for μg = 6.6 D. The values obtained are compared with those of p-cyano-N,N-dimethylaniline (CDMA) determined using different methods.

Influence of N-methyl-N-nitrosourea, testosterone, and N-(4-hydroxyphenyl)-all-trans-retinamide on prostate cancer induction in Wistar-Unilever rats.

PubMed

McCormick, D L; Rao, K V; Dooley, L; Steele, V E; Lubet, R A; Kelloff, G J; Bosland, M C

1998-08-01

The influence of chemical carcinogen, hormonal stimulation, and chronic dietary administration of the synthetic retinoid, N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), on the induction of prostate cancer in male Wistar-Unilever rats was determined. Three different tumor induction regimens were used: (a) a single i.v. dose of 50 mg of N-methyl-N-nitrosourea (MNU) per kg body weight, followed by chronic androgen stimulation via s.c. implantation of two silastic capsules containing 40 mg testosterone each; (b) a single i.v. dose of 50 mg of MNU per kg body weight (no testosterone treatment); and (c) chronic androgen stimulation with implanted testosterone capsules (no MNU treatment). In a fourth series of animals, the incidence of spontaneous prostate tumors was determined in groups of rats receiving neither carcinogen nor hormone stimulation. Within each series, parallel groups of animals were fed a control (vehicle-supplemented) diet or control diet supplemented with 4-HPR beginning 1 day after carcinogen administration; retinoid administration was continuous until termination of the study at 450 days. The incidence of accessory sex gland cancer in rats treated sequentially with MNU + testosterone was >60%, in comparison with cancer incidences of <20% in rats receiving MNU only and <5% in rats treated with testosterone only. No spontaneous accessory sex gland tumors were observed in rats receiving no carcinogen and no testosterone. Tumor induction in the accessory sex glands by MNU + testosterone was relatively specific for the prostate: the incidence of carcinoma of the dorsolateral/anterior prostate was more than 5-fold greater than the incidence of cancer present only in the seminal vesicle. 4-HPR conferred no protection against cancer induction in the prostate by any regimen of MNU and/or testosterone. These results demonstrate the importance of both carcinogen exposure and hormone stimulation on the induction of neoplasia in the prostate of Wistar

Formation of O2-methylthymine in poly(dA-dT) on methylation with N-methyl-N-nitrosourea and dimethyl sulphate. Evidence that O2-methylthymine does not miscode during DNA synthesis.

PubMed Central

Saffhill, R; Abbott, P J

1978-01-01

The alternating co-polymer has been methylated with either N methyl-N-nitrosourea (MNU) or dimethyl sulphate (DMS) and the levels of the various methylated thymidines (O2-methylthymidine, 3-methylthymidine and O4-methylthymidine) measured. MNU produced all three compounds whereas DMS only produced 3-methylthymidine and O2-methylthymidine at detectable levels. These results have been combined with our earlier results concerning the misincorporation of dGMP with E. coli DNA polymerase using MNU-methylated poly(dA-dT). These results indicate that O2-methylthymidine does not miscode during DNA synthesis. PMID:353735

Behavior of N-ethyl perfluorooctane sulfonamido acetic acid (N-EtFOSAA) in biosolids amended soil-plant microcosms of seven plant species: Accumulation and degradation.

PubMed

Wen, Bei; Pan, Ying; Shi, Xiaoli; Zhang, Hongna; Hu, Xiaoyu; Huang, Honglin; Lv, Jitao; Zhang, Shuzhen

2018-06-13

Perfluorooctane sulfonate (PFOS) precursors have been found extensively in sewage sludge and biosolids-amended soils. The degradation of these precursors are regarded as a significant source of PFOS in the environment. In this study, the accumulation of N-ethyl perfluorooctane sulfonamido acetic acid (N-EtFOSAA) in the plants of seven species, namely alfalfa, lettuce, maize, mung bean, radish, ryegrass, and soybean from biosolids-amended soil, and the degradation kinetics of N-EtFOSAA in soil-plant microcosms were evaluated over 60 days. N-EtFOSAA was found in the roots of all plant species, while was not in stems and leaves. The root concentration factors of N-EtFOSAA ranged 0.52-1.37 (pmol/g root )/(pmol/g soil ). Stepwise multiple regression analysis was used to elucidate the accumulation of N-EtFOSAA in the roots of plants. The results showed that the root protein and lipid contents explain 85.0% of the variation in root N-EtFOSAA levels (P < 0.05). Four degradation products, including N-ethyl perfluorooctane sulfonamide (N-EtFOSA), perfluorooctane sulfonamide acetate (FOSAA), perfluorooctane sulfonamide (FOSA) and PFOS were found in soils and plant roots, stems and leaves, indicating the degradation of N-EtFOSAA in soil-plant system. Degradation kinetics fitted a first-order kinetic model well. Degradation rate constants of N-EtFOSAA in the microcosms with plants ranged 0.063-0.165 d -1 , which was 1.40-3.6 times higher than those without plants. Degradation rate constant of maize was relatively higher than those of other plant species. The results is the first to reveal N-EtFOSAA accumulation in plants and degradation in soil-plant microcosms. Copyright © 2018. Published by Elsevier B.V.

Immunity against mouse thymus-leukemia antigen (TL) protects against development of lymphomas induced by a chemical carcinogen, N-butyl-N-nitrosourea.

PubMed

Tsujimura, Kunio; Obata, Yuichi; Matsudaira, Yasue; Ozeki, Satoshi; Taguchi, Osamu; Nishida, Keiko; Okanami, Yuko; Akatsuka, Yoshiki; Kuzushima, Kiyotaka; Takahashi, Toshitada

2004-11-01

Mouse thymus-leukemia antigens (TL) are aberrantly expressed on T lymphomas in C57BL/6 (B6) and C3H/He (C3H) mice, while they are not expressed on normal T lymphocytes in these strains. When N-butyl-N-nitrosourea (NBU), a chemical carcinogen, was administered orally to B6 and C3H strains, lymphoma development was slower than in T3(b)-TL gene-transduced counterpart strains expressing TL ubiquitously as self-antigens, suggesting that anti-TL immunity may play a protective role. In addition, the development of lymphomas was slightly slower in C3H than in B6, which seems to be in accordance with the results of skin graft experiments indicating that both cellular and humoral immunities against TL were stronger in C3H than B6 mice. The interesting finding that B lymphomas derived from a T3(b)-TL transgenic strain (C3H background) expressing a very high level of TL were rejected in C3H, but not in H-2K(b) transgenic mice (C3H background), raises the possibility that TL-specific effector T cell populations are eliminated and/or energized to a certain extent by interacting with H-2K(b) molecules.

Evaluation of the DNA damaging potential of cannabis cigarette smoke by the determination of acetaldehyde derived N2-ethyl-2'-deoxyguanosine adducts.

PubMed

Singh, Rajinder; Sandhu, Jatinderpal; Kaur, Balvinder; Juren, Tina; Steward, William P; Segerbäck, Dan; Farmer, Peter B

2009-06-01

Acetaldehyde is an ubiquitous genotoxic compound that has been classified as a possible carcinogen to humans. It can react with DNA to form primarily a Schiff base N(2)-ethylidene-2'-deoxyguanosine (N(2)-ethylidene-dG) adduct. An online column-switching valve liquid chromatography tandem mass spectrometry (LC-MS/MS) selected reaction monitoring (SRM) method was developed for the determination of N(2)-ethylidene-dG adducts in DNA following reduction with sodium cyanoborohydride (NaBH(3)CN) to the chemically stable N(2)-ethyl-2'-deoxyguanosine (N(2)-ethyl-dG) adduct. Accurate quantitation of the adduct was obtained by the addition of the [(15)N(5)]N(2)-ethyl-dG stable isotope-labeled internal standard prior to enzymatic hydrolysis of the DNA samples to 2'-deoxynucleosides with the incorporation of NaBH(3)CN in the DNA hydrolysis buffer. The method required 50 microg of hydrolyzed DNA on column for the analysis, and the limit of detection for N(2)-ethyl-dG was 2.0 fmol. The analysis of calf thymus DNA treated in vitro with acetaldehyde (ranging from 0.5 to 100 mM) or with the smoke generated from 1, 5, and 10 cannabis cigarettes showed linear dose-dependent increases in the level of N(2)-ethyl-dG adducts (r = 0.954 and r = 0.999, respectively). Similar levels (332.8 +/- 21.9 vs 348.4 +/- 19.1 adducts per 10(8) 2'-deoxynucleosides) of N(2)-ethyl-dG adducts were detected following the exposure of calf thymus DNA to 10 tobacco or 10 cannabis cigarettes. No significant difference was found in the levels of N(2)-ethyl-dG adducts in human lung DNA obtained from nonsmokers (n = 4) and smokers (n = 4) with the average level observed as 13.3 +/- 0.7 adducts per 10(8) 2'-deoxynucleosides. No N(2)-ethyl-dG adducts were detected in any of the DNA samples following analysis with the omission of NaBH(3)CN from the DNA hydrolysis buffer. In conclusion, these results provide evidence for the DNA damaging potential of cannabis smoke, implying that the consumption of cannabis

Pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes of rats with mammary gland cancer induced by N-methyl nitrosourea.

PubMed

Carrera, M P; Ramírez-Expósito, M J; Valenzuela, M T; García, M J; Mayas, M D; Arias de Saavedra, J M; Sánchez, R; Pérez, M C; Martínez-Martos, J M

2005-02-01

Pyrrolidon carboxypeptidase is an omega-peptidase that hydrolyses N-terminal pyroglutamyl residues from biologically active peptides such as gonadotropin-releasing and thyrotrophin-releasing hormones. We previously described a decrease in both rat and human pyrrolidon carboxypeptidase activity with breast cancer, suggesting that gonadotropin-releasing hormone may be an important local intracrine, autocrine and/or paracrine hormonal factor in the pathogenesis of breast cancer while playing a role in the tumoral process. However, the other susceptible substrate of pyrrolidon carboxypeptidase, thyrotrophin-releasing hormone, may also be modified with breast cancer, supporting an association between breast cancer and thyroid disorders. The present work analyses soluble and membrane-bound pyrrolidon carboxypeptidase activities in the hypothalamus-pituitary-thyroid and hypothalamus-pituitary-ovary axes in N-methyl nitrosourea-induced breast cancer in rats. Our aim was to determine the possible relationship between gonadotropin-releasing hormone and thyrotrophin-releasing hormone regulation through pyrrolidon carboxypeptidase activity. We propose that pyrrolidon carboxypeptidase activity dysregulation at various local and systemic levels may participate in the initiation, promotion and progression of breast cancer induced in rat by N-methyl nitrosourea through the increase in gonadotropin-releasing hormone. Since pyrrolidon carboxypeptidase activity also acts on thyrotrophin-releasing hormone, the dysregulation of this enzyme's activity could indirectly affect hypothalamus-pituitary-thyroid axis function, and thus potentially represent a link between the diseases of thyroid and breast cancer.

Increased phospho-AKT is associated with loss of the androgen receptor during the progression of N-methyl-N-nitrosourea-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Wang, Shihua; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2005-07-01

Characterization of molecular events during N-methyl-N-nitrosourea (MNU)-induced rat prostate carcinogenesis enhances the utility of this model for the preclinical assessment of preventive strategies. Androgen independence is typical of advanced human prostate cancer and may occur through multiple mechanisms including the loss of androgen receptor (AR) expression and the activation of alternative signaling pathways. We examined the interrelationships between AR and p-AKT expression by immunohistochemical staining during MNU-androgen-induced prostate carcinogenesis in male Wistar-Unilever rats. Histone nuclear staining and image analysis was employed to assess parallel changes in chromatin and nuclear structure. The percentage of AR positive nuclei decreased (P < 0.01) as carcinogenesis progressed: hyperplasia (92%), atypical hyperplasia (92%), well-differentiated adenocarcinoma (57%), moderately-differentiated adenocarcinoma (19%), and poorly-differentiated adenocarcinoma (10%). Conversely, p-AKT staining increased significantly during carcinogenesis. Sparse staining was observed in normal tissues (0.2% of epithelial area) and hyperplastic lesions (0.1%), while expression increased significantly (P < 0.001) in atypical hyperplasia (7.6%), well-differentiated adenocarcinoma (16.7%), moderately-differentiated adenocarcinoma (19.6%), and poorly-differentiated adenocarcinoma (17.4%). In parallel, nuclear morphometry revealed increased nuclear size, greater irregularity, and lower DNA compactness as cancers became more poorly differentiated. In the MNU model, the progressive evolution of dominant tumor cell populations showing an increase in p-AKT in parallel with a decline in AR staining suggests that activation of AKT signaling may be one of several mechanisms contributing to androgen insensitivity during prostate cancer progression. Our observations mimic findings suggested by human studies and support the relevance of the MNU model in preclinical studies of

Nucleotide excision repair modulates the cytotoxic and mutagenic effects of N-n-butyl-N-nitrosourea in cultured mammalian cells as well as in mouse splenocytes in vivo.

PubMed

Bol, S A; van Steeg, H; van Oostrom, C T; Tates, A D; Vrieling, H; de Groot, A J; Mullenders, L H; van Zeeland, A A; Jansen, J G

1999-05-01

The butylating agent N-n-butyl-N-nitrosourea (BNU) was employed to study the role of nucleotide excision repair (NER) in protecting mammalian cells against the genotoxic effects of monofunctional alkylating agents. The direct acting agent BNU was found to be mutagenic in normal and XPA mouse splenocytes after a single i.p. treatment in vivo. After 25 and 35 mg/kg BNU, but not after 75 mg/ kg, 2- to 3-fold more hprt mutants were detected in splenocytes from XPA mice than from normal mice. Using O6-alkylguanine-DNA alkyltransferase (AGT)-deficient hamster cells, it was found that NER-deficient CHO UV5 cells carrying a mutation in the ERCC-2 gene were 40% more mutable towards lesions induced by BNU when compared with parental NER-proficient CHO AA8 cells. UV5 cells were 1.4-fold more sensitive to the cytotoxic effects of BNU compared with AA8 cells. To investigate whether this increased sensitivity of NER-deficient cells is modulated by AGT activity, cell survival studies were performed in human and mouse primary fibroblasts as well. BNU was 2.7-fold more toxic for mouse XPA fibroblasts compared with normal mouse fibroblasts. Comparable results were found for human fibroblasts. Taken together these data indicate that the role of NER in protecting rodent cells against the mutagenic and cytotoxic effects of the alkylating agent BNU depends on AGT.

Synthesis, Structural and Antioxidant Studies of Some Novel N-Ethyl Phthalimide Esters

PubMed Central

Chandraju, Siddegowda; Win, Yip-Foo; Tan, Weng Kang; Quah, Ching Kheng; Fun, Hoong-Kun

2015-01-01

A series of N-ethyl phthalimide esters 4(a-n) were synthesized and characterized by spectroscopic studies. Further, the molecular structure of majority of compounds were analysed by single crystal X-ray diffraction studies. The X-ray analysis revealed the importance of substituents on the crystal stability and molecular packing. All the synthesized compounds were tested for in vitro antioxidant activity by DPPH radical scavenging, FRAP and CUPRAC methods. Few of them have shown good antioxidant activity. PMID:25742494

Synthesis, structural and antioxidant studies of some novel N-ethyl phthalimide esters.

PubMed

Chidan Kumar, C S; Loh, Wan-Sin; Chandraju, Siddegowda; Win, Yip-Foo; Tan, Weng Kang; Quah, Ching Kheng; Fun, Hoong-Kun

2015-01-01

A series of N-ethyl phthalimide esters 4(a-n) were synthesized and characterized by spectroscopic studies. Further, the molecular structure of majority of compounds were analysed by single crystal X-ray diffraction studies. The X-ray analysis revealed the importance of substituents on the crystal stability and molecular packing. All the synthesized compounds were tested for in vitro antioxidant activity by DPPH radical scavenging, FRAP and CUPRAC methods. Few of them have shown good antioxidant activity.

A new class of nitrosoureas. 4. Synthesis and antitumor activity of disaccharide derivatives of 3,3-disubstituted 1-(2-chloroethyl)-1-nitrosoureas.

PubMed

Tsujihara, K; Ozeki, M; Morikawa, T; Kawamori, M; Akaike, Y; Arai, Y

1982-04-01

A series of 33 N-(2-chloroethyl)-N-nitrosocarbamoyl derivatives of N-substituted glycosylamines has been prepared and tested for antitumor activities. The compounds were obtained by reaction of glycosylamines with isocyanate, followed by nitrosation with N2O4. Structure-activity relationships of these trisubstituted nitrosoureas were investigated by varying the N-substituents and disaccharide groups and by comparing them with the corresponding disubstituted analogues. A large number of the nitrosoureas bearing a maltosyl group exhibited strong antitumor activities against leukemia L1210 and Ehrlich ascites carcinoma, and 60-day survivors against leukemia L1210 were found at the optimal dose for these derivatives. In contrast, the lactosyl and the melibiosyl derivatives were almost inactive. The most interesting compound in this series, the 3-isobutyl-3-maltosyl derivative (37), was tested against leukemia L1210 by single and multiple treatment. Its therapeutic ratio (96.3) obtained by multiple treatment is 3 times larger than that (31.5) obtained by single treatment, suggesting a possible clinical utility of 37 by multiple treatment. The favorable effect of a maltosyl moiety in this class of compounds is discussed.

Dopaminergic neurotoxicity of S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, and S-methyl-N,N-diethylthiocarbamate (MeDETC) in Caenorhabditis elegans

PubMed Central

Caito, Samuel W.; Valentine, William M.; Aschner, Michael

2013-01-01

Epidemiological studies corroborate a correlation between pesticide use and Parkinson’s disease (PD). Thiocarbamate and dithiocarbamate pesticides are widely used and produce neurotoxicity in the peripheral nervous system. Recent evidence from rodent studies suggests that these compounds also cause dopaminergic (DAergic) dysfunction and altered protein processing, two hallmarks of PD. However, DAergic neurotoxicity has yet to be documented. We assessed DAergic dysfunction in Caenorhabditis elegans (C. elegans) to investigate the ability of thiocarbamate pesticides to induce DAergic neurodegeneration. Acute treatment with either S-ethyl N,N-dipropylthiocarbamate (EPTC), molinate, or a common reactive intermediate of dithiocarbamate and thiocarbamate metabolism, S-methyl-N,N-diethylthiocarbamate (MeDETC), to gradual loss of DAergic cell morphology and structure over the course of 6 days in worms expressing green fluorescent protein (GFP) under a DAergic cell specific promoter. HPLC analysis revealed decreased DA content in the worms immediately following exposure to MeDETC, EPTC, and molinate. Additionally, worms treated with the three test compounds showed a drastic loss of DAergic-dependent behavior over a time course similar to changes in DAergic cell morphology. Alterations in the DAergic system were specific, as loss of cell structure and neurotransmitter content was not observed in cholinergic, glutamatergic, or GABAergic systems. Overall, our data suggest that thiocarbamate pesticides promote neurodegeneration and DAergic cell dysfunction in C. elegans, and may be an environmental risk factor for PD. PMID:23786526

Multicomponent Synthesis of a N-Protected Alpha-Amino Ester: Ethyl 2-((4-Methoxyphenyl)Amino)-3-Phenylpropanoate

ERIC Educational Resources Information Center

Le Gall, Erwan; Pignon, Antoine

2012-01-01

This laboratory experiment describes the preparation of a N-protected phenylalanine ethyl ester by a zinc-mediated Mannich-like multicomponent reaction between benzyl bromide, "p"-anisidine, and ethyl glyoxylate. The one-step reaction involves the in situ metallation of benzyl bromide into a benzylzinc reagent and its addition onto imine (Barbier…

Spin labeled amino acid nitrosourea derivatives--synthesis and antitumour activity.

PubMed

Zheleva, A; Raikov, Z; Ilarionova, M; Todorov, D

1995-01-01

The synthesis of three spin labeled derivatives of N-[N'-(chloroethyl)-N'-nitrosocarbamoyl] amino acids is reported. The new nitrosoureas are obtained by condensation of the corresponding N-[N'-(2-chloroethyl)-N'-nitrosocarbamoyl] amino acid with 2,2,6,6-tetramethyl-1-oxyl-4-aminopiperidine using dicyclohexylcarbodiimide. Their chemical structures are confirmed by elemental analysis, IR, MS, and EPR spectroscopy. All newly synthesized compounds showed high antitumour activity against the lymphoid leukemia L1210 in BDF1 mice.

Organ differences in the impact of p27(kip1) deficiency on carcinogenesis induced by N-methyl-N-nitrosourea.

PubMed

Ogawa, Kumiko; Murasaki, Toshiya; Sugiura, Satoshi; Nakanishi, Makoto; Shirai, Tomoyuki

2013-06-01

To evaluate the impact of p27 on carcinogenesis in various organs, N-methyl-N-nitrosourea (MNU), a direct-acting alkylating agent, was given to p27 knock-out mice. Groups of 20-40 male and female mice with null, hetero- or wild-type p27 alleles were given drinking water containing 240 ppm MNU or distilled water every other week for five cycles. The incidence and multiplicity of the induced proliferative lesions were then histologically evaluated at weeks 14 and 20. MNU treatment induced various lesions including squamous hyperplasia and squamous cell carcinoma in the forestomach, atypical hyperplasia and adenocarcinomas in the fundic and pyloric glands, adenomas and adenocarcinomas in the duodenum, malignant lymphomas in the thymus, liver, kidney and spleen and alveolar hyperplasia, adenomas, adenocarcinomas and malignant lymphomas in the lung. Although the incidences of the lesions in the forestomach, fundic and pyloric glands did not differ among the p27 genotypes, those of alveolar hyperplasia of the lung and malignant lymphoma of the thymus were significantly increased in p27-null males as compared with both wild- and hetero-type animals. Moreover, in both p27(+/+) and p27(+/-) cases, the rates for p27-positive cells were obviously increased in proliferative lesions of the pyloric gland and the lung. However, an increased rate of p27-positive cells was not observed in malignant lymphoma of the thymus. These findings suggest that p27 does not control the cell cycle equally in all organs affected by MNU-induced carcinogenesis. Copyright © 2011 John Wiley & Sons, Ltd.

Interrelationships among angiogenesis, proliferation, and apoptosis in the tumor microenvironment during N-methyl-N-nitrosourea androgen-induced prostate carcinogenesis in rats.

PubMed

Liao, Zhiming; Boileau, Thomas W-M; Erdman, John W; Clinton, Steven K

2002-10-01

Proliferation, apoptosis and angiogenesis are critical biologic processes altered during carcinogenesis. Surrogate biomarkers of these processes represent potential intermediate endpoints for short-term intervention studies with preventive and therapeutic agents. We examined the interrelationships among these processes during prostate carcinogenesis induced by N-methyl-N-nitrosourea (MNU) in male Wistar-Unilever rats. Immunohistochemical and digital image analysis techniques were used to evaluate the proliferation index, the apoptotic index and microvessel density (MVD) in tissue representing stages of prostate carcinogenesis. The proliferation index in the normal glandular epithelium of the prostate is lower than that observed in hyperplastic foci and atypical hyperplasia (P < 0.01) and is further increased in carcinoma (P < 0.01). Apoptosis in the normal prostate epithelium or hyperplastic lesions is lower than in adenocarcinoma (P < 0.01). In parallel to proliferation index, MVD increases as prostate cancer progresses. As tumors enlarge, we observed a predictable change in biomarker expression within the tumor microenvironment. We examined prostate tumors vertical line 1 cm in diameter and biomarker expression was quantified within the peripheral (outer 1-2 mm), central (perinecrotic) and intermediate (remaining) areas of each tumor. The proliferation index is higher (P < 0.01) in the intermediate area than either in the peripheral area or central area. Similarly, the vascular density in the intermediate area is higher (P < 0.01) than either in the peripheral or central area. The apoptotic index is higher (P < 0.05) in the central perinecrotic core than that in either the intermediate or the peripheral area. In conclusion, we observe that angiogenesis, proliferation and apoptosis are linked biological processes predictably altered temporally and spatially during prostate carcinogenesis in the MNU model. These biomarker changes are similar to those reported in

Synthesis and serotonergic activity of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT(1B)-like receptor.

PubMed

Moloney, G P; Martin, G R; Mathews, N; Milne, A; Hobbs, H; Dodsworth, S; Sang, P Y; Knight, C; Williams, M; Maxwell, M; Glen, R C

1999-07-15

The synthesis and vascular 5-HT(1B)-like receptor activity of a novel series of substituted 2, N-benzylcarboxamido-5-(2-ethyl-1-dioxoimidazolidinyl)-N, N-dimethyltryptamine derivatives are described. Modifications to the 5-ethylene-linked heterocycle and to substituents on the 2-benzylamide side chain have been explored. Several compounds were identified which exhibited affinity at the vascular 5-HT(1B)-like receptor of pK(B) > 7.0, up to 100-fold selectivity over alpha(1)-adrenoceptor affinity and 5-HT(2A) receptor affinity, and which exhibited a favorable pharmacokinetic profile. N-Benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(4,4-dimethyl-2, 5-dioxo-1-imidazolidinyl)ethyl]-1H-indole-2-carboxamide (23) was identified as a highly potent, silent (as judged by the inability of angiotensin II to unmask 5-HT(1B)-like receptor-mediated agonist activity in the rabbit femoral artery), and competitive vascular 5-HT(1B)-like receptor antagonist with a plasma elimination half-life of approximately 4 h in dog plasma and with good oral bioavailability. The selectivity of compounds from this series for the vascular 5-HT(1B)-like receptors over other receptor subtypes is discussed as well as a proposed mode of binding to the receptor pharmacophore. It has been proposed that the aromatic ring of the 2, N-benzylcarboxamide group can occupy an aromatic binding site rather than the indole ring. The resulting conformation allows an amine-binding site to be occupied by the ethylamine nitrogen and a hydrogen-bonding site to be occupied by one of the hydantoin carbonyls. The electronic nature of the 2,N-benzylcarboxamide aromatic group as well as the size of substituents on this aromatic group is crucial for producing potent and selective antagonists. The structural requirement on the 3-ethylamine side chain incorporating the protonatable nitrogen is achieved by the bulky 2, N-benzylcarboxamide group and its close proximity to the 3-side chain.

Upper limits for the ethyl-cyanide abundances in TMC-1 and L134N - Chemical implications

NASA Technical Reports Server (NTRS)

Minh, Y. C.; Irvine, W. M.

1991-01-01

Interstellar ethyl-cyanide has been sought via its 2(02)-1(01) transition towards two cold, dark clouds, and upper limits of the total column densities of 3 x 10 to the 12th/sq cm and 2 x 10 to the 12th/sq cm for TMC-1 and L134N, respectively. The 2(02)-1(01) transition of vynil cyanide, previously identified in TMC-1 by Matthews and Sears (1983b), was also observed. The detection of vinyl cyanide and the nondetection of ethyl cyanide in TMC-1 are consistent with gas phase ion-molecule chemical models, and there is thus no necessity of invoking grain surface synthesis for vinyl cyanide in cold clouds.

Differences in sensitivity of murine spermatogonia and somatic cells in vivo to sister-chromatid exchange induction by nitrosoureas.

PubMed

Morales-Ramírez, P; Cruz-Vallejo, V; Rodríguez-Reyes, R

2001-07-01

Previously published data indicate that spermatogonia (SPG) are less sensitive to a sister-chromatid exchange (SCE) induction for different mutagens. In an earlier study, we have observed that bromodeoxyuridine (BrdU) substituted murine SPG are less sensitive to SCE induction by gamma ray in cells, than bone marrow (BM) and salivary gland (SG) cells in vivo. This was interpreted to mean that SPG are more efficient in DNA repair or are less prone to SCE induction. That the lower induction of SCE could be due to a reduced accessibility of mutagens to the SPG by virtue of a physiological barrier, was discarded by using gamma radiation. The aim of the present study was to establish whether or not there are differences in SCE induction by nitrosoureas among SPG, SG and BM cells with BrdU substituted or unsubstituted DNA. It was observed that SCE induction by methylnitrosourea (MNU) or by ethylnitrosourea (ENU) in SPG was, respectively, five and two times lower than in SG, and ten and three times lower than in BM. In SPG after BrdU incorporation, there was no increase in efficiency of SCE induction; in fact, there was even a slight decrease by exposure to MNU or ENU. BM and SG cells showed an increased efficiency in SCE induction after BrdU incorporation. This implies that SPG are also less sensitive to SCE induction by nitrosoureas, which cause a different kind of damage from previously assayed mutagens.

Nuclear spatial delocalization silences electron density oscillations in 2-phenyl-ethyl-amine (PEA) and 2-phenylethyl-N,N-dimethylamine (PENNA) cations

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

Jenkins, Andrew J.; Vacher, Morgane; Bearpark, Michael J.

2016-03-14

We simulate electron dynamics following ionization in 2-phenyl-ethyl-amine and 2-phenylethyl-N,N-dimethylamine as examples of systems where 3 coupled cationic states are involved. We study two nuclear effects on electron dynamics: (i) coupled electron-nuclear motion and (ii) nuclear spatial delocalization as a result of the zero-point energy in the neutral molecule. Within the Ehrenfest approximation, our calculations show that the coherent electron dynamics in these molecules is not lost as a result of coupled electron-nuclear motion. In contrast, as a result of nuclear spatial delocalization, dephasing of the oscillations occurs on a time scale of only a few fs, long before anymore » significant nuclear motion can occur. The results have been rationalized using a semi-quantitative model based upon the gradients of the potential energy surfaces.« less

Alkylarylnitrosoureas--stability in aqueous solution, partition coefficient, alkylating activity and its relationship to SCE induction in Chinese hamster V 79-E cells.

PubMed

Mendel, J; Thust, R; Schwarz, H

1982-01-01

The alkylating activity, chemical stability in aqueous solution (pH 7.0; 37 degrees C), and partition coefficient (octanol/water) of the following compounds were determined: 1-methyl-3-phenyl-1-nitrosourea (MPNU), 1-ethyl-3-phenyl-1-nitrosourea (EPNU), 1-isopropyl-3-phenyl-1-nitrosourea (i-PrPNU), 1-methyl-3-(p-fluorophenyl)-1-nitrosourea (F-MPNU), 1-methyl-3-(p-chlorophenyl)-1-nitrosourea (Cl-MPNU), 1-methyl-3-(p-bromophenyl)-1-nitrosourea (Br-MPNU), 1,3-dimethyl-3-phenyl-1-nitrosourea (DMPNU), and 1-methyl-3-naphthyl-1-nitrosocarbamate (NCA). 1-Methyl-1-nitrosourea (MNU) and 1-ethyl-1-nitrosourea (ENU) were used for the comparison. THe rate of decomposition in aqueous solution is discussed concerning the influences of the substituents at the 1- and 3-N-atom. The mono- and disubstituted N-nitrosoureas showed a coarse correlation between alkylating activity and SCE induction in Chinese hamster V 79-E cells. On the other hand, this correlation is missing in the case of NCA, which is a potent SCE inducer despite relatively low alkylating activity. DMPNU is the strongest SCE inducer, but this compound shows a high stability in aqueous solution and, consequently, we were not able to detect an alkylating activity.

2'-O-[2-[2-(N,N-Dimethylamino)ethoxy]ethyl] Modified Antisense Oligonucleotides: Symbiosis of Charge Interaction Factors and Stereoelectronic Effects

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

Prhavc, M.; Prakash, T.P.; Minasov, G.

Oligonucleotides with a novel, 2'-O-[2-[2-(N,N-dimethylamino)ethoxy]ethyl] (2'-O-DMAEOE) modification have been synthesized. This modification, a cationic analogue of the 2'-O-(2-methoxyethyl) (2'-O-MOE) modification, exhibits high binding affinity to target RNA (but not to DNA) and exceptional resistance to nuclease degradation. Analysis of the crystal structure of a self-complementary oligonucleotide containing a single 2'-O-DMAEOE modification explains the importance of charge factors and gauche effects on the observed antisense properties. 2'-O-DMAEOE modified oligonucleotides are ideal candidates for antisense drugs.

Rotational isomers of N-(β-phenylpropionyl)alanine ethyl dithioester: a Raman spectroscopic and MO study

NASA Astrophysics Data System (ADS)

Fausto, R.; Teixeira-Dias, J. J. C.; Tonge, P. J.; Carey, P. R.

1994-07-01

Raman spectra of N-(β-phenylpropionyl)alanine ethyl dithioester (C 6H 5CH 2CH 2C(O)NHCH(CH 3)C(S)SC 2H 5) in CCl 4 and CH 3CN solutions were measured as a function of temperature and the enthalpy differences (Δ H) between rotational isomers differing by internal rotation around the NHCH(CH 3) and CH(CH 3)C(S) bonds (forms A, B and C 5) were evaluated from relative band intensities. The spectroscopic results are consistent with a greater thermodynamical stability of the B-type conformer, where the N and S (thiol) atoms are in close contact. In addition, a comparison of the measured Δ H(A-B) for the present molecules with previously reported values for a series of similar glycine-based ethyl dithioesters shows that the presence of the extra CH 3 group at the α-carbon atom leads to a stabilization of the B-type conformer relative to the A-type form in the alanine-based dithioester. Semiempirical AM1 molecular orbital calculations were also performed on the title molecule and on its glycine analogue, N(β-phenylpropionyl)glycine ethyl dithioester. In general terms, the results of these calculations agree with the experimental findings, thus providing good theoretical support for the experimental data.

Determination of nitrosourea compounds in brain tissue by gas chromatography and electron capture detection.

PubMed

Hassenbusch, S J; Colvin, O M; Anderson, J H

1995-07-01

A relatively simple, high-sensitivity gas chromatographic assay is described for nitrosourea compounds, such as BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] and MeCCNU [1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea], in small biopsy samples of brain and other tissues. After extraction with ethyl acetate, secondary amines in BCNU and MeCCNU are derivatized with trifluoroacetic anhydride. Compounds are separated and quantitated by gas chromatography using a capillary column with temperature programming and an electron capture detector. Standard curves of BCNU indicate a coefficient of variance of 0.066 +/- 0.018, a correlation coefficient of 0.929, and an extraction efficiency from whole brain of 68% with a minimum detectable amount of 20 ng in 5-10 mg samples. The assay has been facile and sensitive in over 1000 brain biopsy specimens after intravenous and intraarterial infusions of BCNU.

Proline analogue of nitrosourea as a new cytotoxic prodrug.

PubMed

Stankiewicz-Kranc, Anna; Bielawska, Anna; Bielawski, Krzysztof; Skrzydlewska, Elzbieta

2009-11-01

Carmustine is frequently used as anticancer drug. High toxicity and low selectivity reduces the application of this drug. Though, there is a necessity to find new compounds characterized by similar therapeutic effects but a higher selectivity and safety. As a result, the proline analogue of nitrosourea, N-[N'-(2-bromophenyl)-N'-nitrosocarbamoyl]proline (AC), has been synthesized. The aim of this study was to compare the influence of carmustine and the proline analogue of nitrosourea on the antioxidant abilities of fibroblasts and leukemia cells, MOLT4. It was shown that carmustine as well as AC cause an increase in hydrogen peroxide concentration in normal and neoplastic cells. Incubation with both compounds led to a diminution of the activity of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and reductase. Changes in activity / level of antioxidant parameters were accompanied by augmentation of lipid and oxidative protein modifications. In conclusion, carmustine and AC cause changes in the antioxidative system of normal and MOLT4 cells and are a reason of oxidative stress formation.

Nitrosoureas: a review of experimental antitumor activity.

PubMed

Schabel, F M

1976-06-01

The chemical class of drugs known as the nitrosoureas are a recently developed group of very active alkylating-agent anticancer drugs which are best represented by BCNU, CCNU, and methyl-CCNU (meCCNU). The nitrosoureas are among the most active, if not the most active, anticancer drugs both quantitatively (log kill of sensitive tumor cells in vivo) and qualitatively (spectrum of mouse, rat, and hamster tumors responding to treatment). Therapeutic anticancer activity of the nitrosoureas has been consistently observed with oral as well as parenteral administration. The nitrosoureas are clearly the most active group of anticancer drugs observed against experimental meningeal leukemias and intracerebrally implanted transplantable primary tumors of central nervous system origin (eg, gliomas, ependymoblastomas, and astrocytomas in mice and hamsters). The nitrosoureas have been observed to be less than additive in lethal toxicity for vital normal cells in the mouse in combination with representatives of the other major classes of anticancer agents, eg, purine antagonists, pyrimidine antagonists, inhibitors of DNA polymerase(s) or ribonucleotide reductase(s), mitotic inhibitors, drugs that bind to or intercalate with DNA, and other alkylating agents. Therapeutic synergism against one or more transplantable or spontaneous tumors of mice, rats, or hamsters with one of several nitrosoureas in two-drug combinations with representatives of most of the major classes of anticancer agents listed above has been reported. With a number of advanced-stages mouse tumors, generally considered to be refractory to treatment with most anticancer agents, long-term cures have been obtained with combination-drug or combined-modality (surgery plus chemotherapy) treatment. The demonstrated lack of cross-resistance of several leukemias and solid tumors of mice selected for resistance to BCNU, meCCNU, or other alkylating agents suggests that the widely held opinion that all alkylating agents are

Nardilysin regulates inflammation, metaplasia, and tumors in murine stomach.

PubMed

Kimura, Yuto; Ikuta, Kozo; Kimura, Takeshi; Chiba, Tsutomu; Oshima, Hiroko; Oshima, Masanobu; Nishi, Eiichiro; Seno, Hiroshi

2017-02-23

Chronic inflammation contributes to a wide variety of human disorders. In the stomach, longstanding gastritis often results in structural alterations in the gastric mucosa, including metaplastic changes and gastric cancers. Therefore, it is important to elucidate factors that are involved in gastric inflammation. Nardilysin (N-arginine dibasic convertase; Nrdc) is a metalloendopeptidase of the M16 family that promotes ectodomain shedding of the precursor forms of various growth factors and cytokines by enhancing the protease activities of a disintegrin and metalloproteinase (ADAM) proteins. Here, we have demonstrated that Nrdc crucially regulates gastric inflammation caused by Helicobacter felis infection or forced expression of prostaglandin E 2 in K19-C2mE mice. Metaplastic changes following gastric inflammation were suppressed by the deletion of Nrdc. Furthremore, the deletion of Nrdc significantly suppressed N-methyl-N-nitrosourea (MNU)-induced gastric tumorigenesis in the murine stomach. These data may lead to a global therapeutic approach against various gastric disorders by targeting Nrdc.

Bromidotetra­kis­(1H-2-ethyl-5-methyl­imidazole-κN 3)copper(II) bromide

PubMed Central

Godlewska, Sylwia; Baranowska, Katarzyna; Socha, Joanna; Dołęga, Anna

2011-01-01

The CuII ion in the title compound, [CuBr(C6H10N2)4]Br, is coordinated in a square-based-pyramidal geometry by the N atoms of four imidazole ligands and a bromide anion in the apical site. Both the CuII and Br− atoms lie on a crystallographic fourfold axis. In the crystal, the [CuBr(C6H10N2)4]+ complex cations are linked to the uncoordinated Br− anions (site symmetry ) by N—H⋯Br hydrogen bonds, generating a three-dimensional network. The ethyl group of the imidazole ligand was modelled as disordered over two orientations with occupancies of 0.620 (8) and 0.380 (8). PMID:22199662

n-Ethyl Pentylone-Related Deaths in Alabama.

PubMed

Atherton, Daniel; Dye, Daniel; Robinson, C Andrew; Beck, Rachel

2018-05-16

n-Ethyl pentylone (NEP) is a chemical substance derived from cathinone. Synthetic cathinones are an evolving group of drugs with stimulating, mind-altering effects sometimes referred to as novel or new psychoactive substances (NPS). There is scarce information in the medical literature regarding forensic cases in which NEP is detected in toxicological testing. We present four fatalities involving NEP from Alabama in 2017. Deaths were attributed to NEP toxicity in two cases (peripheral blood concentrations of 0.121 and 0.953 mg/L) and injuries caused by gunshot wounds in two cases (peripheral blood concentrations of 0.045 and 0.031 mg/L). One case involving NEP described an individual who exhibited classic CNS-stimulant induced erratic behavior before being found dead. These cases enhance the forensic literature regarding specific NPS like NEP and provide contextual reference for professionals considering the significance of NEP in toxicological interpretation. © 2018 American Academy of Forensic Sciences.

Postischemic Treatment With Ethyl Pyruvate Prevents Adenosine Triphosphate Depletion, Ameliorates Inflammation, and Decreases Thrombosis in a Murine Model of Hind-Limb Ischemia and Reperfusion

PubMed Central

Crawford, Robert S.; Albadawi, Hassan; Atkins, Marvin D.; Jones, John J.; Conrad, Mark F.; Austen, William G.; Fink, Mitchell P.; Watkins, Michael T.

2011-01-01

Introduction Experiments were designed to investigate the effects of ethyl pyruvate (EP) in a murine model of hind-limb ischemia-reperfusion (IR) injury. Methods C57BL6 mice underwent 90 minutes of unilateral ischemia followed by 24 hours of reperfusion using two treatment protocols. For the preischemic treatment (pre-I) protocol, mice (n = 6) were given 300 mg/kg EP before ischemia, followed by 150 mg/kg of EP just before reperfusion and at 6 hours and 12 hours after reperfusion. In a postischemic treatment (post-I) protocol, mice (n = 7) were treated with 300 mg/kg EP at the end of the ischemic period, then 15 minutes later, and 2 hours after reperfusion and 150 mg/kg of EP at 4 hours, 6 hours, 10 hours, 16 hours, and 22 hours after reperfusion. Controls mice for both protocols were treated with lactated Ringers alone at time intervals identical to EP. Skeletal muscle levels of adenosine triphosphate (ATP), interleukin-1β, keratinocyte chemoattractant protein, and thrombin antithrombin-3 complex were measured. Skeletal muscle architectural integrity was assessed microscopically. Results ATP levels were higher in mice treated with EP compared with controls under the both treatment protocols (p = 0.02). Interleukin-1β, keratinocyte chemoattractant protein, thrombin antithrombin-3 complex (p < 0.05), and the percentage of injured fibers (p < 0.0001) were significantly decreased in treated versus control mice under the both protocols. Conclusion Muscle fiber injury and markers of tissue thrombosis and inflammation were reduced, and ATP was preserved with EP in pre-I and post-I protocols. Further investigation of the efficacy of EP to modulate IR injury in a larger animal model of IR injury is warranted. PMID:21217488

Biocatalytic Asymmetric Synthesis of (1R, 2S)-N-Boc-vinyl-ACCA Ethyl Ester with a Newly Isolated Sphingomonas aquatilis.

PubMed

Zhu, Shaozhou; Shi, Ying; Zhang, Xinyu; Zheng, Guojun

2018-02-01

1-amino cyclopropane-1-carboxylic acid (ACCA) and its derivatives are essential pharmacophoric unit that widely used in drug research and development. Specifically, (1R, 2S)-N-Boc-vinyl-ACCA ethyl ester (vinyl-ACCA) is a key chiral intermediate in the synthesis of highly potent hepatitis C virus (HCV) NS3/4A protease inhibitors such as asunaprevir and simeprevir. Developing strategies for the asymmetric synthesis of vinyl-ACCA is thus extremely high demand. In this study, 378 bacterial strains were isolated from soil samples using N-Boc-vinyl-ACCA ethyl ester as the sole carbon source and were screened for esterase activity. Fourteen of which worked effectively for the asymmetric synthesis of (1R, 2S)-N-Boc-1-vinyl ACCA ethyl ester. The strain CY-2, identified as Sphingomonas aquatilis, which showed the highest stability and enantioselectivity was selected as whole cell biocatalyst for further study. A systematic study of all factors influencing the enzymatic hydrolysis was performed. Under optimized conditions, resolution of rac-vinyl-ACCA to (1R, 2S)-N-Boc-1-vinyl ACCA ethyl ester with 88.2% ee and 62.4% conversion (E = 9) was achieved. Besides, S. aquatilis was also used to transform other 10 different substrates. Notably, it was found that 7 of them could be stereoselectively hydrolyzed, especially for (1R,2S)-1-amino-vinyl-ACCA ethyl ester hydrochloride (99.6% ee, E>200). Our investigations provide a new efficient whole cell biocatalyst for resolution of ACCA and might be developed for industry application.

N(4)C-ethyl-N(4)C cross-linked DNA: synthesis and characterization of duplexes with interstrand cross-links of different orientations.

PubMed

Noronha, Anne M; Noll, David M; Wilds, Christopher J; Miller, Paul S

2002-01-22

The preparation and physical properties of short DNA duplexes that contain a N(4)C-ethyl-N(4)C interstrand cross-link are described. Duplexes that contain an interstrand cross-link between mismatched C-C residues and duplexes in which the C residues of a -CG- or -GC- step are linked to give "staggered" interstrand cross-links were prepared using a novel N(4)C-ethyl-N(4)C phosphoramidite reagent. Duplexes with the C-C mismatch cross-link have UV thermal transition temperatures that are 25 degrees C higher than the melting temperatures of control duplexes in which the cross-link is replaced with a G-C base pair. It appears that this cross-link stabilizes adjacent base pairs and does not perturb the structure of the helix, a conclusion that is supported by the CD spectrum of this duplex and by molecular models. An even higher level of stabilization, 49 degrees C, is seen with the duplex that contains a -CG- staggered cross-link. Molecular models suggest that this cross-link may induce propeller twisting in the cross-linked base pairs, and the CD spectrum of this duplex exhibits an unusual negative band at 298 nm, although the remainder of the spectrum is similar to that of B-form DNA. Mismatched C-C or -CG- staggered cross-linked duplexes that have complementary overhanging ends can undergo self-ligation catalyzed by T4 DNA ligase. Analysis of the ligated oligomers by nondenaturing polyacrylamide gel electrophoresis shows that the resulting oligomers migrate in a manner similar to that of a mixture of non-cross-linked control oligomers and suggests that these cross-links do not result in significant bending of the helix. However, the orientation of the staggered cross-link can have a significant effect on the structure and stability of the cross-linked duplex. Thus, the thermal stability of the duplex that contains a -GC- staggered cross-link is 10 degrees C lower than the melting temperature of the control, non-cross-linked duplex. Unlike the -CG- staggered cross

2-chloroethanol formation as evidence for a 2-chloroethyl alkylating intermediate during chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea.

PubMed

Reed, D J; May, H E; Boose, R B; Gregory, K M; Beilstein, M A

1975-03-01

Chemical degradation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea or 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea in buffer under physiological conditions resulted in the formation of a significant quantity of 2-chlorethanol (18 to 25% of the initial nitrosourea concentration). Other degradation products observed included acetaldehyde (5 to 10%), vinyl chloride (1 to 2%), ethylene (1 to 2%), and cyclohexylamine (32%), but not 1,3-dicyclohexylurea. The 2-chlorethyl moiety of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea was trapped with halide ions, CI-, BR-, and I-, to form the corresponding dihaloethanes which were identified by gas chromatography-mass spectrometry techniques. High-pressure liquid chromatographic procedures were developed for the separation and quantiation of the nitrosoureas and many of their degradation products. It is postulated that a new mode of 1(2-chloreoethyl)-3-cyclohexyl-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea degradation can occur that is not the loss of the chloro group as chloride ion, but the loss of the N-3 hydrogen as a proton. Then the corresponding isocyanate and 2-chloroethyidiazene hydroxide are formed, with the latter intermidiate becoming an alkylating species, possibly in part as a 2-chloroethyl carbonium ion.

Heat capacities and thermal diffusivities of n-alkane acid ethyl esters—biodiesel fuel components

NASA Astrophysics Data System (ADS)

Bogatishcheva, N. S.; Faizullin, M. Z.; Nikitin, E. D.

2017-09-01

The heat capacities and thermal diffusivities of ethyl esters of liquid n-alkane acids C n H2 n-1O2C2H5 with the number of carbon atoms in the parent acid n = 10, 11, 12, 14, and 16 are measured. The heat capacities are measured using a DSC 204 F1 Phoenix heat flux differential scanning calorimeter (Netzsch, Germany) in the temperature range of 305-375 K. Thermal diffusivities are measured by means of laser flash method on an LFA-457 instrument (Netzsch, Germany) at temperatures of 305-400 K. An equation is derived for the dependence of the molar heat capacities of the investigated esters on temperature. It is shown that the dependence of molar heat capacity C p,m (298.15 K) on n ( n = 1-6) is close to linear. The dependence of thermal diffusivity on temperature in the investigated temperature range is described by a first-degree polynomial, but thermal diffusivity a (298.15 K) as a function of n has a minimum at n = 5.

Protective effect of zinc on N-methyl-N-nitrosourea and testosterone-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley rats.

PubMed

Banudevi, Sivanantham; Elumalai, Perumal; Sharmila, Govindaraj; Arunkumar, Ramachandran; Senthilkumar, Kalimuthu; Arunakaran, Jagadeesan

2011-09-01

Previous studies have suggested that zinc exerts anticarcinogenic and antiproliferative effects against prostate cancer both in vitro and in rat ventral prostate. Zinc accumulation diminishes early in the course of prostate malignancy and it inhibits the growth of several carcinoma cells through induction of cell cycle arrest and apoptosis. In this study, we have investigated the influence of zinc on N-methyl-N-nitrosourea (MNU) and testosterone (T)-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley (SD) rats. The results indicate that zinc plays an important role in prostate carcinogenesis. Increased tumor incidence was accompanied by a decrease in prostatic acid phosphatase activity, citrate, zinc, glutathione-S-transferase, reduced glutathione, p53, B-cell lymphoma protein (Bcl-2)-associated X protein and caspase-3 levels in MNU + T-treated rats. On the contrary, significantly increased phase I drug metabolizing enzyme activities, lipid peroxide, hydrogen peroxide, proliferating cell nuclear antigen, Bcl-2 and Bcl-X(L) protein levels were observed in the dorsolateral prostate of MNU + T-treated rats. Simultaneous zinc supplementation significantly reversed these effects in MNU + T-treated rats. Signs of dysplasia, a characteristic of prostatic intraepithelial neoplasia, were evident in the dorsolateral prostatic tissue sections by MNU + T administration. However, zinc supplementation has reversed these effects in the dorsolateral prostatic histoarchitecture. These results suggest that zinc may act as an essential trace element against MNU and testosterone-induced prostatic preneoplastic progression in SD rats.

DFT investigations of phosphotriesters hydrolysis in aqueous solution: a model for DNA single strand scission induced by N-nitrosoureas.

PubMed

Liu, Tingting; Zhao, Lijiao; Zhong, Rugang

2013-02-01

DNA phosphotriester adducts are common alkylation products of DNA phosphodiester moiety induced by N-nitrosoureas. The 2-hydroxyethyl phosphotriester was reported to hydrolyze more rapidly than other alkyl phosphotriesters both in neutral and in alkaline conditions, which can cause DNA single strand scission. In this work, DFT calculations have been employed to map out the four lowest activation free-energy profiles for neutral and alkaline hydrolysis of triethyl phosphate (TEP) and diethyl 2-hydroxyethyl phosphate (DEHEP). All the hydrolysis pathways were illuminated to be stepwise involving an acyclic or cyclic phosphorane intermediate for TEP or DEHEP, respectively. The rate-limiting step for all the hydrolysis reactions was found to be the formation of phosphorane intermediate, with the exception of DEHEP hydrolysis in alkaline conditions that the decomposition process turned out to be the rate-limiting step, owing to the extraordinary low formation barrier of cyclic phosphorane intermediate catalyzed by hydroxide. The rate-limiting barriers obtained for the four reactions are all consistent with the available experimental information concerning the corresponding hydrolysis reactions of phosphotriesters. Our calculations performed on the phosphate triesters hydrolysis predict that the lower formation barriers of cyclic phosphorane intermediates compared to its acyclic counter-part should be the dominant factor governing the hydrolysis rate enhancement of DEHEP relative to TEP both in neutral and in alkaline conditions.

Synergism between microwave irradiation and enzyme catalysis in transesterification of ethyl-3-phenylpropanoate with n-butanol.

PubMed

Yadav, Ganapati D; Pawar, Sandip V

2012-04-01

Lipase catalyzed transesterification was investigated to study the synergistic effect of microwave irradiation and enzyme catalysis. Transesterification of ethyl-3-phenylpropanoate with n-butanol was chosen as the model reaction using immobilized enzymes such as Novozyme 435, Lipozyme RMIM and Lipozyme TL IM with microwave irradiation. Novozyme 435 was the best catalyst. The effect of various parameters affecting the conversion and initial rates of transesterification were studied to establish kinetics and mechanism. There is synergism between enzyme catalysis and microwave irradiation. The analysis of initial rate data and progress curve data showed that the reaction obeys the Ping-Pong bi-bi mechanism with inhibition by n-butanol. The theoretical predictions and experimental data match very well. These studies were also extended to other alcohols such as 2-phenyl-1-propanol, n-octanol, benzyl alcohol, iso-amyl alcohol, 2-hexanol and 2-pentanol under otherwise similar conditions. Copyright © 2012. Published by Elsevier Ltd.

Postnatal exposure to N-ethyl-N-nitrosurea disrupts the subventricular zone in adult rodents.

PubMed

Capilla-Gonzalez, V; Gil-Perotin, S; Garcia-Verdugo, J M

2010-12-01

N-ethyl-N-nitrosurea (ENU), a type of N-nitrous compound (NOC), has been used as inductor for brain tumours due to its mutagenic effect on the rodent embryo. ENU also affected adult neurogenesis when administered during pregnancy. However, no studies have investigated the effect of ENU when exposured during adulthood. For this purpose, three experimental groups of adult mice were injected with ENU at different doses and killed shortly after exposure. When administered in adult mice, ENU did not form brain tumours but led to a disruption of the subventricular zone (SVZ), an adult neurogenic region. Analyses of the samples revealed a reduction in the numbers of neural progenitors compared with control animals, and morphological changes in ependymal cells. A significant decrease in proliferation was tested in vivo with 5-bromo-2-deoxyuridine administration and confirmed in vitro with a neurosphere assay. Cell death, assessed as active-caspase-3 reactivity, was more prominent in treated animals and cell death-related populations increased in parallel. Two additional groups were maintained for 45 and 120 days after five doses of ENU to study the potential regeneration of the SVZ, but only partial recovery was detected. In conclusion, exposure to ENU alters the organization of the SVZ and causes partial exhaustion of the neurogenic niche. The functional repercussion of these changes remains unknown, but exposure to NOCs implies a potential risk that needs further evaluation. © 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)-Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview.

PubMed

Tsikas, Dimitrios; Schwedhelm, Kathrin S; Surdacki, Andrzej; Giustarini, Daniela; Rossi, Ranieri; Kukoc-Modun, Lea; Kedia, George; Ückert, Stefan

2018-02-01

S -Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation (NO + ) and a thiolate (RS - ), the base of the corresponding acids RSH. The smallest S -nitrosothiol is HSNO and derives from hydrogen sulfide (HSH, H 2 S). The most common physiological S -nitrosothiols are derived from the amino acid L-cysteine (CysSH). Thus, the simplest S -nitrosothiol is S -nitroso-L-cysteine (CysSNO). CysSNO is a spontaneous potent donor of nitric oxide (NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate (cGMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation. Like NO, CysSNO is a short-lived species and occurs physiologically at concentrations around 1 nM in human blood. CysSNO can be formed from CysSH and higher oxides of NO including nitrous acid (HONO) and its anhydride (N 2 O 3 ). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NO + group is reversibly transferred to another thiolate. By this way numerous RSNO can be formed such as the low-molecular-mass S -nitroso- N -acetyl-L-cysteine (SNAC) and S -nitroso-glutathione (GSNO), and the high-molecular-mass S -nitrosol-L-cysteine hemoglobin (HbCysSNO) present in erythrocytes and S -nitrosol-L-cysteine albumin (AlbCysSNO) present in plasma at concentrations of the order of 200 nM. All above mentioned RSNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free RSNO. Thus, we prepared the ethyl ester of SNAC, the S -nitroso- N -acetyl-L-cysteine ethyl ester (SNACET), from synthetic N -acetyl-L-cysteine ethyl ester (NACET). Both NACET and SNACET have improved pharmacological features over N -acetyl-L-cysteine (NAC) and S -nitroso- N -acetyl-L-cysteine (SNAC), respectively, including higher oral bioavailability. SNACET

Quantification of four major metabolites of embryotoxic N-methyl- and N-ethyl-2-pyrrolidone in human urine by cooled-injection gas chromatography and isotope dilution mass spectrometry.

