Sample records for cdk1 targets srs2

  1. CDK1 Inhibition Targets the p53-NOXA-MCL1 Axis, Selectively Kills Embryonic Stem Cells, and Prevents Teratoma Formation

    Directory of Open Access Journals (Sweden)

    Noelle E. Huskey


    Full Text Available Embryonic stem cells (ESCs have adopted an accelerated cell-cycle program with shortened gap phases and precocious expression of cell-cycle regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs. We examined the effect of CDK inhibition on the pathways regulating proliferation and survival of ESCs. We found that inhibiting cyclin-dependent kinase 1 (CDK1 leads to activation of the DNA damage response, nuclear p53 stabilization, activation of a subset of p53 target genes including NOXA, and negative regulation of the anti-apoptotic protein MCL1 in human and mouse ESCs, but not differentiated cells. We demonstrate that MCL1 is highly expressed in ESCs and loss of MCL1 leads to ESC death. Finally, we show that clinically relevant CDK1 inhibitors prevent formation of ESC-derived tumors and induce necrosis in established ESC-derived tumors. Our data demonstrate that ES cells are uniquely sensitive to CDK1 inhibition via a p53/NOXA/MCL1 pathway.

  2. CDK1 structures reveal conserved and unique features of the essential cell cycle CDK (United States)

    Brown, Nicholas R.; Korolchuk, Svitlana; Martin, Mathew P.; Stanley, Will A.; Moukhametzianov, Rouslan; Noble, Martin E. M.; Endicott, Jane A.


    CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1-Cks1 and CDK1-cyclin B-Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2-cyclin A, CDK1-cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors.

  3. Fimbrin phosphorylation by metaphase Cdk1 regulates actin cable dynamics in budding yeast. (United States)

    Miao, Yansong; Han, Xuemei; Zheng, Liangzhen; Xie, Ying; Mu, Yuguang; Yates, John R; Drubin, David G


    Actin cables, composed of actin filament bundles nucleated by formins, mediate intracellular transport for cell polarity establishment and maintenance. We previously observed that metaphase cells preferentially promote actin cable assembly through cyclin-dependent kinase 1 (Cdk1) activity. However, the relevant metaphase Cdk1 targets were not known. Here we show that the highly conserved actin filament crosslinking protein fimbrin is a critical Cdk1 target for actin cable assembly regulation in budding yeast. Fimbrin is specifically phosphorylated on threonine 103 by the metaphase cyclin-Cdk1 complex, in vivo and in vitro. On the basis of conformational simulations, we suggest that this phosphorylation stabilizes fimbrin's N-terminal domain, and modulates actin filament binding to regulate actin cable assembly and stability in cells. Overall, this work identifies fimbrin as a key target for cell cycle regulation of actin cable assembly in budding yeast, and suggests an underlying mechanism.

  4. Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression. (United States)

    Landry, Benjamin D; Mapa, Claudine E; Arsenault, Heather E; Poti, Kristin E; Benanti, Jennifer A


    To maintain genome stability, regulators of chromosome segregation must be expressed in coordination with mitotic events. Expression of these late cell cycle genes is regulated by cyclin-dependent kinase (Cdk1), which phosphorylates a network of conserved transcription factors (TFs). However, the effects of Cdk1 phosphorylation on many key TFs are not known. We find that elimination of Cdk1-mediated phosphorylation of four S-phase TFs decreases expression of many late cell cycle genes, delays mitotic progression, and reduces fitness in budding yeast. Blocking phosphorylation impairs degradation of all four TFs. Consequently, phosphorylation-deficient mutants of the repressors Yox1 and Yhp1 exhibit increased promoter occupancy and decreased expression of their target genes. Interestingly, although phosphorylation of the transcriptional activator Hcm1 on its N-terminus promotes its degradation, phosphorylation on its C-terminus is required for its activity, indicating that Cdk1 both activates and inhibits a single TF. We conclude that Cdk1 promotes gene expression by both activating transcriptional activators and inactivating transcriptional repressors. Furthermore, our data suggest that coordinated regulation of the TF network by Cdk1 is necessary for faithful cell division.

  5. Enrichment of Cdk1-cyclins at DNA double-strand breaks stimulates Fun30 phosphorylation and DNA end resection. (United States)

    Chen, Xuefeng; Niu, Hengyao; Yu, Yang; Wang, Jingjing; Zhu, Shuangyi; Zhou, Jianjie; Papusha, Alma; Cui, Dandan; Pan, Xuewen; Kwon, Youngho; Sung, Patrick; Ira, Grzegorz


    DNA double-strand breaks (DSBs) are one of the most cytotoxic types of DNA lesion challenging genome integrity. The activity of cyclin-dependent kinase Cdk1 is essential for DSB repair by homologous recombination and for DNA damage signaling. Here we identify the Fun30 chromatin remodeler as a new target of Cdk1. Fun30 is phosphorylated by Cdk1 on Serine 28 to stimulate its functions in DNA damage response including resection of DSB ends. Importantly, Cdk1-dependent phosphorylation of Fun30-S28 increases upon DNA damage and requires the recruitment of Fun30 to DSBs, suggesting that phosphorylation increases in situ at the DNA damage. Consistently, we find that Cdk1 and multiple cyclins become highly enriched at DSBs and that the recruitment of Cdk1 and cyclins Clb2 and Clb5 ensures optimal Fun30 phosphorylation and checkpoint activation. We propose that the enrichment of Cdk1-cyclin complexes at DSBs serves as a mechanism for enhanced targeting and modulating of the activity of DNA damage response proteins.

  6. Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles. (United States)

    Liu, Yang; Zhu, Yan-Hua; Mao, Cheng-Qiong; Dou, Shuang; Shen, Song; Tan, Zi-Bin; Wang, Jun


    There is no effective clinical therapy yet for triple-negative breast cancer (TNBC) without particular human epidermal growth factor receptor-2, estrogen and progesterone receptor expression. In this study, we report a molecularly targeted and synthetic lethality-based siRNA therapy for TNBC treatment, using cationic lipid assisted poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PLA) nanoparticles as the siRNA carrier. It is demonstrated that only in c-Myc overexpressed TNBC cells, while not in normal mammary epithelial cells, delivery of siRNA targeting cyclin-dependent kinase 1 (CDK1) with the nanoparticle carrier (NPsiCDK1) induces cell viability decreasing and cell apoptosis through RNAi-mediated CDK1 expression inhibition, indicating the synthetic lethality between c-Myc with CDK1 in TNBC cells. Moreover, systemic delivery of NPsiCDK1 is able to suppress tumor growth in mice bearing SUM149 and BT549 xenograft and cause no systemic toxicity or activate the innate immune response, suggesting the therapeutic promise with such nanoparticles carrying siCDK1 for c-Myc overexpressed triple negative breast cancer.

  7. Suppression of Vimentin Phosphorylation by the Avian Reovirus p17 through Inhibition of CDK1 and Plk1 Impacting the G2/M Phase of the Cell Cycle (United States)

    Chiu, Hung-Chuan; Huang, Wei-Ru; Liao, Tsai-Ling; Wu, Hung-Yi; Munir, Muhammad; Shih, Wing-Ling; Liu, Hung-Jen


    The p17 protein of avian reovirus (ARV) causes cell cycle retardation in a variety of cell lines; however, the underlying mechanism(s) by which p17 regulates the cell cycle remains largely unknown. We demonstrate for the first time that p17 interacts with CDK1 and vimentin as revealed by reciprocal co-immunoprecipitation and GST pull-down assays. Both in vitro and in vivo studies indicated that direct interaction of p17 and CDK1/vimentin was mapped within the amino terminus (aa 1–60) of p17 and central region (aa 27–118) of CDK1/vimentin. Furthermore, p17 was found to occupy the Plk1-binding site within the vimentin, thereby blocking Plk1 recruitment to CDK1-induced vimentin phosphorylation at Ser 56. Interaction of p17 to CDK1 or vimentin interferes with CDK1-catalyzed phosphorylation of vimentin at Ser 56 and subsequently vimentin phosphorylation at Ser 82 by Plk1. Furthermore, we have identified upstream signaling pathways and cellular factor(s) targeted by p17 and found that p17 regulates inhibitory phosphorylation of CDK1 and blocks vimentin phosphorylation at Ser 56 and Ser 82. The p17-mediated inactivation of CDK1 is dependent on several mechanisms, which include direct interaction with CDK1, p17-mediated suppression of Plk1 by activating the Tpr/p53 and ATM/Chk1/PP2A pathways, and p17-mediated cdc25C degradation via an ubiquitin- proteasome pathway. Additionally, depletion of p53 with a shRNA as well as inhibition of ATM and vimentin by inhibitors diminished virus yield while Tpr and CDK1 knockdown increased virus yield. Taken together, results demonstrate that p17 suppresses both CDK1 and Plk1functions, disrupts vimentin phosphorylation, causes G2/M cell cycle arrest and thus benefits virus replication. PMID:27603133

  8. NPM phosphorylation stimulates Cdk1, overrides G2/M checkpoint and increases leukemic blasts in mice. (United States)

    Du, Wei; Zhou, Yun; Pike, Suzette; Pang, Qishen


    An elevated level of nucleophosmin (NPM) is often found in actively proliferative cells including human tumors. To identify the regulatory role for NPM phosphorylation in proliferation and cell cycle control, a series of mutants targeting the consensus cyclin-dependent kinase (CDK) phosphorylation sites was created to mimic or abrogate either single-site or multi-site phosphorylation. Simultaneous inactivation of two CDK phosphorylation sites at Ser10 and Ser70 (NPM-AA) induced G(2)/M cell cycle arrest, phosphorylation of Cdk1 at Tyr15 (Cdc2(Tyr15)) and increased cytoplasmic accumulation of Cdc25C. Strikingly, stress-induced Cdk1(Tyr15) and Cdc25C sequestration was suppressed by expression of a phosphomimetic NPM mutant created on the same CDK sites (S10E/S70E, NPM-EE). Further analysis revealed that phosphorylation of NPM at both Ser10 and Ser70 was required for proper interaction between Cdk1 and Cdc25C. Moreover, NPM-EE directly bound to Cdc25C and prevented phosphorylation of Cdc25C at Ser216 during mitosis. Finally, NPM-EE overrided stress-induced G(2)/M arrest and increased leukemia blasts in a NOD/SCID xenograft model. Thus, these findings reveal a novel function of NPM on regulation of cell cycle progression, in which phosphorylation of NPM controls cell cycle progression at G(2)/M transition through modulation of Cdk1 and Cdc25C activities.

  9. Influence of CDK1 and CDK2 siRNA interference on tumor cell cycle and cell apoptosis%CDK1、CDK2 siRNA干扰对肿瘤细胞凋亡和细胞周期的影响

    Institute of Scientific and Technical Information of China (English)

    Hui Xiao; Wanjun Gong; Jingpeng Cao; Xiaolan Li; Deding Tao; Junbo Hu; Jianping Gong


    Objective: We investigated the influence of CDK1 and CDK2 expression inhibited by cotransfection of CDK1 and CDK2 siRNA on cell cycle and apoptosis, explored the exact role of cell cycle master regulator in tumor cell apoptosis process. Methods: The siRNA targeting the CDK1 and CDK2 genes were synthesized and simultaneously cotransfected into Hela cells by lipofectamine 2000.48 or 60 h after the cotransfection, CDK1 and CDK2 protein expressions were examined by Western blot. Cell cycle distribution was analyzed by flow cytometry. Cell apoptosis was detected by the Annexin V/PI method. The changes of the transfected cell morphological under a microscope after Wright-Giemsa Staining were studied. Results: CDK1 and CDK2 protein expression was decreased at 48 or 60 h after cotransfection. The accumulation of the G2/M and S phase population in cell cycle of the cotrensfected cells at 48 or 60 h after transfection was enhanced obviously compared with control. The ratio of apoptotic cell of cotransfected cells at 48 or 60 h after transfection was increased significantly compared with control. More binucleate or multinucleate cells among cotransfected cells were observed under the microscope. Conclu- sion: The decreased expression of CDK1 and CDK2 by cotransfection of CDK1 and CDK2 siRNA not only leads to tumor cell cycle arrest in S phase and G2/M phase, but also induces tumor cell apoptosis.

  10. Waves of Cdk1 Activity in S Phase Synchronize the Cell Cycle in Drosophila Embryos. (United States)

    Deneke, Victoria E; Melbinger, Anna; Vergassola, Massimo; Di Talia, Stefano


    Embryos of most metazoans undergo rapid and synchronous cell cycles following fertilization. While diffusion is too slow for synchronization of mitosis across large spatial scales, waves of Cdk1 activity represent a possible process of synchronization. However, the mechanisms regulating Cdk1 waves during embryonic development remain poorly understood. Using biosensors of Cdk1 and Chk1 activities, we dissect the regulation of Cdk1 waves in the Drosophila syncytial blastoderm. We show that Cdk1 waves are not controlled by the mitotic switch but by a double-negative feedback between Cdk1 and Chk1. Using mathematical modeling and surgical ligations, we demonstrate a fundamental distinction between S phase Cdk1 waves, which propagate as active trigger waves in an excitable medium, and mitotic Cdk1 waves, which propagate as passive phase waves. Our findings show that in Drosophila embryos, Cdk1 positive feedback serves primarily to ensure the rapid onset of mitosis, while wave propagation is regulated by S phase events.

  11. Cloning and Expression of Neospora caninum SRS2 Gene%新孢子虫 SRS2基因的克隆及原核表达

    Institute of Scientific and Technical Information of China (English)

    邢小勇; 王权; 温峰琴; 郝宝成; 项海涛; 胡永浩


      To construct recombinant plasmid expressing Neospora caninum SRS2,the SRS2 gene from a Neospora caninum strain was amplified by PCR with a pair of primers designed according to the sequence in GenBank.A 998 bp gene was amplified and cloned into the vector PET-32a.The expression of SRS2 protein was induced by IPTG .SDS-PAGE analysis indicated that the expressed recombinant protein of SRS2 was about 54 kD.The Western blot analysis confirmed the recombinant protein was recognized by positive serum anti- Neospora caninum.The study provided a foundation for further study on the diagnosis and vaccine of neosporosis.%  为构建表达新孢子虫重组蛋白 SRS2原核表达系统,本研究以新孢子虫基因组为模板 PCR 扩增 SRS2蛋白部分基因,获得大小约为998bp 的目的片段,并克隆到大肠杆菌 PET-32a 载体中,IPTG 诱导重组大肠杆菌,通过 SDS-PAGE 和免疫印迹分析表达产物并鉴定其生物学活性。经 SDS-PAGE 分析,表达的重组 SRS2蛋白分子量约为54kD,免疫印迹结果表明,表达的重组蛋白与牛抗新孢子虫阳性血清反应形成一条特异性蛋白条带。本实验为进一步研究诊断和治疗新孢子虫病奠定了基础。

  12. The Set1/COMPASS histone H3 methyltransferase helps regulate mitosis with the CDK1 and NIMA mitotic kinases in Aspergillus nidulans. (United States)

    Govindaraghavan, Meera; Anglin, Sarah Lea; Osmani, Aysha H; Osmani, Stephen A


    Mitosis is promoted and regulated by reversible protein phosphorylation catalyzed by the essential NIMA and CDK1 kinases in the model filamentous fungus Aspergillus nidulans. Protein methylation mediated by the Set1/COMPASS methyltransferase complex has also been shown to regulate mitosis in budding yeast with the Aurora mitotic kinase. We uncover a genetic interaction between An-swd1, which encodes a subunit of the Set1 protein methyltransferase complex, with NIMA as partial inactivation of nimA is poorly tolerated in the absence of swd1. This genetic interaction is additionally seen without the Set1 methyltransferase catalytic subunit. Importantly partial inactivation of NIMT, a mitotic activator of the CDK1 kinase, also causes lethality in the absence of Set1 function, revealing a functional relationship between the Set1 complex and two pivotal mitotic kinases. The main target for Set1-mediated methylation is histone H3K4. Mutational analysis of histone H3 revealed that modifying the H3K4 target residue of Set1 methyltransferase activity phenocopied the lethality seen when either NIMA or CDK1 are partially functional. We probed the mechanistic basis of these genetic interactions and find that the Set1 complex performs functions with CDK1 for initiating mitosis and with NIMA during progression through mitosis. The studies uncover a joint requirement for the Set1 methyltransferase complex with the CDK1 and NIMA kinases for successful mitosis. The findings extend the roles of the Set1 complex to include the initiation of mitosis with CDK1 and mitotic progression with NIMA in addition to its previously identified interactions with Aurora and type 1 phosphatase in budding yeast.

  13. CDK-1 Inhibition in G2 Stabilizes Kinetochore-Microtubules in the following Mitosis. (United States)

    Gayek, A Sophia; Ohi, Ryoma


    Cell proliferation is driven by cyclical activation of cyclin-dependent kinases (CDKs), which produce distinct biochemical cell cycle phases. Mitosis (M phase) is orchestrated by CDK-1, complexed with mitotic cyclins. During M phase, chromosomes are segregated by a bipolar array of microtubules called the mitotic spindle. The essential bipolarity of the mitotic spindle is established by the kinesin-5 Eg5, but factors influencing the maintenance of spindle bipolarity are not fully understood. Here, we describe an unexpected link between inhibiting CDK-1 before mitosis and bipolar spindle maintenance. Spindles in human RPE-1 cells normally collapse to monopolar structures when Eg5 is inhibited at metaphase. However, we found that inhibition of CDK-1 in the G2 phase of the cell cycle improved the ability of RPE-1 cells to maintain spindle bipolarity without Eg5 activity in the mitosis immediately after release from CDK-1 inhibition. This improved bipolarity maintenance correlated with an increase in the stability of kinetochore-microtubules, the subset of microtubules that link chromosomes to the spindle. The improvement in bipolarity maintenance after CDK-1 inhibition in G2 required both the kinesin-12 Kif15 and increased stability of kinetochore-microtubules. Consistent with increased kinetochore-microtubule stability, we find that inhibition of CDK-1 in G2 impairs mitotic fidelity by increasing the incidence of lagging chromosomes in anaphase. These results suggest that inhibition of CDK-1 in G2 causes unpredicted effects in mitosis, even after CDK-1 inhibition is relieved.

  14. A SRS2 homolog from Arabidopsis thaliana disrupts recombinogenic DNA intermediates and facilitates single strand annealing. (United States)

    Blanck, Sandra; Kobbe, Daniela; Hartung, Frank; Fengler, Karin; Focke, Manfred; Puchta, Holger


    Genetic and biochemical analyses of SRS2 homologs in fungi indicate a function in the processing of homologous recombination (HR) intermediates. To date, no SRS2 homologs have been described and analyzed in higher eukaryotes. Here, we report the first biochemical characterization of an SRS2 homolog from a multicellular eukaryote, the plant Arabidopsis thaliana. We studied the basic properties of AtSRS2 and were able to show that it is a functional 3'- to 5'-helicase. Furthermore, we characterized its biochemical function on recombinogenic intermediates and were able to show the unwinding of nicked Holliday junctions (HJs) and partial HJs (PX junctions). For the first time, we demonstrated strand annealing activity for an SRS2 homolog and characterized its strand pairing activity in detail. Our results indicate that AtSRS2 has properties that enable it to be involved in different steps during the processing of recombination intermediates. On the one hand, it could be involved in the unwinding of an elongating invading strand from a donor strand, while on the other hand, it could be involved in the annealing of the elongated strand at a later step.

  15. Cdk1 plays matchmaker for the Polo-like kinase and its activator SPAT-1/Bora. (United States)

    Tavernier, Nicolas; Panbianco, Costanza; Gotta, Monica; Pintard, Lionel


    Mitosis is orchestrated by several protein kinases including Cdks, Plks and Aurora kinases. Despite considerable progress toward understanding the individual function of these protein kinases, how their activity is coordinated in space and time during mitosis is less well understood. In a recent article published in the Journal of Cell Biology, we show that CDK-1 regulates PLK-1 activity during mitosis in C. elegans embryos through multisite phosphorylation of the PLK-1 activator SPAT-1 (Aurora Borealis, Bora in human). SPAT-1 variants mutated on CDK-1 phosphorylation sites results in severe delays in mitotic entry, mimicking embryos lacking spat-1 or plk-1 function. We further show that SPAT-1 phosphorylation by CDK-1 promotes its binding to PLK-1 and stimulates PLK-1 phosphorylation on its activator T-loop by Aurora A kinase in vitro. Likewise, we find that phosphorylation of Bora by Cdk1 promotes phosphorylation of human Plk1 by Aurora A suggesting that this mechanism is conserved in humans. These results indicate that Cdk1 regulates Plk1 by boosting its kinase activity. Here we discuss these recent findings and open questions regarding the regulation of Plk1/PLK-1 by Cdk1/CDK-1 and Bora/SPAT-1.

  16. Distinct Cdk1 requirements during single-strand annealing, noncrossover, and crossover recombination.

    Directory of Open Access Journals (Sweden)

    Camilla Trovesi


    Full Text Available Repair of DNA double-strand breaks (DSBs by homologous recombination (HR in haploid cells is generally restricted to S/G2 cell cycle phases, when DNA has been replicated and a sister chromatid is available as a repair template. This cell cycle specificity depends on cyclin-dependent protein kinases (Cdk1 in Saccharomyces cerevisiae, which initiate HR by promoting 5'-3' nucleolytic degradation of the DSB ends. Whether Cdk1 regulates other HR steps is unknown. Here we show that yku70Δ cells, which accumulate single-stranded DNA (ssDNA at the DSB ends independently of Cdk1 activity, are able to repair a DSB by single-strand annealing (SSA in the G1 cell cycle phase, when Cdk1 activity is low. This ability to perform SSA depends on DSB resection, because both resection and SSA are enhanced by the lack of Rad9 in yku70Δ G1 cells. Furthermore, we found that interchromosomal noncrossover recombinants are generated in yku70Δ and yku70Δ rad9Δ G1 cells, indicating that DSB resection bypasses Cdk1 requirement also for carrying out these recombination events. By contrast, yku70Δ and yku70Δ rad9Δ cells are specifically defective in interchromosomal crossover recombination when Cdk1 activity is low. Thus, Cdk1 promotes DSB repair by single-strand annealing and noncrossover recombination by acting mostly at the resection level, whereas additional events require Cdk1-dependent regulation in order to generate crossover outcomes.

  17. Synchronization of interphase events depends neither on mitosis nor on cdk1. (United States)

    Laronne, Ayelet; Rotkopf, Shay; Hellman, Asaf; Gruenbaum, Yosef; Porter, Andrew C G; Brandeis, Michael


    Human HT2-19 cells with a conditional cdk1 mutation stop dividing upon cdk1 inactivation and undergo multiple rounds of endoreplication. We show herein that major cell cycle events remain synchronized in these endoreplicating cells. DNA replication alternates with gap phases and cell cycle-specific cyclin E expression is maintained. Centrosomes duplicate in synchrony with chromosome replication, giving rise to polyploid cells with multiple centrosomes. Centrosome migration, a typical prophase event, also takes place in endoreplicating cells. The timing of these events is unaffected by cdk1 inactivation compared with normally dividing cells. Nuclear lamina breakdown, in contrast, previously shown to be dependent on cdk1, does not take place in endoreplicating HT2-19 cells. Moreover, breakdown of all other major components of the nuclear lamina, like the inner nuclear membrane proteins and nuclear pore complexes, seems also to depend on cdk1. Interestingly, the APC/C ubiquitin ligase is activated in these endoreplicating cells by fzr but not by fzy. The oscillations of interphase events are thus independent of cdk1 and of mitosis but may depend on APC/Cfzr activity.

  18. Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2. (United States)

    Satyanarayana, Ande; Berthet, Cyril; Lopez-Molina, Javier; Coppola, Vincenzo; Tessarollo, Lino; Kaldis, Philipp


    It was believed that Cdk2-cyclin E complexes are essential to drive cells through the G1-S phase transition. However, it was discovered recently that the mitotic kinase Cdk1 (Cdc2a) compensates for the loss of Cdk2. In the present study, we tested whether Cdk2 can compensate for the loss of Cdk1. We generated a knockin mouse in which the Cdk2 cDNA was knocked into the Cdk1 locus (Cdk1Cdk2KI). Substitution of both copies of Cdk1 by Cdk2 led to early embryonic lethality, even though Cdk2 was expressed from the Cdk1 locus. In addition, we generated Cdk2-/- Cdk1+/Cdk2KI mice in which one copy of Cdk2 and one copy of Cdk1 were expressed from the Cdk1 locus and the Cdk2 gene was deleted from the endogenous Cdk2 locus. We found that both male and female Cdk2-/- Cdk1+/Cdk2KI mice were sterile, similar to Cdk2-/- mice, even though they expressed the Cdk2 protein from the Cdk1 locus in testes. The translocational and cell cycle properties of knockin Cdk2 in Cdk2-/- Cdk1+/Cdk2KI cells were comparable to those of endogenous Cdk2, but we detected premature transcriptional activation of Cdk1 during liver regeneration in the absence of Cdk2. This study provides evidence of the molecular differences between Cdk2 and Cdk1 and highlights that the timing of transcriptional activation and the genetic locus play important roles in determining the function of Cdk proteins in vivo.

  19. Metabolism and pharmacokinetics of 8-hydroxypiperidinylmethyl-baicalein (BA-j) as a novel selective CDK1 inhibitor in monkey. (United States)

    Guo, Hong-Min; Sun, Yu-Ming; Zhang, Shi-Xuan; Ju, Xiu-Lan; Xie, Ai-Yun; Li, Jing; Zou, Liang; Sun, Xiao-Dan; Li, Hai-Liang; Zheng, Yang


    Cyclin-dependent kinase 1 (CDK1) is the only necessary CDK in the cell proliferation process and a new target in the research and development of anti-cancer drugs. 8-Hydroxypiperidinemethyl-baicalein (BA-j) is a Mannich base derivative of baicalein (BA) isolated from Scutellaria baicalensis, as a novel selective CDK1 inhibitor. 12 metabolites of BA-j in the monkey urine were identified by LC-MS-MS and (1)H NMR. The major metabolic pathways of BA-j, by capturing oxygen free radicals ((.)O2(-)) and releasing peroxides (H2O2), are degraded into active intermediate metabolite dihydroflavonol, then into main metabolite M179 by Shiff reaction, second metabolite M264 by sulfation, trace amount of metabolite M559 by glucuronidation UGT1A9, and without metabolism by CYP3A4. The metabolic process of BA-j by regulating intracellular reactive oxygen species (ROS) was related with BA-j selectively inducing apoptosis in cancer cells. Pharmacokinetics of 10mg/kg oral BA-j in monkey by HPLC-UV was best fitted to a two-compartment open model, with t1/2(β) of 4.2h, Cmax 25.4μM at 2h, and Vd 12.6L, meaning the drug distributing widely in body fluids with no special selectivity to certain tissues, and being able to permeate through the blood-brain barrier. The protein binding rate of BA-j was 91.8%. BA-j has excellent druggability for oral administration or injection, and it may be developed into a novel anti-cancer drug as a selective CDK1 inhibitor.

  20. Mitotic-dependent phosphorylation of leukemia-associated RhoGEF (LARG) by Cdk1. (United States)

    Helms, Michelle C; Grabocka, Elda; Martz, Matthew K; Fischer, Christopher C; Suzuki, Nobuchika; Wedegaertner, Philip B


    Rho GTPases are integral to the regulation of actin cytoskeleton-dependent processes, including mitosis. Rho and leukemia-associated Rho guanine-nucleotide exchange factor (LARG), also known as ARHGEF12, are involved in mitosis as well as diseases such as cancer and heart disease. Since LARG has a role in mitosis and diverse signaling functions beyond mitosis, it is important to understand the regulation of the protein through modifications such as phosphorylation. Here we report that LARG undergoes a mitotic-dependent and cyclin-dependent kinase 1 (Cdk1) inhibitor-sensitive phosphorylation. Additionally, LARG is phosphorylated at the onset of mitosis and dephosphorylated as cells exit mitosis, concomitant with Cdk1 activity. Furthermore, using an in vitro kinase assay, we show that LARG can be directly phosphorylated by Cdk1. Through expression of phosphonull mutants that contain non-phosphorylatable alanine mutations at potential Cdk1 S/TP sites, we demonstrate that LARG phosphorylation occurs in both termini. Using phosphospecific antibodies, we confirm that two sites, serine 190 and serine 1176, are phosphorylated during mitosis in a Cdk1-dependent manner. In addition, these phosphospecific antibodies show phosphorylated LARG at specific mitotic locations, namely the mitotic organizing centers and flanking the midbody. Lastly, RhoA activity assays reveal that phosphonull LARG is more active in cells than phosphomimetic LARG. Our data thus identifies LARG as a phosphoregulated RhoGEF during mitosis.

  1. Cloning and Prokaryotic Expression of NcSRS2 Gene of Neospora caninum%犬新孢子虫NcSRS2基因片段的克隆及原核表达

    Institute of Scientific and Technical Information of China (English)

    丁德; 贾立军; 其木格; 薛书江; 张守发


    以含有犬新孢子虫NcSRS2基因的质粒pMD18-NcSRS2为模板,应用PCR方法扩增NcSRS2基因,将该基因片段克隆至原核表达栽体pGEX-4T-2,构建了重组表达质粒pGEX-NcSRS2,转化大肠杆菌BL21中并诱导表达.结果显示,克隆的基因片段长1100bp,SDS-PAGE、Western blotting分析显示,重组质粒pGEX-NcSRS2在大肠杆菌中得到了高效表达.

  2. Genetic labelling and application of the isoproturon-mineralizing Sphingomonas sp. strain SRS2 in soil and rhizosphere

    DEFF Research Database (Denmark)

    Kristensen, K.E.; Jacobsen, C.S.; Hansen, L.H.;


    AIMS: To construct a luxAB-labelled Sphingomonas sp. strain SRS2 maintaining the ability to mineralize the herbicide isoproturon and usable for monitoring the survival and distribution of strain SRS2 on plant roots in laboratory systems. METHODS AND RESULTS: We inserted the mini-Tn5-luxAB marker ...

  3. Cdk1 phosphorylation of the kinetochore protein Nsk1 prevents error-prone chromosome segregation. (United States)

    Chen, Jun-Song; Lu, Lucy X; Ohi, Melanie D; Creamer, Kevin M; English, Chauca; Partridge, Janet F; Ohi, Ryoma; Gould, Kathleen L


    Cdk1 controls many aspects of mitotic chromosome behavior and spindle microtubule (MT) dynamics to ensure accurate chromosome segregation. In this paper, we characterize a new kinetochore substrate of fission yeast Cdk1, Nsk1, which promotes proper kinetochore-MT (k-MT) interactions and chromosome movements in a phosphoregulated manner. Cdk1 phosphorylation of Nsk1 antagonizes Nsk1 kinetochore and spindle localization during early mitosis. A nonphosphorylatable Nsk1 mutant binds prematurely to kinetochores and spindle, cementing improper k-MT attachments and leading to high rates of lagging chromosomes that missegregate. Accordingly, cells lacking nsk1 exhibit synthetic growth defects with mutations that disturb MT dynamics and/or kinetochore structure, and lack of proper phosphoregulation leads to even more severe defects. Intriguingly, Nsk1 is stabilized by binding directly to the dynein light chain Dlc1 independently of the dynein motor, and Nsk1-Dlc1 forms chainlike structures in vitro. Our findings establish new roles for Cdk1 and the Nsk1-Dlc1 complex in regulating the k-MT interface and chromosome segregation.

  4. Phosphorylation by Cdk1 induces Plk1-mediated vimentin phosphorylation during mitosis

    NARCIS (Netherlands)

    Yamaguchi, Tomoya; Goto, Hidemasa; Yokoyama, Tomoya; Silljé, Herman; Hanisch, Anja; Uldschmid, Andreas; Takai, Yasushi; Oguri, Takashi; Nigg, Erich A; Inagaki, Masaki


    Several kinases phosphorylate vimentin, the most common intermediate filament protein, in mitosis. Aurora-B and Rho-kinase regulate vimentin filament separation through the cleavage furrow-specific vimentin phosphorylation. Cdk1 also phosphorylates vimentin from prometaphase to metaphase, but its si

  5. Cdc25 Phosphatases Are Required for Timely Assembly of CDK1-Cyclin B at the G2/M Transition* (United States)

    Timofeev, Oleg; Cizmecioglu, Onur; Settele, Florian; Kempf, Tore; Hoffmann, Ingrid


    Progression through mitosis requires the coordinated regulation of Cdk1 kinase activity. Activation of Cdk1 is a multistep process comprising binding of Cdk1 to cyclin B, relocation of cyclin-kinase complexes to the nucleus, activating phosphorylation of Cdk1 on Thr161 by the Cdk-activating kinase (CAK; Cdk7 in metazoans), and removal of inhibitory Thr14 and Tyr15 phosphorylations. This dephosphorylation is catalyzed by the dual specific Cdc25 phosphatases, which occur in three isoforms in mammalian cells, Cdc25A, -B, and -C. We find that expression of Cdc25A leads to an accelerated G2/M phase transition. In Cdc25A-overexpressing cells, Cdk1 exhibits high kinase activity despite being phosphorylated on Tyr15. In addition, Tyr15-phosphorylated Cdk1 binds more cyclin B in Cdc25A-overexpressing cells compared with control cells. Consistent with this observation, we demonstrate that in human transformed cells, Cdc25A and Cdc25B, but not Cdc25C phosphatases have an effect on timing and efficiency of cyclin-kinase complex formation. Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short hairpin RNA has a reverse effect, leading to a substantial decrease in amounts of cyclin B-bound Cdk1 in G2 and mitosis. Importantly, we find that Cdc25A overexpression leads to an activation of Cdk7 and increase in Thr161 phosphorylation of Cdk1. In conclusion, our data suggest that complex assembly and dephosphorylation of Cdk1 at G2/M is tightly coupled and regulated by Cdc25 phosphatases. PMID:20360007

  6. Cdk1/cyclin B-mediated phosphorylation stabilizes SREBP1 during mitosis. (United States)

    Bengoechea-Alonso, Maria T; Ericsson, Johan


    Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors control the biosynthesis of cholesterol and other lipids, and lipid synthesis is critical for cell growth and proliferation. We recently found that the mature forms of SREBP1a and SREBP1c are hyperphosphorylated in mitotic cells, giving rise to a phosphoepitope recognized by the mitotic protein monoclonal-2 (MPM-2) antibody. In addition, we found that mature SREBP1 was stabilized in a phosphorylation-dependent manner during mitosis. We have now mapped the major MPM-2 epitope to a serine residue, S439, in the C terminus of mature SREBP1. Using phosphorylation-specific antibodies, we demonstrate that endogenous SREBP1 is phosphorylated on S439 specifically during mitosis. Mature SREBP1 interacts with the Cdk1/cyclin B complex in mitotic cells and we demonstrate that Cdk1 phosphorylates S439, both in vitro and in vivo. Our results suggest that Cdk1-mediated phosphorylation of S439 stabilizes mature SREBP1 during mitosis, thereby preserving a critical pool of active transcription factors to support lipid synthesis. Taken together with our previous work, the current study suggests that SREBP1 may provide a link between lipid synthesis, proliferation and cell growth. This hypothesis was supported by our observation that siRNA-mediated inactivation of SREBP1 arrested cells in the G(1) phase of the cell cycle, thereby attenuating cell growth.

  7. Brain-derived neurotrophic factor-dependent cdk1 inhibition prevents G2/M progression in differentiating tetraploid neurons. (United States)

    Ovejero-Benito, María C; Frade, José M


    Neurodegeneration is often associated with DNA synthesis in neurons, the latter usually remaining for a long time as tetraploid cells before dying by apoptosis. The molecular mechanism preventing G2/M transition in these neurons remains unknown, but it may be reminiscent of the mechanism that maintains tetraploid retinal ganglion cells (RGCs) in a G2-like state during normal development, thus preventing their death. Here we show that this latter process, known to depend on brain-derived neurotrophic factor (BDNF), requires the inhibition of cdk1 by TrkB. We demonstrate that a subpopulation of chick RGCs previously shown to become tetraploid co-expresses TrkB and cdk1 in vivo. By using an in vitro system that recapitulates differentiation and cell cycle re-entry of chick retinal neurons we show that BDNF, employed at concentrations specific for the TrkB receptor, reduces the expression of cdk1 in TrkB-positive, differentiating neurons. In this system, BDNF also inhibits the activity of both endogenous cdk1 and exogenously-expressed cdk1/cyclin B1 complex. This inhibition correlates with the phosphorylation of cdk1 at Tyr15, an effect that can be prevented with K252a, a tyrosine kinase inhibitor commonly used to prevent the activity of neurotrophins through their Trk receptors. The effect of BDNF on cdk1 activity is Tyr15-specific since BDNF cannot prevent the activity of a constitutively active form of cdk1 (Tyr15Phe) when expressed in differentiating retinal neurons. We also show that BDNF-dependent phosphorylation of cdk1 at Tyr15 could not be blocked with MK-1775, a Wee1-selective inhibitor, indicating that Tyr15 phosphorylation in cdk1 does not seem to occur through the canonical mechanism observed in proliferating cells. We conclude that the inhibition of both expression and activity of cdk1 through a BDNF-dependent mechanism contributes to the maintenance of tetraploid RGCs in a G2-like state.

  8. Exploratory Factor Analysis of SRS-2 Teacher Ratings for Youth with ASD. (United States)

    Nelson, Andrew T; Lopata, Christopher; Volker, Martin A; Thomeer, Marcus L; Toomey, Jennifer A; Dua, Elissa


    This study examined the factor structure and internal consistency of special education teaching staff ratings on the Social Responsiveness Scale-2 (SRS-2; Constantino and Gruber 2012), as well as the percentage of ratings falling above pre-established cut scores, for a sample of lower-functioning youth with autism spectrum disorder (ASD; n = 264). Results of the exploratory factor analysis yielded a four-factor correlated solution. The individual factors and total score demonstrated satisfactory internal consistency reliability for screening purposes. When applying the lowest pre-established cut score (T ≥ 60; minimum indication of clinically significant symptoms/impairments), 85 % of the sample had ratings in that range or higher (more severe). Implications for assessment and future research are provided.

  9. Subcloning and expression of the NcSRS2 gene fragment of Neospora caninum%新孢子虫NcSRS2基因的亚克隆和表达

    Institute of Scientific and Technical Information of China (English)

    余劲术; 刘群; 汪明


    本研究根据NcSRS2基因序列设计合成一对引物,将上、下游引物分别引入EcoRI,XhoI酶切位点,用PCR技术从pGEX-NcSRS2重组质粒扩增截去N端疏水氨基酸序列NcSRS2的基因片段(以下称dNcSRS2),插入到pGEX-6p-1质粒的多克隆位点,转化大肠杆菌BL21感受态细胞,于氨苄阳性LB培养平板上筛选阳性克隆,酶切及PCR鉴定;经IPTG诱导在E.coli中表达,用SDS-PAGE和免疫印迹分析表达产物并纯化.结果表明,新孢子虫dNcSRS2基因体外扩增产物与预期值相符,约1041bp;所构建pGEX-dNcSRS2重组质粒经双酶切与PCR鉴定,与预期结果一致;SDS-PAGE和免疫印迹显示,表达融合蛋白的分子量约为62.6 kD,表达效率为32.3%,该蛋白具有特异的免疫反应性,为新孢子虫病诊断试剂盒的研制和疫苗的研制奠定了基础.

  10. Dual control by Cdk1 phosphorylation of the budding yeast APC/C ubiquitin ligase activator Cdh1. (United States)

    Höckner, Sebastian; Neumann-Arnold, Lea; Seufert, Wolfgang


    The antagonism between cyclin-dependent kinases (Cdks) and the ubiquitin ligase APC/C-Cdh1 is central to eukaryotic cell cycle control. APC/C-Cdh1 targets cyclin B and other regulatory proteins for degradation, whereas Cdks disable APC/C-Cdh1 through phosphorylation of the Cdh1 activator protein at multiple sites. Budding yeast Cdh1 carries nine Cdk phosphorylation sites in its N-terminal regulatory domain, most or all of which contribute to inhibition. However, the precise role of individual sites has remained unclear. Here, we report that the Cdk phosphorylation sites of yeast Cdh1 are organized into autonomous subgroups and act through separate mechanisms. Cdk sites 1-3 had no direct effect on the APC/C binding of Cdh1 but inactivated a bipartite nuclear localization sequence (NLS) and thereby controlled the partitioning of Cdh1 between cytoplasm and nucleus. In contrast, Cdk sites 4-9 did not influence the cell cycle-regulated localization of Cdh1 but prevented its binding to the APC/C. Cdk sites 4-9 reside near two recently identified APC/C interaction motifs in a pattern conserved with the human Cdh1 orthologue. Thus a Cdk-inhibited NLS goes along with Cdk-inhibited APC/C binding sites in yeast Cdh1 to relay the negative control by Cdk1 phosphorylation of the ubiquitin ligase APC/C-Cdh1.

  11. Construction of Prokaryotic Expression Plasmid of NcSRS2 Gene of Neospora caninum%犬新孢子虫NcSRS2基因原核表达质粒的构建

    Institute of Scientific and Technical Information of China (English)

    丁德; 梁晚枫; 田野; 田万年; 贾立军; 张守发


    根据已发表的犬新孢子虫NcSRS2基因序列,设计1对含有EcoRⅠ和NotⅠ酶切位点的引物.以提取犬新孢子虫虫体基因组DNA为模板,应用PCR扩增获得NcSRS2 ORF基因片段,将此基因片段克隆到pMD18-T Simple载体上,用EcoRⅠ和NotⅠ双酶切该片段,回收得到含有两个酶切位点黏端的NcSRS2 ORF基因,将此基因片段克隆至相同酶切回收后的PGEM-4T-2原核表达载体中,获得重组质粒pGEX-NcSRS2,经PCR鉴定,限制性内切酶分析和克隆片段序列测定比较,证实了重组质粒的正确性.

  12. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation. (United States)

    Velásquez, Celestino; Cheng, Erdong; Shuda, Masahiro; Lee-Oesterreich, Paula J; Pogge von Strandmann, Lisa; Gritsenko, Marina A; Jacobs, Jon M; Moore, Patrick S; Chang, Yuan


    Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonical sites (T37, T46, S65, and T70) and the noncanonical S83 site, resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. Although S83 phosphorylation of 4E-BP1 does not affect general cap-dependent translation, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus small T antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

  13. 牛新孢子虫NcSRS2基因腺病毒穿梭载体的构建及在293细胞中的表达%Construction of bovine Neospora caninum NcSRS2 adenovirus shuttle vector and expression of NcSRS2 gene in 293 cells

    Institute of Scientific and Technical Information of China (English)

    贾立军; 张守发; 刘明明


    应用PCR技术扩增牛新孢子虫NcSRS2基因,纯化PCR产物后与克隆载体pMD18-T Simple Vector连接,将PCR、酶切鉴定及测序分析正确的pMD-18T-NcSRS2重组质粒进行EcoRⅠ和XbaⅠ双酶切,克隆至相同酶切回收后的腺病毒穿梭载体pCR259中,再将PCR、酶切鉴定正确的pCR259-NcSRS2重组质粒转染293细胞,应用IF-AT和Western-blotting技术检测重组质粒在293细胞中的表达情况。结果显示,扩增的牛新孢子虫NcSRS2基因长度为1 227bp,与GenBank中发表的NcSRS2(AF061249)核苷酸序列同源性为99%,构建的pCR259-NcSRS2重组质粒在293细胞中得到瞬时表达,表达蛋白的相对分子质量为43 000,具有较好的反应原性。本试验为新孢子虫病腺病毒载体疫苗的构建奠定了基础。%In this research,bovine Neospora caninum NcSRS2 gene was amplified by PCR.The purified PCR products were ligated with pMD18-T simple vector.After enzyme digestion and sequence analysis,the correct pMD-18T-NcSRS2 gene was digested by EcoRⅠand XbaⅠ,and cloned into the adenovirus shuttle vector pCR259 which was digested by the same enzymes.The correct pCR259-NcSRS2 recombinant plasmid was transfected into 293 cells.The expression of recombinant plasmid in 293 cells was detected by IFAT and Western-blotting.The result shows that the length of bovine Neospora caninum NcSRS2 gene is 1 227 bp.which has 99% homology with sequence and sequence in GenBank.The pCR259-NcSRS2 recombinant plasmid could transiently express in 293 cells.The molecular weight of the expressed protein which has good reactionogenicity is 43 000.This research laid the foundation for the construction of Neospora caninum vector-adenovirus vaccine

  14. Phosphorylation of the centrosomal protein, Cep169, by Cdk1 promotes its dissociation from centrosomes in mitosis. (United States)

    Mori, Yusuke; Inoue, Yoko; Taniyama, Yuki; Tanaka, Sayori; Terada, Yasuhiko


    Cep169 is a centrosomal protein conserved among vertebrates. In our previous reports, we showed that mammalian Cep169 interacts and collaborates with CDK5RAP2 to regulate microtubule (MT) dynamics and stabilization. Although Cep169 is required for MT regulation, its precise cellular function remains largely elusive. Here we show that Cep169 associates with centrosomes during interphase, but dissociates from these structures from the onset of mitosis, although CDK5RAP2 (Cep215) is continuously located at the centrosomes throughout cell cycle. Interestingly, treatment with purvalanol A, a Cdk1 inhibitor, nearly completely blocked the dissociation of Cep169 from centrosomes during mitosis. In addition, mass spectrometry analyses identified 7 phosphorylated residues of Cep169 corresponding to consensus phosphorylation sequence for Cdk1. These data suggest that the dissociation of Cep169 from centrosomes is controlled by Cdk1/Cyclin B during mitosis, and that Cep169 might regulate MT dynamics of mitotic spindle.

  15. Construction of an Eukaryotic Expression Plasmid for NcSRS2 Gene of Neospora caninum%犬新孢子虫NcSRS2基因真核表达质粒的构建

    Institute of Scientific and Technical Information of China (English)

    赵占中; 刘群; 汪明


    根据犬新孢子虫NcSRS2基因序列,设计了1对含有Kozak序列、PstⅠ和XbaⅠ酶切位点的引物,以含有NcSRS2基因的质粒P43为模板,经PCR扩增获得NcSRS2 ORF基因片段,用PstⅠ和XbaⅠ双酶切该片段,回收得到含有以上2个酶切位点黏端的NcSR2 ORF基因,将此基因片段克隆至相同酶切回收后的pcDNA3.1(+)真核表达载体中,获得重组质粒pcNCSRS2.经PCR鉴定、限制性内切酶分析和克隆片段序列测定、比较,证实了重组质粒的正确性.

  16. Human Cdc14B promotes progression through mitosis by dephosphorylating Cdc25 and regulating Cdk1/cyclin B activity.

    Directory of Open Access Journals (Sweden)

    Indra Tumurbaatar

    Full Text Available Entry into and progression through mitosis depends on phosphorylation and dephosphorylation of key substrates. In yeast, the nucleolar phosphatase Cdc14 is pivotal for exit from mitosis counteracting Cdk1-dependent phosphorylations. Whether hCdc14B, the human homolog of yeast Cdc14, plays a similar function in mitosis is not yet known. Here we show that hCdc14B serves a critical role in regulating progression through mitosis, which is distinct from hCdc14A. Unscheduled overexpression of hCdc14B delays activation of two master regulators of mitosis, Cdc25 and Cdk1, and slows down entry into mitosis. Depletion of hCdc14B by RNAi prevents timely inactivation of Cdk1/cyclin B and dephosphorylation of Cdc25, leading to severe mitotic defects, such as delay of metaphase/anaphase transition, lagging chromosomes, multipolar spindles and binucleation. The results demonstrate that hCdc14B-dependent modulation of Cdc25 phosphatase and Cdk1/cyclin B activity is tightly linked to correct chromosome segregation and bipolar spindle formation, processes that are required for proper progression through mitosis and maintenance of genomic stability.

  17. Cdk1, but not Cdk2, is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. (United States)

    Adhikari, Deepak; Zheng, Wenjing; Shen, Yan; Gorre, Nagaraju; Ning, Yao; Halet, Guillaume; Kaldis, Philipp; Liu, Kui


    Mammalian oocytes are arrested at the prophase of meiosis I during fetal or postnatal development, and the meiosis is resumed by the preovulatory surge of luteinizing hormone. The in vivo functional roles of cyclin-dependent kinases (Cdks) during the resumption of meiosis in mammalian oocytes are largely unknown. Previous studies have shown that deletions of Cdk3, Cdk4 or Cdk6 in mice result in viable animals with normal oocyte maturation, indicating that these Cdks are not essential for the meiotic maturation of oocytes. In addition, conventional knockout of Cdk1 and Cdk2 leads to embryonic lethality and postnatal follicular depletion, respectively, making it impossible to study the functions of Cdk1 and Cdk2 in oocyte meiosis. In this study, we generated conditional knockout mice with oocyte-specific deletions of Cdk1 and Cdk2. We showed that the lack of Cdk1, but not of Cdk2, leads to female infertility due to a failure of the resumption of meiosis in the oocyte. Re-introduction of Cdk1 mRNA into Cdk1-null oocytes largely resumed meiosis. Thus, Cdk1 is the sole Cdk that is essential and sufficient to drive resumption of meiosis in mouse oocytes. We also found that Cdk1 maintains the phosphorylation status of protein phosphatase 1 and lamin A/C in oocytes in order for meiosis resumption to occur.

  18. Desmin phosphorylation by Cdk1 is required for efficient separation of desmin intermediate filaments in mitosis and detected in murine embryonic/newborn muscle and human rhabdomyosarcoma tissues. (United States)

    Makihara, Hiroyuki; Inaba, Hironori; Enomoto, Atsushi; Tanaka, Hiroki; Tomono, Yasuko; Ushida, Kaori; Goto, Mitsuo; Kurita, Kenichi; Nishida, Yoshihiro; Kasahara, Kousuke; Goto, Hidemasa; Inagaki, Masaki


    Desmin is a type III intermediate filament (IF) component protein expressed specifically in muscular cells. Desmin is phosphorylated by Aurora-B and Rho-kinase specifically at the cleavage furrow from anaphase to telophase. The disturbance of this phosphorylation results in the formation of unusual long bridge-like IF structures (IF-bridge) between two post-mitotic (daughter) cells. Here, we report that desmin also serves as an excellent substrate for the other type of mitotic kinase, Cdk1. Desmin phosphorylation by Cdk1 loses its ability to form IFs in vitro. We have identified Ser6, Ser27, and Ser31 on murine desmin as phosphorylation sites for Cdk1. Using a site- and phosphorylation-state-specific antibody for Ser31 on desmin, we have demonstrated that Cdk1 phosphorylates desmin in entire cytoplasm from prometaphase to metaphase. Desmin mutations at Cdk1 sites exhibit IF-bridge phenotype, the frequency of which is significantly increased by the addition of Aurora-B and Rho-kinase site mutations to Cdk1 site mutations. In addition, Cdk1-induced desmin phosphorylation is detected in mitotic muscular cells of murine embryonic/newborn muscles and human rhabdomyosarcoma specimens. Therefore, Cdk1-induced desmin phosphorylation is required for efficient separation of desmin-IFs and generally detected in muscular mitotic cells in vivo.

  19. Tracking Neospora caninum parasites using chimera monoclonal antibodies against its surface antigen-related sequences (rNcSRS2). (United States)

    Dong, Jinhua; Otsuki, Takahiro; Kato, Tatsuya; Park, Enoch Y


    Neosporosis, an infectious disease of cattle and dogs, causes an abortion in cattle, which has a major damage on the dairy industry worldwide. Tracking of Neospora caninum parasite that is responsible for neosporosis is required for the prevention of this infectious disease. We developed three chimera monoclonal antibodies consist of variable regions of murine antibody and constant regions of human antibody against N. caninum. Recombinant surface antigen-related sequence 2 (rNcSRS2) of N. caninum was expressed in silkworm larvae, and immunized in mice to obtain phage displaying antibody library. Through three rounds of selection, three antibodies, A6, E1 and H3, were isolated and bound to rNcSRS2 with nanomolar to micromolar affinity. In immunofluorescent staining assays, A6 and E1 bound to N. caninum strain Nc-Liv, demonstrating a successful tracking of the parasite. H3 clone bound to rNcSRS2 but not to a truncated protein without glycosylphosphatidylinositol (GPI) anchor domain in the carboxyl terminal. Amino acid sequences of A6 and E1 were similar, but that of H3 differed in the CDR-H1 region, which might be the reason of their difference of affinity. These antibodies are thought to be useful for prevention of cattle from neosporosis.

  20. Mastl is required for timely activation of APC/C in meiosis I and Cdk1 reactivation in meiosis II. (United States)

    Adhikari, Deepak; Diril, M Kasim; Busayavalasa, Kiran; Risal, Sanjiv; Nakagawa, Shoma; Lindkvist, Rebecca; Shen, Yan; Coppola, Vincenzo; Tessarollo, Lino; Kudo, Nobuaki R; Kaldis, Philipp; Liu, Kui


    In mitosis, the Greatwall kinase (called microtubule-associated serine/threonine kinase like [Mastl] in mammals) is essential for prometaphase entry or progression by suppressing protein phosphatase 2A (PP2A) activity. PP2A suppression in turn leads to high levels of Cdk1 substrate phosphorylation. We have used a mouse model with an oocyte-specific deletion of Mastl to show that Mastl-null oocytes resume meiosis I and reach metaphase I normally but that the onset and completion of anaphase I are delayed. Moreover, after the completion of meiosis I, Mastl-null oocytes failed to enter meiosis II (MII) because they reassembled a nuclear structure containing decondensed chromatin. Our results show that Mastl is required for the timely activation of anaphase-promoting complex/cyclosome to allow meiosis I exit and for the rapid rise of Cdk1 activity that is needed for the entry into MII in mouse oocytes.

  1. Cdk1 Phosphorylates Drosophila Sas-4 to Recruit Polo to Daughter Centrioles and Convert Them to Centrosomes. (United States)

    Novak, Zsofia A; Wainman, Alan; Gartenmann, Lisa; Raff, Jordan W


    Centrosomes and cilia are organized by a centriole pair comprising an older mother and a younger daughter. Centriole numbers are tightly regulated, and daughter centrioles (which assemble in S phase) cannot themselves duplicate or organize centrosomes until they have passed through mitosis. It is unclear how this mitotic "centriole conversion" is regulated, but it requires Plk1/Polo kinase. Here we show that in flies, Cdk1 phosphorylates the conserved centriole protein Sas-4 during mitosis. This creates a Polo-docking site that helps recruit Polo to daughter centrioles and is required for the subsequent recruitment of Asterless (Asl), a protein essential for centriole duplication and mitotic centrosome assembly. Point mutations in Sas-4 that prevent Cdk1 phosphorylation or Polo docking do not block centriole disengagement during mitosis, but block efficient centriole conversion and lead to embryonic lethality. These observations can explain why daughter centrioles have to pass through mitosis before they can duplicate and organize a centrosome.

  2. Phosphorylation of SAMHD1 by Cyclin A2/CDK1 Regulates Its Restriction Activity toward HIV-1

    Directory of Open Access Journals (Sweden)

    Alexandra Cribier


    Full Text Available SAMHD1 restricts HIV-1 replication in myeloid and quiescent CD4+ T cells. Here, we show that SAMHD1 restriction activity is regulated by phosphorylation. SAMHD1 interacts with cyclin A2/cdk1 only in cycling cells. Cyclin A2/CDK1 phosphorylates SAMHD1 at the Threonine 592 residue both in vitro and in vivo. Phosphorylation of SAMHD1 Thr592 correlates with loss of its ability to restrict HIV-1. Indeed, while PMA treatment of proliferating THP1 cells results in reduced Thr592 phosphorylation, activation of resting peripheral blood mononuclear cells (PBMCs and purified quiescent CD4+ T cells results in increased phosphorylation of SAMHD1 Thr592. Interestingly, we found that treatment of cells by type 1 interferon reduced Thr592 phosphorylation, reinforcing the link between the phosphorylation of SAMHD1 and its antiviral activity. Unlike wild-type SAMHD1, a phosphorylation-defective mutant was able to restrict HIV-1 replication in both PMA-treated and untreated cells. Our results uncover the phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviral activity.

