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Sample records for 4a 4b 4d

  1. Comparison of the Pharmacological Profiles of Selective PDE4B and PDE4D Inhibitors in the Central Nervous System

    PubMed Central

    Zhang, Chong; Xu, Ying; Zhang, Han-Ting; Gurney, Mark E.; O’Donnell, James M.

    2017-01-01

    Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase 4 (PDE4) has been proposed as a potential treatment for a series of neuropsychological conditions such as depression, anxiety and memory loss. However, the specific involvement of each of the PDE4 subtypes (PDE4A, 4B and 4C) in different categories of behavior has yet to be elucidated. In the present study, we compared the possible pharmacological effects of PDE4B and PDE4D selective inhibitors, A-33 and D159687, in mediating neurological function in mice. Both compounds were equally potent in stimulating cAMP signaling in the mouse hippocampal cell line HT-22 leading to an increase in CREB phosphorylation. In contrast, A-33 and D159687 displayed distinct neuropharmacological effects in mouse behavioral tests. A-33 has an antidepressant-like profile as indicated by reduced immobility time in the forced swim and tail suspension tasks, as well as reduced latency to feed in the novelty suppressed feeding test. D159687, on the other hand, had a procognitive profile as it improved memory in the novel object recognition test but had no antidepressant or anxiolytic benefit. The present data suggests that inhibitors targeting specific subtypes of PDE4 may exhibit differential pharmacological effects and aid a more efficient pharmacotherapy towards neuropsychological conditions. PMID:28054669

  2. Characterization of Dengue Virus NS4A and NS4B Protein Interaction

    PubMed Central

    Zou, Jing; Xie, Xuping; Wang, Qing-Yin; Dong, Hongping; Lee, Michelle Yueqi; Kang, Congbao

    2015-01-01

    ABSTRACT Flavivirus replication is mediated by a membrane-associated replication complex where viral membrane proteins NS2A, NS2B, NS4A, and NS4B serve as the scaffold for the replication complex formation. Here, we used dengue virus serotype 2 (DENV-2) as a model to characterize viral NS4A-NS4B interaction. NS4A interacts with NS4B in virus-infected cells and in cells transiently expressing NS4A and NS4B in the absence of other viral proteins. Recombinant NS4A and NS4B proteins directly bind to each other with an estimated Kd (dissociation constant) of 50 nM. Amino acids 40 to 76 (spanning the first transmembrane domain, consisting of amino acids 50 to 73) of NS4A and amino acids 84 to 146 (also spanning the first transmembrane domain, consisting of amino acids 101 to 129) of NS4B are the determinants for NS4A-NS4B interaction. Nuclear magnetic resonance (NMR) analysis suggests that NS4A residues 17 to 80 form two amphipathic helices (helix α1, comprised of residues 17 to 32, and helix α2, comprised of residues 40 to 47) that associate with the cytosolic side of endoplasmic reticulum (ER) membrane and helix α3 (residues 52 to 75) that transverses the ER membrane. In addition, NMR analysis identified NS4A residues that may participate in the NS4A-NS4B interaction. Amino acid substitution of these NS4A residues exhibited distinct effects on viral replication. Three of the four NS4A mutations (L48A, T54A, and L60A) that affected the NS4A-NS4B interaction abolished or severely reduced viral replication; in contrast, two NS4A mutations (F71A and G75A) that did not affect NS4A-NS4B interaction had marginal effects on viral replication, demonstrating the biological relevance of the NS4A-NS4B interaction to DENV-2 replication. Taken together, the study has provided experimental evidence to argue that blocking the NS4A-NS4B interaction could be a potential antiviral approach. IMPORTANCE Flavivirus NS4A and NS4B proteins are essential components of the ER membrane

  3. The epidemic dynamics of hepatitis C virus subtypes 4a and 4d in Saudi Arabia

    PubMed Central

    Al-Qahtani, Ahmed A.; Baele, Guy; Khalaf , Nisreen; Suchard, Marc A.; Al-Anazi, Mashael R.; Abdo, Ayman A.; Sanai, Faisal M.; Al-Ashgar, Hamad I.; Khan, Mohammed Q.; Al-Ahdal, Mohammed N.; Lemey, Philippe; Vrancken, Bram

    2017-01-01

    The relatedness between viral variants sampled at different locations through time can provide information pertinent to public health that cannot readily be obtained through standard surveillance methods. Here, we use virus genetic data to identify the transmission dynamics that drive the hepatitis C virus subtypes 4a (HCV4a) and 4d (HCV4d) epidemics in Saudi Arabia. We use a comprehensive dataset of newly generated and publicly available sequence data to infer the HCV4a and HCV4d evolutionary histories in a Bayesian statistical framework. We also introduce a novel analytical method for an objective assessment of the migration intensity between locations. We find that international host mobility patterns dominate over within country spread in shaping the Saudi Arabia HCV4a epidemic, while this may be different for the HCV4d epidemic. This indicates that the subtypes 4a and 4d burden can be most effectively reduced by combining the prioritized screening and treatment of Egyptian immigrants with domestic prevention campaigns. Our results highlight that the joint investigation of evolutionary and epidemiological processes can provide valuable public health information, even in the absence of extensive metadata information. PMID:28322313

  4. Monoclonal antipeptide antibodies against amino acid residues 1101-1106 of human C4 distinguish C4A from C4B.

    PubMed

    Reilly, B D; Levine, P; Rothbard, J; Skanes, V M

    1991-01-01

    Comparison of amino acid sequences of the alpha-chain fragment of human C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 in which the aspartic acid-histidine substitution at position 1106 may be related to the amide and ester bond forming properties of these molecules. Peptides containing twelve amino acid residues of the C4A- or C4B-specific sequences were synthesized and injected into female Balb/c mice. Serum from 2 mice, one immunized with the C4A-specific peptide and the other with the C4B-specific peptide, gave strong isotype-specific responses in an enzyme-linked immunosorbent assay against affinity-purified C4A3 and C4B2B1. Spleen cells from these mice were fused with the mouse myeloma SP2/0-Ag 14, and two cloned cell lines, AII-1 and BII-1, were established from hybrids. Enzyme-linked immunosorbent assay and western blotting of monoclonal antibodies AII-1 and BII-1 show that the former reacts with the C4A but not with the C4B alpha-chain and the latter with C4B but not with the C4A alpha-chain. Furthermore, immunoblotting of C4 allelic variants showed that AII-1 reacted with all C4A allotypes tested, including A6, A4, A3 and A2, whereas BII-1 reacted with all C4B allotypes tested, including B5, B3, B2, and B1.

  5. Mutation testing in melanoma families: INK4A, CDK4 and INK4D

    PubMed Central

    Newton Bishop, J A; Harland, M; Bennett, D C; Bataille, V; Goldstein, A M; Tucker, M A; Ponder, B A J; Cuzick, J; Selby, P; Bishop, D T

    1999-01-01

    The INK4A gene which codes for the cyclin-dependent kinase (CDK) inhibitor INK4A or p16 underlies susceptibility to melanoma in some families. Germline mutations in the gene that codes for the target protein of p16, CDK4, underlie susceptibility in very rare families. We report mutation screening of the INK4A and CDK4 genes in 42 UK families. A total of nine families were identified with INK4A mutations and none with CDK4 exon 2 mutations. These mutations were in 8/22 (35%) families with three or more cases of melanoma and 1/20 (5%) families with only two cases. In one of these nine families a novel single base pair substitution was identified, Gly67Arg. In an attempt to identify another melanoma susceptibility gene, a member of the INK4 family, the p19 INK4D gene has been studied. The p19 gene was sequenced in DNA from the 42 UK families and six additional US families. No mutations were identified. © 1999 Cancer Research Campaign PMID:10390011

  6. Specificity of the hepatitis C virus NS3 serine protease: effects of substitutions at the 3/4A, 4A/4B, 4B/5A, and 5A/5B cleavage sites on polyprotein processing.

    PubMed Central

    Kolykhalov, A A; Agapov, E V; Rice, C M

    1994-01-01

    Cleavage at four sites (3/4A, 4A/4B, 4B/5A, and 5A/5B) in the hepatitis C virus polyprotein requires a viral serine protease activity residing in the N-terminal one-third of the NS3 protein. Sequence comparison of the residues flanking these cleavage sites reveals conserved features including an acidic residue (Asp or Glu) at the P6 position, a Cys or Thr residue at the P1 position, and a Ser or Ala residue at the P1' position. In this study, we used site-directed mutagenesis to assess the importance of these and other residues for NS3 protease-dependent cleavages. Substitutions at the P7 to P2' positions of the 4A/4B site had varied effects on cleavage efficiency. Only Arg at the P1 position or Pro at P1' substantially blocked processing at this site. Leu was tolerated at the P1 position, whereas five other substitutions allowed various degrees of cleavage. Substitutions with positively charged or other hydrophilic residues at the P7, P3, P2, and P2' positions did not reduce cleavage efficiency. Five substitutions examined at the P6 position allowed complete cleavage, demonstrating that an acidic residue at this position is not essential. Parallel results were obtained with substrates containing an active NS3 protease domain in cis or when the protease domain was supplied in trans. Selected substitutions blocking or inhibiting cleavage at the 4A/4B site were also examined at the 3/4A, 4B/5A, and 5A/5B sites. For a given substitution, a site-dependent gradient in the degree of inhibition was observed, with a 3/4A site being least sensitive to mutagenesis, followed by the 4A/4B, 4B/5A, and 5A/5B sites. In most cases, mutations abolishing cleavage at one site did not affect processing at the other serine protease-dependent sites. However, mutations at the 3/4A site which inhibited cleavage also interfered with processing at the 4B/5A site. Finally, during the course of these studies an additional NS3 protease-dependent cleavage site has been identified in the NS4B

  7. The gene history of zebrafish tlr4a and tlr4b is predictive of their divergent functions.

    PubMed

    Sullivan, Con; Charette, Jeremy; Catchen, Julian; Lage, Christopher R; Giasson, Gregory; Postlethwait, John H; Millard, Paul J; Kim, Carol H

    2009-11-01

    Mammalian immune responses to LPS exposure are typified by the robust induction of NF-kappaB and IFN-beta responses largely mediated by TLR4 signal transduction pathways. In contrast to mammals, Tlr4 signal transduction pathways in nontetrapods are not well understood. Comprehensive syntenic and phylogenetic analyses support our hypothesis that zebrafish tlr4a and tlr4b genes are paralogous rather than orthologous to human TLR4. Furthermore, we provide evidence to support our assertion that the in vivo responsiveness of zebrafish to LPS exposure is not mediated by Tlr4a and Tlr4b paralogs because they fail to respond to LPS stimulation in vitro. Zebrafish Tlr4a and Tlr4b paralogs were also unresponsive to heat-killed Escherichia coli and Legionella pneumophila. Using chimeric molecules in which portions of the zebrafish Tlr4 proteins were fused to portions of the mouse TLR4 protein, we show that the lack of responsiveness to LPS was most likely due to the inability of the extracellular portions of zebrafish Tlr4a and Tlr4b to recognize the molecule, rather than to changes in their capacities to transduce signals through their Toll/IL-1 receptor (TIR) domains. Taken together, these findings strongly support the notion that zebrafish tlr4a and tlr4b paralogs have evolved to provide alternative ligand specificities to the Tlr immune defense system in this species. These data demonstrate that intensive examination of gene histories when describing the Tlr proteins of basally diverging vertebrates is required to obtain fuller appreciation of the evolution of their function. These studies provide the first evidence for the functional evolution of a novel Tlr.

  8. Substitution of a single amino acid (aspartic acid for histidine) converts the functional activity of human complement C4B to C4A.

    PubMed Central

    Carroll, M C; Fathallah, D M; Bergamaschini, L; Alicot, E M; Isenman, D E

    1990-01-01

    The C4B isotype of the fourth component of human complement (C4) displays 3- to 4-fold greater hemolytic activity than does its other isotype C4A. This correlates with differences in their covalent binding efficiencies to erythrocytes coated with antibody and complement C1. C4A binds to a greater extent when C1 is on IgG immune aggregates. The differences in covalent binding properties correlate only with amino acid changes between residues 1101 and 1106 (pro-C4 numbering)--namely, Pro-1101, Cys-1102, Leu-1105, and Asp-1106 in C4A and Leu-1101, Ser-1102, Ile-1105, and His-1106 in C4B, which are located in the C4d region of the alpha chain. To more precisely identify the residues that are important for the functional differences, C4A-C4B hybrid proteins were constructed by using recombinant DNA techniques. Comparison of these by hemolytic assay and binding to IgG aggregates showed that the single substitution of aspartic acid for histidine at position 1106 largely accounted for the change in functional activity and nature of the chemical bond formed (ester vs. amide). Surprisingly, substitution of a neutral residue, alanine, for histidine at position 1106 resulted in an increase in binding to immune aggregates without subsequent reduction in the hemolytic activity. This result strongly suggests that position 1106 is not "catalytic" as previously proposed but interacts sterically/electrostatically with potential acceptor sites and serves to "select" binding sites on potential acceptor molecules. Images PMID:2395880

  9. Distinct and overlapping functions of the cullin E3 ligase scaffolding proteins CUL4A and CUL4B

    PubMed Central

    Hannah, Jeffrey

    2016-01-01

    The cullin 4 subfamily of genes includes CUL4A and CUL4B, which share a mostly identical amino acid sequence aside from the elongated N-terminal region in CUL4B. Both act as scaffolding proteins for modular cullin RING ligase 4 (CRL4) complexes which promote the ubiquitination of a variety of substrates. CRL4 function is vital to cells as loss of both genes or their shared substrate adaptor protein DDB1 halts proliferation and eventually leads to cell death. Due to their high structural similarity, CUL4A and CUL4B share a substantial overlap in function. However, in some cases, differences in subcellular localization, spatiotemporal expression patterns and stress-inducibility preclude functional compensation. In this review, we highlight the most essential functions of the CUL4 genes in: DNA repair and replication, chromatin-remodeling, cell cycle regulation, embryogenesis, hematopoiesis and spermatogenesis. CUL4 genes are also clinically relevant as dysregulation can contribute to the onset of cancer and CRL4 complexes are often hijacked by certain viruses to promote viral replication and survival. Also, mutations in CUL4B have been implicated in a subset of patients suffering from syndromic X-linked intellectual disability (AKA mental retardation). Interestingly, the antitumor effects of immunomodulatory drugs are caused by their binding to the CRL4CRBN complex and re-directing the E3 ligase towards the Ikaros transcription factors IKZF1 and IKZF3. Because of their influence over key cellular functions and relevance to human disease, CRL4s are considered promising targets for therapeutic intervention. PMID:26344709

  10. Cell surface trafficking of TLR1 is differentially regulated by the chaperones PRAT4A and PRAT4B.

    PubMed

    Hart, Bryan E; Tapping, Richard I

    2012-05-11

    The subcellular localization of Toll-like receptors (TLRs) is critical to their ability to function as innate immune sensors of microbial infection. We previously reported that an I602S polymorphism of human TLR1 is associated with aberrant trafficking of the receptor to the cell surface, loss of responses to TLR1 agonists, and differential susceptibility to diseases caused by pathogenic mycobacteria. Through an extensive analysis of receptor deletion and point mutants we have discovered that position 602 resides within a short 6 amino acid cytoplasmic region that is required for TLR1 surface expression. This short trafficking motif, in conjunction with the adjacent transmembrane domain, is sufficient to direct TLR1 to the cell surface. A serine at position 602 interrupts this trafficking motif and prevents cell surface expression of TLR1. Additionally, we have found that ER-resident TLR chaperones, PRAT4A and PRAT4B, act as positive and negative regulators of TLR1 surface trafficking, respectively. Importantly, either over-expression of PRAT4A or knock-down of PRAT4B rescues cell surface expression of the TLR1 602S variant. We also report that IFN-γ treatment of primary human monocytes derived from homozygous 602S individuals rescues TLR1 cell surface trafficking and cellular responses to soluble agonists. This event appears to be mediated by PRAT4A whose expression is strongly induced in human monocytes by IFN-γ. Collectively, these results provide a mechanism for the differential trafficking of TLR1 I602S variants, and highlight the distinct roles for PRAT4A and PRAT4B in the regulation of TLR1 surface expression.

  11. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant.

    PubMed Central

    Erdogan, S; Houslay, M D

    1997-01-01

    The cAMP phosphodiesterase (PDE) 3 and PDE4 isoforms provide the major cAMP-hydrolysing PDE activities in Jurkat T-cells, with additional contributions from the PDE1 and PDE2 isoforms. Challenge of cells with the adenylate cyclase activator forskolin led to a rapid, albeit transient, increase in PDE3 activity occurring over the first 45 min, followed by a sustained increase in PDE3 activity which began after approximately 3 h and continued for at least 24 h. Only this second phase of increase in PDE3 activity was blocked by the transcriptional inhibitor actinomycin D. After approximately 3 h of exposure to forskolin, PDE4 activity had increased, via a process that could be inhibited by actinomycin D, and it remained elevated for at least a 24 h period. Such actions of forskolin were mimicked by cholera toxin and 8-bromo-cAMP. Forskolin increased intracellular cAMP concentrations in a time-dependent fashion and its action was enhanced when PDE induction was blocked with actinomycin D. Reverse transcription (RT)-PCR analysis, using generic primers designed to detect transcripts representing enzymically active products of the four PDE4 genes, identified transcripts for PDE4A and PDE4D but not for PDE4B or PDE4C in untreated Jurkat T-cells. Forskolin treatment did not induce transcripts for either PDE4B or PDE4C; however, it reduced the RT-PCR signal for PDE4A transcripts and markedly enhanced that for PDE4D transcripts. Using RT-PCR primers for PDE4 splice variants, a weak signal for PDE4D1 was evident in control cells whereas, in forskolin-treated cells, clear signals for both PDE4D1 and PDE4D2 were detected. RT-PCR analysis of the PDE4A species indicated that it was not the PDE4A isoform PDE-46 (PDE4A4B). Immunoblotting of control cells for PDE4 forms identified a single PDE4A species of approximately 118 kDa, which migrated distinctly from the PDE4A4B isoform PDE-46, with immunoprecipitation analyses showing that it provided all of the PDE4 activity in control

  12. Cleavage at a novel site in the NS4A region by the yellow fever virus NS2B-3 proteinase is a prerequisite for processing at the downstream 4A/4B signalase site.

    PubMed Central

    Lin, C; Amberg, S M; Chambers, T J; Rice, C M

    1993-01-01

    Flavivirus proteins are produced by co- and posttranslational proteolytic processing of a large polyprotein by both host- and virus-encoded proteinases. The viral serine proteinase, which consists of NS2B and NS3, is responsible for cleavage of at least four dibasic sites (2A/2B, 2B/3, 3/4A, and 4B/5) in the nonstructural region. Since the amino acid sequence preceding NS4B shares characteristics with signal peptides used for translocation of nascent polypeptides into the lumen of the endoplasmic reticulum, it has been proposed that cleavage at the 4A/4B site is mediated by a cellular signal peptidase. In this report, cell-free translation and in vivo transient expression assays were used to study processing in the NS4 region of the yellow fever virus polyprotein. With a construct which contained NS4B preceded by 17 residues constituting the putative signal peptide (sig4B), membrane-dependent cleavage at the 4A/4B site was demonstrated in vitro. Surprisingly, processing of NS4A-4B was not observed in cell-free translation studies, and in vivo expression of several yellow fever virus polyproteins revealed that the 4A/4B cleavage occurred only during coexpression of NS2B and the proteinase domain of NS3. Examination of mutant derivatives of the NS3 proteinase domain demonstrated that cleavage at the 4A/4B site correlated with expression of an active NS2B-3 proteinase. From these results, we propose a model in which the signalase cleavage generating the N terminus of NS4B requires a prior NS2B-3 proteinase-mediated cleavage at a novel site (called the 4A/2K site) which is conserved among flaviviruses and located 23 residues upstream of the signalase site. In support of this model, mutations at the 4A/4B signalase site did not eliminate processing in the NS4 region. In contrast, substitutions at the 4A/2K site, which were engineered to block NS2B-3 proteinase-mediated cleavage, eliminated signalase cleavage at the 4A/4B site. In addition, the size of the 3(502)-4A

  13. KDM4B and KDM4A promote endometrial cancer progression by regulating androgen receptor, c-myc, and p27kip1

    PubMed Central

    Kwan, Suet-Ying; Chen, Limo; Chen, Jin-Hong; Ying, Zuo-Lin; Zhou, Ye; Gu, Wei; Wang, Li-Hua; Cheng, Wei-Wei; Zeng, Jianfang; Wan, Xiao-Ping; Mok, Samuel C.; Wong, Kwong-Kwok; Bao, Wei

    2015-01-01

    Epidemiological evidence suggests that elevated androgen levels and genetic variation related to the androgen receptor (AR) increase the risk of endometrial cancer (EC). However, the role of AR in EC is poorly understood. We report that two members of the histone demethylase KDM4 family act as major regulators of AR transcriptional activityin EC. In the MFE-296 cell line, KDM4B and AR upregulate c-myc expression, while in AN3CA cells KDM4A and AR downregulate p27kip1. Additionally, KDM4B expression is positively correlated with AR expression in EC cell lines with high baseline AR expression, while KDM4A and AR expression are positively correlated in low-AR cell lines. In clinical specimens, both KDM4B and KDM4A expression are significantly higher in EC tissues than that in normal endometrium. Finally, patients with alterations in AR, KDM4B, KDM4A, and c-myc have poor overall and disease-free survival rates. Together, these findings demonstrate that KDM4B and KDM4A promote EC progression by regulating AR activity. PMID:26397136

  14. Coriolis Interactions in the nu2, nu4a, nu4b, and nu3a States of Phosphine-d1

    PubMed

    Kshirsagar; Job

    1997-10-01

    Spectra of the nu4a (HPH bend) and nu4b (HPD bend) bands of the PH2D molecule have been recorded and analyzed. The Coriolis interactions between the two states as well as the various Coriolis interactions of the nu4a and nu4b states with the nu2 state have been included in the analysis. Several new assignments of transitions which occur with enhanced intensity in the nu2 band also have been made. The parameters of the nu4a and nu4b states, improved parameters of the nu2 state, and the interaction parameters have been determined. The data on the nu3a band of PH2D have been reanalyzed by taking into account the b-axis Coriolis interaction of the nu3a state with the 2nu2 state. Copyright 1997 Academic Press. Copyright 1997Academic Press

  15. Roles of p15Ink4b and p16Ink4a in myeloid differentiation and RUNX1-ETO-associated acute myeloid leukemia

    PubMed Central

    Ko, Rose M.; Kim, Hyung-Gyoon; Wolff, Linda; Klug, Christopher A.

    2008-01-01

    Inactivation of p15Ink4b expression by promoter hypermethylation occurs in up to 80% of acute myeloid leukemia (AML) cases and is particularly common in the FAB-M2 subtype of AML, which is characterized by the presence of the RUNX1-ETO translocation in 40% of cases. To establish whether the loss of p15Ink4b contributes to AML progression in association with RUNX1-ETO, we have expressed the RUNX1-ETO fusion protein from a retroviral vector in hematopoietic progenitor cells isolated from wild-type, p15Ink4b or p16Ink4a knockout bone marrow. Analysis of lethally irradiated recipient mice reconstituted with RUNX1-ETO-expressing cells showed that neither p15Ink4b or p16Ink4a loss significantly accelerated disease progression over the time period of one year post-transplantation. Loss of p15Ink4b alone resulted in increased myeloid progenitor cell frequencies in bone marrow by 10 months post-transplant and a 19-fold increase in the frequency of Lin-c-Kit+Sca-1+ (LKS) cells that was not associated with expansion of long-term reconstituting HSC. These results strongly suggest that p15Ink4b loss must be accompanied by additional oncogenic changes for RUNX1-ETO-associated AML to develop. PMID:18037485

  16. Complement components C2, C3, and C4 (C4A and C4B) and BF polymorphisms in populations of the Indian subcontinent.

    PubMed

    Ad'hiah, A H; Papiha, S S

    1996-10-01

    Genetic polymorphisms of the complement components (five loci: C2, C3, C4A, C4B, and BF) have been investigated in the Telugu-speaking Hindu population of Hyderabad, Andhra Pradesh, India, and the Bangali-speaking Muslim population of Dacca, Bangladesh. The available data are compared to understand the genetic variation of complement components in populations of the Indian subcontinent. The C3*F and BF*F alleles show wide frequency variations in different ethnic groups of India. The range of variation in the C3*F allele is intermediate between European whites and southeast Asian populations, whereas the BF*F allele places the Indian frequencies between European whites and African blacks. This is the first population study to investigate the C2 and C4 (C4A and C4B) polymorphisms in two distinct groups of the Indian subcontinent. For the C2 polymorphism only the C2*B variant allele was observed, and its frequency was slightly higher than in European populations. In both populations the C4A and C4B loci were highly polymorphic, with a high frequency of the null alleles C4A*QO and C4B*QO, which may account for the greater susceptibility to certain autoimmune diseases in populations of South Asia.

  17. eIF4B stimulates eIF4A ATPase and unwinding activities by direct interaction through its 7-repeats region.

    PubMed

    Andreou, Alexandra Zoi; Harms, Ulf; Klostermeier, Dagmar

    2017-01-02

    Eukaryotic translation initiation starts with binding of the eIF4F complex to the 5'-m(7)G cap of the mRNA. Recruitment of the 43S pre-initiation complex (PIC), formed by the 40S ribosomal subunit and other translation initiation factors, leads to formation of the 48S PIC that then scans the 5'-untranslated region (5'-UTR) toward the start codon. The eIF4F complex consists of eIF4E, the cap binding protein, eIF4A, a DEAD-box RNA helicase that is believed to unwind secondary structures in the 5'-UTR during scanning, and eIF4G, a scaffold protein that binds to both eIF4E and eIF4A. The ATPase and helicase activities of eIF4A are jointly stimulated by eIF4G and the translation initiation factor eIF4B. Yeast eIF4B mediates recruitment of the 43S PIC to the cap-bound eIF4F complex by interacting with the 40S subunit and possibly with eIF4A. However, a direct interaction between yeast eIF4A and eIF4B has not been demonstrated yet. Here we show that eIF4B binds to eIF4A in the presence of RNA and ADPNP, independent of the presence of eIF4G. A stretch of seven moderately conserved repeats, the r1-7 region, is responsible for complex formation, for modulation of the conformational energy landscape of eIF4A by eIF4B, and for stimulating the RNA-dependent ATPase- and ATP-dependent RNA unwinding activities of eIF4A. The isolated r1-7 region only slightly stimulates eIF4A conformational changes and activities, suggesting that communication of the repeats with other regions of eIF4B is required for full stimulation of eIF4A activity, for recruitment of the PIC to the mRNA and for translation initiation.