PubMed

Schindler, Birgit K; Koslitz, Stephan; Meier, Swetlana; Belov, Vladimir N; Koch, Holger M; Weiss, Tobias; Brüning, Thomas; Käfferlein, Heiko U

2012-04-17

N-Methyl- and N-ethyl-2-pyrollidone (NMP and NEP) are frequently used industrial solvents and were shown to be embryotoxic in animal experiments. We developed a sensitive, specific, and robust analytical method based on cooled-injection (CIS) gas chromatography and isotope dilution mass spectrometry to analyze 5-hydroxy-N-ethyl-2-pyrrolidone (5-HNEP) and 2-hydroxy-N-ethylsuccinimide (2-HESI), two newly identified presumed metabolites of NEP, and their corresponding methyl counterparts (5-HNMP, 2-HMSI) in human urine. The urine was spiked with deuterium-labeled analogues of these metabolites. The analytes were separated from urinary matrix by solid-phase extraction and silylated prior to quantification. Validation of this method was carried out by using both, spiked pooled urine samples and urine samples from 56 individuals of the general population with no known occupational exposure to NMP and NEP. Interday and intraday imprecision was better than 8% for all metabolites, while the limits of detection were between 5 and 20 μg/L depending on the analyte. The high sensitivity of the method enables us to quantify NMP and NEP metabolites at current environmental exposures by human biomonitoring.

Development of thermosensitive poly(n-isopropylacrylamide-co-((2-dimethylamino) ethyl methacrylate))-based nanoparticles for controlled drug release

NASA Astrophysics Data System (ADS)

Peng, Cheng-Liang; Tsai, Han-Min; Yang, Shu-Jyuan; Luo, Tsai-Yueh; Lin, Chia-Fu; Lin, Wuu-Jyh; Shieh, Ming-Jium

2011-07-01

Thermosensitive nanoparticles based on poly(N-isopropylacrylamide-co-((2-dimethylamino)ethylmethacrylate)) (poly(NIPA-co-DMAEMA)) copolymers were successfully fabricated by free radical polymerization. The lower critical solution temperature (LCST) of the synthesized nanoparticles was 41 °C and a temperature above which would cause the nanoparticles to undergo a volume phase transition from 140 to 100 nm, which could result in the expulsion of encapsulated drugs. Therefore, we used the poly(NIPA-co-DMAEMA) nanoparticles as a carrier for the controlled release of a hydrophobic anticancer agent, 7-ethyl-10-hydroxy-camptothecin (SN-38). The encapsulation efficiency and loading content of SN-38-loaded nanoparticles at an SN-38/poly(NIPA-co-DMAEMA) ratio of 1/10 (D/P = 1/10) were about 80% and 6.293%, respectively. Moreover, the release profile of SN-38-loaded nanoparticles revealed that the release rate at 42 °C (above LCST) was higher than that at 37 °C (below LCST), which demonstrated that the release of SN-38 could be controlled by increasing the temperature. The cytotoxicity of the SN-38-loaded poly(NIPA-co-DMAEMA) nanoparticles was investigated in human colon cancer cells (HT-29) to compare with the treatment of an anticancer drug, Irinotecan® (CPT-11). The antitumor efficacy evaluated in a C26 murine colon tumor model showed that the SN-38-loaded nanoparticles in combination with hyperthermia therapy efficiently suppressed tumor growth. The results indicate that these thermo-responsive nanoparticles are potential carriers for controlled drug delivery.

Photodynamic Therapy of the Murine LM3 Tumor Using Meso-Tetra (4-N,N,N-Trimethylanilinium) Porphine.

PubMed

Colombo, L L; Juarranz, A; Cañete, M; Villanueva, A; Stockert, J C

2007-12-01

Photodynamic therapy (PDT) of cancer is based on the cytotoxicity induced by a photosensitizer in the presence of oxygen and visible light, resulting in cell death and tumor regression. This work describes the response of the murine LM3 tumor to PDT using meso-tetra (4-N,N,N-trimethylanilinium) porphine (TMAP). BALB/c mice with intradermal LM3 tumors were subjected to intravenous injection of TMAP (4 mg/kg) followed 24 h later by blue-red light irradiation (λmax: 419, 457, 650 nm) for 60 min (total dose: 290 J/cm(2)) on depilated and glycerol-covered skin over the tumor of anesthetized animals. Control (drug alone, light alone) and PDT treatments (drug + light) were performed once and repeated 48 h later. No significant differences were found between untreated tumors and tumors only treated with TMAP or light. PDT-treated tumors showed almost total but transitory tumor regression (from 3 mm to less than 1 mm) in 8/9 animals, whereas no regression was found in 1/9. PDT response was heterogeneous and each tumor showed different regression and growth delay. The survival of PDT-treated animals was significantly higher than that of TMAP and light controls, showing a lower number of lung metastasis but increased tumor-draining lymph node metastasis. Repeated treatment and reduction of tissue light scattering by glycerol could be useful approaches in studies on PDT of cancer.

Photodynamic Therapy of the Murine LM3 Tumor Using Meso-Tetra (4-N,N,N-Trimethylanilinium) Porphine

PubMed Central

Colombo, L. L.; Juarranz, A.; Cañete, M.; Villanueva, A.; Stockert, J. C.

2007-01-01

Photodynamic therapy (PDT) of cancer is based on the cytotoxicity induced by a photosensitizer in the presence of oxygen and visible light, resulting in cell death and tumor regression. This work describes the response of the murine LM3 tumor to PDT using meso-tetra (4-N,N,N-trimethylanilinium) porphine (TMAP). BALB/c mice with intradermal LM3 tumors were subjected to intravenous injection of TMAP (4 mg/kg) followed 24 h later by blue-red light irradiation (λmax: 419, 457, 650 nm) for 60 min (total dose: 290 J/cm2) on depilated and glycerol-covered skin over the tumor of anesthetized animals. Control (drug alone, light alone) and PDT treatments (drug + light) were performed once and repeated 48 h later. No significant differences were found between untreated tumors and tumors only treated with TMAP or light. PDT-treated tumors showed almost total but transitory tumor regression (from 3 mm to less than 1 mm) in 8/9 animals, whereas no regression was found in 1/9. PDT response was heterogeneous and each tumor showed different regression and growth delay. The survival of PDT-treated animals was significantly higher than that of TMAP and light controls, showing a lower number of lung metastasis but increased tumor-draining lymph node metastasis. Repeated treatment and reduction of tissue light scattering by glycerol could be useful approaches in studies on PDT of cancer. PMID:23675051

New method to measure the carbamoylating activity of nitrosoureas by electron paramagnetic resonance spectroscopy.

PubMed

Gadzheva, V; Ichimori, K; Raikov, Z; Nakazawa, H

1997-08-01

A new method for measuring the carbamoylating activity of nitrosoureas and isocyanates using electron paramagnetic resonance (EPR) spectroscopy is described. The extent and time course of carbamoylation reaction of chloroethyl isocyanate and a series of 9 nitrosoureas toward amino group of 4-amino-2,2,6,6-tetramethyl-piperidine-1-oxyl were examined with both the EPR method and the HPLC method which has been proposed by Brubaker et al. [Biochem. Pharmacol. 35:2359 (1986)]. Spin-labeled nitrosoureas we synthesized are included in this study since they have less toxicity or more efficiency than commercially available drug in some cases. The concentration of carbamoylated product was easily determined with the EPR spectra. There is a very high correlation (r = 0.982, t = 2.58, N = 10, p < 0.001) between the EPR and HPLC methods. Spin-labeled nitrosoureas showed lower carbamoylating activity than non-labeled analogues. The carbamoylating activity for these nitrosourea depended on the reactivity of isocyanate intermediate and almost independent of their half life. This rapid and simple EPR method is suitable for the detailed investigation of the rate and extent of carbamoylation reaction.

Analysis of the expression level and methylation of tumor protein p53, phosphatase and tensin homolog and mutS homolog 2 in N-methyl-N-nitrosourea-induced thymic lymphoma in C57BL/6 mice.

PubMed

Huo, Xueyun; Li, Zhenkun; Zhang, Shuangyue; Li, Changlong; Guo, Meng; Lu, Jing; Lv, Jianyi; Du, Xiaoyan; Chen, Zhenwen

2017-10-01

Tumorigenesis is often caused by somatic mutation or epigenetic changes in genes that regulate aspects of cell death, proliferation and survival. Although the functions of multiple tumor suppressor genes have been well studied in isolation, how these genes cooperate during the progression of a single tumor remains unclear in numerous cases. The present study used N-methyl-N-nitrosourea (MNU), one of the most potent mutagenic nitrosourea compounds, to induce thymic lymphoma in C57BL/6J mice. Subsequently, the protein expression levels of phosphatase and tensin homolog (PTEN), transformation protein 53 and mutS homolog 2 (MSH2) were evaluated concomitantly in the thymus, liver, kidney and spleen of MNU-treated mice by western blotting. To determine whether changes in expression level were due to aberrant epigenetic regulation, the present study further examined the methylation status of each gene by MassARRAY analysis. During the tumorigenesis process of an MNU-induced single thymic lymphoma, the expression level of PTEN was revealed to be reduced in thymic lymphoma samples but not in normal or non-tumor thymus tissue samples. Furthermore, a marked reduction of P53 expression levels were demonstrated in thymic lymphomas and spleens with a metastatic tumor. Conversely, MSH2 upregulation was identified only in liver, kidney, and spleen samples that were infiltrated by thymic lymphoma cells. Furthermore, the present study revealed that a number of 5'-C-phosphate-G-3' sites located in the promoter of aberrantly expressed genes had significantly altered methylation statuses. These results improve the understanding of the course of mutagen-induced cancer, and highlight that epigenetic regulation may serve an important function in cancer.

Quantification of residual EDU (N-ethyl-N'-(dimethylaminopropyl) carbodiimide (EDC) hydrolyzed urea derivative) and other residual by LC-MS/MS.

PubMed

Lei, Q Paula; Lamb, David H; Shannon, Anthony G; Cai, Xinxing; Heller, Ronald K; Huang, Michael; Zablackis, Earl; Ryall, Robert; Cash, Patricia

2004-12-25

An LC-MS/MS method for determination of the break down product of N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide (EDC) urea derivative, EDU, has been developed and validated for monitoring the residual coupling reagents. Results indicate that the method exhibits suitable specificity, sensitivity, precision, linearity and accuracy for quantification of residual EDU in the presence of meningococcal polysaccharide-diphtheria toxoid conjugate vaccine and other vaccine matrix compounds. The assay has been validated for a detection range of 10-100 ng/mL and then successfully transferred to quality control (QC) lab. This same method has also been applied to the determination of residual diaminohexane (DAH) in the presence of EDU. LC-MS/MS has proven to be useful as a quick and sensitive approach for simultaneous determination of multiple residual compounds in glycoconjugate vaccine samples.

Investigations into the Immunotoxicity and Allergic Potential Induced by Topical Application of N-Butylbenzenesulfonamide (NBBS) in a Murine Model

PubMed Central

Marrocco, Antonella; Meade, B. Jean; Long, Carrie M.; Lukomska, Ewa; Marshall, Nikki B.; Anderson, Stacey E.

2015-01-01

N-Butylbenzene sulfonamide (NBBS) is a commonly used plasticizer found in numerous products. Due to its extensive use, lack of adequate toxicological data, and suspicion of toxicity based on the presence of structural alerts, it was nominated to the National Toxicology Program for comprehensive toxicological testing. The purpose of this study was to evaluate the potential for hypersensitivity and immune suppression following dermal exposure to NBBS using a murine model. NBBS tested negative in a combined irritancy/local lymph node assay (LLNA), classifying it as nonirritating and nonsensitizing. To estimate the immunosuppressive potential of NBBS, assays that assessed immunotoxicity were performed, including the immumnoglobulin (Ig) M response to T-cell-dependent antigen sheep red blood cells (SRBC), using the plaque-forming cell (PFC) assay and immune cell phenotyping. After a 28-d treatment with NBBS, mice exposed to the lowest concentration (25% NBBS) showed a significant increase in IgM-producing B cells in the spleen. No marked changes were identified in immune cell markers in the lymph node. In contrast to body weight, a significant elevation in kidney and liver weight was observed following dermal exposure to all concentrations of NBBS. These results demonstrate that dermal exposure to NBBS, other than liver and kidney toxicity, did not apparently induce immunotoxicity in a murine model. PMID:26291892

Spectrophotometric Determination of Nitrogen Oxides in the Air with 2-N-Ethyl-5-Naphthol-7-Sulfonic Acid

NASA Astrophysics Data System (ADS)

Huang, Y.; Shi, W.; Zhang, C.; Wen, H.

2017-09-01

For the determination of nitrogen oxides in the air, the structure of diazo and coupling compounds was studied and tested by experiments. The conditions and methods of diazo and coupling reactions were investigated. Furthermore, a spectrophotometric method using sulfanilamide as a diazo compound and 2-N-ethyl-5-naphthol-7-sulfonic acid (N-ethyl J acid) as a coupling compound was proposed. The maximum absorption wavelength of sulfanilamide-Nethyl J acid azo compound was at 478 nm. The molar absorptivity was 4.31 × 104 L/(mol × cm) with a recovery of 98.7-100.9% and RSD of 1.85%. For nitrogen oxides, the determinate limit of this measurement was 0.015 mg/m3 and the determinate range 0.024-2.0 mg/m3. Moreover, a high degree of correlation was observed between the results obtained by the proposed method and the standard methods. The proposed method can be easily applied to determine nitrogen oxides in the air.

Spin labelled nitrosoureas and triazenes and their non-labelled clinically used analogues--a comparative study on their physicochemical properties and antimelanomic effects.

PubMed

Zheleva, A M; Gadjeva, V G

2001-01-16

Physicochemical properties, such as half life time (tau0.5), alkylating and carbamoylating activity and in vivo antimelanomic effects against B16 melanoma of spin labeled (containing nitroxyl free radical moiety) amino acid nitrosoureas, synthesized in our laboratory, have been studied and compared to those of the antitumor drug N'-cyclohexyl-N-(2-chloroethyl)-N-nitrosourea (lomustine, CCNU). We have shown that the introduction of amino acid moieties and the replacement of cyclohexylamine with nitroxyl moiety leads to a faster decomposition, higher alkylating, lower carbamoylating activity, better antimelanomic activity and lower general toxicity, when compared to those of CCNU. It was also established that spin labeled triazenes, previously synthesized by us, were more stable in phosphate saline than their nonlabeled analogue, 5-(3,3-dimethyltriazene-1-yl)-imidazole-4-carboxamide (dacarbazine, DTIC). A higher cytotoxicity to B16 melanoma cells than to YAC-1 and lymphocytes was demonstrated for all spin labeled triazenes, in comparison with DTIC. An assumption has been made to explain the lower general toxicity of the spin labeled nitrosoureas compared to that of CCNU. Based on the results presented, we accept that a new trend for synthesis of more selective and less toxic nitrosourea and triazene derivatives as potential antimelanomic drugs might be developed.

Genome-wide allelotyping of a new in vitro model system reveals early events in breast cancer progression.

PubMed

Li, Zheng; Meng, Zhen Hang; Sayeed, Aejaz; Shalaby, Refaat; Ljung, Britt-Marie; Dairkee, Shanaz H

2002-10-15

Toward the goal of identifying early genetic losses, which mediate the release of human breast epithelium from replicative suppression leading to cellular immortalization, we have used a newly developed in vitro model system. This system consists of epithelial cultures derived from noncancerous breast tissue, treated with the chemical carcinogen N-ethyl-N-nitrosourea, and continuously passaged to yield cell populations culminating in the immortal phenotype. Genome-wide allelotyping of early passage N-ethyl-N-nitrosourea-exposed cell populations revealed aberrations at >10% (18 of 169) loci examined. Allelic losses encompassing chromosomes 6q24-6q27, implicating immortalization-associated candidate genes, hZAC and SEN6, occurred in two independently derived cell lines before the Hayflick limit. Additional LOH sites were present in one cell line at 3p11-3p26, 11p15, and 20p12-13. Allelic losses reported in this cell line preceded detectable levels of telomerase activity and the occurrence of p53-related aberrations. Information gained from the search for early immortalization-associated genetic deletions in cultured cells was applied in a novel approach toward the analysis of morphologically normal terminal ductal lobular units microdissected from 20 cases of ductal carcinoma in situ. Notably, clonal allelic losses at chromosome 3p24 and 6q24 were an early occurrence in adjoining terminal ductal lobular units of a proportion of primary tumors, which displayed loss of heterozygosity (3 of 11 and 3 of 6, respectively). The biological insights provided by the new model system reported here strongly suggest that early allelic losses delineated in immortalized cultures and validated in vivo could serve as surrogate endpoints to assist in the identification and intervention of high-risk benign breast tissue, which sustains the potential for continuous proliferation.

Subacute exposure to N-ethyl perfluorooctanesulfonamidoethanol results in the formation of perfluorooctanesulfonate and alters superoxide dismutase activity in female rats.

PubMed

Xie, Wei; Wu, Qian; Kania-Korwel, Izabela; Tharappel, Job C; Telu, Sanjay; Coleman, Mitchell C; Glauert, Howard P; Kannan, Kurunthachalam; Mariappan, S V S; Spitz, Douglas R; Weydert, Jamie; Lehmler, Hans-Joachim

2009-10-01

Perfluorooctanesulfonamides, such as N-ethyl perfluorooctanesulfonamidoethanol (N-EtFOSE), are large scale industrial chemicals but their disposition and toxicity are poorly understood despite significant human exposure. The hypothesis that subacute exposure to N-EtFOSE, a weak peroxisome proliferator, causes a redox imbalance in vivo was tested using the known peroxisome proliferator, ciprofibrate, as a positive control. Female Sprague-Dawley rats were treated orally with N-EtFOSE, ciprofibrate or corn oil (vehicle) for 21 days, and levels of N-EtFOSE and its metabolites as well as markers of peroxisome proliferation and oxidative stress were assessed in serum, liver and/or uterus. The N-EtFOSE metabolite profile in liver and serum was in good agreement with reported in vitro biotransformation pathways in rats and the metabolite levels decreasing in the order perfluorooctanesulfonate > perfluorooctanesulfonamide ~ N-ethyl perfluorooctanesulfonamidoacetate > perfluorooctanesulfonamidoethanol approximately N-EtFOSE. Although N-EtFOSE treatment significantly decreased the growth rate, increased relative liver weight and activity of superoxide dismutases (SOD) in liver and uterus (total SOD, CuZnSOD and MnSOD), a metabolic study revealed no differences in the metabolome in serum from N-EtFOSE-treated and control animals. Ciprofibrate treatment increased liver weight and peroxisomal acyl Co-A oxidase activity in the liver and altered antioxidant enzyme activities in the uterus and liver. According to NMR metabolomic studies, ciprofibrate treated animals had altered serum lipid profiles compared to N-EtFOSE-treated and control animals, whereas putative markers of peroxisome proliferation in serum were not affected. Overall, this study demonstrates the biotransformation of N-EtFOSE to PFOS in rats that is accompanied by N-EtFOSE-induced alterations in antioxidant enzyme activity.

Modeling the Conformation-Specific Infrared Spectra of N-Alkylbenzenes

NASA Astrophysics Data System (ADS)

Tabor, Daniel P.; Sibert, Edwin; Hewett, Daniel M.; Korn, Joseph A.; Zwier, Timothy S.

2016-06-01

Conformation-specific UV-IR double resonance spectra are presented for n-alkylbenzenes. With the aid of a local mode Hamiltonian that includes the effects of stretch-bend Fermi coupling, the spectra of ethyl, n-propyl, and n-butylbenzene are assigned to individual conformers. These molecules allow for further development of the work on a first principles method for calculating alkyl stretch spectra. Due to the consistency of the anharmonic couplings from conformer to conformer, construction of the model Hamiltonian for a given conformer only requires a harmonic frequency calculation at the conformer's minimum geometry as an input. The model Hamiltonian can be parameterized with either density functional theory or MP2 electronic structure calculations. The relative strengths and weaknesses of these methods are evaluated, including their predictions of the relative energetics of the conformers. Finally, the IR spectra for conformers that have the alkyl chain bend back and interact with the π cloud of the benzene ring are modeled.

N-acetylglucosamine increases symptoms and fungal burden in a murine model of oral candidiasis.

PubMed

Ishijima, Sanae A; Hayama, Kazumi; Takahashi, Miki; Holmes, Ann R; Cannon, Richard D; Abe, Shigeru

2012-04-01

The amino sugar N-acetylglucosamine (GlcNAc) is an in vitro inducer of the hyphal mode of growth of the opportunistic pathogen Candida albicans. The development of hyphae by C. albicans is considered to contribute to the pathogenesis of mucosal oral candidiasis. GlcNAc is also a commonly used nutritional supplement for the self-treatment of conditions such as arthritis. To date, no study has investigated whether ingestion of GlcNAc has an effect on the in vivo growth of C. albicans or the pathogenesis of a C. albicans infection. Using a murine model of oral candidiasis, we have found that administration of GlcNAc, but not glucose, increased oral symptoms of candidiasis and fungal burden. Groups of mice were given GlcNAc in either water or in a viscous carrier, i.e., 1% methylcellulose. There was a dose-dependent relationship between GlcNAc concentration and the severity of oral symptoms. Mice given the highest dose of GlcNAc, 45.2 mM, also showed a significant increase in fungal burden, and increased histological evidence of infection compared to controls given water alone. We propose that ingestion of GlcNAc, as a nutritional supplement, may have an impact on oral health in people susceptible to oral candidiasis.

The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent.

PubMed

Nathan, Pradeep J; Lu, Kristy; Gray, M; Oliver, C

2006-01-01

L-theanine (N-ethyl-L-glutamine) or theanine is a major amino acid uniquely found in green tea. L-theanine has been historically reported as a relaxing agent, prompting scientific research on its pharmacology. Animal neurochemistry studies suggest that L-theanine increases brain serotonin, dopamine, GABA levels and has micromolar affinities for AMPA, Kainate and NMDA receptors. In addition has been shown to exert neuroprotective effects in animal models possibly through its antagonistic effects on group 1 metabotrophic glutamate receptors. Behavioural studies in animals suggest improvement in learning and memory. Overall, L-theanine displays a neuropharmacology suggestive of a possible neuroprotective and cognitive enhancing agent and warrants further investigation in animals and humans.

Subacute Exposure to N-Ethyl Perfluorooctanesulfonamidoethanol Results in the Formation of Perfluorooctanesulfonate and Alters Superoxide Dismutase Activity in Female Rats

PubMed Central

Xie, Wei; Wu, Qian; Kania-Korwel, Izabela; Tharappel, Job C.; Telu, Sanjay; Coleman, Mitchell C.; Glauert, Howard P.; Kannan, Kurunthachalam; Santhana Mariappan, S. V.; Spitz, Douglas R.; Weydert, Jamie; Lehmler, Hans-Joachim

2009-01-01

Perfluorooctanesulfonamides, such as N-ethyl perfluorooctanesulfonamidoethanol (N-EtFOSE), are large scale industrial chemicals but their disposition and toxicity are poorly understood despite significant human exposure. The hypothesis that subacute exposure to N-EtFOSE, a weak peroxisome proliferator, causes a redox imbalance in vivo was tested using the known peroxisome proliferator, ciprofibrate, as a positive control. Female Sprague-Dawley rats were treated orally with N-EtFOSE, ciprofibrate or corn oil (vehicle) for 21 days, and levels of N-EtFOSE and its metabolites as well as markers of peroxisome proliferation and oxidative stress were assessed in serum, liver and/or uterus. The N-EtFOSE metabolite profile in liver and serum was in good agreement with reported in vitro biotransformation pathways in rats and the metabolite levels decreasing in the order perfluorooctanesulfonate ≫ perfluorooctanesulfonamide ∼ N-ethyl perfluorooctanesulfonamidoacetate ≫ perfluorooctanesulfonamidoethanol ∼ N-EtFOSE. Although N-EtFOSE treatment significantly decreased the growth rate, increased relative liver weight and activity of superoxide dismutases (SOD) in liver and uterus (total SOD, CuZnSOD and MnSOD), a metabolic study revealed no differences in the metabolome in serum from N-EtFOSE-treated and control animals. Ciprofibrate treatment increased liver weight and peroxisomal acyl Co-A oxidase activity in the liver and altered antioxidant enzyme activities in the uterus and liver. According to NMR metabolomic studies, ciprofibrate treated animals had altered serum lipid profiles compared to N-EtFOSE-treated and control animals, whereas putative markers of peroxisome proliferation in serum were not affected. Overall, this study demonstrates the biotransformation of N-EtFOSE to PFOS in rats that is accompanied by N-EtFOSE-induced alterations in antioxidant enzyme activity. PMID:19544052

An experimental study of the combined effects of n-hexane and methyl ethyl ketone.

PubMed Central

Takeuchi, Y; Ono, Y; Hisanaga, N; Iwata, M; Aoyama, M; Kitoh, J; Sugiura, Y

1983-01-01

This study was intended to determine whether or not methyl ethyl ketone (MEK) enhances the neurotoxicity of n-hexane at low concentration and after long term exposure. Separate groups of eight rats were exposed to 100 ppm n-hexane, 200 ppm MEK, 100 ppm n-hexane plus 200 ppm MEK, or fresh air in an exposure chamber for 12 hours a day for 24 weeks. The body weight, motor nerve conduction velocity (MCV), distal motor latency (DL), and mixed nerve conduction velocities (MNCVs) were measured before exposure and after four, eight, 12, 16, 20, and 24 weeks' exposure. One rat of each group was histopathologically examined after 24 weeks' exposure. Exposure of 100 ppm n-hexane did not significantly decrease the functions of the peripheral nerve throughout the experiment. Exposure to 200 ppm MEK significantly increased MCV and MNCVs and decreased DL after four weeks' exposure, but at this later stage no significant changes were found throughout the experiment by comparison with the controls. Mixed exposure to 100 ppm n-hexane plus 200 ppm MEK significantly decreased by comparison with the controls. On histopathological examination of the tail nerve, however, no changes were found in any of the exposed groups or the controls. These results suggest that MEK might enhance the neurotoxicity of n-hexane at a low concentration, and mixed exposures to n-hexane and MEK should be avoided. PMID:6830718

Optimal dose selection of N-methyl-N-nitrosourea for the rat comet assay to evaluate DNA damage in organs with different susceptibility to cytotoxicity.

PubMed

Kitamoto, Sachiko; Matsuyama, Ryoko; Uematsu, Yasuaki; Ogata, Keiko; Ota, Mika; Yamada, Toru; Miyata, Kaori; Funabashi, Hitoshi; Saito, Koichi

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where cytotoxicity is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of rats given three oral doses of N-methyl-N-nitrosourea (MNU) up to the maximum tolerated dose based on systemic toxicity. MNU significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that MNU has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose MNU significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that MNU has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic toxicity such as mortality and clinical observations. The present study shows that when serious cytotoxicity is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response. Copyright © 2015 Elsevier B.V. All rights reserved.

Yersinia outer proteins (YOPS) E, K and N are antigenic but non-protective compared to V antigen, in a murine model of bubonic plague.

PubMed

Leary, S E; Griffin, K F; Galyov, E E; Hewer, J; Williamson, E D; Holmström, A; Forsberg, A; Titball, R W

1999-03-01

The pathogenic Yersiniae produce a range of virulence proteins, encoded by a 70 kb plasmid, which are essential for infection, and also form part of a contact-dependent virulence mechanism. One of these proteins, V antigen, has been shown to confer a high level of protection against parenteral infection with Y. pestis in murine models, and is considered to be a protective antigen. In this study, the protective efficacy of V antigen has been compared in the same model with that of other proteins (YopE, YopK and YopN), which are part of the contact-dependent virulence mechanism. Mice immunised with two intraperitoneal doses of V antigen or each of the Yops, administered with either Alhydrogel or interleukin-12, produced high antigen-specific serum IgG titres. As shown in previous studies, V+Alhydrogel was fully protective, and 5/5 mice survived a subcutaneous challenge with 90 or 9x10(3) LD50's of Y. pestis GB. In addition, these preliminary studies also showed that V+IL-12 was partially protective: 4/5 or 3/5 mice survived a challenge with 90 or 9x10(3) LD50's, respectively. In contrast, none of the mice immunised with the Yops survived the challenges, and there was no significant delay in the mean time to death compared to mice receiving a control protein. These results show that using two different vaccine regimens, Yops E, K and N, failed to elicit protective immune responses in a murine model of plague, whereas under the same conditions, V antigen was fully or partially protective. Copyright 1999 Academic Press.

Towards optimizing the sequence of bevacizumab and nitrosoureas in recurrent malignant glioma.

PubMed

Wiestler, Benedikt; Radbruch, Alexander; Osswald, Matthias; Combs, Stephanie E; Jungk, Christine; Winkler, Frank; Bendszus, Martin; Unterberg, Andreas; Platten, Michael; Wick, Wolfgang; Wick, Antje

2014-03-01

Studies on the monoclonal VEGF-A antibody bevacizumab gave raise to questions regarding the lack of an overall survival benefit, the optimal timing in the disease course and potential combination and salvage therapies. We retrospectively assessed survival, radiological progression type on bevacizumab and efficacy of salvage therapies in 42 patients with recurrent malignant gliomas who received bevacizumab and nitrosourea sequentially. 15 patients received bevacizumab followed by nitrosourea at progression and 27 patients vice versa. Time to treatment failure, defined as time from initiation of one to failure of the other treatment, was similar in both groups (9.6 vs. 9.2 months, log rank p = 0.19). Progression-free survival on nitrosoureas was comparable in both groups, while progression-free survival on bevacizumab was longer in the group receiving bevacizumab first (5.3 vs. 4.1 months, log rank p = 0.03). Survival times were similar for patients with grade III (n = 9) and grade IV (n = 33) tumors. Progression-free survival on bevacizumab for patients developing contrast-enhancing T1 progression was longer than for patients who displayed a non-enhancing T2 progression. However, post-progression survival times after bevacizumab failure were not different. Earlier treatment with bevacizumab was not associated with better outcome in this series. The fact that earlier as compared to later bevacizumab treatment does not result in a different time to treatment failure highlights the challenge for first-line or recurrence trials with bevacizumab to demonstrate an overall survival benefit if crossover of bevacizumab-naïve patients after progression occurs.

MOLECULAR ANALYSIS OF MUTATIONS INDUCED BY MUTAGENS IN THE TK GENE OF MOUSE LYMPHOMA CELLS

EPA Science Inventory

MOLECULAR ANALYSIS OF MUTATIONS INDUCED BY BROMATE AND N- ETHYL-N-NITROSOUREA IN THE TK GENE OF MOUSE L YMPHOMA CELLS

The mouse lymphoma assay is widely used to identify chemical mutagens The Tk +1- gene located on an autosome in mouse lymphoma cells may recover a wide ra...

Structure of N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide by combined X-ray powder diffraction, 13C solid-state NMR and molecular modelling.

PubMed

Hangan, Adriana; Borodi, Gheorghe; Filip, Xenia; Tripon, Carmen; Morari, Cristian; Oprean, Luminita; Filip, Claudiu

2010-12-01

The crystal structure solution of the title compound is determined from microcrystalline powder using a multi-technique approach that combines X-ray powder diffraction (XRPD) data analysis based on direct-space methods with information from (13)C solid-state NMR (SSNMR), and molecular modelling using the GIPAW (gauge including projector augmented-wave) method. The space group is Pbca with one molecule in the asymmetric unit. The proposed methodology proves very useful for unambiguously characterizing the supramolecular arrangement adopted by the N-(5-ethyl-[1,3,4]-thiadiazole-2-yl)toluenesulfonamide molecules in the crystal, which consists of extended double strands held together by C-H···π non-covalent interactions.

Orientation of N-(1-(2-chlorophenyl)-2-(2-nitrophenyl)ethyl)-4-methylbenzenesulfonamide on silver nanoparticles: SERS studies.

PubMed

Anuratha, M; Jawahar, A; Umadevi, M; Sathe, V G; Vanelle, P; Terme, T; Meenakumari, V; Milton Franklin Benial, A

2014-10-15

In the present study, the silver nanoparticles were synthesized using a solution combustion method with urea as fuel. The prepared silver nanoparticles show an FCC crystalline structure with particle size of 59nm. FESEM image shows the prepared silver is a rod like structure. The surface-enhanced Raman scattering (SERS) spectrum indicates that the N-(1-(2-chlorophenyl)-2-(2-nitrophenyl)ethyl)-4-methylbenzenesulfonamide (CS) molecule adsorbed on the silver nanoparticles. The spectral analysis reveals that the sulfonamide is adsorbed by tilted orientation on the silver surface. The Hatree Fock calculations were also performed to predict the vibrational motions of CS. This present investigation has been a model system to deduce the interaction of drugs with DNA. Copyright © 2014 Elsevier B.V. All rights reserved.

Antioxidant potential of n-butanol fraction from extract of Jasminum mesnyi Hance leaves.

PubMed

Borar, Sakshi; Punia, Priyanka; Kalia, A N

2011-01-01

Methanolic extract of Jasminum mesnyi Hance leaves having antidiabetic activity was subjected to fractionation to obtain antioxidant and antihyperglycemic rich fraction. Different concentrations of ethyl acetate and n-butanol fractions were subjected to antioxidant assay by DPPH method, nitric oxide scavenging activity and reducing power assay. The fractions showed dose dependent free radical scavenging property in all the models. IC50 values for ethyl acetate and n-butanol fractions were 153.45 +/- 6.65 and 6.22 +/- 0.25 microg/ml, respectively, as compared to L-ascorbic acid and rutin (as standards; IC50 values 6.54 +/- 0.24 and 5.43 +/- 0.21 microg/ml, respectively) in DPPH model. In nitric oxide scavenging activity, IC50 values were 141.54 +/- 9.95 microg/ml, 35.12 +/- 1.58 microg/ml, 21.06 +/- 0.95 microg/ml and 29.93 +/- 0.32 microg/ml for ethyl acetate, n-butanol fractions, L-ascorbic acid and rutin, respectively. n-Butanol fraction showed a good reducing potential and better free radical scavenging activity as compared to ethyl acetate fraction. Potent antioxidant n-butanol fraction showed better oral glucose tolerance test (antihyperglycemic) at par with metformin (standard drug), n-Butanol fraction contained secoiridoid glycosides which might be responsible for both antioxidant and antihyperglycemic activity.

Noncompetitive inhibition of indolethylamine-N-methyltransferase by N,N-dimethyltryptamine and N,N-dimethylaminopropyltryptamine.

PubMed

Chu, Uyen B; Vorperian, Sevahn K; Satyshur, Kenneth; Eickstaedt, Kelsey; Cozzi, Nicholas V; Mavlyutov, Timur; Hajipour, Abdol R; Ruoho, Arnold E

2014-05-13

Indolethylamine-N-methyltransferase (INMT) is a Class 1 transmethylation enzyme known for its production of N,N-dimethyltryptamine (DMT), a hallucinogen with affinity for various serotonergic, adrenergic, histaminergic, dopaminergic, and sigma-1 receptors. DMT is produced via the action of INMT on the endogenous substrates tryptamine and S-adenosyl-l-methionine (SAM). The biological, biochemical, and selective small molecule regulation of INMT enzyme activity remain largely unknown. Kinetic mechanisms for inhibition of rabbit lung INMT (rabINMT) by the product, DMT, and by a new novel tryptamine derivative were determined. After Michaelis-Menten and Lineweaver-Burk analyses had been applied to study inhibition, DMT was found to be a mixed competitive and noncompetitive inhibitor when measured against tryptamine. The novel tryptamine derivative, N-[2-(1H-indol-3-yl)ethyl]-N',N'-dimethylpropane-1,3-diamine (propyl dimethyl amino tryptamine or PDAT), was shown to inhibit rabINMT by a pure noncompetitive mechanism when measured against tryptamine with a Ki of 84 μM. No inhibition by PDAT was observed at 2 mM when it was tested against structurally similar Class 1 methyltransferases, such as human phenylethanolamine-N-methyltransferase (hPNMT) and human nicotinamide-N-methyltransferase (hNNMT), indicating selectivity for INMT. The demonstration of noncompetitive mechanisms for INMT inhibition implies the presence of an inhibitory allosteric site. In silico analyses using the computer modeling software Autodock and the rabINMT sequence threaded onto the human INMT (hINMT) structure (Protein Data Bank entry 2A14 ) identified an N-terminal helix-loop-helix non-active site binding region of the enzyme. The energies for binding of DMT and PDAT to this region of rabINMT, as determined by Autodock, were -6.34 and -7.58 kcal/mol, respectively. Assessment of the allosteric control of INMT may illuminate new biochemical pathway(s) underlying the biology of INMT.

Effect of total hydroalcholic extract of Nigella sativa and its n-hexane and ethyl acetate fractions on ACHN and GP-293 cell lines.

PubMed

Shahraki, Samira; Khajavirad, Abolfazl; Shafei, Mohammad Naser; Mahmoudi, Mahmoud; Tabasi, Nafisa Sadat

2016-01-01

Medicinal plants are noted for their many advantages including the ability to treat diseases such as cancer. In this study, we examined the antitumor effect of the medicinal plant Nigella sativa on the morphology, survival, and apoptosis of ACHN (human renal adenocarcinoma) and GP-293 (normal renal epithelial) cell lines. From a hydroalcoholic extract of N. sativa, n-hexane and ethyl acetate fractions were extracted. Cells were treated with various concentrations of total hydroalcholic extract and n-hexane and ethyl acetate fractions; cell viability, morphological changes, and apoptosis were then determined. Results were presented as mean ± standard error of the mean (SEM). One-way analysis of variance (ANOVA) was applied for the statistical analysis of the data. The total extract and the fractions in a dose- and time-dependent manner reduced the cell viability in ACHN with no effect on the GP-293 cell line. In addition, the total extract resulted in more morphological changes in the ACHN cells compared to the GP-293 cells. The effect of the total extract in inducing apoptosis after 48 hours in the ACHN cell line was greater than in GP-293. In addition, the effect of the two fractions was lower than the total extract at all used concentrations. Therefore, the effect of total extract and n-hexane and ethyl acetate fractions of N. sativa on cell viability and apoptosis in the ACHN cell line is greater than in the GP-293 cell line. However, the effect of the total extract is higher than either of the two fractions on their own.

Promoting effects of potassium dibasic phosphate on early-stage renal carcinogenesis in unilaterally nephrectomized rats treated with N-ethyl-N-hydroxyethylnitrosamine.

PubMed

Hiasa, Y; Konishi, N; Nakaoka, S; Nakamura, T; Nishii, K; Ohshima, M

1992-07-01

The effects of potassium dibasic phosphate (PDP), potassium aluminum sulfate (PAS) and copper sulfate (CS) on early-stage renal carcinogenesis were investigated in unilaterally nephrectomized male Wistar rats after N-ethyl-N-hydroxyethylnitrosamine (EHEN) administration. After feeding 1,000 ppm EHEN, or basal diet for 2 weeks and removal of the left kidney at week 3, male Wistar rats were divided into 8 groups of 20 rats each. These groups received the following dietary treatments: 50,000 ppm PDP, 50,000 ppm PAS, 5,000 ppm CS or basal diet, respectively, for 18 weeks from weeks 3 to 20. The average numbers of adenomatous hyperplasias counted as preneoplastic lesions in the EHEN with 50,000 ppm PDP group were significantly higher than in the EHEN alone group or the EHEN followed by 50,000 ppm PAS or 5,000 ppm CS group. The treatment with 50,000 ppm PDP induced renal calcification and promoted the development of preneoplastic lesions in unilaterally nephrectomized rats treated with EHEN, but that with 50,000 ppm PAS or 5,000 ppm CS did not.

A field trial of ethyl hexanediol against Aedes dorsalis in Sonoma County, California.

PubMed

Rutledge, L C; Hooper, R L; Wirtz, R A; Gupta, R K

1989-09-01

The repellent ethyl hexanediol (2-ethyl-1,3-hexanediol) was tested against the mosquito Aedes dorsalis in a coastal salt marsh in California. The experimental design incorporated a linear regression model, sequential treatments and a proportional end point (95%) for protection time. The protection time of 0.10 mg/cm2 ethyl hexanediol was estimated at 0.8 h. This time is shorter than that obtained previously for deet (N,N-diethyl-3-methylbenzamide) against Ae. dorsalis (4.4 h).

[Virulence of Sporothrix globosa in murine models].

PubMed

Cruz Choappa, Rodrigo; Pérez Gaete, Salomón; Rodríguez Badilla, Valentina; Vieille Oyarzo, Peggy; Opazo Sanchez, Héctor

The sporothricosis disease is an infection caused by species included in Sporothrix schenkii complex. Verify the virulence of a strain of S. globosa using two different concentrations of inoculum by intraperitoneally and subcutaneously, into a mouse model. Nonrandomized pilot study, in murine inoculated with a strain of S. globosa (CBS 14.076M) by intraperitoneally and subcutaneously with inoculum concentrations of 0.5 and 4 McFarland. For this purpose 18 rodents CF-1 (ISP, Santiago, Chile) were used. The studied strain did not induce illness or injury on animals, they all survived and neither the tissue culture nor the histopathological analysis showed fungal growth or suggestive infection by organ abnormalities. The S. globosa strain did not present any virulence enough to cause disease at 0.5 and 4.0 McFarland concentration inoculum when inoculated in both intraperitoneally and subcutaneously, in murine models. Copyright © 2016 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

Enhancement of nitrosourea cytotoxicity by misonidazole in vitro: correlation with carbamoylating potential.

PubMed Central

Mulcahy, R. T.; Dembs, N. L.; Ublacker, G. A.

1984-01-01

We have investigated the relationships between nitrosourea structure and physicochemical properties and the ability of misonidazole (MISO) to potentiate nitrosourea cytotoxicity in an in vitro model system. EMT-6/Ro tumour cells were exposed in suspension to each of 9 different nitrosourea anti-tumour drugs under hypoxic and aerobic culture conditions. Additional cultures were similarly treated with nitrosoureas in the presence of 1.0 mM MISO. Seven of the 9 nitrosoureas did not demonstrate any selective toxicity toward aerobic or hypoxic cells. In contrast, chlorozotocin (CHLZ) was slightly more toxic toward hypoxic cells while Bis-OH CyNU more effectively killed aerobic cells. The addition of MISO to the drug treatment enhanced the effectiveness of all the nitrosoureas under hypoxic conditions, with the exception of CHLZ which was uninfluenced by MISO. The magnitude of the MISO dose enhancement factor (DEF, defined as the ratio of drug doses required to reduce cell survival to S = 10(-3) in 4 hours in the absence and presence of 1.0 mM MISO) for each combination was examined as a function of the relative carbamoylating or alkylating activity of the nitrosourea included in that combination. Such an analysis revealed a significant (P less than 0.05) positive correlation between relative carbamoylating potency and DEF. No significant (P greater than 0.20) relationship could be established for DEF and alkylating activity. PMID:6704305

Glutathione Ethyl Ester Supplementation during Pancreatic Islet Isolation Improves Viability and Transplant Outcomes in a Murine Marginal Islet Mass Model

PubMed Central

Raposo do Amaral, Alexandre S.; Pawlick, Rena L.; Rodrigues, Erika; Costal, Flavia; Pepper, Andrew; Ferreira Galvão, Flávio H.; Correa-Giannella, Maria Lucia; Shapiro, A. M.James

2013-01-01

Background The success of pancreatic islet transplantation still faces many challenges, mainly related to cell damage during islet isolation and early post-transplant. The increased generation of reactive oxygen species (ROS) during islet isolation and the consumption of antioxidant defenses appear to be an important pathway related to islet damage. Methodology/Principal Findings In the present study we evaluated whether supplementation of glutathione-ethyl-ester (GEE) during islet isolation could improve islet viability and transplant outcomes in a murine marginal islet mass model. We also cultured human islets for 24 hours in standard CMRL media with or without GEE supplementation. Supplementation of GEE decreased the content of ROS in isolated islets, leading to a decrease in apoptosis and maintenance of islet viability. A higher percentage of mice transplanted with a marginal mass of GEE treated islets became euglycemic after transplant. The supplementation of 20 mM GEE in cultured human islets significantly reduced the apoptosis rate in comparison to untreated islets. Conclusions/Significance GEE supplementation was able to decrease the apoptosis rate and intracellular content of ROS in isolated islets and might be considered a potential intervention to improve islet viability during the isolation process and maintenance in culture before islet transplantation. PMID:23424628

A Novel Murine Candidiasis Model with Severe Colonization in the Stomach Induced by N-acetylglucosamine-treatment and Its Scoring System Based on Local Characteristic Stomach Symptoms.

PubMed

Ishijima, Sanae A; Abe, Shigeru

2015-01-01

We developed a novel murine candidiasis model of the gastrointestinal tract using N-acetylglucosamine ( GlcNAc ) as a tool to aggravate symptoms. Forty-eight hours after intragastrically inoculating Candida albicans cells to immunosuppressed and GlcNAc-treated mice, vigorously accumulating patchy whitish plaques were observed on their inner stomach surface. Candida cells colonizing the plaques consisted of both yeast and mycelia, and were directly stained with Calcofluor White M2R. Aggravation of the candidiasis symptoms was dependent on GlcNAc concentration in drinking water, wherein administration of 50 mM GlcNAc not only severely worsened stomach symptoms, but also significantly increased Candida cell number in the stomach and small intestine. The aggravation effect of GlcNAc was enhanced by addition of sedative chemical chlorpromazine chloride after inoculation. In order to semi-quantitatively assess colonization by Candida in the stomach, we devised a new symptom scoring system that represents the extent of the patchy whitish plaques on the mucosal epithelium of the stomach. Histochemical analysis of Candida-infected tissues revealed not only a large amount of thick Candida mycelia invading mucosal epithelial stomach tissues but also infiltrating inflammatory cells. These results suggest that this murine gastrointestinal candidiasis model could serve as a useful tool for evaluating the protective activity of antifungal agents, probiotics, or functional foods against gastrointestinal candidiasis. Furthermore, from another point of view, this novel murine model could also be used to analyze the pathological mechanisms behind the translocation of C. albicans across intestinal barriers, which results in systemic Candida dissemination and infection.

Fv1-like restriction of N-tropic replication-competent murine leukaemia viruses in mCAT-1-expressing human cells.

PubMed

Aagaard, Lars; Mikkelsen, Jacob Giehm; Warming, Søren; Duch, Mogens; Pedersen, Finn Skou

2002-02-01

To study the replication of murine leukaemia viruses in human cells we have used full-length as well as EGFP-tagged ecotropic viruses in combination with mCAT-1-expressing human cells. We present results showing that N-tropic murine leukaemia viruses are restricted in both infection and replication in such cells while B-tropic viruses, modified at capsid position 110, escape restriction. These results support a recently reported Fv1-like restriction in mammalian cells. We extend the analysis of Fv1-like restriction by demonstrating that NB-tropic viruses also escape restriction and human mCAT-1-expressing cells are thus similar to murine Fv1(b) cells with respect to infection though the ecotropic receptor pathway.

Gd@C82 metallofullerenes for neutron capture therapy—fullerene solubilization by poly(ethylene glycol)-block-poly(2-(N, N-diethylamino)ethyl methacrylate) and resultant efficacy in vitro

PubMed Central

Horiguchi, Yukichi; Kudo, Shinpei; Nagasaki, Yukio

2011-01-01

Poly(ethylene glycol)-block-poly(2-(N,N-diethylamino)ethyl methacrylate) (PEG-b-PAMA) was found to solubilize fullerenes such as C60, and this technique was applied to metallofullerenes. Gd@C82 was easily dissolved in water in the presence of PEG-b-PAMA without any covalent derivatization, forming a transparent complex about 20–30 nm in diameter. Low cytotoxicity was confirmed in vitro. Neutron irradiation of cultured cells (colon-26 adenocarcinoma) with Gd@C82-PEG-b-PAMA-complexed nanoparticles showed effective cytotoxicity, indicating the effective emission of gamma rays and internal conversion electrons produced from the neutron capture reaction of Gd. This result suggests a potentially valuable approach to gadolinium-based neutron capture therapy. PMID:27877415

The mechanism of protection from 5 (N-ethyl-N-isopropyl)amiloride differs from that of ischemic preconditioning in rabbit heart.

PubMed

Sato, H; Miki, T; Vallabhapurapu, R P; Wang, P; Liu, G S; Cohen, M V; Downey, J M

1997-10-01

We investigated the effects of 5-(N-ethyl-N-isopropyl)amiloride (EIPA) on infarction in isolated rabbit hearts and cardiomyocytes. Thirty min of regional ischemia caused 29.6 +/- 2.8% of the risk zone to infarct in untreated Krebs buffer-perfused hearts. Treatment with EIPA (1 microM) for 20 min starting either 15 min before ischemia or 15 min after the onset of ischemia significantly reduced infarction to 5.4 +/- 2.0% and 7.0 +/- 1.0%, respectively (p < 0.01 versus untreated hearts). In both cases salvage was very similar to that seen with ischemic preconditioning (PC) (7.1 +/- 1.5% infarction). Unlike the case with ischemic preconditioning, however, protection from EIPA was not blocked by 50 microM polymyxin B, a PKC inhibitor, or 1 microM glibenclamide, a KATP channel blocker. Forty-five min of regional ischemia caused 51.0 +/- 2.9% infarction in untreated hearts. Ischemic preconditioning reduced infarction to 23.4 +/- 3.1% (p < 0.001 versus untreated hearts). In these hearts with longer periods of ischemia pretreatment with EIPA reduced infarction similarly to 28.8 +/- 2.1% (p < 0.01 versus untreated hearts). However, when EIPA was combined with ischemic PC, no further reduction in infarction was seen (23.8 +/- 3.5% infarction). To further elucidate the mechanism of EIPA's cardioprotective effect, this agent was also examined in isolated rabbit cardiomyocytes. Preconditioning caused a delay of about 30 min in the progressive increase in osmotic fragility that occurs during simulated ischemia. In contrast, EIPA had no effect on the time course of ischemia-induced osmotic fragility. Furthermore, EIPA treatment did not alter the salutary effect of ischemic preconditioning when the two were combined in this model. We conclude that Na+/H+ exchange inhibition limits myocardial infarction in the isolated rabbit heart by a mechanism which is quite different from that of ischemic preconditioning. Despite the apparently divergent mechanisms, EIPA's cardioprotective

2′-O-[2-[(N,N-dimethylamino)oxy]ethyl]-modified oligonucleotides inhibit expression of mRNA in vitro and in vivo

PubMed Central

Prakash, Thazha P.; Johnston, Joseph F.; Graham, Mark J.; Condon, Thomas P.; Manoharan, Muthiah

2004-01-01

Synthesis and antisense activity of oligonucleotides modified with 2′-O-[2-[(N,N-dimethylamino)oxy] ethyl] (2′-O-DMAOE) are described. The 2′-O-DMAOE-modified oligonucleotides showed superior metabolic stability in mice. The phosphorothioate oligonucleotide ‘gapmers’, with 2′-O-DMAOE- modified nucleoside residues at the ends and 2′-deoxy nucleosides residues in the central region, showed dose-dependent inhibition of mRNA expression in cell culture for two targets. ‘Gapmer’ oligonucleotides have one or two 2′-O-modified regions and a 2′-deoxyoligonucleotide phosphorothioate region that allows RNase H digestion of target mRNA. To determine the in vivo potency and efficacy, BalbC mice were treated with 2′-O-DMAOE gapmers and a dose-dependent reduction in the targeted C-raf mRNA expression was observed. Oligonucleotides with 2′-O-DMAOE modifications throughout the sequences reduced the intercellular adhesion molecule-1 (ICAM-1) protein expression very efficiently in HUVEC cells with an IC50 of 1.8 nM. The inhibition of ICAM-1 protein expression by these uniformly modified 2′-O-DMAOE oligonucleotides may be due to selective interference with the formation of the translational initiation complex. These results demonstrate that 2′-O-DMAOE- modified oligonucleotides are useful for antisense-based therapeutics when either RNase H-dependent or RNase H-independent target reduction mechanisms are employed. PMID:14762210

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease.

PubMed

Potter, Paul K; Bowl, Michael R; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E; Simon, Michelle M; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V; Law, Gemma; MacLaren, Robert E; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H; Foster, Russell G; Jackson, Ian J; Peirson, Stuart N; Thakker, Rajesh V; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D M

2016-08-18

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss.

Novel gene function revealed by mouse mutagenesis screens for models of age-related disease

PubMed Central

Potter, Paul K.; Bowl, Michael R.; Jeyarajan, Prashanthini; Wisby, Laura; Blease, Andrew; Goldsworthy, Michelle E.; Simon, Michelle M.; Greenaway, Simon; Michel, Vincent; Barnard, Alun; Aguilar, Carlos; Agnew, Thomas; Banks, Gareth; Blake, Andrew; Chessum, Lauren; Dorning, Joanne; Falcone, Sara; Goosey, Laurence; Harris, Shelley; Haynes, Andy; Heise, Ines; Hillier, Rosie; Hough, Tertius; Hoslin, Angela; Hutchison, Marie; King, Ruairidh; Kumar, Saumya; Lad, Heena V.; Law, Gemma; MacLaren, Robert E.; Morse, Susan; Nicol, Thomas; Parker, Andrew; Pickford, Karen; Sethi, Siddharth; Starbuck, Becky; Stelma, Femke; Cheeseman, Michael; Cross, Sally H.; Foster, Russell G.; Jackson, Ian J.; Peirson, Stuart N.; Thakker, Rajesh V.; Vincent, Tonia; Scudamore, Cheryl; Wells, Sara; El-Amraoui, Aziz; Petit, Christine; Acevedo-Arozena, Abraham; Nolan, Patrick M.; Cox, Roger; Mallon, Anne-Marie; Brown, Steve D. M.

2016-01-01

Determining the genetic bases of age-related disease remains a major challenge requiring a spectrum of approaches from human and clinical genetics to the utilization of model organism studies. Here we report a large-scale genetic screen in mice employing a phenotype-driven discovery platform to identify mutations resulting in age-related disease, both late-onset and progressive. We have utilized N-ethyl-N-nitrosourea mutagenesis to generate pedigrees of mutagenized mice that were subject to recurrent screens for mutant phenotypes as the mice aged. In total, we identify 105 distinct mutant lines from 157 pedigrees analysed, out of which 27 are late-onset phenotypes across a range of physiological systems. Using whole-genome sequencing we uncover the underlying genes for 44 of these mutant phenotypes, including 12 late-onset phenotypes. These genes reveal a number of novel pathways involved with age-related disease. We illustrate our findings by the recovery and characterization of a novel mouse model of age-related hearing loss. PMID:27534441

Concentration dependent survival and neural differentiation of murine embryonic stem cells cultured on polyethylene glycol dimethacrylate hydrogels possessing a continuous concentration gradient of n-cadherin derived peptide His-Ala-Val-Asp-Lle.

PubMed

Lim, Hyun Ju; Mosley, Matthew C; Kurosu, Yuki; Smith Callahan, Laura A

2017-07-01

N-cadherin cell-cell signaling plays a key role in the structure and function of the nervous system. However, few studies have incorporated bioactive signaling from n-cadherin into tissue engineering matrices. The present study uses a continuous gradient approach in polyethylene glycol dimethacrylate hydrogels to identify concentration dependent effects of n-cadherin peptide, His-Ala-Val-Asp-Lle (HAVDI), on murine embryonic stem cell survival and neural differentiation. The n-cadherin peptide was found to affect the expression of pluripotency marker, alkaline phosphatase, in murine embryonic stem cells cultured on n-cadherin peptide containing hydrogels in a concentration dependent manner. Increasing n-cadherin peptide concentrations in the hydrogels elicited a biphasic response in neurite extension length and mRNA expression of neural differentiation marker, neuron-specific class III β-tubulin, in murine embryonic stem cells cultured on the hydrogels. High concentrations of n-cadherin peptide in the hydrogels were found to increase the expression of apoptotic marker, caspase 3/7, in murine embryonic stem cells compared to that of murine embryonic stem cell cultures on hydrogels containing lower concentrations of n-cadherin peptide. Increasing the n-cadherin peptide concentration in the hydrogels facilitated greater survival of murine embryonic stem cells exposed to increasing oxidative stress caused by hydrogen peroxide exposure. The combinatorial approach presented in this work demonstrates concentration dependent effects of n-cadherin signaling on mouse embryonic stem cell behavior, underscoring the need for the greater use of systematic approaches in tissue engineering matrix design in order to understand and optimize bioactive signaling in the matrix for tissue formation. Single cell encapsulation is common in tissue engineering matrices. This eliminates cellular access to cell-cell signaling. N-cadherin, a cell-cell signaling molecule, plays a vital role in

SYNERGISTIC EFFECT OF HALIDE IONS ON THE CORROSION INHIBITION OF MILD STEEL IN SULPHURIC ACID USING METHYL, N-METHYL ETHYL AND ETHYL SUBSTITUTED γ-2,c-6-DIPHENYL PIPERIDIN-4-ONE SEMICARBAZONES

NASA Astrophysics Data System (ADS)

Priya, V. Shanmuga; Rani, C. Uma; Velrani, S.