  3. Survivin基因及CDK1基因联合靶向shRNA真核表达载体的构建%Constructing recombinant survivin and CDK1 tandem shRNAs pU6-M4 plasmid

    Institute of Scientific and Technical Information of China (English)

    陈淑萍; 符生苗; 周红桃; 蔡俊宏; 李成学; 王福利; 许茂轩


    目的:构建靶向Survivin基因及CDK1基因的短发夹样RNA (Short hairpin RNA,shRNA)真核表达载体。方法根据Genbank报道的Survivin序列及CDK1序列,遵循shRNA设计原则设计并合成各自靶向的Survivin、CDK1基因的shRNA寡核苷酸序列,构建pU6-shRNA-Survivin重组质粒、pU6-shRNA-CDK1重组质粒及pU6-shRNA-Survivin-U6-shRNA-CDK1双基因序列串联重组质粒,并进行限制性内切酶酶切及基因测序鉴定。结果经酶切及测序结果分析,pU6-shRNA-Survivin重组质粒、pU6-shRNA-CDK1重组质粒及pU6-shR-NA-Survivin-U6-shRNA-CDK1双基因系列串联重组质粒均成功构建。结论成功构建Survivin基因及CDK1基因联合靶向shRNA重组质粒,为进一步研究Survivin基因和CDK1基因联合干扰提供了新的方法。%Objective To construct recombinant survivin and CDK1 tandem shRNAs pU6-M4 plasmids. Methods Sequences of survivin and CDK1 and the restriction enzyme cutting sites of them were designed and synthe-sized based on the date from GeneBank. Recombinant plasmids of pU6-M4-Survivin-shRNA and pU6-M4-CDK1-shR-NA were constructed and identified. Two determined plasmids were digested by restriction endonucleases then taped by T4 DNA ligase. The ligated products were transformed into competent TH5a cells, and then the recombinant clones were identified by sequencing. Results Restriction enzyme cleave identification and sequencing proved that recombi-nant survivin and CDK1 tandem shRNAs pU6-M4 plasmids were successfully constructed. Conclusion Recombi-nant survivin and CDK1 tandem shRNAs pU6-M4 plasmids were correctly constructed.

  4. 表达牛源犬新孢子虫NcSRS2基因重组腺病毒的构建及免疫原性分析%Construction of a Recombinant Adenovirus Expressing NcSRS2 Protein of Bovine Neospora Caninum and Immunogenicity Analysis of the Protein

    Institute of Scientific and Technical Information of China (English)

    贾立军; 于龙政; 张守发


    为构建牛源犬新孢子虫NcSRS2基因重组腺病毒,并分析其免疫原性,PCR扩增牛源犬新孢子虫NcSRS2基因,构建克隆质粒pMD18-T-NcSRS2、重组腺病毒穿梭质粒pCR259-NcSRS2及表达质粒Transpose-AdNcSRS2,脂质体介导转染QBI-HEK293细胞,包装重组腺病毒Ad5-NcSRS2,PCR检测重组腺病毒NcSRS2基因,IFAT和Western blotting检测NcSRS2基因在QBI-HEK293细胞中的表达,测定病毒滴度后,收集病毒液免疫BALB/c小鼠,间接ELISA检测小鼠血清IgG抗体水平.结果显示,扩增的牛源犬新孢子虫NcSRS2基因大小为1 227 bp,与GenBank中发表的NcSRS2( AF061249)核苷酸序列相似性为99%;重组腺病毒Ad5-NcSRS2在293细胞中包装成功,表达蛋白的相对分子质量为43 ku,具有较好的反应原性;测得重组腺病毒Ad5-NcSRS2滴度为109TCID50·mL-1,间接ELISA检测二免后3周BALB/c小鼠血清中IgG抗体效价达1 ∶ 2 048.本研究成功构建了具有良好免疫原性的重组腺病毒Ad5-NcSRS2,为牛源犬新孢子虫NcSRS2基因重组腺病毒载体疫苗的研制奠定了基础.%In order to construct a recombinant adenovirus expressing NcSRS2 protein of bovine Neospora Caninum, NcSRS2 gene of bovine Neospora Caninum was amplified by PCR, pMD18-T-NcSRS2, pCR259-NcSRS2 and Transpose-Ad-NcSRS2 were constructed in this research. Coated with liposome, Transpose-Ad-NcSRS2 was transfected into QBI-HEK293 cells to package recombinant adenovirus Ad5-NcSRS2. Recombinant adenovirus NcSRS2 gene was detected by PCR. The expression of NcSRS2 gene in QBI-HEK293 cells was detected by IFAT and Western blotting. After the virus titer was determined, the virus fluid was collected to inoculate BALB/c mice and IgG antibody levels in the sera were measured by indirect ELISA. The size of NcSRS2 gene was 1 227 bp. The nucleotide sequence of the gene shared 99% homology with that in GenBank (AF061249). Recombinant adenovirus Ad5-NcSRS2 was successfully packaged in 293 cells. The protein

  5. CDK-1 and two B-type cyclins promote PAR-6 stabilization during polarization of the early C. elegans embryo.

    Directory of Open Access Journals (Sweden)

    Alexia Rabilotta

    Full Text Available In the C. elegans embryo, formation of an antero-posterior axis of polarity relies on signaling by the conserved PAR proteins, which localize asymmetrically in two mutually exclusive groups at the embryonic cortex. Depletion of any PAR protein causes a loss of polarity and embryonic lethality. A genome-wide RNAi screen previously identified two B-type cyclins, cyb-2.1 and cyb-2.2, as suppressors of par-2(it5ts lethality. We found that the loss of cyb-2.1 or cyb-2.2 suppressed the lethality and polarity defects of par-2(it5ts mutants and that these cyclins act in cell polarity with their cyclin-dependent kinase partner, CDK-1. Interestingly, cyb-2.1; cyb-2.2 double mutants did not show defects in cell cycle progression or timing of polarity establishment, suggesting that they regulate polarity independently of their typical role in cell cycle progression. Loss of both cyclin genes or of cdk-1 resulted in a decrease in PAR-6 levels in the embryo. Furthermore, the activity of the cullin CUL-2 was required to achieve suppression of par-2 lethality when both cyclins were absent. Our results support a model in which CYB-2.1/2/CDK-1 antagonize CUL-2 activity to promote stabilization of PAR-6 levels during polarization of the early C. elegans embryo. They also suggest that CYB-2.1 and CYB-2.2 contribute to the coupling of cell cycle progression and asymmetric segregation of cell fate determinants.

  6. Cdk1, PKCδ and calcineurin-mediated Drp1 pathway contributes to mitochondrial fission-induced cardiomyocyte death

    Energy Technology Data Exchange (ETDEWEB)

    Zaja, Ivan [Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Bai, Xiaowen, E-mail: [Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Liu, Yanan; Kikuchi, Chika; Dosenovic, Svjetlana; Yan, Yasheng; Canfield, Scott G. [Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Bosnjak, Zeljko J. [Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States); Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226 (United States)


    Highlights: • Drp1-mediated increased mitochondrial fission but not fusion is involved the cardiomyocyte death during anoxia-reoxygenation injury. • Reactive oxygen species are upstream initiators of mitochondrial fission. • Increased mitochondrial fission is resulted from Cdk1-, PKCδ-, and calcineurin-mediated Drp1 pathways. - Abstract: Myocardial ischemia–reperfusion (I/R) injury is one of the leading causes of death and disability worldwide. Mitochondrial fission has been shown to be involved in cardiomyocyte death. However, molecular machinery involved in mitochondrial fission during I/R injury has not yet been completely understood. In this study we aimed to investigate molecular mechanisms of controlling activation of dynamin-related protein 1 (Drp1, a key protein in mitochondrial fission) during anoxia-reoxygenation (A/R) injury of HL1 cardiomyocytes. A/R injury induced cardiomyocyte death accompanied by the increases of mitochondrial fission, reactive oxygen species (ROS) production and activated Drp1 (pSer616 Drp1), and decrease of inactivated Drp1 (pSer637 Drp1) while mitochondrial fusion protein levels were not significantly changed. Blocking Drp1 activity with mitochondrial division inhibitor mdivi1 attenuated cell death, mitochondrial fission, and Drp1 activation after A/R. Trolox, a ROS scavenger, decreased pSer616 Drp1 level and mitochondrial fission after A/R. Immunoprecipitation assay further indicates that cyclin dependent kinase 1 (Cdk1) and protein kinase C isoform delta (PKCδ) bind Drp1, thus increasing mitochondrial fission. Inhibiting Cdk1 and PKCδ attenuated the increases in pSer616 Drp1, mitochondrial fission, and cardiomyocyte death. FK506, a calcineurin inhibitor, blocked the decrease in expression of inactivated pSer637 Drp1 and mitochondrial fission. Our findings reveal the following novel molecular mechanisms controlling mitochondrial fission during A/R injury of cardiomyocytes: (1) ROS are upstream initiators of

  7. Regulation of the Candida albicans Hypha-Inducing Transcription Factor Ume6 by the CDK1 Cyclins Cln3 and Hgc1 (United States)

    Mendelsohn, Sigal; Pinsky, Mariel; Weissman, Ziva


    ABSTRACT The ability to switch between proliferation as yeast cells and development into hyphae is a hallmark of Candida albicans. The switch to hyphal morphogenesis depends on external inducing conditions, but its efficiency is augmented in stationary-phase cells. Ume6, a transcription factor that is itself transcriptionally induced under hypha-promoting conditions, is both necessary and sufficient for hyphal morphogenesis. We found that Ume6 is regulated posttranslationally by the cell cycle kinase Cdc28/Cdk1, which reduces Ume6 activity via different mechanisms using different cyclins. Together with the cyclin Hgc1, Cdk1 promotes degradation of Ume6 via the SCFCDC4 ubiquitin ligase. Since HGC1 is a key transcriptional target of Ume6, this results in a negative-feedback loop between Hgc1 and Ume6. In addition, we found that Cln3, a G1 cyclin that is essential for cell cycle progression and yeast proliferation, suppresses hyphal morphogenesis and that Cln3 suppresses Ume6 activity both in the heterologous Saccharomyces cerevisiae system and in C. albicans itself. This activity of Cln3 may provide the basis for the antagonistic relationship between yeast proliferation and hyphal development in C. albicans. IMPORTANCE The yeast to hypha (mold) morphogenetic switch of Candida albicans plays a role in its virulence and constitutes a diagnostic trait for this organism, the most prevalent systemic fungal pathogen in industrialized countries. It has long been known that hyphae are most efficiently induced from stationary cultures. Here, a molecular basis for this observation is provided. The G1 cyclin Cln3, an essential promoter of yeast proliferation, was found to suppress hyphal induction. Suppression of hyphal induction is achieved by inhibition of the activity of the central activator of hyphal morphogenesis, the transcription factor Ume6. Thus, levels of Cln3 control the switch between proliferation of C. albicans as individual yeast cells and development into

  8. Pro-recombination role of Srs2 protein requires SUMO (small ubiquitin-like modifier) but is independent of PCNA (proliferating cell nuclear antigen) interaction

    DEFF Research Database (Denmark)

    Kolesar, Peter; Altmannova, Veronika; Pinela da Silva, Sonia Cristina;


    -interacting motif (SIM) of Srs2 is important for the interaction with several recombination factors. Lack of SIM, but not proliferating cell nuclear antigen (PCNA)-interacting motif (PIM), leads to increased cell death under circumstances requiring homologous recombination for DNA repair. Simultaneous mutation...

  9. Test Review: Constantino, J. N., & Gruber, C. P. (2012). "Social Responsiveness Scale-Second Edition" ("SRS-2"). Torrance, CA: Western Psychological Services (United States)

    Bruni, Teryn P.


    This article reviews the Social Responsiveness Scale-Second Edition (SRS-2), a 65-item rating scale measuring deficits in social behavior associated with Autism Spectrum Disorder (ASD), as outlined by the "Diagnostic and Statistical Manual of Mental Disorders" (4th ed., text rev.; "DSM-IV-TR"; American Psychiatric Association,…

  10. Generation and immunity testing of a recombinant adenovirus expressing NcSRS2-NcGRA7 fusion protein of bovine Neospora caninum. (United States)

    Jia, Li-Jun; Zhang, Shou-Fa; Qian, Nian-Chao; Xuan, Xue-Nan; Yu, Long-Zheng; Zhang, Xue-Mei; Liu, Ming-Ming


    Neospora caninum is the etiologic agent of bovine neosporosis, which affects the reproductive performance of cattle worldwide. The transmembrane protein, NcSRS2, and dense-granule protein, NcGRA7, were identified as protective antigens based on their ability to induce significant protective immune responses in murine neosporosis models. In the current study, NcSRS2 and NcGRA7 genes were spliced by overlap-extension PCR in a recombinant adenovirus termed Ad5-NcSRS2-NcGRA 7, expressing the NcSRS2-NcGRA7 gene, and the efficacy was evaluated in mice. The results showed that the titer of the recombinant adenovirus was 10(9)TCID50/ml. Three weeks post-boost immunization (w.p.b.i.), the IgG antibody titer in sera was as high as 1:4,096. IFN-γ and IL-4 levels were significantly different from the control group (P<0.01). This research established a solid foundation for the development of a recombinant adenovirus vaccine against bovine N. caninum.

  11. Hyperphosphorylation by cyclin B/CDK1 in mitosis resets CUX1 DNA binding clock at each cell cycle. (United States)

    Sansregret, Laurent; Gallo, David; Santaguida, Marianne; Leduy, Lam; Harada, Ryoko; Nepveu, Alain


    The p110 CUX1 homeodomain protein participates in the activation of DNA replication genes in part by increasing the affinity of E2F factors for the promoters of these genes. CUX1 expression is very weak in quiescent cells and increases during G(1). Biochemical activities associated with transcriptional activation by CUX1 are potentiated by post-translational modifications in late G(1), notably a proteolytic processing event that generates p110 CUX1. Constitutive expression of p110 CUX1, as observed in some transformed cells, leads to accelerated entry into the S phase. In this study, we investigated the post-translation regulation of CUX1 during mitosis and the early G(1) phases of proliferating cells. We observed a major electrophoretic mobility shift and a complete inhibition of DNA binding during mitosis. We show that cyclin B/CDK1 interacts with CUX1 and phosphorylates it at multiple sites. Serine to alanine replacement mutations at 10 SP dipeptide sites were required to restore DNA binding in mitosis. Passage into G(1) was associated with the degradation of some p110 CUX1 proteins, and the remaining proteins were gradually dephosphorylated. Indirect immunofluorescence and subfractionation assays using a phospho-specific antibody showed that most of the phosphorylated protein remained in the cytoplasm, whereas the dephosphorylated protein was preferentially located in the nucleus. Globally, our results indicate that the hyperphosphorylation of CUX1 by cyclin B/CDK1 inhibits its DNA binding activity in mitosis and interferes with its nuclear localization following cell division and formation of the nuclear membrane, whereas dephosphorylation and de novo synthesis contribute to gradually restore CUX1 expression and activity in G(1).

  12. 牛源犬新孢子虫NcSRS2-NcGRA7融合基因的克隆与生物信息学分析%Cloning and bioinformatics analysis of NcSRS2-NcGRA7 fusion gene of bovine Neospora caninum

    Institute of Scientific and Technical Information of China (English)

    贾立军; 张守发; 谷振甲


    为了解牛源犬新孢子虫NcSRS2-NcGRA7融合基因的生物学特性,本试验提取牛源犬新孢子虫基因组DNA,应用PCR技术扩增犬新孢子虫表面蛋白基因NcSRS2和致密颗粒蛋白基因NcGRA7,SOE-PCR技术拼接NcSRS2和NcGRA7基因,构建NcSRS2-NcGRA7融合基因重组克隆质粒,并进行PCR鉴定、双酶切鉴定及生物信息学分析.结果,NcSRS2基因扩增片段大小为1 061 bp,NcGRA7基因扩增片段大小为364 bp,NcSRS2-NcGRA7融合基因扩增片段大小为1 482 bp;获得重组克隆质粒pMD18-NcSRS2-NcGRA7经PCR鉴定、双酶切鉴定正确;测序分析表明,与Gen-Bank中已发表的美国株犬新孢子虫(AF061249、AF176649)核苷酸序列同源性为99%;经DNAman等软件分析,预测NcSRS2-NcGRA7融合蛋白抗原指数较高,融合蛋白二级结构以α-螺旋和β-折叠为主,三级结构中2种蛋白独立折叠,并借助Linker互相连接,功能互不影响.本试验为牛源犬新孢子虫NcSRS2-NcGRA7融合蛋白的免疫学研究奠定了基础.%In order to understand the biological characteristic of NcSRS2-NcGRA7 fusion gene of bovine Neospora Caninum,genomic DNA of N.caninum was extracted.The surface protein gene NcSRS2 and granule protein gene NcGRA7 were amplified by PCR,respectively.Nc-SRS2-NcGRA7 fusion gene was synthesized by SOE-PCR.The NcSRS2-NcGRA7 cloning vector was constructed and identified by PCR amplification,double digestion and bioinformatic analysis.The results showed that the sizes of NcSRS2,NcGRA7 and NcSRS2-NcGRA7 were 1061 bp,364 bp and 1482 bp,respectively.The cloning vector was demonstrated to be correct by PCR and double digestion.Sequencing analysis showed that the nucleotide sequences of NcSRS2 and NcGRA7 shared 99% homology with those published in GenBank (AF061249,AF176649).Prediction analysis by DNAman software indicated that the antigen index of NcSRS2-NcGRA7 was high.The main secondary structure of the fusion protein was mainly composed of α-helix and

  13. Evaluation and comparison of 3D-QSAR CoMSIA models for CDK1, CDK5, and GSK-3 inhibition by paullones

    DEFF Research Database (Denmark)

    Kunick, Conrad; Lauenroth, Kathrin; Wieking, Karen;


    With a view to the rational design of selective GSK-3beta inhibitors, 3D-QSAR CoMSIA models were developed for the inhibition of the three serine/threonine kinases CDK1/cyclin B, CDK5/p25, and GSK-3beta by compounds from the paullone inhibitor family. The models are based on the kinase inhibition...

  14. Pin1-mediated Sp1 phosphorylation by CDK1 increases Sp1 stability and decreases its DNA-binding activity during mitosis. (United States)

    Yang, Hang-Che; Chuang, Jian-Ying; Jeng, Wen-Yih; Liu, Chia-I; Wang, Andrew H-J; Lu, Pei-Jung; Chang, Wen-Chang; Hung, Jan-Jong


    We have shown that Sp1 phosphorylation at Thr739 decreases its DNA-binding activity. In this study, we found that phosphorylation of Sp1 at Thr739 alone is necessary, but not sufficient for the inhibition of its DNA-binding activity during mitosis. We demonstrated that Pin1 could be recruited to the Thr739(p)-Pro motif of Sp1 to modulate the interaction between phospho-Sp1 and CDK1, thereby facilitating CDK1-mediated phosphorylation of Sp1 at Ser720, Thr723 and Thr737 during mitosis. Loss of the C-terminal end of Sp1 (amino acids 741-785) significantly increased Sp1 phosphorylation, implying that the C-terminus inhibits CDK1-mediated Sp1 phosphorylation. Binding analysis of Sp1 peptides to Pin1 by isothermal titration calorimetry indicated that Pin1 interacts with Thr739(p)-Sp1 peptide but not with Thr739-Sp1 peptide. X-ray crystallography data showed that the Thr739(p)-Sp1 peptide occupies the active site of Pin1. Increased Sp1 phosphorylation by CDK1 during mitosis not only stabilized Sp1 levels by decreasing interaction with ubiquitin E3-ligase RNF4 but also caused Sp1 to move out of the chromosomes completely by decreasing its DNA-binding activity, thereby facilitating cell cycle progression. Thus, Pin1-mediated conformational changes in the C-terminal region of Sp1 are critical for increased CDK1-mediated Sp1 phosphorylation to facilitate cell cycle progression during mitosis.

  15. CDK1-mediated phosphorylation of the RIIalpha regulatory subunit of PKA works as a molecular switch that promotes dissociation of RIIalpha from centrosomes at mitosis. (United States)

    Carlson, C R; Witczak, O; Vossebein, L; Labbé, J C; Skålhegg, B S; Keryer, G; Herberg, F W; Collas, P; Taskén, K


    Protein kinase A regulatory subunit RIIalpha is tightly bound to centrosomal structures during interphase through interaction with the A-kinase anchoring protein AKAP450, but dissociates and redistributes from centrosomes at mitosis. The cyclin B-p34(cdc2) kinase (CDK1) has been shown to phosphorylate RIIalpha on T54 and this has been proposed to alter the subcellular localization of RIIalpha. We have made stable transfectants from an RIIalpha-deficient leukemia cell line (Reh) that expresses either wild-type or mutant RIIalpha (RIIalpha(T54E)). When expressed, RIIalpha detaches from centrosomes at mitosis and dissociates from its centrosomal location in purified nucleus-centrosome complexes by incubation with CDK1 in vitro. By contrast, centrosomal RIIalpha(T54E) is not redistributed at mitosis, remains mostly associated with centrosomes during all phases of the cell cycle and cannot be solubilized by CDK1 in vitro. Furthermore, RIIalpha is solubilized from particular cell fractions and changes affinity for AKAP450 in the presence of CDK1. D and V mutations of T54 also reduce affinity for the N-terminal RII-binding domain of AKAP450, whereas small neutral residues do not change affinity detected by surface plasmon resonance. In addition, only RIIalpha(T54E) interacts with AKAP450 in a RIPA-soluble extract from mitotic cells. Finally, microtubule repolymerization from mitotic centrosomes of the RIIalpha(T54E) transfectant is poorer and occurs at a lower frequency than that of RIIalpha transfectants. Our results suggest that T54 phosphorylation of RIIalpha by CDK1 might serve to regulate the centrosomal association of PKA during the cell cycle.

  16. The SRS2 suppressor of rad6 mutations of Saccharomyces cerevisiae acts by channeling DNA lesions into the RAD52 DNA repair pathway

    Energy Technology Data Exchange (ETDEWEB)

    Schiestl, R.H.; Prakash, S.; Prakash, L. (Univ. of Rochester School of Medicine, NY (USA))


    rad6 mutants of Saccharomyces cerevisiae are defective in the repair of damaged DNA, DNA damage induced mutagenesis, and sporulation. In order to identify genes that can substitute for RAD6 function, the authors have isolated genomic suppressors of the UV sensitivity of rad6 deletion (rad6{Delta}) mutations and show that they also suppress the {gamma}-ray sensitivity but not the UV mutagenesis or sporulation defects of rad6. The suppressors show semidominance for suppression of UV sensitivity and dominance for suppression of {gamma}-ray sensitivity. The six suppressor mutations they isolated are all alleles of the same locus and are also allelic to a previously described suppressor of the rad6-1 nonsense mutation, SRS2. They show that suppression of rad6{Delta} is dependent on the RAD52 recombinational repair pathway since suppression is not observed in the rad6{Delta} SRS2 strain containing an additional mutation in either the RAD51, RAD52, RAD54, RAD55 or RAD57 genes. Possible mechanisms by which SRS2 may channel unrepaired DNA lesions into the RAD52 DNA repair pathway are discussed.

  17. Cdk1 Phosphorylates SPAT-1/Bora to Promote Plk1 Activation in C. elegans and Human Cells

    Directory of Open Access Journals (Sweden)

    Yann Thomas


    Full Text Available The conserved Bora protein is a Plk1 activator, essential for checkpoint recovery after DNA damage in human cells. Here, we show that Bora interacts with Cyclin B and is phosphorylated by Cyclin B/Cdk1 at several sites. The first 225 amino acids of Bora, which contain two Cyclin binding sites and three conserved phosphorylated residues, are sufficient to promote Plk1 phosphorylation by Aurora A in vitro. Mutating the Cyclin binding sites or the three conserved phosphorylation sites abrogates the ability of the N terminus of Bora to promote Plk1 activation. In human cells, Bora-carrying mutations of the three conserved phosphorylation sites cannot sustain mitotic entry after DNA damage. In C. elegans embryos, mutation of the three conserved phosphorylation sites in SPAT-1, the Bora ortholog, results in a severe mitotic entry delay. Our results reveal a crucial and conserved role of phosphorylation of the N terminus of Bora for Plk1 activation and mitotic entry.

  18. ATF7 is stabilized during mitosis in a CDK1-dependent manner and contributes to cyclin D1 expression. (United States)

    Schaeffer, Etienne; Vigneron, Marc; Sibler, Annie-Paule; Oulad-Abdelghani, Mustapha; Chatton, Bruno; Donzeau, Mariel


    The transcription factor ATF7 undergoes multiple post-translational modifications, each of which has distinct effects upon ATF7 function. Here, we show that ATF7 phosphorylation on residue Thr112 exclusively occurs during mitosis, and that ATF7 is excluded from the condensed chromatin. Both processes are CDK1/cyclin B dependent. Using a transduced neutralizing monoclonal antibody directed against the Thr112 epitope in living cells, we could demonstrate that Thr112 phosphorylation protects endogenous ATF7 protein from degradation, while it has no effect on the displacement of ATF7 from the condensed chromatin. The crucial role of Thr112 phosphorylation in stabilizing ATF7 protein during mitosis was confirmed using phospho-mimetic and phospho-deficient mutants. Finally, silencing ATF7 by CRISPR/Cas9 technology leads to a decrease of cyclin D1 protein expression levels. We propose that mitotic stabilized ATF7 protein re-localizes onto chromatin at the end of telophase and contributes to induce the cyclin D1 gene expression.

  19. Jumping the nuclear envelop barrier: Improving polyplex-mediated gene transfection efficiency by a selective CDK1 inhibitor RO-3306. (United States)

    Zhou, Xuefei; Liu, Xiangrui; Zhao, Bingxiang; Liu, Xin; Zhu, Dingcheng; Qiu, Nasha; Zhou, Quan; Piao, Ying; Zhou, Zhuxian; Tang, Jianbin; Shen, Youqing


    Successful transfection of plasmid DNA (pDNA) requires intranuclear internalization of pDNA effectively and the nuclear envelope appears to be one of the critical intracellular barriers for polymer mediated pDNA delivery. Polyethylenimine (PEI), as the classic cationic polymer, compact the negatively charged pDNA tightly and make up stable polyplexes. The polyplexes are too large to enter the nuclear through nuclear pores and it is believed that the nuclear envelope breakdown in mitosis could facilitate the nuclear entry of polyplexes. To jump the nuclear envelope barrier, we used a selective and reversible CDK1 inhibitor RO-3306 to control the G2/M transition of the cell cycle and increased the proportion of mitotic cells which have disappeared nuclear envelope during transfection. Herein, we show that RO-3306 remarkably increases the transfection efficiency of PEI polyplexes through enhanced nuclear localization of PEI and pDNA. However, RO-3306 is less effective to the charge-reversal polymer poly[(2-acryloyl)ethyl(p-boronic acid benzyl)diethylammonium bromide] (B-PDEAEA) which responses to cellular stimuli and releases free pDNA in cytoplasm. Our findings not only offer new opportunities for improving non-viral based gene delivery but also provide theoretical support for the rational design of novel functional polymers for gene delivery. We also report current data showing that RO-3306 synergizes TRAIL gene induced apoptosis in cancer cells.

  20. Cloning and prokaryotic expression of the NcSRS2 gene from Xinjiang Nc-1 strain of Neospora caninum%犬新孢子虫新疆Nc-1株NcSRS2基因的克隆及原核表达

    Institute of Scientific and Technical Information of China (English)

    杨帆; 陈亮; 王莲芳; 巴音查汗


    根据GenBank中犬新孢子虫NcSRS2基因序列设计了1对引物,从新孢子虫病阳性牛血液中提取总DNA,经PCR扩增NcSRS2基因,将其插入原核表达质粒pGEX-4T-2中,重组质粒pGEX-4T-NcSRS2经测序确定后,转入表达菌株BL21,优化其表达条件,并探讨了GST-NcSRS2蛋白的生物活性.结果显示,在37℃条件下,经终浓度为0.5 mmol/L的IPTG诱导表达4 h后,获得融合蛋白.Western-blot分析表明该融合蛋白可与相应抗体发生特异性结合,rELISA检测与弓形虫和布鲁氏菌阳性血清无交叉反应.

  1. Comparison of indirect ELISA based on recombinant protein NcSRS2 and IFAT for detection of Neospora caninum antibodies in sheep Comparação entre ELISA baseado no antígeno recombinante NcSRS2 e RIFI para detecção de anticorpos de Neospora caninum em ovinos

    Directory of Open Access Journals (Sweden)

    Renato Andreotti


    Full Text Available Neospora caninum, an Apicomplexan parasite that can causes abortion, is responsible for considerable economic and reproductive losses in livestock. The purpose of the present study was to determine whether recombinant NcSRS2 is a suitable indirect ELISA antigen for determining specific immune response to N. caninum in sheep. A total of 441 serum samples were subjected to IFAT and rNcSRS2 based-ELISA, with both tests performing similarly. The sensitivity and specificity of indirect ELISA were 98.6 and 98.3%, respectively. The kappa index shows 0.98 concordance between the two tests, which is considered excellent. Seroprevalences of 30.8 and 32.0% were detected by IFAT and indirect ELISA, respectively, showing these tests did not differ significantly on this measure (p > 0.05. Serological analysis showed that HisG tag was detected by Western Blotting recognizing rNcSRS2 protein. The potential value of rNcSRS2-based ELISA as a highly specific and sensitive tool for serological diagnosis is also supported by the strong agreement found between IFAT and ELISA. The results support the potential use of recombinant protein NcSRS2 as an antigen in indirect ELISA in sheep.Neospora caninum é um parasito Apicomplexa que pode causar abortos e é reconhecido como agente importante responsável por perdas econômicas e reprodutivas. Este estudo avaliou a proteína recombinante NcSRS2 como antígeno para ELISA indireto na determinação de resposta imune para N. caninum em ovinos. 441 amostras de soro foram analisadas por IFAT e ELISA indireto com rNcSRS2 e ambos os testes revelaram comportamento similar. A sensibilidade e especificidade de ELISA indireto foram 98,6 e 98,3%, respectivamente. O índice kappa mostrou uma concordância entre os dois testes com valor de 0,98, que é considerado excelente. Prevalências de 30,8 e 32,0% detectadas por IFAT e ELISA indireto, respectivamente, mostraram que os testes não diferiram significativamente nesse aspecto (P

  2. Construction of a eukaryotic expression vector and its expression of NcSAG1-NcSRS2 fusion gene of Neospora caninum%新孢子虫SAG1-SRS2融合基因真核表达质粒的构建及表达

    Institute of Scientific and Technical Information of China (English)

    卢计委; 刘群; 汪明


    根据犬新孢子虫NcSAG1-NcSRS2融合基因序列,设计了1对含有Kozak序列、终止密码子、BamH Ⅰ和XhoⅠ酶切位点的引物,以含有NcSAG1-NcSRS2融合基因的质粒pGEX-tNcP43-P36为模板,经PCR 扩增获得NcSAG1-NcSRS2融合基因片段,用BamH Ⅰ和XhoⅠ双酶切该片段,回收得到含有以上2 个酶切位点黏端的NcSAG1-NcSRS2融合基因,将此基因片段克隆至相同酶切回收后的pcDNA3.1 (+) 真核表达载体中,获得重组质粒pcNCSAG1-SRS2.经PCR 鉴定、限制性内切酶酶切分析和克隆片段序列测定、比较,证实了重组质粒的正确性.将构建好的真核表达质粒转染到COS-7细胞中进行瞬时表达,经免疫荧光检测,证实了该载体能在细胞内进行蛋白表达.

  3. p21 Inhibits Cdk1 in the absence of Cdk2 to maintain the G1/S phase DNA damage checkpoint. (United States)

    Satyanarayana, Ande; Hilton, Mary Beth; Kaldis, Philipp


    Cdk1 was proposed to compensate for the loss of Cdk2. Here we present evidence that this is possible due to premature translocation of Cdk1 from the cytoplasm to the nucleus in the absence of Cdk2. We also investigated the consequence of loss of Cdk2 on the maintenance of the G1/S DNA damage checkpoint. Cdk2(-/-) mouse embryonic fibroblasts in vitro as well as regenerating liver cells after partial hepatectomy (PH) in Cdk2(-/-) mice, arrest promptly at the G1/S checkpoint in response to gamma-irradiation due to activation of p53 and p21 inhibiting Cdk1. Furthermore re-entry into S phase after irradiation was delayed in Cdk2(-/-) cells due to prolonged and impaired DNA repair activity. In addition, Cdk2(-/-) mice were more sensitive to lethal irradiation compared to wild-type and displayed delayed resumption of DNA replication in regenerating liver cells. Our results suggest that the G1/S DNA damage checkpoint is intact in the absence of Cdk2, but Cdk2 is important for proper repair of the damaged DNA.

  4. Regulation of the G1/S Transition in Hepatocytes: Involvement of the Cyclin-Dependent Kinase Cdk1 in the DNA Replication

    Directory of Open Access Journals (Sweden)

    Anne Corlu


    Full Text Available A singular feature of adult differentiated hepatocytes is their capacity to proliferate allowing liver regeneration. This review emphasizes the literature published over the last 20 years that established the most important pathways regulating the hepatocyte cell cycle. Our article also aimed at illustrating that many discoveries in this field benefited from the combined use of in vivo models of liver regeneration and in vitro models of primary cultures of human and rodent hepatocytes. Using these models, our laboratory has contributed to decipher the different steps of the progression into the G1 phase and the commitment to S phase of proliferating hepatocytes. We identified the mitogen dependent restriction point located at the two-thirds of the G1 phase and the concomitant expression and activation of both Cdk1 and Cdk2 at the G1/S transition. Furthermore, we demonstrated that these two Cdks contribute to the DNA replication. Finally, we provided strong evidences that Cdk1 expression and activation is correlated to extracellular matrix degradation upon stimulation by the pro-inflammatory cytokine TNFα leading to the identification of a new signaling pathway regulating Cdk1 expression at the G1/S transition. It also further confirms the well-orchestrated regulation of liver regeneration via multiple extracellular signals and pathways.

  5. CDK1-dependent inhibition of the E3 ubiquitin ligase CRL4CDT2 ensures robust transition from S Phase to Mitosis. (United States)

    Rizzardi, Lindsay F; Coleman, Kate E; Varma, Dileep; Matson, Jacob P; Oh, Seeun; Cook, Jeanette Gowen


    Replication-coupled destruction of a cohort of cell cycle proteins ensures efficient and precise genome duplication. Three proteins destroyed during replication via the CRL4(CDT2) ubiquitin E3 ligase, CDT1, p21, and SET8 (PR-SET7), are also essential or important during mitosis, making their reaccumulation after S phase a critical cell cycle event. During early and mid-S phase and during DNA repair, proliferating cell nuclear antigen (PCNA) loading onto DNA (PCNA(DNA)) triggers the interaction between CRL4(CDT2) and its substrates, resulting in their degradation. We have discovered that, beginning in late S phase, PCNA(DNA) is no longer sufficient to trigger CRL4(CDT2)-mediated degradation. A CDK1-dependent mechanism that blocks CRL4(CDT2) activity by interfering with CDT2 recruitment to chromatin actively protects CRL4(CDT2) substrates. We postulate that deliberate override of replication-coupled destruction allows anticipatory accumulation in late S phase. We further show that (as for CDT1) de novo SET8 reaccumulation is important for normal mitotic progression. In this manner, CDK1-dependent CRL4(CDT2) inactivation contributes to efficient transition from S phase to mitosis.

  6. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

    Energy Technology Data Exchange (ETDEWEB)

    Velásquez, Celestino; Cheng, Erdong; Shuda, Masahiro; Lee-Oesterreich, Paula J.; Pogge von Strandmann, Lisa; Gritsenko, Marina A.; Jacobs, Jon M.; Moore, Patrick S.; Chang, Yuan


    mTOR-directed 4E-BP1 phosphorylation promotes cap-dependent translation and tumorigen-esis. During mitosis, CDK1 substitutes for mTOR and fully phosphorylates 4E-BP1 at canoni-cal as well a non-canonical S83 site resulting in a mitosis-specific hyperphosphorylated δ isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. While S83 phosphorylation of 4E-BP1 does not affect in vitro cap-dependent translation, nor eIF4G/4E-BP1 cap-binding, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus (MCV) small T (sT) antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain-of-function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

  7. Inactivation of Cdk1/Cyclin B in metaphase-arrested mouse FT210 cells induces exit from mitosis without chromosome segregation or cytokinesis and allows passage through another cell cycle. (United States)

    Paulson, James R


    It is well known that inactivation of Cdk1/Cyclin B is required for cells to exit mitosis. The work reported here tests the hypothesis that Cdk1/Cyclin B inactivation is not only necessary but also sufficient to induce mitotic exit and reestablishment of the interphase state. This hypothesis predicts that inactivation of Cdk1 in metaphase-arrested cells will induce the M to G1-phase transition. It is shown that when mouse FT210 cells (in which Cdk1 is temperature-sensitive) are arrested in metaphase and then shifted to their non-permissive temperature, they rapidly exit mitosis as evidenced by reassembly of interphase nuclei, decondensation of chromosomes, and dephosphorylation of histones H1 and H3. The resulting interphase cells are functionally normal as judged by their ability to progress through another cell cycle. However, they have double the normal number of chromosomes because they previously bypassed anaphase, chromosome segregation, and cytokinesis. These results, taken together with other observations in the literature, strongly suggest that in mammalian cells, inactivation of Cdk1/cyclin B is the trigger for mitotic exit and reestablishment of the interphase state.

  8. Parvovirus B19 NS1 protein induces cell cycle arrest at G2-phase by activating the ATR-CDC25C-CDK1 pathway (United States)

    Xu, Peng; Zhou, Zhe; Xiong, Min; Zou, Wei; Deng, Xuefeng; Ganaie, Safder S.; Peng, Jianxin; Liu, Kaiyu; Wang, Shengqi; Ye, Shui Qing


    Human parvovirus B19 (B19V) infection of primary human erythroid progenitor cells (EPCs) arrests infected cells at both late S-phase and G2-phase, which contain 4N DNA. B19V infection induces a DNA damage response (DDR) that facilitates viral DNA replication but is dispensable for cell cycle arrest at G2-phase; however, a putative C-terminal transactivation domain (TAD2) within NS1 is responsible for G2-phase arrest. To fully understand the mechanism underlying B19V NS1-induced G2-phase arrest, we established two doxycycline-inducible B19V-permissive UT7/Epo-S1 cell lines that express NS1 or NS1mTAD2, and examined the function of the TAD2 domain during G2-phase arrest. The results confirm that the NS1 TAD2 domain plays a pivotal role in NS1-induced G2-phase arrest. Mechanistically, NS1 transactivated cellular gene expression through the TAD2 domain, which was itself responsible for ATR (ataxia-telangiectasia mutated and Rad3-related) activation. Activated ATR phosphorylated CDC25C at serine 216, which in turn inactivated the cyclin B/CDK1 complex without affecting nuclear import of the complex. Importantly, we found that the ATR-CHK1-CDC25C-CDK1 pathway was activated during B19V infection of EPCs, and that ATR activation played an important role in B19V infection-induced G2-phase arrest. PMID:28264028

  9. AZD5438, an Inhibitor of Cdk1, 2, and 9, Enhances the Radiosensitivity of Non-Small Cell Lung Carcinoma Cells

    Energy Technology Data Exchange (ETDEWEB)

    Raghavan, Pavithra; Tumati, Vasu; Yu Lan [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Chan, Norman [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada); Tomimatsu, Nozomi [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Burma, Sandeep [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Simmons Comprehensive Cancer Center, Dallas, Texas (United States); Bristow, Robert G. [Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Hospital, University Health Network, University of Toronto, Ontario (Canada); Saha, Debabrata, E-mail: [Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas (United States); Simmons Comprehensive Cancer Center, Dallas, Texas (United States)


    Purpose: Radiation therapy (RT) is one of the primary modalities for treatment of non-small cell lung cancer (NSCLC). However, due to the intrinsic radiation resistance of these tumors, many patients experience RT failure, which leads to considerable tumor progression including regional lymph node and distant metastasis. This preclinical study evaluated the efficacy of a new-generation cyclin-dependent kinase (Cdk) inhibitor, AZD5438, as a radiosensitizer in several NSCLC models that are specifically resistant to conventional fractionated RT. Methods and Materials: The combined effect of ionizing radiation and AZD5438, a highly specific inhibitor of Cdk1, 2, and 9, was determined in vitro by surviving fraction, cell cycle distribution, apoptosis, DNA double-strand break (DSB) repair, and homologous recombination (HR) assays in 3 NSCLC cell lines (A549, H1299, and H460). For in vivo studies, human xenograft animal models in athymic nude mice were used. Results: Treatment of NSCLC cells with AZD5438 significantly augmented cellular radiosensitivity (dose enhancement ratio rangeing from 1.4 to 1.75). The degree of radiosensitization by AZD5438 was greater in radioresistant cell lines (A549 and H1299). Radiosensitivity was enhanced specifically through inhibition of Cdk1, prolonged G{sub 2}-M arrest, inhibition of HR, delayed DNA DSB repair, and increased apoptosis. Combined treatment with AZD5438 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.2-1.7. Conclusions: This study supports the evaluation of newer generation Cdk inhibitors, such as AZD5438, as potent radiosensitizers in NSCLC models, especially in tumors that demonstrate variable intrinsic radiation responses.

  10. Effects of kaempferol on cell cycle status and CyclinB1,Cdk1 mRNA expressions in CNE-2 cells%山奈酚对CNE-2细胞周期及CyclinB1、Cdk1mRNA表达的影响

    Institute of Scientific and Technical Information of China (English)

    陈育华; 吴国才; 王珍; 周碧云


    Aim: To study the effects of kaempferol on cell cycle status and CyclinB1, Cdk1 mRNA expressions in CNE-2 cells. Methods:CNE-2 cells were treated with 0,20,40,60,80,and 100 μmol/L kaempferol. 24,48 and 72 h later, proliferation was determined by MTT assay;24 and 48 h later,cell cycle was detected by flow cytometry;24 h later,the expressions of CyclinBl and Cdkl mRNA were detected by RT-PCR. Results:The CNE-2 cell growth ability was inhibited by kaempferol in a time- and dose-dependent manned Fdose =385. 194,Ftime =237. 324,Finteraetion =13.757,P <0.001 );CNE-2 cells was blocked in G2/M phase ( P<0.05 );the expressions of CyclinB1 and Cdk1 mRNA decreased with the increase of kaempferol dose ( F = 95. 682,154. 871 ,P < 0. 001 ). Conclusion: Kaempferol can block CNE-2 cells in G2/M phase through decreasing the expressions of CyclinBl and Cdkl mRNA,and inhibit the cell proliferation.%目的:观察山奈酚对鼻咽癌CNE-2细胞周期分布及细胞周期素B1(CyclinB1)、细胞周期依赖性蛋白激酶1(Cdk1)表达的影响.方法:分别用0、20、40、60、80和100 μmol/L的山奈酚处理CNE-2细胞.处理24、48和72 h后,应用MTT法测定CNE-2细胞活力;处理24和48 h后用流式细胞术检测细胞周期;处理24 h后用RT-PCR技术检测细胞CyclinB1及Cdk1 mRNA的表达水平.结果:随山奈酚作用剂量的增加和作用时间的延长,CNE-2细胞活力逐渐降低(F浓度=385.194,F时间=237.324,F浓度×时间=13.757,P<0.001,细胞被阻滞于G2/M期(P<0.05);CNE-2细胞中CyclinB1和Cdk1 mRNA的表达量随山奈酚作用浓度的增加而逐渐降低(F=95.682、154.871,P<0.001).结论:山奈酚可能通过下调CNE-2细胞CyclinB1和Cdk1 mRNA的表达水平,诱导G2/M期阻滞,抑制其增殖.

  11. Bisacylimidoselenocarbamates cause G2/M arrest associated with the modulation of CDK1 and Chk2 in human breast cancer MCF-7 cells. (United States)

    Lamberto, Iranzu; Plano, Daniel; Moreno, Esther; Font, María; Palop, Juan Antonio; Sanmartín, Carmen; Encío, Ignacio


    Bisacylimidoselenocarbamate derivatives (BSC) are potent anticancer agents with a strong cytotoxic activity against different types of tumour cells. Based in phosphatidylserine exposure on the cell membranes we show that BSC treatment resulted in enhanced cell death in leukaemia CCRF-CEM cells. DNA fragmentation detection in breast adenocarcinoma MCF-7 cells showed that BSC triggered cell death is concentration and time dependent. We also show that two of these compounds, BSC 3g and 3n, cause cell-cycle arrest in the late G2/M in MCF-7 cells. Consistent with this, a reduction in CDK1 and CDK2 expression with no change in cyclin A an B1 was observed in this cell line. Activation of caspase-2 was also detected. However, the involvement of the caspase-dependent pathway in the process of cell death induced by either BSC 3g or 3n is discarded since cell death could not be prevented by pretreatment with the pancaspase inhibitor z-VAD-fmk. Moreover, since reduced levels of p21(CIP1) and Chk2 proteins but no change in p53 levels could be detected in MCF-7 cells after BSC 3g or 3n treatment our results suggest that BSC treated cells die from lethal mitosis.

  12. Matefin/SUN-1 Phosphorylation on Serine 43 Is Mediated by CDK-1 and Required for Its Localization to Centrosomes and Normal Mitosis in C. elegans Embryos

    Directory of Open Access Journals (Sweden)

    Noam Zuela


    Full Text Available Matefin/SUN-1 is an evolutionary conserved C. elegans inner nuclear membrane SUN-domain protein. By creating a bridge with the KASH-domain protein ZYG-12, it connects the nucleus to cytoplasmic filaments and organelles. Matefin/SUN-1 is expressed in the germline where it undergoes specific phosphorylation at its N-terminal domain, which is required for germline development and homologous chromosome pairing. The maternally deposited matefin/SUN-1 is then essential for embryonic development. Here, we show that in embryos, serine 43 of matefin/SUN-1 (S43 is phosphorylated in a CDK-1 dependent manner and is localized throughout the cell cycle mostly to centrosomes. By generating animals expressing phosphodead S43A and phosphomimetic S43E mutations, we show that phosphorylation of S43 is required to maintain centrosome integrity and function, as well as for the localization of ZYG-12 and lamin. Expression of S43E in early embryos also leads to an increase in chromatin structural changes, decreased progeny and to almost complete embryonic lethality. Down regulation of emerin further increases the occurrence of chromatin organization abnormalities, indicating possible collaborative roles for these proteins that is regulated by S43 phosphorylation. Taken together, these results support a role for phosphorylation of serine 43 in matefin/SUN-1 in mitosis.

  13. Establishment of Recombinant dNcSRS2 Protein Based Indirect ELISA for Detection of Antibody against Neospora caninum and Its Application%新孢子虫dNcSRS2重组蛋白间接ELISA的建立及其应用

    Institute of Scientific and Technical Information of China (English)

    刘晶; 余劲术; 刘群; 汪明



  14. Kaempferol induces autophagy through AMPK and AKT signaling molecules and causes G2/M arrest via downregulation of CDK1/cyclin B in SK-HEP-1 human hepatic cancer cells. (United States)

    Huang, Wen-Wen; Tsai, Shih-Chang; Peng, Shu-Fen; Lin, Meng-Wei; Chiang, Jo-Hua; Chiu, Yu-Jen; Fushiya, Shinji; Tseng, Michael T; Yang, Jai-Sing


    Kaempferol belongs to the flavonoid family and has been used in traditional folk medicine. Here, we investigated the antitumor effects of kaempferol on cell cycle arrest and autophagic cell death in SK-HEP-1 human hepatic cancer cells. Kaempferol decreased cell viability as determined by MTT assays and induced a G2/M phase cell cycle arrest in a concentration-dependent manner. Kaempferol did not induce DNA fragmentation, apoptotic bodies or caspase-3 activity in SK-HEP-1 cells as determined by DNA gel electrophoresis, DAPI staining and caspase-3 activity assays, respectively. In contrast, kaempferol is involved in the autophagic process. Double-membrane vacuoles, lysosomal compartments, acidic vesicular organelles and cleavage of microtubule-associated protein 1 light chain 3 (LC3) were observed by transmission electron microscopy, LysoΤracker red staining, GFP-fluorescent LC3 assays and acridine orange staining, respectively. In SK-HEP-1 cells, kaempferol increased the protein levels of p-AMPK, LC3-II, Atg 5, Atg 7, Atg 12 and beclin 1 as well as inhibited the protein levels of CDK1, cyclin B, p-AKT and p-mTOR. Taken together, CDK1/cyclin B expression and the AMPK and AKT signaling pathways contributed to kaempferol-induced G2/M cell cycle arrest and autophagic cell death in SK-HEP-1 human hepatic cancer cells. These results suggest that kaempferol may be useful for long-term cancer prevention.

  15. A mitotic phosphorylation feedback network connects Cdk1, Plk1, 53BP1, and Chk2 to inactivate the G(2)/M DNA damage checkpoint

    DEFF Research Database (Denmark)

    van Vugt, Marcel A T M; Gardino, Alexandra K; Linding, Rune;


    the DNA damage response. We demonstrate that the non-enzymatic checkpoint adaptor protein 53BP1 is an in vivo target of the cell cycle kinases Cyclin-dependent kinase-1 and Polo-like kinase-1 (Plk1). We show that Plk1 binds 53BP1 during mitosis and that this interaction is required for proper inactivation......DNA damage checkpoints arrest cell cycle progression to facilitate DNA repair. The ability to survive genotoxic insults depends not only on the initiation of cell cycle checkpoints but also on checkpoint maintenance. While activation of DNA damage checkpoints has been studied extensively, molecular...... of the DNA damage checkpoint. 53BP1 mutants that are unable to bind Plk1 fail to restart the cell cycle after ionizing radiation-mediated cell cycle arrest. Importantly, we show that Plk1 also phosphorylates the 53BP1-binding checkpoint kinase Chk2 to inactivate its FHA domain and inhibit its kinase activity...

  16. Optimization of the analogue-sensitive Cdc2/Cdk1 mutant by in vivo selection eliminates physiological limitations to its use in cell cycle analysis. (United States)

    Aoi, Yuki; Kawashima, Shigehiro A; Simanis, Viesturs; Yamamoto, Masayuki; Sato, Masamitsu


    Analogue-sensitive (as) mutants of kinases are widely used to selectively inhibit a single kinase with few off-target effects. The analogue-sensitive mutant cdc2-as of fission yeast (Schizosaccharomyces pombe) is a powerful tool to study the cell cycle, but the strain displays meiotic defects, and is sensitive to high and low temperature even in the absence of ATP-analogue inhibitors. This has limited the use of the strain for use in these settings. Here, we used in vivo selection for intragenic suppressor mutations of cdc2-as that restore full function in the absence of ATP-analogues. The cdc2-asM17 underwent meiosis and produced viable spores to a similar degree to the wild-type strain. The suppressor mutation also rescued the sensitivity of the cdc2-as strain to high and low temperature, genotoxins and an anti-microtubule drug. We have used cdc2-asM17 to show that Cdc2 activity is required to maintain the activity of the spindle assembly checkpoint. Furthermore, we also demonstrate that maintenance of the Shugoshin Sgo1 at meiotic centromeres does not require Cdc2 activity, whereas localization of the kinase aurora does. The modified cdc2-asM17 allele can be thus used to analyse many aspects of cell-cycle-related events in fission yeast.

  17. Targeting cell cycle regulators in hematologic malignancies

    Directory of Open Access Journals (Sweden)

    Eiman eAleem


    Full Text Available Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia, and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219, pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638 as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

  18. Development and preliminary application of indirect ELISA diagnostic method for Neospora caninum in dairy cattle%奶牛新孢子虫重组蛋白NcSRS2t间接ELISA方法的建立及初步应用

    Institute of Scientific and Technical Information of China (English)

    王春仁; 李志莲; 翟延庆; 倪宏波; 陈爱华; 陈佳; 王宇


    以纯化的犬新孢子虫(Neospora caninum)重组蛋白 NcSRS2t为抗原包被酶标板,通过对间接ELISA 各反应条件的优化,确定了最佳反应条件.采用已建立的间接ELISA反应条件,对218份阴性血清的检测结果进行统计学分析,确定了间接ELISA的判定标准,即OD450nm值大于等于O.32为阳性,小于O.32为阴性.应用建立的间接ELISA方法对128份阴性血清和50份阳性血清(经IDEXX公司新孢子虫抗体检测试剂盒证实)进行检测,结果表明,闻接ELISA方法的特异性为93.0%,敏感性为90.0%.采用本试验建立的新孢子虫间接ELISA 诊断方法对黑龙江省克山、海林、双城、甘南、克东、富裕、牡丹江、大庆等8个县(市)奶牛场的540份奶牛血清进行了检测.结果表明,被检的540份奶牛血清样本中奶牛新孢子虫的抗体阳性率为13.33%.该间接ELISA 诊断方法的建立及初步应用为新孢子虫病诊断试剂盒的研制和新孢子虫病的预防研究奠定了基础.

  19. A regimen combining the Wee1 inhibitor AZD1775 with HDAC inhibitors targets human acute myeloid leukemia cells harboring various genetic mutations. (United States)

    Zhou, L; Zhang, Y; Chen, S; Kmieciak, M; Leng, Y; Lin, H; Rizzo, K A; Dumur, C I; Ferreira-Gonzalez, A; Dai, Y; Grant, S


    AZD1775 targets the cell cycle checkpoint kinase Wee1 and potentiates genotoxic agent cytotoxicity through p53-dependent or -independent mechanisms. Here, we report that AZD1775 interacted synergistically with histone deacetylase inhibitors (HDACIs, for example, Vorinostat), which interrupt the DNA damage response, to kill p53-wild type (wt) or -deficient as well as FLT3-ITD leukemia cells in association with pronounced Wee1 inhibition and diminished cdc2/Cdk1 Y15 phosphorylation. Similarly, Wee1 shRNA knockdown significantly sensitized cells to HDACIs. Although AZD1775 induced Chk1 activation, reflected by markedly increased Chk1 S296/S317/S345 phosphorylation leading to inhibitory T14 phosphorylation of cdc2/Cdk1, these compensatory responses were sharply abrogated by HDACIs. This was accompanied by premature mitotic entry, multiple mitotic abnormalities and accumulation of early S-phase cells displaying increased newly replicated DNA, culminating in robust DNA damage and apoptosis. The regimen was active against patient-derived acute myelogenous leukemia (AML) cells harboring either wt or mutant p53 and various next-generation sequencing-defined mutations. Primitive CD34(+)/CD123(+)/CD38(-) populations enriched for leukemia-initiating progenitors, but not normal CD34(+) hematopoietic cells, were highly susceptible to this regimen. Finally, combining AZD1775 with Vorinostat in AML murine xenografts significantly reduced tumor burden and prolonged animal survival. A strategy combining Wee1 with HDACI inhibition warrants further investigation in AML with poor prognostic genetic aberrations.

  20. Target Laboratory (United States)

    Federal Laboratory Consortium — [Part of the ATLAS user facility.] The Physics Division operates a target development laboratory that produces targets and foils of various thickness and substrates,...

  1. Identification of cell-specific targets of sumoylation during mouse spermatogenesis. (United States)

    Xiao, Yuxuan; Pollack, Daniel; Andrusier, Miriam; Levy, Avi; Callaway, Myrasol; Nieves, Edward; Reddi, Prabhakara; Vigodner, Margarita


    Recent findings suggest diverse and potentially multiple roles of small ubiquitin-like modifier (SUMO) in testicular function and spermatogenesis. However, SUMO targets remain uncharacterized in the testis due to the complex multicellular nature of testicular tissue, the inability to maintain and manipulate spermatogenesis in vitro, and the technical challenges involved in identifying low-abundance endogenous SUMO targets. In this study, we performed cell-specific identification of sumoylated proteins using concentrated cell lysates prepared with de-sumoylation inhibitors from freshly purified spermatocytes and spermatids. One-hundred and twenty proteins were uniquely identified in the spermatocyte and/or spermatid fractions. The identified proteins are involved in the regulation of transcription, stress response, microRNA biogenesis, regulation of major enzymatic pathways, nuclear-cytoplasmic transport, cell-cycle control, acrosome biogenesis, and other processes. Several proteins with important roles during spermatogenesis were chosen for further characterization by co-immunoprecipitation, co-localization, and in vitro sumoylation studies. GPS-SUMO Software was used to identify consensus and non-consensus sumoylation sites within the amino acid sequences of the proteins. The analyses confirmed the cell-specific sumoylation and/or SUMO interaction of several novel, previously uncharacterized SUMO targets such as CDK1, RNAP II, CDC5, MILI, DDX4, TDP-43, and STK31. Furthermore, several proteins that were previously identified as SUMO targets in somatic cells (KAP1 and MDC1) were identified as SUMO targets in germ cells. Many of these proteins have a unique role in spermatogenesis and during meiotic progression. This research opens a novel avenue for further studies of SUMO at the level of individual targets.