  18. Association between C4, C4A, and C4B copy number variations and susceptibility to autoimmune diseases: a meta-analysis

    PubMed Central

    Li, Na; Zhang, Jun; Liao, Dan; Yang, Lu; Wang, Yingxiong; Hou, Shengping

    2017-01-01

    Although several studies have investigated the association between C4, C4A, and C4B gene copy number variations (CNVs) and susceptibility to autoimmune diseases, the results remain inconsistency for those diseases. Thus, in this study, a comprehensive meta-analysis was conducted to assess the role of C4, C4A, and C4B CNVs in autoimmune diseases in different ethnic groups. A total of 16 case-control studies described in 12 articles (8663 cases and 11099 controls) were included in this study. The pooled analyses showed that a low C4 gene copy number (GCN) (<4) was treated as a significant risk factor (odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.19–1.78) for autoimmune diseases compared with a higher GCN (>4). The pooled statistical results revealed that low C4 (<4) and low C4A (<2) GCNs could be risk factors for systemic lupus erythematosus (SLE) in Caucasian populations. Additionally, the correlation between C4B CNVs and all type of autoimmune diseases could not be confirmed by the current meta-analysis (OR = 1.07, 95% CI = 0.93–1.24). These data suggest that deficiency or absence of C4 and C4A CNVs may cause susceptibility to SLE. PMID:28205620

  19. The Function of HMG-Box Transcription Factors Sox4a and Sox4b in Zebrafish Bone Development and Homeostasis

    NASA Astrophysics Data System (ADS)

    Aceto, J.; Motte, P.; Martial, J. A.; Muller, M.

    2008-06-01

    In mammals, the Sox4 gene is involved in development of endocardial crests, the brain, the lung, teeth, gonads and lymphocytes. Recently, Sox4 was shown to control bone mass and mineralization in mice. In zebrafish, two homologs for the mammalian Sox4 are present, sox4a and sox4b. Here we investigate the function of the sox4a and sox4b genes in cartilage and bone development in zebrafish. Therefore, we focus our attention on the first bone structures to be formed, the head skeleton and more precisely the pharyngeal cartilage. We show that both genes are expressed in the pharyngeal region, albeit at different time points during development. Double in situ hybridization experiments are used to exactly define the particular tissues where they are expressed. Furthermore, microinjection experiments of antisense oligonucleotides are used to block translation of these specific genes and to define their precise function during cartilage and bone development.

  20. The plasma membrane Ca2+ pump isoform 4a differs from isoform 4b in the mechanism of calmodulin binding and activation kinetics: implications for Ca2+ signaling.

    PubMed

    Caride, Ariel J; Filoteo, Adelaida G; Penniston, John T; Strehler, Emanuel E

    2007-08-31

    The inhibition by the regulatory domain and the interaction with calmodulin (CaM) vary among plasma membrane calcium pump (PMCA) isoforms. To explore these differences, the kinetics of CaM effects on PMCA4a were investigated and compared with those of PMCA4b. The maximal apparent rate constant for CaM activation of PMCA4a was almost twice that for PMCA4b, whereas the rates of activation for both isoforms showed similar dependence on Ca2+. The inactivation of PMCA4a by CaM removal was also faster than for PMCA4b, and Ca2+ showed a much smaller effect (2- versus 30-fold modification). The rate constants of the individual steps that determine the overall rates were obtained from stopped-flow experiments in which binding of TA-CaM was observed by changes in its fluorescence. TA-CaM binds to two conformations of PMCA4a, an "open" conformation with high activity, and a "closed" one with lower activity. Compared with PMCA4b (Penheiter, A. R., Bajzer, Z., Filoteo, A. G., Thorogate, R., Török, K., and Caride, A. J. (2003) Biochemistry 41, 12115-12124), the model for PMCA4a predicts less inhibition in the closed form and a much faster equilibrium between the open and closed forms. Based on the available kinetic parameters, we determined the constants to fit the shape of a Ca2+ signal in PMCA4b-overexpressing Chinese hamster ovary cells. Using the constants for PMCA4a, and allowing small variations in parameters of other systems contributing to a Ca2+ signal, we then simulated the effect of PMCA4a on the shape of a Ca2+ signal in Chinese hamster ovary cells. The results reproduce the published data (Brini, M., Coletto, L., Pierobon, N., Kraev, N., Guerini, D., and Carafoli, E. (2003) J. Biol. Chem. 278, 24500-24508), and thereby demonstrate the importance of altered regulatory kinetics for the different functional properties of PMCA isoforms.

  1. The NS4A Cofactor Dependent Enhancement of HCV NS3 Protease Activity Correlates with a 4D Geometrical Measure of the Catalytic Triad Region

    PubMed Central

    Hamad, Hamzah A.; Thurston, Jeremy; Teague, Thomas; Ackad, Edward; Yousef, Mohammad S.

    2016-01-01

    We are developing a 4D computational methodology, based on 3D structure modeling and molecular dynamics simulation, to analyze the active site of HCV NS3 proteases, in relation to their catalytic activity. In our previous work, the 4D analyses of the interactions between the catalytic triad residues (His57, Asp81, and Ser139) yielded divergent, gradual and genotype-dependent, 4D conformational instability measures, which strongly correlate with the known disparate catalytic activities among genotypes. Here, the correlation of our 4D geometrical measure is extended to intra-genotypic alterations in NS3 protease activity, due to sequence variations in the NS4A activating cofactor. The correlation between the 4D measure and the enzymatic activity is qualitatively evident, which further validates our methodology, leading to the development of an accurate quantitative metric to predict protease activity in silico. The results suggest plausible “communication” pathways for conformational propagation from the activation subunit (the NS4A cofactor binding site) to the catalytic subunit (the catalytic triad). The results also strongly suggest that the well-sampled (via convergence quantification) structural dynamics are more connected to the divergent catalytic activity observed in HCV NS3 proteases than to rigid structures. The method could also be applicable to predict patients’ responses to interferon therapy and better understand the innate interferon activation pathway. PMID:27936126

  2. Methylation of CpG island of p14(ARK), p15(INK4b) and p16(INK4a) genes in coke oven workers.

    PubMed

    Zhang, H; Li, X; Ge, L; Yang, J; Sun, J; Niu, Q

    2015-02-01

    To detect the blood genomic DNA methylation in coke oven workers and find a possible early screening index for occupational lung cancer, 74 coke oven workers as the exposed group and 47 water pump workers as the controls were surveyed, and urine samples and peripheral blood mononuclear cells (PBMCs) were collected. Airborne benzo[a]pyrene (B[a]P) levels in workplace and urinary 1-hydroxypyrene (1-OH-Py) levels were determined by high-performance liquid chromatography. DNA damage of PBMCs and the p14(ARK), p15(INK4b) and p16(INK4a) gene CpG island methylation in the promoter region were detected by comet assay and methylation-specific polymerase chain reaction techniques, respectively. Results show that compared with the controls, concentration of airborne B[a]Ps was elevated in the coke plant, and urinary 1-OH-Py's level and DNA olive tail moment in comet assay were significantly increased in the coke oven workers, and p14(ARK), p15(INK4b) and p16(INK4a) gene methylation rates were also significantly increased. With the working years and urinary 1-OH-Py's level, the rates of p14(ARK) and p16(INK4a) gene methylation were significantly increased while that of p15(INK4b) gene methylation displayed no statistical change. We conclude that PBMCs' p14(ARK) and p16(INK4a) gene methylation may be used for screening and warning lung cancer in coke oven workers.

  3. NOGO-A/RTN4A and NOGO-B/RTN4B are simultaneously expressed in epithelial, fibroblast and neuronal cells and maintain ER morphology

    PubMed Central

    Rämö, Olli; Kumar, Darshan; Gucciardo, Erika; Joensuu, Merja; Saarekas, Maiju; Vihinen, Helena; Belevich, Ilya; Smolander, Olli-Pekka; Qian, Kui; Auvinen, Petri; Jokitalo, Eija

    2016-01-01

    Reticulons (RTNs) are a large family of membrane associated proteins with various functions. NOGO-A/RTN4A has a well-known function in limiting neurite outgrowth and restricting the plasticity of the mammalian central nervous system. On the other hand, Reticulon 4 proteins were shown to be involved in forming and maintaining endoplasmic reticulum (ER) tubules. Using comparative transcriptome analysis and qPCR, we show here that NOGO-B/RTN4B and NOGO-A/RTN4A are simultaneously expressed in cultured epithelial, fibroblast and neuronal cells. Electron tomography combined with immunolabelling reveal that both isoforms localize preferably to curved membranes on ER tubules and sheet edges. Morphological analysis of cells with manipulated levels of NOGO-B/RTN4B revealed that it is required for maintenance of normal ER shape; over-expression changes the sheet/tubule balance strongly towards tubules and causes the deformation of the cell shape while depletion of the protein induces formation of large peripheral ER sheets. PMID:27786289

  4. NOGO-A/RTN4A and NOGO-B/RTN4B are simultaneously expressed in epithelial, fibroblast and neuronal cells and maintain ER morphology.

    PubMed

    Rämö, Olli; Kumar, Darshan; Gucciardo, Erika; Joensuu, Merja; Saarekas, Maiju; Vihinen, Helena; Belevich, Ilya; Smolander, Olli-Pekka; Qian, Kui; Auvinen, Petri; Jokitalo, Eija

    2016-10-27

    Reticulons (RTNs) are a large family of membrane associated proteins with various functions. NOGO-A/RTN4A has a well-known function in limiting neurite outgrowth and restricting the plasticity of the mammalian central nervous system. On the other hand, Reticulon 4 proteins were shown to be involved in forming and maintaining endoplasmic reticulum (ER) tubules. Using comparative transcriptome analysis and qPCR, we show here that NOGO-B/RTN4B and NOGO-A/RTN4A are simultaneously expressed in cultured epithelial, fibroblast and neuronal cells. Electron tomography combined with immunolabelling reveal that both isoforms localize preferably to curved membranes on ER tubules and sheet edges. Morphological analysis of cells with manipulated levels of NOGO-B/RTN4B revealed that it is required for maintenance of normal ER shape; over-expression changes the sheet/tubule balance strongly towards tubules and causes the deformation of the cell shape while depletion of the protein induces formation of large peripheral ER sheets.

  5. Purification and characterization of two novel antimicrobial peptides Subpeptin JM4-A and Subpeptin JM4-B produced by Bacillus subtilis JM4.

    PubMed

    Wu, Shimei; Jia, Shifang; Sun, Dandan; Chen, Meiling; Chen, Xiuzhu; Zhong, Jin; Huan, Liandong

    2005-11-01

    An antimicrobial peptides-producing strain was isolated from soil and identified as Bacillus subtilis JM4 according to biochemical tests and 16S rDNA sequence analysis. The corresponding antimicrobial peptides were purified to homogeneity by ammonium sulfate precipitation, sequential SP-Sepharose Fast Flow, Sephadex G-25 and C18 reverse-phase chromatography, and in the final purification step, two active fractions were harvested, designated as Subpeptin JM4-A and Subpeptin JM4-B. The molecular weights, determined by mass spectrometry, were 1422.71 Da for Subpeptin JM4-A and 1422.65 Da for Subpeptin JM4-B, respectively. Amino acid sequencing showed that they differed from each other only at the seventh amino acid except for three unidentified residues, and the two peptides had no significant sequence homology to the known peptides in the database, indicating that they are two novel antimicrobial peptides. In addition, characteristic measurements indicated that both peptides had a relatively broad inhibitory spectrum and remained active over a wide pH and temperature range.

  6. Mutational analysis of genes p14ARF, p15INK4b, p16INK4a, and PTEN in human nervous system tumors.

    PubMed

    Almeida, L O; Custódio, A C; Araújo, J J; Rey, J A; Almeida, J R W; Santos, M J; Clara, C A; Casartelli, C

    2008-05-27

    Cancer is one of the most common and severe problems in clinical medicine, and nervous system tumors represent about 2% of the types of cancer. The central role of the nervous system in the maintenance of vital activities and the functional consequences of the loss of neurons can explain how severe brain cancers are. The cell cycle is a highly complex process, with a wide number of regulatory proteins involved, and such proteins can suffer alterations that transform normal cells into malignant ones. The INK4 family members (CDK inhibitors) are the cell cycle regulators that block the progression of the cycle through the R point, causing an arrest in G1 stage. The p14ARF (alternative reading frame) gene is a tumor suppressor that inhibits p53 degradation during the progression of the cell cycle. The PTEN gene is related to the induction of growth suppression through cell cycle arrest, to apoptosis and to the inhibition of cell adhesion and migration. The purpose of the present study was to assess the mutational state of the genes p14ARF, p15INK4b, p16INK4a, and PTEN in 64 human nervous system tumor samples. Homozygous deletions were found in exon 2 of the p15INK4b gene and exon 3 of the p16INK4a gene in two schwannomas. Three samples showed a guanine deletion (63 codon) which led to a loss of heterozygosity in the p15 gene, and no alterations could be seen in the PTEN gene. Although the group of patients was heterogeneous, our results are in accordance with other different studies that indicate that homozygous deletion and loss of heterozygosity in the INK4 family members are frequently observed in nervous system tumors.

  7. AtCCR4a and AtCCR4b are Involved in Determining the Poly(A) Length of Granule-bound starch synthase 1 Transcript and Modulating Sucrose and Starch Metabolism in Arabidopsis thaliana.

    PubMed

    Suzuki, Yuya; Arae, Toshihiro; Green, Pamela J; Yamaguchi, Junji; Chiba, Yukako

    2015-05-01

    Removing the poly(A) tail is the first and rate-limiting step of mRNA degradation and apparently an effective step not only for modulating mRNA stability but also for translation of many eukaryotic transcripts. Carbon catabolite repressor 4 (CCR4) has been identified as a major cytoplasmic deadenylase in Saccharomyces cerevisiae. The Arabidopsis thaliana homologs of the yeast CCR4, AtCCR4a and AtCCR4b, were identified by sequence-based analysis; however, their role and physiological significance in plants remain to be elucidated. In this study, we revealed that AtCCR4a and AtCCR4b are localized to cytoplasmic mRNA processing bodies, which are specific granules consisting of many enzymes involved in mRNA turnover. Double mutants of AtCCR4a and AtCCR4b exhibited tolerance to sucrose application but not to glucose. The levels of sucrose in the seedlings of the atccr4a/4b double mutants were reduced, whereas no difference was observed in glucose levels. Further, amylose levels were slightly but significantly increased in the atccr4a/4b double mutants. Consistent with this observation, we found that the transcript encoding granule-bound starch synthase 1 (GBSS1), which is responsible for amylose synthesis, is accumulated to a higher level in the atccr4a/4b double mutant plants than in the control plants. Moreover, we revealed that GBSS1 has a longer poly(A) tail in the double mutant than in the control plant, suggesting that AtCCR4a and AtCCR4b can influence the poly(A) length of transcripts related to starch metabolism. Our results collectively suggested that AtCCR4a and AtCCR4b are involved in sucrose and starch metabolism in A. thaliana.

  8. A single-amino acid substitution in West Nile virus 2K peptide between NS4A and NS4B confers resistance to lycorine, a flavivirus inhibitor

    PubMed Central

    Zou, Gang; Puig-Basagoiti, Francesc; Zhang, Bo; Qing, Min; Chen, Liqiang; Pankiewicz, Krzysztof W.; Felczak, Krzysztof; Yuan, Zhiming; Shi, Pei-Yong

    2017-01-01

    Lycorine potently inhibits flaviviruses in cell culture. At 1.2-μM concentration, lycorine reduced viral titers of West Nile (WNV), dengue, and yellow fever viruses by 102- to 104-fold. However, the compound did not inhibit an alphavirus (Western equine encephalitis virus) or a rhabdovirus (vesicular stomatitis virus), indicating a selective antiviral spectrum. The compound exerts its antiviral activity mainly through suppression of viral RNA replication. A Val→Met substitution at the 9th amino acid position of the viral 2K peptide (spanning the endoplasmic reticulum membrane between NS4A and NS4B proteins) confers WNV resistance to lycorine, through enhancement of viral RNA replication. Initial chemistry synthesis demonstrated that modifications of the two hydroxyl groups of lycorine can increase the compound’s potency, while reducing its cytotoxicity. Taken together, the results have established lycorine as a flavivirus inhibitor for antiviral development. The lycorine-resistance results demonstrate a direct role of the 2K peptide in flavivirus RNA synthesis. PMID:19062063

  9. Accidental Conical Intersections in Mixed Trimers of Potassium and Rubidium: a Vibronic Analysis of the 4^4B_2 and 3^4A_1 States

    NASA Astrophysics Data System (ADS)

    Hauser, A. W.; Auböck, G.; Callegari, C.; Ernst, W. E.

    2010-06-01

    We compare the 3^4A_1 and 4^4B_2 states of homonuclear and heteronuclear alkali trimers formed of potassium and rubidium. The Multireference Rayleigh Schrödinger Perturbation Theory of second order is applied to obtain the corresponding adiabatic potential energy surfaces. In the case of homonuclear trimers these pairs of states correspond to the two branches of the E×{}e Jahn-Teller distorted 2^4E^' state. For heteronuclear trimers, the vibrational modes Q_x and Q_y are no longer degenerate, but the two electronic states still show a conical intersection at obtuse (KRb_2) or acute (K_2Rb) isosceles geometries. Spectroscopic consequences of this situation are discussed, vibronic spectra are predicted and compared to LIF spectra obtained in helium droplet isolation spectroscopy experiments of our group. J. Nagl, G. Auböck, A.W. Hauser, O. Allard, C. Callegari and W.E. Ernst, Phys. Rev. Lett. 100, 063001 (2008) J. Nagl, G. Auböck, A.W. Hauser, O. Allard, C. Callegari and W.E. Ernst, J. Chem. Phys. 128, 154320 (2008)

  10. APEX-CHAMP+ high-J CO observations of low-mass young stellar objects. III. NGC 1333 IRAS 4A/4B envelope, outflow, and ultraviolet heating

    NASA Astrophysics Data System (ADS)

    Yıldız, Umut A.; Kristensen, Lars E.; van Dishoeck, Ewine F.; Belloche, Arnaud; van Kempen, Tim A.; Hogerheijde, Michiel R.; Güsten, Rolf; van der Marel, Nienke

    2012-06-01

    Context. The NGC 1333 IRAS 4A and IRAS 4B sources are among the most well-studied Stage 0 low-mass protostars, which drive prominent bipolar outflows. Spectrally resolved molecular emission lines provide crucial information about the physical and chemical structure of the circumstellar material as well as the dynamics of the different components. Most studies have so far concentrated on the colder parts (T ≤ 30 K) of these regions. Aims: The aim is to characterize the warmer parts of the protostellar envelope using the new generation of submillimeter instruments. This will allow us to quantify the feedback of the protostars on their surroundings in terms of shocks, ultraviolet (UV) heating, photodissociation, and outflow dispersal. Methods: The dual frequency 2 × 7 pixel 650/850 GHz array receiver CHAMP+ mounted on APEX was used to obtain a fully sampled, large-scale ~4' × 4' map at 9″ resolution of the IRAS 4A/4B region in the 12CO J = 6-5 line. Smaller maps were observed in the 13CO 6-5 and [C i] J = 2-1 lines. In addition, a fully sampled 12CO J = 3-2 map made with HARP-B on the JCMT is presented and deep isotopolog observations are obtained at selected outflow positions to constrain the optical depth. Complementary Herschel-HIFI and ground-based lines of CO and its isotopologs, from J = 1-0 up to 10-9 (Eu/k ≈ 300 K), are collected at the source positions and used to construct velocity-resolved CO ladders and rotational diagrams. Radiative-transfer models of the dust and lines are used to determine the temperatures and masses of the outflowing and photon-heated gas and infer the CO abundance structure. Results: Broad CO emission-line profiles trace entrained shocked gas along the outflow walls, which have an average temperature of ~100 K. At other positions surrounding the outflow and the protostar, the 6-5 line profiles are narrow indicating UV excitation. The narrow 13CO 6-5 data directly reveal the UV heated gas distribution for the first time. The

  11. Gene Copy-Number Variations (CNVs) and Protein Levels of Complement C4A and C4B as Novel Biomarkers for Partial Disease Remissions in New-Onset Type 1 Diabetes Patients

    PubMed Central

    Kingery, Suzanne E.; Wu, Yee Ling; Zhou, Bi; Hoffman, Robert P.; Yu, C. Yung

    2014-01-01

    Objective To determine the roles of complement C4A and C4B gene CNVs and their plasma protein concentrations in residual insulin secretion and loss of pancreatic beta-cell function in new-onset type 1 diabetes patients. Methods We studied 34 patients of European ancestry with new-onset type 1 diabetes, aged between 3 and 17 years (10.7±3.45), at Nationwide Children's Hospital in Columbus, Ohio. Gene copy-number and size variations of complement C4A and C4B were determined by genomic Southern blot analyses. C4A and C4B protein phenotypes were elucidated by immunofixation and radial immunodiffusion. Two-digit HLA-DRB1 genotypes were determined by sequence-specific PCR. At 1 month and 9-month post diagnosis, stimulated C-peptide levels were measured after a standardized mixed-meal tolerance test. Results The diploid gene copy-numbers of C4A varied from 0 to 4, and those of C4B from 0 to 3. Patients with higher copy-number of C4A or higher C4A plasma protein concentrations at diagnosis had higher C-peptide levels at 1 month post diagnosis (p=0.008; p=0.008). When controlled by the Z-score of body-mass index, C4A copy-numbers, C4A protein concentrations, the age of disease-onset, the number of HLA-DR3 but not DR4 alleles were significant parameters in determining C-peptide levels. At 9-month post diagnosis, 42.3% of patients remained in partial remission, and these patients were characterized by lower total C4B copy-numbers or lower C4B protein concentrations (p=0.02, p=0.0004). Conclusions C4A appears to associate with the protection of residual beta-cell function in new-onset type 1 diabetes; C4B is correlated with the end of disease remission at 9-month post diagnosis. PMID:22151770

  12. Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B.

    PubMed

    Özeş, Ali R; Feoktistova, Kateryna; Avanzino, Brian C; Fraser, Christopher S

    2011-09-30

    Eukaryotic initiation factor (eIF) 4A is a DEAD-box helicase that stimulates translation initiation by unwinding mRNA secondary structure. The accessory proteins eIF4G, eIF4B, and eIF4H enhance the duplex unwinding activity of eIF4A, but the extent to which they modulate eIF4A activity is poorly understood. Here, we use real-time fluorescence assays to determine the kinetic parameters of duplex unwinding and ATP hydrolysis by these initiation factors. To ensure efficient duplex unwinding, eIF4B and eIF4G cooperatively activate the duplex unwinding activity of eIF4A. Our data reveal that eIF4H is much less efficient at stimulating eIF4A unwinding activity than eIF4B, implying that eIF4H is not able to completely substitute for eIF4B in duplex unwinding. By monitoring unwinding and ATPase assays under identical conditions, we demonstrate that eIF4B couples the ATP hydrolysis cycle of eIF4A with strand separation, thereby minimizing nonproductive unwinding events. Using duplex substrates with altered GC contents but similar predicted thermal stabilities, we further show that the rate of formation of productive unwinding complexes is strongly influenced by the local stability per base pair, in addition to the stability of the entire duplex. This finding explains how a change in the GC content of a hairpin is able to influence translation initiation while maintaining the overall predicted thermal stability.

  13. Luminescent Immunoprecipitation System (LIPS) for Detection of Autoantibodies Against ATP4A and ATP4B Subunits of Gastric Proton Pump H+,K+-ATPase in Atrophic Body Gastritis Patients

    PubMed Central

    Lahner, Edith; Brigatti, Cristina; Marzinotto, Ilaria; Carabotti, Marilia; Scalese, Giulia; Davidson, Howard W; Wenzlau, Janet M; Bosi, Emanuele; Piemonti, Lorenzo; Annibale, Bruno; Lampasona, Vito

    2017-01-01

    Objectives: Circulating autoantibodies targeting the H+/K+-ATPase proton pump of gastric parietal cells are considered markers of autoimmune gastritis, whose diagnostic accuracy in atrophic body gastritis, the pathological lesion of autoimmune gastritis, remains unknown. This study aimed to assess autoantibodies against ATP4A and ATP4B subunits of parietal cells H+, K+-ATPase in atrophic body gastritis patients and controls. Methods: One-hundred and four cases with atrophic body gastritis and 205 controls were assessed for serological autoantibodies specific for ATP4A or ATP4B subunits using luminescent immunoprecipitation system (LIPS). Recombinant luciferase-reporter-fused-antigens were expressed by in vitro transcription-translation (ATP4A) or after transfection in Expi293F cells (ATP4B), incubated with test sera, and immune complexes recovered using protein-A-sepharose. LIPS assays were compared with a commercial enzyme immunoassay (EIA) for parietal cell autoantibodies. Results: ATP4A and ATP4B autoantibody titers were higher in cases compared to controls (P<0.0001). The area under the receiver-operating characteristic curve was 0.98 (95% CI 0.965–0.996) for ATP4A, and 0.99 (95% CI 0.979–1.000) for ATP4B, both higher as compared with that of EIA: 0.86 (95% CI 0.809–0.896), P<0.0001. Sensitivity-specificity were 100–89% for ATP4A and 100–90% for ATP4B assay. Compared with LIPS, EIA for parietal cell autoantibodies showed a lower sensitivity (72%, P<0.0001) at a similar specificity (92%, P=0.558). Conclusions: Positivity to both, ATP4A and ATP4B autoantibodies is closely associated with atrophic body gastritis. Both assays had the highest sensitivity, at the cost of diagnostic accuracy (89 and 90% specificity), outperforming traditional EIA. Once validated, these LIPS assays should be valuable screening tools for detecting biomarkers of damaged atrophic oxyntic mucosa. PMID:28102858

  14. An allele-specific PCR system for rapid detection and discrimination of the CYP2C19∗4A, ∗4B, and ∗17 alleles: implications for clopidogrel response testing.

    PubMed

    Scott, Stuart A; Tan, Qian; Baber, Usman; Yang, Yao; Martis, Suparna; Bander, Jeffrey; Kornreich, Ruth; Hulot, Jean-Sébastien; Desnick, Robert J

    2013-11-01

    CYP2C19 is involved in the metabolism of clinically relevant drugs, including the antiplatelet prodrug clopidogrel, which has prompted interest in clinical CYP2C19 genotyping. The CYP2C19∗4B allele is defined by both gain-of-function [c.-806C>T (∗17)] and loss-of-function [c.1A>G (∗4)] variants on the same haplotype; however, current genotyping and sequencing assays are unable to determine the phase of these variants. Thus, the aim of this study was to develop an assay that could rapidly detect and discriminate the related ∗4A, ∗4B, and ∗17 alleles. An allele-specific PCR assay, composed of four unique primer mixes that specifically interrogate the defining ∗17 and ∗4 variants, was developed by using samples (n = 20) with known genotypes, including the ∗4A, ∗4B, and/or ∗17 alleles. The assay was validated by testing 135 blinded samples, and the results were correlated with CYP2C19 genotyping and allele-specific cloning/sequencing. Importantly, among the six ∗4 carriers in the validation cohort, after allele-specific PCR testing both samples with a ∗1/∗4 genotype were reclassified to ∗1/∗4A, all three samples with a ∗4/∗17 genotype were reclassified to ∗1/∗4B, and a sample with a ∗4/∗17/∗17 genotype was reclassified to ∗4B/∗17. In conclusion, this rapid and robust allele-specific PCR assay can refine CYP2C19 genotyping and metabolizer phenotype classification by determining the phase of the defining ∗17 and ∗4 variants, which may have utility when testing CYP2C19 for clopidogrel response.