The synergistic effect of halide ions such as KCl, KBr and KI on the corrosion inhibition of mild steel in 1 N sulphuric acid by γ-2,c-6-diphenyl-t-3-methyl piperdin-4-ones with semicarbazone (01SC), γ-2,c-6-diphenyl-N-methyl-t-3-ethyl piperdin-4-ones with semicarbazone (02SC) and 2,6-diphenyl-t-3-ethyl piperdin-4-one with semicarbazone (03SC) has been examined by weight loss method, potentiodynamic polarization measurements and electrochemical AC impedance spectroscopy. Results show that substituted γ-2,c-6-diphenyl piperidin-4-ones with semicarbazone act as the perfect corrosion inhibitors and their inhibition efficiency increases with the addition of halide ions. The inhibitor (01SC) shows the inhibition efficiency of 78.28% (0.2mM) by using a weight loss method. The influence of I-, Br- and Cl- anions raises the inhibition efficiency of the substituted 2,6-diphenyl piperidin-4-ones with semicarbazone due to the synergistic effect. The synergistic effect of halide ions was formed in the following order: KI > KBr > KCl.

[Cancer chemotherapy with special reference to pharmacokinetics of nitrosoureas].

PubMed

Wakui, A

1982-08-01

This paper provides an overview of cancer chemotherapy with special reference to the pharmacokinetics of the nitrosoureas. At physiological PH, the chloroethylnitrosoureas can be decomposed into an isocyanate and 2-chloroethyl diazene hydroxide. Therefore, it is clear that they have both alkylation and carbamoylation actions. In addition to the spontaneous chemical dissociation, the nitrosoureas can be metabolized by liver microsomal enzymes to more polar hydroxylated products, and certain nitrosoureas can be denitrosated by these enzymes to the parent urea. Since the lipid-soluble nitrosoureas and some of the water-soluble nitrosoureas such as ACNU and MCNU demonstrated to cross the blood-brain barrier, they have been used in the treatment of primary brain tumors and tumors and tumors of metastatic origin. It has been demonstrated from the results of our study and other reports that the alkylation of DNA by ACNU progresses more slowly as compared with that of other alkylating agents. This is an important finding in relation to the appearance of delayed myelosuppression of the nitrosoureas and in the design of dose schedules of these agents. The major clinical emphasis has been directed towards the more active chloroethylnitrosoureas with reduced myelosuppression, and attempts are now made for this purpose. Unfortunately, the results of phase I and II trials of the newly developed nitrosoureas suggest that these agents produce delayed and cumulative bone marrow toxicity. Antitumor activity of the nitrosoureas is frequestly observed in chronic myelocytic leukemia, malignant lymphoma, brain tumors and small cell carcinoma of the lung, and less frequently in gastrointestinal carcinoma, multiple myeloma and malignant melanoma. In order to enhance clinical effects of the nitrosoureas, further investigation of the design in therapeutic schedules on the basis of their pharmacokinetic characteristics will be needed.

[Chemotherapeutic characterization of new nitrosourea compounds].

PubMed

Zeller, W J; Berger, M R; Eisenbrand, G; Petru, E

1988-01-01

The development of new nitrosoureas is described using selected examples. Results obtained with water-soluble analogs and with compounds linked to biomolecules as for instance amino acids, oligopeptides and steroids, are presented. The pronounced antineoplastic effect of some water-soluble analogs is paralleled by an increased rate of DNA-interstrand cross-links and by an increased suppression of hematopoietic stem cells. The suppression of bone marrow stem cells is followed by their rapid regeneration. Water-soluble nitrosoureas induce significant less inhibition of glutathione reductase as compared with established compounds. With regard to long-term toxicity and carcinogenicity water-soluble are superior to established compounds as for instance BCNU. Linking of the nitrosourea moiety to amino acids and oligopeptides led to some analogs with outstanding therapeutic ratio. Out of a group of steroid-linked nitrosoureas, CNC-L-alanine-estradiol-17-ester (CNC-ala-17-E2) is chosen to demonstrate the possibility of reducing bone marrow toxicity despite unchanged or increased therapeutic activity by attachment of the nitrosourea moiety to a steroid. Results of a comparative interspecies in vitro evaluation of CNC-ala-17-E2 in transplanted MXT mammary carcinoma of the mouse, MNU-induced autochthonous rat mammary carcinoma and primary human mammary carcinomas are presented and the question is discussed to what extent in vitro activity of such receptor agents using the tumor stem cell assay reflects their in vivo activity.

Noncompetitive Inhibition of Indolethylamine-N-methyltransferase by N,N-Dimethyltryptamine and N,N-Dimethylaminopropyltryptamine

PubMed Central

2015-01-01

Indolethylamine-N-methyltransferase (INMT) is a Class 1 transmethylation enzyme known for its production of N,N-dimethyltryptamine (DMT), a hallucinogen with affinity for various serotonergic, adrenergic, histaminergic, dopaminergic, and sigma-1 receptors. DMT is produced via the action of INMT on the endogenous substrates tryptamine and S-adenosyl-l-methionine (SAM). The biological, biochemical, and selective small molecule regulation of INMT enzyme activity remain largely unknown. Kinetic mechanisms for inhibition of rabbit lung INMT (rabINMT) by the product, DMT, and by a new novel tryptamine derivative were determined. After Michaelis–Menten and Lineweaver–Burk analyses had been applied to study inhibition, DMT was found to be a mixed competitive and noncompetitive inhibitor when measured against tryptamine. The novel tryptamine derivative, N-[2-(1H-indol-3-yl)ethyl]-N′,N′-dimethylpropane-1,3-diamine (propyl dimethyl amino tryptamine or PDAT), was shown to inhibit rabINMT by a pure noncompetitive mechanism when measured against tryptamine with a Ki of 84 μM. No inhibition by PDAT was observed at 2 mM when it was tested against structurally similar Class 1 methyltransferases, such as human phenylethanolamine-N-methyltransferase (hPNMT) and human nicotinamide-N-methyltransferase (hNNMT), indicating selectivity for INMT. The demonstration of noncompetitive mechanisms for INMT inhibition implies the presence of an inhibitory allosteric site. In silico analyses using the computer modeling software Autodock and the rabINMT sequence threaded onto the human INMT (hINMT) structure (Protein Data Bank entry 2A14) identified an N-terminal helix–loop–helix non-active site binding region of the enzyme. The energies for binding of DMT and PDAT to this region of rabINMT, as determined by Autodock, were −6.34 and −7.58 kcal/mol, respectively. Assessment of the allosteric control of INMT may illuminate new biochemical pathway(s) underlying the biology of INMT

Comparison of new nitrosoureas esters with modified steroidal nucleus for cytogenetic and antineoplastic activity.

PubMed

Hussein, A; Mioglou-Kalouptsi, E; Papageorgiou, A; Karapidaki, I; Iakovidou-Kritsi, Z; Lialiaris, T; Xrysogelou, E; Camoutsis, C; Mourelatos, D

2007-01-01

Nitrosourea is decomposed under physiological conditions to react with biological macromolecules by two mechanisms: alkylation (with proteins and nucleic acids) and carbamoylation (with proteins but not nucleic acids). It has been suggested that the alkylating action is responsible for the therapeutic effects of nitrosoureas, and that the carbamoylation activity leads to toxicity effects. In order to reduce systemic toxicity and improve specificity and distribution for cancer therapy, 2-haloethyl nitrosourea has been esterified with modified steroids, which are used as biological platforms for transporting the alkylating agent to the tumor site in a specific manner. The cytogenetic and antineoplastic effect were studied of seven newly synthesized esters of N,N-bis(2-chloroethyl)alanyl carboxyl derivatives with a modified steroidal nucleus (compounds 1-7). As a very sensitive indicator of genotoxicity the Sister Chromatid Exchange (SCE) assay was used and as a valuable marker of cytostatic activity the cell Proliferation Rate Index (PRI) in cultures of normal human lymphocytes was used. The order of magnitude of the cytogenetic activity on a molar basis (15, 30, 120 microM) of the compounds was 7>6>3>5>2>4>1. The most active compound 7 has an enlarged (seven carbon atoms) A ring modified with a lactam group (-NHCO-) with the nitrosourea moiety esterified at position 17 In the group of seven substances a correlation was observed between the magnitude of SCE response and the depression in PRI (r=-O, 65, p<0.001). According to the criterion of activity of National Cancer Institute (NCI), the order of antineoplastic activity of compounds on lymphoid L1210 leukemia is 7>6>2>5>4>3>1 and on lympocytic P388 leukemia cells is 7>2>6>5>4>3>1. The present results are in agreement with previous suggestions that the effectiveness in cytogenetic activity may well be correlated with antitumor effects [T/C: 248% for the compound 7 in 250 mg/kg b.w.; T/C: mean survival time of drug

Synthesis and property of solvatochromic fluorophore based on D-pi-A molecular system: 2-[[3-cyano-4-(N-ethyl-N-(2-hydroxyethyl)amino)styryl]-5,5-dimethylfuran-2(5H)-ylidene]malononitrile dye.

PubMed

Son, Young-A; Gwon, Seon-Yeong; Lee, Sue-Yoen; Kim, Sung-Hoon

2010-01-01

2-[[3-Cyano-4-(N-ethyl-N-(2-hydroxyethyl)amino)styryl]-5,5-dimethylfuran-2(5H)-ylidene]malononitrile styryl dye was prepared by the condensation of 4-[(2-hydroxy-ethyl)-methyl-amino]-benzaldehyde (donor moiety) with 2-cyanomethylene-3-cyano-4,5,5-trimethyl-2,5-dihydrofuran (acceptor moiety). The corresponding design, synthesis and solvatochromic characteristics of the intramolecular charge-transfer (ICT) dye chromophore were discussed and determined. Optical properties such as absorption and fluorescence emission spectra were monitored in several solvent media with different polarity. In this determination, the prepared dye chromophore showed positive solvatochromism effect and the resulting solvatochromic characteristics were studied with semiempirical calculations. The energy potentials of this dye chromophore such as HOMO and LUMO values were calculated by computational simulation approaches using Material Studio 4.3. Furthermore, the functions as a molecular switching sensor with pH stimulation of alkali-acid addition were determined in DMSO, which was operated by deprotonation/protonation effects based on intramolecular charge-transfer system. Copyright 2009 Elsevier B.V. All rights reserved.

Mechanism of uptake of nitrosoureas by L5178Y lymphoblasts in vitro.

PubMed

Begleiter, A; Lam, H P; Goldenberg, G J

1977-04-01

The mechanism of uptake of nitrosoureas by L5178Y cells in vitro was investigated. A time course of the uptake of radioactivity on incubation of L5178Y lymphoblast with [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea was linear for 30 min and then entered a plateau phase; it was markedly temperature dependent. A similar time course for cells incubated with [14C]ethylene-labeled 1-(2-chlorethyl)-3-cyclohexyl-1-nitrosourea reached equilibrium rapidly, was temperature independent, and resulted in a relatively low level of uptake of radioactivity. However, cells treated with 3-[cyclohexyl-14C]-1-(2-chlorethyl)-1-nitrosourea had a time course that was linear for 30 min, resulted in much higher levels of uptake of radioactivity, and was strongly temperature dependent. These findings, at least for 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, suggest that some drug decomposition precedes uptake. The percentage of radioactivity found in the cell sap fraction was at least 85% of total cell activity when cells were incubated with any of the three 14C-labeled nitrosoureas. Furthermore, thin-layer chromatography of the cell sap fraction revealed the presence of free intact drug. These findings indicate that intracellular uptake of intact nitrosoureas occurred. A time course of uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea reached equilibrium rapidly with cell/medium distribution ratios of 0.2 to 0.6 and was temperature independent. The addition of excess unlabeled 1,3-bis(2-chlorethyl)-1-nitrosourea or 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea had no effect on uptake of [14C]-1,3-bis(2-chloroethyl)-1-nitrosourea, These findings suggest that uptake of intact 1,3-bis(2-chloroethyl)-1-nitrosourea was by passive diffusion. A time course of the uptake of intact 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with either [14C]ethylene- or ring-labeled drug rapidly reached equilibrium, was temperature independent, and attained a cell/medium ratio greater than unity. Uptake of 1

Uptake of acetaldehyde-modified (ethylated) low-density lipoproteins by mouse peritoneal macrophages.

PubMed

Wehr, Hanna; Mirkiewicz, Ewa; Rodo, Maria; Bednarska-Makaruk, Malgorzata

2002-04-01

The uptake of acetaldehyde-modified (ethylated) low-density lipoproteins (LDLs) by murine peritoneal macrophages is described and compared with the uptake of acetylated LDLs. The fluorescent marker DiI was used. No competition between ethylated and acetylated LDLs was observed. Ethylated LDL uptake was not inhibited by polyinosinic acid or fucoidin. Our conclusion is that uptake of ethylated and acetylated LDLs can be done by two different receptors.

Eicosapentaenoic and docosahexaenoic acid ethyl esters differentially enhance B-cell activity in murine obesity[S

PubMed Central

Teague, Heather; Harris, Mitchel; Fenton, Jenifer; Lallemand, Perrine; Shewchuk, Brian M.; Shaikh, Saame Raza

2014-01-01

EPA and DHA are not biologically equivalent; however, their individual activity on B cells is unknown. We previously reported fish oil enhanced murine B-cell activity in obesity. To distinguish between the effects of EPA and DHA, we studied the ethyl esters of EPA and DHA on murine B-cell function as a function of time. We first demonstrate that EPA and DHA maintained the obese phenotype, with no improvements in fat mass, adipose inflammatory cytokines, fasting insulin, or glucose clearance. We then tested the hypothesis that EPA and DHA would increase the frequency of splenic B cells. EPA and DHA differentially enhanced the frequency and/or percentage of select B-cell subsets, correlating with increased natural serum IgM and cecal IgA. We next determined the activities of EPA and DHA on ex vivo production of cytokines upon lipopolysaccharide stimulation of B cells. EPA and DHA, in a time-dependent manner, enhanced B-cell cytokines with DHA notably increasing IL-10. At the molecular level, EPA and DHA differentially enhanced the formation of ordered microdomains but had no effect on Toll-like receptor 4 mobility. Overall, the results establish differential effects of EPA and DHA in a time-dependent manner on B-cell activity in obesity, which has implications for future clinical studies. PMID:24837990

Antileukemic Efficacy of Continuous vs Discontinuous Dexamethasone in Murine Models of Acute Lymphoblastic Leukemia

PubMed Central

Ramsey, Laura B.; Janke, Laura J.; Payton, Monique A.; Cai, Xiangjun; Paugh, Steven W.; Karol, Seth E.; Kamdem, Landry Kamdem; Cheng, Cheng; Williams, Richard T.; Jeha, Sima; Pui, Ching-Hon; Evans, William E.; Relling, Mary V.

2015-01-01

Osteonecrosis is one of the most common, serious, toxicities resulting from the treatment of acute lymphoblastic leukemia. In recent years, pediatric acute lymphoblastic leukemia clinical trials have used discontinuous rather than continuous dosing of dexamethasone in an effort to reduce the incidence of osteonecrosis. However, it is not known whether discontinuous dosing would compromise antileukemic efficacy of glucocorticoids. Therefore, we tested the efficacy of discontinuous dexamethasone against continuous dexamethasone in murine models bearing human acute lymphoblastic leukemia xenografts (n = 8 patient samples) or murine BCR-ABL+ acute lymphoblastic leukemia. Plasma dexamethasone concentrations (7.9 to 212 nM) were similar to those achieved in children with acute lymphoblastic leukemia using conventional dosages. The median leukemia-free survival ranged from 16 to 59 days; dexamethasone prolonged survival from a median of 4 to 129 days in all seven dexamethasone-sensitive acute lymphoblastic leukemias. In the majority of cases (7 of 8 xenografts and the murine BCR-ABL model) we demonstrated equal efficacy of the two dexamethasone dosing regimens; whereas for one acute lymphoblastic leukemia sample, the discontinuous regimen yielded inferior antileukemic efficacy (log-rank p = 0.002). Our results support the clinical practice of using discontinuous rather than continuous dexamethasone dosing in patients with acute lymphoblastic leukemia. PMID:26252865

Beneficial effects of spin-labelled nitrosourea on CCNU-induced oxidative stress in rat blood compared with vitamin E.

PubMed

Gadjeva, V; Kuchukova, D; Tolekova, A; Tanchev, S

2005-07-01

This study was carried out to determine the effects of a recently synthesized 1-ethyl-3-[4-(2,2,6,6-tetra-methylpiperidine-1-oxyl)]-1-nitrosourea (SLENU), compared with vitamin E as a positive control, on 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU)-induced oxidative stress in rats. We determined plasma malonyl dialdehyde (MDA) levels and the activities of erythrocyte superoxide dismutase (SOD) and catalase (CAT). Forty two white albino healthy rats were treated once daily for 30 days with oral preparations of CCNU (12.5 mg/kg and 25 mg/kg), SLENU (25-200 mg/kg), and combinations of these. The CCNU-induced increase in plasma MDA level and the usual decrease in erythrocyte SOD and CAT activities were reversed by SLENU, but not by vitamin E. We have previously demonstrated that SLENU is a superoxide scavenger. A combination of our present findings with previous results thus leads us to proposing a new chemotherapeutic combination of CCNU and SLENU that is devoid of high toxicity.

Box-modeling of 15N/14N in mammals.

PubMed

Balter, Vincent; Simon, Laurent; Fouillet, Hélène; Lécuyer, Christophe

2006-03-01

The 15N/14N signature of animal proteins is now commonly used to understand their physiology and quantify the flows of nutrient in trophic webs. These studies assume that animals are predictably 15N-enriched relative to their food, but the isotopic mechanism which accounts for this enrichment remains unknown. We developed a box model of the nitrogen isotope cycle in mammals in order to predict the 15N/14N ratios of body reservoirs as a function of time, N intake and body mass. Results of modeling show that a combination of kinetic isotope fractionation during the N transfer between amines and equilibrium fractionation related to the reversible conversion of N-amine into ammonia is required to account for the well-established approximately 4 per thousand 15N-enrichment of body proteins relative to the diet. This isotopic enrichment observed in proteins is due to the partial recycling of 15N-enriched urea and the urinary excretion of a fraction of the strongly 15N-depleted ammonia reservoir. For a given body mass and diet delta15N, the isotopic compositions are mainly controlled by the N intake. Increase of the urea turnover combined with a decrease of the N intake lead to calculate a delta15N increase of the proteins, in agreement with the observed increase of collagen delta15N of herbivorous animals with aridity. We further show that the low delta15N collagen values of cave bears cannot be attributed to the dormancy periods as it is commonly thought, but inversely to the hyperphagia behavior. This model highlights the need for experimental investigations performed with large mammals in order to improve our understanding of natural variations of delta15N collagen.

Treatment of mycosis fungoides with topical nitrosourea compounds: Further studies.

PubMed

Zackheim, H S; Epstein, E H

1975-12-01

Twenty-six patients with mycosis fungoides were treated topically with three nitrosourea compounds: carmustine (BCNU), lomustine (CCNU), and 1-methyl-1-nitrosourea. A high percentage experienced good to excellent results. Remissions following treatment of individual lesions varied from one month to at least three years. Remissions following total body surface treatment varied from two weeks to at least four months. Two of 13 patients treated over the entire body suffered temporary bone marrow depression, indluding one with severe pancytopenia. This toxic effect was attributed to lomustine and was not seen in patients treated with carmustine alone. Thirteen patients highly allergic to mechlorethamine hydrochloride showed no cross-sensitivity to nitrosourea compounds. A primary irritant dermatitis occurred in about one half of the patients and telangiectasia in two. Two patients developed hypersensitivity to nitrosourea compounds. Carmustine is the preferred nitrosourea compound for topical therapy of mycosis fungoides.

Enantioselective quantitation of the ecstasy compound (R)- and (S)-N-ethyl-3,4-methylenedioxyamphetamine and its major metabolites in human plasma and urine.

PubMed

Buechler, Jochen; Schwab, Matthias; Mikus, Gerd; Fischer, Beate; Hermle, Leo; Marx, Claudia; Grön, Georg; Spitzer, Manfred; Kovar, Karl Artur

2003-08-15

An enantioselective HPLC method has been developed and validated for the stereospecific analysis of N-ethyl-3,4-methylenedioxyamphetamine (MDE) and its major metabolites N-ethyl-4-hydroxy-3-methoxyamphetamine (HME) and 3,4-methylenedioxyamphetamine (MDA). These compounds have been analyzed both from human plasma and urine after administration of 70 mg pure MDE-hydrochloride enantiomers to four subjects. The samples were prepared by hydrolysis of the o-glucuronate and sulfate conjugates using beta-glucuronidase/arylsulfatase and solid-phase extraction with a cation-exchange phase. A chiral stationary protein phase (chiral-CBH) was used for the stereoselective determination of MDE, HME and MDA in a single HPLC run using sodium dihydrogenphosphate, ethylendiaminetetraacetic acid disodium salt and isopropanol as the mobile phase (pH 6.44) and fluorimetric detection (lambda(ex) 286 nm, lambda(em) 322 nm). Moreover, a suitable internal standard (N-ethyl-3,4-methylenedioxybenzylamine) was synthesized and qualified for quantitation purposes. The method showed high recovery rates (>95%) and limits of quantitation for MDE and MDA of 5 ng/ml and for HME of 10 ng/ml. The RSDs for all working ranges of MDE, MDA and HME in plasma and urine, respectively, were less than 1.5%. After validation of the analytical methods in plasma and urine samples pharmacokinetic parameters were calculated. The plasma concentrations of (R)-MDE exceeded those of the S-enantiomer (ratio R:S of the area under the curve, 3.1) and the plasma half time of (R)-MDE was longer than that of (S)-MDE (7.9 vs. 4.0 h). In contrast, the stereochemical disposition of the MDE metabolites HME and MDA was reversed. Concentrations of the (S)-metabolites in plasma of volunteers were much higher than those of the (R)-enantiomers.

Rpl27a mutation in the sooty foot ataxia mouse phenocopies high p53 mouse models

PubMed Central

Terzian, Tamara; Dumble, Melissa; Arbab, Farinaz; Thaller, Christina; Donehower, Lawrence A; Lozano, Guillermina; Justice, Monica J; Roop, Dennis R; Box, Neil F

2013-01-01

Ribosomal stress is an important, yet poorly understood, mechanism that results in activation of the p53 tumour suppressor. We present a mutation in the ribosomal protein Rpl27a gene (sooty foot ataxia mice), isolated through a sensitized N-ethyl-N-nitrosourea (ENU) mutagenesis screen for p53 pathway defects, that shares striking phenotypic similarities with high p53 mouse models, including cerebellar ataxia, pancytopenia and epidermal hyperpigmentation. This phenocopy is rescued in a haploinsufficient p53 background. A detailed examination of the bone marrow in these mice identified reduced numbers of haematopoietic stem cells and a p53-dependent c-Kit down-regulation. These studies suggest that reduced Rpl27a increases p53 activity in vivo, further evident with a delay in tumorigenesis in mutant mice. Taken together, these data demonstrate that Rpl27a plays a crucial role in multiple tissues and that disruption of this ribosomal protein affects both development and transformation. PMID:21674502

Effects of methylphenidate on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4).

PubMed

Hauser, Joachim; Reissmann, Andreas; Sontag, Thomas-A; Tucha, Oliver; Lange, Klaus W

2017-05-01

The aim of this study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on attention in rats as measured using the 5-choice-serial-reaction-time task (5CSRTT) and to investigate whether methylphenidate has effects on DSP4-treated rats. Methylphenidate is a noradrenaline and dopamine reuptake inhibitor and commonly used in the pharmacological treatment of individuals with attention deficit/hyperactivity disorder (ADHD). Wistar rats were trained in the 5CSRTT and treated with one of three doses of DSP4 or saline. Following the DSP4 treatment rats were injected with three doses of methylphenidate or saline and again tested in the 5CSRTT. The treatment with DSP4 caused a significant decline of performance in the number of correct responses and a decrease in response accuracy. A reduction in activity could also be observed. Whether or not the cognitive impairments are due to attention deficits or changes in explorative behaviour or activity remains to be investigated. The treatment with methylphenidate had no beneficial effect on the rats' performance regardless of the DSP4 treatment. In the group without DSP4 treatment, methylphenidate led to a reduction in response accuracy and bidirectional effects in regard to parameters related to attention. These findings support the role of noradrenaline in modulating attention and call for further investigations concerning the effects of methylphenidate on attentional processes in rats.

Comparison of vectorial ion transport in primary murine airway and human sinonasal air-liquid interface cultures, models for studies of cystic fibrosis, and other airway diseases.

PubMed

Zhang, Shaoyan; Fortenberry, James A; Cohen, Noam A; Sorscher, Eric J; Woodworth, Bradford A

2009-01-01

The purpose of this study was to compare vectorial ion transport within murine trachea, murine nasal septa, and human sinonasal cultured epithelium. Our hypothesis is that murine septal epithelium, rather than trachea, will more closely mimic the electrophysiology properties of human sinonasal epithelium. Epithelium from murine trachea, murine septa, and human sinonasal tissue were cultured at an air-liquid interface to confluence and full differentiation. A limited number of homozygous dF508 epithelia were also cultured. Monolayers were mounted in modified Ussing chambers to investigate pharmacologic manipulation of ion transport. The change in forskolin-stimulated current (delta-I(SC), expressed as micro-A/cm(2)) in murine septal (n = 19; 16.84 +/- 2.09) and human sinonasal (n = 18; 12.15 +/- 1.93) cultures was significantly increased over murine tracheal cultures (n = 15; 6.75 +/- 1.35; p = 0.035 and 0.0005, respectively). Forskolin-stimulated I(SC) was inhibited by the specific cystic fibrosis transmembrane regulator (CFTR) inhibitor INH-172 (5 microM). No forskolin-stimulated I(SC) was shown in cultures of dF508 homozygous murine septal epithelium (n = 3). Murine septal I(SC) was largely inhibited by amiloride (12.03 +/- 0.66), whereas human sinonasal cultures had a very limited response (0.70 +/- 0.47; p < 0.0001). The contribution of CFTR to stimulated chloride current as measured by INH-172 was highly significantly different between all groups (murine septa, 19.51 +/- 1.28; human sinonasal, 11.12 +/- 1.58; murine trachea, 4.85 +/- 0.49; p < 0.0001). Human sinonasal and murine septal epithelial cultures represent a useful model for studying CFTR activity and may provide significant advantages over lower airway tissues for investigating upper and lower respiratory pathophysiology.

Evaluation of Brain Nuclear Medicine Imaging Tracers in a Murine Model of Sepsis-Associated Encephalopathy.

PubMed

Szöllősi, Dávid; Hegedűs, Nikolett; Veres, Dániel S; Futó, Ildikó; Horváth, Ildikó; Kovács, Noémi; Martinecz, Bernadett; Dénes, Ádám; Seifert, Daniel; Bergmann, Ralf; Lebeda, Ondřej; Varga, Zoltán; Kaleta, Zoltán; Szigeti, Krisztián; Máthé, Domokos

2018-05-07

The purpose of this study was to evaluate a set of widely used nuclear medicine imaging agents as possible methods to study the early effects of systemic inflammation on the living brain in a mouse model of sepsis-associated encephalopathy (SAE). The lipopolysaccharide (LPS)-induced murine systemic inflammation model was selected as a model of SAE. C57BL/6 mice were used. A multimodal imaging protocol was carried out on each animal 4 h following the intravenous administration of LPS using the following tracers: [ 99m Tc][2,2-dimethyl-3-[(3E)-3-oxidoiminobutan-2-yl]azanidylpropyl]-[(3E)-3-hydroxyiminobutan-2-yl]azanide ([ 99m Tc]HMPAO) and ethyl-7-[ 125 I]iodo-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate ([ 125 I]iomazenil) to measure brain perfusion and neuronal damage, respectively; 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) to measure cerebral glucose uptake. We assessed microglia activity on another group of mice using 2-[6-chloro-2-(4-[ 125 I]iodophenyl)-imidazo[1,2-a]pyridin-3-yl]-N-ethyl-N-methyl-acetamide ([ 125 I]CLINME). Radiotracer uptakes were measured in different brain regions and correlated. Microglia activity was also assessed using immunohistochemistry. Brain glutathione levels were measured to investigate oxidative stress. Significantly reduced perfusion values and significantly enhanced [ 18 F]FDG and [ 125 I]CLINME uptake was measured in the LPS-treated group. Following perfusion compensation, enhanced [ 125 I]iomazenil uptake was measured in the LPS-treated group's hippocampus and cerebellum. In this group, both [ 18 F]FDG and [ 125 I]iomazenil uptake showed highly negative correlation to perfusion measured with ([ 99m Tc]HMPAO uptake in all brain regions. No significant differences were detected in brain glutathione levels between the groups. The CD45 and P2Y12 double-labeling immunohistochemistry showed widespread microglia activation in the LPS-treated group. Our results suggest that [ 125 I]CLINME and [ 99m Tc

Defining Simple nD Operations Based on Prosmatic nD Objects

NASA Astrophysics Data System (ADS)

Arroyo Ohori, K.; Ledoux, H.; Stoter, J.

2016-10-01

An alternative to the traditional approaches to model separately 2D/3D space, time, scale and other parametrisable characteristics in GIS lies in the higher-dimensional modelling of geographic information, in which a chosen set of non-spatial characteristics, e.g. time and scale, are modelled as extra geometric dimensions perpendicular to the spatial ones, thus creating a higher-dimensional model. While higher-dimensional models are undoubtedly powerful, they are also hard to create and manipulate due to our lack of an intuitive understanding in dimensions higher than three. As a solution to this problem, this paper proposes a methodology that makes nD object generation easier by splitting the creation and manipulation process into three steps: (i) constructing simple nD objects based on nD prismatic polytopes - analogous to prisms in 3D -, (ii) defining simple modification operations at the vertex level, and (iii) simple postprocessing to fix errors introduced in the model. As a use case, we show how two sets of operations can be defined and implemented in a dimension-independent manner using this methodology: the most common transformations (i.e. translation, scaling and rotation) and the collapse of objects. The nD objects generated in this manner can then be used as a basis for an nD GIS.

Feasibility and scalability of spring parameters in distraction enterogenesis in a murine model.

PubMed

Huynh, Nhan; Dubrovsky, Genia; Rouch, Joshua D; Scott, Andrew; Stelzner, Matthias; Shekherdimian, Shant; Dunn, James C Y

2017-07-01

Distraction enterogenesis has been investigated as a novel treatment for short bowel syndrome (SBS). With variable intestinal sizes, it is critical to determine safe, translatable spring characteristics in differently sized animal models before clinical use. Nitinol springs have been shown to lengthen intestines in rats and pigs. Here, we show spring-mediated intestinal lengthening is scalable and feasible in a murine model. A 10-mm nitinol spring was compressed to 3 mm and placed in a 5-mm intestinal segment isolated from continuity in mice. A noncompressed spring placed in a similar fashion served as a control. Spring parameters were proportionally extrapolated from previous spring parameters to accommodate the smaller size of murine intestines. After 2-3 wk, the intestinal segments were examined for size and histology. Experimental group with spring constants, k = 0.2-1.4 N/m, showed intestinal lengthening from 5.0 ± 0.6 mm to 9.5 ± 0.8 mm (P < 0.0001), whereas control segments lengthened from 5.3 ± 0.5 mm to 6.4 ± 1.0 mm (P < 0.02). Diameter increased similarly in both groups. Isolated segment perforation was noted when k ≥ 0.8 N/m. Histologically, lengthened segments had increased muscularis thickness and crypt depth in comparison to normal intestine. Nitinol springs with k ≤ 0.4 N/m can safely yield nearly 2-fold distraction enterogenesis in length and diameter in a scalable mouse model. Not only does this study derive the safe ranges and translatable spring characteristics in a scalable murine model for patients with short bowel syndrome, it also demonstrates the feasibility of spring-mediated intestinal lengthening in a mouse, which can be used to study underlying mechanisms in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

Decomposition reactions of (hydroxyalkyl) nitrosoureas and related compounds: possible relationship to carcinogenicity.

PubMed

Singer, S S

1985-08-01

(Hydroxyalkyl)nitrosoureas and the related cyclic carbamates N-nitrosooxazolidones are potent carcinogens. The decompositions of four such compounds, 1-nitroso-1-(2-hydroxyethyl)urea (I), 3-nitrosooxazolid-2-one (II), 1-nitroso-1-(2-hydroxypropyl)urea (III), and 5-methyl-3-nitrosooxazolid-2-one (IV), in aqueous buffers at physiological pH were studied to determine if any obvious differences in decomposition pathways could account for the variety of tumors obtained from these four compounds. The products predicted by the literature mechanisms for nitrosourea and nitrosooxazolidone decompositions (which were derived from experiments at pH 10-12) were indeed the products formed, including glycols, active carbonyl compounds, epoxides, and, from the oxazolidones, cyclic carbonates. Furthermore, it was shown that in pH 6.4-7.4 buffer epoxides were stable reaction products. However, in the presence of hepatocytes, most of the epoxide was converted to glycol. The analytical methods developed were then applied to the analysis of the decomposition products of some related dialkylnitrosoureas, and similar results were obtained. The formation of chemically reactive secondary products and the possible relevance of these results to carcinogenesis studies are discussed.

Mechanism of action of (2-haloethyl)nitrosoureas on DNA. Isolation and reactions of postulated 2-(alkylimino)-3-nitrosooxazolidine intermediates in the decomposition of 1,3-bis(2-chloroethyl)-, 1-(2-chloroethyl)-3-cyclohexyl-, and 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)-1-nitrosourea.

PubMed

Lown, J W; Chauhan, S M

1981-03-01

Three examples of the postulated but hitherto unisolated 2-(alkylimino)-3-nitrosooxazolidines (2) have been prepared containing cyclohexyl, trans-4-methylcyclohexyl, and 2-chloroethyl groups at the 2 position, respectively. These compounds correspond to intermediates previously postulated to be formed in the aqueous decomposition of the antitumor agents 1-(2-chloroethyl)-3-cyclohexyl- (CCNU), 1-(2-chloroethyl)-3-(4'-trans-methylcyclohexyl)- (MeCCNU), and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), respectively, Compounds 2 decompose under physiological conditions to give a range of products similar to those formed from the corresponding (2-chloroethyl)nitrosoureas, including the hitherto unrecognized 2-hydroxyethl N-alkylcarbamates (9). Compounds 2a and 2b are converted with hydrochloric acid into CCNU and MeCCNU, respectively, suggesting that 2a and 2b may be reaction intermediates of decomposition. The corresponding 3-alkyl-1-nitroso-1-(2-hydroxyethyl)ureas (4) were characterized and, since they also decompose to give the same products as 2, may arise from the ring opening of 2. The intermediacy of compounds 4 can explain the formation of hydroxyethylated nucleosides isolated by other workers from the reaction of (2-chloroethyl)nitrosoureas on polynucleotides.

Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma.

PubMed

Firinci, Fatih; Karaman, Meral; Baran, Yusuf; Bagriyanik, Alper; Ayyildiz, Zeynep Arikan; Kiray, Muge; Kozanoglu, Ilknur; Yilmaz, Osman; Uzuner, Nevin; Karaman, Ozkan

2011-08-01

Asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. Mesenchymal stem cells (MSCs) are promising for the development of novel therapies in regenerative medicine. This study aimed to examine the efficacy of MSCs on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: Group 1 (control group, n=6), Group 2 (ovalbumin induced asthma only, n=10), Group 3 (ovalbumin induced asthma + MSCs, n=10), and Group 4 (MSCs only, n=10). Histological findings (basement membrane, epithelium, subepithelial smooth muscle thickness, numbers of goblet and mast cells) of the airways and MSC migration were evaluated by light, electron, and confocal microscopes. In Group 3, all early histopathological changes except epithelial thickness and all of the chronic changes were significantly ameliorated when compared with Group 2. Evaluation with confocal microscopy showed that no noteworthy amount of MSCs were present in the lung tissues of Group 4 while significant amount of MSCs was detected in Group 3. Serum NO levels in Group 3, were significantly lower than Group 2. The results of this study revealed that MSCs migrated to lung tissue and ameliorated bronchial asthma in murine model. Further studies are needed to evaluate the efficacy of MSCs for the treatment of asthma. Copyright © 2011 Elsevier B.V. All rights reserved.

Evaluation of genotoxic activity of maleic hydrazide, ethyl methane sulfonate, and N-nitroso diethylamine in Tradescantia.

PubMed

Alvarez-Moya, C; Santerre-Lucas, A; Zúñiga-González, G; Torres-Bugarín, O; Padilla-Camberos, E; Feria-Velasco, A

2001-01-01

To assess the genotoxic activity of N-nitroso diethylamine (NDEA), maleic hydrazide (MH), and ethyl methane sulfonate (EMS) using two systems: the comet assay on nuclei from Tradescantia, and the pink mutation test on Tradescantia staminal hairs (clone 4430). Tradescantia cups was obtained from Laboratorio de Citogenética y Mutagénesis del Centro de Ciencias de la Atmósfera de la Universidad Nacional Autónoma de México and treated with: N-nitroso diethylamine (NDEA) at 1, 5, 10 mM, maleic hydrazide (MH) at 1, 5, 10 mM and ethyl methane sulfonate (EMS) at 15, 30 and 45 mM; and used in both pink mutation assay and comet assay using cellular nuclei from Tradescantia staminal hairs. The observation of staminal hair was realized along eight days (6-14) after treatment), flowers produced day 14 after treatment were utilized done according to Underbrink. In previous reports on plants, were comet assay was used, breaking cellular wall and separating by centrifugation gradient are necessary. Here, nuclei from staminal hairs were obtained by squashing the cells (is not necessary to utilize to break special procedure cellular wall), collected using a nylon mesh of 80 Mm and next the comet assay was applied. Student's T test was the statistical test used for analyzing the comet assay data. Both assays showed a great sensitivity to the studied mutagens. A relationship between the dose-pink event and the dose-tail length was evident. Even though the Tradescantia mutation assay is a sensitive test with MH and EMS, low doses of NDEA were not able to induce a significant increase in the pink event frequencies; however, the comet assay was able to detect the mutagenic effect of NDEA at the same dose. Thus, it is clear that the comet assay is highly sensitive to the lowest dose of chemical mutagens. The comet assay on nuclei from Tradescantia staminal hairs is a useful tool to monitor genotoxic agents; it is simple, highly sensitive, and faster than the pink mutation test.

No Promoting Effect of Ethyl Tertiary-butyl Ether (ETBE) on Rat Urinary Bladder Carcinogenesis Initiated with N-Butyl-N-(4-hydroxybutyl)nitrosamine

PubMed Central

Hagiwara, Akihiro; Imai, Norio; Doi, Yuko; Suguro, Mayuko; Kawabe, Mayumi; Furukawa, Fumio; Nagano, Kasuke; Fukushima, Shoji

2013-01-01

The effects of ethyl tertiary-butyl ether (ETBE) on two-stage urinary bladder carcinogenesis in male F344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were investigated at various dose levels with regard to possible promoting activity. Groups of 30 rats were given drinking water containing 500 ppm BBN, as an initiator, for 4 weeks and starting one week thereafter received ETBE by gavage (daily, 7 days/week) at dose levels of 0 (control), 100, 300, 500 or 1000 mg/kg/day until experimental week 36. No statistically significant differences in incidences of preneoplastic lesions, papillomas, and carcinomas of the urinary bladder were evident in rats treated with 100–1000 mg/kg/day ETBE as compared with control values. Furthermore, the average numbers of preneoplastic or neoplastic lesions per unit length of basement membrane in rats given 100–1000 mg/kg/day ETBE were also comparable to control values. However, papillomatosis of the urinary bladder was found in 4 out of 30 rats (13%) in the group given 1000 mg/kg/day ETBE, and soft stones in the urinary bladder were found in 3 out of these 4 rats. The results thus demonstrated that ETBE did not exert promotional activity on urinary bladder carcinogenesis. However, papillomatosis of the urinary bladder developed in small numbers of the rats given ETBE at 1000 mg/kg/day but not in rats given 500 mg/kg/day or lower doses. PMID:24526807

AGT, N-Burge partitions and {{W}}_N minimal models

NASA Astrophysics Data System (ADS)

Belavin, Vladimir; Foda, Omar; Santachiara, Raoul

2015-10-01

Let {B}_{N,n}^{p,p', H} be a conformal block, with n consecutive channels χ ι , ι = 1, ⋯ n, in the conformal field theory {M}_N^{p,p'× {M}^{H} , where {M}_N^{p,p' } is a {W}_N minimal model, generated by chiral spin-2, ⋯ spin- N currents, and labeled by two co-prime integers p and p', 1 < p < p', while {M}^{H} is a free boson conformal field theory. {B}_{N,n}^{p,p', H} is the expectation value of vertex operators between an initial and a final state. Each vertex operator is labelled by a charge vector that lives in the weight lattice of the Lie algebra A N - 1, spanned by weight vectors {overrightarrow{ω}}_1,\\cdots, {overrightarrow{ω}}_{N-1} . We restrict our attention to conformal blocks with vertex operators whose charge vectors point along {overrightarrow{ω}}_1 . The charge vectors that label the initial and final states can point in any direction.

Murine respiratory mycoplasmosis (MRM) in C57BL/6N and C3H/HeN mice: strain differences in early host responses and exacerbation by nitrogen dioxide

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

Parker, R.F.

1987-01-01

The studies reported here used genetic differences in susceptibility of C57BL/6N and C3H/HeN mice and exacerbation of the disease by nitrogen dioxide (NO/sub 2/) as tools in assessing the role of early host responses in the pathogenesis of MRM. The two strains did not differ in susceptibility to infection, but C3H/HeN mice were more susceptible to and had increased severity of lung lesions 14 days after intranasal inoculation as determined by 50% biological endpoints and morphometric analysis of tissues. Exposure to NO/sub 2/ for 4 hours prior to exposure to infectious aerosols exacerbated murine respiratory mycoplasmosis (MRM) by 7 daysmore » after exposure in both mouse strains. NO/sub 2/ appeared to affect host lung defense mechanisms responsible for limiting mycoplasmal growth in the lungs. The NO/sub 2/ exposure concentration required for this effect varied with the genetic background of the host, the dose of mycoplasmas administered, and the endpoint measured. Pulmonary clearance of radiolabeled M. pulmonis was determined in both mouse strains, and in C57BL/6N mice exposed to NO/sub 2/.« less

Serpina3n accelerates tissue repair in a diabetic mouse model of delayed wound healing.

PubMed

Hsu, I; Parkinson, L G; Shen, Y; Toro, A; Brown, T; Zhao, H; Bleackley, R C; Granville, D J

2014-10-09

Chronic, non-healing wounds are a major complication of diabetes and are characterized by chronic inflammation and excessive protease activity. Although once thought to function primarily as a pro-apoptotic serine protease, granzyme B (GzmB) can also accumulate in the extracellular matrix (ECM) during chronic inflammation and cleave ECM proteins that are essential for proper wound healing, including fibronectin. We hypothesized that GzmB contributes to the pathogenesis of impaired diabetic wound healing through excessive ECM degradation. In the present study, the murine serine protease inhibitor, serpina3n (SA3N), was administered to excisional wounds created on the dorsum of genetically induced type-II diabetic mice. Wound closure was monitored and skin wound samples were collected for analyses. Wound closure, including both re-epithelialization and contraction, were significantly increased in SA3N-treated wounds. Histological and immunohistochemical analyses of SA3N-treated wounds revealed a more mature, proliferative granulation tissue phenotype as indicated by increased cell proliferation, vascularization, fibroblast maturation and differentiation, and collagen deposition. Skin homogenates from SA3N-treated wounds also exhibited greater levels of full-length intact fibronectin compared with that of vehicle wounds. In addition, GzmB-induced detachment of mouse embryonic fibroblasts correlated with a rounded and clustered phenotype that was prevented by SA3N. In summary, topical administration of SA3N accelerated wound healing. Our findings suggest that GzmB contributes to the pathogenesis of diabetic wound healing through the proteolytic cleavage of fibronectin that is essential for normal wound closure, and that SA3N promotes granulation tissue maturation and collagen deposition.

Nitrosoureas in the Management of Malignant Gliomas.

PubMed

Brandes, Alba A; Bartolotti, Marco; Tosoni, Alicia; Franceschi, Enrico

2016-02-01

Nitrosoureas represent one of the most active classes of agents in the treatment of high-grade gliomas and glioblastoma. In clinical practice, the most commonly used compounds are lomustine (either alone or in combination with procarbazine and vincristine), carmustine, and fotemustine. Given their toxicity profile and subsequent to the introduction of temozolomide in clinical practice, most of these agents were moved to the recurrent setting. This review focuses on the role of the nitrosoureas currently used in clinical practice for the treatment of malignant gliomas.

The effect of isoprenaline on induction of tumours by methyl nitrosourea in the salivary and mammary glands of female wistar rats.

PubMed Central

Parkin, R.; Neale, S.

1976-01-01

Pretreatment of rats with isoprenaline sulphate (IPR) stimulated DNA synthesis in both salivary and mammary gland tissues. Salivary gland tumours induced by N-methyl-N-nitrosourea (MNU) were observed for the first time in rats, but occurred only in IPR-pretreated animals given MNU during the period of IPR-stimulated DNA synthesis. The cumulative index of MNU-induced mammary tumours and the number of tumours per tumour-bearing rat were increased by IPR-pretreament only if the animals received MNU during the period of IPR-stimulated DNA synthesis. PMID:974007

Heteropolyhedral silver compounds containing the polydentate ligand N,N,O-E-[6-(hydroxyimino)ethyl]-1,3,7-trimethyllumazine. Preparation, spectral and XRD structural study and AIM calculations.

PubMed

Jiménez-Pulido, Sonia B; Hueso-Ureña, Francisco; Fernández-Liencres, M Paz; Fernández-Gómez, Manuel; Moreno-Carretero, Miguel N

2013-01-14

The oxime derived from 6-acetyl-1,3,7-trimethyllumazine (1) ((E-6-(hydroxyimino)ethyl)-1,3,7-trimethylpteridine-2,4(1H,3H)-dione, DLMAceMox) has been prepared and its molecular and crystal structure determined from spectral and XRD data. The oxime ligand was reacted with silver nitrate, perchlorate, thiocyanate, trifluoromethylsulfonate and tetrafluoroborate to give complexes with formulas [Ag(2)(DLMAceMox)(2)(NO(3))(2)](n) (2), [Ag(2)(DLMAceMox)(2)(ClO(4))(2)](n) (3), [Ag(2)(DLMAceMox)(2)(SCN)(2)] (4), [Ag(2)(DLMAceMox)(2)(CF(3)SO(3))(2)(CH(3)CH(2)OH)]·CH(3)CH(2)OH (5) and [Ag(DLMAceMox)(2)]BF(4) (6). Single-crystal XRD studies show that the asymmetrical residual unit of complexes 2, 3 and 5 contains two quite different but connected silver centers (Ag1-Ag2, 2.9-3.2 Å). In addition to this, the Ag1 ion displays coordination with the N5 and O4 atoms from both lumazine moieties and a ligand (nitrato, perchlorato or ethanol) bridging to another disilver unit. The Ag2 ion is coordinated to the N61 oxime nitrogens, a monodentate and a (O,O)-bridging nitrato/perchlorato or two monodentate O-trifluoromethylsulfonato anions. The coordination polyhedra can be best described as a strongly distorted octahedron (around Ag1) and a square-based pyramid (around Ag2). The Ag-N and Ag-O bond lengths range between 2.22-2.41 and 2.40-2.67 Å, respectively. Although the structure of 4 cannot be resolved by XRD, it is likely to be similar to those described for 2, 3 and 5, containing Ag-Ag units with S-thiocyanato terminal ligands. Finally, the structure of the tetrafluoroborate compound 6 is mononuclear with a strongly distorted tetrahedral AgN(4) core (Ag-N, 2.27-2.43 Å). Always, the different Ag-N distances found clearly point to the more basic character of the oxime N61 nitrogen atom when compared with the pyrazine N5 one. A topological analysis of the electron density within the framework provided by the quantum theory of atoms in molecules (QTAIM) using DFT(M06L) levels of

Assessment of new biocompatible poly(N-(morpholino)ethyl methacrylate)-based copolymers by transfection of immortalized keratinocytes.

PubMed

Van Overstraeten-Schlögel, Nancy; Shim, Yong-Ho; Tevel, Virginie; Piel, Géraldine; Piette, Jacques; Dubois, Philippe; Raes, Martine

2012-02-01

Skin carcinomas are among the most commonly diagnosed tumors in the world. In this study, we investigated the transfection of immortalized keratinocytes, used as an in vitro model for skin carcinoma, using the antisense technology and poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA)-based copolymers. In order to improve the transfection efficiency of the classic PDMAEMA polymers, copolymers were synthesized including a poly(N-morpholino)ethylmethacrylate) (PMEMA) moiety for an improved proton-sponge effect, intended to favour the release of the oligonucleotide from the acidic endosome. These copolymers were synthesized either statistically (with alternating PDMAEMA and PMEMA fragments) or in blocks (one PDMAEMA block followed by one PMEMA block). MTT assays were performed using the PDMAEMA-PMEMA copolymers and revealed no significant cytotoxicity of these polymers at an N/P ratio of 7.3. Using fluorescent oligonucleotides and analyzing transfection efficiency by flow cytometry, we noticed no significant differences between the two kinds of copolymers. However copolymers with a higher DMAEMA content and a higher Mn were also those displaying the highest vectorization efficiency. Confocal microscopy showed that these copolymers induced a fine granular distribution of the transfected antisense oligonucleotides inside the cells. We also assessed the functionality of the transfected antisense oligonucleotide by transfecting immortalized GFP expressing keratinocytes with a GFP antisense oligonucleotide using these copolymers. A significant silencing was achieved with a PDMAEMA-PMEMA in block copolymer (Mn=41,000, 89 % PDMAEMA). Together, these results suggest that PDMAEMA-PMEMA copolymers combining low toxicity, vectorization and proton sponge properties, can be efficiently used to transfect immortalized keratinocytes and so open new perspectives in the therapy of skin carcinomas as well as of other skin diseases of genetic or immunological origin. © 2012 Informa

Modeling abundance using multinomial N-mixture models

USGS Publications Warehouse

Royle, Andy

2016-01-01

Multinomial N-mixture models are a generalization of the binomial N-mixture models described in Chapter 6 to allow for more complex and informative sampling protocols beyond simple counts. Many commonly used protocols such as multiple observer sampling, removal sampling, and capture-recapture produce a multivariate count frequency that has a multinomial distribution and for which multinomial N-mixture models can be developed. Such protocols typically result in more precise estimates than binomial mixture models because they provide direct information about parameters of the observation process. We demonstrate the analysis of these models in BUGS using several distinct formulations that afford great flexibility in the types of models that can be developed, and we demonstrate likelihood analysis using the unmarked package. Spatially stratified capture-recapture models are one class of models that fall into the multinomial N-mixture framework, and we discuss analysis of stratified versions of classical models such as model Mb, Mh and other classes of models that are only possible to describe within the multinomial N-mixture framework.

(E)-N'-[1-(Thio-phen-2-yl)ethyl-idene]isonicotinohydrazide.

PubMed

Dileep, C S; Abdoh, M M M; Chakravarthy, M P; Mohana, K N; Sridhar, M A

2012-10-01

In the title compound, C(12)H(11)N(3)OS, the dihedral angle between the pyridine and thio-phene rings is 46.70 (9)° and the C-N-N-C torsion angle is 178.61 (15)°. In the crystal, inversion dimers linked by pairs of N-H⋯O hydrogen bonds generate R(2) (2)(8) loops.

N-substituted imidazolines and ethylenediamines and their action on alpha- and beta-adrenergic receptors.

PubMed

Hamada, A; Yaden, E L; Horng, J S; Ruffolo, R R; Patil, P N; Miller, D D

1985-09-01

A series of N-substituted imidazolines and ethylenediamines were synthesized and examined for their activity in alpha- and beta-adrenergic systems. The length of the intermediate side chain between the catechol and imidazoline ring or the amine of the ethylenediamine segment was shown to affect the adrenergic activity. N-[2-(3,4-Dihydroxyphenyl)ethyl]imidazoline hydrochloride (2) and N-[2-(3,4-dihydroxyphenyl)ethyl]ethylenediamine dihydrochloride (4), both with two methylene groups between the catechol and amine segment, were found to be somewhat selective for alpha 2-adrenergic receptors while 1-(3,4-dihydroxybenzyl)imidazoline hydrochloride (1) and N-2-(3,4-dihydroxybenzyl)ethylenediamine dihydrochloride (3), both with one methylene group between the catechol and amine segment, were more selective for alpha1-adrenergic receptors in a pithed rat model. Of the four compounds examined, only compound 2 showed significant direct activity on beta1- and beta2-adrenergic receptors.

Developmental toxic effects of N-ethyl-2-pyrrolidone administered orally to rats.

PubMed

Saillenfait, A M; Gallissot, F; Sabaté, J P

2007-01-01

The developmental toxicity of N-ethyl-2-pyrrolidone (NEP) was studied in Sprague-Dawley rats after oral administration. Pregnant rats were given NEP at doses of 0 (distilled water), 50, 250, 500 and 750 mg kg(-1) day(-1), by gavage (5 ml kg(-1)), on gestational days (GD) 6-20. Maternal toxicity, as evidenced by reduction in body weight gain and food consumption, was observed in all NEP groups at the beginning of treatment (GD 6-9). The incidence of resorptions was significantly increased at 500 mg kg(-1) day(-1), and reached 83% at 750 mg kg(-1) day(-1). There was a dose-related decrease in fetal weight, which was significantly lower than control at 250 mg kg(-1) day(-1) and higher doses. The incidence of malformed fetuses per litter and the number of litters with malformed fetuses were significantly increased at 500 and 750 mg kg(-1) day(-1). Malformations mainly consisted of edema, anal atresia with absent tail, cardiovascular defects and fused cervical arches. Ossification of skull bones and sternebrae was significantly reduced at 500 and 750 mg kg(-1) day(-1). The incidence of supernumerary ribs was significantly elevated at 250 mg kg(-1) day(-1) and higher doses. In conclusion, NEP administered by gavage is embryotoxic and teratogenic at maternal toxic doses. (c) 2007 John Wiley & Sons, Ltd.

Evolution reversed: the ability to bind iron restored to the N-lobe of the murine inhibitor of carbonic anhydrase by strategic mutagenesis.

PubMed

Mason, Anne B; Judson, Gregory L; Bravo, Maria Cristina; Edelstein, Andrew; Byrne, Shaina L; James, Nicholas G; Roush, Eric D; Fierke, Carol A; Bobst, Cedric E; Kaltashov, Igor A; Daughtery, Margaret A

2008-09-16

The murine inhibitor of carbonic anhydrase (mICA) is a member of the superfamily related to the bilobal iron transport protein transferrin (TF), which binds a ferric ion within a cleft in each lobe. Although the gene encoding ICA in humans is classified as a pseudogene, an apparently functional ICA gene has been annotated in mice, rats, cows, pigs, and dogs. All ICAs lack one (or more) of the amino acid ligands in each lobe essential for high-affinity coordination of iron and the requisite synergistic anion, carbonate. The reason why ICA family members have lost the ability to bind iron is potentially related to acquiring a new function(s), one of which is inhibition of certain carbonic anhydrase (CA) isoforms. A recombinant mutant of the mICA (W124R/S188Y) was created with the goal of restoring the ligands required for both anion (Arg124) and iron (Tyr188) binding in the N-lobe. Absorption and fluorescence spectra definitively show that the mutant binds ferric iron in the N-lobe. Electrospray ionization mass spectrometry confirms the presence of both ferric iron and carbonate. At the putative endosomal pH of 5.6, iron is released by two slow processes indicative of high-affinity coordination. Induction of specific iron binding implies that (1) the structure of mICA resembles those of other TF family members and (2) the N-lobe can adopt a conformation in which the cleft closes when iron binds. Because the conformational change in the N-lobe indicated by metal binding does not impact the inhibitory activity of mICA, inhibition of CA was tentatively assigned to the C-lobe. Proof of this assignment is provided by limited trypsin proteolysis of porcine ICA.

