Atypical E2f functions are critical for pancreas polyploidization.

PubMed

Matondo, Ramadhan B; Moreno, Eva; Toussaint, Mathilda J M; Tooten, Peter C J; van Essen, Saskia C; van Liere, Elsbeth A; Youssef, Sameh A; Bongiovanni, Laura; de Bruin, Alain

2018-01-01

The presence of polyploid cells in the endocrine and exocrine pancreas has been reported for four decades. In rodents, pancreatic polyploidization is initiated after weaning and the number of polyploid cells increases with age. Surprisingly the molecular regulators and biological functions of polyploidization in the pancreas are still unknown. We discovered that atypical E2f activity is essential for polyploidization in the pancreas, using an inducible Cre/LoxP approach in new-born mice to delete ubiquitously the atypical E2f transcription factors, E2f7 and E2f8. In contrast to its critical role in embryonic survival, conditional deletion of both of both atypical E2fs in newborn mice had no impact on postnatal survival and mice lived until old age. However, deficiency of E2f7 or E2f8 alone was sufficient to suppress polyploidization in the pancreas and associated with only a minor decrease in blood serum levels of glucose, insulin, amylase and lipase under 4 hours starvation condition compared to wildtype littermates. In mice with fewer pancreatic polyploid cells that were fed ad libitum, no major impact on hormones or enzymes levels was observed. In summary, we identified atypical E2fs to be essential for polyploidization in the pancreas and discovered that postnatal induced loss of both atypical E2fs in many organs is compatible with life until old age.

E2F transcription factors and digestive system malignancies: how much do we know?

PubMed

Evangelou, Konstantinos; Havaki, Sophia; Kotsinas, Athanassios

2014-08-07

The E2F proteins comprise a family of 8 members that function as transcription factors. They are key targets of the retinoblastoma protein (RB) and were initially divided into groups of activators and repressors. Accumulating data suggest that there is no specific role for each individual E2F member. Instead, each E2F can exert a variety of cellular effects, some of which represent opposing ones. For instance, specific E2Fs can activate transcription and repression, promote or hamper cell proliferation, augment or inhibit apoptosis, all being dependent on the cellular context. This complexity reflects the importance that these transcription factors have on a cell's fate. Thus, delineating the specific role for each E2F member in specific malignancies, although not easy, is a challenging and continuously pursued task, especially in view of potential E2F targeted therapies. Therefore, several reviews are continuously trying to evaluate available data on E2F status in various malignancies. Such reviews have attempted to reach a consensus, often in the simplistic form of oncogenes or tumor suppressor genes for the E2Fs. However they frequently miss spatial and temporal alterations of these factors during tumor development, which should also be considered in conjunction with the status of the regulatory networks that these factors participate in. In the current ''Letter to the Editor'', we comment on the flaws, misinterpretations and omissions in one such review article published recently in the World Journal of Gastroenterology regarding the role of E2Fs in digestive system malignancies.

Brief Report: Efficacy and Safety of Switching to Coformulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide (E/C/F/TAF) in Virologically Suppressed Women.

PubMed

Hodder, Sally; Squires, Kathleen; Kityo, Cissy; Hagins, Debbie; Avihingsanon, Anchalee; Kido, Anna; Jiang, Shuping; Kulkarni, Rima; Cheng, Andrew; Cao, Huyen

2018-06-01

The integrase inhibitor regimen [elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (TDF)] demonstrated superior efficacy when compared with a protease inhibitor regimen [ritonavir-boosted atazanavir (ATV + RTV) and FTC/TDF] in 575 treatment-naive women at week 48. We investigated the efficacy, safety, and tolerability of switching to a TAF-based, single-tablet regimen containing elvitegravir, cobicistat, FTC, and tenofovir alafenamide (E/C/F/TAF) versus remaining on ATV + RTV plus FTC/TDF. After completing the initial randomized, blinded phase, virologically suppressed (HIV-1 RNA <50 copies/mL) women on ATV + RTV plus FTC/TDF were rerandomized (3:1) to receive open-label E/C/F/TAF versus remaining on their current regimen. The primary end point was proportion of participants with plasma HIV-1 RNA <50 copies per milliliter at week 48 (U.S. FDA snapshot algorithm), with a prespecified noninferiority margin of 12%. Safety [adverse events (AEs)] and tolerability were also assessed. Of 575 women originally randomized and treated in the blinded phase, 159 were rerandomized to switch to E/C/F/TAF and 53 to remain on ATV + RTV plus FTC/TDF. At week 48, virologic suppression was maintained in 150 (94%) of women on E/C/F/TAF and 46 (87%) on ATV + RTV plus FTC/TDF [difference 7.5% (95% confidence interval -1.2% to 19.4%)], demonstrating noninferiority of E/C/F/TAF to ATV + RTV and FTC/TDF. Incidence of AEs was similar between groups; study drug-related AEs were more common with E/C/F/TAF (11% versus 4%). Switching to E/C/F/TAF was noninferior to continuing ATV + RTV plus FTC/TDF in maintaining virologic suppression and was well tolerated at 48 weeks.

Cytoplasmic E2f4 forms organizing centres for initiation of centriole amplification during multiciliogenesis

PubMed Central

Mori, Munemasa; Hazan, Renin; Danielian, Paul S.; Mahoney, John E.; Li, Huijun; Lu, Jining; Miller, Emily S.; Zhu, Xueliang; Lees, Jacqueline A.; Cardoso, Wellington V.

2017-01-01

Abnormal development of multiciliated cells is a hallmark of a variety of human conditions associated with chronic airway diseases, hydrocephalus and infertility. Multiciliogenesis requires both activation of a specialized transcriptional program and assembly of cytoplasmic structures for large-scale centriole amplification that generates basal bodies. It remains unclear, however, what mechanism initiates formation of these multiprotein complexes in epithelial progenitors. Here we show that this is triggered by nucleocytoplasmic translocation of the transcription factor E2f4. After inducing a transcriptional program of centriole biogenesis, E2f4 forms apical cytoplasmic organizing centres for assembly and nucleation of deuterosomes. Using genetically altered mice and E2F4 mutant proteins we demonstrate that centriole amplification is crucially dependent on these organizing centres and that, without cytoplasmic E2f4, deuterosomes are not assembled, halting multiciliogenesis. Thus, E2f4 integrates nuclear and previously unsuspected cytoplasmic events of centriole amplification, providing new perspectives for the understanding of normal ciliogenesis, ciliopathies and cancer. PMID:28675157

Silencing of E2F3 suppresses tumor growth of Her2+ breast cancer cells by restricting mitosis.

PubMed

Lee, Miyoung; Oprea-Ilies, Gabriela; Saavedra, Harold I

2015-11-10

The E2F transcriptional activators E2F1, E2F2 and E2F3a regulate many important cellular processes, including DNA replication, apoptosis and centrosome duplication. Previously, we demonstrated that silencing E2F1 or E2F3 suppresses centrosome amplification (CA) and chromosome instability (CIN) in Her2+ breast cancer cells without markedly altering proliferation. However, it is unknown whether and how silencing a single E2F activator, E2F3, affects malignancy of human breast cancer cells. Thus, we injected HCC1954 Her2+ breast cancer cells silenced for E2F3 into mammary fat pads of immunodeficient mice and demonstrated that loss of E2F3 retards tumor growth. Surprisingly, silencing of E2F3 led to significant reductions in mitotic indices relative to vector controls, while the percentage of cells undergoing S phase were not affected. Nek2 is a mitotic kinase commonly upregulated in breast cancers and a critical regulator of Cdk4- or E2F-mediated CA. In this report, we found that Nek2 overexpression rescued back the CA caused by silencing of shE2F3. However, the effects of Nek2 overexpression in affecting tumor growth rates of shE2F3 and shE2F3; GFP cells were inconclusive. Taken together, our results indicate that E2F3 silencing decreases mammary tumor growth by reducing percentage of cells undergoing mitosis.

Bioactive constituents from Chinese natural medicines. XXII. Absolute structures of new megastigmane glycosides, sedumosides E1, E2, E3, F1, F2, and G, from Sedum sarmentosum (Crassulaceae).

PubMed

Morikawa, Toshio; Zhang, Yi; Nakamura, Seikou; Matsuda, Hisashi; Muraoka, Osamu; Yoshikawa, Masayuki

2007-03-01

Six new megastigmane glycosides, sedumosides E1, E2, E3, F1, F2, and G, were isolated from the whole plant of Sedum sarmentosum (Crassulaceae). The structures of new constituents including the absolute configuration were elucidated on the basis of chemical and physicochemical evidence.

E2F Activators Signal and Maintain Centrosome Amplification in Breast Cancer Cells

PubMed Central

Lee, Mi-Young; Moreno, Carlos S.

2014-01-01

Centrosomes ensure accurate chromosome segregation by directing spindle bipolarity. Loss of centrosome regulation results in centrosome amplification, multipolar mitosis and aneuploidy. Since centrosome amplification is common in premalignant lesions and breast tumors, it is proposed to play a central role in breast tumorigenesis, a hypothesis that remains to be tested. The coordination between the cell and centrosome cycles is of paramount importance to maintain normal centrosome numbers, and the E2Fs may be responsible for regulating these cycles. However, the role of E2F activators in centrosome amplification is unclear. Because E2Fs are deregulated in Her2+ cells displaying centrosome amplification, we addressed whether they signal this abnormal process. Knockdown of E2F1 or E2F3 in Her2+ cells decreased centrosome amplification without significantly affecting cell cycle progression, whereas the overexpression of E2F1, E2F2, or E2F3 increased centrosome amplification in MCF10A mammary epithelial cells. Our results revealed that E2Fs affect the expression of proteins, including Nek2 and Plk4, known to influence the cell/centrosome cycles and mitosis. Downregulation of E2F3 resulted in cell death and delays/blocks in cytokinesis, which was reversed by Nek2 overexpression. Nek2 overexpression enhanced centrosome amplification in Her2+ breast cancer cells silenced for E2F3, revealing a role for the E2F activators in maintaining centrosome amplification in part through Nek2. PMID:24797070

E2F activators signal and maintain centrosome amplification in breast cancer cells.

PubMed

Lee, Mi-Young; Moreno, Carlos S; Saavedra, Harold I

2014-07-01

Centrosomes ensure accurate chromosome segregation by directing spindle bipolarity. Loss of centrosome regulation results in centrosome amplification, multipolar mitosis and aneuploidy. Since centrosome amplification is common in premalignant lesions and breast tumors, it is proposed to play a central role in breast tumorigenesis, a hypothesis that remains to be tested. The coordination between the cell and centrosome cycles is of paramount importance to maintain normal centrosome numbers, and the E2Fs may be responsible for regulating these cycles. However, the role of E2F activators in centrosome amplification is unclear. Because E2Fs are deregulated in Her2(+) cells displaying centrosome amplification, we addressed whether they signal this abnormal process. Knockdown of E2F1 or E2F3 in Her2(+) cells decreased centrosome amplification without significantly affecting cell cycle progression, whereas the overexpression of E2F1, E2F2, or E2F3 increased centrosome amplification in MCF10A mammary epithelial cells. Our results revealed that E2Fs affect the expression of proteins, including Nek2 and Plk4, known to influence the cell/centrosome cycles and mitosis. Downregulation of E2F3 resulted in cell death and delays/blocks in cytokinesis, which was reversed by Nek2 overexpression. Nek2 overexpression enhanced centrosome amplification in Her2(+) breast cancer cells silenced for E2F3, revealing a role for the E2F activators in maintaining centrosome amplification in part through Nek2.

NmF2 and hmF2 measurements at 95° E and 127° E around the EIA northern crest during 2010-2014

NASA Astrophysics Data System (ADS)

Kalita, Bitap Raj; Bhuyan, Pradip Kumar; Yoshikawa, Akimasa

2015-11-01

The characteristics of the F2 layer parameters NmF2 and hmF2 over Dibrugarh (27.5° N, 95° E, 17° N geomagnetic, 43° dip) measured by a Canadian Advanced Digital Ionosonde (CADI) for the period of August 2010 to July 2014 are reported for the first time from this low mid-latitude station lying within the daytime peak of the longitudinal wave number 4 structure of equatorial anomaly (EIA) around the northern edge of anomaly crest. Equinoctial asymmetry is clearly observed at all solar activity levels whereas the midday winter anomaly is observed only during high solar activity years and disappears during the temporary dip in solar activity in 2013 but forenoon winter anomaly can be observed even at moderate solar activity. The NmF2/hmF2 variations over Dibrugarh are compared with that of Okinawa (26.5° N, 127° E, 17° N geomagnetic), and the eastward propagation speed of the wave number 4 longitudinal structure from 95° E to 127° E is estimated. The speed is found to be close to the theoretical speed of the wave number 4 (WN4) structure. The correlation of daily NmF2 over Dibrugarh and Okinawa with solar activity exhibits diurnal and seasonal variations. The highest correlation in daytime is observed during the forenoon hours in equinox. The correlation of daily NmF2 (linear or non-linear) with solar activity exhibits diurnal variation. A tendency for amplification with solar activity is observed in the forenoon and late evening period of March equinox and the postsunset period of December solstice. NmF2 saturation effect is observed only in the midday period of equinox. Non-linear variation of neutral composition at higher altitudes and variation of recombination rates with solar activity via temperature dependence may be related to the non-linear trend. The noon time maximum NmF2 over Dibrugarh exhibits better correlation with equatorial electrojet (EEJ) than with solar activity and, therefore, new low-latitude NmF2 index is proposed taking both solar

E2F1 transcription is induced by genotoxic stress through ATM/ATR activation.

PubMed

Carcagno, Abel L; Ogara, María F; Sonzogni, Silvina V; Marazita, Mariela C; Sirkin, Pablo F; Ceruti, Julieta M; Cánepa, Eduardo T

2009-05-01

E2F1, a member of the E2F family of transcription factors, plays a critical role in controlling both cell cycle progression and apoptotic cell death in response to DNA damage and oncogene activation. Following genotoxic stresses, E2F1 protein is stabilized by phosphorylation and acetylation driven to its accumulation. The aim of the present work was to examine whether the increase in E2F1 protein levels observed after DNA damage is only a reflection of an increase in E2F1 protein stability or is also the consequence of enhanced transcription of the E2F1 gene. The data presented here demonstrates that UV light and other genotoxics induce the transcription of E2F1 gene in an ATM/ATR dependent manner, which results in increasing E2F1 mRNA and protein levels. After genotoxic stress, transcription of cyclin E, an E2F1 target gene, was significantly induced. This induction was the result of two well-differentiated effects, one of them dependent on de novo protein synthesis and the other on the protein stabilization. Our results strongly support a transcriptional effect of DNA damaging agents on E2F1 expression. The results presented herein uncover a new mechanism involving E2F1 in response to genotoxic stress.

A specific, nonproliferative role for E2F-5 in choroid plexus function revealed by gene targeting

PubMed Central

Lindeman, Geoffrey J.; Dagnino, Lina; Gaubatz, Stefan; Xu, Yuhui; Bronson, Roderick T.; Warren, Henry B.; Livingston, David M.

1998-01-01

Homozygous E2F-5 knockout embryos and mice have been generated. Although embryonic development appeared normal, newborn mice developed nonobstructive hydrocephalus, suggesting excessive cerebrospinal fluid (CSF) production. Although the CSF-producing choroid plexus displayed normal cellular organization, it contained abundant electron-lucent epithelial cells, consistent with excessive CSF secretory activity. Moreover, E2F-5 CNS expression in normal animals was largely confined to the choroid plexus. Cell cycle kinetics were not perturbed in homozygous knockout embryo fibroblasts. Thus, E2F-5 is not essential for cell proliferation. Rather, it affects the secretory behavior of a differentiated neural tissue. PMID:9553039

Copy number variations of E2F1: a new genetic risk factor for testicular cancer.

PubMed

Rocca, Maria Santa; Di Nisio, Andrea; Marchiori, Arianna; Ghezzi, Marco; Opocher, Giuseppe; Foresta, Carlo; Ferlin, Alberto

2017-03-01

Testicular germ cell tumor (TGCT) is one of the most heritable forms of cancer. In last years, many evidence suggested that constitutional genetic factors, mainly single nucleotide polymorphisms, can increase its risk. However, the possible contribution of copy number variations (CNVs) in TGCT susceptibility has not been substantially addressed. Indeed, an increasing number of studies have focused on the effect of CNVs on gene expression and on the role of these structural genetic variations as risk factors for different forms of cancer. E2F1 is a transcription factor that plays an important role in regulating cell growth, differentiation, apoptosis and response to DNA damage. Therefore, deficiency or overexpression of this protein might significantly influence fundamental biological processes involved in cancer development and progression, including TGCT. We analyzed E2F1 CNVs in 261 cases with TGCT and 165 controls. We found no CNVs in controls, but 17/261 (6.5%) cases showed duplications in E2F1 Blot analysis demonstrated higher E2F1 expression in testicular samples of TGCT cases with three copies of the gene. Furthermore, we observed higher phosphorylation of Akt and mTOR in samples with E2F1 duplication. Interestingly, normal, non-tumoral testicular tissue in patient with E2F1 duplication showed lower expression of E2F1 and lower AKT/mTOR phosphorylation with respect to adjacent tumor tissue. Furthermore, increased expression of E2F1 obtained in vitro in NTERA-2 testicular cell line induced increased AKT/mTOR phosphorylation. This study suggests for the first time an involvement of E2F1 CNVs in TGCT susceptibility and supports previous preliminary data on the importance of AKT/mTOR signaling pathway in this cancer. © 2017 Society for Endocrinology.

Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1

PubMed Central

Zheng, Shunsheng; Moehlenbrink, Jutta; Lu, Yi-Chien; Zalmas, Lykourgos-Panagiotis; Sagum, Cari A.; Carr, Simon; McGouran, Joanna F.; Alexander, Leila; Fedorov, Oleg; Munro, Shonagh; Kessler, Benedikt; Bedford, Mark T.; Yu, Qiang; La Thangue, Nicholas B.

2014-01-01

Summary The mechanisms that underlie and dictate the different biological outcomes of E2F-1 activity have yet to be elucidated. We describe the residue-specific methylation of E2F-1 by the asymmetric dimethylating protein arginine methyltransferase (PRMT) 1 and symmetric dimethylating PRMT5, and relate the marks to different functional consequences of E2F-1 activity. Methylation by PRMT1 hinders methylation by PRMT5, which augments E2F-1-dependent apoptosis, whereas PRMT5-dependent methylation favours proliferation by antagonising methylation by PRMT1. The ability of E2F-1 to prompt apoptosis in DNA damaged cells coincides with enhanced PRMT1 methylation. In contrast, cyclin A binding to E2F-1 impedes PRMT1 methylation and augments PRMT5 methylation, thus ensuring that E2F-1 is locked into its cell cycle progression mode. The Tudor domain protein p100-TSN reads the symmetric methylation mark, and binding of p100-TSN down-regulates E2F-1 apoptotic activity. Our results define an exquisite level of precision in the reader-writer interplay that governs the biological outcome of E2F-1 activity. PMID:24076217

The Empirical Canadian High Arctic Ionospheric Model (E-CHAIM): NmF2 and hmF2 specification

NASA Astrophysics Data System (ADS)

Themens, David; Thayyil Jayachandran, P.

2017-04-01

It is well known that the International Reference Ionosphere (IRI) suffers reduced accuracy in its representation of monthly median ionospheric electron density at high latitudes (Themens et al. 2014, Themens et al. 2016). These inaccuracies are believed to stem from a historical lack of data from these regions. Now, roughly thirty and forty years after the development of the original URSI and CCIR foF2 maps, respectively, there exists a much larger dataset of high latitude observations of ionospheric electron density. These new measurements come in the form of new ionosonde deployments, such as those of the Canadian High Arctic Ionospheric Network, the CHAMP, GRACE, and COSMIC radio occultation missions, and the construction of the Poker Flat, Resolute, and EISCAT Incoherent Scatter Radar systems. These new datasets afford an opportunity to revise the IRI's representation of the high latitude ionosphere. For this purpose, we here introduce the Empirical Canadian High Arctic Ionospheric Model (E-CHAIM), which incorporates all of the above datasets, as well as the older observation records, into a new climatological representation of the high latitude ionosphere. In this presentation, we introduce the NmF2 and hmF2 portions of the model, focusing on both climatological and storm-time representations, and present a validation of the new model with respect to ionosonde observations from four high latitude stations. A comparison with respect to IRI performance is also presented, where we see improvements by up to 70% in the representation of peak electron density through using the new E-CHAIM model. In terms of RMS errors, the E-CHAIM model is shown to represent a near-universal improvement over the IRI, sometimes by more than 1 MHz in foF2. For peak height, the E-CHAIM model demonstrates overall RMS errors of 13km at each test site compared to values of 18-35km for the IRI, depending on location. Themens, D.R., P. T. Jayachandran, et al. (2014). J. Geophys. Res. Space

The Cdk4-E2f1 pathway regulates early pancreas development by targeting Pdx1+ progenitors and Ngn3+ endocrine precursors

PubMed Central

Kim, So Yoon; Rane, Sushil G.

2011-01-01

Cell division and cell differentiation are intricately regulated processes vital to organ development. Cyclin-dependent kinases (Cdks) are master regulators of the cell cycle that orchestrate the cell division and differentiation programs. Cdk1 is essential to drive cell division and is required for the first embryonic divisions, whereas Cdks 2, 4 and 6 are dispensable for organogenesis but vital for tissue-specific cell development. Here, we illustrate an important role for Cdk4 in regulating early pancreas development. Pancreatic development involves extensive morphogenesis, proliferation and differentiation of the epithelium to give rise to the distinct cell lineages of the adult pancreas. The cell cycle molecules that specify lineage commitment within the early pancreas are unknown. We show that Cdk4 and its downstream transcription factor E2f1 regulate mouse pancreas development prior to and during the secondary transition. Cdk4 deficiency reduces embryonic pancreas size owing to impaired mesenchyme development and fewer Pdx1+ pancreatic progenitor cells. Expression of activated Cdk4R24C kinase leads to increased Nkx2.2+ and Nkx6.1+ cells and a rise in the number and proliferation of Ngn3+ endocrine precursors, resulting in expansion of the β cell lineage. We show that E2f1 binds and activates the Ngn3 promoter to modulate Ngn3 expression levels in the embryonic pancreas in a Cdk4-dependent manner. These results suggest that Cdk4 promotes β cell development by directing E2f1-mediated activation of Ngn3 and increasing the pool of endocrine precursors, and identify Cdk4 as an important regulator of early pancreas development that modulates the proliferation potential of pancreatic progenitors and endocrine precursors. PMID:21490060

Competing E2 and SN2 Mechanisms for the F- + CH3CH2I Reaction.

PubMed

Yang, Li; Zhang, Jiaxu; Xie, Jing; Ma, Xinyou; Zhang, Linyao; Zhao, Chenyang; Hase, William L

2017-02-09

Anti-E2, syn-E2, inv-, and ret-S N 2 reaction channels for the gas-phase reaction of F - + CH 3 CH 2 I were characterized with a variety of electronic structure calculations. Geometrical analysis confirmed synchronous E2-type transition states for the elimination of the current reaction, instead of nonconcerted processes through E1cb-like and E1-like mechanisms. Importantly, the controversy concerning the reactant complex for anti-E2 and inv-S N 2 paths has been clarified in the present work. A positive barrier of +19.2 kcal/mol for ret-S N 2 shows the least feasibility to occur at room temperature. Negative activation energies (-16.9, -16.0, and -4.9 kcal/mol, respectively) for inv-S N 2, anti-E2, and syn-E2 indicate that inv-S N 2 and anti-E2 mechanisms significantly prevail over the eclipsed elimination. Varying the leaving group for a series of reactions F - + CH 3 CH 2 Y (Y = F, Cl, Br, and I) leads to monotonically decreasing barriers, which relates to the gradually looser TS structures following the order F > Cl > Br > I. The reactivity of each channel nearly holds unchanged except for the perturbation between anti-E2 and inv-S N 2. RRKM calculation reveals that the reaction of the fluorine ion with ethyl iodide occurs predominately via anti-E2 elimination, and the inv-S N 2 pathway is suppressed, although it is energetically favored. This phenomenon indicates that, in evaluating the competition between E2 and S N 2 processes, the kinetic or dynamical factors may play a significant role. By comparison with benchmark CCSD(T) energies, MP2, CAM-B3LYP, and M06 methods are recommended to perform dynamics simulations of the title reaction.

[Induced abortion using prostaglandin E2 and F2alpha gel].

PubMed

Lippert, T H; Modly, T

1974-01-01

In this study of 20 patients in the 13th-17th week of pregnancy abortion was induced with intrauterine, extraamniotic application of prostaglandins (PG) E2 or F2 in gel form. The gel composition was as follows: 4% tylose MH 300, 2% glycerine, 1% chlorhexidine digluconate, 83% sterile distilled water and 10% PG stock solution. Both PGE2 and PGF2 gels were used. Final concentration was 2.5 mg E2 or 2.5 mg F2 per g of gel. Gel was applied via transcervical, extraamniotic polyethylene catheter every 2-3 hours. Results: PGE2-gel was used in 14 cases. After 3-4 applications both fetus and placenta were expelled. Average dose used was 4.6 mg E2/patient. First contractions started in 30 minutes; induction to expulsion time was 11 hours 35 minutes. F2-gel given to 6 patients resulted in expulsion of the fetus in all cases but placenta needed removal by curettage in 4 patients. Average dose per patient was 17.7 mg of F2; first contractions in 30 minutes, average expulsion time 17 hours 38 minutes. With both PGs there were painful contractions which were controlled with a combination of pentazocine and Valium. PGE2 caused vomiting in 5 patients. No increased bleeding or postabortion infection occurred. Follow-up curettage was done in all patients to ensure removal of all tissues. Overall evaluation of the PG-gels was considered good. PG stability in gel form is good; during 8 months of preservation in sterile aluminum tubes at -25 degrees Celsius no decline in clinical effectiveness was noted. The gel application is less expensive than the slow-injection pump method.

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes

PubMed Central

Singh, Randeep K.; Dagnino, Lina

2017-01-01

The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation. Analysis of the structural determinants that govern these processes revealed a central role for S403 and T433. In particular, substitution of these two amino acid residues with non-phosphorylatable alanine (E2F1 ST/A) interferes with E2F1 nuclear export, K11- and K48-linked polyubiquitylation and degradation in differentiated keratinocytes. In contrast, replacement of S403 and T433 with phosphomimetic aspartic acid to generate a pseudophosphorylated E2F1 mutant protein (E2F1 ST/D) generates a protein that is regulated in a manner indistinguishable from that of wild type E2F1. Cdh1 is an activating cofactor that interacts with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, promoting proteasomal degradation of various substrates. We found that Cdh1 associates with E2F1 in keratinocytes. Inhibition or RNAi-mediated silencing of Cdh1 prevents E2F1 degradation in response to differentiation signals. Our results reveal novel regulatory mechanisms that jointly modulate post-translational modifications and downregulation of E2F1, which are necessary for proper epidermal keratinocyte differentiation. PMID:27903963

CDH1 regulates E2F1 degradation in response to differentiation signals in keratinocytes.

PubMed

Singh, Randeep K; Dagnino, Lina

2017-01-17

The E2F1 transcription factor plays key roles in skin homeostasis. In the epidermis, E2F1 expression is essential for normal proliferation of undifferentiated keratinocytes, regeneration after injury and DNA repair following UV radiation-induced photodamage. Abnormal E2F1 expression promotes nonmelanoma skin carcinoma. In addition, E2F1 must be downregulated for proper keratinocyte differentiation, but the relevant mechanisms involved remain poorly understood. We show that differentiation signals induce a series of post-translational modifications in E2F1 that are jointly required for its downregulation. Analysis of the structural determinants that govern these processes revealed a central role for S403 and T433. In particular, substitution of these two amino acid residues with non-phosphorylatable alanine (E2F1 ST/A) interferes with E2F1 nuclear export, K11- and K48-linked polyubiquitylation and degradation in differentiated keratinocytes. In contrast, replacement of S403 and T433 with phosphomimetic aspartic acid to generate a pseudophosphorylated E2F1 mutant protein (E2F1 ST/D) generates a protein that is regulated in a manner indistinguishable from that of wild type E2F1. Cdh1 is an activating cofactor that interacts with the anaphase-promoting complex/cyclosome (APC/C) ubiquitin E3 ligase, promoting proteasomal degradation of various substrates. We found that Cdh1 associates with E2F1 in keratinocytes. Inhibition or RNAi-mediated silencing of Cdh1 prevents E2F1 degradation in response to differentiation signals. Our results reveal novel regulatory mechanisms that jointly modulate post-translational modifications and downregulation of E2F1, which are necessary for proper epidermal keratinocyte differentiation.

E2F1 transcription factor and its impact on growth factor and cytokine signaling.

PubMed

Ertosun, Mustafa Gokhan; Hapil, Fatma Zehra; Osman Nidai, Ozes

2016-10-01

E2F1 is a transcription factor involved in cell cycle regulation and apoptosis. The transactivation capacity of E2F1 is regulated by pRb. In its hypophosphorylated form, pRb binds and inactivates DNA binding and transactivating functions of E2F1. The growth factor stimulation of cells leads to activation of CDKs (cyclin dependent kinases), which in turn phosphorylate Rb and hyperphosphorylated Rb is released from E2F1 or E2F1/DP complex, and free E2F1 can induce transcription of several genes involved in cell cycle entry, induction or inhibition of apoptosis. Thus, growth factors and cytokines generally utilize E2F1 to direct cells to either fate. Furthermore, E2F1 regulates expressions of various cytokines and growth factor receptors, establishing positive or negative feedback mechanisms. This review focuses on the relationship between E2F1 transcription factor and cytokines (IL-1, IL-2, IL-3, IL-6, TGF-beta, G-CSF, LIF), growth factors (EGF, KGF, VEGF, IGF, FGF, PDGF, HGF, NGF), and interferons (IFN-α, IFN-β and IFN-γ). Copyright © 2016 Elsevier Ltd. All rights reserved.

E2F1-mediated human POMC expression in ectopic Cushing's syndrome.

PubMed

Araki, Takako; Liu, Ning-Ai; Tone, Yukiko; Cuevas-Ramos, Daniel; Heltsley, Roy; Tone, Masahide; Melmed, Shlomo

2016-11-01

Cushing's syndrome is caused by excessive adrenocorticotropic hormone (ACTH) secretion derived from pituitary corticotroph tumors (Cushing disease) or from non-pituitary tumors (ectopic Cushing's syndrome). Hypercortisolemic features of ectopic Cushing's syndrome are severe, and no definitive treatment for paraneoplastic ACTH excess is available. We aimed to identify subcellular therapeutic targets by elucidating transcriptional regulation of the human ACTH precursor POMC (proopiomelanocortin) and ACTH production in non-pituitary tumor cells and in cell lines derived from patients with ectopic Cushing's syndrome. We show that ectopic hPOMC transcription proceeds independently of pituitary-specific Tpit/Pitx1 and demonstrate a novel E2F1-mediated transcriptional mechanism regulating hPOMC We identify an E2F1 cluster binding to the proximal hPOMC promoter region (-42 to +68), with DNA-binding activity determined by the phosphorylation at Ser-337. hPOMC mRNA expression in cancer cells was upregulated (up to 40-fold) by the co-expression of E2F1 and its heterodimer partner DP1. Direct and indirect inhibitors of E2F1 activity suppressed hPOMC gene expression and ACTH by modifying E2F1 DNA-binding activity in ectopic Cushing's cell lines and primary tumor cells, and also suppressed paraneoplastic ACTH and cortisol levels in xenografted mice. E2F1-mediated hPOMC transcription is a potential target for suppressing ACTH production in ectopic Cushing's syndrome. © 2016 Society for Endocrinology.

Sibling rivalry in the E2F family.

PubMed

Trimarchi, Jeffrey M; Lees, Jacqueline A

2002-01-01

The E2F transcription factor family determines whether or not a cell will divide by controlling the expression of key cell-cycle regulators. The individual E2Fs can be divided into distinct subgroups that act in direct opposition to one another to promote either cellular proliferation or cell-cycle exit and terminal differentiation. What is the underlying molecular basis of this 'push-me-pull-you' regulation, and what are its biological consequences?

Measurement of the electron structure function F2e at LEP energies

NASA Astrophysics Data System (ADS)

Abdallah, J.; Abreu, P.; Adam, W.; Adzic, P.; Albrecht, T.; Alemany-Fernandez, R.; Allmendinger, T.; Allport, P. P.; Amaldi, U.; Amapane, N.; Amato, S.; Anashkin, E.; Andreazza, A.; Andringa, S.; Anjos, N.; Antilogus, P.; Apel, W.-D.; Arnoud, Y.; Ask, S.; Asman, B.; Augustin, J. E.; Augustinus, A.; Baillon, P.; Ballestrero, A.; Bambade, P.; Barbier, R.; Bardin, D.; Barker, G. J.; Baroncelli, A.; Battaglia, M.; Baubillier, M.; Becks, K.-H.; Begalli, M.; Behrmann, A.; Belous, K.; Ben-Haim, E.; Benekos, N.; Benvenuti, A.; Berat, C.; Berggren, M.; Bertrand, D.; Besancon, M.; Besson, N.; Bloch, D.; Blom, M.; Bluj, M.; Bonesini, M.; Boonekamp, M.; Booth, P. S. L.; Borisov, G.; Botner, O.; Bouquet, B.; Bowcock, T. J. V.; Boyko, I.; Bracko, M.; Brenner, R.; Brodet, E.; Bruckman, P.; Brunet, J. M.; Buschbeck, B.; Buschmann, P.; Calvi, M.; Camporesi, T.; Canale, V.; Carena, F.; Castro, N.; Cavallo, F.; Chapkin, M.; Charpentier, Ph.; Checchia, P.; Chierici, R.; Chliapnikov, P.; Chudoba, J.; Chung, S. U.; Cieslik, K.; Collins, P.; Contri, R.; Cosme, G.; Cossutti, F.; Costa, M. J.; Crennell, D.; Cuevas, J.; D'Hondt, J.; da Silva, T.; da Silva, W.; Della Ricca, G.; de Angelis, A.; de Boer, W.; de Clercq, C.; de Lotto, B.; de Maria, N.; de Min, A.; de Paula, L.; di Ciaccio, L.; di Simone, A.; Doroba, K.; Drees, J.; Eigen, G.; Ekelof, T.; Ellert, M.; Elsing, M.; Espirito Santo, M. C.; Fanourakis, G.; Fassouliotis, D.; Feindt, M.; Fernandez, J.; Ferrer, A.; Ferro, F.; Flagmeyer, U.; Foeth, H.; Fokitis, E.; Fulda-Quenzer, F.; Fuster, J.; Gandelman, M.; Garcia, C.; Gavillet, Ph.; Gazis, E.; Gokieli, R.; Golob, B.; Gomez-Ceballos, G.; Gonçalves, P.; Graziani, E.; Grosdidier, G.; Grzelak, K.; Guy, J.; Haag, C.; Hallgren, A.; Hamacher, K.; Hamilton, K.; Haug, S.; Hauler, F.; Hedberg, V.; Hennecke, M.; Hoffman, J.; Holmgren, S.-O.; Holt, P. J.; Houlden, M. A.; Jackson, J. N.; Jarlskog, G.; Jarry, P.; Jeans, D.; Johansson, E. K.; Jonsson, P.; Joram, C.; Jungermann, L.; Kapusta, F.; Katsanevas, S.; Katsoufis, E.; Kernel, G.; Kersevan, B. P.; Kerzel, U.; King, B. T.; Kjaer, N. J.; Kluit, P.; Kokkinias, P.; Kourkoumelis, C.; Kouznetsov, O.; Krumstein, Z.; Kucharczyk, M.; Lamsa, J.; Leder, G.; Ledroit, F.; Leinonen, L.; Leitner, R.; Lemonne, J.; Lepeltier, V.; Lesiak, T.; Liebig, W.; Liko, D.; Lipniacka, A.; Lopes, J. H.; Lopez, J. M.; Loukas, D.; Lutz, P.; Lyons, L.; MacNaughton, J.; Malek, A.; Maltezos, S.; Mandl, F.; Marco, J.; Marco, R.; Marechal, B.; Margoni, M.; Marin, J.-C.; Mariotti, C.; Markou, A.; Martinez-Rivero, C.; Masik, J.; Mastroyiannopoulos, N.; Matorras, F.; Matteuzzi, C.; Mazzucato, F.; Mazzucato, M.; Mc Nulty, R.; Meroni, C.; Migliore, E.; Mitaroff, W.; Mjoernmark, U.; Moa, T.; Moch, M.; Moenig, K.; Monge, R.; Montenegro, J.; Moraes, D.; Moreno, S.; Morettini, P.; Mueller, U.; Muenich, K.; Mulders, M.; Mundim, L.; Murray, W.; Muryn, B.; Myatt, G.; Myklebust, T.; Nassiakou, M.; Navarria, F.; Nawrocki, K.; Nemecek, S.; Nicolaidou, R.; Nikolenko, M.; Oblakowska-Mucha, A.; Obraztsov, V.; Olshevski, A.; Onofre, A.; Orava, R.; Osterberg, K.; Ouraou, A.; Oyanguren, A.; Paganoni, M.; Paiano, S.; Palacios, J. P.; Palka, H.; Papadopoulou, Th. D.; Pape, L.; Parkes, C.; Parodi, F.; Parzefall, U.; Passeri, A.; Passon, O.; Peralta, L.; Perepelitsa, V.; Perrotta, A.; Petrolini, A.; Piedra, J.; Pieri, L.; Pierre, F.; Pimenta, M.; Piotto, E.; Podobnik, T.; Poireau, V.; Pol, M. E.; Polok, G.; Pozdniakov, V.; Pukhaeva, N.; Pullia, A.; Radojicic, D.; Rebecchi, P.; Rehn, J.; Reid, D.; Reinhardt, R.; Renton, P.; Richard, F.; Ridky, J.; Rivero, M.; Rodriguez, D.; Romero, A.; Ronchese, P.; Roudeau, P.; Rovelli, T.; Ruhlmann-Kleider, V.; Ryabtchikov, D.; Sadovsky, A.; Salmi, L.; Salt, J.; Sander, C.; Savoy-Navarro, A.; Schwickerath, U.; Sekulin, R.; Siebel, M.; Sisakian, A.; Slominski, W.; Smadja, G.; Smirnova, O.; Sokolov, A.; Sopczak, A.; Sosnowski, R.; Spassov, T.; Stanitzki, M.; Stocchi, A.; Strauss, J.; Stugu, B.; Szczekowski, M.; Szeptycka, M.; Szumlak, T.; Szwed, J.; Tabarelli, T.; Tegenfeldt, F.; Timmermans, J.; Tkatchev, L.; Tobin, M.; Todorovova, S.; Tomé, B.; Tonazzo, A.; Tortosa, P.; Travnicek, P.; Treille, D.; Tristram, G.; Trochimczuk, M.; Troncon, C.; Turluer, M.-L.; Tyapkin, I. A.; Tyapkin, P.; Tzamarias, S.; Uvarov, V.; Valenti, G.; van Dam, P.; van Eldik, J.; van Remortel, N.; van Vulpen, I.; Vegni, G.; Veloso, F.; Venus, W.; Verdier, P.; Verzi, V.; Vilanova, D.; Vitale, L.; Vrba, V.; Wahlen, H.; Washbrook, A. J.; Weiser, C.; Wicke, D.; Wickens, J.; Wilkinson, G.; Winter, M.; Witek, M.; Yushchenko, O.; Zalewska, A.; Zalewski, P.; Zavrtanik, D.; Zhuravlov, V.; Zimin, N. I.; Zintchenko, A.; Zupan, M.; Delphi Collaboration

2014-10-01

The hadronic part of the electron structure function F2e has been measured for the first time, using e+e- data collected by the DELPHI experiment at LEP, at centre-of-mass energies of √{ s} = 91.2- 209.5 GeV. The data analysis is simpler than that of the measurement of the photon structure function. The electron structure function F2e data are compared to predictions of phenomenological models based on the photon structure function. It is shown that the contribution of large target photon virtualities is significant. The data presented can serve as a cross-check of the photon structure function F2γ analyses and help in refining existing parameterisations.