  2. Identification of cell-specific targets of sumoylation during mouse spermatogenesis (United States)

    Xiao, Yuxuan; Pollack, Daniel; Andrusier, Miriam; Levy, Avi; Callaway, Myrasol; Nieves, Edward; Reddi, Prabhakara; Vigodner, Margarita


    Recent findings suggest diverse and potentially multiple roles of SUMO in testicular function and spermatogenesis. However, SUMO targets remain uncharacterized in the testis due to the complex multicellular nature of testicular tissue, the inability to maintain and manipulate spermatogenesis in vitro, and the technical challenges involved in identifying low-abundance endogenous SUMO targets. In this study, we performed cell-specific identification of sumoylated proteins using concentrated cell lysates prepared with de-sumoylation inhibitors from freshly purified spermatocytes and spermatids. One-hundred and twenty proteins were uniquely identified in the spermatocyte and/or spermatid fractions. The identified proteins are involved in the regulation of transcription, stress response, microRNA biogenesis, regulation of major enzymatic pathways, nuclear-cytoplasmic transport, cell cycle control, acrosome biogenesis, and other processes. Several proteins with important roles during spermatogenesis were chosen for further characterization by co-immunoprecipitation, co-localization and in-vitro sumoylation studies. GPS-SUMO software was used to identify consensus and non-consensus sumoylation sites within the amino acid sequences of the proteins. The analyses confirmed the cell-specific sumoylation and/or SUMO interaction of several novel, previously uncharacterized SUMO targets such as CDK1, RNAP II, CDC5, MILI, DDX4, TDP-43 and STK31. Furthermore, several proteins that were previously identified as SUMO targets in somatic cells (e.g., KAP1, MDC1) were identified as SUMO targets in germ cells. Many of these proteins have a unique role in spermatogenesis and during meiotic progression. This research opens a novel avenue for further studies of SUMO at the level of individual targets. PMID:26701181

  3. Disjunction of conjoined twins: Cdk1, Cdh1 and separation of centrosomes

    Directory of Open Access Journals (Sweden)

    Surana Uttam


    Full Text Available Abstract Accurate transmission of chromosomes from parent to progeny cell requires assembly of a bipolar spindle. Centrosomes (spindle pole body in yeast are critical for the biogenesis of this complex mitotic apparatus since they confer bipolarity on the spindle and serve as the site of microtubule polymerization. In each division cycle, the centrosome is duplicated and the sister-centrosomes move away from each other, forming the two poles of the spindle. While the structure and the duplication of centrosomes have been investigated extensively, the understanding of the control of their segregation remains scant. Recent findings are beginning to yield insights into the regulation of centrosome segregation in yeast and its link to the mitotic kinase.

  4. Antiproton Target

    CERN Multimedia


    Antiproton target used for the AA (antiproton accumulator). The first type of antiproton production target used from 1980 to 1982 comprised a rod of copper 3mm diameter and 120mm long embedded in a graphite cylinder that was itself pressed into a finned aluminium container. This assembly was air-cooled and it was used in conjunction with the Van der Meer magnetic horn. In 1983 Fermilab provided us with lithium lenses to replace the horn with a view to increasing the antiproton yield by about 30%. These lenses needed a much shorter target made of heavy metal - iridium was chosen for this purpose. The 50 mm iridium rod was housed in an extension to the original finned target container so that it could be brought very close to the entrance to the lithium lens. Picture 1 shows this target assembly and Picture 2 shows it mounted together with the lithium lens. These target containers had a short lifetime due to a combination of beam heating and radiation damage. This led to the design of the water-cooled target in...

  5. Targeting cyclin B1 inhibits proliferation and sensitizes breast cancer cells to taxol

    Directory of Open Access Journals (Sweden)

    Strebhardt Klaus


    Full Text Available Abstract Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1, is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy.

  6. Targeted Learning

    CERN Document Server

    van der Laan, Mark J


    The statistics profession is at a unique point in history. The need for valid statistical tools is greater than ever; data sets are massive, often measuring hundreds of thousands of measurements for a single subject. The field is ready to move towards clear objective benchmarks under which tools can be evaluated. Targeted learning allows (1) the full generalization and utilization of cross-validation as an estimator selection tool so that the subjective choices made by humans are now made by the machine, and (2) targeting the fitting of the probability distribution of the data toward the targe

  7. Expression, purification and antigenicity of Neospora caninum-antigens using silkworm larvae targeting for subunit vaccines. (United States)

    Otsuki, Takahiro; Dong, Jinhua; Kato, Tatsuya; Park, Enoch Y


    Infection of Neospora caninum causes abortion in cattle, which has a serious worldwide impact on the economic performance of the dairy and beef industries. Now, inexpensive and efficacious vaccines are required to protect cattle from neosporosis in livestock industry. In this study, N. caninum surface antigen 1 (SAG1) and SAG1-related sequence 2 (SRS2) were expressed in hemolymph of silkworm larvae as a soluble form. Expressed SAG1 and SRS2 clearly showed antigenicity against N. caninum-positive sera of cow. SAG1 and SRS2 were purified to near homogeneity from hemolymph of silkworm larvae using anti-FLAG M2 antibody agarose: approximately 1.7 mg of SAG1 from 10 silkworm larvae and 370 μg of SRS2 from 17 silkworm larvae. Mice that were injected by antigens induced antibodies against SAG1 and SRS2. This study indicates that it is possible that this silkworm expression system leads to a large-scale production of N. caninum-antigens with biological function and low production cost. Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid expression system paves the way to produce largely and rapidly these recombinant antigens for its application to subunit vaccines against neosporosis in cattle.

  8. Target Space $\

    CERN Document Server

    Huggett, Nick


    This paper investigates the significance of T-duality in string theory: the indistinguishability with respect to all observables, of models attributing radically different radii to space -- larger than the observable universe, or far smaller than the Planck length, say. Two interpretational branch points are identified and discussed. First, whether duals are physically equivalent or not: by considering a duality of the familiar simple harmonic oscillator, I argue that they are. Unlike the oscillator, there are no measurements 'outside' string theory that could distinguish the duals. Second, whether duals agree or disagree on the radius of 'target space', the space in which strings evolve according to string theory. I argue for the latter position, because the alternative leaves it unknown what the radius is. Since duals are physically equivalent yet disagree on the radius of target space, it follows that the radius is indeterminate between them. Using an analysis of Brandenberger and Vafa (1989), I explain wh...

  9. Identification of a Selective G1-Phase Benzimidazolone Inhibitor by a Senescence-Targeted Virtual Screen Using Artificial Neural Networks

    Directory of Open Access Journals (Sweden)

    Alan E. Bilsland


    Full Text Available Cellular senescence is a barrier to tumorigenesis in normal cells, and tumor cells undergo senescence responses to genotoxic stimuli, which is a potential target phenotype for cancer therapy. However, in this setting, mixed-mode responses are common with apoptosis the dominant effect. Hence, more selective senescence inducers are required. Here we report a machine learning–based in silico screen to identify potential senescence agonists. We built profiles of differentially affected biological process networks from expression data obtained under induced telomere dysfunction conditions in colorectal cancer cells and matched these to a panel of 17 protein targets with confirmatory screening data in PubChem. We trained a neural network using 3517 compounds identified as active or inactive against these targets. The resulting classification model was used to screen a virtual library of ~2M lead-like compounds. One hundred and forty-seven virtual hits were acquired for validation in growth inhibition and senescence-associated β-galactosidase assays. Among the found hits, a benzimidazolone compound, CB-20903630, had low micromolar IC50 for growth inhibition of HCT116 cells and selectively induced senescence-associated β-galactosidase activity in the entire treated cell population without cytotoxicity or apoptosis induction. Growth suppression was mediated by G1 blockade involving increased p21 expression and suppressed cyclin B1, CDK1, and CDC25C. In addition, the compound inhibited growth of multicellular spheroids and caused severe retardation of population kinetics in long-term treatments. Preliminary structure-activity and structure clustering analyses are reported, and expression analysis of CB-20903630 against other cell cycle suppressor compounds suggested a PI3K/AKT-inhibitor–like profile in normal cells, with different pathways affected in cancer cells.

  10. 新孢子虫NcSRS2基因的克隆和亚克隆

    Institute of Scientific and Technical Information of China (English)

    翟延庆; 李利; 王春仁


    新孢子虫病是由犬新孢子虫(Neospora caninum)寄生于牛、羊、犬等多种动物细胞内引起的一种原虫病。犬新孢子虫的终末宿主主要为犬,也有山狗作为其终末宿主的报道;中间宿主种类繁多,包括犬、牛、羊、马等家畜及灰狐、红狐、南美洲负鼠等多种野生动物。

  11. Dynactin helps target Polo-like kinase 1 to kinetochores via its left-handed beta-helical p27 subunit. (United States)

    Yeh, Ting-Yu; Kowalska, Anna K; Scipioni, Brett R; Cheong, Frances Ka Yan; Zheng, Meiying; Derewenda, Urszula; Derewenda, Zygmunt S; Schroer, Trina A


    Dynactin is a protein complex required for the in vivo function of cytoplasmic dynein, a microtubule (MT)-based motor. Dynactin binds both dynein and MTs via its p150(Glued) subunit, but little is known about the 'pointed-end complex' that includes the protein subunits Arp11, p62 and the p27/p25 heterodimer. Here, we show that the p27/p25 heterodimer undergoes mitotic phosphorylation by cyclin-dependent kinase 1 (Cdk1) at a single site, p27 Thr186, to generate an anchoring site for polo-like kinase 1 (Plk1) at kinetochores. Removal of p27/p25 from dynactin results in reduced levels of Plk1 and its phosphorylated substrates at kinetochores in prometaphase, which correlates with aberrant kinetochore-MT interactions, improper chromosome alignment and abbreviated mitosis. To investigate the structural implications of p27 phosphorylation, we determined the structure of human p27. This revealed an unusual left-handed β-helix domain, with the phosphorylation site located within a disordered, C-terminal segment. We conclude that dynactin plays a previously undescribed regulatory role in the spindle assembly checkpoint by recruiting Plk1 to kinetochores and facilitating phosphorylation of important downstream targets.

  12. A scalable method for molecular network reconstruction identifies properties of targets and mutations in acute myeloid leukemia. (United States)

    Ong, Edison; Szedlak, Anthony; Kang, Yunyi; Smith, Peyton; Smith, Nicholas; McBride, Madison; Finlay, Darren; Vuori, Kristiina; Mason, James; Ball, Edward D; Piermarocchi, Carlo; Paternostro, Giovanni


    A key aim of systems biology is the reconstruction of molecular networks. We do not yet, however, have networks that integrate information from all datasets available for a particular clinical condition. This is in part due to the limited scalability, in terms of required computational time and power, of existing algorithms. Network reconstruction methods should also be scalable in the sense of allowing scientists from different backgrounds to efficiently integrate additional data. We present a network model of acute myeloid leukemia (AML). In the current version (AML 2.1), we have used gene expression data (both microarray and RNA-seq) from 5 different studies comprising a total of 771 AML samples and a protein-protein interactions dataset. Our scalable network reconstruction method is in part based on the well-known property of gene expression correlation among interacting molecules. The difficulty of distinguishing between direct and indirect interactions is addressed by optimizing the coefficient of variation of gene expression, using a validated gold-standard dataset of direct interactions. Computational time is much reduced compared to other network reconstruction methods. A key feature is the study of the reproducibility of interactions found in independent clinical datasets. An analysis of the most significant clusters, and of the network properties (intraset efficiency, degree, betweenness centrality, and PageRank) of common AML mutations demonstrated the biological significance of the network. A statistical analysis of the response of blast cells from 11 AML patients to a library of kinase inhibitors provided an experimental validation of the network. A combination of network and experimental data identified CDK1, CDK2, CDK4, and CDK6 and other kinases as potential therapeutic targets in AML.

  13. α-Santalol, a skin cancer chemopreventive agent with potential to target various pathways involved in photocarcinogenesis. (United States)

    Santha, Sreevidya; Dwivedi, Chandradhar


    This study is designed to investigate the chemopreventive effect and molecular mechanisms of α-santalol on UVB-induced skin tumor development in SKH-1 hairless mouse, a widely used model for human photocarcinogenesis. A dose of UVB radiation (30 mJ cm(-2) day(-1)) that is in the range of human sunlight exposure was used for the initiation and promotion of tumor. Topical treatment of mice with α-santalol (10%, wt/vol in acetone) caused reduction in tumor incidence, multiplicity and volume. In our study, the anticarcinogenic action of α-santalol against UVB-induced photocarcinogenesis was found to be associated with inhibition of inflammation and epidermal cell proliferation, cell cycle arrest and induction of apoptosis. α-Santalol pretreatment strongly inhibited UVB-induced epidermal hyperplasia and thickness of the epidermis, expression of proliferation and inflammation markers proliferating cell nuclear antigen (PCNA), Ki-67 and cyclooxygenase 2 (Cox-2). Significant decrease in the expression of cyclins A, B1, D1 and D2 and cyclin-dependent kinases (Cdk)s Cdk1 (Cdc2), Cdk2, Cdk4 and Cdk6 and an upregulated expression of cyclin-dependent kinase (CDK) inhibitor Cip1/p21 were found in α-santalol pretreated group. Furthermore, an elevated level of cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP) were observed in α-santalol-treated group. Our data suggested that α-santalol is a safer and promising skin cancer chemopreventive agent with potential to target various pathways involved in photocarcinogenesis.

  14. The cell cycle rallies the transcription cycle: Cdc28/Cdk1 is a cell cycle-regulated transcriptional CDK. (United States)

    Chymkowitch, Pierre; Enserink, Jorrit M


    In the budding yeast Saccharomyces cerevisiae, the cyclin-dependent kinases (CDKs) Kin28, Bur1 and Ctk1 regulate basal transcription by phosphorylating the carboxyl-terminal domain (CTD) of RNA polymerase II. However, very little is known about the involvement of the cell cycle CDK Cdc28 in the transcription process. We have recently shown that, upon cell cycle entry, Cdc28 kinase activity boosts transcription of a subset of genes by directly stimulating the basal transcription machinery. Here, we discuss the biological significance of this finding and give our view of the kinase-dependent role of Cdc28 in regulation of RNA polymerase II.

  15. Electrically charged targets (United States)

    Goodman, Ronald K.; Hunt, Angus L.


    Electrically chargeable laser targets and method for forming such charged targets in order to improve their guidance along a predetermined desired trajectory. This is accomplished by the incorporation of a small amount of an additive to the target material which will increase the electrical conductivity thereof, and thereby enhance the charge placed upon the target material for guidance thereof by electrostatic or magnetic steering mechanisms, without adversely affecting the target when illuminated by laser energy.

  16. Targeted Cancer Therapies (United States)

    ... targeted therapies are directed against HER-2, including trastuzumab (Herceptin®), which is approved to treat certain breast and ... traditional chemotherapy drugs. For example, the targeted therapy trastuzumab (Herceptin®) has been used in combination with docetaxel , ...

  17. High Power Cryogenic Targets

    Energy Technology Data Exchange (ETDEWEB)

    Gregory Smith


    The development of high power cryogenic targets for use in parity violating electron scattering has been a crucial ingredient in the success of those experiments. As we chase the precision frontier, the demands and requirements for these targets have grown accordingly. We discuss the state of the art, and describe recent developments and strategies in the design of the next generation of these targets.

  18. Development of distributed target

    CERN Document Server

    Yu Hai Jun; Li Qin; Zhou Fu Xin; Shi Jin Shui; Ma Bing; Chen Nan; Jing Xiao Bing


    Linear introduction accelerator is expected to generate small diameter X-ray spots with high intensity. The interaction of the electron beam with plasmas generated at the X-ray converter will make the spot on target increase with time and debase the X-ray dose and the imaging resolving power. A distributed target is developed which has about 24 pieces of thin 0.05 mm tantalum films distributed over 1 cm. due to the structure adoption, the distributed target material over a large volume decreases the energy deposition per unit volume and hence reduces the temperature of target surface, then reduces the initial plasma formalizing and its expansion velocity. The comparison and analysis with two kinds of target structures are presented using numerical calculation and experiments, the results show the X-ray dose and normalized angle distribution of the two is basically the same, while the surface of the distributed target is not destroyed like the previous block target

  19. Targeted cancer therapies

    Institute of Scientific and Technical Information of China (English)

    Li Yan; Neal Rosen; Carlos Arteaga


    With unprecedented understanding of molecular events underlying human cancer in this genomic era, a large number of drugs specifically targeting hypothesized oncogenic drivers to which tumors are potentially addicted to have been developed and continue to be developed. These targeted cancer therapies are being actively tested in clinical trials with mixed successes. This editorial provides an overview on successful targeted cancer drugs on the market and those drugs that are in late clinical development stages. Importantly, the article lays out main challenges in developing molecular targeted therapies and potential path forward to overcome these challenges, as well as opportunities for China in this new era of targeted agents. The editorial serves as an introduction to the Targeted Cancer Therapies serias that will review in depth of major pathways and drugs targeting these pathways to be published in the coming issues of the Chinese Journal of Cancer.

  20. Targeted tumor radiotherapy

    Directory of Open Access Journals (Sweden)

    Unak Perihan


    Full Text Available Targeted tumor radiotherapy is selectively delivery of curative doses of radiation to malignant sites. The aim of the targeted tumor radiotherapy is to use the radionuclides which have high LET particle emissions conjugated to appropriate carrier molecules. The radionuclides are selectively collected by tumor cells, depositing lethal doses to tumor cells while no admission occur to normal cells. In theory, targeted radiotherapy has several advantages over conventional radiotherapy since it allows a high radiation dose to be administered without causing normal tissue toxicity, although there are some limitations in the availability of appropriate targeting agents and in the calculations of administered doses. Therefore, for routine clinical applications more progress is still needed. In this article, the potential use of targeted tumor radiotherapy is briefly reviewed. More general aspects and considerations, such as potential radionuclides, mechanisms of tumor targeting was also outlined.

  1. Targeting Notch to target cancer stem cells. (United States)

    Pannuti, Antonio; Foreman, Kimberly; Rizzo, Paola; Osipo, Clodia; Golde, Todd; Osborne, Barbara; Miele, Lucio


    The cellular heterogeneity of neoplasms has been at the center of considerable interest since the "cancer stem cell hypothesis", originally formulated for hematologic malignancies, was extended to solid tumors. The origins of cancer "stem" cells (CSC) or tumor-initiating cells (TIC; henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of subpopulations of tumor cells with stem-like characteristics has significant therapeutic implications. The stem-like phenotype includes indefinite self-replication, pluripotency, and, importantly, resistance to chemotherapeutics. Thus, it is plausible that CSCs, regardless of their origin, may escape standard therapies and cause disease recurrences and/or metastasis after apparently complete remissions. Consequently, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. The Notch pathway is one of the most intensively studied putative therapeutic targets in CSC, and several investigational Notch inhibitors are being developed. However, successful targeting of Notch signaling in CSC will require a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to prove safe and effective. Additionally, to determine which patients are most likely to benefit from treatment with Notch-targeting therapeutics, reliable biomarkers to measure pathway activity in CSC from specific tumors will have to be identified and validated. This article summarizes the most recent developments in the field of Notch-targeted cancer therapeutics, with emphasis on CSC.

  2. The ISOLDE target robots

    CERN Multimedia

    Maximilein Brice


    ISOLDE targets need to be changed frequently, around 80 times per year. The high radiation levels do not permit this to be done by human hands and the target changes are effected by 2 industrial robots (picture _01). On the left, in the distance, the front-end of the GPS (General Purpose Separator) is seen, while the HRS (High Resolution Separator) is at the right. Also seen are the doors to the irradiated-target storage.

  3. Target Window Reliability

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)


    The target window design implemented and tested in experiments at ANL have performed without failure for the available beam of 6 mm FWHM on a 12 mm diameter target. However, scaling that design to a 25 mm diameter target size for a 12 mm FWHM beam has proven problematic. Combined thermal and mechanical (pressure induced) stresses and strains are too high to maintain the small coolant gaps and provide adequate fatigue lifetime.

  4. Moving Target Defense

    CERN Document Server

    Jajodia, Sushil; Swarup, Vipin; Wang, Cliff; Wang, X Sean


    Moving Target Defense: Creating Asymmetric Uncertainty for Cyber Threats was developed by a group of leading researchers. It describes the fundamental challenges facing the research community and identifies new promising solution paths. Moving Target Defense which is motivated by the asymmetric costs borne by cyber defenders takes an advantage afforded to attackers and reverses it to advantage defenders. Moving Target Defense is enabled by technical trends in recent years, including virtualization and workload migration on commodity systems, widespread and redundant network connectivity, instr

  5. Targeted Radionuclide Therapy

    Directory of Open Access Journals (Sweden)

    David Cheng


    Full Text Available Targeted radiotherapy is an evolving and promising modality of cancer treatment. The killing of cancer cells is achieved with the use of biological vectors and appropriate radionuclides. Among the many advantages of this approach are its selectiveness in delivering the radiation to the target, relatively less severe and infrequent side effects, and the possibility of assessing the uptake by the tumor prior to the therapy. Several different radiopharmaceuticals are currently being used by various administration routes and targeting mechanisms. This article aims to briefly review the current status of targeted radiotherapy as well as to outline the advantages and disadvantages of radionuclides used for this purpose.

  6. Bayesian multiple target tracking

    CERN Document Server

    Streit, Roy L


    This second edition has undergone substantial revision from the 1999 first edition, recognizing that a lot has changed in the multiple target tracking field. One of the most dramatic changes is in the widespread use of particle filters to implement nonlinear, non-Gaussian Bayesian trackers. This book views multiple target tracking as a Bayesian inference problem. Within this framework it develops the theory of single target tracking, multiple target tracking, and likelihood ratio detection and tracking. In addition to providing a detailed description of a basic particle filter that implements

  7. Target Assembly Facility (United States)

    Federal Laboratory Consortium — The Target Assembly Facility integrates new armor concepts into actual armored vehicles. Featuring the capability ofmachining and cutting radioactive materials, it...

  8. Targeting the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Kenny, P.A.; Lee, G.Y.; Bissell, M.J.


    Despite some notable successes cancer remains, for the most part, a seemingly intractable problem. There is, however, a growing appreciation that targeting the tumor epithelium in isolation is not sufficient as there is an intricate mutually sustaining synergy between the tumor epithelial cells and their surrounding stroma. As the details of this dialogue emerge, new therapeutic targets have been proposed. The FDA has already approved drugs targeting microenvironmental components such as VEGF and aromatase and many more agents are in the pipeline. In this article, we describe some of the 'druggable' targets and processes within the tumor microenvironment and review the approaches being taken to disrupt these interactions.

  9. miR-26a and its target CKS2 modulate cell growth and tumorigenesis of papillary thyroid carcinoma.

    Directory of Open Access Journals (Sweden)

    Mingli Lv

    Full Text Available BACKGROUND: While many studies have shown that levels of miR-26a are lower in papillary thyroid carcinoma (PTC, the role and mechanism of miR-26a in PTC are unclear. METHOD: We used database searches to select potential mRNA targets of miR-26a. Anti-miR-26a, miR-26a mimic, siRNA for CKS2 and their effects on cell growth, cell-cycle distribution and colony formation were evaluated. We also evaluate the over-expressed miR-26a in TPC-1 cells in severe combined immune-deficient mice. We used luciferase reporter assays, real-time PCR and western blot analysis to measure the expression and activity of miR-26a, CKS2, and related factors such as cyclin B1, cyclin A, cdk1, bcl-xl and Akt. Finally, we measured the relationship between the levels of miR-26a and CKS2 in PTC and normal thyroid tissues. RESULTS: Relative to normal thyroid tissues, miR-26a is consistently down-regulated in TPC specimens, and CKS2 was identified as a potential target. Up-regulated miR-26a expression or down-regulated CKS2 expression in TPC-1 and CGTH W3 cells lines caused G2 phase-arrest. Decreased miR-26a expression or increased CKS2 expression could have inverse function on PTC cell lines. CyclinB1, cyclinA, bcl-xl and AKt are indirectly regulated by miR-26a in a CKS2-dependent manner. Finally, CKS2 is overexpressed in PTC specimens relative to normal thyroid tissue, and a significant inverse correlation exists between miR-26a and CKS2 expression in clinical PTC specimens. CONCLUSION: Our data indicate that miR-26a functions as a growth-suppressive miRNA in PTC, and that its suppressive effects are mediated mainly by repressing CKS2 expression.

  10. Vibrotactile target saliency

    NARCIS (Netherlands)

    Toet, A.; Groen, E.l.; Oosterbeek, M.T.J.; Hooge, I.T.C.


    We tested the saliency of a single vibrotractile target (T) among 2 to 7 nontargets (N), presented by 8 tactors that were equally distributed over a horizontal band around the torso. Targets and nontargets had different pulse duration, but the same activation period and no onset asynchrony. T-N simi

  11. Strategic Targeted Advertising

    NARCIS (Netherlands)

    A. Galeotti; J.L. Moraga-Gonzalez (José Luis)


    textabstractWe present a strategic game of pricing and targeted-advertising. Firms can simultaneously target price advertisements to different groups of customers, or to the entire market. Pure strategy equilibria do not exist and thus market segmentation cannot occur surely. Equilibria exhibit rand

  12. The CNGS target

    CERN Multimedia

    Patrice Loïez


    The CERN Neutrinos to Gran Sasso (CNGS) target ‘magazine’ of five target units. Each unit contains a series of 10-cm long graphite rods distributed over a length of 2 m. It is designed to maximize the number of secondary particles produced and hence the number of neutrinos. One unit is used at a time to prevent over heating.

  13. Nuclear target development

    Energy Technology Data Exchange (ETDEWEB)

    Greene, J.P.; Thomas, G.E.


    The Physics Division operates a target development laboratory that produces thin foil targets needed for experiments performed at the ATLAS and Dynamitron accelerators. Targets are not only produced for the Physics Division but also for other divisions and occasionally for other laboratories and universities. In the past year, numerous targets were fabricated by vacuum evaporation either as self-supporting foils or on various substrates. Targets produced included Ag, Au, {sup 10,11}B, {sup 138}Ba, Be, {sup 12}C, {sup 40}Ca, {sup 116}Cd, {sup 155,160}Gd, {sup 76}Ge, In, LID, {sup 6}LiH, Melamine, Mg, {sup 142,150}Nd, {sup 58}Ni, {sup 206,208}Pb, {sup 194}Pt, {sup 28}Si, {sup 144,148}Sm, {sup 120,122,124}Sn, Ta, {sup 130}Te, ThF{sub 4}, {sup 46,50}Ti, TiH, U, UF{sub 4}, {sup 182}W and {sup 170}Yb. Polypropylene and aluminized polypropylene, along with metallized Mylar were produced for experiments at ATLAS. A number of targets of {sup 11}B of various thickness were made for the DEP 2-MeV Van de Graff accelerator. An increased output of foils fabricated using our small rolling mill included targets of Au, C, {sup 50}Cr, Cu, {sup 155,160}Gd, Mg, {sup 58}Ni, {sup 208}Pb, {sup 105,110}Pd. Sc, Ti, and {sup 64,66}Zn.

  14. AA antiproton production target

    CERN Multimedia


    The first version of the antiproton production target was a tungsten rod, 11 cm long and 3 mm in diameter. The rod was embedded in graphite, pressure-seated into an outer casing of stainless steel. At the entrance to the target assembly was a scintillator screen, imprinted with circles every 5 mm in radius, which allowed to precisely aim the 26 GeV high-intensity proton beam from the PS onto the centre of the target rod. The scintillator screen was a 1 mm thick plate of Cr-doped alumina. See also 7903034 and 7905091.

  15. Internal polarized targets

    Energy Technology Data Exchange (ETDEWEB)

    Kinney, E.R.; Coulter, K.; Gilman, R.; Holt, R.J.; Kowalczyk, R.S.; Napolitano, J.; Potterveld, D.H.; Young, L. (Argonne National Lab., IL (USA)); Mishnev, S.I.; Nikolenko, D.M.; Popov, S.G.; Rachek, I.A.; Temnykh, A.B.; Toporkov, D.K.; Tsentalovich, E.P.; Wojtsekhowski, B.B. (AN SSSR, Novosibirsk (USSR). Inst. Yadernoj Fiziki)


    Internal polarized targets offer a number of advantages over external targets. After a brief review of the basic motivation and principles behind internal polarized targets, the technical aspects of the atomic storage cell will be discussed in particular. Sources of depolarization and the means by which their effects can be ameliorated will be described, especially depolarization by the intense magnetic fields arising from the circulating particle beam. The experience of the Argonne Novosibirsk collaboration with the use of a storage cell in a 2 GeV electron storage ring will be the focus of this technical discussion. 17 refs., 11 figs.

  16. STIS target acquisition (United States)

    Kraemer, Steve; Downes, Ron; Katsanis, Rocio; Crenshaw, Mike; McGrath, Melissa; Robinson, Rich


    We describe the STIS autonomous target acquisition capabilities. We also present the results of dedicated tests executed as part of Cycle 7 calibration, following post-launch improvements to the Space Telescope Imaging Spectrograph (STIS) flight software. The residual pointing error from the acquisitions are < 0.5 CCD pixels, which is better than preflight estimates. Execution of peakups show clear improvement of target centering for slits of width 0.1 sec or smaller. These results may be used by Guest Observers in planning target acquisitions for their STIS programs.

  17. Target Price Accuracy

    Directory of Open Access Journals (Sweden)

    Alexander G. Kerl


    Full Text Available This study analyzes the accuracy of forecasted target prices within analysts’ reports. We compute a measure for target price forecast accuracy that evaluates the ability of analysts to exactly forecast the ex-ante (unknown 12-month stock price. Furthermore, we determine factors that explain this accuracy. Target price accuracy is negatively related to analyst-specific optimism and stock-specific risk (measured by volatility and price-to-book ratio. However, target price accuracy is positively related to the level of detail of each report, company size and the reputation of the investment bank. The potential conflicts of interests between an analyst and a covered company do not bias forecast accuracy.

  18. Issues in Target Tracking (United States)


    the CUSUM (Page) test yields the quickest detection of a change of distribution for the case of i.i.d. observations [3]. In fact, in a (highly...11. Autocorrelation of the CUSUM increments, sn, under H1 (target present). Issues in Target Tracking RTO-EN-SET-157(2010...restrictive condition that the increments of the cumulative sum, sn, be i.i.d. [3], [22]. Fig. 11 plots the autocorrelation of the CUSUM increments as a

  19. An ISOLDE target unit

    CERN Multimedia

    Maximilien Brice


    A good dozen different targets are available for ISOLDE, made of different materials and equipped with different kinds of ion-sources, according to the needs of the experiments. Each separator (GPS: general purpose; HRS: high resolution) has its own target. Because of the high radiation levels, robots effect the target changes, about 80 times per year. In the standard unit shown in picture _01, the target is the cylindrical object in the front. It contains uranium-carbide kept at a temperature of 2200 deg C, necessary for the isotopes to be able to escape. At either end, one sees the heater current leads, carrying 700 A. The Booster beam, some 3E13 protons per pulse, enters the target from left. The evaporated isotope atoms enter a hot-plasma ion source (the black object behind the target). The whole unit sits at 60 kV potential (pulsed in synchronism with the arrival of the Booster beam) which accelerates the ions (away from the viewer) towards one of the 2 separators.

  20. The Sinuous Target

    Energy Technology Data Exchange (ETDEWEB)

    Zwaska, R. [Fermilab


    We report on the concept for a target material comprised of a multitude of interlaced wires of small dimension. This target material concept is primarily directed at high-power neutrino targets where the thermal shock is large due to small beam sizes and short durations; it also has applications to other high-power targets, particularly where the energy deposition is great or a high surface area is preferred. This approach ameliorates the problem of thermal shock by engineering a material with high strength on the micro-scale, but a very low modulus of elasticity on the meso-scale. The low modulus of elasticity is achieved by constructing the material of spring-like wire segments much smaller than the beam dimension. The intrinsic bends of the wires will allow them to absorb the strain of thermal shock with minimal stress. Furthermore, the interlaced nature of the wires provides containment of any segment that might become loose. We will discuss the progress on studies of analogue materials and fabrication techniques for sinuous target materials.

  1. Production Target Design Report

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dale, Gregory E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Olivas, Eric Richard [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)


    The Northstar 99Mo production target, a cylindrical length of 100Mo rod, has evolved considerably since its first conception.  The cylinder was very early sliced into disks to increase the heat transfer area, first to 1 mm thick disks then to the current 0.5 mm thick.  The coolant was changed early in the target development from water to helium to eliminate corrosion and dissolution.  The diameter has increased from initially 6 mm to 12 mm, the current diameter of the test target now at ANL, to nominally 28 mm (26-30.6 mm, depending upon optimal beam spot size and shape).  The length has also changed to improve the production to cost ratio, so now the target is nominally 41 mm long (excluding coolant gaps between disks), and irradiated on both ends.  This report summarizes the current status of the plant target design.

  2. Targeted assets risk analysis. (United States)

    Bouwsema, Barry


    Risk assessments utilising the consolidated risk assessment process as described by Public Safety Canada and the Centre for Security Science utilise the five threat categories of natural, human accidental, technological, human intentional and chemical, biological, radiological, nuclear or explosive (CBRNE). The categories of human intentional and CBRNE indicate intended actions against specific targets. It is therefore necessary to be able to identify which pieces of critical infrastructure represent the likely targets of individuals with malicious intent. Using the consolidated risk assessment process and the target capabilities list, coupled with the CARVER methodology and a security vulnerability analysis, it is possible to identify these targeted assets and their weaknesses. This process can help emergency managers to identify where resources should be allocated and funding spent. Targeted Assets Risk Analysis (TARA) presents a new opportunity to improve how risk is measured, monitored, managed and minimised through the four phases of emergency management, namely, prevention, preparation, response and recovery. To reduce risk throughout Canada, Defence Research and Development Canada is interested in researching the potential benefits of a comprehensive approach to risk assessment and management. The TARA provides a framework against which potential human intentional threats can be measured and quantified, thereby improving safety for all Canadians.

  3. Targeted Phototherapy (newer phototherapy

    Directory of Open Access Journals (Sweden)



    Full Text Available Conventional phototherapy uses a whole body cabinet or body part machine such as hand, foot or scalp machines. They have many disadvantages due to which new phototherapy technique was then developed to overcome this situation. This new technique is called targeted phototherapy which includes excimer laser, intense pulse light system (IPL, photodynamic therapy and ultraviolet (UV light source with a sophisticated delivery system which is easy to be operated by hands. The mechanisms of action of targeted phototherapy systems are similar to those in conventional UVB/UVA therapy. They have many advantages like less chances of side effects, avoidance of exposure of unnecessary sites, faster response, shortening of the duration of treatments. But they have disadvantages like high costs and inability to use for extensive areas. This review article discusses targeted phototherapy in considerable to the mechanism of actions and advantages and disadvantages in comparison to the conventional phototherapy.

  4. Modelling Recycling Targets

    DEFF Research Database (Denmark)

    hill, amanda; Leinikka Dall, Ole; Andersen, Frits Møller


    Within the European Union (EU) a paradigm shift is currently occurring in the waste sector, where EU waste directives and national waste strategies are placing emphasis on resource efficiency and recycling targets. The most recent Danish resource strategy calculates a national recycling rate of 22......% for household waste, and sets an ambitious goal of a 50% recycling rate by 2020. This study integrates the recycling target into the FRIDA model to project how much waste and from which streams should be diverted from incineration to recycling in order to achieve the target. Furthermore, it discusses how...... the existing technological, organizational and legislative frameworks may affect recycling activities. The results of the analysis show that with current best practice recycling rates, the 50% recycling rate cannot be reached without recycling of household biowaste. It also shows that all Danish municipalities...

  5. Setting reference targets

    Energy Technology Data Exchange (ETDEWEB)

    Ruland, R.E.


    Reference Targets are used to represent virtual quantities like the magnetic axis of a magnet or the definition of a coordinate system. To explain the function of reference targets in the sequence of the alignment process, this paper will first briefly discuss the geometry of the trajectory design space and of the surveying space, then continue with an overview of a typical alignment process. This is followed by a discussion on magnet fiducialization. While the magnetic measurement methods to determine the magnetic centerline are only listed (they will be discussed in detail in a subsequent talk), emphasis is given to the optical/mechanical methods and to the task of transferring the centerline position to reference targets.

  6. Cooled particle accelerator target (United States)

    Degtiarenko, Pavel V.


    A novel particle beam target comprising: a rotating target disc mounted on a retainer and thermally coupled to a first array of spaced-apart parallel plate fins that extend radially inwardly from the retainer and mesh without physical contact with a second array of spaced-apart parallel plate fins that extend radially outwardly from and are thermally coupled to a cooling mechanism capable of removing heat from said second array of spaced-apart fins and located within the first array of spaced-apart parallel fins. Radiant thermal exchange between the two arrays of parallel plate fins provides removal of heat from the rotating disc. A method of cooling the rotating target is also described.

  7. AA antiproton production target

    CERN Multimedia


    The first version of the antiproton production target was a tungsten rod, 11 cm long (actually a row of 11 rods, each 1 cm long) and 3 mm in diameter. The rod was embedded in graphite, pressure-seated into an outer casing made of stainless steel. The casing had fins for forced-air cooling. In this picture, the 26 GeV high-intensity beam from the PS enters from the right, where a scintillator screen, with circles every 5 mm in radius, permits precise aim at the target centre. See also 7903034 and 7905094.

  8. Targeting peroxiredoxins against leukemia. (United States)

    Liu, Chuan-Xu; Zhou, Hu-Chen; Yin, Qian-Qian; Wu, Ying-Li; Chen, Guo-Qiang


    Peroxiredoxins (Prx), a family of small non-seleno peroxidases, are important regulators for cellular reactive oxygen species (ROS), which contribute to many signaling pathways and pathogenesis of diseases. Targeting redox homeostasis is being developed as a promising therapeutic strategy for many diseases such as cancers. This mini-review attempts to focus on our recent discoveries on adenanthin as the first natural molecule to specifically target the resolving cysteines of Prx I and Prx II and thus inhibit their peroxidase activities, and its role in differentiation induction in vitro and in vivo of acute myeloid leukemic cells.

  9. Cancer immunotherapy targeting neoantigens. (United States)

    Lu, Yong-Chen; Robbins, Paul F


    Neoantigens are antigens encoded by tumor-specific mutated genes. Studies in the past few years have suggested a key role for neoantigens in cancer immunotherapy. Here we review the discoveries of neoantigens in the past two decades and the current advances in neoantigen identification. We also discuss the potential benefits and obstacles to the development of effective cancer immunotherapies targeting neoantigens.

  10. Microenvironmental targets in sarcoma

    Directory of Open Access Journals (Sweden)

    Monika eEhnman


    Full Text Available Sarcomas are rare malignant tumors affecting all age groups. They are typically classified according to their resemblance to corresponding normal tissue. Their heterogeneous features, for example in terms of disease-driving genetic aberrations and body location, complicate both disease classification and development of novel treatment regimens. Many years of failure of improved patient outcome in clinical trials has lead to the conclusion that novel targeted therapies are likely needed in combination with current multimodality regimens. Sarcomas have not, in contrast to the common carcinomas, been the subject for larger systematic studies on how tumor behavior relates to characteristics of the tumor microenvironment. There is consequently an urgent need for identifying suitable molecular targets, not only in tumor cells, but also in the tumor microenvironment. This review discusses preclinical and clinical data about potential molecular targets in sarcomas. Studies on targeted therapies involving the tumor microenvironment are prioritized. A greater understanding of the biological context is expected to facilitate more successful design of future clinical trials in sarcoma.

  11. Major Targets for 2010

    Institute of Scientific and Technical Information of China (English)


    @@ This year, the main targets we have set for economic and social development are: increasing GDP by approximately 8 percent, creating jobs for more than 9 million people, keeping the urban registered unemployment rate no higher than 4.6 percent, holding the rise in consumer prices to around 3 percent, and improving the balance of payments.

  12. Target chambers for gammashpere

    Energy Technology Data Exchange (ETDEWEB)

    Carpenter, M.P.; Falout, J.W.; Nardi, B.G. [and others


    One of our responsibilities for Gammasphere, was designing and constructing two target chambers and associated beamlines to be used with the spectrometer. The first chamber was used with the early implementation phase of Gammasphere, and consisted of two spun-Al hemispheres welded together giving a wall thickness of 0.063 inches and a diameter of 12 inches.

  13. ISOLDE back on target

    CERN Multimedia

    Anaïs Schaeffer


    Today, Friday 1 August, the ISOLDE installation, supplied by the beams of the PS Booster, restarted its physics programme. After a shutdown of almost a year and a half, there was a real buzz in the air as the first beam of protons hit the target of the first post-LS1 ISOLDE experiment.   One of the new target-handling robots installed by ISOLDE during LS1. Many improvements have been made to the ISOLDE installation during LS1. One of the main projects was the installation of new robots for handling the targets (see photo 1). “Our targets are bombarded by protons from the PS Booster’s beams and become very radioactive,” explains Maria Jose Garcia Borge, spokesperson for the ISOLDE collaboration. “They therefore need to be handled carefully, which is where the robots come in. The robots we had until now were already over 20 years old and were starting to suffer from the effects of radiation. So LS1 was a perfect opportunity to replace them with more moder...

  14. Targeted Therapy for Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Quinn, Thomas [Alphamed, Jackson, TN (United States); Moore, Herbert [Alphamed, Jackson, TN (United States)


    The research project entitled,” Targeted Therapy for Melanoma,” was focused on investigating the use of kidney protection measures to lower the non-specific kidney uptake of the radiolabeled Pb-DOTA-ReCCMSH peptide. Previous published work demonstrated that the kidney exhibited the highest non-target tissue uptake of the 212Pb/203Pb radiolabeled melanoma targeting peptide DOTA-ReCCMSH. The radiolabeled alpha-melanocyte stimulating hormone (α-MSH) peptide analog DOTA-Re(Arg11)CCMSH, which binds the melanocortin-1 receptor over-expressed on melanoma tumor cells, has shown promise as a PRRT agent in pre-clinical studies. High tumor uptake of 212Pb labeled DOTA-Re(Arg11)CCMSH resulted in tumor reduction or eradication in melanoma therapy studies. Of particular note was the 20-50% cure rate observed when melanoma mice were treated with alpha particle emitter 212Pb. However, as with most PRRT agents, high radiation doses to the kidneys where observed. To optimize tumor treatment efficacy and reduce nephrotoxicity, the tumor to kidney uptake ratio must be improved. Strategies to reduce kidney retention of the radiolabeled peptide, while not effecting tumor uptake and retention, can be broken into several categories including modification of the targeting peptide sequence and reducing proximal tubule reabsorption.

  15. Racemic (RSC,SRS-(2-{[1-allyloxycarbonyl-3-(methylsulfanylpropyl]iminomethyl}phenyl-κ3S,N,C1chloridoplatinum(II

    Directory of Open Access Journals (Sweden)

    Katsuhiro Isozaki


    Full Text Available The title compound, [Pt(C15H18NO2SCl], was obtained by the cyclometallation reaction of cis-bis(benzonitriledichloridoplatinum(II with N-benzylidene-l-methionine allyl ester in refluxing toluene. The PtII atom has a square-planar geometry and is tetra-coordinated by the Cl atom and the C, N and S atoms from the benzylidene methionine ester ligand. In the crystal structure, the S atoms show opposite chiral configurations with respect to the α-carbon of the methionine, reducing steric repulsion between the methyl and allyl ester groups.

  16. Polarization discrimination between repeater false-target and radar target

    Institute of Scientific and Technical Information of China (English)

    SHI LongFei; WANG XueSong; XIAO ShunPing


    High fidelity repeater false-target badly affects a radar system's detecting, tracking, and data processing. It is an available approach of confronting false-target for radar that discriminates firstly and then eliminates. Whereas for the technique progress about the repeater false-target jam, it is more and more difficult to discriminate this jam in the time-domain, frequency-domain, or space-domain. The technique using polarization information to discriminate the target and false-target is discussed in this paper. With the difference that false-target signal vector's polarization ratio is fixed and target echo signal vector's polarization ratio is variational along with radar transmission signal's polarization, we transform the discrimination problem to beeline distinguish problem in the 2-dim complex space. The distributing characteristic expression of the false-target discrimination statistic is constructed, with which the discrimination ratio of false-target is analyzed. For the target case, the decomposed model of target scattering matrix and the concept of distinguish quantity are proposed. Then, the discrimination ratio of target can be forecasted according to target distinguish quantity. Thus, the performance of discrimination method has been analyzed integrally. The simulation results demonstrate the method in this paper is effective on the discrimination of target and false-target.

  17. Gene Targeting in Neuroendocrinology. (United States)

    Candlish, Michael; De Angelis, Roberto; Götz, Viktoria; Boehm, Ulrich


    Research in neuroendocrinology faces particular challenges due to the complex interactions between cells in the hypothalamus, in the pituitary gland and in peripheral tissues. Within the hypothalamus alone, attempting to target a specific neuronal cell type can be problematic due to the heterogeneous nature and level of cellular diversity of hypothalamic nuclei. Because of the inherent complexity of the reproductive axis, the use of animal models and in vivo experiments are often a prerequisite in reproductive neuroendocrinology. The advent of targeted genetic modifications, particularly in mice, has opened new avenues of neuroendocrine research. Within this review, we evaluate various mouse models used in reproductive neuroendocrinology and discuss the different approaches to generate genetically modified mice, along with their inherent advantages and disadvantages. We also discuss a variety of versatile genetic tools with a focus on their potential use in reproductive neuroendocrinology.

  18. Modelling Recycling Targets

    DEFF Research Database (Denmark)

    Hill, Amanda Louise; Leinikka Dall, Ole; Andersen, Frits M.


    the existing technological, organizational and legislative frameworks may affect recycling activities. The results of the analysis show that with current best practice recycling rates, the 50% recycling rate cannot be reached without recycling of household biowaste. It also shows that all Danish municipalities...... will need to make efforts to recover all recyclable fractions, and that the increased recycling efforts of only selected municipalities will not be sufficient to reach the target.......Within the European Union (EU) a paradigm shift is currently occurring in the waste sector, where EU waste directives and national waste strategies are placing emphasis on resource efficiency and recycling targets. The most recent Danish resource strategy calculates a national recycling rate of 22...

  19. Foucault on targets. (United States)

    Lynch, John


    This paper seeks to gain an insight into the behavior of a large NHS trust, in its attempt to meet a 90 percent patient access target, in a week long national audit in March 2003. Why did individuals act in dramatically different ways to their norm over this period. The work of Michel Foucault is used to explore these issues. The discourses of power, knowledge, discipline and governmentality are identified as key foucaudian themes that offer an alternative interpretation of how individuals behave in their place of work. The importance of the historical context of discourse within the NHS cannot be underestimated in shaping the behavior of individuals and groups today. Power and knowledge permeate NHS organizations through disciplinary practices and dressage. Governmentality seeks to maintain the status quo through disciplinary processes such as national healthcare targets. The natural response of NHS organizations is therefore, to seek order and conformity rather than disorder and conflict.

  20. Recognizing occluded MSTAR targets (United States)

    Bhanu, Bir; Jones, Grinnell, III


    This paper presents an approach for recognizing occluded vehicle targets in Synthetic Aperture Radar (SAR) images. Using quasi-invariant local features, SAR scattering center locations and magnitudes, a recognition algorithm is presented that successfully recognizes highly occluded versions of actual vehicles from the MSTAR public data. Extensive experimental results are presented to show the effect of occlusion on recognition performance in terms of Probability of Correct Identification, Receiver Operating Characteristic (ROC) curves and confusion matrices. The effect of occlusion on performance of this recognition algorithm is accurately predicted. Combined effects such as occlusion and measured positional noise, as well as occlusion and other observed extended operating conditions (e.g., articulation) are also addressed. Although excellent forced recognition results can be achieved at very high (70%) occlusion, practical limitations are found due to the similarity of unoccluded confuser vehicles to highly occluded targets.

  1. Targeting biodefense markets. (United States)

    Olinger, Gene Garrard


    The "World Vaccine Congress 2009" held in Washington D.C. (April 20-23, 2009) sponsored several sessions focused on the vaccine market targeting biodefense. On day one of the congress, a panel discussion outlined the federal progress in medical countermeasure preparedness that included emerging infections, influenza, and biodefense focuses. The second day, a session focused on the biodefense vaccine market with both government and industry members discussing the opportunities and challenges associated with the budding market.

  2. Implementing Target Value Design. (United States)

    Alves, Thais da C L; Lichtig, Will; Rybkowski, Zofia K


    An alternative to the traditional way of designing projects is the process of target value design (TVD), which takes different departure points to start the design process. The TVD process starts with the client defining an allowable cost that needs to be met by the design and construction teams. An expected cost in the TVD process is defined through multiple interactions between multiple stakeholders who define wishes and others who define ways of achieving these wishes. Finally, a target cost is defined based on the expected profit the design and construction teams are expecting to make. TVD follows a series of continuous improvement efforts aimed at reaching the desired goals for the project and its associated target value cost. The process takes advantage of rapid cycles of suggestions, analyses, and implementation that starts with the definition of value for the client. In the traditional design process, the goal is to identify user preferences and find solutions that meet the needs of the client's expressed preferences. In the lean design process, the goal is to educate users about their values and advocate for a better facility over the long run; this way owners can help contractors and designers to identify better solutions. This article aims to inform the healthcare community about tools and techniques commonly used during the TVD process and how they can be used to educate and support project participants in developing better solutions to meet their needs now as well as in the future.

  3. Follicular penetration and targeting. (United States)

    Lademann, Jürgen; Otberg, Nina; Jacobi, Ute; Hoffman, Robert M; Blume-Peytavi, Ulrike


    In the past, intercellular penetration was assumed to be the most important penetration pathway of topically applied substances. First hints that follicular penetration needs to be taken into consideration were confirmed by recent investigations, presented during the workshop "Follicular Penetration and Targeting" at the 4th Intercontinental Meeting of Hair Research Societies", in Berlin 2004. Hair follicles represent an efficient reservoir for the penetration of topically applied substances with subsequent targeting of distinct cell populations, e.g., nestin-expressing follicular bulge cells. The volume of this reservoir can be determined by differential stripping technology. The follicular penetration processes are significantly influenced by the state of the follicular infundibulum; recent experimental investigations could demonstrate that it is essential to distinguish between open and closed hair follicles. Topically applied substances can only penetrate into open hair follicle. Knowledge of follicular penetration is of high clinical relevance for functional targeting of distinct follicular regions. Human hair follicles show a hair-cycle-dependent variation of the dense neuronal and vascular network. Moreover, during hair follicle cycling with initiation of anagen, newly formed vessels occur. Thus, the potential of nestin-expressing hair follicle stem cells to form neurons and blood vessels was investigated.

  4. Targeted therapy for sarcomas

    Directory of Open Access Journals (Sweden)

    Forscher C


    Full Text Available Charles Forscher,1 Monica Mita,2 Robert Figlin3 1Sarcoma Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 2Experimental Therapeutics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; 3Academic Development Program, Samuel Oschin Comprehensive Cancer Institute, and Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA Abstract: Sarcomas are tumors of mesenchymal origin that make up approximately 1% of human cancers. They may arise as primary tumors in either bone or soft tissue, with approximately 11,280 soft tissue tumors and 2,650 bone tumors diagnosed each year in the United States. There are at least 50 different subtypes of soft tissue sarcoma, with new ones described with ever-increasing frequency. One way to look at sarcomas is to divide them into categories on the basis of their genetic make-up. One group of sarcomas has an identifiable, relatively simple genetic signature, such as the X:18 translocation seen in synovial sarcoma or the 11:22 translocation seen in Ewing's sarcoma. These specific abnormalities often lead to the presence of fusion proteins, such as EWS-FLI1 in Ewing's sarcoma, which are helpful as diagnostic tools and may become therapeutic targets in the future. Another group of sarcomas is characterized by complex genetic abnormalities as seen in leiomyosarcoma, osteosarcoma, and undifferentiated sarcoma. It is important to keep these distinctions in mind when contemplating the development of targeted agents for sarcomas. Different abnormalities in sarcoma could be divided by tumor subtype or by the molecular or pathway abnormality. However, some existing drugs or drugs in development may interfere with or alter more than one of the presented pathways. Keywords: sarcoma, targeted agents, tyrosine kinase inhibitors, mTor inhibition

  5. Targeting Prostate Cancer Metastasis (United States)


    AWARD NUMBER: W81XWH-14-1-0412 TITLE: "Targeting Prostate Cancer Metastasis " PRINCIPAL INVESTIGATOR: Yong Teng CONTRACTING ORGANIZATION: Prost a t e Cancer Metastasi s Sb. GRANT NUMBER W81XWH- 14- 1- 0 41 2 Sc. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Sd. PROJECT NUMBER YongTeng Se...r egulator in contr olling metastasis of p r ost a t e cancer and i nhi b i t i ng i t prevent s met ast asis . There are no drugs available to tar

  6. Open Targets: a platform for therapeutic target identification and validation (United States)

    Koscielny, Gautier; An, Peter; Carvalho-Silva, Denise; Cham, Jennifer A.; Fumis, Luca; Gasparyan, Rippa; Hasan, Samiul; Karamanis, Nikiforos; Maguire, Michael; Papa, Eliseo; Pierleoni, Andrea; Pignatelli, Miguel; Platt, Theo; Rowland, Francis; Wankar, Priyanka; Bento, A. Patrícia; Burdett, Tony; Fabregat, Antonio; Forbes, Simon; Gaulton, Anna; Gonzalez, Cristina Yenyxe; Hermjakob, Henning; Hersey, Anne; Jupe, Steven; Kafkas, Şenay; Keays, Maria; Leroy, Catherine; Lopez, Francisco-Javier; Magarinos, Maria Paula; Malone, James; McEntyre, Johanna; Munoz-Pomer Fuentes, Alfonso; O'Donovan, Claire; Papatheodorou, Irene; Parkinson, Helen; Palka, Barbara; Paschall, Justin; Petryszak, Robert; Pratanwanich, Naruemon; Sarntivijal, Sirarat; Saunders, Gary; Sidiropoulos, Konstantinos; Smith, Thomas; Sondka, Zbyslaw; Stegle, Oliver; Tang, Y. Amy; Turner, Edward; Vaughan, Brendan; Vrousgou, Olga; Watkins, Xavier; Martin, Maria-Jesus; Sanseau, Philippe; Vamathevan, Jessica; Birney, Ewan; Barrett, Jeffrey; Dunham, Ian


    We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at PMID:27899665

  7. Low intensity beam target unit

    CERN Multimedia


    This is a wheel fitted with many targets around its periphery (each with three longitudinally arranged thin rods) of which one is placed into the beam via a rotation of the wheel. Upstream of each target is placed a luminescent screen, aligbed on each target axis and viewed with a TV camera, to make sure that one is hitting the target. This target unit was probably used to study target's behaviour (like beam heating). Gualtiero Del Torre stands on the left, Pierre Gerdil on the right.

  8. Targeting adipose tissue

    Directory of Open Access Journals (Sweden)

    Haas Bodo


    Full Text Available Abstract Two different types of adipose tissues can be found in humans enabling them to respond to starvation and cold: white adipose tissue (WAT is generally known and stores excess energy in the form of triacylglycerol (TG, insulates against cold, and serves as a mechanical cushion. Brown adipose tissue (BAT helps newborns to cope with cold. BAT has the capacity to uncouple the mitochondrial respiratory chain, thereby generating heat rather than adenosine triphosphate (ATP. The previously widely held view was that BAT disappears rapidly after birth and is no longer present in adult humans. Using positron emission tomography (PET, however, it was recently shown that metabolically active BAT occurs in defined regions and scattered in WAT of the adult and possibly has an influence on whole-body energy homeostasis. In obese individuals adipose tissue is at the center of metabolic syndrome. Targeting of WAT by thiazolidinediones (TZDs, activators of peroxisome proliferator-activated receptor γ (PPARγ a ‘master’ regulator of fat cell biology, is a current therapy for the treatment of type 2 diabetes. Since its unique capacity to increase energy consumption of the body and to dissipate surplus energy as heat, BAT offers new perspectives as a therapeutic target for the treatment of obesity and associated diseases such as type 2 diabetes and metabolic syndrome. Recent discoveries of new signaling pathways of BAT development give rise to new therapeutic possibilities in order to influence BAT content and activity.

  9. Target Housing Material Options

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)


    With gas cooling, heat transfer coefficients are low compared to water. The benefit of gas from a heat transfer point of view is that there is really no upper temperature limit for the coolant, as compared to water, which is limited ultimately by the critical point, and in practice the critical heat flux. In our case with parallel flow channels, water is limited to even lower operating limits by nucleate boiling. So gas can get as hot as the containment material will allow, but to get the density and heat transfer up to something reasonable, we must also increase pressure, thus increasing stress on the containment, namely the front and back faces. We are designing to ASME BPVC, which, for most materials allows a maximum stress of UTS/3. So we want the highest possible UTS. For reference, the front face stress in the 12 mm target at 300 psi was about 90 MPa. The inconel 718 allowable stress at 900°C is 1/3 of 517 or 172 MPa. So we are in a very safe place, but the uTS is dropping rapidly with temperature above 900°C. As we increase target diameter, the challenge will be to keep the stress down. We are probably looking at keeping the allowable at or above the present value, and at as high a temperature as possible.

  10. Targeted therapy in melanoma. (United States)

    Kudchadkar, Ragini R; Smalley, Keiran S M; Glass, L Frank; Trimble, James S; Sondak, Vernon K


    Since the discovery of activating mutations in the BRAF oncogene in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. We review the latest developments in our understanding of the role of BRAF/MEK/ERK pathway signaling in melanoma, and the development of inhibitors of this pathway. We also explore alternative mutations seen in melanoma, such as NRAS, KIT, GNAQ, and GNA11, and the drug development that is ongoing based on this biology. Strategies for the management of the vexing clinical problem of BRAF inhibitor resistance, primarily via combination therapy, are outlined. With the recent approval of the BRAF inhibitor vemurafenib for stage IV metastatic melanoma, use of this agent is expanding in the United States. Thus, management of the skin toxicities of this agent, such as squamous cell carcinomas, "acneiform" eruptions, hand-foot syndrome, and panniculitis, will be a growing problem facing dermatologists today. We discuss the toxicities of targeted agents in use for melanoma, in particular the dermatologic effects and the management of these skin toxicities.