Large-N solution of the heterotic CP(N-1) model with twisted masses

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

Bolokhov, Pavel A.; Department of Physics and Astronomy, University of Victoria, Victoria, BC, V8P 1A1; Shifman, Mikhail

2010-07-15

We address a number of unanswered questions in the N=(0,2)-deformed CP(N-1) model with twisted masses. In particular, we complete the program of solving the CP(N-1) model with twisted masses in the large-N limit. In A. Gorsky, M. Shifman, and A. Yung, Phys. Rev. D 73, 065011 (2006), a nonsupersymmetric version of the model with the Z{sub N} symmetric twisted masses was analyzed in the framework of Witten's method. In M. Shifman and A. Yung, Phys. Rev. D 77, 125017 (2008), this analysis was extended: the large-N solution of the heterotic N=(0,2) CP(N-1) model with no twisted masses was found. Heremore » we solve this model with the twisted masses switched on. Dynamical scenarios at large and small m are studied (m is the twisted-mass scale). We found three distinct phases and two phase transitions on the m plane. Two phases with the spontaneously broken Z{sub N} symmetry are separated by a phase with unbroken Z{sub N}. This latter phase is characterized by a unique vacuum and confinement of all U(1) charged fields (''quarks''). In the broken phases (one of them is at strong coupling) there are N degenerate vacua and no confinement, similarly to the situation in the N=(2,2) model. Supersymmetry is spontaneously broken everywhere except a circle |m|={Lambda} in the Z{sub N}-unbroken phase. Related issues are considered. In particular, we discuss the mirror representation for the heterotic model in a certain limiting case.« less

Complexities and sequence similarities of mRNA populations of cholinergic (NS20-Y) and adrenergic (N1E-115) murine neuroblastoma cell lines.

PubMed

Strauss, W L

1990-07-01

The clonal murine neuroblastoma cell lines NS20-Y and N1E-115 have been proposed as models for examining the commitment of neural crest cells to either the cholinergic or adrenergic phenotype, respectively. The validity of this model depends in part on the extent to which these two cell lines have diverged as a result of their transformed, rather than neuronal properties. In order to quantitate differences in gene expression between NS20-Y and N1E-115 cells, the mRNA complexity of each cell type was determined. An analysis of the kinetics of hybridization of NS20-Y cell mRNA with cDNA prepared from NS20-Y cell mRNA demonstrated the presence of approximately 11,700 mRNA species assuming an average length of 1900 nucleotides. A similar analysis using mRNA isolated from N1E-115 cells and cDNA prepared from N1E-115 cell mRNA demonstrated that the adrenergic cell line expressed approximately 11,600 mRNA species. The species of mRNA expressed by each cell line were resolved into high, intermediate, and low abundance populations. In order to determine whether mRNAs were expressed by the cholinergic, but not by the adrenergic cell line, NS20-Y cDNA was hybridized to an excess of N1E-115 cell mRNA. An analysis of the solution hybridization kinetics from this procedure demonstrated that the two cell lines do not differ significantly in the nucleotide complexity of their mRNA populations. The extensive similarity between the two mRNA populations suggests that only a small number of genes are expressed differentially between the two cell lines and supports their use as models for the differentiation of cholinergic and adrenergic neurons.

Usefulness of Icosapent Ethyl (Eicosapentaenoic Acid Ethyl Ester) in Women to Lower Triglyceride Levels (Results from the MARINE and ANCHOR Trials).

PubMed

Mosca, Lori; Ballantyne, Christie M; Bays, Harold E; Guyton, John R; Philip, Sephy; Doyle, Ralph T; Juliano, Rebecca A

2017-02-01

There are limited data on the efficacy and safety of triglyceride (TG)-lowering agents in women. We conducted subgroup analyses of the effects of icosapent ethyl (a high-purity prescription form of the ethyl ester of the omega-3 fatty acid, eicosapentaenoic acid) on TG levels (primary efficacy variable) and other atherogenic and inflammatory parameters in a total of 215 women with a broad range of TG levels (200-2000 mg/dl) enrolled in two 12-week placebo-controlled trials: MARINE (n = 18; placebo, n = 18) and ANCHOR (n = 91; placebo, n = 88). Icosapent ethyl 4 g/day significantly reduced TG levels from baseline to week 12 versus placebo in both MARINE (-22.7%; p = 0.0327) and ANCHOR (-21.5%; p <0.0001) without increasing low-density lipoprotein cholesterol levels. Significant improvements were also observed in non-high-density lipoprotein cholesterol levels in MARINE (-15.7%; p = 0.0082) and ANCHOR (-14.2%; p <0.0001) and total cholesterol levels in MARINE (-14.9%; p = 0.0023) and ANCHOR (-12.1%; p <0.0001), along with significant increases of >500% in eicosapentaenoic acid levels in plasma and red blood cells (all p <0.001). Icosapent ethyl was well tolerated, with adverse-event profiles comparable with findings in the overall studies. In conclusion, icosapent ethyl 4 g/day significantly reduced TG levels and other atherogenic parameters in women without increasing low-density lipoprotein cholesterol levels compared with placebo; the clinical implications of these findings are being evaluated in the REDUCtion of Cardiovascular Events With Eicosapentaenoic Acid [EPA]-Intervention Trial (REDUCE-IT) cardiovascular outcomes study. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

North American coral snake antivenin for the neutralization of non-native elapid venoms in a murine model.

PubMed

Richardson, William H; Tanen, David A; Tong, Tri C; Betten, David P; Carstairs, Shaun D; Williams, Saralyn R; Cantrell, Frank L; Clark, Richard F

2006-02-01

North American coral snake antivenin (CSAV; Wyeth Antivenin [Micrurus fulvius], equine origin) is approved for the treatment of coral snake envenomations in the United States. The coral snake is the only elapid that is native to North America, but envenomations from non-native elapids are occurring more commonly in this country. This study was designed to evaluate the efficacy of CSAV in the neutralization of two exotic elapid envenomations: Naja naja (Indian cobra) and Dendroaspis polylepsis (black mamba). A randomized, blinded, placebo-controlled murine model of intraperitoneal venom injection was employed. Venom potency was determined in preliminary dosing studies. Study animals then were divided into five groups: 1) N. naja venom + CSAV, 2) N. naja venom + 0.9% normal saline (NS), 3) D. polylepsis venom + CSAV, 4) D. polylepsis venom + NS, and 5) CSAV + NS. The venom dose was chosen to be twice the estimated LD50. The amount of CSAV injected was ten times the amount necessary for neutralization of a 2 x LD50 dose of M. f. fulvius venom in a murine model. Statistical analysis included Fisher's exact and log-rank testing to compare survival rates and times. Preliminary studies estimated the venom LD50 to be 2.58 mg/kg and 0.45 mg/kg, respectively, for the N. naja and D. polylepsis. A significant difference was shown in comparison of survival times between CSAV-venom groups and normal saline-venom groups despite all animals in both treatment and control arms dying. Animals receiving CSAV and N. naja venom survived (mean +/- SD) 24.4 +/- 3.0 minutes, versus 17.8 +/- 1.3 minutes in the control group (p < 0.001), whereas those receiving CSAV and D. polylepsis venom survived 203.8 +/- 37.0 minutes versus 130.0 +/- 42.6 minutes in the control group (p < 0.001). All animals in the CSAV + NS group survived to the conclusion of the study. When premixed with venom, CSAV increased survival time in a murine model of intraperitoneal N. naja and D. polylepsis venom injection

[Evaluation of Fusarium spp. pathogenicity in plant and murine models].

PubMed

Forero-Reyes, Consuelo M; Alvarado-Fernández, Angela M; Ceballos-Rojas, Ana M; González-Carmona, Lady C; Linares-Linares, Melva Y; Castañeda-Salazar, Rubiela; Pulido-Villamarín, Adriana; Góngora-Medina, Manuel E; Cortés-Vecino, Jesús A; Rodríguez-Bocanegra, María X

The genus Fusarium is widely recognized for its phytopathogenic capacity. However, it has been reported as an opportunistic pathogen in immunocompetent and immunocompromised patients. Thus, it can be considered a microorganism of interest in pathogenicity studies on different hosts. Therefore, this work evaluated the pathogenicity of Fusarium spp. isolates from different origins in plants and animals (murine hosts). Twelve isolates of Fusarium spp. from plants, animal superficial mycoses, and human superficial and systemic mycoses were inoculated in tomato, passion fruit and carnation plants, and in immunocompetent and immunosuppressed BALB/c mice. Pathogenicity tests in plants did not show all the symptoms associated with vascular wilt in the three plant models; however, colonization and necrosis of the vascular bundles, regardless of the species and origin of the isolates, showed the infective potential of Fusarium spp. in different plant species. Moreover, the pathogenicity tests in the murine model revealed behavioral changes. It was noteworthy that only five isolates (different origin and species) caused mortality. Additionally, it was observed that all isolates infected and colonized different organs, regardless of the species and origin of the isolates or host immune status. In contrast, the superficial inoculation test showed no evidence of epidermal injury or colonization. The observed results in plant and murine models suggest the pathogenic potential of Fusarium spp. isolates in different types of hosts. However, further studies on pathogenicity are needed to confirm the multihost capacity of this genus. Copyright © 2017 Asociación Argentina de Microbiología. Publicado por Elsevier España, S.L.U. All rights reserved.

N-alpha-Cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt, as an inactivator of hepatitis B surface antigen.

PubMed Central

Sugimoto, Y; Toyoshima, S

1979-01-01

N-alpha-Cocoyl-L-arginine ethyl ester, DL-pyroglutamic acid salt (CAE), exhibited a strong inactivating effect on hepatitis B surface antigen. Concentrations of CAE required for 50 and 100% inactivation of the antigen were 0.01 to 0.025% and 0.025 to 0.05% respectively. CAE completely inactivated hepatitis B surface antigen at the lowest concentration compared with various compounds including about 500 amino acid derivatives, sodium hypochlorite, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, and some detergents. Furthermore, CAE inactivated vaccinia virus, herpes simplex virus, and influenza virus, whereas poliovirus was not inactivated at all. The results suggest that the inactivating effects of CAE are related to interaction with lipid-containing viral envelopes. PMID:228595

Enzymatic hydrolysis of cellulose pretreated with ionic liquids and N-methyl Morpholine N-Oxide

NASA Astrophysics Data System (ADS)

Yau Li, Elizabeth

The effect of N-methyl Morpholine N-Oxide (NMMO), 1-ethyl-3-methyl-imidazolium acetate ([Emim]Ac) and 1-ethyl-3-methyl-imidazolium diethyl phosphate ([Emim]DEP) on pretreatment and enzymatic hydrolysis of dissolving pulp was studied. X-ray diffraction measurements of regenerated cellulose from these solvents showed that solvent pretreatment reduces the crystallinity of cellulose. However, crystallinity might not be a major factor affecting the in-situ enzymatic hydrolysis of cellulose in these solvents. Although regenerated cellulose from [Emim]DEP showed the lowest crystallinity index (˜15%), in-situ enzymatic hydrolysis of cellulose dissolved in NMMO showed the highest cellulose conversion (68% compared to 65% for [Emim]Ac and 37% for [Emim]DEP at enzyme loading of 122 FPU/g). Moreover, results showed that enzymes could tolerate up to NMMO concentration of 100 g/L and still yield full conversion of cellulose. Since it is not necessary to remove all the NMMO, less amount of water will be required for the washing step and thus the process will be more economical. The HCH-1 model was used in an attempt to model the enzymatic hydrolysis of cellulose in NMMO. With the incorporation of NMMO inhibition and a factor to account for unreacted cellulose, the model was able to correlate the experimental data of the enzymatic hydrolysis of cellulose (6.68 g/L) at various NMMO concentrations (0, 50, 100, 150 and 250 g/L). However, the experimental results also suggest that NMMO might be deactivating the enzymes rather than inhibiting them. More studies need to be done at varying cellulose, NMMO and enzyme concentrations to find the exact nature of this deactivation of NMMO.

Temperature-Induced Phase Separation in Molecular Assembly of Nanotubes Comprising Amphiphilic Polypeptide with Poly( N-Ethyl Glycine) in Water by a Hydrophilic-Region Driven Type Mechanism.

PubMed

Hattori, Tetsuya; Itagaki, Toru; Uji, Hirotaka; Kimura, Shunsaku

2018-06-20

Two kinds of amphiphilic polypeptides having different types of hydrophilic polypeptoids, poly(sarcosine)-b-(L-Leu-Aib)6 (ML12) and poly(N-ethyl glycine)-b-(L-Leu-Aib)6 (EL12), were self-assembled via two paths to phase-separated nanotubes. One path was via sticking ML12 nanotubes with EL12 nanotubes, and the other was a preparation from a mixture of ML12 and EL12 in solution. In either case, nanotubes showed temperature-induced phase separation along the long axis, which was observed by two methods of labeling one phase with gold nanoparticles and fluorescence resonance energy transfer between the components. The phase-separation was ascribed to aggregation of poly(N-ethyl glycine) blocks over the cloud point temperature. The addition of 5% trifluoroethanol was needed for the phase separation, because the tight association of the helices in the hydrophobic region should be loosened to allow lateral diffusion of the components to be separated. The phase-separation in molecular assemblies in water based on the hydrophilic-region driven type mechanism therefore requires sophisticated balances of association forces exerting among the hydrophilic and hydrophobic regions of the amphiphilic polypeptoids.

Low-dose radiation attenuates chemical mutagenesis in vivo.

PubMed

Kakinuma, Shizuko; Yamauchi, Kazumi; Amasaki, Yoshiko; Nishimura, Mayumi; Shimada, Yoshiya

2009-09-01

The biological effects of low-dose radiation are not only of social concern but also of scientific interest. The radioadaptive response, which is defined as an increased radioresistance by prior exposure to low-dose radiation, has been extensively studied both in vitro and in vivo. Here we briefly review the radioadaptive response with respect to mutagenesis, survival rate, and carcinogenesis in vivo, and introduce our recent findings of cross adaptation in mouse thymic cells, that is, the suppressive effect of repeated low-dose radiation on mutation induction by the alkylating agent N-ethyl-N-nitrosourea.

A covariant model for the gamma N -> N(1535) transition at high momentum transfer

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

G. Ramalho, M.T. Pena

2011-08-01

A relativistic constituent quark model is applied to the gamma N -> N(1535) transition. The N(1535) wave function is determined by extending the covariant spectator quark model, previously developed for the nucleon, to the S11 resonance. The model allows us to calculate the valence quark contributions to the gamma N -> N(1535) transition form factors. Because of the nucleon and N(1535) structure the model is valid only for Q^2> 2.3 GeV^2. The results are compared with the experimental data for the electromagnetic form factors F1* and F2* and the helicity amplitudes A_1/2 and S_1/2, at high Q^2.

Expression in mammalian cells of the Escherichia coli O6 alkylguanine-DNA-alkyltransferase gene ogt reduces the toxicity of alkylnitrosoureas.

PubMed Central

Harris, L. C.; Margison, G. P.

1993-01-01

V79 Chinese hamster cells expressing either the O6-alkylguanine-DNA-alkyltransferase (ATase) encoded by the E. coli ogt gene or a truncated version of the E. coli ada gene have been exposed to various alkylnitrosoureas to investigate the contribution of ATase repairable lesions to the toxicity of these compounds. Both ATases are able to repair O6-alkylguanine (O6-AlkG) and O4-alkylthymine (O4-AlkT) but the ogt ATase is more efficient in the repair of O4-methylthymine (O4-MeT) and higher alkyl derivatives of O6-AlkG than is the ada ATase. Expression of the ogt ATase provided greater protection against the toxic effects of the alkylating agents then the ada ATase particularly with N-ethyl-N-nitrosourea (ENU) and N-butyl-N-nitrosourea (BNU) to which the ada ATase expressing cells were as sensitive as parent vector transfected cells. Although ogt was expressed at slightly higher levels than the truncated ada in the transfected cells, this could not account for the differential protection observed. For-N-methyl-N-nitrosourea (MNU) the increased protection in ogt-transfected cells is consistent with O4-MeT acting as a toxic lesion. For the longer chain alkylating agents and chloroethylating agents, the protection afforded by the ogt protein may be a consequence of the more efficient repair of O6-AlkG, O4-AlkT or both of these lesions in comparison with the ada-encoded ATase. Images Figure 2 Figure 3 PMID:8512805

Benzofuroxan derivatives N-Br and N-I induce intrinsic apoptosis in melanoma cells by regulating AKT/BIM signaling and display anti metastatic activity in vivo.

PubMed

Farias, C F; Massaoka, M H; Girola, N; Azevedo, R A; Ferreira, A K; Jorge, S D; Tavares, L C; Figueiredo, C R; Travassos, L R

2015-10-27

Malignant melanoma is an aggressive type of skin cancer, and despite recent advances in treatment, the survival rate of the metastatic form remains low. Nifuroxazide analogues are drugs based on the substitution of the nitrofuran group by benzofuroxan, in view of the pharmacophore similarity of the nitro group, improving bioavailability, with higher intrinsic activity and less toxicity. Benzofuroxan activity involves the intracellular production of free-radical species. In the present work, we evaluated the antitumor effects of different benzofuroxan derivatives in a murine melanoma model. B16F10-Nex2 melanoma cells were used to investigate the antitumor effects of Benzofuroxan derivatives in vitro and in a syngeneic melanoma model in C57Bl/6 mice. Cytotoxicity, morphological changes and reactive oxygen species (ROS) were assessed by a diphenyltetrasolium reagent, optical and fluorescence microscopy, respectively. Annexin-V binding and mitochondrial integrity were analyzed by flow cytometry. Western blotting and colorimetry identified cell signaling proteins. Benzofuroxan N-Br and N-I derivatives were active against murine and human tumor cell lines, exerting significant protection against metastatic melanoma in a syngeneic model. N-Br and N-I induce apoptosis in melanoma cells, evidenced by specific morphological changes, DNA condensation and degradation, and phosphatidylserine translocation in the plasma membrane. The intrinsic mitochondrial pathway in B16F10-Nex2 cells is suggested owing to reduced outer membrane potential in mitochondria, followed by caspase -9, -3 activation and cleavage of PARP. The cytotoxicity of N-Br and N-I in B16F10-Nex2 cells is mediated by the generation of ROS, inhibited by pre-incubation of the cells with N-acetylcysteine (NAC). The induction of ROS by N-Br and N-I resulted in the inhibition of AKT activation, an important molecule related to tumor cell survival, followed by upregulation of BIM. We conclude that N-Br and N-I are

Gradient flow of O(N) nonlinear sigma model at large N

DOE PAGES

Aoki, Sinya; Kikuchi, Kengo; Onogi, Tetsuya

2015-04-28

Here, we study the gradient flow equation for the O(N) nonlinear sigma model in two dimensions at large N. We parameterize solution of the field at flow time t in powers of bare fields by introducing the coefficient function X n for the n-th power term (n = 1, 3, ··· ). Reducing the flow equation by keeping only the contributions at leading order in large N, we obtain a set of equations for X n ’s, which can be solved iteratively starting from n = 1. For n = 1 case, we find an explicit form of the exactmore » solution. Using this solution, we show that the two point function at finite flow time t is finite. As an application, we obtain the non-perturbative running coupling defined from the energy density. We also discuss the solution for n = 3 case.« less

Passive potassium transport in LK sheep red cells. Modification by N- ethyl maleimide

PubMed Central

1983-01-01

Passive K transport, as modified by N-ethyl maleimide (NEM), was studied in erythrocytes of the low-K (LK) phenotype of sheep. Brief (5- min) treatment with NEM at less than 0.5 mM caused inhibition of passive K influx; NEM at concentrations greater than 0.5 mM caused stimulation of K influx. NEM had similar effects on K efflux. The treatments with NEM did not affect cell volumes (passive K transport in LK cells is sensitive to changes in cell volume). The stimulation of K transport by high [NEM] was also not a consequence of an effect on the metabolic state of the cells. Passive K transport in LK cells is dependent on Cl (it is inhibited in Cl-free media; it may be K/Cl cotransport). NEM had no effect on K influx in Cl-free (NO3- substituted) media. Pretreatment of the cells with anti-L antiserum (L antigen is found on LK cells and not on HK cells) prevented stimulation of K influx by NEM, but did not prevent inhibition. Therefore, NEM modifies the Cl-dependent K transport pathway at two separate sites, a low-affinity site, at which it stimulates, and a high-affinity site, at which it inhibits. Anti-L antibody prevents NEM's action, but only at the low-affinity site. PMID:6875508

In vitro and in vivo antileishmanial and trypanocidal studies of new N-benzene- and N-naphthalenesulfonamide derivatives.

PubMed

Galiana-Roselló, Cristina; Bilbao-Ramos, Pablo; Dea-Ayuela, M Auxiliadora; Rolón, Miriam; Vega, Celeste; Bolás-Fernández, Francisco; García-España, Enrique; Alfonso, Jorge; Coronel, Cathia; González-Rosende, M Eugenia

2013-11-27

We report in vivo and in vitro antileishmanial and trypanocidal activities of a new series of N-substituted benzene and naphthalenesulfonamides 1-15. Compounds 1-15 were screened in vitro against Leishmania infantum , Leishmania braziliensis , Leishmania guyanensis , Leishmania amazonensis , and Trypanosoma cruzi . Sulfonamides 6e, 10b, and 10d displayed remarkable activity and selectivity toward T. cruzi epimastigotes and amastigotes. 6e showed significant trypanocidal activity on parasitemia in a murine model of acute Chagas disease. Moreover, 6e, 8c, 9c, 12c, and 14d displayed interesting IC50 values against Leishmania spp promastigotes as well as L. amazonensis and L. infantum amastigotes. 9c showed excellent in vivo activity (up to 97% inhibition of the parasite growth) in a short-term treatment murine model for acute infection by L. infantum. In addition, the effect of compounds 9c and 14d on tubulin as potential target was assessed by confocal microscopy analysis applied to L. infantum promastigotes.

Modeling and optimization of a double-well double-barrier GaN/AlGaN/GaN/AlGaN resonant tunneling diode

NASA Astrophysics Data System (ADS)

Liu, Yang; Gao, Bo; Gong, Min; Shi, Ruiying

2017-06-01

The influence of a GaN layer as a sub-quantum well for an AlGaN/GaN/AlGaN double barrier resonant tunneling diode (RTD) on device performance has been investigated by means of numerical simulation. The introduction of the GaN layer as the sub-quantum well turns the dominant transport mechanism of RTD from the 3D-2D model to the 2D-2D model and increases the energy difference between tunneling energy levels. It can also lower the effective height of the emitter barrier. Consequently, the peak current and peak-to-valley current difference of RTD have been increased. The optimal GaN sub-quantum well parameters are found through analyzing the electrical performance, energy band, and transmission coefficient of RTD with different widths and depths of the GaN sub-quantum well. The most pronounced electrical parameters, a peak current density of 5800 KA/cm2, a peak-to-valley current difference of 1.466 A, and a peak-to-valley current ratio of 6.35, could be achieved by designing RTD with the active region structure of GaN/Al0.2Ga0.8 N/GaN/Al0.2Ga0.8 N (3 nm/1.5 nm/1.5 nm/1.5 nm).

Poly[[[μ3-N′-(carboxymethyl)ethylene­di­amine-N,N,N′-triacetato]dysprosium(III)] trihydrate

PubMed Central

Zhuang, Xiaomei; Long, Qingping; Wang, Jun

2010-01-01

In the title coordination polymer, {[Dy(C10H13N2O8)]·3H2O}n, the dysprosium(III) ion is coordinated by two N atoms and six O atoms from three different (carb­oxy­meth­yl)ethyl­ene­diamine­triacetate ligands in a distorted square-anti­prismatic geometry. The ligands connect the metal atoms, forming layers parallel to the ab plane. O—H⋯O hydrogen bonds further assemble adjacent layers into a three-dimensional supra­molecular network. PMID:21588859

Suppression of methylmercury-induced MIP-2 expression by N-acetyl-L-cysteine in murine RAW264.7 macrophage cell line.

PubMed

David, Juliet; Nandakumar, Athira; Muniroh, Muflihatul; Akiba, Suminori; Yamamoto, Megumi; Koriyama, Chihaya

2017-11-09

The aim of this study is to examine the inflammatory-cytokine expressions in the presence of non-cytotoxic dose of methylmercury (MeHg) in murine macrophages, which is suspected to play an important role in brain damage caused by MeHg exposure. We focused on murine macrophage inflammatory protein-2 (MIP-2), keratinocyte chemoattractant (KC), and monocyte chemoattractant protein-5 (MCP-5). MIP-2 and KC are murine functional homologues of human IL-8 and MCP-5 for human MCP-1. Furthermore, we examined the suppressive effect of N-acetyl-L-cysteine (NAC) on the MeHg-induced inflammatory cytokines. In a murine RAW264.7 macrophage cell line, MeHg-induced cytokine expressions were measured using real-time PCR. The suppressive effect of NAC was examined by putting it into the culture medium together with MeHg (co-treatment). In addition, pre- and post-treatment experiments were conducted, in which the cells were treated with NAC before and after MeHg exposure, respectively. Exposure to a non-cytotoxic dose of MeHg up-regulated the mRNA expression of MIP-2 and MCP-5. On the other hand, KC expression was not induced in the presence of MeHg. Effect of MeHg on MIP-2 expressions was suppressed by pre-, co-, and post-treatment with NAC. However, the suppressive effect of pre-treatment was less than the post-treatment, which was as effective as co-treatment. In functional homologues of human IL-8, only MIP-2 expression, not KC, was activated in the presence of non-cytotoxic dose of MeHg in murine RAW264.7 macrophage cell line. The more evident inhibitory effect of NAC observed in post-treatment experiments suggests a possible involvement of intracellular activities such as antioxidant effects.

Distinct pathways for repairing mutagenic lesions induced by methylating and ethylating agents

PubMed Central

Negishi, Tomoe

2013-01-01

DNA alkylation damage can be repaired by nucleotide excision repair (NER), base excision repair (BER) or by direct removal of alkyl groups from modified bases by O 6-alkylguanine DNA alkyltransferase (AGT; E.C. 2.1.1.63). DNA mismatch repair (MMR) is also likely involved in this repair. We have investigated alkylation-induced mutagenesis in a series of NER- or AGT-deficient Escherichia coli strains, alone or in combination with defects in the MutS, MutL or MutH components of MMR. All strains used contained the Fʹprolac from strain CC102 (FʹCC102) episome capable of detecting specifically lac GC to AT reverse mutations resulting from O 6-alkylguanine. The results showed the repair of O 6-methylguanine to be performed by AGT ≫ MMR > NER in order of importance, whereas the repair of O 6-ethylguanine followed the order NER > AGT > MMR. Studies with double mutants showed that in the absence of AGT or NER repair pathways, the lack of MutS protein generally increased mutant frequencies for both methylating and ethylating agents, suggesting a repair or mutation avoidance role for this protein. However, lack of MutL or MutH protein did not increase alkylation-induced mutagenesis under these conditions and, in fact, reduced mutagenesis by the N-alkyl-N-nitrosoureas MNU and ENU. The combined results suggest that little or no alkylation damage is actually corrected by the mutHLS MMR system; instead, an as yet unspecified interaction of MutS protein with alkylated DNA may promote the involvement of a repair system other than MMR to avoid a mutagenic outcome. Furthermore, both mutagenic and antimutagenic effects of MMR were detected, revealing a dual function of the MMR system in alkylation-exposed cells. PMID:23446177

Effect of antecedent terrestrial land-use on C and N cycling in created wetlands

NASA Astrophysics Data System (ADS)

McCalley, C. K.; Al Graiti, T.; Williams, T.; Huang, S.; McGowan, M. B.; Eddingsaas, N. C.; Tyler, A. C.

2017-12-01

Land-use legacies and their interaction with both management actions and climate variability has a poorly characterized impact on the development of ecosystem functions and the trajectory of climate-carbon feedbacks. The complex structure-function relationships in wetlands foster delivery of valuable, climate sensitive, ecosystem services (carbon sequestration, nutrient removal, flood control, etc.) but also make them susceptible to colonization by invasive plants and lead to emission of key greenhouse gases. This project uses created wetland ecosystems as a model to understand how heterogeneity in antecedent conditions interacts with management options to create unique structure-function scenarios and a range of climate feedback outcomes. We utilized ongoing experiments in created wetlands that differ in antecedent conditions (crop agriculture, livestock grazing) and investigated how management options (invasive species removal, organic matter addition) interact with legacy impacts to promote key ecosystem functions, including greenhouse gas emissions, carbon sequestration, denitrification and plant biodiversity. The effects of antecedent land-use on soil chemistry, coupled with hydrologic patterns resulted in wetlands with divergent C and N dynamics despite their similar creation history. Additionally, the occurrence of extreme weather events (drought and excessive flooding) during the study period highlighted the overarching role that increased climate variability will play in determining key ecosystem processes in wetlands. Responses to management were linked to hydro-period: while organic matter addition successfully increased soil organic matter to more closely replicate natural systems at all sites, it had the largest impact on C and N cycling when soils were saturated. Overall, environmental conditions that promoted saturated soils, both those shaped by human activities or climate extremes, enhanced primary productivity, nutrient removal and greenhouse gas

[CuCl(n)](2-n) ion-pair species in 1-ethyl-3-methylimidazolium chloride ionic liquid-water mixtures: ultraviolet-visible, X-ray absorption fine structure, and density functional theory characterization.

PubMed

Li, Guosheng; Camaioni, Donald M; Amonette, James E; Zhang, Z Conrad; Johnson, Timothy J; Fulton, John L

2010-10-07

We studied the coordination environment about Cu(II) in a pure ionic liquid, 1-ethyl-3-methylimidazolium chloride ([EMIM]Cl), and in binary mixtures of this compound with water across the entire range of compositions, using a combination of X-ray absorption fine structure (XAFS), ultraviolet-visible (UV-vis) spectroscopy, and electronic structure calculations. Our results show a series of stages in the ion pairing of the divalent cation, Cu(II), including the contact ion pairing of Cu(2+) with multiple Cl(-) ligands to form various CuCl(n)((2-n)) polyanions, as well as the subsequent solvation and ion pairing of the polychlorometallate anion with the EMIM(+) cation. Ion-pair formation is strongly promoted in [EMIM]Cl by the low dielectric constant and by the extensive breakdown of the water hydrogen-bond network in [EMIM]Cl-water mixtures. The CuCl(4)(2-) species dominates in the [EMIM]Cl solvent, and calculations along with spectroscopy show that its geometry distorts to C(2) symmetry compared to D(2d) in the gas phase. These results are important in understanding catalysis and separation processes involving transition metals in ionic liquid systems.

Development of resting membrane potentials in differentiating murine neuroblastoma cells (N1E-115) evaluated by flow cytometry.

PubMed

Kisaalita, W S; Bowen, J M

1997-09-01

With the aid of a voltage-sensitive oxonol dye, flow cytometry was used to measure relative changes in resting membrane potential (V(m)) and forward angle light scatter (FALS) profiles of a differentiating/differentiated murine neuroblastoma cell line (N1E-115). Electrophysiological differentiation was characterized by V(m) establishment. The (V(m))-time profile was found to be seed cell concentration-dependent for cell densities of less than 2 × 10(4) cells/cm(2). At higher initial cell densities, under differentiating culture conditions, V(m) development commenced on day 2 and reached a steady-state on day 12. The relative distribution of differentiated cells between low and high FALS has been proposed as a potential culture electrophysiological differentiation state index. These experiments offer a general methodology to characterize cultured excitable cells of nervous system origin, with respect to electrophysiological differentiation. This information is valuable in studies employing neuroblastoma cells as in vitro screening models for safety/hazard evaluation and/or risk assessment of therapeutical and industrial chemicals under development.

Intramolecular cyclization of N-phenyl N'(2-chloroethyl)ureas leads to active N-phenyl-4,5-dihydrooxazol-2-amines alkylating β-tubulin Glu198 and prohibitin Asp40.

PubMed

Trzeciakiewicz, Anna; Fortin, Sébastien; Moreau, Emmanuel; C-Gaudreault, René; Lacroix, Jacques; Chambon, Christophe; Communal, Yves; Chezal, Jean-Michel; Miot-Noirault, Elisabeth; Bouchon, Bernadette; Degoul, Françoise

2011-05-01

The cyclization of anticancer drugs into active intermediates has been reported mainly for DNA alkylating molecules including nitrosoureas. We previously defined the original cytotoxic mechanism of anticancerous N-phenyl-N'-(2-chloroethyl)ureas (CEUs) that involves their reactivity towards cellular proteins and not against DNA; two CEU subsets have been shown to alkylate β-tubulin and prohibitin leading to inhibition of cell proliferation by G₂/M or G₁/S cell cycle arrest. In this study, we demonstrated that cyclic derivatives of CEUs, N-phenyl-4,5-dihydrooxazol-2-amines (Oxas) are two- to threefold more active than CEUs and share the same cytotoxic properties in B16F0 melanoma cells. Moreover, the CEU original covalent binding by an ester linkage on β-tubulin Glu198 and prohibitin Asp40 was maintained with Oxas. Surprisingly, we observed that Oxas were spontaneously formed from CEUs in the cell culture medium and were also detected within the cells. Our results suggest that the intramolecular cyclization of CEUs leads to active Oxas that should then be considered as the key intermediates for protein alkylation. These results will be useful for the design of new prodrugs for cancer chemotherapy. Copyright © 2011 Elsevier Inc. All rights reserved.

Study of. lambda. parameters and crossover phenomena in SU(N) x SU(N) sigma models in two dimensions

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

Shigemitsu, J; Kogut, J B

1981-01-01

The spin system analogues of recent studies of the string tension and ..lambda.. parameters of SU(N) gauge theories in 4 dimensions are carried out for the SU(N) x SU(N) and O(N) models in 2 dimensions. The relations between the ..lambda.. parameters of both the Euclidean and Hamiltonian formulation of the lattice models and the ..lambda.. parameter of the continuum models are obtained. The one loop finite renormalization of the speed of light in the lattice Hamiltonian formulations of the O(N) and SU(N) x SU(N) models is calculated. Strong coupling calculations of the mass gaps of these spin models are donemore » for all N and the constants of proportionality between the gap and the ..lambda.. parameter of the continuum models are obtained. These results are contrasted with similar calculations for the SU(N) gauge models in 3+1 dimensions. Identifying suitable coupling constants for discussing the N ..-->.. infinity limits, the numerical results suggest that the crossover from weak to strong coupling in the lattice O(N) models becomes less abrupt as N increases while the crossover for the SU(N) x SU(N) models becomes more abrupt. The crossover in SU(N) gauge theories also becomes more abrupt with increasing N, however, at an even greater rate than in the SU(N) x SU(N) spin models.« less

Asymptotic freedom in certain S O (N ) and S U (N ) models

NASA Astrophysics Data System (ADS)

Einhorn, Martin B.; Jones, D. R. Timothy

2017-09-01

We calculate the β -functions for S O (N ) and S U (N ) gauge theories coupled to adjoint and fundamental scalar representations, correcting longstanding, previous results. We explore the constraints on N resulting from requiring asymptotic freedom for all couplings. When we take into account the actual allowed behavior of the gauge coupling, the minimum value of N in both cases turns out to be larger than realized in earlier treatments. We also show that in the large N limit, both models have large regions of parameter space corresponding to total asymptotic freedom.

Optical model potential analysis of n ¯ A and n A interactions

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

Lee, Teck-Ghee; Wong, Cheuk-Yin

In this study, we use a momentum-dependent optical model potential to analyze the annihilation cross sections of the antineutronmore » $$\\overline{n}$$ on C, Al, Fe, Cu, Ag, Sn, and Pb nuclei for projectile momenta p lab ≲ 500 MeV / c . We obtain a good description of annihilation cross section data of Barbina et al. [Nucl. Phys. A 612, 346 (1997)] and of Astrua et al. [Nucl. Phys. A 697, 209 (2002)] which exhibit an interesting dependence of the cross sections on p lab as well as on the target mass number A. We also obtain the neutron (n) nonelastic reaction cross sections for the same targets. Comparing the $nA$ reaction cross sections σ$$nA\\atop{rec}$$ to the $$\\overline{n}A$$ annihilation cross sections σ $$\\overline{n}A$$ ann, we find that σ $$\\overline{n}A$$ ann is significantly larger than σ$$nA\\atop{rec}$$, that is, theσ $$\\overline{n}A$$ ann / σ$$nA\\atop{rec}$$ cross section ratio lies between the values of about 1.5 to 4.0 in the momentum region where comparison is possible. The dependence of the $$\\overline{n}$$ annihilation cross section on the projectile charge is also examined in comparison with the antiproton $$\\overline{p}$$. Here we predict the $$\\overline{p}A$$ annihilation cross section on the simplest assumption that both $$\\overline{p}A$$ and $$\\overline{n}A$$ interactions have the same nuclear part of the optical potential but differ only in the electrostatic Coulomb interaction. Finally, deviation from a such simple model extrapolation in measurements will provide new information on the difference between $$\\overline{n}A$$ and $$\\overline{p}A$$ potentials.« less

Optical model potential analysis of n ¯ A and n A interactions

DOE PAGES

Lee, Teck-Ghee; Wong, Cheuk-Yin

2018-05-25

In this study, we use a momentum-dependent optical model potential to analyze the annihilation cross sections of the antineutronmore » $$\\overline{n}$$ on C, Al, Fe, Cu, Ag, Sn, and Pb nuclei for projectile momenta p lab ≲ 500 MeV / c . We obtain a good description of annihilation cross section data of Barbina et al. [Nucl. Phys. A 612, 346 (1997)] and of Astrua et al. [Nucl. Phys. A 697, 209 (2002)] which exhibit an interesting dependence of the cross sections on p lab as well as on the target mass number A. We also obtain the neutron (n) nonelastic reaction cross sections for the same targets. Comparing the $nA$ reaction cross sections σ$$nA\\atop{rec}$$ to the $$\\overline{n}A$$ annihilation cross sections σ $$\\overline{n}A$$ ann, we find that σ $$\\overline{n}A$$ ann is significantly larger than σ$$nA\\atop{rec}$$, that is, theσ $$\\overline{n}A$$ ann / σ$$nA\\atop{rec}$$ cross section ratio lies between the values of about 1.5 to 4.0 in the momentum region where comparison is possible. The dependence of the $$\\overline{n}$$ annihilation cross section on the projectile charge is also examined in comparison with the antiproton $$\\overline{p}$$. Here we predict the $$\\overline{p}A$$ annihilation cross section on the simplest assumption that both $$\\overline{p}A$$ and $$\\overline{n}A$$ interactions have the same nuclear part of the optical potential but differ only in the electrostatic Coulomb interaction. Finally, deviation from a such simple model extrapolation in measurements will provide new information on the difference between $$\\overline{n}A$$ and $$\\overline{p}A$$ potentials.« less

In vitro antioxidant activity of phenolic-enriched extracts from Zhangping Narcissus tea cake and their inhibition on growth and metastatic capacity of 4T1 murine breast cancer cells* #

PubMed Central

Ying, Le; Kong, De-dong; Gao, Yuan-yuan; Yan, Feng; Wang, Yue-fei; Xu, Ping

2018-01-01

Phenolics, as the main bioactive compounds in tea, have been suggested to have potential in the prevention of various human diseases. However, little is known about phenolics and their bioactivity in Zhangping Narcissue tea cake which is considered the most special kind of oolong tea. To unveil its bioactivity, three phenolic-enriched extracts were obtained from Zhangping Narcissue tea cake using ethyl acetate, n-butanol, and water. Their main chemical compositions and in vitro bioactivity were analyzed by high-performance liquid chromatography (HPLC) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). The ethyl acetate fraction (ZEF) consisted of higher content of phenolics, flavonoids, procyanidins, and catechin monomers (including epigallocatechin gallate (EGCG), epicatechin gallate (ECG), and gallocatechin gallate (GCG)) than n-butanol fraction (ZBF) and water fraction (ZWF). ZEF exhibited the strongest antioxidant capacity in vitro due to its abundant bioactive compounds. This was validated by Pearson correlation and hierarchical clustering analyses. ZEF also showed a remarkable inhibition on the growth, migration, and invasion of 4T1 murine breast cancer cells. PMID:29504313

Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells.

PubMed

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L; Park, John K

2008-07-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.

Nitrosoureas Inhibit the Stathmin Mediated Migration and Invasion of Malignant Glioma Cells

PubMed Central

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L.; Park, John K.

2008-01-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement related processes. Scratch-wound healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down regulation of cellular stathmin levels and in the absence and presence of sub-lethal nitrosourea (CCNU; [1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]) concentrations. We demonstrate that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μM, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain and that nitrosoureas may have therapeutic benefits in addition to their anti-proliferative effects. PMID:18593927

Three-dimensional modeling of n+-nu-n+ and p+-pi-p+ semiconducting devices for analog ULSI microelectronics

NASA Astrophysics Data System (ADS)

Gillet, Jean-Numa; Degorce, Jean-Yves; Belisle, Jonathan; Meunier, Michel

2004-03-01

Three-dimensional modeling of n^+-ν -n^+ and p^+-π -p^+ semiconducting devices for analog ULSI microelectronics Jean-Numa Gillet,^a,b Jean-Yves Degorce,^a Jonathan Bélisle^a and Michel Meunier.^a,c ^a École Polytechnique de Montréal, Dept. of Engineering Physics, CP 6079, Succ. Centre-vile, Montréal, Québec H3C 3A7, Canada. ^b Corresponding author. Email: Jean-Numa.Gillet@polymtl.ca ^c Also with LTRIM Technologies, 140-440, boul. A.-Frappier, Laval, Québec H7V 4B4, Canada. We present for the first time three-dimensional (3-D) modeling of n^+-ν -n^+ and p^+-π -p^+ semiconducting resistors, which are fabricated by laser-induced doping in a gateless MOSFET and present significant applications for analog ULSI microelectronics. Our modeling software is made up of three steps. The two first concerns modeling of a new laser-trimming fabrication process. With the molten-silicon temperature distribution obtained from the first, we compute in the second the 3-D dopant distribution, which creates the electrical link through the device gap. In this paper the emphasis is on the third step, which concerns 3-D modeling of the resistor electronic behavior with a new tube multiplexing algorithm (TMA). The device current-voltage (I-V) curve is usually obtained by solving three coupled partial differential equations with a finite-element method. A 3-D device as our resistor cannot be modeled with this classical method owing to its prohibitive computational cost in three dimensions. This problem is however avoided by our TMA, which divides the 3-D device into one-dimensional (1-D) multiplexed tubes. In our TMA 1-D systems of three ordinary differential equations are solved to determine the 3-D device I-V curve, which substantially increases computation speed compared with the classical method. Numerical results show a good agreement with experiments.

New nitrosoureas and their spin-labeled derivatives influence dopa-oxidase activity of tyrosinase.

PubMed

Rachkova, M; Raikova, E; Raikov, Z

1991-06-01

Tyrosinase is a key enzyme in melanine biosynthesis. The modulating effect of cytostatic agents on DOPA-oxidase activity of tyrosinase could be linked with the drug treatment of melanoma tumors. Two groups of nitrosoureas which influence DOPA-oxidase activity of tyrosinase were studied: new nitrosoureas and their spin-labeled derivatives synthesized in our laboratory. Using Burnett's spectrophotometric method (Burnett et al., 1967) the following effects were established: inhibition by CCNU, inhibition and the activating effects of the other investigated nitrosoureas depend on their physicochemical half-life. The predominant activating effect of the spin-labeled derivatives is due to the nitroxyl radical present in these compounds.

Synthesis, characterization, and application of novel biodegradable self-assembled 2-(N-phthalimido) ethyl-palmitate nanoparticles for cancer therapy

NASA Astrophysics Data System (ADS)

Kasoju, Naresh; Bora, Debajeet K.; Bhonde, Ramesh R.; Bora, Utpal

2010-03-01

We report the synthesis of novel biodegradable nanoparticles (NPs) which can kill the cancer cells without any additional drug loading. The NP was a self-assembled form of a phthalimide based conjugate, in which the phthalimide moiety was responsible for the anticancer activity. We describe the synthesis of a novel 2-(N-phthalimido) ethyl palmitate (PHEP-Pal) conjugate and subsequent preparation of NPs by a simple self assembly process. The successful synthesis of conjugate was confirmed by various characterization studies including nuclear magnetic resonance spectroscope, Fourier transform infrared spectroscope, TOF-liquid chromatography mass spectroscope, differential scanning calorimetry, and X-ray diffraction unit. The synthesis, shape, size, and size distribution of PHEP-Pal NPs were determined by transmission electron microscope, atomic force microscope, and dynamic light scattering technique. Finally, cell culture studies using A549 and HeLa cells were done to evaluate the anticancer effect of PHEP-Pal NPs, which demonstrated the potency of these NPs for use in cancer chemotherapy.

Development of a murine model of blunt hepatic trauma.

PubMed

Nemzek-Hamlin, Jean A; Hwang, Haejin; Hampel, Joseph A; Yu, Bi; Raghavendran, Krishnan

2013-10-01

Despite the prevalence of blunt hepatic trauma in humans, there are few rodent models of blunt trauma that can be used to study the associated inflammatory responses. We present a mouse model of blunt hepatic trauma that was created by using a cortical contusion device. Male mice were anesthetized with ketamine-xylazine-buprenorphine and placed in left lateral recumbency. A position of 2 mm ventral to the posterior axillary line and 5 mm caudal to the costal margin on the right side was targeted for impact. An impact velocity of 6 m/s and a piston depth of 12 mm produced a consistent pattern of hepatic injury with low mortality. All mice that recovered from anesthesia survived without complication for the length of the study. Mice were euthanized at various time points (n = 5 per group) until 7 d after injury for gross examination and collection of blood and peritoneal lavage fluids. Some mice were reanesthetized for serial monitoring of hepatic lesions via MRI. At 2 h after trauma, mice consistently displayed laceration, hematoma, and discoloration of the right lateral and caudate liver lobes, with intraabdominal hemorrhage but no other gross injuries. Blood and peritoneal lavage fluid were collected from all mice for cytokine analysis. At 2 h after trauma, there were significant increases in plasma IL10 as well as peritoneal lavage fluid IL6 and CXCL1/KC; however, these levels decreased within 24 h. At 7 d after trauma, the mice had regained body weight, and the hepatic lesions, which initially had increased in size during the first 48 h, had returned to their original size. In summary, this technique produced a reliable, low mortality, murine model that recreates features of blunt abdominal liver injury in human subjects with similar acute inflammatory response.

Derivation of a human equivalent concentration for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid

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

Teeguarden, Justin G.; Deisinger, P. J.; Poet, Torka S.

2005-05-01

The metabolic series (family) approach for risk assessment uses a dosimetry-based analysis to develop toxicity information for a group of metabolically linked compounds using pharmacokinetic (PK) data for each compound and toxicity data for the parent compound. An initial physiologically-based pharmacokinetic (PBPK) model was developed to support the implementation of the metabolic series approach for n-butyl acetate and its subsequent metabolites, n-butanol, and n-butyric acid (the butyl series) (Barton et al. 2000). In conjunction with pilot pharmacokinetic studies, the model was used to design the definitive intravenous (i.v.) PK studies. Rats were implanted with dual indwelling cannulae and administered testmore » compounds by i.v. bolus dose, i.v. infusion, or by inhalation in a recirculating closed chamber. Hepatic, vascular and extravascular metabolic constants for metabolism were estimated by fitting the model to the blood time course data from these experiments. The respiratory bioavailability of n-butyl acetate and n-butanol was estimated from closed chamber inhalation studies and measured ventilation rates. The resulting butyl series PBPK model successfully reproduces the blood time course of these compounds following i.v. administration, and inhalation exposure to n-butyl acetate and n-butanol. A fully scaled human version of the model successfully reproduces arterial blood n-butanol kinetics following inhalation exposure to n-butanol. These validated i.v (rat) and inhalation route models (rat, butyl acetate, n-butanol; human, butanol only) can be used to support species and dose-route extrapolations required for risk assessment of butyl series family of compounds. Further, this work demonstrates the usefulness of i.v. kinetic data for parameterization of systemic metabolism and the value of collaboration between experimentalists and kineticists in the development of PBPK models. The product of this effort, validated rat and human PBPK models for the

Self-consistent large- N analytical solutions of inhomogeneous condensates in quantum ℂP N - 1 model

NASA Astrophysics Data System (ADS)

Nitta, Muneto; Yoshii, Ryosuke

2017-12-01

We give, for the first time, self-consistent large- N analytical solutions of inhomogeneous condensates in the quantum ℂP N - 1 model in the large- N limit. We find a map from a set of gap equations of the ℂP N - 1 model to those of the Gross-Neveu (GN) model (or the gap equation and the Bogoliubov-de Gennes equation), which enables us to find the self-consistent solutions. We find that the Higgs field of the ℂP N - 1 model is given as a zero mode of solutions of the GN model, and consequently only topologically non-trivial solutions of the GN model yield nontrivial solutions of the ℂP N - 1 model. A stable single soliton is constructed from an anti-kink of the GN model and has a broken (Higgs) phase inside its core, in which ℂP N - 1 modes are localized, with a symmetric (confining) phase outside. We further find a stable periodic soliton lattice constructed from a real kink crystal in the GN model, while the Ablowitz-Kaup-Newell-Segur hierarchy yields multiple solitons at arbitrary separations.

MUTANT FREQUENCY AND MUTATIONAL SPECTRA IN THETK AND HPRT GENES OF N-ETHYL-N-NITROSOUREA TREATED MOUSE LYMPHOMA CELLS

EPA Science Inventory

Abstract

The mouse lymphoma assay (MLA) utilizing the Tk locus is widely used to identify chemical mutagens. The autosomal location of the Tk locus allows for the detection of a wide range of mutational events, from point mutations to chromosome alterations. However, the ...

Structural-conformational aspects of tRNA complexation with chloroethyl nitrosourea derivatives: A molecular modeling and spectroscopic investigation.

PubMed

Agarwal, Shweta; Tyagi, Gunjan; Chadha, Deepti; Mehrotra, Ranjana

2017-01-01

Chloroethyl nitrosourea derivatives (CENUs) represent an important family of anticancer chemotherapeutic agents, which are used in the treatment of different types of cancer such as brain tumors, resistant or relapsed Hodgkin's disease, small cell lung cancer and malignant melanoma. This work focuses towards understanding the interaction of chloroethyl nitrosourea derivatives; lomustine, nimustine and semustine with tRNA using spectroscopic approach in order to elucidate their auxiliary anticancer action mechanism inside the cell. Attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR), Fourier transform infrared difference spectroscopy, circular dichroism spectroscopy and UV-visible spectroscopy were employed to investigate the binding parameters of tRNA-CENUs complexation. Results of present study demonstrate that all CENUs, studied here, interact with tRNA through guanine nitrogenous base residues and possibly further crosslink cytosine residues in paired region of tRNA. Moreover, spectral data collected for nimustine-tRNA and semustine-tRNA complex formation indicates towards the groove-directed-alkylation as their anti-malignant action, which involves the participation of uracil moiety located in major groove of tRNA. Besides this, tRNA-CENUs adduct formation did not alter the native conformation of biopolymer and tRNA remains in A-form after its interaction with all three nitrosourea derivatives studied. The binding constants (K a ) estimated for tRNA complexation with lomustine, nimustine and semustine are 2.55×10 2 M -1 , 4.923×10 2 M -1 and 4.223×10 2 M -1 respectively, which specify weak type of CENU's binding with tRNA. Moreover, molecular modeling simulations were also performed to predict preferential binding orientation of CENUs with tRNA that corroborates well with spectral outcomes. The findings, presented here, recognize tRNA binding properties of CENUs that can further help in rational designing of more specific and

Second-Nearest-Neighbor Effects upon N NMR Shieldings in Models for Solid Si 3N 4and C 3N 4

NASA Astrophysics Data System (ADS)

Tossell, J. A.

1997-07-01

NMR shifts are generally determined mainly by the nearest-neighbor environment of an atom, with fairly small changes in the shift arising from differences in the second-nearest-neighbor environment. Previous calculations on the (SiH3)3N molecule used as a model for the local environment of N in crystalline α- and β-Si3N4gave N NMR shieldings much larger than those measured in the solids and gave the wrong order for the shifts of the inequivalent N sites (e.g., N1 and N2 in β-Si3N4). We have now calculated the N NMR shieldings in larger molecular models for the N2 site of β-Si3N4and have found that the N2 shielding is greatly reduced when additional N1 atoms (second-nearest-neighbors to the central N2) are included. The calculated N2 shieldings (using the GIAO method with the 6-31G* basis set and 6-31G* SCF optimized geometries) are 288.1, 244.7, and 206.0 ppm for the molecules (SiH3)3N, Si6N5H15, and Si9N9H21(central N2), respectively, while the experimental shielding of N2 in β-Si3N4is about 155 ppm. Second-nearest-neighbor effects of only slightly smaller magnitude are calculated for the analog C molecules. At the same time, the effects of molecule size upon Si NMR shieldings and N electric field gradients are small. The local geometries at the N2-like Ns in C6N5H15and C9N9H21are calculated to be planar, consistent with the planar local geometry recently calculated for N in crystalline C3N4using density functional theory.

Furfuryl ethyl ether: important aging flavor and a new marker for the storage conditions of beer.

PubMed

Vanderhaegen, Bart; Neven, Hedwig; Daenen, Luk; Verstrepen, Kevin J; Verachtert, Hubert; Derdelinckx, Guy

2004-03-24

Recently, it was reported that furfuryl ethyl ether is an important flavor compound indicative of beer storage and aging conditions. A study of the reaction mechanism indicates that furfuryl ethyl ether is most likely formed by protonation of furfuryl alcohol or furfuryl acetate followed by S(N)2-substitution of the leaving group by the nucleophilic ethanol. For the reaction in beer, a pseudo-first-order reaction kinetics was derived. A close correlation was found between the values predicted by the kinetic model and the actual furfuryl ethyl ether concentration evolution during storage of beer. Furthermore, 10 commercial beers of different types, aged during 4 years in natural conditions, were analyzed, and it was found that the furfuryl ethyl ether flavor threshold was largely exceeded in each type of beer. In these natural aging conditions, lower pH, darker color, and higher alcohol content were factors that enhanced furfuryl ethyl ether formation. On the other hand, sulfite clearly reduced furfuryl ethyl ether formation. All results show that the furfuryl ethyl ether concentration is an excellent time-temperature integrator for beer storage.

Antiangiogenic effects and mechanisms of trans-ethyl p-methoxycinnamate from Kaempferia galanga L.

PubMed

He, Zhi-Heng; Yue, Grace Gar-Lee; Lau, Clara Bik-San; Ge, Wei; But, Paul Pui-Hay

2012-11-14

Kaempferia galanga L. (Zingiberaceae) is an aromatic herb and a popular spice used as a condiment in Asian cuisine. The ethanol extract of the dried plant and its successive four subfractions were investigated on zebrafish model by quantitative endogenous alkaline phosphatase assay. Both n-hexane and ethyl acetate fractions had antiangiogenic activity, and two major active components (trans-ethyl p-methoxycinnamate and kaempferol) showed potent antiangiogenic effects on wild-type zebrafish. Because of its much stronger effect and no antiangiogenic activity reported, trans-ethyl p-methoxycinnamate was further investigated for its action mechanism. It dose dependently inhibited vessel formation on both wild- and Tg(fli1a:EGFP)y1-type zebrafish embryos. The semiquantitative reverse transcription polymerase chain reaction assay suggested that trans-ethyl p-methoxycinnamate affects multiple molecular targets related to angiogenesis. In vitro, it specifically inhibited the migration and tube formation of human umbilical vein endothelial cells. In vivo, it could block bFGF-induced vessel formation on Matrigel plug assay.

Relating Alfvén Wave Heating Model to Observations of a Solar Active Region

NASA Astrophysics Data System (ADS)

Yoritomo, J. Y.; Van Ballegooijen, A. A.