E2F1 promote the aggressiveness of human colorectal cancer by activating the ribonucleotide reductase small subunit M2

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

Fang, Zejun; Gong, Chaoju; Liu, Hong

2015-08-21

As the ribonucleotide reductase small subunit, the high expression of ribonucleotide reductase small subunit M2 (RRM2) induces cancer and contributes to tumor growth and invasion. In several colorectal cancer (CRC) cell lines, we found that the expression levels of RRM2 were closely related to the transcription factor E2F1. Mechanistic studies were conducted to determine the molecular basis. Ectopic overexpression of E2F1 promoted RRM2 transactivation while knockdown of E2F1 reduced the levels of RRM2 mRNA and protein. To further investigate the roles of RRM2 which was activated by E2F1 in CRC, CCK-8 assay and EdU incorporation assay were performed. Overexpression ofmore » E2F1 promoted cell proliferation in CRC cells, which was blocked by RRM2 knockdown attenuation. In the migration and invasion tests, overexpression of E2F1 enhanced the migration and invasion of CRC cells which was abrogated by silencing RRM2. Besides, overexpression of RRM2 reversed the effects of E2F1 knockdown partially in CRC cells. Examination of clinical CRC specimens demonstrated that both RRM2 and E2F1 were elevated in most cancer tissues compared to the paired normal tissues. Further analysis showed that the protein expression levels of E2F1 and RRM2 were parallel with each other and positively correlated with lymph node metastasis (LNM), TNM stage and distant metastasis. Consistently, the patients with low E2F1 and RRM2 levels have a better prognosis than those with high levels. Therefore, we suggest that E2F1 can promote CRC proliferation, migration, invasion and metastasis by regulating RRM2 transactivation. Understanding the role of E2F1 in activating RRM2 transcription will help to explain the relationship between E2F1 and RRM2 in CRC and provide a novel predictive marker for diagnosis and prognosis of the disease. - Highlights: • E2F1 promotes RRM2 transactivation in CRC cells. • E2F1 promotes the proliferation of CRC cells by activating RRM2. • E2F1 promotes the migration

Repression of transcriptional activity of C/EBPalpha by E2F-dimerization partner complexes.

PubMed

Zaragoza, Katrin; Bégay, Valérie; Schuetz, Anja; Heinemann, Udo; Leutz, Achim

2010-05-01

The transcription factor CCAAT/enhancer-binding protein alpha (C/EBPalpha) coordinates proliferation arrest and the differentiation of myeloid progenitors, adipocytes, hepatocytes, keratinocytes, and cells of the lung and placenta. C/EBPalpha transactivates lineage-specific differentiation genes and inhibits proliferation by repressing E2F-regulated genes. The myeloproliferative C/EBPalpha BRM2 mutant serves as a paradigm for recurrent human C-terminal bZIP C/EBPalpha mutations that are involved in acute myeloid leukemogenesis. BRM2 fails to repress E2F and to induce adipogenesis and granulopoiesis. The data presented here show that, independently of pocket proteins, C/EBPalpha interacts with the dimerization partner (DP) of E2F and that C/EBPalpha-E2F/DP interaction prevents both binding of C/EBPalpha to its cognate sites on DNA and transactivation of C/EBP target genes. The BRM2 mutant, in addition, exhibits enhanced interaction with E2F-DP and reduced affinity toward DNA and yet retains transactivation potential and differentiation competence that becomes exposed when E2F/DP levels are low. Our data suggest a tripartite balance between C/EBPalpha, E2F/DP, and pocket proteins in the control of proliferation, differentiation, and tumorigenesis.

Geraniol suppresses prostate cancer growth through down-regulation of E2F8.

PubMed

Lee, Sanghoon; Park, Yu Rang; Kim, Su-Hwa; Park, Eun-Jung; Kang, Min Ji; So, Insuk; Chun, Jung Nyeo; Jeon, Ju-Hong

2016-10-01

Geraniol, an acyclic dietary monoterpene, has been found to suppress cancer survival and growth. However, the molecular mechanism underlying the antitumor action of geraniol has not been investigated at the genome-wide level. In this study, we analyzed the microarray data obtained from geraniol-treated prostate cancer cells. Geraniol potently altered a gene expression profile and primarily down-regulated cell cycle-related gene signatures, compared to linalool, another structurally similar monoterpene that induces no apparent phenotypic changes. Master regulator analysis using the prostate cancer-specific regulatory interactome identified that the transcription factor E2F8 as a specific target molecule regulates geraniol-specific cell cycle signatures. Subsequent experiments confirmed that geraniol down-regulated E2F8 expression and the knockdown of E2F8 was sufficient to suppress cell growth by inducing G 2 /M arrest. Epidemiological analysis showed that E2F8 is up-regulated in metastatic prostate cancer and associated with poor prognosis. These results indicate that E2F8 is a crucial transcription regulator controlling cell cycle and survival in prostate cancer cells. Therefore, our study provides insight into the role of E2F8 in prostate cancer biology and therapeutics. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Status of development of LCOS projection displays for F-22A, F/A-18E/F, and JSF cockpits

NASA Astrophysics Data System (ADS)

Kalmanash, Michael H.

2001-09-01

Projection display technology has been found to be an attractive alternative to direct view flat panel displays in many avionics applications. The projection approach permits compact high performance systems to be tailored to specific platform needs while using a complement of commercial off the shelf (COTS) components, including liquid crystal on silicon (LCOS) microdisplay imagers. A common projection engine used on multiple platforms enables improved performance, lower cost and shorter development cycles. This paper provides a status update for projection displays under development for the F-22A, the F/A-18E/F and the Lockheed Joint Strike Fighter (JSF) aircraft.

Synergistic cooperation of MDM2 and E2F1 contributes to TAp73 transcriptional activity

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

Kasim, Vivi, E-mail: vivikasim78@gmail.com; Huang, Can; Zhang, Jing

2014-07-04

Highlights: • MDM2 is a novel positive regulator of TAp73 transcriptional activity. • MDM2 colocalizes together and physically interacts with E2F1. • Synergistic cooperation of MDM2 and E2F1 is crucial for TAp73 transcription. • MDM2 regulates TAp73 transcriptional activity in a p53-independent manner. - Abstract: TAp73, a structural homologue of p53, plays an important role in tumorigenesis. E2F1 had been reported as a transcriptional regulator of TAp73, however, the detailed mechanism remains to be elucidated. Here we reported that MDM2-silencing reduced the activities of the TAp73 promoters and the endogenous TAp73 expression level significantly; while MDM2 overexpression upregulated them. Wemore » further revealed that the regulation of TAp73 transcriptional activity occurs as a synergistic effect of MDM2 and E2F1, most probably through their physical interaction in the nuclei. Furthermore, we also suggested that MDM2 might be involved in DNA damage-induced TAp73 transcriptional activity. Finally, we elucidated that MDM2-silencing reduced the proliferation rate of colon carcinoma cells regardless of the p53 status. Our data show a synergistic effect of MDM2 and E2F1 on TAp73 transcriptional activity, suggesting a novel regulation pathway of TAp73.« less

Comparison of foE and M(3000)F2 variability at Ibadan, Singapore and Slough

NASA Astrophysics Data System (ADS)

Somoye, E. O.; Onori, E. O.; Akala, A. O.

2013-01-01

The variability, VR, of critical frequency of E-layer, foE, and ionospheric propagation factor, M(3000)F2 at Ibadan (7.4°N, 3.9°E, 6°S dip) is investigated for local time, seasonal and solar cycle variations. Latitudinal influence of these characteristics is sought by comparison with foE VR and M(3000)F2 VR of Slough ( 51.5°N, 359.4°E, 66.5°N dip) in the European sector, and Singapore (1.3°N,103.8°E, 17.6°S dip) in the Asian sector. While the pattern of foE VR is similar to those of other F2 characteristics with characteristic peaks around dawn and dusk, M(3000)F2 VR shows no clear diurnal trend.A lower bound of foE VR is usually 3% while the maximum VR ranges between 8% and13% at post-sunrise and pre-sunset hours at all the epochs, M(3000)F2 VR is however lower during MSA (about 9%) than during LSA and HSA when it is 4% to about 12-14%. Generally, daytime M(3000)F2 VR is greater than that of foE VR by between 5% and 10%. Furthermore, no latitudinal difference is observed in both characteristics during both HSA and MSA. While nighttime M(3000)F2 VR is about half that of nighttime foF2 VR (the critical frequency of F2-layer ) VR, daytime VR of both characteristics are about equal during the three epochs at Ibadan. For Slough, nighttime M(3000)F2 VR and nighttime foF2 VR as well as the daytime VR of both characteristics are about equal. This difference is most likely due to latitudinal effect.

Proposed Revisions to MIL-F-8785C Related to Flight Safety of Augmented Aircraft. Volume 2. Appendices A through F, References

DTIC Science & Technology

1982-04-01

for Step 6h Command - Configuration FO, Fl, F6 , F4, F2 .................................................. ....... 309 C-15 Frequency Response of e/Fs...Configuration FO, Fl, F6 , F4, F2.. 312 C-16 Time History for Step Sh Command - Configuration L21, L71, L72, L73...505 T= 2 sec 2 F4 .465 4 sec F6 .453 6 sEc where F indicates unaugmented F-1l1A and the number following F indicates T2 in sec, except 0 : stable, 1

Development of E-Learning Materials for Machining Safety Education

NASA Astrophysics Data System (ADS)

Nakazawa, Tsuyoshi; Mita, Sumiyoshi; Matsubara, Masaaki; Takashima, Takeo; Tanaka, Koichi; Izawa, Satoru; Kawamura, Takashi

We developed two e-learning materials for Manufacturing Practice safety education: movie learning materials and hazard-detection learning materials. Using these video and sound media, students can learn how to operate machines safely with movie learning materials, which raise the effectiveness of preparation and review for manufacturing practice. Using these materials, students can realize safety operation well. Students can apply knowledge learned in lectures to the detection of hazards and use study methods for hazard detection during machine operation using the hazard-detection learning materials. Particularly, the hazard-detection learning materials raise students‧ safety consciousness and increase students‧ comprehension of knowledge from lectures and comprehension of operations during Manufacturing Practice.

52. 2E corridor, from intersection of 2F corridor, second floor, ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

52. 2E corridor, from intersection of 2F corridor, second floor, building 500, looking east - Offutt Air Force Base, Strategic Air Command Headquarters & Command Center, Headquarters Building, 901 SAC Boulevard, Bellevue, Sarpy County, NE

MicroRNA-424/E2F6 feedback loop modulates cell invasion, migration and EMT in endometrial carcinoma

PubMed Central

Lu, Zheng; Nian, Zhou; Jingjing, Zhang; Tao, Luo; Quan, Li

2017-01-01

Our previous study explored the roles of microRNA-424 (miR-424) in the development of endometrial carcinoma (EC) and analyzed the miR-424/E2F7 axis in EC cell growth. In this study, we investigated the status of miR-424 in human endometrial cancer tissues, which were collected from a cohort of Zunyi patients. We found that the expression level of miR-424 was associated with clinical tumor stage, cell differentiation, lymph node metastasis and cell migration ability. Cell function experiments demonstrated that miR-424 overexpression suppressed the invasion and migration abilities of endometrial carcinoma cells in vitro. Bioinformatic predictions and dual-luciferase reporter assays suggested E2F6 as a possible target of miR-424. RT-PCR and western blot assays demonstrated that miR-424 transfection reduced the expression level of E2F6, while inhibiting miR-424 with ASO-miR-424 (antisense oligonucleotides of miR-424) increased the expression level of E2F6. Cell function experiments indicated that E2F6 transfection rescued the EC cell phenotype induced by miR-424. In addition, we also found that E2F6 negatively regulated miR-424 expression in EC cells. In summary, our results demonstrated that the miR-424/E2F6 feedback loop modulates cell invasion, migration and EMT in EC and that the miR-424/E2Fs regulation network may serve as a new and potentially important therapeutic target in EC. PMID:29371986

Aberrant Retinoblastoma (RB)-E2F Transcriptional Regulation Defines Molecular Phenotypes of Osteosarcoma*

PubMed Central

Scott, Milcah C.; Sarver, Aaron L.; Tomiyasu, Hirotaka; Cornax, Ingrid; Van Etten, Jamie; Varshney, Jyotika; O'Sullivan, M. Gerard; Subramanian, Subbaya; Modiano, Jaime F.

2015-01-01

We previously identified two distinct molecular subtypes of osteosarcoma through gene expression profiling. These subtypes are associated with distinct tumor behavior and clinical outcomes. Here, we describe mechanisms that give rise to these molecular subtypes. Using bioinformatic analyses, we identified a significant association between deregulation of the retinoblastoma (RB)-E2F pathway and the molecular subtype with worse clinical outcomes. Xenotransplantation models recapitulated the corresponding behavior for each osteosarcoma subtype; thus, we used cell lines to validate the role of the RB-E2F pathway in regulating the prognostic gene signature. Ectopic RB resets the patterns of E2F regulated gene expression in cells derived from tumors with worse clinical outcomes (molecular phenotype 2) to those comparable with those observed in cells derived from tumors with less aggressive outcomes (molecular phenotype 1), providing a functional association between RB-E2F dysfunction and altered gene expression in osteosarcoma. DNA methyltransferase and histone deacetylase inhibitors similarly reset the transcriptional state of the molecular phenotype 2 cells from a state associated with RB deficiency to one seen with RB sufficiency. Our data indicate that deregulation of RB-E2F pathway alters the epigenetic landscape and biological behavior of osteosarcoma. PMID:26378234

Pressure-induced magnetic collapse and metallization of TlF e1.6S e2

NASA Astrophysics Data System (ADS)

Naumov, P. G.; Filsinger, K.; Shylin, S. I.; Barkalov, O. I.; Ksenofontov, V.; Qi, Y.; Palasyuk, T.; Schnelle, W.; Medvedev, S. A.; Greenblatt, M.; Felser, C.

2017-08-01

The crystal structure, magnetic ordering, and electrical resistivity of TlF e1.6S e2 were studied at high pressures. Below ˜7 GPa , TlF e1.6S e2 is an antiferromagnetically ordered semiconductor with a ThC r2S i2 -type structure. The insulator-to-metal transformation observed at a pressure of ˜7 GPa is accompanied by a loss of magnetic ordering and an isostructural phase transition. In the pressure range ˜7.5 -11 GPa a remarkable downturn in resistivity, which resembles a superconducting transition, is observed below 15 K. We discuss this feature as the possible onset of superconductivity originating from a phase separation in a small fraction of the sample in the vicinity of the magnetic transition.

Stochastic E2F activation and reconciliation of phenomenological cell-cycle models.

PubMed

Lee, Tae J; Yao, Guang; Bennett, Dorothy C; Nevins, Joseph R; You, Lingchong

2010-09-21

The transition of the mammalian cell from quiescence to proliferation is a highly variable process. Over the last four decades, two lines of apparently contradictory, phenomenological models have been proposed to account for such temporal variability. These include various forms of the transition probability (TP) model and the growth control (GC) model, which lack mechanistic details. The GC model was further proposed as an alternative explanation for the concept of the restriction point, which we recently demonstrated as being controlled by a bistable Rb-E2F switch. Here, through a combination of modeling and experiments, we show that these different lines of models in essence reflect different aspects of stochastic dynamics in cell cycle entry. In particular, we show that the variable activation of E2F can be described by stochastic activation of the bistable Rb-E2F switch, which in turn may account for the temporal variability in cell cycle entry. Moreover, we show that temporal dynamics of E2F activation can be recast into the frameworks of both the TP model and the GC model via parameter mapping. This mapping suggests that the two lines of phenomenological models can be reconciled through the stochastic dynamics of the Rb-E2F switch. It also suggests a potential utility of the TP or GC models in defining concise, quantitative phenotypes of cell physiology. This may have implications in classifying cell types or states.

The NAMPT/E2F2/SIRT1 axis promotes proliferation and inhibits p53-dependent apoptosis in human melanoma cells.

PubMed

Zhao, Hailong; Tang, Weiwei; Chen, Xiaowen; Wang, Siyu; Wang, Xianyan; Xu, Haiyan; Li, Lijuan

2017-11-04

Melanoma is the most common primary malignant neoplasm in adults, causing more deaths than any other skin cancer, necessitating the development of new target-based approaches. Current evidence suggests SIRT1, the mammalian nicotinamide adenine dinucleotide (NAD + )-dependent protein deacetylase, and nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD + biosynthetic enzyme, together comprise a novel systemic regulatory network to play a pivotal role in cell proliferation and apoptosis. Nevertheless, how the regulation of this cofactor interfaces with signal transduction network remains poorly understood in melanoma. Here, we report NAMPT is highly expressed in melanomaassociated with poor overall survival in patients. Pharmacological and genetic inhibition of NAMPT decreased NAD + levels and melanoma cell proliferation capacity, and NAMPT knockdown induced apoptosis through the activity of the tumor suppressor p53. Next, we demonstrate NAMPT regulates the transcription factor E2F family member 2 (E2F2) in the apoptosis process. Downstream, E2F2 control the mRNA and protein levels of SIRT1. Finally, we find NAMPT mediates the apoptosis resistance of melanoma cells through NAMPT-E2F2-SIRT1 axis, more than NAD + -driven transcriptional program. Accordingly, our results demonstrated that NAMPT is a prognostic marker in melanoma, and the identificationofNAMPT-E2F2-SIRT1 pathway establishes another link between NAMPT and apoptosis events in melanoma, with therapeutic implications for this deadly cancer. Copyright © 2017 Elsevier Inc. All rights reserved.

E2F3a gene expression has prognostic significance in childhood acute lymphoblastic leukemia.

PubMed

Wang, Kai-Ling; Mei, Yan-Yan; Cui, Lei; Zhao, Xiao-Xi; Li, Wei-Jing; Gao, Chao; Liu, Shu-Guang; Jiao, Ying; Liu, Fei-Fei; Wu, Min-Yuan; Ding, Wei; Li, Zhi-Gang

2014-10-01

To study E2F3a expression and its clinical significance in children with acute lymphoblastic leukemia (ALL). We quantified E2F3a expression at diagnosis in 148 children with ALL by real-time PCR. In the test cohort (n = 48), receiver operating characteristic (ROC) curve was used to find the best cut-off point to divide the patients into E2F3a low- and high-expression groups. The prognostic significance of E2F3a expression was investigated in the test cohort and confirmed in the validation cohort (n = 100). The correlations of E2F3a expression with the clinical features and treatment outcome of these patients were analyzed. ROC curve analysis indicated that the best cut-off point of E2F3a expression was 0.3780. In the test cohort, leukemia-free survival (LFS) and event-free survival (EFS) of the low-expression group were lower than those of the high-expression group (log rank: P = 0.026 for both). This finding was verified in the validation cohort. LFS, EFS, and overall survival were also lower in the low-expression group than in the high-expression group (log rank, P = 0.015, 0.008, and 0.002 respectively). E2F3a low expression was correlated with the existence of BCR-ABL fusion. An algorithm composed of E2F3a expression and minimal residual disease (MRD) could predict relapse or induction failure more precisely than current risk stratification. These results were still significant in the ALL patients without BCR-ABL fusion. Low expression of E2F3a was associated with inferior prognosis in childhood ALL. An algorithm composed of E2F3a expression and MRD could predict relapse or induction failure more precisely than that of the current risk stratification. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Development of f2/f1 ratio functions in humans

NASA Astrophysics Data System (ADS)

Vento, Barbara A.; Durrant, John D.; Sabo, Diane L.; Boston, J. Robert

2004-05-01

Otoacoustic emissions (OAEs) presumably represent active processes within the cochlea fundamental to frequency-selectivity in peripheral auditory function. Maturation of the cochlear amplifier, vis-a-vis frequency encoding or selectivity, has yet to be fully characterized in humans. The purpose of this study was to further investigate the maturation of features of the f2/f1 frequency ratio (Distortion Product OAE amplitude X f2/f1 ratio) presumed to reflect cochlear frequency selectivity. A cross-sectional, multivariate study was completed comparing three age groups: pre-term infants, term infants and young adult subjects. Frequency ratio functions were analyzed at three f2 frequencies-2000, 4000 and 6000 Hz. An analysis included an estimation of the optimal ratio (OR) and a bandwidth-like measure (Q3). Analysis revealed significant interactions of age x frequency x gender for optimal ratio and a significant interaction of age x frequency for Q3. Consistent and statistically significant differences for both OR and Q3 were found in female subjects and when f2=2 or 6 kHz. This supports research by others [Abdala, J. Acoust. Soc. Am. 114, 3239-3250 (2003)] suggesting that the development of cochlear active mechanisms may still be somewhat in flux at least through term birth Furthermore, OAEs appear to demonstrate gender differences in the course of such maturational changes.

ns2np4 (n = 4, 5) lone pair triplets whirling in M*F2E3 (M* = Kr, Xe): Stereochemistry and ab initio analyses

NASA Astrophysics Data System (ADS)

Galy, Jean; Matar, Samir F.

2017-02-01

The stereochemistry of ns2np4 (n = 4, 5) lone pair LP characterizing noble gas Kr and Xe (labeled M*) in M*F2 difluorides is examined within coherent crystal chemistry and ab initio visualizations. M*2+ in such oxidation state brings three lone pairs (E) and difluorides are formulated M*F2E3. The analyses use electron localization function (ELF) obtained within density functional theory calculations showing the development of the LP triplets whirling {E3} quantified in the relevant chemical systems. Detailed ELF data analyses allowed showing that in α KrF2E3 and isostructural XeF2E3 difluorides the three E electronic clouds merge or hybridize into a torus and adopt a perfect gyration circle with an elliptical section, while in β KrF2 the network architecture deforms the whole torus into an ellipsoid shape. Original precise metrics are provided for the torus in the different compounds under study. In KrF2 the geometric changes upon β → α phase transition is schematized and mechanisms for the transformation with temperature or pressure are proposed. The results are further highlighted by electronic band structure calculations which show similar features of equal band gaps of 3 eV in both α and β KrF2 and a reorganization of frontier orbitals due to the different orientations of the F-Kr-F linear molecule in the two tetragonal structures.

Inhibition of E2F1 activity and cell cycle progression by arsenic via retinoblastoma protein.

PubMed

Sheldon, Lynn A

2017-01-01

The regulation of cell cycle progression by steroid hormones and growth factors is important for maintaining normal cellular processes including development and cell proliferation. Deregulated progression through the G1/S and G2/M cell cycle transitions can lead to uncontrolled cell proliferation and cancer. The transcription factor E2F1, a key cell cycle regulator, targets genes encoding proteins that regulate cell cycle progression through the G1/S transition as well as proteins important in DNA repair and apoptosis. E2F1 expression and activity is inhibited by inorganic arsenic (iAs) that has a dual role as a cancer therapeutic and as a toxin that leads to diseases including cancer. An understanding of what underlies this dichotomy will contribute to understanding how to use iAs as a more effective therapeutic and also how to treat cancers that iAs promotes. Here, we show that quiescent breast adenocarcinoma MCF-7 cells treated with 17-β estradiol (E2) progress through the cell cycle, but few cells treated with E2 + iAs progress from G1 into S-phase due to a block in cell cycle progression. Our data support a model in which iAs inhibits the dissociation of E2F1 from the tumor suppressor, retinoblastoma protein (pRB) due to changes in pRB phosphorylation which leads to decreased E2F1 transcriptional activity. These findings present an explanation for how iAs can disrupt cell cycle progression through E2F1-pRB and has implications for how iAs acts as a cancer therapeutic as well as how it may promote tumorigenesis through decreased DNA repair.

YB-1, the E2F Pathway, and Regulation of Tumor Cell Growth

PubMed Central

Samuel, Weini; Cao, Helen; Patel, Rachna; Mehta, Reena; Stern, J. Lewis; Reid, Glen; Woolley, Adele G.; Miller, Lance D.; Black, Michael A; Shelling, Andrew N.; Print, Cristin G.; Braithwaite, Antony W.

2012-01-01

Background Y-box binding factor 1 (YB-1) has been associated with prognosis in many tumor types. Reduced YB-1 expression inhibits tumor cell growth, but the mechanism is unclear. Methods YB-1 mRNA levels were compared with tumor grade and histology using microarray data from 771 breast cancer patients and with disease-free survival and distant metastasis–free survival using data from 375 of those patients who did not receive adjuvant therapy. Microarrays were further searched for genes that had correlated expression with YB-1 mRNA. Small interfering RNA (siRNA) was used to study the effects of reduced YB-1 expression on growth of three tumor cell lines (MCF-7 breast, HCT116 colon, and A549 lung cancer cells), on tumorigenesis by A549 cells in nude mice, and on global transcription in the three cancer cell lines. Reporter gene assays were used to determine whether YB-1 siRNAs affected the expression of E2F1, and chromatin immunoprecipitation was used to determine whether YB-1 bound to various E2F promoters as well as E2F1-regulated promoters. All P values were from two-sided tests. Results YB-1 levels were elevated in more aggressive tumors and were strongly associated with poor disease-free survival and distant metastasis–free survival. YB-1 expression was often associated with the expression of genes with E2F sites in their promoters. Cells expressing YB-1 siRNA grew substantially more slowly than control cells and formed tumors less readily in nude mice. Transcripts that were altered in cancer cell lines with YB-1 siRNA included 32 genes that are components of prognostic gene expression signatures. YB-1 regulated expression of an E2F1 promoter–reporter construct in A549 cells (eg, relative E2F1 promoter activity with control siRNA = 4.04; with YB-1 siRNA = 1.40, difference= −2.64, 95% confidence interval = −3.57 to −1.71, P < .001) and bound to the promoters of several well-defined E2F1 target genes. Conclusion YB-1 expression is associated with the

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

PubMed

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

2010-11-10

Regulation of gene expression requires transcription factor binding to specific DNA elements, and a large body of work has focused on the identification of such sequences. However, it is becoming increasingly clear that eukaryotic transcription factors can exhibit widespread, nonfunctional binding to genomic DNA sites. Conversely, some of these proteins, such as E2F, can also modulate gene expression by binding to non-consensus elements. E2F comprises a family of transcription factors that play key roles in a wide variety of cellular functions, including survival, differentiation, activation during tissue regeneration, metabolism, and proliferation. E2F factors bind to the Erb3-binding protein 1 (EBP1) promoter in live cells. We now show that E2F binding to the EBP1 promoter occurs through two tandem DNA elements that do not conform to typical consensus E2F motifs. Exogenously expressed E2F1 activates EBP1 reporters lacking one, but not both sites, suggesting a degree of redundancy under certain conditions. E2F1 increases the levels of endogenous EBP1 mRNA in breast carcinoma and other transformed cell lines. In contrast, in non-transformed primary epidermal keratinocytes, E2F, together with the retinoblastoma family of proteins, appears to be involved in decreasing EBP1 mRNA abundance in response to growth inhibition by transforming growth factor-β1. Thus, E2F is likely a central coordinator of multiple responses that culminate in regulation of EBP1 gene expression, and which may vary depending on cell type and context.

mTORC1 and CK2 coordinate ternary and eIF4F complex assembly

PubMed Central

Gandin, Valentina; Masvidal, Laia; Cargnello, Marie; Gyenis, Laszlo; McLaughlan, Shannon; Cai, Yutian; Tenkerian, Clara; Morita, Masahiro; Balanathan, Preetika; Jean-Jean, Olivier; Stambolic, Vuk; Trost, Matthias; Furic, Luc; Larose, Louise; Koromilas, Antonis E.; Asano, Katsura; Litchfield, David; Larsson, Ola; Topisirovic, Ivan

2016-01-01

Ternary complex (TC) and eIF4F complex assembly are the two major rate-limiting steps in translation initiation regulated by eIF2α phosphorylation and the mTOR/4E-BP pathway, respectively. How TC and eIF4F assembly are coordinated, however, remains largely unknown. We show that mTOR suppresses translation of mRNAs activated under short-term stress wherein TC recycling is attenuated by eIF2α phosphorylation. During acute nutrient or growth factor stimulation, mTORC1 induces eIF2β phosphorylation and recruitment of NCK1 to eIF2, decreases eIF2α phosphorylation and bolsters TC recycling. Accordingly, eIF2β mediates the effect of mTORC1 on protein synthesis and proliferation. In addition, we demonstrate a formerly undocumented role for CK2 in regulation of translation initiation, whereby CK2 stimulates phosphorylation of eIF2β and simultaneously bolsters eIF4F complex assembly via the mTORC1/4E-BP pathway. These findings imply a previously unrecognized mode of translation regulation, whereby mTORC1 and CK2 coordinate TC and eIF4F complex assembly to stimulate cell proliferation. PMID:27040916

ERBB2 Deficiency Alters an E2F-1-Dependent Adaptive Stress Response and Leads to Cardiac Dysfunction

PubMed Central

Perry, Marie-Claude; Dufour, Catherine R.; Eichner, Lillian J.; Tsang, David W. K.; Deblois, Geneviève; Muller, William J.

2014-01-01

The tyrosine kinase receptor ERBB2 is required for normal development of the heart and is a potent oncogene in breast epithelium. Trastuzumab, a monoclonal antibody targeting ERBB2, improves the survival of breast cancer patients, but cardiac dysfunction is a major side effect of the drug. The molecular mechanisms underlying how ERBB2 regulates cardiac function and why trastuzumab is cardiotoxic remain poorly understood. We show here that ERBB2 hypomorphic mice develop cardiac dysfunction that mimics the side effects observed in patients treated with trastuzumab. We demonstrate that this phenotype is related to the critical role played by ERBB2 in cardiac homeostasis and physiological hypertrophy. Importantly, genetic and therapeutic reduction of ERBB2 activity in mice, as well as ablation of ERBB2 signaling by trastuzumab or siRNAs in human cardiomyocytes, led to the identification of an impaired E2F-1-dependent genetic program critical for the cardiac adaptive stress response. These findings demonstrate the existence of a previously unknown mechanistic link between ERBB2 and E2F-1 transcriptional activity in heart physiology and trastuzumab-induced cardiac dysfunction. PMID:25246633

Targeting the eIF4F translation initiation complex: a critical nexus for cancer development.

PubMed

Pelletier, Jerry; Graff, Jeremy; Ruggero, Davide; Sonenberg, Nahum

2015-01-15

Elevated protein synthesis is an important feature of many cancer cells and often arises as a consequence of increased signaling flux channeled to eukaryotic initiation factor 4F (eIF4F), the key regulator of the mRNA-ribosome recruitment phase of translation initiation. In many cellular and preclinical models of cancer, eIF4F deregulation results in changes in translational efficiency of specific mRNA classes. Importantly, many of these mRNAs code for proteins that potently regulate critical cellular processes, such as cell growth and proliferation, enhanced cell survival and cell migration that ultimately impinge on several hallmarks of cancer, including increased angiogenesis, deregulated growth control, enhanced cellular survival, epithelial-to-mesenchymal transition, invasion, and metastasis. By being positioned as the molecular nexus downstream of key oncogenic signaling pathways (e.g., Ras, PI3K/AKT/TOR, and MYC), eIF4F serves as a direct link between important steps in cancer development and translation initiation. Identification of mRNAs particularly responsive to elevated eIF4F activity that typifies tumorigenesis underscores the critical role of eIF4F in cancer and raises the exciting possibility of developing new-in-class small molecules targeting translation initiation as antineoplastic agents. ©2014 American Association for Cancer Research.

miR-132 targeting E2F5 suppresses cell proliferation, invasion, migration in ovarian cancer cells

PubMed Central

Tian, Hang; Hou, Lei; Xiong, Yu-Mei; Huang, Jun-Xiang; Zhang, Wen-Hua; Pan, Yong-Ying; Song, Xing-Rong

2016-01-01

Accumulating evidence showed that microRNA-132 (miR-132) are involved in development and progression of several types of cancers, however, the function and underlying molecular mechanism of miR-132 in ovarian cancer remains unclear. In this study we investigated the biological roles and molecular mechanism of miR-132 in ovarian cancer. Here, we found that that the expression levels of miR-132 were dramatically decreased in ovarian cancer cell lines and clinical ovarian cancer tissue samples. Then, we found that introduction of miR-132 significantly suppressed the proliferation, colony formation, migration and invasion of ovarian cancer cells. Mechanism investigation revealed that miR-132 inhibited the expression of transcription factor E2F5 by specifically targeting its mRNA 3’UTR. Moreover, the expression level of E2F5 was significantly increased in ovarian cancer tissues than in the adjacent normal tissues, and its expression was inversely correlated with miR-132 expression in clinical ovarian cancer tissues. Additionally, silencing E2F5 was able to inhibit the proliferation, colony formation, migration and invasion of ovarian cancer cells, parallel to the effect of miR-132 overexpression on the ovarian cancer cells. Meanwhile, overexpression of E2F5 reversed the inhibition effect mediated by miR-132 overexpression. These results indicate that miR-132 suppresses the cell proliferation, invasion, migration in ovarian cancer cells by targeting E2F5. PMID:27186275

miR-132 targeting E2F5 suppresses cell proliferation, invasion, migration in ovarian cancer cells.