  15. International Conference on Harmonisation; guidance on Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 4A on Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests General Chapter; availability. Notice.

    PubMed

    2009-04-08

    The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions; Annex 4A: Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests General Chapter." The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The guidance provides the results of the ICH Q4B evaluation of the Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests General Chapter harmonized text from each of the three pharmacopoeias (United States, European, and Japanese) represented by the Pharmacopoeial Discussion Group (PDG). The guidance conveys recognition of the three pharmacopoeial methods by the three ICH regulatory regions and provides specific information regarding the recognition. The guidance is intended to recognize the interchangeability between the local regional pharmacopoeias, thus avoiding redundant testing in favor of a common testing strategy in each regulatory region. In the Federal Register of February 21, 2008 (73 FR 9575), FDA made available a guidance on the Q4B process entitled "Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions."

  16. Anxiogenic-Like Behavioral Phenotype of Mice Deficient in Phosphodiesterase 4B (PDE4B)

    PubMed Central

    Zhang, Han-Ting; Huang, Ying; Masood, Anbrin; Stolinski, Lisa R; Li, Yunfeng; Zhang, Lei; Dlaboga, Daniel; Jin, S-L Catherine; Conti, Marco; O’Donnell, James M

    2009-01-01

    Phosphodiesterase-4 (PDE4), an enzyme that catalyzes the hydrolysis of cyclic AMP and plays a critical role in controlling its intracellular concentration, has been implicated in depression- and anxiety-like behaviors. However, the functions of the four PDE4 subfamilies (PDE4A, PDE4B, PDE4C, and PDE4D) remain largely unknown. In animal tests sensitive to anxiolytics, antidepressants, memory enhancers, or analgesics, we examined the behavioral phenotype of mice deficient in PDE4B (PDE4B−/−). Immunoblot analysis revealed loss of PDE4B expression in the cerebral cortex and amygdala of PDE4B−/− mice. The reduction of PDE4B expression was accompanied by decreases in PDE4 activity in the brain regions of PDE4B−/− mice. Compared to PDE4B + / + littermates, PDE4B−/− mice displayed anxiogenic-like behavior, as evidenced by decreased head-dips and time spent in head-dipping in the holeboard test, reduced transitions and time on the light side in the light–dark transition test, and decreased initial exploration and rears in the open-field test. Consistent with anxiogenic-like behavior, PDE4B−/− mice displayed increased levels of plasma corticosterone. In addition, these mice also showed a modest increase in the proliferation of neuronal cells in the hippocampal dentate gyrus. In the forced-swim test, PDE4B−/− mice exhibited decreased immobility; however, this was not supported by the results from the tail-suspension test. PDE4B−/− mice did not display changes in memory, locomotor activity, or nociceptive responses. Taken together, these results suggest that the PDE4B subfamily is involved in signaling pathways that contribute to anxiogenic-like effects on behavior PMID:17700644

  17. Structural Basis for the Design of Selective Phosphodiesterase 4B Inhibitors

    PubMed Central

    Fox, David; Burgin, Alex B.; Gurney, Mark E.

    2014-01-01

    Phosphodiesterase-4B (PDE4B) regulates the pro-inflammatory Toll Receptor –Tumor Necrosis Factor α (TNFα) pathway in monocytes, macrophages and microglial cells. As such, it is an important, although under-exploited molecular target for anti-inflammatory drugs. This is due in part to the difficulty of developing selective PDE4B inhibitors as the amino acid sequence of the PDE4 active site is identical in all PDE4 subtypes (PDE4A-D). We show that highly selective PDE4B inhibitors can be designed by exploiting sequence differences outside the active site. Specifically, PDE4B selectivity can be achieved by capture of a C-terminal regulatory helix, now termed CR3 (Control Region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D). The reciprocal mutations in PDE4B and PDE4D cause a 70-80 fold shift in selectivity. Our structural studies show that CR3 is flexible and can adopt multiple orientations and multiple registries in the closed conformation. The new co-crystal structure with bound ligand provides a guide map for the design of PDE4B selective anti-inflammatory drugs. PMID:24361374

  18. Endothelial nitric oxide synthase (eNOS) T-786C, 4a4b, and G894T polymorphisms and male infertility: study for idiopathic asthenozoospermia and meta-analysis.

    PubMed

    Song, Pingping; Zou, Shasha; Chen, Tingting; Chen, Jianhua; Wang, Yanan; Yang, Juanjuan; Song, Zhijian; Jiang, Huayu; Shi, Huijuan; Huang, Yiran; Li, Zheng; Shi, Yongyong; Hu, Hongliang

    2015-02-01

    Recent studies on the eNOS gene and male infertility show that expression of eNOS regulates normal spermatogenesis in the testis, and the eNOS gene variants (T-786C, 4a4b, and G894T) are potentially involved in impairment of spermatogenesis and sperm function. Thus, we conducted this association and meta-analysis study to further validate whether variants of those three loci affected the risk of idiopathic asthenozoospermia (AZS) and male infertility. Approximately 340 Chinese idiopathic AZS patients and 342 healthy men were included for this case-control study, genotyped by gel electrophoresis analysis or direct sequencing of PCR products. The eNOS mRNA isolated from the semen of patients was further examined by quantitative real-time PCR. Also, a meta-analysis of association between eNOS gene polymorphisms and male infertility was performed. A significant association was identified on allelic level between 4a4b variant and AZS in our study (chi-squared = 7.53, corrected P = 0.018, odds ratio (OR) = 1.808), while there were no significant difference of T-786C and G894T for asthenozoospermia in both genotype and allele distributions. In addition, expression of eNOS was up-regulated in patients compared with controls (about 2.4-fold, P < 0.001). Furthermore, the results of the meta-analysis support the conclusion that the T-786C and 4a4b loci were associated with male infertility in both Asian and Caucasian populations. Our study provides genetic evidence for the eNOS gene being a risk factor for idiopathic AZS and male infertility. Considering genetic differences among populations and complex pathogenesis of male infertility, more validating studies using independent samples are suggested in the future.

  19. Conspirators in a capital crime: co-deletion of p18INK4c and p16INK4a/p14ARF/p15INK4b in glioblastoma multiforme.

    PubMed

    Solomon, David A; Kim, Jung-Sik; Jean, Walter; Waldman, Todd

    2008-11-01

    Glioblastoma multiforme (GBM) is one of the most dreaded cancer diagnoses due to its poor prognosis and the limited treatment options. Homozygous deletion of the p16(INK4a)/p14(ARF)/p15(INK4b) locus is among the most common genetic alterations in GBM. Two recent studies have shown that deletion and mutation of another INK4 family member, p18(INK4c), also drives the pathogenesis of GBM. This minireview will discuss the known roles for p18(INK4c) in the initiation and progression of cancer and suggest opportunities for future studies.

  20. Results of hydrologic tests and water-chemistry analyses, wells H-4A, H-4B, and H-4C, at the proposed waste isolation pilot plant site, southeastern New Mexico

    USGS Publications Warehouse

    Mercer, Jerry W.; Davis, Paul; Dennehy, K.F.; Goetz, C.L.

    1981-01-01

    Data were collected during hydrologic testing at wells H-4A, H-4B, and H-4C in the southern part of the proposed Waste Isolation Pilot Plant site in southeastern New Mexico. The three water-bearing zones tested, the Magenta and Culebra Dolomite Members of the Rustler Formation and the Rustler Formation-Salado Formation contact, yield water to wells at rates less than 0.9 gallon per minute. Throughout the testing, water-pressure response in the tested zone was monitored by a pressure transducer system. Shut-in and slug tests were conducted to acquire the data from which the following values were derived. Calculated transmissivities for the Magenta, Culebra and the Rustler-Salado contact at wells H-4A, H-4B, and H-4C were 0.06, 0.9, and 0.0006 foot squared per day respectively. Water samples from the Magenta and Culebra had dissolved-solids concentrations of 22,300 and 18,100 milligrams per liter, respectively. The major chemical constituents of ground-water samples from these two zones were sodium, chloride, and sulfate. Water samples from the Rustler-Salado contact had a dissolved-solids concentration of 322,000 milligrams per liter and magnesium, sodium, and chloride were the major constituents. Radium-226, a naturally occurring radioactive element, was present in samples from all three zones. (USGS)

  1. Species-specific but not genotype-specific primary and secondary isotype-specific NSP4 antibody responses in gnotobiotic calves and piglets infected with homologous host bovine (NSP4[A]) or porcine (NSP4[B]) rotavirus.

    PubMed

    Yuan, Lijuan; Honma, Shinjiro; Ishida, Shin-Ichi; Yan, Xiao-Yi; Kapikian, Albert Z; Hoshino, Yasutaka

    2004-12-05

    Using recombinant baculoviruses expressing rotavirus NSP4 [A], [B], [C], and [D] genotypes of bovine, porcine, human, simian, or murine origin, we analyzed serum antibody responses to NSP4s in gnotobiotic calves and piglets infected by the oral/alimentary or intraamniotic route with bovine (NSP4[A]) (Wyatt, R.G., Mebus, C.A., Yolken, R.H., Kalica, A.R., James, H.D., Jr., Kapikian, A.Z., Chanock, R.M., 1979. Rotaviral immunity in gnotobiotic calves: heterologous resistance to human virus induced by bovine virus. Science 203(4380), 548-550) or porcine (NSP4[B]) (Hoshino, Y., Saif, L.J., Sereno, M.M., Chanock, R.M., Kapikian, A.Z., 1988. Infection immunity of piglets to either VP3 or VP7 outer capsid protein confers resistance to challenge with a virulent rotavirus bearing the corresponding antigen. J. Virol. 62(3), 744-748) rotaviruses. Following primary infection and challenge with virulent rotaviruses, the animals developed higher or significantly higher antibody titers to homologous host homotypic NSP4s than to heterologous host homotypic or heterologous host heterotypic NSP4s, indicating that antibody responses were species specific rather than genotype specific. Antibody responses to NSP4s corresponded closely with the phylogenetic relationships of NSP4s within a species-specific region of amino acids (aa) 131-141. In contrast, NSP4 genotypes determined by amino acid full-length sequence identity predicted poorly their "serotypes". In piglets, antibodies to NSP4 induced by previous oral infection failed to confer protection against challenge from a porcine rotavirus bearing serotypically different VP4 and VP7 but essentially identical NSP4 to the porcine rotavirus in primary infection. Thus, in an approach to immunization with a live oral rotavirus vaccine, the NSP4 protein does not appear to play an important role in protection against rotavirus disease and infection.

  2. Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A).

    PubMed

    Amanullah, A; Hoffman, B; Liebermann, D A

    2000-07-15

    The transcription factor E2F-1 has been postulated to play a crucial role in the control of cell cycle progression because of its ability to be bound and regulated by the retinoblastoma gene product (pRb). Exogenous expression of E2F-1, under growth restrictive conditions, was shown to result in p53-dependent programmed cell death. The consequences of deregulated expression of E2F-1 on terminal differentiation of hematopoietic cells in the absence of E2F-1-mediated apoptosis, as well as mechanistic insights into how deregulated E2F-1 may affect terminal differentiation, have not been established. The autonomously proliferating M1 myeloblastic leukemia cell line, which is null for p53 expression and can be induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation with concomitant loss of leukemogenicity, provides a particularly attractive model system to address these issues. Deregulated and continued expression of E2F-1 blocked the IL-6-induced terminal differentiation program at an early blast stage, giving rise to immature cells, which continued to proliferate without undergoing apoptosis and retained their leukemogenic phenotype. Although E2F-1 blocked IL-6-mediated terminal differentiation and its associated growth arrest, it did not prevent the rapid induction of both p15(INK4B) and p16(INK4A), inhibition of cdk4 kinase activity, and subsequent hypophosphorylation of pRb. The results obtained imply that genetic alterations that both impair p53 function and deregulate E2F-1 expression may render hematopoietic cells refractory to the induction of differentiation and are, thereby, likely to play a major role in the progression of leukemias. (Blood. 2000;96:475-482)

  3. Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells.

    PubMed

    Yasaei, H; Gilham, E; Pickles, J C; Roberts, T P; O'Donovan, M; Newbold, R F

    2013-01-10

    Immortalization (senescence bypass) is a critical rate-limiting step in the malignant transformation of mammalian somatic cells. Human cells must breach at least two distinct senescence barriers to permit unfettered clonal evolution during cancer development: (1) stress- or oncogene-induced premature senescence (SIPS/OIS), mediated via the p16-Rb and/or ARF-p53-p21 tumour-suppressive pathways, and (2) replicative senescence triggered by telomere shortening. In contrast, because their telomerase is constitutively active, cells from small rodents possess only the SIPS/OIS barrier, and are therefore useful for studying SIPS/OIS bypass in isolation. Dermal fibroblasts from the Syrian hamster (SHD cells) are exceptionally resistant to spontaneous SIPS bypass, but it can be readily induced following exposure to a wide range of chemical and physical carcinogens. Here we show that a spectrum of carcinogen-specific mutational and epigenetic alterations involving the INK4A (p16), p53 and INK4B (p15) genes are associated with induced SIPS bypass. With ionizing radiation, immortalization is invariably accompanied by efficient biallelic deletion of the complete INK4/CDKN2 locus. In comparison, SHD cells immortalized by the powerful polycyclic hydrocarbon carcinogen benzo(a)pyrene display transversion point mutations in the DNA-binding domain of p53 coupled with INK4 alterations such as loss of expression of p15. Epimutational silencing of p16 is the primary event associated with immortalization by nickel, a human non-genotoxic carcinogen. As SIPS/OIS bypass is a prerequisite for the immortalization of normal diploid human epithelial cells, our results with the SHD model will provide a basis for delineating combinations of key molecular changes underpinning this important event in human carcinogenesis.

  4. 4-D photoacoustic tomography.

    PubMed

    Xiang, Liangzhong; Wang, Bo; Ji, Lijun; Jiang, Huabei

    2013-01-01

    Photoacoustic tomography (PAT) offers three-dimensional (3D) structural and functional imaging of living biological tissue with label-free, optical absorption contrast. These attributes lend PAT imaging to a wide variety of applications in clinical medicine and preclinical research. Despite advances in live animal imaging with PAT, there is still a need for 3D imaging at centimeter depths in real-time. We report the development of four dimensional (4D) PAT, which integrates time resolutions with 3D spatial resolution, obtained using spherical arrays of ultrasonic detectors. The 4D PAT technique generates motion pictures of imaged tissue, enabling real time tracking of dynamic physiological and pathological processes at hundred micrometer-millisecond resolutions. The 4D PAT technique is used here to image needle-based drug delivery and pharmacokinetics. We also use this technique to monitor 1) fast hemodynamic changes during inter-ictal epileptic seizures and 2) temperature variations during tumor thermal therapy.

  5. 4-D Photoacoustic Tomography

    NASA Astrophysics Data System (ADS)

    Xiang, Liangzhong; Wang, Bo; Ji, Lijun; Jiang, Huabei

    2013-01-01

    Photoacoustic tomography (PAT) offers three-dimensional (3D) structural and functional imaging of living biological tissue with label-free, optical absorption contrast. These attributes lend PAT imaging to a wide variety of applications in clinical medicine and preclinical research. Despite advances in live animal imaging with PAT, there is still a need for 3D imaging at centimeter depths in real-time. We report the development of four dimensional (4D) PAT, which integrates time resolutions with 3D spatial resolution, obtained using spherical arrays of ultrasonic detectors. The 4D PAT technique generates motion pictures of imaged tissue, enabling real time tracking of dynamic physiological and pathological processes at hundred micrometer-millisecond resolutions. The 4D PAT technique is used here to image needle-based drug delivery and pharmacokinetics. We also use this technique to monitor 1) fast hemodynamic changes during inter-ictal epileptic seizures and 2) temperature variations during tumor thermal therapy.

  6. Strong HCV NS3/4a, NS4b, NS5a, NS5b-specific cellular immune responses induced in Rhesus macaques by a novel HCV genotype 1a/1b consensus DNA vaccine.

    PubMed

    Latimer, Brian; Toporovski, Roberta; Yan, Jian; Pankhong, Panyupa; Morrow, Matthew P; Khan, Amir S; Sardesai, Niranjan Y; Welles, Seth L; Jacobson, Jeffrey M; Weiner, David B; Kutzler, Michele A

    2014-01-01

    Chronic HCV is a surreptitious disease currently affecting approximately 3% of the world's population that can lead to liver failure and cancer decades following initial infection. However, there are currently no vaccines available for the prevention of chronic HCV. From patients who acutely resolve HCV infection, it is apparent that a strong and broad cytotoxic T lymphocyte (CTL) response is important in HCV clearance. DNA vaccines are naked plasmid DNA molecules that encode pathogen antigens to induce a pathogen-specific immune response. They are inexpensive to produce and have an excellent safety profile in animals and humans. Additionally, DNA vaccines are able to induce strong CTL responses, making them well-suited for an HCV vaccine. We aimed to maximize vaccine recipients' opportunity to induce a broad T cell response with a novel antigenic sequence, multi-antigen vaccine strategy. We have generated DNA plasmids encoding consensus sequences of HCV genotypes 1a and 1b non-structural proteins NS3/4a, NS4b, NS5a, and NS5b. Rhesus macaques were used to study the immunogenicity of these constructs. Four animals were immunized 3 times, 6 weeks apart, at a dose of 1.0mg per antigen construct, as an intramuscular injection followed by in vivo electroporation, which greatly increases DNA uptake by local cells. Immune responses were measured 2 weeks post-immunization regimen (PIR) in immunized rhesus macaques and showed a broad response to multiple HCV nonstructural antigens, with up to 4680 spot-forming units per million peripheral blood mononuclear cells (PBMCs) as measured by Interferon-γ ELISpot. In addition, multiparametric flow cytometry detected HCV-specific CD4+ and CD8+ T cell responses by intracellular cytokine staining and detected HCV-specific CD107a+/GrzB+ CD8+ T cells indicating an antigen specific cytolytic response 2 weeks PIR compared with baseline measurements. At the final study time point, 6 weeks PIR, HCV-specific CD45RA- memory-like T cells

  7. Synthesis, biological activities and pharmacokinetic properties of new fluorinated derivatives of selective PDE4D inhibitors.

    PubMed

    Brullo, Chiara; Massa, Matteo; Villa, Carla; Ricciarelli, Roberta; Rivera, Daniela; Pronzato, Maria Adelaide; Fedele, Ernesto; Barocelli, Elisabetta; Bertoni, Simona; Flammini, Lisa; Bruno, Olga

    2015-07-01

    A new series of selective PDE4D inhibitors has been designed and synthesized by replacing 3-methoxy group with 3-difluoromethoxy isoster moiety in our previously reported cathecolic structures. All compounds showed a good PDE4D3 inhibitory activity, most of them being inactive toward other PDE4 isoforms (PDE4A4, PDE4B2 and PDE4C2). Compound 3b, chosen among the synthesized compounds as the most promising in terms of inhibitory activity, selectivity and safety, showed an improved pharmacokinetic profile compared to its non fluorinated analogue. Spontaneous locomotor activity, assessed in an open field apparatus, showed that, differently from rolipram and diazepam, selective PDE4D inhibitors, such as compounds 3b, 5b and 7b, did not affect locomotion, whereas compound 1b showed a tendency to reduce the distance traveled and to prolong the immobility period, possibly due to a poor selectivity.

  8. Amino acid residues 1101-1105 of the isotypic region of human C4B is important to the covalent binding activity of complement component C4.

    PubMed

    Reilly, B D; Levine, R P; Skanes, V M

    1991-11-01

    The C4A and C4B isotypes of human C4 show certain functional differences that stem from their relative preference for transacylation to amino (-NH2) vs hydroxyl (-OH) nucleophiles, respectively, on complement-activating surfaces. Comparison of amino acid sequences of the alpha-chain fragment of C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 are the only consistent structural difference between isotype, i.e., Pro, Cys, Pro, Val, Leu, Asp in C4A and Leu, Ser, Pro, Val Ile, His in C4B. These residues may be responsible either in part or entirely for properties associated with isotype. To examine the functional role of residues 1101-1106 in C4B-mediated hemolysis, whole serum or immunopurified human C4 with allotypes, A3B1, A3, B2B1, or B1 were preincubated in the presence or absence of an antipeptide mAb (BII-1) specific for amino acid residues 1101-1105 of C4B. Sensitized sheep E and C4-deficient guinea pig serum was then added and lysis measured by absorbance at 415 nm. Our results show lysis of antibody-sensitized sheep E is inhibited by antibody and C4B2B1, C4B1, or C4A3B1 but not antibody and C4A3. The interference of hemolysis by BII-1 could not be explained by inhibition of activation of C4B or inhibition of C3 or C5 convertase activity. Furthermore, results from uptake experiments show that BII-1 interferes with the covalent binding activity of C4B, indicating residues 1101-1105 play a role in the covalent binding reaction of C4B to the target E-antibody complex.

  9. Boeing F4B-4

    NASA Technical Reports Server (NTRS)

    1932-01-01

    The Boeing F4B-4 was seen to differ from earlier F4Bs in having a vertical fin with slightly more area. The Boeing model 235 was not fitted with a NACA cowling, but rather the less efficient 'Townend' ring around the Pratt & Whitney Wasp radials cylinders. This aircraft was much used by both the Navy and the Army Air Corps in the late 1920's and early 1930's. The Army variation was known as the P-12E. The engine cowling was a British development known as the 'Townend' ring. It differed from the NACA cowling and was less effective in reducing the drag.

  10. Characteristics of potential repository wastes: Volume 4, Appendix 4A, Nuclear reactors at educational institutions of the United States; Appendix 4B, Data sheets for nuclear reactors at educational institutions; Appendix 4C, Supplemental data for Fort St. Vrain spent fuel; Appendix 4D, Supplemental data for Peach Bottom 1 spent fuel; Appendix 4E, Supplemental data for Fast Flux Test Facility

    SciTech Connect

    Not Available

    1992-07-01

    Volume 4 contains the following appendices: nuclear reactors at educational institutions in the United States; data sheets for nuclear reactors at educational institutions in the United States(operational reactors and shut-down reactors); supplemental data for Fort St. Vrain spent fuel; supplemental data for Peach Bottom 1 spent fuel; and supplemental data for Fast Flux Test Facility.

  11. The HMG-box transcription factor Sox4b is required for pituitary expression of gata2a and specification of thyrotrope and gonadotrope cells in zebrafish.

    PubMed

    Quiroz, Yobhana; Lopez, Mauricio; Mavropoulos, Anastasia; Motte, Patrick; Martial, Joseph A; Hammerschmidt, Matthias; Muller, Marc

    2012-06-01

    The pituitary is a complex gland comprising different cell types each secreting specific hormones. The extensive network of signaling molecules and transcription factors required for determination and terminal differentiation of specific cell types is still not fully understood. The SRY-like HMG-box (SOX) transcription factor Sox4 plays important roles in many developmental processes and has two homologs in zebrafish, Sox4a and Sox4b. We show that the sox4b gene is expressed in the pituitary anlagen starting at 24 h after fertilization (hpf) and later in the entire head region including the pituitary. At 48 hpf, sox4b mRNA colocalizes with that for TSH (tshβ), glycoprotein subunit α (gsuα), and the Zn finger transcription factor Gata2a. Loss of Sox4b function, using morpholino knockdown or expression of a dominant-negative Sox4 mutant, leads to a drastic decrease in tshβ and gsuα expression and reduced levels of gh, whereas other anterior pituitary gland markers including prl, slβ, pomc, and lim3 are not affected. Sox4b is also required for expression of gata2a in the pituitary. Knockdown of gata2a leads to decreased tshβ and gsuα expression at 48 hpf, similar to sox4b morphants. Injection of gata2a mRNA into sox4b morphants rescued tshβ and gsuα expression in thyrotrope cells. Finally, sox4b or gata2a knockdown causes a significant decrease of gonadotropin expression (lhβ and fshβ) at 4 d after fertilization. In summary, our results indicate that Sox4b is expressed in zebrafish during pituitary development and plays a crucial role in the differentiation of thyrotrope and gonadotrope cells through induction of gata2a expression in the developing pituitary.

  12. Selective Phosphodiesterase 4B Inhibitors: A Review

    PubMed Central

    Azam, Mohammed Afzal; Tripuraneni, Naga Srinivas

    2014-01-01

    Abstract Phosphodiesterase 4B (PDE4B) is a member of the phosphodiesterase family of proteins that plays a critical role in regulating intracellular levels of cyclic adenosine monophosphate (cAMP) by controlling its rate of degradation. It has been demonstrated that this isoform is involved in the orchestra of events which includes inflammation, schizophrenia, cancers, chronic obstructive pulmonary disease, contractility of the myocardium, and psoriatic arthritis. Phosphodiesterase 4B has constituted an interesting target for drug development. In recent years, a number of PDE4B inhibitors have been developed for their use as therapeutic agents. In this review, an up-to-date status of the inhibitors investigated for the inhibition of PDE4B has been given so that this rich source of structural information of presently known PDE4B inhibitors could be helpful in generating a selective and potent inhibitor of PDE4B. PMID:25853062

  13. Molecular cloning, expression pattern, and chromosomal localization of human CDKN2D/INK4d, an inhibitor of cyclin D-dependent kinases

    SciTech Connect

    Okuda, Tsukasa; Shurtleff, S.A.; Downing, J.R.

    1995-10-10

    Progression through the G1 phase of the cell cycle is dependent on the activity of holoenzymes formed between D-type cyclins and their catalytic partners, the cyclin-dependent kinases cdk4 and cdk6. p16{sup INK4a} p15{sup INK4b}, and p18{sup INK4c}, a group of structurally related proteins, function as specific inhibitors of the cyclin D-dependent kinases and are likely to play physiologic roles as specific regulators of these kinases in vivo. A new member of the INK4 gene family, murine INK4d, has recently been identified. Here we report the isolation of human INK4d (gene symbol CDKN2D), which is 86 identical at the amino acid level to the murine clone and {approximately}44% identical to each of the other human INK4 family members. The INK4d gene is ubiquitously expressed as a single 1.4-kb mRNA with the highest levels detected in thymus, spleen, peripheral blood leukocytes, fetal liver, brain, and testes. The abundance of INK4d mRNA oscillates in a cell-cycle-dependent manner with expression lowest at mid G1 and maximal during S phase. Using a P1-phage genomic clone of INK4d for fluorescence in situ hybridization analysis, the location of this gene was mapped to chromosome 19p13. No rearrangements or deletions of the INK4d gene were observed in Southern blot analysis of selected cases of pediatric acute lymphoblastic leukemia (ALL) containing a variant (1;19)(q23;p13) translocation that lacks rearrangement of either E2A or PBX1, or in ALL cases containing homozygous or hemizygous deletions of the related genes, INK4a and INK4b. 39 refs., 3 figs.