2012-12-01

We compared images from the Solar Dynamics Observatory's (SDO) Atmospheric Imaging Assembly (AIA) with simulations of propagating and dissipating Alfvén waves from a three-dimensional magnetohydrodynamic (MHD) model (van Ballegooijen et. al 2011; Asgari-Targhi & van Ballegooijen 2012). The goal was to search for observational evidence of Alfvén waves in the solar corona and understand their role in coronal heating. We looked at one particular active region on the 5th of May 2012. Certain distinct loops in the SDO/AIA observations were selected and expanded. Movies were created from these selections in an attempt to discover transverse motions that may be Alfvén waves. Using a magnetogram of that day and the corresponding synoptic map, a potential field model was created for the active region. Three-dimensional MHD models for several loops in different locations in the active region were created. Each model specifies the temperature, pressure, magnetic field strength, average heating rate, and other parameters along the loop. We find that the heating is intermittent in the loops and reflection occurs at the transition region. For loops at larger and larger height, a point is reached where thermal non-equilibrium occurs. In the center this critical height is much higher than in the periphery of the active region. Lastly, we find that the average heating rate and coronal pressure decrease with increasing height in the corona. This research was supported by an NSF grant for the Smithsonian Astrophysical Observatory (SAO) Solar REU program and a SDO/AIA grant for the Smithsonian Astrophysical Observatory.

Ethyl pyruvate inhibits hypoxic pulmonary vasoconstriction and attenuates pulmonary artery cytokine expression

PubMed Central

Tsai, Ben M.; Lahm, Tim; Morrell, Eric D.; Crisostomo, Paul R.; Markel, Troy; Wang, Meijing; Meldrum, Daniel R.

2009-01-01

Hypoxic pulmonary vasoconstriction is a common consequence of acute lung injury and may be mediated by increased local production of proinflammatory cytokines. Ethyl pyruvate is a novel anti-inflammatory agent that has been shown to downregulate proinflammatory genes following hemorrhagic shock; however, its effects on hypoxic pulmonary vasoconstriction are unknown. We hypothesized that ethyl pyruvate would inhibit hypoxic pulmonary vasoconstriction and downregulate pulmonary artery cytokine expression during hypoxia. To study this, isometric force displacement was measured in isolated rat pulmonary artery rings (n=8/group) during hypoxia (95% N2/5% CO2) with or without prior ethyl pyruvate (10 mM) treatment. Following 60 minutes of hypoxia, pulmonary artery rings were analyzed for TNF-α and IL-1 mRNA via RT-PCR. Ethyl pyruvate inhibited hypoxic pulmonary artery contraction (4.49±2.32% vs. 88.80±5.68% hypoxia alone) and attenuated the hypoxic upregulation of pulmonary artery TNF and IL-1 mRNA (p<0.05). These data indicate that: 1) hypoxia increases pulmonary artery vasoconstriction and proinflammatory cytokine gene expression; 2) ethyl pyruvate decreases hypoxic pulmonary vasoconstriction and downregulates hypoxia-induced pulmonary artery proinflammatory cytokine gene expression; and 3) ethyl pyruvate may represent a novel therapeutic adjunct in the treatment of acute lung injury. PMID:17574585

A new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis by means of high-pressure liquid chromatography for pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites.

PubMed

Betsch, B; Berger, M R; Spiegelhalder, B

1990-09-01

Estradiol-linked nitrosoureas are offering new perspectives in the antineoplastic chemotherapy of estradiol-receptor positive mammary carcinomas. In such a molecule estradiol has the function of a carrier which brings about a specific accumulation of the anticancer drug in estradiol-receptor containing tumor cells. However, there is only little knowledge about the pharmacokinetic behavior of this new group of anticancer agents. For that reason a new comprehensive technique of catheterisation, blood sampling, sample preparation and sample analysis with high-pressure liquid chromatography (HPLC) for preclinical pharmacokinetic studies with estradiol-linked nitrosoureas and their metabolites has been developed. N-(2-Chloroethyl)-N-nitroso-carbamoyl-L-alanine-estradiol-17-ester (CNC-alanine-estradiol-17-ester) and N-(2-chloroethyl)-N-nitroso-carbamoyl-L-alanine (CNC-alanine) were used as test compounds. The drugs were tested in female Sprague-Dawley rats with chemically induced mammary carcinomas. The laboratory animals were supplied with two catheters prior to the pharmacokinetic experiments. The blood samples were drawn from the vena cava catheter after the drug had been applied through a vena jugularis catheter. The compounds were extracted from plasma with C18 silicagel reversed phase cartridges. The clean-up technique delivered clear samples only slightly contaminated with the biological matrix. The recovery from plasma was 75 +/- 5% for the hormone-linked CNC-alanine-estradiol-17-ester and 70 +/- 5% for the unlinked CNC-alanine. The analysis was carried out by means of HPLC.(ABSTRACT TRUNCATED AT 250 WORDS)

Isospin decomposition of γ N → N * transitions within a dynamical coupled-channels model

DOE PAGES

Kamano, Hiroyuki; Nakamura, S. X.; Lee, T. -S. H.; ...

2016-07-07

Here, by extending the dynamical coupled-channels analysis performed in our previous work to include the available data of photoproduction of pi mesons off neutrons, the transition amplitudes for the photoexcitation of the neutron-to-nucleon resonances, γn → N*, at the resonance pole positions are determined. The combined fits to the data for both the proton- and neutron-target reactions also revise our results for the resonance pole positions and the γp → N* transition amplitudes. Our results allow an isospin decomposition of the γN → N* transition amplitudes for the isospin I = 1/2 N* resonances, which is necessary for testing hadronmore » structure models and gives crucial inputs for constructing models of neutrino-induced reactions in the nucleon resonance region.« less

Ultrathin silicon oxynitride layer on GaN for dangling-bond-free GaN/insulator interface.

PubMed

Nishio, Kengo; Yayama, Tomoe; Miyazaki, Takehide; Taoka, Noriyuki; Shimizu, Mitsuaki

2018-01-23

Despite the scientific and technological importance of removing interface dangling bonds, even an ideal model of a dangling-bond-free interface between GaN and an insulator has not been known. The formation of an atomically thin ordered buffer layer between crystalline GaN and amorphous SiO 2 would be a key to synthesize a dangling-bond-free GaN/SiO 2 interface. Here, we predict that a silicon oxynitride (Si 4 O 5 N 3 ) layer can epitaxially grow on a GaN(0001) surface without creating dangling bonds at the interface. Our ab initio calculations show that the GaN/Si 4 O 5 N 3 structure is more stable than silicon-oxide-terminated GaN(0001) surfaces. The electronic properties of the GaN/Si 4 O 5 N 3 structure can be tuned by modifying the chemical components near the interface. We also propose a possible approach to experimentally synthesize the GaN/Si 4 O 5 N 3 structure.

Icosapent ethyl (eicosapentaenoic acid ethyl ester): Effects on remnant-like particle cholesterol from the MARINE and ANCHOR studies.

PubMed

Ballantyne, Christie M; Bays, Harold E; Philip, Sephy; Doyle, Ralph T; Braeckman, Rene A; Stirtan, William G; Soni, Paresh N; Juliano, Rebecca A

2016-10-01

Remnant-like particle cholesterol (RLP-C) is atherogenic and may increase atherosclerotic cardiovascular disease risk. Icosapent ethyl is a high-purity prescription eicosapentaenoic acid ethyl ester (approved as an adjunct to diet to reduce triglyceride [TG] levels in adult patients with TGs ≥500 mg/dL [≥5.65 mmol/L] at 4 g/day). In the MARINE and ANCHOR studies, icosapent ethyl reduced TG and other atherogenic lipid parameter levels without increasing low-density lipoprotein cholesterol (LDL-C) levels. This exploratory analysis evaluated the effects of icosapent ethyl on calculated and directly measured RLP-C. MARINE (TGs ≥500 and ≤2000 mg/dL [≥5.65 mmol/L and ≤22.6 mmol/L]) and ANCHOR (TGs ≥200 and <500 mg/dL [≥2.26 and <5.65 mmol/L] despite statin-controlled LDL-C) were phase 3, 12-week, double-blind studies that randomized adult patients to icosapent ethyl 4 g/day, 2 g/day, or placebo. This analysis assessed median percent change from baseline to study end in directly measured (immunoseparation assay) RLP-C levels (MARINE, n = 218; ANCHOR, n = 252) and calculated RLP-C levels in the full populations. Icosapent ethyl 4 g/day significantly reduced directly measured RLP-C levels -29.8% (p = 0.004) in MARINE and -25.8% (p = 0.0001) in ANCHOR versus placebo, and also reduced directly measured RLP-C levels to a greater extent in subgroups with higher versus lower baseline TG levels, in patients receiving statins versus no statins (MARINE), and in patients receiving medium/higher-intensity versus lower-intensity statins (ANCHOR). Strong correlations were found between calculated and directly measured RLP-C for baseline, end-of-treatment, and percent change values in ANCHOR and MARINE (0.73-0.92; p < 0.0001 for all). Icosapent ethyl 4 g/day significantly reduced calculated and directly measured RLP-C levels versus placebo in patients with elevated TG levels from the MARINE and ANCHOR studies. Copyright © 2016 The Authors

Local effect of zoledronic acid on new bone formation in posterolateral spinal fusion with demineralized bone matrix in a murine model.

PubMed

Zwolak, Pawel; Farei-Campagna, Jan; Jentzsch, Thorsten; von Rechenberg, Brigitte; Werner, Clément M

2018-01-01

Posterolateral spinal fusion is a common orthopaedic surgery performed to treat degenerative and traumatic deformities of the spinal column. In posteriolateral spinal fusion, different osteoinductive demineralized bone matrix products have been previously investigated. We evaluated the effect of locally applied zoledronic acid in combination with commercially available demineralized bone matrix putty on new bone formation in posterolateral spinal fusion in a murine in vivo model. A posterolateral sacral spine fusion in murine model was used to evaluate the new bone formation. We used the sacral spine fusion model to model the clinical situation in which a bone graft or demineralized bone matrix is applied after dorsal instrumentation of the spine. In our study, group 1 received decortications only (n = 10), group 2 received decortication, and absorbable collagen sponge carrier, group 3 received decortication and absorbable collagen sponge carrier with zoledronic acid in dose 10 µg, group 4 received demineralized bone matrix putty (DBM putty) plus decortication (n = 10), and group 5 received DBM putty, decortication and locally applied zoledronic acid in dose 10 µg. Imaging was performed using MicroCT for new bone formation assessment. Also, murine spines were harvested for histopathological analysis 10 weeks after surgery. The surgery performed through midline posterior approach was reproducible. In group with decortication alone there was no new bone formation. Application of demineralized bone matrix putty alone produced new bone formation which bridged the S1-S4 laminae. Local application of zoledronic acid to demineralized bone matrix putty resulted in significant increase of new bone formation as compared to demineralized bone matrix putty group alone. A single local application of zoledronic acid with DBM putty during posterolateral fusion in sacral murine spine model increased significantly new bone formation in situ in our model. Therefore, our

Transport features of nano-hydroxylapatite (n-HA) embedded silicone rubber (SR) systems: influence of SR/n-HA interaction, degree of reinforcement and morphology.

PubMed

M, Bindu; G, Unnikrishnan

2017-09-27

We report the transport characteristics of silicone rubber/nano-hydroxylapatite (SR/n-HA) systems at room temperature with reference to the effects of n-HA loading, morphology and penetrant nature, using toluene, xylene, ethyl acetate and butyl acetate in the liquid phase and methanol, ethanol, 1-propanol, 2-propanol and butanol in the vapour phase as probe molecules. The interaction between the n-HA particles and SR matrix has been confirmed by FTIR analysis. As the n-HA content in the SR matrix increased, the penetrant uptake has been found to decrease. The observations have been correlated with the density and void content of the systems. Scanning electron microscopy images have been found to be complementary to the observed transport features. The reinforcement effect of n-HA particles on the SR matrix has been verified by Kraus equation. Molecular mass between the cross links has been observed to decrease with an increase in n-HA loading. The results have been compared with affine, phantom network, parallel, series and Maxwell models. The transport data have been complemented by observations on biological fluid uptake with urea, d-glucose, KI, saline water, phosphate buffer and artificial urine as the media.

SEM Based CARMA Time Series Modeling for Arbitrary N.

PubMed

Oud, Johan H L; Voelkle, Manuel C; Driver, Charles C

2018-01-01

This article explains in detail the state space specification and estimation of first and higher-order autoregressive moving-average models in continuous time (CARMA) in an extended structural equation modeling (SEM) context for N = 1 as well as N > 1. To illustrate the approach, simulations will be presented in which a single panel model (T = 41 time points) is estimated for a sample of N = 1,000 individuals as well as for samples of N = 100 and N = 50 individuals, followed by estimating 100 separate models for each of the one-hundred N = 1 cases in the N = 100 sample. Furthermore, we will demonstrate how to test the difference between the full panel model and each N = 1 model by means of a subject-group-reproducibility test. Finally, the proposed analyses will be applied in an empirical example, in which the relationships between mood at work and mood at home are studied in a sample of N = 55 women. All analyses are carried out by ctsem, an R-package for continuous time modeling, interfacing to OpenMx.

Spectroscopic (FT-IR and UV-Vis) and theoretical (HF and DFT) investigation of 2-Ethyl-N-[(5-nitrothiophene-2-yl)methylidene]aniline

NASA Astrophysics Data System (ADS)

Ceylan, Ümit; Tarı, Gonca Özdemir; Gökce, Halil; Ağar, Erbil

2016-04-01

Crystal structure of the title compound, 2-Ethyl-N-[(5-nitrothiophene-2-yl)methylidene]aniline, C13H12N2O2S, has been synthesized and characterized by FT-IR and UV-Vis spectrum. The compound crystallized in the monoclinic space group P 21/c with a = 11.3578 (4) Å, b = 7.4923 (2) Å, c = 14.9676 (6) Å and β = 99.589 (3)° and Z = 4 in the unit cell. The molecular geometry was also calculated using the Gaussian 03 software and structure was optimized using the HF and DFT/B3LYP methods with the 6-311++G(d,p) basis set in ground state. Using the TD-DFT method, the electronic absorption spectra of the title compound was computed in both the gas phase and ethanol solvent. The harmonic vibrational frequencies of the title compound were calculated using the same methods with the 6-311++G(d,p) basis set. The calculated results were compared with the experimental determination results of the compound. It was seen that the optimized structure was in excellent agreement with the X-ray crystal structure. The energetic behaviors of the title compound in solvent media were examined using the HF and DFT/B3LYP methods with the 6-311++G(d,p) basis set applying the polarizable continuum model (PCM). In addition, the molecular orbitals (FMOs) analysis, molecular electrostatic potential (MEP), nonlinear optical and thermodynamic properties of the title compound were performed using the same methods with the 6-311++G(d,p) basis set.

The Interface Influence in TiN/SiN x Multilayer Nanocomposite Under Irradiation

NASA Astrophysics Data System (ADS)

Uglov, V. V.; Safronov, I. V.; Kvasov, N. T.; Remnev, G. E.; Shimanski, V. I.

2018-01-01

The paper focuses on studying the kinetics of radiation-induced point defects formed in TiN/SiN x multilayer nanocomposites with account of their generation, diffusion recombination, and the influence of sinks functioning as interfaces. In order to describe the kinetics in nanocrystalline TiN and amorphous SiN x phases, a finite-difference method is used to solve the system of balance kinetic equations for absolute defect concentrations depending on the spatiotemporal variables. A model of the disclination-dislocation interface structure is used to study the absorption of radiation-induced point defects on the boundaries in created stress fields. It is shown that the interface effectively absorbs point defects in these phases of TiN/SiN x multilayer nanocomposite, thereby reducing their amount within the space between phases. This behavior of point defects partially explains a mechanism of the radiation resistance in this type of nanocomposites.

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models

PubMed Central

Pohling, Christoph; Natarajan, Arutselvan; Witney, Timothy H.; Kaur, Jasdeep; Xu, Lingyun; Gowrishankar, Gayatri; D’Souza, Aloma L; Murty, Surya; Schick, Sophie; Chen, Liyin; Wu, Nicholas; Khaw, Phoo; Mischel, Paul; Abbasi, Taher; Usmani, Shahabuddin; Mallick, Parag

2017-01-01

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O’Neill (J Neurooncol 107: 359–364, 2012). An extract from the winter cherry plant (Withania somnifera), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985–1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3–5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 μM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 μM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM. PMID:26650066

AshwaMAX and Withaferin A inhibits gliomas in cellular and murine orthotopic models.

PubMed

Chang, Edwin; Pohling, Christoph; Natarajan, Arutselvan; Witney, Timothy H; Kaur, Jasdeep; Xu, Lingyun; Gowrishankar, Gayatri; D'Souza, Aloma L; Murty, Surya; Schick, Sophie; Chen, Liyin; Wu, Nicholas; Khaw, Phoo; Mischel, Paul; Abbasi, Taher; Usmani, Shahabuddin; Mallick, Parag; Gambhir, Sanjiv S

2016-01-01

Glioblastoma multiforme (GBM) is an aggressive, malignant cancer Johnson and O'Neill (J Neurooncol 107: 359-364, 2012). An extract from the winter cherry plant (Withania somnifera ), AshwaMAX, is concentrated (4.3 %) for Withaferin A; a steroidal lactone that inhibits cancer cells Vanden Berghe et al. (Cancer Epidemiol Biomark Prev 23: 1985-1996, 2014). We hypothesized that AshwaMAX could treat GBM and that bioluminescence imaging (BLI) could track oral therapy in orthotopic murine models of glioblastoma. Human parietal-cortical glioblastoma cells (GBM2, GBM39) were isolated from primary tumors while U87-MG was obtained commercially. GBM2 was transduced with lentiviral vectors that express Green Fluorescent Protein (GFP)/firefly luciferase fusion proteins. Mutational, expression and proliferative status of GBMs were studied. Intracranial xenografts of glioblastomas were grown in the right frontal regions of female, nude mice (n = 3-5 per experiment). Tumor growth was followed through BLI. Neurosphere cultures (U87-MG, GBM2 and GBM39) were inhibited by AshwaMAX at IC50 of 1.4, 0.19 and 0.22 µM equivalent respectively and by Withaferin A with IC50 of 0.31, 0.28 and 0.25 µM respectively. Oral gavage, every other day, of AshwaMAX (40 mg/kg per day) significantly reduced bioluminescence signal (n = 3 mice, p < 0.02, four parameter non-linear regression analysis) in preclinical models. After 30 days of treatment, bioluminescent signal increased suggesting onset of resistance. BLI signal for control, vehicle-treated mice increased and then plateaued. Bioluminescent imaging revealed diffuse growth of GBM2 xenografts. With AshwaMAX, GBM neurospheres collapsed at nanomolar concentrations. Oral treatment studies on murine models confirmed that AshwaMAX is effective against orthotopic GBM. AshwaMAX is thus a promising candidate for future clinical translation in patients with GBM.

Validating soil denitrification models based on laboratory N_{2} and N_{2}O fluxes and underlying processes derived by stable isotope approaches

NASA Astrophysics Data System (ADS)

Well, Reinhard; Böttcher, Jürgen; Butterbach-Bahl, Klaus; Dannenmann, Michael; Deppe, Marianna; Dittert, Klaus; Dörsch, Peter; Horn, Marcus; Ippisch, Olaf; Mikutta, Robert; Müller, Carsten; Müller, Christoph; Senbayram, Mehmet; Vogel, Hans-Jörg; Wrage-Mönnig, Nicole

2016-04-01

, denitrification control factors will be varied in the initial settings (pore volume, plant residues, mineral N, pH) but also over time, where moisture, temperature, and mineral N will be manipulated according to typical time patterns in the field. This will be realized by including precipitation events, fertilization (via irrigation), drainage (via water potential) and temperature in the course of incubations. Moreover, oxygen concentration will be varied to simulate anaerobic events. These data will be used to calibrate the newly to develop DASIM models as well as existing denitrification models. One goal of DASIM is to create a public data base as a joint basis for model testing by denitrification modellers. Therefore we invite contributions of suitable data-sets from the scientific community. Requirements will be briefly outlined.

Several novel N-donor tridentate ligands formed in chemical studies of new fac-Re(CO)3 complexes relevant to fac-99mTc(CO)3 radiopharmaceuticals: attack of a terminal amine on coordinated acetonitrile.

PubMed

Perera, Theshini; Marzilli, Patricia A; Fronczek, Frank R; Marzilli, Luigi G

2010-03-01

To evaluate syntheses of fac-[Re(CO)(3)L](+) complexes in organic solvents, we treated fac-[Re(CO)(3)(CH(3)CN)(3)]PF(6)/BF(4) in acetonitrile with triamine ligands (L). When L had two primary or two tertiary terminal amine groups, the expected fac-[Re(CO)(3)L](+) complexes formed. In contrast, N,N-dimethyldiethylenetriamine (N,N-Me(2)dien) formed an unusual compound, fac-[Re(CO)(3)(DAE)]BF(4) {DAE = (Z)-N'-(2-(2-(dimethylamino)ethylamino)ethyl)acetimidamide = (Me(2)NCH(2)CH(2))NH(CH(2)CH(2)N=C(NH(2))Me)}. DAE is formed by addition of acetonitrile to the N,N-Me(2)dien terminal primary amine, converting this sp(3) nitrogen to an sp(2) nitrogen with a double bond to the original acetonitrile sp carbon. The three Ns bound to Re derive from N,N-Me(2)dien. The pathway to fac-[Re(CO)(3)(DAE)]BF(4) is suggested by a second unusual compound, fac-[Re(CO)(3)(MAE)]PF(6) {MAE = N-methyl-N-(2-(methyl-(2-(methylamino)ethyl)amino)ethyl)acetimidamide = MeN(H)-CH(2)CH(2)-N(Me)-CH(2)CH(2)-N(Me)-C(Me)=NH}, isolated after treating fac-[Re(CO)(3)(CH(3)CN)(3)]PF(6) with N,N',N''-trimethyldiethylenetriamine (N,N',N''-Me(3)dien). MAE chelates via a terminal and a central sp(3) N from N,N',N''-Me(3)dien and via one sp(2) NH in a C(Me)=NH group. This group is derived from acetonitrile by addition of the other N,N',N''-Me(3)dien terminal amine to the nitrile carbon. This addition creates an endocyclic NMe group within a seven-membered chelate ring. The structure and other properties of fac-[Re(CO)(3)(MAE)]PF(6) allow us to propose a reaction scheme for the formation of the unprecedented DAE ligand. The new compounds advance our understanding of the spectral and structural properties of Re analogues of (99m)Tc radiopharmaceuticals.

Mannose-binding lectin contributes to deleterious inflammatory response in pandemic H1N1 and avian H9N2 infection.

PubMed

Ling, Man To; Tu, Wenwei; Han, Yan; Mao, Huawei; Chong, Wai Po; Guan, Jing; Liu, Ming; Lam, Kwok Tai; Law, Helen K W; Peiris, J S Malik; Takahashi, K; Lau, Yu Lung

2012-01-01

Mannose-binding lectin (MBL) is a pattern-recognition molecule, which functions as a first line of host defense. Pandemic H1N1 (pdmH1N1) influenza A virus caused massive infection in 2009 and currently circulates worldwide. Avian influenza A H9N2 (H9N2/G1) virus has infected humans and has the potential to be the next pandemic virus. Antiviral function and immunomodulatory role of MBL in pdmH1N1 and H9N2/G1 virus infection have not been investigated. In this study, MBL wild-type (WT) and MBL knockout (KO) murine models were used to examine the role of MBL in pdmH1N1 and H9N2/G1 virus infection. Our study demonstrated that in vitro, MBL binds to pdmH1N1 and H9N2/G1 viruses, likely via the carbohydrate recognition domain of MBL. Wild-type mice developed more severe disease, as evidenced by a greater weight loss than MBL KO mice during influenza virus infection. Furthermore, MBL WT mice had enhanced production of proinflammatory cytokines and chemokines compared with MBL KO mice, suggesting that MBL could upregulate inflammatory responses that may potentially worsen pdmH1N1 and H9N2/G1 virus infections. Our study provided the first in vivo evidence that MBL may be a risk factor during pdmH1N1 and H9N2/G1 infection by upregulating proinflammatory response.

Wavelength Effect on the Action of a N-Phenylimide S-23142 and a Diphenylether Acifluorfen-Ethyl in Cotyledons of Cucumber (Cucumis sativus L.) Seedlings 1

PubMed Central

Sato, Ryo; Nagano, Eiki; Oshio, Hiromichi; Kamoshita, Katsuzo; Furuya, Masaki

1987-01-01

Specific wavelengths of light required for expression of phytotoxic activity of S-23142 (N-[4-chloro-2-fluoro-5-propargyloxy]phenyl-3,4,5,6-tetra- hydrophthalimide) and acifluorfen-ethyl (ethyl-5-[2-chloro-4-(trifluoromethyl)phenoxy]-2-nitro benzoic acid) were determined in cotyledons of cucumber seedlings using the Okazaki Large Spectrograph. Leakage of amino acids from the cotyledons was measured as an indication of the phytotoxic activity. The wavelength effects showed common major peaks of activity at 550 and 650 nanometers and a minor peak at 450 nanometers for both herbicides, indicating a common primary photoreaction. Concomitant application of DCMU (3-[3,4-dichlorophenyl]-1,1-dimethylurea) with S-23142 had little influence on the effective wavelengths for S-23142 activity. Light of 450 and 650 nanometers was relatively less effective in achlorophyllous tissue grown in far red light than in green tissue. These results strongly suggest that the phytotoxic action of S-23142 and diphenylethers involves multiple photoreactions and that one of the photoreceptor pigments may be chlorophyll or its related pigment, although photosynthesis is not involved. PMID:16665819

Heparan sulfates and the decrease of N-glycans promote early adipogenic differentiation rather than myogenesis of murine myogenic progenitor cells.

PubMed

Grassot, Vincent; Bouchatal, Amel; Da Silva, Anne; Chantepie, Sandrine; Papy-Garcia, Dulce; Maftah, Abderrahman; Gallet, Paul-François; Petit, Jean-Michel

In vitro, extracted muscle satellite cells, called myogenic progenitor cells, can differentiate either in myotubes or preadipocytes, depending on environmental factors and the medium. Transcriptomic analyses on glycosylation genes during satellite cells differentiation into myotubes showed that 31 genes present a significant variation of expression at the early stages of murine myogenic progenitor cells (MPC) differentiation. In the present study, we analyzed the expression of 383 glycosylation related genes during murine MPC differentiation into preadipocytes and compared the data to those previously obtained during their differentiation into myotubes. Fifty-six glycosylation related genes are specifically modified in their expression during early adipogenesis. The variations correspond mainly to: a decrease of N-glycans, and of alpha (2,3) and (2,6) linked sialic acids, and to a high level of heparan sulfates. A high amount of TGF-β1 in extracellular media during early adipogenesis was also observed. It seems that the increases of heparan sulfates and TGF-β1 favor pre-adipogenic differentition of MPC and possibly prevent their myogenic differentiation. Copyright © 2016 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.

Polyelectrolyte complexes between (cross-linked) N-carboxyethylchitosan and (quaternized) poly[2-(dimethylamino)ethyl methacrylate]: preparation, characterization, and antibacterial properties.

PubMed

Yancheva, Elena; Paneva, Dilyana; Maximova, Vera; Mespouille, Laetitia; Dubois, Philippe; Manolova, Nevena; Rashkov, Iliya

2007-03-01

Novel polyelectrolyte complexes (PECs) between N-carboxyethylchitosan (CECh) and well-defined (quaternized) poly[2-(dimethylamino)ethyl methacrylate] (PDMAEMA) have been obtained. The modification of chitosan into CECh allows the preparation of PECs in a pH range in which chitosan cannot form complexes. The CECh/PDMAEMA complex is formed in a narrow pH range around 7. The quaternization of the tertiary amino groups of PDMAEMA enables complex formation with CECh both in neutral and in alkaline medium. Cross-linked CECh is also capable of forming complexes with (quaternized) PDMAEMA. The antibacterial activity of (cross-linked) CECh, (quaternized) PDMAEMA, and their complexes against Escherichia coli has been evaluated. In contrast to (quaternized) PDMAEMA, (cross-linked) CECh exhibits no antibacterial activity. The complex formation between cross-linked CECh and (quaternized) PDMAEMA results in a loss of the inherent antibacterial activity of the latter in neutral medium. In acidic medium, the complexes exhibit strong antibacterial activity due to complex disintegration and release of (quaternized) PDMAEMA.

Identification of radiolytic products from N-nitrosodimethylamine and N-nitrosopyrrolidine by gas chromatography and mass spectrometry

NASA Astrophysics Data System (ADS)

Ahn, Hyun-Joo; Lee, Cherl-Ho; Kim, Jae-Hyun; Han, Sang-Bae; Jo, Cheorun; Kim, Sung; Byun, Myung-Woo

2004-01-01

The radiolytic products of N-nitrosodimethylamine (NDMA) and N-nitrosopyrrolidine (NPYR) dissolved in dichloromethane (DCM) were identified after gamma irradiation. The UV spectra of NDMA and NPYR indicated that irradiation reduced the typical peak of NDMA at 258 nm and NPYR at 260 nm.The major radiolytic components identified in irradiated NDMA were ethyl acetate and 2-dimethyl propanol. The irradiated NPYR dissolved in DCM and produced 2-butanone and 2-methyl-6-propyl piperidine as the major radiolytic components. 2-Methyl-6-propyl piperidine was the component detected in the greatest concentration in irradiated NPYR.

Viscosities of nonelectrolyte liquid mixtures. II. Binary mixtures of n-hexane with alkanoates and bromoalkanoates

NASA Astrophysics Data System (ADS)

Oswal, S. L.; Dave, J. P.

1992-11-01

Viscosity measurements are reported for mixtures of ethyl ethanoate, ethyl propionate, ethyl butyrate, ethyl-2-bromopropionate, ethyl-3-bromopropionate, ethyl-2-bromobutyrate, and ethyl-4-bromobutyrate with n-hexane at 303.15 K. The viscosity data have been correlated with equations of Grunberg and Nissan, of McAllister, and of Auslaender. Furthermore, excess Gibbs energies of activation ΔG * E of viscous flow have been calculated with Eyring's theory of absolute reaction rates and values of ΔG * E for the present binary mixtures have been explained in terms of the dipole-dipole interaction in alkanoates and the intramolecular Br...O interaction in bromoalkanoates.

Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model

PubMed Central

Laube, Beth L.; Afshar-Mohajer, Nima; Koehler, Kirsten; Chen, Gang; Lazarus, Philip; Collaco, Joseph M.; McGrath-Morrow, Sharon A.

2017-01-01

Objective To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs. Methods C57BL/6 male mice (age 10.5 ±2.4 weeks) were exposed for 20min/day to E-cigarette aerosol generated by a Joyetech 510-T® E-cig containing either 0% nicotine (N)/propylene glycol (PG) for 1 week (n = 6), or 3 weeks (n = 9), or 2.4% N/PG for one week (n = 6), or 3 weeks (n = 9), followed by measurement of MCC. Control mice (n = 15) were not exposed to PG alone, or N/PG. MCC was assessed by gamma camera following aspiration of 99mtechnetium aerosol and was expressed as the amount of radioactivity removed from both lungs over 6 hours (MCC6hrs). Venous blood was assayed for cotinine levels in control mice and in mice exposed for 3-weeks to PG alone and N/PG. Results MCC6hrs in control mice and in mice acutely exposed to PG alone and N/PG was similar, averaging (±1 standard deviation) 8.6±5.2%, 7.5±2.8% and 11.2±5.9%, respectively. In contrast, chronic exposure to PG alone stimulated MCC6hrs (17.2 ±8.0)% and this stimulation was significantly blunted following chronic exposure to N/PG (8.7 ±4.6)% (p < .05). Serum cotinine levels were <0.5ng/ml in control mice and in mice exposed to PG alone, whereas, N/PG exposed mice averaged 14.6 ± 12.0 ng/ml. Conclusions In this murine model, a chronic, daily, 20 min-exposure to N/PG, but not an acute exposure, slowed MCC, compared to exposure to PG alone and led to systemic absorption of nicotine. PMID:28651446

The carcinogenicity of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU).

PubMed

Warzok, R; Martin, J; Mendel, J; Thust, R; Schwarz, H

1983-01-01

In long-term experiments with Hooded rats the carcinogenic potential of 1-methyl-3(p-bromophenyl)-1-nitrosourea (Br-MPNU) could be demonstrated for the first time. Br-MPNU is formed also endogenously after combined administration of 1-methyl-3(p-bromophenyl)-urea (Br-MPU) and sodium nitrite. After repeated intragastric administration of 0.33 mmol Br-MPU and 0.73 mmol NaNO2 per kg b.w. papillomas and carcinomas of the forestomach developed in 83%. After repeated administration of 0.28 mmol Br-MPNU per kg b.w. these neoplasms were observed in 88%. The comparison of results obtained in similar experiments with 1-methyl-3-phenyl-1-nitrosourea shows that bromine substitution led to a reduction of the carcinogenic activity. The present paper is part of a complex program studying the interrelationships between structure, physico-chemical properties, mutagenicity and carcinogenicity of nitrosoureas.

Production and characterization of murine models of classic and intermediate maple syrup urine disease

PubMed Central

Homanics, Gregg E; Skvorak, Kristen; Ferguson, Carolyn; Watkins, Simon; Paul, Harbhajan S

2006-01-01

Background Maple Syrup Urine Disease (MSUD) is an inborn error of metabolism caused by a deficiency of branched-chain keto acid dehydrogenase. MSUD has several clinical phenotypes depending on the degree of enzyme deficiency. Current treatments are not satisfactory and require new approaches to combat this disease. A major hurdle in developing new treatments has been the lack of a suitable animal model. Methods To create a murine model of classic MSUD, we used gene targeting and embryonic stem cell technologies to create a mouse line that lacked a functional E2 subunit gene of branched-chain keto acid dehydrogenase. To create a murine model of intermediate MSUD, we used transgenic technology to express a human E2 cDNA on the knockout background. Mice of both models were characterized at the molecular, biochemical, and whole animal levels. Results By disrupting the E2 subunit gene of branched-chain keto acid dehydrogenase, we created a gene knockout mouse model of classic MSUD. The homozygous knockout mice lacked branched-chain keto acid dehydrogenase activity, E2 immunoreactivity, and had a 3-fold increase in circulating branched-chain amino acids. These metabolic derangements resulted in neonatal lethality. Transgenic expression of a human E2 cDNA in the liver of the E2 knockout animals produced a model of intermediate MSUD. Branched-chain keto acid dehydrogenase activity was 5–6% of normal and was sufficient to allow survival, but was insufficient to normalize circulating branched-chain amino acids levels, which were intermediate between wildtype and the classic MSUD mouse model. Conclusion These mice represent important animal models that closely approximate the phenotype of humans with the classic and intermediate forms of MSUD. These animals provide useful models to further characterize the pathogenesis of MSUD, as well as models to test novel therapeutic strategies, such as gene and cellular therapies, to treat this devastating metabolic disease. PMID

Catalyst-free ethyl biodiesel production from rice bran under subcritical condition

NASA Astrophysics Data System (ADS)

Zullaikah, Siti; Afifudin, Riza; Amalia, Rizky

2015-12-01

In-situ ethyl biodiesel production from rice bran under subcritical water and ethanol with no catalyst was employed. This process is environmentally friendly and is very flexible in term of feedstock utilization since it can handle relatively high moisture and free fatty acids (FFAs) contents. In addition, the alcohol, i.e. bioethanol, is a non-toxic, biodegradable, and green raw material when produced from non-edible biomass residues, leading to a 100% renewable biodiesel. The fatty acid ethyl esters (FAEEs, ethyl biodiesel) are better than fatty acid methyl esters (FAMEs, methyl biodiesel) in terms of fuel properties, including cetane number, oxidation stability and cold flow properties. The influences of the operating variables such as reaction time (1 - 10 h), ethanol concentration (12.5 - 87.5%), and pressurizing gas (N2 and CO2) on the ethyl biodiesel yield and purity have been investigated systematically while the temperature and pressure were kept constant at 200 °C and 40 bar. The optimum results were obtained at 5 h reaction time and 75% ethanol concentration using CO2 as compressing gas. Ethyl biodiesel yield and purity of 58.78% and 61.35%, respectively, were obtained using rice bran with initial FFAs content of 37.64%. FFAs level was reduced to 14.22% with crude ethyl biodiesel recovery of 95.98%. Increasing the reaction time up to 10 h only increased the yield and purity by only about 3%. Under N2 atmosphere and at the same operating conditions (5h and 75% ethanol), ethyl biodiesel yield and purity decreased to 54.63% and 58.07%, respectively, while FFAs level was increased to 17.93% and crude ethyl biodiesel recovery decreased to 87.32%.

Novel model of a AlGaN/GaN high electron mobility transistor based on an artificial neural network

NASA Astrophysics Data System (ADS)

Cheng, Zhi-Qun; Hu, Sha; Liu, Jun; Zhang, Qi-Jun

2011-03-01

In this paper we present a novel approach to modeling AlGaN/GaN high electron mobility transistor (HEMT) with an artificial neural network (ANN). The AlGaN/GaN HEMT device structure and its fabrication process are described. The circuit-based Neuro-space mapping (neuro-SM) technique is studied in detail. The EEHEMT model is implemented according to the measurement results of the designed device, which serves as a coarse model. An ANN is proposed to model AlGaN/GaN HEMT based on the coarse model. Its optimization is performed. The simulation results from the model are compared with the measurement results. It is shown that the simulation results obtained from the ANN model of AlGaN/GaN HEMT are more accurate than those obtained from the EEHEMT model. Project supported by the National Natural Science Foundation of China (Grant No. 60776052).

Optical model potential analysis of n ¯A and n A interactions

NASA Astrophysics Data System (ADS)

Lee, Teck-Ghee; Wong, Cheuk-Yin

2018-05-01

We use a momentum-dependent optical model potential to analyze the annihilation cross sections of the antineutron n ¯ on C, Al, Fe, Cu, Ag, Sn, and Pb nuclei for projectile momenta plab ≲500 MeV /c . We obtain a good description of annihilation cross section data of Barbina et al. [Nucl. Phys. A 612, 346 (1997), 10.1016/S0375-9474(96)00331-4] and of Astrua et al. [Nucl. Phys. A 697, 209 (2002), 10.1016/S0375-9474(01)01252-0] which exhibit an interesting dependence of the cross sections on plab as well as on the target mass number A . We also obtain the neutron (n ) nonelastic reaction cross sections for the same targets. Comparing the n A reaction cross sections σrecn A to the n ¯A annihilation cross sections σannn ¯A, we find that σannn ¯A is significantly larger than σrecn A, that is, the σannn ¯A/σrecn A cross section ratio lies between the values of about 1.5 to 4.0 in the momentum region where comparison is possible. The dependence of the n ¯ annihilation cross section on the projectile charge is also examined in comparison with the antiproton p ¯. Here we predict the p ¯A annihilation cross section on the simplest assumption that both p ¯A and n ¯A interactions have the same nuclear part of the optical potential but differ only in the electrostatic Coulomb interaction. Deviation from a such simple model extrapolation in measurements will provide new information on the difference between n ¯A and p ¯A potentials.

N- and O-Glycosylation in the Murine Synaptosome*

PubMed Central

Trinidad, Jonathan C.; Schoepfer, Ralf; Burlingame, Alma L.; Medzihradszky, Katalin F.

2013-01-01

We present the first large scale study characterizing both N- and O-linked glycosylation in a site-specific manner on hundreds of proteins. We demonstrate that a lectin-affinity fractionation step using wheat germ agglutinin enriches not only peptides carrying intracellular O-GlcNAc, but also those bearing ER/Golgi-derived N- and O-linked carbohydrate structures. Liquid chromatography-MS (LC/MS) analysis with high accuracy precursor mass measurements and high sensitivity ion trap electron-transfer dissociation (ETD) were utilized for structural characterization of glycopeptides. Our results reveal both the identity of the precise sites of glycosylation and information on the oligosaccharide structures possible on these proteins. We report a novel iterative approach that allowed us to interpret the ETD data set directly without making prior assumptions about the nature and distribution of oligosaccharides present in our glycopeptide mixture. Over 2500 unique N- and O-linked glycopeptides were identified on 453 proteins. The extent of microheterogeneity varied extensively, and up to 19 different oligosaccharides were attached at a given site. We describe the presence of the well-known mucin-type structures for O-glycosylation, an EGF-domain-specific fucosylation and a rare O-mannosylation on the transmembrane phosphatase Ptprz1. Finally, we identified three examples of O-glycosylation on tyrosine residues. PMID:23816992

N- and O-glycosylation in the murine synaptosome.

PubMed

Trinidad, Jonathan C; Schoepfer, Ralf; Burlingame, Alma L; Medzihradszky, Katalin F

2013-12-01

We present the first large scale study characterizing both N- and O-linked glycosylation in a site-specific manner on hundreds of proteins. We demonstrate that a lectin-affinity fractionation step using wheat germ agglutinin enriches not only peptides carrying intracellular O-GlcNAc, but also those bearing ER/Golgi-derived N- and O-linked carbohydrate structures. Liquid chromatography-MS (LC/MS) analysis with high accuracy precursor mass measurements and high sensitivity ion trap electron-transfer dissociation (ETD) were utilized for structural characterization of glycopeptides. Our results reveal both the identity of the precise sites of glycosylation and information on the oligosaccharide structures possible on these proteins. We report a novel iterative approach that allowed us to interpret the ETD data set directly without making prior assumptions about the nature and distribution of oligosaccharides present in our glycopeptide mixture. Over 2500 unique N- and O-linked glycopeptides were identified on 453 proteins. The extent of microheterogeneity varied extensively, and up to 19 different oligosaccharides were attached at a given site. We describe the presence of the well-known mucin-type structures for O-glycosylation, an EGF-domain-specific fucosylation and a rare O-mannosylation on the transmembrane phosphatase Ptprz1. Finally, we identified three examples of O-glycosylation on tyrosine residues.

Hydroxide as general base in the saponification of ethyl acetate.

PubMed

Mata-Segreda, Julio F

2002-03-13

The second-order rate constant for the saponification of ethyl acetate at 30.0 degrees C in H(2)O/D(2)O mixtures of deuterium atom fraction n (a proton inventory experiment) obeys the relation k(2)(n) = 0.122 s(-1) M(-1) (1 - n + 1.2n) (1 - n + 0.48n)/(1 - n + 1.4n) (1 - n + 0.68n)(3). This result is interpreted as a process where formation of the tetrahedral intermediate is the rate-determining step and the transition-state complex is formed via nucleophilic interaction of a water molecule with general-base assistance from hydroxide ion, opposite to the direct nucleophilic collision commonly accepted. This mechanistic picture agrees with previous heavy-atom kinetic isotope effect data of Marlier on the alkaline hydrolysis of methyl formate.

Biomechanical Properties of Murine Meniscus Surface via AFM-based Nanoindentation

PubMed Central

Li, Qing; Doyran, Basak; Gamer, Laura W.; Lu, X. Lucas; Qin, Ling; Ortiz, Christine; Grodzinsky, Alan J.; Rosen, Vicki; Han, Lin

2015-01-01

This study aimed to quantify the biomechanical properties of murine meniscus surface. Atomic force microscopy (AFM)-based nanoindentation was performed on the central region, proximal side of menisci from 6- to 24-week old male C57BL/6 mice using microspherical tips (Rtip ≈ 5 μm) in PBS. A unique, linear correlation between indentation depth, D, and response force, F, was found on menisci from all age groups. This non-Hertzian behavior is likely due to the dominance of tensile resistance by the collagen fibril bundles on meniscus surface that are mostly aligned along the circumferential direction observed on 12-week old menisci. The indentation resistance was calculated as both the effective stiffness, Sind = dF/dD, and the effective modulus, Eind, via the isotropic Hertz model. Values of Sind and Eind were found to depend on indentation rate, suggesting the existence of poro-viscoelasticity. These values do not significantly vary with anatomical sites, lateral versus medial compartments, or mouse age. In addition, Eind of meniscus surface (e.g., 6.1 ± 0.8 MPa for 12 weeks of age, mean ± SEM, n = 13) was found to be significantly higher than those of meniscus surfaces in other species, and of murine articular cartilage surface (1.4 ± 0.1 MPa, n = 6). In summary, these results provided the first direct mechanical knowledge of murine knee meniscus tissues. We expect this understanding to serve as a mechanics-based benchmark for further probing the developmental biology and osteoarthritis symptoms of meniscus in various murine models. PMID:25817332

Modified n-level, n - 1-mode Tavis-Cummings model and algebraic Bethe ansatz

NASA Astrophysics Data System (ADS)

Skrypnyk, T.

2018-01-01

Using the quantum group technique we construct a one-parametric family of integrable modifications of the n-level, n-1 mode Tavis-Cummings Hamiltonian possessing an additional Stark-type term. We show that in the ‘quasiclassical’ limit the constructed Hamiltonian transforms into the integrable Hamiltonian of the quantum n-level, n-1 mode Tavis-Cummings model with the equal interaction strengths considered in Skrypnyk (2008 J. Phys. A: Math. Theor. 41 475202, 2009 J. Math. Phys. 50 103523). We diagonalize the constructed ‘modified’ Tavis-Cummings Hamiltonian and its second order integrals of motion using the nested Bethe ansatz.

Pentamethylcyclopentadienyl-rhodium and iridium complexes containing (N^N and N^O) bound chloroquine analogue ligands: synthesis, characterization and antimalarial properties.

PubMed

Ekengard, Erik; Kumar, Kamlesh; Fogeron, Thibault; de Kock, Carmen; Smith, Peter J; Haukka, Matti; Monari, Magda; Nordlander, Ebbe

2016-03-07

The synthesis and characterization of twenty new pentamethylcyclopentadienyl-rhodium and iridium complexes containing N^N and N^O-chelating chloroquine analogue ligands are described. The in vitro antimalarial activity of the new ligands as well as the complexes was evaluated against the chloroquine sensitive (CQS) NF54 and the chloroquine resistant (CQR) Dd2 strains of Plasmodium falciparum. The antimalarial activity was found to be good to moderate; although all complexes are less active than artesunate, some of the ligands and complexes showed better activity than chloroquine (CQ). In particular, rhodium complexes were found to be considerably more active than iridium complexes against the CQS NF54 strain. Salicylaldimine Schiff base ligands having electron-withdrawing groups (F, Cl, Br, I and NO2) in para position of the salicyl moiety and their rhodium complexes showed good antiplasmodial activity against both the CQS-NF54 and the CQR-Dd2 strains. The crystal structures of (η(5)-pentamethylcyclopentadienyl){N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)} chlororhodium(III) chloride and (η(5)-pentamethylcyclopentadienyl){(4-chloro-2-(((2-((7-chloroquinolin-4-yl)amino)ethyl)imino)methyl)phenolate)}chlororhodium(III) chloride are reported. The crystallization of the amino-pyridyl complex (η(5)-pentamethylcyclopentadienyl){(N(1)-(7-chloroquinolin-4-yl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine)}chloroiridium(III) chloride in acetone resulted in the formation of the imino-pyridyl derivative (η(5)-pentamethylcyclopentadienyl){(N1-(7-chloroquinolin-4-yl)-N2-(pyridin-2-ylmethylene)ethane-1,2-diamine)}chloroiridium(III) chloride, the crystal structure of which is also reported.

Mannose-Binding Lectin Contributes to Deleterious Inflammatory Response in Pandemic H1N1 and Avian H9N2 Infection

PubMed Central

Ling, Man To; Tu, Wenwei; Han, Yan; Mao, Huawei; Chong, Wai Po; Guan, Jing; Liu, Ming; Lam, Kwok Tai; Law, Helen K. W.; Peiris, J. S. Malik; Takahashi, K.

2012-01-01

Background. Mannose-binding lectin (MBL) is a pattern-recognition molecule, which functions as a first line of host defense. Pandemic H1N1 (pdmH1N1) influenza A virus caused massive infection in 2009 and currently circulates worldwide. Avian influenza A H9N2 (H9N2/G1) virus has infected humans and has the potential to be the next pandemic virus. Antiviral function and immunomodulatory role of MBL in pdmH1N1 and H9N2/G1 virus infection have not been investigated. Methods. In this study, MBL wild-type (WT) and MBL knockout (KO) murine models were used to examine the role of MBL in pdmH1N1 and H9N2/G1 virus infection. Results. Our study demonstrated that in vitro, MBL binds to pdmH1N1 and H9N2/G1 viruses, likely via the carbohydrate recognition domain of MBL. Wild-type mice developed more severe disease, as evidenced by a greater weight loss than MBL KO mice during influenza virus infection. Furthermore, MBL WT mice had enhanced production of proinflammatory cytokines and chemokines compared with MBL KO mice, suggesting that MBL could upregulate inflammatory responses that may potentially worsen pdmH1N1 and H9N2/G1 virus infections. Conclusions. Our study provided the first in vivo evidence that MBL may be a risk factor during pdmH1N1 and H9N2/G1 infection by upregulating proinflammatory response. PMID:22080095

SEQUENCE ANALYSIS OF MUTATIONS INDUCED BY N-ETHYL-N-NITROSOUREA IN THE TK AND HPRT GENES OF MOUSE LYMPHOMA CELLS.

EPA Science Inventory

The mouse lymphoma assay is widely used to identify chemicals that are capable of inducing mutational damages. The Tk+/- gene located on an autosome in mouse lymphoma cells may recover a wider range of mutational events than the X-linked Hprt locus. However, chemical-induced muta...

Nitric oxide donors attenuate clongenic potential in rat C6 glioma cells treated with alkylating chemotherapeutic agents.

PubMed

Yang, Jir-Jei; Yin, Jiu-Haw; Yang, Ding-I

2007-05-11

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) kills tumor cells via multiple actions including alkylation and carbamoylation. Previously, we have reported that formation of S-nitrosoglutathione (GSNO) in glioma cells overexpressing inducible nitric oxide synthase (iNOS) contributed to nitric oxide (NO)-dependent carbamoylating chemoresistance against BCNU. To further characterize the effects of NO on alkylating cytotoxicity, colony formation assay was applied to evaluate the effects of various NO donors on rat C6 glioma cells challenged with alkylating agents. We demonstrate that NO donors including GSNO, diethylamine NONOate (DEA/NO), and sodium nitroprusside (SNP) substantially reduced the extent of colony formation in glioma cells treated with alkylating agents, namely methyl methanesulfonate (MMS), N-methyl-N-nitrosourea (MNU), and N-ethyl-N-nitrosourea (ENU). Without alkylating agents these NO-releasing agents alone had no effects on clongenic potential of rat C6 glioma cells. Among these three NO donors used, the effectiveness in potentiating alkylating cytotoxicity is in the order of "GSNO>DEA/NO>SNP" when applied at the same dosages. GSNO also exerted similar synergistic actions reducing the extents of colony formation when co-administrated with 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-hydrazine (compound #1), another alkylating agent that mimics the chloroethylating action of BCNU. Together with our previous findings, we propose that NO donors may be used as adjunct chemotherapy with alkylating agents for such malignant brain tumors as glioblastoma multiforme (GBM). In contrast, production of NO as a result of iNOS induction, such as that occurring after surgical resection of brain tumors, may compromise the efficacy of carbamoylating chemotherapy.

Functional renormalization group approach to SU(N ) Heisenberg models: Real-space renormalization group at arbitrary N

NASA Astrophysics Data System (ADS)

Buessen, Finn Lasse; Roscher, Dietrich; Diehl, Sebastian; Trebst, Simon

2018-02-01

The pseudofermion functional renormalization group (pf-FRG) is one of the few numerical approaches that has been demonstrated to quantitatively determine the ordering tendencies of frustrated quantum magnets in two and three spatial dimensions. The approach, however, relies on a number of presumptions and approximations, in particular the choice of pseudofermion decomposition and the truncation of an infinite number of flow equations to a finite set. Here we generalize the pf-FRG approach to SU (N )-spin systems with arbitrary N and demonstrate that the scheme becomes exact in the large-N limit. Numerically solving the generalized real-space renormalization group equations for arbitrary N , we can make a stringent connection between the physically most significant case of SU(2) spins and more accessible SU (N ) models. In a case study of the square-lattice SU (N ) Heisenberg antiferromagnet, we explicitly demonstrate that the generalized pf-FRG approach is capable of identifying the instability indicating the transition into a staggered flux spin liquid ground state in these models for large, but finite, values of N . In a companion paper [Roscher et al., Phys. Rev. B 97, 064416 (2018), 10.1103/PhysRevB.97.064416] we formulate a momentum-space pf-FRG approach for SU (N ) spin models that allows us to explicitly study the large-N limit and access the low-temperature spin liquid phase.

Optical monitoring of glucose demand and vascular delivery in a preclinical murine model

NASA Astrophysics Data System (ADS)

Frees, Amy; Rajaram, Narasimhan; McCachren, Sam; Vaz, Alex; Dewhirst, Mark; Ramanujam, Nimmi

2014-03-01

Targeted therapies such as PI3K inhibition can affect tumor vasculature, and hence delivery of imaging agents like FDG, while independently modifying intrinsic glucose demand. Therefore, it is important to identify whether perceived changes in glucose uptake are caused by vascular or true metabolic changes. This study sought to develop an optical strategy for quantifying tissue glucose uptake free of cross-talk from tracer delivery effects. Glucose uptake kinetics were measured using a fluorescent D-glucose derivative 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-Dglucose (2-NBDG), and 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-deoxy-L-glucose (2-NBDLG) was used as a control to report on non-specific uptake. Vascular oxygenation (SO2) was calculated from wavelength-dependent hemoglobin absorption. We have previously shown that the rate of 2-NBDG delivery in vivo profoundly affects perceived demand. In this study, we investigated the potential of the ratio of 2-NBDG uptake to the rate of delivery (2-NBDG60/RD) to report on 2-NBDG demand in vivo free from confounding delivery effects. In normal murine tissue, we show that 2-NBDG60/RD can distinguish specific uptake from non-specific cell membrane binding, whereas fluorescence intensity alone cannot. The ratio 2-NBDG60/RD also correlates with blood glucose more strongly than 2-NBDG60 does in normal murine tissue. Additionally, 2-NBDG60/RD can distinguish normal murine tissue from a murine metastatic tumor across a range of SO2 values. The results presented here indicate that the ratio of 2-NBDG uptake to the rate of 2-NBDG delivery (2- NBDG60/RD) is superior to 2-NBDG intensity alone for quantifying changes in glucose demand.

Crystal structure of poly[N,N-diethyl-2-hy-droxy-ethan-1-aminium [μ3-cyanido-κ(3) C:C:N-di-μ-cyanido-κ(4) C:N-dicuprate(I)

PubMed

Corfield, Peter W R; Cleary, Emma; Michalski, Joseph F

2016-07-01

In the title compound, {(C6H16NO)[Cu2(CN)3]} n , the cyanide groups link the Cu(I) atoms into an open three-dimensional anionic network, with the mol-ecular formula Cu2(CN)3 (-). One Cu(I) atom is tetra-hedrally bound to four CN groups, and the other Cu(I) atom is bonded to three CN groups in an approximate trigonal-planar coordination. The tetra-hedrally coordinated Cu(I) atoms are linked into centrosymmetric dimers by the C atoms of two end-on bridging CN groups which bring the Cu(I) atoms into close contact at 2.5171 (7) Å. Two of the cyanide groups bonded to the Cu(I) atoms with trigonal-planar surrounding link the dimeric units into columns along the a axis, and the third links the columns together to form the network. The N,N-di-ethyl-ethano-lamine mol-ecules used in the synthesis have become protonated at the N atoms and are situated in cavities in the network, providing charge neutrality, with no covalent inter-actions between the cations and the anionic network.

In the search for new anticancer drugs XII. Synthesis and biological evaluation of spin labeled nitrosoureas.

PubMed

Sosnovsky, G; Li, S W

1985-04-15

The spin labeled nitrosourea 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6- tetramethyl-piperidinyl)-1-nitrosourea (SLCNU, 4) and its analogues 5-7 were synthesized either by a regio-selective method or by a conventional route via the nitrosation of the spin labeled intermediates (11a-e). Nitrosation of the ureas 11a-e with dinitrogen tetraoxide resulted in better yields than those obtained with sodium nitrite. The nitrosoureas 4-8 were tested for their anticancer activity against the lymphocytic leukemia P388 in mice. Thus, either at the equal molar dose or at the dose of equal toxicity level, the SLCNU (4) was found to be more active than the clinically used CCNU (1). Unlike CCNU (1) whose LD50 is 56 mg/kg, the SLCNU (4) possesses a low toxicity (LD50 123 mg/kg). Therefore, SLCNU (4) is a promising new entry into the nitrosourea class of anticancer drugs.

A step-by-step approach to study the influence of N-acetylation on the adjuvanticity of N,N,N-trimethyl chitosan (TMC) in an intranasal nanoparticulate influenza virus vaccine.