  11. A Note on Inflation Targeting. (United States)

    Lai, Ching-chong; Chang, Juin-jen


    Presents a pedagogical graphical exposition to illustrate the stabilizing effect of price target zones. Finds that authorities' commitment to defend a price target zone affects the public's inflation expectations and, in turn, reduces actual inflation. (RLH)

  12. Bradycardia During Targeted Temperature Management

    DEFF Research Database (Denmark)

    Thomsen, Jakob Hartvig; Nielsen, Niklas; Hassager, Christian


    OBJECTIVES: Bradycardia is common during targeted temperature management, likely being a physiologic response to lower body temperature, and has recently been associated with favorable outcome following out-of-hospital cardiac arrest in smaller observational studies. The present study sought...... to confirm this finding in a large multicenter cohort of patients treated with targeted temperature management at 33°C and explore the response to targeted temperature management targeting 36°C. DESIGN: Post hoc analysis of a prospective randomized study. SETTING: Thirty-six ICUs in 10 countries. PATIENTS......: We studied 447 (targeted temperature management = 33°C) and 430 (targeted temperature management = 36°C) comatose out-of-hospital cardiac arrest patients with available heart rate data, randomly assigned in the targeted temperature management trial from 2010 to 2013. INTERVENTIONS: Targeted...

  13. Scaling of exploding pusher targets

    Energy Technology Data Exchange (ETDEWEB)

    Nuckolls, J.H.


    A theory of exploding pusher laser pusher targets is compared to results of LASNEX calculations and to Livermore experiments. A scaling relationship is described which predicts the optimum target/pulse combinations as a function of the laser power.

  14. Double-negative feedback between S-phase cyclin-CDK and CKI generates abruptness in the G1/S switch

    Directory of Open Access Journals (Sweden)

    Rainis eVenta


    Full Text Available The G1/S transition is a crucial decision point in the cell cycle. At G1/S, there is an abrupt switch from a state of high CDK inhibitor (CKI levels and low S-phase CDK activity to a state of high S-phase CDK activity and degraded CKI. In budding yeast, this transition is triggered by phosphorylation of the Cdk1 inhibitor Sic1 at multiple sites by G1-phase CDK (Cln1,2-Cdk1 and S-phase CDK (Clb5,6-Cdk1 complexes. Using mathematical modeling we demonstrate that the mechanistic basis for the abruptness and irreversibility of the G1/S transition is the highly specific phosphorylation of Sic1 by S-phase CDK complex. This switch is generated by a double negative feedback loop in which S-CDK1 phosphorylates Sic1, thus targeting it for destruction, and thereby liberating further S-CDK1 from the inhibitory Sic1-S-CDK1 complex. Our model predicts that the abruptness of the switch depends upon a strong binding affinity within the Sic1-S-CDK inhibitory complex. In vitro phosphorylation analysis using purified yeast proteins revealed that free Clb5-Cdk1 can create positive feedback by phosphorylating Sic1 that is bound in the inhibitory complex, and that Sic1 inhibits Clb5-Cdk1 with a sub-nanomolar inhibition constant. Our model also predicts that if the G1-phase CDK complex is too efficient at targeting Sic1 for destruction, then G1/S becomes a smooth and readily reversible transition. We propose that the optimal role for the G1-phase CDK in the switch would not be to act as a kinase activity directly responsible for abrupt degradation of CKI, but rather to act as a priming signal that initiates a positive feedback loop driven by emerging free S-phase CDK.

  15. ORION laser target diagnostics

    Energy Technology Data Exchange (ETDEWEB)

    Bentley, C. D.; Edwards, R. D.; Andrew, J. E.; James, S. F.; Gardner, M. D.; Comley, A. J.; Vaughan, K.; Horsfield, C. J.; Rubery, M. S.; Rothman, S. D.; Daykin, S.; Masoero, S. J.; Palmer, J. B.; Meadowcroft, A. L.; Williams, B. M.; Gumbrell, E. T.; Fyrth, J. D.; Brown, C. R. D.; Hill, M. P.; Oades, K. [Plasma Physics Department, Atomic Weapons Establishment, Aldermaston, Reading, Berkshire RG7 4PR (United Kingdom); and others


    The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

  16. [Targeted therapies for melanoma]. (United States)

    Leiter, U; Meier, F; Garbe, C


    Since the discovery of activating mutations in the BRAF oncogene and also stimulation of immune mediated antitumor response in melanoma, there has been remarkable progress in the development of targeted therapies for unresectable and metastatic melanoma. This article addresses the latest developments of BRAF/MEK/ERK pathway signaling. In addition, the development of drugs to attack alternative mutations in melanoma, such as NRAS and KIT is described. Strategies for the management of BRAF inhibitor resistance, such as with combination therapy, are outlined. Antitumor immune therapies with monoclonal antibodies such as ipilimumab which acts by promoting T-cell activation or antibody blockade of programmed death-1 (PD-1) led to a long term response in metastatic melanoma. Results of latest clinical studies including the toxicity profile are described. Due to selective kinase inhibitors and immune checkpoint blockade, the therapy of unresectable metastatic melanoma has greatly improved and long-term survival of patients with metastatic melanoma seems a real possibility.

  17. ORION laser target diagnostics. (United States)

    Bentley, C D; Edwards, R D; Andrew, J E; James, S F; Gardner, M D; Comley, A J; Vaughan, K; Horsfield, C J; Rubery, M S; Rothman, S D; Daykin, S; Masoero, S J; Palmer, J B; Meadowcroft, A L; Williams, B M; Gumbrell, E T; Fyrth, J D; Brown, C R D; Hill, M P; Oades, K; Wright, M J; Hood, B A; Kemshall, P


    The ORION laser facility is one of the UK's premier laser facilities which became operational at AWE in 2010. Its primary mission is one of stockpile stewardship, ORION will extend the UK's experimental plasma physics capability to the high temperature, high density regime relevant to Atomic Weapons Establishment's (AWE) program. The ORION laser combines ten laser beams operating in the ns regime with two sub ps short pulse chirped pulse amplification beams. This gives the UK a unique combined long pulse/short pulse laser capability which is not only available to AWE personnel but also gives access to our international partners and visiting UK academia. The ORION laser facility is equipped with a comprehensive suite of some 45 diagnostics covering optical, particle, and x-ray diagnostics all able to image the laser target interaction point. This paper focuses on a small selection of these diagnostics.

  18. Targeting of Antibodies using Aptamers



    The chapter presents a methodology for the rapid selection of aptamers against antibody targets. It is a detailed account of the various methodological steps that describe the selection of aptamers, including PCR steps, buffers to be used, target immobilisation, partitioning and amplification of aptamers, clonning and sequencing, to results in high affinity and specificity ligands for the chosen target antibody.

  19. EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage (United States)

    Kuroda, Shinji; Tam, Justina; Roth, Jack A; Sokolov, Konstantin; Ramesh, Rajagopal


    Background We have previously demonstrated the epidermal growth factor receptor (EGFR)-targeted hybrid plasmonic magnetic nanoparticles (225-NP) produce a therapeutic effect in human lung cancer cell lines in vitro. In the present study, we investigated the molecular mechanism of 225-NP-mediated antitumor activity both in vitro and in vivo using the EGFR-mutant HCC827 cell line. Methods The growth inhibitory effect of 225-NP on lung tumor cells was determined by cell viability and cell-cycle analysis. Protein expression related to autophagy, apoptosis, and DNA-damage were determined by Western blotting and immunofluorescence. An in vivo efficacy study was conducted using a human lung tumor xenograft mouse model. Results The 225-NP treatment markedly reduced tumor cell viability at 72 hours compared with the cell viability in control treatment groups. Cell-cycle analysis showed the percentage of cells in the G2/M phase was reduced when treated with 225-NP, with a concomitant increase in the number of cells in Sub-G1 phase, indicative of cell death. Western blotting showed LC3B and PARP cleavage, indicating 225-NP-treatment activated both autophagy- and apoptosis-mediated cell death. The 225-NP strongly induced γH2AX and phosphorylated histone H3, markers indicative of DNA damage and mitosis, respectively. Additionally, significant γH2AX foci formation was observed in 225-NP-treated cells compared with control treatment groups, suggesting 225-NP induced cell death by triggering DNA damage. The 225-NP-mediated DNA damage involved abrogation of the G2/M checkpoint by inhibiting BRCA1, Chk1, and phospho-Cdc2/CDK1 protein expression. In vivo therapy studies showed 225-NP treatment reduced EGFR phosphorylation, increased γH2AX foci, and induced tumor cell apoptosis, resulting in suppression of tumor growth. Conclusion The 225-NP treatment induces DNA damage and abrogates G2/M phase of the cell cycle, leading to cellular apoptosis and suppression of lung tumor growth

  20. EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage

    Directory of Open Access Journals (Sweden)

    Kuroda S


    G2/M checkpoint by inhibiting BRCA1, Chk1, and phospho-Cdc2/CDK1 protein expression. In vivo therapy studies showed 225-NP treatment reduced EGFR phosphorylation, increased γH2AX foci, and induced tumor cell apoptosis, resulting in suppression of tumor growth. Conclusion: The 225-NP treatment induces DNA damage and abrogates G2/M phase of the cell cycle, leading to cellular apoptosis and suppression of lung tumor growth both in vitro and in vivo. Our findings provide a rationale for combining 225-NP with other DNA-damaging agents for achieving enhanced anticancer activity. Keywords: lung cancer, epidermal growth factor receptor, autophagy

  1. Emerging targets in migraine. (United States)

    Hoffmann, Jan; Goadsby, Peter J


    Migraine is a common and highly disabling neurological disorder. Despite the complexity of its pathophysiology, substantial advances have been achieved over the past 20 years in its understanding, as well as the development of pharmacological treatment options. The development of serotonin 5-HT(1B/1D) receptor agonists ("triptans") substantially improved the acute treatment of migraine attacks. However, many migraineurs do not respond satisfactorily to triptans and cardiovascular co-morbidities limit their use in a significant number of patients. As migraine is increasingly considered to be a disorder of the brain, and preclinical and clinical data indicate that the observed vasodilation is merely an epiphenomenon, research has recently focused on the development of neurally acting compounds that lack vasoconstrictor properties. This review highlights the most important pharmacological targets for which compounds have been developed that are highly likely to enter or have already advanced into clinical trials for the acute and preventive treatment of migraine. In this context, preclinical and clinical data on compounds acting on calcitonin gene-related peptide or its receptor, the 5-HT(1F) receptor, nitric oxide synthase, and acid-sensing ion channel blockers are discussed.

  2. EURISOL High Power Targets

    CERN Document Server

    Kadi, Y; Lindroos, M; Ridikas, D; Stora, T; Tecchio, L; CERN. Geneva. BE Department


    Modern Nuclear Physics requires access to higher yields of rare isotopes, that relies on further development of the In-flight and Isotope Separation On-Line (ISOL) production methods. The limits of the In-Flight method will be applied via the next generation facilities FAIR in Germany, RIKEN in Japan and RIBF in the USA. The ISOL method will be explored at facilities including ISAC-TRIUMF in Canada, SPIRAL-2 in France, SPES in Italy, ISOLDE at CERN and eventually at the very ambitious multi-MW EURISOL facility. ISOL and in-flight facilities are complementary entities. While in-flight facilities excel in the production of very short lived radioisotopes independently of their chemical nature, ISOL facilities provide high Radioisotope Beam (RIB) intensities and excellent beam quality for 70 elements. Both production schemes are opening vast and rich fields of nuclear physics research. In this article we will introduce the targets planned for the EURISOL facility and highlight some of the technical and safety cha...

  3. Magnetic targeted drug delivery

    Directory of Open Access Journals (Sweden)

    Timothy Wiedmann


    Full Text Available Lung cancer is the most common cause of death from cancer in both men and women. Treatment by intravenous or oral administration of chemotherapy agents results in serious and often treatment-limiting side effects. Delivery of drugs directly to the lung by inhalation of an aerosol holds the promise of achieving a higher concentration in the lung with lower blood levels. To further enhance the selective lung deposition, it may be possible to target deposition by using external magnetic fields to direct the delivery of drug coupled to magnetic particles. Moreover, alternating magnetic fields can be used to induce particle heating, which in turn controls the drug release rate with the appropriate thermal sensitive material.With this goal, superparamagetic nanoparticles (SPNP were prepared and characterized, and enhanced magnetic deposition was demonstrated in vitro and in vivo. SPNPs were also incorporated into a lipid-based/SPNP aerosol formulation, and drug release was shown to be controlled by thermal activation. Because of the inherent imaging potential of SPNPs, this use of nanotechnology offers the possibility of coupling the diagnosis of lung cancer to drug release, which perhaps will ultimately provide the “magic bullet” that Paul Ehrlich originally sought.

  4. The target effect: visual memory for unnamed search targets. (United States)

    Thomas, Mark D; Williams, Carrick C


    Search targets are typically remembered much better than other objects even when they are viewed for less time. However, targets have two advantages that other objects in search displays do not have: They are identified categorically before the search, and finding them represents the goal of the search task. The current research investigated the contributions of both of these types of information to the long-term visual memory representations of search targets. Participants completed either a predefined search or a unique-object search in which targets were not defined with specific categorical labels before searching. Subsequent memory results indicated that search target memory was better than distractor memory even following ambiguously defined searches and when the distractors were viewed significantly longer. Superior target memory appears to result from a qualitatively different representation from those of distractor objects, indicating that decision processes influence visual memory.

  5. Facility target insert shielding assessment

    Energy Technology Data Exchange (ETDEWEB)

    Mocko, Michal [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)


    Main objective of this report is to assess the basic shielding requirements for the vertical target insert and retrieval port. We used the baseline design for the vertical target insert in our calculations. The insert sits in the 12”-diameter cylindrical shaft extending from the service alley in the top floor of the facility all the way down to the target location. The target retrieval mechanism is a long rod with the target assembly attached and running the entire length of the vertical shaft. The insert also houses the helium cooling supply and return lines each with 2” diameter. In the present study we focused on calculating the neutron and photon dose rate fields on top of the target insert/retrieval mechanism in the service alley. Additionally, we studied a few prototypical configurations of the shielding layers in the vertical insert as well as on the top.

  6. The OLYMPUS internal hydrogen target

    Energy Technology Data Exchange (ETDEWEB)

    Bernauer, J.C., E-mail: [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA 02139 (United States); Carassiti, V.; Ciullo, G. [Istituto Nazionale di Fisica Nucleare and Università, 44100 Ferrara (Italy); Henderson, B.S. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA 02139 (United States); Ihloff, E.; Kelsey, J. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA 02139 (United States); MIT-Bates Linear Accelerator Center, Middleton, MA 01949 (United States); Lenisa, P. [Istituto Nazionale di Fisica Nucleare and Università, 44100 Ferrara (Italy); Milner, R. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA 02139 (United States); MIT-Bates Linear Accelerator Center, Middleton, MA 01949 (United States); Schmidt, A. [Massachusetts Institute of Technology, Laboratory for Nuclear Science, Cambridge, MA 02139 (United States); Statera, M. [Istituto Nazionale di Fisica Nucleare and Università, 44100 Ferrara (Italy)


    An internal hydrogen target system was developed for the OLYMPUS experiment at DESY, in Hamburg, Germany. The target consisted of a long, thin-walled, tubular cell within an aluminum scattering chamber. Hydrogen entered at the center of the cell and exited through the ends, where it was removed from the beamline by a multistage pumping system. A cryogenic coldhead cooled the target cell to counteract heating from the beam and increase the density of hydrogen in the target. A fixed collimator protected the cell from synchrotron radiation and the beam halo. A series of wakefield suppressors reduced heating from beam wakefields. The target system was installed within the DORIS storage ring and was successfully operated during the course of the OLYMPUS experiment in 2012. Information on the design, fabrication, and performance of the target system is reported.

  7. Oxide Fiber Targets at ISOLDE

    CERN Document Server

    Köster, U; Carminati, D; Catherall, R; Cederkäll, J; Correia, J G; Crepieux, B; Dietrich, M; Elder, K; Fedosseev, V; Fraile-Prieto, L M; Franchoo, S; Fynbo, H O U; Georg, U; Giles, T; Joinet, A; Jonsson, O C; Kirchner, R; Lau, C; Lettry, Jacques; Maier, H J; Mishin, V I; Oinonen, M; Peräjärvi, K; Ravn, H L; Rinaldi, T; Santana-Leitner, M; Wahl, U; Weissman, L


    Many elements are rapidly released from oxide matrices. Some oxide powder targets show a fast sintering, thus losing their favorable release characteristics. Loosely packed oxyde fiber targets are less critical since they may maintain their open structure even when starting to fuse together at some contact points. The experience with various oxyde fiber targets (titania, zirconia, ceria and thoria) used in the last years at ISOLDE is reviewed. For short-lived isotopes of Cu, Ga and Xe the zirconia and ceria targets respectively provided significantly higher yields than any other target (metal foils, oxide powders, etc.) tested before. Titania fibers, which were not commercially available, were produced in a relic process by impregnation of a rayon felt in a titanium chloride solution and subsequent calcination by heating the dried felt in air. Thoria fibers were obtained either by the same process or by burning commercial gas lantern mantle cloth. In the future a beryllia fiber target could be used to produce...

  8. Learning About Intervention Target Zones


    Klein, Michael W; Karen K. Lewis


    This paper provides a framework for evaluating how market participants' beliefs about foreign exchange target zones change as they learn about central bank intervention policy. In order to examine this behavior, we first generalize the standard target zone model to allow for intra-marginal intervention. Intra-marginal intervention implies that the position of market participants' beliefs about the target zone can be determined from their beliefs about the likelihood of intervention. As an app...

  9. Data Mining for Target Marketing (United States)

    Levin, Nissan; Zahavi, Jacob

    Targeting is the core of marketing management. It is concerned with offering the right product/service to the customer at the right time and using the proper channel. In this chapter we discuss how Data Mining modeling and analysis can support targeting applications. We focus on three types of targeting models: continuous-choice models, discrete-choice models and in-market timing models, discussing alternative modeling for each application and decision making. We also discuss a range of pitfalls that one needs to be aware of in implementing a data mining solution for a targeting problem.

  10. Inflation Targeting and Inflation Persistence

    Institute of Scientific and Technical Information of China (English)



    This paper argues that the adoption of an inflation target reduces the persistence of inflation.We develop the theoretical literature on inflation persistence by introducing a Taylor Rule for monetary policy into a model of persistence and showing that inflation targets reduce inflation persistence.We investigate changes in the time series properties of inflation in seven countries that introduced inflation targets in the late 1980s or early 1990s.We find that the persistence of inflation is greatly reduced or eliminated following the introduction of inflation targets.

  11. Limits of Inflation Targeting Strategy

    Directory of Open Access Journals (Sweden)

    Aura Niculescu


    Full Text Available This paper evaluates the trade-off between output volatility and the variability of the inflation rate around its target (Romanian case. The optimal choice for National Bank of Romania (NBR, in our opinion, is the flexible inflation targeting. For this purpose, NBR must explain the loss function and the optimal monetary policy rule. We then argued that this Romanian authority – NBR – can substantially improve its credibility under inflation targeting policy regime by becoming more accountable and transparent. Is the direct inflation targeting the best choice for the monetary policy regime in Romanian economy?

  12. Target engagement in lead generation. (United States)

    Durham, Timothy B; Blanco, Maria-Jesus


    The pharmaceutical industry is currently facing multiple challenges, in particular the low number of new drug approvals in spite of the high level of R&D investment. In order to improve target selection and assess properly the clinical hypothesis, it is important to start building an integrated drug discovery approach during Lead Generation. This should include special emphasis on evaluating target engagement in the target tissue and linking preclinical to clinical readouts. In this review, we would like to illustrate several strategies and technologies for assessing target engagement and the value of its application to medicinal chemistry efforts.

  13. Therapeutic Targeting of Telomerase

    Directory of Open Access Journals (Sweden)

    Kathrin Jäger


    Full Text Available Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT, which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer. Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies. Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination

  14. Transverse target spin asymmetries on a proton target at COMPASS

    CERN Document Server

    Richter, Andreas


    Transversity and transverse momentum-dependent parton distribution functions (TMDs) are been measured in semi-inclusive deep inelastic scattering (SIDIS) by using a transversely polarized target at the COMPASS experiment. COMPASS is a fixed target experiment at the CERN M2 beamline, which provides a 160GeV/c polarized m+ beam. In the years 2002-2004 COMPASS has collected data with a transversely polarized deuteron 6LiD target. In 2007, COMPASS has used for the first time a proton NH3 target. To access transversity COMPASS has used three different quark polarimeters: the Collins effect, responsible for an azimuthal asymmetry in the single hadron distribution, azimuthal target spin asymmetries of charged hadron pairs and the transverse polarisation of L hyperons. Beside this also the Sivers asymmetry arising from the correlation between the transverse nucleon spin and the quark intrinsic transverse momentum was measured. European

  15. ISOLDE target zone control room

    CERN Multimedia


    Operating the ISOLDE target handling robots from the dedicated control room in building 197. Monitors showing the movements of the robots (GPS in this case) in the target zone. The footage shows the actual operation by the operator as well as the different equipment such as camera electronics, camera motor controls, camera monitors and Kuka robot controls touch panel.

  16. The Bering Target Tracking Instrumentation

    DEFF Research Database (Denmark)

    Denver, Troelz; Jørgensen, John Leif; Betto, Maurizio;


    The key science instrument on the Bering satellite mission is a relative small telescope with an entrance aperture of 300 mm and a focal length between 500 and 1000 mm. The detection of potential targets is performed by one of the target scanning advanced stellar compasses (ASCs). This procedure...

  17. Treating rheumatoid arthritis to target

    DEFF Research Database (Denmark)

    Smolen, Josef S; Breedveld, Ferdinand C; Burmester, Gerd R


    BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards...

  18. Targeting vaccines to dendritic cells

    DEFF Research Database (Denmark)

    Foged, Camilla; Sundblad, Anne; Hovgaard, Lars


    delivery systems (DDS) with adjuvant effect that target DC directly and induce optimal immune responses. This paper will review the current knowledge of DC physiology as well as the progress in the field of novel vaccination strategies that directly or indirectly aim at targeting DC....

  19. Treating rheumatoid arthritis to target

    DEFF Research Database (Denmark)

    Smolen, Josef S; Aletaha, Daniel; Bijlsma, Johannes W J;


    BACKGROUND: Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA). OBJECTIVE: /st> To develop recommendations for achieving optimal therapeutic outcomes in RA. METHODS...

  20. Oxide fiber targets at ISOLDE

    DEFF Research Database (Denmark)

    Köster, U.; Bergmann, U.C.; Carminati, D.


    Many elements are rapidly released from oxide matrices. Some oxide powder targets show a fast sintering, thus losing their favorable release characteristics. Loosely packed oxide fiber targets are less critical since they may maintain their open structure even when starting to fuse together at so...

  1. Dual targeting of peroxisomal proteins

    Directory of Open Access Journals (Sweden)

    Julia eAst


    Full Text Available Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed.

  2. Target-Searching on Percolation

    Institute of Scientific and Technical Information of China (English)


    We study target-searching processes on a percolation, on which a hunter tracks a target by smelling odors it emits. The odor intensity is supposed to be inversely proportional to the distance it propagates. The Monte Carlo simulation is performed on a 2-dimensional bond-percolation above the threshold. Having no idea of the location of the target, the hunter determines its moves only by random attempts in each direction. For lager percolation connectivity p (>~) 0.90, it reveals a scaling law for the searching time versus the distance to the position of the target. The scaling exponent is dependent on the sensitivity of the hunter. For smaller p, the scaling law is broken and the probability of finding out the target significantly reduces. The hunter seems trapped in the cluster of the percolation and can hardly reach the goal.

  3. Ocular toxicity of targeted therapies. (United States)

    Renouf, Daniel J; Velazquez-Martin, Juan P; Simpson, Rand; Siu, Lillian L; Bedard, Philippe L


    Molecularly targeted agents are commonly used in oncology practice, and many new targeted agents are currently being tested in clinical trials. Although these agents are thought to be more specific and less toxic then traditional cytotoxic chemotherapy, they are associated with a variety of toxicities, including ocular toxicity. Many of the molecules targeted by anticancer agents are also expressed in ocular tissues. We reviewed the literature for described ocular toxicities associated with both approved and investigational molecularly targeted agents. Ocular toxicity has been described with numerous approved targeted agents and also seems to be associated with several classes of agents currently being tested in early-phase clinical trials. We discuss the proposed pathogenesis, monitoring guidelines, and management recommendations. It is important for oncologists to be aware of the potential for ocular toxicity, with prompt recognition of symptoms that require referral to an ophthalmologist. Ongoing collaboration between oncologists and ocular disease specialists is critical as the use of molecularly targeted agents continues to expand and novel targeted drug combinations are developed.

  4. Targeting Peace: Understanding UN and EU Targeted Sanctions



    In recent years, the international community has increasingly come to abandon the use of comprehensive sanctions in favour of targeted sanctions. Unlike adopting a coercive strategy on entire states, actors like the United Nations (UN) and the European Union (EU) have come to resort to measures that are aimed at individuals, groups and government members. Targeted sanctions involve adopting measures such as asset freezes, travel bans, commodity sanctions, as well as arms embargoes. Eriksson a...

  5. Targeted biopharmaceuticals for cancer treatment. (United States)

    Zhou, Lufang; Xu, Ningning; Sun, Yan; Liu, Xiaoguang Margaret


    Cancer is a complex invasive genetic disease that causes significant mortality rate worldwide. Protein-based biopharmaceuticals have significantly extended the lives of millions of cancer patients. This article reviews the biological function and application of targeted anticancer biopharmaceuticals. We first discuss the specific antigens and core pathways that are used in the development of targeted cancer therapy. The innovative monoclonal antibodies, non-antibody proteins, and small molecules targeting these antigens or pathways are then reviewed. Finally, the current challenges in anticancer biopharmaceuticals development and the potential solutions to address these challenges are discussed.

  6. Tracking Target and Spiral Waves

    DEFF Research Database (Denmark)

    Jensen, Flemming G.; Sporring, Jon; Nielsen, Mads;


    A new algorithm for analyzing the evolution of patterns of spiral and target waves in large aspect ratio chemical systems is introduced. The algorithm does not depend on finding the spiral tip but locates the center of the pattern by a new concept, called the spiral focus, which is defined...... by the evolutes of the actual spiral or target wave. With the use of Gaussian smoothing, a robust method is developed that permits the identification of targets and spirals foci independently of the wave profile. Examples of an analysis of long image sequences from experiments with the Belousov...

  7. Strategically targeting MYC in cancer (United States)

    Posternak, Valeriya; Cole, Michael D.


    MYC is a major driver of cancer cell growth and mediates a transcriptional program spanning cell growth, the cell cycle, metabolism, and cell survival. Many efforts have been made to deliberately target MYC for cancer therapy. A variety of compounds have been generated to inhibit MYC function or stability, either directly or indirectly. The most direct inhibitors target the interaction between MYC and MAX, which is required for DNA binding. Unfortunately, these compounds do not have the desired pharmacokinetics and pharmacodynamics for in vivo application. Recent studies report the indirect inhibition of MYC through the development of two compounds, JQ1 and THZ1, which target factors involved in unique stages of transcription. These compounds appear to have significant therapeutic value for cancers with high levels of MYC, although some effects are MYC-independent. These approaches serve as a foundation for developing novel compounds to pharmacologically target MYC-driven cancers. PMID:27081479

  8. Gene targeting with retroviral vectors

    Energy Technology Data Exchange (ETDEWEB)

    Ellis, J.; Bernstein, A. (Toronto Univ., ON (Canada))


    The authors have designed and constructed integration-defective retroviral vectors to explore their potential for gene targeting in mammalian cells. Two nonoverlapping deletion mutants of the bacterial neomycin resistance (neo) gene were used to detect homologous recombination events between viral and chromosomal sequences. Stable neo gene correction events were selected at a frequency of approximately 1 G418/sup r/ cell per 3 x 10/sup 6/ infected cells. Analysis of the functional neo gene in independent targeted cell clones indicated that unintegrated retroviral linear DNA recombined with the target by gene conversion for variable distances into regions of nonhomology. In addition, transient neo gene correction events which were associated with the complete loss of the chromosomal target sequences were observed. These results demonstrated that retroviral vectors can recombine with homologous chromosomal sequences in rodent and human cells.

  9. Gene targeting in malaria parasites. (United States)

    Ménard, R; Janse, C


    Gene targeting, which permits alteration of a chosen gene in a predetermined way by homologous recombination, is an emerging technology in malaria research. Soon after the development of techniques for stable transformation of red blood cell stages of Plasmodium falciparum and Plasmodium berghei, genes of interest were disrupted in the two species. The main limitations of gene targeting in malaria parasites result from the intracellular growth and slow replication of these parasites. On the other hand, the technology is facilitated by the very high rate of homologous recombination following transformation with targeting constructs (approximately 100%). Here, we describe (i) the vector design and the type of mutation that may be generated in a target locus, (ii) the selection and screening strategies that can be used to identify clones with the desired modification, and (iii) the protocol that was used for disrupting the circumsporozoite protein (CS) and thrombospondin-related anonymous protein (TRAP) genes of P. berghei.

  10. Targeted therapy for pediatric glioma

    NARCIS (Netherlands)

    A.K. Olow


    This thesis assesses molecular underpinnings of responses to promising targeted agents for pediatric tumors of Central Nervous System (CNS), incorporating preclinical testing of novel and translatable combination therapies to define the best therapy for each tumor cell specific molecular aberration.

  11. After treat-to-target

    DEFF Research Database (Denmark)

    Wakefield, Richard J; D'Agostino, Maria Antonietta; Naredo, Esperanza;


    have recently formed a research network - the Targeted Ultrasound Initiative (TUI) group. The statement proposes that targeting therapy to PD activity provides superior outcomes compared with treating to clinical targets alone and introduces the rationale for a new randomised trial using targeted...... defined by clinical remission criteria (disease activity score, simplified disease activity index, etc) does not always equate to the complete absence of inflammation as measured by new sensitive imaging techniques such as ultrasound (US) . There is evidence that imaging synovitis is frequently found...... in these patients and associated with adverse clinical and functional outcomes. This article reviews the data regarding remission, ultrasound imaging and outcomes in patients with RA to provide the background to a consensus statement from an international collaboration of ultrasonographers and rheumatologists who...

  12. Targeted therapy: tailoring cancer treatment

    Institute of Scientific and Technical Information of China (English)

    Min Yan; Quentin Qiang Liu


    Targeted therapies include small-molecule inhibitors and monoclonal antibodies,have made treatment more tumor-specific and less toxic,and have opened new possibilities for tailoring cancer treatment.Nevertheless,there remain several challenges to targeted therapies,including molecular identification,drug resistance,and exploring reliable biomarkers.Here,we present several selected signaling pathways and molecular targets involved in human cancers including Aurora kinases,PI3K/mTOR signaling,FOXO-FOXM1 axis,and MDM2/MDM4-p53 interaction.Understanding the molecular mechanisms for tumorigenesis and development of drug resistance will provide new insights into drug discovery and design of therapeutic strategies for targeted therapies.

  13. "Cavitation in a Mercury Target"

    Energy Technology Data Exchange (ETDEWEB)

    West, C.D.


    Recent theoretical work on the formation of bubble nucleation centers by energetic particles leads to some reasonably credible calculations of the maximum negative pressure that might be sustained without bubble formation in the mercury target of the Spallation Neutron Source.

  14. Cavitation in a Mercury Target

    Energy Technology Data Exchange (ETDEWEB)

    West, C.D.


    Recent theoretical work on the formation of bubble nucleation centers by energetic particles leads to some reasonably credible calculations of the maximum negative pressure that might be sustained without bubble formation in the mercury target of the Spallation Neutron Source.

  15. Physics of Automatic Target Recognition

    CERN Document Server

    Sadjadi, Firooz


    Physics of Automatic Target Recognition addresses the fundamental physical bases of sensing, and information extraction in the state-of-the art automatic target recognition field. It explores both passive and active multispectral sensing, polarimetric diversity, complex signature exploitation, sensor and processing adaptation, transformation of electromagnetic and acoustic waves in their interactions with targets, background clutter, transmission media, and sensing elements. The general inverse scattering, and advanced signal processing techniques and scientific evaluation methodologies being used in this multi disciplinary field will be part of this exposition. The issues of modeling of target signatures in various spectral modalities, LADAR, IR, SAR, high resolution radar, acoustic, seismic, visible, hyperspectral, in diverse geometric aspects will be addressed. The methods for signal processing and classification will cover concepts such as sensor adaptive and artificial neural networks, time reversal filt...

  16. National Ignition Facility Target Chamber

    Energy Technology Data Exchange (ETDEWEB)

    Wavrik, R W; Cox, J R; Fleming, P J


    On June 11, 1999 the Department of Energy dedicated the single largest piece of the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory (LLNL) in Livermore, California. The ten (10) meter diameter aluminum target high vacuum chamber will serve as the working end of the largest laser in the world. The output of 192 laser beams will converge at the precise center of the chamber. The laser beams will enter the chamber in two by two arrays to illuminate 10 millimeter long gold cylinders called hohlraums enclosing 2 millimeter capsule containing deuterium, tritium and isotopes of hydrogen. The two isotopes will fuse, thereby creating temperatures and pressures resembling those found only inside stars and in detonated nuclear weapons, but on a minute scale. The NIF Project will serve as an essential facility to insure safety and reliability of our nation's nuclear arsenal as well as demonstrating inertial fusion's contribution to creating electrical power. The paper will discuss the requirements that had to be addressed during the design, fabrication and testing of the target chamber. A team from Sandia National Laboratories (SNL) and LLNL with input from industry performed the configuration and basic design of the target chamber. The method of fabrication and construction of the aluminum target chamber was devised by Pitt-Des Moines, Inc. (PDM). PDM also participated in the design of the chamber in areas such as the Target Chamber Realignment and Adjustment System, which would allow realignment of the sphere laser beams in the event of earth settlement or movement from a seismic event. During the fabrication of the target chamber the sphericity tolerances had to be addressed for the individual plates. Procedures were developed for forming, edge preparation and welding of individual plates. Construction plans were developed to allow the field construction of the target chamber to occur parallel to other NIF construction activities. This

  17. Target Oriented Drugs against Leishmania. (United States)


    the leishmanial source. Leishmanial strains L32 Leishmania tropica LRC L32 L137 Leishmania tropica LRC L137 L52 Leishmania donovani LRC L52 These...RESOLUTION TEST CHAR] 0REPORT NUMBER I TARGET ORIENTED DRUGS AGAINST LEISHMANIA (First Annual Summary Report) 0URI ZEHAVI, PhD and JOSEPH EL-ON, PhD...GOVT ACCESSION NO. 3. RE PIENT.S CATALOG NUMBER A....*( - ) S. TYPE OF REPORT & PERIOD COVERED TARGET ORIENTED DRUGS AGAINST LEISHMANIA 6 FIRST

  18. Targeted immunotherapy in Hodgkin lymphoma

    DEFF Research Database (Denmark)

    Hutchings, Martin


    In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13.......In this issue of Blood, Rothe et al introduce a new principle of targeted Hodgkin lymphoma (HL) immunotherapy in their report from a phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13....

  19. Nanotechnology of emerging targeting systems. (United States)

    Smith, S S


    Recent developments in the design and testing of complex nanoscale payload-carrying systems (i.e. systems with payloads that do not exceed 100 nm in size) are the focus of this brief review. Emerging systems include targeted single-walled nanotubes, viral capsids, dendrimers, gold nanoparticles, milled boron carbide nanoparticles, and protein nucleic acid assemblies. Significant advances are emerging with each of these bionanotechnological approaches to cellular targeting.

  20. Target-local Gromov compactness

    CERN Document Server

    Fish, Joel W


    We prove a version of Gromov's compactness theorem for pseudo-holomorphic curves which holds locally in the target symplectic manifold. This result applies to sequences of curves with an unbounded number of free boundary components, and in families of degenerating target manifolds which have unbounded geometry (e.g. no uniform energy threshold). Core elements of the proof regard curves as submanifolds (rather than maps) and then adapt methods from the theory of minimal surfaces.

  1. Nanotechnology of emerging targeting systems (United States)

    SMITH, S. S.


    Recent developments in the design and testing of complex nanoscale payload-carrying systems (i.e. systems with payloads that do not exceed 100 nm in size) are the focus of this brief review. Emerging systems include targeted single-walled nanotubes, viral capsids, dendrimers, gold nanoparticles, milled boron carbide nanoparticles, and protein nucleic acid assemblies. Significant advances are emerging with each of these bionanotechnological approaches to cellular targeting. PMID:21687833

  2. Radiation target analysis of RNA. (United States)

    Benstein, S L; Kempner, E


    Ribozymes are polynucleotide molecules with intrinsic catalytic activity, capable of cleaving nucleic acid substrates. Large RNA molecules were synthesized containing a hammerhead ribozyme moiety of 52 nucleotides linked to an inactive leader sequence, for total lengths of either 262 or 1226 nucleotides. Frozen RNAs were irradiated with high energy electrons. Surviving ribozyme activity was determined using the ability of the irradiated ribozymes to cleave a labeled substrate. The amount of intact RNA remaining was determined from the same irradiated samples by scanning the RNA band following denaturing gel electrophoresis. Radiation target analyses of these data revealed a structural target size of 80 kDa and a ribozyme activity target size of 15 kDa for the smaller ribozyme, and 319 kDa and 16 kDa, respectively, for the larger ribozyme. The disparity in target size for activity versus structure indicates that, in contrast to proteins, there is no spread of radiation damage far from the primary site of ionization in RNA molecules. The smaller target size for activity indicates that only primary ionizations occurring in the specific active region are effective. This is similar to the case for oligosaccharides. We concluded that the presence of the ribose sugar in the polymer chain restricts radiation damage to a small region and prevents major energy transfer throughout the molecule. Radiation target analysis should be a useful technique for evaluating local RNA:RNA and RNA:protein interactions in vitro.

  3. Oxide fiber targets at ISOLDE

    Energy Technology Data Exchange (ETDEWEB)

    Koester, U. E-mail:; Bergmann, U.C.; Carminati, D.; Catherall, R.; Cederkaell, J.; Correia, J.G.; Crepieux, B.; Dietrich, M.; Elder, K.; Fedoseyev, V.N.; Fraile, L.; Franchoo, S.; Fynbo, H.; Georg, U.; Giles, T.; Joinet, A.; Jonsson, O.C.; Kirchner, R.; Lau, Ch.; Lettry, J.; Maier, H.J.; Mishin, V.I.; Oinonen, M.; Peraejaervi, K.; Ravn, H.L.; Rinaldi, T.; Santana-Leitner, M.; Wahl, U.; Weissman, L


    Many elements are rapidly released from oxide matrices. Some oxide powder targets show a fast sintering, thus losing their favorable release characteristics. Loosely packed oxide fiber targets are less critical since they may maintain their open structure even when starting to fuse together at some contact points. The experience with various oxide fiber targets (titania, zirconia, ceria and thoria) used in the last years at ISOLDE is reviewed. For short-lived isotopes of Cu, Ga and Xe the zirconia and ceria targets respectively provided significantly higher yields than any other target (metal foils, oxide powders, etc.) tested before. Titania fibers, which were not commercially available, were produced in a relic process by impregnation of a rayon felt in a titanium chloride solution and subsequent calcination by heating the dried felt in air. Thoria fibers were obtained either by the same process or by burning commercial gas lantern mantle cloth. In the future a beryllia fiber target could be used to produce very intense {sup 6}He beams (order of 10{sup 13} ions per second) via the {sup 9}Be(n,{alpha}) reaction using spallation neutrons.

  4. Killing cells by targeting mitosis. (United States)

    Manchado, E; Guillamot, M; Malumbres, M


    Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis. As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.

  5. Target-oriented chaos control

    Energy Technology Data Exchange (ETDEWEB)

    Dattani, Justine [Centre for Mathematical Biology, Department of Mathematical Sciences, University of Bath, Bath BA2 7AY (United Kingdom); Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA (United Kingdom); Blake, Jack C.H. [Centre for Mathematical Biology, Department of Mathematical Sciences, University of Bath, Bath BA2 7AY (United Kingdom); Hilker, Frank M., E-mail: [Centre for Mathematical Biology, Department of Mathematical Sciences, University of Bath, Bath BA2 7AY (United Kingdom)


    Designing intervention methods to control chaotic behavior in dynamical systems remains a challenging problem, in particular for systems that are difficult to access or to measure. We propose a simple, intuitive technique that modifies the values of the state variables directly toward a certain target. The intervention takes into account the difference to the target value, and is a combination of traditional proportional feedback and constant feedback methods. It proves particularly useful when the target corresponds to the equilibrium of the uncontrolled system, and is available or can be estimated from expert knowledge (e.g. in biology and economy). -- Highlights: → We propose a chaos control method that forces the system to a certain target. → The intervention takes into account the difference to the target value. → It can be seen as a combination of proportional and constant feedback methods. → The method is very robust and highly efficient in the long-term. → It is particularly applicable when suitable target values are known or available.

  6. Unification of automatic target tracking and automatic target recognition (United States)

    Schachter, Bruce J.


    The subject being addressed is how an automatic target tracker (ATT) and an automatic target recognizer (ATR) can be fused together so tightly and so well that their distinctiveness becomes lost in the merger. This has historically not been the case outside of biology and a few academic papers. The biological model of ATT∪ATR arises from dynamic patterns of activity distributed across many neural circuits and structures (including retina). The information that the brain receives from the eyes is "old news" at the time that it receives it. The eyes and brain forecast a tracked object's future position, rather than relying on received retinal position. Anticipation of the next moment - building up a consistent perception - is accomplished under difficult conditions: motion (eyes, head, body, scene background, target) and processing limitations (neural noise, delays, eye jitter, distractions). Not only does the human vision system surmount these problems, but it has innate mechanisms to exploit motion in support of target detection and classification. Biological vision doesn't normally operate on snapshots. Feature extraction, detection and recognition are spatiotemporal. When vision is viewed as a spatiotemporal process, target detection, recognition, tracking, event detection and activity recognition, do not seem as distinct as they are in current ATT and ATR designs. They appear as similar mechanism taking place at varying time scales. A framework is provided for unifying ATT and ATR.

  7. Mannose receptor-targeted vaccines. (United States)

    Keler, Tibor; Ramakrishna, Venky; Fanger, Michael W


    Targeting antigens to endocytic receptors on professional antigen-presenting cells (APCs) represents an attractive strategy to enhance the efficacy of vaccines. Such APC-targeted vaccines have an exceptional ability to guide exogenous protein antigens into vesicles that efficiently process the antigen for major histocompatibility complex class I and class II presentation. Efficient targeting not only requires high specificity for the receptor that is abundantly expressed on the surface of APCs, but also the ability to be rapidly internalised and loaded into compartments that contain elements of the antigen-processing machinery. The mannose receptor (MR) and related C-type lectin receptors are particularly designed to sample antigens (self and non-self), much like pattern recognition receptors, to integrate the innate with adaptive immune responses. In fact, a variety of approaches involving delivery of antigens to the MR have demonstrated effective induction of potent cellular and humoral immune responses. Yet, although several lines of evidence in diverse experimental systems attest to the efficacy of targeted vaccine strategies, it is becoming increasingly clear that additional signals, such as those afforded by adjuvants, may be critical to elicit sustained immunity. Therefore, MR-targeted vaccines are likely to be most efficacious in vivo when combined with agents that elicit complementary activation signals. Certainly, a better understanding of the mechanism associated with the induction of immune responses as a result of targeting antigens to the MR, will be important in exploiting MR-targeted vaccines not only for mounting immune defenses against cancer and infectious disease, but also for specific induction of tolerance in the treatment of autoimmune disease.

  8. CPHD filter derivation for extended targets

    CERN Document Server

    Orguner, Umut


    This document derives the CPHD filter for extended targets. Only the update step is derived here. Target generated measurements, false alarms and prior are all assumed to be independent identically distributed cluster processes. We also prove here that the derived CPHD filter for extended targets reduce to PHD filter for extended targets and CPHD filter for standard targets under suitable assumptions.

  9. Neuroinflammation: a potential therapeutic target. (United States)

    Craft, Jeffrey M; Watterson, D Martin; Van Eldik, Linda J


    The increased appreciation of the importance of glial cell-propagated inflammation (termed 'neuroinflammation') in the progression of pathophysiology for diverse neurodegenerative diseases, has heightened interest in the rapid discovery of neuroinflammation-targeted therapeutics. Efforts include searches among existing drugs approved for other uses, as well as development of novel synthetic compounds that selectively downregulate neuroinflammatory responses. The use of existing drugs to target neuroinflammation has largely met with failure due to lack of efficacy or untoward side effects. However, the de novo development of new classes of therapeutics based on targeting selective aspects of glia activation pathways and glia-mediated pathophysiologies, versus targeting pathways of quantitative importance in non-CNS inflammatory responses, is yielding promising results in preclinical animal models. The authors briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to onset or progression of neurodegenerative diseases. The authors conclude with opinions based on recent experimental proofs of concept using preclinical animal models of pathophysiology. The focus is on Alzheimer's disease, but the concepts are transferrable to other neurodegenerative disorders with an inflammatory component.

  10. Integrin Targeted Delivery of Chemotherapeutics

    Directory of Open Access Journals (Sweden)

    Kai Chen, Xiaoyuan Chen


    Full Text Available Targeted delivery of chemotherapeutics is defined in the sense, that is, to maximize the therapeutic index of a chemotherapeutic agent by strictly localizing its pharmacological activity to the site or tissue of action. Integrins are a family of heterodimeric transmembrane glycoproteins involved in a wide range of cell-to-extracellular matrix (ECM and cell-to-cell interactions. As cell surface receptors, integrins readily interact with extracellular ligands and play a vital role in angiogenesis, leukocytes function and tumor development, which sets up integrins as an excellent target for chemotherapy treatment. The peptide ligands containing the arginine-glycine-aspartic acid (RGD, which displays a strong binding affinity and selectivity to integrins, particularly to integrin αvβ3, have been developed to conjugate with various conventional chemotherapeutic agents, such as small molecules, peptides and proteins, and nanoparticle-carried drugs for integtrin targeted therapeutic studies. This review highlights the recent advances in integrin targeted delivery of chemotherapeutic agents with emphasis on target of integrin αvβ3, and describes the considerations for the design of the diverse RGD peptide-chemotherapeutics conjugates and their major applications.

  11. Target-Centric Network Modeling

    DEFF Research Database (Denmark)

    Mitchell, Dr. William L.; Clark, Dr. Robert M.

    In Target-Centric Network Modeling: Case Studies in Analyzing Complex Intelligence Issues, authors Robert Clark and William Mitchell take an entirely new approach to teaching intelligence analysis. Unlike any other book on the market, it offers case study scenarios using actual intelligence repor....... Working through these cases, students will learn to manage and evaluate realistic intelligence accounts.......In Target-Centric Network Modeling: Case Studies in Analyzing Complex Intelligence Issues, authors Robert Clark and William Mitchell take an entirely new approach to teaching intelligence analysis. Unlike any other book on the market, it offers case study scenarios using actual intelligence......, and collaborative sharing in the process of creating a high-quality, actionable intelligence product. The case studies reflect the complexity of twenty-first century intelligence issues by dealing with multi-layered target networks that cut across political, economic, social, technological, and military issues...

  12. Antibiotic drugs targeting bacterial RNAs

    Directory of Open Access Journals (Sweden)

    Weiling Hong


    Full Text Available RNAs have diverse structures that include bulges and internal loops able to form tertiary contacts or serve as ligand binding sites. The recent increase in structural and functional information related to RNAs has put them in the limelight as a drug target for small molecule therapy. In addition, the recognition of the marked difference between prokaryotic and eukaryotic rRNA has led to the development of antibiotics that specifically target bacterial rRNA, reduce protein translation and thereby inhibit bacterial growth. To facilitate the development of new antibiotics targeting RNA, we here review the literature concerning such antibiotics, mRNA, riboswitch and tRNA and the key methodologies used for their screening.

  13. The SPES direct UCx target (United States)

    Andrighetto, A.; Antonucci, C.; Barbui, M.; Carturan, S.; Cervellera, F.; Cevolani, S.; Cinausero, M.; Colombo, P.; Dainelli, A.; di Bernardo, P.; Gramegna, F.; Maggioni, G.; Meneghetti, G.; Petrovich, C.; Piga, L.; Prete, G.; Rizzi, V.; Tonezzer, M.; Zafiropoulos, D.; Zanonato, P.


    A possible solution for a target system aimed at the production of exotic nuclei as a result of high energy fissions in 238U compounds has been analyzed. The proposed configuration is constituted by a primary proton beam (40 MeV, 0.2 mA) directly impinging on uranium carbide disks inserted within a cylindrical carbon box. This system has been conceived to obtain both a high number of neutron rich atoms (originated from about 1013 fissions/s) and a low power deposition in the target. In order to extract the fission fragments, the box has to be hold at 2000○C. The thermal analysis shows the capability of the thermal radiation to cool the disks with a reasonable margin below the material melting point. Moreover, the analyses of the thermo-mechanical behaviour and of the effusion times confirm the promising features of this target configuration.

  14. Targeted nanoparticles for colorectal cancer

    DEFF Research Database (Denmark)

    Cisterna, Bruno A.; Kamaly, Nazila; Choi, Won Il;


    Colorectal cancer (CRC) is highly prevalent worldwide, and despite notable progress in treatment still leads to significant morbidity and mortality. The use of nanoparticles as a drug delivery system has become one of the most promising strategies for cancer therapy. Targeted nanoparticles could...... take advantage of differentially expressed molecules on the surface of tumor cells, providing effective release of cytotoxic drugs. Several efforts have recently reported the use of diverse molecules as ligands on the surface of nanoparticles to interact with the tumor cells, enabling the effective...... delivery of antitumor agents. Here, we present recent advances in targeted nanoparticles against CRC and discuss the promising use of ligands and cellular targets in potential strategies for the treatment of CRCs....

  15. 3-Bromopyruvate: targets and outcomes. (United States)

    Shoshan, Maria C


    The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.

  16. A Cryogenic Infrared Calibration Target (United States)

    Wollack, E. J.; Kinzer, R. E., Jr.; Rinehart, S. A.


    A compact cryogenic calibration target is presented that has a peak diffuse reflectance, R < or = 0.003, from 800 to 4800/cm (12 - 2 microns ). Upon expanding the spectral range under consideration to 400-10,000/ cm-1 (25 - 1 microns) the observed performance gracefully degrades to R < or = 0.02 at the band edges. In the implementation described, a high-thermal-conductivity metallic substrate is textured with a pyramidal tiling and subsequently coated with a thin lossy dielectric coating that enables high absorption and thermal uniformity across the target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to approx.4 K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials-Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder-are characterized and presented

  17. Materials considerations in accelerator targets (United States)

    Peacock, H. B.; Iyer, N. C.; Louthan, M. R.


    Future nuclear materials production and/or the burn-up of long lived radioisotopes may be accomplished through the capture of spallation produced neutrons in accelerators. Aluminum clad-lead and/or lead alloys has been proposed as a spallation target. Aluminum was the cladding choice because of the low neutron absorption cross section, fast radioactivity decay, high thermal conductivity, and excellent fabricability. Metallic lead and lead oxide powders were considered for the target core with the fabrication options being casting or powder metallurgy (PM). Scoping tests to evaluate gravity casting, squeeze casting, and casting and swaging processes showed that, based on fabricability and heat transfer considerations, squeeze casting was the preferred option for manufacture of targets with initial core cladding contact. Thousands of aluminum clad aluminum-lithium alloy core targets and control rods for tritium production have been fabricated by coextrusion processes and successfully irradiated in the SRS reactors. Tritium retention in, and release from, the coextruded product was modeled from experimental and operational data. The model assumed that tritium atoms, formed by the 6Li(n,a)3He reaction, were produced in solid solution in the Al-Li alloy. Because of the low solubility of hydrogen isotopes in aluminum alloys, the irradiated Al-Li rapidly became supersaturated in tritium. Newly produced tritium atoms were trapped by lithium atoms to form a lithium tritide. The effective tritium pressure required for trap or tritide stability was the equilibrium decomposition pressure of tritium over a lithium tritide-aluminum mixture. The temperature dependence of tritium release was determined by the permeability of the cladding to tritium and the local equilibrium at the trap sites. The model can be used to calculate tritium release from aluminum clad, aluminum-lithium alloy targets during postulated accelerator operational and accident conditions. This paper describes

  18. Targeting α-synuclein oligomers

    DEFF Research Database (Denmark)

    van Diggelen, Femke


    . Although there is currently no cure for PD, αSn oligomers (αSOs) are a potential therapeutic target, but a major drawback it that little is known about the nature of PD-associated αSOs. The scientific literature describes a wide variety of protocols to generate αSOs in vitro, with a subsequent......+/K+ ATPase, V-type ATPase, VDAC, CaMKII and Rab-3A. The identification of these targets is a first step towards unravelling the toxic pathways which are activated upon synaptic binding of extracellularly added αSOs, and hopefully will contribute to the discovery of new disease modifying compounds, which can...

  19. Prediction of underwater target strength

    Institute of Scientific and Technical Information of China (English)

    WANG TongQing; Mohammad Amjad


    A model as well as its numerical method to calculate target strength of rigid body using Lighthill's acoustic analogy approach which developed from the propeller aircraft sound field study have been presented. The cases of ellipsoid target has been used to demonstrate the approach. The comparison of the numerical results with that of analytical formulation provides a satisfactory check for the validity of the approach. Some reasonable results have been discussed. The advantage of the present model is that it is suitable for any arbitrarily shaped rigid body moving with small Mach number.

  20. Targeted therapies for cutaneous melanoma. (United States)

    Kee, Damien; McArthur, Grant


    Melanoma is resistant to cytotoxic therapy, and treatment options for advanced disease have been limited historically. However, improved understanding of melanoma driver mutations, particularly those involving the mitogen-activated protein kinase pathway, has led to the development of targeted therapies that are effective in this previously treatment-refractory disease. In cutaneous melanomas with BRAF V600 mutations the selective RAF inhibitors, vemurafenib and dabrafenib, and the MEK inhibitor, trametinib, have demonstrated survival benefits. Early signals of efficacy have also been demonstrated with MEK inhibitors in melanomas with NRAS mutations, and KIT inhibitors offer promise in melanomas driven through activation of their target receptor.

  1. The Bering Autonomous Target Detection

    DEFF Research Database (Denmark)

    Jørgensen, John Leif; Denver, Troelz; Betto, Maurizio


    An autonomous asteroid target detection and tracking method has been developed. The method features near omnidirectionality and focus on high speed operations and completeness of search of the near space rather than the traditional faint object search methods, employed presently at the larger...... telescopes. The method has proven robust in operation and is well suited for use onboard spacecraft. As development target for the method and the associated instrumentation the asteroid research mission Bering has been used. Onboard a spacecraft, the autonomous detection is centered around the fully...

  2. Targeting autophagy in neurodegenerative diseases. (United States)

    Vidal, René L; Matus, Soledad; Bargsted, Leslie; Hetz, Claudio


    The most prevalent neurodegenerative disorders involve protein misfolding and the aggregation of specific proteins. Autophagy is becoming an attractive target to treat neurodegenerative disorders through the selective degradation of abnormally folded proteins by the lysosomal pathway. However, accumulating evidence indicates that autophagy impairment at different regulatory steps may contribute to the neurodegenerative process. Thus, a complex scenario is emerging where autophagy may play a dual role in neurodegenerative diseases by causing the downstream effect of promoting the degradation of misfolded proteins and an upstream effect where its deregulation perturbs global proteostasis, contributing to disease progression. Challenges in the future development of therapeutic strategies to target the autophagy pathway are discussed.

  3. [Biotherapy targeting the immune system]. (United States)

    Frenzel, Laurent


    The use of monoclonal antibody targeted therapy has changed the management of several diseases, including in hematology and immunology. The panel of the present available biotherapies allows a specific action at various stages of the immune response. Indeed, some of these molecules can target the naive T cell at the immunological synapse or the way of TH1, TH17 and regulatory T cell. Others may be more specific for the B cell and immunoglobulin. Some will even be active on both B and T cells.

  4. Dynamics of aerial target pursuit (United States)

    Pal, S.


    During pursuit and predation, aerial species engage in multitasking behavior that involve simultaneous target detection, tracking, decision-making, approach and capture. The mobility of the pursuer and the target in a three dimensional environment during predation makes the capture task highly complex. Many researchers have studied and analyzed prey capture dynamics in different aerial species such as insects and bats. This article focuses on reviewing the capture strategies adopted by these species while relying on different sensory variables (vision and acoustics) for navigation. In conclusion, the neural basis of these capture strategies and some applications of these strategies in bio-inspired navigation and control of engineered systems are discussed.