PubMed

Tian, Hang; Hou, Lei; Xiong, Yu-Mei; Huang, Jun-Xiang; Zhang, Wen-Hua; Pan, Yong-Ying; Song, Xing-Rong

2016-01-01

Accumulating evidence showed that microRNA-132 (miR-132) are involved in development and progression of several types of cancers, however, the function and underlying molecular mechanism of miR-132 in ovarian cancer remains unclear. In this study we investigated the biological roles and molecular mechanism of miR-132 in ovarian cancer. Here, we found that that the expression levels of miR-132 were dramatically decreased in ovarian cancer cell lines and clinical ovarian cancer tissue samples. Then, we found that introduction of miR-132 significantly suppressed the proliferation, colony formation, migration and invasion of ovarian cancer cells. Mechanism investigation revealed that miR-132 inhibited the expression of transcription factor E2F5 by specifically targeting its mRNA 3'UTR. Moreover, the expression level of E2F5 was significantly increased in ovarian cancer tissues than in the adjacent normal tissues, and its expression was inversely correlated with miR-132 expression in clinical ovarian cancer tissues. Additionally, silencing E2F5 was able to inhibit the proliferation, colony formation, migration and invasion of ovarian cancer cells, parallel to the effect of miR-132 overexpression on the ovarian cancer cells. Meanwhile, overexpression of E2F5 reversed the inhibition effect mediated by miR-132 overexpression. These results indicate that miR-132 suppresses the cell proliferation, invasion, migration in ovarian cancer cells by targeting E2F5.

Signalling in the epidermis: the E2F cell cycle regulatory pathway in epidermal morphogenesis, regeneration and transformation.

PubMed

Ivanova, Iordanka A; D'Souza, Sudhir J A; Dagnino, Lina

2005-01-01

The epidermis is the outermost layer in the skin, and it is the first line of defence against the environment. The epidermis also provides a barrier against loss of fluids and electrolytes, which is crucial for life. Essential in the maintenance of this tissue is its ability to continually self-renew and regenerate after injury. These two characteristics are critically dependent on the ability of the principal epidermal cell type, the keratinocyte, to proliferate and to respond to differentiation cues. Indeed, the epidermis is a multilayered tissue composed of keratinocyte stem cells and their differentiated progeny. Central for the control of cell proliferation is the E2F transcription factor regulatory network. This signaling network also includes cyclins, cdk, cdk inhibitors and the retinoblastoma (pRb) family of proteins. The biological importance of the E2F/pRb pathway is emphasized by the fact that a majority of human tumours exhibit alterations that disrupt the ability of pRb proteins to inhibit E2F, leading to permanent activation of the latter. Further, E2F is essential for normal epidermal regeneration after injury. Other member of the E2F signaling pathway are also involved in epidermal development and pathophysiology. Thus, whereas the pRb family of proteins is essential for epidermal morphogenesis, abnormal regulation of cyclins and E2F proteins results in tumorgenesis in this tissue. In this review, we discuss the role of each member of this important growth regulatory network in epidermal formation, homeostasis and carcinogenesis.

Signalling In The Epidermis: The E2f Cell Cycle Regulatory Pathway In Epidermal Morphogenesis, Regeneration And Transformation

PubMed Central

2005-01-01

The epidermis is the outermost layer in the skin, and it is the first line of defence against the environment. The epidermis also provides a barrier against loss of fluids and electrolytes, which is crucial for life. Essential in the maintenance of this tissue is its ability to continually self-renew and regenerate after injury. These two characteristics are critically dependent on the ability of the principal epidermal cell type, the keratinocyte, to proliferate and to respond to differentiation cues. Indeed, the epidermis is a multilayered tissue composed of keratinocyte stem cells and their differentiated progeny. Central for the control of cell proliferation is the E2F transcription factor regulatory network. This signaling network also includes cyclins, cdk, cdk inhibitors and the retinoblastoma (pRb) family of proteins. The biological importance of the E2F/pRb pathway is emphasized by the fact that a majority of human tumours exhibit alterations that disrupt the ability of pRb proteins to inhibit E2F, leading to permanent activation of the latter. Further, E2F is essential for normal epidermal regeneration after injury. Other member of the E2F signaling pathway are also involved in epidermal development and pathophysiology. Thus, whereas the pRb family of proteins is essential for epidermal morphogenesis, abnormal regulation of cyclins and E2F proteins results in tumorgenesis in this tissue. In this review, we discuss the role of each member of this important growth regulatory network in epidermal formation, homeostasis and carcinogenesis. PMID:15951853

E2F1 interactions with hHR23A inhibit its degradation and promote DNA repair.

PubMed

Singh, Randeep K; Dagnino, Lina

2016-05-03

Nucleotide excision repair (NER) is a major mechanism for removal of DNA lesions induced by exposure to UV radiation in the epidermis. Recognition of damaged DNA sites is the initial step in their repair, and requires multiprotein complexes that contain XPC and hHR23 proteins, or their orthologues. A variety of transcription factors are also involved in NER, including E2F1. In epidermal keratinocytes, UV exposure induces E2F1 phosphorylation, which allows it to recruit various NER factors to sites of DNA damage. However, the relationship between E2F1 and hHR23 proteins vis-à-vis NER has remained unexplored. We now show that E2F1 and hHR23 proteins can interact, and this interaction stabilizes E2F1, inhibiting its proteasomal degradation. Reciprocally, E2F1 regulates hHR23A subcellular localization, recruiting it to sites of DNA photodamage. As a result, E2F1 and hHR23A enhance DNA repair following exposure to UV radiation, contributing to genomic stability in the epidermis.

E2F1 interactions with hHR23A inhibit its degradation and promote DNA repair

PubMed Central

Singh, Randeep K.; Dagnino, Lina

2016-01-01

Nucleotide excision repair (NER) is a major mechanism for removal of DNA lesions induced by exposure to UV radiation in the epidermis. Recognition of damaged DNA sites is the initial step in their repair, and requires multiprotein complexes that contain XPC and hHR23 proteins, or their orthologues. A variety of transcription factors are also involved in NER, including E2F1. In epidermal keratinocytes, UV exposure induces E2F1 phosphorylation, which allows it to recruit various NER factors to sites of DNA damage. However, the relationship between E2F1 and hHR23 proteins vis-à-vis NER has remained unexplored. We now show that E2F1 and hHR23 proteins can interact, and this interaction stabilizes E2F1, inhibiting its proteasomal degradation. Reciprocally, E2F1 regulates hHR23A subcellular localization, recruiting it to sites of DNA photodamage. As a result, E2F1 and hHR23A enhance DNA repair following exposure to UV radiation, contributing to genomic stability in the epidermis. PMID:27028861

Recombination reactions of 5-eV O(3P) atoms on a MgF2 surface

NASA Technical Reports Server (NTRS)

Orient, O. J.; Chutjian, A.; Murad, E.

1990-01-01

A source of hyperthermal, ground-state, impurity-free, atomic oxygen of an energy variable in the range 2-100 eV has been developed. Experimental results are presented of emission spectra in the wavelength range 250-850 nm produced by collisions of 5-eV O(3P) atoms with adsorbed NO and CO molecules on a MgF2 surface.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization.

PubMed

Qi, Qian-Rong; Zhao, Xu-Yu; Zuo, Ru-Juan; Wang, Tong-Song; Gu, Xiao-Wei; Liu, Ji-Long; Yang, Zeng-Ming

2015-01-01

Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans.

Involvement of atypical transcription factor E2F8 in the polyploidization during mouse and human decidualization

PubMed Central

Qi, Qian-Rong; Zhao, Xu-Yu; Zuo, Ru-Juan; Wang, Tong-Song; Gu, Xiao-Wei; Liu, Ji-Long; Yang, Zeng-Ming

2015-01-01

Polyploid decidual cells are specifically differentiated cells during mouse uterine decidualization. However, little is known about the regulatory mechanism and physiological significance of polyploidization in pregnancy. Here we report a novel role of E2F8 in the polyploidization of decidual cells in mice. E2F8 is highly expressed in decidual cells and regulated by progesterone through HB-EGF/EGFR/ERK/STAT3 signaling pathway. E2F8 transcriptionally suppresses CDK1, thus triggering the polyploidization of decidual cells. E2F8-mediated polyploidization is a response to stresses which are accompanied by decidualization. Interestingly, polyploidization is not detected during human decidualization with the down-regulation of E2F8, indicating differential expression of E2F8 may lead to the difference of decidual cell polyploidization between mice and humans. PMID:25892397

F199E substitution reduced toxicity of Clostridium perfringens epsilon toxin by depriving the receptor binding capability.

PubMed

Kang, Jingjing; Gao, Jie; Yao, Wenwu; Kang, Lin; Gao, Shan; Yang, Hao; Ji, Bin; Li, Ping; Liu, Jing; Yao, Jiahao; Xin, Wenwen; Zhao, Baohua; Wang, Jinglin

2017-07-03

Epsilon toxin (ETX), a potent toxin, is produced by types B and D strains of Clostridium perfringens, which could cause severe diseases in humans and domestic animals. Mutant rETX F199E was previously demonstrated to be a good vaccine candidate. However, the mechanism concerned remains unknown. To clarify how F199E substitution reduced ETX toxicity, we performed a series of experiments. The results showed that the cell-binding and pore-forming ability of rETX F199E was almost abolished. We speculated that F199E substitution reduced toxicity by depriving the receptor binding capability of ETX, which contributed to the hypothesis that domain I of ETX is responsible for cell binding. In addition, our data suggested that ETX could cause Ca 2+ release from intracellular Ca 2+ stores, which may underlie an alternate pathway leading to cell death. Furthermore, ETX induced crenation of the MDCK cells was observed, with sags and crests first appearing on the surface of condensed MDCK cells, according to scanning electron microscopy. The data also demonstrated the safety and potentiality of rETX F199E as a vaccine candidate for humans. In summary, findings of this work potentially contribute to a better understanding of the pathogenic mechanism of ETX and the development of vaccine against diseases caused by ETX, using mutant proteins.

A lentiviral vector with expression controlled by E2F-1: A potential tool for the study and treatment of proliferative diseases

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

Strauss, Bryan E.; Patricio, Juliana Rotelli; Program in Biotechnology, University of Sao Paulo

2006-10-06

We have constructed a lentiviral vector with expression limited to cells presenting active E2F-1 protein, a potential advantage for gene therapy of proliferative diseases. For the FE2FLW vector, the promoter region of the human E2F-1 gene was utilized to drive expression of luciferase cDNA, included as a reporter of viral expression. Primary, immortalized, and transformed cells were transduced with the FE2FLW vector and cell cycle alterations were induced with serum starvation/replacement, contact inhibition or drug treatment, revealing cell cycle-dependent changes in reporter activity. Forced E2F-1 expression, but not E2F-2 or E2F-3, increased reporter activity, indicating a major role for thismore » factor in controlling expression from the FE2FLW virus. We show the utility of this vector as a reporter of E2F-1 and proliferation-dependent cellular alterations upon cytotoxic/cytostatic treatment, such as the introduction of tumor suppressor genes. We propose that the FE2FLW vector may be a starting point for the development of gene therapy strategies for proliferative diseases, such as cancer or restinosis.« less

E2 and SN2 Reactions of X(-) + CH3CH2X (X = F, Cl); an ab Initio and DFT Benchmark Study.

PubMed

Bento, A Patrícia; Solà, Miquel; Bickelhaupt, F Matthias

2008-06-01

We have computed consistent benchmark potential energy surfaces (PESs) for the anti-E2, syn-E2, and SN2 pathways of X(-) + CH3CH2X with X = F and Cl. This benchmark has been used to evaluate the performance of 31 popular density functionals, covering local-density approximation, generalized gradient approximation (GGA), meta-GGA, and hybrid density-functional theory (DFT). The ab initio benchmark has been obtained by exploring the PESs using a hierarchical series of ab initio methods [up to CCSD(T)] in combination with a hierarchical series of Gaussian-type basis sets (up to aug-cc-pVQZ). Our best CCSD(T) estimates show that the overall barriers for the various pathways increase in the order anti-E2 (X = F) < SN2 (X = F) < SN2 (X = Cl) ∼ syn-E2 (X = F) < anti-E2 (X = Cl) < syn-E2 (X = Cl). Thus, anti-E2 dominates for F(-) + CH3CH2F, and SN2 dominates for Cl(-) + CH3CH2Cl, while syn-E2 is in all cases the least favorable pathway. Best overall agreement with our ab initio benchmark is obtained by representatives from each of the three categories of functionals, GGA, meta-GGA, and hybrid DFT, with mean absolute errors in, for example, central barriers of 4.3 (OPBE), 2.2 (M06-L), and 2.0 kcal/mol (M06), respectively. Importantly, the hybrid functional BHandH and the meta-GGA M06-L yield incorrect trends and qualitative features of the PESs (in particular, an erroneous preference for SN2 over the anti-E2 in the case of F(-) + CH3CH2F) even though they are among the best functionals as measured by their small mean absolute errors of 3.3 and 2.2 kcal/mol in reaction barriers. OLYP and B3LYP have somewhat higher mean absolute errors in central barriers (5.6 and 4.8 kcal/mol, respectively), but the error distribution is somewhat more uniform, and as a consequence, the correct trends are reproduced.

The E2F3—Oncomir 1 axis is activated in Wilms Tumor

PubMed Central

Kort, Eric J.; Farber, Leslie; Tretiakova, Maria; Petillo, David; Furge, Kyle A.; Yang, Ximing J.; Cornelius, Albert; Teh, Bin T.

2008-01-01

Oncomir-1 is an oncogenic cluster of microRNAs located on chromosome 13. Previous in vitro studies demonstrated that it is transcriptionally regulated by the transcription factor E2F3. In this report we combine expression profiling of both messenger RNA (mRNA) and micro RNAs (miRNA) in Wilms tumor (WT) samples to provide the first evidence that the E2F3—Oncomir 1 axis, previously identified in cell culture, is deregulated in primary human tumors. Analysis of RNA expression signatures demonstrated that an E2F3 gene signature was activated in all Wilms tumor samples analyzed, in contrast to other kidney tumors. This finding was validated by immunohistochemistry (IHC) on the protein level. Expression of E2F3 was lowest in early stage tumors, and highest in metastatic tissue. Expression profiling of miRNAs in WT showed that expression of each measured member of the Oncomir-1 family was highest in WT relative to other kidney tumor subtypes. Quantitative polymerase chain reaction (PCR) confirmed that these microRNAs were overexpressed in Wilms tumor relative to normal kidney tissue. These results suggest that the E2F3—Oncomir-1 axis is activated in Wilms tumor. Our study also demonstrates the utility of integrated genomics combining gene signature analysis with miRNA expression profiling to identify protein-miRNA interactions that are perturbed in disease states. PMID:18519660

Metabolism of styrene to styrene oxide and vinylphenols in cytochrome P450 2F2- and P450 2E1-knockout mouse liver and lung microsomes

PubMed Central

Shen, Shuijie; Li, Lei; Ding, Xinxin; Zheng, Jiang

2014-01-01

Pulmonary toxicity of styrene is initiated by cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main cytochrome P450 (CYP) enzymes responsible for styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of styrene metabolites (i.e. styrene oxide and 4-vinylphenol) and pulmonary toxicity of styrene, using Cyp2e1- and Cyp2f2-null mouse models. Dramatic decrease in the formation of styrene glycol and 4-vinylphenol was found in Cyp2f2-null mouse lung microsomes, relative to that in the wild-type mouse lung microsomes. However, no significant difference in the production of the styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knock–out and wild-type mice were treated with styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by styrene. Cyp2e1-null mice displayed similar susceptibility to lung toxicity of styrene as the wild-type animals. However, Cyp2f2-null mice were resistant to styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of styrene. The latter enzyme plays an important role in styrene-induced pulmonary toxicity. Both styrene oxide and 4-vinylphenol are suggested to participate in the development of lung injury induced by styrene. PMID:24320693

Metabolism of styrene to styrene oxide and vinylphenols in cytochrome P450 2F2- and P450 2E1-knockout mouse liver and lung microsomes.

PubMed

Shen, Shuijie; Li, Lei; Ding, Xinxin; Zheng, Jiang

2014-01-21

Pulmonary toxicity of styrene is initiated by cytochromes P450-dependent metabolic activation. P450 2E1 and P450 2F2 are considered to be two main cytochrome P450 enzymes responsible for styrene metabolism in mice. The objective of the current study was to determine the correlation between the formation of styrene metabolites (i.e., styrene oxide and 4-vinylphenol) and pulmonary toxicity of styrene, using Cyp2e1- and Cyp2f2-null mouse models. A dramatic decrease in the formation of styrene glycol and 4-vinylphenol was found in Cyp2f2-null mouse lung microsomes relative to that in the wild-type mouse lung microsomes; however, no significant difference in the production of the styrene metabolites was observed between lung microsomes obtained from Cyp2e1-null and the wild-type mice. The knockout and wild-type mice were treated with styrene (6.0 mmol/kg, ip), and cell counts and LDH activity in bronchoalveolar lavage fluids were monitored to evaluate the pulmonary toxicity induced by styrene. Cyp2e1-null mice displayed a susceptibility to lung toxicity of styrene similar to that of the wild-type animals; however, Cyp2f2-null mice were resistant to styrene-induced pulmonary toxicity. In conclusion, both P450 2E1 and P450 2F2 are responsible for the metabolic activation of styrene. The latter enzyme plays an important role in styrene-induced pulmonary toxicity. Both styrene oxide and 4-vinylphenol are suggested to participate in the development of lung injury induced by styrene.

Fluorine Kα X-Ray Emission Spectra of MgF2, CaF2, SrF2 and BaF2

NASA Astrophysics Data System (ADS)

Sugiura, Chikara; Konishi, Wataru; Shoji, Shizuko; Kojima, Shinjiro

1990-11-01

The fluorine Kα emission spectra in fluorescence from a series of alkaline-earth fluorides MF2 (M=Mg, Ca, Sr and Ba) are measured with a high-resolution two-crystal vacuum spectrometer. An anomalously low intensity of the K1L1 satellite peak arising from 1s-1(2s2p)-1 initial states is observed for SrF2. The measured emission spectra are presented along with the UPS spectra of the F- 2p valence bands obtained by Poole et al. and the fluorine K absorption-edge spectra by Oizumi et al. By using these spectra, the first peak or shoulder in the fluorine K absorption-edge spectra is identified as being due to a core exciton which is formed below the bottom of the conduction band. The binding energy of the exciton is estimated to be 1.3(± 0.3), 1.1(± 0.2), 1.0(± 0.2) and 1.7(± 0.2) eV for MgF2, CaF2, SrF2 and BaF2, respectively.

F2-isoprostanes and F4-neuroprostanes as markers of intracranial aneurysm development.

PubMed

Syta-Krzyżanowska, Anna; Jarocka-Karpowicz, Iwona; Kochanowicz, Jan; Turek, Grzegorz; Rutkowski, Robert; Gorbacz, Krzysztof; Mariak, Zenon; Skrzydlewska, Elżbieta

2018-04-24

Intracranial aneurysms are common, occurring in about 1-2% of the population. Saccular aneurysm is a pouch-like pathological dilatation of an intracranial artery that develops when the cerebral artery wall becomes too weak to resist hemodynamic pressure and distends. The aim of this study was to determine whether the development of intracranial aneurysms and subarachnoid hemorrhage (SAH) affects neuronal phospholipid metabolism, and what influence different invasive treatments have on brain free radical phospholipid metabolism. The level of polyunsaturated fatty acid (PUFA) cyclization products - F2-isoprostanes and F4-neuroprostanes - was examined using liquid chromatography - mass spectrometry (LC-MS) in the plasma of patients with brain aneurysm and resulting subarachnoid hemorrhage. It was revealed that an aneurysm leads to the enhancement of lipid peroxidation with a significant increase in plasma F2-isoprostanes and F4-neuroprostanes (more than 3-fold and 11-fold, respectively) in comparison to healthy subjects. The rupture of an aneurysm results in hemorrhage and an additional increase in examined prostaglandin derivatives. The embolization and clipping of aneurysms contribute to a gradual restoration of metabolic homeostasis in brain cells, which is visible in the decrease in PUFA cyclization products. The results indicate that aneurysm development is associated with enhanced inflammation and oxidative stress, factors which favor lipid peroxidation, particularly in neurons, whose membranes are rich in docosahexaenoic acid, a precursor of F4-neuroprostanes.

Mitochondrial ribosomal protein S18-2 is highly expressed in endometrial cancers along with free E2F1

PubMed Central

Iurchenko, Natalia; Kovalevska, Larysa; Stip, Maria C; Budnikova, Daria; Andersson, Sonia; Polischuk, Ludmila; Buchynska, Lubov; Kashuba, Elena

2016-01-01

Endometrial cancer (EC) is one of the most frequent causes of cancer death among women in developed countries. Histopathological diagnosis and imaging techniques for EC are limited, thus new prognostic markers are needed to offer patients the best treatment and follow-up. In the present paper we showed that the level of mitochondrial ribosomal protein MRPS18-2 (S18-2) increased in EC compared with the normal endometrium and hyperplasia, based on a study of 42 patient biopsies. Importantly, high expression of free E2F1 in EC correlates well with high S18-2 expression. The EC cell line HEC-1-A, which overexpresses S18-2 constitutively, showed an increased proliferation capacity in vitro and in vivo (in SCID mice). Moreover, pan-keratin, beta-catenin and E-cadherin signals are diminished in these cells, compared to the parental HEC-1-A line, in contrast to vimentin signal that is increased. This may be associated with epithelial-mesenchymal cell transition (EMT). We conclude that high expression of S18-2 and free E2F1, and low pan-keratin, beta-catenin, and E-cadherin signals might be a good set of prognostic markers for EC. PMID:26959119

Identification of novel posttranscriptional targets of the BCR/ABL oncoprotein by ribonomics: requirement of E2F3 for BCR/ABL leukemogenesis

PubMed Central

Eiring, Anna M.; Neviani, Paolo; Santhanam, Ramasamy; Oaks, Joshua J.; Chang, Ji Suk; Notari, Mario; Willis, William; Gambacorti-Passerini, Carlo; Volinia, Stefano; Marcucci, Guido; Caligiuri, Michael A.; Leone, Gustavo W.

2008-01-01

Several RNA binding proteins (RBPs) have been implicated in the progression of chronic myelogenous leukemia (CML) from the indolent chronic phase to the aggressively fatal blast crisis. In the latter phase, expression and function of specific RBPs are aberrantly regulated at transcriptional or posttranslational levels by the constitutive kinase activity of the BCR/ABL oncoprotein. As a result, altered expression/function of RBPs leads to increased resistance to apoptotic stimuli, enhanced survival, growth advantage, and differentiation arrest of CD34+ progenitors from patients in CML blast crisis. Here, we identify the mRNAs bound to the hnRNP-A1, hnRNP-E2, hnRNP-K, and La/SSB RBPs in BCR/ABLtransformed myeloid cells. Interestingly, we found that the mRNA encoding the transcription factor E2F3 associates to hnRNP-A1 through a conserved binding site located in the E2F3 3′ untranslated region (UTR). E2F3 levels were up-regulated in CML-BCCD34+ in a BCR/ABL kinase– and hnRNP-A1 shuttling–dependent manner. Moreover, by using shRNA-mediated E2F3 knock-down and BCR/ABL-transduced lineage-negative bone marrow cells from E2F3+/+ and E2F3−/− mice, we show that E2F3 expression is important for BCR/ABL clonogenic activity and in vivo leukemogenic potential. Thus, the complexity of the mRNA/RBP network, together with the discovery of E2F3 as an hnRNP-A1–regulated factor, outlines the relevant role played by RBPs in posttranscriptional regulation of CML development and progression. PMID:17925491

Operational competency development in E and F grade nursing staff: preparation for management.

PubMed

Porter, S; Anderson, L; Chetty, A; Dyker, S; Murphy, F; Cheyne, H; Latto, D; Grant, A; McLachlan, M; Wild, P; McDonald, A; Kettles, A M

2006-07-01

There is limited literature for operational management competency development in E and F grade nursing staff. These grades of nursing staff have to take over from G grade nurses ward managers on a regular basis. With human resources doing less of the operational management and taking more of an advisory role, nursing staff are now required to deal with disciplinary procedures and other management issues in a more consistent manner. Therefore, this development programme in a Scottish primary care NHS psychiatric service was designed to enable E and F grade nurses to take over from ward managers and to enable ward managers to 'succession plan' for times when they will be absent. The literature is reviewed, the background to the development programme described and the design of the development programme is explained. The results from both the pilot study (n=13) and first group (n=8) through the course are presented, evaluated discussed.

Functional interaction of CCAAT/enhancer-binding-protein-α basic region mutants with E2F transcription factors and DNA.

PubMed

Kowenz-Leutz, Elisabeth; Schuetz, Anja; Liu, Qingbin; Knoblich, Maria; Heinemann, Udo; Leutz, Achim

2016-07-01

The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) regulates cell cycle arrest and terminal differentiation of neutrophils and adipocytes. Mutations in the basic leucine zipper domain (bZip) of C/EBPα are associated with acute myeloid leukemia. A widely used murine transforming C/EBPα basic region mutant (BRM2) entails two bZip point mutations (I294A/R297A). BRM2 has been discordantly described as defective for DNA binding or defective for interaction with E2F. We have separated the two BRM2 mutations to shed light on the intertwined reciprocity between C/EBPα-E2F-DNA interactions. Both, C/EBPα I294A and R297A retain transactivation capacity and interaction with E2F-DP. The C/EBPα R297A mutation destabilized DNA binding, whereas the C/EBPα I294A mutation enhanced binding to DNA. The C/EBPα R297A mutant, like BRM2, displayed enhanced interaction with E2F-DP but failed to repress E2F-dependent transactivation although both mutants were readily suppressed by E2F1 for transcription through C/EBP cis-regulatory sites. In contrast, the DNA binding enhanced C/EBPα I294A mutant displayed increased repression of E2F-DP mediated transactivation and resisted E2F-DP mediated repression. Thus, the efficient repression of E2F dependent S-phase genes and the activation of differentiation genes reside in the balanced DNA binding capacity of C/EBPα. Copyright © 2016 Elsevier B.V. All rights reserved.

Parameters to Maximize 2f2-f1 Distortion Product Otoacoustic Emission Levels

ERIC Educational Resources Information Center

Horn, Jennifer H.; Pratt, Shiela R.; Durrant, John D.

2008-01-01

Purpose: Past research has established parameters for the 2f1-f2 distortion product otoacoustic emissions (DPOAEs) that enhance response levels (e.g., L1 - L2 = 10 dB; f2/f1 = 1.22; L1, L2 = 65, 55 dB SPL). These same parameters do not optimize 2f2-f1 DPOAEs. Therefore, this study was conducted to evaluate more completely those parameters that…

E2F transcription factor 2 variants as predictive biomarkers for recurrence risk in patients with squamous cell carcinoma of the oropharynx.

PubMed

Li, Yuncheng; Sturgis, Erich M; Zhu, Lijun; Cao, Xiaoli; Wei, Qingyi; Zhang, Hua; Li, Guojun

2017-04-01

Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1 008 patients. A log-rank test and multivariable Cox models were used to assess the associations. Compared with patients with variant genotypes of E2F2-rs2742976 and E2F2-rs3218123, patients with common homozygous genotypes had better disease-free survival (both log-rank, P < 0.001) and lower SCCOP recurrence risk (HR, 0.4, 95% CI, 0.3-0.6 and HR, 0.3, 95% CI, 0.2-0.5, respectively) after multivariable adjustment. Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of E2F2-rs2742976 and E2F2-rs3218123 had better disease-free survival rates (both log-rank, P < 0.001) and lower recurrence risk (HR, 0.1, 95% CI, 0.1-0.4 and HR, 0.1, 95% CI, 0.0-0.2, respectively) than patients with variant genotypes. However, no significant differences were found for the other three polymorphisms. After combining the risk genotypes of the five polymorphisms and using the high-risk group (2-5 risk genotypes) as the reference group, we found that the low-risk groups (0 or 1 risk genotype) had significantly lower recurrence risk among all patients (HR, 0.4, 95% CI, 0.3-0.6) and among HPV16-positive patients (HR, 0.2, 95% CI, 0.1-0.5). Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Overexpression of E2F3 promotes proliferation of functional human β cells without induction of apoptosis

PubMed Central

Rady, Brian; Chen, Yanmei; Vaca, Pilar; Wang, Qian; Wang, Yong; Salmon, Patrick; Oberholzer, José

2013-01-01

The mechanisms that control proliferation, or lack thereof, in adult human β cells are poorly understood. Controlled induction of proliferation could dramatically expand the clinical application of islet cell transplantation and represents an important component of regenerative approaches to a functional cure of diabetes. Adult human β cells are particularly resistant to common proliferative targets and often dedifferentiate during proliferation. Here we show that expression of the transcription factor E2F3 has a role in regulating β-cell quiescence and proliferation. We found human islets have virtually no expression of the pro-proliferative G1/S transcription factors E2F1–3, but an abundance of inhibitory E2Fs 4–6. In proliferative human insulinomas, inhibitory E2Fs were absent, while E2F3 is expressed. Using this pattern as a “roadmap” for proliferation, we demonstrated that ectopic expression of nuclear E2F3 induced significant expansion of insulin-positive cells in both rat and human islets. These cells did not undergo apoptosis and retained their glucose-responsive insulin secretion, showing the ability to reverse diabetes in mice. Our results suggest that E2F4–6 may help maintain quiescence in human β cells and identify E2F3 as a novel target to induce proliferation of functional β cells. Refinement of this approach may increase the islets available for cell-based therapies and research and could provide important cues for understanding in vivo proliferation of β cells. PMID:23907129

ROS Production Is Essential for the Apoptotic Function of E2F1 in Pheochromocytoma and Neuroblastoma Cell Lines

PubMed Central

Espada, Lilia; Meo-Evoli, Nathalie; Sancho, Patricia; Real, Sebastian; Fabregat, Isabel; Ambrosio, Santiago; Tauler, Albert

2012-01-01

In this study we demonstrate that accumulation of reactive oxygen species (ROS) is essential for E2F1 mediated apoptosis in ER-E2F1 PC12 pheochromocytoma, and SH-SY5Y and SK-N-JD neuroblastoma stable cell lines. In these cells, the ER-E2F1 fusion protein is expressed in the cytosol; the addition of 4-hydroxytamoxifen (OHT) induces its translocation to the nucleus and activation of E2F1target genes. Previously we demonstrated that, in ER-E2F1 PC12 cells, OHT treatment induced apoptosis through activation of caspase-3. Here we show that caspase-8 activity did not change upon treatment with OHT. Moreover, over-expression of Bcl-xL arrested OHT-induced apoptosis; by contrast, over-expression of c-FLIP, did not have any effect on OHT-induced apoptosis. OHT addition induces BimL expression, its translocation to mitochondria and activation of Bax, which is paralleled by diminished mitochondrial enrichment of Bcl-xL. Treatment with a Bax-inhibitory peptide reduced OHT-induced apoptosis. These results point out the essential role of mitochondria on the apoptotic process driven by E2F1. ROS accumulation followed E2F1 induction and treatment with the antioxidant N-acetylcysteine, inhibited E2F1-induced Bax translocation to mitochondria and subsequent apoptosis. The role of ROS in mediating OHT-induced apoptosis was also studied in two neuroblastoma cell lines, SH-SY5Y and SK-N-JD. In SH-SY5Y cells, activation of E2F1 by the addition of OHT induced ROS production and apoptosis, whereas over-expression of E2F1 in SK-N-JD cells failed to induce either response. Transcriptional profiling revealed that many of the genes responsible for scavenging ROS were down-regulated following E2F1-induction in SH-SY5Y, but not in SK-N-JD cells. Finally, inhibition of GSK3β blocked ROS production, Bax activation and the down regulation of ROS scavenging genes. These findings provide an explanation for the apparent contradictory role of E2F1 as an apoptotic agent versus a cell cycle activator

Perspective on the reactions between F- and CH3CH2F: the free energy landscape of the E2 and SN2 reaction channels.

PubMed

Ensing, Bernd; Klein, Michael L

2005-05-10

Recently, we computed the 3D free energy surface of the base-induced elimination reaction between F(-) and CH(3)CH(2)F by using a powerful technique within Car-Parrinello molecular dynamics simulation. Here, the set of three order parameters is expanded to six, which allows the study of the competing elimination and substitution reactions simultaneously. The power of the method is exemplified by the exploration of the six-dimensional free energy landscape, sampling, and mapping out the eight stable states as well as the connecting bottlenecks. The free energy profile and barrier along the E2 and S(N)2 reaction channels are refined by using umbrella sampling. The two mechanisms do not share a common "E2C-like" transition state. Comparison with the zero temperature profiles shows a particularly significant entropy contribution to the S(N)2 channel.

HER2 signaling drives DNA anabolism and proliferation through SRC-3 phosphorylation and E2F1-regulated genes

PubMed Central

Nikolai, Bryan C.; Lanz, Rainer B.; York, Brian; Dasgupta, Subhamoy; Mitsiades, Nicholas; Creighton, Chad J.; Tsimelzon, Anna; Hilsenbeck, Susan G.; Lonard, David M.; Smith, Carolyn L.; O’Malley, Bert W.

2016-01-01

Approximately 20% of early-stage breast cancers display amplification or overexpression of the ErbB2/HER2 oncogene, conferring poor prognosis and resistance to endocrine therapy. Targeting HER2+ tumors with trastuzumab or the receptor tyrosine kinase (RTK) inhibitor lapatinib significantly improves survival, yet tumor resistance and progression of metastatic disease still develop over time. While the mechanisms of cytosolic HER2 signaling are well studied, nuclear signaling components and gene regulatory networks that bestow therapeutic resistance and limitless proliferative potential are incompletely understood. Here, we use biochemical and bioinformatic approaches to identify effectors and targets of HER2 transcriptional signaling in human breast cancer. Phosphorylation and activity of the Steroid Receptor Coactivator-3 (SRC-3) is reduced upon HER2 inhibition, and recruitment of SRC-3 to regulatory elements of endogenous genes is impaired. Transcripts regulated by HER2 signaling are highly enriched with E2F1 binding sites and define a gene signature associated with proliferative breast tumor subtypes, cell cycle progression, and DNA replication. We show that HER2 signaling promotes breast cancer cell proliferation through regulation of E2F1-driven DNA metabolism and replication genes together with phosphorylation and activity of the transcriptional coactivator SRC-3. Furthermore, our analyses identified a cyclin dependent kinase (CDK) signaling node that, when targeted using the CDK4/6 inhibitor Palbociclib, defines overlap and divergence of adjuvant pharmacological targeting. Importantly, lapatinib and palbociclib strictly block de novo synthesis of DNA, mostly through disruption of E2F1 and its target genes. These results have implications for rational discovery of pharmacological combinations in pre-clinical models of adjuvant treatment and therapeutic resistance. PMID:26833126

A novel mechanism of E2F1 regulation via nucleocytoplasmic shuttling: determinants of nuclear import and export.

PubMed

Ivanova, Iordanka A; Vespa, Alisa; Dagnino, Lina

2007-09-01

E2F1 is a transcription factor central for cell survival, proliferation, and repair following genomic insult. Depending on the cell type and conditions, E2F1 can induce apoptosis in transformed cells, behaving as a tumour suppressor, or impart growth advantages favouring tumour formation. The pleiotropic functions of E2F1 are a likely consequence of its ability to transcriptionally control a wide variety of target genes, and require tight regulation of its activity at multiple levels. Although sequestration of proteins to particular cellular compartments is a well-established regulatory mechanism, virtually nothing is known about its contribution to modulation of E2F1 target gene expression. We have examined the subcellular trafficking of E2F1 and, contrary to the widely held notion that this factor is constitutively nuclear, we now demonstrate that it is subjected to continuous nucleocytoplasmic shuttling. We have also defined two nuclear localization domains and a nuclear export region, which mediates CRM1-dependent transit out of the nucleus. The predominant subcellular location of E2F1 is likely determined by the balance between the activity of nuclear import and export domains, and can be modulated by differentiation stimuli in epidermal cells. Thus, we have identified a hitherto unrecognized mechanism to control E2F1 function through modulation of its subcellular localization.

Effects of Al content and annealing on the phases formation, lattice parameters, and magnetization of A lxF e2B2 (x =1.0 ,1.1 ,1.2 ) alloys

NASA Astrophysics Data System (ADS)

Levin, E. M.; Jensen, B. A.; Barua, R.; Lejeune, B.; Howard, A.; McCallum, R. W.; Kramer, M. J.; Lewis, L. H.

2018-03-01

AlF e2B2 is a ferromagnet with the Curie temperature around 300 K and has the potential to be an outstanding rare-earth free candidate for magnetocaloric applications. However, samples prepared from the melt contain additional phases which affect the functional response of the AlF e2B2 phase. We report on the effects of Al content in samples with the initial (nominal) composition of A lxF e2B2 , where x =1.0 , 1.1, and 1.2 prepared by arc-melting followed by suction casting and annealing. The as-cast A lxF e2B2 alloys contain AlF e2B2 as well as additional phases, including the primary solidifying FeB and A l13F e4 compounds, which are ferromagnetic and paramagnetic, respectively, at 300 K. The presence of these phases makes it difficult to extract the intrinsic magnetic properties of AlF e2B2 phase. Annealing of A lxF e2B2 alloys at 1040 °C for 3 days allows for reaction of the FeB with A l13F e4 to form the AlF e2B2 phase, significantly reduces the amount of additional phases, and results in nearly pure AlF e2B2 phase as confirmed with XRD, magnetization, scanning electron microscopy, and electronic transport. The values of the magnetization, effective magnetic moment per Fe atom, specific heat capacity, electrical resistivity, and Seebeck coefficient for the AlF e2B2 compound have been established.