  14. Familial C4B Deficiency and Immune Complex Glomerulonephritis

    PubMed Central

    Soto, K; Wu, YL; Ortiz, A; Aparício, SR; Yu, CY

    2010-01-01

    Homozygous complement C4B deficiency is described in a Southern European young female patient with Membranoproliferative Glomerulonephritis (MPGN) type III characterized by renal biopsies with strong complement C4 and IgG deposits. Low C4 levels were independent of clinical evolution or type of immunosuppression and were found in three other family members without renal disease or infections. HLA typing revealed that the patient has homozygous A*02, Cw*06, B*50 at the class I region, and DRB1*08 and DQB1*03 at the class II region. Genotypic and phenotypic studies demonstrated that the patient has homozygous monomodular RCCX in the HLA class III region, with single long C4A genes coding for C4A3 and complete C4B deficiency. Her father, mother, son and niece have heterozygous C4B deficiency. The patient’s deceased brother had a history of Henoch-Schönlein Purpura (HSP), an immune complex-mediated proliferative glomerulonephritis. These findings challenge the putative pathophysiological roles of C4A and C4B and underscore the need to perform functional assays, C4 allotyping and genotyping on patients with persistently low serum levels of a classical pathway complement component and glomerulopathy associated with immune deposits. PMID:20580617

  15. Familial C4B deficiency and immune complex glomerulonephritis.

    PubMed

    Soto, K; Wu, Y L; Ortiz, A; Aparício, S R; Yu, C Y

    2010-10-01

    Homozygous complement C4B deficiency is described in a Southern European young female patient with Membranoproliferative Glomerulonephritis (MPGN) type III characterized by renal biopsies with strong complement C4 and IgG deposits. Low C4 levels were independent of clinical evolution or type of immunosuppression and were found in three other family members without renal disease or infections. HLA typing revealed that the patient has homozygous A*02, Cw*06, B*50 at the class I region, and DRB1*08 and DQB1*03 at the class II region. Genotypic and phenotypic studies demonstrated that the patient has homozygous monomodular RCCX in the HLA class III region, with single long C4A genes coding for C4A3 and complete C4B deficiency. Her father, mother, son and niece have heterozygous C4B deficiency. The patient's deceased brother had a history of Henoch-Schönlein Purpura (HSP), an immune complex-mediated proliferative glomerulonephritis. These findings challenge the putative pathophysiological roles of C4A and C4B and underscore the need to perform functional assays, C4 allotyping and genotyping on patients with persistently low serum levels of a classical pathway complement component and glomerulopathy associated with immune deposits.

  16. RDR-4B doppler weather radar with forward looking wind shear detection capability

    NASA Technical Reports Server (NTRS)

    Grasley, Steven S.

    1992-01-01

    The topics are presented in viewgraph form and include the following: Bendix/King atmospheric transport and dispersion (ATAD) position; RDR-4A technical baseline; RTA-4A characteristics; RDR-4 antenna characteristics; modification of RDR-4A to RDR-4B; RDR-4A functional block diagram; RDR-4B characteristics; development/test plan; CV-580 testing capability; CV-580 test results; Continental A300 test configuration; Continental Data Recording Program operational considerations; Continental A300 test results; and display considerations.

  17. 4-D OCT in Developmental Cardiology

    NASA Astrophysics Data System (ADS)

    Jenkins, Michael W.; Rollins, Andrew M.

    Although strong evidence exists to suggest that altered cardiac function can lead to CHDs, few studies have investigated the influential role of cardiac function and biophysical forces on the development of the cardiovascular system due to a lack of proper in vivo imaging tools. 4-D imaging is needed to decipher the complex spatial and temporal patterns of biomechanical forces acting upon the heart. Numerous solutions over the past several years have demonstrated 4-D OCT imaging of the developing cardiovascular system. This chapter will focus on these solutions and explain their context in the evolution of 4-D OCT imaging. The first sections describe the relevant techniques (prospective gating, direct 4-D imaging, retrospective gating), while later sections focus on 4-D Doppler imaging and measurements of force implementing 4-D OCT Doppler. Finally, the techniques are summarized, and some possible future directions are discussed.

  18. Advances in 4D radiation therapy for managing respiration: part I - 4D imaging.

    PubMed

    Hugo, Geoffrey D; Rosu, Mihaela

    2012-12-01

    Techniques for managing respiration during imaging and planning of radiation therapy are reviewed, concentrating on free-breathing (4D) approaches. First, we focus on detailing the historical development and basic operational principles of currently-available "first generation" 4D imaging modalities: 4D computed tomography, 4D cone beam computed tomography, 4D magnetic resonance imaging, and 4D positron emission tomography. Features and limitations of these first generation systems are described, including necessity of breathing surrogates for 4D image reconstruction, assumptions made in acquisition and reconstruction about the breathing pattern, and commonly-observed artifacts. Both established and developmental methods to deal with these limitations are detailed. Finally, strategies to construct 4D targets and images and, alternatively, to compress 4D information into static targets and images for radiation therapy planning are described.

  19. Intrathecal injection of phosphodiesterase 4B-specific siRNA attenuates neuropathic pain in rats with L5 spinal nerve ligation.

    PubMed

    Ji, Qing; Di, Yan; He, Xiaoyun; Liu, Qingzhen; Liu, Jian; Li, Weiyan; Zhang, Lidong

    2016-02-01

    Phosphodiesterase 4 (PDE4) is an adenosine cyclic 3,5-monophosphate-specific degradative enzyme, which is closely associated with the inflammatory response. Among its four subtypes (A-D), it remains unclear which one exerts suppressive effects on inflammation and reduces neuropathic pain. The present study aimed to examine the modulation of neuroinflammation by PDE4 subtypes in the spinal cord of a rat model of L5 spinal nerve ligation (SNL)-induced neuropathic pain. The expression levels of PDE4A-D were measured in the lumbar spinal cords of naïve rats. The rats were then divided into seven groups: The sham group (sham surgery + saline), the saline group (SNL + saline), the vehicle group (SNL + Lipofectamine® RNAiMAX), the mismatch small interfering (si)RNA group (SNL + mismatch siRNA), the PDE4A-siRNA group (SNL + PDE4A-siRNA), the PDE4B-siRNA group (SNL + PDE4B-siRNA) and the PDE4D-siRNA group (SNL + PDE4D-siRNA). In order to determine behavioral changes, mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were recorded. The mRNA and protein expression levels of PDE4s were also detected. Furthermore, the association between behavioral changes and individual subtypes of PDE4 were studied following intrathecal administration of PDE4A, B and D-specific siRNA. The expression levels of protein kinases, including phosphorylated-extracellular signal-regulated kinases (p-ERK), and inflammatory cytokines were measured, in order to explore the underlying mechanisms. Subtypes A, B and D, but not C, were detected in the naïve rats. After SNL, both MWT and TWL were reduced. The mRNA and protein expression levels of PDE4A, B and D were significantly upregulated after 2, 4, 6 and 8 days of SNL. Subtype-specific siRNA significantly suppressed the elevated expression levels; however, only rats treated with PDE4B siRNA exhibited improved MWT and TWL. Further analysis of the PDE4B siRNA-treated rats demonstrated that 8 days after SNL, the intensity of p

  20. DISC1, PDE4B, and NDE1 at the centrosome and synapse

    SciTech Connect

    Bradshaw, Nicholas J.; Ogawa, Fumiaki; Antolin-Fontes, Beatriz; Chubb, Jennifer E.; Carlyle, Becky C.; Christie, Sheila; Claessens, Antoine; Porteous, David J.; Millar, J. Kirsty

    2008-12-26

    Disrupted-In-Schizophrenia 1 (DISC1) is a risk factor for schizophrenia and other major mental illnesses. Its protein binding partners include the Nuclear Distribution Factor E Homologs (NDE1 and NDEL1), LIS1, and phosphodiesterases 4B and 4D (PDE4B and PDE4D). We demonstrate that NDE1, NDEL1 and LIS1, together with their binding partner dynein, associate with DISC1, PDE4B and PDE4D within the cell, and provide evidence that this complex is present at the centrosome. LIS1 and NDEL1 have been previously suggested to be synaptic, and we now demonstrate localisation of DISC1, NDE1, and PDE4B at synapses in cultured neurons. NDE1 is phosphorylated by cAMP-dependant Protein Kinase A (PKA), whose activity is, in turn, regulated by the cAMP hydrolysis activity of phosphodiesterases, including PDE4. We propose that DISC1 acts as an assembly scaffold for all of these proteins and that the NDE1/NDEL1/LIS1/dynein complex is modulated by cAMP levels via PKA and PDE4.

  1. Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis*

    PubMed Central

    Yin, Yan; Liu, Liren; Yang, Chenyi; Lin, Congxing; Veith, George Michael; Wang, Caihong; Sutovsky, Peter; Zhou, Pengbo; Ma, Liang

    2016-01-01

    CUL4B ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequence and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation of Cul4a in mice led to male infertility because of aberrant meiotic progression. In the present study, we generated Cul4b germ cell-specific conditional knock-out (Cul4bVasa),as well as Cul4b global knock-out (Cul4bSox2) mouse, to investigate its roles in spermatogenesis. Germ cell-specific deletion of Cul4b led to male infertility, despite normal testicular morphology and comparable numbers of spermatozoa. Notably, significantly impaired sperm mobility caused by reduced mitochondrial activity and glycolysis level were observed in the majority of the mutant spermatozoa, manifested by low, if any, sperm ATP production. Furthermore, Cul4bVasa spermatozoa exhibited defective arrangement of axonemal microtubules and flagella outer dense fibers. Our mass spectrometry analysis identified INSL6 as a novel CUL4B substrate in male germ cells, evidenced by its direct polyubiquination and degradation by CUL4B E3 ligase. Nevertheless, Cul4b global knock-out males lost their germ cells in an age-dependent manner, implying failure of maintaining the spermatogonial stem cell niche in somatic cells. Taken together, our results show that CUL4B is indispensable to spermatogenesis, and it functions cell autonomously in male germ cells to ensure spermatozoa motility, whereas it functions non-cell-autonomously in somatic cells to maintain spermatogonial stemness. Thus, CUL4B links two distinct spermatogenetic processes to a single E3 ligase, highlighting the significance of ubiquitin modification during spermatogenesis. PMID:26846852

  2. Optimized PET imaging for 4D treatment planning in radiotherapy: the virtual 4D PET strategy.

    PubMed

    Gianoli, Chiara; Riboldi, Marco; Fontana, Giulia; Giri, Maria G; Grigolato, Daniela; Ferdeghini, Marco; Cavedon, Carlo; Baroni, Guido

    2015-02-01

    The purpose of the study is to evaluate the performance of a novel strategy, referred to as "virtual 4D PET", aiming at the optimization of hybrid 4D CT-PET scan for radiotherapy treatment planning. The virtual 4D PET strategy applies 4D CT motion modeling to avoid time-resolved PET image acquisition. This leads to a reduction of radioactive tracer administered to the patient and to a total acquisition time comparable to free-breathing PET studies. The proposed method exploits a motion model derived from 4D CT, which is applied to the free-breathing PET to recover respiratory motion and motion blur. The free-breathing PET is warped according to the motion model, in order to generate the virtual 4D PET. The virtual 4D PET strategy was tested on images obtained from a 4D computational anthropomorphic phantom. The performance was compared to conventional motion compensated 4D PET. Tests were also carried out on clinical 4D CT-PET scans coming from seven lung and liver cancer patients. The virtual 4D PET strategy was able to recover lesion motion, with comparable performance with respect to the motion compensated 4D PET. The compensation of the activity blurring due to motion was successfully achieved in terms of spill out removal. Specific limitations were highlighted in terms of partial volume compensation. Results on clinical 4D CT-PET scans confirmed the efficacy in 4D PET count statistics optimization, as equal to the free-breathing PET, and recovery of lesion motion. Compared to conventional motion compensation strategies that explicitly require 4D PET imaging, the virtual 4D PET strategy reduces clinical workload and computational costs, resulting in significant advantages for radiotherapy treatment planning.

  3. Los Alamos National Laboratory 4D Database

    SciTech Connect

    Atencio, Julian J.

    2014-05-02

    4D is an integrated development platform - a single product comprised of the components you need to create and distribute professional applications. You get a graphical design environment, SQL database, a programming language, integrated PHP execution, HTTP server, application server, executable generator, and much more. 4D offers multi-platform development and deployment, meaning whatever you create on a Mac can be used on Windows, and vice-versa. Beyond productive development, 4D is renowned for its great flexibility in maintenance and modification of existing applications, and its extreme ease of implementation in its numerous deployment options. Your professional application can be put into production more quickly, at a lower cost, and will always be instantly scalable. 4D makes it easy, whether you're looking to create a classic desktop application, a client-server system, a distributed solution for Web or mobile clients - or all of the above!

  4. 4D flow imaging with MRI

    PubMed Central

    Stankovic, Zoran; Allen, Bradley D.; Garcia, Julio; Jarvis, Kelly B.

    2014-01-01

    Magnetic resonance imaging (MRI) has become an important tool for the clinical evaluation of patients with cardiovascular disease. Since its introduction in the late 1980s, 2-dimensional phase contrast MRI (2D PC-MRI) has become a routine part of standard-of-care cardiac MRI for the assessment of regional blood flow in the heart and great vessels. More recently, time-resolved PC-MRI with velocity encoding along all three flow directions and three-dimensional (3D) anatomic coverage (also termed ‘4D flow MRI’) has been developed and applied for the evaluation of cardiovascular hemodynamics in multiple regions of the human body. 4D flow MRI allows for the comprehensive evaluation of complex blood flow patterns by 3D blood flow visualization and flexible retrospective quantification of flow parameters. Recent technical developments, including the utilization of advanced parallel imaging techniques such as k-t GRAPPA, have resulted in reasonable overall scan times, e.g., 8-12 minutes for 4D flow MRI of the aorta and 10-20 minutes for whole heart coverage. As a result, the application of 4D flow MRI in a clinical setting has become more feasible, as documented by an increased number of recent reports on the utility of the technique for the assessment of cardiac and vascular hemodynamics in patient studies. A number of studies have demonstrated the potential of 4D flow MRI to provide an improved assessment of hemodynamics which might aid in the diagnosis and therapeutic management of cardiovascular diseases. The purpose of this review is to describe the methods used for 4D flow MRI acquisition, post-processing and data analysis. In addition, the article provides an overview of the clinical applications of 4D flow MRI and includes a review of applications in the heart, thoracic aorta and hepatic system. PMID:24834414

  5. GL4D: a GPU-based architecture for interactive 4D visualization.

    PubMed

    Chu, Alan; Fu, Chi-Wing; Hanson, Andrew J; Heng, Pheng-Ann

    2009-01-01

    This paper describes GL4D, an interactive system for visualizing 2-manifolds and 3-manifolds embedded in four Euclidean dimensions and illuminated by 4D light sources. It is a tetrahedron-based rendering pipeline that projects geometry into volume images, an exact parallel to the conventional triangle-based rendering pipeline for 3D graphics. Novel features include GPU-based algorithms for real-time 4D occlusion handling and transparency compositing; we thus enable a previously impossible level of quality and interactivity for exploring lit 4D objects. The 4D tetrahedrons are stored in GPU memory as vertex buffer objects, and the vertex shader is used to perform per-vertex 4D modelview transformations and 4D-to-3D projection. The geometry shader extension is utilized to slice the projected tetrahedrons and rasterize the slices into individual 2D layers of voxel fragments. Finally, the fragment shader performs per-voxel operations such as lighting and alpha blending with previously computed layers. We account for 4D voxel occlusion along the 4D-to-3D projection ray by supporting a multi-pass back-to-front fragment composition along the projection ray; to accomplish this, we exploit a new adaptation of the dual depth peeling technique to produce correct volume image data and to simultaneously render the resulting volume data using 3D transfer functions into the final 2D image. Previous CPU implementations of the rendering of 4D-embedded 3-manifolds could not perform either the 4D depth-buffered projection or manipulation of the volume-rendered image in real-time; in particular, the dual depth peeling algorithm is a novel GPU-based solution to the real-time 4D depth-buffering problem. GL4D is implemented as an integrated OpenGL-style API library, so that the underlying shader operations are as transparent as possible to the user.

  6. Shadow-driven 4D haptic visualization.

    PubMed

    Zhang, Hui; Hanson, Andrew

    2007-01-01

    Just as we can work with two-dimensional floor plans to communicate 3D architectural design, we can exploit reduced-dimension shadows to manipulate the higher-dimensional objects generating the shadows. In particular, by taking advantage of physically reactive 3D shadow-space controllers, we can transform the task of interacting with 4D objects to a new level of physical reality. We begin with a teaching tool that uses 2D knot diagrams to manipulate the geometry of 3D mathematical knots via their projections; our unique 2D haptic interface allows the user to become familiar with sketching, editing, exploration, and manipulation of 3D knots rendered as projected imageson a 2D shadow space. By combining graphics and collision-sensing haptics, we can enhance the 2D shadow-driven editing protocol to successfully leverage 2D pen-and-paper or blackboard skills. Building on the reduced-dimension 2D editing tool for manipulating 3D shapes, we develop the natural analogy to produce a reduced-dimension 3D tool for manipulating 4D shapes. By physically modeling the correct properties of 4D surfaces, their bending forces, and their collisions in the 3D haptic controller interface, we can support full-featured physical exploration of 4D mathematical objects in a manner that is otherwise far beyond the experience accessible to human beings. As far as we are aware, this paper reports the first interactive system with force-feedback that provides "4D haptic visualization" permitting the user to model and interact with 4D cloth-like objects.

  7. 4D-Var Developement at GMAO

    NASA Technical Reports Server (NTRS)

    Pelc, Joanna S.; Todling, Ricardo; Akkraoui, Amal El

    2014-01-01

    The Global Modeling and Assimilation Offce (GMAO) is currently using an IAU-based 3D-Var data assimilation system. GMAO has been experimenting with a 3D-Var-hybrid version of its data assimilation system (DAS) for over a year now, which will soon become operational and it will rapidly progress toward a 4D-EnVar. Concurrently, the machinery to exercise traditional 4DVar is in place and it is desirable to have a comparison of the traditional 4D approach with the other available options, and evaluate their performance in the Goddard Earth Observing System (GEOS) DAS. This work will also explore the possibility for constructing a reduced order model (ROM) to make traditional 4D-Var computationally attractive for increasing model resolutions. Part of the research on ROM will be to search for a suitably acceptable space to carry on the corresponding reduction. This poster illustrates how the IAU-based 4D-Var assimilation compares with our currently used IAU-based 3D-Var.

  8. New insights into the wheat chromosome 4D structure and virtual gene order, revealed by survey pyrosequencing

    PubMed Central

    Helguera, Marcelo; Rivarola, Máximo; Clavijo, Bernardo; Martis, Mihaela M.; Vanzetti, Leonardo S.; González, Sergio; Garbus, Ingrid; Leroy, Phillippe; Šimková, Hana; Valárik, Miroslav; Caccamo, Mario; Doležel, Jaroslav; Mayer, Klaus F.X.; Feuillet, Catherine; Tranquilli, Gabriela; Paniego, Norma; Echenique, Viviana

    2015-01-01

    Survey sequencing of the bread wheat (Triticum aestivum L.) genome (AABBDD) has been approached through different strategies delivering important information. However, the current wheat sequence knowledge is not complete. The aim of our study is to provide different and complementary set of data for chromosome 4D. A survey sequence was obtained by pyrosequencing of flow-sorted 4DS (7.2×) and 4DL (4.1×) arms. Single ends (SE) and long mate pairs (LMP) reads were assembled into contigs (223 Mb) and scaffolds (65 Mb) that were aligned to Aegilops tauschii draft genome (DD), anchoring 34 Mb to chromosome 4. Scaffolds annotation rendered 822 gene models. A virtual gene order comprising 1973 wheat orthologous gene loci and 381 wheat gene models was built. This order was largely consistent with the scaffold order determined based on a published high density map from the Ae. tauschii chromosome 4, using bin-mapped 4D ESTs as a common reference. The virtual order showed a higher collinearity with homeologous 4B compared to 4A. Additionally, a virtual map was constructed and ∼5700 genes (∼2200 on 4DS and ∼3500 on 4DL) predicted. The sequence and virtual order obtained here using the 454 platform were compared with the Illumina one used by the IWGSC, giving complementary information. PMID:25711827

  9. Interactive animation of 4D performance capture.

    PubMed

    Casas, Dan; Tejera, Margara; Guillemaut, Jean-Yves; Hilton, Adrian

    2013-05-01

    A 4D parametric motion graph representation is presented for interactive animation from actor performance capture in a multiple camera studio. The representation is based on a 4D model database of temporally aligned mesh sequence reconstructions for multiple motions. High-level movement controls such as speed and direction are achieved by blending multiple mesh sequences of related motions. A real-time mesh sequence blending approach is introduced, which combines the realistic deformation of previous nonlinear solutions with efficient online computation. Transitions between different parametric motion spaces are evaluated in real time based on surface shape and motion similarity. Four-dimensional parametric motion graphs allow real-time interactive character animation while preserving the natural dynamics of the captured performance.

  10. Respiratory gating and 4-D tomotherapy

    SciTech Connect

    Zhang Tiezhi

    2004-12-01

    Helical tomotherapy is a new intensity-modulated radiotherapy (IMRT) delivery process developed at the University of Wisconsin and TomoTherapy Inc. Tomotherapy may be of advantage in lung cancer treatment due to its rotational delivery mode. As with conventional IMRT delivery, however, intrafraction respiratory motion during a tomotherapy treatment causes unnecessary radiation to the healthy tissue. Possible solutions to these problems associated with intrafraction motion have been studied in this thesis. A spirometer is useful for monitoring breathing because of its direct correlation with lung volume changes. However, its inherent drift prevents its application in long-term breathing monitoring. With calibration and stabilization algorithms, a spirometer is able to provide accurate, long-term lung volume change measurements. Such a spirometer system is most suited for deep inspiration breath-hold (DIBH) treatments. An improved laser-spirometer combined system has also been developed for target tracking in 4-D treatment. Spirometer signals are used to calibrate the displacement measurements into lung volume changes, thereby eliminating scaling errors from daily setup variations. The laser displacement signals may also be used to correct spirometer drifts during operation. A new 4-D treatment technique has been developed to account for intrafraction motion in treatment planning. The patient's breathing and the beam delivery are synchronized, and the target motion/deformation is incorporated into treatment plan optimization. Results show that this new 4D treatment technique significantly reduces motion effects and provides improved patient tolerance.

  11. Discover natural compounds as potential phosphodiesterase-4B inhibitors via computational approaches.

    PubMed

    Li, Jing; Zhou, Nan; Liu, Wen; Li, Jianzong; Feng, Yu; Wang, Xiaoyun; Wu, Chuanfang; Bao, Jinku

    2016-05-01

    cAMP, intracellular cyclic adenosine monophosphate, is a ubiquitous second messenger that plays a key role in many physiological processes. PDE4B which can reduce the cAMP level by hydrolyzing cAMP to 5'-AMP has become a therapeutic target for the treatment of human diseases such as respiratory disorders, inflammation diseases, neurological and psychiatric disorders. However, the use of currently available PDE4B inhibitors is restricted due to serious side effects caused by targeting PDE4D. Hence, we are attempting to find out subfamily-selective PDE4B inhibitors from natural products, using computer-aided approaches such as virtual screening, docking, and molecular dynamics simulation. Finally, four potential PDE4B-selective inhibitors (ZINC67912770, ZINC67912780, ZINC72320169, and ZINC28882432) were found. Compared to the reference drug (roflumilast), they scored better during the virtual screening process. Binding free energy for them was -317.51, -239.44, -215.52, and -165.77 kJ/mol, better than -129.05 kJ/mol of roflumilast. The pharmacophore model of the four candidate inhibitors comprised six features, including one hydrogen bond donor, four hydrogen bond acceptors, and one aromatic ring feature. It is expected that our study will pave the way for the design of potent PDE4B-selective inhibitors of new drugs to treat a wide variety of diseases such as asthma, COPD, psoriasis, depression, etc.

  12. Active origami by 4D printing

    NASA Astrophysics Data System (ADS)

    Ge, Qi; Dunn, Conner K.; Qi, H. Jerry; Dunn, Martin L.

    2014-09-01

    Recent advances in three dimensional (3D) printing technology that allow multiple materials to be printed within each layer enable the creation of materials and components with precisely controlled heterogeneous microstructures. In addition, active materials, such as shape memory polymers, can be printed to create an active microstructure within a solid. These active materials can subsequently be activated in a controlled manner to change the shape or configuration of the solid in response to an environmental stimulus. This has been termed 4D printing, with the 4th dimension being the time-dependent shape change after the printing. In this paper, we advance the 4D printing concept to the design and fabrication of active origami, where a flat sheet automatically folds into a complicated 3D component. Here we print active composites with shape memory polymer fibers precisely printed in an elastomeric matrix and use them as intelligent active hinges to enable origami folding patterns. We develop a theoretical model to provide guidance in selecting design parameters such as fiber dimensions, hinge length, and programming strains and temperature. Using the model, we design and fabricate several active origami components that assemble from flat polymer sheets, including a box, a pyramid, and two origami airplanes. In addition, we directly print a 3D box with active composite hinges and program it to assume a temporary flat shape that subsequently recovers to the 3D box shape on demand.

  13. 4d Spectra from BPS Quiver Dualities

    NASA Astrophysics Data System (ADS)

    Espahbodi, Sam

    We attack the question of BPS occupancy in a wide class of 4d N = 2 quantum field theories. We first review the Seiberg-Witten approach to finding the low energy Wilsonian effective action actions of such theories. In particular, we analyze the case of Gaiotto theories, which provide a large number of non-trivial examples in a unified framework. We then turn to understanding the massive BPS spectrum of such theories, and in particular their relation to BPS quivers. We present a purely 4d characterization of BPS quivers, and explain how a quiver's representation theory encodes the solution to the BPS occupancy problem. Next, we derive a so called mutation method, based on exploiting quiver dualities, to solve the quiver's representation theory. This method makes previously intractable calculations nearly trivial in many examples. As a particular highlight, we apply our methods to understand strongly coupled chambers in ADE SYM gauge theories with matter. Following this, we turn to the general story of quivers for theories of the Gaiotto class. We present a geometric approach to attaining quivers for the rank 2 theories, leading to a very elegant solution which includes a specification of quiver superpotentials. Finally, we solve these theories by an unrelated method based on gauging flavor symmetries in their various dual weakly coupled Lagrangian descriptions. After seeing that this method agrees in the rank 2 case, we will apply our new approach to the case of rank n.

  14. Advances in 4D radiation therapy for managing respiration: part II - 4D treatment planning.

    PubMed

    Rosu, Mihaela; Hugo, Geoffrey D

    2012-12-01

    The development of 4D CT imaging technology made possible the creation of patient models that are reflective of respiration-induced anatomical changes by adding a temporal dimension to the conventional 3D, spatial-only, patient description. This had opened a new venue for treatment planning and radiation delivery, aimed at creating a comprehensive 4D radiation therapy process for moving targets. Unlike other breathing motion compensation strategies (e.g. breath-hold and gating techniques), 4D radiotherapy assumes treatment delivery over the entire respiratory cycle - an added bonus for both patient comfort and treatment time efficiency. The time-dependent positional and volumetric information holds the promise for optimal, highly conformal, radiotherapy for targets experiencing movements caused by respiration, with potentially elevated dose prescriptions and therefore higher cure rates, while avoiding the uninvolved nearby structures. In this paper, the current state of the 4D treatment planning is reviewed, from theory to the established practical routine. While the fundamental principles of 4D radiotherapy are well defined, the development of a complete, robust and clinically feasible process still remains a challenge, imposed by limitations in the available treatment planning and radiation delivery systems.