PubMed

Verheul, Rolf J; Hagenaars, Niels; van Es, Thomas; van Gaal, Ethlinn V B; de Jong, Pascal H J L F; Bruijns, Sven; Mastrobattista, Enrico; Slütter, Bram; Que, Ivo; Heldens, Jacco G M; van den Bosch, Han; Glansbeek, Harrie L; Hennink, Wim E; Jiskoot, Wim

2012-03-12

Recently we reported that reacetylation of N,N,N-trimethyl chitosan (TMC) reduced the adjuvant effect of TMC in mice after intranasal (i.n.) administration of whole inactivated influenza virus (WIV) vaccine. The aim of the present study was to elucidate the mechanism of this lack of adjuvanticity. Reacetylated TMC (TMC-RA, degree of acetylation 54%) was compared with TMC (degree of acetylation 17%) at six potentially critical steps in the induction of an immune response after i.n. administration in mice. TMC-RA was degraded in a nasal wash to a slightly larger extent than TMC. The local i.n. distribution and nasal clearance of WIV were similar for both TMC types. Fluorescently labeled WIV was taken up more efficiently by Calu-3 cells when formulated with TMC-RA compared to TMC and both TMCs significantly reduced transport of WIV over a Calu-3 monolayer. Murine bone-marrow derived dendritic cell activation was similar for plain WIV, and WIV formulated with TMC-RA or TMC. The inferior adjuvant effect in mice of TMC-RA over that of TMC might be caused by a slightly lower stability of TMC-RA-WIV in the nasal cavity, rather than by any of the other factors studied in this paper. Copyright © 2011 Elsevier B.V. All rights reserved.

n-3 PUFA esterified to glycerol or as ethyl esters reduce non-fasting plasma triacylglycerol in subjects with hypertriglyceridemia: a randomized trial.

PubMed

Hedengran, Anne; Szecsi, Pal B; Dyerberg, Jørn; Harris, William S; Stender, Steen

2015-02-01

To date, treatment of hypertriglyceridemia with long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) has been investigated solely in fasting and postprandial subjects. However, non-fasting triacylglycerols are more strongly associated with risk of cardiovascular disease. The objective of this study was to investigate the effect of long-chain n-3 PUFA on non-fasting triacylglycerol levels and to compare the effects of n-3 PUFA formulated as acylglycerol (AG-PUFA) or ethyl esters (EE-PUFA). The study was a double-blinded randomized placebo-controlled interventional trial, and included 120 subjects with non-fasting plasma triacylglycerol levels of 1.7-5.65 mmol/L (150-500 mg/dL). The participants received approximately 3 g/day of AG-PUFA, EE-PUFA, or placebo for a period of eight weeks. The levels of non-fasting plasma triacylglycerols decreased 28% in the AG-PUFA group and 22% in the EE-PUFA group (P < 0.001 vs. placebo), with no significant difference between the two groups. The triacylglycerol lowering effect was evident after four weeks, and was inversely correlated with the omega-3 index (EPA + DHA content in erythrocyte membranes). The omega-3 index increased 63.2% in the AG-PUFA group and 58.5% in the EE-PUFA group (P < 0.001). Overall, the heart rate in the AG-PUFA group decreased by three beats per minute (P = 0.045). High-density lipoprotein (HDL) cholesterol increased in the AG-PUFA group (P < 0.001). Neither total nor non-HDL cholesterol changed in any group. Lipoprotein-associated phospholipase A2 (LpPLA2) decreased in the EE-PUFA group (P = 0.001). No serious adverse events were observed. Supplementation with long-chain n-3 PUFA lowered non-fasting triacylglycerol levels, suggestive of a reduction in cardiovascular risk. Regardless of the different effects on heart rate, HDL, and LpPLA2 that were observed, compared to placebo, AG-PUFA, and EE-PUFA are equally effective in reducing non-fasting triacylglycerol levels.

Mutations in α-Tubulin Cause Abnormal Neuronal Migration in Mice and Lissencephaly in Humans

PubMed Central

Keays, David A.; Tian, Guoling; Poirier, Karine; Huang, Guo-Jen; Siebold, Christian; Cleak, James; Oliver, Peter L.; Fray, Martin; Harvey, Robert J.; Molnár, Zoltán; Piñon, Maria C.; Dear, Neil; Valdar, William; Brown, Steve D.M.; Davies, Kay E.; Rawlins, J. Nicholas P.; Cowan, Nicholas J.; Nolan, Patrick; Chelly, Jamel; Flint, Jonathan

2007-01-01

Summary The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of α-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders. PMID:17218254

Modeling and simulation of InGaN/GaN quantum dots solar cell

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

Aissat, A., E-mail: sakre23@yahoo.fr; LASICOMLaboratory, Faculty of Sciences, University of Blida 1; Benyettou, F.

2016-07-25

Currently, quantum dots have attracted attention in the field of optoelectronics, and are used to overcome the limits of a conventional solar cell. Here, an In{sub 0.25}Ga{sub 0.75}N/GaN Quantum Dots Solar Cell has been modeled and simulated using Silvaco Atlas. Our results show that the short circuit current increases with the insertion of the InGaN quantum dots inside the intrinsic region of a GaN pin solar cell. In contrary, the open circuit voltage decreases. A relative optimization of the conversion efficiency of 54.77% was achieved comparing a 5-layers In{sub 0.25}Ga{sub 0.75}N/GaN quantum dots with pin solar cell. The conversion efficiencymore » begins to decline beyond 5-layers quantum dots introduced. Indium composition of 10 % improves relatively the efficiency about 42.58% and a temperature of 285 K gives better conversion efficiency of 13.14%.« less

Analytical characterization of seventeen ring-substituted N,N-diallyltryptamines

PubMed Central

Brandt, Simon D.; Kavanagh, Pierce V.; Dowling, Geraldine; Talbot, Brian; Westphal, Folker; Meyer, Markus R.; Maurer, Hans H.; Halberstadt, Adam L.

2017-01-01

Many N,N-dialkylated tryptamines show psychoactive properties in humans and the number of derivatives involved in multidisciplinary areas of research has grown over the last few decades. Whereas some derivatives form the basis of a range of medicinal products, others are predominantly encountered as recreational drugs, and in some cases, the areas of therapeutic and recreational use can overlap. In recent years, 5-methoxy-N,N-diallyltryptamine (5-MeO-DALT) has appeared as a new psychoactive substance (NPS) and ‘research chemical’ whereas 4-acetoxy-DALT and the ring-unsubstituted DALT have only been detected very recently. Strategies pursued in the authors’ laboratories included the preparation and biological evaluation of previously unreported N,N-diallyltryptamines (DALTs). This report describes the analytical characterization of seventeen DALTs. Fifteen DALTs were prepared by a microwave-accelerated Speeter and Anthony procedure following established procedures developed previously in the authors’ laboratories. In addition to DALT, the substances included in this study were 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 4,5-ethylenedioxy-, 5-methyl-, 5-methoxy-, 5-methoxy-2-methyl-, 5-ethoxy-, 5-fluoro-, 5-fluoro-2-methyl-, 5-chloro-, 5-bromo-, 5,6-methylenedioxy-, 6-fluoro-, 7-methyl, and 7-ethyl-DALT, respectively. The DALTs were characterized by nuclear magnetic resonance spectroscopy (NMR), gas chromatography (GC) quadrupole and ion trap (EI/CI) mass spectrometry (MS), low and high mass accuracy MS/MS, ultraviolet diode array detection and GC solid-state infrared analysis, respectively. A comprehensive collection of spectral data was obtained that are provided to research communities who face the challenge of encountering newly emerging substances where analytical data are not available. These data are also relevant to researchers who might wish to explore the clinical and non-clinical uses of these substances. PMID:27100373

Detailed kinetic modeling study of n-pentanol oxidation

DOE PAGES

Heufer, K. Alexander; Sarathy, S. Mani; Curran, Henry J.; ...

2012-09-28

To help overcome the world’s dependence upon fossil fuels, suitable biofuels are promising alternatives that can be used in the transportation sector. Recent research on internal combustion engines shows that short alcoholic fuels (e.g., ethanol or n-butanol) have reduced pollutant emissions and increased knock resistance compared to fossil fuels. Although higher molecular weight alcohols (e.g., n-pentanol and n-hexanol) exhibit higher reactivity that lowers their knock resistance, they are suitable for diesel engines or advanced engine concepts, such as homogeneous charge compression ignition (HCCI), where higher reactivity at lower temperatures is necessary for engine operation. The present study presents a detailedmore » kinetic model for n-pentanol based on modeling rules previously presented for n-butanol. This approach was initially validated using quantum chemistry calculations to verify the most stable n-pentanol conformation and to obtain C–H and C–C bond dissociation energies. In addition, the proposed model has been validated against ignition delay time data, speciation data from a jet-stirred reactor, and laminar flame velocity measurements. Overall, the model shows good agreement with the experiments and permits a detailed discussion of the differences between alcohols and alkanes.« less

Z/sub n/ Baxter model: Critical behavior

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

Tracy, C.A.

1986-07-01

The Z/sub n/ Baxter Model is an exactly solvable lattice model in the special case of the Belavin parametrization. We calculate the critical behavior of Prob/sub n/ (q = w/sup k/) using techniques developed in number theory in the study of the congruence properties of p(m), the number of unrestricted partitions of an integer m.

Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model

PubMed Central

Lozovaya, N.; Gataullina, S.; Tsintsadze, T.; Tsintsadze, V.; Pallesi-Pocachard, E.; Minlebaev, M.; Goriounova, N. A.; Buhler, E.; Watrin, F.; Shityakov, S.; Becker, A. J.; Bordey, A.; Milh, M.; Scavarda, D.; Bulteau, C.; Dorfmuller, G.; Delalande, O.; Represa, A.; Cardoso, C.; Dulac, O.; Ben-Ari, Y.; Burnashev, N.

2014-01-01

Tuberous sclerosis complex (TSC), caused by dominant mutations in either TSC1 or TSC2 tumour suppressor genes is characterized by the presence of brain malformations, the cortical tubers that are thought to contribute to the generation of pharmacoresistant epilepsy. Here we report that tuberless heterozygote Tsc1+/− mice show functional upregulation of cortical GluN2C-containing N-methyl-D-aspartate receptors (NMDARs) in an mTOR-dependent manner and exhibit recurrent, unprovoked seizures during early postnatal life (N2C-mediated currents in spiny stellate cells promotes excessive temporal integration of persistent NMDAR-mediated recurrent excitation and seizure generation. Accordingly, specific GluN2C/D antagonists block seizures in Tsc1+/− mice in vivo and in vitro. Likewise, GluN2C expression is upregulated in TSC human surgical resections, and a GluN2C/D antagonist reduces paroxysmal hyperexcitability. Thus, GluN2C receptor constitutes a promising molecular target to treat epilepsy in TSC patients. PMID:25081057

Psychedelic N,N-Dimethyltryptamine and 5-Methoxy-N,N-Dimethyltryptamine Modulate Innate and Adaptive Inflammatory Responses through the Sigma-1 Receptor of Human Monocyte-Derived Dendritic Cells

PubMed Central

Szabo, Attila; Kovacs, Attila

2014-01-01

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor. PMID:25171370

Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells.

PubMed

Szabo, Attila; Kovacs, Attila; Frecska, Ede; Rajnavolgyi, Eva

2014-01-01

The orphan receptor sigma-1 (sigmar-1) is a transmembrane chaperone protein expressed in both the central nervous system and in immune cells. It has been shown to regulate neuronal differentiation and cell survival, and mediates anti-inflammatory responses and immunosuppression in murine in vivo models. Since the details of these findings have not been elucidated so far, we studied the effects of the endogenous sigmar-1 ligands N,N-dimethyltryptamine (NN-DMT), its derivative 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and the synthetic high affinity sigmar-1 agonist PRE-084 hydrochloride on human primary monocyte-derived dendritic cell (moDCs) activation provoked by LPS, polyI:C or pathogen-derived stimuli to induce inflammatory responses. Co-treatment of moDC with these activators and sigma-1 receptor ligands inhibited the production of pro-inflammatory cytokines IL-1β, IL-6, TNFα and the chemokine IL-8, while increased the secretion of the anti-inflammatory cytokine IL-10. The T-cell activating capacity of moDCs was also inhibited, and dimethyltryptamines used in combination with E. coli or influenza virus as stimulators decreased the differentiation of moDC-induced Th1 and Th17 inflammatory effector T-cells in a sigmar-1 specific manner as confirmed by gene silencing. Here we demonstrate for the first time the immunomodulatory potential of NN-DMT and 5-MeO-DMT on human moDC functions via sigmar-1 that could be harnessed for the pharmacological treatment of autoimmune diseases and chronic inflammatory conditions of the CNS or peripheral tissues. Our findings also point out a new biological role for dimethyltryptamines, which may act as systemic endogenous regulators of inflammation and immune homeostasis through the sigma-1 receptor.

Implications of incorporating N cycling and N limitations on primary production in an individual-based dynamic vegetation model

NASA Astrophysics Data System (ADS)

Smith, B.; Wårlind, D.; Arneth, A.; Hickler, T.; Leadley, P.; Siltberg, J.; Zaehle, S.

2014-04-01

The LPJ-GUESS dynamic vegetation model uniquely combines an individual- and patch-based representation of vegetation dynamics with ecosystem biogeochemical cycling from regional to global scales. We present an updated version that includes plant and soil N dynamics, analysing the implications of accounting for C-N interactions on predictions and performance of the model. Stand structural dynamics and allometric scaling of tree growth suggested by global databases of forest stand structure and development were well reproduced by the model in comparison to an earlier multi-model study. Accounting for N cycle dynamics improved the goodness of fit for broadleaved forests. N limitation associated with low N-mineralisation rates reduces productivity of cold-climate and dry-climate ecosystems relative to mesic temperate and tropical ecosystems. In a model experiment emulating free-air CO2 enrichment (FACE) treatment for forests globally, N limitation associated with low N-mineralisation rates of colder soils reduces CO2 enhancement of net primary production (NPP) for boreal forests, while some temperate and tropical forests exhibit increased NPP enhancement. Under a business-as-usual future climate and emissions scenario, ecosystem C storage globally was projected to increase by ca. 10%; additional N requirements to match this increasing ecosystem C were within the high N supply limit estimated on stoichiometric grounds in an earlier study. Our results highlight the importance of accounting for C-N interactions in studies of global terrestrial N cycling, and as a basis for understanding mechanisms on local scales and in different regional contexts.

Implications of incorporating N cycling and N limitations on primary production in an individual-based dynamic vegetation model

NASA Astrophysics Data System (ADS)

Smith, B.; Wårlind, D.; Arneth, A.; Hickler, T.; Leadley, P.; Siltberg, J.; Zaehle, S.

2013-11-01

The LPJ-GUESS dynamic vegetation model uniquely combines an individual- and patch-based representation of vegetation dynamics with ecosystem biogeochemical cycling from regional to global scales. We present an updated version that includes plant and soil N dynamics, analysing the implications of accounting for C-N interactions on predictions and performance of the model. Stand structural dynamics and allometric scaling of tree growth suggested by global databases of forest stand structure and development were well-reproduced by the model in comparison to an earlier multi-model study. Accounting for N cycle dynamics improved the goodness-of-fit for broadleaved forests. N limitation associated with low N mineralisation rates reduces productivity of cold-climate and dry-climate ecosystems relative to mesic temperate and tropical ecosystems. In a model experiment emulating free-air CO2 enrichment (FACE) treatment for forests globally, N-limitation associated with low N mineralisation rates of colder soils reduces CO2-enhancement of NPP for boreal forests, while some temperate and tropical forests exhibit increased NPP enhancement. Under a business-as-usual future climate and emissions scenario, ecosystem C storage globally was projected to increase by c. 10%; additional N requirements to match this increasing ecosystem C were within the high N supply limit estimated on stoichiometric grounds in an earlier study. Our results highlight the importance of accounting for C-N interactions not only in studies of global terrestrial C cycling, but to understand underlying mechanisms on local scales and in different regional contexts.

Characterization of 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([Emim][Tf2N])∕TX-100∕cyclohexane ternary microemulsion: investigation of photoinduced electron transfer in this RTIL containing microemulsion.

PubMed

Sarkar, Souravi; Pramanik, Rajib; Ghatak, Chiranjib; Rao, Vishal Govind; Sarkar, Nilmoni

2011-02-21

In this study we have characterized a ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethyl- sulfonyl)imide containing ternary nonaqueous microemulsion ([Emim][Tf(2)N]∕∕TX-100∕cyclo- hexane). The phase behavior and dynamic light scattering study show that the [Emim][Tf(2)N]∕TX-100∕cyclohexane three component system can form microemulsion with [Emim][Tf(2)N] as polar core at suitable condition. We have investigated photoinduced electron transfer (PET) using dimethyl aniline as electron donor and several Coumarin dyes as electron acceptor molecules at two different R values (R = [ionic liquid]∕[surfactant]) to observe how the dynamics of the PET rate is affected in this type of confined microenvironment compared to that of the PET dynamics in neat ionic liquid and other pure solvent media. The plot of observed k(q) values with the free energy change (ΔG(0)) for electron transfer reaction shows an apparent inversion in the observed rate as predicted by the Marcus theory.

Sulphur and oxygen sequestration of n-C37 and n-C38 unsaturated ketones in an immature kerogen and the release of their carbon skeletons during early stages of thermal maturation

USGS Publications Warehouse

Koopmans, M.P.; Schaeffer-Reiss, C.; De Leeuw, J. W.; Lewan, M.D.; Maxwell, J.R.; Schaeffer, P.; Sinninghe, Damste J.S.

1997-01-01

Sedimentary rock from the Gessoso-solfifera Formation (Messinian) in the Vena del Gesso Basin (northern Italy) containing immature (Ro = 0.25%) S-rich organic matter was artificially matured by hydrous pyrolysis at temperatures from 160 to 330??C for 72 h to study the diagenetic fate of n-C37 and n-C38 di-and tri-unsaturated methyl and ethyl ketones (alkenones) biosynthesised by several prymnesiophyte algae. During early diagenesis, the alkenones are incorporated into the kerogen by both sulphur and oxygen cross-linking as indicated by chemical degradation experiments with the kerogen of the unheated sample. Heating at temperatures between 160 and 260??C, which still represents early stages of thermal maturation, produces large amounts (up to 1 mg/g TOC) of S-bound, O-bound, and both S-and O-bound n-C37 and n-C38 skeletons, saturated n-C37 and n-C38 methyl, ethyl, and mid-chain ketones, C37 and C38 mid-chain 2,5-di-n-alkylthiophenes, C37 and C38 1,2-di-n-alkylbenzenes, and C37 and C38 n-alkanes. With increasing thermal maturation, three forms of the n-C37 and n-C38 skeletons are relatively stable (saturated hydrocarbons, 1,2-di-n-alkylbenzenes and saturated ketones), whereas the S-and O-bound skeletons are relatively labile. These results suggest that in natural situations saturated ketones with an n-C37 and n-C38 skeleton can be expected as well as the corresponding hydrocarbons. Copyright ?? 1997 Elsevier Science Ltd.

Sulphur and oxygen sequestration of n-C 37 and n-C 38 unsaturated ketones in an immature kerogen and the release of their carbon skeletons during early stages of thermal maturation

NASA Astrophysics Data System (ADS)

Koopmans, Martin P.; Schaeffer-Reiss, Christine; de Leeuw, Jan W.; Lewan, Michael D.; Maxwell, James R.; Schaeffer, Philippe; Sinninghe Damsté, Jaap S.

1997-06-01

Sedimentary rock from the Gessoso-solfifera Formation (Messinian) in the Vena del Gesso Basin (northern Italy) containing immature ( Ro = 0.25%) S-rich organic matter was artificially matured by hydrous pyrolysis at temperatures from 160 to 330°C for 72 h to study the diagenetic fate of n-C 37 and n-C 38 di- and tri-unsaturated methyl and ethyl ketones (alkenones) biosynthesised by several prymnesiophyte algae. During early diagenesis, the alkenones are incorporated into the kerogen by both sulphur and oxygen cross-linking as indicated by chemical degradation experiments with the kerogen of the unheated sample. Heating at temperatures between 160 and 260°C, which still represents early stages of thermal maturation, produces large amounts (up to 1 mg/g TOC) of S-bound, O-bound, and both S- and O-bound n-C 37 and n-C 38 skeletons, saturated n-C 37 and n-C38 methyl, ethyl, and mid-chain ketones, C 37 and C 38 mid-chain 2,5-di- n-alkylthiophenes, C 37 and C 38 1,2-di- n-alkylbenzenes, and C 37 and C 38n-alkanes. With increasing thermal maturation, three forms of the n-C 37 and n-C 38 skeletons are relatively stable (saturated hydrocarbons, 1,2-di- n-alkylbenzenes and saturated ketones), whereas the S- and O-bound skeletons are relatively labile. These results suggest that in natural situations saturated ketones with an n-C 37 and n-C 38 skeleton can be expected as well as the corresponding hydrocarbons.

Investigations of vibrational spectra and bioactivity of novel anticancer drug N-(6-ferrocenyl-2-naphthoyl)-gamma-amino butyric acid ethyl ester

NASA Astrophysics Data System (ADS)

Sudhi, Geethu; Rajina, S. R.; Praveen, S. G.; Xavier, T. S.; Kenny, Peter T. M.; Jaiswal-Nagar, D.; Binoy, J.

2017-10-01

The bioactivity of compounds is mainly dependent on molecular structure and the present work aims to explore the bonding features responsible for biological activity of novel anticancer drug N-(6-ferrocenyl-2-naphthoyl)-gamma-amino butyric acid ethyl ester (FNGABEE). In the present study, we investigate the molecular structural properties of newly synthesized title compound through experimental and quantum chemical studies. The detailed vibrational analysis has been performed using FT IR and FT Raman spectrum, aided by DFT computed geometry, vibrational spectrum, Eigen vector distribution and PED, at B3LYP/6-311 ++G(d,p) level. The resonance structure of naphthalene, different from that of benzene, revealed by molecular structure has been investigated using Csbnd C and Cdbnd C stretching modes. The proton transfer in amide has been analyzed to obtain spectral distinction between different carbonyl and Csbnd N groups which point to the reactive sites responsible for binding with DNA and bovine serum albumin (BSA). The spectral distinction between eclipsed and staggered form of ferrocene has been analyzed. The molecular docking of FNGABEE with BSA and DNA has been performed to find the strength of binding and the moieties responsible for the interactions. The experimental binding studies of FNGABEE with BSA and DNA has been performed using UV absorption spectroscopy and fluorometric assay, to find the nature and strength of binding.

Destruction of carcinogenic and mutagenic N-nitrosamides in laboratory wastes.

PubMed

Lunn, G; Sansone, E B; Andrews, A W; Castegnaro, M; Malaveille, C; Michelon, J; Brouet, I; Keefer, L K

1984-01-01

The chemical degradation of five N-nitrosamides used widely for the experimental induction of cancer has been studied with the goal of identifying, and experimentally validating, reliable methods that can be recommended for the destruction of carcinogenic N-nitrosoureas and related compounds in laboratory wastes. Although data are not yet complete, preliminary evidence indicates that none of the five methods studied thus far is ideal for hazard-control purposes. Decomposition with 1 mol/L potassium hydroxide solution destroyed the N-nitrosamides, but generated diazoalkanes, which are carcinogenic, toxic and potentially explosive. Treatment with strong acid in the presence of sulfamic acid or iron filings completely decomposed all N-nitrosamides without forming diazoalkanes, but failed in the presence of solvents which were immiscible with water. Cleavage with hydrogen bromide in glacial acetic acid proceeded to a point of maximum degradation, following which gradual reformation of the N-nitrosamide was observed; this resynthesis could be avoided by carefully bubbling nitrogen through the reaction mixture, but degradation was slow or failed completely in the presence of hydroxylic solvents. Permanganate oxidation was effective in sulfuric acid solution, but was incomplete when an alcohol or dimethyl sulfoxide was present. Salmonella typhimurium tester strains TA1535, TA1530 and TA100, which detect base-pair substitutions in DNA, detected mutagenic degradation products in each of the destruction methods, with the exception of the hydrobromic acid/acetic acid procedure.

n-3 Fatty acids combined with flavan-3-ols prevent steatosis and liver injury in a murine model of NAFLD.

PubMed

Vauzour, David; Rodriguez-Ramiro, Ildefonso; Rushbrook, Simon; Ipharraguerre, Ignacio R; Bevan, Damon; Davies, Susan; Tejera, Noemi; Mena, Pedro; de Pascual-Teresa, Sonia; Del Rio, Daniele; Gavrilovic, Jelena; Minihane, Anne Marie

2018-01-01

Non-alcoholic fatty liver disease (NAFLD) affects 25% of adults and at present no licensed medication has been approved. Despite its complex patho-physiology, dietary strategies aiming at delaying or preventing NAFLD have taken a reductionist approach, examining the impact of single components. Accumulating evidence suggests that n-3 LC-PUFAs are efficacious in regulating lipogenesis and fatty acid oxidation. In addition, plant derived flavonoids are also emerging as a dietary strategy for NAFLD prevention, with efficacy attributed to their insulin sensitising and indirect antioxidant effects. Based on knowledge of their complementary molecular targets, we aimed to demonstrate that the combination of n-3 LC-PUFA (n-3) and flavan-3-ols (FLAV) prevents NAFLD. In a high-fat high-fructose (HF/HFr) fed C57Bl/6J mouse model, the independent and interactive impact of n-3 and FLAV on histologically defined NAFLD, insulin sensitivity, weight gain, intestinal and hepatic gene expression, intestinal bile acids were examined. Only the combination of FLAV and n-3 (FLAVn-3) prevented steatosis as evidenced by a strong reduction in hepatocyte ballooning. While FLAV reduced body (-28-30%), adipose tissue (-45-50%) weights and serum insulin (-22-25%) as observed following an intra-peritoneal glucose tolerance test, n-3 downregulated the expression of Srebf1 and the lipogenic genes (Acaca, Fasn). Significant impacts of interventions on intestinal bile acid metabolism, farnesoid X receptor (Fxr) signalling in the intestine and liver, and hepatic expression of fatty acid transporters (Fabp4, Vldlr, Cd36) were also evident. FLAVn-3 may be a novel intervention for NAFLD. Future research should aim to demonstrate its efficacy in the prevention and treatment of human NAFLD. Copyright © 2017 Elsevier B.V. All rights reserved.

A human monoclonal anti-TNF alpha antibody (adalimumab) reduces airway inflammation and ameliorates lung histology in a murine model of acute asthma.

PubMed

Catal, F; Mete, E; Tayman, C; Topal, E; Albayrak, A; Sert, H

2015-01-01

A few experimental studies related to asthma have unveiled the beneficial effects of TNF alpha blocking agents on the airway histology, cytokine levels in bronchoalveolar lavage and bronchial hyper-responsiveness. In the current study, we aimed to assess the effect of adalimumab on the inflammation and histology of asthma in a murine model. Twelve-week-old BALB/c (H-2d/d) female rats (n=18) were allocated into three groups, including (group I) control (phosphate-buffered saline was implemented), (group II) asthma induced with OVA (n=6), and (group III) asthma induced with OVA+treated with adalimumab (n=6). Rats were executed on the 28th day of the study. The lung samples were fixed in 10% neutral buffered formalin. Lung parenchyma, alveolus, peribronchial and perivascular inflammation were assessed. Lung pathological scoring was performed. Severity of lung damage was found to be reduced significantly in the asthma induced with OVA+treated with adalimumab group. When compared with the untreated group, adalimumab significantly reduced the inflammatory cells around the bronchi and bronchioles, and reduced inflammation of the alveolar wall and alveolar wall thickness as well (median score=1, p=0.52). Peribronchial smooth muscle hypertrophy and oedema were significantly reduced after adalimumab administration. Adalimumab (a human monoclonal anti-TNF alpha antibody) therapy significantly reduced the severity of lung damage by decreasing cellular infiltration and improvement on the lung histology in a murine model of acute asthma. Copyright © 2013 SEICAP. Published by Elsevier Espana. All rights reserved.

Experimental and modeling study of fuel interactions with an alkyl nitrate cetane enhancer, 2-ethyl-hexyl nitrate

DOE PAGES

Goldsborough, S. S.; Johnson, M. V.; Banyon, C.; ...

2014-07-15

Our study investigates the autoignition behavior of two gasoline surrogates doped with an alkyl nitrate cetane enhancer, 2-ethyl-hexyl nitrate (2EHN) to better understand dopant interactions with the fuels, including influences of accelerating kinetic pathways and enhanced exothermicity. A primary reference fuel (PRF) blend of n-heptane/iso-octane, and a toluene reference fuel (TRF) blend of n-heptane/iso-octane/toluene are used where the aromatic fraction of the latter is set to 20% (liquid volume), while the content of n-heptane is adjusted so that the overall reactivity of the undoped fuels is similar, e.g., Anti-Knock Index (AKI) of similar to 91, Cetane Number (CN) similar tomore » 25. Doping levels of 0.1, 1.0 and 3.0% (liquid volume basis) are used where tests are conducted within a rapid compression machine (RCM) at a compressed pressure of 21 bar, covering temperatures from 675 to 1025 K with stoichiometric fuel-oxygen ratios at O-2 = 11.4%. At the experimental conditions, it is found that the doping effectiveness of 2EHN is fairly similar between the two fuels, though 2EHN is more effective in the aromatic blend at the lowest temperatures, while it is slightly more effective in the non-aromatic blend at intermediate temperatures. Furthermore, kinetic modeling of the experiments indicates that although some of the reactivity trends can be captured using a detailed model, the extents of predicted Cetane Number enhancement by 2EHN are too large, while differences in fuel interactions for the two fuels result in excessive stimulation of the non-aromatic blend. Sensitivity analysis using the kinetic model indicates that the CH 2O and CH 3O 2 chemistry are very sensitive to the dopant at all conditions. The rate of 2EHN decomposition is only important at low temperatures where its decomposition rate is slow due to the high activation energy of the reaction. At higher temperatures, dopant-derived 3-heptyl radicals are predicted to play an important role

Synthesis and structural study of N-isopropenylbenzimidazolone

NASA Astrophysics Data System (ADS)

Mondieig, D.; Negrier, Ph.; Leger, J. M.; Lakhrissi, L.; El Assyry, A.; Lakhrissi, B.; Essassi, E. M.; Benali, B.; Boucetta, A.

2015-05-01

The synthesis and the crystal structure of the N-isopropenylbenzimidazolone (C10H10N2O) are presented. The synthesis was performed by Meth-Cohen method by reaction of o-phenylenediamine with ethyl acetoacetate in refluxed xylene. The single crystal structure was determined at room temperature by means of X-rays diffraction. The crystal system is monoclinic, with space group C2/c and eight molecules per unit cell. The unit cell dimensions are: a = 15.978(1) Å, b = 6.100(2) Å, c = 18.222(2) Å, β = 90.16(1)° and V = 1776.0(6) Å3.

Modeling N Cycling during Succession after Forest Disturbance: an Analysis of N Mining and Retention Hypothesis

NASA Astrophysics Data System (ADS)

Zhou, Z.; Ollinger, S. V.; Ouimette, A.; Lovett, G. M.; Fuss, C. B.; Goodale, C. L.

2017-12-01

Dissolved inorganic nitrogen losses at the Hubbard Brook Experimental Forest (HBEF), New Hampshire, USA, have declined in recent decades, a pattern that counters expectations based on prevailing theory. An unbalanced ecosystem nitrogen (N) budget implies there is a missing component for N sink. Hypotheses to explain this discrepancy include increasing rates of denitrification and accumulation of N in mineral soil pools following N mining by plants. Here, we conducted a modeling analysis fused with field measurements of N cycling, specifically examining the hypothesis relevant to N mining and retention in mineral soils. We included simplified representations of both mechanisms, N mining and retention, in a revised ecosystem process model, PnET-SOM, to evaluate the dynamics of N cycling during succession after forest disturbance at the HBEF. The predicted N mining during the early succession was regulated by a metric representing a potential demand of extra soil N for large wood growth. The accumulation of nitrate in mineral soil pools was a function of the net aboveground biomass accumulation and soil N availability and parameterized based on field 15N tracer incubation data. The predicted patterns of forest N dynamics were consistent with observations. The addition of the new algorithms also improved the predicted DIN export in stream water with an R squared of 0.35 (P<0.01) aganist observations. Predicted mining processes had an average rate of 7.4 kgNha-1yr-1 and Predicted rates of N retention processes were 5.2 kgNha-1yr-1, both of which were in line with estimates only based on field data. The predicted trend of low DIN export could continue for another 70 years to pay back the mined N in mineral soils. Predicted ecosystem N balance showed that N gas loss could account for 14-46% of the total N deposition, the soil mining about 103% during the early succession, and soil retention about 35% at the current forest stage at the HBEF.

Modeling and simulation of enhancement mode p-GaN Gate AlGaN/GaN HEMT for RF circuit switch applications

NASA Astrophysics Data System (ADS)

Panda, D. K.; Lenka, T. R.

2017-06-01

An enhancement mode p-GaN gate AlGaN/GaN HEMT is proposed and a physics based virtual source charge model with Landauer approach for electron transport has been developed using Verilog-A and simulated using Cadence Spectre, in order to predict device characteristics such as threshold voltage, drain current and gate capacitance. The drain current model incorporates important physical effects such as velocity saturation, short channel effects like DIBL (drain induced barrier lowering), channel length modulation (CLM), and mobility degradation due to self-heating. The predicted I d-V ds, I d-V gs, and C-V characteristics show an excellent agreement with the experimental data for both drain current and capacitance which validate the model. The developed model was then utilized to design and simulate a single-pole single-throw (SPST) RF switch.

Recurrent milk aspiration produces changes in airway mechanics, lung eosinophilia, and goblet cell hyperplasia in a murine model.

PubMed

Janahi, I A; Elidemir, O; Shardonofsky, F R; Abu-Hassan, M N; Fan, L L; Larsen, G L; Blackburn, M R; Colasurdo, G N

2000-12-01

Recurrent aspiration of milk into the respiratory tract has been implicated in the pathogenesis of a variety of inflammatory lung disorders including asthma. However, the lack of animal models of aspiration-induced lung injury has limited our knowledge of the pathophysiological characteristics of this disorder. This study was designed to evaluate the effects of recurrent milk aspiration on airway mechanics and lung cells in a murine model. Under light anesthesia, BALB/c mice received daily intranasal instillations of whole cow's milk (n = 7) or sterile physiologic saline (n = 9) for 10 d. Respiratory system resistance (Rrs) and dynamic elastance (Edyn,rs) were measured in anesthetized, tracheotomized, paralyzed and mechanically ventilated mice 24 h after the last aspiration of milk. Rrs and Edyn,rs were derived from transrespiratory and plethysmographic pressure signals. In addition, airway responses to increasing concentrations of i.v. methacholine (Mch) were determined. Airway responses were measured in terms of PD(100) (dose of Mch causing 100% increase from baseline Rrs) and Rrs,max (% increase from baseline at the maximal plateau response) and expressed as % control (mean +/- SE). We found recurrent milk aspiration did not affect Edyn and baseline Rrs values. However, airway responses to Mch were increased after milk aspiration when compared with control mice. These changes in airway mechanics were associated with an increased percentage of lymphocytes and eosinophils in the bronchoalveolar lavage, mucus production, and lung inflammation. Our findings suggest that recurrent milk aspiration leads to alterations in airway function, lung eosinophilia, and goblet cell hyperplasia in a murine model.

An anisotropic, hyperelastic model for skin: experimental measurements, finite element modelling and identification of parameters for human and murine skin.

PubMed

Groves, Rachel B; Coulman, Sion A; Birchall, James C; Evans, Sam L

2013-02-01

The mechanical characteristics of skin are extremely complex and have not been satisfactorily simulated by conventional engineering models. The ability to predict human skin behaviour and to evaluate changes in the mechanical properties of the tissue would inform engineering design and would prove valuable in a diversity of disciplines, for example the pharmaceutical and cosmetic industries, which currently rely upon experiments performed in animal models. The aim of this study was to develop a predictive anisotropic, hyperelastic constitutive model of human skin and to validate this model using laboratory data. As a corollary, the mechanical characteristics of human and murine skin have been compared. A novel experimental design, using tensile tests on circular skin specimens, and an optimisation procedure were adopted for laboratory experiments to identify the material parameters of the tissue. Uniaxial tensile tests were performed along three load axes on excised murine and human skin samples, using a single set of material parameters for each skin sample. A finite element model was developed using the transversely isotropic, hyperelastic constitutive model of Weiss et al. (1996) and was embedded within a Veronda-Westmann isotropic material matrix, using three fibre families to create anisotropic behaviour. The model was able to represent the nonlinear, anisotropic behaviour of the skin well. Additionally, examination of the optimal material coefficients and the experimental data permitted quantification of the mechanical differences between human and murine skin. Differences between the skin types, most notably the extension of the skin at low load, have highlighted some of the limitations of murine skin as a biomechanical model of the human tissue. The development of accurate, predictive computational models of human tissue, such as skin, to reduce, refine or replace animal models and to inform developments in the medical, engineering and cosmetic fields, is a

Models Robustness for Simulating Drainage and NO3-N Fluxes

NASA Astrophysics Data System (ADS)

Jabro, Jay; Jabro, Ann

2013-04-01

Computer models simulate and forecast appropriate agricultural practices to reduce environmental impact. The objectives of this study were to assess and compare robustness and performance of three models -- LEACHM, NCSWAP, and SOIL-SOILN--for simulating drainage and NO3-N leaching fluxes in an intense pasture system without recalibration. A 3-yr study was conducted on a Hagerstown silt loam to measure drainage and NO3-N fluxes below 1 m depth from N-fertilized orchardgrass using intact core lysimeters. Five N-fertilizer treatments were replicated five times in a randomized complete block experimental design. The models were validated under orchardgrass using soil, water and N transformation rate parameters and C pools fractionation derived from a previous study conducted on similar soils under corn. The model efficiency (MEF) of drainage and NO3-N fluxes were 0.53, 0.69 for LEACHM; 0.75, 0.39 for NCSWAP; and 0.94, 0.91for SOIL-SOILN. The models failed to produce reasonable simulations of drainage and NO3-N fluxes in January, February and March due to limited water movement associated with frozen soil and snow accumulation and melt. The differences between simulated and measured NO3-N leaching and among models' performances may also be related to soil N and C transformation processes embedded in the models These results are a monumental progression in the validation of computer models which will lead to continued diffusion across diverse stakeholders.

Searching for trans ethyl methyl ether in Orion KL.

PubMed

Tercero, B; Cernicharo, J; López, A; Brouillet, N; Kolesniková, L; Motiyenko, R A; Margulès, L; Alonso, J L; Guillemin, J-C

2015-10-01

We report on the tentative detection of trans ethyl methyl ether (tEME), t-CH 3 CH 2 OCH 3 , through the identification of a large number of rotational lines from each one of the spin states of the molecule towards Orion KL. We also search for gauche-trans-n-propanol, Gt-n-CH 3 CH 2 CH 2 OH, an isomer of tEME in the same source. We have identified lines of both species in the IRAM 30 m line survey and in the ALMA Science Verification data. We have obtained ALMA maps to establish the spatial distribution of these species. Whereas tEME mainly arises from the compact ridge component of Orion, Gt-n-propanol appears at the emission peak of ethanol (south hot core). The derived column densities of these species at the location of their emission peaks are ≤(4.0 ± 0.8) × 10 15 cm -2 and ≤(1.0 ± 0.2)× 10 15 cm -2 for tEME and Gt-n-propanol, respectively. The rotational temperature is ~100 K for both molecules. We also provide maps of CH 3 OCOH, CH 3 CH 2 OCOH, CH 3 OCH 3 , CH 3 OH, and CH 3 CH 2 OH to compare the distribution of these organic saturated O-bearing species containing methyl and ethyl groups in this region. Abundance ratios of related species and upper limits to the abundances of non-detected ethers are provided. We derive an abundance ratio N (CH 3 OCH 3 )/ N (tEME) ≥ 150 in the compact ridge of Orion.

DNA crosslinking and cytotoxicity in normal and transformed human cells treated with antitumor nitrosoureas.

PubMed Central

Erickson, L C; Bradley, M O; Ducore, J M; Ewig, R A; Kohn, K W

1980-01-01

Normal (IMR-90) and simian virus 40-transformed (VA-13) human embryo cells were treated with antitumor nitrosoureas, and the effects on cell viability and cell DNA were compared. All six nitrosoureas tested were more toxic to VA-13 cells than to IMR-90 cells as measured by decrease in cell proliferation or in colony formation. The nitrosoureas capable of generating alkylisocyanates produced a smaller difference between the cell types than did derivatives lacking this capacity. DNA damage was measured by alkaline elution in cells treated with four chloroethylnitrosoureas. Whereas VA-13 cells exhibited dose-dependent interstrand crosslinking, little or none was detected in IMR-90 cells. The IMR-90 cells, however, exhibited at least as much DNA-protein crosslinking as did VA-13 cells. The results can be interpreted in terms of a possible difference in DNA repair between the cell lines. PMID:6928639

A new family of N dimensional superintegrable double singular oscillators and quadratic algebra Q(3) ⨁ so(n) ⨁ so(N-n)

NASA Astrophysics Data System (ADS)

Fazlul Hoque, Md; Marquette, Ian; Zhang, Yao-Zhong

2015-11-01

We introduce a new family of N dimensional quantum superintegrable models consisting of double singular oscillators of type (n, N-n). The special cases (2,2) and (4,4) have previously been identified as the duals of 3- and 5-dimensional deformed Kepler-Coulomb systems with u(1) and su(2) monopoles, respectively. The models are multiseparable and their wave functions are obtained in (n, N-n) double-hyperspherical coordinates. We obtain the integrals of motion and construct the finitely generated polynomial algebra that is the direct sum of a quadratic algebra Q(3) involving three generators, so(n), so(N-n) (i.e. Q(3) ⨁ so(n) ⨁ so(N-n)). The structure constants of the quadratic algebra itself involve the Casimir operators of the two Lie algebras so(n) and so(N-n). Moreover, we obtain the finite dimensional unitary representations (unirreps) of the quadratic algebra and present an algebraic derivation of the degenerate energy spectrum of the superintegrable model.

Creating 13C- and 15N-enriched tree leaf litter for decomposition experiments

NASA Astrophysics Data System (ADS)

Szlavecz, K. A.; Pitz, S.; Chang, C.; Bernard, M.

2013-12-01

Labeling plant material with heavy isotopes of carbon and nitrogen can produce a traceable nutrient signal that can be followed into the different trophic levels and decomposer food web. We treated 60 tree saplings with 13C-enriched CO2 gas and 15N-enriched ammonium nitrate over a three-month period to create dually-labeled plant material for future decomposition experiments. The trees included both early (Red maple, Sweetgum, Tulip poplar) and late (American beech, White oak) successional deciduous tree species, and a conifer, White pine. We constructed a 2.4 m × 2.4 m × 2.4 m environmental chamber that was climate-controlled using an air conditioning system. An Arduino microcontroller interfaced with a Vaisala GMP343 CO2 probe maintained a CO2 concentration between 500-520 ppm by controlling a solenoid valve on the CO2 tank regulator. The trees were placed into the chamber in August 2012 and remained until senescence unless they were lost to death or disease. Ammonium nitrate was added twice, in September and October. Leaf samples were collected prior to the start of the experiment and after senescence, whereas root samples were collected only in December. Samples were dried, ground and analyzed using an isotope ratio mass spectrometer. American beech and White oak had 40% mortality, and 34% of tulip poplar trees were removed because of powdery mildew overgrowth or death. Most tulip poplar trees exhibited a second leaf out following senescence in late September. Nearly 1 kg of litter was produced with tulip poplar representing over half of the total mass. Levels of enrichment varied greatly by species. Beech (-14.2‰) and White oak (-4.8‰) had low levels of enrichment in comparison to early successional species such as Sweetgum (41.7‰) and Tulip poplar (30.7‰ [first leaf fall] and 238.0‰ [second leaf fall]). Leaf enrichment with 15N followed a similar pattern, though it was achieved at a higher level with δ15N values varying from 271.6‰ to 1354.2�

Bromidotetra-kis-(2-ethyl-1H-imidazole-κN (3))copper(II) bromide.

PubMed

Godlewska, Sylwia; Kelm, Harald; Krüger, Hans-Jörg; Dołęga, Anna

2012-12-01

The Cu(II) ion in the title mol-ecular salt, [CuBr(C5H8N2)4]Br, is coordinated in a square-pyramidal geometry by four N atoms of imidazole ligands and one bromide anion in the apical position. In the crystal, the ions are linked by N-H⋯Br hydrogen bonds involving both the coordinating and the free bromide species as acceptors. A C-H⋯Br inter-action is also observed. Overall, a three-dimensional network results.

Synthesis of CO2/N2-triggered reversible stability-controllable poly(2-(diethylamino)ethyl methacrylate)-grafted-AuNPs by surface-initiated atom transfer radical polymerization.

PubMed

Kitayama, Yukiya; Takeuchi, Toshifumi

2014-10-28

CO2/N2-triggered stability-controllable gold nanoparticles (AuNPs) grafted with poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) layers (PDEAEMA-g-AuNPs) were synthesized by the surface-initiated atom transfer radical polymerization of DEAEMA with AuNPs bearing the bis[2-(2-bromoisobutyryloxy)undecyl] layer (grafting from method). Extension of the PDEAEMA chain length increased the stability of the PDEAEMA-g-AuNPs in CO2-bubbled water because of the electrosteric repulsion of the protonated PDEAEMA layer. The chain-length-dependent stability of PDEAEMA-g-AuNPs was confirmed by DLS and UV-vis spectra by using the localized surface plasmon resonance property of the AuNPs, where the extinction wavelength was shifted toward shorter wavelength with increasing PDEAEMA chain length. The reversible stability change with the gas stimuli of CO2/N2 was also successfully demonstrated. Finally, the transfer across the immiscible interface between water and organic solvent was successfully demonstrated by N2-triggered insolubilization of PDEAEMA layer on AuNPs in the aqueous phase, leading to the successful collection of AuNPs using organic solvent from the aqueous phase. Our "grafting from" method of reversible stability-controllable AuNPs can be applied to develop advanced materials such as reusable optical AuNP-based nanosensors because the molecular recognition layer can be constructed by two-step polymerization.

Regulation of spermidine/spermine N1-acetyltransferase in L6 cells by polyamines and related compounds.

PubMed Central

Erwin, B G; Pegg, A E

1986-01-01

Exposure of rat L6 cells in culture to exogenous polyamines led to a very large increase in the activity of spermidine/spermine N1-acetyltransferase. Spermine was more potent than spermidine in bringing about this increase, but in both cases the elevated acetyltransferase activity increased the cellular conversion of spermidine into putrescine. The N1-acetyltransferase turned over very rapidly in the L6 cells, with a half-life of 9 min after spermidine and 18 min after spermine. A wide variety of synthetic polyamine analogues also brought about a substantial induction of spermidine/spermine N1-acetyltransferase activity. These included sym-norspermidine, sym-norspermine, sym-homospermidine, N4-substituted spermidine derivatives, 1,3,6-triaminohexane, 1,4,7-triaminoheptane and deoxyspergualin, which were comparable with spermidine in their potency, and N1N8-bis(ethyl)spermidine, N1N9-bis(ethyl)homospermidine, methylglyoxal bis(guanylhydrazone), ethylglyoxal bis(guanylhydrazone) and 1,1'-[(methylethanediylidene)dinitrilo]bis(3-amino-guanidine ), which were even more active than spermidine. It is suggested that these polyamine analogues may bring about a decrease in cellular polyamines not only by inhibiting biosynthesis but by stimulating the degradation of spermidine into putrescine. PMID:3800951

40 CFR 721.9672 - Amides, tall-oil fatty, N-[2-[2-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide...

Code of Federal Regulations, 2013 CFR

2013-07-01

...-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1-piperazineethanamine and sulfur dioxide; fatty acids, tall-oil reaction products with sulfur...)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1...

40 CFR 721.9672 - Amides, tall-oil fatty, N-[2-[2-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide...

Code of Federal Regulations, 2011 CFR

2011-07-01

...-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1-piperazineethanamine and sulfur dioxide; fatty acids, tall-oil reaction products with sulfur...)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1...

40 CFR 721.9672 - Amides, tall-oil fatty, N-[2-[2-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide...

Code of Federal Regulations, 2010 CFR

2010-07-01

...-hydroxyethyl)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1-piperazineethanamine and sulfur dioxide; fatty acids, tall-oil reaction products with sulfur...)amino]ethyl], reaction products with sulfur dioxide; fatty acids, tall-oil, reaction products with 1...

Spatially explicit dynamic N-mixture models

USGS Publications Warehouse

Zhao, Qing; Royle, Andy; Boomer, G. Scott

2017-01-01

Knowledge of demographic parameters such as survival, reproduction, emigration, and immigration is essential to understand metapopulation dynamics. Traditionally the estimation of these demographic parameters requires intensive data from marked animals. The development of dynamic N-mixture models makes it possible to estimate demographic parameters from count data of unmarked animals, but the original dynamic N-mixture model does not distinguish emigration and immigration from survival and reproduction, limiting its ability to explain important metapopulation processes such as movement among local populations. In this study we developed a spatially explicit dynamic N-mixture model that estimates survival, reproduction, emigration, local population size, and detection probability from count data under the assumption that movement only occurs among adjacent habitat patches. Simulation studies showed that the inference of our model depends on detection probability, local population size, and the implementation of robust sampling design. Our model provides reliable estimates of survival, reproduction, and emigration when detection probability is high, regardless of local population size or the type of sampling design. When detection probability is low, however, our model only provides reliable estimates of survival, reproduction, and emigration when local population size is moderate to high and robust sampling design is used. A sensitivity analysis showed that our model is robust against the violation of the assumption that movement only occurs among adjacent habitat patches, suggesting wide applications of this model. Our model can be used to improve our understanding of metapopulation dynamics based on count data that are relatively easy to collect in many systems.

Kinematics of the SgrB2(N-LMH) Molecular Core

NASA Technical Reports Server (NTRS)

Hollis, J. M.; Pedelty, J. A.; Boboltz, D. A.; Liu, S.-Y.; Snyder, L. E.; Palmer, Patrick; Lovas, F. J.; Jewell, P. R.

2003-01-01

Ethyl cyanide (CH3CH2CN) emission and absorption have been imaged with the Very Large Array (VLA) toward SgrB2(N-LMH) by means of the 5(sub 15)-4(sub 14) rotational transition at 43.5 GHz (lambda approx. 7 mm). The 1.5" x 1.4" VLA beam shows two principal sources of ethyl cyanide emission: an unresolved source approx. 5" north of the LMH that is kinematically consistent with simple expansion, contraction, or small-scale turbulence, and the resolved LMH core source itself that shows kinematics indicating an edge-on rotating disk that extends 23" (approx. 0.1 pc) in the approximate east-west direction. A search for the 7(sub 07)-6(sub 06) rotational transition of the amino acid glycine (NH2CH2COOH) at 43.7 GHz toward SgrB2(N-LMH) gave negative results.

Structural characterization of selenium and selenium-diiodine analogues of the antithyroid drug 6-n-propyl-2-thiouracil and its alkyl derivatives.

PubMed

Antoniadis, Constantinos D; Blake, Alexander J; Hadjikakou, Sotiris K; Hadjiliadis, Nick; Hubberstey, Peter; Schröder, Martin; Wilson, Claire

2006-08-01

The structures of four selenium analogues of the antithyroid drug 6-n-propyl-2-thiouracil [systematic name: 2,3-dihydro-6-n-propyl-2-thioxopyrimidin-4(1H)-one], namely 6-methyl-2-selenouracil, C(5)H(6)N(2)OSe (1), 6-ethyl-2-selenouracil, C(6)H(8)N(2)OSe (2), 6-n-propyl-2-selenouracil, C(7)H(10)N(2)OSe (3), and 6-isopropyl-2-selenouracil, C(7)H(10)N(2)OSe (4), are described, along with that of the dichloromethane monosolvate of 6-isopropyl-2-selenouracil, C(7)H(10)N(2)OSe.CH(2)Cl(2) (4.CH(2)Cl(2)). The extended structure of (1) is a two-dimensional sheet of topology 6(3) with a brick-wall architecture. The extended structures of (2) and (4) are analogous, being based on a chain of eight-membered R(8)(6)(32) hydrogen-bonded rings. In (3) and (4.CH(2)Cl(2)), R(2)(2)(8) hydrogen bonding links molecules into chains. 6-n-Propyl-2-selenouracil.I(2), C(7)H(10)N(2)OSe.I(2) (7), is a charge-transfer complex with a ;spoke' structure, the extended structure of which is based on a linear chain formed principally by intermolecular N-H...O hydrogen bonds. Re-crystallization of 6-ethyl-2-selenouracil or (7) from acetone gave crystals of the diselenides [N-(6'-ethyl-4'-pyrimidone)(6-ethyl-2-selenouracil)(2)(Se-Se)].2H(2)O (9.2H(2)O) or [N-(6'-n-propyl-4'-pyrimidone)(6-n-propyl-2-selenouracil)(2)(Se-Se)] (10), respectively: these have similar extended chain structures formed via N-H...O and C-H...O hydrogen bonds, stacked to give two-dimensional sheets. Re-crystallization of (7) from methanol/acetonitrile led via deselenation to the formation of crystals of 6-n-propyl-2-uracil (11), in which six symmetry-related molecules combine to form a six-membered R(6)(6)(24) hydrogen-bonded ring, with each pair of molecules linked by an R(2)(2)(8) motif.

Comparison of influence of carmustine and new proline analog of nitrosourea on antioxidant system in breast carcinoma cells (MCF-7).

PubMed

Stankiewicz-Kranc, Anna; Miltyk, Wojciech; Skrzydlewska, Elzbieta

2010-01-01

The high toxicity and low selectivity of carmustine restrict its application in anticancer therapy. Therefore, proline analogs of nitrosourea have been synthesized to obtain compounds whose action on neoplastic cells is characterized by higher selectivity. The present studies have aimed at examining the influence of carmustine and a new proline analog of nitrosourea on the redox system of fibroblasts and breast cancer cells (MCF-7). Carmustine and the proline analog of nitrosourea caused an increase in hydrogen peroxide concentration both in fibroblasts and MCF-7 cells. Moreover, administration of carmustine and the new analog of nitrosourea caused a decrease in the activity of antioxidant enzymes. Observed changes in the antioxidant system correlated with an increase in concentration of dityrosine, as well as a decrease in tryptophan concentration. Changes in the antioxidant system were also accompanied by intensification of the lipid peroxidation process. In conclusion, carmustine and proline analog of nitrosourea produce similar changes in the antioxidant system in normal and cancer cells and are responsible for oxidative stress.

A Model for Evaluating Topical Antimicrobial Efficacy against Methicillin-Resistant Staphylococcus aureus Biofilms in Superficial Murine Wounds

PubMed Central

Renick, Paul J.; Tetens, Shannon P.; Carson, Dennis L.

2012-01-01

A wound biofilm model was created by adapting a superficial infection model. Partial-thickness murine wounds were inoculated with methicillin-resistant Staphylococcus aureus (MRSA). Dense biofilm communities developed at the wound surface after 24 h as demonstrated by microscopy and quantitative microbiology. Common topical antimicrobial agents had reduced efficacy when treatment was initiated 24 h after inoculation compared to 4 h after inoculation. This model provides a rapid in vivo test for new agents to treat wound biofilm infections. PMID:22644024

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

Toki, Hideaki; Minowa, Osamu; Inoue, Maki

Dominant mutations in the Serca2 gene, which encodes sarco(endo)plasmic reticulum calcium-ATPase, predispose mice to gastrointestinal epithelial carcinoma [1–4] and humans to Darier disease (DD) [14–17]. In this study, we generated mice harboring N-ethyl-N-nitrosourea (ENU)-induced allelic mutations in Serca2: three missense mutations and one nonsense mutation. Mice harboring these Serca2 mutations developed tumors that were categorized as either early onset squamous cell tumors (SCT), with development similar to null-type knockout mice [2,4] (aggressive form; M682, M814), or late onset tumors (mild form; M1049, M1162). Molecular analysis showed no aberration in Serca2 mRNA or protein expression levels in normal esophageal cells ofmore » any of the four mutant heterozygotes. There was no loss of heterozygosity at the Serca2 locus in the squamous cell carcinomas in any of the four lines. The effect of each mutation on Ca{sup 2+}-ATPase activity was predicted using atomic-structure models and accumulated mutated protein studies, suggesting that putative complete loss of Serca2 enzymatic activity may lead to early tumor onset, whereas mutations in which Serca2 retains residual enzymatic activity result in late onset. We propose that impaired Serca2 gene product activity has a long-term effect on squamous cell carcinogenesis from onset to the final carcinoma stage through an as-yet unrecognized but common regulatory pathway. -- Highlights: •Novel mutations in murine Serca2 caused early onset or late onset of tumorigenesis. •They also caused higher or lower incidence of Darier Disease phenotype. •3D structure model suggested the former mutations led to severer defect on ATPase. •Driver gene mutations via long-range effect on Ca2+ distributions are suggested.« less

A Mutant Mouse with a Highly Specific Contextual Fear-Conditioning Deficit Found in an N-Ethyl-N-Nitrosourea (ENU) Mutagenesis Screen

ERIC Educational Resources Information Center

Pletcher, Mathew T.; Wiltshire, Tim; Tarantino, Lisa M.; Mayford, Mark; Reijmers, Leon G.; Coats, Jennifer K.