  5. Manifold knowledge extraction and target recognition (United States)

    Chao, Cai; Hua, Zhou


    Advanced mammalian target identification derived from the perception of target's manifold and measurement manifolddistance. It does not rely on object's segmented accuracy, not depend on target's variety model, and adapt to a range of changes on targets. In this paper, based on the existed manifold learning algorithm, set up a new bionic automatic target recognition model, discussed the targets manifold knowledge acquisition and the knowledge expression architecture, gave a manifold knowledge-based new method for automatic target recognition. Experiments show that the new method has a strong adaptability to targets various transform, and has a very high correctly identification probability.


    Institute of Scientific and Technical Information of China (English)



    Since the conventional open-loop optimal targeting of chaos is very sensitive to noise, a close-loop optimal targeting method is proposed to improve the targeting performance under noise. The present optimal targeting model takes into consideration both precision and speed of the targeting procedure. The parameters, rather than the output, of the targeting controller, are directly optimized to obtain optimal chaos targeting. Analysis regarding the mechanism is given from physics aspect and numerical experiment on the Hénon map is carried out to compare the targeting performance under noise between the close-loop and the open-loop methods.

  7. Targeted Therapies in Endometrial Cancer

    Directory of Open Access Journals (Sweden)

    Selen Dogan


    Full Text Available Endometrial cancer is the most common genital cancer in developed world. It is generally diagnosed in early stage and it has a favorable prognosis. However, advanced staged disease and recurrences are difficult to manage. There are some common genetic alterations related to endometrial carcinogenesis in similar fashion to other cancers. Personalized medicine, which means selection of best suited treatment for an individual, has gain attention in clinical care of patients in recent years. Targeted therapies were developed as a part of personalized or %u201Ctailored%u201D medicine and specifically acts on a target or biologic pathway. There are quite a number of molecular alteration points in endometrial cancer such as PTEN tumor suppressor genes, DNA mismatch repair genes, PI3K/AKT/mTOR pathway and p53 oncogene which all might be potential candidates for tailored targeted therapy. In recent years targeted therapies has clinical application in ovarian cancer patients and in near future with the advent of new agents these %u201Ctailored%u201D drugs will be in market for routine clinical practice in endometrial cancer patients, in primary disease and recurrences as well.

  8. Targeted Advertising and Social Status

    NARCIS (Netherlands)

    N. Vikander (Nick)


    textabstractThis paper shows how a firm can use non-targeted advertising to exploit consumers' desire for social status. A monopolist sells multiple varieties of a good to consumers who each care about what others believe about his wealth. Advertising allows consumers both to buy different varieties

  9. Bacterial Cytotoxins Target Rho GTPases (United States)

    Schmidt, Gudula; Aktories, Klaus


    Low molecular mass GTPases of the Rho family, which are involved in the regulation of the actin cytoskeleton and in various signal transduction processes, are the eukaryotic targets of bacterial protein toxins. The toxins covalently modify Rho proteins by ADP ribosylation, glucosylation, and deamidation, thereby inactivating and activating the GTPases.

  10. CERN neutrino project on target

    CERN Multimedia


    Scientists at CERN announced the completion of the target assembly for the CERN neutrinos to Gran Sasso project, CNGS. On schedule for start-up in May 2006, CNGS will send a beam of neutrinos through the Earth to the Gran Sasso laboratory 730 km away in Italy in a bid to unravel the mysteries of nature's most elusive particles (½ page)

  11. Natural products to target inflammation

    NARCIS (Netherlands)

    Allijn, Iris Eva


    Chapter 1 Most Western lifestyle diseases such as type 2 diabetes mellitus, cardiovascular disease and cancer have a chronic inflammatory process at its base. Therefore, inflammation is an important therapeutic target. Due to their potency, steroidal drugs dominate the current treatment of inflammat

  12. Uranium briquettes for irradiation target

    Energy Technology Data Exchange (ETDEWEB)

    Saliba-Silva, Adonis Marcelo; Garcia, Rafael Henrique Lazzari; Martins, Ilson Carlos; Carvalho, Elita Fontenele Urano de; Durazzo, Michelangelo, E-mail: saliba@ipen.b [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)


    Direct irradiation on targets inside nuclear research or multiple purpose reactors is a common route to produce {sup 99}Mo-{sup 99m}Tc radioisotopes. Nevertheless, since the imposed limits to use LEU uranium to prevent nuclear armament production, the amount of uranium loaded in target meats has physically increased and new processes have been proposed for production. Routes using metallic uranium thin film and UAl{sub x} dispersion have been used for this purpose. Both routes have their own issues, either by bringing difficulties to disassemble the aluminum case inside hot cells or by generating great amount of alkaline radioactive liquid rejects. A potential route might be the dispersion of powders of LEU metallic uranium and nickel, which are pressed as a blend inside a die and followed by pulse electroplating of nickel. The electroplating provides more strength to the briquettes and creates a barrier for gas evolution during neutronic disintegration of {sup 235}U. A target briquette platted with nickel encapsulated in an aluminum case to be irradiated may be an alternative possibility to replace other proposed targets. This work uses pulse Ni-electroplating over iron powder briquette to simulate the covering of uranium by nickel. The following parameters were applied 10 times for each sample: 900Hz, -0.84A/square centimeters with duty cycle of 0.1 in Watts Bath. It also presented the optical microscopy analysis of plated microstructure section. (author)

  13. Tumor targeting via integrin ligands

    Directory of Open Access Journals (Sweden)

    Udaya Kiran eMarelli


    Full Text Available Selective and targeted delivery of drugs to tumors is a major challenge for an effective cancer therapy and also to overcome the side effects associated with current treatments. Overexpression of various receptors on tumor cells is a characteristic structural and biochemical aspect of tumors and distinguishes them from physiologically normal cells. This abnormal feature is therefore suitable for selectively directing anticancer molecules to tumors by using ligands that can preferentially recognize such receptors. Several subtypes of integrin receptors that are crucial for cell adhesion, cell signaling, cell viability and motility have been shown to have an upregulated expression on cancer cells. Thus, ligands that recognize specific integrin subtypes represent excellent candidates to be conjugated to drugs or drug carrier systems and be targeted to tumors. In this regard, integrins recognizing the RGD cell adhesive sequence have been extensively targeted for tumor specific drug delivery. Here we review key recent examples on the presentation of RGD-based integrin ligands by means of distinct drug delivery systems, and discuss the prospects of such therapies to specifically target tumor cells.

  14. High power neutron production targets

    Energy Technology Data Exchange (ETDEWEB)

    Wender, S. [Los Alamos National Lab., NM (United States)


    The author describes issues of concern in the design of targets and associated systems for high power neutron production facilities. The facilities include uses for neutron scattering, accelerator driven transmutation, accelerator production of tritium, short pulse spallation sources, and long pulse spallation sources. Each of these applications requires a source with different design needs and consequently different implementation in practise.

  15. Particle physics using nuclear targets

    Energy Technology Data Exchange (ETDEWEB)

    Ferbel, T.


    The use of nuclear targets in particle physics is discussed and some recent results obtained in studies of hadronic interactions on nuclei summarized. In particular experimental findings on inclusive production and on coherent dissociation of mesons and baryons at high energies are presented. 41 references.

  16. Exploring targeted therapies in oncology

    NARCIS (Netherlands)

    Mom, Constantijne Helene


    Targeted therapy in oncology is treatment directed at specific biological pathways and processes that play a critical role in carcinogenesis. Increased knowledge regarding the molecular changes underlying tumor progression and metastatis has resulted in the development of agents that are designed to

  17. Targeted therapy using alpha emitters (United States)

    Vaidyanathan, Ganesan; Zalutsky, Michael R.


    Radionuclides such as and which decay by the emission of -particles are attractive for certain applications of targeted radiotherapy. The tissue penetration of and -particles is equivalent to only a few cell diameters, offering the possibility of combining cell-specific targeting with radiation of similar range. Unlike the -particles emitted by radionuclides such as and , -particles are radiation of high linear energy transfer and thus greater biological effectiveness. Several approaches have been explored for targeted radiotherapy with - and -labelled substances including colloids, monoclonal antibodies, metabolic precursors, receptor-avid ligands and other lower molecular weight molecules. An additional agent which exemplifies the promise of -emitting radiopharmaceuticals is meta-[]astatobenzylguanidine. The toxicity of this compound under single-cell conditions, determined both by []thymidine incorporation and by limiting dilution clonogenic assays, for human neuroblastoma cells is of the order of 1000 times higher than that of meta-[]iodobenzylguanidine. For meta-[]astatobenzylguanidine, the value was equivalent to only atoms bound per cell. These results suggest that meta-[]astatobenzylguanidine might be valuable for the targeted radiotherapy of micrometastatic neuroblastomas.

  18. Targeted Therapies for Kidney Cancer (United States)

    ... The most common side effects seen with this drug include fatigue, rash, diarrhea, increases in blood pressure, and redness, pain, swelling, ... other targets that help cancer cells grow. This drug is taken as a ... effects are nausea, diarrhea, changes in skin or hair color, mouth sores, ...

  19. Targeted multi-pinhole SPECT

    Energy Technology Data Exchange (ETDEWEB)

    Branderhorst, Woutjan; Blezer, Erwin L.A. [University Medical Centre Utrecht, Image Sciences Institute and Rudolf Magnus Institute of Neuroscience, Utrecht (Netherlands); Vastenhouw, Brendan; Have, Frans van der; Beekman, Freek J. [University Medical Centre Utrecht, Image Sciences Institute and Rudolf Magnus Institute of Neuroscience, Utrecht (Netherlands); Molecular Imaging Laboratories BV, Utrecht (Netherlands); Delft University of Technology, Section of Radiation Detection and Medical Imaging, Applied Sciences, Delft (Netherlands); Bleeker, Wim K. [Genmab BV, Utrecht (Netherlands)


    Small-animal single photon emission computed tomography (SPECT) with focused multi-pinhole collimation geometries allows scanning modes in which large amounts of photons can be collected from specific volumes of interest. Here we present new tools that improve targeted imaging of specific organs and tumours, and validate the effects of improved targeting of the pinhole focus. A SPECT system with 75 pinholes and stationary detectors was used (U-SPECT-II). An XYZ stage automatically translates the animal bed with a specific sequence in order to scan a selected volume of interest. Prior to stepping the animal through the collimator, integrated webcams acquire images of the animal. Using sliders, the user designates the desired volume to be scanned (e.g. a xenograft or specific organ) on these optical images. Optionally projections of an atlas are overlaid semiautomatically to locate specific organs. In order to assess the effects of more targeted imaging, scans of a resolution phantom and a mouse myocardial phantom, as well as in vivo mouse cardiac and tumour scans, were acquired with increased levels of targeting. Differences were evaluated in terms of count yield, hot rod visibility and contrast-to-noise ratio. By restricting focused SPECT scans to a 1.13-ml resolution phantom, count yield was increased by a factor 3.6, and visibility of small structures was significantly enhanced. At equal noise levels, the small-lesion contrast measured in the myocardial phantom was increased by 42%. Noise in in vivo images of a tumour and the mouse heart was significantly reduced. Targeted pinhole SPECT improves images and can be used to shorten scan times. Scan planning with optical cameras provides an effective tool to exploit this principle without the necessity for additional X-ray CT imaging. (orig.)

  20. Targeting targeted agents: open issues for clinical trial design

    Directory of Open Access Journals (Sweden)

    Giannarelli Diana


    Full Text Available Abstract Molecularly targeted agents for the treatment of solid tumors had entered the market in the last 5 years, with a great impact upon both the scientific community and the society. Many randomized phase III trials conducted in recent years with new targeted agents, despite previous data coming from preclinical research and from phase II trials were often promising, have produced disappointingly negative results. Some other trials have actually met their primary endpoint, demonstrating a statistically significant result favouring the experimental treatment. Unfortunately, with a few relevant exceptions, this advantage is often small, if not negligible, in absolute terms. The difference between statistical significance and clinical relevance should always be considered when translating clinical trials' results in the practice. The reason why this 'revolution' did not significantly impact on cancer treatment to displace chemotherapy from the patient' bedside is in part due to complicated, and in many cases, unknown, mechanisms of action of such drugs; indeed, the traditional way the clinical investigators were used to test the efficacy of 'older' chemotherapeutics, has become 'out of date' from the methodological perspective. As these drugs should be theoretically tailored upon featured bio-markers expressed by the patients, the clinical trial design should follow new rules based upon stronger hypotheses than those developed so far. Indeed, the early phases of basic and clinical drug development are crucial in the correct process which is able to correctly identify the target (when present. Targeted trial designs can result in easier studies, with less, better selected, and supported by stronger proofs of response evidences, patients, in order to not waste time and resources.

  1. Emerging targets in human lymphoma: targeting the MYD88 mutation

    Directory of Open Access Journals (Sweden)

    Wang JQ


    Full Text Available James Q Wang,* Yogesh S Jeelall,* Keisuke Horikawa* Department of Immunology, The John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia *All authors contributed equally to this manuscript Abstract: B cell neoplasms co-opt the molecular machinery of normal B cells for their survival. Technological advances in cancer genomics has significantly contributed to uncovering the root cause of aggressive lymphomas, revealing a previously unknown link between TLR signaling and B cell neoplasm. Recurrent oncogenic mutations in MYD88 have been found in 39% of the activated B cell-like subtype of diffuse large B cell lymphoma (ABC DLBCL. Interestingly, 29% of ABC DLBCL have a single amino acid substitution of proline for the leucine at position 265 (L265P, and the exact same variant has also been identified in a number of lymphoid malignancies. The MYD88 L265P variant was recently identified in 90% of Wadenstrom's macroglobulinemia patients. These recent developments warrant the need for novel diagnostic tools as well as targeted therapeutics. In this review, we discuss the physiological functions of MYD88 and focus on its role in B cell lymphomas, evaluating the potential for targeting oncogenic MYD88 in lymphoma. Keywords: MYD88, L265P mutation, lymphoma, targeted therapy

  2. Progress of gene targeting in mouse

    Institute of Scientific and Technical Information of China (English)


    Gene targeting is a powerful approach of study- ing the genefunction in vivo. Specific genetic modifications, including simple gene disruption, point mutations, large chromosomal deletions and rearrangements, targeted incor- poration of foreign genes, could be introduced into the mouse genome by gene targeting. Recent studies make it possible to do the gene targeting with temporal and spatial control.


    Institute of Scientific and Technical Information of China (English)

    Gao Gui; Kuang Gangyao; Jiang Yongmei; Wang Baosun; Gao Sheng


    A successful algorithm for detecting target groups is presented. Firstly, A global Constant False Alarm Rate (CFAR) detector is utilized to locate the potential target regions, and then the features are computed for target discrimination based on voting mechanism. Finally, Target groups are extracted. The results of experiments show the validity of this algorithm.

  4. Downstream targets of WRKY33. (United States)

    Petersen, Klaus; Fiil, Berthe Katrine; Mundy, John; Petersen, Morten


    Innate immunity signaling pathways in both animals and plants are regulated by mitogen-activated protein kinase (MAPK) cascades. In a recent publication we show that MPK4 and its substrate MKS1 interact with WRKY33 in vivo, and that WRKY33 is released from complexes with MPK4 upon infection. Transcriptome analysis of a wrky33 loss-of-function mutant identified a subset of defense-related genes as putative targets of WRKY33. These genes include PAD3 and CYP71A13, which encode cytochrome P450 monoxygenases required for synthesis of the antimicrobial phytoalexin camalexin. Chromatin immunoprecipitation confirmed that WRKY33 bound the promoter of PAD3 when plants were inoculated with pathogens. Here we further discuss the involvement of two other targets of WRKY33, NUDT6 and ROF2 in defense responses against invading pathogens.

  5. Downstream targets of WRKY33

    DEFF Research Database (Denmark)

    Petersen, Klaus; Fiil, Berthe Katrine; Mundy, John;


    Innate immunity signaling pathways in both animals and plants are regulated by mitogen-activated protein kinase (MAPK) cascades. In a recent publication we show that MPK4 and its substrate MKS1 interact with WRKY33 in vivo, and that WRKY33 is released from complexes with MPK4 upon infection....... Transcriptome analysis of a wrky33 loss-of-function mutant identified a subset of defense-related genes as putative targets of WRKY33. These genes include PAD3 and CYP71A13, which encode cytochrome P450 monoxygenases required for synthesis of the antimicrobial phytoalexin camalexin. Chromatin...... immunoprecipitation confirmed that WRKY33 bound the promoter of PAD3 when plants were inoculated with pathogens. Here we further discuss the involvement of two other targets of WRKY33, NUDT6 and ROF2 in defense responses against invading pathogens....

  6. Gastrointestinal hormones and their targets

    DEFF Research Database (Denmark)

    Rehfeld, Jens F.


    Gastrointestinal hormones are peptides released from endocrine cells and neurons in the digestive tract. More than 30 hormone genes are currently known to be expressed in the gastrointestinal tract, which makes the gut the largest hormone producing organ in the body. Modern biology makes......, paracrine, spermiocrine secretion etc.), so the same peptide may act as a blood-borne hormone, a neurotransmitter, a local growth factor, or a fertility factor. The molecular targets of each bioactive peptide are specific G-protein coupled receptors expressed in the cell membranes of different target cells...... it feasible to conceive the hormones under five headings: The structural homology groups a majority of the hormones into nine families, each of which is assumed to originate from one ancestral gene. The individual hormone gene often has multiple phenotypes due to alternative splicing, tandem organization...

  7. CNOOC Lifts 2011 Production Target

    Institute of Scientific and Technical Information of China (English)


    @@ China National Offshore Oil Corporation (CNOOC), China's top offshore oil and gas producer, has lifted its 2011 production target by up to 11 percent as new projects at home and overseas come on stream.The offshore oil giant, with a market capitalization of about US$105 billion, said in a statement released in late January 2011 that it aimed to produce between 355 and 365 million barrels of oil equivalent (BOE).Oil prices climbed 15 percent in 2010 on the back of expectations that a global economic recovery will drive the demand.Analysts are similarly bullish for 2011, predicting crude prices to trade at around US$100 for the year.CNOOC, the smallest of China's triumvirate of energy companies that also includes CNPC and Sinopee, said it targeted US$8.8 billion in capital expenditure for 2011.

  8. Endocrine disruptors targeting ERbeta function. (United States)

    Swedenborg, E; Pongratz, I; Gustafsson, J-A


    Endocrine disruptive chemicals (EDCs) circulating in the environment constitute a risk to ecosystems, wildlife and human health. Oestrogen receptor (ER) alpha and beta are targeted by various kinds of EDCs but the molecular mechanisms and long-term consequences of exposure are largely unknown. Some biological effects of EDCs are mediated by the aryl hydrocarbon receptor (AhR), which is a key player in the cellular defence against xenobiotic substances. Adding complexity to the picture, there is also accumulating evidence that AhR-ER pathways have an intricate interplay at multiple levels. In this review, we discuss some EDCs that affect the oestrogen pathway by targeting ERbeta. Furthermore, we describe some effects of AhR activities on the oestrogen system. Mechanisms as well as potential adverse effects on human health are discussed.

  9. Recurring Utterances - Targeting a Breakthrough

    Directory of Open Access Journals (Sweden)

    Jacqueline Stark


    The most interesting phenomenon is KB’s production of words from former sessions indicating that they are still ‘active’ and the production of completely novel incorrect words. The observable features indicate that immediate auditory processing is possible in the form of repeating target words. However, as soon as KB must retrieve information from the (semantic lexicon, even after being able to correctly ‘repeat’ the target word several times, he responds with a RU, perseveration, or paraphasia. Several of his productions can be characterized as aphasic confabulations which stem from a memory gap. Thus, although KB’s language impairment is severe, his responses across time indicate that step-by-step a breakthrough is being made.

  10. Genome engineering with targetable nucleases. (United States)

    Carroll, Dana


    Current technology enables the production of highly specific genome modifications with excellent efficiency and specificity. Key to this capability are targetable DNA cleavage reagents and cellular DNA repair pathways. The break made by these reagents can produce localized sequence changes through inaccurate nonhomologous end joining (NHEJ), often leading to gene inactivation. Alternatively, user-provided DNA can be used as a template for repair by homologous recombination (HR), leading to the introduction of desired sequence changes. This review describes three classes of targetable cleavage reagents: zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR/Cas RNA-guided nucleases (RGNs). As a group, these reagents have been successfully used to modify genomic sequences in a wide variety of cells and organisms, including humans. This review discusses the properties, advantages, and limitations of each system, as well as the specific considerations required for their use in different biological systems.

  11. Classical scattering from oscillating targets

    Energy Technology Data Exchange (ETDEWEB)

    Papachristou, P.K.; Diakonos, F.K.; Constantoudis, V.; Schmelcher, P.; Benet, L


    We study planar classical scattering from an oscillating heavy target whose dynamics defines a five-dimensional phase space. Although the system possesses no periodic orbits, and thus topological chaos is not present, the scattering functions display a variety of structures on different time scales. These structures are due to scattering events with a strong energy transfer from the projectile to the moving disk resulting in low-velocity peaks. We encounter initial conditions for which the projectile exhibits infinitely many bounces with the oscillating disk. Our numerical investigations are supported by analytical results on a specific model with a simple time-law. The observed properties possess universal character for scattering off oscillating targets.

  12. Antihyperlipidemic therapies targeting PCSK9. (United States)

    Weinreich, Michael; Frishman, William H


    Hyperlipidemia is a major cause of cardiovascular disease despite the availability of first-line cholesterol-lowering agents such as statins. A new therapeutic approach to lowering low-density lipoprotein-cholesterol (LDL-C) acts by blocking LDL-receptor degradation by serum proprotein convertase subtilisin kexin 9 (PCSK9). Human monoclonal antibodies that target PCSK9 and its interaction with the LDL receptor are now in clinical trials (REGN727/SAR23653, AMG145, and RN316). These agents are administered by either subcutaneous or intravenous routes, and have been shown to have major LDL-C and apolipoprotein B effects when combined with statins. A phase III clinical trial program evaluating clinical endpoints is now in progress. Other PCSK9-targeted approaches are in early stages of investigation, including natural inhibitors of PCSK9, RNA interference, and antisense inhibitors.

  13. Navy Advertising: Targeting Generation Z (United States)


    influence the navy recruiting and advertising goals. Results from our study can influence advertisement targeting goals and also better aid in the...250 advertising studies to deduce a formula on how advertising works . They developed a framework, seen in Figure 2, to help classify the advertising...advertising works : What do we really know? Journal of Marketing, 63(1), 26-43. By using the framework and classifying studies into different models

  14. Nonlinear Acoustic Characterization of Targets (United States)


    matching so as to transmit as much energy as possible into the test object. In addition to this limitation, ultrasound is only able to measure range by...metric arrays for standoff analysis of targets. In 1982, Yoneyama[4] discussed the nonlinear interaction of ultrasound with air as the “scattering of... cavitation effect. This produces a rectification at higher frequencies just as a diode does in an electrical circuit. This natural rectification allows

  15. The Automatic Measurement of Targets

    DEFF Research Database (Denmark)

    Höhle, Joachim


    The automatic measurement of targets is demonstrated by means of a theoretical example and by an interactive measuring program for real imagery from a réseau camera. The used strategy is a combination of two methods: the maximum correlation coefficient and the correlation in the subpixel range. F...... interactive software is also part of a computer-assisted learning program on digital photogrammetry....

  16. Electronic warfare target location methods

    CERN Document Server

    Poisel, Richard


    Describing the mathematical development underlying current and classical methods of geolocating electronic systems that are emitting, this newly revised and greatly expanded edition of a classic Artech House book offers practical guidance in electronic warfare target location. The Second Edition features a wealth of additional material including new chapters on time delay estimation, direction finding techniques, and the MUSIC algorithm. This practical resource provides you with critical design information on geolocation algorithms, and establishes the fundamentals of existing algorithms as a

  17. Targeted Communication and Investor Attention


    Boulland, Romain; Degeorge, François; Ginglinger, Edith


    In the spirit of Merton (1987) we find that targeted communication by firms raises investor attention. Continental European firms using English-language commercial press wires to disseminate corporate press releases exhibit less drift and more trading volume after their earnings announcements than firms that do not, consistent with communication on English speaking wires raising investor attention. Continental European firms using English-language commercial press wires also receive more pres...

  18. Cancer Immunotherapy of Targeting Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    JianmeiHou; LingTian; YuquanWei


    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.

  19. Targeting inflammation in metabolic syndrome. (United States)

    Welty, Francine K; Alfaddagh, Abdulhamied; Elajami, Tarec K


    The metabolic syndrome (MetS) is comprised of a cluster of closely related risk factors, including visceral adiposity, insulin resistance, hypertension, high triglyceride, and low high-density lipoprotein cholesterol; all of which increase the risk for the development of type 2 diabetes and cardiovascular disease. A chronic state of inflammation appears to be a central mechanism underlying the pathophysiology of insulin resistance and MetS. In this review, we summarize recent research which has provided insight into the mechanisms by which inflammation underlies the pathophysiology of the individual components of MetS including visceral adiposity, hyperglycemia and insulin resistance, dyslipidemia, and hypertension. On the basis of these mechanisms, we summarize therapeutic modalities to target inflammation in the MetS and its individual components. Current therapeutic modalities can modulate the individual components of MetS and have a direct anti-inflammatory effect. Lifestyle modifications including exercise, weight loss, and diets high in fruits, vegetables, fiber, whole grains, and low-fat dairy and low in saturated fat and glucose are recommended as a first line therapy. The Mediterranean and dietary approaches to stop hypertension diets are especially beneficial and have been shown to prevent development of MetS. Moreover, the Mediterranean diet has been associated with reductions in total and cardiovascular mortality. Omega-3 fatty acids and peroxisome proliferator-activated receptor α agonists lower high levels of triglyceride; their role in targeting inflammation is reviewed. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone blockers comprise pharmacologic therapies for hypertension but also target other aspects of MetS including inflammation. Statin drugs target many of the underlying inflammatory pathways involved in MetS.

  20. Multisensor Target Detection And Classification (United States)

    Ruck, Dennis W.; Rogers, Steven K.; Mills, James P.; Kabrisky, Matthew


    In this paper a new approach to the detection and classification of tactical targets using a multifunction laser radar sensor is developed. Targets of interest are tanks, jeeps, trucks, and other vehicles. Doppler images are segmented by developing a new technique which compensates for spurious doppler returns. Relative range images are segmented using an approach based on range gradients. The resultant shapes in the segmented images are then classified using Zernike moment invariants as shape descriptors. Two classification decision rules are implemented: a classical statistical nearest-neighbor approach and a multilayer perceptron architecture. The doppler segmentation algorithm was applied to a set of 180 real sensor images. An accurate segmentation was obtained for 89 percent of the images. The new doppler segmentation proved to be a robust method, and the moment invariants were effective in discriminating the tactical targets. Tanks were classified correctly 86 percent of the time. The most important result of this research is the demonstration of the use of a new information processing architecture for image processing applications.

  1. Renal Toxicities of Targeted Therapies. (United States)

    Abbas, Anum; Mirza, Mohsin M; Ganti, Apar Kishor; Tendulkar, Ketki


    With the incorporation of targeted therapies in routine cancer therapy, it is imperative that the array of toxicities associated with these agents be well-recognized and managed, especially since these toxicities are distinct from those seen with conventional cytotoxic agents. This review will focus on these renal toxicities from commonly used targeted agents. This review discusses the mechanisms of these side effects and management strategies. Anti-vascular endothelial growth factor (VEGF) agents including the monoclonal antibody bevacizumab, aflibercept (VEGF trap), and anti-VEGF receptor (VEGFR) tyrosine kinase inhibitors (TKIs) all cause hypertension, whereas some of them result in proteinuria. Monoclonal antibodies against the human epidermal growth factor receptor (HER) family of receptors, such as cetuximab and panitumumab, cause electrolyte imbalances including hypomagnesemia and hypokalemia due to the direct nephrotoxic effect of the drug on renal tubules. Cetuximab may also result in renal tubular acidosis. The TKIs, imatinib and dasatinib, can result in acute or chronic renal failure. Rituximab, an anti-CD20 monoclonal antibody, can cause acute renal failure following initiation of therapy because of the onset of acute tumor lysis syndrome. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, can result in proteinuria. Discerning the renal adverse effects resulting from these agents is essential for safe treatment strategies, particularly in those with pre-existing renal disease.

  2. A Cryogenic Infrared Calibration Target

    CERN Document Server

    Wollack, Edward J; Rinehart, Stephan A


    A compact cryogenic calibration target is presented that has a peak diffuse reflectance, $R \\le 0.003$, from $800-4,800\\,{\\rm cm}^{-1}$ $(12-2\\,\\mu$m). Upon expanding the spectral range under consideration to $400-10,000\\,{\\rm cm}^{-1}$ $(25-1\\,\\mu$m) the observed performance gracefully degrades to $R \\le 0.02$ at the band edges. In the implementation described, a high-thermal-conductivity metallic substrate is textured with a pyramidal tiling and subsequently coated with a thin lossy dielectric coating that enables high absorption and thermal uniformity across the target. The resulting target assembly is lightweight, has a low-geometric profile, and has survived repeated thermal cycling from room temperature to $\\sim4\\,$K. Basic design considerations, governing equations, and test data for realizing the structure described are provided. The optical properties of selected absorptive materials -- Acktar Fractal Black, Aeroglaze Z306, and Stycast 2850 FT epoxy loaded with stainless steel powder -- are character...


    Institute of Scientific and Technical Information of China (English)

    SUN Xue-mei(孙雪梅); BRADY Ben


    This review evaluates the role of Glivec in the treatment of chronic myelogenous leukemia and other malignant tumors. Preclinical and clinical evidence showed that Glivec demonstrated a potent and specific inhibition on BCR-ABL positive leukemias and other malignant tumors in which overexpression of c-kit and PDGFR-β played a major role in their pathogenesis. Glivec has induced complete hematologic responses in up to 98% of patients evaluated in clinical trials. It's a very successful drug that supported the idea of targeted therapy through inhibition of tyrosine kinases. Although it's still in the early stages of clinical development and the resistance to Glivec remains to be a problem needed further study, a great deal has been learned from these research and observation. And with the increasing data, molecular targeting therapy will play much more important role in the treatment of malignant tumors. With the better understanding of the pathogenesis of malignant tumors, well-designed drugs targeting the specific molecular abnormalities with higher efficacy and lower side effect will benefit numerous patients with malignant tumors.

  4. Fixed Target Collisions at STAR (United States)

    Meehan, Kathryn C.


    The RHIC Beam Energy Scan (BES) program was proposed to look for the turn-off of signatures of the quark gluon plasma (QGP), search for a possible QCD critical point, and study the nature of the phase transition between hadronic and partonic matter. Previous results have been used to claim that the onset of deconfinement occurs at a center-of-mass energy of 7 GeV. Data from lower energies are needed to test if this onset occurs. The goal of the STAR Fixed-Target Program is to extend the collision energy range in BES II to energies that are likely below the onset of deconfinement. Currently, STAR has inserted a gold target into the beam pipe and conducted test runs at center-of-mass energies of 3.9 and 4.5 GeV. Tests have been done with both Au and Al beams. First physics results from a Coulomb potential analysis of Au + Au fixed-target collisions are presented and are found to be consistent with results from previous experiments. Furthermore, the Coulomb potential, which is sensitive to the Z of the projectile and degree of baryonic stopping, will be compared to published results from the AGS.

  5. Targeted therapies in hepatocellular carcinoma. (United States)

    Bronte, F; Bronte, G; Cusenza, S; Fiorentino, E; Rolfo, C; Cicero, G; Bronte, E; Di Marco, V; Firenze, A; Angarano, G; Fontana, T; Russo, A


    The onset of hepatocellular carcinoma (HCC) is related to the development of non-neoplastic liver disease, such as viral infections and cirrhosis. Even though patients with chronic liver diseases undergo clinical surveillance for early diagnosis of HCC, this cancer is often diagnosed in advanced stage. In this case locoregional treatment is not possible and systemic therapies are the best way to control it. Until now sorafenib, a Raf and multi-kinase inhibitor has been the best, choice to treat HCC systemically. It showed a survival benefit in multicenter phase III trials. However the proper patient setting to treat is not well defined, since the results in Child-Pugh B patients are conflicting. To date various new target drugs are under developed and other biological treatments normally indicated in other malignancies are under investigation also for HCC. These strategies aim to target the different biological pathways implicated in HCC development and progression. The target drugs studied in HCC include anti-VEGF and anti-EGFR monoclonal antibodies, tyrosine kinase inhibitors and mTOR inhibitors. The most important challenge is represented by the best integration of these drugs with standard treatments to achieve improvement in overall survival and quality of life.

  6. Targeted gene flow for conservation. (United States)

    Kelly, Ella; Phillips, Ben L


    Anthropogenic threats often impose strong selection on affected populations, causing rapid evolutionary responses. Unfortunately, these adaptive responses are rarely harnessed for conservation. We suggest that conservation managers pay close attention to adaptive processes and geographic variation, with an eye to using them for conservation goals. Translocating pre-adapted individuals into recipient populations is currently considered a potentially important management tool in the face of climate change. Targeted gene flow, which involves moving individuals with favorable traits to areas where these traits would have a conservation benefit, could have a much broader application in conservation. Across a species' range there may be long-standing geographic variation in traits or variation may have rapidly developed in response to a threatening process. Targeted gene flow could be used to promote natural resistance to threats to increase species resilience. We suggest that targeted gene flow is a currently underappreciated strategy in conservation that has applications ranging from the management of invasive species and their impacts to controlling the impact and virulence of pathogens.

  7. Mitochondrially targeted fluorescent redox sensors. (United States)

    Yang, Kylie; Kolanowski, Jacek L; New, Elizabeth J


    The balance of oxidants and antioxidants within the cell is crucial for maintaining health, and regulating physiological processes such as signalling. Consequently, imbalances between oxidants and antioxidants are now understood to lead to oxidative stress, a physiological feature that underlies many diseases. These processes have spurred the field of chemical biology to develop a plethora of sensors, both small-molecule and fluorescent protein-based, for the detection of specific oxidizing species and general redox balances within cells. The mitochondrion, in particular, is the site of many vital redox reactions. There is therefore a need to target redox sensors to this particular organelle. It has been well established that targeting mitochondria can be achieved by the use of a lipophilic cation-targeting group, or by utilizing natural peptidic mitochondrial localization sequences. Here, we review how these two approaches have been used by a number of researchers to develop mitochondrially localized fluorescent redox sensors that are already proving useful in providing insights into the roles of reactive oxygen species in the mitochondria.

  8. Phenotypic screens targeting neurodegenerative diseases. (United States)

    Zhang, Minhua; Luo, Guangrui; Zhou, Yanjiao; Wang, Shaohui; Zhong, Zhong


    Neurodegenerative diseases affect millions of people worldwide, and the incidences increase as the population ages. Disease-modifying therapy that prevents or slows disease progression is still lacking, making neurodegenerative diseases an area of high unmet medical need. Target-based drug discovery for disease-modifying agents has been ongoing for many years, without much success due to incomplete understanding of the molecular mechanisms underlying neurodegeneration. Phenotypic screening, starting with a disease-relevant phenotype to screen for compounds that change the outcome of biological pathways rather than activities at certain specific targets, offers an alternative approach to find small molecules or targets that modulate the key characteristics of neurodegeneration. Phenotypic screens that focus on amelioration of disease-specific toxins, protection of neurons from degeneration, or promotion of neuroregeneration could be potential fertile grounds for discovering therapeutic agents for neurodegenerative diseases. In this review, we will summarize the progress of compound screening using these phenotypic-based strategies for this area, with a highlight on unique considerations for disease models, assays, and screening methodologies. We will further provide our perspectives on how best to use phenotypic screening to develop drug leads for neurodegenerative diseases.

  9. Classical Geometry and Target Space Duality



    This is the written version of lectures presented at Cargese 95. A new formulation for a ``restricted'' type of target space duality in classical two dimensional nonlinear sigma models is presented. The main idea is summarized by the analogy: euclidean geometry is to riemannian geometry as toroidal target space duality is to ``restricted'' target space duality. The target space is not required to possess symmetry. These lectures only discuss the local theory. The restricted target space duali...

  10. Method for forming electrically charged laser targets (United States)

    Goodman, Ronald K.; Hunt, Angus L.


    Electrically chargeable laser targets and method for forming such charged targets in order to improve their guidance along a predetermined desired trajectory. This is accomplished by the incorporation of a small amount of an additive to the target material which will increase the electrical conductivity thereof, and thereby enhance the charge placed upon the target material for guidance thereof by electrostatic or magnetic steering mechanisms, without adversely affecting the target when illuminated by laser energy.

  11. Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation. (United States)

    Jiang, Hai; Wu, Jianchun; He, Chen; Yang, Wending; Li, Honglin


    Cyclin-dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint. More recently, Wang et al. (2007) found that C53/LZAP may function as a tumor suppressor by way of inhibiting NF-kappaB signaling. We report here the identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexpression. Intriguingly, we found that C53 interacts with Chk1 and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response.

  12. A tumor suppressor C53 protein antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation (United States)

    Jiang, Hai; Wu, Jianchun; He, Chen; Yang, Wending; Li, Honglin


    Cyclin dependent kinase 1 (Cdk1)/cyclin B1 complex is the driving force for mitotic entry, and its activation is tightly regulated by the G2/M checkpoint. We originally reported that a novel protein C53 (also known as Cdk5rap3 and LZAP) potentiates DNA damage-induced cell death by modulating the G2/M checkpoint (1). More recently, Wang et al (2007) found that C53/LZAP may function as a tumor suppressor via inhibiting NF-κB signaling (2). We report here identification of C53 protein as a novel regulator of Cdk1 activation. We found that knockdown of C53 protein causes delayed Cdk1 activation and mitotic entry. During DNA damage response, activation of checkpoint kinase 1 and 2 (Chk1 and Chk2) is partially inhibited by C53 overexrepsssion. Intriguingly, we found that C53 interacts with checkpoint kinase 1 (Chk1) and antagonizes its function. Moreover, a portion of C53 protein is localized at the centrosome, and centrosome-targeting C53 potently promotes local Cdk1 activation. Taken together, our results strongly suggest that C53 is a novel negative regulator of checkpoint response. By counteracting Chk1, C53 promotes Cdk1 activation and mitotic entry in both unperturbed cell cycle progression and DNA damage response. PMID:19223857

  13. Experimental identification of microRNA targets

    DEFF Research Database (Denmark)

    Ørom, Ulf Andersson; Lund, Anders H


    microRNAs are small RNAs that regulate protein synthesis post-transcriptionally. Animal microRNAs recognize their targets by incomplete base pairing to sequence motifs most often present in the 3' untranslated region of their target mRNAs. This partial complementarity vastly expands the repertoire...... of potential targets and constitutes a problem for computational target prediction. Although computational analyses have shed light on important aspects of microRNA target recognition, several questions remain regarding how microRNAs can recognize and regulate their targets. Forward experimental approaches...... allow for an unbiased study of microRNA target recognition and may unveil novel, rare or uncommon target binding patterns. In this review we focus on animal microRNAs and the experimental approaches that have been described for identification of their targets....

  14. LIFE Target Fabrication Research Plan Sept 2008

    Energy Technology Data Exchange (ETDEWEB)

    Miles, R; Biener, J; Kucheyev, S; Montesanti, R; Satcher, J; Spadaccini, C; Rose, K; Wang, M; Hamza, A; Alexander, N; Brown, L; Hund, J; Petzoldt, R; Sweet, W; Goodin, D


    The target-system for the baseline LIFE fast-ignition target was analyzed to establish a preliminary estimate for the costs and complexities involved in demonstrating the technologies needed to build a prototype LIFE plant. The baseline fast-ignition target upon which this analysis was developed is shown in Figure 1.0-1 below. The LIFE target-system incorporates requirements for low-cost, high throughput manufacture, high-speed, high accuracy injection of the target into the chamber, production of sufficient energy from implosion and recovery and recycle of the imploded target material residue. None of these functions has been demonstrated to date. Existing target fabrication techniques which lead to current 'hot spot' target costs of {approx}$100,000 per target and at a production rate of 2/day are unacceptable for the LIFE program. Fabrication techniques normally used for low-cost, low accuracy consumer products such as toys must be adapted to the high-accuracy LIFE target. This will be challenge. A research program resulting is the demonstration of the target-cycle technologies needed for a prototype LIFE reactor is expected to cost {approx}$51M over the course of 5 years. The effort will result in targets which will cost an estimated $0.23/target at a rep-rate of 20 Hz or about 1.73M targets/day.

  15. Targeted Nanotechnology in Glioblastoma Multiforme (United States)

    Glaser, Talita; Han, Inbo; Wu, Liquan; Zeng, Xiang


    Gliomas, and in particular glioblastoma multiforme, are aggressive brain tumors characterized by a poor prognosis and high rates of recurrence. Current treatment strategies are based on open surgery, chemotherapy (temozolomide) and radiotherapy. However, none of these treatments, alone or in combination, are considered effective in managing this devastating disease, resulting in a median survival time of less than 15 months. The efficiency of chemotherapy is mainly compromised by the blood-brain barrier (BBB) that selectively inhibits drugs from infiltrating into the tumor mass. Cancer stem cells (CSCs), with their unique biology and their resistance to both radio- and chemotherapy, compound tumor aggressiveness and increase the chances of treatment failure. Therefore, more effective targeted therapeutic regimens are urgently required. In this article, some well-recognized biological features and biomarkers of this specific subgroup of tumor cells are profiled and new strategies and technologies in nanomedicine that explicitly target CSCs, after circumventing the BBB, are detailed. Major achievements in the development of nanotherapies, such as organic poly(propylene glycol) and poly(ethylene glycol) or inorganic (iron and gold) nanoparticles that can be conjugated to metal ions, liposomes, dendrimers and polymeric micelles, form the main scope of this summary. Moreover, novel biological strategies focused on manipulating gene expression (small interfering RNA and clustered regularly interspaced short palindromic repeats [CRISPR]/CRISPR associated protein 9 [Cas 9] technologies) for cancer therapy are also analyzed. The aim of this review is to analyze the gap between CSC biology and the development of targeted therapies. A better understanding of CSC properties could result in the development of precise nanotherapies to fulfill unmet clinical needs.

  16. Targeted Radionuclide Therapy of Melanoma. (United States)

    Norain, Abdullah; Dadachova, Ekaterina


    An estimated 60,000 individuals in the United States and 132,000 worldwide are yearly diagnosed with melanoma. Until recently, treatment options for patients with stages III-IV metastatic disease were limited and offered marginal, if any, improvement in overall survival. The situation changed with the introduction of B-RAF inhibitors and anti-cytotoxic T-lymphocyte antigen 4 and anti-programmed cell death protein 1 immunotherapies into the clinical practice. With only some patients responding well to the immune therapies and with very serious side effects and high costs of immunotherapy, there is still room for other approaches for the treatment of metastatic melanoma. Targeted radionuclide therapy of melanoma could be divided into the domains of radioimmunotherapy (RIT), radiolabeled peptides, and radiolabeled small molecules. RIT of melanoma is currently experiencing a renaissance with the clinical trials of alpha-emitter (213)Bi-labeled and beta-emitter (188)Rhenium-labeled monoclonal antibodies in patients with metastatic melanoma producing encouraging results. The investigation of the mechanism of efficacy of melanoma RIT points at killing of melanoma stem cells by RIT and involvement of immune system such as complement-dependent cytotoxicity. The domain of radiolabeled peptides for targeted melanoma therapy has been preclinical so far, with work concentrated on radiolabeled peptide analogues of melanocyte-stimulating hormone receptor and on melanin-binding peptides. The field of radiolabeled small molecule produced radioiodinated benzamides that cross the cellular membrane and bind to the intracellular melanin. The recent clinical trial demonstrated measurable antitumor effects and no acute or midterm toxicities. We are hopeful that the targeted radionuclide therapy of metastatic melanoma would become a clinical reality as a stand-alone therapy or in combination with the immunotherapies such as anti-PD1 programmed cell death protein 1 monoclonal antibodies

  17. Targeted Therapy in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Murray Baron


    Full Text Available Targeted therapies use an understanding of the pathophysiology of a disease in an individual patient. Although targeted therapy for systemic sclerosis (SSc, scleroderma has not yet reached the level of patient-specific treatments, recent developments in the understanding of the global pathophysiology of the disease have led to new treatments based on the cells and pathways that have been shown to be involved in the disease pathogenesis. The presence of a B cell signature in skin biopsies has led to the trial of rituximab, an anti-CD20 antibody, in SSc. The well-known properties of transforming growth factor (TGF-β in promoting collagen synthesis and secretion has led to a small trial of fresolimumab, a human IgG4 monoclonal antibody capable of neutralizing TGF-β. Evidence supporting important roles for interleukin-6 in the pathogenesis of SSc have led to a large trial of tocilizumab in SSc. Soluble guanylate cyclase (sGC is an enzyme that catalyzes the production of cyclic guanosine monophosphate (cGMP upon binding of nitric oxide (NO to the sGC molecule. Processes such as cell growth and proliferation are regulated by cGMP. Evidence that sGC may play a role in SSc has led to a trial of riociguat, a molecule that sensitizes sGC to endogenous NO. Tyrosine kinases (TKs are involved in a wide variety of physiologic and pathological processes including vascular remodeling and fibrogenesis such as occurs in SSc. This has led to a trial of nintedanib, a next-generation tyrosine-kinase (TK inhibitor which targets multiple TKs, in SSc.

  18. The challenge of targeting metastasis. (United States)

    Fidler, Isaiah J; Kripke, Margaret L


    Metastases that are resistant to conventional therapy are the major cause of death from cancer. In most patients, metastasis has already occurred by the time of diagnosis. Thus, the prevention of metastasis is unlikely to be of therapeutic benefit. The biological heterogeneity of metastases presents a major obstacle to treatment. However, the growth and survival of metastases depend on interactions between tumor cells and host homeostatic mechanisms. Targeting these interactions, in addition to the tumor cells, can produce synergistic therapeutic effects against existing metastases.

  19. Conotoxins: Molecular and Therapeutic Targets (United States)

    Lewis, Richard J.

    Marine molluscs known as cone snails produce beautiful shells and a complex array of over 50,000 venom peptides evolved for prey capture and defence. Many of these peptides selectively modulate ion channels and transporters, making them a valuable source of new ligands for studying the role these targets play in normal and disease physiology. A number of conopeptides reduce pain in animal models, and several are now in pre-clinical and clinical development for the treatment of severe pain often associated with diseases such as cancer. Less than 1% of cone snail venom peptides are pharmacologically characterised.

  20. Radar Imaging for Moving Targets (United States)


    solution as scatt (x)  Gk (x ’, x)(x ’)D  inc (x ’)  scatt (x ’) d 3x ’ (3.3) This is a Lippmann- Schwinger equation. It can be observed...boundary conditions for a known target. It is also important to note that there are several aspects to the Lippmann- Schwinger equation: 27 (1...can also be approached using the Lippmann- Schwinger equation as a model for scatt . B. LINEARIZED DATA MODEL (TIME-VARYING SYSTEMS) Besides using

  1. Zinc metalloproteins as medicinal targets. (United States)

    Anzellotti, A I; Farrell, N P


    Zinc bioinorganic chemistry has emphasized the role of the metal ion on the structure and function of the protein. There is, more recently, an increasing appreciation of the role of zinc proteins in a variety of human diseases. This critical review, aimed at both bioinorganic and medicinal chemists, shows how apparently widely-diverging diseases share the common mechanistic approaches of targeting the essential function of the metal ion to inhibit activity. Protein structure and function is briefly summarized in the context of its clinical relevance. The status of current and potential inhibitors is discussed along with the prospects for future developments (162 references).

  2. Introduction to radar target recognition

    CERN Document Server

    Tait, P


    This new text provides an overview of the radar target recognition process and covers the key techniques being developed for operational systems. It is based on the fundamental scientific principles of high resolution radar, and explains how the techniques can be used in real systems, taking into account the characteristics of practical radar system designs and component limitations. It also addresses operational aspects, such as how high resolution modes would fit in with other functions such as detection and tracking. Mathematics is kept to a minimum and the complex techniques and issues are

  3. Targeting ECM Disrupts Cancer Progression. (United States)

    Venning, Freja A; Wullkopf, Lena; Erler, Janine T


    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression.

  4. Targeting ECM Disrupts Cancer Progression (United States)

    Venning, Freja A.; Wullkopf, Lena; Erler, Janine T.


    Metastatic complications are responsible for more than 90% of cancer-related deaths. The progression from an isolated tumor to disseminated metastatic disease is a multistep process, with each step involving intricate cross talk between the cancer cells and their non-cellular surroundings, the extracellular matrix (ECM). Many ECM proteins are significantly deregulated during the progression of cancer, causing both biochemical and biomechanical changes that together promote the metastatic cascade. In this review, the influence of several ECM proteins on these multiple steps of cancer spread is summarized. In addition, we highlight the promising (pre-)clinical data showing benefits of targeting these ECM macromolecules to prevent cancer progression. PMID:26539408

  5. Assessing protein kinase target similarity

    DEFF Research Database (Denmark)

    Gani, Osman A; Thakkar, Balmukund; Narayanan, Dilip


    : focussed chemical libraries, drug repurposing, polypharmacological design, to name a few. Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate......" of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, "the devil is in the details." Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled...

  6. Properties of protein drug target classes.

    Directory of Open Access Journals (Sweden)

    Simon C Bull

    Full Text Available Accurate identification of drug targets is a crucial part of any drug development program. We mined the human proteome to discover properties of proteins that may be important in determining their suitability for pharmaceutical modulation. Data was gathered concerning each protein's sequence, post-translational modifications, secondary structure, germline variants, expression profile and drug target status. The data was then analysed to determine features for which the target and non-target proteins had significantly different values. This analysis was repeated for subsets of the proteome consisting of all G-protein coupled receptors, ion channels, kinases and proteases, as well as proteins that are implicated in cancer. Machine learning was used to quantify the proteins in each dataset in terms of their potential to serve as a drug target. This was accomplished by first inducing a random forest that could distinguish between its targets and non-targets, and then using the random forest to quantify the drug target likeness of the non-targets. The properties that can best differentiate targets from non-targets were primarily those that are directly related to a protein's sequence (e.g. secondary structure. Germline variants, expression levels and interactions between proteins had minimal discriminative power. Overall, the best indicators of drug target likeness were found to be the proteins' hydrophobicities, in vivo half-lives, propensity for being membrane bound and the fraction of non-polar amino acids in their sequences. In terms of predicting potential targets, datasets of proteases, ion channels and cancer proteins were able to induce random forests that were highly capable of distinguishing between targets and non-targets. The non-target proteins predicted to be targets by these random forests comprise the set of the most suitable potential future drug targets, and should therefore be prioritised when building a drug development programme.

  7. String theory in target space

    Energy Technology Data Exchange (ETDEWEB)

    Boels, Rutger H.; Hansen, Tobias [II. Institut für Theoretische Physik, Universität Hamburg,Luruper Chaussee 149, D- 22761 Hamburg (Germany)


    It is argued that the complete S-matrix of string theory at tree level in a flat background can be obtained from a small set of target space properties, without recourse to the worldsheet description. The main non-standard inputs are (generalised) Britto-Cachazo-Feng-Witten shifts, as well as the monodromy relations for open string theory and the Kawai-Lewellen-Tye relations for closed string theory. The roots of the scattering amplitudes and especially their appearance in the residues at the kinematic poles are central to the story. These residues determine the amplitudes through on-shell recursion relations. Several checks of the formalism are presented, including a computation of the Koba-Nielsen amplitude in the bosonic string. Furthermore the question of target space unitarity is (re-)investigated. For the Veneziano amplitude this question is reduced by Poincaré invariance, unitarity and locality to that of positivity of a particular numerical sum. Interestingly, this analysis produces the main conditions of the no-ghost theorem on dimension and intercept from the first three poles of this amplitude.

  8. Targeted therapies in gastroesophageal cancer. (United States)

    Kasper, Stefan; Schuler, Martin


    Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer.

  9. Seismoelectric imaging of shallow targets (United States)

    Haines, S.S.; Pride, S.R.; Klemperer, S.L.; Biondi, B.


    We have undertaken a series of controlled field experiments to develop seismoelectric experimental methods for near-surface applications and to improve our understanding of seismoelectric phenomena. In a set of off-line geometry surveys (source separated from the receiver line), we place seismic sources and electrode array receivers on opposite sides of a man-made target (two sand-filled trenches) to record separately two previously documented seismoelectric modes: (1) the electromagnetic interface response signal created at the target and (2) the coseismic electric fields located within a compressional seismic wave. With the seismic source point in the center of a linear electrode array, we identify the previously undocumented seismoelectric direct field, and the Lorentz field of the metal hammer plate moving in the earth's magnetic field. We place the seismic source in the center of a circular array of electrodes (radial and circumferential orientations) to analyze the source-related direct and Lorentz fields and to establish that these fields can be understood in terms of simple analytical models. Using an off-line geometry, we create a multifold, 2D image of our trenches as dipping layers, and we also produce a complementary synthetic image through numerical modeling. These images demonstrate that off-line geometry (e.g., crosswell) surveys offer a particularly promising application of the seismoelectric method because they effectively separate the interface response signal from the (generally much stronger) coseismic and source-related fields. ?? 2007 Society of Exploration Geophysicists.

  10. Targeting vaccines to dendritic cells. (United States)

    Foged, Camilla; Sundblad, Anne; Hovgaard, Lars


    Dendritic cells (DC) are specialized antigen presenting cells (APC) with a remarkable ability to take up antigens and stimulate major histocompatibility complex (MHC)-restricted specific immune responses. Recent discoveries have shown that their role in initiating primary immune responses seems to be far superior to that of B-cells and macrophages. DC are localized at strategic places in the body at sites used by pathogens to enter the organism, and are thereby in an optimal position to capture antigens. In general, vaccination strategies try to mimic the invasiveness of the pathogens. DC are considered to play a central role for the provocation of primary immune responses by vaccination. A rational way of improving the potency and safety of new and already existing vaccines could therefore be to direct vaccines specifically to DC. There is a need for developing multifunctional vaccine drug delivery systems (DDS) with adjuvant effect that target DC directly and induce optimal immune responses. This paper will review the current knowledge of DC physiology as well as the progress in the field of novel vaccination strategies that directly or indirectly aim at targeting DC.

  11. Targeting FGFR Signaling in Cancer. (United States)

    Touat, Mehdi; Ileana, Ecaterina; Postel-Vinay, Sophie; André, Fabrice; Soria, Jean-Charles


    The fibroblast growth factor signaling pathway (FGFR signaling) is an evolutionary conserved signaling cascade that regulates several basic biologic processes, including tissue development, angiogenesis, and tissue regeneration. Substantial evidence indicates that aberrant FGFR signaling is involved in the pathogenesis of cancer. Recent developments of deep sequencing technologies have allowed the discovery of frequent molecular alterations in components of FGFR signaling among several solid tumor types. Moreover, compelling preclinical models have demonstrated the oncogenic potential of these aberrations in driving tumor growth, promoting angiogenesis, and conferring resistance mechanisms to anticancer therapies. Recently, the field of FGFR targeting has exponentially progressed thanks to the development of novel agents inhibiting FGFs or FGFRs, which had manageable safety profiles in early-phase trials. Promising treatment efficacy has been observed in different types of malignancies, particularly in tumors harboring aberrant FGFR signaling, thus offering novel therapeutic opportunities in the era of precision medicine. The most exciting challenges now focus on selecting patients who are most likely to benefit from these agents, increasing the efficacy of therapies with the development of novel potent compounds and combination strategies, and overcoming toxicities associated with FGFR inhibitors. After examination of the basic and translational research studies that validated the oncogenic potential of aberrant FGFR signaling, this review focuses on recent data from clinical trials evaluating FGFR targeting therapies and discusses the challenges and perspectives for the development of these agents.

  12. Targeted Molecular Therapies for SBMA. (United States)

    Rinaldi, Carlo; Malik, Bilal; Greensmith, Linda


    Spinal and bulbar muscular atrophy (SBMA) is a late-onset neuromuscular disease caused by a polyglutamine expansion in the androgen receptor gene which results in progressive spinal and bulbar motor neuron degeneration, and muscle atrophy. Although the causative genetic defect is known, until recently, the molecular pathogenesis of the disease was unclear, resulting in few, if any, targets for therapy development. However, over the past decade, our understanding of the pathomechanisms that play a role in SBMA has increased dramatically, and several of these pathways and mechanisms have now been investigated as possible therapeutic targets. In this review, we discuss some of the key pathomechanisms implicated in SBMA and describe some of the therapeutic strategies that have been tested in SBMA to date, which fall into four main categories: (i) gene silencing; (ii) protein quality control and/or increased protein degradation; (iii) androgen deprivation; and (iv) modulation of AR function. Finally, it is also now clear that in addition to a greater understanding of the molecular mechanisms that underlie disease, the development of an effective disease modifying therapy for SBMA will require the coordinated, collaborative effort of research teams with diverse areas of expertise, clinicians, pharmaceutical companies as well as patient groups.

  13. Tamoxifen Resistance: Emerging Molecular Targets

    Directory of Open Access Journals (Sweden)

    Milena Rondón-Lagos


    Full Text Available 17β-Estradiol (E2 plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer.