  15. Soft Route to 4D Tomography

    NASA Astrophysics Data System (ADS)

    Taillandier-Thomas, Thibault; Roux, Stéphane; Hild, François

    2016-07-01

    Based on the assumption that the time evolution of a sample observed by computed tomography requires many less parameters than the definition of the microstructure itself, it is proposed to reconstruct these changes based on the initial state (using computed tomography) and very few radiographs acquired at fixed intervals of time. This Letter presents a proof of concept that for a fatigue cracked sample its kinematics can be tracked from no more than two radiographs in situations where a complete 3D view would require several hundreds of radiographs. This 2 order of magnitude gain opens the way to a "computed" 4D tomography, which complements the recent progress achieved in fast or ultrafast computed tomography, which is based on beam brightness, detector sensitivity, and signal acquisition technologies.

  16. Cell Autonomous and Nonautonomous Function of CUL4B in Mouse Spermatogenesis.

    PubMed

    Yin, Yan; Liu, Liren; Yang, Chenyi; Lin, Congxing; Veith, George Michael; Wang, Caihong; Sutovsky, Peter; Zhou, Pengbo; Ma, Liang

    2016-03-25

    CUL4B ubiquitin ligase belongs to the cullin-RING ubiquitin ligase family. Although sharing many sequence and structural similarities, CUL4B plays distinct roles in spermatogenesis from its homologous protein CUL4A. We previously reported that genetic ablation ofCul4ain mice led to male infertility because of aberrant meiotic progression. In the present study, we generated Cul4bgerm cell-specific conditional knock-out (Cul4b(Vasa)),as well asCul4bglobal knock-out (Cul4b(Sox2)) mouse, to investigate its roles in spermatogenesis. Germ cell-specific deletion of Cul4bled to male infertility, despite normal testicular morphology and comparable numbers of spermatozoa. Notably, significantly impaired sperm mobility caused by reduced mitochondrial activity and glycolysis level were observed in the majority of the mutant spermatozoa, manifested by low, if any, sperm ATP production. Furthermore,Cul4b(Vasa)spermatozoa exhibited defective arrangement of axonemal microtubules and flagella outer dense fibers. Our mass spectrometry analysis identified INSL6 as a novel CUL4B substrate in male germ cells, evidenced by its direct polyubiquination and degradation by CUL4B E3 ligase. Nevertheless,Cul4bglobal knock-out males lost their germ cells in an age-dependent manner, implying failure of maintaining the spermatogonial stem cell niche in somatic cells. Taken together, our results show that CUL4B is indispensable to spermatogenesis, and it functions cell autonomously in male germ cells to ensure spermatozoa motility, whereas it functions non-cell-autonomously in somatic cells to maintain spermatogonial stemness. Thus, CUL4B links two distinct spermatogenetic processes to a single E3 ligase, highlighting the significance of ubiquitin modification during spermatogenesis.

  17. Controlled Source 4D Seismic Imaging

    NASA Astrophysics Data System (ADS)

    Luo, Y.; Morency, C.; Tromp, J.

    2009-12-01

    Earth's material properties may change after significant tectonic events, e.g., volcanic eruptions, earthquake ruptures, landslides, and hydrocarbon migration. While many studies focus on how to interpret observations in terms of changes in wavespeeds and attenuation, the oil industry is more interested in how we can identify and locate such temporal changes using seismic waves generated by controlled sources. 4D seismic analysis is indeed an important tool to monitor fluid movement in hydrocarbon reservoirs during production, improving fields management. Classic 4D seismic imaging involves comparing images obtained from two subsequent seismic surveys. Differences between the two images tell us where temporal changes occurred. However, when the temporal changes are small, it may be quite hard to reliably identify and characterize the differences between the two images. We propose to back-project residual seismograms between two subsequent surveys using adjoint methods, which results in images highlighting temporal changes. We use the SEG/EAGE salt dome model to illustrate our approach. In two subsequent surveys, the wavespeeds and density within a target region are changed, mimicking possible fluid migration. Due to changes in material properties induced by fluid migration, seismograms recorded in the two surveys differ. By back propagating these residuals, the adjoint images identify the location of the affected region. An important issue involves the nature of model. For instance, are we characterizing only changes in wavespeed, or do we also consider density and attenuation? How many model parameters characterize the model, e.g., is our model isotropic or anisotropic? Is acoustic wave propagation accurate enough or do we need to consider elastic or poroelastic effects? We will investigate how imaging strategies based upon acoustic, elastic and poroelastic simulations affect our imaging capabilities.

  18. Accelerated hepatocellular carcinoma development in CUL4B transgenic mice.

    PubMed

    Yuan, Jupeng; Jiang, Baichun; Zhang, Aizhen; Qian, Yanyan; Tan, Haining; Gao, Jiangang; Shao, Changshun; Gong, Yaoqin

    2015-06-20

    Cullin 4B (CUL4B) is a component of the Cullin 4B-Ring E3 ligase (CRL4B) complex that functions in proteolysis and in epigenetic regulation. CUL4B possesses tumor-promoting properties and is markedly upregulated in many types of human cancers. To determine the role of CUL4B in liver tumorigenesis, we generated transgenic mice that expressed human CUL4B in livers and other tissues and evaluated the development of spontaneous and chemically-induced hepatocellular carcinomas. We observed that CUL4B transgenic mice spontaneously developed liver tumors at a high incidence at old ages and exhibited enhanced DEN-induced hepatocarcinogenesis. There was a high proliferation rate in the livers of CUL4B transgenic mice that was accompanied by increased levels of Cdk1, Cdk4 and cyclin D1 and decreased level of p16. The transgenic mice also exhibited increased compensatory proliferation after DEN-induced liver injury, which was accompanied by activation of Akt, Erk, p38 and NF-κB. We also found that Prdx3 was downregulated and that DEN induced a higher level of reactive oxygen species in the livers of transgenic mice. Together, our results demonstrate a critical role of CUL4B in hepatocarcinogenesis in mice.

  19. Opening the Black Box of ICT4D: Advancing Our Understanding of ICT4D Partnerships

    ERIC Educational Resources Information Center

    Park, Sung Jin

    2013-01-01

    The term, Information and Communication Technologies for Development (ICT4D), pertains to programs or projects that strategically use ICTs (e.g. mobile phones, computers, and the internet) as a means toward the socio-economic betterment for the poor in developing contexts. Gaining the political and financial support of the international community…

  20. Variants in CUL4B are Associated with Cerebral Malformations

    PubMed Central

    Vulto-van Silfhout, Anneke T.; Nakagawa, Tadashi; Bahi-Buisson, Nadia; Haas, Stefan A.; Hu, Hao; Bienek, Melanie; Vissers, Lisenka E.L.M.; Gilissen, Christian; Tzschach, Andreas; Busche, Andreas; Müsebeck, Jörg; Rump, Patrick; Mathijssen, Inge B.; Avela, Kristiina; Somer, Mirja; Doagu, Fatma; Philips, Anju K.; Rauch, Anita; Baumer, Alessandra; Voesenek, Krysta; Poirier, Karine; Vigneron, Jacqueline; Amram, Daniel; Odent, Sylvie; Nawara, Magdalena; Obersztyn, Ewa; Lenart, Jacek; Charzewska, Agnieszka; Lebrun, Nicolas; Fischer, Ute; Nillesen, Willy M.; Yntema, Helger G.; Järvelä, Irma; Ropers, Hans-Hilger; de Vries, Bert B.A.; Brunner, Han G.; van Bokhoven, Hans; Raymond, F. Lucy; Willemsen, Michèl A.A.P.; Chelly, Jamel; Xiong, Yue; Barkovich, A. James; Kalscheuer, Vera M.; Kleefstra, Tjitske; de Brouwer, Arjan P.M.

    2015-01-01

    Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B. PMID:25385192

  1. Variants in CUL4B are associated with cerebral malformations.

    PubMed

    Vulto-van Silfhout, Anneke T; Nakagawa, Tadashi; Bahi-Buisson, Nadia; Haas, Stefan A; Hu, Hao; Bienek, Melanie; Vissers, Lisenka E L M; Gilissen, Christian; Tzschach, Andreas; Busche, Andreas; Müsebeck, Jörg; Rump, Patrick; Mathijssen, Inge B; Avela, Kristiina; Somer, Mirja; Doagu, Fatma; Philips, Anju K; Rauch, Anita; Baumer, Alessandra; Voesenek, Krysta; Poirier, Karine; Vigneron, Jacqueline; Amram, Daniel; Odent, Sylvie; Nawara, Magdalena; Obersztyn, Ewa; Lenart, Jacek; Charzewska, Agnieszka; Lebrun, Nicolas; Fischer, Ute; Nillesen, Willy M; Yntema, Helger G; Järvelä, Irma; Ropers, Hans-Hilger; de Vries, Bert B A; Brunner, Han G; van Bokhoven, Hans; Raymond, F Lucy; Willemsen, Michèl A A P; Chelly, Jamel; Xiong, Yue; Barkovich, A James; Kalscheuer, Vera M; Kleefstra, Tjitske; de Brouwer, Arjan P M

    2015-01-01

    Variants in cullin 4B (CUL4B) are a known cause of syndromic X-linked intellectual disability. Here, we describe an additional 25 patients from 11 families with variants in CUL4B. We identified nine different novel variants in these families and confirmed the pathogenicity of all nontruncating variants. Neuroimaging data, available for 15 patients, showed the presence of cerebral malformations in ten patients. The cerebral anomalies comprised malformations of cortical development (MCD), ventriculomegaly, and diminished white matter volume. The phenotypic heterogeneity of the cerebral malformations might result from the involvement of CUL-4B in various cellular pathways essential for normal brain development. Accordingly, we show that CUL-4B interacts with WDR62, a protein in which variants were previously identified in patients with microcephaly and a wide range of MCD. This interaction might contribute to the development of cerebral malformations in patients with variants in CUL4B.

  2. Spatiotemporal directional analysis of 4D echocardiography

    NASA Astrophysics Data System (ADS)

    Angelini-Casadevall, Elsa D.; Laine, Andrew F.; Takuma, Shin; Homma, Shunichi

    2000-12-01

    Speckle noise corrupts ultrasonic data by introducing sharp changes in an echocardiographic image intensity profile, while attenuation alters the intensity of equally significant cardiac structures. These properties introduce inhomogeneity in the spatial domain and suggests that measures based on phase information rather than intensity are more appropriate for denoising and cardiac border detection. The present analysis method relies on the expansion of temporal ultrasonic volume data on complex exponential wavelet-like basis functions called Brushlets. These basis functions decompose a signal into distinct patterns of oriented textures. Projected coefficients are associated with distinct 'brush strokes' of a particular size and orientation. 4D overcomplete brushlet analysis is applied to temporal echocardiographic values. We show that adding the time dimension in the analysis dramatically improves the quality and robustness of the method without adding complexity in the design of a segmentation tool. We have investigated mathematical and empirical methods for identifying the most 'efficient' brush stroke sizes and orientations for decomposition and reconstruction on both phantom and clinical data. In order to determine the 'best tiling' or equivalently, the 'best brushlet basis', we use an entorpy-based information cost metric function. Quantitative validation and clinical applications of this new spatio-temporal analysis tool are reported for balloon phantoms and clinical data sets.

  3. PROCEEDINGS: 1993 SO2 CONTROL SYMPOSIUM - VOLUME 2. SESSIONS 4A, 4B, AND 5A

    EPA Science Inventory

    The report documents more than 100 presentations at the 1993 SO2 Control Symposium in Boston, MA, August 24-27, 1993. The presentations covered a wide range of topics: industry's strategies for dealing with Clean Air Act Amendments of 1990, including Phase I strategies, the emiss...

  4. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2010 CFR

    2011-04-01

    ... 17 Commodity and Securities Exchanges 3 2011-04-01 2011-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  5. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2010 CFR

    2012-04-01

    ... 17 Commodity and Securities Exchanges 3 2012-04-01 2012-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  6. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2010 CFR

    2000-04-01

    ... 17 Commodity and Securities Exchanges 3 2000-04-01 2000-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a) Each application for an order under section 304(d)...

  7. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2010 CFR

    2005-04-01

    ... 17 Commodity and Securities Exchanges 3 2005-04-01 2005-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a)...

  8. High resolution crystal structure of human Dim2/TXNL4B

    Technology Transfer Automated Retrieval System (TEKTRAN)

    TXNL4A (thioredoxin like 4A) is an essential protein conserved from yeast to human and is a component of the pre-mRNA splicing machinery. TXNL4B was identified as a TXNL4 family protein that also interacts with prp6, an integral component of the U4/U6•U5 tri-snRNP complex, and was shown to function...

  9. Phosphorylation of mammalian initiation factor eIF-4B

    SciTech Connect

    Duncan, R.F.; Milburn, S.C.; Cooper, R.; Gould, K.; Hunter, T.; Hershey, J.W.B.

    1987-05-01

    The phosphorylation of initiation factors appears to be an important mechanism for regulating the rate of translation in mammalian cells. eIF-4B (80 kDa) purified from HeLa cells exhibits a complex array of 8 to 12 spots when analyzed by 2-dimensional isoelectric focusing - SDS polyacrylamide gel electrophoresis. A similar array of eIF-4B spots is seen when total lysate proteins are analyzed by immunoblotting with anti-eIF-4B antiserum or with antibodies affinity-purified from the most basic eIF-4B spot. The multiple forms of eIF-4B are due to phosphorylation, since all but the most basic spot are labeled with (/sup 32/P)phosphate in vivo and the action of alkaline phosphatase in vitro reduces the array to only two spots. Tryptic peptide maps of phosphopeptides from each of the various isoelectric variants of eIF-4B show a similar complexity, suggesting that a number of different sites are phosphorylated in a random order. When serum-deprived HeLa cells are treated with phorbol ester, both the protein synthesis rate and the extent of eIF-4B phosphorylation increase, suggesting that C kinase may be a regulator of translation. Purified C kinase phosphorylates a number of pure initiation factors in vitro, but eIF-4B is the strongest target protein. When pure eIF-4B is treated, the entire mass of eIF-4B is shifted to the most acidic spots, indicating very strong phosphorylation. Attempts are being made to detect differences in the in vitro activities of the non-phosphorylated and highly phosphorylated forms.

  10. 4D electron microscopy: principles and applications.

    PubMed

    Flannigan, David J; Zewail, Ahmed H

    2012-10-16

    achievable with short intense pulses containing a large number of electrons, however, are limited to tens of nanometers and nanoseconds, respectively. This is because Coulomb repulsion is significant in such a pulse, and the electrons spread in space and time, thus limiting the beam coherence. It is therefore not possible to image the ultrafast elementary dynamics of complex transformations. The challenge was to retain the high spatial resolution of a conventional TEM while simultaneously enabling the temporal resolution required to visualize atomic-scale motions. In this Account, we discuss the development of four-dimensional ultrafast electron microscopy (4D UEM) and summarize techniques and applications that illustrate the power of the approach. In UEM, images are obtained either stroboscopically with coherent single-electron packets or with a single electron bunch. Coulomb repulsion is absent under the single-electron condition, thus permitting imaging, diffraction, and spectroscopy, all with high spatiotemporal resolution, the atomic scale (sub-nanometer and femtosecond). The time resolution is limited only by the laser pulse duration and energy carried by the electron packets; the CCD camera has no bearing on the temporal resolution. In the regime of single pulses of electrons, the temporal resolution of picoseconds can be attained when hundreds of electrons are in the bunch. The applications given here are selected to highlight phenomena of different length and time scales, from atomic motions during structural dynamics to phase transitions and nanomechanical oscillations. We conclude with a brief discussion of emerging methods, which include scanning ultrafast electron microscopy (S-UEM), scanning transmission ultrafast electron microscopy (ST-UEM) with convergent beams, and time-resolved imaging of biological structures at ambient conditions with environmental cells.

  11. Motion4D-library extended

    NASA Astrophysics Data System (ADS)

    Müller, Thomas

    2011-06-01

    The new version of the Motion4D-library now also includes the integration of a Sachs basis and the Jacobi equation to determine gravitational lensing of pointlike sources for arbitrary spacetimes.New version program summaryProgram title: Motion4D-libraryCatalogue identifier: AEEX_v3_0Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEEX_v3_0.htmlProgram obtainable from: CPC Program Library, Queen's University, Belfast, N. IrelandLicensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.htmlNo. of lines in distributed program, including test data, etc.: 219 441No. of bytes in distributed program, including test data, etc.: 6 968 223Distribution format: tar.gzProgramming language: C++Computer: All platforms with a C++ compilerOperating system: Linux, WindowsRAM: 61 MbytesClassification: 1.5External routines: Gnu Scientic Library (GSL) (http://www.gnu.org/software/gsl/)Catalogue identifier of previous version: AEEX_v2_0Journal reference of previous version: Comput. Phys. Comm. 181 (2010) 703Does the new version supersede the previous version?: YesNature of problem: Solve geodesic equation, parallel and Fermi-Walker transport in four-dimensional Lorentzian spacetimes. Determine gravitational lensing by integration of Jacobi equation and parallel transport of Sachs basis.Solution method: Integration of ordinary differential equations.Reasons for new version: The main novelty of the current version is the extension to integrate the Jacobi equation and the parallel transport of the Sachs basis along null geodesics. In combination, the change of the cross section of a light bundle and thus the gravitational lensing effect of a spacetime can be determined. Furthermore, we have implemented several new metrics.Summary of revisions: The main novelty of the current version is the integration of the Jacobi equation and the parallel transport of the Sachs basis along null geodesics. The corresponding set of equations readd2xμdλ2=-Γρ

  12. Category 4b - A Regulatory Alternative to TMDLs

    EPA Pesticide Factsheets

    The paper describes the extent to which states have successfully employed TMDL alternatives to address impaired waters and assigned these waters to Category 4b, and includes several Washington State examples.

  13. Nanog regulates primordial germ cell migration through Cxcr4b.

    PubMed

    Sánchez-Sánchez, Ana Virginia; Camp, Esther; Leal-Tassias, Aránzazu; Atkinson, Stuart P; Armstrong, Lyle; Díaz-Llopis, Manuel; Mullor, José L

    2010-09-01

    Gonadal development in vertebrates depends on the early determination of primordial germ cells (PGCs) and their correct migration to the sites where the gonads develop. Several genes have been implicated in PGC specification and migration in vertebrates. Additionally, some of the genes associated with pluripotency, such as Oct4 and Nanog, are expressed in PGCs and gonads, suggesting a role for these genes in maintaining pluripotency of the germ lineage, which may be considered the only cell type that perpetually maintains stemness properties. Here, we report that medaka Nanog (Ol-Nanog) is expressed in the developing PGCs. Depletion of Ol-Nanog protein causes aberrant migration of PGCs and inhibits expression of Cxcr4b in PGCs, where it normally serves as the receptor of Sdf1a to guide PGC migration. Moreover, chromatin immunoprecipitation analysis demonstrates that Ol-Nanog protein binds to the promoter region of Cxcr4b, suggesting a direct regulation of Cxcr4b by Ol-Nanog. Simultaneous overexpression of Cxcr4b mRNA and depletion of Ol-Nanog protein in PGCs rescues the migration defective phenotype induced by a loss of Ol-Nanog, whereas overexpression of Sdf1a, the ligand for Cxcr4b, does not restore proper PGC migration. These results indicate that Ol-Nanog mediates PGC migration by regulating Cxcr4b expression.

  14. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 17 Commodity and Securities Exchanges 3 2013-04-01 2013-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a) Each application for an order under section 304(d)...

  15. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 17 Commodity and Securities Exchanges 4 2014-04-01 2014-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a) Each application for an order under section 304(d)...

  16. 17 CFR 260.4d-8 - Content.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 17 Commodity and Securities Exchanges 3 2010-04-01 2010-04-01 false Content. 260.4d-8 Section 260.4d-8 Commodity and Securities Exchanges SECURITIES AND EXCHANGE COMMISSION (CONTINUED) GENERAL RULES AND REGULATIONS, TRUST INDENTURE ACT OF 1939 Rules Under Section 304 § 260.4d-8 Content. (a) Each application for an order under section 304(d)...

  17. Killing Weeds with 2,4-D. Extension Bulletin 389.

    ERIC Educational Resources Information Center

    Lee, Oliver C.

    Discussed is the use of the herbicide 2,4-D. Though written for farmers and agricultural workers, the pamphlet considers turf weed control and use of 2,4-D near ornamental plants. Aspects of the use of this herbicide covered are: (1) the common forms of 2,4-D; (2) plant responses and tolerances to the herbicide; (3) dilution and concentration of…

  18. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  19. 32 CFR 1645.4 - Exclusion from Class 4-D.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... MINISTERS OF RELIGION § 1645.4 Exclusion from Class 4-D. A registrant is excluded from Class 4-D when his... duly ordained minister of religion in accordance with the ceremonial rite or discipline of a church... principles of religion and administer the ordinances of public worship, as embodied in the creed...

  20. 4D Printing with Mechanically Robust, Thermally Actuating Hydrogels.

    PubMed

    Bakarich, Shannon E; Gorkin, Robert; in het Panhuis, Marc; Spinks, Geoffrey M

    2015-06-01

    A smart valve is created by 4D printing of hydrogels that are both mechanically robust and thermally actuating. The printed hydrogels are made up of an interpenetrating network of alginate and poly(N-isopropylacrylamide). 4D structures are created by printing the "dynamic" hydrogel ink alongside other static materials.

  1. A Genetic Interaction between Hepatitis C Virus NS4B and NS3 Is Important for RNA Replication▿

    PubMed Central

    Paredes, Anne M.; Blight, Keril J.

    2008-01-01

    Hepatitis C virus (HCV) nonstructural protein 4B (NS4B), a poorly characterized integral membrane protein, is thought to function as a scaffold for replication complex assembly; however, functional interactions with the other HCV nonstructural proteins within this complex have not been defined. We report that a Con1 chimeric subgenomic replicon containing the NS4B gene from the closely related H77 isolate is defective for RNA replication in a transient assay, suggesting that H77 NS4B is unable to productively interact with the Con1 replication machinery. The H77 NS4B sequences that proved detrimental for Con1 RNA replication resided in the predicted N- and C-terminal cytoplasmic domains as well as the central transmembrane region. Selection for Con1 derivatives that could utilize the entire H77 NS4B or hybrid Con1-H77 NS4B proteins yielded mutants containing single amino acid substitutions in NS3 and NS4A. The second-site mutations in NS3 partially restored the replication of Con1 chimeras containing the N-terminal or transmembrane domains of H77 NS4B. In contrast, the deleterious H77-specific sequences in the C terminus of NS4B, which mapped to a cluster of four amino acids, were completely suppressed by second-site substitutions in NS3. Collectively, these results provide the first evidence for a genetic interaction between NS4B and NS3 important for productive HCV RNA replication. PMID:18715921

  2. Sema4d is required for the development of the hindbrain boundary and skeletal muscle in zebrafish

    SciTech Connect

    Yang, Jie; Zeng, Zhen; Wei, Juncheng; Jiang, Lijun; Ma, Quanfu; Wu, Mingfu; Huang, Xiaoyuan; Ye, Shuangmei; Li, Ye; Ma, Ding; Gao, Qinglei

    2013-04-05

    Highlights: ► Sema4d was expressed at all developmental stages of zebrafish. ► Knockdown of sema4d in embryos resulted in defects in the hindbrain and the trunk structure. ► Knockdown of sema4d in embryos upregulated the expression of three hindbrain rhombomere markers. ► Knockdown of sema4d in embryos increased the expression of myogenic regulatory factors. ► Knockdown of sema4d in embryos resulted in an obvious increase of cell apoptosis. -- Abstract: Semaphorin4d (SEMA4D), also known as CD100, an oligodendrocyte secreted R-Ras GTPase-activating protein (GAP), affecting axonal growth is involved in a range of processes including cell adhesion, motility, angiogenesis, immune responses and tumour progression. However, its actual physiological mechanisms and its role in development remain unclear. This study has focused on the role of sema4d in the development and expression patterns in zebrafish embryos and the effect of its suppression on development using sema4d-specific antisense morpholino-oligonucleotides. In this study the knockdown of sema4d, expressed at all developmental stages, lead to defects in the hindbrain and trunk structure of zebrafish embryos. In addition, these phenotypes appeared to be associated with the abnormal expression of three hindbrain rhombomere boundary markers, wnt1, epha4a and foxb1.2, and two myogenic regulatory factors, myod and myog. Further, a notable increase of cell apoptosis appeared in the sema4d knockdown embryos, while no obvious reduction in cell proliferation was observed. Collectively, these data suggest that sema4d plays an important role in the development of the hindbrain and skeletal muscle.

  3. Pyrazolopyridines as potent PDE4B inhibitors: 5-Heterocycle SAR

    SciTech Connect

    Mitchell, Charlotte J.; Ballantine, Stuart P.; Coe, Diane M.; Cook, Caroline M.; Delves, Christopher J.; Dowle, Mike D.; Edlin, Chris D.; Hamblin, J. Nicole; Holman, Stuart; Johnson, Martin R.; Jones, Paul S.; Keeling, Sue E.; Kranz, Michael; Lindvall, Mika; Lucas, Fiona S.; Neu, Margarete; Solanke, Yemisi E.; Somers, Don O.; Trivedi, Naimisha A.; Wiseman, Joanne O.

    2012-05-03

    Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-{alpha} production from isolated human peripheral blood mononuclear cells.

  4. MCNP4B{sup {trademark}} verification and validation

    SciTech Connect

    Hendricks, J.S.; Court, J.D.

    1996-08-01

    Several new features and bug fixes have been incorporated into the new release of MCNP. As required by the MCNP Software Quality Assurance Plan, these changes to the code and the test set are documented here for user reference. This document summarizes the new MCNP4B features and corrections, separated into major and minor groupings. Also included are a code cleanup section and a section delineating problems identified in LA-12839 which have not been corrected. Finally, we document the MCNP4B test set modifications and explain how test set coverage has been improved.

  5. Experimental validation of a 4D elastic registration algorithm.

    PubMed

    Leung, Corina; Hashtrudi-Zaad, Keyvan; Foroughi, Pezhman; Abolmaesumi, Purang

    2008-01-01

    This paper presents an extensive validation study of an elastic registration algorithm for dynamic 3D ultrasound images (also known as a 4D image). The registration algorithm uses attribute vectors from both a fixed and previous moving images to perform feature-based alignment of a series of images. The 4D method reduces computational requirements and increases the effective search space for the location of corresponding features, resulting in enhanced registration speed when compared to a static 3D registration technique. Experimental analysis revealed up to 32% improvement in speed when using the 4D method, which makes the algorithm attractive for real-time applications.

  6. RAMONA-4B code for BWR systems analysis

    SciTech Connect

    Cheng, H.S.; Rohatgi, U.S.