E2F1/TS Immunophenotype and Survival of Patients with Colorectal Cancer Treated with 5FU-Based Adjuvant Therapy.

PubMed

Sulzyc-Bielicka, Violetta; Domagala, Pawel; Bielicki, Dariusz; Safranow, Krzysztof; Rogowski, Wojciech; Domagala, Wenancjusz

2016-07-01

The predictive value of thymidylate synthase (TS) expression alone for 5FU-based treatment of colorectal cancer (CRC) has not been clinically confirmed. Little is known on the association of expression of E2F1, which controls the transcription of genes encoding proteins engaged in DNA synthesis including TS, and survival of patients with CRC. The purpose of this study is to assess the correlation between expression of both E2F1 and TS in CRCs and survival of patients administered adjuvant 5FU-based chemotherapy, in order to find a better predictor of treatment outcome than expression of TS or E2F1 alone. Nuclear TS and E2F1 were detected by immunohistochemistry in tissue microarrays from 190 CRCs (Astler-Coller stage B2 or C). Multivariate analysis identified significant association of the combined E2F1+TS+ immunophenotype with worse OS (HR = 3,78, P = 0,009) and DFS (HR = 2,30, P = 0,03) of patients with colon cancer. There were significant differences between E2F1+TS+ and E2F1-TS- Kaplan-Meier survival curves in relation to DFS (P = 0.008) and OS (P = 0.01). About 37 and 31 % difference in 3-year DFS and OS respectively were seen between patients with E2F1+TS+ vs. E2F1-TS- colon cancer immunophenotype. The E2F1+TS+ immunophenotype may be a marker of poor prognosis (the worst DFS and OS) of patients with colon cancer treated with 5FU-based adjuvant therapy. A subgroup of patients with this immunophenotype may require different and perhaps more aggressive treatment than 5FU-based chemotherapy. Thus, the combined E2F1/TS immunophenotype could be a potential indicator of colon cancer sensitivity to 5FU.

Safety, Health, and Fire Prevention Guide for Hospital Safety Managers

DTIC Science & Technology

1993-03-01

Safety committee S 2-5 Oxygen quality assurance program 0 2-6 Safety and fire prevention library 0 2-7 Safety services to Dental Activities • 2-8...Chapter 2 Safety Management 2-1. Safety policy statement Health Services Command (HSC) Supplement (Suppl) 1 to Army Regulation (AR) 385-10 and the...Management. (b) The medical staff. (c) The nursing service . (d) Logistics. (e) Nutritional care. (f) Preventive medicine. * 2-3 USAEHA TG No. 152 March 1993 (g

Modulation of E2F activity in primary mouse B cells following stimulation via surface IgM and CD40 receptors.

PubMed

Lam, E W; Glassford, J; van der Sman, J; Banerji, L; Pizzey, A R; Shaun, N; Thomas, B; Klaus, G G

1999-10-01

Since signals via CD40 and the B cell receptor are known to synergize to induce B cell activation, we have analyzed the pocket protein/E2F complexes in mouse B lymphocytes following stimulation by anti-IgM, anti-CD40, alone or together. We find that E2F4 and DP1 form the predominant E2F heterodimers in the G0 and G1 phases of the cell cycle, complexed with hypophosphorylated p130. During late G1 and S phase this complex is replaced by at least three different E2F complexes, one of which is an E2F complex containing p107 or pRB as well as two "free" E2F complexes consisting of E2F4/DP1 and E2F1-3/DP1. These effects were mirrored by the levels and phosphorylation status of the three pocket proteins. We also observed an increase in electrophoretic mobility of DP1 and E2F4 as B cells progressed from G0 into early G1, resulting from their dephosphorylation. This is known to correlate with a decrease in DNA binding capacity of these proteins and could also be important for derepression of genes negatively regulated through E2F sites in their promoters. These results therefore indicate that the pRB/E2F pathway integrates proliferative signals emanating from the sIgM and CD40 receptors.

Effects of disorder on the intrinsically hole-doped iron-based superconductor KC a2F e4A s4F2 by cobalt substitution

NASA Astrophysics Data System (ADS)

Ishida, Junichi; Iimura, Soshi; Hosono, Hideo

2017-11-01

In this paper, the effects of cobalt substitution on the transport and electronic properties of the recently discovered iron-based superconductor KC a2F e4A s4F2 , with Tc=33 K , are reported. This material is an unusual superconductor showing intrinsic hole conduction (0.25 holes /F e2 + ). Upon doping of Co, the Tc of KC a2(Fe1-xC ox) 4A s4F2 gradually decreased, and bulk superconductivity disappeared when x ≥0.25 . Conversion of the primary carrier from p type to n type upon Co-doping was clearly confirmed by Hall measurements, and our results are consistent with the change in the calculated Fermi surface. Nevertheless, neither spin density wave (SDW) nor an orthorhombic phase, which are commonly observed for nondoped iron-based superconductors, was observed in the nondoped or electron-doped samples. The electron count in the 3 d orbitals and structural parameters were compared with those of other iron-based superconductors to show that the physical properties can be primarily ascribed to the effects of disorder.

A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites.

PubMed Central

Sellers, W R; Rodgers, J W; Kaelin, W G

1995-01-01

An intact T/E1A-binding domain (the pocket) is necessary, but not sufficient, for the retinoblastoma protein (RB) to bind to DNA-protein complexes containing E2F and for RB to induce a G1/S block. Indirect evidence suggests that the binding of RB to E2F may, in addition to inhibiting E2F transactivation function, generate a complex capable of functioning as a transrepressor. Here we show that a chimera in which the E2F1 transactivation domain was replaced with the RB pocket could, in a DNA-binding and pocket-dependent manner, mimic the ability of RB to repress transcription and induce a cell cycle arrest. In contrast, a transdominant negative E2F1 mutant that is capable of blocking E2F-dependent transactivation did not. Fusion of the RB pocket to a heterologous DNA-binding domain unrelated to E2F likewise generated a transrepressor protein when scored against a suitable reporter. These results suggest that growth suppression by RB is due, at least in part, to transrepression mediated by the pocket domain bound to certain promoters via E2F. Images Fig. 4 Fig. 5 PMID:8524800

lncRNA-HIT promotes cell proliferation of non-small cell lung cancer by association with E2F1.

PubMed

Yu, L; Fang, F; Lu, S; Li, X; Yang, Y; Wang, Z

2017-05-01

Lung cancer is the leading cause of cancer-related death around the world. Long noncoding RNA (lncRNA) has pivotal roles in cancer occurrence and development. However, only a few lncRNAs have been functionally characterized. In the present study, we investigated the effects of lncRNA-HIT (HOXA transcript induced by TGFβ) expression on non-small cell lung cancer (NSCLC) cell phenotype with the gain-of-function and loss-of-function assays. We found that ectopic expression or knockdown of lncRNA-HIT markedly increased or decreased NSCLC cell proliferation, respectively. Moreover, we also showed that lncRNA-HIT interacted with E2F1 to regulate its target genes, such as Survivin, FOXM1, SKP2, NELL2 and DOK1. Collectively, our findings indicated that lncRNA-HIT affected the proliferation of NSCLC cells at least in part via regulating the occupancy of E2F1 in the promoter regions of its target genes. The lncRNA-HIT-E2F1 complex may be a potential target for NSCLC treatment.

The association of GSK3 beta with E2F1 facilitates nerve growth factor-induced neural cell differentiation.

PubMed

Zhou, Fangfang; Zhang, Long; Wang, Aijun; Song, Bo; Gong, Kai; Zhang, Lihai; Hu, Min; Zhang, Xiufang; Zhao, Nanming; Gong, Yandao

2008-05-23

It is widely acknowledged that E2F1 and GSK3beta are both involved in the process of cell differentiation. However, the relationship between E2F1 and GSK3beta in cell differentiation has yet to be discovered. Here, we provide evidence that in the differentiation of PC12 cells induced by nerve growth factor (NGF), GSK3beta was increased at both the mRNA and protein levels, whereas E2F1 at these two levels was decreased. Both wild-type GSK3beta and its kinase-defective mutant GSK3beta KM can inhibit E2F1 by promoting its ubiquitination through physical interaction. In addition, the colocalization of GSK3beta and E2F1 and their subcellular distribution, regulated by NGF, were observed in the process of PC12 differentiation. At the tissue level, GSK3beta colocalized and interacted with E2F1 in mouse hippocampus. Furthermore, GSK3beta facilitated neurite outgrowth by rescuing the promoter activities of Cdk inhibitors p21 and p15 from the inhibition caused by E2F1. To summarize, our findings suggest that GSK3beta can promote the ubiquitination of E2F1 via physical interaction and thus inhibit its transcription activity in a kinase activity independent manner, which plays an important role in the NGF-induced PC12 differentiation.

LOFT L2-3 blowdown experiment safety analyses D, E, and G; LOCA analyses H, K, K1

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

Perryman, J.L.; Keeler, C.D.; Saukkoriipi, L.O.

1978-12-01

Three calculations using conservative off-nominal conditions and evaluation model options were made using RELAP4/MOD5 for blowdown-refill and RELAP4/MOD6 for reflood for Loss-of-Fluid Test Experiment L2-3 to support the experiment safety analysis effort. The three analyses are as follows: Analysis D: Loss of commercial power during Experiment L2-3; Analysis E: Hot leg quick-opening blowdown valve (QOBV) does not open during Experiment L2-3; and Analysis G: Cold leg QOBV does not open during Experiment L2-3. In addition, the results of three LOFT loss-of-coolant accident (LOCA) analyses using a power of 56.1 MW and a primary coolant system flow rate of 3.6 millionmore » 1bm/hr are presented: Analysis H: Intact loop 200% hot leg break; emergency core cooling (ECC) system B unavailable; Analysis K: Pressurizer relief valve stuck in open position; ECC system B unavailable; and Analysis K1: Same as analysis K, but using a primary coolant system flow rate of 1.92 million 1bm/hr (L2-4 pre-LOCE flow rate). For analysis D, the maximum cladding temperature reached was 1762/sup 0/F, 22 sec into reflood. In analyses E and G, the blowdowns were slower due to one of the QOBVs not functioning. The maximum cladding temperature reached in analysis E was 1700/sup 0/F, 64.7 sec into reflood; for analysis G, it was 1300/sup 0/F at the start of reflood. For analysis H, the maximum cladding temperature reached was 1825/sup 0/F, 0.01 sec into reflood. Analysis K was a very slow blowdown, and the cladding temperatures followed the saturation temperature of the system. The results of analysis K1 was nearly identical to analysis K; system depressurization was not affected by the primary coolant system flow rate.« less

Comparison of ionospheric F2 peak parameters foF2 and hmF2 with IRI2001 at Hainan

NASA Astrophysics Data System (ADS)

Wang, X.; Shi, J. K.; Wang, G. J.; Gong, Y.

2009-06-01

Monthly median values of foF2, hmF2 and M(3000)F2 parameters, with quarter-hourly time interval resolution for the diurnal variation, obtained with DPS4 digisonde at Hainan (19.5°N, 109.1°E; Geomagnetic coordinates: 178.95°E, 8.1°N) are used to investigate the low-latitude ionospheric variations and comparisons with the International Reference Ionosphere (IRI) model predictions. The data used for the present study covers the period from February 2002 to April 2007, which is characterized by a wide range of solar activity, ranging from high solar activity (2002) to low solar activity (2007). The results show that (1) Generally, IRI predictions follow well the diurnal and seasonal variation patterns of the experimental values of foF2, especially in the summer of 2002. However, there are systematic deviation between experimental values and IRI predictions with either CCIR or URSI coefficients. Generally IRI model greatly underestimate the values of foF2 from about noon to sunrise of next day, especially in the afternoon, and slightly overestimate them from sunrise to about noon. It seems that there are bigger deviations between IRI Model predictions and the experimental observations for the moderate solar activity. (2) Generally the IRI-predicted hmF2 values using CCIR M(3000)F2 option shows a poor agreement with the experimental results, but there is a relatively good agreement in summer at low solar activity. The deviation between the IRI-predicted hmF2 using CCIR M(3000)F2 and observed hmF2 is bigger from noon to sunset and around sunrise especially at high solar activity. The occurrence time of hmF2 peak (about 1200 LT) of the IRI model predictions is earlier than that of observations (around 1500 LT). The agreement between the IRI hmF2 obtained with the measured M(3000)F2 and the observed hmF2 is very good except that IRI overestimates slightly hmF2 in the daytime in summer at high solar activity and underestimates it in the nighttime with lower values near

E2F1 and NF-κB: Key Mediators of Inflammation-associated Cancers and Potential Therapeutic Targets.

PubMed

Huang, Yulin; Chen, Rui; Zhou, Jianwei

2016-01-01

Inflammation is the fundamental protective response; however disordered immuno-response can cause chronic human disease, including cancer. Inflammatory cells and mediators are essential to the tumor microenvironment and dissection of this complex molecular and cellular milieu may elucidate a connection between cancer and inflammation and help to identify potential novel therapeutic targets. Thus, focusing on transcription factor NF-κB and E2F1 in inflammation-associated cancer is urgent. NF-κB activation is prevalent in carcinomas, mainly driven by inflammatory cytokines in the tumor microenvironment. E2F1 is also involved in regulating immune responses. Understanding the crosstalk between the two pathways may contribute to the development of novel anti-cancer drugs.

F14A System Safety Program Plan

DTIC Science & Technology

1981-09-03

by block number) Electromagnetic Pulse (EMP) Safety Plans Test Program EMP Testing F14 Aircraft Plans 20 ABSTRACT (Continue on reverse side if...compromising completion of the required experimental tasks. This document addresses the safety aspect of performing an Electromagnetic Pulse (EMP) test

Painful Charcot-Marie-Tooth neuropathy type 2E/1F due to a novel NEFL mutation.

PubMed

Doppler, Kathrin; Kunstmann, Erdmute; Krüger, Stefan; Sommer, Claudia

2017-05-01

Charcot-Marie-Tooth neuropathy (CMT) 2E/1F is caused by mutations in the neurofilament light-chain polypeptide (NEFL) gene. Giant axons are a histological hallmark frequently seen in nerves of patients with CMT2E. We describe the case of a 43-year-old patient with a painful, predominantly sensory neuropathy. The patient's sural nerve biopsy showed multiple giant axons. Genetic sequencing of the NEFL gene revealed that the patient was heterozygous for an altered sequence of the gene, c.816C>G, p.Asn272Lys, which has not yet been described in CMT2E/1F. In contrast to other cases of CMT2E/1F, where motor symptoms are predominant, pain was the most disabling symptom in this patient. Muscle Nerve 55: 752-755, 2017. © 2016 Wiley Periodicals, Inc.

Single Cell Analysis to locate the Restriction Point with respect to E2F Expression

NASA Astrophysics Data System (ADS)

Pimienta, R.; Johnson, A.

2011-12-01

The restriction point is a G1-phase checkpoint that regulates passage through the cell cycle and is misregulated in all known types of cancer. The Rb-E2F switch is thought to be one of the most relevant molecular mechanisms which regulate the restriction point in mammalian cells. However, recent experiments have brought the timing of the restriction point into question. In previous studies, cells were analyzed as populations and this prevented an accurate determination of the restriction point. By creating and analyzing an E2F-GFP reporter in single cells, we can pinpoint the timing of E2F activation and determine whether it coincides with the restriction point. Using calcium phosphate and Fugene,we transfected human embryonic kidney (293T) cells with a CMV-GFP plasmid and an E2F-GFP reporter. Based on our results, it appears that calcium phosphate is more effective than Fugene at transfecting mammalian cells. The calcium phosphate transfection had 9.59% more fluorescent cells than Fugene. However, this result only occurred with the CMV-GFP plasmid and not the E2F-GFP reporter, which was not properly expressed in human embryonic kidney (293T) cells. We will continue troubleshooting to fix this reporter as we proceed with our research. Once the reporter is properly cloned, we will transfect it into retinal pigmented epithelial (RPE1-hTERT) cells using the calcium phosphate method. RPE1-hTERT cells are an immortalized with telomerase and are more close to normal cells than tumor-derived cell lines. Through this research we will better comprehend commitment to the mammalian cell cycle.

AML1 is overexpressed in patients with myeloproliferative neoplasms and mediates JAK2V617F-independent overexpression of NF-E2

PubMed Central

Wang, Wei; Schwemmers, Sven; Hexner, Elizabeth O.

2010-01-01

The transcription factor NF-E2 is overexpressed in the majority of patients with polycythemia vera (PV). Concomitantly, 95% of these patients carry the JAK2V617F mutation. Although NF-E2 levels correlate with JAK2V671F allele burden in some PV cohorts, the molecular mechanism causing aberrant NF-E2 expression has not been described. Here we show that NF-E2 expression is also increased in patients with essential thrombocythemia and primary myelofibrosis independent of the presence of the JAK2V617F mutation. Characterization of the NF-E2 promoter revealed multiple functional binding sites for AML1/RUNX-1. Chromatin immunoprecipitation demonstrated AML1 binding to the NF-E2 promoter in vivo. Moreover, AML1 binding to the NF-E2 promoter was significantly increased in granulocytes from PV patients compared with healthy controls. AML1 mRNA expression was elevated in patients with PV, essential thrombocythemia, and primary myelofibrosis both in the presence and absence of JAK2V617F. In addition, AML1 and NF-E2 expression were highly correlated. RNAi-mediated suppression of either AML1 or of its binding partner CBF-β significantly decreased NF-E2 expression. Moreover, expression of the leukemic fusion protein AML/ETO drastically decreased NF-E2 protein levels. Our data identify NF-E2 as a novel AML1 target gene and delineate a role for aberrant AML1 expression in mediating elevated NF-E2 expression in MPN patients. PMID:20339092

THE ROLE OF THE RETINOBLASTOMA/E2F1 TUMOR SUPPRESSOR PATHWAY IN THE LESION RECOGNITION STEP OF NUCLEOTIDE EXCISION REPAIR

PubMed Central

Lin, Patrick S.; McPherson, Lisa A.; Chen, Aubrey Y.; Sage, Julien; Ford, James M.

2009-01-01

The retinoblastoma Rb/E2F tumor suppressor pathway plays a major role in the regulation of mammalian cell cycle progression. The pRb protein, along with closely related proteins p107 and p130, exerts its anti-proliferative effects by binding to the E2F family of transcription factors known to regulate essential genes throughout the cell cycle. We sought to investigate the role of the Rb/E2F1 pathway in the lesion recognition step of nucleotide excision repair (NER) in mouse embryonic fibroblasts (MEFs). Rb−/−;p107−/−;p130−/− MEFs repaired both cyclobutane pyrimidine dimers (CPD) and 6-4 photoproducts (6-4PPs) at higher efficiency than did wildtype cells following UV-C irradiation. The expression of damaged DNA binding gene DDB2 involved in the DNA lesion recognition step was elevated in the Rb family-deficient MEFs. To determine if the enhanced DNA repair in the absence of the Rb gene family is due to the derepression of E2F1, we assayed the ability of E2F1-deficient cells to repair damaged DNA and demonstrated that E2F1−/− MEFs are impaired for the removal of both CPDs and 6-4PPs. Furthermore, wildtype cells induced a higher expression of DDB2 and xeroderma pigmentosum gene XPC transcript levels than did E2F1−/− cells following UV-C irradiation. Using an E2F SiteScan algorithm, we uncovered a putative E2F-responsive element in the XPC promoter upstream of the transcription start site. We showed with chromatin immunoprecipitation assays the binding of E2F1 to the XPC promoter in a UV-dependent manner, suggesting that E2F1 is a transcriptional regulator of XPC. Our study identifies a novel E2F1 gene target and further supports the growing body of evidence that the Rb/E2F1 tumor suppressor pathway is involved in the regulation of the DNA lesion recognition step of nucleotide excision repair. PMID:19376752

OPERATION CASTLE. Radiological Safety. Volume 2

DTIC Science & Technology

1985-09-01

d.’ That, orcopt as noted sbovo, a radiolocical safety program similar to that of CaSTIS, bo planned for future operations» e. That research and...sane manner as that for liONGEL’iT, indicated l60 nr/hr at 1830M, 3 March« The infinity dose of the UTHUK natives was computed at 58r« The decision...status of /JLUK mt pot up f o» .. consideratioa aprroxlmatoly 200CM, 2 March. This atoll ha» a reported. ^ population of 401; The infinity dose wa

E2f1 mediates high glucose-induced neuronal death in cultured mouse retinal explants.

PubMed

Wang, Yujiao; Zhou, Yi; Xiao, Lirong; Zheng, Shijie; Yan, Naihong; Chen, Danian

2017-10-02

Diabetic retinopathy (DR) is the most common complication of diabetes and remains one of the major causes of blindness in the world; infants born to diabetic mothers have higher risk of developing retinopathy of prematurity (ROP). While hyperglycemia is a major risk factor, the molecular and cellular mechanisms underlying DR and diabetic ROP are poorly understood. To explore the consequences of retinal cells under high glucose, we cultured wild type or E2f1 -/- mouse retinal explants from postnatal day 8 with normal glucose, high osmotic or high glucose media. Explants were also incubated with cobalt chloride (CoCl 2 ) to mimic the hypoxic condition. We showed that, at 7 days post exposure to high glucose, retinal explants displayed elevated cell death, ectopic cell division and intact retinal vascular plexus. Cell death mainly occurred in excitatory neurons, such as ganglion and bipolar cells, which were also ectopically dividing. Many Müller glial cells reentered the cell cycle; some had irregular morphology or migrated to other layers. High glucose inhibited the hyperoxia-induced blood vessel regression of retinal explants. Moreover, inactivation of E2f1 rescued high glucose-induced ectopic division and cell death of retinal neurons, but not ectopic cell division of Müller glial cells and vascular phenotypes. This suggests that high glucose has direct but distinct effects on retinal neurons, glial cells and blood vessels, and that E2f1 mediates its effects on retinal neurons. These findings shed new light onto mechanisms of DR and the fetal retinal abnormalities associated with maternal diabetes, and suggest possible new therapeutic strategies.

Managing risk in healthcare: understanding your safety culture using the Manchester Patient Safety Framework (MaPSaF).

PubMed

Parker, Dianne

2009-03-01

To provide sufficient information about the Manchester Patient Safety Framework (MaPSaF) to allow healthcare professionals to assess its potential usefulness. The assessment of safety culture is an important aspect of risk management, and one in which there is increasing interest among healthcare organizations. Manchester Patient Safety Framework offers a theory-based framework for assessing safety culture, designed specifically for use in the NHS. The framework covers multiple dimensions of safety culture, and five levels of safety culture development. This allows the generation of a profile of an organization's safety culture in terms of areas of relative strength and challenge, which can be used to identify focus issues for change and improvement. Manchester Patient Safety Framework provides a useful method for engaging healthcare professionals in assessing and improving the safety culture in their organization, as part of a programme of risk management.

Differentiation and injury-repair signals modulate the interaction of E2F and pRB proteins with novel target genes in keratinocytes.

PubMed

Chang, Wing Y; Andrews, Joseph; Carter, David E; Dagnino, Lina

2006-08-01

E2F transcription factors are central to epidermal morphogenesis and regeneration after injury. The precise nature of E2F target genes involved in epidermal formation and repair has yet to be determined. Identification of these genes is essential to understand how E2F proteins regulate fundamental aspects of epidermal homeostasis and transformation. We have conducted a genome-wide screen using CpG island microarray analysis to identify novel promoters bound by E2F3 and E2F5 in human keratinocytes. We further characterized several of these genes, and determined that multiple E2F and retinoblastoma (pRb) family proteins associate with them in exponentially proliferating cells. We also assessed the effect on E2F and pRb binding to those genes in response to differentiation induced by bone morphogenetic protein-6 (BMP-6), or to activation of repair mechanisms induced by transforming growth factor-beta (TGF-beta). These studies demonstrate promoter- and cytokine-specific changes in binding profiles of E2F and/or pRb family proteins. For example, E2F1, 3, 4 and p107 were recruited to the N-myc promoter in cells treated with BMP-6, whereas E2F1, 3, 4, 5, p107 and p130 were bound to this promoter in the presence of TGF-beta. Functionally, these different interactions resulted in transcriptional repression by BMP-6 and TGF-beta of the N-myc gene, via mechanisms that involved E2F binding to the promoter and association with pRb-family proteins. Thus, multiple combinations of E2F and pRb family proteins may associate with and transcriptionally regulate a given target promoter in response to differentiation and injury-repair stimuli in epidermal keratinocytes.

Elevated autophagy gene expression in adipose tissue of obese humans: A potential non-cell-cycle-dependent function of E2F1

PubMed Central

Haim, Yulia; Blüher, Matthias; Slutsky, Noa; Goldstein, Nir; Klöting, Nora; Harman-Boehm, Ilana; Kirshtein, Boris; Ginsberg, Doron; Gericke, Martin; Guiu Jurado, Esther; Kovsan, Julia; Tarnovscki, Tanya; Kachko, Leonid; Bashan, Nava; Gepner, Yiftach; Shai, Iris; Rudich, Assaf

2015-01-01

Autophagy genes' expression is upregulated in visceral fat in human obesity, associating with obesity-related cardio-metabolic risk. E2F1 (E2F transcription factor 1) was shown in cancer cells to transcriptionally regulate autophagy. We hypothesize that E2F1 regulates adipocyte autophagy in obesity, associating with endocrine/metabolic dysfunction, thereby, representing non-cell-cycle function of this transcription factor. E2F1 protein (N=69) and mRNA (N=437) were elevated in visceral fat of obese humans, correlating with increased expression of ATG5 (autophagy-related 5), MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β), but not with proliferation/cell-cycle markers. Elevated E2F1 mainly characterized the adipocyte fraction, whereas MKI67 (marker of proliferation Ki-67) was elevated in the stromal-vascular fraction of adipose tissue. In human visceral fat explants, chromatin-immunoprecipitation revealed body mass index (BMI)-correlated increase in E2F1 binding to the promoter of MAP1LC3B, but not to the classical cell cycle E2F1 target, CCND1 (cyclin D1). Clinically, omental fat E2F1 expression correlated with insulin resistance, circulating free-fatty-acids (FFA), and with decreased circulating ADIPOQ/adiponectin, associations attenuated by adjustment for autophagy genes. Overexpression of E2F1 in HEK293 cells enhanced promoter activity of several autophagy genes and autophagic flux, and sensitized to further activation of autophagy by TNF. Conversely, mouse embryonic fibroblast (MEF)-derived adipocytes from e2f1 knockout mice (e2f1−/−) exhibited lower autophagy gene expression and flux, were more insulin sensitive, and secreted more ADIPOQ. Furthermore, e2f1−/− MEF-derived adipocytes, and autophagy-deficient (by Atg7 siRNA) adipocytes were resistant to cytokines-induced decrease in ADIPOQ secretion. Jointly, upregulated E2F1 sensitizes adipose tissue autophagy to inflammatory stimuli, linking visceral obesity to adipose and systemic

SNHG16 contributes to breast cancer cell migration by competitively binding miR-98 with E2F5.

PubMed

Cai, Chang; Huo, Qiang; Wang, Xiaolong; Chen, Bing; Yang, Qifeng

2017-04-01

Long noncoding RNAs (lncRNAs) have been proved to play important roles in cellular processes of cancer, including the development, proliferation, and migration of cancer cells. In the present study, we demonstrated small nucleolar RNA host gene 16 (SNHG16) as an oncogene on cell migration in breast cancer. Expression levels of SNHG16 were found to be frequently higher in breast cancer tissues than in the paired noncancerous tissues. Gain- and loss-of-function studies proved that SNHG16 significantly promoted breast cancer cell migration. We predicted SNHG16 as a competitive endogenous RNA (ceRNA) of E2F transcription factor 5 protein (E2F5) via competition for the shared miR-98 through bioinformatics analysis, and proved this regulation using relative quantitative real-time PCR (qRT-PCR), western blot, RNA immunoprecipitation (RIP) assay and luciferase reporter assay. In addition, we identified a positive correlation between SNHG16 and E2F5 in breast cancer tissues. Furthermore, we demonstrated that forced expression of miR-98 could partially abrogate SNHG16-mediated increase of breast cancer cells migration, suggesting that SNHG16 promoted cell migration in a miR-98 dependent manner. Taken together, our findings indicated that SNHG16 induces breast cancer cell migration by competitively binding miR-98 with E2F5, and SNHG16 can serve as a potential therapeutic target for breast cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Domain structure and reorientation in CoF e2O4

NASA Astrophysics Data System (ADS)

Abes, M.; Koops, C. T.; Hrkac, S. B.; McCord, J.; Urs, N. O.; Wolff, N.; Kienle, L.; Ren, W. J.; Bouchenoire, L.; Murphy, B. M.; Magnussen, O. M.

2016-05-01

The microscopic processes underlying magnetostriction in ferrites were studied for the case of CoF e2O4 single crystals by high-resolution in situ x-ray diffraction and complementary magnetic microscopy techniques. The data support the reports of Yang and Ren [Phys. Rev. B 77, 014407 (2008), 10.1103/PhysRevB.77.014407] that magnetostriction in these materials originates from the switching of crystallographic domains, similar to ferroelastic or ferroelectric domain switching, and reveals the presence of two coexisting tetragonal spinel structures, corresponding to domains of high and of low strain. The latter alternate in the crystal, separated by 90° domain boundaries, and can be explained by the effect of internal stress emerging during the transition into the ferrimagnetic phase. During magnetization of the sample two structural transitions are observed: a conversion of the transversal into axial domains at 1.95 kOe and a growth of the high-strain domains at the cost of the low-strain axial domains at 2.8 kOe. These microscopic changes are in good agreement with the macroscopic magnetization and magnetostriction behavior of CoF e2O4 .

E2F transcription factor-1 deficiency reduces pathophysiology in the mouse model of Duchenne muscular dystrophy through increased muscle oxidative metabolism.

PubMed

Blanchet, Emilie; Annicotte, Jean-Sébastien; Pradelli, Ludivine A; Hugon, Gérald; Matecki, Stéfan; Mornet, Dominique; Rivier, François; Fajas, Lluis

2012-09-01

E2F1 deletion leads to increased mitochondrial number and function, increased body temperature in response to cold and increased resistance to fatigue with exercise. Since E2f1-/- mice show increased muscle performance, we examined the effect of E2f1 genetic inactivation in the mdx background, a mouse model of Duchenne muscular dystrophy (DMD). E2f1-/-;mdx mice demonstrated a strong reduction of physiopathological signs of DMD, including preservation of muscle structure, decreased inflammatory profile, increased utrophin expression, resulting in better endurance and muscle contractile parameters, comparable to normal mdx mice. E2f1 deficiency in the mdx genetic background increased the oxidative metabolic gene program, mitochondrial activity and improved muscle functions. Interestingly, we observed increased E2F1 protein levels in DMD patients, suggesting that E2F1 might represent a promising target for the treatment of DMD.

Photoemission study of CaF2- and SrF2-GaAs(110) interfaces formed at room temperature

NASA Astrophysics Data System (ADS)

Mao, D.; Young, K.; Kahn, A.; Zanoni, R.; McKinley, J.; Margaritondo, G.

1989-06-01

Interfaces formed by evaporating CaF2 or SrF2 on room-temperature GaAs(110) are studied with synchrotron-radiation photoemission spectroscopy. The fluoride films grow uniformly on the GaAs surface. The deposition of CaF2 and SrF2 induces a large initial band bending on p-type GaAs (~0.9 eV) and a small initial band bending on n-type GaAs (~0.25 eV). The valence band is dominated by the F 2p peak which shifts toward high binding energies by ~1.5 eV after the deposition of >=16 Å fluoride. This shift reflects an increase in the valence-band offset between the two materials as the film forms. The final band offsets are estimated at 7.7 and 8.0 eV for CaF2 and SrF2, respectively, and are in qualitative agreement with those expected from the fluoride-Si data. Core-level measurements indicate that no reaction or decomposition of the MF2 molecule takes place at the interface. The F 2s core-level line shape and the increase in the binding-energy separation of F 2s and Ca 3p with increasing coverage suggest the presence of an interface F component. Contrary to the CaF2/Si case, no measurable Ca-substrate bonding effect is observed. The dissociative effect of uv irradiation on the CaF2 film is also investigated.

E2F1 somatic mutation within miRNA target site impairs gene regulation in colorectal cancer.

PubMed

Lopes-Ramos, Camila M; Barros, Bruna P; Koyama, Fernanda C; Carpinetti, Paola A; Pezuk, Julia; Doimo, Nayara T S; Habr-Gama, Angelita; Perez, Rodrigo O; Parmigiani, Raphael B

2017-01-01

Genetic studies have largely concentrated on the impact of somatic mutations found in coding regions, and have neglected mutations outside of these. However, 3' untranslated regions (3' UTR) mutations can also disrupt or create miRNA target sites, and trigger oncogene activation or tumor suppressor inactivation. We used next-generation sequencing to widely screen for genetic alterations within predicted miRNA target sites of oncogenes associated with colorectal cancer, and evaluated the functional impact of a new somatic mutation. Target sequencing of 47 genes was performed for 29 primary colorectal tumor samples. For 71 independent samples, Sanger methodology was used to screen for E2F1 mutations in miRNA predicted target sites, and the functional impact of these mutations was evaluated by luciferase reporter assays. We identified germline and somatic alterations in E2F1. Of the 100 samples evaluated, 3 had germline alterations at the MIR205-5p target site, while one had a somatic mutation at MIR136-5p target site. E2F1 gene expression was similar between normal and tumor tissues bearing the germline alteration; however, expression was increased 4-fold in tumor tissue that harbored a somatic mutation compared to that in normal tissue. Luciferase reporter assays revealed both germline and somatic alterations increased E2F1 activity relative to wild-type E2F1. We demonstrated that somatic mutation within E2F1:MIR136-5p target site impairs miRNA-mediated regulation and leads to increased gene activity. We conclude that somatic mutations that disrupt miRNA target sites have the potential to impact gene regulation, highlighting an important mechanism of oncogene activation.

The effect of FeF2 on the magneto-optic response in FeF2/Fe/FeF2 sandwiches

NASA Astrophysics Data System (ADS)

Pištora, J.; Lesňák, M.; Lišková, E.; Višňovský, Š.; Harward, I.; Maslankiewicz, P.; Balin, K.; Celinski, Z.; Mistrík, J.; Yamaguchi, T.; Lopusnik, R.; Vlček, J.

2010-04-01

The room temperature optical constants n and k of MBE grown FeF2 films are reported. Because of poor chemical stability, FeF2 had to be coated with a protective Au layer. Reflection spectral ellipsometry in the photon energy range between 1.3 and 5.2 eV was performed on structures with a typical profile Au(0.5 nm)/FeF2(120 nm)/Au(30 nm)/Ag(20 nm)/Fe(0.6 nm) grown on GaAs(0 0 1) substrate. The spectra of n and k in FeF2 were subsequently employed in the design of FeF2/Fe/FeF2 sandwiches considered as magneto-optic (MO) sensors for weak microwave currents. Their MO response was evaluated using reflection MO (Kerr) spectroscopy at polar magnetization. The present results may be of interest in MO studies of magnetic nanostructures with Fe/FeF2/Fe, including MO magnetometry and MO magnetic domain imaging.

ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage

PubMed Central

Jin, Ya-Qiong; An, Guo-Shun; Ni, Ju-Hua; Li, Shu-Yan; Jia, Hong-Ti

2014-01-01

The nucleolus plays a major role in ribosome biogenesis. Most genotoxic agents disrupt nucleolar structure and function, which results in the stabilization/activation of p53, inducing cell cycle arrest or apoptosis. Likewise, transcription factor E2F1 as a DNA damage responsive protein also plays roles in cell cycle arrest, DNA repair, or apoptosis in response to DNA damage through transcriptional response and protein–protein interaction. Furthermore, E2F1 is known to be involved in regulating rRNA transcription. However, how E2F1 displays in coordinating DNA damage and nucleolar stress is unclear. In this study, we demonstrate that ATM-dependent E2F1 accumulation in the nucleolus is a characteristic feature of nucleolar stress in early response to DNA damage. We found that at the early stage of DNA damage, E2F1 accumulation in the nucleolus was an ATM-dependent and a common event in p53-suficient and -deficient cells. Increased nucleolar E2F1 was sequestered by the nucleolar protein p14ARF, which repressed E2F1-dependent rRNA transcription initiation, and was coupled with S phase. Our data indicate that early accumulation of E2F1 in the nucleolus is an indicator for nucleolar stress and a component of ATM pathway, which presumably buffers elevation of E2F1 in the nucleoplasm and coordinates the diversifying mechanisms of E2F1 acts in cell cycle progression and apoptosis in early response to DNA damage. PMID:24675884

ATM-dependent E2F1 accumulation in the nucleolus is an indicator of ribosomal stress in early response to DNA damage.