  14. Aquaporins as potential drug targets

    Institute of Scientific and Technical Information of China (English)

    Fang WANG; Xue-chao FENG; Yong-ming LI; Hong YANG; Tong-hui MA


    The aquaporins (AQP) are a family of integral membrane proteins that selectively transport water and,in some cases,small neutral solutes such as glycerol and urea.Thirteen mammalian AQP have been molecularly identified and localized to various epithelial,endothelial and other tissues.Phenotype studies of transgenic mouse models of AQP knockout,mutation,and in some cases humans with AQP mutations have demonstrated essential roles for AQP in mammalian physiology and pathophysiology,including urinary concentrating function,exocrine glandular fluid secretion,brain edema formation,regulation of intracranial and intraocular pressure,skin hydration,fat metabolism,tumor angiogenesis and cell migration.These studies suggest that AQP may be potential drug targets for not only new diuretic reagents for various forms of pathological water retention,but also targets for novel therapy of brain edema,inflammatory disease,glaucoma,obesity,and cancer.However,potent AQP modulators for in vivo application remain to be discovered.

  15. String theory in target space

    CERN Document Server

    Boels, Rutger H


    It is argued that the complete S-matrix of string theory at tree level in a flat background can be obtained from a small set of target space properties, without recourse to the worldsheet description. The main non-standard inputs are (generalised) Britto-Cachazo-Feng-Witten shifts, as well as the monodromy relations for open string theory and the Kawai-Lewellen-Tye relations for closed string theory. The roots of the scattering amplitudes and especially their appearance in the residues at the kinematic poles are central to the story. These residues determine the amplitudes through on-shell recursion relations. Several checks of the formalism are presented, including a computation of the Koba-Nielsen amplitude in the bosonic string. Furthermore the question of target space unitarity is (re-)investigated. For the Veneziano amplitude this question is reduced by Poincare invariance, unitarity and locality to that of positivity of a particular numerical sum. Interestingly, this analysis produces the main condition...

  16. String theory in target space (United States)

    Boels, Rutger H.; Hansen, Tobias


    It is argued that the complete S-matrix of string theory at tree level in a flat background can be obtained from a small set of target space properties, without recourse to the worldsheet description. The main non-standard inputs are (generalised) Britto-Cachazo-Feng-Witten shifts, as well as the monodromy relations for open string theory and the Kawai-Lewellen-Tye relations for closed string theory. The roots of the scattering amplitudes and especially their appearance in the residues at the kinematic poles are central to the story. These residues determine the amplitudes through on-shell recursion relations. Several checks of the formalism are presented, including a computation of the Koba-Nielsen amplitude in the bosonic string. Furthermore the question of target space unitarity is (re-)investigated. For the Veneziano amplitude this question is reduced by Poincaré invariance, unitarity and locality to that of positivity of a particular numerical sum. Interestingly, this analysis produces the main conditions of the no-ghost theorem on dimension and intercept from the first three poles of this amplitude.

  17. Combinatorial microRNA target predictions

    DEFF Research Database (Denmark)

    Krek, Azra; Grün, Dominic; Poy, Matthew N.


    MicroRNAs are small noncoding RNAs that recognize and bind to partially complementary sites in the 3' untranslated regions of target genes in animals and, by unknown mechanisms, regulate protein production of the target transcript1, 2, 3. Different combinations of microRNAs are expressed...... in different cell types and may coordinately regulate cell-specific target genes. Here, we present PicTar, a computational method for identifying common targets of microRNAs. Statistical tests using genome-wide alignments of eight vertebrate genomes, PicTar's ability to specifically recover published microRNA...... targets, and experimental validation of seven predicted targets suggest that PicTar has an excellent success rate in predicting targets for single microRNAs and for combinations of microRNAs. We find that vertebrate microRNAs target, on average, roughly 200 transcripts each. Furthermore, our results...

  18. Targets culture wastes energy on wrong things. (United States)

    Fyffe, Theresa


    Healthcare targets have been in the news a lot - and not in ways that offer comfortable reading. Missed emergency department waiting-time targets and patients waiting longer for treatments have made headlines.

  19. Targets and processes for fabricating same

    Energy Technology Data Exchange (ETDEWEB)

    Adams, Jesse D; Malekos, Steven; Le Galloudec, Nathalie; Korgan, Grant; Cowan, Thomas; Sentoku, Yasuhiko


    In particular embodiments, the present disclosure provides targets including a metal layer and defining a hollow inner surface. The hollow inner surface has an internal apex. The distance between at least two opposing points of the internal apex is less than about 15 .mu.m. In particular examples, the distance is less than about 1 .mu.m. Particular implementations of the targets are free standing. The targets have a number of disclosed shaped, including cones, pyramids, hemispheres, and capped structures. The present disclosure also provides arrays of such targets. Also provided are methods of forming targets, such as the disclosed targets, using lithographic techniques, such as photolithographic techniques. In particular examples, a target mold is formed from a silicon wafer and then one or more sides of the mold are coated with a target material, such as one or more metals.

  20. Purity of targets prepared on Cu substrates (United States)

    Méens, A.; Rossini, I.; Sens, J. C.


    The purity of several elemental self-supporting targets usually prepared by evaporation onto soluble Cu substrates has been studied. The targets were analysed by Rutherford backscattering and instrumental neutron activation analysis. Because of the high percentage of Cu observed in some Si targets, further measurements, including transmission electron microscopy, have been performed on Si targets deposited by e-gun bombardment onto Cu and ion-beam sputtering onto betaine.

  1. Evaluation and validation of drug targets

    Institute of Scientific and Technical Information of China (English)



    Drug target is one of the key factors for discovering and developing new drugs. To find and validate drug targets is a crucial technique required in drug discovery by the strategy of high throughput screening. Based on the knowledge of molecular biology, human genomics and proteomics, it has been predicted that 5000 to 10000 drug targets exist in human. So, it is important orocedure to evaluate and validate the drug targets.

  2. Terahertz-based target typing.

    Energy Technology Data Exchange (ETDEWEB)

    Lyo, Sungkwun Kenneth; Wanke, Michael Clement; Reno, John Louis; Shaner, Eric Arthur; Grine, Albert D.; Barrick, Todd A.


    The purpose of this work was to create a THz component set and understanding to aid in the rapid analysis of transient events. This includes the development of fast, tunable, THz detectors, along with filter components for use with standard detectors and accompanying models to simulate detonation signatures. The signature effort was crucial in order to know the spectral range to target for detection. Our approach for frequency agile detection was to utilize plasmons in the channel of a specially designed field-effect transistor called the grating-gate detector. Grating-gate detectors exhibit narrow-linewidth, broad spectral tunability through application of a gate bias, and no angular dependence in their photoresponse. As such, if suitable sensitivity can be attained, they are viable candidates for Terahertz multi-spectral focal plane arrays.

  3. Therapeutic target for protozoal diseases (United States)

    Rathore, Dharmendar; Jani, Dewal; Nagarkatti, Rana


    A novel Fasciclin Related Adhesive Protein (FRAP) from Plasmodium and related parasites is provided as a target for therapeutic intervention in diseases caused by the parasites. FRAP has been shown to play a critical role in adhesion to, or invasion into, host cells by the parasite. Furthermore, FRAP catalyzes the neutralization of heme by the parasite, by promoting its polymerization into hemozoin. This invention provides methods and compositions for therapies based on the administration of protein, DNA or cell-based vaccines and/or antibodies based on FRAP, or antigenic epitopes of FRAP, either alone or in combination with other parasite antigens. Methods for the development of compounds that inhibit the catalytic activity of FRAP, and diagnostic and laboratory methods utilizing FRAP are also provided.

  4. Synchronous identification of friendly targets (United States)

    Telle, John M.; Roger, Stutz A.


    A synchronous communication targeting system for use in battle. The present invention includes a transceiver having a stabilizing oscillator, a synchronous amplifier and an omnidirectional receiver, all in electrical communication with each other. A remotely located beacon is attached to a blackbody radiation source and has an amplitude modulator in electrical communication with a optical source. The beacon's amplitude modulator is set so that the optical source transmits radiation frequency at approximately the same or lower amplitude than that of the blackbody radiation source to which the beacon is attached. The receiver from the transceiver is adapted to receive frequencies approximately at or below blackbody radiation signals and sends such signals to the synchronous amplifier. The synchronous amplifier then rectifies and amplifies those signals which correspond to the predetermined frequency to therefore identify whether the blackbody radiation source is friendly or not.

  5. Communicating to heterogeneous target groups

    DEFF Research Database (Denmark)

    Pedersen, Karsten

    that such grammatical changes have positive effects on the intelligibility of texts. The attempts to document such effects are scarce and that is one of the backgrounds for my involvement in the project. If I am able to show that the changes do have an effect, the literature on conveying professional communication......The paper proposal is part of a full-scale discourse analysis of a series of service information pamphlets published by the county of Ringkjøbing in Western Denmark. The project is an investigation of various aspects of the fact that government agencies as well as local and regional authorities...... very often have to communicate to rather heterogeneous target groups that have little more in common than a certain geographical habitat. That goes against most schoolbook teaching in the field of communication, but is none the less the terms with which that kind of communication has to live...

  6. TARGET 2 and Settlement Finality

    Directory of Open Access Journals (Sweden)



    Full Text Available This article examines how TARGET 2 as system implements the idea of settlement finality regulated by Directive 98/26 EC of the European parliament and of the Council of 19 May 1998 on settlement finality in payment and securities settlement systems (Settlement Finality Directive and Directive 2009/44/EC of the European parliament and of the Council of 6 May 2009 amending Directive 98/26/EC on settlement finality in payment and securities settlement systems and Directive 2002/47/EC on financial collateral arrangements as regards linked systems and credit claims (Directive 2009/44/EC. As the title of the arti and finality of the settlement in this system.

  7. Behavioral targeting: a European legal perspective

    NARCIS (Netherlands)

    Zuiderveen Borgesius, F.


    Behavioral targeting, or online profiling, is a hotly debated topic. Much of the collection of personal information on the Internet is related to behavioral targeting, although research suggests that most people don't want to receive behaviorally targeted advertising. The World Wide Web Consortium i

  8. Acoustic Signal Feature Extraction of Vehicle Targets

    Institute of Scientific and Technical Information of China (English)

    蓝金辉; 马宝华; 李科杰


    Acoustic signal feature extraction is an important part of target recognition. The mechanisms for producing acoustic signals and their propagation are analyzed to extract the features of the radiated noise from different targets. Analysis of the acoustic spectra of typical vehicle targets acquired outdoors shows that the vehicles can be classified based on the acoustic spectra and amplitudes.

  9. Target manifold formation using a quadratic SDF (United States)

    Hester, Charles F.; Risko, Kelly K. D.


    Synthetic Discriminant Function (SDF) formulation of correlation filters provides constraints for forming target subspaces for a target set. In this paper we extend the SDF formulation to include quadratic constraints and use this solution to form nonlinear manifolds in the target space. The theory for forming these manifolds will be developed and demonstrated with data.

  10. Studies of release properties of ISOLDE targets

    CERN Document Server

    Peräjärvi, K; Fedosseev, V; Joinet, A; Köster, U; Lau, C; Lettry, Jacques; Ravn, H L; Santana-Leitner, M


    Off-line release rates of Be, Mg, S, Mn and Kr from refractory materials were studied. Mn yields were determined from a ZrO2 target and Kr yields from a SrO and ZrO2 targets. A Monte Carlo code to optimize ISOLDE targets was introduced.

  11. 40 CFR 35.9020 - Planning targets. (United States)


    ... STATE AND LOCAL ASSISTANCE Financial Assistance for the National Estuary Program § 35.9020 Planning targets. The EPA Assistant Administrator for Water develops planning targets each year to help each... 40 Protection of Environment 1 2010-07-01 2010-07-01 false Planning targets. 35.9020 Section...

  12. Moringa oleifera Lam: Targeting Chemoprevention. (United States)

    Karim, Nurul Ashikin Abd; Ibrahim, Muhammad Din; Kntayya, Saie Brindha; Rukayadi, Yaya; Hamid, Hazrulizawati Abd; Razis, Ahmad Faizal Abdull


    Moringa oleifera Lam, family Moringaceae, is a perennial plant which is called various names, but is locally known in Malaysia as "murungai" or "kelor". Glucomoringin, a glucosinolate with from M. oleifera is a major secondary metabolite compound. The seeds and leaves of the plant are reported to have the highest amount of glucosinolates. M. oleifera is well known for its many uses health and benefits. It is claimed to have nutritional, medicinal and chemopreventive potentials. Chemopreventive effects of M. oleifera are expected due to the existence of glucosinolate which it is reported to have the ability to induce apoptosis in anticancer studies. Furthermore, chemopreventive value of M. oleifera has been demonstrated in studies utilizing its leaf extract to inhibit the growth of human cancer cell lines. This review highlights the advantages of M. oleifera targeting chemoprevention where glucosinolates could help to slow the process of carcinogenesis through several molecular targets. It is also includes inhibition of carcinogen activation and induction of carcinogen detoxification, anti-inflammatory, anti-tumor cell proliferation, induction of apoptosis and inhibition of tumor angiogenesis. Finally, for synergistic effects of M. oleifera with other drugs and safety, essential for chemoprevention, it is important that it safe to be consumed by human body and works well. Although there is promising evidence about M. oleifera in chemoprevention, extensive research needs to be done due to the expected rise of cancer in coming years and to gain more information about the mechanisms involved in M. oleifera influence, which could be a good source to inhibit several major mechanisms involved in cancer development.

  13. Electrophilic eicosanoids: Signaling and targets. (United States)

    Pérez-Sala, Dolores


    Electrophilic eicosanoids are reactive mediators that arise by non-enzymatic transformations of arachidonic acid or of its products and display varied biological actions. Various electrophilic eicosanoids have shown anti-proliferative and anti-inflammatory effects, which have elicited a great interest in their study as potential therapeutic agents. A key feature of these compounds is their ability to covalently modify proteins, thus altering their structure and function. The modification of several components of the NF-κB pathway contributes to the anti-inflammatory effects of electrophilic eicosanoids, whereas addition to redox-sensitive proteins plays a key role in the antioxidant response. However, electrophilic eicosanoids may also have a dark side, and accumulating evidence points towards their involvement in neurotoxicity and/or neurodegeneration. The ability of some electrophilic eicosanoids to induce protein oligomerization or aggregation through various mechanisms may contribute to these effects. Biochemical and proteomic studies have led to the identification of numerous protein targets for modification by electrophilic eicosanoids, the number of which continues to expand, revealing novel potential functions for these compounds and providing a basis for their pleiotropic effects. The ample number of targets identified, together with the non-enzymatic nature of the modification argue against the potential specificity or regulation of electrophilic eicosanoid action. However, protein modification displays selectivity depending on structural features of the proteins and of the electrophilic compounds as well as on context factors such as cell type and GSH availability. Understanding the factors which control the extent and selectivity of protein modification by electrophilic eicosanoids is therefore essential to elucidate their pathophysiological roles and therapeutic potential in specific settings.

  14. Targeting Cancer with Antisense Oligomers

    Energy Technology Data Exchange (ETDEWEB)

    Hnatowich, DJ


    With financial assistance from the Department of Energy, we have shown definitively that radiolabeled antisense DNAs and other oligomers will accumulate in target cancer cells in vitro and in vivo by an antisense mechanism. We have also shown that the number of mRNA targets for our antisense oligomers in the cancer cell types that we have investigated so far is sufficient to provide and antisense image and/or radiotherapy of cancer in mice. These studies have been reported in about 10 publications. However our observation over the past several years has shown that radiolabeled antisense oligomers administered intravenously in their native and naked form will accumulate and be retained in target xenografts by an antisense mechanism but will also accumulate at high levels in normal organs such as liver, spleen and kidneys. We have investigated unsuccessfully several commercially available vectors. Thus the use of radiolabeled antisense oligomers for the imaging of cancer must await novel approaches to delivery. This laboratory has therefore pursued two new paths, optical imaging of tumor and Auger radiotherapy. We are developing a novel method of optical imaging tumor using antisense oligomers with a fluorophore is administered while hybridized with a shorter complementary oligomer with an inhibitor. In culture and in tumored mice that the duplex remains intact and thus nonfluorescent until it encounters its target mRNA at which time it dissociates and the antisense oligomer binds along with its fluorophore to the target. Simultaneous with the above, we have also observed, as have others, that antisense oligomers migrate rapidly and quantitatively to the nucleus upon crossing cell membranes. The Auger electron radiotherapy path results from this observation since the nuclear migration properties could be used effectively to bring and to retain in the nucleus an Auger emitting radionuclide such as 111In or 125I bound to the antisense oligomer. Since the object becomes

  15. Improved Targeting of Cancers with Nanotherapeutics

    DEFF Research Database (Denmark)

    Foster, Christian; Watson, Andre; Kaplinsky, Joseph John;


    Targeted cancer nanotherapeutics offers numerous opportunities for the selective uptake of toxic chemotherapies within tumors and cancer cells. The unique properties of nanoparticles, such as their small size, large surface-to-volume ratios, and the ability to achieve multivalency of targeting...... ligands on their surface, provide superior advantages for nanoparticle-based drug delivery to a variety of cancers. This review highlights various key concepts in the design of targeted nanotherapeutics for cancer therapy, and discusses physicochemical parameters affecting nanoparticle targeting, along...... with recent developments for cancer-targeted nanomedicines....

  16. Targeting nominal income growth or inflation?

    DEFF Research Database (Denmark)

    Jensen, Henrik


    Within a simple New Keynesian model emphasizing forward-looking behavior of private agents, I evaluate optimal nominal income growth targeting versus optimal inflation targeting. When the economy is mainly subject to shocks that do not involve monetary policy trade-offs for society, inflation...... targeting is preferable. Otherwise, nominal income growth targeting may be superior because it induces inertial policy making, which improves the inflation-output-gap trade-off. Somewhat paradoxically, inflation targeting may be relatively less favorable the more society dislikes inflation, and the more...... persistent are the effects of inflation-generating shocks...

  17. The trajectory of the target probability effect. (United States)

    Hon, Nicholas; Yap, Melvin J; Jabar, Syaheed B


    The effect of target probability on detection times is well-established: Even when detection accuracy is high, lower probability targets are detected more slowly than higher probability ones. Although this target probability effect on detection times has been well-studied, one aspect of it has remained largely unexamined: How the effect develops over the span of an experiment. Here, we investigated this issue with two detection experiments that assessed different target probability ratios. Conventional block segment analysis and linear mixed-effects modeling converged on two key findings. First, we found that the magnitude of the target probability effect increases as one progresses through a block of trials. Second, we found, by examining the trajectories of the low- and high-probability targets, that this increase in effect magnitude was driven by the low-probability targets. Specifically, we found that low-probability targets were detected more slowly as a block of trials progressed. Performance to high-probability targets, on the other hand, was largely invariant across the block. The latter finding is of particular interest because it cannot be reconciled with accounts that propose that the target probability effect is driven by the high-probability targets.

  18. Infrared signature generation of airborne targets (United States)

    Whalen, Michael R.


    This report proposes a generic methodology for generating infrared signatures of airborne targets. The various issues, assumptions and simplifications utilized in signature studies are outlines to insure baseline consistency among future models and evaluation tools. More specifically, the target is characterized on a component level, and the at-aperture signature is generated by the correct inclusion of atmospheric transmission. While the technique and general concepts may apply to all airborne targets, this study places emphasis on cruise missiles and related targets due to their low contrast. For these targets, the background signature becomes more important as both the emitted target radiance and the reflected background radiance contribute to the overall signature. Example target signatures generated using the proposed methodology will be presented following the discussion of signature modeling.

  19. Design and Implementation of SCSI Target Emulator

    Institute of Scientific and Technical Information of China (English)


    A SCSI target emulator is used in a storage area network (SAN) environment to simulate the behavior of a SCSI target for processing and responding to I/O requests issued by initiators. The SCSI target emulator works with general storage devices with multiple transport protocols. The target emulator utilizes a protocol conversion module that translates the SCSI protocols to a variety of storage devices and implements the multi-RAID-level configuration and storage visualization functions. Moreover, the target emulator implements RAM caching, multi-queuing, and request merging to effectively improve the I/O response speed of the general storage devices. The throughput and average response times of the target emulator for block sizes of 4 KB to 128 KB are 150% faster for reads and 67% faster for writes than the existing emulator. With a block size of 16 KB, the I/O latency of the target emulator is only about 20% that of the existing emulator.

  20. Targeting tumor suppressor genes for cancer therapy. (United States)

    Liu, Yunhua; Hu, Xiaoxiao; Han, Cecil; Wang, Liana; Zhang, Xinna; He, Xiaoming; Lu, Xiongbin


    Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies and targeted therapies that specifically modulate the activity of one or more proteins involved in cancer. Major advances have been achieved in targeted cancer therapies in the past few decades, which is ascribed to the increasing understanding of molecular mechanisms for cancer initiation and progression. Consequently, monoclonal antibodies and small molecules have been developed to interfere with a specific molecular oncogenic target. Targeting gain-of-function mutations, in general, has been productive. However, it has been a major challenge to use standard pharmacologic approaches to target loss-of-function mutations of tumor suppressor genes. Novel approaches, including synthetic lethality and collateral vulnerability screens, are now being developed to target gene defects in p53, PTEN, and BRCA1/2. Here, we review and summarize the recent findings in cancer genomics, drug development, and molecular cancer biology, which show promise in targeting tumor suppressors in cancer therapeutics.

  1. Targeted alpha therapy for cancer

    Energy Technology Data Exchange (ETDEWEB)

    Allen, Barry J [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Raja, Chand [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Rizvi, Syed [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Li Yong [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Tsui, Wendy [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Zhang, David [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Song, Emma [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Qu, C F [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Kearsley, John [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Graham, Peter [Centre for Experimental Radiation Oncology, St George Cancer Care Centre, Gray St, Kogarah 2217, NSW (Australia); Thompson, John [Sydney Melanoma Unit, Royal Prince Alfred Hospital, Camperdown 2050 NSW (Australia)


    Targeted alpha therapy (TAT) offers the potential to inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The practicality and efficacy of TAT is tested by in vitro and in vivo studies in melanoma, leukaemia, colorectal, breast and prostate cancers, and by a phase 1 trial of intralesional TAT for melanoma. The alpha-emitting radioisotope used is Bi-213, which is eluted from the Ac-225 generator and chelated to a cancer specific monoclonal antibody (mab) or protein (e.g. plasminogen activator inhibitor-2 PAI2) to form the alpha-conjugate (AC). Stable alpha-ACs have been produced which have been tested for specificity and cytotoxicity in vitro against melanoma (9.2.27 mab), leukaemia (WM60), colorectal (C30.6), breast (PAI2, herceptin), ovarian (PAI2, herceptin, C595), prostate (PAI2, J591) and pancreatic (PAI2, C595) cancers. Subcutaneous inoculation of 1-1.5 million human cancer cells into the flanks of nude mice causes tumours to grow in all mice. Tumour growth is compared for untreated controls, nonspecific AC and specific AC, for local (subcutaneous) and systemic (tail vein or intraperitoneal) injection models. The {sup 213}Bi-9.2.27 AC is injected into secondary skin melanomas in stage 4 patients in a dose escalation study to determine the effective tolerance dose, and to measure kinematics to obtain the equivalent dose to organs. In vitro studies show that TAT is one to two orders of magnitude more cytotoxic to targeted cells than non-specific ACs, specific beta emitting conjugates or free isotopes. In vivo local TAT at 2 days post-inoculation completely prevents tumour formation for all cancers tested so far. Intra-lesional TAT can completely regress advanced sc melanoma but is less successful for breast and prostate cancers. Systemic TAT inhibits the growth of sc melanoma xenografts and gives almost complete control of breast and prostate cancer tumour growth. Intralesional doses up to 450 {mu

  2. 26 CFR 1.430(d)-1 - Determination of target normal cost and funding target. (United States)


    ... 26 Internal Revenue 5 2010-04-01 2010-04-01 false Determination of target normal cost and funding target. 1.430(d)-1 Section 1.430(d)-1 Internal Revenue INTERNAL REVENUE SERVICE, DEPARTMENT OF THE TREASURY (CONTINUED) INCOME TAX (CONTINUED) INCOME TAXES Certain Stock Options § 1.430(d)-1 Determination of target normal cost and funding target....

  3. Terrorist targeting and energy security

    Energy Technology Data Exchange (ETDEWEB)

    Toft, Peter; Duero, Arash; Bieliauskas, Arunas [Institute of Energy, Joint Research Center of the European Commission, P.O. Box 2, 1755 ZG Petten (Netherlands)


    Sudden, short-term disruptions seriously endangering energy security can be triggered by a variety of events - among them attacks by terrorists. This study investigates terrorist attack practices against energy infrastructures and discusses how we may understand them. Our results indicate that attacks against energy infrastructures are comparatively few. Also, we find no strong connection between the ideologies of various terrorist groups and their proclivity to attack. In addition, the highly disproportionate number of attacks in a handful of countries highlights the strong geographic concentration of attacks. To explain these findings, we analyze terrorist targeting incentives including intimidation levels, symbolism, attack feasibility, and concerns for stakeholders. We argue that terrorists in general have comparatively few incentives to attack energy supply infrastructures based on our assessment of these factors. Moreover, higher levels of terrorist incidents in states more prone to internal violent conflict may suggest stronger incentives to attack energy infrastructures. When outlining energy security policies, the low frequency of worldwide attacks coupled with the high concentration of attacks in certain unstable countries should be taken into consideration. Energy importing countries could benefit from developing strategies to increase stability in key energy supply and/or transit countries facing risks of internal instability. (author)

  4. Drug targeting through pilosebaceous route. (United States)

    Chourasia, Rashmi; Jain, Sanjay K


    Local skin targeting is of interest for the pharmaceutical and the cosmetic industry. A topically applied substance has basically three possibilities to penetrate into the skin: transcellular, intercellular, and follicular. The transfollicular path has been largely ignored because hair follicles constitute only 0.1% of the total skin. The hair follicle is a skin appendage with a complex structure containing many cell types that produce highly specialised proteins. The hair follicle is in a continuous cycle: anagen is the hair growth phase, catagen the involution phase and telogen is the resting phase. Nonetheless, the hair follicle has great potential for skin treatment, owing to its deep extension into the dermis and thus provides much deeper penetration and absorption of compounds beneath the skin than seen with the transdermal route. In the case of skin diseases and of cosmetic products, delivery to sweat glands or to the pilosebaceous unit is essential for the effectiveness of the drug. Increased accumulation in the pilosebaceous unit could treat alopecia, acne and skin cancer more efficiently and improve the effect of cosmetic substances and nutrients. Therefore, we review herein various drug delivery systems, including liposomes, niosomes, microspheres, nanoparticles, nanoemulsions, lipid nanocarriers, gene therapy and discuss the results of recent researches. We also review the drugs which have been investigated for pilosebaceous delivery.

  5. Targeting hedgehog in hematologic malignancy. (United States)

    Irvine, David A; Copland, Mhairi


    The Hedgehog pathway is a critical mediator of embryonic patterning and organ development, including hematopoiesis. It influences stem cell fate, differentiation, proliferation, and apoptosis in responsive tissues. In adult organisms, hedgehog pathway activity is required for aspects of tissue maintenance and regeneration; however, there is increasing awareness that abnormal hedgehog signaling is associated with malignancy. Hedgehog signaling is critical for early hematopoietic development, but there is controversy over its role in normal hematopoiesis in adult organisms where it may be dispensable. Conversely, hedgehog signaling appears to be an important survival and proliferation signal for a spectrum of hematologic malignancies. Furthermore, hedgehog signaling may be critical for the maintenance and expansion of leukemic stem cells and therefore provides a possible mechanism to selectively target these primitive cell subpopulations, which are resistant to conventional chemotherapy. Indeed, phase 1 clinical trials of hedgehog pathway inhibitors are currently underway to test this hypothesis in myeloid leukemias. This review covers: (1) the hedgehog pathway and its role in normal and malignant hematopoiesis, (2) the recent development of clinical grade small molecule inhibitors of the pathway, and (3) the potential utility of hedgehog pathway inhibition as a therapeutic strategy in hemato-oncology.

  6. Double-layered target and identification method of individual target correlated with evaporation residues

    Energy Technology Data Exchange (ETDEWEB)

    Kaji, D., E-mail:; Morimoto, K.


    A double-layered target system and an identification method (target ID) for individual targets mounted on a rotating wheel using correlation with evaporation residues were newly developed for the study of superheavy elements (SHE). The target system can be used in three modes: conventional single-layered mode, double-layered mode, and energy-degrader mode. The target ID method can be utilized for masking a target, measuring an excitation function without changing the beam energy from the accelerator, and searching for SHE nuclides using multiple targets during a single irradiation.

  7. Target injection methods for inertial fusion energy (United States)

    Petzoldt, Ronald W.; Moir, Ralph W.


    We have studied four methods to inject IFE targets: the gas gun, electrostatic accelerator, induction accelerator, and rail gun. We recommend a gas gun for indirect drive targets because they can support a gas pressure load on one end and can slide along the gun barrel without damage. With the gas gun, the amount of gas required for each target (about 10 to 100 mg) is acceptable; for other types of targets, a sabot would be necessary. A cam and poppet valve arrangement is recommended for gas flow control. An electrostatic accelerator is attractive for use with lightweight spherical direct drive targets. Since there is no physical contact between the target and the injector, there will be no wear of either component during the injection process. An induction accelerator has an advantage of no electrical contact between the target and the injector. Physical contact is not even necessary, so the wear should be minimal. It requires a cylindrical conductive target sleeve which is a substantial added mass. A rail gun is a simpler device than an electrostatic accelerator or induction accelerator. It requires electrical contact between the target and the rails and may have a significant wear rate. The wear in a vacuum could be reduced by use of a solid lubricant such as MoS2. The total required accuracy of target injection, tracking and beam pointing of +/- 0.4 mm appears achievable but will require development and experimental verification.

  8. Target injection methods for inertial fusion energy

    Energy Technology Data Exchange (ETDEWEB)

    Petzoldt, R.W.; Moir, R.W.


    We have studied four methods to inject IFE targets: the gas gun, electrostatic accelerator, induction accelerator, and rail gun. We recommend a gas gun for indirect drive targets because they can support a gas pressure load on one end and can slide along the gun barrel without damage. With the gas gun, the amount of gas required for each target (about 10 to 100 mg) is acceptable; for other types of targets, a sabot would be necessary. A cam and poppet valve arrangement is recommended for gas flow control. An electrostatic accelerator is attractive for use with lightweight spherical direct drive targets. Since there is no physical contact between the target and the injector, there will be no wear of either component during the injection process. An induction accelerator has an advantage of no electrical contact between the target and the injector. Physical contact is not even necessary, so the wear should be minimal. It requires a cylindrical conductive target sleeve which is a substantial added mass. A rail gun is a simpler device than an electrostatic accelerator or induction accelerator. It requires electrical contact between the target and the rails and may have a significant wear rate. The wear in a vacuum could be reduced by use of a solid lubricant such as MoS{sub 2}. The total required accuracy of target injection, tracking and beam pointing of {plus_minus}0.4 mm appears achievable but will require development and experimental verification.

  9. Fluid mechanics aspects of magnetic drug targeting. (United States)

    Odenbach, Stefan


    Experiments and numerical simulations using a flow phantom for magnetic drug targeting have been undertaken. The flow phantom is a half y-branched tube configuration where the main tube represents an artery from which a tumour-supplying artery, which is simulated by the side branch of the flow phantom, branches off. In the experiments a quantification of the amount of magnetic particles targeted towards the branch by a magnetic field applied via a permanent magnet is achieved by impedance measurement using sensor coils. Measuring the targeting efficiency, i.e. the relative amount of particles targeted to the side branch, for different field configurations one obtains targeting maps which combine the targeting efficiency with the magnetic force densities in characteristic points in the flow phantom. It could be shown that targeting efficiency depends strongly on the magnetic field configuration. A corresponding numerical model has been set up, which allows the simulation of targeting efficiency for variable field configuration. With this simulation good agreement of targeting efficiency with experimental data has been found. Thus, the basis has been laid for future calculations of optimal field configurations in clinical applications of magnetic drug targeting. Moreover, the numerical model allows the variation of additional parameters of the drug targeting process and thus an estimation of the influence, e.g. of the fluid properties on the targeting efficiency. Corresponding calculations have shown that the non-Newtonian behaviour of the fluid will significantly influence the targeting process, an aspect which has to be taken into account, especially recalling the fact that the viscosity of magnetic suspensions depends strongly on the magnetic field strength and the mechanical load.

  10. Memory for found targets interferes with subsequent performance in multiple-target visual search. (United States)

    Cain, Matthew S; Mitroff, Stephen R


    Multiple-target visual searches--when more than 1 target can appear in a given search display--are commonplace in radiology, airport security screening, and the military. Whereas 1 target is often found accurately, additional targets are more likely to be missed in multiple-target searches. To better understand this decrement in 2nd-target detection, here we examined 2 potential forms of interference that can arise from finding a 1st target: interference from the perceptual salience of the 1st target (a now highly relevant distractor in a known location) and interference from a newly created memory representation for the 1st target. Here, we found that removing found targets from the display or making them salient and easily segregated color singletons improved subsequent search accuracy. However, replacing found targets with random distractor items did not improve subsequent search accuracy. Removing and highlighting found targets likely reduced both a target's visual salience and its memory load, whereas replacing a target removed its visual salience but not its representation in memory. Collectively, the current experiments suggest that the working memory load of a found target has a larger effect on subsequent search accuracy than does its perceptual salience.

  11. Mitochondria: a target for bacteria. (United States)

    Lobet, Elodie; Letesson, Jean-Jacques; Arnould, Thierry


    Eukaryotic cells developed strategies to detect and eradicate infections. The innate immune system, which is the first line of defence against invading pathogens, relies on the recognition of molecular patterns conserved among pathogens. Pathogen associated molecular pattern binding to pattern recognition receptor triggers the activation of several signalling pathways leading to the establishment of a pro-inflammatory state required to control the infection. In addition, pathogens evolved to subvert those responses (with passive and active strategies) allowing their entry and persistence in the host cells and tissues. Indeed, several bacteria actively manipulate immune system or interfere with the cell fate for their own benefit. One can imagine that bacterial effectors can potentially manipulate every single organelle in the cell. However, the multiple functions fulfilled by mitochondria especially their involvement in the regulation of innate immune response, make mitochondria a target of choice for bacterial pathogens as they are not only a key component of the central metabolism through ATP production and synthesis of various biomolecules but they also take part to cell signalling through ROS production and control of calcium homeostasis as well as the control of cell survival/programmed cell death. Furthermore, considering that mitochondria derived from an ancestral bacterial endosymbiosis, it is not surprising that a special connection does exist between this organelle and bacteria. In this review, we will discuss different mitochondrial functions that are affected during bacterial infection as well as different strategies developed by bacterial pathogens to subvert functions related to calcium homeostasis, maintenance of redox status and mitochondrial morphology.

  12. Application of VNIIRS for target tracking (United States)

    Blasch, Erik; Kahler, Bart


    The Motion Imagery Standards Board (MISB) has created the Video National Imagery Interpretability Rating Scale (VNIIRS). VNIIRS extends NIIRS to scene characterization from streaming video to include object recognition of various targets for a given size. To apply VNIIRs for target tracking, there is a need to understand the operating conditions of the sensor type, environmental phenomenon, and target behavior (SET). In this paper, we explore VNIIRS for target tracking given the sensor resolution to support the relative tracking performance using track success. The relative assessment can be used in relation to the absolute target size associated with the VNIIRS. In a notional analysis, we determine the issues and capabilities of using VNIIRS video quality ratings to determine track success. The outcome of the trade study is an experiment to understand how to use VNIIRS can support target tracking evaluation.

  13. Development on dynamic nuclear polarized targets

    CERN Document Server

    Penttila, S I


    Our interest in understanding the spin content of the nucleon has left its marks on the recent development of the dynamic nuclear polarized (DNP) targets. This can be seen from the targets developed at CERN and SLAC for the measurement of the polarized spin structure functions in deep inelastic scattering. The results of the experiments indicated that less than 30% of the nucleon spin is carried by the quarks. This unpredicted small value initiated planning of new polarized target experiments to determine the gluon polarization on the nucleon using polarized real photons and polarized /sup 6/LiD targets. In several facilities very intense polarized photon beams are available at a wide energy range. During the next few years these photon beams with DNP targets will be used to test the fundamental GDH sum rule. Other DNP target developments are also discussed. (61 refs).

  14. Attentional processing of multiple targets and distractors. (United States)

    Munneke, Jaap; Fait, Elisa; Mazza, Veronica


    We assessed the functioning of attention when multiple relevant objects are intermingled with multiple distractors, measuring two electrophysiological subcomponents of the N2pc that have been associated, respectively, with target selection and distractor suppression: the target negativity (Nt) and the distractor positivity (Pd). To this aim, we orthogonally manipulated the number of targets and distractors in an enumeration task. The Nt was modulated by target, but not distractor numerosity, suggesting that an increase in target numerosity leads to an increase in attentional resources needed to form individual representations of the targets. In contrast, the number of distractors did not differentially alter the Pd. We hypothesize that distractors sharing similar visual features can be processed (and possibly suppressed) as a set, without the need for individuation.

  15. Liquid Hydrogen Target for the COMPASS experiment

    CERN Document Server

    Bremer, J; Duday-Chanat, L; Geyer, R; Mallot, G K; Pirotte, O; Vullierme, B


    A liquid hydrogen target has been developed for the COMPASS experiment at CERN. The target has a diameter of 40 mm and a length of 2.5 meter, creating an active volume of about 3 liter of liquid hydrogen. The cylindrical part of the target wall is formed by a Kapton® foil strip, wound and glued to a thickness of 0.125 mm. The Kapton® foil is used to minimize the energy loss of the particles, scattered or created within the target volume, crossing the target boundary. The two end-caps enclosing the target volume have been fabricated from Mylar®. The system is cooled with a 30 W at 20 K cryocooler, delivering the cooling capacity for the cool-down as well as for the continuous operation of the system.

  16. Protection Related to High-power Targets

    CERN Document Server

    Plum, M A


    Target protection is an important part of machine protection. The beam power in high-intensity accelerators is high enough that a single wayward pulse can cause serious damage. Today's high-power targets operate at the limit of available technology, and are designed for a very narrow range of beam parameters. If the beam pulse is too far off centre, or if the beam size is not correct, or if the beam density is too high, the target can be seriously damaged. We will start with a brief introduction to high-power targets and then move to a discussion of what can go wrong, and what are the risks. Next we will discuss how to control the beam-related risk, followed by examples from a few different accelerator facilities. We will finish with a detailed example of the Oak Ridge Spallation Neutron Source target tune up and target protection.

  17. From monetary to exchange rate targets

    Directory of Open Access Journals (Sweden)

    M.J. ARTIS


    Full Text Available This paper was presented at the Fourth International Seminar on European Economic and Monetary Union, held in Copenhagen in March of 1981. The author takes up the theoretical issues in the framework of both static and dynamic analysis. He argues, on the basis of the criterion of minimising the variance of prices around their target value, that an exchange-rate target outperforms a monetary target under most conceivable types of disturbances in a static analysis. 

  18. Main Development Targets for CNOOC in 2000

    Institute of Scientific and Technical Information of China (English)


    @@ In order to obtain stable reserves and create scope economic management, the China National Offshore Oil Corporation (CNOOC) officially put forward the main development target and main sci-tech sector target of the Ninth Five-Year Plan in July, 1995. These targets aim to make CNOOC as an international group corporation,including exploration and development of oil and gas,refining, petrochemicals, chemical fertilizer, power generation, unitizing sales network of up and down stream.

  19. Inflation targeting and product market deregulation


    Moretti, Laura


    I evaluate the effect of inflation targeting on inflation and how it interacts with product market deregulation during the disinflationary process in the 1990s. Using a sample of 21 OECD countries, I show that, after controlling for product market deregulation, the effect of inflation targeting is quantitatively important and statistically significant. Moreover, product market deregulation also matters in particular in countries that adopted an inflation targeting regime. I propose a New Keyn...

  20. Novel Acoustic Scattering Processes for Target Discrimination (United States)


    Scattering Processes for Target Discrimination 5a. CONTRACT NUMBER 5b. GRANT NUMBER N000141010093 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Marston...10-1-0093 December 2014 Novel Acoustic Scattering Processes for Target Discrimination Philip L. Marston, Principal Investigator Physics and...Target Discrimination (2010) Philip L. Marston Physics and Astronomy Dept., Washington State University, Pullman, WA 99164-2814 phone: (509) 335

  1. Target tracking based on frequency spectrum amplitude

    Institute of Scientific and Technical Information of China (English)

    Guo Huidong; Zhang Xinhua; Xia Zhijun


    The amplitude of frequency spectrum can be integrated with probabilistic data association (PDA) to distinguish the target with clutter echoes, especially in low SNR underwater environment. A new target-tracking algorithm is presented which adopts the amplitude of frequency spectrum to improve target tracking in clutter. The probabilistic density distribution of frequency spectrum amplitude is analyzed. By simulation, the results show that the algorithm is superior to PDA. This approach enhances stability for the association probability and increases the performance of target tracking.

  2. ISAC target operation with high proton currents

    CERN Document Server

    Dombsky, M; Schmor, P; Lane, M


    The TRIUMF-ISAC facility target stations were designed for ISOL target irradiations with up to 100 mu A proton beam currents. Since beginning operation in 1998, ISAC irradiation currents have progressively increased from initial values of approx 1 mu A to present levels of up to 40 mu A on refractory metal foil targets. In addition, refractory carbide targets have operated at currents of up to 15 mu A for extended periods. The 1-40 mu A operational regime is achieved by tailoring each target to the thermal requirements dictated by material properties such as beam power deposition, thermal conductivity and maximum operating temperature of the target material. The number of heat shields on each target can be varied in order to match the effective emissivity of the target surface for the required radiative power dissipation. Targets of different thickness, surface area and volume have been investigated to study the effect of diffusion and effusion delays on the yield of radioisotopes. For yields of short-lived p...

  3. Target studies for surface muon production (United States)

    Berg, F.; Desorgher, L.; Fuchs, A.; Hajdas, W.; Hodge, Z.; Kettle, P.-R.; Knecht, A.; Lüscher, R.; Papa, A.; Rutar, G.; Wohlmuther, M.


    Meson factories are powerful drivers of diverse physics programs. With beam powers already in the MW-regime attention has to be turned to target and beam line design to further significantly increase surface muon rates available for experiments. For this reason we have explored the possibility of using a neutron spallation target as a source of surface muons by performing detailed Geant4 simulations with pion production cross sections based on a parametrization of existing data. While the spallation target outperforms standard targets in the backward direction by more than a factor 7 it is not more efficient than standard targets viewed under 90°. Not surprisingly, the geometry of the target plays a large role in the generation of surface muons. Through careful optimization, a gain in surface muon rate of between 30% and 60% over the standard "box-like" target used at the Paul Scherrer Institute could be achieved by employing a rotated slab target. An additional 10% gain could also be possible by utilizing novel target materials such as, e.g., boron carbide.

  4. Project Plan Remote Target Fabrication Refurbishment Project

    Energy Technology Data Exchange (ETDEWEB)

    Bell, Gary L [ORNL; Taylor, Robin D [ORNL


    In early FY2009, the DOE Office of Science - Nuclear Physics Program reinstated a program for continued production of {sup 252}Cf and other transcurium isotopes at the Radiochemical Engineering Development Center (REDC) at Oak Ridge National Laboratory (ORNL). The FY2009 major elements of the workscope are as follows: (1) Recovery and processing of seven transuranium element targets undergoing irradiation at the High Flux Isotope Reactor (HFIR) at ORNL; (2) Development of a plan to manufacture new targets for irradiation beginning in early- to mid-FY10 to supply irradiated targets for processing Campaign 75 (TRU75); and (3) Refurbishment of the target manufacturing equipment to allow new target manufacture in early FY10 The {sup 252}Cf product from processing Campaign 74 (recently processed and currently shipping to customers) is expected to supply the domestic demands for a period of approximately two years. Therefore it is essential that new targets be introduced for irradiation by the second quarter of FY10 (HFIR cycle 427) to maintain supply of {sup 252}Cf; the average irradiation period is {approx}10 HFIR cycles, requiring about 1.5 calendar years. The strategy for continued production of {sup 252}Cf depends upon repairing and refurbishing the existing pellet and target fabrication equipment for one additional target production campaign. This equipment dates from the mid-1960s to the late 1980s, and during the last target fabrication campaign in 2005- 2006, a number of component failures and operations difficulties were encountered. It is expected that following the target fabrication and acceptance testing of the targets that will supply material for processing Campaign 75 a comprehensive upgrade and replacement of the remote hot-cell equipment will be required prior to subsequent campaigns. Such a major refit could start in early FY 2011 and would take about 2 years to complete. Scope and cost estimates for the repairs described herein were developed, and

  5. Two target localization using passive monopulse radar

    KAUST Repository

    Jardak, Seifallah


    The simultaneous lobing technique, also known as monopulse technique, has been widely used for fast target localization and tracking purposes. Many works focused on accurately localizing one or two targets laying within a narrow beam centered around the monopulse antenna boresight direction. In this work, however, a new approach uses the outputs of a four quadrant antenna receiver to rapidly localize two point targets present in the hemisphere. A second set of antennas can be required to localize two targets sharing the same elevation or azimuth angles. To combine the outputs of both antenna sets and enhance the estimation performance of the algorithm, two methods are presented and compared.

  6. The drug target genes show higher evolutionary conservation than non-target genes. (United States)

    Lv, Wenhua; Xu, Yongdeng; Guo, Yiying; Yu, Ziqi; Feng, Guanglong; Liu, Panpan; Luan, Meiwei; Zhu, Hongjie; Liu, Guiyou; Zhang, Mingming; Lv, Hongchao; Duan, Lian; Shang, Zhenwei; Li, Jin; Jiang, Yongshuai; Zhang, Ruijie


    Although evidence indicates that drug target genes share some common evolutionary features, there have been few studies analyzing evolutionary features of drug targets from an overall level. Therefore, we conducted an analysis which aimed to investigate the evolutionary characteristics of drug target genes. We compared the evolutionary conservation between human drug target genes and non-target genes by combining both the evolutionary features and network topological properties in human protein-protein interaction network. The evolution rate, conservation score and the percentage of orthologous genes of 21 species were included in our study. Meanwhile, four topological features including the average shortest path length, betweenness centrality, clustering coefficient and degree were considered for comparison analysis. Then we got four results as following: compared with non-drug target genes, 1) drug target genes had lower evolutionary rates; 2) drug target genes had higher conservation scores; 3) drug target genes had higher percentages of orthologous genes and 4) drug target genes had a tighter network structure including higher degrees, betweenness centrality, clustering coefficients and lower average shortest path lengths. These results demonstrate that drug target genes are more evolutionarily conserved than non-drug target genes. We hope that our study will provide valuable information for other researchers who are interested in evolutionary conservation of drug targets.

  7. ISOLDE target zone control room HD

    CERN Multimedia


    Operating the ISOLDE target handling robots from the dedicated control room in building 197. Monitors showing the movements of the robots (GPS in this case) in the target zone. The footage shows the actual operation by the operator as well as the different equipment such as camera electronics, camera motor controls, camera monitors and Kuka robot controls touch panel.

  8. Technical Design Report, Second Target Station

    Energy Technology Data Exchange (ETDEWEB)

    Galambos, John D. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Anderson, David E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bechtol, D. [HDR, Inc., Chattanooga, TN (United States); Bethea, Katie L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Brown, N. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Carden, W. F. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Chae, Steven M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Clark, A. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Counce, Deborah M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Craft, K. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Crofford, Mark T. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Collins, Richard M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Cousineau, Sarah M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Curry, Douglas E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Cutler, Roy I. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Dayton, Michael J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Dean, Robert A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Deibele, Craig E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Doleans, Marc [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Dye, T. [HDR, Inc., Chattanooga, TN (United States); Eason, Bob H. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Eckroth, James A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Fincrock, C. [HDR, Inc., Chattanooga, TN (United States); Fritts, S. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Gallmeier, Franz X. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Gawne, Ken R. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hartman, Steven M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Herwig, Kenneth W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Hess, S. [HDR, Inc., Chattanooga, TN (United States); Holmes, Jeffrey A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Horak, Charlie M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Howell, Matthew P. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Iverson, Erik B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jacobs, Lorelei L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Jones, Larry C. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Johnson, B. [HDR, Inc., Chattanooga, TN (United States); Johnson, S. [HDR, Inc., Chattanooga, TN (United States); Kasemir, Kay [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Kim, Sang-Ho [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Laughon, Gregory J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Lu, W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Mahoney, Kelly L. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Mammosser, John [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); McManamy, T. [McManamy Consulting, Inc., Knoxville, TN (United States); Michilini, M. [HDR, Inc., Chattanooga, TN (United States); Middendorf, Mark E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); O' Neal, Ed [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Nemec, B. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Peters, Roy Cecil [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Plum, Michael A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Reagan, G. [Barge Waggoner Sumner & Cannon, Inc., Nashville, TN (United States); Remec, Igor [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Rennich, Mark J. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Riemer, Bernie [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Saethre, Robert B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Schubert, James Phillip [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Shishlo, Andrei P. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Smith, C. Craig [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Strong, William Herb [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Tallant, Kathie M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Tennant, David Alan [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Thibadeau, Barbara M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Trumble, S. [HDR, Inc., Chattanooga, TN (United States); Trotter, Steven M. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Wang, Z. [Institute of Modern Physics (IMP), Chinese Academy of Sciences (China); Webb, Steven B. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Williams, Derrick C. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); White, Karen S. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Zhao, Jinkui [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)


    The Second Target Station (STS) is a proposed upgrade for SNS. It includes a doubling of the accelerator power and an additional instrument hall. The new instrument hall will receive a 467 kW 10 Hz beam. The parameters and preliminary design aspects of the STS are presented for the accelerator, target systems, instrument hall, instruments and civil construction aspects.

  9. Targeted Magnetic Hyperthermia for Lung Cancer (United States)


    O R R EC TE D PR O O F 928 were evident. In contrast, MRI scans of treated mice showed 929 no signs of intra-thoracic lung cancer (Fig. 4). The...mice that received SPIO-loaded nanoemulsion 1010 (either targeted or non-targeted) appeared hypointense, in- 1011 dicating SPIO accumulation in these

  10. Target Studies for Surface Muon Production

    CERN Document Server

    Berg, F; Fuchs, A; Hajdas, W; Hodge, Z; Kettle, P -R; Knecht, A; Lüscher, R; Papa, A; Rutar, G; Wohlmuther, M


    Meson factories are powerful drivers of diverse physics programmes. With beam powers already in the MW-regime attention has to be turned to target and beam line design to further significantly increase surface muon rates available for experiments. For this reason we have explored the possibility of using a neutron spallation target as a source of surface muons by performing detailed Geant4 simulations with pion production cross sections based on a parametrization of existing data. While the spallation target outperforms standard targets in the backward direction by more than a factor 7 it is not more efficient than standard targets viewed under 90{\\deg}. Not surprisingly, the geometry of the target plays a large role in the generation of surface muons. Through careful optimization, a gain in surface muon rate of between 30 - 60% over the standard "box-like" target used at the Paul Scherrer Institute could be achieved by employing a rotated slab target. An additional 10% gain could also be possible by utilizin...

  11. Targeting herpesvirus reliance of the chemokine system

    DEFF Research Database (Denmark)

    Rosenkilde, Mette M; Kledal, Thomas N


    acquired homologs of both chemokines and chemokine receptors belonging to the 7 transmembrane (7TM) spanning, G protein-coupled receptor family. 7TM receptors are very efficient drug targets and are currently the most popular class of investigational drug targets. A notable trait for the virus encoded...

  12. Inflation targeting and interest rate policy

    NARCIS (Netherlands)

    Verhagen, W.H.


    The thesis contains a collection of papers on issues in inflation targeting and its implications for the way interest rates are set. In this respect, the first part deals with two largely positive issues: the effect of inflation forecast targeting on the term structure of interest rates and the impl

  13. Inflation Targeting in Emerging Market Countries


    Frederic S. Mishkin


    This paper outlines what inflation targeting involves for emerging market/transition countries and discusses the advantages and disadvantages of this monetary policy strategy. The discussion suggests that although inflation targeting is not a panacea and may not be appropriate for many emerging market countries, it can be a highly useful monetary policy strategy in a number of them.

  14. Prodrug applications for targeted cancer therapy. (United States)

    Giang, Irene; Boland, Erin L; Poon, Gregory M K


    Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.

  15. Receptor-targeted metalloradiopharmaceuticals. Final technical report

    Energy Technology Data Exchange (ETDEWEB)

    Green, Mark A.


    Copper (II) and platinum (II) coordination complexes were prepared and characterized. These complexes were designed to afford structural homology with steroidal and non-steroidal estrogens for possible use as receptor-targeted radiopharmaceuticals. While weak affinity for the estrogen receptor was detectable, none would appear to have sufficient receptor-affinity for estrogen-receptor-targeted imaging or therapy.

  16. 28 CFR 55.17 - Targeting. (United States)


    ... REGARDING LANGUAGE MINORITY GROUPS Minority Language Materials and Assistance § 55.17 Targeting. The term...). “Targeting” refers to a system in which the minority language materials or assistance required by the Act are... targeting system will normally fulfill the Act's minority language requirements if it is designed...

  17. What "helps" tumors evade vascular targeting treatment?

    Institute of Scientific and Technical Information of China (English)

    SI Zhi-chao; LIU Jie


    Objective To throw a light on the possible factors which might induce resistance of vascular targeting treatment in tumors by reviewing the recent publications in the field of tumor angiogenesis and vascular targeting treatment.Data sources The data used in this review were mainly from Medline and PubMed for relevant English language articles published from 1971 to January 2008. The search terms were "angiogenesis", "vascular targeting treatment" and "endothelial progenitor cells".Study selection Articles involved in the possible influence factors during angiogenesis and vascular targeting treatment were selected, including angiogenic or anti-angiogenic mechanism, tumor vasculature, tumor cells, cancer stem cells and endothelial progenitor cells.Results As a promising strategy vascular targeting treatment still has experimental and clinical setbacks which may term tumor vasculature's resistance to anti-angiogenesis agents. There are several possible explanations for such a resistance that might account for clinical and preclinical failures of anti-angiogenic treatment against tumor.Proangiogenic effect of hypoxia, normal tumor vasculature, escape of tumor cells and tumor vasculogenesis are included.This review reveals some clues which might be helpful to direct future research in order to remove obstacles to vascular targeting treatment.Conclusions Generally and undoubtedly vascular targeting treatment remains a promising strategy. But we still have to realize the existence of a challenging future. Further research is required to enhance our knowledge of vascular targeting treatment strategy before it could make a more substantial success.

  18. Target Tracking and Interception by Aggressive Honeybees (United States)


    targets can hinder, prevent or endanger attacks to the centrally-located targets. Figure 15. Percentage of strikes (totalling 100%) to each of the...adjusted, 53  to minimize the drag that is produced by the medium through which they move. For example, 54  sharks , tuna and mackerel possess fusiform shapes

  19. Targeted inhibition of tumor growth and angiogenesis

    NARCIS (Netherlands)

    van der Meel, R.


    Two main strategies have been pursued for the development of an effective and targeted anti-cancer treatment. The first strategy comprised the generation of a targeted nanomedicine for the inhibition of tumor cell proliferation by blocking growth factor receptor pathways. The epidermal growth factor

  20. Waiting-time targets. Early learners. (United States)

    Moore, Alison


    Thirteen 'early achiever' sites have volunteered to deliver the new 18-week target ahead of schedule. The sites have highlighted recurring issues for trusts aiming for 18 weeks: orthopaedics, audiology, endoscopy and some smaller specialties have all proved challenging. The target should be seen as a vital step towards a 'no unnecessary delay' system of working and thinking.

  1. A rotating target for Ra production

    NARCIS (Netherlands)

    Sohani, M.; Wilschut, H. W.


    A target wheel with pyrolytic graphite targets is designed and constructed at the TRI mu P facility to boost the production rate of Ra isotopes. Simulation, design properties and production results are discussed. (C) 2012 Elsevier B.V. All rights reserved.

  2. Mathematical modelling of magnetically targeted drug delivery

    Energy Technology Data Exchange (ETDEWEB)

    Grief, Andrew D. [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail:; Richardson, Giles [Theoretical Mechanics, School of Mathematical Sciences, University of Nottingham, University Park, Nottingham NG7 2RD (United Kingdom)]. E-mail:


    A mathematical model for targeted drug delivery using magnetic particles is developed. This includes a diffusive flux of particles arising from interactions between erythrocytes in the microcirculation. The model is used to track particles in a vessel network. Magnetic field design is discussed and we show that it is impossible to specifically target internal regions using an externally applied field.

  3. Population ageing and public finance targets


    Heikki Oksanen


    The paper incorporates intergenerational fairness into a framework to analyse long-term sustainability of public finances under population ageing. It establishes a link between ageing-related public expenditure projections and public finance targets, thereby clarifying the connection between pension reforms and general government budget balance and debt targets.