    1996-12-31

    The RAMONA-4B code is a coupled thermal-hydraulic, 3D kinetics code for plant transient analyses of a complete Boiling Water Reactor (BWR) system including Reactor Pressure Vessel (RPV), Balance of Plant (BOP) and containment. The complete system representation enables an integrated and coupled systems analysis of a BWR without recourse to prescribed boundary conditions.

  7. The calculated magnetic, electronic and thermodynamic properties of Ce3Co29Si4B10 compound

    NASA Astrophysics Data System (ADS)

    Huo, Jin-Rong; Wang, Xiao-Xu; Hu, Yao-Wen; Zhang, Guo-Hua; Cheng, Hai-Xia; Li, Lu; Qian, Ping

    2016-05-01

    The magnetic moment, lattice parameter and atom fraction coordinates for Ce3Co29Si4B10 are calculated by the first-principles GGA+U method, and the results indicate that the calculated and experimental values are basically accordant when U=2.6 eV. We study the interaction effect and orbital hybridization between Co and Ce atoms. The projected density of states at U=2.6 eV which provided by Co-2c, Ce-2b and Ce-4d sites are contrasted with else U values. Meanwhile the electron density of states for different sites and the distance between various atoms are exhibited. In addition, the thermodynamic properties of Ce3Co29Si4B10 are evaluated by using a series of interatomic pair potentials.

  8. Substitutional 4d and 5d impurities in graphene.

    PubMed

    Alonso-Lanza, Tomás; Ayuela, Andrés; Aguilera-Granja, Faustino

    2016-08-21

    We describe the structural and electronic properties of graphene doped with substitutional impurities of 4d and 5d transition metals. The adsorption energies and distances for 4d and 5d metals in graphene show similar trends for the later groups in the periodic table, which are also well-known characteristics of 3d elements. However, along earlier groups the 4d impurities in graphene show very similar adsorption energies, distances and magnetic moments to the 5d ones, which can be related to the influence of the 4d and 5d lanthanide contraction. Surprisingly, within the manganese group, the total magnetic moment of 3 μB for manganese is reduced to 1 μB for technetium and rhenium. We find that compared with 3d elements, the larger size of the 4d and 5d elements causes a high degree of hybridization with the neighbouring carbon atoms, reducing spin splitting in the d levels. It seems that the magnetic adjustment of graphene could be significantly different if 4d or 5d impurities are used instead of 3d impurities.

  9. Oscillator strengths and branching fractions of 4d75p-4d75s Rh II transitions

    NASA Astrophysics Data System (ADS)

    Bouazza, Safa

    2017-01-01

    This work reports semi-empirical determination of oscillator strengths, transition probabilities and branching fractions for Rh II 4d75p-4d75s transitions in a wide wavelength range. The angular coefficients of the transition matrix, beforehand obtained in pure SL coupling with help of Racah algebra are transformed into intermediate coupling using eigenvector amplitudes of these two configuration levels determined for this purpose; The transition integral was treated as free parameter in the least squares fit to experimental oscillator strength (gf) values found in literature. The extracted value: <4d75s|r1|4d75p> =2.7426 ± 0.0007 is slightly smaller than that computed by means of ab-initio method. Subsequently to oscillator strength evaluations, transition probabilities and branching fractions were deduced and compared to those obtained experimentally or through another approach like pseudo-relativistic Hartree-Fock model including core-polarization effects.

  10. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer

    PubMed Central

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R.

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects. PMID:26910109

  11. Soil matrix and macropore biodegradation of 2,4-D

    SciTech Connect

    Pivetz, B.E.; Steenhuis, T.S.

    1995-07-01

    Preferential flow of pesticides in macropores can lead to decreased travel times through the vadose zone and increased groundwater contamination. Macropores, however, may present a favorable environment for biodegradation because of greater oxygen, nutrient, and substrate supply, and higher microbial populations in earthworm burrows, compared to the soil matrix. The biodegradation of 2,4-dichlorophenoxyacetic acid (2,4-D) was measured in macropores and soil matrix of packed soil columns (7.0-cm diam., 10-cm length) and undisturbed cores contained as well-defined artificial macropore and the undisturbed cores contained earthworm-burrow macropores. A 50 {mu}g/L 2,4-D solution was continuously applied to the unsaturated soil surface and breakthrough curves (BTCs) indicating pesticide loss in the effluent were obtained from the soil matrix and macropore flow paths. Biodegradation rates were calculated separately for each flow path by comparing the BTCs to BTCs representing abiotic conditions, and dividing the 2,4-D loss by the travel time through each flow path. The biodegradation rates increased with time in both flow paths, and the final biodegradation rate in the macropore region surpassed that of the matrix, presumably because of increased microbial populations in the macropore. Complete loss of the 2,4-D in both flow paths was observed after continuous application of 2,4-D for 400 h, with maximum column-averaged 2,4-D loss rates of 0.879 {mu}g/(L h) in the matrix and 1.073 {mu}g/(L h) in the macropore. Biodegradation of 2,4-D was also observed in the macropore and matrix regions of the undisturbed soil cores. 19 refs., 7 figs., 2 tabs.

  12. Semaphorin 4D Promotes Skeletal Metastasis in Breast Cancer.

    PubMed

    Yang, Ying-Hua; Buhamrah, Asma; Schneider, Abraham; Lin, Yi-Ling; Zhou, Hua; Bugshan, Amr; Basile, John R

    2016-01-01

    Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects.

  13. 4D Imaging of Protein Aggregation in Live Cells

    PubMed Central

    Kaganovich, Daniel

    2013-01-01

    One of the key tasks of any living cell is maintaining the proper folding of newly synthesized proteins in the face of ever-changing environmental conditions and an intracellular environment that is tightly packed, sticky, and hazardous to protein stability1. The ability to dynamically balance protein production, folding and degradation demands highly-specialized quality control machinery, whose absolute necessity is observed best when it malfunctions. Diseases such as ALS, Alzheimer's, Parkinson's, and certain forms of Cystic Fibrosis have a direct link to protein folding quality control components2, and therefore future therapeutic development requires a basic understanding of underlying processes. Our experimental challenge is to understand how cells integrate damage signals and mount responses that are tailored to diverse circumstances. The primary reason why protein misfolding represents an existential threat to the cell is the propensity of incorrectly folded proteins to aggregate, thus causing a global perturbation of the crowded and delicate intracellular folding environment1. The folding health, or "proteostasis," of the cellular proteome is maintained, even under the duress of aging, stress and oxidative damage, by the coordinated action of different mechanistic units in an elaborate quality control system3,4. A specialized machinery of molecular chaperones can bind non-native polypeptides and promote their folding into the native state1, target them for degradation by the ubiquitin-proteasome system5, or direct them to protective aggregation inclusions6-9. In eukaryotes, the cytosolic aggregation quality control load is partitioned between two compartments8-10: the juxtanuclear quality control compartment (JUNQ) and the insoluble protein deposit (IPOD) (Figure 1 - model). Proteins that are ubiquitinated by the protein folding quality control machinery are delivered to the JUNQ, where they are processed for degradation by the proteasome. Misfolded

  14. Discovery of Dengue Virus NS4B Inhibitors

    PubMed Central

    Wang, Qing-Yin; Dong, Hongping; Zou, Bin; Karuna, Ratna; Wan, Kah Fei; Zou, Jing; Susila, Agatha; Yip, Andy; Shan, Chao; Yeo, Kim Long; Xu, Haoying; Ding, Mei; Chan, Wai Ling; Gu, Feng; Seah, Peck Gee; Liu, Wei; Lakshminarayana, Suresh B.; Kang, CongBao; Lescar, Julien; Blasco, Francesca; Smith, Paul W.

    2015-01-01

    ABSTRACT The four serotypes of dengue virus (DENV-1 to -4) represent the most prevalent mosquito-borne viral pathogens in humans. No clinically approved vaccine or antiviral is currently available for DENV. Here we report a spiropyrazolopyridone compound that potently inhibits DENV both in vitro and in vivo. The inhibitor was identified through screening of a 1.8-million-compound library by using a DENV-2 replicon assay. The compound selectively inhibits DENV-2 and -3 (50% effective concentration [EC50], 10 to 80 nM) but not DENV-1 and -4 (EC50, >20 μM). Resistance analysis showed that a mutation at amino acid 63 of DENV-2 NS4B (a nonenzymatic transmembrane protein and a component of the viral replication complex) could confer resistance to compound inhibition. Genetic studies demonstrate that variations at amino acid 63 of viral NS4B are responsible for the selective inhibition of DENV-2 and -3. Medicinal chemistry improved the physicochemical properties of the initial “hit” (compound 1), leading to compound 14a, which has good in vivo pharmacokinetics. Treatment of DENV-2-infected AG129 mice with compound 14a suppressed viremia, even when the treatment started after viral infection. The results have proven the concept that inhibitors of NS4B could potentially be developed for clinical treatment of DENV infection. Compound 14a represents a potential preclinical candidate for treatment of DENV-2- and -3-infected patients. IMPORTANCE Dengue virus (DENV) threatens up to 2.5 billion people and is now spreading in many regions in the world where it was not previously endemic. While there are several promising vaccine candidates in clinical trials, approved vaccines or antivirals are not yet available. Here we describe the identification and characterization of a spiropyrazolopyridone as a novel inhibitor of DENV by targeting the viral NS4B protein. The compound potently inhibits two of the four serotypes of DENV (DENV-2 and -3) both in vitro and in vivo. Our

  15. True 4D Image Denoising on the GPU.

    PubMed

    Eklund, Anders; Andersson, Mats; Knutsson, Hans

    2011-01-01

    The use of image denoising techniques is an important part of many medical imaging applications. One common application is to improve the image quality of low-dose (noisy) computed tomography (CT) data. While 3D image denoising previously has been applied to several volumes independently, there has not been much work done on true 4D image denoising, where the algorithm considers several volumes at the same time. The problem with 4D image denoising, compared to 2D and 3D denoising, is that the computational complexity increases exponentially. In this paper we describe a novel algorithm for true 4D image denoising, based on local adaptive filtering, and how to implement it on the graphics processing unit (GPU). The algorithm was applied to a 4D CT heart dataset of the resolution 512  × 512  × 445  × 20. The result is that the GPU can complete the denoising in about 25 minutes if spatial filtering is used and in about 8 minutes if FFT-based filtering is used. The CPU implementation requires several days of processing time for spatial filtering and about 50 minutes for FFT-based filtering. The short processing time increases the clinical value of true 4D image denoising significantly.

  16. Motion management with phase-adapted 4D-optimization

    NASA Astrophysics Data System (ADS)

    Nohadani, Omid; Seco, Joao; Bortfeld, Thomas

    2010-09-01

    Cancer treatment with ionizing radiation is often compromised by organ motion, in particular for lung cases. Motion uncertainties can significantly degrade an otherwise optimized treatment plan. We present a spatiotemporal optimization method, which takes into account all phases of breathing via the corresponding 4D-CTs and provides a 4D-optimal plan that can be delivered throughout all breathing phases. Monte Carlo dose calculations are employed to warrant for highest dosimetric accuracy, as pertinent to study motion effects in lung. We demonstrate the performance of this optimization method with clinical lung cancer cases and compare the outcomes to conventional gating techniques. We report significant improvements in target coverage and in healthy tissue sparing at a comparable computational expense. Furthermore, we show that the phase-adapted 4D-optimized plans are robust against irregular breathing, as opposed to gating. This technique has the potential to yield a higher delivery efficiency and a decisively shorter delivery time.

  17. 3D/4D sonography - any safety problem.

    PubMed

    Pooh, Ritsuko K; Maeda, Kazuo; Kurjak, Asim; Sen, Cihat; Ebrashy, Alaa; Adra, Abdallah; Dayyabu, Aliyu Labaran; Wataganara, Tuangsit; de Sá, Renato Augusto Moreira; Stanojevic, Milan

    2016-03-01

    Gray-scale image data are processed in 3D ultrasound by repeated scans of multiple planes within a few seconds to achieve one surface rendering image and three perpendicular plane images. The 4D image is achieved by repeating 3D images in short intervals, i.e. 3D and 4D ultrasound are based on simple B-mode images. During 3D/4D acquisition, a fetus in utero is exposed by ultrasound beam for only a few seconds, and it is as short as real-time B-mode scanning. Therefore, simple 3D imaging is as safe as a simple B-mode scan. The 4D ultrasound is also as safe as a simple B-mode scan, but the ultrasound exposure should be shorter than 30 min. The thermal index (TI) and mechanical index (MI) should both be lower than 1.0, and the ultrasound study is regulated by the Doppler ultrasound if it is combined with simple 3D or 4D ultrasound. Recently, some articles have reported the functional changes of animal fetal brain neuronal cells and liver cell apoptosis with Doppler ultrasound. We discuss cell apoptosis by ultrasound in this report. Diagnostic ultrasound safety is achieved by controlling the output pulse and continuous ultrasound waves using thermal and mechanical indices, which should be <1.0 in abdominal and transvaginal scan, pulsed Doppler, as well as 3D and 4D ultrasound. The lowest spatial peak temporal average (SPTA) intensity of the ultrasound to suppress cultured cell growth is 240 mW/cm2, below which no ultrasound effect has been reported. An ultrasound user must be trained to recognize the ultrasound bioeffects; thermal and mechanical indices, and how to reduce these when they are higher than 1.0 on the monitor display; and guide the proper use of the ultrasound under the ALARA principle, because the user is responsible for ensuring ultrasound safety.

  18. The 4-D approach to visual control of autonomous systems

    NASA Technical Reports Server (NTRS)

    Dickmanns, Ernst D.

    1994-01-01

    Development of a 4-D approach to dynamic machine vision is described. Core elements of this method are spatio-temporal models oriented towards objects and laws of perspective projection in a foward mode. Integration of multi-sensory measurement data was achieved through spatio-temporal models as invariants for object recognition. Situation assessment and long term predictions were allowed through maintenance of a symbolic 4-D image of processes involving objects. Behavioral capabilities were easily realized by state feedback and feed-foward control.

  19. 4D ultrasound imaging - ethically justifiable in India?

    PubMed

    Indiran, Venkatraman

    2017-01-01

    Four-dimensional (4D) ultrasound (real-time volume sonography), which has been used in the West since the last decade for the determination of gender as well as for bonding and entertainment of the parents, has become widely available in India in this decade. Here, I would like to discuss the ethical issues associated with 4D ultrasonography in India. These are self-referral, the use of the technology for non-medical indications, a higher possibility of the disclosure of the foetus' gender and safety concerns.

  20. Emerging Applications of Abdominal 4D Flow MRI

    PubMed Central

    Roldán-Alzate, Alejandro; Francois, Christopher J.; Wieben, Oliver; Reeder, Scott B.

    2016-01-01

    OBJECTIVE Comprehensive assessment of abdominal hemodynamics is crucial for many clinical diagnoses but is challenged by a tremendous complexity of anatomy, normal physiology, and a wide variety of pathologic abnormalities. This article introduces 4D flow MRI as a powerful technique for noninvasive assessment of the hemodynamics of abdominal vascular territories. CONCLUSION Four-dimensional flow MRI provides clinicians with a more extensive and straightforward approach to evaluate disorders that affect blood flow in the abdomen. This review presents a series of clinical cases to illustrate the utility of 4D flow MRI in the comprehensive assessment of the abdominal circulation. PMID:27187681

  1. Characterization of Nuclear Localization Signal in the N Terminus of CUL4B and Its Essential Role in Cyclin E Degradation and Cell Cycle Progression*

    PubMed Central

    Zou, Yongxin; Mi, Jun; Cui, Jinpeng; Lu, Defen; Zhang, Xiyu; Guo, Chenhong; Gao, Guimin; Liu, Qiji; Chen, Bingxi; Shao, Changshun; Gong, Yaoqin

    2009-01-01

    CUL4A and CUL4B, which are derived from the same ancestor, CUL4, encode scaffold proteins that organize cullin-RING ubiquitin ligase (E3) complexes. Recent genetic studies have shown that germ line mutation in CUL4B can cause mental retardation, short stature, and other abnormalities in humans. CUL4A was observed to be overexpressed in breast and hepatocellular cancers, although no germ line mutation in human CUL4A has been reported. Although CUL4A has been known to be involved in a number of cellular processes, including DNA repair and cell cycle regulation, little is known about whether CUL4B has similar functions. In this report, we tested the functional importance of CUL4B in cell proliferation and characterized the nuclear localization signal (NLS) that is essential for its function. We found that RNA interference silencing of CUL4B led to an inhibition of cell proliferation and a prolonged S phase, due to the overaccumulation of cyclin E, a substrate targeted by CUL4B for ubiquitination. We showed that, unlike CUL4A and other cullins that carry their NLS in their C termini, NLS in CUL4B is located in its N terminus, between amino acid 37 and 40, KKRK. This NLS could bind to importin α1, α3, and α5. NLS-deleted CUL4B was distributed in cytoplasm and failed to promote cell proliferation. Therefore, the nuclear localization of CUL4B mediated by NLS is critical for its normal function in cell proliferation. PMID:19801544

  2. Enterococcus faecalis promotes osteoclastogenesis and semaphorin 4D expression.

    PubMed

    Wang, Shuai; Deng, Zuhui; Seneviratne, Chaminda J; Cheung, Gary S P; Jin, Lijian; Zhao, Baohong; Zhang, Chengfei

    2015-10-01

    Enterococcus faecalis is considered a major bacterial pathogen implicated in endodontic infections and contributes considerably to periapical periodontitis. This study aimed to investigate the potential mechanisms by which E. faecalis accounts for the bone destruction in periapical periodontitis in vitro. Osteoclast precursor RAW264.7 cells were treated with E. faecalis ATCC 29212 and a wild strain of E. faecalis derived clinically from an infected root canal. The results showed that, to some extent, E. faecalis induced the RAW264.7 cells to form tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclast-like cells. This pathogen markedly stimulated RAW264.7 cells to express semaphorin 4D (Sema4D), which inhibits bone formation. Once RAW264.7 cells were primed by low-dose receptor activator of nuclear factor-kappa B ligand (RANKL), E. faecalis could significantly increase the production of TRAP-positive multinucleated cells and up-regulate the expression of osteoclast-specific markers, including NFATc1, TRAP and cathepsin K. Both p38 and ERK1/2 MAPK signaling pathways were activated by E. faecalis in RANKL-primed RAW264.7 cells, and meanwhile the expression of Sema4D was highly increased. In conclusion, E. faecalis may greatly contribute to the bone resorption in periapical periodontitis by promoting RANKL-dependent osteoclastogenesis and expression of Sema4D through activation of p38 and ERK1/2 MAPK signaling pathways.

  3. The technology and performance of 4D ultrasound.

    PubMed

    Obruchkov, Sergei

    2008-01-01

    Recent developments in 4D ultrasound imaging technology allow clinicians to obtain not only rich visual information but also quantitative data that can be used for diagnosis and treatment. Some argue that the extension of 2D ultrasound is unnecessary and does not offer any benefits to diagnosis, while others argue that it is possible to better assess an abnormality in 3D than 2D. Anatomy can be reconstructed in perspectives that were never seen with conventional 2D US imaging. Advanced rendering techniques in three dimensions can be customized to be sensitive to specific pathology, thus making diagnosis more accurate. Volume and function of certain anatomical components can be measured with greater accuracy. This article reviews physical principles behind the ultrasound technology, how they are applied to advance the field of ultrasound imaging, and maybe reach its limits. Advances in ultrasound technology make 4D ultrasound imaging faster and less dependent on the operator's expertise, thus opening up more research possibilities in the fields of data processing and visualization. Currently, 4D ultrasound is extensively used in the field of obstetrics and interven-tional radiology. The goal of 4D ultrasound is to overcome the limitations posed by its predecessor technology and to be more clinically useful as an imaging tool.

  4. 2,4-Dichlorophenoxyacetic acid (2,4-D)

    Integrated Risk Information System (IRIS)

    2,4 - Dichlorophenoxyacetic acid ( 2,4 - D ) ; CASRN 94 - 75 - 7 Human health assessment information on a chemical substance is included in the IRIS database only after a comprehensive review of toxicity data , as outlined in the IRIS assessment development process . Sections I ( Health Hazard Asses

  5. 4D flow mri post-processing strategies for neuropathologies

    NASA Astrophysics Data System (ADS)

    Schrauben, Eric Mathew

    4D flow MRI allows for the measurement of a dynamic 3D velocity vector field. Blood flow velocities in large vascular territories can be qualitatively visualized with the added benefit of quantitative probing. Within cranial pathologies theorized to have vascular-based contributions or effects, 4D flow MRI provides a unique platform for comprehensive assessment of hemodynamic parameters. Targeted blood flow derived measurements, such as flow rate, pulsatility, retrograde flow, or wall shear stress may provide insight into the onset or characterization of more complex neuropathologies. Therefore, the thorough assessment of each parameter within the context of a given disease has important medical implications. Not surprisingly, the last decade has seen rapid growth in the use of 4D flow MRI. Data acquisition sequences are available to researchers on all major scanner platforms. However, the use has been limited mostly to small research trials. One major reason that has hindered the more widespread use and application in larger clinical trials is the complexity of the post-processing tasks and the lack of adequate tools for these tasks. Post-processing of 4D flow MRI must be semi-automated, fast, user-independent, robust, and reliably consistent for use in a clinical setting, within large patient studies, or across a multicenter trial. Development of proper post-processing methods coupled with systematic investigation in normal and patient populations pushes 4D flow MRI closer to clinical realization while elucidating potential underlying neuropathological origins. Within this framework, the work in this thesis assesses venous flow reproducibility and internal consistency in a healthy population. A preliminary analysis of venous flow parameters in healthy controls and multiple sclerosis patients is performed in a large study employing 4D flow MRI. These studies are performed in the context of the chronic cerebrospinal venous insufficiency hypothesis. Additionally, a

  6. A region rich in aspartic acid, arginine, tyrosine, and glycine (DRYG) mediates eukaryotic initiation factor 4B (eIF4B) self-association and interaction with eIF3.

    PubMed Central

    Méthot, N; Song, M S; Sonenberg, N

    1996-01-01

    The binding of mRNA to the ribosome is mediated by eukaryotic initiation factors eukaryotic initiation factor 4F (eIF4F), eIF4B, eIF4A, and eIF3, eIF4F binds to the mRNA cap structure and, in combination with eIF4B, is believed to unwind the secondary structure in the 5' untranslated region to facilitate ribosome binding. eIF3 associates with the 40S ribosomal subunit prior to mRNA binding. eIF4B copurifies with eIF3 and eIF4F through several purification steps, suggesting the involvement of a multisubunit complex during translation initiation. To understand the mechanism by which eIF4B promotes 40S ribosome binding to the mRNA, we studied its interactions with partner proteins by using a filter overlay (protein-protein [far Western]) assay and the two-hybrid system. In this report, we show that eIF4B self-associates and also interacts directly with the p170 subunit of eIF3. A region rich in aspartic acid, arginine, tyrosine, and glycine, termed the DRYG domain, is sufficient for self-association of eIF4B, both in vitro and in vivo, and for interaction with the p170 subunit of eIF3. These experiments suggest that eIF4B participates in mRNA-ribosome binding by acting as an intermediary between the mRNA and eIF3, via a direct interaction with the p170 subunit of eIF3. PMID:8816444

  7. 4D MR imaging using robust internal respiratory signal

    NASA Astrophysics Data System (ADS)

    Hui, CheukKai; Wen, Zhifei; Stemkens, Bjorn; Tijssen, R. H. N.; van den Berg, C. A. T.; Hwang, Ken-Pin; Beddar, Sam

    2016-05-01

    The purpose of this study is to investigate the feasibility of using internal respiratory (IR) surrogates to sort four-dimensional (4D) magnetic resonance (MR) images. The 4D MR images were constructed by acquiring fast 2D cine MR images sequentially, with each slice scanned for more than one breathing cycle. The 4D volume was then sorted retrospectively using the IR signal. In this study, we propose to use multiple low-frequency components in the Fourier space as well as the anterior body boundary as potential IR surrogates. From these potential IR surrogates, we used a clustering algorithm to identify those that best represented the respiratory pattern to derive the IR signal. A study with healthy volunteers was performed to assess the feasibility of the proposed IR signal. We compared this proposed IR signal with the respiratory signal obtained using respiratory bellows. Overall, 99% of the IR signals matched the bellows signals. The average difference between the end inspiration times in the IR signal and bellows signal was 0.18 s in this cohort of matching signals. For the acquired images corresponding to the other 1% of non-matching signal pairs, the respiratory motion shown in the images was coherent with the respiratory phases determined by the IR signal, but not the bellows signal. This suggested that the IR signal determined by the proposed method could potentially correct the faulty bellows signal. The sorted 4D images showed minimal mismatched artefacts and potential clinical applicability. The proposed IR signal therefore provides a feasible alternative to effectively sort MR images in 4D.

  8. Combined convective and diffusive simulations: VERB-4D comparison with 17 March 2013 Van Allen Probes observations: VERB-4D

    SciTech Connect

    Shprits, Yuri Y.; Kellerman, Adam C.; Drozdov, Alexander Y.; Spence, Harlan E.; Reeves, Geoffrey D.; Baker, Daniel N.

    2015-11-19

    Our study focused on understanding the coupling between different electron populations in the inner magnetosphere and the various physical processes that determine evolution of electron fluxes at different energies. Observations during the 17 March 2013 storm and simulations with a newly developed Versatile Electron Radiation Belt-4D (VERB-4D) are presented. This analysis of the drift trajectories of the energetic and relativistic electrons shows that electron trajectories at transitional energies with a first invariant on the scale of ~100 MeV/G may resemble ring current or relativistic electron trajectories depending on the level of geomagnetic activity. Simulations with the VERB-4D code including convection, radial diffusion, and energy diffusion are presented. Sensitivity simulations including various physical processes show how different acceleration mechanisms contribute to the energization of energetic electrons at transitional energies. In particular, the range of energies where inward transport is strongly influenced by both convection and radial diffusion are studied. Our results of the 4-D simulations are compared to Van Allen Probes observations at a range of energies including source, seed, and core populations of the energetic and relativistic electrons in the inner magnetosphere.

  9. Combined convective and diffusive simulations: VERB-4D comparison with 17 March 2013 Van Allen Probes observations: VERB-4D

    DOE PAGES

    Shprits, Yuri Y.; Kellerman, Adam C.; Drozdov, Alexander Y.; ...

    2015-11-19

    Our study focused on understanding the coupling between different electron populations in the inner magnetosphere and the various physical processes that determine evolution of electron fluxes at different energies. Observations during the 17 March 2013 storm and simulations with a newly developed Versatile Electron Radiation Belt-4D (VERB-4D) are presented. This analysis of the drift trajectories of the energetic and relativistic electrons shows that electron trajectories at transitional energies with a first invariant on the scale of ~100 MeV/G may resemble ring current or relativistic electron trajectories depending on the level of geomagnetic activity. Simulations with the VERB-4D code including convection,more » radial diffusion, and energy diffusion are presented. Sensitivity simulations including various physical processes show how different acceleration mechanisms contribute to the energization of energetic electrons at transitional energies. In particular, the range of energies where inward transport is strongly influenced by both convection and radial diffusion are studied. Our results of the 4-D simulations are compared to Van Allen Probes observations at a range of energies including source, seed, and core populations of the energetic and relativistic electrons in the inner magnetosphere.« less

  10. Generation and characterization of a Cyp4b1 null mouse and the role of CYP4B1 in the activation and toxicity of Ipomeanol.