PubMed

Jin, Ya-Qiong; An, Guo-Shun; Ni, Ju-Hua; Li, Shu-Yan; Jia, Hong-Ti

2014-01-01

The nucleolus plays a major role in ribosome biogenesis. Most genotoxic agents disrupt nucleolar structure and function, which results in the stabilization/activation of p53, inducing cell cycle arrest or apoptosis. Likewise, transcription factor E2F1 as a DNA damage responsive protein also plays roles in cell cycle arrest, DNA repair, or apoptosis in response to DNA damage through transcriptional response and protein-protein interaction. Furthermore, E2F1 is known to be involved in regulating rRNA transcription. However, how E2F1 displays in coordinating DNA damage and nucleolar stress is unclear. In this study, we demonstrate that ATM-dependent E2F1 accumulation in the nucleolus is a characteristic feature of nucleolar stress in early response to DNA damage. We found that at the early stage of DNA damage, E2F1 accumulation in the nucleolus was an ATM-dependent and a common event in p53-suficient and -deficient cells. Increased nucleolar E2F1 was sequestered by the nucleolar protein p14ARF, which repressed E2F1-dependent rRNA transcription initiation, and was coupled with S phase. Our data indicate that early accumulation of E2F1 in the nucleolus is an indicator for nucleolar stress and a component of ATM pathway, which presumably buffers elevation of E2F1 in the nucleoplasm and coordinates the diversifying mechanisms of E2F1 acts in cell cycle progression and apoptosis in early response to DNA damage.

Transformation of arachidonate into 6-oxoprostaglandin F1 alpha, thromboxane B2 and prostaglandin E2 by sheep lung microsomal fraction.

PubMed Central

Tai, H H; Yuan, B; Wu, A T

1978-01-01

In the presence of haemoglobin and isoproterenol, the microsomal fraction of sheep lung catalysed the conversion of arachidonate predominantly into thromboxane B2 and to a lesser extent into 6-oxoprostaglandin F1alpha. Very little prostaglandin E2 and prostaglandin F2alpha were formed. If reduced glutathione was added in combination with haemoglobin and isoproterenol, the synthesis of prostaglandin E2 was favoured over that of thromboxane B2 and 6-oxoprostaglandin F1alpha. The identities of these products were confirmed by t.l.c. and by combined g.l.c.-mass spectrometry. These results indicate that microsomal fraction of sheep lung possesses active prostaglandin synthase, prostacyclin synthase and thromboxane synthase activities. PMID:637853

E2F1-mediated upregulation of p19INK4d determines its periodic expression during cell cycle and regulates cellular proliferation.

PubMed

Carcagno, Abel L; Marazita, Mariela C; Ogara, María F; Ceruti, Julieta M; Sonzogni, Silvina V; Scassa, María E; Giono, Luciana E; Cánepa, Eduardo T

2011-01-01

A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an additional mechanism to limit E2F activity.

E2F1-Mediated Upregulation of p19INK4d Determines Its Periodic Expression during Cell Cycle and Regulates Cellular Proliferation

PubMed Central

Carcagno, Abel L.; Marazita, Mariela C.; Ogara, María F.; Ceruti, Julieta M.; Sonzogni, Silvina V.; Scassa, María E.; Giono, Luciana E.; Cánepa, Eduardo T.

2011-01-01

Background A central aspect of development and disease is the control of cell proliferation through regulation of the mitotic cycle. Cell cycle progression and directionality requires an appropriate balance of positive and negative regulators whose expression must fluctuate in a coordinated manner. p19INK4d, a member of the INK4 family of CDK inhibitors, has a unique feature that distinguishes it from the remaining INK4 and makes it a likely candidate for contributing to the directionality of the cell cycle. p19INK4d mRNA and protein levels accumulate periodically during the cell cycle under normal conditions, a feature reminiscent of cyclins. Methodology/Principal Findings In this paper, we demonstrate that p19INK4d is transcriptionally regulated by E2F1 through two response elements present in the p19INK4d promoter. Ablation of this regulation reduced p19 levels and restricted its expression during the cell cycle, reflecting the contribution of a transcriptional effect of E2F1 on p19 periodicity. The induction of p19INK4d is delayed during the cell cycle compared to that of cyclin E, temporally separating the induction of these proliferative and antiproliferative target genes. Specific inhibition of the E2F1-p19INK4d pathway using triplex-forming oligonucleotides that block E2F1 binding on p19 promoter, stimulated cell proliferation and increased the fraction of cells in S phase. Conclusions/Significance The results described here support a model of normal cell cycle progression in which, following phosphorylation of pRb, free E2F induces cyclin E, among other target genes. Once cyclinE/CDK2 takes over as the cell cycle driving kinase activity, the induction of p19 mediated by E2F1 leads to inhibition of the CDK4,6-containing complexes, bringing the G1 phase to an end. This regulatory mechanism constitutes a new negative feedback loop that terminates the G1 phase proliferative signal, contributing to the proper coordination of the cell cycle and provides an

HBV core promoter mutations promote cellular proliferation through E2F1-mediated upregulation of S-phase kinase-associated protein 2 transcription.

PubMed

Huang, Yuehua; Tai, Andrew W; Tong, Shuping; Lok, Anna S F

2013-06-01

Hepatitis B virus (HBV) core promoter (CP) mutations have been associated with an increased risk of hepatocellular carcinoma (HCC) in clinical studies. We previously reported that a combination of CP mutations seen in HCC patients, expressed in HBx gene, increased SKP2 (S-phase kinase-associated protein 2) expression, thereby promoting cellular proliferation. Here, we investigate the possible mechanisms by which CP mutations upregulate SKP2. We used immunoblotting and ATPlite assay to validate the effect of CP mutations in full-length HBV genome on cell cycle regulator levels and cell proliferation. Activation of SKP2 mRNA was assessed by quantitative real-time PCR in primary human hepatocytes (PHH) and HCC cell lines. Effect of CP mutations on SKP2 promoter activity was determined by luciferase assay. Target regulation of E2F1 on SKP2 was analyzed by siRNAs. CP mutations in full-length HBV genome upregulated SKP2 expression, thereby downregulating cell cycle inhibitors and accelerating cellular proliferation. CP mutations enhanced SKP2 promoter activity but had no effect on SKP2 protein stability. Mapping of the SKP2 promoter identified a region necessary for activation by CP mutations that contains an E2F1 response element. Knocking down E2F1 reduced the effects of CP mutations on SKP2 and cellular proliferation. The effect of CP mutations on E2F1 might be mediated through hyperphosphorylation of RB. HBV CP mutations enhance SKP2 transcription by activating the E2F1 transcription factor and in turn downregulate cell cycle inhibitors, thus providing a potential mechanism for an association between CP mutations and HCC. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

F199E substitution reduced toxicity of Clostridium perfringens epsilon toxin by depriving the receptor binding capability

PubMed Central

Kang, Jingjing; Gao, Jie; Yao, Wenwu; Kang, Lin; Gao, Shan; Yang, Hao; Ji, Bin; Li, Ping; Liu, Jing; Yao, Jiahao; Xin, Wenwen; Zhao, Baohua; Wang, Jinglin

2017-01-01

ABSTRACT Epsilon toxin (ETX), a potent toxin, is produced by types B and D strains of Clostridium perfringens, which could cause severe diseases in humans and domestic animals. Mutant rETXF199E was previously demonstrated to be a good vaccine candidate. However, the mechanism concerned remains unknown. To clarify how F199E substitution reduced ETX toxicity, we performed a series of experiments. The results showed that the cell-binding and pore-forming ability of rETXF199E was almost abolished. We speculated that F199E substitution reduced toxicity by depriving the receptor binding capability of ETX, which contributed to the hypothesis that domain I of ETX is responsible for cell binding. In addition, our data suggested that ETX could cause Ca2+ release from intracellular Ca2+ stores, which may underlie an alternate pathway leading to cell death. Furthermore, ETX induced crenation of the MDCK cells was observed, with sags and crests first appearing on the surface of condensed MDCK cells, according to scanning electron microscopy. The data also demonstrated the safety and potentiality of rETXF199E as a vaccine candidate for humans. In summary, findings of this work potentially contribute to a better understanding of the pathogenic mechanism of ETX and the development of vaccine against diseases caused by ETX, using mutant proteins. PMID:28304231

Safety, pharmacokinetics, metabolism and radiation dosimetry of 18F-tetrafluoroborate (18F-TFB) in healthy human subjects.

PubMed

Jiang, Huailei; Schmit, Nicholas R; Koenen, Alex R; Bansal, Aditya; Pandey, Mukesh K; Glynn, Robert B; Kemp, Bradley J; Delaney, Kera L; Dispenzieri, Angela; Bakkum-Gamez, Jamie N; Peng, Kah-Whye; Russell, Stephen J; Gunderson, Tina M; Lowe, Val J; DeGrado, Timothy R

2017-10-27

18 F-Tetrafluoroborate ( 18 F-TFB) is a promising iodide analog for PET imaging of thyroid cancer and sodium/iodide symporter (NIS) reporter activity in viral therapy applications. The aim of this study was to evaluate the safety, pharmacokinetics, biodistribution, and radiation dosimetry of high-specific activity 18 F-TFB in healthy human subjects. 18 F-TFB was synthesized with specific activity of 3.2 ± 1.3 GBq/μmol (at the end of synthesis). Dynamic and whole-body static PET/CT scans over 4 h were performed after intravenous administration of 18 F-TFB (333-407 MBq) in four female and four male healthy volunteers (35 ± 11 years old). Samples of venous blood and urine were collected over the imaging period and analyzed by ion-chromatography HPLC to determine tracer stability. Vital signs and clinical laboratory safety assays were measured to evaluate safety. 18 F-TFB administration was well tolerated with no significant findings on vital signs and no clinically meaningful changes in clinical laboratory assays. Left-ventricular blood pool time-activity curves showed a multi-phasic blood clearance of 18 F-radioactivity with the two rapid clearance phases over the first 20 min, followed by a slower clearance phase. HPLC analysis showed insignificant 18 F-labeled metabolites in the blood and urine over the length of the study (4 h). High uptakes were seen in the thyroid, stomach, salivary glands, and bladder. Urinary clearance of 18 F-TFB was prominent. Metabolic stability was evidenced by low accumulation of 18 F-radioactivity in the bone. Effective doses were 0.036 mSv/MBq in males and 0.064 mSv/MBq in females (p = 0.08, not significant). This initial study in healthy human subjects showed 18 F-TFB was safe and distributed in the human body similar to other iodide analogs. These data support further translational studies with 18 F-TFB as NIS gene reporter and imaging biomarker for thyroid cancer and other disease processes that import iodide.

77 FR 35850 - Safety Zone; F/V Deep Sea, Penn Cove, WA

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-15

... 1625-AA00 Safety Zone; F/V Deep Sea, Penn Cove, WA AGENCY: Coast Guard, DHS. ACTION: Temporary final rule. SUMMARY: The Coast Guard is establishing a safety zone around the Fishing Vessel (F/V) Deep Sea... with the sunken F/V Deep Sea. B. Basis and Purpose On the evening of May 13, 2012, the F/V Deep Sea...

E2F mediates enhanced alternative polyadenylation in proliferation.

PubMed

Elkon, Ran; Drost, Jarno; van Haaften, Gijs; Jenal, Mathias; Schrier, Mariette; Oude Vrielink, Joachim A F; Agami, Reuven

2012-07-02

The majority of mammalian genes contain multiple poly(A) sites in their 3' UTRs. Alternative cleavage and polyadenylation are emerging as an important layer of gene regulation as they generate transcript isoforms that differ in their 3' UTRs, thereby modulating genes' response to 3' UTR-mediated regulation. Enhanced cleavage at 3' UTR proximal poly(A) sites resulting in global 3' UTR shortening was recently linked to proliferation and cancer. However, mechanisms that regulate this enhanced alternative polyadenylation are unknown. Here, we explored, on a transcriptome-wide scale, alternative polyadenylation events associated with cellular proliferation and neoplastic transformation. We applied a deep-sequencing technique for identification and quantification of poly(A) sites to two human cellular models, each examined under proliferative, arrested and transformed states. In both cell systems we observed global 3' UTR shortening associated with proliferation, a link that was markedly stronger than the association with transformation. Furthermore, we found that proliferation is also associated with enhanced cleavage at intronic poly(A) sites. Last, we found that the expression level of the set of genes that encode for 3'-end processing proteins is globally elevated in proliferation, and that E2F transcription factors contribute to this regulation. Our results comprehensively identify alternative polyadenylation events associated with cellular proliferation and transformation, and demonstrate that the enhanced alternative polyadenylation in proliferative conditions results not only in global 3' UTR shortening but also in enhanced premature cleavage in introns. Our results also indicate that E2F-mediated co-transcriptional regulation of 3'-end processing genes is one of the mechanisms that links enhanced alternative polyadenylation to proliferation.

E2F mediates enhanced alternative polyadenylation in proliferation

PubMed Central

2012-01-01

Background The majority of mammalian genes contain multiple poly(A) sites in their 3' UTRs. Alternative cleavage and polyadenylation are emerging as an important layer of gene regulation as they generate transcript isoforms that differ in their 3' UTRs, thereby modulating genes' response to 3' UTR-mediated regulation. Enhanced cleavage at 3' UTR proximal poly(A) sites resulting in global 3' UTR shortening was recently linked to proliferation and cancer. However, mechanisms that regulate this enhanced alternative polyadenylation are unknown. Results Here, we explored, on a transcriptome-wide scale, alternative polyadenylation events associated with cellular proliferation and neoplastic transformation. We applied a deep-sequencing technique for identification and quantification of poly(A) sites to two human cellular models, each examined under proliferative, arrested and transformed states. In both cell systems we observed global 3' UTR shortening associated with proliferation, a link that was markedly stronger than the association with transformation. Furthermore, we found that proliferation is also associated with enhanced cleavage at intronic poly(A) sites. Last, we found that the expression level of the set of genes that encode for 3'-end processing proteins is globally elevated in proliferation, and that E2F transcription factors contribute to this regulation. Conclusions Our results comprehensively identify alternative polyadenylation events associated with cellular proliferation and transformation, and demonstrate that the enhanced alternative polyadenylation in proliferative conditions results not only in global 3' UTR shortening but also in enhanced premature cleavage in introns. Our results also indicate that E2F-mediated co-transcriptional regulation of 3'-end processing genes is one of the mechanisms that links enhanced alternative polyadenylation to proliferation. PMID:22747694

E2F4 Promotes Neuronal Regeneration and Functional Recovery after Spinal Cord Injury in Zebrafish

PubMed Central

Sasagawa, Shota; Nishimura, Yuhei; Hayakawa, Yuka; Murakami, Soichiro; Ashikawa, Yoshifumi; Yuge, Mizuki; Okabe, Shiko; Kawaguchi, Koki; Kawase, Reiko; Tanaka, Toshio

2016-01-01

Mammals exhibit poor recovery after spinal cord injury (SCI), whereas non-mammalian vertebrates exhibit significant spontaneous recovery after SCI. The mechanisms underlying this difference have not been fully elucidated; therefore, the purpose of this study was to investigate these mechanisms. Using comparative transcriptome analysis, we demonstrated that genes related to cell cycle were significantly enriched in the genes specifically dysregulated in zebrafish SCI. Most of the cell cycle-related genes dysregulated in zebrafish SCI were down-regulated, possibly through activation of e2f4. Using a larval zebrafish model of SCI, we demonstrated that the recovery of locomotive function and neuronal regeneration after SCI were significantly inhibited in zebrafish treated with an E2F4 inhibitor. These results suggest that activation of e2f4 after SCI may be responsible, at least in part, for the significant recovery in zebrafish. This provides novel insight into the lack of recovery after SCI in mammals and informs potential therapeutic strategies. PMID:27242526

Transcription factors ETF, E2F, and SP-1 are involved in cytokine-independent proliferation of murine hepatocytes.

PubMed

Zellmer, Sebastian; Schmidt-Heck, Wolfgang; Godoy, Patricio; Weng, Honglei; Meyer, Christoph; Lehmann, Thomas; Sparna, Titus; Schormann, Wiebke; Hammad, Seddik; Kreutz, Clemens; Timmer, Jens; von Weizsäcker, Fritz; Thürmann, Petra A; Merfort, Irmgard; Guthke, Reinhard; Dooley, Steven; Hengstler, Jan G; Gebhardt, Rolf

2010-12-01

The cellular basis of liver regeneration has been intensely investigated for many years. However, the mechanisms initiating hepatocyte "plasticity" and priming for proliferation are not yet fully clear. We investigated alterations in gene expression patterns during the first 72 hours of C57BL/6N mouse hepatocyte culture on collagen monolayers (CM), which display a high basal frequency of proliferation in the absence of cytokines. Although many metabolic genes were down-regulated, genes related to mitogen-activated protein kinase (MAPK) signaling and cell cycle were up-regulated. The latter genes showed an overrepresentation of transcription factor binding sites (TFBS) for ETF (TEA domain family member 2), E2F1 (E2F transcription factor 1), and SP-1 (Sp1 transcription factor) (P < 0.001), all depending on MAPK signaling. Time-dependent increase of ERK1/2 phosphorylation occurred during the first 48 hours (and beyond) in the absence of cytokines, accompanied by an enhanced bromodeoxyuridine labeling index of 20%. The MEK inhibitor PD98059 blunted these effects indicating MAPK signaling as major trigger for this cytokine-independent proliferative response. In line with these in vitro findings, liver tissue of mice challenged with CCl(4) displayed hepatocytes with intense p-ERK1/2 staining and nuclear SP-1 and E2F1 expression. Furthermore, differentially expressed genes in mice after partial hepatectomy contained overrepresented TFBS for ETF, E2F1, and SP-1 and displayed increased expression of E2F1. Cultivation of murine hepatocytes on CM primes cells for proliferation through cytokine-independent activation of MAPK signaling. The transcription factors ETF, E2F1, and SP-1 seem to play a pronounced role in mediating proliferation-dependent differential gene expression. Similar events, but on a shorter time-scale, occur very early after liver damage in vivo. Copyright © 2010 American Association for the Study of Liver Diseases.

E-Safety and Web 2.0 for Children Aged 11-16

ERIC Educational Resources Information Center

Sharples, M.; Graber, R.; Harrison, C.; Logan, K.

2009-01-01

This paper reports findings from a survey and interviews with children aged 11-16 years, teachers and parents on their attitudes to e-safety in relation to social networking and media creation (Web 2.0) and their practices at school and at home. The results showed that 74% of the children surveyed have used social network (SN) sites and that a…

Transactivation of micrornA-320 by microRNA-383 regulates granulosa cell functions by targeting E2F1 and SF-1 proteins.

PubMed

Yin, Mianmian; Wang, Xiaorong; Yao, Guidong; Lü, Mingrong; Liang, Meng; Sun, Yingpu; Sun, Fei

2014-06-27

Our previous studies have shown that microRNA-320 (miR-320) is one of the most down-regulated microRNAs (miRNA) in mouse ovarian granulosa cells (GCs) after TGF-β1 treatment. However, the underlying mechanisms of miR-320 involved in GC function during follicular development remain unknown. In this study, we found that pregnant mare serum gonadotropin treatment resulted in the suppression of miR-320 expression in a time-dependent manner. miR-320 was mainly expressed in GCs and oocytes of mouse ovarian follicles in follicular development. Overexpression of miR-320 inhibited estradiol synthesis and proliferation of GCs through targeting E2F1 and SF-1. E2F1/SF-1 mediated miR-320-induced suppression of GC proliferation and of GC steroidogenesis. FSH down-regulated the expression of miR-320 and regulated the function of miR-320 in mouse GCs. miR-383 promoted the expression of miR-320 and enhanced miR-320-mediated suppression of GC proliferation. Injection of miR-320 into the ovaries of mice partially promoted the production of testosterone and progesterone but inhibited estradiol release in vivo. Moreover, the expression of miR-320 and miR-383 was up-regulated in the follicular fluid of polycystic ovarian syndrome patients, although the expression of E2F1 and SF-1 was down-regulated in GCs. These data demonstrated that miR-320 regulates the proliferation and steroid production by targeting E2F1 and SF-1 in the follicular development. Understanding the regulation of miRNA biogenesis and function in the follicular development will potentiate the usefulness of miRNA in the treatment of reproduction and some steroid-related disorders. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Comparison of Ion Chemistries in Octafluoro-2-butene (2-C4F8) and in Octfluorocyclobutane (c-C4F8)

NASA Astrophysics Data System (ADS)

Jiao, Charles; Dejoseph, Charles; Garscadden, Alan

2007-10-01

2-C4F8 is one of the promising candidates to replace c-C4F8 that has been widely used for dielectric etching but is not environmentally friendly. In this study we have investigated electron impact ionization and ion-molecule reactions of 2-C4F8 using Fourier transform mass spectrometry (FTMS), and compared the results with those of c-C4F8 we have studied previously. Electron impact ionization of 2-C4F8 produces 15 ionic species including C4F7,8^+, C3F3,5,6^+, C2F4^+ and CF1-3^+ as the major ions. The total ionization cross section of 2-C4F8 reaches a maximum of 1.8x10-15 cm^2 at 90 eV. The ionization is dominated by the channel forming the parent ion C4F8^+ from 12 to 18 eV, and by the channel forming C3F5^+ from 18 to 70 eV. After 70 eV, CF3^+ becomes the dominant product ion. Among the major ions generated from the electron impact ionization of 2-C4F8, only CF^+, CF2^+ and CF3^+ are found to react with 2-C4F8, via F^- abstraction or charge transfer mechanism. The charge transfer reaction of Ar^++2-C4F8 produces primarily C4F7^+.

MGA, L3MBTL2 and E2F6 determine genomic binding of the non-canonical Polycomb repressive complex PRC1.6

PubMed Central

Stielow, Bastian; Finkernagel, Florian; Stiewe, Thorsten

2018-01-01

Diverse Polycomb repressive complexes 1 (PRC1) play essential roles in gene regulation, differentiation and development. Six major groups of PRC1 complexes that differ in their subunit composition have been identified in mammals. How the different PRC1 complexes are recruited to specific genomic sites is poorly understood. The Polycomb Ring finger protein PCGF6, the transcription factors MGA and E2F6, and the histone-binding protein L3MBTL2 are specific components of the non-canonical PRC1.6 complex. In this study, we have investigated their role in genomic targeting of PRC1.6. ChIP-seq analysis revealed colocalization of MGA, L3MBTL2, E2F6 and PCGF6 genome-wide. Ablation of MGA in a human cell line by CRISPR/Cas resulted in complete loss of PRC1.6 binding. Rescue experiments revealed that MGA recruits PRC1.6 to specific loci both by DNA binding-dependent and by DNA binding-independent mechanisms. Depletion of L3MBTL2 and E2F6 but not of PCGF6 resulted in differential, locus-specific loss of PRC1.6 binding illustrating that different subunits mediate PRC1.6 loading to distinct sets of promoters. Mga, L3mbtl2 and Pcgf6 colocalize also in mouse embryonic stem cells, where PRC1.6 has been linked to repression of germ cell-related genes. Our findings unveil strikingly different genomic recruitment mechanisms of the non-canonical PRC1.6 complex, which specify its cell type- and context-specific regulatory functions. PMID:29381691

Prostaglandin E and F2 alpha receptors in human myometrium during the menstrual cycle and in pregnancy and labor

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

Giannopoulos, G.; Jackson, K.; Kredentser, J.

The binding of prostaglandins E1 and F2 alpha has been studied in the human myometrium and cervix during the menstrual cycle and in the myometrium of pregnant patients at term before and during labor. Tritium-labeled prostaglandin E1 and F2 alpha binding was saturable and reversible. Scatchard analysis of tritium-labeled prostaglandin E1 binding was linear, which suggests a single class of high-affinity binding sites with an estimated apparent equilibrium dissociation constant of 2.5 to 5.4 nmol/L and inhibitor affinities of 0.9, 273, 273, and 217 nmol/L for prostaglandins E2, A1, B1, and F2 alpha, respectively. Scatchard analysis of tritium-labeled prostaglandin F2more » alpha, binding was also linear, but the affinity of these binding sites was much lower, with an average dissociation constant of 50 nmol/L and inhibitor affinities of 1.6, 2.2, and 11.2 nmol/L for prostaglandins E1, E2, and A1, respectively. In nonpregnant patients, the concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were similar in the myometrium during the proliferative and secretory phases of the menstrual cycle, but the concentration of these sites was much lower in the cervix. The concentration of the tritium-labeled prostaglandin E1 binding sites was significantly lower in the myometrium of pregnant patients at term than in the myometrium of nonpregnant patients. The concentrations and affinities of tritium-labeled prostaglandin E1 binding sites were not significantly different in the upper and lower myometrium of pregnant patients at term or in the myometrium of such patients before and during labor. The concentrations of the tritium-labeled prostaglandin F2 alpha binding sites during the menstrual cycle and in pregnancy at term were similar to those of tritium-labeled prostaglandin E1 binding sites.« less

Substituent effects in a series of 1,7-C[subscript 60](R[subscript F])[subscript 2] compounds (R[subscript F] = CF[subscript 3], C[subscript 2]F[subscript 5], n-C[subscrip 3]F[subscript 7], i-C[subscript 3]F[subscript 7], n-C[subscript 4]F[subscript 9], s-C[subscript 4]F[subscript 9], n-C[subscript 8]F[subscript 17]): electron affinities, reduction potentials and E(LUMO) values are not always correlated

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

Kuvychko, Igor V.; Whitaker, James B.; Larson, Bryon W.

2013-04-08

A series of seven structurally-similar compounds with different pairs of R{sub F} groups were prepared, characterized spectroscopically, and studied by electrochemical methods (cyclic and square-wave voltammetry), low-temperature anion photoelectron spectroscopy, and DFT calculations (five of the compounds are reported here for the first time). This is the first time that a set of seven R{sub F} groups have been compared with respect to their relative effects on E{sub 1/2}(0/-), electron affinity (EA), and the DFT-calculated LUMO energy. The compounds, 1,7-C{sub 60}(R{sub F}){sub 2} (R{sub F} = CF{sub 3}, C{sub 2}F{sub 5}, i-C{sub 3}F{sub 7}, n-C{sub 3}F{sub 7}, s-C{sub 4}F{sub 9},more » n-C{sub 4}F{sub 9} and n-C{sub 8}F{sub 21}), were found to have statistically different electron affinities (EA), at the {+-}10 meV level of uncertainty, but virtually identical first reduction potentials, at the {+-}10 mV level of uncertainty. The lack of a correlation between EA and E{sub 1/2}(0/-), and between E(LUMO) and E{sub 1/2}(0/-), for such similar compounds is unprecedented and suggests that explanations for differences in figures of merit for materials and/or devices that are based on equating easily measurable E{sub 1/2}(0/-) values with EAs or E(LUMO) values should be viewed with caution. The solubilities of the seven compounds in toluene varied by nearly a factor of six, but in an unpredictable way, with the C{sub 2}F{sub 5} and s-C{sub 4}F{sub 9} compounds being the most soluble and the i-C{sub 3}F{sub 7} compound being the least soluble. The effects of the different R{sub F} groups on EAs, E(LUMO) values, and solubilities should help fluorine chemists choose the right R{sub F} group to design new materials with improved morphological, electronic, optical, and/or magnetic properties.« less

Comparative expression analysis of POU4F1, POU4F2 and ISL1 in developing mouse cochleovestibular ganglion neurons

PubMed Central

Deng, Min; Yang, Hua; Xie, Xiaoling; Liang, Guoqing; Gan, Lin

2014-01-01

POU-homeodomain and LIM-homeodomain transcription factors are expressed in developing projection neurons within retina, inner ear, dorsal root ganglion, and trigeminal ganglion, and play synergistic roles in their differentiation and survival. Here, using immunohistochemistry, we present a comparative analysis of the spatiotemporal expression pattern of POU4F1, POU4F2, and ISL1 during the development of cochleovestibular ganglion (CVG) neurons in mouse inner ear. At early stages, when otic neurons are first detected in the otic epithelium (OE) and migrate into periotic mesenchyme to form the CVG, POU4F1 and ISL1 are co-expressed in a majority of the delaminated CVG neurons, which are marked by NEUROD1 expression, but POU4F1 is absent in the otic epithelium. The onset of POU4F2 expression starts after that of POU4F1 and ISL1, and is observed in the NEUROD1-negative, post-mitotic CVG neurons. When the CVG neurons innervate the vestibular and cochlear sensory organs, the expression of POU4F1, POU4F2, and ISL1 continues in both vestibular and spiral ganglion cells. Later in development, POU4F1 expression becomes down-regulated in a majority of spiral ganglion (SG) neurons and more neurons express POU4F2 expression while ISL1 expression is maintained. The differential as well as overlapping expression of POU4F1, POU4F2, and ISL1 combined with previous studies suggests possible functional interaction and regulatory relationship of these transcription factors in the development of inner ear neurons. PMID:24709358

Can Clinical Skills Be Taught Online? Comparing Skill Development between Online and F2F Students Using a Blinded Review

ERIC Educational Resources Information Center

Wilke, Dina J.; King, Erin; Ashmore, Margaret; Stanley, Craig

2016-01-01

This study compared the development of clinical assessment and intervention skills between students enrolled in a face-to-face (F2F) or an asynchronous online clinical social work class. All students from three semesters of F2F (n = 74) and online (n = 78) sections of an MSW clinical class taught by the same instructor were included. Two…

Methodological development of topographic correction in 2D/3D ToF-SIMS images using AFM images

NASA Astrophysics Data System (ADS)

Jung, Seokwon; Lee, Nodo; Choi, Myungshin; Lee, Jungmin; Cho, Eunkyunng; Joo, Minho

2018-02-01

Time-of-flight secondary-ion mass spectrometry (ToF-SIMS) is an emerging technique that provides chemical information directly from the surface of electronic materials, e.g. OLED and solar cell. It is very versatile and highly sensitive mass spectrometric technique that provides surface molecular information with their lateral distribution as a two-dimensional (2D) molecular image. Extending the usefulness of ToF-SIMS, a 3D molecular image can be generated by acquiring multiple 2D images in a stack. These imaging techniques by ToF-SIMS provide an insight into understanding the complex structures of unknown composition in electronic material. However, one drawback in ToF-SIMS is not able to represent topographical information in 2D and 3D mapping images. To overcome this technical limitation, topographic information by ex-situ technique such as atomic force microscopy (AFM) has been combined with chemical information from SIMS that provides both chemical and physical information in one image. The key to combine two different images obtained from ToF-SIMS and AFM techniques is to develop the image processing algorithm, which performs resize and alignment by comparing the specific pixel information of each image. In this work, we present methodological development of the semiautomatic alignment and the 3D structure interpolation system for the combination of 2D/3D images obtained by ToF-SIMS and AFM measurements, which allows providing useful analytical information in a single representation.

Cranberry extract inhibits in vitro adhesion of F4 and F18+Escherichia coli to pig intestinal epithelium and reduces in vivo excretion of pigs orally challenged with F18+ verotoxigenic E. coli.

PubMed

Coddens, Annelies; Loos, Michaela; Vanrompay, Daisy; Remon, Jean Paul; Cox, Eric

2017-04-01

F4 + E. coli and F18 + E. coli infections are an important threat for pig industry worldwide. Antibiotics are commonly used to treat infected piglets, but the emerging development of resistance against antibiotics raises major concerns. Hence, alternative therapies to prevent pigs from F4 + E. coli and F18 + E. coli infections need to be developed. Since cranberry previously showed anti-adhesive activity against uropathogenic E. coli, we aimed to investigate whether cranberry extract could also inhibit binding of F4 + E. coli and F18 + E. coli to pig intestinal epithelium. Using the in vitro villus adhesion assay, we found that low concentrations of cranberry extract (20μg or 100μg/ml) have strong inhibitory activity on F4 + E. coli (75.3%, S.D.=9.31 or 95.8%, S.D.=2.56, respectively) and F18 + E. coli adherence (100% inhibition). This effect was not due to antimicrobial activity. Moreover, cranberry extract (10mg or 100mg) could also abolish in vivo binding of F4 and F18 fimbriae to the pig intestinal epithelium in ligated loop experiments. Finally, two challenge experiments with F18 + E. coli were performed to address the efficacy of in-feed or water supplemented cranberry extract. No effect could be observed in piglets that received cranberry extract only in feed (1g/kg or 10g/kg). However, supplementation of feed (10g/kg) and drinking water (1g/L) significantly decreased excretion and diarrhea. The decreased infection resulted in a decreased serum antibody response indicating reduced exposure to F18 + E. coli. Copyright © 2017 Elsevier B.V. All rights reserved.

KDM4A Coactivates E2F1 to Regulate the PDK-Dependent Metabolic Switch between Mitochondrial Oxidation and Glycolysis.

PubMed

Wang, Ling-Yu; Hung, Chiu-Lien; Chen, Yun-Ru; Yang, Joy C; Wang, Junjian; Campbell, Mel; Izumiya, Yoshihiro; Chen, Hong-Wu; Wang, Wen-Ching; Ann, David K; Kung, Hsing-Jien

2016-09-13

The histone lysine demethylase KDM4A/JMJD2A has been implicated in prostate carcinogenesis through its role in transcriptional regulation. Here, we describe KDM4A as a E2F1 coactivator and demonstrate a functional role for the E2F1-KDM4A complex in the control of tumor metabolism. KDM4A associates with E2F1 on target gene promoters and enhances E2F1 chromatin binding and transcriptional activity, thereby modulating the transcriptional profile essential for cancer cell proliferation and survival. The pyruvate dehydrogenase kinases (PDKs) PDK1 and PDK3 are direct targets of KDM4A and E2F1 and modulate the switch between glycolytic metabolism and mitochondrial oxidation. Downregulation of KDM4A leads to elevated activity of pyruvate dehydrogenase and mitochondrial oxidation, resulting in excessive accumulation of reactive oxygen species. The altered metabolic phenotypes can be partially rescued by ectopic expression of PDK1 and PDK3, indicating a KDM4A-dependent tumor metabolic regulation via PDK. Our results suggest that KDM4A is a key regulator of tumor metabolism and a potential therapeutic target for prostate cancer. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Vaccinia virus proteins A36 and F12/E2 show strong preferences for different kinesin light chain isoforms.

PubMed

Gao, William N D; Carpentier, David C J; Ewles, Helen A; Lee, Stacey-Ann; Smith, Geoffrey L

2017-08-01

Vaccinia virus (VACV) utilizes microtubule-mediated trafficking at several stages of its life cycle, of which virus egress is the most intensely studied. During egress VACV proteins A36, F12 and E2 are involved in kinesin-1 interactions; however, the roles of these proteins remain poorly understood. A36 forms a direct link between virions and kinesin-1, yet in its absence VACV egress still occurs on microtubules. During a co-immunoprecipitation screen to seek an alternative link between virions and kinesin, A36 was found to bind isoform KLC1 rather than KLC2. The F12/E2 complex associates preferentially with the C-terminal tail of KLC2, to a region that overlaps the binding site of cellular 14-3-3 proteins. F12/E2 displaces 14-3-3 from KLC and, unlike 14-3-3, does not require phosphorylation of KLC for its binding. The region determining the KLC1 specificity of A36 was mapped to the KLC N-terminal heptad repeat region that is responsible for its association with kinesin heavy chain. Despite these differing binding properties F12/E2 can co-operatively enhance A36 association with KLC, particularly when using a KLC1-KLC2 chimaera that resembles several KLC1 spliceforms and can bind A36 and F12/E2 efficiently. This is the first example of a pathogen encoding multiple proteins that co-operatively associate with kinesin-1. © 2017 The Authors. Traffic published by John Wiley & Sons Ltd.

Cdc6 is regulated by E2F and is essential for DNA replication in mammalian cells.

PubMed

Yan, Z; DeGregori, J; Shohet, R; Leone, G; Stillman, B; Nevins, J R; Williams, R S

1998-03-31

Cdc6 has a critical regulatory role in the initiation of DNA replication in yeasts, but its function in mammalian cells has not been characterized. We show here that Cdc6 is expressed selectively in proliferating but not quiescent mammalian cells, both in culture and within tissues of intact animals. During the transition from a growth-arrested to a proliferative state, transcription of mammalian Cdc6 is regulated by E2F proteins, as revealed by a functional analysis of the human Cdc6 promoter and by the ability of exogenously expressed E2F proteins to stimulate the endogenous Cdc6 gene. Immunodepletion of Cdc6 by microinjection of anti-Cdc6 antibody blocks initiation of DNA replication in a human tumor cell line. We conclude that expression of human Cdc6 is regulated in response to mitogenic signals though transcriptional control mechanisms involving E2F proteins, and that Cdc6 is required for initiation of DNA replication in mammalian cells.