  4. NIF Target Assembly Metrology Methodology and Results

    Energy Technology Data Exchange (ETDEWEB)

    Alger, E. T. [General Atomics, San Diego, CA (United States); Kroll, J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Dzenitis, E. G. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Montesanti, R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Hughes, J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Swisher, M. [IAP, Livermore, CA (United States); Taylor, J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Segraves, K. [IAP, Livermore, CA (United States); Lord, D. M. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Reynolds, J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Castro, C. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Edwards, G. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)


    During our inertial confinement fusion (ICF) experiments at the National Ignition Facility (NIF) we require cryogenic targets at the 1-cm scale to be fabricated, assembled, and metrologized to micron-level tolerances. During assembly of these ICF targets, there are physical dimensmetrology is completed using optical coordinate measurement machines that provide repeatable measurements with micron precision, while also allowing in-process data collection for absolute accuracy in assembly. To date, 51 targets have been assembled and metrologized, and 34 targets have been successfully fielded on NIF relying on these metrology data. In the near future, ignition experiments on NIF will require tighter tolerances and more demanding target assembly and metrology capability. Metrology methods, calculations, and uncertainty estimates will be discussed. Target diagnostic port alignment, target position, and capsule location results will be reviewed for the 2009 Energetics Campaign. The information is presented via control charts showing the effect of process improvements that were made during target production. Certain parameters, including capsule position, met the 2009 campaign specifications but will have much tighter requirements in the future. Finally, in order to meet these new requirements assembly process changes and metrology capability upgrades will be necessary.

  5. Exploiting novel molecular targets in gastrointestinal cancers

    Institute of Scientific and Technical Information of China (English)


    Novel molecular targets are being discovered as we learn more about the aberrant processes underlying various cancers. Efforts to translate this knowledge are starting to impact on the care of patients with gastrointestinal cancers. The epidermal growth factor receptor (EGFR) pathway and angiogenesis have been targeted successfully in colorectal cancer with cetuximab, panitunumab and bevacizumab. Similarly, EGFR-targeting with erlotinib yielded significant survival benefit in pancreatic cancer when combined with gemcitabine. The multi-targeting approach with sorafenib has made it the first agent to achieve significant survival benefit in hepatocellular carcinoma. Efforts to exploit the dysregulated Akt/mTOR pathway in GI cancer therapy are ongoing. These molecular targets can be disrupted by various approaches, including the use of monoclonal antibody to intercept extracellular ligands and disrupt receptor-ligand binding, and small molecule inhibitors that interrupt the activation of intracellular kinases.

  6. Epicardial fat: a new cardiovascular therapeutic target. (United States)

    Iacobellis, Gianluca


    Epicardial fat is the visceral fat depot of the heart. Given its rapid metabolism, organ fat specificity and simple objective measurability, epicardial fat can serve as target for pharmaceutical agents targeting the adipose tissue. Epicardial fat has shown to significantly respond to thiazolidinediones, glucagon like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors and statins. Epicardial fat may represent a measurable risk factor and modifiable therapeutic target. Targeted pharmaceutical interventions may allow the epicardial fat to resume its physiological role. A drug-induced browning effect on epicardial fat suggests the development of pharmacological strategies to increase energy consumption. The potential of modulating the epicardial fat transcriptome with targeted pharmacological agents can open new avenues in the pharmacotherapy of cardio-metabolic diseases.

  7. The Jefferson Lab frozen spin target

    Energy Technology Data Exchange (ETDEWEB)

    Keith, C.D., E-mail: [Thomas Jefferson National Accelerator Facility, Newport News, VA 23606 (United States); Brock, J.; Carlin, C.; Comer, S.A.; Kashy, D. [Thomas Jefferson National Accelerator Facility, Newport News, VA 23606 (United States); McAndrew, J. [School of Physics, University of Edinburgh, Edinburgh (United Kingdom); Meekins, D.G.; Pasyuk, E.; Pierce, J.J.; Seely, M.L. [Thomas Jefferson National Accelerator Facility, Newport News, VA 23606 (United States)


    A frozen spin polarized target, constructed at Jefferson Lab for use inside a large acceptance spectrometer, is described. The target has been utilized for photoproduction measurements with polarized tagged photons of both longitudinal and circular polarization. Protons in TEMPO-doped butanol were dynamically polarized to approximately 90% outside the spectrometer at 5 T and 200-300 mK. Photoproduction data were acquired with the target inside the spectrometer at a frozen-spin temperature of approximately 30 mK with the polarization maintained by a thin, superconducting coil installed inside the target cryostat. A 0.56 T solenoid was used for longitudinal target polarization and a 0.50 T dipole for transverse polarization. Spin-lattice relaxation times as high as 4000 h were observed. We also report polarization results for deuterated propanediol doped with the trityl radical OX063.

  8. Progress on LMJ targets for ignition

    Energy Technology Data Exchange (ETDEWEB)

    Cherfils-Clerouin, C; Boniface, C; Bonnefille, M; Dattolo, E; Galmiche, D; Gauthier, P; Giorla, J; Laffite, S; Liberatore, S; Loiseau, P; Malinie, G; Masse, L; Masson-Laborde, P E; Monteil, M C; Poggi, F; Seytor, P; Wagon, F; Willien, J L, E-mail: catherine.cherfils@cea.f [CEA, DAM, DIF, F-91297 Arpajon (France)


    Targets designed to produce ignition on the Laser Megajoule (LMJ) are being simulated in order to set specifications for target fabrication. The LMJ experimental plans include the attempt of ignition and burn of an ICF capsule with 160 laser beams, delivering up to 1.4 MJ and 380 TW. New targets needing reduced laser energy with only a small decrease in robustness have then been designed for this purpose. Working specifically on the coupling efficiency parameter, i.e. the ratio of the energy absorbed by the capsule to the laser energy, has led to the design of a rugby-ball shaped cocktail hohlraum; with these improvements, a target based on the 240-beam A1040 capsule can be included in the 160-beam laser energy-power space. Robustness evaluations of these different targets shed light on critical points for ignition, which can trade off by tightening some specifications or by preliminary experimental and numerical tuning experiments.

  9. Performance Targets and External Market Prices

    DEFF Research Database (Denmark)

    Hansen, Allan; Friis, Ivar; Vámosi, Tamás S.

    In this paper we explore the processes of ‘bringing the market inside the firm’ to set performance targets and benchmark production workers productivity. We analyze attempts to use external suppliers’ bids in target setting in a Danish manufacturing company. The case study illustrates how...... the implementation of external market information in target setting – well known in transfer pricing, relative performance evaluation, beyond budgeting, target costing, piece rates systems and value based management – relate to challenging motivation and information problem. The analysis and discussion of those...... problems, in particular those related to accounting for the internal performance (that are going to be compared with the external target), calculating the ‘inside’ costs and defining controllability, contributes to the management accounting as well as the piece-rate literature....

  10. Design of the NIF Cryogenic Target System

    Energy Technology Data Exchange (ETDEWEB)

    Gibson, C; Baltz, J; Malsbury, T; Atkinson, D; Brugmann, V; Coffield, F; Edwards, O; Haid, B; Locke, S; Shiromizu, S; Skulina, K


    The United States Department of Energy has embarked on a campaign to conduct credible fusion ignition experiments on the National Ignition Facility (NIF) at the Lawrence Livermore National Laboratory in 2010. The target assembly specified for this campaign requires the formation of a deuterium/tritium (DT) fuel ice layer in a 2 mm diameter capsule at the center of a 9 mm long by 5 mm diameter cylinder, called a hohlraum. The ice layer must be formed and maintained at temperatures below 20 K. At laser shot time, the target is positioned at the center of the NIF target chamber, aligned to the laser beams and held stable to less than 7 {micro}m rms. We have completed the final design of the Cryogenic Target System and are integrating the devices necessary to create, characterize and position the cryogenic target for ignition experiments. These designs, with supporting analysis and prototype test results, will be presented.

  11. Targeted Radionuclide Therapy of Human Tumors

    Directory of Open Access Journals (Sweden)

    Sergey V. Gudkov


    Full Text Available Targeted radionuclide therapy is one of the most intensively developing directions of nuclear medicine. Unlike conventional external beam therapy, the targeted radionuclide therapy causes less collateral damage to normal tissues and allows targeted drug delivery to a clinically diagnosed neoplastic malformations, as well as metastasized cells and cellular clusters, thus providing systemic therapy of cancer. The methods of targeted radionuclide therapy are based on the use of molecular carriers of radionuclides with high affinity to antigens on the surface of tumor cells. The potential of targeted radionuclide therapy has markedly grown nowadays due to the expanded knowledge base in cancer biology, bioengineering, and radiochemistry. In this review, progress in the radionuclide therapy of hematological malignancies and approaches for treatment of solid tumors is addressed.

  12. Radiochemical aspects of liquid mercury spallation targets

    CERN Document Server

    Neuhausen, Joerg; Eichler, Bernd; Eller, Martin; Horn, Susanne; Schumann, Dorothea; Stora, Thierry


    Liquid metal spallation targets using mercury as target material are used in state-of-the-art high power pulsed neutron sources that have been constructed in the USA and Japan within the last decade. Similar target concepts were also proposed for next generation ISOL, beta-beam and neutrino facilities. A large amount of radioactivity will be induced in the liquid metal during operation caused by the interaction of the target material with the intense proton beam. This radioactivity - carried by a wide range of radioisotopes of all the elements of the periodic table from hydrogen up to thallium - must be considered for the assessment of safe operation and maintenance procedures as well as for a final disposal of the used target material and components. This report presents an overview on chemical investigations performed in our laboratory that deal with the behavior of radionuclides in proton irradiated mercury samples. The solubility of elements in mercury was calculated using thermodynamical data obtained by...

  13. Ecosystem Targets - Defining target levels for ecosystem components: a socio-ecological approach (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Ecological indicators can facilitate Ecosystem-based Management, but only if targets for indicators exist. Because targets are an expression of the desired state of...

  14. Cooperative target convergence using multiple agents

    Energy Technology Data Exchange (ETDEWEB)

    Kwok, K.S.; Driessen, B.J.


    This work considers the problem of causing multiple (100`s) autonomous mobile robots to converge to a target and provides a follow-the-leader approach to the problem. Each robot has only a limited-range sensor for sending the target and also larger but also limited-range robot-to-robot communication capability. Because of the small amount of information available to the robots, a practical approach to improve convergence to the target is to have a robot follow the robot with the best quality of information. Specifically, each robot emits a signal that informs in-range robots what its status is. A robot has a status value of 0 if it is itself in range of the target. A robot has a status of 1 if it is not in range of the target but is in communication range of a robot that is in range of the target. A robot has a status of 2 if it is not in range of the target but is within range of another robot that has status 1, and so on. Of all the mobile robots that any given robot is in range of, it follows the one with the best status. The emergent behavior is the ant-like trails of robots following each other toward the target. If the robot is not in range of another robot that is either in range of the target or following another robot, the robot will assign-1 to its quality-of-information, and will execute an exhaustive search. The exhaustive search will continue until it encounters either the target or another robot with a nonnegative quality-of-information. The quality of information approach was extended to the case where each robot only has two-bit signals informing it of distance to in-range robots.

  15. Prazosin Displays Anticancer Activity against Human Prostate Cancers: Targeting DNA, Cell Cycle

    Directory of Open Access Journals (Sweden)

    Ssu-Chia Lin


    Full Text Available Quinazoline-based α1,-adrenoceptor antagonists, in particular doxazosin, terazosin, are suggested to display antineoplastic activity against prostate cancers. However, there are few studies elucidating the effect of prazosin. In this study, prazosin displayed antiproliferative activity superior to that of other α1-blockers, including doxazosin, terazosin, tamsulosin, phentolamine. Prazosin induced G2 checkpoint arrest, subsequent apoptosis in prostate cancer PC-3, DU-145, LNCaP cells. In p53-null PC-3 cells, prazosin induced an increase in DNA str, breaks, ATM/ATR checkpoint pathways, leading to the activation of downstream signaling cascades, including Cdc25c phosphorylation at Ser216, nuclear export of Cdc25c, cyclin-dependent kinase (Cdk 1 phosphorylation at Tyr15. The data, together with sustained elevated cyclin A levels (other than cyclin B1 levels, suggested that Cdki activity was inactivated by prazosin. Moreover, prazosin triggered mitochondria-mediated, caspaseexecuted apoptotic pathways in PC-3 cells. The oral administration of prazosin significantly reduced tumor mass in PC-3-derived cancer xenografts in nude mice. In summary, we suggest that prazosin is a potential antitumor agent that induces cell apoptosis through the induction of DNA damage stress, leading to Cdki inactivation, G2 checkpoint arrest. Subsequently, mitochondriamediated caspase cascades are triggered to induce apoptosis in PC-3 cells.

  16. Search for Two Categories of Target Produces Fewer Fixations to Target-Color Items (United States)

    Menneer, Tamaryn; Stroud, Michael J.; Cave, Kyle R.; Li, Xingshan; Godwin, Hayward J.; Liversedge, Simon P.; Donnelly, Nick


    Searching simultaneously for metal threats (guns and knives) and improvised explosive devices (IEDs) in X-ray images is less effective than 2 independent single-target searches, 1 for metal threats and 1 for IEDs. The goals of this study were to (a) replicate this dual-target cost for categorical targets and to determine whether the cost remains…

  17. Multiplexed modular genetic targeting of quantum dots. (United States)

    Saurabh, Saumya; Beck, Lauren E; Maji, Suvrajit; Baty, Catherine J; Wang, Yi; Yan, Qi; Watkins, Simon C; Bruchez, Marcel P


    While DNA-directed nanotechnology is now a well-established platform for bioinspired nanoscale assembly in vitro, the direct targeting of various nanomaterials in living biological systems remains a significant challenge. Hybrid biological systems with integrated and targeted nanomaterials may have interesting and exploitable properties, so methods for targeting various nanomaterials to precise biological locations are required. Fluorescence imaging has benefited from the use of nanoparticles with superior optical properties compared to fluorescent organic dyes or fluorescent proteins. While single-particle tracking (SPT) in living cells with genetically encoded proteins is limited to very short trajectories, the high photon output of genetically targeted and multiplexed quantum dots (QDs) would enable long-trajectory analysis of multiple proteins. However, challenges with genetic targeting of QDs limit their application in these experiments. In this report, we establish a modular method for targeting QD nanoparticles selectively to multiple genetically encoded tags by precomplexing QD-streptavidin conjugates with cognate biotinylated hapten molecules. This approach enables labeling and SPT of multiple genetically encoded proteins on living cells at high speed and can label expressed proteins in the cytosol upon microinjection into living cells. While we demonstrate labeling with three distinct QD conjugates, the approach can be extended to other specific hapten-affinity molecule interactions and alternative nanoparticles, enabling precise directed targeting of nanoparticles in living biological systems.

  18. Discovery of functional antibodies targeting ion channels. (United States)

    Wilkinson, Trevor C I; Gardener, Matthew J; Williams, Wendy A


    Ion channels play critical roles in physiology and disease by modulation of cellular functions such as electrical excitability, secretion, cell migration, and gene transcription. Ion channels represent an important target class for drug discovery that has been largely addressed, to date, using small-molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative formats of biologics. Antibodies display high specificity and affinity for their target antigen, and they have the potential to target ion channels very selectively. Nevertheless, isolating antibodies to this target class is challenging due to the difficulties in expression and purification of ion channels in a format suitable for antibody drug discovery in addition to the complexity of screening for function. In this article, we will review the current state of ion channel biologics discovery and the progress that has been made. We will also highlight the challenges in isolating functional antibodies to these targets and how these challenges may be addressed. Finally, we also illustrate successful approaches to isolating functional monoclonal antibodies targeting ion channels by way of a number of case studies drawn from recent publications.

  19. Novel Targeted Therapies for Metastatic Melanoma. (United States)

    Iams, Wade T; Sosman, Jeffrey A; Chandra, Sunandana

    Oncogene-targeted therapy is a major component of precision oncology, and although patients with metastatic melanoma have experienced improved outcomes with this strategy, there are a number of potential therapeutic targets currently under study that may further increase the drug armamentarium for this patient population. In this review, we discuss the landscape of targeted therapies for patients with advanced melanoma, focusing on oncogene mutation-specific targets. In patients with typical BRAF V600-mutant melanoma, combination BRAF and MEK inhibition has surpassed outcomes compared with monotherapy with BRAF or MEK inhibition alone, and current strategies seek to address inevitable resistance mechanisms. For patients with NRAS-mutant melanoma, MEK inhibitor monotherapy and combined MEK and CDK4/6 inhibition are burgeoning strategies; for patients with KIT-mutant melanoma, tyrosine kinase inhibition is being leveraged, and for NF-1-mutant melanoma, mTOR and MEK inhibition is being actively evaluated. In patients with atypical, non-V600 BRAF-mutant melanoma, MEK inhibitor monotherapy is the potential novel targeted approach on the horizon. For advanced uveal melanoma, novel targets such as IMCgp100 and glembatumumab have shown activity in early studies. We review additional strategies that remain in the preclinical and early clinical pipeline, so there is much hope for the future of targeted agents for distinct molecular cohorts of patients with advanced melanoma.

  20. Target Injector and Sabot Remover for IFE (United States)

    Yoshida, Hiroki; Kameyama, Nobukazu


    Target injectors for IFE are required to inject targets to the reactor center at a velocity of over 100 m/s with accuracy of several millimeters. A target injector system with a magnetic sabot remover is developed to demonstrate injection of polystyrene targets. A typical target used in this study is 4.0 mm in diameter and 0.8 mg in weight. It is inserted in to an aluminum sabot that is 9.2 mm in outer diameter and 40 mm in length. They are accelerated together by a pneumatic gun. Before injection into the reactor, the sabot is removed for laser irradiation. The sabot remover is composed of Neodymium magnets array that generates Lorentz force as a result of interaction between the magnets' field and induced current on the sabot. The Neodymium magnets are 14 mm at inner diameter and 316 mT on its surface. The magnetic array is designed and optimized its magnets number for complete target extraction. The theoretically and experimentally confirmed deceleration rate of the sabot is 60.2 m/s/s per one meter. The targets are shot into the vacuum chamber after extraction from the sabot at accelerated velocity of 30 m/s. The experimentally obtained injection accuracy is 5.3 mm in horizontal direction and 4.8 mm in vertical direction.

  1. COMPASS polarized target for Drell-Yan

    CERN Document Server

    Pešek, M


    In the COMPASS Drell–Yan experiment the pion beam with momen tum of 190 GeV/ c and in- tensity up to 10 8 pions/s will interact with transversely polarized proton t arget producing muon pair via Drell–Yan process. The solid-state NH 3 will be polarized by dynamic nuclear polar- ization. Maximum polarization reached during data taking i s expected to be up to 90%. The non-interacting beam and other particles produced inside t he target will be stopped in the hadron absorber after the target. Two target cells, sepparated by a 20 cm gap in between, each 55 cm long and 4 cm in diameter give the target material volume about 691 cm 3 . The target platform needs to be moved by 2.3 m in upstream dire ction from the position used in previous experiments in order to accomodate the absorber. D uring the beam time higher radiation is expected in the area of the control room. Thus a new target r emote control system is needed. The target magnet is undergoing a substantial upgrade. Drell–Yan data taking is expected t...

  2. Design of the LBNF Beamline Target Station

    Energy Technology Data Exchange (ETDEWEB)

    Tariq, S. [Fermilab; Ammigan, K. [Fermilab; Anderson, K.; ; Buccellato, S. A. [Fermilab; Crowley, C. F. [Fermilab; Hartsell, B. D. [Fermilab; Hurh, P. [Fermilab; Hylen, J. [Fermilab; Kasper, P. [Fermilab; Krafczyk, G. E. [Fermilab; Lee, A. [Fermilab; Lundberg, B. [Fermilab; Reitzner, S. D. [Fermilab; Sidorov, V. [Fermilab; Stefanik, A. M. [Fermilab; Tropin, I. S. [Fermilab; Vaziri, K. [Fermilab; Williams, K. [Fermilab; Zwaska, R. M. [Fermilab; Densham, C. [RAL, Didcot


    The Long Baseline Neutrino Facility (LBNF) project will build a beamline located at Fermilab to create and aim an intense neutrino beam of appropriate energy range toward the DUNE detectors at the SURF facility in Lead, South Dakota. Neutrino production starts in the Target Station, which consists of a solid target, magnetic focusing horns, and the associated sub-systems and shielding infrastructure. Protons hit the target producing mesons which are then focused by the horns into a helium-filled decay pipe where they decay into muons and neutrinos. The target and horns are encased in actively cooled steel and concrete shielding in a chamber called the target chase. The reference design chase is filled with air, but nitrogen and helium are being evaluated as alternatives. A replaceable beam window separates the decay pipe from the target chase. The facility is designed for initial operation at 1.2 MW, with the ability to upgrade to 2.4 MW, and is taking advantage of the experience gained by operating Fermilab’s NuMI facility. We discuss here the design status, associated challenges, and ongoing R&D and physics-driven component optimization of the Target Station.

  3. Hypersonic sliding target tracking in near space

    Directory of Open Access Journals (Sweden)

    Xiang-yu Zhang


    Full Text Available To improve the tracking accuracy of hypersonic sliding target in near space, the influence of target hypersonic movement on radar detection and tracking is analyzed, and an IMM tracking algorithm is proposed based on radial velocity compensating and cancellation processing of high dynamic biases under the earth centered earth fixed (ECEF coordinate. Based on the analysis of effect of target hypersonic movement, a measurement model is constructed to reduce the filter divergence which is caused by the model mismatch. The high dynamic biases due to the target hypersonic movement are approximately compensated through radial velocity estimation to achieve the hypersonic target tracking at low systematic biases in near space. The high dynamic biases are further eliminated by the cancellation processing of different radars, in which the track association problem can be solved when the dynamic biases are low. An IMM algorithm based on constant acceleration (CA, constant turning (CT and Singer models is used to achieve the hypersonic sliding target tracking in near space. Simulation results show that the target tracking in near space can be achieved more effectively by using the proposed algorithm.

  4. ZFN-Site searches genomes for zinc finger nuclease target sites and off-target sites

    Directory of Open Access Journals (Sweden)

    Iseli Christian


    Full Text Available Abstract Background Zinc Finger Nucleases (ZFNs are man-made restriction enzymes useful for manipulating genomes by cleaving target DNA sequences. ZFNs allow therapeutic gene correction or creation of genetically modified model organisms. ZFN specificity is not absolute; therefore, it is essential to select ZFN target sites without similar genomic off-target sites. It is important to assay for off-target cleavage events at sites similar to the target sequence. Results ZFN-Site is a web interface that searches multiple genomes for ZFN off-target sites. Queries can be based on the target sequence or can be expanded using degenerate specificity to account for known ZFN binding preferences. ZFN off-target sites are outputted with links to genome browsers, facilitating off-target cleavage site screening. We verified ZFN-Site using previously published ZFN half-sites and located their target sites and their previously described off-target sites. While we have tailored this tool to ZFNs, ZFN-Site can also be used to find potential off-target sites for other nucleases, such as TALE nucleases. Conclusions ZFN-Site facilitates genome searches for possible ZFN cleavage sites based on user-defined stringency limits. ZFN-Site is an improvement over other methods because the FetchGWI search engine uses an indexed search of genome sequences for all ZFN target sites and possible off-target sites matching the half-sites and stringency limits. Therefore, ZFN-Site does not miss potential off-target sites.

  5. BRVAAF and performance analysis for target detection

    Institute of Scientific and Technical Information of China (English)


    A bistatic range-velocity-acceleration ambiguity function (BRVAAF) is proposed. The model of radar measurements of an accelerating target involving the time delay, Doppler frequency and Doppler rate is given. The relationships between these measurements and the parameters of the bistatic geometry, target position, velocity and acceleration are derived. Moreover, the effects of the bistatic geometry factors on these measurements are analyzed. Besides, the two relationships of the bistatic integration loss and the bistatic optimum integration time with these factors are built and their change trends are described respectively. This research is helpful to analyze the influences of the bistatic geometry factors on the target detection and signal processing.

  6. Characteristics of Hostile and Friendly Takeover Targets


    Randall Morck; Andrei Shleifer; Vishny, Robert W.


    Compared to an average Fortune 500 firm, a target of a hostile takeover is smaller, older, has a lower Tobin's Q, invests less of its income, and is growing more slowly. The low Q seems to be an industry-specific rather than a firm-specific effect. In addition, a hostile target is less likely to be run by a member of the founding family, and has lower officer ownership, than the average firm. In contrast, a target of a friendly acquisitions is smaller and younger than an average Fortune 500 f...

  7. Antiproton production target of the AA

    CERN Multimedia

    Photographic Service


    The target rods were initially of tungsten, later of iridium. Diameters were around 3 mm and the lengths 60-110 mm. The rod is embedded in graphite, pressed into an aluminium body with cooling fins for forced air cooling. The 26 GeV proton beam from the PS was focused to the dimension of the rod. To aim precisely at its centre, the target was fitted with a scintillator screen, with circles at every 5 mm radius. Both scintillator and target had to stand pulses of 1.4E13 protons every 4.8 s, without interruption for many months.

  8. Stereotactic radiosurgery: a "targeted" therapy for cancer

    Institute of Scientific and Technical Information of China (English)

    Ming Zeng; Liang-Fu Han


    The developments of medicine always follow innovations in science and technology.In the past decade,such innovations have made cancer-related targeted therapies possible.In general,the term "targeted therapy" has been used in reference to cellular and molecular level oriented therapies.However,improvements in the delivery and planning of traditional radiation therapy have also provided cancer patients more options for "targeted" treatment,notably stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT).In this review,the progress and controversies of SRS and SBRT are discussed to show the role of stereotactic radiation therapy in the ever evolving multidisciplinary care of cancer patients.

  9. Target Cultural Issues in College English Teaching

    Institute of Scientific and Technical Information of China (English)

    WAN Xin


    With the passage time, China has been playing a increasingly important role in world stage, so what a current college English classroom needs is not a mere mastery of English language, but an overall understanding of target culture. In order to at-tain this goal, analysis concerning the current situation of target cultural teaching in college English teaching classroom should be done, and suggestions about target cultural teaching in college English teaching classroom should be put forward. By doing so, students will not only improve their linguistic competence, but also will enhance their inter-cultural performance.

  10. Performance Simulations of Moving Target Search Algorithms

    Directory of Open Access Journals (Sweden)

    Peter K. K. Loh


    Full Text Available The design of appropriate moving target search (MTS algorithms for computer-generated bots poses serious challenges as they have to satisfy stringent requirements that include computation and execution efficiency. In this paper, we investigate the performance and behaviour of existing moving target search algorithms when applied to search-and-capture gaming scenarios. As part of the investigation, we also introduce a novel algorithm known as abstraction MTS. We conduct performance simulations with a game bot and moving target within randomly generated mazes of increasing sizes and reveal that abstraction MTS exhibits competitive performance even with large problem spaces.

  11. Automatic Target Detection Using Wavelet Transform

    Directory of Open Access Journals (Sweden)

    Ganesan L


    Full Text Available Automatic target recognition (ATR involves processing images for detecting, classifying, and tracking targets embedded in a background scene. This paper presents an algorithm for detecting a specified set of target objects embedded in visual images for an ATR application. The developed algorithm employs a novel technique for automatically detecting man-made and non-man-made single, two, and multitargets from nontarget objects, located within a cluttered environment by evaluating nonoverlapping image blocks, where block-by-block comparison of wavelet cooccurrence feature is done. The results of the proposed algorithm are found to be satisfactory.

  12. Automated High Throughput Drug Target Crystallography

    Energy Technology Data Exchange (ETDEWEB)

    Rupp, B


    The molecular structures of drug target proteins and receptors form the basis for 'rational' or structure guided drug design. The majority of target structures are experimentally determined by protein X-ray crystallography, which as evolved into a highly automated, high throughput drug discovery and screening tool. Process automation has accelerated tasks from parallel protein expression, fully automated crystallization, and rapid data collection to highly efficient structure determination methods. A thoroughly designed automation technology platform supported by a powerful informatics infrastructure forms the basis for optimal workflow implementation and the data mining and analysis tools to generate new leads from experimental protein drug target structures.

  13. Novel targeted therapies for eosinophilic disorders (United States)

    Wechsler, Michael E.; Fulkerson, Patricia C.; Bochner, Bruce S.; Gauvreau, Gail M.; Gleich, Gerald J.; Henkel, Tim; Kolbeck, Roland; Mathur, Sameer K.; Ortega, Hector; Patel, Jatin; Prussin, Calman; Renzi, Paolo; Rothenberg, Marc E.; Roufosse, Florence; Simon, Dagmar; Simon, Hans-Uwe; Wardlaw, Andrew; Weller, Peter F.; Klion, Amy D.


    Hypereosinophilic syndromes (HESs) are a diverse group of conditions characterized by clinical manifestations attributable to eosinophilia and eosinophilic infiltration of tissues. HESs are chronic disorders with significant morbidity and mortality. Although the availability of targeted chemotherapeutic agents, including imatinib, has improved quality of life and survival in some patients with HESs, additional agents with increased efficacy and decreased toxicity are sorely needed. The purpose of this review is to provide an overview of eosinophil biology with an emphasis on potential targets of pharmacotherapy and to provide a summary of potential eosinophil-targeting agents, including those in development, in clinical trials, or approved for other disorders. PMID:22935585


    Institute of Scientific and Technical Information of China (English)

    A. B. El-Rayes; Abd El-Moneim A. Mohamed; Hamdy M. Abou Gabal


    A target is assumed to move according to a Brownian motion on the real line.The searcher starts from the origin and moves in the two directions from the starting point.The object is to detect the target.The purpose of this paper is to find the conditions under which the expected value of the first meeting time of the searcher and the target is finite,and to show the existence of a search plan which made this expected value minimum.

  15. Resource implications of a national health target

    DEFF Research Database (Denmark)

    Jones, Peter; Sopina, Liza Elizaveta; Ashton, Toni


    of clinical/service managers in ED throughout New Zealand determined the type and cost of resources used for the target. Responses to the target were classified according to their impact in ED, the hospital and the community. Quantifiable resource changes were assigned a financial value and grouped......, with estimated total expenditure of over NZ$52 m. The majority of expenditure occurred in ED (60.8%) and hospital (38.7%) with little spent in the community. New staff accounted for 76.5% of expenditure. Per capita expenditure in the ED was associated with improved target performance (r = 0.48, P = 0...

  16. Targets for a Neutral Kaon Beam

    Energy Technology Data Exchange (ETDEWEB)

    Keith, Christopher [Thomas Jefferson National Accelerator Facility (TJNAF), Newport News, VA (United States)


    A secondary beam of neutral Kaons is under consideration for Hall D at Jefferson Lab to perform spectroscopic studies of hyperons produced by K 0 L particles scattering from proton and deuteron targets. The proposed physics program would utilize the GlueX detector package currently installed in Hall D. This contribution looks at potential targets for use in the new facility, paying close attention to the existing infrastructure of GlueX and Hall D. Unpolarized cryotargets of liquid hydrogen and deuerium, as well as polarized solid targets of protons and deuterons are examined.

  17. Diagnostics for High Power Targets and Dumps

    CERN Document Server

    Gschwendtner, E


    High power targets are generally used for neutrino, antiproton, neutron and secondary beam production whereas dumps are needed in beam waste management. In order to guarantee an optimized and safe use of these targets and dumps, reliable instrumentation is needed; the diagnostics in high power beams around targets and dumps is reviewed. The suite of beam diagnostics devices used in such extreme environments is discussed, including their role in commissioning and operation. The handling and maintenance of the instrumentation components in high radiation areas is also addressed.

  18. Radar automatic target recognition (ATR) and non-cooperative target recognition (NCTR)

    CERN Document Server

    Blacknell, David


    The ability to detect and locate targets by day or night, over wide areas, regardless of weather conditions has long made radar a key sensor in many military and civil applications. However, the ability to automatically and reliably distinguish different targets represents a difficult challenge. Radar Automatic Target Recognition (ATR) and Non-Cooperative Target Recognition (NCTR) captures material presented in the NATO SET-172 lecture series to provide an overview of the state-of-the-art and continuing challenges of radar target recognition. Topics covered include the problem as applied to th

  19. TargetMine, an integrated data warehouse for candidate gene prioritisation and target discovery.

    Directory of Open Access Journals (Sweden)

    Yi-An Chen

    Full Text Available Prioritising candidate genes for further experimental characterisation is a non-trivial challenge in drug discovery and biomedical research in general. An integrated approach that combines results from multiple data types is best suited for optimal target selection. We developed TargetMine, a data warehouse for efficient target prioritisation. TargetMine utilises the InterMine framework, with new data models such as protein-DNA interactions integrated in a novel way. It enables complicated searches that are difficult to perform with existing tools and it also offers integration of custom annotations and in-house experimental data. We proposed an objective protocol for target prioritisation using TargetMine and set up a benchmarking procedure to evaluate its performance. The results show that the protocol can identify known disease-associated genes with high precision and coverage. A demonstration version of TargetMine is available at

  20. Targeted molecular trait stacking in cotton through targeted double-strand break induction. (United States)

    D'Halluin, Kathleen; Vanderstraeten, Chantal; Van Hulle, Jolien; Rosolowska, Joanna; Van Den Brande, Ilse; Pennewaert, Anouk; D'Hont, Kristel; Bossut, Martine; Jantz, Derek; Ruiter, Rene; Broadhvest, Jean


    Recent developments of tools for targeted genome modification have led to new concepts in how multiple traits can be combined. Targeted genome modification is based on the use of nucleases with tailor-made specificities to introduce a DNA double-strand break (DSB) at specific target loci. A re-engineered meganuclease was designed for specific cleavage of an endogenous target sequence adjacent to a transgenic insect control locus in cotton. The combination of targeted DNA cleavage and homologous recombination-mediated repair made precise targeted insertion of additional trait genes (hppd, epsps) feasible in cotton. Targeted insertion events were recovered at a frequency of about 2% of the independently transformed embryogenic callus lines. We further demonstrated that all trait genes were inherited as a single genetic unit, which will simplify future multiple-trait introgression.

  1. Consumer responses to ethnic targeted marketing

    NARCIS (Netherlands)

    A.-S.I.A. Lenoir (Anne-Sophie); S. Puntoni (Stefano)


    markdownabstract__Abstract__ Marketing is impacted more than ever by demographic change, to the extent that practitioners targeting ethnic groups should re-think their approach depending upon the strength with which different generations identify with their cultural heritage.

  2. Logarithm Laws and Shrinking Target Properties

    Indian Academy of Sciences (India)

    J S Athreya


    We survey some of the recent developments in the study of logarithm laws and shrinking target properties for various families of dynamical systems. We discuss connections to geometry, diophantine approximation and probability theory.

  3. Targeting influenza virosomes to ovarian carcinoma cells

    NARCIS (Netherlands)

    Mastrobattista, E; Schoen, P; Wilschut, J; Crommelin, DJA; Storm, G


    Reconstituted influenza virus envelopes (virosomes) containing the viral hemagglutinin (HA) have attracted attention as delivery vesicles for cytosolic drug delivery as they possess membrane fusion activity. Here, we show that influenza virosomes can be targeted towards ovarian carcinoma cells (OVCA

  4. Observer's Interface for Solar System Target Specification (United States)

    Roman, Anthony; Link, Miranda; Moriarty, Christopher; Stansberry, John A.


    When observing an asteroid or comet with HST, it has been necessary for the observer to manually enter the target's orbital elements into the Astronomer's Proposal Tool (APT). This allowed possible copy/paste transcription errors from the observer's source of orbital elements data. In order to address this issue, APT has now been improved with the capability to identify targets in and then download orbital elements from JPL Horizons. The observer will first use a target name resolver to choose the intended target from the Horizons database, and then download the orbital elements from Horizons directly into APT. A manual entry option is also still retained if the observer does not wish to use elements from Horizons. This new capability is available for HST observing, and it will also be supported for JWST observing. The poster shows examples of this new interface.

  5. Fabrication of Simple Step-Target

    Institute of Scientific and Technical Information of China (English)


    <正>Step-target was used to measure the shock velocity. If we can measure the shock velocity and particle velocity together, we get one point in the shock compress line. If we measure a series of shock velocity

  6. The expected radiation damage of CSNS target (United States)

    Yin, W.; Yu, Q. Z.; Lu, Y. L.; Wang, S. L.; Tong, J. F.; Liang, T. J.


    The radiation damage to the tungsten target and its SS316 vessel for Chinese Spallation Neutron Source (CSNS) has been estimated with a Monte-Carlo simulation code MCNPX2.5.0. We compare the effects on the radiation damage due to two different proton beam profiles: a uniform distribution and a Gaussian distribution. We also discuss the dependence of the radiation damage estimation on different physics models. The results show the peak displacement productions in vessel and the fourth target plate are 2.5 and 5.5 dpa/y, respectively, under a Gaussian proton beam. The peak helium productions in the vessel and the fourth target are 305 and 353 appm/y, respectively, under the same proton beam. Based on these results and the allowable dpa values we have estimated the lifetime of the tungsten target and its vessel.

  7. Target Visualization at the National Ignition Facility

    Energy Technology Data Exchange (ETDEWEB)

    Potter, Daniel Abraham [Univ. of California, Davis, CA (United States)


    As the National Ignition Facility continues its campaign to achieve ignition, new methods and tools will be required to measure the quality of the targets used to achieve this goal. Techniques have been developed to measure target surface features using a phase-shifting diffraction interferometer and Leica Microsystems confocal microscope. Using these techniques we are able to produce a detailed view of the shell surface, which in turn allows us to refine target manufacturing and cleaning processes. However, the volume of data produced limits the methods by which this data can be effectively viewed by a user. This paper introduces an image-based visualization system for data exploration of target shells at the National Ignition Facility (NIF) at Lawrence Livermore National Laboratory. It aims to combine multiple image sets into a single visualization to provide a method of navigating the data in ways that are not possible with existing tools.

  8. Magnetized Target Fusion Driven by Plasma Liners (United States)

    Thio, Y. C. Francis; Cassibry, Jason; Eskridge, Richard; Kirkpatrick, Ronald C.; Knapp, Charles E.; Lee, Michael; Martin, Adam; Smith, James; Wu, S. T.; Rodgers, Stephen L. (Technical Monitor)


    For practical applications of magnetized target fusion, standoff drivers to deliver the imploding momentum flux to the target plasma remotely are required. Quasi-spherically converging plasma jets have been proposed as standoff drivers for this purpose. The concept involves the dynamic formation of a quasi-spherical plasma liner by the merging of plasma jets, and the use of the liner so formed to compress a spheromak or a field reversed configuration (FRC). Theoretical analysis and computer modeling of the concept are presented. It is shown that, with the appropriate choice of the flow parameters in the liner and the target, the impact between the liner and the target plasma can be made to be shockless in the liner or to generate at most a very weak shock in the liner. Additional information is contained in the original extended abstract.

  9. Parametric estimation of ultra wideband radar targets

    Institute of Scientific and Technical Information of China (English)

    Fan Ping; Jing Zhanrong


    Based on the analysis of impulse response properties, a scattering model of ultra wideband (UWB) radar targets is developed to estimate the target parameters exactly. With this model, two algorithms of multiple signal classification (MUSIC), and matrix pencil (MP), are introduced to calculate the scattering center parame-ters of targets and their performances are compared. The simulation experiments show that there are no differ-ences in the estimation precision of MUSIC and MP methods when the signal-to-noise ratio (SNR) is larger than 13 dB. However, the MP method has a better performance than that of MUSIC method when the SNR is smaller than 13 dB. Besides, the time consuming of MP method is leas than that of MUSIC method. Therefore, the MP algorithm is preferred for the parametric estimation of UWB radar targets.

  10. Enhancing proton acceleration by using composite targets

    CERN Document Server

    Bulanov, S S; Schroeder, C B; Bulanov, S V; Esirkepov, T Zh; Kando, M; Pegoraro, F; Leemans, W P


    Efficient laser ion acceleration requires high laser intensities, which can only be obtained by tightly focusing laser radiation. In the radiation pressure acceleration regime, where the tightly focused laser driver leads to the appearance of the fundamental limit for the maximum attainable ion energy, this limit corresponds to the laser pulse group velocity as well as to another limit connected with the transverse expansion of the accelerated foil and consequent onset of the foil transparency. These limits can be relaxed by using composite targets, consisting of a thin foil followed by a near critical density slab. Such targets provide guiding of a laser pulse inside a self-generated channel and background electrons, being snowplowed by the pulse, compensate for the transverse expansion. The use of composite targets results in a significant increase in maximum ion energy, compared to a single foil target case.

  11. Magnetic biosensor system to detect biological targets

    KAUST Repository

    Li, Fuquan


    Magneto-resistive sensors in combination with magnetic beads provide sensing platforms, which are small in size and highly sensitive. These platforms can be fully integrated with microchannels and electronics to enable devices capable of performing complex tasks. Commonly, a sandwich method is used that requires a specific coating of the sensor\\'s surface to immobilize magnetic beads and biological targets on top of the sensor. This paper concerns a micro device to detect biological targets using magnetic concentration, magnetic as well as mechanical trapping and magnetic sensing. Target detection is based on the size difference between bare magnetic beads and magnetic beads with targets attached. This method remedies the need for a coating layer and reduces the number of steps required to run an experiment. © 2012 IEEE.

  12. WTS - Risk Based Resource Targeting (RBRT) - (United States)

    Department of Transportation — The Risk Based Resource Targeting (RBRT) application supports a new SMS-structured process designed to focus on safety oversight of systems and processes rather than...

  13. Does target viewing time influence perceived reachability? (United States)

    Gabbard, Carl; Ammar, Diala


    This study examined the influence of target viewing time on perceived (estimates of) reachability. Right-handed participants were asked to judge the simulated reachability of midline targets using their dominant limb in viewing conditions of 150 ms, 500 ms, 1 s and 2 s. Responses were compared to actual maximum reach. In reference to percent error, interestingly, the 150 ms condition revealed the least error at peripersonal targets and the most inaccuracy with distal (extrapersonal) targets. This condition was also distinct with a significant overestimation bias -- a common observation in earlier studies. However, with increasing viewing time this bias was reduced. These data provide evidence that 150 ms is effective for estimating reach within one's general peripersonal workspace. However, with judgments distal from that point, more time enhanced accuracy, with 500 ms and 1 s being optimal. Overall results are discussed relative to perceptual effectiveness in programming reaching movements.

  14. Discovering the 'Magic' of Target Marketing. (United States)

    Grier, Linda J.; Ackenbom, Charles R.


    Describes target marketing of children's summer camps, emphasizing the benefits of collaborative advertising campaigns. Discusses the scope and economics of four model campaigns. Outlines the design, implementation, and evaluation of collaborative marketing projects. (SV)

  15. Therapeutic Approaches to Target Cancer Stem Cells

    Energy Technology Data Exchange (ETDEWEB)

    Diaz, Arlhee, E-mail:; Leon, Kalet [Department of Systems Biology, Center of Molecular Immunology, 216 Street, PO Box 16040, Atabey, Havana 11600 (Cuba)


    The clinical relevance of cancer stem cells (CSC) remains a major challenge for current cancer therapies, but preliminary findings indicate that specific targeting may be possible. Recent studies have shown that these tumor subpopulations promote tumor angiogenesis through the increased production of VEGF, whereas the VEGF neutralizing antibody bevacizumab specifically inhibits CSC growth. Moreover, nimotuzumab, a monoclonal antibody against the epidermal growth factor receptor (EGFR) with a potent antiangiogenic activity, has been shown by our group to reduce the frequency of CSC-like subpopulations in mouse models of brain tumors when combined with ionizing radiation. These studies and subsequent reports from other groups support the relevance of approaches based on molecular-targeted therapies to selectively attack CSC. This review discusses the relevance of targeting both the EGFR and angiogenic pathways as valid approaches to this aim. We discuss the relevance of identifying better molecular markers to develop drug screening strategies that selectively target CSC.

  16. Texture metric that predicts target detection performance (United States)

    Culpepper, Joanne B.


    Two texture metrics based on gray level co-occurrence error (GLCE) are used to predict probability of detection and mean search time. The two texture metrics are local clutter metrics and are based on the statistics of GLCE probability distributions. The degree of correlation between various clutter metrics and the target detection performance of the nine military vehicles in complex natural scenes found in the Search_2 dataset are presented. Comparison is also made between four other common clutter metrics found in the literature: root sum of squares, Doyle, statistical variance, and target structure similarity. The experimental results show that the GLCE energy metric is a better predictor of target detection performance when searching for targets in natural scenes than the other clutter metrics studied.

  17. Targeted therapies in upper gastrointestinal cancer

    NARCIS (Netherlands)

    Kordes, S.


    Upper gastrointestinal (GI) cancers, as esophageal, gastric and pancreatic cancer, are still highly lethal diseases, in spite of advances in surgery, radiotherapy, chemotherapy and specific targeted therapy. Especially when patients are diagnosed with locally advanced or metastasized disease, upper

  18. IMS Mitigation Target Areas - 2010 [ds673 (United States)

    California Department of Resources — Mitigation Target Areas (MTA) were developed by the California Department of Fish and Game for the Interim Mitigation Strategy (IMS). The MTAs are an identification...

  19. Enhancing proton acceleration by using composite targets

    Energy Technology Data Exchange (ETDEWEB)

    Bulanov, S. S.; Esarey, E.; Schroeder, C. B.; Bulanov, S. V.; Esirkepov, T. Zh.; Kando, M.; Pegoraro, F.; Leemans, W. P.


    Efficient laser ion acceleration requires high laser intensities, which can only be obtained by tightly focusing laser radiation. In the radiation pressure acceleration regime, where the tightly focused laser driver leads to the appearance of the fundamental limit for the maximum attainable ion energy, this limit corresponds to the laser pulse group velocity as well as to another limit connected with the transverse expansion of the accelerated foil and consequent onset of the foil transparency. These limits can be relaxed by using composite targets, consisting of a thin foil followed by a near critical density slab. Such targets provide guiding of a laser pulse inside a self-generated channel and background electrons, being snowplowed by the pulse, compensate for the transverse expansion. The use of composite targets results in a significant increase in maximum ion energy, compared to a single foil target case.

  20. Characterizing Health Information for Different Target Audiences. (United States)

    Sun, Yueping; Hou, Zhen; Hou, Li; Li, Jiao


    Different groups of audiences in health care: health professionals and health consumers, each have different information needs. Health monographs targeting different audiences are created by leveraging readers' background knowledge. The NCI's Physician Data Query (PDQ®) Cancer Information Summaries provide parallel cancer information and education resources with different target audiences. In this paper, we used targeted audience-specific cancer information PDQs to measure characteristic differences on the element level between audiences. In addition, we compared vocabulary coverage. Results show a significant difference between the professional and patient version of cancer monographs in both content organization and vocabulary. This study provides a new view to assess targeted audience-specific health information, and helps editors to improve the quality and readability of health information.

  1. "UCx fission targets oxidation test stand"

    CERN Document Server

    Lacroix, Rachel


    "Set up a rig dedicated to the oxidation of UCx and define a procedure for repeatable, reliable and safe method for converting UC2 fission targets into an acceptable uranium carbide oxide waste for subsequent disposal by the Swiss Authorities."

  2. Nuclear Targeting Terms for Engineers and Scientists

    Energy Technology Data Exchange (ETDEWEB)

    St Ledger, John W. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)


    The Department of Defense has a methodology for targeting nuclear weapons, and a jargon that is used to communicate between the analysts, planners, aircrews, and missile crews. The typical engineer or scientist in the Department of Energy may not have been exposed to the nuclear weapons targeting terms and methods. This report provides an introduction to the terms and methodologies used for nuclear targeting. Its purpose is to prepare engineers and scientists to participate in wargames, exercises, and discussions with the Department of Defense. Terms such as Circular Error Probable, probability of hit and damage, damage expectancy, and the physical vulnerability system are discussed. Methods for compounding damage from multiple weapons applied to one target are presented.

  3. Kansas Water Quality Action Targeting System (KATS) (United States)

    Kansas Data Access and Support Center — This system is a revision of the original KATS system developed in 1990 as a tool to aid resource managers target Kansas valuable and vulnerable water resources for...

  4. Potential targets for lung squamous cell carcinoma (United States)

    Researchers have identified potential therapeutic targets in lung squamous cell carcinoma, the second most common form of lung cancer. The Cancer Genome Atlas (TCGA) Research Network study comprehensively characterized the lung squamous cell carcinoma gen

  5. Ion channels: molecular targets of neuroactive insecticides. (United States)

    Raymond-Delpech, Valérie; Matsuda, Kazuhiko; Sattelle, Benedict M; Rauh, James J; Sattelle, David B


    Many of the insecticides in current use act on molecular targets in the insect nervous system. Recently, our understanding of these targets has improved as a result of the complete sequencing of an insect genome, i.e., Drosophila melanogaster. Here we examine the recent work, drawing on genetics, genomics and physiology, which has provided evidence that specific receptors and ion channels are targeted by distinct chemical classes of insect control agents. The examples discussed include, sodium channels (pyrethroids, p,p'-dichlorodiphenyl-trichloroethane (DDT), dihydropyrazoles and oxadiazines); nicotinic acetylcholine receptors (cartap, spinosad, imidacloprid and related nitromethylenes/nitroguanidines); gamma-aminobutyric acid (GABA) receptors (cyclodienes, gamma-BHC and fipronil) and L-glutamate receptors (avermectins). Finally, we have examined the molecular basis of resistance to these molecules, which in some cases involves mutations in the molecular target, and we also consider the future impact of molecular genetic technologies in our understanding of the actions of neuroactive insecticides.

  6. The Evolution of Air Force Targeting (United States)


    the idea of the “strategic” application of air power. German Zeppelin raids on London in 1917 are probably the first known uses of air forces beyond...bombardment led to an increasing emphasis on targeting. Then- Maj Donald Wilson, an instructor at the ACTS, believed that attack- ing a few critical targets...the organic industrial, economic, and civic systems that maintained the life of the enemy nation itself.13 This doctrine led to an even greater

  7. Probe Array Correction With Strong Target Interactions (United States)


    measurements, bistatic scattering cross section, array mutual impedances, Lorentz reciprocity theorem 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF...ABSTRACT: SAR 18. NUMBER OF PAGES 50 19a. NAME OF RESPONSIBLE PERSON (Monitor) a. REPORT Unclassified b. ABSTRACT Unclassified c. THIS...fields scattered by a target. The measurements are made with the objective of estimating the far zone bistatic scattering from the target using

  8. Artifacts in Radar Imaging of Moving Targets (United States)


    leads to the wrong object localization and defocusing on the image. For SAR , a moving target’s physical location varies throughout the imaging...Imaging, Synthetic Aperture Radar, Bistatic Radar, Multistatic Radar, Moving Targets, Backprojection 15. NUMBER OF PAGES 133 16. PRICE CODE 17...broadening and range errors were introduced by target motion. This leads to incorrect object localization and defocusing on the image. For SAR , a

  9. Polarization Null Characteristics of Simple Targets (United States)


    propagation distance to the target, which is a very large number of wavelengths. Modelo 2 w, at can therefore be considered to be a random phase, uniformly...multiplied by a (sin x)Ix factor. There are also triple bounce, partial mirroring, and shadowing effects: for the thin fuselages considered here, these...the sphere, the linear wire target, the n-nounce corner reflector, the left/right winding helices , the cone-tip/ogival and/or spherical capped

  10. The History of Target-Controlled Infusion. (United States)

    Struys, Michel M R F; De Smet, Tom; Glen, John Iain B; Vereecke, Hugo E M; Absalom, Anthony R; Schnider, Thomas W


    Target-controlled infusion (TCI) is a technique of infusing IV drugs to achieve a user-defined predicted ("target") drug concentration in a specific body compartment or tissue of interest. In this review, we describe the pharmacokinetic principles of TCI, the development of TCI systems, and technical and regulatory issues addressed in prototype development. We also describe the launch of the current clinically available systems.

  11. New targets for drug discovery against malaria.

    Directory of Open Access Journals (Sweden)

    Guido Santos

    Full Text Available A mathematical model which predicts the intraerythrocytic stages of Plasmodium falciparum infection was developed using data from malaria-infected mice. Variables selected accounted for levels of healthy red blood cells, merozoite (Plasmodium asexual phase infected red blood cells, gametocyte (Plasmodium sexual phase infected red blood cells and a phenomenological variable which accounts for the mean activity of the immune system of the host. The model built was able to reproduce the behavior of three different scenarios of malaria. It predicts the later dynamics of malaria-infected humans well after the first peak of parasitemia, the qualitative response of malaria-infected monkeys to vaccination and the changes observed in malaria-infected mice when they are treated with antimalarial drugs. The mathematical model was used to identify new targets to be focused on drug design. Optimization methodologies were applied to identify five targets for minimizing the parasite load; four of the targets thus identified have never before been taken into account in drug design. The potential targets include: 1 increasing the death rate of the gametocytes, 2 decreasing the invasion rate of the red blood cells by the merozoites, 3 increasing the transformation of merozoites into gametocytes, 4 decreasing the activation of the immune system by the gametocytes, and finally 5 a combination of the previous target with decreasing the recycling rate of the red blood cells. The first target is already used in current therapies, whereas the remainders are proposals for potential new targets. Furthermore, the combined target (the simultaneous decrease of the activation of IS by gRBC and the decrease of the influence of IS on the recycling of hRBC is interesting, since this combination does not affect the parasite directly. Thus, it is not expected to generate selective pressure on the parasites, which means that it would not produce resistance in Plasmodium.

  12. An analytical high value target acquisition model


    Becker, Kevin J.


    Approved for public release; distribution is unlimited An Analytical High Value Target (HVT) acquisition model is developed for a generic anti-ship cruise missile system. the target set is represented as a single HVT within a field of escorts. The HVT's location is described by a bivariate normal probability distribution. the escorts are represented by a spatially homogeneous Poisson random field surrounding the HVT. Model output consists of the probability that at least one missile of...

  13. Bayesian target tracking based on particle filter

    Institute of Scientific and Technical Information of China (English)


    For being able to deal with the nonlinear or non-Gaussian problems, particle filters have been studied by many researchers. Based on particle filter, the extended Kalman filter (EKF) proposal function is applied to Bayesian target tracking. Markov chain Monte Carlo (MCMC) method, the resampling step, etc novel techniques are also introduced into Bayesian target tracking. And the simulation results confirm the improved particle filter with these techniques outperforms the basic one.

  14. Definitions of radioisotope thick target yields

    Energy Technology Data Exchange (ETDEWEB)

    Otuka, Naohiko [International Atomic Energy Agency, Wien (Austria). Nuclear Data Section; Takacs, Sandor [Hungarian Academy of Science, Debrecen (Hungary). Inst. of Nuclear Research


    Definitions of thick target yields are reviewed in relation to their documentation for the experimental nuclear reaction data library (database). Researchers reporting experimental thick target yields are urged to define their yields clearly with an appropriate unit in order to compile them in the experimental data library (EXFOR) in a consistent manner, and also to properly utilise them for comparison with other experimental and evaluated yields.

  15. Classification of Radar Targets Using Invariant Features (United States)


    deployed for a stationary target to extract scattering centers from the raw SAR radar data (also known as the Video Phase History or VPH ), and on the target. These scattering center tracks are subtracted from the VPH to generate the residual VPH , and more scattering centers are...successively extracted until an acceptable amount of the VPH is characterized. The multiple sensors generate multiple two-dimensional views, and the 3D MAGI

  16. Inflation targeting and disinflation in Serbia


    Savić, Nebojša; Pitić, Goran; Nedeljković, Milan


    This paper provides a brief overview of the existing monetary policy strategies and their advantages and weaknesses. The analysis highlights the strengths of the flexible inflation targeting regime and its role in disinflation processes in countries with high inflation history. It then focuses on Serbia and discusses monetary policy instruments within the flexible inflation targeting regime which have spurred the stabilization of inflation at a low level over the past three years. In addition...

  17. Qualitative differential games with two targets (United States)

    Getz, W. M.; Leitmann, G.


    So-called differential games of kind (qualitative games) were considered involving two or more players each of whom possesses a target toward which he wished to steer the response of a dynamical system that was under the control of all players. Sufficient conditions were derived, which assure termination on a particular player's target. In general, these conditions were constructive in that they permited construction of a winning (terminating) strategy for a player. The theory is illustrated by a pursuit-evasion problem.

  18. Orbital Evasive Target Tracking and Sensor Management (United States)


    orbits to simulate the space resource management for situation awareness. We adopted NASA’s General Mission Analysis Tool ( GMAT ) for space target...realistic satellite orbits to simulate the space resource management for situation awareness. We adopted NASA’s General Mission Analysis Tool ( GMAT ...Analysis Tool ( GMAT ) for space target tracking with multiple space borne observers. The results indicate that the game theoretic approach is more effective

  19. Targeting Discoidin Domain Receptors in Prostate Cancer (United States)


    1 AWARD NUMBER: W81XWH-15-1-0226 TITLE: Targeting Discoidin Domain Receptors in Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Rafael Fridman...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER W81XWH-15-1-0226 Targeting Discoidin Domain Receptors in Prostate Cancer 5b. GRANT NUMBER W81XWH-15...DDRs in prostate cancer . During the first funding period, we conducted immunohistochemical studies by staining a 200 case Grade/Stage tissue

  20. Recent Development of Anticancer Therapeutics Targeting Akt


    Morrow, John K.; Du-Cuny, Lei; Chen, Lu; Meuillet, Emmanuelle J.; Eugene A Mash; Powis, Garth; Zhang, Shuxing


    The serine/threonine kinase Akt has proven to be a significant signaling target, involved in various biological functions. Because of its cardinal role in numerous cellular responses, Akt has been implicated in many human diseases, particularly cancer. It has been established that Akt is a viable and feasible target for anticancer therapeutics. Analysis of all Akt kinases reveals conserved homology for an N-terminal regulatory domain, which contains a pleckstrin-homology (PH) domain for cellu...