    PubMed

    Parkinson, Oliver T; Liggitt, H Denny; Rettie, Allan E; Kelly, Edward J

    2013-08-01

    4-Ipomeanol (IPO) is a prototypical pulmonary toxin that requires P450-mediated metabolic activation to reactive intermediates in order to elicit its toxic effects. CYP4B1 is a pulmonary enzyme that has been shown, in vitro, to have a high capacity for bioactivating IPO. In order to determine, unambiguously, the role of CYP4B1 in IPO bioactivation in vivo, we generated Cyp4b1 null mice following targeted disruption of the gene downstream of exon 1. Cyp4b1 (-/-) mice are viable and healthy, with no overt phenotype, and no evidence of compensatory upregulation of other P450 isoforms in any of the tissues examined. Pulmonary and renal microsomes prepared from male Cyp4b1 (-/-) mice exhibited no detectable expression of the protein and catalyzed the in vitro bioactivation of IPO at < 10% of the rates observed in tissue microsomes from Cyp4b1 (+/+) animals. Administration of IPO (20mg/kg) to Cyp4b1 (+/+) mice resulted in characteristic lesions in the lung, and to a lesser extent in the kidney, which were completely absent in Cyp4b1 (-/-) mice. We conclude that CYP4B1 is a critical enzyme for the bioactivation of IPO in vivo and that the Cyp4b1 (-/-) mouse is a useful model for studying CYP4B1-dependent metabolism and toxicity.

  11. SU-E-T-790: Validation of 4D Measurement-Guided Dose Reconstruction (MGDR) with OCTAVIUS 4D System

    SciTech Connect

    Lee, V; Leung, R; Wong, M; Law, G; Lee, K; Tung, S; Chan, M; Blanck, O

    2015-06-15

    Purpose: To validate the MGDR of OCTAVIUS 4D system (PTW, Freiburg, Germany) for quality assurance (QA) of volumetric-modulated arc radiotherapy (VMAT). Methods: 4D-MGDR measurements were divided into two parts: 1) square fields from 2×2 to 25×25 cm{sup 2} at 0°, 10° and 45° gantry, and 2) 8 VMAT plans (5 nasopharyngeal and 3 prostate) collapsed to gantry 40° in QA mode in Monaco v5.0 (Elekta, CMS, Maryland Heights, MO) were delivered on the OCTAVIUS 4D phantom with the OCTAVIUS 1500 detector plane perpendicular to either the incident beam to obtain the reconstructed dose (OCTA4D) or the 0° gantry axis to obtain the raw doses (OCTA3D) in Verisoft 6.1 (PTW, Freiburg, Germany). Raw measurements of OCTA3D were limited to < 45° gantry to avoid >0.5% variation of detector angular response with respect to 0° gantry as determined previously. Reconstructed OCTA4D and raw OCTA3D doses for all plans were compared at the same detector plane using γ criteria of 2% (local dose)/2mm and 3%/3mm criteria. Results: At gantry 0° and 10°, the γ results for all OCTA4D on detector plane coinciding with OCTA3D were over 90% at 2%/2mm except for the largest field (25×25 cm{sup 2} ) showing >88%. For square field at 45° gantry, γ passing rate is > 90% for fields smaller than 15x 15cm2 but < 80% for field size of 20 x20 cm{sup 2} upward. For VMAT, γ results showed 94% and 99% passing rate at 2%/2mm and 3%/3mm, respectively. Conclusion: OCTAVIUS 4D system has compromised accuracy in reconstructing dose away from the central beam axis, possibly due to the off-axis softening correction and errors of the percent depth dose data necessary as input for MGDR. Good results in VMAT delivery suggested that the system is relatively reliable for VMAT with small segments.

  12. Improved Respiratory Navigator Gating for Thoracic 4D flow MRI

    PubMed Central

    van Ooij, Pim; Semaan, Edouard; Schnell, Susanne; Giri, Shivraman; Stankovic, Zoran; Carr, James; Barker, Alex J.; Markl, Michael

    2016-01-01

    Background Thoracic and abdominal 4D flow MRI is typically acquired in combination with navigator respiration control which can result in highly variable scan efficiency (Seff) and thus total scan time due to inter-individual variability in breathing patterns. The aim of this study was to test the feasibility of an improved respiratory control strategy based on diaphragm navigator gating with fixed Seff, respiratory driven phase encoding, and a navigator training phase. Methods 4D flow MRI of the thoracic aorta was performed in 10 healthy subjects at 1.5T and 3T systems for the in-vivo assessment of aortic time-resolved 3D blood flow velocities. For each subject, four 4D flow scans (1: conventional navigator gating, 2–4: new implementation with fixed Seff =60%, 80% and 100%) were acquired. Data analysis included semi-quantitative evaluation of image quality of the 4D flow magnitude images (image quality grading on a four point scale), 3D segmentation of the thoracic aorta, and voxel-by-voxel comparisons of systolic 3D flow velocity vector fields between scans. Results Conventional navigator gating resulted in variable Seff = 74±13% (range = 56% – 100%) due to inter-individual variability of respiration patterns. For scans 2–4, the the new navigator implementation was able to achieve predictable total scan times with stable Seff, only depending on heart rate. Semi- and fully quantitative analysis of image quality in 4D flow magnitude images was similar for the new navigator scheme compared to conventional navigator gating. For aortic systolic 3D velocities, good agreement was found between all new navigator settings (scan 2–4) with the conventional navigator gating (scan 1) with best performance for Seff = 80% (mean difference = −0.01; limits od agreement = 0.23, Pearson’s ρ=0.89, p <0.001). No significant differences for image quality or 3D systolic velocities were found for 1.5T compared to 3T. Conclusions The findings of this study demonstrate the

  13. 4D CT sorting based on patient internal anatomy

    NASA Astrophysics Data System (ADS)

    Li, Ruijiang; Lewis, John H.; Cerviño, Laura I.; Jiang, Steve B.

    2009-08-01

    Respiratory motion during free-breathing computed tomography (CT) scan may cause significant errors in target definition for tumors in the thorax and upper abdomen. A four-dimensional (4D) CT technique has been widely used for treatment simulation of thoracic and abdominal cancer radiotherapy. The current 4D CT techniques require retrospective sorting of the reconstructed CT slices oversampled at the same couch position. Most sorting methods depend on external surrogates of respiratory motion recorded by extra instruments. However, respiratory signals obtained from these external surrogates may not always accurately represent the internal target motion, especially when irregular breathing patterns occur. We have proposed a new sorting method based on multiple internal anatomical features for multi-slice CT scan acquired in the cine mode. Four features are analyzed in this study, including the air content, lung area, lung density and body area. We use a measure called spatial coherence to select the optimal internal feature at each couch position and to generate the respiratory signals for 4D CT sorting. The proposed method has been evaluated for ten cancer patients (eight with thoracic cancer and two with abdominal cancer). For nine patients, the respiratory signals generated from the combined internal features are well correlated to those from external surrogates recorded by the real-time position management (RPM) system (average correlation: 0.95 ± 0.02), which is better than any individual internal measures at 95% confidence level. For these nine patients, the 4D CT images sorted by the combined internal features are almost identical to those sorted by the RPM signal. For one patient with an irregular breathing pattern, the respiratory signals given by the combined internal features do not correlate well with those from RPM (correlation: 0.68 ± 0.42). In this case, the 4D CT image sorted by our method presents fewer artifacts than that from the RPM signal. Our

  14. SECONDARY ECLIPSE PHOTOMETRY OF WASP-4b WITH WARM SPITZER

    SciTech Connect

    Beerer, Ingrid M.; Knutson, Heather A.; Burrows, Adam; Fortney, Jonathan J.; Laughlin, Gregory; Agol, Eric; Cowan, Nicolas B.; Charbonneau, David; Desert, Jean-Michel; Deming, Drake; Langton, Jonathan; Lewis, Nikole K.; Showman, Adam P.

    2011-01-20

    We present photometry of the giant extrasolar planet WASP-4b at 3.6 and 4.5 {mu}m taken with the Infrared Array Camera on board the Spitzer Space Telescope as part of Spitzer's extended warm mission. We find secondary eclipse depths of 0.319% {+-} 0.031% and 0.343% {+-} 0.027% for the 3.6 and 4.5 {mu}m bands, respectively, and show model emission spectra and pressure-temperature profiles for the planetary atmosphere. These eclipse depths are well fit by model emission spectra with water and other molecules in absorption, similar to those used for TrES-3 and HD 189733b. Depending on our choice of model, these results indicate that this planet has either a weak dayside temperature inversion or no inversion at all. The absence of a strong thermal inversion on this highly irradiated planet is contrary to the idea that highly irradiated planets are expected to have inversions, perhaps due the presence of an unknown absorber in the upper atmosphere. This result might be explained by the modestly enhanced activity level of WASP-4b's G7V host star, which could increase the amount of UV flux received by the planet, therefore reducing the abundance of the unknown stratospheric absorber in the planetary atmosphere as suggested in Knutson et al. We also find no evidence for an offset in the timing of the secondary eclipse and place a 2{sigma} upper limit on |ecos {omega}| of 0.0024, which constrains the range of tidal heating models that could explain this planet's inflated radius.

  15. Brain tissue segmentation in 4D CT using voxel classification

    NASA Astrophysics Data System (ADS)

    van den Boom, R.; Oei, M. T. H.; Lafebre, S.; Oostveen, L. J.; Meijer, F. J. A.; Steens, S. C. A.; Prokop, M.; van Ginneken, B.; Manniesing, R.

    2012-02-01

    A method is proposed to segment anatomical regions of the brain from 4D computer tomography (CT) patient data. The method consists of a three step voxel classification scheme, each step focusing on structures that are increasingly difficult to segment. The first step classifies air and bone, the second step classifies vessels and the third step classifies white matter, gray matter and cerebrospinal fluid. As features the time averaged intensity value and the temporal intensity change value were used. In each step, a k-Nearest-Neighbor classifier was used to classify the voxels. Training data was obtained by placing regions of interest in reconstructed 3D image data. The method has been applied to ten 4D CT cerebral patient data. A leave-one-out experiment showed consistent and accurate segmentation results.

  16. A new spin foam model for 4D gravity

    NASA Astrophysics Data System (ADS)

    Freidel, Laurent; Krasnov, Kirill

    2008-06-01

    Starting from Plebanski formulation of gravity as a constrained BF theory we propose a new spin foam model for 4D Riemannian quantum gravity that generalizes the well-known Barrett Crane model and resolves the inherent to it ultra-locality problem. The BF formulation of 4D gravity possesses two sectors: gravitational and topological ones. The model presented here is shown to give a quantization of the gravitational sector, and is dual to the recently proposed spin foam model of Engle et al which, we show, corresponds to the topological sector. Our methods allow us to introduce the Immirzi parameter into the framework of spin foam quantization. We generalize some of our considerations to the Lorentzian setting and obtain a new spin foam model in that context as well.

  17. 4D embryonic cardiography using gated optical coherence tomography

    NASA Astrophysics Data System (ADS)

    Jenkins, M. W.; Rothenberg, F.; Roy, D.; Nikolski, V. P.; Hu, Z.; Watanabe, M.; Wilson, D. L.; Efimov, I. R.; Rollins, A. M.

    2006-01-01

    Simultaneous imaging of very early embryonic heart structure and function has technical limitations of spatial and temporal resolution. We have developed a gated technique using optical coherence tomography (OCT) that can rapidly image beating embryonic hearts in four-dimensions (4D), at high spatial resolution (10-15 μm), and with a depth penetration of 1.5 - 2.0 mm that is suitable for the study of early embryonic hearts. We acquired data from paced, excised, embryonic chicken and mouse hearts using gated sampling and employed image processing techniques to visualize the hearts in 4D and measure physiologic parameters such as cardiac volume, ejection fraction, and wall thickness. This technique is being developed to longitudinally investigate the physiology of intact embryonic hearts and events that lead to congenital heart defects.

  18. Intelligent Vehicle Systems: A 4D/RCS Approach

    SciTech Connect

    Madhavan, Raj

    2007-04-01

    This book presents new research on autonomous mobility capabilities and shows how technological advances can be anticipated in the coming two decades. An in-depth description is presented on the theoretical foundations and engineering approaches that enable these capabilities. Chapter 1 provides a brief introduction to the 4D/RCS reference model architecture and design methodology that has proven successful in guiding the development of autonomous mobility systems. Chapters 2 through 7 provide more detailed descriptions of research that has been conducted and algorithms that have been developed to implement the various aspects of the 4D/RCS reference model architecture and design methodology. Chapters 8 and 9 discuss applications, performance measures, and standards. Chapter 10 provides a history of Army and DARPA research in autonomous ground mobility. Chapter 11 provides a perspective on the potential future developments in autonomous mobility.

  19. 4D flow cardiovascular magnetic resonance consensus statement.

    PubMed

    Dyverfeldt, Petter; Bissell, Malenka; Barker, Alex J; Bolger, Ann F; Carlhäll, Carl-Johan; Ebbers, Tino; Francios, Christopher J; Frydrychowicz, Alex; Geiger, Julia; Giese, Daniel; Hope, Michael D; Kilner, Philip J; Kozerke, Sebastian; Myerson, Saul; Neubauer, Stefan; Wieben, Oliver; Markl, Michael

    2015-08-10

    Pulsatile blood flow through the cavities of the heart and great vessels is time-varying and multidirectional. Access to all regions, phases and directions of cardiovascular flows has formerly been limited. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) has enabled more comprehensive access to such flows, with typical spatial resolution of 1.5×1.5×1.5 - 3×3×3 mm(3), typical temporal resolution of 30-40 ms, and acquisition times in the order of 5 to 25 min. This consensus paper is the work of physicists, physicians and biomedical engineers, active in the development and implementation of 4D Flow CMR, who have repeatedly met to share experience and ideas. The paper aims to assist understanding of acquisition and analysis methods, and their potential clinical applications with a focus on the heart and greater vessels. We describe that 4D Flow CMR can be clinically advantageous because placement of a single acquisition volume is straightforward and enables flow through any plane across it to be calculated retrospectively and with good accuracy. We also specify research and development goals that have yet to be satisfactorily achieved. Derived flow parameters, generally needing further development or validation for clinical use, include measurements of wall shear stress, pressure difference, turbulent kinetic energy, and intracardiac flow components. The dependence of measurement accuracy on acquisition parameters is considered, as are the uses of different visualization strategies for appropriate representation of time-varying multidirectional flow fields. Finally, we offer suggestions for more consistent, user-friendly implementation of 4D Flow CMR acquisition and data handling with a view to multicenter studies and more widespread adoption of the approach in routine clinical investigations.

  20. Repairing Stevenson's step in the 4d Ising model

    NASA Astrophysics Data System (ADS)

    Balog, Janos; Niedermayer, Ferenc; Weisz, Peter

    2006-05-01

    In a recent paper Stevenson claimed that analysis of the data on the wave function renormalization constant near the critical point of the 4d Ising model is not consistent with analytical expectations. Here we present data with improved statistics and show that the results are indeed consistent with conventional wisdom once one takes into account the uncertainty of lattice artifacts in the analytical computations.

  1. Phosphodiesterase 4D gene polymorphisms in sudden sensorineural hearing loss.

    PubMed

    Chien, Chen-Yu; Tai, Shu-Yu; Wang, Ling-Feng; Hsi, Edward; Chang, Ning-Chia; Wang, Hsun-Mo; Wu, Ming-Tsang; Ho, Kuen-Yao

    2016-09-01

    The phosphodiesterase 4D (PDE4D) gene has been reported as a risk gene for ischemic stroke. The vascular factors are between the hypothesized etiologies of sudden sensorineural hearing loss (SSNHL), and this genetic effect might be attributed for its role in SSNHL. We hypothesized that genetic variants of the PDE4D gene are associated with susceptibility to SSNHL. We conducted a case-control study with 362 SSNHL cases and 209 controls. Three single nucleotide polymorphisms (SNPs) were selected. The genotypes were determined using TaqMan technology. Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated according to three inheritance modes. We carried out sex-specific analysis to analyze the overall data. All three SNPs were in HWE. When subjects were stratified by sex, the genetic effect was only evident in females but not in males. The TT genotype of rs702553 exhibited an adjusted odds ratio (OR) of 3.83 (95 % confidence interval = 1.46-11.18) (p = 0.006) in female SSNHL. The TT genotype of SNP rs702553 was associated with female SSNHL under the recessive model (p = 0.004, OR 3.70). In multivariate logistic regression analysis, TT genotype of rs702553 was significantly associated with female SSNHL (p = 0.0043, OR 3.70). These results suggest that PDE4D gene polymorphisms influence the susceptibility for the development of SSNHL in the southern Taiwanese female population.

  2. Real-time 4D ultrasound mosaicing and visualization.

    PubMed

    Brattain, Laura J; Howe, Robert D

    2011-01-01

    Intra-cardiac 3D ultrasound imaging has enabled new minimally invasive procedures. Its narrow field of view, however, limits its efficacy in guiding beating heart procedures where geometrically complex and spatially extended moving anatomic structures are often involved. In this paper, we present a system that performs electrocardiograph gated 4D mosaicing and visualization of 3DUS volumes. Real-time operation is enabled by GPU implementation. The method is validated on phantom and porcine heart data.

  3. 2D:4D Ratio and its Implications in Medicine

    PubMed Central

    Jeevanandam, Saravanakumar

    2016-01-01

    Digit ratios, especially 2D:4D ratio, a potential proxy marker for prenatal androgen exposure shows sexual dimorphism. Existing literature and recent research show accumulating evidence on 2D:4D ratio showing correlations with various phenotypic traits in humans. Ratio of 2D:4D is found to correlate negatively to testosterone and positively to oestrogen in the foetus. Interestingly, it is constant since birth and not influenced by the adult hormone levels. Usually, males have lower ratios when compared to females. Prenatal androgen exposure and therefore, digit ratios have been reported to be associated with numerical competencies, spatial skills, handedness, cognitive abilities, academic performance, sperm counts, personalities and prevalence of obesity, migraine, eating disorders, depression, myopia, autism etc. The authors have attempted to write a brief account on the digit ratios and the dimorphism observed in various physiological, psychological and behavioural traits. Also, the authors have discussed the relevant molecular basics and the methods of measurement of digit ratios. PMID:28208851

  4. 4D-Flow validation, numerical and experimental framework

    NASA Astrophysics Data System (ADS)

    Sansom, Kurt; Liu, Haining; Canton, Gador; Aliseda, Alberto; Yuan, Chun

    2015-11-01

    This work presents a group of assessment metrics of new 4D MRI flow sequences, an imaging modality that allows for visualization of three-dimensional pulsatile flow in the cardiovascular anatomy through time-resolved three-dimensional blood velocity measurements from cardiac-cycle synchronized MRI acquisition. This is a promising tool for clinical assessment but lacks a robust validation framework. First, 4D-MRI flow in a subject's stenotic carotid bifurcation is compared with a patient-specific CFD model using two different boundary condition methods. Second, Particle Image Velocimetry in a patient-specific phantom is used as a benchmark to compare the 4D-MRI in vivo measurements and CFD simulations under the same conditions. Comparison of estimated and measureable flow parameters such as wall shear stress, fluctuating velocity rms, Lagrangian particle residence time, will be discussed, with justification for their biomechanics relevance and the insights they can provide on the pathophysiology of arterial disease: atherosclerosis and intimal hyperplasia. Lastly, the framework is applied to a new sequence to provide a quantitative assessment. A parametric analysis on the carotid bifurcation pulsatile flow conditions will be presented and an accuracy assessment provided.

  5. Electron photon verification calculations using MCNP4B

    SciTech Connect

    Gierga, D.P.; Adams, K.J.

    1998-07-01

    MCNP4B was released in February 1997 with significant enhancements to electron/photon transport methods. These enhancements have been verified against a wide range of published electron/photon experiments, spanning high energy bremsstrahlung production to electron transmission and reflection. Three sets of bremsstrahlung experiments were simulated. The first verification calculations for bremsstrahlung production used the experimental results in Faddegon for 15 MeV electrons incident on lead, aluminum, and beryllium targets. The calculated integrated bremsstrahlung yields, the bremsstrahlung energy spectra, and the mean energy of the bremsstrahlung beam were compared with experiment. The impact of several MCNP tally options and physics parameters was explored in detail. The second was the experiment of O`Dell which measured the bremsstrahlung spectra from 10 and 20.9 MeV electrons incident on a gold/tungsten target. The final set was a comparison of relative experimental spectra with calculated results for 9.66 MeV electrons incident on tungsten based on the experiment of Starfelt and Koch. The transmission experiments of Ebert were also studied, including comparisons of transmission coefficients for 10.2 MeV electrons incident on carbon, silver, and uranium foils. The agreement between experiment and simulation was usually within two standard deviations of the experimental and calculational errors.

  6. 4D seismic data acquisition method during coal mining

    NASA Astrophysics Data System (ADS)

    Du, Wen-Feng; Peng, Su-Ping

    2014-06-01

    In order to observe overburden media changes caused by mining processing, we take the fully-mechanized working face of the BLT coal mine in Shendong mine district as an example to develop a 4D seismic data acquisition methodology during coal mining. The 4D seismic data acquisition is implemented to collect 3D seismic data four times in different periods, such as before mining, during the mining process and after mining to observe the changes of the overburden layer during coal mining. The seismic data in the research area demonstrates that seismic waves are stronger in energy, higher in frequency and have better continuous reflectors before coal mining. However, all this is reversed after coal mining because the overburden layer has been mined, the seismic energy and frequency decrease, and reflections have more discontinuities. Comparing the records collected in the survey with those from newly mined areas and other records acquired in the same survey with the same geometry and with a long time for settling after mining, it clearly shows that the seismic reflections have stronger amplitudes and are more continuous because the media have recovered by overburden layer compaction after a long time of settling after mining. By 4D seismic acquisition, the original background investigation of the coal layers can be derived from the first records, then the layer structure changes can be monitored through the records of mining action and compaction action after mining. This method has laid the foundation for further research into the variation principles of the overburden layer under modern coal-mining conditions.

  7. Digit ratio (2D:4D), salivary testosterone, and handedness.

    PubMed

    Beaton, Alan A; Rudling, Nick; Kissling, Christian; Taurines, Regine; Thome, Johannes

    2011-03-01

    The length of the index finger relative to that of the ring finger, the 2D:4D ratio, has been taken to be a marker of the amount of testosterone (T) that was present in the foetal environment (Manning, Scutt, Wilson, & Lewis-Jones, 1998). It has also been suggested (Geschwind & Galaburda, 1987) that elevated levels of foetal T are associated with left-handedness and that adult levels of circulating T might relate to foetal levels (Jamison, Meier, & Campbell, 1993). We used multiple regression analyses to investigate whether there is any relationship between either left or right hand 2D:4D ratio and handedness. We also examined whether adult levels of salivary T (or cortisol, used as a control hormone) predict digit ratio and/or handedness. Although the 2D:4D ratio of neither the left nor the right hand was related to handedness, the difference between the digit ratios of the right and left hands, D(R-L), was a significant predictor of handedness and of the performance difference between the hands on a peg-moving task, supporting previous findings (Manning & Peters, 2009; Manning et al., 1998; Manning, Trivers, Thornhill, & Singh, 2000; Stoyanov, Marinov, & Pashalieva, 2009). Adult circulating T levels did not predict the digit ratio of the left or right hand; nor was there a significant relationship between concentrations of salivary T (or cortisol) and either hand preference or asymmetry in manual skill. We suggest that the association between D(R-L) and hand preference arises because D(R-L) is a correlate of sensitivity to T in the developing foetus.

  8. CMT4D (NDRG1 mutation): genotype-phenotype correlations.

    PubMed

    Ricard, Emilie; Mathis, Stéphane; Magdelaine, Corinne; Delisle, Marie-Bernadette; Magy, Laurent; Funalot, Benoît; Vallat, Jean-Michel

    2013-09-01

    Charcot-Marie-Tooth (CMT) disease is a heterogeneous condition with a large number of clinical, electrophysiological and pathological phenotypes. More than 40 genes are involved. We report a child of gypsy origin with an autosomal recessive demyelinating phenotype. Clinical data, familial history, and electrophysiological studies were in favor of a CMT4 sub-type. The characteristic N-Myc downstream-regulated gene 1 (NDRG1) mutation responsible for this CMT4D phenotype was confirmed: p.R148X. The exact molecular function of the NDRG1 protein has yet to be elucidated.

  9. 4D micro-CT using fast prospective gating

    NASA Astrophysics Data System (ADS)

    Guo, Xiaolian; Johnston, Samuel M.; Qi, Yi; Johnson, G. Allan; Badea, Cristian T.

    2012-01-01

    Micro-CT is currently used in preclinical studies to provide anatomical information. But, there is also significant interest in using this technology to obtain functional information. We report here a new sampling strategy for 4D micro-CT for functional cardiac and pulmonary imaging. Rapid scanning of free-breathing mice is achieved with fast prospective gating (FPG) implemented on a field programmable gate array. The method entails on-the-fly computation of delays from the R peaks of the ECG signals or the peaks of the respiratory signals for the triggering pulses. Projection images are acquired for all cardiac or respiratory phases at each angle before rotating to the next angle. FPG can deliver the faster scan time of retrospective gating (RG) with the regular angular distribution of conventional prospective gating for cardiac or respiratory gating. Simultaneous cardio-respiratory gating is also possible with FPG in a hybrid retrospective/prospective approach. We have performed phantom experiments to validate the new sampling protocol and compared the results from FPG and RG in cardiac imaging of a mouse. Additionally, we have evaluated the utility of incorporating respiratory information in 4D cardiac micro-CT studies with FPG. A dual-source micro-CT system was used for image acquisition with pulsed x-ray exposures (80 kVp, 100 mA, 10 ms). The cardiac micro-CT protocol involves the use of a liposomal blood pool contrast agent containing 123 mg I ml-1 delivered via a tail vein catheter in a dose of 0.01 ml g-1 body weight. The phantom experiment demonstrates that FPG can distinguish the successive phases of phantom motion with minimal motion blur, and the animal study demonstrates that respiratory FPG can distinguish inspiration and expiration. 4D cardiac micro-CT imaging with FPG provides image quality superior to RG at an isotropic voxel size of 88 µm and 10 ms temporal resolution. The acquisition time for either sampling approach is less than 5 min. The

  10. 4D micro-CT using fast prospective gating.