E6/E7-P53-POU2F1-CTHRC1 axis promotes cervical cancer metastasis and activates Wnt/PCP pathway

PubMed Central

Zhang, Rong; Lu, Huan; Lyu, Yuan-yuan; Yang, Xiao-mei; Zhu, Lin-yan; Yang, Guang-dong; Jiang, Peng-cheng; Re, Yuan; Song, Wei-wei; Wang, Jin-hao; Zhang, Can-can; Gu, Fei; Luo, Tian-jiao; Wu, Zhi-yong; Xu, Cong-jian

2017-01-01

Cervical cancer is an infectious cancer and the most common gynecologic cancer worldwide. E6/E7, the early genes of the high-risk mucosal human papillomavirus type, play key roles in the carcinogenic process of cervical cancer. However, little was known about its roles in modulating tumor microenvironment, particular extracellular matrix (ECM). In this study, we found that E6/E7 could regulate multiple ECM proteins, especially collagen triple helix repeat containing 1 (CTHRC1). CTHRC1 is highly expressed in cervical cancer tissue and serum and closely correlated with clinicopathological parameters. CTHRC1 promotes cervical cancer cell migration and invasion in vitro and metastasis in vivo. E6/E7 regulates the expression of CTHRC1 in cervical cancer by E6/E7-p53-POU2F1 (POU class 2 homeobox 1) axis. Futhermore, CTHRC1 activates Wnt/PCP signaling pathway. Take together, E6/E7-p53-POU2F1-CTHRC1 axis promotes cervical cancer cell invasion and metastasis and may act as a potential therapeutic target for interventions against cervical cancer invasion and metastasis. PMID:28303973

The evaluation of anoxia responsive E2F DNA binding activity in the red eared slider turtle, Trachemys scripta elegans.

PubMed

Biggar, Kyle K; Storey, Kenneth B

2018-01-01

In many cases, the DNA-binding activity of a transcription factor does not change, while its transcriptional activity is greatly influenced by the make-up of bound proteins. In this study, we assessed the protein composition and DNA-binding ability of the E2F transcription factor complex to provide insight into cell cycle control in an anoxia tolerant turtle through the use of a modified ELISA protocol. This modification also permits the use of custom DNA probes that are tailored to a specific DNA binding region, introducing the ability to design capture probes for non-model organisms. Through the use of EMSA and ELISA DNA binding assays, we have successfully determined the in vitro DNA binding activity and complex dynamics of the Rb/E2F cell cycle regulatory mechanisms in an anoxic turtle, Trachemys scripta elegans . Repressive cell cycle proteins (E2F4, Rb, HDAC4 and Suv39H1) were found to significantly increase at E2F DNA-binding sites upon anoxic exposure in anoxic turtle liver. The lack of p130 involvement in the E2F DNA-bound complex indicates that anoxic turtle liver may maintain G 1 arrest for the duration of stress survival.

The evaluation of anoxia responsive E2F DNA binding activity in the red eared slider turtle, Trachemys scripta elegans

PubMed Central

Biggar, Kyle K.

2018-01-01

In many cases, the DNA-binding activity of a transcription factor does not change, while its transcriptional activity is greatly influenced by the make-up of bound proteins. In this study, we assessed the protein composition and DNA-binding ability of the E2F transcription factor complex to provide insight into cell cycle control in an anoxia tolerant turtle through the use of a modified ELISA protocol. This modification also permits the use of custom DNA probes that are tailored to a specific DNA binding region, introducing the ability to design capture probes for non-model organisms. Through the use of EMSA and ELISA DNA binding assays, we have successfully determined the in vitro DNA binding activity and complex dynamics of the Rb/E2F cell cycle regulatory mechanisms in an anoxic turtle, Trachemys scripta elegans. Repressive cell cycle proteins (E2F4, Rb, HDAC4 and Suv39H1) were found to significantly increase at E2F DNA-binding sites upon anoxic exposure in anoxic turtle liver. The lack of p130 involvement in the E2F DNA-bound complex indicates that anoxic turtle liver may maintain G1 arrest for the duration of stress survival. PMID:29770276

Divalent europium doped CaF 2 and BaF 2 nanocrystals from ionic liquids

DOE PAGES

Anghel, Sergiu; Golbert, Sebastian; Meijerink, Andries; ...

2016-10-11

A new, facile and quick synthesis method for Eu 2+ doped the alkaline earth fluorides was developed using ionic liquids as solvent, precursor and capping agent. Reductive atmosphere and very high temperatures were avoided, while still attaining the desired structure, small particle sizes and divalent oxidation state of the lanthanide. Here, this opens the door for the development of new Ln 2+ doped nanomaterials. Here, the successful Eu 2+ incorporation was proven by optical spectroscopic measurements which showed the spin and parity allowed f-d transitions of Eu 2+ in CaF 2:Eu 2+/BaF 2:Eu 2+. 4f 7-4f 7 transitions could bemore » observed at low temperatures (7 K).« less

Origin of field-induced discontinuous phase transitions in N d2F e17

NASA Astrophysics Data System (ADS)

Diop, L. V. B.; Kuz'min, M. D.; Skokov, K. P.; Skourski, Y.; Gutfleisch, O.

2018-02-01

Magnetic properties of a trigonal ferromagnet N d2F e17 have been studied on single crystals in steady (14 T) and pulsed (32 T) magnetic fields. The easy-magnetization direction lies close to the [120] axis, deviating from the basal plane by 2 .9∘ (at T =5 K ). Of particular interest is the low-temperature magnetization process along the high-symmetry axis [001], which is the hard direction. This process is discontinuous and involves two first-order phase transitions (FOMPs). One of them (at 20 T) is a symmetry FOMP similar to that observed in S m2F e17 . The second transition (at 10.4 T) is unusual: as the magnetization turns abruptly toward the applied field, it also changes its azimuthal orientation (the angle φ ) by 60∘. Both transitions can be reasonably accounted for by the presence of a significant sixth-order trigonal anisotropy term.

F-111E IPCS in flight

NASA Technical Reports Server (NTRS)

1975-01-01

This NASA Dryden Flight Research Center photograph taken in 1975 shows the General Dynamic IPCS/F-111E Aardvark with a camouflage paint pattern. This prototype F-111E was used during the flight testing of the Integrated Propulsion Control System (IPCS). The wings of the IPCS/F-111E are swept back to near 60 degrees for supersonic flight. During the same period as F-111 TACT program, an F-111E Aardvark (#67-0115) was flown at the NASA Flight Research Center to investigate an electronic versus a conventional hydro-mechanical controlled engine. The program called integrated propulsion control system (IPCS) was a joint effort by NASA's Lewis Research Center and Flight Research Center, the Air Force's Flight Propulsion Laboratory and the Boeing, Honeywell and Pratt & Whitney companies. The left engine of the F-111E was selected for modification to an all electronic system. A Pratt & Whitney TF30-P-9 engine was modified and extensively laboratory, and ground-tested before installation into the F-111E. There were 14 IPCS flights made from 1975 through 1976. The flight demonstration program proved an engine could be controlled electronically, leading to a more efficient Digital Electronic Engine Control System flown in the F-15.

Two decades of pharmacovigilance and clinical experience with highly purified rabies immunoglobulin F(ab')2 fragments.

PubMed

Reveneau, Elisa; Cottin, Pascale; Rasuli, Anvar

2017-03-01

Rabies is a worldwide zoonotic viral disease with no specific treatment once symptoms occur; manifest disease is almost always fatal. WHO recommendations for exposed individuals include immediate attention to the wound and use of rabies immunoglobulin and/or vaccine for post-exposure prophylaxis (PEP). Here, we provide an overview of the clinical experience with a highly purified preparation of F(ab') 2 fragments from equine rabies immunoglobulin (F(ab') 2 pERIG; Favirab TM ) in rabies PEP. Areas covered: Our review comprises a retrospective analysis of adverse event reports in the Sanofi Pasteur global pharmacovigilance database for F(ab') 2 pERIG, including adverse event reports from eight Sanofi Pasteur-sponsored clinical trials and post-market surveillance data collected between 1995 and 2014. The general safety profile of F(ab') 2 pERIG is discussed, as are the occurrence of rare anaphylactic reactions, and suspected intervention failure. Expert commentary: Over 20 years of clinical development and post-licensure experience has established the safety and effectiveness of F(ab') 2 pERIG (Favirab TM ) in rabies PEP.

Interrupted E2F1-miR-34c-SCF negative feedback loop by hyper-methylation promotes colorectal cancer cell proliferation

PubMed Central

Yang, Shu; Wu, Bo; Sun, Haimei; Ji, Fengqing; Sun, Tingyi; Zhao, Yan; Zhou, Deshan

2015-01-01

Tumour suppressor miR-34c deficiency resulted from hyper-methylation in its promoter is believed to be one of the main causes of colorectal cancer (CRC). Till date, miR-34c has been validated as a direct target of p53; but previous evidence suggested other transcription factor(s) must be involved in miR-34c transcription. In the present study, we in the first place identified a core promoter region (−1118 to −883 bp) of pre-miR-34c which was embedded within a hyper-methylated CpG island. Secondly, E2F1 promoted miR-34c transcription by physical interaction with the miR-34c promoter at site −897 to −889 bp. The transcriptional activating effect of E2F1 on miR-34c was in a p53 independent manner but profoundly promoted in the presence of p53 with exposure to 5-aza-2′-deoxycytidine (DAC). Thirdly, stem cell factor (SCF), a miR-34c target, was specifically reduced upon an introduction of E2F1 which lead to suppression of CRC cell proliferation. The E2F1-suppressed cell proliferation was partially abrogated by additional miR-34c inhibitor, indicating that the anti-proliferation effect of E2F1 was probably through activating miR-34c-SCF axis. Finally, SCF/KIT signalling increased E2F1 production by reducing its proteosomal degradation dependent on PI3K/Akt-GSK3β pathway. In conclusion, our results suggested the existence of E2F1-miR-34c-SCF negative feedback loop which was interrupted by the hyper-methylation of miR-34c promoter in CRC cells and increased cell proliferation. PMID:26704889

Telomerase Reverse Transcriptase Deficiency Prevents Neointima Formation Through Chromatin Silencing of E2F1 Target Genes.

PubMed

Endorf, Elizabeth B; Qing, Hua; Aono, Jun; Terami, Naoto; Doyon, Geneviève; Hyzny, Eric; Jones, Karrie L; Findeisen, Hannes M; Bruemmer, Dennis

2017-02-01

Aberrant proliferation of smooth muscle cells (SMC) in response to injury induces pathological vascular remodeling during atherosclerosis and neointima formation. Telomerase is rate limiting for tissue renewal and cell replication; however, the physiological role of telomerase in vascular diseases remains to be determined. The goal of the present study was to determine whether telomerase reverse transcriptase (TERT) affects proliferative vascular remodeling and to define the molecular mechanism by which TERT supports SMC proliferation. We first demonstrate high levels of TERT expression in replicating SMC of atherosclerotic and neointimal lesions. Using a model of guidewire-induced arterial injury, we demonstrate decreased neointima formation in TERT-deficient mice. Studies in SMC isolated from TERT-deficient and TERT overexpressing mice with normal telomere length established that TERT is necessary and sufficient for cell proliferation. TERT deficiency did not induce a senescent phenotype but resulted in G1 arrest albeit hyperphosphorylation of the retinoblastoma protein. This proliferative arrest was associated with stable silencing of the E2F1-dependent S-phase gene expression program and not reversed by ectopic overexpression of E2F1. Finally, chromatin immunoprecipitation and accessibility assays revealed that TERT is recruited to E2F1 target sites and promotes chromatin accessibility for E2F1 by facilitating the acquisition of permissive histone modifications. These data indicate a previously unrecognized role for TERT in neointima formation through epigenetic regulation of proliferative gene expression in SMC. © 2016 American Heart Association, Inc.

M2-F2 on ramp

NASA Image and Video Library

1966-02-24

The M2-F2 Lifting Body is seen here on the ramp at the NASA Dryden Flight Research Center. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers -- the M2-F2 and the HL-10, both built by the Northrop Corporation. The "M" refers to "manned" and "F" refers to "flight" version. "HL" comes from "horizontal landing" and 10 is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the "F1" -- was on July 12, 1966. Milt Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft was modified to also carry the lifting bodies. Thompson was dropped from the B-52's wing pylon mount at an altitude of 45,000 feet on that maiden glide flight. The M2-F2 weighed 4,620 pounds, was 22 feet long, and had a width of about 10 feet. On May 10, 1967, during the sixteenth glide flight leading up to powered flight, a landing accident severely damaged the vehicle and seriously injured the NASA pilot, Bruce Peterson. NASA pilots and researchers realized the M2-F2 had lateral control problems, even though it had a stability augmentation control system. When the M2-F2 was rebuilt at Dryden and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. The M2-F2/F3 was the first of the heavy-weight, entry-configuration lifting bodies. Its successful development as a research test vehicle answered many of the generic questions about these vehicles. NASA donated the M2-F3 vehicle to the Smithsonian Institute in December 1973. It is currently hanging in the Air and Space Museum along with the X-15 aircraft number 1, which was its hangar partner at Dryden from 1965 to 1969.

Krüppel-like factor 1 mutations and expression of hemoglobins F and A2 in homozygous hemoglobin E syndrome.

PubMed

Tepakhan, Wanicha; Yamsri, Supawadee; Fucharoen, Goonnapa; Sanchaisuriya, Kanokwan; Fucharoen, Supan

2015-07-01

The basis for variability of hemoglobin (Hb) F in homozygous Hb E disease is not well understood. We have examined multiple mutations of the Krüppel-like factor 1 (KLF1) gene; an erythroid specific transcription factor and determined their associations with Hbs F and A2 expression in homozygous Hb E. Four KLF1 mutations including G176AfsX179, T334R, R238H, and -154 (C-T) were screened using specific PCR assays on 461 subjects with homozygous Hb E and 100 normal controls. None of these four mutations were observed in 100 normal controls. Among 461 subjects with homozygous Hb E, 306 had high (≥5 %) and 155 had low (<5 %) Hb F. DNA analysis identified the KLF1 mutations in 35 cases of the former group with high Hb F, including the G176AfsX179 mutation (17/306 = 5.6 %), T334R mutation (9/306 = 2.9 %), -154 (C-T) mutation (7/306 = 2.3 %), and R328H mutation (2/306 = 0.7 %). Only two subjects in the latter group with low Hb F carried the G176AfsX179 and -154 (C-T) mutations. Significant higher Hb A2 level was observed in those of homozygous Hb E with the G176AfsX179 mutation as compared to those without KLF1 mutations. These results indicate that KLF1 is among the genetic factors associated with increased Hbs F and A2, and in combination with other factors could explain the variabilities of these Hb expression in Hb E syndrome.

Circular RNA hsa_circ_0008039 promotes breast cancer cell proliferation and migration by regulating miR-432-5p/E2F3 axis.

PubMed

Liu, Yanhua; Lu, Cuntao; Zhou, Yizhou; Zhang, Zhihong; Sun, Li

2018-07-20

As the development of sequencing technology, more and more circular RNAs (circRNAs) are identified in human cancer tissues. Increasing evidences imply circRNAs are important regulators in tumor progression. Nevertheless, how circRNAs participate in breast cancer development and progression is not well understood. In the present study, we identified a novel circRNA hsa_circ_0008039 with upregulated expression level in breast cancer tissues. By functional experiments, we found that hsa_circ_0008039 depletion significantly suppressed the proliferation, arrested cell-cycle progression and reduced migration in breast cancer. Mechanistic investigations suggested that hsa_circ_0008039 served as a competing endogenous RNA (ceRNA) of miR-432-5p. Subsequently, E2F3 was identified as the functional target of miR-432-5p and overexpression of hsa_circ_0008039 elevated E2F3 expression in breast cancer. On the whole, our study indicated that hsa_circ_0008039 exerted oncogenic roles in breast cancer and suggested the hsa_circ_0008039/miR-432-5p/E2F3 axis might be a potential therapeutic target. Copyright © 2018 Elsevier Inc. All rights reserved.

Spread-F occurrences and relationships with foF2 and h'F at low- and mid-latitudes in China

NASA Astrophysics Data System (ADS)

Wang, Ning; Guo, Lixin; Zhao, Zhenwei; Ding, Zonghua; Lin, Leke

2018-04-01

Ionospheric irregularities are an important phenomenon in scientific studies and applications of radio-wave propagation. Spread-F echoes in ionograms are a type of high-frequency band irregularities that include frequency spread-F (FSF), range spread-F (RSF), and mixed spread-F (MSF) events. In this study, we obtained spread-F data from four ionosondes at low- and mid-latitudes near the 120°E chain in China during the 23rd solar cycle. We used these data to investigate spread-F occurrence percentages and variations with local time, season, latitude, and solar activity. The four ionosondes were located at Haikou (HK) (20°N, 110.34°E), Guangzhou (GZ) (23.14°N, 113.36°E), Beijing (BJ) (40.11°N, 116.28°E), and Changchun (CC) (43.84°N, 125.28°E). We also present possible correlations between spread-Fs and other ionospheric parameters, such as the critical frequency of the F2-layer (foF2) and the virtual height of the bottom-side F-layer (h'F). In particular, we investigated the possible threshold of the foF2 affecting the FSF and the relationship between the h'F and the RSF. The main conclusions are as follows: (a) the FSF occurrence percentages were anti-correlated with solar activity at all four sites; meanwhile, RSF occurrence rates increased with the increase in solar activity at HK, but not at the other three sites; (b) FSF occurrence rates were larger at the mid-latitudes than expected, while FSFs occurred more often after midnight; (c) the highest FSF occurrence rates mostly appeared during the summer months, while RSFs occurred mostly in the equinoctial months of 2000-2002 at HK and GZ; (d) a lower foF2 was suitable for FSF events; nevertheless, h'F and RSF occurrences satisfied the parabolic relationship; (e) the foF2 thresholds for FSFs were 15, 14, 7.6, and 7.8 MHz at HK, GZ, BJ, and CC, respectively. The h'Fs occurring between 240 and 290 km were more favorable for RSF occurrences. These results are important for understanding ionospheric

E2F mediates induction of the Sp1-controlled promoter of the human DNA polymerase ɛ B-subunit gene POLE2

PubMed Central

Huang, Deqi; Jokela, Maarit; Tuusa, Jussi; Skog, Sven; Poikonen, Kari; Syväoja, Juhani E.

2001-01-01

The B-subunits of replicative DNA polymerases from Archaea to humans belong to the same protein family, suggesting that they share a common fundamental function. We report here the gene structure for the B-subunit of human DNA polymerase ɛ (POLE2), whose expression and transcriptional regulation is typical for replication proteins with some unique features. The 75 bp core promoter region, located within exon 1, contains an Sp1 element that is a critical determinant of promoter activity as shown by the luciferase reporter, electrophoretic mobility shift and DNase I footprinting assays. Two overlapping E2F elements adjacent to the Sp1 element are essential for full promoter activity and serum response. Binding sites for E2F1 and NF-1 reside immediately downstream from the core promoter region. Our results suggest that human POLE2 is regulated by two E2F–pocket protein complexes, one associated with Sp1 and the other with NF-1. So far, only one replicative DNA polymerase B-subunit gene promoter, POLA2 encoding the B-subunit of DNA polymerase α, has been characterized. Mitogenic activation of the POLE2 promoter by an E2F-mediated mechanism resembles that of POLA2, but the regulation of basal promoter activity is different between these two genes. PMID:11433027

Triptolide abrogates growth of colon cancer and induces cell cycle arrest by inhibiting transcriptional activation of E2F.

PubMed

Oliveira, Amanda; Beyer, Georg; Chugh, Rohit; Skube, Steven J; Majumder, Kaustav; Banerjee, Sulagna; Sangwan, Veena; Li, Lihua; Dawra, Rajinder; Subramanian, Subbaya; Saluja, Ashok; Dudeja, Vikas

2015-06-01

Despite significant progress in diagnostics and therapeutics, over 50 thousand patients die from colorectal cancer annually. Hence, there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies, colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase release, and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F-dependent genes, E2F1- retinoblastoma protein (Rb) binding, and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically, we demonstrate that at low concentrations triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Therefore, we conclude

The eIF4F and eIFiso4F Complexes of Plants: An Evolutionary Perspective

PubMed Central

Patrick, Ryan M.; Browning, Karen S.

2012-01-01

Translation initiation in eukaryotes requires a number of initiation factors to recruit the assembled ribosome to mRNA. The eIF4F complex plays a key role in initiation and is a common target point for regulation of protein synthesis. Most work on the translation machinery of plants to date has focused on flowering plants, which have both the eIF4F complex (eIF4E and eIF4G) as well as the plant-specific eIFiso4F complex (eIFiso4E and eIFiso4G). The increasing availability of plant genome sequence data has made it possible to trace the evolutionary history of these two complexes in plants, leading to several interesting discoveries. eIFiso4G is conserved throughout plants, while eIFiso4E only appears with the evolution of flowering plants. The eIF4G N-terminus, which has been difficult to annotate, appears to be well conserved throughout the plant lineage and contains two motifs of unknown function. Comparison of eIFiso4G and eIF4G sequence data suggests conserved features unique to eIFiso4G and eIF4G proteins. These findings have answered some questions about the evolutionary history of the two eIF4F complexes of plants, while raising new ones. PMID:22611336

E4F1 deficiency results in oxidative stress–mediated cell death of leukemic cells

PubMed Central

Hatchi, Elodie; Rodier, Genevieve; Lacroix, Matthieu; Caramel, Julie; Kirsh, Olivier; Jacquet, Chantal; Schrepfer, Emilie; Lagarrigue, Sylviane; Linares, Laetitia Karine; Lledo, Gwendaline; Tondeur, Sylvie; Dubus, Pierre

2011-01-01

The multifunctional E4F1 protein was originally discovered as a target of the E1A viral oncoprotein. Growing evidence indicates that E4F1 is involved in key signaling pathways commonly deregulated during cell transformation. In this study, we investigate the influence of E4F1 on tumorigenesis. Wild-type mice injected with fetal liver cells from mice lacking CDKN2A, the gene encoding Ink4a/Arf, developed histiocytic sarcomas (HSs), a tumor originating from the monocytic/macrophagic lineage. Cre-mediated deletion of E4F1 resulted in the death of HS cells and tumor regression in vivo and extended the lifespan of recipient animals. In murine and human HS cell lines, E4F1 inactivation resulted in mitochondrial defects and increased production of reactive oxygen species (ROS) that triggered massive cell death. Notably, these defects of E4F1 depletion were observed in HS cells but not healthy primary macrophages. Short hairpin RNA–mediated depletion of E4F1 induced mitochondrial defects and ROS-mediated death in several human myeloid leukemia cell lines. E4F1 protein is overexpressed in a large subset of human acute myeloid leukemia samples. Together, these data reveal a role for E4F1 in the survival of myeloid leukemic cells and support the notion that targeting E4F1 activities might have therapeutic interest. PMID:21708927

Tandem E2F Binding Sites in the Promoter of the p107 Cell Cycle Regulator Control p107 Expression and Its Cellular Functions

PubMed Central

Burkhart, Deborah L.; Wirt, Stacey E.; Zmoos, Anne-Flore; Kareta, Michael S.; Sage, Julien

2010-01-01

The retinoblastoma tumor suppressor (Rb) is a potent and ubiquitously expressed cell cycle regulator, but patients with a germline Rb mutation develop a very specific tumor spectrum. This surprising observation raises the possibility that mechanisms that compensate for loss of Rb function are present or activated in many cell types. In particular, p107, a protein related to Rb, has been shown to functionally overlap for loss of Rb in several cellular contexts. To investigate the mechanisms underlying this functional redundancy between Rb and p107 in vivo, we used gene targeting in embryonic stem cells to engineer point mutations in two consensus E2F binding sites in the endogenous p107 promoter. Analysis of normal and mutant cells by gene expression and chromatin immunoprecipitation assays showed that members of the Rb and E2F families directly bound these two sites. Furthermore, we found that these two E2F sites controlled both the repression of p107 in quiescent cells and also its activation in cycling cells, as well as in Rb mutant cells. Cell cycle assays further indicated that activation of p107 transcription during S phase through the two E2F binding sites was critical for controlled cell cycle progression, uncovering a specific role for p107 to slow proliferation in mammalian cells. Direct transcriptional repression of p107 by Rb and E2F family members provides a molecular mechanism for a critical negative feedback loop during cell cycle progression and tumorigenesis. These experiments also suggest novel therapeutic strategies to increase the p107 levels in tumor cells. PMID:20585628

First somatic mutation of E2F1 in a critical DNA binding residue discovered in well-differentiated papillary mesothelioma of the peritoneum

PubMed Central

2011-01-01

Background Well differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare variant of epithelial mesothelioma of low malignancy potential, usually found in women with no history of asbestos exposure. In this study, we perform the first exome sequencing of WDPMP. Results WDPMP exome sequencing reveals the first somatic mutation of E2F1, R166H, to be identified in human cancer. The location is in the evolutionarily conserved DNA binding domain and computationally predicted to be mutated in the critical contact point between E2F1 and its DNA target. We show that the R166H mutation abrogates E2F1's DNA binding ability and is associated with reduced activation of E2F1 downstream target genes. Mutant E2F1 proteins are also observed in higher quantities when compared with wild-type E2F1 protein levels and the mutant protein's resistance to degradation was found to be the cause of its accumulation within mutant over-expressing cells. Cells over-expressing wild-type E2F1 show decreased proliferation compared to mutant over-expressing cells, but cell proliferation rates of mutant over-expressing cells were comparable to cells over-expressing the empty vector. Conclusions The R166H mutation in E2F1 is shown to have a deleterious effect on its DNA binding ability as well as increasing its stability and subsequent accumulation in R166H mutant cells. Based on the results, two compatible theories can be formed: R166H mutation appears to allow for protein over-expression while minimizing the apoptotic consequence and the R166H mutation may behave similarly to SV40 large T antigen, inhibiting tumor suppressive functions of retinoblastoma protein 1. PMID:21955916

Peroxisome Proliferator-Activated Receptor β/δ Cross Talks with E2F and Attenuates Mitosis in HRAS-Expressing Cells

PubMed Central

Zhu, Bokai; Khozoie, Combiz; Bility, Moses T.; Ferry, Christina H.; Blazanin, Nicholas; Glick, Adam B.; Gonzalez, Frank J.

2012-01-01

The role of peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in Harvey sarcoma ras (Hras)-expressing cells was examined. Ligand activation of PPARβ/δ caused a negative selection with respect to cells expressing higher levels of the Hras oncogene by inducing a mitotic block. Mitosis-related genes that are predominantly regulated by E2F were induced to a higher level in HRAS-expressing Pparβ/δ-null keratinocytes compared to HRAS-expressing wild-type keratinocytes. Ligand-activated PPARβ/δ repressed expression of these genes by direct binding with p130/p107, facilitating nuclear translocation and increasing promoter recruitment of p130/p107. These results demonstrate a novel mechanism of PPARβ/δ cross talk with E2F signaling. Since cotreatment with a PPARβ/δ ligand and various mitosis inhibitors increases the efficacy of increasing G2/M arrest, targeting PPARβ/δ in conjunction with mitosis inhibitors could become a suitable option for development of new multitarget strategies for inhibiting RAS-dependent tumorigenesis. PMID:22473992

SH-2F LAMPS Instructional Systems Development: Phase II. Final Report.

ERIC Educational Resources Information Center

Gibbons, Andrew S.; Hymes, Jonah P.

This project was one of four aircrew training development projects in a continuing study of the methodology, effectiveness, and resource requirements of the Instructional Systems Development (ISD) process. This report covers the Phase II activities of a two-phase project for the development of aircrew training for SH-2F anti-submarine warfare…

Development of Flight Safety Prediction Methodology for U. S. Naval Safety Center. Revision 1

DTIC Science & Technology

1970-02-01

Safety Center. The methodology develoned encompassed functional analysis of the F-4J aircraft, assessment of the importance of safety- sensitive ... Sensitivity ... ....... . 4-8 V 4.5 Model Implementation ........ ......... . 4-10 4.5.1 Functional Analysis ..... ........... . 4-11 4. 5. 2 Major...Function Sensitivity Assignment ........ ... 4-13 i 4.5.3 Link Dependency Assignment ... ......... . 4-14 4.5.4 Computer Program for Sensitivity

Deregulated E2F5/p38/SMAD3 Circuitry Reinforces the Pro-Tumorigenic Switch of TGFβ Signaling in Prostate Cancer.

PubMed

Majumder, Subhadipa; Bhowal, Ankur; Basu, Sanmitra; Mukherjee, Pritha; Chatterji, Urmi; Sengupta, Sanghamitra

2016-11-01

Transforming growth factor-β signaling exerts divergent effects on normal and cancer cells, although mechanism underlying this differential behavior remains unclear. In this study, expression of 94 genes pertaining to the TGF-β signaling pathway was compared between tumor and benign tissue samples from the human prostate gland to identify major discriminators driving prostate carcinogenesis. E2F5 was identified as one of the most deregulated genes in prostate cancer tissues, predominantly in samples with Gleason-score 6. Expression of other deregulated components of TGF-β signaling was examined by qRT-PCR, Western blot, and immune-staining. Function of E2F5 and p38 in prostate cancer was investigated using siRNA-treatment of PC3 cell-line followed by analyses of associated components and cell cycle. Observations revealed that E2F5 overexpression was accompanied by significantly higher phosphorylation of SMAD3 at Ser-208 in the linker region (pSMAD3L) and p38 in tumor tissue. A striking difference in SMAD3 phosphorylation, marked by preponderance of pSMAD3L and pSMAD3C (Ser-423 and 425) in tumor and benign tissues, respectively was noted. Co-localization of E2F5 with pSMAD3L in the nuclei of tumor and PC3 cells indicated a functional interface between the proteins. Downregulation of E2F5 and p38 in PC3 cells resulted in marked reduction of phosphorylation of SMAD3 and perturbation of cell cycle with an arrest of cells in G1 . Our findings unearthed that E2F5/p38 axis played a cardinal role in uncontrolled cellular proliferation in prostate cancer through pSMAD3L activation. It also underscores a strong potential for E2F5 to be incorporated as a tool in early detection of prostate cancer. J. Cell. Physiol. 231: 2482-2492, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Epigenetic involvement of Alien/ESET complex in thyroid hormone-mediated repression of E2F1 gene expression and cell proliferation

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

Hong, Wei, E-mail: hongwei@tijmu.edu.cn; College of Basic Medicine, Tianjin Medical University, 300070 Tianjin; Li, Jinru

Highlights: Black-Right-Pointing-Pointer Corepressor Alien interacts with histone methyltransferase ESET in vivo. Black-Right-Pointing-Pointer Alien/ESET complex is recruited to nTRE of T3-responsive gene by liganded TR{beta}1. Black-Right-Pointing-Pointer ESET-mediated H3K9 methylation is required for liganded TR{beta}1-repressed transcription. Black-Right-Pointing-Pointer ESET is involved in T3-repressed G1/S phase transition and proliferation. -- Abstract: The ligand-bound thyroid hormone receptor (TR) is known to repress via a negative TRE (nTRE) the expression of E2F1, a key transcription factor that controls the G1/S phase transition. Alien has been identified as a novel interacting factor of E2F1 and acts as a corepressor of E2F1. The detailed molecular mechanism by whichmore » Alien inhibits E2F1 gene expression remains unclear. Here, we report that the histone H3 lysine 9 (H3K9) methyltransferase (HMT) ESET is an integral component of the corepressor Alien complex and the Alien/ESET complex is recruited to both sites, the E2F1 and the nTRE site of the E2F1 gene while the recruitment to the negative thyroid hormone response element (nTRE) is induced by the ligand-bound TR{beta}1 within the E2F1 gene promoter. We show that, overexpression of ESET promotes, whereas knockdown of ESET releases, the inhibition of TR{beta}1-regulated gene transcription upon T3 stimulation; and H3K9 methylation is required for TR{beta}1-repressed transcription. Furthermore, depletion of ESET impairs thyroid hormone-repressed proliferation as well as the G1/S transition of the cell cycle. Taken together, our data indicate that ESET is involved in TR{beta}1-mediated transcription repression and provide a molecular basis of thyroid hormone-induced repression of proliferation.« less

The Osmium(VIII) Oxofluoro Cations OsO(2)F(3)(+) and F(cis-OsO(2)F(3))(2)(+): Syntheses, Characterization by (19)F NMR Spectroscopy and Raman Spectroscopy, X-ray Crystal Structure of F(cis-OsO(2)F(3))(2)(+)Sb(2)F(11)(-), and Density Functional Theory Calculations of OsO(2)F(3)(+), ReO(2)F(3), and F(cis-OsO(2)F(3))(2)(+).

PubMed

Casteel, William J.; Dixon, David A.; Mercier, Hélène P. A.; Schrobilgen, Gary J.

1996-07-17

Osmium dioxide tetrafluoride, cis-OsO(2)F(4), reacts with the strong fluoride ion acceptors AsF(5) and SbF(5) in anhydrous HF and SbF(5) solutions to form orange salts. Raman spectra are consistent with the formation of the fluorine-bridged diosmium cation F(cis-OsO(2)F(3))(2)(+), as the AsF(6)(-) and Sb(2)F(11)(-) salts, respectively. The (19)F NMR spectra of the salts in HF solution are exchange-averaged singlets occurring at higher frequency than those of the fluorine environments of cis-OsO(2)F(4). The F(cis-OsO(2)F(3))(2)(+)Sb(2)F(11)(-) salt crystallizes in the orthorhombic space group Imma. At -107 degrees C, a = 12.838(3) Å, b = 10.667(2) Å, c = 11.323(2) Å, V = 1550.7(8) Å(3), and Z = 4. Refinement converged with R = 0.0469 [R(w) = 0.0500]. The crystal structure consists of discrete fluorine-bridged F(cis-OsO(2)F(3))(2)(+) and Sb(2)F(11)(-) ions in which the fluorine bridge of the F(cis-OsO(2)F(3))(2)(+) cation is trans to an oxygen atom (Os-O 1.676 Å) of each OsO(2)F(3) group. The angle at the bridge is 155.2(8) degrees with a bridging Os---F(b) distance of 2.086(3) Å. Two terminal fluorine atoms (Os-F 1.821 Å) are cis to the two oxygen atoms (Os-O 1.750 Å), and two terminal fluorine atoms of the OsO(2)F(3) group are trans to one another (1.813 Å). The OsO(2)F(3)(+) cation was characterized by (19)F NMR and by Raman spectroscopy in neat SbF(5) solution but was not isolable in the solid state. The NMR and Raman spectroscopic findings are consistent with a trigonal bipyramidal cation in which the oxygen atoms and a fluorine atom occupy the equatorial plane and two fluorine atoms are in axial positions. Density functional theory calculations show that the crystallographic structure of F(cis-OsO(2)F(3))(2)(+) is the energy-minimized structure and the energy-minimized structures of the OsO(2)F(3)(+) cation and ReO(2)F(3) are trigonal bipyramidal having C(2)(v)() point symmetry. Attempts to prepare the OsOF(5)(+) cation by oxidative fluorination of cis

Development and application of a new method for specific and sensitive enumeration of spores of nonproteolytic Clostridium botulinum types B, E, and F in foods and food materials.

PubMed

Peck, Michael W; Plowman, June; Aldus, Clare F; Wyatt, Gary M; Izurieta, Walter Penaloza; Stringer, Sandra C; Barker, Gary C

2010-10-01

The highly potent botulinum neurotoxins are responsible for botulism, a severe neuroparalytic disease. Strains of nonproteolytic Clostridium botulinum form neurotoxins of types B, E, and F and are the main hazard associated with minimally heated refrigerated foods. Recent developments in quantitative microbiological risk assessment (QMRA) and food safety objectives (FSO) have made food safety more quantitative and include, as inputs, probability distributions for the contamination of food materials and foods. A new method that combines a selective enrichment culture with multiplex PCR has been developed and validated to enumerate specifically the spores of nonproteolytic C. botulinum. Key features of this new method include the following: (i) it is specific for nonproteolytic C. botulinum (and does not detect proteolytic C. botulinum), (ii) the detection limit has been determined for each food tested (using carefully structured control samples), and (iii) a low detection limit has been achieved by the use of selective enrichment and large test samples. The method has been used to enumerate spores of nonproteolytic C. botulinum in 637 samples of 19 food materials included in pasta-based minimally heated refrigerated foods and in 7 complete foods. A total of 32 samples (5 egg pastas and 27 scallops) contained spores of nonproteolytic C. botulinum type B or F. The majority of samples contained <100 spores/kg, but one sample of scallops contained 444 spores/kg. Nonproteolytic C. botulinum type E was not detected. Importantly, for QMRA and FSO, the construction of probability distributions will enable the frequency of packs containing particular levels of contamination to be determined.

Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development.

PubMed

Mao, Chai-An; Agca, Cavit; Mocko-Strand, Julie A; Wang, Jing; Ullrich-Lüter, Esther; Pan, Ping; Wang, Steven W; Arnone, Maria Ina; Frishman, Laura J; Klein, William H

2016-03-16

Pou domain transcription factor Pou4f2 is essential for the development of retinal ganglion cells (RGCs) in the vertebrate retina. A distant orthologue of Pou4f2 exists in the genome of the sea urchin (class Echinoidea) Strongylocentrotus purpuratus (SpPou4f1/2), yet the photosensory structure of sea urchins is strikingly different from that of the mammalian retina. Sea urchins have no obvious eyes, but have photoreceptors clustered around their tube feet disc. The mechanisms that are associated with the development and function of photoreception in sea urchins are largely unexplored. As an initial approach to better understand the sea urchin photosensory structure and relate it to the mammalian retina, we asked whether SpPou4f1/2 could support RGC development in the absence of Pou4f2. To answer this question, we replaced genomic Pou4f2 with an SpPou4f1/2 cDNA. In Pou4f2-null mice, retinas expressing SpPou4f1/2 were outwardly identical to those of wild-type mice. SpPou4f1/2 retinas exhibited dark-adapted electroretinogram scotopic threshold responses, indicating functionally active RGCs. During retinal development, SpPou4f1/2 activated RGC-specific genes and in S. purpuratus, SpPou4f2 was expressed in photoreceptor cells of tube feet in a pattern distinct from Opsin4 and Pax6. Our results suggest that SpPou4f1/2 and Pou4f2 share conserved components of a gene network for photosensory development and they maintain their conserved intrinsic functions despite vast morphological differences in mouse and sea urchin photosensory structures. © 2016 The Authors.

The prohibitin-repressive interaction with E2F1 is rapidly inhibited by androgen signalling in prostate cancer cells

PubMed Central

Koushyar, S; Economides, G; Zaat, S; Jiang, W; Bevan, C L; Dart, D A

2017-01-01

Prohibitin (PHB) is a tumour suppressor molecule with pleiotropic activities across several cellular compartments including mitochondria, cell membrane and the nucleus. PHB and the steroid-activated androgen receptor (AR) have an interplay where AR downregulates PHB, and PHB represses AR. Additionally, their cellular locations and chromatin interactions are in dynamic opposition. We investigated the mechanisms of cell cycle inhibition by PHB and how this is modulated by AR in prostate cancer. Using a prostate cancer cell line overexpressing PHB, we analysed the gene expression changes associated with PHB-mediated cell cycle arrest. Over 1000 gene expression changes were found to be significant and gene ontology analysis confirmed PHB-mediated repression of genes essential for DNA replication and synthesis, for example, MCMs and TK1, via an E2F1 regulated pathway—agreeing with its G1/S cell cycle arrest activity. PHB is known to inhibit E2F1-mediated transcription, and the PHB:E2F1 interaction was seen in LNCaP nuclear extracts, which was then reduced by androgen treatment. Upon two-dimensional western blot analysis, the PHB protein itself showed androgen-mediated charge differentiation (only in AR-positive cells), indicating a potential dephosphorylation event. Kinexus phosphoprotein array analysis indicated that Src kinase was the main interacting intracellular signalling hub in androgen-treated LNCaP cells, and that Src inhibition could reduce this AR-mediated charge differentiation. PHB charge change may be associated with rapid dissociation from chromatin and E2F1, allowing the cell cycle to proceed. The AR and androgens may deactivate the repressive functions of PHB upon E2F1 leading to cell cycle progression, and indicates a role for AR in DNA replication licensing. PMID:28504694

M2-F2 cockpit instrument panels

NASA Image and Video Library

1966-03-27

This photo shows the right side cockpit instrumentation panel of the M2-F2 Lifting Body. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers -- the M2-F2 and the HL-10, both built by the Northrop Corporation. The "M" refers to "manned" and "F" refers to "flight" version. "HL" comes from "horizontal landing" and 10 is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the "F1" -- was on July 12, 1966. Milt Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft was modified to also carry the lifting bodies. Thompson was dropped from the B-52's wing pylon mount at an altitude of 45,000 feet on that maiden glide flight. The M2-F2 weighed 4,620 pounds, was 22 feet long, and had a width of about 10 feet. On May 10, 1967, during the sixteenth glide flight leading up to powered flight, a landing accident severely damaged the vehicle and seriously injured the NASA pilot, Bruce Peterson. NASA pilots and researchers realized the M2-F2 had lateral control problems, even though it had a stability augmentation control system. When the M2-F2 was rebuilt at Dryden and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. The M2-F2/F3 was the first of the heavy-weight, entry-configuration lifting bodies. Its successful development as a research test vehicle answered many of the generic questions about these vehicles. NASA donated the M2-F3 vehicle to the Smithsonian Institute in December 1973. It is currently hanging in the Air and Space Museum along with the X-15 aircraft number 1, which was its hangar partner at Dryden from 1965 to 1969.

M2-F2 cockpit instrument panels

NASA Image and Video Library

1966-03-27

This photo shows the left side cockpit instrumentation panel of the M2-F2 Lifting Body. The success of Dryden's M2-F1 program led to NASA's development and construction of two heavyweight lifting bodies based on studies at NASA's Ames and Langley research centers -- the M2-F2 and the HL-10, both built by the Northrop Corporation. The "M" refers to "manned" and "F" refers to "flight" version. "HL" comes from "horizontal landing" and 10 is for the tenth lifting body model to be investigated by Langley. The first flight of the M2-F2 -- which looked much like the "F1" -- was on July 12, 1966. Milt Thompson was the pilot. By then, the same B-52 used to air launch the famed X-15 rocket research aircraft was modified to also carry the lifting bodies. Thompson was dropped from the B-52's wing pylon mount at an altitude of 45,000 feet on that maiden glide flight. The M2-F2 weighed 4,620 pounds, was 22 feet long, and had a width of about 10 feet. On May 10, 1967, during the sixteenth glide flight leading up to powered flight, a landing accident severely damaged the vehicle and seriously injured the NASA pilot, Bruce Peterson. NASA pilots and researchers realized the M2-F2 had lateral control problems, even though it had a stability augmentation control system. When the M2-F2 was rebuilt at Dryden and redesignated the M2-F3, it was modified with an additional third vertical fin -- centered between the tip fins -- to improve control characteristics. The M2-F2/F3 was the first of the heavy-weight, entry-configuration lifting bodies. Its successful development as a research test vehicle answered many of the generic questions about these vehicles. NASA donated the M2-F3 vehicle to the Smithsonian Institute in December 1973. It is currently hanging in the Air and Space Museum along with the X-15 aircraft number 1, which was its hangar partner at Dryden from 1965 to 1969.

Comparative Study of Multiplet Structures of Mn4+ in K2SiF6, K2GeF6, and K2TiF6 Based on First-Principles Configuration-Interaction Calculations

NASA Astrophysics Data System (ADS)

Novita, Mega; Ogasawara, Kazuyoshi

2012-02-01

We performed first-principles configuration-interaction calculations of multiplet energies for Mn4+ in K2SiF6, K2GeF6, and K2TiF6 crystals. The results indicate that corrections based on a single-electron calculation are effective for the prediction of 4A2 → 4T2 and 4A2 → 4T1a transition energies, while such corrections are not necessary for the prediction of the 4A2 → 2E transition energy. The cluster size dependence of the multiplet energies is small. However, the 4A2 → 2E transition energy is slightly improved by using larger clusters including K ions. The theoretical multiplet energies are improved further by considering the lattice relaxation effect. As a result, the characteristic multiplet energy shifts depending on the host crystal are well reproduced without using any empirical parameters. Although K2GeF6 and K2TiF6 have lower symmetry than K2SiF6, the results indicate that the variation of the multiplet energy is mainly determined by the Mn-F bond length.

DEPDC1 promotes cell proliferation and tumor growth via activation of E2F signaling in prostate cancer.

PubMed

Huang, Lin; Chen, Keng; Cai, Zhao-Peng; Chen, Fu-Chao; Shen, Hui-Yong; Zhao, Wei-Hua; Yang, Song-Jie; Chen, Xu-Biao; Tang, Guo-Xue; Lin, Xi

2017-08-26

DEP domain containing 1 (DEPDC1) is recently reported to be overexpressed in several types of human cancer; however the role of DEPDC1 in prostate cancer remains to be investigated. Herein, we identified that the DEPDC1 mRNA and protein expression levels were dramatically increased in prostate cancer tissues and cell lines. Overexpression of DEPDC1 promoted, but depletion of DEPDC1 inhibited cell proliferation by regulating the G1-S phase cell cycle transition. Importantly, we found that DEPDC1 was essential for the tumor growth and formation of bone metastases of prostate cancer cells in vivo. Finally, we demonstrated that DEPDC1 interacted with E2F1 and increased its transcriptional activity, leading to hyper-activation of E2F signaling in prostate cancer cells. Our findings reveal an oncogenic role of DEPDC1 in prostate cancer progression via activation of E2F signaling, and suggest DEPDC1 might be a potential therapeutic target against the disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Detection of Hearing Loss Using 2f2-f1 and 2f1-f2 Distortion-Product Otoacoustic Emissions

ERIC Educational Resources Information Center

Fitzgerald, Tracy S.; Prieve, Beth A.

2005-01-01

Although many distortion-product otoacoustic emissions (DPOAEs) may be measured in the ear canal in response to 2 pure tone stimuli, the majority of clinical studies have focused exclusively on the DPOAE at the frequency 2f1-f2. This study investigated another DPOAE, 2f2-f1, in an attempt to determine the following: (a) the optimal stimulus…

[miR-503-5p inhibits the proliferation of T24 and EJ bladder cancer cells by interfering with the Rb/E2F signaling pathway].

PubMed

Li, Xiaohui; Han, Xingtao; Yang, Jinhui; Sun, Jiantao; Wei, Pengtao

2017-10-01

Objective To observe the effect of microRNA-503-5p (miR-503-5p) on the growth of T24 and EJ bladder cancer cells, and explore the possible molecular mechanism. Methods The miR-504-5p mimics or miR-NC was transfected into T24 and EJ cells. The target gene of miR-503-5p was predicted by bioinformatics. The expressions of E2F transcription factor 3 (E2F3) mRNA and Rb/E2F signaling pathway mRNA were detected by the real-time quantitative PCR (qPCR). The expressions of Rb/E2F signal pathway proteins E2F3, cyclin E, CDK2, Rb and p-Rb were detected by Western blotting. The cell cycle of bladder cancer cell lines was determined by flow cytometry. MTT assay and plate cloning assay were performed to observe the proliferation ability of bladder cancer cells. Results After miR-503-5p mimics transfection, the expression of miR-503-5p in bladder cancer cells significantly increased. The increased expression of miR-503-5p significantly reduced the expressions of E2F3 mRNA and Rb/E2F signaling pathway mRNA in bladder cancer cells. What's more, the expressions of Rb/E2F signal pathway proteins were down-regulated. The bladder cancer cells were arrested in G0/G1 phase, and their growth was significantly inhibited by miR-503-5p. Conclusion The miR-503-5p over-expression can inhibit the growth of bladder cancer cell lines T24 and EJ by down-regulating the expression of the Rb/E2F signaling pathway.

Development and Application of a New Method for Specific and Sensitive Enumeration of Spores of Nonproteolytic Clostridium botulinum Types B, E, and F in Foods and Food Materials ▿

PubMed Central

Peck, Michael W.; Plowman, June; Aldus, Clare F.; Wyatt, Gary M.; Penaloza Izurieta, Walter; Stringer, Sandra C.; Barker, Gary C.

2010-01-01

The highly potent botulinum neurotoxins are responsible for botulism, a severe neuroparalytic disease. Strains of nonproteolytic Clostridium botulinum form neurotoxins of types B, E, and F and are the main hazard associated with minimally heated refrigerated foods. Recent developments in quantitative microbiological risk assessment (QMRA) and food safety objectives (FSO) have made food safety more quantitative and include, as inputs, probability distributions for the contamination of food materials and foods. A new method that combines a selective enrichment culture with multiplex PCR has been developed and validated to enumerate specifically the spores of nonproteolytic C. botulinum. Key features of this new method include the following: (i) it is specific for nonproteolytic C. botulinum (and does not detect proteolytic C. botulinum), (ii) the detection limit has been determined for each food tested (using carefully structured control samples), and (iii) a low detection limit has been achieved by the use of selective enrichment and large test samples. The method has been used to enumerate spores of nonproteolytic C. botulinum in 637 samples of 19 food materials included in pasta-based minimally heated refrigerated foods and in 7 complete foods. A total of 32 samples (5 egg pastas and 27 scallops) contained spores of nonproteolytic C. botulinum type B or F. The majority of samples contained <100 spores/kg, but one sample of scallops contained 444 spores/kg. Nonproteolytic C. botulinum type E was not detected. Importantly, for QMRA and FSO, the construction of probability distributions will enable the frequency of packs containing particular levels of contamination to be determined. PMID:20709854

Laser-induced fluorescence studies of excited Sr reactions: II. Sr(3P1)+CH3F, C2H5F, C2H4F2

NASA Astrophysics Data System (ADS)

Teule, J. M.; Janssen, M. H. M.; Bulthuis, J.; Stolte, S.

1999-06-01

The vibrational and rotational energy distributions of ground state SrF(X 2Σ) formed in the reactions of electronically excited Sr(3P1) with methylfluoride, ethylfluoride, and 1,1-difluoroethane have been studied by laser-induced fluorescence. Although the reactions of ground state Sr with these reactants are exothermic, no SrF products are observed for those reactions in this study. The fraction of available energy disposed into the sum of rotational and vibrational energy of the SrF(X 2Σ) product is approximately the same for all three reactions, i.e., 40%. The reaction of Sr(3P1) with CH3F results in very low vibrational excitation in the SrF reaction product. The product vibration increases in going to C2H5F and C2H4F2. It is concluded that the alkyl group influences the energy disposal mechanism in these reactions, and some suggestions are given for a partial explanation of the observations.

Penetration of E. coli and F2 bacteriophage into fish tissues.

PubMed

Fattal, B; Dotan, A; Tchorsh, Y; Parpari, L; Shuval, H I

1988-01-01

Throughout the world, fish thrive in rivers, lakes and seawater polluted with wastewater. Furthermore, in some countries, wastewater-enriched fishponds are used for fish cultivation. One of the major constraints in using wastewater for aquaculture is the possible contamination of the fish by enteric pathogens (bacteria and viruses), which may penetrate and accumulate in fish tissue, and constitute a potential public health hazard, especially in countries in which raw fish are consumed. In order to evaluate the infection of fish cultivated in wastewater, controlled experiments were performed to study the penetration of bacteria and bacteriophage inoculated into water tanks in which the fish were maintained. Twenty to thirty Tilapia hybrids (Sarotherodon aureus x S. niloticus), of 100 gr average weight and some 20 cm long were introduced into a 1 m3 plastic tank, containing about 500 l tap water at a temperature of 20 degrees C. High protein fish feed was added at a rate of about 1% of body weight per day. Four experiments were performed using an inoculum of an E. coli strain resistant to streptomycin and nalidixic acid. One hour after inoculation, bacterial concentration was 10(5)-10(6)/ml tank water. Four experiments were carried out with F2 male-specific bacteriophage 10(3)-10(5)/ml tank water. In each experiment two fish were sacrificed at zero time (prior to introduction of inocula), and 1, 5, 24, 48 and 72 or more hours after inoculation. Water samples were withdrawn at the same intervals. The level of microorganisms was tested in the following tissues: digestive tract, skin, spleen, liver and muscle. E. coli assays were performed using the membrane filtration technique; phages were assayed, using E. coli host cells in a plaque assay. The results of the experiments indicate that notwithstanding the high E. coli concentration in the tank water, its level in the edible tissue (muscle) was low, and in no instance higher than the acceptable standard of 400 cfu

Long non-coding RNA H19 promotes glucose metabolism and cell growth in malignant melanoma via miR-106a-5p/E2F3 axis.

PubMed

Luan, Wenkang; Zhou, Zhou; Ni, Xin; Xia, Yun; Wang, Jinlong; Yan, Yulan; Xu, Bin

2018-03-01

lncRNA H19 has been considered as an oncogenic lncRNA in many human tumours. In the present study, we identify the role and molecular mechanism of lncRNA H19 in melanoma. QRT-PCR was used to detect the expression of lncRNA H19 and E2F3 was detected in melanoma tissues. Cell counting kit-8 (CCK8), representative metabolites analysis was used to explore the biological function of lncRNA H19, miR-106a-5p and E2F3 in melanoma cells. Bioinformatics, luciferase reporter assays, MS2-RIP and RNA pull-down assay was used to demonstrate the molecular mechanism of lncRNA H19 in melanoma. We further test the function of lncRNA H19 in vivo though Xenograft tumour assay. We found that lncRNA H19 was increased in melanoma tissue, and lncRNA H19 was correlated with poor prognosis of melanoma patients. miR-106a-5p acts as a tumour suppressor in melanoma by targeting E2F3. E2F3 affects the melanoma cell glucose metabolism and growth. We also demonstrated that lncRNA H19 may function as the sponge of miR-106a-5p to up-regulate E2F3 expression, and consequently promote the glucose metabolism and growth of melanoma. This result elucidates a new mechanism for lncRNA H19 in melanoma development and provides a survival indicator and potential therapeutic target for melanoma patients.

Studying fission neutrons with 2E-2v and 2E

NASA Astrophysics Data System (ADS)

Al-Adili, Ali; Jansson, Kaj; Tarrío, Diego; Hambsch, Franz-Josef; Göök, Alf; Oberstedt, Stephan; Olivier Frégeau, Marc; Gustavsson, Cecilia; Lantz, Mattias; Mattera, Andrea; Prokofiev, Alexander V.; Rakopoulos, Vasileios; Solders, Andreas; Vidali, Marzio; Österlund, Michael; Pomp, Stephan

2018-03-01

This work aims at measuring prompt-fission neutrons at different excitation energies of the nucleus. Two independent techniques, the 2E-2v and the 2E techniques, are used to map the characteristics of the mass-dependent prompt fission neutron multiplicity, v(A), when the excitation energy is increased. The VERDI 2E-2v spectrometer is being developed at JRC-GEEL. The Fission Fragment (FF) energies are measured using two arrays of 16 silicon (Si) detectors each. The FFs velocities are obtained by time-of-flight, measured between micro-channel plates (MCP) and Si detectors. With MCPs placed on both sides of the fission source, VERDI allows for independent timing measurements for both fragments. 252Cf(sf) was measured and the present results revealed particular features of the 2E-2v technique. Dedicated simulations were also performed using the GEF code to study important aspects of the 2E-2v technique. Our simulations show that prompt neutron emission has a non-negligible impact on the deduced fragment data and affects also the shape of v(A). Geometrical constraints lead to a total-kinetic energy-dependent detection efficiency. The 2E technique utilizes an ionization chamber together with two liquid scintillator detectors. Two measurements have been performed, one of 252Cf(sf) and another one of thermal-neutron induced fission in 235U(n,f). Results from 252Cf(sf) are reported here.

Chemical disorder and 207Pb hyperfine fields in the magnetoelectric multiferroic Pb (F e1 /2S b1 /2 ) O3 and its solid solution with Pb (F e1 /2N b1 /2) O3

NASA Astrophysics Data System (ADS)

Zagorodniy, Yu. O.; Kuzian, R. O.; Kondakova, I. V.; Maryško, M.; Chlan, V.; Štěpánková, H.; Olekhnovich, N. M.; Pushkarev, A. V.; Radyush, Yu. V.; Raevski, I. P.; Zalar, B.; Laguta, V. V.; Stephanovich, V. A.

2018-01-01

We report on the results of magnetic susceptibility, electron paramagnetic resonance, and 207Pb nuclear magnetic resonance (NMR) studies of the magnetoelectric multiferroic Pb (F e1 /2S b1 /2 ) O3 (PFS) ceramic, as well as its solid solution with Pb (F e1 /2N b1 /2) O3 (PFN) of different degrees of the 1:1 ordering of magnetic F e3 + and nonmagnetic S b5 + ions. The ordering has been studied by x-ray diffraction (XRD) and NMR methods. In particular, two spectral lines, originating from the ordered and disordered regions, respectively, are resolved in the 207Pb NMR spectra. This demonstrates the presence of spatially heterogeneous ordering where ordered regions are embedded into a disordered matrix. Combining XRD and NMR data, we have determined both the long-range order parameter s and the volume fraction of ordered regions s' for all investigated samples. The values vary in the range s =0 -0.93 and s'=0 -1 . We have found that the 207Pb Fermi contact interaction strongly depends on the disorder in the Fe/Sb positions: whereas it reaches 7.08 MHz in the ordered lattice, it is almost zero in the disordered environment. These results are further supported by the studies of PFS-PFN solid solutions. The analysis of experimental data in terms of density functional theory reveals a noticeably higher hybridization between Pb 6s and Fe 3d orbitals in the ordered case. The ordering of magnetic and nonmagnetic ions has a strong impact on the magnetic properties of PFS, leading to a transformation of the long-range ordered antiferromagnetic phase in chemically ordered samples to the spin glass state already in partially (s =0.35 ) disordered specimens. In our opinion, the difference in the magnetic properties of PFN and PFS is related to the fact that PFN is completely disordered, in contrast to PFS, which is only partially disordered, with small ordered regions existing in the disordered matrix that prevent the percolation of the nearest-neighbor Fe-Fe exchange interaction

Pou4f2-GFP knock-in mouse line: A model for studying retinal ganglion cell development.

PubMed

Zheng, Dongwang; Yang, Xiaoyan; Sheng, Donglai; Yu, Dongliang; Liang, Guoqing; Guo, Luming; Xu, Mei; Hu, Xu; He, Daqiang; Yang, Yang; Wang, Yuying

2016-10-01

Pou4f2 acts as a key node in the comprehensive and step-wise gene regulatory network (GRN) and regulates the development of retinal ganglion cells (RGCs). Accordingly, deletion of Pou4f2 results in RGC axon defects and apoptosis. To investigate the GRN involved in RGC regeneration, we generated a mouse line with a POU4F2-green fluorescent protein (GFP) fusion protein expressed in RGCs. Co-localization of POU4F2 and GFP in the retina and brain of Pou4f2-GFP/+ heterozygote mice was confirmed using immunofluorescence analysis. Compared with those in wild-type mice, the expression patterns of POU4F2 and POU4F1 and the co-expression patterns of ISL1 and POU4F2 were unaffected in Pou4f2-GFP/GFP homozygote mice. Moreover, the quantification of RGCs showed no significant difference between Pou4f2-GFP/GFP homozygote and wild-type mice. These results demonstrated that the development of RGCs in Pou4f2-GFP/GFP homozygote mice was the same as in wild-type mice. Thus, the present Pou4f2-GFP knock-in mouse line is a useful tool for further studies on the differentiation and regeneration of RGCs. © 2016 Wiley Periodicals, Inc.

77 FR 10358 - Acceptance of ASTM F963-11 as a Mandatory Consumer Product Safety Standard

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-22

... Safety. Pursuant to section 106 of the Consumer Product Safety Improvement Act of 2008, ASTM F963-11 will... INFORMATION: On February 10, 2009, section 106(a) of the Consumer Product Safety Improvement Act of 2008... CONSUMER PRODUCT SAFETY COMMISSION 16 CFR Chapter II Acceptance of ASTM F963-11 as a Mandatory...

Optical constants of SrF 2 thin films in the 25-780-eV spectral range

DOE PAGES

Rodriguez-de Marcos, Luis; Larraguert, Juan I.; Aznarez, Jose A.; ...

2013-04-08

The transmittance and the optical constants of SrF 2 thin films, a candidate material for multilayer coatings operating in the extreme ultraviolet and soft x-rays, have been determined in the spectral range of 25–780 eV, in most of which no experimental data were previously available. SrF 2 films of various thicknesses were deposited by evaporation onto room-temperature, thin Al support films, and their transmittance was measured with synchrotron radiation. The transmittance as a function of film thickness was used to calculate the extinction coefficient k at each photon energy. A decrease in density with increasing SrF 2 film thickness wasmore » observed. In the calculation of k, this effect was circumvented by fitting the transmittance versus the product of thickness and density. The real part of the refractive index of SrF 2 films was calculated from k with Kramers-Krönig analysis, for which the measured spectral range was extended both to lower and to higher photon energies with data in the literature combined with interpolations and extrapolations. In conclusion, with the application of f- and inertial sum rules, the consistency of the compiled data was found to be excellent.« less

Avionics Interface Data Summaries: A-10A, EF-111A, F-4E, F-4G, F-15A, F- 16A, F-111A, F-111E, F-111F, RF-4C

DTIC Science & Technology

1979-10-01

AIRCRAFT Flight Control ASA-32( ) Flight Director Computer TBD (Same as non -ARN-101 equipped F-4E aircraft) Air Data Computer CPK-92/A24G-34 Attitude...below. A two-inch separation between cable types is arbitrarily set as a minimum design goal. 3.2.6.4.1 Power and Control Circuits. Roucing and channel...plan in accordance with MIL-STD-461A(3) shall be the controlling document for EMIC design . 3.2.7.1 Design Reuire-nents. The generation of and suscepti

The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm

PubMed Central

Sangkhae, Veena; Etheridge, S. Leah; Kaushansky, Kenneth

2014-01-01

The most frequent contributing factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is the acquisition of a V617F mutation in Janus kinase 2 (JAK2) in hematopoietic stem cells (HSCs). Recent evidence has demonstrated that to drive MPN transformation, JAK2V617F needs to directly associate with a functional homodimeric type I cytokine receptor, suggesting that, although acquiring JAK2V617F may promote disease, there are additional cellular components necessary for MPN development. Here we show that loss of the thrombopoietin (TPO) receptor (MPL) significantly ameliorates MPN development in JAK2V617F+ transgenic mice, whereas loss of TPO only mildly affects the disease phenotype. Specifically, compared with JAK2V617F+ mice, JAK2V617F+Mpl−/− mice exhibited reduced thrombocythemia, neutrophilia, splenomegaly, and neoplastic stem cell pool. The importance of MPL is highlighted as JAK2V617FMpl+/− mice displayed a significantly reduced MPN phenotype, indicating that Mpl level may have a substantial effect on MPN development and severity. Splenomegaly and the increased neoplastic stem cell pool were retained in JAK2V617F+Tpo−/− mice, although thrombocytosis was reduced compared with JAK2V617F+ mice. These results demonstrate that Mpl expression, but not Tpo, is fundamental in the development of JAK2V617F+ MPNs, highlighting an entirely novel target for therapeutic intervention. PMID:25339357

The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm.

PubMed

Sangkhae, Veena; Etheridge, S Leah; Kaushansky, Kenneth; Hitchcock, Ian S

2014-12-18

The most frequent contributing factor in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) is the acquisition of a V617F mutation in Janus kinase 2 (JAK2) in hematopoietic stem cells (HSCs). Recent evidence has demonstrated that to drive MPN transformation, JAK2V617F needs to directly associate with a functional homodimeric type I cytokine receptor, suggesting that, although acquiring JAK2V617F may promote disease, there are additional cellular components necessary for MPN development. Here we show that loss of the thrombopoietin (TPO) receptor (MPL) significantly ameliorates MPN development in JAK2V617F(+) transgenic mice, whereas loss of TPO only mildly affects the disease phenotype. Specifically, compared with JAK2V617F(+) mice, JAK2V617F(+)Mpl(-/-) mice exhibited reduced thrombocythemia, neutrophilia, splenomegaly, and neoplastic stem cell pool. The importance of MPL is highlighted as JAK2V617FMpl(+/-) mice displayed a significantly reduced MPN phenotype, indicating that Mpl level may have a substantial effect on MPN development and severity. Splenomegaly and the increased neoplastic stem cell pool were retained in JAK2V617F(+)Tpo(-/-) mice, although thrombocytosis was reduced compared with JAK2V617F(+) mice. These results demonstrate that Mpl expression, but not Tpo, is fundamental in the development of JAK2V617F(+) MPNs, highlighting an entirely novel target for therapeutic intervention. © 2014 by The American Society of Hematology.

Disruption of Mouse Cytochrome P450 4f14 (Cyp4f14 Gene) Causes Severe Perturbations in Vitamin E Metabolism*

PubMed Central

Bardowell, Sabrina A.; Duan, Faping; Manor, Danny; Swanson, Joy E.; Parker, Robert S.

2012-01-01

Vitamin E is a family of naturally occurring and structurally related lipophilic antioxidants, one of which, α-tocopherol (α-TOH), selectively accumulates in vertebrate tissues. The ω-hydroxylase cytochrome P450–4F2 (CYP4F2) is the only human enzyme shown to metabolize vitamin E. Using cDNA cloning, cell culture expression, and activity assays, we identified Cyp4f14 as a functional murine ortholog of CYP4F2. We then investigated the effect of Cyp4f14 deletion on vitamin E metabolism and status in vivo. Cyp4f14-null mice exhibited substrate-specific reductions in liver microsomal vitamin E-ω-hydroxylase activity ranging from 93% (γ-TOH) to 48% (γ-tocotrienol). In vivo data obtained from metabolic cage studies showed whole-body reductions in metabolism of γ-TOH of 90% and of 68% for δ- and α-TOH. This metabolic deficit in Cyp4f14−/− mice was partially offset by increased fecal excretion of nonmetabolized tocopherols and of novel ω-1- and ω-2-hydroxytocopherols. 12′-OH-γ-TOH represented 41% of whole-body production of γ-TOH metabolites in Cyp4f14−/− mice fed a soybean oil diet. Despite these counterbalancing mechanisms, Cyp4f14-null mice fed this diet for 6 weeks hyper-accumulated γ-TOH (2-fold increase over wild-type littermates) in all tissues and appeared normal. We conclude that CYP4F14 is the major but not the only vitamin E-ω-hydroxylase in mice. Its disruption significantly impairs whole-body vitamin E metabolism and alters the widely conserved phenotype of preferential tissue deposition of α-TOH. This model animal and its derivatives will be valuable in determining the biological actions of specific tocopherols and tocotrienols in vivo. PMID:22665481

A Noncanonical Role for the CKI-RB-E2F Cell Cycle Signaling Pathway in Plant Effector-Triggered Immunity

PubMed Central

Wang, Shui; Gu, Yangnan; Zebell, Sophia G.; Anderson, Lisa K.; Wang, Wei; Mohan, Rajinikanth; Dong, Xinnian

2014-01-01

SUMMARY Effector-triggered immunity (ETI), the major host defense mechanism in plants, is often associated with programmed cell death (PCD). Plants lack close homologs of caspases, the key mediators of PCD in animals. So although the NB-LRR receptors involved in ETI are well studied, how they activate PCD and confer disease resistance remains elusive. We show that the Arabidopsis nuclear envelope protein, CPR5, negatively regulates ETI and the associated PCD through a physical interaction with CYCLIN-DEPENDENT KINASE INHIBITORs (CKIs). Upon ETI induction, CKIs are released from CPR5 to cause over-activation of another core cell cycle regulator, E2F. In cki and e2f mutants, ETI responses induced by both TIR-NB-LRR and CC-NB-LRR classes of immune receptors are compromised. We further show that E2F is deregulated during ETI probably through CKI-mediated hyperphosphorylation of RETINOBLASTOMA-RELATED 1 (RBR1). This study demonstrates that canonical cell cycle regulators also play important noncanonical roles in plant immunity. PMID:25455564

Activation of the Rb/E2F1 pathway by the nonproliferative p38 MAPK during Fas (APO1/CD95)-mediated neuronal apoptosis.

PubMed

Hou, Sheng T; Xie, Xiaoqi; Baggley, Anne; Park, David S; Chen, Gao; Walker, Teena

2002-12-13

Aberrant activation of the Rb/E2F1 pathway in cycling cells, in response to mitogenic or nonmitogenic stress signals, leads to apoptosis through hyperphosphorylation of Rb. To test whether in postmitotic neurons the Rb/E2F1 pathway can be activated by the nonmitogenic stress signaling, we examined the role of the p38 stress-activated protein kinase (SAPK) in regulating Rb phosphorylation in response to Fas (CD95/APO1)-mediated apoptosis of cultured cerebellar granule neurons (CGNs). Anti-Fas antibody induced a dramatic and early activation of p38. Activated p38 was correlated with the induction of hyperphosphorylation of both endogenous and exogenous Rb. The p38-selective inhibitor, SB203580, attenuated such an increase in pRb phosphorylation and significantly protected CGNs from Fas-induced apoptosis. The cyclin-dependent kinase-mediated Rb phosphorylation played a lesser role in this neuronal death paradigm, since cyclin-dependent kinase inhibitors, such as olomoucine, roscovitine, and flavopiridol, did not significantly prevent anti-Fas antibody-evoked neuronal apoptosis. Hyperphosphorylation of Rb by p38 SAPK resulted in the release of Rb-bound E2F1. Increased E2F1 modulated neuronal apoptosis, since E2F1-/- CGNs were significantly less susceptible to Fas-mediated apoptosis in comparison with the wild-type CGNs. Taken together, these studies demonstrate that neuronal Rb/E2F1 is modulated by the nonproliferative p38 SAPK in Fas-mediated neuronal apoptosis.

Jahn-Teller effect on the [TiF 4F 4F int] 6-(C 4v) and [NiF 4F 4F int] 7-(C 4v) clusters embedded into SrF 2 crystals

NASA Astrophysics Data System (ADS)

Ulanov, V. A.; Zhiteitcev, E. R.; Varlamov, A. G.

2007-07-01

By means of EPR method the associative [TiF 4F 4F int] 6-(C 4v) and [NiF 4F 4F int] 7-(C 4v) centers were revealed in the fluorite type SrF 2:Ti and SrF 2:Ni crystals grown by Bridgman method in helium atmosphere containing some amount of a fluorine gas. It was found that at low temperatures the local structures of these associative centers were exposed to a static rhombic distortion. The reasons of such distortions were accounted for by the assumption that the E ⊗ ( b1 + b2) vibronic interaction became effective due to that the ground orbital states of the [TiF 4F 4F int] 6-(C 4v) and [NiF 4F 4F int] 7-(C 4v) centers occurred to be doubly degenerated.

(2E,5E)-2,5-Bis(3-hydroxy-4-methoxybenzylidene) cyclopentanone Exerts Anti-Melanogenesis and Anti-Wrinkle Activities in B16F10 Melanoma and Hs27 Fibroblast Cells.

PubMed

Jung, Hee Jin; Lee, A Kyoung; Park, Yeo Jin; Lee, Sanggwon; Kang, Dongwan; Jung, Young Suk; Chung, Hae Young; Moon, Hyung Ryong

2018-06-11

Ultraviolet (UV) radiation exposure is the primary cause of extrinsic skin aging, which results in skin hyperpigmentation and wrinkling. In this study, we investigated the whitening effect of (2 E ,5 E )-2,5-bis(3-hydroxy-4-methoxybenzylidene)cyclopentanone (BHCP) on B16F10 melanoma and its anti-wrinkle activity on Hs27 fibroblasts cells. BHCP was found to potently inhibit tyrosinase, with 50% inhibition concentration (IC 50 ) values of 1.10 µM and 8.18 µM for monophenolase (l-tyrosine) and diphenolase (l-DOPA), and the enzyme kinetics study revealed that BHCP is a competitive-type tyrosinase inhibitor. Furthermore, BHCP significantly inhibited melanin content and cellular tyrosinase activity, and downregulated the levels of microphthalmia-associated transcription factor (MITF), phosphorylated levels of cAMP response element-binding (CREB) protein, and tyrosinase in α-melanocyte stimulating hormone (α-MSH)-induced B16F10 melanoma cells. Moreover, BHCP inhibited the phosphorylation of p65 and expression of matrix metalloproteinases (MMP-1, MMP-9, MMP-12, and MMP-13) in Hs27 fibroblasts stimulated with UV radiation. Therefore, our results demonstrate that BHCP may be a good candidate for the development of therapeutic agents for diseases associated with hyperpigmentation and wrinkling.

NiF2/NaF:CaF2/Ca Solid-State High-Temperature Battery Cells

NASA Technical Reports Server (NTRS)

West, William; Whitacre, Jay; DelCastillo, Linda

2009-01-01

Experiments and theoretical study have demonstrated the promise of all-solid-state, high-temperature electrochemical battery cells based on NiF2 as the active cathode material, CaF2 doped with NaF as the electrolyte material, and Ca as the active anode material. These and other all-solid-state cells have been investigated in a continuing effort to develop batteries for instruments that must operate in environments much hotter than can be withstood by ordinary commercially available batteries. Batteries of this type are needed for exploration of Venus (where the mean surface temperature is about 450 C), and could be used on Earth for such applications as measuring physical and chemical conditions in geothermal wells and oil wells. All-solid-state high-temperature power cells are sought as alternatives to other high-temperature power cells based, variously, on molten anodes and cathodes or molten eutectic salt electrolytes. Among the all-solid-state predecessors of the present NiF2/NaF:CaF2/Ca cells are those described in "Solid-State High-Temperature Power Cells" (NPO-44396), NASA Tech Briefs, Vol. 32, No. 5 (May 2008), page 40. In those cells, the active cathode material is FeS2, the electrolyte material is a crystalline solid solution of equimolar amounts of Li3PO4 and LiSiO4, and the active anode material is Li contained within an alloy that remains solid in the intended high operational temperature range.