2006-01-01

Targeted mutagenesis in mice has shown that genes from a wide variety of gene families are involved in memory formation. The efficient identification of genes involved in learning and memory could be achieved by random mutagenesis combined with high-throughput phenotyping. Here, we provide the first report of a mutagenesis screen that has…

Split Tolerance in a Murine Model of Heterotopic En Bloc Chest Wall Transplantation

PubMed Central

Oh, Byoungchol; Furtmüller, Georg J.; Malek, Veronika; Fryer, Madeline L.; Brayton, Cory; Walczak, Piotr; Janowski, Miroslaw

2017-01-01

Background: Congenital and acquired chest wall deformities represent a significant challenge to functional reconstruction and may impact feasibility of heart transplantation for patients with end-stage organ failure. In the recent past, the concept of replacing like-with-like tissue by using vascularized composite allografts (VCA) has been enthusiastically employed for reconstruction of complex tissue defects. Methods: In this study, we introduce a novel murine model for en bloc chest wall, heart, and thymus transplantation and thereby the use of complex tissue allografts for reconstruction of both chest wall defects and also end-stage organ failure. Additionally, this model allows us to study the features of combined vascularized bone marrow (VBM), thymus, and heart transplantation on allograft survival and function. Heterotopic chest wall, thymus, and heart transplants were performed in untreated syngeneic and allogeneic combinations and in allogeneic combinations treated with costimulation blockade (CTLA4-Ig and MR-1). Results: Indefinite (ie, 150 d, N = 3) graft survival was observed in syngeneic controls. In untreated recipients of allogeneic grafts, the skin component was rejected after 10 (±1) days, whereas rejection of the heart occurred after 13 (± 1) days (N = 3). Costimulation blockade treatment prolonged survival of the heart and chest wall component (130 d, N = 3) as well as the VBM niche as evidenced by donor-specific chimerism (average: 2.35 ± 1.44%), whereas interestingly, the skin component was rejected after 13 (±1) days. Conclusion: Thus, this novel microsurgical model of VCA combined with solid organ transplantation is technically feasible and results in split tolerance when treated with costimulatory blockade. PMID:29632774

Pilot study of large-scale production of mutant pigs by ENU mutagenesis.

PubMed

Hai, Tang; Cao, Chunwei; Shang, Haitao; Guo, Weiwei; Mu, Yanshuang; Yang, Shulin; Zhang, Ying; Zheng, Qiantao; Zhang, Tao; Wang, Xianlong; Liu, Yu; Kong, Qingran; Li, Kui; Wang, Dayu; Qi, Meng; Hong, Qianlong; Zhang, Rui; Wang, Xiupeng; Jia, Qitao; Wang, Xiao; Qin, Guosong; Li, Yongshun; Luo, Ailing; Jin, Weiwu; Yao, Jing; Huang, Jiaojiao; Zhang, Hongyong; Li, Menghua; Xie, Xiangmo; Zheng, Xuejuan; Guo, Kenan; Wang, Qinghua; Zhang, Shibin; Li, Liang; Xie, Fei; Zhang, Yu; Weng, Xiaogang; Yin, Zhi; Hu, Kui; Cong, Yimei; Zheng, Peng; Zou, Hailong; Xin, Leilei; Xia, Jihan; Ruan, Jinxue; Li, Hegang; Zhao, Weiming; Yuan, Jing; Liu, Zizhan; Gu, Weiwang; Li, Ming; Wang, Yong; Wang, Hongmei; Yang, Shiming; Liu, Zhonghua; Wei, Hong; Zhao, Jianguo; Zhou, Qi; Meng, Anming

2017-06-22

N-ethyl-N-nitrosourea (ENU) mutagenesis is a powerful tool to generate mutants on a large scale efficiently, and to discover genes with novel functions at the whole-genome level in Caenorhabditis elegans, flies, zebrafish and mice, but it has never been tried in large model animals. We describe a successful systematic three-generation ENU mutagenesis screening in pigs with the establishment of the Chinese Swine Mutagenesis Consortium. A total of 6,770 G1 and 6,800 G3 pigs were screened, 36 dominant and 91 recessive novel pig families with various phenotypes were established. The causative mutations in 10 mutant families were further mapped. As examples, the mutation of SOX10 (R109W) in pig causes inner ear malfunctions and mimics human Mondini dysplasia, and upregulated expression of FBXO32 is associated with congenital splay legs. This study demonstrates the feasibility of artificial random mutagenesis in pigs and opens an avenue for generating a reservoir of mutants for agricultural production and biomedical research.

Computational Aspects of N-Mixture Models

PubMed Central

Dennis, Emily B; Morgan, Byron JT; Ridout, Martin S

2015-01-01

The N-mixture model is widely used to estimate the abundance of a population in the presence of unknown detection probability from only a set of counts subject to spatial and temporal replication (Royle, 2004, Biometrics 60, 105–115). We explain and exploit the equivalence of N-mixture and multivariate Poisson and negative-binomial models, which provides powerful new approaches for fitting these models. We show that particularly when detection probability and the number of sampling occasions are small, infinite estimates of abundance can arise. We propose a sample covariance as a diagnostic for this event, and demonstrate its good performance in the Poisson case. Infinite estimates may be missed in practice, due to numerical optimization procedures terminating at arbitrarily large values. It is shown that the use of a bound, K, for an infinite summation in the N-mixture likelihood can result in underestimation of abundance, so that default values of K in computer packages should be avoided. Instead we propose a simple automatic way to choose K. The methods are illustrated by analysis of data on Hermann's tortoise Testudo hermanni. PMID:25314629

Cellular Biochemistry and Cytogenetics in a Rat Lung Tumor Model

DTIC Science & Technology

1984-10-01

lung tumor system the specific aims are: 1. To conduct studies of the effect of 3-methylchlanthrene (MCA) on DNA synthesis and cell proliferation in...alkylation of nucleic acids of the rat by N-methyl-N- nitrosourea , dimethylnitrosamine, dimethylsulfate, and methylmethanesulfonate. Biochem. J. 110:39-47

Thieno[3,2-b]- and thieno[2,3-b]pyrrole bioisosteric analogues of the hallucinogen and serotonin agonist N,N-dimethyltryptamine.

PubMed

Blair, J B; Marona-Lewicka, D; Kanthasamy, A; Lucaites, V L; Nelson, D L; Nichols, D E

1999-03-25

The synthesis and biological activity of 6-[2-(N, N-dimethylamino)ethyl]-4H-thieno[3,2-b]pyrrole (3a) and 4-[2-(N, N-dimethylamino)ethyl]-6H-thieno[2,3-b]pyrrole (3b), thienopyrroles as potential bioisosteres of N,N-dimethyltryptamine (1a), are reported. Hallucinogen-like activity was evaluated in the two-lever drug discrimination paradigm using LSD- and DOI-trained rats. Neither 3a nor 3b substituted for LSD or DOI up to doses of 50 micromol/kg. By comparison, 1a fully substituted in LSD-trained rats. However, 3a and 3b fully substituted for the 5-HT1A agonist LY293284 ((-)-(4R)-6-acetyl-4-(di-n-propylamino)-1,3,4, 5-tetrahydrobenz[c,d]indole). Both 3a and 3b induced a brief "serotonin syndrome" and salivation, an indication of 5-HT1A receptor activation. At the cloned human 5-HT2A receptor 3b had about twice the affinity of 3a. At the cloned human 5-HT2B and 5-HT2C receptors, however, 3a had about twice the affinity of 3b. Therefore, thiophene lacks equivalence as a replacement for the phenyl ring in the indole nucleus of tryptamines that bind to 5-HT2 receptor subtypes and possess LSD-like behavioral effects. Whereas both of the thienopyrroles had lower affinity than the corresponding 1a at 5-HT2 receptors, 3a and 3b had significantly greater affinity than 1a at the 5-HT1A receptor. Thus, thienopyrrole does appear to serve as a potent bioisostere for the indole nucleus in compounds that bind to the serotonin 5-HT1A receptor. These differences in biological activity suggest that serotonin receptor isoforms are very sensitive to subtle changes in the electronic character of the aromatic systems of indole compounds.

Coupling constant for N*(1535)N{rho}

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

Xie Jujun; Graduate University of Chinese Academy of Sciences, Beijing 100049; Wilkin, Colin

2008-05-15

The value of the N*(1535)N{rho} coupling constant g{sub N*N{rho}} derived from the N*(1535){yields}N{rho}{yields}N{pi}{pi} decay is compared with that deduced from the radiative decay N*(1535){yields}N{gamma} using the vector-meson-dominance model. On the basis of an effective Lagrangian approach, we show that the values of g{sub N*N{rho}} extracted from the available experimental data on the two decays are consistent, though the error bars are rather large.

[Ethyl chloride aerosol spray for local anesthesia before arterial puncture: randomized placebo-controlled trial].

PubMed

Ballesteros-Peña, Sendoa; Fernández-Aedo, Irrintzi; Vallejo-De la Hoz, Gorka

2017-06-01

To compare the efficacy of an ethyl chloride aerosol spray to a placebo spray applied in the emergency department to the skin to reduce pain from arterial puncture for blood gas analysis. Single-blind, randomized placebo-controlled trial in an emergency department of Hospital de Basurto in Bilbao, Spain. We included 126 patients for whom arterial blood gas analysis had been ordered. They were randomly assigned to receive application of the experimental ethyl chloride spray (n=66) or a placebo aerosol spray of a solution of alcohol in water (n=60). The assigned spray was applied just before arterial puncture. The main outcome variable was pain intensity reported on an 11-point numeric rating scale. The median (interquartile range) pain level was 2 (1-5) in the experimental arm and 2 (1-4.5) in the placebo arm (P=.72). Topical application of an ethyl chloride spray did not reduce pain caused by arterial puncture.

Prescription n-3 fatty acids, but not eicosapentaenoic acid alone, improve reference memory-related learning ability by increasing brain-derived neurotrophic factor levels in SHR.Cg-Lepr(cp)/NDmcr rats, a metabolic syndrome model.

PubMed

Hashimoto, Michio; Inoue, Takayuki; Katakura, Masanori; Tanabe, Yoko; Hossain, Shahdat; Tsuchikura, Satoru; Shido, Osamu

2013-10-01

Metabolic syndrome is implicated in the decline of cognitive ability. We investigated whether the prescription n-3 fatty acid administration improves cognitive learning ability in SHR.Cg-Lepr(cp)/NDmcr (SHR-cp) rats, a metabolic syndrome model, in comparison with administration of eicosapentaenoic acid (EPA, C20:5, n-3) alone. Administration of TAK-085 [highly purified and concentrated n-3 fatty acid formulation containing EPA ethyl ester and docosahexaenoic acid (DHA, C22:6, n-3) ethyl ester] at 300 mg/kg body weight per day for 13 weeks reduced the number of reference memory-related errors in SHR-cp rats, but EPA alone had no effect, suggesting that long-term TAK-085 administration improves cognitive learning ability in a rat model of metabolic syndrome. However, the working memory-related errors were not affected in either of the rat groups. TAK-085 and EPA administration increased plasma EPA and DHA levels of SHR-cp rats, associating with an increase in EPA and DHA in the cerebral cortex. The TAK-085 administration decreased the lipid peroxide levels and reactive oxygen species in the cerebral cortex and hippocampus of SHR-cp rats, suggesting that TAK-085 increases antioxidative defenses. Its administration also increased the brain-derived neurotrophic factor levels in the cortical and hippocampal tissues of TAK-085-administered rats. The present study suggests that long-term TAK-085 administration is a possible therapeutic strategy for protecting against metabolic syndrome-induced learning decline.

Additive In Vitro Antiplasmodial Effect of N-Alkyl and N-Benzyl-1,10-Phenanthroline Derivatives and Cysteine Protease Inhibitor E64

PubMed Central

Wijayanti, Mahardika Agus; Sholikhah, Eti Nurwening; Hadanu, Ruslin; Jumina, Jumina; Supargiyono, Supargiyono; Mustofa, Mustofa

2010-01-01

Potential new targets for antimalarial chemotherapy include parasite proteases, which are required for several cellular functions during the Plasmodium falciparum life cycle. Four new derivatives of N-alkyl and N-benzyl-1,10-phenanthroline have been synthesized. Those are (1)-N-methyl-1,10-phenanthrolinium sulfate, (1)-N-ethyl-1,10-phenanthrolinium sulfate, (1)-N-benzyl-1,10-phenanthrolinium chloride, and (1)-N-benzyl-1,10-phenanthrolinium iodide. Those compounds had potential antiplasmodial activity with IC50 values from 260.42 to 465.38 nM. Cysteine proteinase inhibitor E64 was used to investigate the mechanism of action of N-alkyl and N-benzyl-1,10-phenanthroline derivatives. A modified fixed-ratio isobologram method was used to study the in vitro interactions between the new compounds with either E64 or chloroquine. The interaction between N-alkyl and N-benzyl-1,10-phenanthroline derivatives and E64 was additive as well as their interactions with chloroquine were also additive. Antimalarial mechanism of chloroquine is mainly on the inhibition of hemozoin formation. As the interaction of chloroquine and E64 was additive, the results indicated that these new compounds had a mechanism of action by inhibiting Plasmodium proteases. PMID:22332022

Supplementation with n-3, n-6, n-9 fatty acids in an insulin-resistance animal model: does it improve VLDL quality?

PubMed

Lucero, D; Olano, C; Bursztyn, M; Morales, C; Stranges, A; Friedman, S; Macri, E V; Schreier, L; Zago, V

2017-05-24

Insulin-resistance (IR), of increased cardiovascular risk, is characterized by the production of altered VLDL with greater atherogenicity. Dietary fatty acids influence the type of circulating VLDL. But, it is not clear how dietary fatty acids impact VLDL characteristics in IR. to evaluate the effects of n-3, n-6 and n-9 fatty acid supplementation on preventing atherogenic alterations in VLDL, in a diet-induced IR rat model. Male Wistar rats (180-200 g) were fed: standard diet (control, n = 8) and a sucrose rich diet (30% sucrose in water/12 weeks, SRD; n = 24). Simultaneously, SRD was subdivided into SRD-C (standard diet), and three other groups supplemented (15% w/w) with: fish oil (SRD-n3), sunflower oil (SRD-n6) and high oleic sunflower oil (SRD-n9). Lipid profile, free fatty acids, glucose, and insulin were measured. Isolated VLDL (d < 1.006 g ml -1 ) was characterized by chemical composition and size (size exclusion-HPLC). In comparison with SRD-C: SRD-n3 showed an improved lipoprotein profile (p < 0.01), with lower levels of insulin and HOMA-IR (p < 0.05). SRD-n6 showed increased levels of HDL-cholesterol and lower insulin levels. SRD-n9 did not exhibit differences in lipid and IR profile, and even favored weight gain and visceral fat. Only SRD-n3 prevented the alterations in VLDL-TG% (54.2 ± 4.4% vs. 68.6 ± 8.2, p < 0.05) and showed lower large VLDL-% (22.5[19.7-35.6] vs. 49.1[15.5-82.0], p < 0.05), while SRD-n6 and SRD-n9 did not show effects. In IR, while n-3 PUFA showed expected favorable effects, supplementation with n-6 PUFA and n-9 MUFA did not prevent atherogenic alterations of VLDL. Thus, the recommendations of supplementation with these fatty acids in general diet should be revised.

A conduction model for contacts to Si-doped AlGaN grown on sapphire and single-crystalline AlN

NASA Astrophysics Data System (ADS)

Haidet, Brian B.; Bryan, Isaac; Reddy, Pramod; Bryan, Zachary; Collazo, Ramón; Sitar, Zlatko

2015-06-01

Ohmic contacts to AlGaN grown on sapphire substrates have been previously demonstrated for various compositions of AlGaN, but contacts to AlGaN grown on native AlN substrates are more difficult to obtain. In this paper, a model is developed that describes current flow through contacts to Si-doped AlGaN. This model treats the current through reverse-biased Schottky barriers as a consequence of two different tunneling-dependent conduction mechanisms in parallel, i.e., Fowler-Nordheim emission and defect-assisted Frenkel-Poole emission. At low bias, the defect-assisted tunneling dominates, but as the potential across the depletion region increases, tunneling begins to occur without the assistance of defects, and the Fowler-Nordheim emission becomes the dominant conduction mechanism. Transfer length method measurements and temperature-dependent current-voltage (I-V) measurements of Ti/Al-based contacts to Si-doped AlGaN grown on sapphire and AlN substrates support this model. Defect-assisted tunneling plays a much larger role in the contacts to AlGaN on sapphire, resulting in nearly linear I-V characteristics. In contrast, contacts to AlGaN on AlN show limited defect-assisted tunneling appear to be only semi-Ohmic.

Vacua and walls of mass-deformed Kähler nonlinear sigma models on S p (N )/U (N )

NASA Astrophysics Data System (ADS)

Arai, Masato; Golubtsova, Anastasia; Park, Chanyong; Shin, Sunyoung

2018-05-01

We study vacua and walls of mass-deformed Kähler nonlinear sigma models on S p (N )/U (N ). We identify elementary walls with the simple roots of U S p (2 N ) and discuss compressed walls, penetrable walls, and multiwalls by using the moduli matrix formalism.

Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity.

PubMed

Isoherranen, Nina; Spiegelstein, Ofer; Bialer, Meir; Zhang, Jing; Merriweather, Michelle; Yagen, Boris; Roeder, Michael; Triplett, Aleata A; Schurig, Volker; Finnell, Richard H

2003-10-01

The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model. All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining. No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA. Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.

PRINT: A Protein Bioconjugation Method with Exquisite N-terminal Specificity

PubMed Central

Sur, Surojit; Qiao, Yuan; Fries, Anja; O’Meally, Robert N.; Cole, Robert N.; Kinzler, Kenneth W.; Vogelstein, Bert; Zhou, Shibin

2015-01-01

Chemical conjugation is commonly used to enhance the pharmacokinetics, biodistribution, and potency of protein therapeutics, but often leads to non-specific modification or loss of bioactivity. Here, we present a simple, versatile and widely applicable method that allows exquisite N-terminal specific modification of proteins. Combining reversible side-chain blocking and protease mediated cleavage of a commonly used HIS tag appended to a protein, we generate with high yield and purity exquisitely site specific and selective bio-conjugates of TNF-α by using amine reactive NHS ester chemistry. We confirm the N terminal selectivity and specificity using mass spectral analyses and show near complete retention of the biological activity of our model protein both in vitro and in vivo murine models. We believe that this methodology would be applicable to a variety of potentially therapeutic proteins and the specificity afforded by this technique would allow for rapid generation of novel biologics. PMID:26678960

4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide - A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation.

PubMed

Mahal, Katharina; Kahlen, Philip; Biersack, Bernhard; Schobert, Rainer

2015-08-15

Histone deacetylases (HDAC) which play a crucial role in cancer cell proliferation are promising drug targets. However, HDAC inhibitors (HDACi) modelled on natural hydroxamic acids such as trichostatin A frequently lead to resistance or even an increased agressiveness of tumours. As a workaround we developed 4-(1-ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide (etacrox), a hydroxamic acid that combines HDAC inhibition with synergistic effects of the 4,5-diarylimidazole residue. Etacrox proved highly cytotoxic against a panel of metastatic and resistant cancer cell lines while showing greater specificity for cancer over non-malignant cells when compared to the approved HDACi vorinostat. Like the latter, etacrox and the closely related imidazoles bimacroxam and animacroxam acted as pan-HDACi yet showed some specificity for HDAC6. Akt signalling and interference with nuclear beta-catenin localisation were elicited by etacrox at lower concentrations when compared to vorinostat. Moreover, etacrox disrupted the microtubule and focal adhesion dynamics of cancer cells and inhibited the proteolytic activity of prometastatic and proangiogenic matrix metalloproteinases. As a consequence, etacrox acted strongly antimigratory and antiinvasive against various cancer cell lines in three-dimensional transwell invasion assays and also antiangiogenic in vivo with respect to blood vessel formation in the chorioallantoic membrane assay. These pleiotropic effects and its water-solubility and tolerance by mice render etacrox a promising new HDACi candidate. Copyright © 2015 Elsevier Inc. All rights reserved.

Modeling Proton Irradiation in AlGaN/GaN HEMTs: Understanding the Increase of Critical Voltage

NASA Astrophysics Data System (ADS)

Patrick, Erin; Law, Mark E.; Liu, Lu; Cuervo, Camilo Velez; Xi, Yuyin; Ren, Fan; Pearton, Stephen J.

2013-12-01

A combination of TRIM and FLOODS models the effect of radiation damage on AlGaN/GaN HEMTs. While excellent fits are obtained for threshold voltage shift, the models do not fully explain the increased reliability observed experimentally. In short, the addition of negatively-charged traps in the GaN buffer layer does not significantly change the electric field at the gate edges at radiation fluence levels seen in this study. We propose that negative trapped charge at the nitride/AlGaN interface actually produces the virtual-gate effect that results in decreasing the magnitude of the electric field at the gate edges and thus the increase in critical voltage. Simulation results including nitride interface charge show significant changes in electric field profiles while the I-V device characteristics do not change.

Current Translational Research and Murine Models For Duchenne Muscular Dystrophy

PubMed Central

Rodrigues, Merryl; Echigoya, Yusuke; Fukada, So-ichiro; Yokota, Toshifumi

2016-01-01

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscle degeneration. Mutations in the DMD gene result in the absence of dystrophin, a protein required for muscle strength and stability. Currently, there is no cure for DMD. Since murine models are relatively easy to genetically manipulate, cost effective, and easily reproducible due to their short generation time, they have helped to elucidate the pathobiology of dystrophin deficiency and to assess therapies for treating DMD. Recently, several murine models have been developed by our group and others to be more representative of the human DMD mutation types and phenotypes. For instance, mdx mice on a DBA/2 genetic background, developed by Fukada et al., have lower regenerative capacity and exhibit very severe phenotype. Cmah-deficient mdx mice display an accelerated disease onset and severe cardiac phenotype due to differences in glycosylation between humans and mice. Other novel murine models include mdx52, which harbors a deletion mutation in exon 52, a hot spot region in humans, and dystrophin/utrophin double-deficient (dko), which displays a severe dystrophic phenotype due the absence of utrophin, a dystrophin homolog. This paper reviews the pathological manifestations and recent therapeutic developments in murine models of DMD such as standard mdx (C57BL/10), mdx on C57BL/6 background (C57BL/6-mdx), mdx52, dystrophin/utrophin double-deficient (dko), mdxβgeo, Dmd-null, humanized DMD (hDMD), mdx on DBA/2 background (DBA/2-mdx), Cmah-mdx, and mdx/mTRKO murine models. PMID:27854202

Genetic modification of haematopoietic cells for combined resistance to podophyllotoxins, other agents covered by MDR1-mediated efflux activity and nitrosoureas.

PubMed

Baum, C; Peinert, S; Carpinteiro, A; Eckert, H G; Fairbairn, L J

2000-05-01

Genetic transfer and expression of drug-resistance functions into haematopoietic stem and progenitor cells is a promising means to overcome both the acute and longterm side-effects of cytotoxic drugs in bone marrow. Here, we describe a functional analysis of a retroviral vector that co-expresses human cDNAs for multidrug resistance 1/P-glycoprotein (MDR1) and a double mutant of O(6)-alkylguanine-alkyltransferase (hATPA/GA) to high levels. The hATPA/GA protein contains two amino acid substitutions that render it resistant to compounds such as O(6)-benzylguanine that inhibit the wild-type protein which is often overexpressed in resistant tumour cells. Evidence for simultaneous drug resistance of genetically modified primary murine progenitor cells to colchicine or the podophyllotoxin etoposide, both covered by MDR1-mediated efflux activity, and the nitrosourea BCNU, which is counteracted by hATPA/GA, is presented using in vitro colony assays.

Immunotherapy with iTreg and nTreg Cells in a Murine Model of Inflammatory Bowel Disease.

PubMed

Haribhai, Dipica; Chatila, Talal A; Williams, Calvin B

2016-01-01

Regulatory T (Treg) cells that express the transcription factor Foxp3 are essential for maintaining tolerance at mucosal interfaces, where they act by controlling inflammation and promoting epithelial cell homeostasis. There are two major regulatory T-cell subsets, "natural" CD4(+) Treg (nTreg) cells that develop in the thymus and "induced" Treg (iTreg) cells that develop from conventional CD4(+) T (Tconv) cells in the periphery. Dysregulated Treg cell responses are associated with autoimmune diseases, including inflammatory bowel disease (IBD) and arthritis. Adoptive transfer of Treg cells can modulate innate and adaptive immune responses and cure disease in animal models, which has generated considerable interest in using Treg cells to treat human autoimmune disease, prevent rejection of transplanted organs, and to control graft-versus-host disease following hematopoietic stem cell transplantation. Herein, we describe our modifications of a treatment model of T-cell transfer colitis designed to allow mechanistic investigation of the two major Treg cell subsets and to compare their specific roles in mucosal tolerance.

A functional murine model of hindlimb demand ischemia.

PubMed

Peck, Michael A; Crawford, Robert S; Abularrage, Christopher J; Patel, Virendra I; Conrad, Mark F; Yoo, Jin Hyung; Watkins, Michael T; Albadawi, Hassan

2010-05-01

To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans. Aged hypercholesterolemic ApoE null mice (ApoE(-/-), n = 13) were subjected to femoral artery ligation (FAL) and allowed to recover from the acute ischemic response. Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral nonischemic limb flux) and clinical ischemic score, mice underwent 2 days of treadmill training (10 min at 10 m/min, incline of 10 degrees ) followed by 60 min of daily treadmill exercise (13 m/min, incline of 10 degrees ) through day 25. An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance. After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The

Dispensable role of myeloid differentiation primary response gene 88 (MyD88) and MyD88-dependent toll-like receptors (TLRs) in a murine model of osteoarthritis.

PubMed

Nasi, Sonia; Ea, Hang-Korng; Chobaz, Véronique; van Lent, Peter; Lioté, Frédéric; So, Alexander; Busso, Nathalie

2014-07-01

The aim of our study was to evaluate the role of cell-membrane expressed TLRs and the signaling molecule MyD88 in a murine model of OA induced by knee menisectomy (surgical partial removal of the medial meniscus [MNX]). OA was induced in 8-10weeks old C57Bl/6 wild-type (WT) female (n=7) mice and in knockout (KO) TLR-1 (n=7), -2 (n=8), -4 (n=9) -6 (n=5), MyD88 (n=8) mice by medial menisectomy, using the sham-operated contralateral knee as a control. Cartilage destruction and synovial inflammation were evaluated by knee joint histology using the OARSI scoring method. Apoptotic chondrocytes and cartilage metabolism (collagen II synthesis and MMP-mediated aggrecan degradation) were analyzed using immunohistochemistry. Operated knees exhibited OA features at 8weeks post-surgery compared to sham-operated ones. In menisectomized TLR-1, -2, -4, and -6 deficient mice, cartilage lesions, synovial inflammation and cartilage metabolism were similar to that in operated WT mice. Accordingly, using the same approach, we found no significant protection in MyD88-deficient mice in terms of OA progression as compared to WT littermates. Deficiency of TLRs or their signalling molecule MyD88 did not impact on the severity of experimental OA. Our results demonstrate that MyD88-dependent TLRs are not involved in this murine OA model. Moreover, the dispensable role of MyD88, which is also an adaptor for IL-1 receptor signaling, suggests that IL-1 is not a key mediator in the development of OA. This latter hypothesis is strengthened by the lack of efficiency of IL-1β antagonist in the treatment of OA. Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.

Copper-induced ammonia N-H functionalization.

PubMed

Álvarez, María; Álvarez, Eleuterio; Fructos, Manuel R; Urbano, Juan; Pérez, Pedro J

2016-10-07

The activation of ammonia has been achieved with the aid of the Tp(Ms)Cu core (Tp(Ms) = hydrotris(3-mesityl-pyrazolyl)borate). Complexes of the general composition Tp(Ms)Cu(amine) (1-4) including the ammonia adduct Tp(Ms)Cu(NH3) (1) have been synthesized and fully spectroscopical- and structurally characterized. Coordinated ammonia in 1 has been reacted with Ph3CPF6 yielding Tp(Ms)Cu(NH2CPh3) (5) as a result of N-H cleavage and N-C bond formation. In a parallel manner the catalytic functionalization of ammonia with ethyl diazoacetate leading to glycinate derivatives has been developed with Tp(Ms)Cu(THF) as the catalyst, in the first example of this transformation with ammonia and a copper-based system.

Synthesis, structure, computational and in-silico anticancer studies of N,N-diethyl-N‧-palmitoylthiourea

NASA Astrophysics Data System (ADS)

Asegbeloyin, Jonnie Niyi; Oyeka, Ebube Evaristus; Okpareke, Obinna; Ibezim, Akachukwu

2018-02-01

A new potential ONS donor ligand N,N-diethyl-N‧-palmitoylthiourea (PACDEA) with the molecular formular C21H42N2OS has been synthesized and characterized by ESI-MS, UV, FTIR 1H and 13C NMR spectroscopy and single X-ray crystallography. The asymmetric molecules crystallized in the centrosymmetric structure of monoclinic crystal system with space group P21/c. In the crystal structure of the compound, molecules are linked in a continuous chain by intermolecular Nsbnd H⋯Odbnd C hydrogen bonds, which stabilized the crystal structure. The palmitoyl moiety and N (2)-ethyl group lie on a plane, while the thiocarbonyl moiety is twisted and lying othorgonal to the plane. Non-covalent interaction (NCI) analysis on the hydrogen bonded solid state structure of the molecule revealed the presence of a significant number of non-covalent interactions including intermolecular hydrogen bonding interactions, Csbnd Hsbnd -lone pair interactions, weak Van der Waals interactions, and steric/ring closure interactions. The NCI analysis also showed the presence of intramolecular stabilizing Csbnd H⋯Odbnd C and Csbnd H⋯Sdbnd C interactions. Docking simulation revealed that the compound interacted favourably with ten selected validated anticancer drug targets, which is an indication that the compound could possess some anticancer properties.

A novel Phex mutation with defective glycosylation causes hypophosphatemia and rickets in mice.

PubMed

Xiong, Xiwen; Qi, Xin; Ge, Xiaomei; Gu, Pengyu; Zhao, Jing; Zhao, Qingshun; Gao, Xiang

2008-01-01

N-ethyl-N-nitrosourea (ENU) mutagenesis is a phenotype-driven approach with potential to assign function to every locus in the mouse genome. In this article, we describe a new mutation, Pug, as a mouse model for X-linked hypophosphatemic rickets (XLH) in human. Mice carrying the Pug mutation exhibit abnormal phenotypes including growth retardation, hypophosphatemia and decreased bone mineral density (BMD). The new mutation was mapped to X-chromosome between 65.4 cM and 66.6 cM, where Phex gene resides. Sequence analysis revealed a unique T-to-C transition mutation resulting in Phe-to-Ser substitution at amino acid 80 of PHEX protein. In vitro studies of Pug mutation demonstrated that PHEX(pug) was incompletely glycosylated and sequestrated in the endoplasmic reticulum region of cell, whereas wild-type PHEX could be fully glycosylated and transported to the plasma membrane to exert its function as an endopeptidase. Taken together, the Pug mutant directly confirms the role of Phex in phosphate homeostasis and normal skeletal development and may serves as a new disease model of human hypophosphatemic rickets.

Z/sub n/ Baxter model: symmetries and the Belavin parametrization

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

Richey, M.P.; Tracy, C.A.

1986-02-01

The Z/sub n/ Baxter model is an exactly solvable lattice model in the special case of the Belavin parametrization. For this parametrization the authors calculate the partition function in an antiferromagnetic region and the order parameter in a ferromagnetic region. They find that the order parameter is expressible in terms of a modular function of level n which for n=2 is the Onsager-Yang-Baxter result. In addition they determine the symmetry group of the finite lattice partition function for the general Z/sub n/ Baxter model.

Surplus N in US maize production: Informing data-driven policies using the Adapt-N model

NASA Astrophysics Data System (ADS)

Sela, Shai; van-Es, Harold; McLellan, Eileen; Margerison, Rebecca; Melkonian, Jeff

2016-04-01

scenarios, applying a split application of a modest starter followed by the majority of N applied at sidedress was found to have on average the lowest total N applied amount and N surplus. A split application was found to reduce environmental losses by 46% and 17% compared with fall and spring pre-plant N applications (respectively). These results could be used to inform environmental policies and business models to reduce environmental costs associated with maize production in the U.S.

Resurgence and dynamics of O(N) and Grassmannian sigma models

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

Dunne, Gerald V.; Unsal, Mithat

Here, we study the non-perturbative dynamics of the two dimensional O( N) and Grassmannian sigma models by using compactification with twisted boundary conditions on R× S 1, semi-classical techniques and resurgence. While the O(N) model has no instantons for N > 3, it has (non-instanton) saddles on R 2, which we call 2d-saddles. On R× S 1, the resurgent relation between perturbation theory and non-perturbative physics is encoded in new saddles, which are associated with the affine root system of the o( N) algebra. These events may be viewed as fractionalizations of the 2d-saddles. The first beta function coefficient, givenmore » by the dual Coxeter number, can then be intepreted as the sum of the multiplicities (dual Kac labels) of these fractionalized objects. Surprisingly, the new saddles in O( N) models in compactified space are in one-to-one correspondence with monopole-instanton saddles in SO( N) gauge theory on R 3×S 1. The Grassmannian sigma models Gr( N, M) have 2d instantons, which fractionalize into N kink-instantons. The small circle dynamics of both sigma models can be described as a dilute gas of the one-events and two-events, bions. One-events are the leading source of a variety of non-perturbative effects, and produce the strong scale of the 2d theory in the compactified theory. We show that in both types of sigma models the neutral bion emulates the role of IR-renormalons. We also study the topological theta angle dependence in both the O(3) model and Gr( N, M), and describe the multi-branched structure of the observables in terms of the theta-angle dependence of the saddle amplitudes, providing a microscopic argument for Haldane’s conjecture.« less

Resurgence and dynamics of O(N) and Grassmannian sigma models

DOE PAGES

Dunne, Gerald V.; Unsal, Mithat

2015-09-29

Here, we study the non-perturbative dynamics of the two dimensional O( N) and Grassmannian sigma models by using compactification with twisted boundary conditions on R× S 1, semi-classical techniques and resurgence. While the O(N) model has no instantons for N > 3, it has (non-instanton) saddles on R 2, which we call 2d-saddles. On R× S 1, the resurgent relation between perturbation theory and non-perturbative physics is encoded in new saddles, which are associated with the affine root system of the o( N) algebra. These events may be viewed as fractionalizations of the 2d-saddles. The first beta function coefficient, givenmore » by the dual Coxeter number, can then be intepreted as the sum of the multiplicities (dual Kac labels) of these fractionalized objects. Surprisingly, the new saddles in O( N) models in compactified space are in one-to-one correspondence with monopole-instanton saddles in SO( N) gauge theory on R 3×S 1. The Grassmannian sigma models Gr( N, M) have 2d instantons, which fractionalize into N kink-instantons. The small circle dynamics of both sigma models can be described as a dilute gas of the one-events and two-events, bions. One-events are the leading source of a variety of non-perturbative effects, and produce the strong scale of the 2d theory in the compactified theory. We show that in both types of sigma models the neutral bion emulates the role of IR-renormalons. We also study the topological theta angle dependence in both the O(3) model and Gr( N, M), and describe the multi-branched structure of the observables in terms of the theta-angle dependence of the saddle amplitudes, providing a microscopic argument for Haldane’s conjecture.« less

Dietary n-3 PUFA affect TcR-mediated activation of purified murine T cells and accessory cell function in co-cultures

PubMed Central

CHAPKIN, R S; ARRINGTON, J L; APANASOVICH, T V; CARROLL, R J; MCMURRAY, D N

2002-01-01

Diets enriched in n-3 polyunsaturated fatty acids (PUFA) suppress several functions of murine splenic T cells by acting directly on the T cells and/or indirectly on accessory cells. In this study, the relative contribution of highly purified populations of the two cell types to the dietary suppression of T cell function was examined. Mice were fed diets containing different levels of n-3 PUFA; safflower oil (SAF; control containing no n-3 PUFA), fish oil (FO) at 2% and 4%, or 1% purified docosahexaenoic acid (DHA) for 2 weeks. Purified (>90%) T cells were obtained from the spleen, and accessory cells (>95% adherent, esterase-positive) were obtained by peritoneal lavage. Purified T cells or accessory cells from each diet group were co-cultured with the alternative cell type from every other diet group, yielding a total of 16 different co-culture combinations. The T cells were stimulated with either concanavalin A (ConA) or antibodies to the T cell receptor (TcR)/CD3 complex and the costimulatory molecule CD28 (αCD3/αCD28), and proliferation was measured after four days. Suppression of T cell proliferation in the co-cultures was dependent upon the dose of dietary n-3 PUFA fed to mice from which the T cells were derived, irrespective of the dietary treatment of accessory cell donors. The greatest dietary effect was seen in mice consuming the DHA diet (P = 0·034 in the anova; P = 0·0053 in the Trend Test), and was observed with direct stimulation of the T cell receptor and CD28 costimulatory ligand, but not with ConA. A significant dietary effect was also contributed accessory cells (P = 0·033 in the Trend Test). We conclude that dietary n-3 PUFA affect TcR-mediated by T cell activation by both direct and indirect (accessory cell) mechanisms. PMID:12296847

Perfluorooctanesulfonate (PFOS) Conversion from N-Ethyl-N-(2-hydroxyethyl)-perfluorooctanesulfonamide (EtFOSE) in male Sprague Dawley rats after inhalation exposure

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

Chang, Sue, E-mail: s.chang@mmm.com

Ethyl-N-(2-hydroxyethyl)-perfluorooctanesulfonamide (EtFOSE) was one of the key building blocks for many of the perfluorooctanesulfonyl-based chemistry and laboratory studies have shown that EtFOSE can metabolically degrade to perfluorooctanesulfonate (PFOS). Non-occupational contribution sources to PFOS are thought to occur in general population via diets, drinking water, air and dust. For workers, however, the exposure route was mostly airborne and the exposure source was predominantly to precursor compounds such as EtFOSE. We undertook this study to investigate how much EtFOSE was converted to PFOS in the serum for male rats after 6 h of exposure to EtFOSE vapor (whole body) at ambient temperature,more » which simulated a work place exposure scenario. There were no abnormal clinical observations and all rats gained weight during study. Interim tail-vein blood samples, collected up to 21 days after exposure, were analyzed for Et-FOSE and PFOS concentrations by LC-MS/MS. Upon inhalation exposure, the biotransformation of EtFOSE to PFOS in serum in the male rats was rapid and very little EtFOSE was detected in the serum within 24 h after EtFOSE exposure. The highest conversion to PFOS in serum after exposure to EtFOSE vapor appeared to occur between Day 8−14 post exposure. Considering the potential surface and fur adsorption of test compound in the whole-body exposure system, our data would support that at least 10% of the inhaled EtFOSE was biotransformed to PFOS in the serum based on the range of lower 95% CI (confidence interval) values. This information is valuable because it quantitatively translates EtFOSE exposure into serum PFOS concentration, which serves as a matrix for internal dosimetry (of PFOS exposure) that can be used as an anchor across species as well as between different exposure routes. - Highlights: • First inhalation study reported in rats that investigates the conversion of a major precursor compound (EtFOSE) to form PFOS. • Systemic

Murine models of H. pylori-induced gastritis and gastric adenocarcinoma.

PubMed

Krueger, Sabine; Roessner, Albert; Kuester, Doerthe

2011-10-15

Laboratory mice have become one of the best animal species for mechanistic studies in gastrointestinal research. Their abundant genetic information, the way of causing carcinogenesis easily by transgenic and gene knockout techniques, limited effort in time and costs, and their practicability provide advantages over other animal models. Meanwhile, several murine practical models have been established for the investigation of the initiation, expansion, and progression of gastritis and gastric carcinoma, for assessing the effects of bacterial, genetic and environmental factors, and for evaluating therapeutic and preventive strategies in gastric diseases. This article gives a review of murine models of gastritis and gastric cancer, placing emphasis on the models associated with Helicobacter pylori infection and techniques used in our laboratory. We discuss matters of murine gastric anatomy, as well as techniques of infection, tissue preparation, and histology. Copyright © 2011 Elsevier GmbH. All rights reserved.

Murine Endogenous Retroviruses Are Detectable in Patient-Derived Xenografts but Not in Patient-Individual Cell Lines of Human Colorectal Cancer.

PubMed

Bock, Stephanie; Mullins, Christina S; Klar, Ernst; Pérot, Philippe; Maletzki, Claudia; Linnebacher, Michael

2018-01-01

Endogenous retroviruses are remnants of retroviral infections. In contrast to their human counterparts, murine endogenous retroviruses (mERV) still can synthesize infectious particles and retrotranspose. Xenotransplanted human cells have occasionally been described to be mERV infected. With genetic engineered mice and patient-derived xenografts (PDXs) on the rise as eminent research tools, we here systematically investigated, if different tumor models harbor mERV infections. Relevant mERV candidates were first preselected by next generation sequencing (NGS) analysis of spontaneous lymphomas triggered by colorectal cancer (CRC) PDX tissue. Two primer systems were designed for each of these candidates (AblMLV, EcoMLV, EndoPP, MLV, and preXMRV) and implemented in an quantitative real-time (RT-qPCR) screen using murine tissues ( n = 11), PDX-tissues ( n = 22), PDX-derived cell lines ( n = 13), and patient-derived tumor cell lines ( n = 14). The expression levels of mERV varied largely both in the PDX samples and in the mouse tissues. No mERV signal was, however, obtained from cDNA or genomic DNA of CRC cell lines. Expression of EcoMLV was higher in PDX than in murine tissues; for EndoPP it was the opposite. These two were thus further investigated in 40 additional PDX. In addition, four patient-derived cell lines free of any mERV expression were subcutaneously injected into immunodeficient mice. Outgrowing cell-derived xenografts barely expressed EndoPP. In contrast, the expression of EcoMLV was even higher than in surrounding mouse tissues. This expression gradually vanished within few passages of re-cultivated cells. In summary, these results strongly imply that: (i) PDX and murine tissues in general are likely to be contaminated by mERV, (ii) mERV are expressed transiently and at low level in fresh PDX-derived cell cultures, and (iii) mERV integration into the genome of human cells is unlikely or at least a very rare event. Thus, mERVs are stowaways present in

Defects in N/Ge coimplanted GaN studied by positron annihilation

NASA Astrophysics Data System (ADS)

Nakano, Yoshitaka; Kachi, Tetsu

2002-01-01

We have applied positron annihilation spectroscopy to study the depth distributions and species of defects in N-, Ge-, and N/Ge-implanted GaN at dosages of 1×1015 cm-2. For all the implanted samples, Ga vacancies introduced by ion-implantation are found to diffuse into much deeper regions of the GaN layers during the implantation and to change into some other vacancy-type defects by the annealing at 1300 °C. In particular, markedly different defects turn out to be newly created in the electrically activated regions for both the Ge- and N/Ge-implanted samples after annealing, indicating that these new defects are probably associated with the presence of the implanted Ge dopant atoms.

The stability of N-[2-(4-o-fluorophenylpiperazin-1-yl)ethyl]-2,5-dimethyl-1 -phenylpyrrole-3,4-dicarboximide in aqueous-organic solutions.

PubMed

Zajac, Marianna; Sobczak, Agnieszka; Malinka, Wiesław; Redzicka, Aleksandra

2010-01-01

The first-order reaction of solvolysis of N-[2-(4-o-fluorophenylpiperazin-1-yl)ethyl]-2,5-dimethyl-1-phenylpyrrole-3,4-dicarboximide (PDI) was investigated as a function of pH at 333, 328, 323, 318 and 308 K in the pH range 1.11 - 12.78. The decomposition of PDI was followed by the HPLC method (Nucleosil 10-C8 column (250 x 4 mm I.D., dp = 10 microm), mobile phase: 0.018 mol/L ammonia acetate - acetonitrile (40: 60 v/v), UV detector: 240 nm, flow rate: 1 mL/min. Specific acid-base catalysis involves solvolysis of the undissociated molecules of PDI catalyzed by hydroxide ions and spontaneous solvolysis of the undissociated and monoprotonated forms of PDI under the influence of solvents. The thermodynamic parameters of the reactions--activation energy (E(a)), enthalpy (DH(#)), entropy (DS(#))--were calculated.

Model for large magnetoresistance effect in p–n junctions

NASA Astrophysics Data System (ADS)

Cao, Yang; Yang, Dezheng; Si, Mingsu; Shi, Huigang; Xue, Desheng

2018-06-01

We present a simple model based on the classic Shockley model to explain the magnetotransport in nonmagnetic p–n junctions. Under a magnetic field, the evaluation of the carrier to compensate Lorentz force establishes the necessary space-charge region distribution. The calculated current–voltage (I–V) characteristics under various magnetic fields demonstrate that the conventional nonmagnetic p–n junction can exhibit an extremely large magnetoresistance effect, which is even larger than that in magnetic materials. Because the large magnetoresistance effect that we discussed is based on the conventional p–n junction device, our model provides new insight into the development of semiconductor magnetoelectronics.

Immunotherapy of Alzheimer's disease (AD): from murine models to anti-amyloid beta (Abeta) human monoclonal antibodies.

PubMed

Geylis, Valeria; Steinitz, Michael

2006-01-01

The deposition of amyloid beta (Abeta) protein is a key pathological feature in Alzheimer's disease (AD). In murine models of AD, both active and passive immunization against Abeta induce a marked reduction in amyloid brain burden and an improvement in cognitive functions. Preliminary results of a prematurely terminated clinical trial where AD patients were actively vaccinated with aggregated Abeta bear resemblance to those documented in murine models. Passive immunization of AD patients with anti-Abeta antibodies, in particular human antibodies, is a strategy that provides a more cautious management and control of any undesired side effects. Sera of all healthy adults contain anti-Abeta IgG autoimmune antibodies. Hence antigen-committed human B-cells are easily immortalized by Epstein-Barr virus (EBV) into anti-Abeta secreting cell lines. Two anti-Abeta human monoclonal antibodies which we recently prepared bind to the N-terminus of Abeta peptide and were shown to stain amyloid plaques in non-fixed brain sections from an AD patient. It is anticipated that specifically selected anti-Abeta human monoclonal antibodies could reduce and inhibit deposits of amyloid in brain while avoiding the cognitive decline that characterizes AD. In the future, this type of antibody may prove to be a promising immune therapy for the disease.

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer.

PubMed

Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

2017-06-07

To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI ( P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites ( P = 0.009), liver metastasis ( P = 0.035), and decreased survival time ( P = 0.022). N-syndecan expression was significantly associated with tumor size ( P = 0.025), but not with survival time ( P = 0.539). High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer.

[Intravenous ethyl alcohol in metabolic resuscitation].

PubMed

Agolini, G; Lipartiti, T; Zaffiri, O; Musso, L; Belloni, G P

1980-11-01

Intravenously administered ethyl alcohol may be effective as analgesic and hypotensive peripheric vasoactive drug. In the Intensive Care Departments parenteral ethanol administration is infrequent because no "sure dosage" can be suggested in adults and children. Liver, kidney and C.N.S. diseases can worsen; foetopathy can follow. Drug-ethanol interaction may be particularly important for some patients admitted in Intensive Care Departments. Often the potential caloric support cannot be fully utilized ("empty" calories) and seldom hyperventilation, hyperlactacidemia and impaired protein synthesis can follow.

Acute and chronic in vivo effects of exposure to nicotine and propylene glycol from an E-cigarette on mucociliary clearance in a murine model.

PubMed

Laube, Beth L; Afshar-Mohajer, Nima; Koehler, Kirsten; Chen, Gang; Lazarus, Philip; Collaco, Joseph M; McGrath-Morrow, Sharon A

2017-04-01

To determine the effect of an acute (1 week) and chronic (3 weeks) exposure to E-cigarette (E-cig) emissions on mucociliary clearance (MCC) in murine lungs. C57BL/6 male mice (age 10.5 ± 2.4 weeks) were exposed for 20 min/day to E-cigarette aerosol generated by a Joyetech 510-T ® E-cig containing either 0% nicotine (N)/propylene glycol (PG) for 1 week (n = 6), or 3 weeks (n = 9), or 2.4% N/PG for one week (n = 6), or 3 weeks (n = 9), followed by measurement of MCC. Control mice (n = 15) were not exposed to PG alone, or N/PG. MCC was assessed by gamma camera following aspiration of 99m technetium aerosol and was expressed as the amount of radioactivity removed from both lungs over 6 hours (MCC6hrs). Venous blood was assayed for cotinine levels in control mice and in mice exposed for 3-weeks to PG alone and N/PG. MCC6hrs in control mice and in mice acutely exposed to PG alone and N/PG was similar, averaging (±1 standard deviation) 8.6 ± 5.2%, 7.5 ± 2.8% and 11.2 ± 5.9%, respectively. In contrast, chronic exposure to PG alone stimulated MCC6hrs (17.2 ± 8.0)% and this stimulation was significantly blunted following chronic exposure to N/PG (8.7 ± 4.6)% (p < .05). Serum cotinine levels were <0.5 ng/ml in control mice and in mice exposed to PG alone, whereas, N/PG exposed mice averaged 14.6 ± 12.0 ng/ml. In this murine model, a chronic, daily, 20 min-exposure to N/PG, but not an acute exposure, slowed MCC, compared to exposure to PG alone and led to systemic absorption of nicotine.

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

PubMed

Kulke, Matthew H; Hörsch, Dieter; Caplin, Martyn E; Anthony, Lowell B; Bergsland, Emily; Öberg, Kjell; Welin, Staffan; Warner, Richard R P; Lombard-Bohas, Catherine; Kunz, Pamela L; Grande, Enrique; Valle, Juan W; Fleming, Douglas; Lapuerta, Pablo; Banks, Phillip; Jackson, Shanna; Zambrowicz, Brian; Sands, Arthur T; Pavel, Marianne

2017-01-01

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

Ethyl 2-{N-[N-(4-chloro-6-methoxy­pyrimidin-2-yl)carbamo­yl]sulfamo­yl}benzoate

PubMed Central

Lu, Chui; Li, Fang-Shi; Yu, Da-Sheng; Yao, Wei; Liu, Yin-Hong

2008-01-01

The asymmetric unit of the title compound, C15H15ClN4O6S, contains two independent mol­ecules, in which the pyrimidine and benzene rings are oriented at dihedral angles of 75.21 (3) and 86.00 (3)°. Intra­molecular N—H⋯N and C—H⋯O hydrogen bonds result in the formation of two five- and two six-membered rings. The six-membered rings have flattened-boat conformations, while the five-membered rings adopt envelope conformations. In the crystal structure, inter­molecular N—H⋯O hydrogen bonds link the mol­ecules. PMID:21202882

Increased levels of the acetaldehyde-derived DNA adduct N 2-ethyldeoxyguanosine in oral mucosa DNA from Rhesus monkeys exposed to alcohol

PubMed Central

Balbo, Silvia; Juanes, Rita Cervera; Khariwala, Samir; Baker, Erich J.; Daunais, James B.; Grant, Kathleen A.

2016-01-01

Alcohol is a human carcinogen. A causal link has been established between alcohol drinking and cancers of the upper aerodigestive tract, colon, liver and breast. Despite this established association, the underlying mechanisms of alcohol-induced carcinogenesis remain unclear. Various mechanisms may come into play depending on the type of cancer; however, convincing evidence supports the concept that ethanol’s major metabolite acetaldehyde may play a major role. Acetaldehyde can react with DNA forming adducts which can serve as biomarkers of carcinogen exposure and potentially of cancer risk. The major DNA adduct formed from this reaction is N 2-ethylidenedeoxyguanosine, which can be quantified as its reduced form N 2-ethyl-dG by LC-ESI-MS/MS. To investigate the potential use of N 2-ethyl-dG as a biomarker of alcohol-induced DNA damage, we quantified this adduct in DNA from the oral, oesophageal and mammary gland tissues from rhesus monkeys exposed to alcohol drinking over their lifetimes and compared it to controls. N 2-Ethyl-dG levels were significantly higher in the oral mucosa DNA of the exposed animals. Levels of the DNA adduct measured in the oesophageal mucosa of exposed animals were not significantly different from controls. A correlation between the levels measured in the oral and oesophageal DNA, however, was observed, suggesting a common source of formation of the DNA adducts. N 2-Ethyl-dG was measured in mammary gland DNA from a small cohort of female animals, but no difference was observed between exposed animals and controls. These results support the hypothesis that acetaldehyde induces DNA damage in the oral mucosa of alcohol-exposed animals and that it may play role in the alcohol-induced carcinogenic process. The decrease of N 2-ethyl-dG levels in exposed tissues further removed from the mouth also suggests a role of alcohol metabolism in the oral cavity, which may be considered separately from ethanol liver metabolism in the investigation of

Searching for trans ethyl methyl ether in Orion KL★,★★

PubMed Central

Tercero, B.; Cernicharo, J.; López, A.; Brouillet, N.; Kolesniková, L.; Motiyenko, R. A.; Margulès, L.; Alonso, J. L.; Guillemin, J.-C.

2015-01-01

We report on the tentative detection of trans ethyl methyl ether (tEME), t-CH3CH2OCH3, through the identification of a large number of rotational lines from each one of the spin states of the molecule towards Orion KL. We also search for gauche-trans-n-propanol, Gt-n-CH3CH2CH2OH, an isomer of tEME in the same source. We have identified lines of both species in the IRAM 30 m line survey and in the ALMA Science Verification data. We have obtained ALMA maps to establish the spatial distribution of these species. Whereas tEME mainly arises from the compact ridge component of Orion, Gt-n-propanol appears at the emission peak of ethanol (south hot core). The derived column densities of these species at the location of their emission peaks are ≤(4.0 ± 0.8) × 1015 cm−2 and ≤(1.0 ± 0.2)× 1015 cm−2 for tEME and Gt-n-propanol, respectively. The rotational temperature is ~100 K for both molecules. We also provide maps of CH3OCOH, CH3CH2OCOH, CH3OCH3, CH3OH, and CH3CH2OH to compare the distribution of these organic saturated O-bearing species containing methyl and ethyl groups in this region. Abundance ratios of related species and upper limits to the abundances of non-detected ethers are provided. We derive an abundance ratio N(CH3OCH3)/N(tEME) ≥ 150 in the compact ridge of Orion. PMID:26869726

Regulation of c- and N-myc expression during induced differentiation of murine neuroblastoma cells.

PubMed

Larcher, J C; Vayssière, J L; Lossouarn, L; Gros, F; Croizat, B

1991-04-01

Using clones N1E-115 and N1A-103 from mouse neuroblastoma C1300, a comparative analysis of c- and N-myc gene expression was undertaken both in proliferating cells and in cultures exposed to conditions which induce differentiation. Under the latter conditions, while N1E-115 cells extend abundant neurites and express many biochemical features of mature neurons, clone N1A-103 stops dividing and expresses certain neurospecific markers but is unable to differentiate morphologically. In both clones, chemical agents, i.e. 1-methyl cyclohexane carboxylic acid (CCA) or dimethyl sulfoxide (DMSO), induce a decrease in c-myc expression. Similar results were found for N-myc gene in N1E-115 cells, but in contrast, in clone N1A-103, N-myc expression is increased with CCA and not modified with DMSO. Globally, this study favours the hypothesis that changes in c-myc expression would correspond to cell division blockade and differentiation, while modulations in N-myc are more closely related to an early phase of terminal differentiation.

Proline-linked nitrosoureas as prolidase-convertible prodrugs in human breast cancer cells.