  1. Targeting ESR1-Mutant Breast Cancer (United States)


    AWARD NUMBER: W81XWH-14-1-0359 TITLE: Targeting ESR1-Mutant Breast Cancer PRINCIPAL INVESTIGATOR: Dr. Sarat Chandarlapaty CONTRACTING...31 Aug 2015 4. TITLE AND SUBTITLE Targeting ESR1-Mutant Breast Cancer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-14-1-0359 5c. PROGRAM ELEMENT...mutations found in breast cancer using both structural and cell based assays. We have now have evidence for the effects of the most recurrent

  2. Target-related neologism formation in jargonaphasia. (United States)

    Christman, S S


    Neologistic demisyllables produced by three subjects with jargonaphasia (Christman, 1990, 1992) were compared to target demisyllables to determine whether phonological patterns underlying target-related neology could be captured by the Sonority Sequencing Principle independently of phonotactics. Results revealed that substitution errors replaced most intended segments with obstruents, despite the absence of phonotactic restrictions that might have conditioned the errors. Findings suggest a default pattern of segment selection to which the phonological system reverts when normal processing is otherwise blocked.


    Directory of Open Access Journals (Sweden)



    Full Text Available The purpose of this paper is to define the inflation targeting strategy and its characteristics. Inflation targeting is a monetary policy strategy in which the central bank projected estimates and makes public, or “target” inflation rate and then, attempts to steer actual inflation towards the target through the use of interest rate changes and other monetary tools. Early proposals of monetary systems targeting the price level or the inflation rate, rather then exchange rate, followed the general crisis of the gold standard after the World War I. Inflation is usually measured as the change of prices for consumer goods, called Consumer Price Index (CPI. Inflation targeting assumes that this figure accurately represents growth or money supply, but is not always the case. The most serious exception occurs when factors external to the national economy are the cause of the price increase. A more essential objection to the strategy of inflation targeting is that it does not really comprise a specific set of monetary policy recommendation would traditional monetarism did, but just constitutes an explicit statement of the aims of the monetary authority.

  4. Test of a High Power Target Design

    CERN Multimedia


    %IS343 :\\\\ \\\\ A high power tantalum disc-foil target (RIST) has been developed for the proposed radioactive beam facility, SIRIUS, at the Rutherford Appleton Laboratory. The yield and release characteristics of the RIST target design have been measured at ISOLDE. The results indicate that the yields are at least as good as the best ISOLDE roll-foil targets and that the release curves are significantly faster in most cases. Both targets use 20 -25 $\\mu$m thick foils, but in a different internal geometry.\\\\ \\\\Investigations have continued at ISOLDE with targets having different foil thickness and internal geometries in an attempt to understand the release mechanisms and in particular to maximise the yield of short lived isotopes. A theoretical model has been developed which fits the release curves and gives physical values of the diffusion constants.\\\\ \\\\The latest target is constructed from 2 $\\mu$m thick tantalum foils (mass only 10 mg) and shows very short release times. The yield of $^{11}$Li (half-life of ...

  5. Achieving the Renewable Energy Target for Jamaica

    Directory of Open Access Journals (Sweden)

    Abdullahi Olabode ABDULKADRI


    Full Text Available ieving the Renewable Energy Target for Jamaica Abstract: The high cost of energy in Jamaica, one of the highest in the Caribbean region, is usually cited as a hindrance to industrial development and efficiency, especially in the manufacturing sector. High energy cost is also considered to be a national energy security issue and the government is taking steps to ensure adequate supply of energy at affordable prices. In the current National Development Plan, the government has set a target for renewable energy sources to supply 20% of the country's energy need by the year 2030. Using a linear programing model of energy planning, we examine how realistically this target could be achieved. Our findings indicate that the 20% renewable energy target is technically achievable with the optimal plan showing a mixture of wind power, hydropower and bagasse power but no solar power. However, when the timeline for investment in new generating capacities that will ensure the attainment of the target is considered, it becomes highly improbable that the target will be met. This study fills the gap that exists in evidence-based analysis of energy policy in Jamaica.

  6. Biotherapies in systemic lupus erythematosus: New targets. (United States)

    Lazaro, Estibaliz; Scherlinger, Marc; Truchetet, Marie-Elise; Chiche, Laurent; Schaeverbeke, Thierry; Blanco, Patrick; Richez, Christophe


    Systemic lupus erythematosus (SLE) is an autoimmune disease with a polymorphic presentation. The variability in the clinical expression and severity of SLE makes new treatments both essential and challenging to develop. Several biotherapies targeting different pathophysiological pathways have been developed over the past 15 years. The results of Phase II trials were encouraging but rarely borne out by Phase III trials. Recent data, which are discussed in detail in this review, allowed belimumab - a monoclonal antibody against BLyS (B-lymphocyte stimulator) - to become the first biotherapy approved for use in SLE. Other molecules targeting B cells include the two anti-BLyS antibodies tabalumab and blisibimod; atacicept, which targets both BLyS and APRIL (a proliferation-inducing ligand); and the monoclonal antibody to CD22 epratuzumab. The rekindling of interest in the B-cell pathway has also driven new clinical research into rituximab, a monoclonal antibody targeting CD20 with evaluations of new strategies. A new and promising approach is the use of inhibitors of the type 1 interferon (IFN) pathway, of which the most promising is anifrolumab, a monoclonal antibody targeting the type 1 IFN receptor. In this review, we discuss study findings and their clinical relevance, present the most promising targets, and analyze possible explanations to negative results, such as inappropriate patient selection and treatment response criteria or the erratic use of high-dose glucocorticoid therapy.

  7. Discovering drug targets through the web. (United States)

    Wishart, David S


    Traditionally, drug-target discovery is a "wet-bench" experimental process, depending on carefully designed genetic screens, biochemical tests and cellular assays to identify proteins and genes that are associated with a particular disease or condition. However, recent advances in DNA sequencing, transcript profiling, protein identification and protein quantification are leading to a flood of genomic and proteomic data that is, or potentially could be, linked to disease data. The quantity of data generated by these high throughput methods is forcing scientists to re-think the way they do traditional drug-target discovery. In particular it is leading them more and more towards identifying potential drug targets using computers. In fact, drug-target identification is now being done as much on the desk-top as on the bench-top. This review focuses on describing how drug-target discovery can be done in silico (i.e. via computer) using a variety of bioinformatic resources that are freely available on the web. Specifically, it highlights a number of web-accessible sequence databases, automated genome annotation tools, text mining tools; and integrated drug/sequence databases that can be used to identify drug targets for both endogenous (genetic and epigenetic) diseases as well as exogenous (infectious) diseases.

  8. Allegany Ballistics Lab: sensor test target system (United States)

    Eaton, Deran S.


    Leveraging the Naval Surface Warfare Center, Indian Head Division's historical experience in weapon simulation, Naval Sea Systems Command commissioned development of a remote-controlled, digitally programmable Sensor Test Target as part of a modern, outdoor hardware-in-the-loop test system for ordnance-related guidance, navigation and control systems. The overall Target system design invokes a sciences-based, "design of automated experiments" approach meant to close the logistical distance between sensor engineering and developmental T&E in outdoor conditions over useful real world distances. This enables operating modes that employ broad spectrum electromagnetic energy in many a desired combination, variably generated using a Jet Engine Simulator, a multispectral infrared emitter array, optically enhanced incandescent Flare Simulators, Emitter/Detector mounts, and an RF corner reflector kit. As assembled, the recently tested Sensor Test Target prototype being presented can capably provide a full array of useful RF and infrared target source simulations for RDT&E use with developmental and existing sensors. Certain Target technologies are patent pending, with potential spinoffs in aviation, metallurgy and biofuels processing, while others are variations on well-established technology. The Sensor Test Target System is planned for extended installation at Allegany Ballistics Laboratory (Rocket Center, WV).

  9. Rotating target wheel for the FMA

    Energy Technology Data Exchange (ETDEWEB)

    Back, B.B.; Davids, C.N.; Falout, J. [and others


    In anticipation of high intensity beams that will be available from the PII-ECR source injector to ATLAS, a new rotating target wheel was developed for the sliding seal chamber at the FMA. The wheel is 9 inch in diameter and contains up to ten targets. The rotation of the wheel is achieved by a DC motor, a ferrofluidic feedthrough, and a gear mechanism that allows both target rotation and changing the target angle relative to the beam. The nominal rotation speed is 1000 RPM, although higher speeds can be achieved if necessary. The assembly is equipped with an absolute encoder which is read out via a newly developed CAMAC module. This module provides the following main functions: (1) a TTL signal to be used for sweeping the beam when a target frame is about to pass through the beam, (2) a read-out of the target position that can be included in the data event structure, (3) programmable set points for the beam-off signal. The system is presently being tested and will be used in experiments scheduled for March 1995.

  10. Update on the targeted therapy of melanoma. (United States)

    Johnson, Douglas B; Sosman, Jeffrey A


    Melanoma is the most aggressive of the cutaneous malignancies, causing more than 9,000 deaths in the past year in the United States. Historically, systemic therapies have been largely ineffective, because melanoma is usually resistant to cytotoxic chemotherapy. However, during the past few years, several targeted therapies have proved effective in this challenging disease. These recent advances have been facilitated by an improved understanding of the driving genetic aberrations of melanoma, particularly mutations in the mitogen-activated protein kinase (MAPK) pathway. Vemurafenib, a BRAF inhibitor, demonstrated an overall survival advantage in phase III trials and is an appropriate option for first-line therapy in metastatic BRAF mutant melanoma. Dabrafenib, another BRAF inhibitor, and trametinib, a MEK inhibitor, also have been shown to be effective in phase III trials for BRAF mutant melanoma and may be additional treatment options as monotherapy or in combination pending regulatory approval. Additionally, imatinib is a promising targeted therapy for patients whose tumors harbor a KIT mutation in exons 11 and 13. Although these targeted agents cause objective responses and clinical benefit in patients with metastatic melanoma, resistance invariably develops. New targets and strategies to overcome acquired resistance are urgently needed. Furthermore, no effective targeted therapy has been developed for NRAS mutant tumors or in melanomas with as yet unknown driver mutations. In this review, we discuss current molecular targeted treatment options and promising ongoing research to develop new strategies to treat melanoma.

  11. The SPES High Power ISOL production target (United States)

    Andrighetto, A.; Corradetti, S.; Ballan, M.; Borgna, F.; Manzolaro, M.; Scarpa, D.; Monetti, A.; Rossignoli, M.; Silingardi, R.; Mozzi, A.; Vivian, G.; Boratto, E.; De Ruvo, L.; Sattin, N.; Meneghetti, G.; Oboe, R.; Guerzoni, M.; Margotti, A.; Ferrari, M.; Zenoni, A.; Prete, G.


    SPES (Selective Production of Exotic Species) is a facility under construction at INFN-LNL (Istituto Nazionale di Fisica Nucleare - Laboratori Nazionali di Legnaro), aimed to produce intense neutron-rich radioactive ion beams (RIBs). These will be obtained using the ISOL (Isotope Separation On-Line) method, bombarding a uranium carbide target with a proton beam of 40MeV energy and currents up to 200μA. The target configuration was designed to obtain a high number of fissions, up to 1013 per second, low power deposition and fast release of the produced isotopes. The exotic isotopes generated in the target are ionized, mass separated and re-accelerated by the ALPI superconducting LINAC at energies of 10AMeV and higher, for masses in the region of A = 130 amu , with an expected rate on the secondary target up to 109 particles per second. In this work, recent results on the R&D activities regarding the SPES RIB production target-ion source system are reported.

  12. Screening closing scenarios for tactical targets (United States)

    Sefcik, Jason A.; Lee, Harry C.; Olson, Teresa L. P.


    The first step in an automatic image target acquisition system is determining the location of candidate objects. Screening for targets must also be done within a tactical scenario timeframe. The screening process must only require a portion of the processing workload since other algorithms must execute in the same time frame. The detection of these candidate objects is allocated to two functions within the same algorithm. The first is a pre-screener and other is a clutter rejection component that will categorize the object nomination into target or non-target classes. This paper describes a screener that meets the necessary requirements for tactical operations. It uses the magnitude and direction of the image gradient. Locations are nominated by looking at local neighborhoods in this gradient space. Regions of interest are then selected and various features are extracted. These features are selected both for their information content and their ease of calculation. Using a Bayes approach, target candidates are selected as plausible targets of interest.

  13. Game theoretic sensor management for target tracking (United States)

    Shen, Dan; Chen, Genshe; Blasch, Erik; Pham, Khanh; Douville, Philip; Yang, Chun; Kadar, Ivan


    This paper develops and evaluates a game-theoretic approach to distributed sensor-network management for target tracking via sensor-based negotiation. We present a distributed sensor-based negotiation game model for sensor management for multi-sensor multi-target tacking situations. In our negotiation framework, each negotiation agent represents a sensor and each sensor maximizes their utility using a game approach. The greediness of each sensor is limited by the fact that the sensor-to-target assignment efficiency will decrease if too many sensor resources are assigned to a same target. It is similar to the market concept in real world, such as agreements between buyers and sellers in an auction market. Sensors are willing to switch targets so that they can obtain their highest utility and the most efficient way of applying their resources. Our sub-game perfect equilibrium-based negotiation strategies dynamically and distributedly assign sensors to targets. Numerical simulations are performed to demonstrate our sensor-based negotiation approach for distributed sensor management.

  14. Targeting Signaling Pathways in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Johannes Haybaeck


    Full Text Available Ovarian carcinoma (OC is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR inhibitors, poly-ADP-ribose polymerase (PARP inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity.

  15. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng


    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at

  16. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models. (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng


    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at .



    Ibar ValenZuela, MARÍA CONSUELO


    Las células eucariontes tienen organelos derivados de membrana dentro de los cuales se encuentra el retículo endoplasmático y el aparato de Golgi, los cuales les permiten separar y organizar las distintas funciones celulares. Estos organelos tienen que ser mantenidos en las células hijas durante la división celular, generando las preguntas: ¿qué ocurre cuando las células se dividen? ¿se dividen los organelos existentes o nuevas copias son generadas? ¿cómo esto se encuentra acop...

  18. Millepachine, a novel chalcone, induces G2/M arrest by inhibiting CDK1 activity and causing apoptosis via ROS-mitochondrial apoptotic pathway in human hepatocarcinoma cells in vitro and in vivo. (United States)

    Wu, Wenshuang; Ye, Haoyu; Wan, Li; Han, Xiaolei; Wang, Guangcheng; Hu, Jia; Tang, Minhai; Duan, Xingmei; Fan, Yi; He, Shichao; Huang, Li; Pei, Heying; Wang, Xuewei; Li, Xiuxia; Xie, Caifeng; Zhang, Ronghong; Yuan, Zhu; Mao, Yongqiu; Wei, Yuquan; Chen, Lijuan


    In this study, we reported millepachine (MIL), a novel chalcone compound for the first time isolated from Millettia pachycarpa Benth (Leguminosae), induced cell cycle arrest and apoptosis in human hepatocarcinoma cells in vitro and in vivo. In in vitro screening experiments, MIL showed strong antiproliferation activity in several human cancer cell lines, especially in HepG2 cells with an IC50 of 1.51 µM. Therefore, we chose HepG2 and SK-HEP-1 cells to study MIL's antitumor mechanism. Flow cytometry showed that MIL induced a G2/M arrest and apoptosis in a dose-dependent manner. Western blot demonstrated that MIL-induced G2/M arrest was correlated with the inhibition of cyclin-dependent kinase 1 activity, including a remarkable decrease in cell division cycle (cdc) 2 synthesis, the accumulation of phosphorylated-Thr14 and decrease of phosphorylation at Thr161 of cdc2. This effect was associated with the downregulation of cdc25C and upmodulation of checkpoint kinase 2 in response to DNA damage. MIL also activated caspase 9 and caspase 3, and significantly increased the ratio of Bax/Bcl-2 and stimulated the release of cytochrome c into cytosol, suggesting MIL induced apoptosis via mitochondrial apoptotic pathway. Associated with those effects, MIL also induced the generation of reactive oxygen species. In HepG2 tumor-bearing mice models, MIL remarkably and dose dependently inhibited tumor growth. Treatment of mice with MIL (20mg/kg intravenous [i.v.]) caused more than 65% tumor inhibition without cardiac damage compared with 47.57% tumor reduction by 5mg/kg i.v. doxorubicin with significant cardiac damage. These effects suggested that MIL and its easily modified structural derivative might be a potential lead compound for antitumor drug.

  19. Modeling target erosion during reactive sputtering

    Energy Technology Data Exchange (ETDEWEB)

    Strijckmans, K., E-mail:; Depla, D.


    Highlights: • The erosion of a target is simulated with the RSD2013 software during reactive magnetron sputtering. • The influence of redeposition on the target state and on the hysteresis is explained. • The racetrack formation along the hysteresis and as function of the redeposition is quantified. • Comparison of the racetrack and the sputter profile shows clear differences. - Abstract: The influence of the reactive sputter conditions on the racetrack and the sputter profile for an Al/O{sub 2} DC reactive sputter system is studied by modeling. The role of redeposition, i.e. the deposition of sputtered material back on the target, is therefore taken into account. The used model RSD2013 is capable of simulating the effect of redeposition on the target condition in a spatial resolved way. Comparison between including and excluding redeposition in the RSD2013 model shows that the in-depth oxidation profile of the target differs. Modeling shows that it is important to distinguish between the formed racetrack, i.e. the erosion depth profile, and the sputter profile. The latter defines the distribution of the sputtered atoms in the vacuum chamber. As the target condition defines the sputter yield, it does determine the racetrack and the sputter profile of the planar circular target. Both the shape of the racetrack and the sputter profile change as function of the redeposition fraction as well as function of the oxygen flow change. Clear asymmetries and narrowing are observed for the racetrack shape. Similar effects are noticed for the sputter profile but to a different extent. Based on this study, the often heard misconception that the racetrack shape defines the distribution of the sputtered atoms during reactive sputtering is proven to be wrong.

  20. Transorbital target localization in the porcine model (United States)

    DeLisi, Michael P.; Mawn, Louise A.; Galloway, Robert L.


    Current pharmacological therapies for the treatment of chronic optic neuropathies such as glaucoma are often inadequate due to their inability to directly affect the optic nerve and prevent neuron death. While drugs that target the neurons have been developed, existing methods of administration are not capable of delivering an effective dose of medication along the entire length of the nerve. We have developed an image-guided system that utilizes a magnetically tracked flexible endoscope to navigate to the back of the eye and administer therapy directly to the optic nerve. We demonstrate the capabilities of this system with a series of targeted surgical interventions in the orbits of live pigs. Target objects consisted of NMR microspherical bulbs with a volume of 18 μL filled with either water or diluted gadolinium-based contrast, and prepared with either the presence or absence of a visible coloring agent. A total of 6 pigs were placed under general anesthesia and two microspheres of differing color and contrast content were blindly implanted in the fat tissue of each orbit. The pigs were scanned with T1-weighted MRI, image volumes were registered, and the microsphere containing gadolinium contrast was designated as the target. The surgeon was required to navigate the flexible endoscope to the target and identify it by color. For the last three pigs, a 2D/3D registration was performed such that the target's coordinates in the image volume was noted and its location on the video stream was displayed with a crosshair to aid in navigation. The surgeon was able to correctly identify the target by color, with an average intervention time of 20 minutes for the first three pigs and 3 minutes for the last three.

  1. Layout optimization for multilayer overlay targets (United States)

    Binns, L. A.; Smith, N. P.; Ausschnitt, C. P.; Morningstar, J.; Muth, W.; Schneider, J.; Yerdon, R.


    A novel overlay target developed by IBM and Accent Optical Technologies, Blossom, allows simultaneous overlay measurements of multiple layers (currently, up to 28) with a single target. This is achieved by a rotationally symmetric arrangement of small (4 micron) targets in a 50 micron square area, described more fully in a separate paper. In this paper, we examine the lessons learned in developing and testing the Blossom design. We start by examining proximity effects; the spacing of adjacent targets means that both the precision-like Total Measurement Uncertainty (TMU) and accuracy of a measurement can be affected by proximity of features. We use a mixture of real and modelled data to illustrate this problem, and find that the layout of Blossom reduces the proximity-induced bias. However, we do find that in certain cases proximity effects can increase the TMU of a particular measurement. The solution is to ensure that parts of the target that interact detrimentally are maximally separated. We present a solution to this, viewing the problem as a constrained Travelling Salesman Problem. We have imposed some global constraints, for example printing front-end and back-end layers on separate targets, and consistency with the overlay measurement strategy. Initially, we assume that pairwise measurements are either critical or non-critical, and optimize the layout so that the critical layers are both not placed adjacent to any prior or intermediate-layer features. We then build upon this structure, to consider the effect of low-energy implants (that cannot be seen once processed) and site re-use possibilities. Beyond this, we also investigate the impact of more strategic optimizations, for example, tuning the number of features on each layer. In each case, we present on-product performance data achieved, and modelled data on some additional target variants / extreme cases.

  2. Normalization for triple-target microarray experiments

    Directory of Open Access Journals (Sweden)

    Magniette Frederic


    Full Text Available Abstract Background Most microarray studies are made using labelling with one or two dyes which allows the hybridization of one or two samples on the same slide. In such experiments, the most frequently used dyes are Cy3 and Cy5. Recent improvements in the technology (dye-labelling, scanner and, image analysis allow hybridization up to four samples simultaneously. The two additional dyes are Alexa488 and Alexa494. The triple-target or four-target technology is very promising, since it allows more flexibility in the design of experiments, an increase in the statistical power when comparing gene expressions induced by different conditions and a scaled down number of slides. However, there have been few methods proposed for statistical analysis of such data. Moreover the lowess correction of the global dye effect is available for only two-color experiments, and even if its application can be derived, it does not allow simultaneous correction of the raw data. Results We propose a two-step normalization procedure for triple-target experiments. First the dye bleeding is evaluated and corrected if necessary. Then the signal in each channel is normalized using a generalized lowess procedure to correct a global dye bias. The normalization procedure is validated using triple-self experiments and by comparing the results of triple-target and two-color experiments. Although the focus is on triple-target microarrays, the proposed method can be used to normalize p differently labelled targets co-hybridized on a same array, for any value of p greater than 2. Conclusion The proposed normalization procedure is effective: the technical biases are reduced, the number of false positives is under control in the analysis of differentially expressed genes, and the triple-target experiments are more powerful than the corresponding two-color experiments. There is room for improving the microarray experiments by simultaneously hybridizing more than two samples.

  3. Statistical Inference for Data Adaptive Target Parameters. (United States)

    Hubbard, Alan E; Kherad-Pajouh, Sara; van der Laan, Mark J


    Consider one observes n i.i.d. copies of a random variable with a probability distribution that is known to be an element of a particular statistical model. In order to define our statistical target we partition the sample in V equal size sub-samples, and use this partitioning to define V splits in an estimation sample (one of the V subsamples) and corresponding complementary parameter-generating sample. For each of the V parameter-generating samples, we apply an algorithm that maps the sample to a statistical target parameter. We define our sample-split data adaptive statistical target parameter as the average of these V-sample specific target parameters. We present an estimator (and corresponding central limit theorem) of this type of data adaptive target parameter. This general methodology for generating data adaptive target parameters is demonstrated with a number of practical examples that highlight new opportunities for statistical learning from data. This new framework provides a rigorous statistical methodology for both exploratory and confirmatory analysis within the same data. Given that more research is becoming "data-driven", the theory developed within this paper provides a new impetus for a greater involvement of statistical inference into problems that are being increasingly addressed by clever, yet ad hoc pattern finding methods. To suggest such potential, and to verify the predictions of the theory, extensive simulation studies, along with a data analysis based on adaptively determined intervention rules are shown and give insight into how to structure such an approach. The results show that the data adaptive target parameter approach provides a general framework and resulting methodology for data-driven science.

  4. Determination of spallation residues in thin target: toward an hybrid reactor lead target simulation

    Energy Technology Data Exchange (ETDEWEB)

    Audouin, L.; Tassan-Got, L.; Bernas, M.; Rejmund, F.; Stephan, C.; Taieb, J. [Paris-11 Univ., 91- Orsay (France). Inst. de Physique Nucleaire; Enqvist, T.; Armbruster, P.; Ricciardi, M.V.; Schmidt, K.H. [GSI, Planckstrasse 1, Darmstadt (Germany); Boudard, A.; Fernandez, B.; Legrain, R.; Leray, S.; Volant, C.; Wlazlo, W. [CEA Saclay, Dept. d' Astrophysique, de Physique des Particules, de Physique Nucleaire et de l' Instrumentation Associee, 91 - Gif sur Yvette (France); Benlliure, J.; Casajeros, E.; Pereira, J. [University of Santiago de Compostella (Spain); Czajkowski, S. [Centre d' Etudes Nucleaires de Bordeaux Gradignan, CENBG, CNRS-IN2P3, 33 - Gradignan (France)


    The production of spallation primary residual nuclei in thin target has been studied by measurement of isotopic yields distributions for several systems. Issues relevant for the design of accelerator-driven systems are presented. Monte-Carlo code abilities to reproduce data are studied in details; it is shown that calculations do not reproduce data in a satisfactory way. Future work orientations leading to an improvement of thin targets calculations and ultimately to a thick target simulation are discussed. (author)

  5. Target-based drug discovery for human African trypanosomiasis: selection of molecular target and chemical matter. (United States)

    Gilbert, Ian H


    Target-based approaches for human African trypanosomiasis (HAT) and related parasites can be a valuable route for drug discovery for these diseases. However, care needs to be taken in selection of both the actual drug target and the chemical matter that is developed. In this article, potential criteria to aid target selection are described. Then the physiochemical properties of typical oral drugs are discussed and compared to those of known anti-parasitics.

  6. Frnakenstein: multiple target inverse RNA folding

    Directory of Open Access Journals (Sweden)

    Lyngsø Rune B


    Full Text Available Abstract Background RNA secondary structure prediction, or folding, is a classic problem in bioinformatics: given a sequence of nucleotides, the aim is to predict the base pairs formed in its three dimensional conformation. The inverse problem of designing a sequence folding into a particular target structure has only more recently received notable interest. With a growing appreciation and understanding of the functional and structural properties of RNA motifs, and a growing interest in utilising biomolecules in nano-scale designs, the interest in the inverse RNA folding problem is bound to increase. However, whereas the RNA folding problem from an algorithmic viewpoint has an elegant and efficient solution, the inverse RNA folding problem appears to be hard. Results In this paper we present a genetic algorithm approach to solve the inverse folding problem. The main aims of the development was to address the hitherto mostly ignored extension of solving the inverse folding problem, the multi-target inverse folding problem, while simultaneously designing a method with superior performance when measured on the quality of designed sequences. The genetic algorithm has been implemented as a Python program called Frnakenstein. It was benchmarked against four existing methods and several data sets totalling 769 real and predicted single structure targets, and on 292 two structure targets. It performed as well as or better at finding sequences which folded in silico into the target structure than all existing methods, without the heavy bias towards CG base pairs that was observed for all other top performing methods. On the two structure targets it also performed well, generating a perfect design for about 80% of the targets. Conclusions Our method illustrates that successful designs for the inverse RNA folding problem does not necessarily have to rely on heavy biases in base pair and unpaired base distributions. The design problem seems to become more

  7. An Archer's Perceived Form Scales the "Hitableness" of Archery Targets (United States)

    Lee, Yang; Lee, Sih; Carello, Claudia; Turvey, M. T.


    For skills that involve hitting a target, subsequent judgments of target size correlate with prior success in hitting that target. We used an archery context to examine the judgment-success relationship with varied target sizes in the absence of explicit knowledge of results. Competitive archers shot at targets 50 m away that varied in size among…

  8. The use of targeted and non-targeted advertising to enrich skin cancer screening samples. (United States)

    Katris, P; Donovan, R J; Gray, B N


    The purpose of this study was to determine whether the risk factor profile of persons attending skin cancer screening clinics could be enriched by appropriate advertising prior to the screening events. Eleven screening clinics were held in eight rural and three suburban communities. Matched communities were randomly assigned to either a target or non-target condition. Targeted communities received an advertisement designed to attract high-risk individuals. The advertisement listed a number of risk factors and encouraged readers with one or more of the listed risk factors to attend the screening. Non-targeted communities received a general advertisement requesting individuals who felt they were at risk of skin cancer to attend the clinic. Risk factor profiles of all participants were measured on the factors listed in the targeted advertisement. The risk factor profiles of screenees and the referral rates for skin lesions requiring attention were significantly higher in the targeted communities than in the non-targeted communities. Lesions suspicious of malignant melanoma or Hutchinson's melanotic freckle also were higher, but not statistically significant, in the targeted communities. Population samples attending community-based skin cancer screening clinics can be enriched by appropriate targeted advertising prior to the screening events. This has important implications for determining the potential cost-effectiveness of population screening programmes.

  9. M cell targeting by a Claudin 4 targeting peptide can enhance mucosal IgA responses

    Directory of Open Access Journals (Sweden)

    Lo David D


    Full Text Available Abstract Background Mucosal immune surveillance is thought to be largely achieved through uptake by specialized epithelial M cells. We recently identified Claudin 4 as an M cell target receptor and developed a Claudin 4 targeting peptide (CPE that can mediate uptake of nanoparticles through Nasal Associated Lymphoid Tissue (NALT M cells. Methods Recombinant influenza hemagglutinin (HA and a version with the CPE peptide at the C-terminal end was used to immunize mice by the intranasal route along with a single dose of cholera toxin as an adjuvant. Serum and mucosal IgG and IgA responses were tested for reactivity to HA. Results We found that the recombinant HA was immunogenic on intranasal administration, and inclusion of the CPE targeting peptide induced higher mucosal IgA responses. This mucosal administration also induced systemic serum IgG responses with Th2 skewing, but targeting did not enhance IgG responses, suggesting that the IgG response to mucosal immunization is independent of the effects of CPE M cell targeting. Conclusions M cell targeting mediated by a Claudin 4-specific targeting peptide can enhance mucosal IgA responses above the response to non-targeted mucosal antigen. Since Claudin 4 has also been found to be regulated in human Peyer's patch M cells, the CPE targeting peptide could be a reasonable platform delivery technology for mucosal vaccination.

  10. Simulation for thick-target yields of transmutation reactions on radioactive targets, based on inverse kinematics (United States)

    Ebata, Shuichiro; Aikawa, Masayuki; Imai, Shotaro


    To dispose of long-lived fission products (LLFP) ejected from nuclear reactor plants is one of the most important tasks on nuclear physics and engineering. The experiments with the radiative target are limited, due to the high radioactivity and chemical property of the target. In consequence, the nuclear reaction data for LLFP are insufficient. In this work, we propose a feasible method to obtain the data for radiative targets using inverse kinematics and simulate specific systems to evaluate the thick-target yields of the nuclear transmutation reactions for LLFP.

  11. Simulation for thick-target yields of transmutation reactions on radioactive targets, based on inverse kinematics

    Directory of Open Access Journals (Sweden)

    Ebata Shuichiro


    Full Text Available To dispose of long-lived fission products (LLFP ejected from nuclear reactor plants is one of the most important tasks on nuclear physics and engineering. The experiments with the radiative target are limited, due to the high radioactivity and chemical property of the target. In consequence, the nuclear reaction data for LLFP are insufficient. In this work, we propose a feasible method to obtain the data for radiative targets using inverse kinematics and simulate specific systems to evaluate the thick-target yields of the nuclear transmutation reactions for LLFP.

  12. CXCR4 and CCR7: Two eligible targets in targeted cancer therapy. (United States)

    Mishan, Mohammad Amir; Ahmadiankia, Naghmeh; Bahrami, Ahmad Reza


    Cancer is one of the most common cause of death in the world with high negative emotional, economic, and social impacts. Conventional therapeutic methods, including chemotherapy and radiotherapy, have not proven satisfactory and relapse is common in most cases. Recent studies have focused on targeted therapy with more precise identification and targeted attacks to the cancer cells. For this purpose, chemokine receptors are proper targets and among them, CXCR4 and CCR7, with a crucial role in cancer metastasis, are being considered as desired candidates for investigation. In this review paper, the most important experimental results are highlighted on the potential targeted therapies based on CXCR4 and CCR7 chemokine receptors.

  13. Thick-target yields of radioactive targets deduced from inverse kinematics

    Energy Technology Data Exchange (ETDEWEB)

    Aikawa, M., E-mail: [Faculty of Science, Hokkaido University, Sapporo 060-0810 (Japan); Ebata, S.; Imai, S. [Meme Media Laboratory, Hokkaido University, Sapporo 060-8628 (Japan)


    The thick-target yield (TTY) is a macroscopic quantity reflected by nuclear reactions and matter properties of targets. In order to evaluate TTYs on radioactive targets, we suggest a conversion method from inverse kinematics corresponding to the reaction of radioactive beams on stable targets. The method to deduce the TTY is theoretically derived from inverse kinematics. We apply the method to the {sup nat}Cu({sup 12}C,X){sup 24}Na reaction to confirm availability. In addition, it is applied to the {sup 137}Cs + {sup 12}C reaction as an example of a radioactive system and discussed a conversion coefficient of a TTY measurement.


    Directory of Open Access Journals (Sweden)

    K. V. Trifonov,


    Full Text Available Subject of Research.The paper deals with operating principles of optical pulse target seekers based on quadrant photodiode when targets are located in short-range field region. Method. Target image shape and light intensity distribution can affect static characteristics and cause appearance of image energy maximums when targets are located in short-range field region. Physical modeling of static characteristics plotting process was carried out. The main idea of the proposed method lies in counting sums of image pixels intensities in every virtual area of the sensor while virtual frame of the whole photodetector is moving over the target image. Main Results. Most probable target illumination directions were analyzed. Critical distances when the first extra image energy maximum appears were calculated for every target illumination directions. Time of missile uncontrollable flight at a near miss distance was also estimated. Practical Relevance. Research results point out that using of control loop proper logic is required to provide reliable target shot down for active and semi-active laser homing systems. Also disabling of such systems should be carried out when targets are located in short-range field region.

  15. Potential Therapeutic Targets in Uterine Sarcomas (United States)

    Cuppens, Tine; Tuyaerts, Sandra; Amant, Frédéric


    Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach. PMID:26576131

  16. Target development for a radioactive ion beam

    Energy Technology Data Exchange (ETDEWEB)

    Arnould, M.; Vanhorenbeeck, J. (Universite Libre de Bruxelles (Belgium). Inst. d' Astronomie et d' Astrophysique); Baeten, F.; Dom, C. (Institut National des Radioelements, Fleurus (Belgium)); Darquennes, D.; Delbar, T.; Jongen, Y.; Lacroix, M.; Lipnik, P.; Loiselet, M.; Ryckewaert, G.; Wa Kitwanga, S.; Vervier, J.; Zaremba, S. (Louvain Univ., Louvain-la-Neuve (Belgium). Centre de Physique Nucleaire; Louvain Univ., Louvain-la-Neuve (Belgium). Lab. de Cyclotron); Huyse, M.; Reusen, G.; Duppen, P. van (Leuven Univ. (Belgium). Inst. voor Kern- en Stralingsfysika)


    A proton bombarded target coupled to an ion source is a key-equipment to produce a cyclotron accelerated Radioactive Ion Beam (RIB). This note concerns the target development for a {sup 13}N ion beam which will be the first one out of a more general project at Louvain-la-Neuve (Report RIB-1988-01). A 30-MeV proton beam of up to 300-{mu}A intensity from the CYCLONE 30 bombards a graphite target to produce the {sup 13}N isotope via the {sup 13}C(p, n){sup 13}N reaction. Two major problems have to be solved: The extraction and transport of {sup 13}N and the beam-heat dissipation. These aspects are somewhat correlated to the temperature dependence of the {sup 13}N release and to the heat conductivity of graphite. A disk shaped target can be cooled through its side-face or through its back-face, and in fact both designs are explored. The extraction yield of the first one varies with the beam intensity up to a maximum value of 46% at 170 {mu}A. For the second one, which is presently under development, the target temperature can be adjusted by a cooled finger of variable length. (orig.).

  17. Potential Therapeutic Targets in Uterine Sarcomas

    Directory of Open Access Journals (Sweden)

    Tine Cuppens


    Full Text Available Uterine sarcomas are rare tumors accounting for 3,4% of all uterine cancers. Even after radical hysterectomy, most patients relapse or present with distant metastases. The very limited clinical benefit of adjuvant cytotoxic treatments is reflected by high mortality rates, emphasizing the need for new treatment strategies. This review summarizes rising potential targets in four distinct subtypes of uterine sarcomas: leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma, and undifferentiated uterine sarcoma. Based on clinical reports, promising approaches for uterine leiomyosarcoma patients include inhibition of VEGF and mTOR signaling, preferably in combination with other targeted or cytotoxic compounds. Currently, the only targeted therapy approved in leiomyosarcoma patients is pazopanib, a multitargeted inhibitor blocking VEGFR, PDGFR, FGFR, and c-KIT. Additionally, preclinical evidence suggests effect of the inhibition of histone deacetylases, tyrosine kinase receptors, and the mitotic checkpoint protein aurora kinase A. In low-grade endometrial stromal sarcomas, antihormonal therapies including aromatase inhibitors and progestins have proven activity. Other potential targets are PDGFR, VEGFR, and histone deacetylases. In high-grade ESS that carry the YWHAE/FAM22A/B fusion gene, the generated 14-3-3 oncoprotein is a putative target, next to c-KIT and the Wnt pathway. The observation of heterogeneity within uterine sarcoma subtypes warrants a personalized treatment approach.

  18. Target Response Adaptation for Correlation Filter Tracking

    KAUST Repository

    Bibi, Adel Aamer


    Most correlation filter (CF) based trackers utilize the circulant structure of the training data to learn a linear filter that best regresses this data to a hand-crafted target response. These circularly shifted patches are only approximations to actual translations in the image, which become unreliable in many realistic tracking scenarios including fast motion, occlusion, etc. In these cases, the traditional use of a single centered Gaussian as the target response impedes tracker performance and can lead to unrecoverable drift. To circumvent this major drawback, we propose a generic framework that can adaptively change the target response from frame to frame, so that the tracker is less sensitive to the cases where circular shifts do not reliably approximate translations. To do that, we reformulate the underlying optimization to solve for both the filter and target response jointly, where the latter is regularized by measurements made using actual translations. This joint problem has a closed form solution and thus allows for multiple templates, kernels, and multi-dimensional features. Extensive experiments on the popular OTB100 benchmark show that our target adaptive framework can be combined with many CF trackers to realize significant overall performance improvement (ranging from 3 %-13.5% in precision and 3.2 %-13% in accuracy), especially in categories where this adaptation is necessary (e.g. fast motion, motion blur, etc.). © Springer International Publishing AG 2016.

  19. Subpixel Target Enhancement in Hyperspectral Images

    Directory of Open Access Journals (Sweden)

    Manoj K. Arora


    Full Text Available Hyperspectral images due to their higher spectral resolution are increasingly being used for various remote sensing applications including information extraction at subpixel level. Typically whenever an object gets spectrally resolved but not spatially, mixed pixels in the images result. Numerous man made and/or natural disparate targets may thus occur inside such mixed pixels giving rise to subpixel target detection problem. Various spectral unmixing models such as linear mixture modeling (LMM are in vogue to recover components of a mixed pixel. Spectral unmixing outputs both the endmember spectrum and their corresponding abundance fractions inside the pixel. It, however, does not provide spatial distribution of these abundance fractions within a pixel. This limits the applicability of hyperspectral data for subpixel target detection. In this paper, a new inverse Euclidean distance based super-resolution mapping method has been presented. In this method, the subpixel target detection is performed by adjusting spatial distribution of abundance fraction within a pixel of an hyperspectral image. Results obtained at different resolutions indicate that super-resolution mapping may effectively be utilized in enhancing the target detection at sub-pixel level.

  20. Molecular Therapeutic Targets for Glioma Angiogenesis

    Directory of Open Access Journals (Sweden)

    Shingo Takano


    Full Text Available Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, v3 integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4 results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

  1. Shift-invariant target in allocation problems. (United States)

    Mandal, Saumen; Biswas, Atanu


    We provide a template for finding target allocation proportions in optimal allocation designs where the target will be invariant for both shifts in location and scale of the response distributions. One possible application of such target allocation proportions is to carry out a response-adaptive allocation. While most of the existing designs are invariant for any change in scale of the underlying distributions, they are not location invariant in most of the cases. First, we indicate this serious flaw in the existing literature and illustrate how this lack of location invariance makes the performance of the designs very poor in terms of allocation for any drastic change in location, such as the changes from degrees centigrade to degrees Fahrenheit. We illustrate that unless a target allocation is location invariant, it might lead to a completely irrelevant and useless target for allocation. Then we discuss how such location invariance can be achieved for general continuous responses. We illustrate the proposed method using some real clinical trial data. We also indicate the possible extension of the procedure for more than two treatments at hand and in the presence of covariates.

  2. New targeted therapies in pancreatic cancer. (United States)

    Seicean, Andrada; Petrusel, Livia; Seicean, Radu


    Patients with pancreatic cancer have a poor prognosis with a median survival of 4-6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways.

  3. Cisplatin Targeting of Bacterial Ribosomal RNA Hairpins

    Directory of Open Access Journals (Sweden)

    Gayani N. P. Dedduwa-Mudalige


    Full Text Available Cisplatin is a clinically important chemotherapeutic agent known to target purine bases in nucleic acids. In addition to major deoxyribonucleic acid (DNA intrastrand cross-links, cisplatin also forms stable adducts with many types of ribonucleic acid (RNA including siRNA, spliceosomal RNAs, tRNA, and rRNA. All of these RNAs play vital roles in the cell, such as catalysis of protein synthesis by rRNA, and therefore serve as potential drug targets. This work focused on platination of two highly conserved RNA hairpins from E. coli ribosomes, namely pseudouridine-modified helix 69 from 23S rRNA and the 790 loop of helix 24 from 16S rRNA. RNase T1 probing, MALDI mass spectrometry, and dimethyl sulfate mapping revealed platination at GpG sites. Chemical probing results also showed platination-induced RNA structural changes. These findings reveal solvent and structural accessibility of sites within bacterial RNA secondary structures that are functionally significant and therefore viable targets for cisplatin as well as other classes of small molecules. Identifying target preferences at the nucleotide level, as well as determining cisplatin-induced RNA conformational changes, is important for the design of more potent drug molecules. Furthermore, the knowledge gained through studies of RNA-targeting by cisplatin is applicable to a broad range of organisms from bacteria to human.

  4. 29 mm Diameter Test Target Design Report

    Energy Technology Data Exchange (ETDEWEB)

    Woloshun, Keith Albert [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dale, Gregory E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Olivas, Eric Richard [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Naranjo, Angela Carol [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Romero, Frank Patrick [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)


    The Northstar target for Mo99 production is made up of Mo100 disks in a stack separated by coolant gaps for helium flow. A number of targets have been tested at ANL for both production of Mo99 and for thermal-hydraulic performance. These have all been with a 12 mm diameter target, even while the production goals have increased the diameter to now 29 mm. A 29 mm diameter target has been designed that is consistent with the ANL beam capabilities and the capabilities of the helium circulation system currently in use at ANL. This target is designed for 500 μA at 35 MeV electrons. While the plant design calls for 42 MeV, the chosen design point is more favorable and higher power given the limits of the ANL accelerator. The intended beam spot size is 12 mm FWHM, but the thermal analysis presented herein conservatively assumed a 10 mm FWHM beam, which results in a 44% higher beam current density at beam center.

  5. Bone targeting for the treatment of osteoporosis. (United States)

    Luhmann, Tessa; Germershaus, Oliver; Groll, Jürgen; Meinel, Lorenz


    Osteoporosis represents a major public health burden especially considering the aging populations worldwide. Drug targeting will be important to better meet these challenges and direct the full therapeutic potential of therapeutics to their intended site of action. This review has been organized in modules, such that scientists working in the field can easily gain specific insight in the field of bone targeting for the drug class they are interested in. We review currently approved and emerging treatment options for osteoporosis and discuss these in light of the benefit these would gain from advanced targeting. In addition, established targeting strategies are reviewed and novel opportunities as well as promising areas are presented along with pharmaceutical strategies how to render novel composites consisting of a drug and a targeting moiety responsive to bone-specific or disease-specific environmental stimuli. Successful implementation of these principles into drug development programs for osteoporosis will substantially contribute to the clinical success of anti-catabolic and anabolic drugs of the future.

  6. Cooperation Mechanisms To Achieve Eu Renewable Targets

    DEFF Research Database (Denmark)

    Klinge Jacobsen, Henrik; Pade, Lise-Lotte; Schröder, Sascha Thorsten


    for cooperation mechanisms such as joint support schemes for promoting renewable energy to meet the 2020 targets. The potential coordination benefits, with more efficient localisation and composition of renewable investment, can be achieved by creating new areas/sub-segments of renewable technologies where...... connection of new capacity to the electricity grid and cost sharing rules for electricity transmission expansion are examined and examples given. The influence of additional renewable capacity on domestic/regional power market prices can be a barrier. The market will be influenced by for example an expansion...... of the wind capacity resulting in lower prices, which will affect existing conventional producers. This development will be opposed by conventional producers, whereas consumers will support such a strategy. A major barrier is the timing of RES targets and the uncertainty regarding future targets. We...

  7. In vivo targeting through click chemistry. (United States)

    Brudno, Yevgeny; Desai, Rajiv M; Kwee, Brian J; Joshi, Neel S; Aizenberg, Michael; Mooney, David J


    Targeting small molecules to diseased tissues as therapy or diagnosis is a significant challenge in drug delivery. Drug-eluting devices implanted during invasive surgery allow the controlled presentation of drugs at the disease site, but cannot be modified once the surgery is complete. We demonstrate that bioorthogonal click chemistry can be used to target circulating small molecules to hydrogels resident intramuscularly in diseased tissues. We also demonstrate that small molecules can be repeatedly targeted to the diseased area over the course of at least one month. Finally, two bioorthogonal reactions were used to segregate two small molecules injected as a mixture to two separate locations in a mouse disease model. These results demonstrate that click chemistry can be used for pharmacological drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.

  8. Target developments program to prepare LMJ campaigns

    Energy Technology Data Exchange (ETDEWEB)

    Collier, R; Bachelet, F; Botrel, R; Breton, O; Chicanne, C; Dauteuil, C H; Durut, F; Fleury, E; Guillot, L; Hermerel, C; Jeannot, L; Legaie, O; Legay, G; Martin, M; Reneaume, B; Theobald, M; Vincent-Viry, O, E-mail: remy.collier@cea.f [Commissariat a l' Energie Atomique, Direction des Applications Militaires, Valduc, F-21120 Is-sur-Tille (France)


    To carry out laser plasma experiments on CEA laser facilities, a R and D program was set up and is still under way to deliver complex targets. For a decade, specific developments are also dedicated to 'Ligne d'Integration Laser' (LIL) in France and Omega facilities (USA). To prepare the targets intended for the first experiments on the Laser 'Megajoule' (LMJ) facility, new developments are required, such as cocktail hohlraum fabrication, gas barrier coating and foam shells developments. For fusion experiments on LMJ, an important program is also under way to elaborate the Cryogenic Target Assembly (CTA), to fill and transport the CTA and to study the conformation process of the DT layer.

  9. [Non oncologic applications of molecular targeted therapies]. (United States)

    Khaled, Wassef; de la Motte Rouge, Thibault; Amirault, Jean-Christophe; Vignot, Stéphane


    Significant improvements in the knowledge of cancer biology have permitted the development of new molecular targeted therapies. Meanwhile, a better understanding of the physiology of various non-cancerous diseases has allowed developing these agents in other areas. This review intends to illustrate these perspectives through examples corresponding to different strategies of molecular-targeted therapies : use of a monoclonal antibody binding a receptor (rituximab and rheumatoid arthritis) or a ligand (bevacizumab and age-related macular degeneration), tyrosine kinase inhibitor (imatinib and systemic sclerosis) or inhibitor of cytoplasmic signal transduction pathways (immunosuppressive and antiproliferative effects of mammalian target of rapamycin [mTOR] inhibitors). Clinical results can draw today what could become molecular medicine of tomorrow.

  10. SNS Target Systems initial operating experience (United States)

    McManamy, T.; Forester, J.


    The SNS mercury target started operation with low beam power when commissioned on April 28, 2006. The beam power has been following a planned ramp up since then and has reached 340 kW as of February 2008. The target systems supporting neutron production include the target and mercury loop, the cryogenic and ambient moderator systems, reflector and vessel systems, bulk shielding and shutters systems, utility systems, remote handling systems and the associated instrumentation and controls. Availability for these systems has improved with time and reached 100% for the first 2000 hour neutron production run in fiscal year 2008. An overview of the operating experience and the planning to support continued power increases to 1.4 MW for these systems will be given in this paper.

  11. Targeting neurons and photons for optogenetics. (United States)

    Packer, Adam M; Roska, Botond; Häusser, Michael


    Optogenetic approaches promise to revolutionize neuroscience by using light to manipulate neural activity in genetically or functionally defined neurons with millisecond precision. Harnessing the full potential of optogenetic tools, however, requires light to be targeted to the right neurons at the right time. Here we discuss some barriers and potential solutions to this problem. We review methods for targeting the expression of light-activatable molecules to specific cell types, under genetic, viral or activity-dependent control. Next we explore new ways to target light to individual neurons to allow their precise activation and inactivation. These techniques provide a precision in the temporal and spatial activation of neurons that was not achievable in previous experiments. In combination with simultaneous recording and imaging techniques, these strategies will allow us to mimic the natural activity patterns of neurons in vivo, enabling previously impossible 'dream experiments'.

  12. EGFR as a therapeutic target in glioblastoma

    Directory of Open Access Journals (Sweden)

    David M Siebert


    Full Text Available The tyrosine kinase receptor epidermal growth factor receptor (EGFR can be activated by several ligands, thus triggering downstream pathways regulating cell growth and survival. Its dysregula­tion is particularly important for the development and progression of astrocytomas. After the description of its role in glioblastomas (WHO grade IV astrocytomas, an overview on the therapeutic strategies target­ing EGFR is provided. It analyzes the past and ongoing trials concerning the small molecule tyro­sine kinase inhibitors, i.e. gefitinib, erlotinib and the combination therapies, the EGFR vaccina­tion strategies, the antibodies directed against EGFR and finally the intracranially administered EGFR-targeted therapies. As our understanding of the underlying molecular aberrancies in glioblastoma grows, our ability to better target specific subtypes of glioblastoma should improve. Molecular biomarker enriched clinical trials may lead to improved patient outcomes.

  13. Target materials for exotic ISOL beams

    CERN Document Server

    Gottberg, A


    The demand for intensity, purity, reliability and availability of short-lived isotopes far from stability is steadily high, and considerably exceeding the supply. In many cases the ISOL (Isotope Separation On-Line) method can provide beams of high intensity and purity. Limitations in terms of accessible chemical species and minimum half-life are driven mainly by chemical reactions and physical processes inside of the thick target. A wide range of materials are in use, ranging from thin metallic foils and liquids to refractory ceramics, while poly-phasic mixed uranium carbides have become the reference target material for most ISOL facilities world-wide. Target material research and development is often complex and especially important post-irradiation analyses are hindered by the high intrinsic radiotoxicity of these materials. However, recent achievements have proven that these investigations are possible if the effort of different facilities is combined, leading to the development of new material matrices t...

  14. Targeting immune checkpoints in malignant glioma (United States)

    Li, Tete; Liu, Yong-Jun; Chen, Wei; Chen, Jingtao


    Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the bodys anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered immune privileged and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma. PMID:27756892

  15. The rationale for targeted therapies in medulloblastoma. (United States)

    MacDonald, Tobey J; Aguilera, Dolly; Castellino, Robert C


    Medulloblastoma (MB) is the most frequent malignant brain tumor in children. Patients with MB who are classified as having high-risk disease or those with recurrent disease respond poorly to current therapies and have an increased risk of MB-related mortality. Preclinical studies and molecular profiling of MB tumors have revealed upregulation or activation of several key signaling pathways such as the sonic hedgehog and WNT pathways. Although the exact mechanisms underlying MB tumorigenesis remain poorly understood, inhibiting these key pathways with molecularly targeted therapies represents an important approach to improving MB outcomes. Several molecularly targeted therapies are already under clinical investigation in MB patients. We discuss current preclinical and clinical data, as well as data from clinical trials of targeted therapies that are either ongoing or in development for MB.

  16. Metalloproteinases: potential therapeutic targets for rheumatoid arthritis. (United States)

    Itoh, Yoshifumi


    In different inflammatory diseases, many metalloproteinases are over expressed and thought to promote progression of the disease. Understanding roles of these enzymes in disease progression as well as in normal homeostasis is crucial to identify target enzymes for the disease. Rheumatoid arthritis (RA) is one of the autoimmune inflammatory diseases in which around 1-2 % of the world populations are suffered from. Roles of metalloproteinases are well documented in RA, but so far none of them is proposed to be a target enzyme. However, there are at least three enzymes that can potentially be molecular targets to inhibit progression of RA. Understanding roles of these enzymes in more detail and developing highly selective inhibitors to these enzymes would be essential for novel antimetalloproteinase therapies in future.

  17. Lone-Actor Terrorist Target Choice. (United States)

    Gill, Paul; Corner, Emily


    Lone-actor terrorist attacks have risen to the forefront of the public's consciousness in the past few years. Some of these attacks were conducted against public officials. The rise of hard-to-detect, low-tech attacks may lead to more public officials being targeted. This paper explores whether different behavioral traits are apparent within a sample of lone-actor terrorists who plotted against high-value targets (including public officials) than within a sample of lone actors who plotted against members of the public. Utilizing a unique dataset of 111 lone-actor terrorists, we test a series of hypotheses related to attack capability and operational security. The results indicate that very little differentiates those who attack high-value targets from those who attack members of the public. We conclude with a series of illustrations to theorize why this may be the case. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Innovations in classical hormonal targets for endometriosis. (United States)

    Pluchino, Nicola; Freschi, Letizia; Wenger, Jean-Marie; Streuli, Isabelle


    Endometriosis is a chronic disease of unknown etiology that affects approximately 10% of women in reproductive age. Several evidences show that endometriosis lesions are associated to hormonal imbalance, including estrogen synthesis, metabolism and responsiveness and progesterone resistance. These hormonal alterations influence the ability of endometrial cells to proliferate, migrate and to infiltrate the mesothelium, causing inflammation, pain and infertility. Hormonal imbalance in endometriosis represents also a target for treatment. We provide an overview on therapeutic strategies based on innovations of classical hormonal mechanisms involved in the development of endometriosis lesions. The development phase of new molecules targeting these pathways is also discussed. Endometriosis is a chronic disease involving young women and additional biological targets of estrogen and progesterone pharmacological manipulation (brain, bone and cardiovascular tissue) need to be carefully considered in order to improve and overcome current limits of long-term medical management of endometriosis.


    Institute of Scientific and Technical Information of China (English)


    A new approach is provided to estimate the state of arbitrarily maneuvering target. In this approach a fuzzy compensator is used to tackle the uncertainty which results from the targets arbitrarily maneuvering. To design the observer of the nonlinear system, the fuzzy T-S model and the receding horizon control strategy are employed. Besides, the design depends on tracking the output error of the model. Compared with the technique used in other articles, the errors between the first estimated value and the true state value of the estimated variable are not strictly required. Numerical simulating results show that the proposed approach can estimate the states of the random maneuvering targets on-line so as to obtain the exact tracking of the target.

  20. [Molecular alterations in melanoma and targeted therapies]. (United States)

    Mourah, Samia; Lebbé, Céleste


    Melanoma is a skin cancer whose incidence is increasing steadily. The recent discovery of frequent and recurrent genetic alterations in cutaneous melanoma allowed a molecular classification of tumors into distinct subgroups, and paved the way for targeted therapy. Several signaling pathways are involved in the progression of this disease with oncogenic mutations affecting signaling pathways: MAPK, PI3K, cAMP and cyclin D1/CDK4. In each of these pathways, several potential therapeutic targets have been identified and specific inhibitors have already been developed and have shown clinical efficacy. The use of these inhibitors is often conditioned by tumors genotyping. In France, melanomas genotyping is supported by the platforms of the National Cancer Institute (INCA), which implemented a national program ensuring access to innovation for personalized medicine. The identification of new targets in melanoma supplies a very active dynamic development of innovative molecules contributing to changing the therapeutic landscape of this pathology.