Prostaglandin E/sub 2/ localization and receptor identification within the developing murine secondary palate

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

Jones, J.

1986-01-01

Transient elevations in murine secondary palatal adenosine 3',5'-monophosphate (cAMP) levels occur during palate ontogeny. Since palatal processes exposed to dibutyryl cAMP differentiate precociously, increases in palatal cAMP levels are of interest. Prostaglandin E/sub 2/ (PGE/sub 2/), which is synthesized by murine embryonic palate mesenchyme cells (MEPM), regulates cAMP levels in adult tissues via specific membrane bound receptors coupled to adenylate cyclase. Therefore, a PGE/sub 2/ receptor-adenylate cyclase systems was proposed in the developing murine secondary palate. Utilizing a radioligand binding assay, it was determined that murine palatal tissue on day 13 of gestation contained PGE/sub 2/ receptors that were saturable,more » of high affinity and low capacity. Specific (/sup 3/H)-PGE/sub 2/ binding was reversible by 30 min. The order of prostanoid binding affinity at specific PGE/sub 2/ binding sites was E/sub 2/ > F/sub 2//sub ..cap alpha../ > A/sub 2/ > E/sub 1/ = D/sub 2/ indicating specificity of the receptor for PGE/sub 2/. The ability of MEPM cells to respond to PGE/sub 2/ with dose-dependent accumulations of intracellular cAMP demonstrated the functional nature of these binding sites. Analysis of palatal PGE/sub 2/ receptor characteristics on days 12 and 14 of palate development indicated temporal alterations in receptor affinity and density during palate ontogeny.« less

26 CFR 5f.103-2 - Public approval of industrial development bonds.

Code of Federal Regulations, 2010 CFR

2010-04-01

.... (d) Method of public approval. For purposes of this section, an issue is approved by a governmental... 26 Internal Revenue 14 2010-04-01 2010-04-01 false Public approval of industrial development bonds... RESPONSIBILITY ACT OF 1982 § 5f.103-2 Public approval of industrial development bonds. (a) General rule. An...

26 CFR 5f.103-2 - Public approval of industrial development bonds.

Code of Federal Regulations, 2013 CFR

2013-04-01

.... (d) Method of public approval. For purposes of this section, an issue is approved by a governmental... 26 Internal Revenue 14 2013-04-01 2013-04-01 false Public approval of industrial development bonds... RESPONSIBILITY ACT OF 1982 § 5f.103-2 Public approval of industrial development bonds. (a) General rule. An...

26 CFR 5f.103-2 - Public approval of industrial development bonds.

Code of Federal Regulations, 2011 CFR

2011-04-01

.... (d) Method of public approval. For purposes of this section, an issue is approved by a governmental... 26 Internal Revenue 14 2011-04-01 2010-04-01 true Public approval of industrial development bonds... RESPONSIBILITY ACT OF 1982 § 5f.103-2 Public approval of industrial development bonds. (a) General rule. An...

26 CFR 5f.103-2 - Public approval of industrial development bonds.

Code of Federal Regulations, 2012 CFR

2012-04-01

.... (d) Method of public approval. For purposes of this section, an issue is approved by a governmental... 26 Internal Revenue 14 2012-04-01 2012-04-01 false Public approval of industrial development bonds... RESPONSIBILITY ACT OF 1982 § 5f.103-2 Public approval of industrial development bonds. (a) General rule. An...

26 CFR 5f.103-2 - Public approval of industrial development bonds.

Code of Federal Regulations, 2014 CFR

2014-04-01

.... (d) Method of public approval. For purposes of this section, an issue is approved by a governmental... 26 Internal Revenue 14 2014-04-01 2013-04-01 true Public approval of industrial development bonds... RESPONSIBILITY ACT OF 1982 § 5f.103-2 Public approval of industrial development bonds. (a) General rule. An...

p53-repressed miRNAs are involved with E2F in a feed-forward loop promoting proliferation

PubMed Central

Brosh, Ran; Shalgi, Reut; Liran, Atar; Landan, Gilad; Korotayev, Katya; Nguyen, Giang Huong; Enerly, Espen; Johnsen, Hilde; Buganim, Yosef; Solomon, Hilla; Goldstein, Ido; Madar, Shalom; Goldfinger, Naomi; Børresen-Dale, Anne-Lise; Ginsberg, Doron; Harris, Curtis C; Pilpel, Yitzhak; Oren, Moshe; Rotter, Varda

2008-01-01

Normal cell growth is governed by a complicated biological system, featuring multiple levels of control, often deregulated in cancers. The role of microRNAs (miRNAs) in the control of gene expression is now increasingly appreciated, yet their involvement in controlling cell proliferation is still not well understood. Here we investigated the mammalian cell proliferation control network consisting of transcriptional regulators, E2F and p53, their targets and a family of 15 miRNAs. Indicative of their significance, expression of these miRNAs is downregulated in senescent cells and in breast cancers harboring wild-type p53. These miRNAs are repressed by p53 in an E2F1-mediated manner. Furthermore, we show that these miRNAs silence antiproliferative genes, which themselves are E2F1 targets. Thus, miRNAs and transcriptional regulators appear to cooperate in the framework of a multi-gene transcriptional and post-transcriptional feed-forward loop. Finally, we show that, similarly to p53 inactivation, overexpression of representative miRNAs promotes proliferation and delays senescence, manifesting the detrimental phenotypic consequence of perturbations in this circuit. Taken together, these findings position miRNAs as novel key players in the mammalian cellular proliferation network. PMID:19034270

Stability analysis of an F/A-18 E/F cable mount m odel

NASA Technical Reports Server (NTRS)

Thompson, Nancy; Farmer, Moses

1994-01-01

A full-span F/A-18 E/F cable mounted wind tunnel model is part of a flutter clearance program at the NASA Langley Transonic Dynamics Tunnel. Parametric analysis of this model using GRUMCBL software was conducted to assess stability for wind tunnel tests. Two configurations of the F/A-18 E/F were examined. The parameters examined were pulley-cable friction, mach number, dynamic pressure, cable geometry, center of gravity location, cable tension, snubbing the model, drag, and test medium. For the nominal cable geometry (Cable Geometry 1), Configuration One was unstable for cases with higher pulley-cable friction coefficients. A new cable geometry (Cable Geometry 3) was determined in which Configuration One was stable for all cases evaluated. Configuration Two with the nominal center of gravity position was found to be unstable for cases with higher pulley-cable friction coefficients; however, the model was stable when the center of gravity moved forward 1/2. The model was tested using the cable mount system during the initial wind tunnel entry and was stable as predicted.

Effect of the addition of MgF2 and NaF on the thermal, optical and magnetic properties of fluoride glasses for sensing applications

NASA Astrophysics Data System (ADS)

Wang, Yujie; Wang, Shuangbao; Deng, Saifu; Liu, Jianting; Zhang, Jiahui

2017-10-01

Optical glass was very important for the development of optical fiber sensor. In this paper, a new type fluoride glass of ZrF4-BaF2-AlF3-NaF-MgF2(ZBANM) was synthesized for sensing application which has low loss and high magneto-optical coefficient, and it was found that the glass system had at least 60% transmittance from 3.5 μm to 7 μm and smallest verdet constant of 4.628E-5/(rad A-1) at 632.8 nm. The relationship among the compositions of sample glass with its thermal property, optical absorptivity and magnetic-optical coefficients was respectively studied with Thermal Gravimetric-Differential Thermal Analyzer, Fourier Transform infrared spectroscopy and a home-made magneto optical bench. The study indicated that transmittance of fluoride glass structure had been obviously improved after moderate content of Mg2+ and Na+ was doped. Simultaneously, with the molar ratio of alkaline-earth ions Mg increased, the Verdet constant of fluoride glass was increased. And the glass structure with composition of 48%ZrF4-24%BaF2-6%AlF3-8%NaF-14%MgF2 exhibited a small molar absorptivity and the largest Verdet constant of 2.853E-4/(rad A-1).

Transcriptional control of stem cell fate by E2Fs and pocket proteins

PubMed Central

Julian, Lisa M.; Blais, Alexandre

2015-01-01

E2F transcription factors and their regulatory partners, the pocket proteins (PPs), have emerged as essential regulators of stem cell fate control in a number of lineages. In mammals, this role extends from both pluripotent stem cells to those encompassing all embryonic germ layers, as well as extra-embryonic lineages. E2F/PP-mediated regulation of stem cell decisions is highly evolutionarily conserved, and is likely a pivotal biological mechanism underlying stem cell homeostasis. This has immense implications for organismal development, tissue maintenance, and regeneration. In this article, we discuss the roles of E2F factors and PPs in stem cell populations, focusing on mammalian systems. We discuss emerging findings that position the E2F and PP families as widespread and dynamic epigenetic regulators of cell fate decisions. Additionally, we focus on the ever expanding landscape of E2F/PP target genes, and explore the possibility that E2Fs are not simply regulators of general ‘multi-purpose’ cell fate genes but can execute tissue- and cell type-specific gene regulatory programs. PMID:25972892

MiR-205-5p and miR-342-3p cooperate in the repression of the E2F1 transcription factor in the context of anticancer chemotherapy resistance

PubMed Central

Lai, Xin; Gupta, Shailendra K; Schmitz, Ulf; Marquardt, Stephan; Knoll, Susanne; Spitschak, Alf; Wolkenhauer, Olaf; Pützer, Brigitte M; Vera, Julio

2018-01-01

High rates of lethal outcome in tumour metastasis are associated with the acquisition of invasiveness and chemoresistance. Several clinical studies indicate that E2F1 overexpression across high-grade tumours culminates in unfavourable prognosis and chemoresistance in patients. Thus, fine-tuning the expression of E2F1 could be a promising approach for treating patients showing chemoresistance. Methods: We integrated bioinformatics, structural and kinetic modelling, and experiments to study cooperative regulation of E2F1 by microRNA (miRNA) pairs in the context of anticancer chemotherapy resistance. Results: We showed that an enhanced E2F1 repression efficiency can be achieved in chemoresistant tumour cells through two cooperating miRNAs. Sequence and structural information were used to identify potential miRNA pairs that can form tertiary structures with E2F1 mRNA. We then employed molecular dynamics simulations to show that among the identified triplexes, miR-205-5p and miR-342-3p can form the most stable triplex with E2F1 mRNA. A mathematical model simulating the E2F1 regulation by the cooperative miRNAs predicted enhanced E2F1 repression, a feature that was verified by in vitro experiments. Finally, we integrated this cooperative miRNA regulation into a more comprehensive network to account for E2F1-related chemoresistance in tumour cells. The network model simulations and experimental data indicate the ability of enhanced expression of both miR-205-5p and miR-342-3p to decrease tumour chemoresistance by cooperatively repressing E2F1. Conclusions: Our results suggest that pairs of cooperating miRNAs could be used as potential RNA therapeutics to reduce E2F1-related chemoresistance. PMID:29464002

Automatic EEG-assisted retrospective motion correction for fMRI (aE-REMCOR).

PubMed

Wong, Chung-Ki; Zotev, Vadim; Misaki, Masaya; Phillips, Raquel; Luo, Qingfei; Bodurka, Jerzy

2016-04-01

Head motions during functional magnetic resonance imaging (fMRI) impair fMRI data quality and introduce systematic artifacts that can affect interpretation of fMRI results. Electroencephalography (EEG) recordings performed simultaneously with fMRI provide high-temporal-resolution information about ongoing brain activity as well as head movements. Recently, an EEG-assisted retrospective motion correction (E-REMCOR) method was introduced. E-REMCOR utilizes EEG motion artifacts to correct the effects of head movements in simultaneously acquired fMRI data on a slice-by-slice basis. While E-REMCOR is an efficient motion correction approach, it involves an independent component analysis (ICA) of the EEG data and identification of motion-related ICs. Here we report an automated implementation of E-REMCOR, referred to as aE-REMCOR, which we developed to facilitate the application of E-REMCOR in large-scale EEG-fMRI studies. The aE-REMCOR algorithm, implemented in MATLAB, enables an automated preprocessing of the EEG data, an ICA decomposition, and, importantly, an automatic identification of motion-related ICs. aE-REMCOR has been used to perform retrospective motion correction for 305 fMRI datasets from 16 subjects, who participated in EEG-fMRI experiments conducted on a 3T MRI scanner. Performance of aE-REMCOR has been evaluated based on improvement in temporal signal-to-noise ratio (TSNR) of the fMRI data, as well as correction efficiency defined in terms of spike reduction in fMRI motion parameters. The results show that aE-REMCOR is capable of substantially reducing head motion artifacts in fMRI data. In particular, when there are significant rapid head movements during the scan, a large TSNR improvement and high correction efficiency can be achieved. Depending on a subject's motion, an average TSNR improvement over the brain upon the application of aE-REMCOR can be as high as 27%, with top ten percent of the TSNR improvement values exceeding 55%. The average

Efficacy and safety of treatment with an anti-m2e monoclonal antibody in experimental human influenza.

PubMed

Ramos, Eleanor L; Mitcham, Jennifer L; Koller, Teri D; Bonavia, Aurelio; Usner, Dale W; Balaratnam, Ganesh; Fredlund, Paul; Swiderek, Kristine M

2015-04-01

The efficacy of TCN-032, a human monoclonal antibody targeting a conserved epitope on M2e, was explored in experimental human influenza. Healthy volunteers were inoculated with influenza A/Wisconsin/67/2005 (H3N2) and received a single dose of the study drug, TCN-032, or placebo 24 hours later. Subjects were monitored for symptoms, viral shedding, and safety, including cytokine measurements. Oseltamivir was administered 7 days after inoculation. Although the primary objective of reducing the proportion of subjects developing any grade ≥2 influenza symptom or pyrexia, was not achieved, TCN-032-treated subjects showed 35% reduction (P = .047) in median total symptom area under the curve (days 1-7) and 2.2 log reduction in median viral load area under the curve (days 2-7) by quantitative polymerase chain reaction (P = .09) compared with placebo-treated subjects. TCN-032 was safe and well tolerated with no additional safety signals after administration of oseltamivir. Serum cytokine levels (interferon γ, tumor necrosis factor α, and interleukin 8 and 10) were similar in both groups. Genotypic and phenotypic analyses showed no difference between virus derived from subjects after TCN-032 treatment and parental strain. These data indicate that TCN-032 may provide immediate immunity and therapeutic benefit in influenza A infection, with no apparent emergence of resistant virus. TCN-032 was safe with no evidence of immune exacerbation based on serum cytokine expression. Clinicaltrials.gov registry number. NCT01719874. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Investigation of the 2f1-f2 and 2f2-f1 distortion product otoacoustic emissions using a computational model of the gerbil ear.

PubMed

Wen, Haiqi; Bowling, Thomas; Meaud, Julien

2018-05-19

In this work, a three-dimensional computational model of the gerbil ear is used to investigate the generation of the 2f 1 -f 2 and 2f 2 -f 1 distortion product otoacoustic emissions (DPOAEs). In order to predict both the distortion and reflection sources, cochlear roughness is modeled by introducing random inhomogeneities in the outer hair cell properties. The model was used to simulate the generation of DPOAEs in response to a two-tone stimulus for various primary stimulus levels and frequency ratios. As in published experiments, the 2f 1 -f 2 DPOAEs are mostly dominated by the distortion component while the 2f 2 -f 1 DPOAEs are dominated by the reflection component; furthermore, the influence of the levels and frequency ratio of the primaries are consistent with measurements. Analysis of the intracochlear response shows that the distortion component has the highest magnitude at all longitudinal locations for the 2f 1 -f 2 distortion product (DP) while the distortion component only dominates close to the DP best place in the case of the 2f 2 -f 1 DP. Decomposition of the intracochlear DPs into forward and reverse waves demonstrates that the 2f 1 -f 2 DP generates reverse waves for both the distortion and reflection components; however, a reverse wave is only generated for the reflection component in the case of the 2f 2 -f 1 DP. As in experiments in the gerbil, the group delay of the reflection component of the DPOAE is between 1× and 2× the forward group delay, which is consistent with the propagation of DP towards the stapes as slow reverse waves. Copyright © 2018 Elsevier B.V. All rights reserved.

Proton irradiation of [18O]O2: production of [18F]F2 and [18F]F2 + [18F] OF2.

PubMed

Bishop, A; Satyamurthy, N; Bida, G; Hendry, G; Phelps, M; Barrio, J R

1996-04-01

The production of 18F electrophilic reagents via the 18O(p,n)18F reaction has been investigated in small-volume target bodies made of aluminum, copper, gold-plated copper and nickel, having straight or conical bore shapes. Three irradiation protocols-single-step, two-step and modified two-step-were used for the recovery of the 18F activity. The single-step irradiation protocol was tested in all the target bodies. Based on the single-step performance, aluminum targets were utilized extensively in the investigation of the two-step and modified two-step irradiation protocols. With an 11-MeV cyclotron and using the two-step irradiation protocol, > 1Ci [18F]F2 was recovered reproducibly from an aluminum target body. Probable radical mechanisms for the formation of OF2 and FONO2 (fluorine nitrate) in the single-step and modified two-step targets are proposed based on the amount of ozone generated and the nitrogen impurity present in the target gases, respectively.

Methods for identifying high collision concentrations for identifying potential safety improvements : development of advanced type 2 safety performance functions.

DOT National Transportation Integrated Search

2016-06-30

This research developed advanced type 2 safety performance functions (SPF) for roadway segments, intersections and ramps on the entire Caltrans network. The advanced type 2 SPFs included geometrics, traffic volume and hierarchical random effects, whi...

High field induced magnetic transitions in the Y0.7E r0.3F e2D4.2 deuteride

NASA Astrophysics Data System (ADS)

Paul-Boncour, V.; Guillot, M.; Isnard, O.; Hoser, A.

2017-09-01

The influence of the partial Er for Y substitution on the crystal structure and magnetic properties of YF e2D4.2 has been investigated by high field magnetization and neutron diffraction experiments. Y0.7E r0.3F e2D4.2 compound crystallizes in the same monoclinic structure as YF e2D4.2 described in P c (P1c1) space group with D atoms located in 18 different tetrahedral interstitial sites. A cell volume contraction of 0.6% is observed upon Er substitution, inducing large modification of the magnetic properties. Electronic effect of D insertion as well as lowering of crystal symmetry are important factors determining the magnetic properties of Fe sublattice, which evolves towards more delocalized behavior and modifying the Er-Fe exchange interactions. In the ground state, the Er and Fe moments are arranged ferrimagnetically within the plane perpendicular to the monoclinic b axis and with average moments mEr=6.4 (3 ) μBEr-1 and mFe=2.0 (1 ) μBFe-1 at 10 K. Upon heating, mEr decreases progressively until TEr=55 K . Between 55 K and 75 K, the Fe sublattice undergoes a first-order ferromagnetic-antiferromagnetic (FM-AFM) transition with a cell volume contraction due to the itinerant metamagnetic behavior of one Fe site. In the AFM structure, mFe decreases until the Néel temperature TN=125 K . At high field, two different types of field induced transitions are observed. The Er moments become parallel to the Fe one and saturates to the E r3 + free ion value, leading to an unusual field induced FM arrangement at a transition field BTrans of only 78 kG below 30 K. Then above TM0=66 K , an AFM-FM transition of the Fe sublattice, accompanied by a cell volume increase is observed. BTrans increases linearly versus temperature and with a larger d BTrans/d T slope than for YF e2D4.2 . This has been explained by the additional contribution of Er induced moments above BTrans.

Dynamic NF-κB and E2F interactions control the priority and timing of inflammatory signalling and cell proliferation

PubMed Central

Ankers, John M; Awais, Raheela; Jones, Nicholas A; Boyd, James; Ryan, Sheila; Adamson, Antony D; Harper, Claire V; Bridge, Lloyd; Spiller, David G; Jackson, Dean A; Paszek, Pawel; Sée, Violaine; White, Michael RH

2016-01-01

Dynamic cellular systems reprogram gene expression to ensure appropriate cellular fate responses to specific extracellular cues. Here we demonstrate that the dynamics of Nuclear Factor kappa B (NF-κB) signalling and the cell cycle are prioritised differently depending on the timing of an inflammatory signal. Using iterative experimental and computational analyses, we show physical and functional interactions between NF-κB and the E2 Factor 1 (E2F-1) and E2 Factor 4 (E2F-4) cell cycle regulators. These interactions modulate the NF-κB response. In S-phase, the NF-κB response was delayed or repressed, while cell cycle progression was unimpeded. By contrast, activation of NF-κB at the G1/S boundary resulted in a longer cell cycle and more synchronous initial NF-κB responses between cells. These data identify new mechanisms by which the cellular response to stress is differentially controlled at different stages of the cell cycle. DOI: http://dx.doi.org/10.7554/eLife.10473.001 PMID:27185527

Luminescence characteristics of Dy3+ activated Na 2Sr 2Mg (BO 3)2F 2: Dy 3+ phosphor

NASA Astrophysics Data System (ADS)

Wani, Javaid A.; Dhoble, N. S.; Dhoble, S. J.

2012-11-01

In this paper, we have reported a new Na 2Sr 2Mg (BO 3)2F 2:Dy 3+ thermoluminescence (TL) phosphor prepared via the wet chemical method. Prepared phosphor was characterized by X-ray powder diffraction, photoluminescence (PL), TL and scanning electronmicroscopy techniques. The scanning electronmicroscopic image of Na 2Sr 2Mg (BO 3)2F 2:Dy 3+ phosphor confirms the micron size of particles. Under the PL study, the characteristic emission spectrum of Dy 3+ corresponding to 4F 9/2→6H 15/2 (481 nm) and 4F 9/2→6H 13/2 (576 nm) transitions was observed. The TL property of the as prepared phosphor was also found to be good. TL intensity of Na 2Sr2Mg(BO 3)F 2:Dy 3+ phosphors at 0.99 kGy exposure of γ-irradiations was compared with standard CaSO 4:Dy phosphor. It was seen that TL intensity of Na 2Sr 2Mg (BO 3)2F 2: Dy 3+ phosphors is 1.1 times less compared with the standard CaSO 4:Dy TL dosimeter phosphor. The kinetic parameters are also discussed in detail. The values of activation energy E (eV) and frequency factor S (s -1) were found to be 0.57 eV and 1.25×106 s-1, respectively.

Initial development of a practical safety audit tool to assess fleet safety management practices.

PubMed

Mitchell, Rebecca; Friswell, Rena; Mooren, Lori

2012-07-01

Work-related vehicle crashes are a common cause of occupational injury. Yet, there are few studies that investigate management practices used for light vehicle fleets (i.e. vehicles less than 4.5 tonnes). One of the impediments to obtaining and sharing information on effective fleet safety management is the lack of an evidence-based, standardised measurement tool. This article describes the initial development of an audit tool to assess fleet safety management practices in light vehicle fleets. The audit tool was developed by triangulating information from a review of the literature on fleet safety management practices and from semi-structured interviews with 15 fleet managers and 21 fleet drivers. A preliminary useability assessment was conducted with 5 organisations. The audit tool assesses the management of fleet safety against five core categories: (1) management, systems and processes; (2) monitoring and assessment; (3) employee recruitment, training and education; (4) vehicle technology, selection and maintenance; and (5) vehicle journeys. Each of these core categories has between 1 and 3 sub-categories. Organisations are rated at one of 4 levels on each sub-category. The fleet safety management audit tool is designed to identify the extent to which fleet safety is managed in an organisation against best practice. It is intended that the audit tool be used to conduct audits within an organisation to provide an indicator of progress in managing fleet safety and to consistently benchmark performance against other organisations. Application of the tool by fleet safety researchers is now needed to inform its further development and refinement and to permit psychometric evaluation. Copyright © 2012 Elsevier Ltd. All rights reserved.

"L.I.F.E.": A School-Based Heart-Health Screening and Intervention Program

ERIC Educational Resources Information Center

Northrup, Karen L.; Cottrell, Lesley A.; Wittberg, Richard A.

2008-01-01

This article describes the development and growth of "Lifestyle Improvements in the Family Environment" ("L.I.F.E."), a school-based heart-health screening and intervention program. The primary goals of "L.I.F.E." through three rounds of grant funding remained constant: (a) to identify cardiovascular risk factors in…

Simultaneous observations of F2 layer stratification and spread F at postmidnight over a northern equatorial anomaly region

NASA Astrophysics Data System (ADS)

Jiang, Chunhua; Yang, Guobin; Deng, Chi; Zhou, Chen; Zhu, Peng; Yokoyama, Tatsuhiro; Song, Huan; Lan, Ting; Ni, Binbin; Zhao, Zhengyu; Zhang, Yuannong

2015-12-01

Simultaneous observations of F2 layer stratification and spread F at postmidnight (00:00 LT to 05:00 LT) were carried out on 22, 23, and 28 November 2013, using ionosondes distributed over a northern equatorial anomaly region at three specific locations, i.e., Puer (PUR, 22.7°N, 101.05°E, dip latitude 12.9°N), Chiang Mai (CMU, 18.8°N, 98.9°E, dip latitude 9.04°N), and Chumphon (CPN, 10.7°N, 99.4°E, dip latitude 0.93°N). The results show that both the PUR and CMU stations observed the F2 layer stratification at postmidnight in the Northern Hemisphere, frequently accompanied with gravity waves (the periods~30-100 min). It is reported that F2 layer stratification at postmidnight can be observed in the Northern Hemisphere for the first time. It is suggested that the thermospheric neutral wind triggered by gravity waves strongly contribute to the altitude dependence of the combined vertical plasma velocity, which consequently poses significant impacts on the occurrence of the low-latitude F2 layer stratification at postmidnight. In addition, the spread F other than F2 layer stratification was observed at the CPN station located at the geomagnetic equator, suggesting that smaller geomagnetic inclination tend to inhibit the postmidnight F2 layer stratification in the equatorial region. Furthermore, on 23 November 2013 a good correlation was identified between the F2 layer stratification at PUR and the spread F at both CMU and CPN, possibly due to that the large-scale gravity waves originating at middle latitudes contribute to the nighttime spread F observed in the low-latitude and equatorial regions.

Bim, a Proapoptotic Protein, Up-regulated via Transcription Factor E2F1-dependent Mechanism, Functions as a Prosurvival Molecule in Cancer*

PubMed Central

Gogada, Raghu; Yadav, Neelu; Liu, Junwei; Tang, Shaohua; Zhang, Dianmu; Schneider, Andrea; Seshadri, Athul; Sun, Leimin; Aldaz, C. Marcelo; Tang, Dean G.; Chandra, Dhyan

2013-01-01

Proapoptotic Bcl-2 homology 3-only protein Bim plays an important role in Bax/Bak-mediated cytochrome c release and apoptosis. Here, we provide evidence for a novel prosurvival function of Bim in cancer cells. Bim was constitutively overexpressed in multiple prostate and breast cancer cells as well as in primary tumor cells. Quantitative real time PCR analysis showed that Bim was transcriptionally up-regulated. We have identified eight endogenous E2F1-binding sites on the Bim promoter using in silico analysis. Luciferase assay demonstrated that Bim expression was E2F1-dependent as mutation of the E2F1-binding sites on the Bim promoter inhibited luciferase activities. In support, E2F1 silencing led to the loss of Bim expression in cancer cells. Bim primarily localized to mitochondrial and cytoskeleton-associated fractions. Bim silencing or microinjection of anti-Bim antibodies into the cell cytoplasm resulted in cell rounding, detachment, and subsequent apoptosis. We observed up-regulation of prosurvival proteins Bcl-xL and Mcl-1, which sequester Bim in cancer cells. In addition, a phosphorylated form of Bim was also elevated in cancer cells. These findings suggest that the constitutively overexpressed Bim may function as a prosurvival molecule in epithelial cancer cells, and phosphorylation and association with Bcl-xL/Mcl-1 block its proapoptotic functions. PMID:23152504

The Role of a Novel Nucleolar Protein in Regulation of E2F1 in Breast Cancer

DTIC Science & Technology

2009-09-01

publication and successful defense of a PhD. 8 References 1. Paik JC, Wang B, Liu K, Lue J , Lin WC. Regulation of E2F1-induced apoptosis by...the nucleolar protein RRP1B. J Biol Chem. 2009 Dec 29. [E-pub ahead of print] 2. Hsieh SM, Look MP, Sieuwerts AM, Foekens JA, Hunter KW. Distinct...factor. J Biol Chem. 2009 Oct 16;284(42):28660-73. 4. Crawford NP, Walker RC, Lukes L, Officewala JS, Williams RW, Hunter KW. The Diasporin Pathway: a

X-ray Excitation Triggers Ytterbium Anomalous Emission in CaF2:Yb but Not in SrF2:Yb.

PubMed

Hughes-Currie, Rosa B; Ivanovskikh, Konstantin V; Wells, Jon-Paul R; Reid, Michael F; Gordon, Robert A; Seijo, Luis; Barandiarán, Zoila

2017-03-16

Materials that luminesce after excitation with ionizing radiation are extensively applied in physics, medicine, security, and industry. Lanthanide dopants are known to trigger crystal scintillation through their fast d-f emissions; the same is true for other important applications as lasers or phosphors for lighting. However, this ability can be seriously compromised by unwanted anomalous emissions often found with the most common lanthanide activators. We report high-resolution X-ray-excited optical (IR to UV) luminescence spectra of CaF 2 :Yb and SrF 2 :Yb samples excited at 8949 eV and 80 K. Ionizing radiation excites the known anomalous emission of ytterbium in the CaF 2 host but not in the SrF 2 host. Wave function-based ab initio calculations of host-to-dopant electron transfer and Yb 2+ /Yb 3+ intervalence charge transfer explain the difference. The model also explains the lack of anomalous emission in Yb-doped SrF 2 excited by VUV radiation.

(2 + 1) resonant enhanced multiphoton ionization of H2 via the E,F 1Sigma(+)g state

NASA Technical Reports Server (NTRS)

Rudolph, H.; Lynch, D. L.; Dixit, S. N.; Mckoy, V.; Huo, Winifred M.

1987-01-01

In this paper, the results of ab initio calculations of photoelectron angular distributions and vibrational branching ratios for the (2 + 1) resonant enhanced multiphoton ionization (REMPI) of H2 via the E,F 1Sigma(+)g state are reported, and these are compared with the experimental data of Anderson et al. (1984). These results show that the observed non-Franck-Condon behavior is predominantly due to the R dependence of the transition matrix elements, and to a lesser degree to the energy dependence. This work presents the first molecular REMPI study employing a correlated wave function to describe the Rydberg-valence mixing in the resonant intermediate state.

Genetic architecture of atherosclerosis dissected by QTL analyses in three F2 intercrosses of apolipoprotein E-null mice on C57BL6/J, DBA/2J and 129S6/SvEvTac backgrounds

PubMed Central

Makhanova, Natalia; Morgan, Andrew P.; Kayashima, Yukako; Makhanov, Andrei; Hiller, Sylvia; Zhilicheva, Svetlana; Xu, Longquan; Pardo-Manuel de Villena, Fernando; Maeda, Nobuyo

2017-01-01

Quantitative trait locus (QTL) analyses of intercross populations between widely used mouse inbred strains provide a powerful approach for uncovering genetic factors that influence susceptibility to atherosclerosis. Epistatic interactions are common in complex phenotypes and depend on genetic backgrounds. To dissect genetic architecture of atherosclerosis, we analyzed F2 progeny from a cross between apolipoprotein E-null mice on DBA/2J (DBA-apoE) and C57BL/6J (B6-apoE) genetic backgrounds and compared the results with those from two previous F2 crosses of apolipoprotein E-null mice on 129S6/SvEvTac (129-apoE) and DBA-apoE backgrounds, and B6-apoE and 129-apoE backgrounds. In these round-robin crosses, in which each parental strain was crossed with two others, large-effect QTLs are expected to be detectable at least in two crosses. On the other hand, observation of QTLs in one cross only may indicate epistasis and/or absence of statistical power. For atherosclerosis at the aortic arch, Aath4 on chromosome (Chr)2:66 cM follows the first pattern, with significant QTL peaks in (DBAx129)F2 and (B6xDBA)F2 mice but not in (B6x129)F2 mice. We conclude that genetic variants unique to DBA/2J at Aath4 confer susceptibility to atherosclerosis at the aortic arch. A similar pattern was observed for Aath5 on chr10:35 cM, verifying that the variants unique to DBA/2J at this locus protect against arch plaque development. However, multiple loci, including Aath1 (Chr1:49 cM), and Aath2 (Chr1:70 cM) follow the second type of pattern, showing significant peaks in only one of the three crosses (B6-apoE x 129-apoE). As for atherosclerosis at aortic root, the majority of QTLs, including Ath29 (Chr9:33 cM), Ath44 (Chr1:68 cM) and Ath45 (Chr2:83 cM), was also inconsistent, being significant in only one of the three crosses. Only the QTL on Chr7:37 cM was consistently suggestive in two of the three crosses. Thus QTL analysis of round-robin crosses revealed the genetic architecture of

Class E/F switching power amplifiers

NASA Technical Reports Server (NTRS)

Hajimiri, Seyed-Ali (Inventor); Aoki, Ichiro (Inventor); Rutledge, David B. (Inventor); Kee, Scott David (Inventor)

2004-01-01

The present invention discloses a new family of switching amplifier classes called class E/F amplifiers. These amplifiers are generally characterized by their use of the zero-voltage-switching (ZVS) phase correction technique to eliminate of the loss normally associated with the inherent capacitance of the switching device as utilized in class-E amplifiers, together with a load network for improved voltage and current wave-shaping by presenting class-F.sup.-1 impedances at selected overtones and class-E impedances at the remaining overtones. The present invention discloses a several topologies and specific circuit implementations for achieving such performance.

Project D. E. A. F. Final Report.

ERIC Educational Resources Information Center

Hairston, Ernest E.

Project D.E.A.F., its introduction and background, purpose, clientele, methodology, and activities, are described. Project D.E.A.F. was established by an expansion grant from the Rehabilitation Service Administration of the Department of Health, Education and Welfare, in cooperation with the Ohio Bureau of Vocational Rehabilitation for the purpose…

Cytochalasin E alters the cytoskeleton and decreases ENaC activity in Xenopus 2F3 cells.

PubMed

Reifenberger, Matthew S; Yu, Ling; Bao, Hui-Fang; Duke, Billie Jeanne; Liu, Bing-Chen; Ma, He-Ping; Alli, Ahmed A; Eaton, Douglas C; Alli, Abdel A

2014-07-01

Numerous reports have linked cytoskeleton-associated proteins with the regulation of epithelial Na(+) channel (ENaC) activity. The purpose of the present study was to determine the effect of actin cytoskeleton disruption by cytochalasin E on ENaC activity in Xenopus 2F3 cells. Here, we show that cytochalasin E treatment for 60 min can disrupt the integrity of the actin cytoskeleton in cultured Xenopus 2F3 cells. We show using single channel patch-clamp experiments and measurements of short-circuit current that ENaC activity, but not its density, is altered by cytochalasin E-induced disruption of the cytoskeleton. In nontreated cells, 8 of 33 patches (24%) had no measurable ENaC activity, whereas in cytochalasin E-treated cells, 17 of 32 patches (53%) had no activity. Analysis of those patches that did contain ENaC activity showed channel open probability significantly decreased from 0.081 ± 0.01 in nontreated cells to 0.043 ± 0.01 in cells treated with cytochalasin E. Transepithelial current from mpkCCD cells treated with cytochalasin E, cytochalasin D, or latrunculin B for 60 min was decreased compared with vehicle-treated cells. The subcellular expression of fodrin changed significantly, and several protein elements of the cytoskeleton decreased at least twofold after 60 min of cytochalasin E treatment. Cytochalasin E treatment disrupted the association between ENaC and myristoylated alanine-rich C-kinase substrate. The results presented here suggest disruption of the actin cytoskeleton by different compounds can attenuate ENaC activity through a mechanism involving changes in the subcellular expression of fodrin, several elements of the cytoskeleton, and destabilization of the ENaC-myristoylated alanine-rich C-kinase substrate complex. Copyright © 2014 the American Physiological Society.

Cytochalasin E alters the cytoskeleton and decreases ENaC activity in Xenopus 2F3 cells

PubMed Central

Reifenberger, Matthew S.; Yu, Ling; Bao, Hui-Fang; Duke, Billie Jeanne; Liu, Bing-Chen; Ma, He-Ping; Eaton, Douglas C.; Alli, Abdel A.