PubMed

Bielawski, Krzysztof; Bielawska, Anna; Słodownik, Tomasz; Bołkun-Skórnicka, Urszula; Muszyńska, Anna

2008-01-01

A number of novel proline-linked nitrosoureas (1-4) were synthesized and examined for cytotoxicity and influence on DNA and collagen biosynthesis in MDA-MB-231 and MCF-7 human breast cancer cells. Evaluation of the cytotoxicity of these compounds employing a MTT assay and inhibition of [(3)H]thymidine incorporation into DNA in both MDA-MB-231 and MCF-7 breast cancer cells demonstrated that compound 2, the most active of the series, proved to be only slightly less potent than carmustine. It has also been found that carmustine did not inhibit MCF&-7 cells prolidase activity, while compounds 1-4 significantly increased its activity, when used at 50-250 microM concentrations. Proline-linked nitrosoureas (1-4) also had lower ability to inhibit collagen biosynthesis in MCF-7 cells, compared to carmustine. The expression of beta(1)-integrin receptor and phosphorylated MAPK, ERK(1) and ERK(2) was significantly decreased in MCF-7 cells incubated for 24 h with 60 microM of compounds 2 and 4 compared to the control, untreated cells, whereas under the same conditions carmustine did not evoke any changes in expression of all these signaling proteins, as shown by Western immunoblot analysis. These results indicate the proline-linked nitrosoureas (1-4), represent multifunctional inhibitors of breast cancer cell growth and metabolism.

Ab initio modeling of zincblende AlN layer in Al-AlN-TiN multilayers

DOE PAGES

Yadav, S. K.; Wang, J.; Liu, X. -Y.

2016-06-13

An unusual growth mechanism of metastable zincblende AlN thin film by diffusion of nitrogen atoms into Al lattice is established. Using first-principles density functional theory, we studied the possibility of thermodynamic stability of AlN as a zincblende phase due to epitaxial strains and interface effect, which fails to explain the formation of zincblende AlN. We then compared the formation energetics of rocksalt and zincblende AlN in fcc Al through direct diffusion of nitrogen atoms to Al octahedral and tetrahedral interstitials. Furthermore, the formation of a zincblende AlN thin film is determined to be a kinetically driven process, not a thermodynamicallymore » driven process.« less

Alternative chemotherapeutic agents: nitrosoureas, cisplatin, irinotecan.

PubMed

Carrillo, Jose A; Munoz, Claudia A

2012-04-01

Irinotecan, cisplatin, and nitrosoureas have a long history of use in brain tumors, with demonstrated efficacy in the adjuvant treatment of malignant gliomas. In the era of temozolomide with concurrent radiotherapy given as the standard of care, their use has shifted to treatment at progression or recurrence. Now with the widespread use of bevacizumab in the recurrent setting, irinotecan and other chemotherapies are seeing increased use in combination with bevacizumab and alone in the recurrent setting. The activity of these chemotherapeutic agents in brain tumors will likely ensure a place in the armamentarium of neuro-oncologists for many years. Published by Elsevier Inc.

T2N as a new tool for robust electrophysiological modeling demonstrated for mature and adult-born dentate granule cells

PubMed Central

Mongiat, Lucas Alberto; Schwarzacher, Stephan Wolfgang

2017-01-01

Compartmental models are the theoretical tool of choice for understanding single neuron computations. However, many models are incomplete, built ad hoc and require tuning for each novel condition rendering them of limited usability. Here, we present T2N, a powerful interface to control NEURON with Matlab and TREES toolbox, which supports generating models stable over a broad range of reconstructed and synthetic morphologies. We illustrate this for a novel, highly detailed active model of dentate granule cells (GCs) replicating a wide palette of experiments from various labs. By implementing known differences in ion channel composition and morphology, our model reproduces data from mouse or rat, mature or adult-born GCs as well as pharmacological interventions and epileptic conditions. This work sets a new benchmark for detailed compartmental modeling. T2N is suitable for creating robust models useful for large-scale networks that could lead to novel predictions. We discuss possible T2N application in degeneracy studies. PMID:29165247

Novel antiprotozoal products: imidazole and benzimidazole N-oxide derivatives and related compounds.

PubMed

Aguirre, Gabriela; Boiani, Mariana; Cerecetto, Hugo; Gerpe, Alejandra; González, Mercedes; Sainz, Yolanda Fernández; Denicola, Ana; De Ocáriz, Carmen Ochoa; Nogal, Juan José; Montero, David; Escario, José Antonio

2004-05-01

The syntheses and biological evaluation of the first anti-protozoa imidazole N-oxide and benzimidazole N-oxide and their derivatives are reported. They were tested in vitro against two different protozoa, Trypanosoma cruzi and Trichomonas vaginalis. Derivative 7c, ethyl-1-(i-butyloxycarbonyloxy)-6-nitrobenzimid-azole-2-carboxylate, displayed activity on both protozoa. Lipophilicity and redox potential were experimentally determined in order to study the relationship with activity of the compounds. These properties are well related with the observed bioactivity. Imidazole and benzimidazole N-oxide derivatives are becoming leaders for further chemical modifications and advanced biological studies.

New, simplified, interpolation method for estimation of microscopic nuclear masses based on the p-factor, P = N/sub P/N/sub N//(N/sub p/+N/sub n/)

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

Haustein, P.E.; Brenner, D.S.; Casten, R.F.

1987-12-10

A new semi-empirical method, based on the use of the P-factor (P = N/sub p/N/sub n//(N/sub p/+N/sub n/)), is shown to simplify significantly the systematics of atomic masses. Its uses is illustrated for actinide nuclei where complicated patterns of mass systematics seen in traditional plots versus Z, N, or isospin are consolidated and transformed into linear ones extending over long isotopic and isotonic sequences. The linearization of the systematics by this procedure provides a simple basis for mass prediction. For many unmeasured nuclei beyond the known mass surface, the P-factor method operates by interpolation among data for known nuclei rathermore » than by extrapolation, as is common in other mass models.« less

Hepatocyte Transplantation Improves Phenotype and Extends Survival in a Murine Model of Intermediate Maple Syrup Urine Disease

PubMed Central

Skvorak, Kristen J; Paul, Harbhajan S; Dorko, Kenneth; Marongiu, Fabio; Ellis, Ewa; Chace, Donald; Ferguson, Carolyn; Gibson, K Michael; Homanics, Gregg E; Strom, Stephen C

2009-01-01

Maple syrup urine disease (MSUD; OMIM 248600) is an inborn error of metabolism of the branched chain α-ketoacid dehydrogenase (BCKDH) complex that is treated primarily by dietary manipulation of branched-chain amino acids (BCAA). Dietary restriction is lifelong and compliance is difficult. Liver transplantation significantly improves outcomes; however, alternative therapies are needed. To test novel therapies such as hepatocyte transplantation (HTx), we previously created a murine model of intermediate MSUD (iMSUD), which closely mimics human iMSUD. LacZ-positive murine donor hepatocytes were harvested and directly injected (105 cells/50 µl) into liver of iMSUD mice (two injections at 1–10 days of age). Donor hepatocytes engrafted into iMSUD recipient liver, increased liver BCKDH activity, improved blood total BCAA/alanine ratio, increased body weight at weaning, and extended the lifespan of HTx-treated iMSUD mice compared to phosphate-buffered saline (PBS)–treated and untreated iMSUD mice. Based on these data demonstrating partial metabolic correction of iMSUD in a murine model, coupled to the fact that multiple transplants are possible to enhance these results, we suggest that HTx represents a promising therapeutic intervention for MSUD that warrants further investigation. PMID:19436271

TRO40303 Ameliorates Alcohol-Induced Pancreatitis Through Reduction of Fatty Acid Ethyl Ester–Induced Mitochondrial Injury and Necrotic Cell Death

PubMed Central

Javed, Muhammad Ahsan; Wen, Li; Awais, Muhammad; Latawiec, Diane; Huang, Wei; Chvanov, Michael; Schaller, Sophie; Bordet, Thierry; Michaud, Magali; Pruss, Rebecca; Tepikin, Alexei; Criddle, David; Sutton, Robert

2018-01-01

Objectives Mitochondrial permeability transition pore inhibition is a promising approach to treat acute pancreatitis (AP). We sought to determine (i) the effects of the mitochondrial permeability transition pore inhibitor 3,5-seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) on murine and human pancreatic acinar cell (PAC) injury induced by fatty acid ethyl esters (FAEEs) or taurolithocholic acid-3-sulfate and (ii) TRO40303 pharmacokinetics and efficacy in experimental alcoholic AP (FAEE-AP). Methods Changes in mitochondrial membrane potential (Δψm), cytosolic Ca2+ ([Ca2+]c), and cell fate were examined in freshly isolated murine or human PACs by confocal microscopy. TRO40303 pharmacokinetics were assessed in cerulein-induced AP and therapeutic efficacy in FAEE-AP induced with palmitoleic acid and ethanol. Severity of AP was assessed by standard biomarkers and blinded histopathology. Results TRO40303 prevented loss of Δψm and necrosis induced by 100 μM palmitoleic acid ethyl ester or 500 μM taurolithocholic acid-3-sulfate in murine and human PACs. Pharmacokinetic analysis found TRO40303 accumulated in the pancreas. A single dose of 3 mg/kg TRO40303 significantly reduced serum amylase (P = 0.043), pancreatic trypsin (P = 0.018), and histopathology scores (P = 0.0058) in FAEE-AP. Conclusions TRO40303 protects mitochondria and prevents necrotic cell death pathway activation in murine and human PACs, ameliorates the severity of FAEE-AP, and is a candidate drug for human AP. PMID:29200128

Performance analysis of junction-less double Gate n-p-n impact ionization MOS transistor (JLDG n-IMOS)

NASA Astrophysics Data System (ADS)

Chauhan, Manvendra Singh; Chauhan, R. K.

2018-04-01

This paper demonstrates a Junction-less Double Gate n-p-n Impact ionization MOS transistor (JLDG n-IMOS) on a very light doped p-type silicon body. Device structure proposed in the paper is based on charge plasma concept. There is no metallurgical junctions in the proposed device and does not need any impurity doping to create the drain and source regions. Due to doping-less nature, the fabrication process is simple for JLDG n-IMOS. The double gate engineering in proposed device leads to reduction in avalanche breakdown via impact ionization, generating large number of carriers in drain-body junction, resulting high ION current, small IOFF current and great improvement in ION/IOFF ratio. The simulation and examination of the proposed device have been performed on ATLAS device simulatorsoftware.

Murine models of breast cancer bone metastasis

PubMed Central

Wright, Laura E; Ottewell, Penelope D; Rucci, Nadia; Peyruchaud, Olivier; Pagnotti, Gabriel M; Chiechi, Antonella; Buijs, Jeroen T; Sterling, Julie A

2016-01-01

Bone metastases cause significant morbidity and mortality in late-stage breast cancer patients and are currently considered incurable. Investigators rely on translational models to better understand the pathogenesis of skeletal complications of malignancy in order to identify therapeutic targets that may ultimately prevent and treat solid tumor metastasis to bone. Many experimental models of breast cancer bone metastases are in use today, each with its own caveats. In this methods review, we characterize the bone phenotype of commonly utilized human- and murine-derived breast cell lines that elicit osteoblastic and/or osteolytic destruction of bone in mice and report methods for optimizing tumor-take in murine models of bone metastasis. We then provide protocols for four of the most common xenograft and syngeneic inoculation routes for modeling breast cancer metastasis to the skeleton in mice, including the intra-cardiac, intra-arterial, orthotopic and intra-tibial methods of tumor cell injection. Recommendations for in vivo and ex vivo assessment of tumor progression and bone destruction are provided, followed by discussion of the strengths and limitations of the available tools and translational models that aid investigators in the study of breast cancer metastasis to bone. PMID:27867497

Uncertainties in United States agricultural N2O emissions: comparing forward model simulations to atmospheric N2O data.

NASA Astrophysics Data System (ADS)

Nevison, C. D.; Saikawa, E.; Dlugokencky, E. J.; Andrews, A. E.; Sweeney, C.

2014-12-01

Atmospheric N2O concentrations have increased from 275 ppb in the preindustrial to about 325 ppb in recent years, a ~20% increase with important implications for both anthropogenic greenhouse forcing and stratospheric ozone recovery. This increase has been driven largely by synthetic fertilizer production and other perturbations to the global nitrogen cycle associated with human agriculture. Several recent regional atmospheric inversion studies have quantified North American agricultural N2O emissions using top-down constraints based on atmospheric N2O data from the National Oceanic and Atmospheric Administration (NOAA) Global Greenhouse Gas Reference Network, including surface, aircraft and tall tower platforms. These studies have concluded that global N2O inventories such as EDGAR may be underestimating the true U.S. anthropogenic N2O source by a factor of 3 or more. However, simple back-of-the-envelope calculations show that emissions of this magnitude are difficult to reconcile with the basic constraints of the global N2O budget. Here, we explore some possible reasons why regional atmospheric inversions might overestimate the U.S. agricultural N2O source. First, the seasonality of N2O agricultural sources is not well known, but can have an important influence on inversion results, particularly when the inversions are based on data that are concentrated in the spring/summer growing season. Second, boundary conditions can strongly influence regional inversions but the boundary conditions used may not adequately account for remote influences on surface data such as the seasonal stratospheric influx of N2O-depleted air. We will present a set of forward model simulations, using the Community Land Model (CLM) and two atmospheric chemistry tracer transport models, MOZART and the Whole Atmosphere Community Climate Model (WACCM), that examine the influence of terrestrial emissions and atmospheric chemistry and dynamics on atmospheric variability in N2O at U.S. and

Design, synthesis, radiolabeling and in vivo evaluation of carbon-11 labeled N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide, a potential Positron Emission Tomography tracer for the dopamine D4 receptors

PubMed Central

Lacivita, Enza; De Giorgio, Paola; Lee, Irene T.; Rodeheaver, Sean I.; Weiss, Bryan A.; Fracasso, Claudia; Caccia, Silvio; Berardi, Francesco; Perrone, Roberto; Zhang, Ming-Rong; Maeda, Jun; Higuchi, Makoto; Suhara, Tetsuya; Schetz, John A.; Leopoldo, Marcello

2010-01-01

Here we describe the design, synthesis, physicochemical, and pharmacological evaluation of D4 dopamine receptor ligands related to N-[2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl]-3-methoxybenzamide (2). Structural features were incorporated to increase affinity for the target receptor, to improve selectivity over D2 and sigma1 receptors, to enable labeling with carbon-11 or fluorine-18, and to adjust lipophilicity within the range considered optimal for brain penetration and low nonspecific binding. Compounds 7 and 13 showed the overall best characteristics: nanomolar affinity for the D4 receptor, > 100-fold selectivity over D2 and D3 dopamine receptor 5-HT1A, 5-HT2A and 5-HT2C serotonin receptors and sigma1 receptors, and logP = 2.37–2.55. Following intraperitoneal administration, both compounds rapidly entered the central nervous system. The methoxy of N-[2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl]-3-methoxybenzamide (7) was radiolabelled with carbon-11 and subjected to PET analysis in non-human primate. [11C]7 time-dependently accumulated to saturation in the posterior eye in the region of the retina, a tissue containing a high density of D4 receptors. PMID:20873719

N-mix for fish: estimating riverine salmonid habitat selection via N-mixture models

USGS Publications Warehouse

Som, Nicholas A.; Perry, Russell W.; Jones, Edward C.; De Juilio, Kyle; Petros, Paul; Pinnix, William D.; Rupert, Derek L.

2018-01-01

Models that formulate mathematical linkages between fish use and habitat characteristics are applied for many purposes. For riverine fish, these linkages are often cast as resource selection functions with variables including depth and velocity of water and distance to nearest cover. Ecologists are now recognizing the role that detection plays in observing organisms, and failure to account for imperfect detection can lead to spurious inference. Herein, we present a flexible N-mixture model to associate habitat characteristics with the abundance of riverine salmonids that simultaneously estimates detection probability. Our formulation has the added benefits of accounting for demographics variation and can generate probabilistic statements regarding intensity of habitat use. In addition to the conceptual benefits, model application to data from the Trinity River, California, yields interesting results. Detection was estimated to vary among surveyors, but there was little spatial or temporal variation. Additionally, a weaker effect of water depth on resource selection is estimated than that reported by previous studies not accounting for detection probability. N-mixture models show great promise for applications to riverine resource selection.

Mutagenicity of streptozotocin and several other nitrosourea compounds in Salmonella typhimurium.

PubMed

Zimmer, D M; Bhuyan, B K

1976-11-01

The following nitrosourea compounds were compared for their ability to induce mutation (to histidine independence) in the histidine-requiring auxotroph Salmonella typhimurium his G46: MNU, streptozotocin (SZ, streptozocin) and its analogs SZA1 and SZA2, and the antitumor drugs BCNU, CCNU and DCNU. At equitoxic doses SZ, SZA1, SZA2 and MNU were almost equally mutagenic causing 150, 42, 140 and 170 mutants/106 survivors at 20% lethal dose (ID20) ALTHOUGH, ON A WIEGHT BASIS, SZ was the most mutagenic of all the compounds tested. At ID20 BCNU, CCNU and DCNU gave about 0.5 mutants/106 survivors. Our results show that these nitrosoureas, in common with many other drugs (such as cyclophosphamide, daunomycin, etc.) used in cancer chemotherapy, are highly mutagenic. The implication of our results in the screening of drugs for their mutagenicity to man is discussed.

On the effect of N-GaN/P-GaN/N-GaN/P-GaN/N-GaN built-in junctions in the n-GaN layer for InGaN/GaN light-emitting diodes.

PubMed

Kyaw, Zabu; Zhang, Zi-Hui; Liu, Wei; Tan, Swee Tiam; Ju, Zhen Gang; Zhang, Xue Liang; Ji, Yun; Hasanov, Namig; Zhu, Binbin; Lu, Shunpeng; Zhang, Yiping; Sun, Xiao Wei; Demir, Hilmi Volkan

2014-01-13

N-GaN/P-GaN/N-GaN/P-GaN/N-GaN (NPNPN-GaN) junctions embedded between the n-GaN region and multiple quantum wells (MQWs) are systematically studied both experimentally and theoretically to increase the performance of InGaN/GaN light emitting diodes (LEDs) in this work. In the proposed architecture, each thin P-GaN layer sandwiched in the NPNPN-GaN structure is completely depleted due to the built-in electric field in the NPNPN-GaN junctions, and the ionized acceptors in these P-GaN layers serve as the energy barriers for electrons from the n-GaN region, resulting in a reduced electron over flow and enhanced the current spreading horizontally in the n- GaN region. These lead to increased optical output power and external quantum efficiency (EQE) from the proposed device.

Surface topography of silicon nitride affects antimicrobial and osseointegrative properties of tibial implants in a murine model.

PubMed

Ishikawa, Masahiro; de Mesy Bentley, Karen L; McEntire, Bryan J; Bal, B Sonny; Schwarz, Edward M; Xie, Chao

2017-12-01

While silicon nitride (Si 3 N 4 ) is an antimicrobial and osseointegrative orthopaedic biomaterial, the contribution of surface topography to these properties is unknown. Using a methicillin-resistant strain of Staphylococcus aureus (MRSA), this study evaluated Si 3 N 4 implants in vitro utilizing scanning electron microscopy (SEM) with colony forming unit (CFU) assays, and later in an established in vivo murine tibia model of implant-associated osteomyelitis. In vitro, the "as-fired" Si 3 N 4 implants displayed significant reductions in adherent bacteria versus machined Si 3 N 4 (2.6 × 10 4 vs. 8.7 × 10 4 CFU, respectively; p < 0.0002). Moreover, SEM imaging demonstrated that MRSA cannot directly adhere to native as-fired Si 3 N 4 . Subsequently, a cross-sectional study was completed in which sterile or MRSA contaminated as-fired and machined Si 3 N 4 implants were inserted into the tibiae of 8-week old female Balb/c mice, and harvested on day 1, 3, 5, 7, 10, or 14 post-operatively for SEM. The findings demonstrated that the antimicrobial activity of the as-fired implants resulted from macrophage clearance of the bacteria during biofilm formation on day 1, followed by osseointegration through the apparent recruitment of mesenchymal stem cells on days 3-5, which differentiated into osteoblasts on days 7-14. In contrast, the antimicrobial behavior of the machined Si 3 N 4 was due to repulsion of the bacteria, a phenomenon that also limited osteogenesis, as host cells were also unable to adhere to the machined surface. Taken together, these results suggest that the in vivo biological behavior of Si 3 N 4 orthopaedic implants is driven by critical features of their surface nanotopography. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 3413-3421, 2017. © 2017 Wiley Periodicals, Inc.

Synthesis of some N-substituted indole derivatives and their biological activities.

PubMed

el-Diwani, H; Nakkady, S S; Hishmat, O H; el-Shabrawy, O A; Mahmoud, S S

1992-03-01

Acylation of 2,3-diphenyl-5-methoxy-indole using ethyl chloroformate or chloroacetyl chloride in dimethylformamide and sodium hydride yielded the N-substituted derivatives 1 and 2, respectively. While Friedel-Crafts acylation using chloroacetyl chloride afforded di-4,6-chloroacetyl derivative 3, the reaction of the N-chloroacetyl derivative 2 with amines, hydrazines, urea, semicarbazide hydrochloride, thiophenol, benzimidazole-2-thiol, thiosemicarbazide, 2-mercaptoethanol and thioglycolic acid was studied. Several of the compounds were tested for their effect on arterial blood pressure, antiinflammatory and ulcerogenic activities.

Electric dipole moment of the deuteron in the standard model with NN - ΛN - ΣN coupling

NASA Astrophysics Data System (ADS)

Yamanaka, Nodoka

2017-07-01

We calculate the electric dipole moment (EDM) of the deuteron in the standard model with | ΔS | = 1 interactions by taking into account the NN - ΛN - ΣN channel coupling, which is an important nuclear level systematics. The two-body problem is solved with the Gaussian Expansion Method using the realistic Argonne v18 nuclear force and the YN potential which can reproduce the binding energies of Λ3H, Λ3He, and Λ4He. The | ΔS | = 1 interbaryon potential is modeled by the one-meson exchange process. It is found that the deuteron EDM is modified by less than 10%, and the main contribution to this deviation is due to the polarization of the hyperon-nucleon channels. The effect of the YN interaction is small, and treating ΛN and ΣN channels as free is a good approximation for the EDM of the deuteron.

Pleiotrophin and N-syndecan promote perineural invasion and tumor progression in an orthotopic mouse model of pancreatic cancer

PubMed Central

Yao, Jun; Zhang, Lu-Lin; Huang, Xu-Mei; Li, Wen-Yao; Gao, She-Gan

2017-01-01

AIM To detect the expression of pleiotrophin (PTN) and N-syndecan in pancreatic cancer and analyze their association with tumor progression and perineural invasion (PNI). METHODS An orthotopic mouse model of pancreatic cancer was created by injecting tumor cells subcapsularly in a root region of the pancreas beneath the spleen. Pancreatic cancer tissues were taken from 36 mice that survived for more than 90 d. PTN and N-syndecan proteins were detected by immunohistochemistry and analyzed for their correlation with pathological features, PNI, and prognosis. RESULTS The expression rates of PTN and N-syndecan proteins were 66.7% and 61.1%, respectively, in cancer tissue. PTN and N-syndecan expression was associated with PNI (P = 0.019 and P = 0.032, respectively). High PTN expression was closely associated with large bloody ascites (P = 0.009), liver metastasis (P = 0.035), and decreased survival time (P = 0.022). N-syndecan expression was significantly associated with tumor size (P = 0.025), but not with survival time (P = 0.539). CONCLUSION High PTN and N-syndecan expression was closely associated with metastasis and poor prognosis, suggesting that they may promote tumor progression and PNI in the orthotopic mouse model of pancreatic cancer. PMID:28638231

Studies on the inhibition of Moloney murine leukemia virus reverse transcriptase by N-tritylamino acids and N-tritylamino acid-nucleotide compounds.

PubMed

Hawtrey, Arthur; Pieterse, Anton; van Zyl, Johann; Van der Bijl, Pieter; Van der Merwe, Marichen; Nel, William; Ariatti, Mario

2008-09-01

N-Acylated derivatives of 8-(6-aminohexyl) amino-adenosine-5 '-phosphate were prepared and studied with regard to their effect on DNA synthesis by the Moloney leukemia virus reverse transcriptase. N-palmitoyl and N-nicotinyl derivatives and bis-8-(6-aminohexyl) amino-5'-AMP inhibited the enzyme partially using poly (rA).oligo d(pT)(16-18) as template-primer with [(3)H]dTTP. In order to increase hydrophobicity in the acyl component tethered to the 8-(6-aminohexyl) amino group on the adenine nucleotide, N-trityl-L-phenylalanine and the N-trityl derivatives of the o, m, and p-fluoro-DL-phenylalanine were initially examined for inhibition of the enzyme using the above template-primer system. The compounds all inhibited the reverse transcriptase with IC(50) values of approximately 60-80 microM. However, when N-trityl-m-fluoro-DL-phenylalanine was coupled to the nucleotide 8-(6-aminohexyl) amino-adenosine-5'-phosphate, the inhibitory activity of this compound increased significantly (IC(50) = 5 microM).

Equivalence of the O( n) vector ferromagnetic and antiferromagnetic models

NASA Astrophysics Data System (ADS)

Sousa, J. Ricardo de

The effective-field renormalization group (EFRG) approach is used to find the Néel temperature ( TN) of the O( n) vector model with antiferromagnetic (AF) interaction. The EFRG method is illustrated by employing approximations in which clusters with one ( N‧=1) and two ( N=2) spins are used. The critical temperature TN is obtained as a function of component ( n) and coordination ( z) numbers. For all values of n and z we show that TN= Tc, where Tc is the Curie temperature for the ferromagnetic (F) case. As a comparison, the results of the quantum Heisenberg model ( n=3) with F and AF interactions are also presented, and we find that TN> Tc, which is different from the classical result Tc= TN.

The electron transport mechanism in ester and its influence on bioactivity in the anticancer drug N-(6-ferrocenyl-2-naphthoyl)-L-alanine-glycine ethyl ester(FNLAGEE)

NASA Astrophysics Data System (ADS)

Sudhi, Geethu; Rajina, S. R.; Praveen, S. G.; Xavier, T. S.; Kenny, Peter T. M.; Binoy, J.

2018-05-01

The reactivity of ester group plays key role in inducing bioactivity of many ferrocenyl biconjugated compounds. The ester reactivity can be explained, based on electron transport mechanism using vibrational spectroscopy, aided by DFT simulation. The FT IR and FT Raman spectral measurements have been carried out for N-(6-ferrocenyl-2-naphthoyl)-L-alanine-glycine ethyl ester (FNLAGEE) and the optimized geometry and vibrational spectra have been computed using DFT method, at B3LYP/LANL2DZ level of theory. The cis conformation of ester and electron transport mechanism, thus analyzed, has been correlated to the geometry and the spectral characteristics of ester. To investigate the bioactivity and binding interactions of the molecule, molecular docking simulations and UV-Vis absorption studies of FNLAGEE with BSA and DNA has been performed.

Aspect Ratio Model for Radiation-Tolerant Dummy Gate-Assisted n-MOSFET Layout.

PubMed

Lee, Min Su; Lee, Hee Chul

2014-01-01

In order to acquire radiation-tolerant characteristics in integrated circuits, a dummy gate-assisted n-type metal oxide semiconductor field effect transistor (DGA n-MOSFET) layout was adopted. The DGA n-MOSFET has a different channel shape compared with the standard n-MOSFET. The standard n-MOSFET has a rectangular channel shape, whereas the DGA n-MOSFET has an extended rectangular shape at the edge of the source and drain, which affects its aspect ratio. In order to increase its practical use, a new aspect ratio model is proposed for the DGA n-MOSFET and this model is evaluated through three-dimensional simulations and measurements of the fabricated devices. The proposed aspect ratio model for the DGA n-MOSFET exhibits good agreement with the simulation and measurement results.

Aspect Ratio Model for Radiation-Tolerant Dummy Gate-Assisted n-MOSFET Layout

PubMed Central

Lee, Min Su; Lee, Hee Chul

2014-01-01

In order to acquire radiation-tolerant characteristics in integrated circuits, a dummy gate-assisted n-type metal oxide semiconductor field effect transistor (DGA n-MOSFET) layout was adopted. The DGA n-MOSFET has a different channel shape compared with the standard n-MOSFET. The standard n-MOSFET has a rectangular channel shape, whereas the DGA n-MOSFET has an extended rectangular shape at the edge of the source and drain, which affects its aspect ratio. In order to increase its practical use, a new aspect ratio model is proposed for the DGA n-MOSFET and this model is evaluated through three-dimensional simulations and measurements of the fabricated devices. The proposed aspect ratio model for the DGA n-MOSFET exhibits good agreement with the simulation and measurement results. PMID:27350975

Crystal structure of azilsartan methyl ester ethyl acetate hemisolvate.

PubMed

Li, Zhengyi; Liu, Rong; Zhu, Meilan; Chen, Liang; Sun, Xiaoqiang

2015-02-01

The title compound, C26H22N4O5 (systematic name: methyl 2-eth-oxy-1-{4-[2-(5-oxo-4,5-di-hydro-1,2,4-oxa-diazol-3-yl)phenyl]benz-yl}-1H-1,3-benzo-diazole-7-carboxyl-ate ethyl acetate hemisolvate), was obtained via cyclization of methyl (Z)-2-eth-oxy-1-{(2'-(N'-hy-droxy-carbamimido-yl)-[1,1'-biphen-yl]-4-yl)meth-yl}-1H-benzo[d]imidazole-7-carboxyl-ate with diphen-yl carbonate. There are two independent mol-ecules (A and B) with different conformations and an ethyl acetate solvent mol-ecule in the asymmetric unit. In mol-ecule A, the dihedral angle between the benzene ring and its attached oxa-diazole ring is 59.36 (17); the dihedral angle between the benzene rings is 43.89 (15) and that between the benzene ring and its attached imidazole ring system is 80.06 (11)°. The corres-ponding dihedral angles in mol-ecule B are 58.45 (18), 50.73 (16) and 85.37 (10)°, respectively. The C-O-C-Cm (m = meth-yl) torsion angles for the eth-oxy side chains attached to the imidazole rings in mol-ecules A and B are 93.9 (3) and -174.6 (3)°, respectively. In the crystal, the components are linked by N-H⋯N and C-H⋯O hydrogen bonds, generating a three-dimensional network. Aromatic π-π stacking inter-actions [shortest centroid-centroid separation = 3.536 (3)Å] are also observed.

Quantitation of N-ethyl-3,4-methylenedioxyamphetamine and its major metabolites in human plasma by high-performance liquid chromatography and fluorescence detection.

PubMed

Brunnenberg, M; Lindenblatt, H; Gouzoulis-Mayfrank, E; Kovar, K A

1998-11-20

A HPLC method has been developed for the analogue of Ecstasy MDE and its major metabolites N-ethyl-4-hydroxy-3-methoxyamphetamine (HME) and 3,4-methylenedioxyamphetamine (MDA) in human plasma. In the course of our investigations we found that the methylenedioxyamphetamines and HME exhibit fluorescence at 322 nm. Therefore the detection could be carried out with a fluorescence (FL) detector. Solid-phase extraction was used for sample preparation and yielded high recovery rates greater than 95%. The limit of quantitation for MDE and its metabolites in the extracts was between 1.5 and 8.9 ng/ml and the method standard deviations were less than 5%. This sensitive, rapid and reliable analytical method has been used successfully in the quantitation of the substances in plasma samples obtained from 14 volunteers in two clinical studies after p.o. administration of 100 to 140 mg MDE*HCI. The maximum plasma concentrations were 235-465 ng/ml (MDE), 67-673 ng/ml (HME) and 7-33 ng/ml (MDA), respectively. Pharmacokinetic parameters have been investigated using the plasma concentration curves.

Antigenotoxic effects of Citrus aurentium L. fruit peel oil on mutagenicity of two alkylating agents and two metals in the Drosophila wing spot test.

PubMed

Demir, Eşref; Kocaoğlu, Serap; Cetin, Huseyin; Kaya, Bülent

2009-07-01

Antigenotoxic effects of Citrus aurentium L. (Rutaceae) fruit peel oil (CPO) in combination with mutagenic metals and alkylating agents were studied using the wing spot test of D. melanogaster. The four reference mutagens, potassium dichromate (K2Cr2O7), cobalt chloride (CoCl2), ethylmethanesulfonate (EMS), and N-ethyl-N-nitrosourea (ENU) were clearly genotoxic. CPO alone at doses from 0.1 to 0.5% in Tween 80 was not mutagenic and did not enhance the mutagenic effect of the reference mutagens. However, antigenotoxic effects of CPO were clearly demonstrated in chronic cotreatments with mutagens and oil, by a significant decrease in wing spots induced by all four mutagens. The D. melanogaster wing spot test was found to be a suitable assay for detecting antigenotoxic effects in vivo. Copyright 2009 Wiley-Liss, Inc.

Artifact suppression in electron paramagnetic resonance imaging of 14N- and 15N-labeled nitroxyl radicals with asymmetric absorption spectra

NASA Astrophysics Data System (ADS)

Takahashi, Wataru; Miyake, Yusuke; Hirata, Hiroshi

2014-10-01

This article describes an improved method for suppressing image artifacts in the visualization of 14N- and 15N-labeled nitroxyl radicals in a single image scan using electron paramagnetic resonance (EPR). The purpose of this work was to solve the problem of asymmetric EPR absorption spectra in spectral processing. A hybrid function of Gaussian and Lorentzian lineshapes was used to perform spectral line-fitting to successfully separate the two kinds of nitroxyl radicals. This approach can process the asymmetric EPR absorption spectra of the nitroxyl radicals being measured, and can suppress image artifacts due to spectral asymmetry. With this improved visualization method and a 750-MHz continuous-wave EPR imager, a temporal change in the distributions of a two-phase paraffin oil and water/glycerin solution system was visualized using lipophilic and hydrophilic nitroxyl radicals, i.e., 2-(14-carboxytetradecyl)-2-ethyl-4,4-dimethyl-3-oxazolidinyloxy (16-DOXYL stearic acid) and 4-hydroxyl-2,2,6,6-tetramethylpiperidine-d17-1-15N-1-oxyl (TEMPOL-d17-15N). The results of the two-phase separation experiment verified that reasonable artifact suppression could be achieved by the present method that deals with asymmetric absorption spectra in the EPR imaging of 14N- and 15N-labeled nitroxyl radicals.

Graphene-Fiber-Based Supercapacitors Favor N-Methyl-2-pyrrolidone/Ethyl Acetate as the Spinning Solvent/Coagulant Combination.

PubMed

He, Nanfei; Pan, Qin; Liu, Yixin; Gao, Wei

2017-07-26

One-dimensional flexible fiber supercapacitors (FSCs) have attracted great interest as promising energy-storage units that can be seamlessly incorporated into textiles via weaving, knitting, or braiding. The major challenges in this field are to develop tougher and more efficient FSCs with a relatively easy and scalable process. Here, we demonstrate a wet-spinning process to produce graphene oxide (GO) fibers from GO dispersions in N-methyl-2-pyrrolidone (NMP), with ethyl acetate as the coagulant. Upon chemical reduction of GO, the resulting NMP-based reduced GO (rGO) fibers (rGO@NMP-Fs) are twice as high in the surface area and toughness but comparable in tensile strength and conductivity as that of the water-based rGO fibers (rGO@H 2 O-Fs). When assembled into parallel FSCs, rGO@NMP-F-based supercapacitors (rGO@NMP-FSCs) offered a specific capacitance of 196.7 F cm -3 (147.5 mF cm -2 ), five times higher than that of rGO@H 2 O-F-based supercapacitors (rGO@H 2 O-FSCs) and also higher than most existing wet-spun rGO-FSCs, as well as those FSCs built with metal wires, graphene/carbon nanotube (CNT) fibers, or even pseudocapacitive materials. In addition, our rGO@NMP-FSCs can provide good bending and cycling stability. The energy density of our rGO@NMP-FSCs reaches ca. 6.8 mWh cm -3 , comparable to that of a Li thin-film battery (4 V/500 μAh).

Crystal structure of ethyl (E)-2-cyano-3-(thio-phen-2-yl)acrylate: two conformers forming a discrete disorder.

PubMed

Castro Agudelo, Brian; Cárdenas, Juan C; Macías, Mario A; Ochoa-Puentes, Cristian; Sierra, Cesar A

2017-09-01

In the title compound, C 10 H 9 NO 2 S, all the non-H atoms, except for the ethyl fragment, lie nearly in the same plane. Despite the mol-ecular planarity, the ethyl fragment presents more than one conformation, giving rise to a discrete disorder, which was modelled with two different crystallographic sites for the eth-oxy O and eth-oxy α-C atoms, with occupancy values of 0.5. In the crystal, the three-dimensional array is mainly directed by C-H⋯(O,N) inter-actions, giving rise to inversion dimers with R 2 2 (10) and R 2 2 (14) motifs and infinite chains running along the [100] direction.

Effect of chitosan, O-carboxymethyl chitosan, and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl] chitosan chloride on overweight and insulin resistance in a murine diet-induced obesity.

PubMed

Liu, Xiaofei; Zhi, Xiaona; Liu, Yunfei; Wu, Bo; Sun, Zhong; Shen, Jun

2012-04-04

Two water-soluble chitosan derivatives, O-carboxymethyl chitosan (O-CM-chitosan) and N-[(2-hydroxy-3-N,N-dimethylhexadecyl ammonium)propyl] chitosan chloride (N-CQ-chitosan), were prepared, and the therapeutic effects of chitosan, O-CM-chitosan, and N-CQ-chitosan on insulin resistance were simultaneously evaluated by rats fed on a high-fat diet. The parameters of high-fat diet-induced rats indicated that chitosan and its two derivatives not only have low cytotoxicity but can control overnutrition by fat and achieve insulin resistance therapy. However, the results in experiment in vivo showed that the therapeutic degree varied by the molecular weight and surface charge of chitosan, O-CM-chitosan, and N-CQ-chitosan. N-CQ-chitosan with a MW of 5 × 10(4) decreased body weight, the ratio of fat to body weight, triglyceride, fasting plasma glucose, fasting plasma insulin, free fatty acid, and leptin by 11, 17, 44, 46, 44, 87, and 64% and increased fecal lipid by 95%, respectively.

Distinct Neural Stem Cell Populations Give Rise to Disparate Brain Tumors in Response to N-MYC

PubMed Central

Swartling, Fredrik J.; Savov, Vasil; Persson, Anders I.; Chen, Justin; Hackett, Christopher S.; Northcott, Paul A.; Grimmer, Matthew R.; Lau, Jasmine; Chesler, Louis; Perry, Arie; Phillips, Joanna J.; Taylor, Michael D.; Weiss, William A.

2012-01-01

SUMMARY The proto-oncogene MYCN is mis-expressed in various types of human brain tumors. To clarify how developmental and regional differences influence transformation, we transduced wild-type or mutationally-stabilized murine N-mycT58A into neural stem cells (NSCs) from perinatal murine cerebellum, brain stem and forebrain. Transplantation of N-mycWT NSCs was insufficient for tumor formation. N-mycT58A cerebellar and brain stem NSCs generated medulloblastoma/primitive neuroectodermal tumors, whereas forebrain NSCs developed diffuse glioma. Expression analyses distinguished tumors generated from these different regions, with tumors from embryonic versus postnatal cerebellar NSCs demonstrating SHH-dependence and SHH-independence, respectively. These differences were regulated in-part by the transcription factor SOX9, activated in the SHH subclass of human medulloblastoma. Our results demonstrate context-dependent transformation of NSCs in response to a common oncogenic signal. PMID:22624711

N2O molecular tagging velocimetry

NASA Astrophysics Data System (ADS)

ElBaz, A. M.; Pitz, R. W.

2012-03-01

A new seeded velocity measurement technique, N2O molecular tagging velocimetry (MTV), is developed to measure velocity in wind tunnels by photochemically creating an NO tag line. Nitrous oxide "laughing gas" is seeded into the air flow. A 193 nm ArF excimer laser dissociates the N2O to O(1D) that subsequently reacts with N2O to form NO. O2 fluorescence induced by the ArF laser "writes" the original position of the NO line. After a time delay, the shifted NO line is "read" by a 226-nm laser sheet and the velocity is determined by time-of-flight. At standard atmospheric conditions with 4% N2O in air, ˜1000 ppm of NO is photochemically created in an air jet based on experiment and simulation. Chemical kinetic simulations predict 800-1200 ppm of NO for 190-750 K at 1 atm and 850-1000 ppm of NO for 0.25-1 atm at 190 K. Decreasing the gas pressure (or increasing the temperature) increases the NO ppm level. The presence of humid air has no significant effect on NO formation. The very short NO formation time (<10 ns) makes the N2O MTV method amenable to low- and high-speed air flow measurements. The N2O MTV technique is demonstrated in air jet to measure its velocity profile. The N2O MTV method should work in other gas flows as well (e.g., helium) since the NO tag line is created by chemical reaction of N2O with O(1D) from N2O photodissociation and thus does not depend on the bulk gas composition.

Effect of Premedications in a Murine Model of Asparaginase Hypersensitivity

PubMed Central

Fernandez, Christian A.; Smith, Colton; Karol, Seth E.; Ramsey, Laura B.; Liu, Chengcheng; Pui, Ching-Hon; Jeha, Sima; Evans, William E.; Finkelman, Fred D.

2015-01-01

A murine model was developed that recapitulates key features of clinical hypersensitivity to Escherichia coli asparaginase. Sensitized mice developed high levels of anti-asparaginase IgG antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge. Sensitized mice had complete inhibition of plasma asparaginase activity (P = 4.2 × 10−13) and elevated levels of mouse mast cell protease 1 (P = 6.1 × 10−3) compared with nonsensitized mice. We investigated the influence of pretreatment with triprolidine, cimetidine, the platelet activating factor (PAF) receptor antagonist CV-6209 [2-(2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl)-1-ethyl-pyridinium chloride], or dexamethasone on the severity of asparaginase-induced allergies. Combining triprolidine and CV-6209 was best for mitigating asparaginase-induced hypersensitivity compared with nonpretreated, sensitized mice (P = 1.2 × 10−5). However, pretreatment with oral dexamethasone was the only agent capable of mitigating the severity of the hypersensitivity (P = 0.03) and partially restoring asparaginase activity (P = 8.3 × 10−4). To rescue asparaginase activity in sensitized mice without requiring dexamethasone, a 5-fold greater dose of asparaginase was needed to restore enzyme activity to a similar concentration as in nonsensitized mice. Our results suggest a role of histamine and PAF in asparaginase-induced allergies and indicate that mast cell–derived proteases released during asparaginase allergy may be a useful marker of clinical hypersensitivity. PMID:25573198

Distinguishing tautomerism in the crystal structure of (Z)-N-(5-ethyl-2,3-di-hydro-1,3,4-thiadiazol-2-ylidene) -4-methylbenzenesulfonamide using DFT-D calculations and {sup 13}C solid-state NMR

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

Li, Xiaozhou; Bond, Andrew D.; Johansson, Kristoffer E.

2014-08-01

The crystal structure of (Z)-N-(5-ethyl-2,3-di-hydro-1,3,4-thiadiazol-2-ylidene) -4-methylbenzenesulfonamide contains an imine tautomer, rather than the previously reported amine tautomer. The tautomers can be distinguished using dispersion-corrected density functional theory calculations and by comparison of calculated and measured {sup 13}C solid-state NMR spectra. The crystal structure of the title compound, C{sub 11}H{sub 13}N{sub 3}O{sub 2}S{sub 2}, has been determined previously on the basis of refinement against laboratory powder X-ray diffraction (PXRD) data, supported by comparison of measured and calculated {sup 13}C solid-state NMR spectra [Hangan et al. (2010 ▶). Acta Cryst. B66, 615–621]. The mol@@ecule is tautomeric, and was reported as an aminemore » tautomer [systematic name: N-(5-ethyl-1,3,4-thia@@diazol-2-yl)-p-toluene@@sulfonamide], rather than the correct imine tautomer. The protonation site on the mol@@ecule’s 1,3,4-thia@@diazole ring is indicated by the inter@@molecular contacts in the crystal structure: N—H⋯O hydrogen bonds are established at the correct site, while the alternative protonation site does not establish any notable inter molecular inter@@actions. The two tautomers provide essentially identical Rietveld fits to laboratory PXRD data, and therefore they cannot be directly distinguished in this way. However, the correct tautomer can be distinguished from the incorrect one by previously reported qu@@anti@@tative criteria based on the extent of structural distortion on optimization of the crystal structure using dispersion-corrected density functional theory (DFT-D) calculations. Calculation of the {sup 13}C SS-NMR spectrum based on the correct imine tautomer also provides considerably better agreement with the measured {sup 13}C SS-NMR spectrum.« less

Gas-phase Conformational Analysis of (R,R)-Tartaric Acid, its Diamide, N,N,N',N'- Tetramethyldiamide and Model Compounds

NASA Astrophysics Data System (ADS)

Hoffmann, Marcin; Szarecka, Agnieszka; Rychlewski, Jacek

A review over most recent ab initio studies carried out at both RHF and MP2 levels on (R,R)-tartaric acid (TA), its diamide (DA), tetramethyldiamide (TMDA) and on three prototypic model systems (each of them constitutes a half of the respective parental molecule), i.e. 2-hydroxyacetic acid (HA), 2-hydroxyacetamide (HD) and 2-hydroxy-N,N-dimethylacetamide (HMD) is presented. (R,R)-tartaric acid and the derivatives have been completely optimized at RHF/6-31G* level and subsequently single-point energies of all conformers have been calculated with the use of second order perturbation theory according to the scheme: MP2/6-31G*//RHF/6-31G*. In the complete optimization of the model molecules at RHF level we have employed relatively large basis sets, augmented with polarisation and diffuse functions, namely 3-21G, 6-31G*, 6-31++G** and 6-311++G**. Electronic correlation has been included with the largest basis set used in this study, i.e. MP2/6-311++G**//RHF/6-311++G** single-point energy calculations have been performed. General confomational preferences of tartaric acid derivatives have been analysed as well as an attempt has been made to define main factors affecting the conformational behaviour of these molecules in the isolated state, in particular, the role and stability of intramolecular hydrogen bonding. In the case of the model compounds, our study principally concerned the conformational preferences and hydrogen bonding structure within the [alpha]-hydroxy-X moiety, where X=COOH, CONH2, CON(CH3)2.

Supergravity backgrounds for deformations of AdS n × S n supercoset string models

DOE PAGES

Lunin, O.; Roiban, R.; Tseytlin, A. A.

2014-12-11

We considermore » type IIB supergravity backgrounds corresponding to the deformed AdS n × S n × T 10 - 2 n supercoset string models of the type constructed in arXiv:1309.5850[2] which depend on one deformation parameter κ. In AdS 2 × S 2 case we find that the deformed metric can be extended to a full supergravity solution with non-trivial dilaton, RR scalar and RR 5-form strength. The solution depends on a free parameter a that should be chosen as a particular function of κ to correspond to the deformed supercoset model. In AdS 3 × S 3 case the full solution supported by the dilaton, RR scalar and RR 3-form strength exists only in the two special cases, a = 0 and a = 1 . We conjecture that there may be a more general one-parameter solution supported by several RR fields that for particular a = a ( κ ) corresponds to the supercoset model. In the most complicated deformed AdS 5 × S 5 case we were able to find only the expressions for the dilaton and the RR scalar. The full solution is likely to be supported by a combination of the 5-form and 3-form field strengths. We comment on the singularity structure of the resulting metric and exact dilaton field.« less

Supergravity backgrounds for deformations of AdS n × S n supercoset string models

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

Lunin, O.; Roiban, R.; Tseytlin, A. A.

We considermore » type IIB supergravity backgrounds corresponding to the deformed AdS n × S n × T 10 - 2 n supercoset string models of the type constructed in arXiv:1309.5850[2] which depend on one deformation parameter κ. In AdS 2 × S 2 case we find that the deformed metric can be extended to a full supergravity solution with non-trivial dilaton, RR scalar and RR 5-form strength. The solution depends on a free parameter a that should be chosen as a particular function of κ to correspond to the deformed supercoset model. In AdS 3 × S 3 case the full solution supported by the dilaton, RR scalar and RR 3-form strength exists only in the two special cases, a = 0 and a = 1 . We conjecture that there may be a more general one-parameter solution supported by several RR fields that for particular a = a ( κ ) corresponds to the supercoset model. In the most complicated deformed AdS 5 × S 5 case we were able to find only the expressions for the dilaton and the RR scalar. The full solution is likely to be supported by a combination of the 5-form and 3-form field strengths. We comment on the singularity structure of the resulting metric and exact dilaton field.« less

Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model

PubMed Central

Borgna, Vincenzo; Villegas, Jaime; Burzio, Verónica A.; Belmar, Sebastián; Araya, Mariela; Jeldes, Emanuel; Lobos-González, Lorena; Silva, Verónica; Villota, Claudio; Oliveira-Cruz, Luciana; Lopez, Constanza; Socias, Teresa; Castillo, Octavio; Burzio, Luis O.

2017-01-01

Knockdown of antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptosis in several human and mouse tumor cell lines, but not normal cells, suggesting this approach for a selective therapy against different types of cancer. Here we show that in vitro knockdown of murine ASncmtRNAs induces apoptotic death of mouse renal adenocarcinoma RenCa cells, but not normal murine kidney epithelial cells. In a syngeneic subcutaneous RenCa model, treatment delayed and even reversed tumor growth. Since the subcutaneous model does not reflect the natural microenviroment of renal cancer, we used an orthotopic model of RenCa cells inoculated under the renal capsule. These studies showed inhibition of tumor growth and metastasis. Direct metastasis assessment by tail vein injection of RenCa cells also showed a drastic reduction in lung metastatic nodules. In vivo treatment reduces survivin, N-cadherin and P-cadherin levels, providing a molecular basis for metastasis inhibition. In consequence, the treatment significantly enhanced mouse survival in these models. Our results suggest that the ASncmtRNAs could be potent and selective targets for therapy against human renal cell carcinoma. PMID:28620146

Mitochondrial ASncmtRNA-1 and ASncmtRNA-2 as potent targets to inhibit tumor growth and metastasis in the RenCa murine renal adenocarcinoma model.

PubMed

Borgna, Vincenzo; Villegas, Jaime; Burzio, Verónica A; Belmar, Sebastián; Araya, Mariela; Jeldes, Emanuel; Lobos-González, Lorena; Silva, Verónica; Villota, Claudio; Oliveira-Cruz, Luciana; Lopez, Constanza; Socias, Teresa; Castillo, Octavio; Burzio, Luis O

2017-07-04

Knockdown of antisense noncoding mitochondrial RNAs (ASncmtRNAs) induces apoptosis in several human and mouse tumor cell lines, but not normal cells, suggesting this approach for a selective therapy against different types of cancer. Here we show that in vitro knockdown of murine ASncmtRNAs induces apoptotic death of mouse renal adenocarcinoma RenCa cells, but not normal murine kidney epithelial cells. In a syngeneic subcutaneous RenCa model, treatment delayed and even reversed tumor growth. Since the subcutaneous model does not reflect the natural microenviroment of renal cancer, we used an orthotopic model of RenCa cells inoculated under the renal capsule. These studies showed inhibition of tumor growth and metastasis. Direct metastasis assessment by tail vein injection of RenCa cells also showed a drastic reduction in lung metastatic nodules. In vivo treatment reduces survivin, N-cadherin and P-cadherin levels, providing a molecular basis for metastasis inhibition. In consequence, the treatment significantly enhanced mouse survival in these models. Our results suggest that the ASncmtRNAs could be potent and selective targets for therapy against human renal cell carcinoma.

Forward Current Transport Mechanisms of Ni/Au—InAlN/AlN/GaN Schottky Diodes

NASA Astrophysics Data System (ADS)

Wang, Xiao-Feng; Shao, Zhen-Guang; Chen, Dun-Jun; Lu, Hai; Zhang, Rong; Zheng, You-Dou

2014-05-01

We fabricate two Ni/Au-In0.17Al0.83N/AlN/GaN Schottky diodes on substrates of sapphire and Si, respectively, and investigate their forward-bias current transport mechanisms by temperature-dependent current-voltage measurements. In the temperature range of 300-485 K, the Schottky barrier heights (SBHs) calculated by using the conventional thermionic-emission (TE) model are strongly positively dependent on temperature, which is in contrast to the negative-temperature-dependent characteristic of traditional semiconductor Schottky diodes. By fitting the forward-bias I-V characteristics using different current transport models, we find that the tunneling current model can describe generally the I-V behaviors in the entire measured range of temperature. Under the high forward bias, the traditional TE mechanism also gives a good fit to the measured I-V data, and the actual barrier heights calculated according to the fitting TE curve are 1.434 and 1.413 eV at 300K for InAlN/AlN/GaN Schottky diodes on Si and the sapphire substrate, respectively, and the barrier height shows a slightly negative temperature coefficient. In addition, a formula is given to estimate SBHs of Ni/Au—InAlN/AlN/GaN Schottky diodes taking the Fermi-level pinning effect into account.

Improved InGaN/GaN light-emitting diodes with a p-GaN/n-GaN/p-GaN/n-GaN/p-GaN current-spreading layer.

PubMed

Zhang, Zi-Hui; Tan, Swee Tiam; Liu, Wei; Ju, Zhengang; Zheng, Ke; Kyaw, Zabu; Ji, Yun; Hasanov, Namig; Sun, Xiao Wei; Demir, Hilmi Volkan

2013-02-25

This work reports both experimental and theoretical studies on the InGaN/GaN light-emitting diodes (LEDs) with optical output power and external quantum efficiency (EQE) levels substantially enhanced by incorporating p-GaN/n-GaN/p-GaN/n-GaN/p-GaN (PNPNP-GaN) current spreading layers in p-GaN. Each thin n-GaN layer sandwiched in the PNPNP-GaN structure is completely depleted due to the built-in electric field in the PNPNP-GaN junctions, and the ionized donors in these n-GaN layers serve as the hole spreaders. As a result, the electrical performance of the proposed device is improved and the optical output power and EQE are enhanced.

Dendritic Immunotherapy Improvement for an Optimal Control Murine Model

PubMed Central

Chimal-Eguía, J. C.; Castillo-Montiel, E.

2017-01-01

Therapeutic protocols in immunotherapy are usually proposed following the intuition and experience of the therapist. In order to deduce such protocols mathematical modeling, optimal control and simulations are used instead of the therapist's experience. Clinical efficacy of dendritic cell (DC) vaccines to cancer treatment is still unclear, since dendritic cells face several obstacles in the host environment, such as immunosuppression and poor transference to the lymph nodes reducing the vaccine effect. In view of that, we have created a mathematical murine model to measure the effects of dendritic cell injections admitting such obstacles. In addition, the model considers a therapy given by bolus injections of small duration as opposed to a continual dose. Doses timing defines the therapeutic protocols, which in turn are improved to minimize the tumor mass by an optimal control algorithm. We intend to supplement therapist's experience and intuition in the protocol's implementation. Experimental results made on mice infected with melanoma with and without therapy agree with the model. It is shown that the dendritic cells' percentage that manages to reach the lymph nodes has a crucial impact on the therapy outcome. This suggests that efforts in finding better methods to deliver DC vaccines should be pursued. PMID:28912828

Structure-activity relationships of substituted N-benzyl piperidines in the GBR series: Synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine, an allosteric modulator of the serotonin transporter.

PubMed

Boos, Terrence L; Greiner, Elisabeth; Calhoun, W Jason; Prisinzano, Thomas E; Nightingale, Barbara; Dersch, Christina M; Rothman, Richard B; Jacobson, Arthur E; Rice, Kenner C

2006-06-01

A series of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-(substituted benzyl) piperidines with substituents at the ortho and meta positions in the aromatic ring of the N-benzyl side chain were synthesized and their affinities and selectivities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) were determined. One analogue, 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-(2-trifluoromethylbenzyl)piperidine (the C(2)-trifluoromethyl substituted compound), has been found to act as an allosteric modulator of hSERT binding and function. It had little affinity for any of the transporters. Several compounds showed affinity for the DAT in the low nanomolar range and displayed a broad range of SERT/DAT selectivity ratios and very little affinity for the NET. The pharmacological tools provided by the availability of compounds with varying transporter affinity and selectivity could be used to obtain additional information about the properties a compound should have to act as a useful pharmacotherapeutic agent for cocaine addiction and help unravel the pharmacological mechanisms relevant to stimulant abuse.