    PubMed

    Guo, Xiaolian; Johnston, Samuel M; Qi, Yi; Johnson, G Allan; Badea, Cristian T

    2012-01-07

    Micro-CT is currently used in preclinical studies to provide anatomical information. But, there is also significant interest in using this technology to obtain functional information. We report here a new sampling strategy for 4D micro-CT for functional cardiac and pulmonary imaging. Rapid scanning of free-breathing mice is achieved with fast prospective gating (FPG) implemented on a field programmable gate array. The method entails on-the-fly computation of delays from the R peaks of the ECG signals or the peaks of the respiratory signals for the triggering pulses. Projection images are acquired for all cardiac or respiratory phases at each angle before rotating to the next angle. FPG can deliver the faster scan time of retrospective gating (RG) with the regular angular distribution of conventional prospective gating for cardiac or respiratory gating. Simultaneous cardio-respiratory gating is also possible with FPG in a hybrid retrospective/prospective approach. We have performed phantom experiments to validate the new sampling protocol and compared the results from FPG and RG in cardiac imaging of a mouse. Additionally, we have evaluated the utility of incorporating respiratory information in 4D cardiac micro-CT studies with FPG. A dual-source micro-CT system was used for image acquisition with pulsed x-ray exposures (80 kVp, 100 mA, 10 ms). The cardiac micro-CT protocol involves the use of a liposomal blood pool contrast agent containing 123 mg I ml(-1) delivered via a tail vein catheter in a dose of 0.01 ml g(-1) body weight. The phantom experiment demonstrates that FPG can distinguish the successive phases of phantom motion with minimal motion blur, and the animal study demonstrates that respiratory FPG can distinguish inspiration and expiration. 4D cardiac micro-CT imaging with FPG provides image quality superior to RG at an isotropic voxel size of 88 μm and 10 ms temporal resolution. The acquisition time for either sampling approach is less than 5 min. The

  11. 4D Flow MRI in Neuroradiology: Techniques and Applications.

    PubMed

    Pereira, Vitor Mendes; Delattre, Benedicte; Brina, Olivier; Bouillot, Pierre; Vargas, Maria Isabel

    2016-04-01

    Assessment of the intracranial flow is important for the understanding and management of cerebral vascular diseases. From brain aneurysms and arteriovenous malformations lesions to intracranial and cervical stenosis, the appraisal of the blood flow can be crucial and influence positively on patients' management. The determination of the intracranial hemodynamics and the collateral pattern seems to play to a major role in the management of these lesions. 4D flow magnetic resonance imaging is a noninvasive phase contrast derived method that has been developed and applied in neurovascular diseases. It has a great potential if followed by further technical improvements and comprehensive and systematic clinical studies.

  12. Actively triggered 4d cone-beam CT acquisition

    SciTech Connect

    Fast, Martin F.; Wisotzky, Eric; Oelfke, Uwe; Nill, Simeon

    2013-09-15

    Purpose: 4d cone-beam computed tomography (CBCT) scans are usually reconstructed by extracting the motion information from the 2d projections or an external surrogate signal, and binning the individual projections into multiple respiratory phases. In this “after-the-fact” binning approach, however, projections are unevenly distributed over respiratory phases resulting in inefficient utilization of imaging dose. To avoid excess dose in certain respiratory phases, and poor image quality due to a lack of projections in others, the authors have developed a novel 4d CBCT acquisition framework which actively triggers 2d projections based on the forward-predicted position of the tumor.Methods: The forward-prediction of the tumor position was independently established using either (i) an electromagnetic (EM) tracking system based on implanted EM-transponders which act as a surrogate for the tumor position, or (ii) an external motion sensor measuring the chest-wall displacement and correlating this external motion to the phase-shifted diaphragm motion derived from the acquired images. In order to avoid EM-induced artifacts in the imaging detector, the authors devised a simple but effective “Faraday” shielding cage. The authors demonstrated the feasibility of their acquisition strategy by scanning an anthropomorphic lung phantom moving on 1d or 2d sinusoidal trajectories.Results: With both tumor position devices, the authors were able to acquire 4d CBCTs free of motion blurring. For scans based on the EM tracking system, reconstruction artifacts stemming from the presence of the EM-array and the EM-transponders were greatly reduced using newly developed correction algorithms. By tuning the imaging frequency independently for each respiratory phase prior to acquisition, it was possible to harmonize the number of projections over respiratory phases. Depending on the breathing period (3.5 or 5 s) and the gantry rotation time (4 or 5 min), between ∼90 and 145

  13. Realistic CT simulation using the 4D XCAT phantom.

    PubMed

    Segars, W P; Mahesh, M; Beck, T J; Frey, E C; Tsui, B M W

    2008-08-01

    The authors develop a unique CT simulation tool based on the 4D extended cardiac-torso (XCAT) phantom, a whole-body computer model of the human anatomy and physiology based on NURBS surfaces. Unlike current phantoms in CT based on simple mathematical primitives, the 4D XCAT provides an accurate representation of the complex human anatomy and has the advantage, due to its design, that its organ shapes can be changed to realistically model anatomical variations and patient motion. A disadvantage to the NURBS basis of the XCAT, however, is that the mathematical complexity of the surfaces makes the calculation of line integrals through the phantom difficult. They have to be calculated using iterative procedures; therefore, the calculation of CT projections is much slower than for simpler mathematical phantoms. To overcome this limitation, the authors used efficient ray tracing techniques from computer graphics, to develop a fast analytic projection algorithm to accurately calculate CT projections directly from the surface definition of the XCAT phantom given parameters defining the CT scanner and geometry. Using this tool, realistic high-resolution 3D and 4D projection images can be simulated and reconstructed from the XCAT within a reasonable amount of time. In comparison with other simulators with geometrically defined organs, the XCAT-based algorithm was found to be only three times slower in generating a projection data set of the same anatomical structures using a single 3.2 GHz processor. To overcome this decrease in speed would, therefore, only require running the projection algorithm in parallel over three processors. With the ever decreasing cost of computers and the rise of faster processors and multi-processor systems and clusters, this slowdown is basically inconsequential, especially given the vast improvement the XCAT offers in terms of realism and the ability to generate 3D and 4D data from anatomically diverse patients. As such, the authors conclude

  14. Oblique sounding using the DPS-4D stations in Europe

    NASA Astrophysics Data System (ADS)

    Mosna, Zbysek; Kouba, Daniel; Koucka Knizova, Petra; Arikan, Feza; Arikan, Orhan; Gok, Gokhan; Rejfek, Lubos

    2016-07-01

    The DPS-4D Digisondes are capable of detection of echoes from neighbouring European stations. Currently, a campaign with high-temporal resolution of 5 min is being run. Further, ionograms from regular vertical sounding with 15 min resolution provide us with oblique reflections together with vertical reflections. We analyzed profiles of electron concentration and basic ionospheric parameters derived from the ionograms. We compared results derived from reflections from the ionosphere above the stations (vertical sounding) with information derived from oblique reflections between the stations. This study is supported by the Joint TUBITAK 114E092 and AS CR 14/001 projects.

  15. Founding Gravitation in 4D Euclidean Space-Time Geometry

    SciTech Connect

    Winkler, Franz-Guenter

    2010-11-24

    The Euclidean interpretation of special relativity which has been suggested by the author is a formulation of special relativity in ordinary 4D Euclidean space-time geometry. The natural and geometrically intuitive generalization of this view involves variations of the speed of light (depending on location and direction) and a Euclidean principle of general covariance. In this article, a gravitation model by Jan Broekaert, which implements a view of relativity theory in the spirit of Lorentz and Poincare, is reconstructed and shown to fulfill the principles of the Euclidean approach after an appropriate reinterpretation.

  16. Exploration of 4D MRI blood flow using stylistic visualization.

    PubMed

    van Pelt, Roy; Oliván Bescós, Javier; Breeuwer, Marcel; Clough, Rachel E; Gröller, M Eduard; ter Haar Romenij, Bart; Vilanova, Anna

    2010-01-01

    Insight into the dynamics of blood-flow considerably improves the understanding of the complex cardiovascular system and its pathologies. Advances in MRI technology enable acquisition of 4D blood-flow data, providing quantitative blood-flow velocities over time. The currently typical slice-by-slice analysis requires a full mental reconstruction of the unsteady blood-flow field, which is a tedious and highly challenging task, even for skilled physicians. We endeavor to alleviate this task by means of comprehensive visualization and interaction techniques. In this paper we present a framework for pre-clinical cardiovascular research, providing tools to both interactively explore the 4D blood-flow data and depict the essential blood-flow characteristics. The framework encompasses a variety of visualization styles, comprising illustrative techniques as well as improved methods from the established field of flow visualization. Each of the incorporated styles, including exploded planar reformats, flow-direction highlights, and arrow-trails, locally captures the blood-flow dynamics and may be initiated by an interactively probed vessel cross-section. Additionally, we present the results of an evaluation with domain experts, measuring the value of each of the visualization styles and related rendering parameters.

  17. 4D Simulation of Explosive Eruption Dynamics at Vesuvius

    NASA Astrophysics Data System (ADS)

    Neri, A.; Esposti Ongaro, T.; Menconi, G.; de'Michieli Vitturi, M.; Cavazzoni, C.; Erbacci, G.; Baxter, P. J.

    2006-12-01

    We applied, using a supercomputer, a new simulation model based on fundamental transport laws to describe the 4D (3D spatial co-ordinates plus time) multiphase flow dynamics of explosive eruptions. The model solves the fundamental transport equations for a multiphase mixture formed by a continuous multi-component gas phase and n solid particulate phases representative of magma fragments (such as ash, crystals, and lapilli). Numerical simulations describe the collapse of the volcanic eruption column and the propagation of pyroclastic density currents, for selected medium scale (sub-Plinian) eruptive scenarios at Vesuvius, Italy. The study shows that 4D multiphase numerical models can illuminate the non-intuitive and internal dynamics of explosive eruptions that cannot otherwise be studied by direct observation or using previous models. In particular, simulations provide crucial insights into the effects of the generation mechanism of the flows - partial collapse vs boiling-over - on their hazard potential, the complex dynamics of the collapsing column, and the influence of Mount Somma on the propagation of PDCs into the circum-Vesuvian area, one of the world's most hazardous volcanic settings.

  18. 488-4D ASH LANDFILL CLOSURE CAP HELP MODELING

    SciTech Connect

    Phifer, M.

    2014-11-17

    At the request of Area Completion Projects (ACP) in support of the 488-4D Landfill closure, the Savannah River National Laboratory (SRNL) has performed Hydrologic Evaluation of Landfill Performance (HELP) modeling of the planned 488-4D Ash Landfill closure cap to ensure that the South Carolina Department of Health and Environmental Control (SCDHEC) limit of no more than 12 inches of head on top of the barrier layer (saturated hydraulic conductivity of no more than 1.0E-05 cm/s) in association with a 25-year, 24-hour storm event is not projected to be exceeded. Based upon Weber 1998 a 25-year, 24-hour storm event at the Savannah River Site (SRS) is 6.1 inches. The results of the HELP modeling indicate that the greatest peak daily head on top of the barrier layer (i.e. geosynthetic clay liner (GCL) or high density polyethylene (HDPE) geomembrane) for any of the runs made was 0.079 inches associated with a peak daily precipitation of 6.16 inches. This is well below the SCDHEC limit of 12 inches.

  19. Atlas construction for dynamic (4D) PET using diffeomorphic transformations.

    PubMed

    Bieth, Marie; Lombaert, Hervé; Reader, Andrew J; Siddiqi, Kaleem

    2013-01-01

    A novel dynamic (4D) PET to PET image registration procedure is proposed and applied to multiple PET scans acquired with the high resolution research tomograph (HRRT), the highest resolution human brain PET scanner available in the world. By extending the recent diffeomorphic log-demons (DLD) method and applying it to multiple dynamic [11C]raclopride scans from the HRRT, an important step towards construction of a PET atlas of unprecedented quality for [11C]raclopride imaging of the human brain has been achieved. Accounting for the temporal dimension in PET data improves registration accuracy when compared to registration of 3D to 3D time-averaged PET images. The DLD approach was chosen for its ease in providing both an intensity and shape template, through iterative sequential pair-wise registrations with fast convergence. The proposed method is applicable to any PET radiotracer, providing 4D atlases with useful applications in high accuracy PET data simulations and automated PET image analysis.

  20. Positive Energy Conditions in 4D Conformal Field Theory

    NASA Astrophysics Data System (ADS)

    Farnsworth, Kara; Luty, Markus; Prilepina, Valentina

    2016-03-01

    We argue that all consistent 4D quantum field theories obey a spacetime-averaged weak energy inequality avgT00 >= - C /L4 , where L is the size of the smearing region, and C is a positive constant that depends on the theory. If this condition is violated, the theory has states that are indistinguishable from states of negative total energy by any local measurement, and we expect instabilities or other inconsistencies. We apply this condition to 4D conformal field theories, and find that it places constraints on the OPE coefficients of the theory. The constraints we find are weaker than the ``conformal collider'' constraints of Hofman and Maldacena. We speculate that there may be theories that violate the Hofman-Maldacena bounds, but satisfy our bounds. In 3D CFTs, the only constraint we find is equivalent to the positivity of 2-point function of the energy-momentum tensor, which follows from unitarity. Our calculations are performed using momentum-space Wightman functions, which are remarkably simple functions of momenta, and may be of interest in their own right.

  1. Positive energy conditions in 4D conformal field theory

    NASA Astrophysics Data System (ADS)

    Farnsworth, Kara; Luty, Markus A.; Prilepina, Valentina

    2016-10-01

    We argue that all consistent 4D quantum field theories obey a spacetime-averaged weak energy inequality < T 00> ≥ - C/L 4, where L is the size of the smearing region, and C is a positive constant that depends on the theory. If this condition is violated, the theory has states that are indistinguishable from states of negative total energy by any local measurement, and we expect instabilities or other inconsistencies. We apply this condition to 4D conformal field theories, and find that it places constraints on the OPE coefficients of the theory. The constraints we find are weaker than the "conformal collider" constraints of Hofman and Maldacena. In 3D CFTs, the only constraint we find is equivalent to the positivity of 2-point function of the energy-momentum tensor, which follows from unitarity. Our calculations are performed using momentum-space Wightman functions, which are remarkably simple functions of momenta, and may be of interest in their own right.

  2. 4D Dynamic Required Navigation Performance Final Report

    NASA Technical Reports Server (NTRS)

    Finkelsztein, Daniel M.; Sturdy, James L.; Alaverdi, Omeed; Hochwarth, Joachim K.

    2011-01-01

    New advanced four dimensional trajectory (4DT) procedures under consideration for the Next Generation Air Transportation System (NextGen) require an aircraft to precisely navigate relative to a moving reference such as another aircraft. Examples are Self-Separation for enroute operations and Interval Management for in-trail and merging operations. The current construct of Required Navigation Performance (RNP), defined for fixed-reference-frame navigation, is not sufficiently specified to be applicable to defining performance levels of such air-to-air procedures. An extension of RNP to air-to-air navigation would enable these advanced procedures to be implemented with a specified level of performance. The objective of this research effort was to propose new 4D Dynamic RNP constructs that account for the dynamic spatial and temporal nature of Interval Management and Self-Separation, develop mathematical models of the Dynamic RNP constructs, "Required Self-Separation Performance" and "Required Interval Management Performance," and to analyze the performance characteristics of these air-to-air procedures using the newly developed models. This final report summarizes the activities led by Raytheon, in collaboration with GE Aviation and SAIC, and presents the results from this research effort to expand the RNP concept to a dynamic 4D frame of reference.

  3. 2D/4D marker-free tumor tracking using 4D CBCT as the reference image.

    PubMed

    Wang, Mengjiao; Sharp, Gregory C; Rit, Simon; Delmon, Vivien; Wang, Guangzhi

    2014-05-07

    Tumor motion caused by respiration is an important issue in image-guided radiotherapy. A 2D/4D matching method between 4D volumes derived from cone beam computed tomography (CBCT) and 2D fluoroscopic images was implemented to track the tumor motion without the use of implanted markers. In this method, firstly, 3DCBCT and phase-rebinned 4DCBCT are reconstructed from cone beam acquisition. Secondly, 4DCBCT volumes and a streak-free 3DCBCT volume are combined to improve the image quality of the digitally reconstructed radiographs (DRRs). Finally, the 2D/4D matching problem is converted into a 2D/2D matching between incoming projections and DRR images from each phase of the 4DCBCT. The diaphragm is used as a target surrogate for matching instead of using the tumor position directly. This relies on the assumption that if a patient has the same breathing phase and diaphragm position as the reference 4DCBCT, then the tumor position is the same. From the matching results, the phase information, diaphragm position and tumor position at the time of each incoming projection acquisition can be derived. The accuracy of this method was verified using 16 candidate datasets, representing lung and liver applications and one-minute and two-minute acquisitions. The criteria for the eligibility of datasets were described: 11 eligible datasets were selected to verify the accuracy of diaphragm tracking, and one eligible dataset was chosen to verify the accuracy of tumor tracking. The diaphragm matching accuracy was 1.88 ± 1.35 mm in the isocenter plane and the 2D tumor tracking accuracy was 2.13 ± 1.26 mm in the isocenter plane. These features make this method feasible for real-time marker-free tumor motion tracking purposes.

  4. 49 CFR 178.50 - Specification 4B welded or brazed steel cylinders.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Specification 4B welded or brazed steel cylinders... FOR PACKAGINGS Specifications for Cylinders § 178.50 Specification 4B welded or brazed steel cylinders. (a) Type, size, and service pressure. A DOT 4B is a welded or brazed steel cylinder with...

  5. 49 CFR 178.50 - Specification 4B welded or brazed steel cylinders.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Specification 4B welded or brazed steel cylinders... FOR PACKAGINGS Specifications for Cylinders § 178.50 Specification 4B welded or brazed steel cylinders. (a) Type, size, and service pressure. A DOT 4B is a welded or brazed steel cylinder with...

  6. 49 CFR 178.50 - Specification 4B welded or brazed steel cylinders.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Specification 4B welded or brazed steel cylinders... FOR PACKAGINGS Specifications for Cylinders § 178.50 Specification 4B welded or brazed steel cylinders. (a) Type, size, and service pressure. A DOT 4B is a welded or brazed steel cylinder with...

  7. 49 CFR 178.50 - Specification 4B welded or brazed steel cylinders.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Specification 4B welded or brazed steel cylinders... FOR PACKAGINGS Specifications for Cylinders § 178.50 Specification 4B welded or brazed steel cylinders. (a) Type, size, and service pressure. A DOT 4B is a welded or brazed steel cylinder with...

  8. SU-E-T-202: Comparison of 4D-Measurement-Guided Dose Reconstructions (MGDR) with COMPASS and OCTAVIUS 4D System

    SciTech Connect

    Leung, R; Wong, M; Lee, V; Law, G; Lee, K; Tung, S; Chan, M; Blanck, O

    2015-06-15

    Purpose: To cross-validate the MGDR of COMPASS (IBA dosimetry, GmbH, Germany) and OCTAVIUS 4D system (PTW, Freiburg, Germany). Methods: Volumetric-modulated arc plans (5 head-and-neck and 3 prostate) collapsed to 40° gantry on the OCTAVIUS 4D phantom in QA mode on Monaco v5.0 (Elekta, CMS, Maryland Heights, MO) were delivered on a Elekta Agility linac. This study was divided into two parts: (1) error-free measurements by gantry-mounted EvolutionXX 2D array were reconstructed in COMPASS (IBA dosimetry, GmbH, Germany), and by OCTAVIUS 1500 array in Versoft v6.1 (PTW, Freiburg, Germany) to obtain the 3D doses (COM4D and OCTA4D). COM4D and OCTA4D were compared to the raw measurement (OCTA3D) at the same detector plane for which OCTAVIUS 1500 was perpendicular to 0° gantry axis while the plans were delivered at gantry 40°; (2) beam steering errors of energy (Hump=-2%) and symmetry (2T=+2%) were introduced during the delivery of 5 plans to compare the MGDR doses COM4D-Hump (COM4D-2T), OCTA4D-Hump (OCTA4D-2T), with raw doses OCTA3D-Hump (OCTA3D-2T) and with OCTA3D to assess the error reconstruction and detection ability of MGDR tools. All comparisons used Υ-criteria of 2%(local dose)/2mm and 3%/3mm. Results: Averaged Υ passing rates were 85% and 96% for COM4D,and 94% and 99% for OCTA4D at 2%/2mm and 3%/3mm criteria respectively. For error reconstruction, COM4D-Hump (COM4D-2T) showed 81% (93%) at 2%/2mm and 94% (98%) at 3%/3mm, while OCTA4D-Hump (OCTA4D-2T) showed 96% (96%) at 2%/2mm and 99% (99%) at 3%/3mm. For error detection, OCTA3D doses were compared to COM4D-Hump (COM4D-2T) showing Υ passing rates of 93% (93%) at 2%/2mm and 98% (98%), and to OCTA4D-Hump (OCTA4D -2T) showing 94% (99%) at 2%/2mm and 81% (96%) at 3%/3mm, respectively. Conclusion: OCTAVIUS MGDR showed better agreement to raw measurements in both error- and error-free comparisons. COMPASS MGDR deviated from the raw measurements possibly owing to beam modeling uncertainty.

  9. 4D XCAT phantom for multimodality imaging research

    SciTech Connect

    Segars, W. P.; Sturgeon, G.; Mendonca, S.; Grimes, Jason; Tsui, B. M. W.

    2010-09-15

    Purpose: The authors develop the 4D extended cardiac-torso (XCAT) phantom for multimodality imaging research. Methods: Highly detailed whole-body anatomies for the adult male and female were defined in the XCAT using nonuniform rational B-spline (NURBS) and subdivision surfaces based on segmentation of the Visible Male and Female anatomical datasets from the National Library of Medicine as well as patient datasets. Using the flexibility of these surfaces, the Visible Human anatomies were transformed to match body measurements and organ volumes for a 50th percentile (height and weight) male and female. The desired body measurements for the models were obtained using the PEOPLESIZE program that contains anthropometric dimensions categorized from 1st to the 99th percentile for US adults. The desired organ volumes were determined from ICRP Publication 89 [ICRP, ''Basic anatomical and physiological data for use in radiological protection: reference values,'' ICRP Publication 89 (International Commission on Radiological Protection, New York, NY, 2002)]. The male and female anatomies serve as standard templates upon which anatomical variations may be modeled in the XCAT through user-defined parameters. Parametrized models for the cardiac and respiratory motions were also incorporated into the XCAT based on high-resolution cardiac- and respiratory-gated multislice CT data. To demonstrate the usefulness of the phantom, the authors show example simulation studies in PET, SPECT, and CT using publicly available simulation packages. Results: As demonstrated in the pilot studies, the 4D XCAT (which includes thousands of anatomical structures) can produce realistic imaging data when combined with accurate models of the imaging process. With the flexibility of the NURBS surface primitives, any number of different anatomies, cardiac or respiratory motions or patterns, and spatial resolutions can be simulated to perform imaging research. Conclusions: With the ability to produce

  10. 4D Light Field Imaging System Using Programmable Aperture

    NASA Technical Reports Server (NTRS)

    Bae, Youngsam

    2012-01-01

    Complete depth information can be extracted from analyzing all angles of light rays emanated from a source. However, this angular information is lost in a typical 2D imaging system. In order to record this information, a standard stereo imaging system uses two cameras to obtain information from two view angles. Sometimes, more cameras are used to obtain information from more angles. However, a 4D light field imaging technique can achieve this multiple-camera effect through a single-lens camera. Two methods are available for this: one using a microlens array, and the other using a moving aperture. The moving-aperture method can obtain more complete stereo information. The existing literature suggests a modified liquid crystal panel [LC (liquid crystal) panel, similar to ones commonly used in the display industry] to achieve a moving aperture. However, LC panels cannot withstand harsh environments and are not qualified for spaceflight. In this regard, different hardware is proposed for the moving aperture. A digital micromirror device (DMD) will replace the liquid crystal. This will be qualified for harsh environments for the 4D light field imaging. This will enable an imager to record near-complete stereo information. The approach to building a proof-ofconcept is using existing, or slightly modified, off-the-shelf components. An SLR (single-lens reflex) lens system, which typically has a large aperture for fast imaging, will be modified. The lens system will be arranged so that DMD can be integrated. The shape of aperture will be programmed for single-viewpoint imaging, multiple-viewpoint imaging, and coded aperture imaging. The novelty lies in using a DMD instead of a LC panel to move the apertures for 4D light field imaging. The DMD uses reflecting mirrors, so any light transmission lost (which would be expected from the LC panel) will be minimal. Also, the MEMS-based DMD can withstand higher temperature and pressure fluctuation than a LC panel can. Robotics need

  11. 4D simulation of explosive eruption dynamics at Vesuvius

    NASA Astrophysics Data System (ADS)

    Neri, Augusto; Esposti Ongaro, Tomaso; Menconi, Gianluca; De'Michieli Vitturi, Mattia; Cavazzoni, Carlo; Erbacci, Giovanni; Baxter, Peter J.

    2007-02-01

    We applied a new simulation model, based on multiphase transport laws, to describe the 4D (3D spatial coordinates plus time) dynamics of explosive eruptions. Numerical experiments, carried out on a parallel supercomputer, describe the collapse of the volcanic eruption column and the propagation of pyroclastic density currents (PDCs), for selected medium scale (sub-Plinian) eruptive scenarios at Vesuvius, Italy. Simulations provide crucial insights into the effects of the generation mechanism of the flows - partial collapse vs boiling-over - on their evolution and hazard potential, the unstable dynamics of the fountain, and the influence of Mount Somma on the propagation of PDCs into the circum-Vesuvian area, one of the world's most hazardous volcanic settings. Results also show that it is possible to characterize the volcanic column behavior in terms of percentage of the mass of pyroclasts collapsed to the ground and how this parameter strongly influences the dynamics and hazard of the associated PDCs.

  12. Chaos in a 4D dissipative nonlinear fermionic model

    NASA Astrophysics Data System (ADS)

    Aydogmus, Fatma

    2015-12-01

    Gursey Model is the only possible 4D conformally invariant pure fermionic model with a nonlinear self-coupled spinor term. It has been assumed to be similar to the Heisenberg's nonlinear generalization of Dirac's equation, as a possible basis for a unitary description of elementary particles. Gursey Model admits particle-like solutions for the derived classical field equations and these solutions are instantonic in character. In this paper, the dynamical nature of damped and forced Gursey Nonlinear Differential Equations System (GNDES) are studied in order to get more information on spinor type instantons. Bifurcation and chaos in the system are observed by constructing the bifurcation diagrams and Poincaré sections. Lyapunov exponent and power spectrum graphs of GNDES are also constructed to characterize the chaotic behavior.

  13. Deformable registration of 4D computed tomography data.

    PubMed

    Rietzel, Eike; Chen, George T Y

    2006-11-01

    Four-dimensional radiotherapy requires deformable registration to track delivered dose across varying anatomical states. Deformable registration based on B-splines was implemented to register 4D computed tomography data to a reference respiratory phase. To assess registration performance, anatomical landmarks were selected across ten respiratory phases in five patients. These point landmarks were transformed according to global registration parameters between different respiratory phases. Registration uncertainties were computed by subtraction of transformed and reference landmark positions. The selection of appropriate registration masks to separate independently moving anatomical subunits is crucial to registration performance. The average registration error for five landmarks for each of five patients was 2.1 mm. This level of accuracy is acceptable for most radiotherapy applications.

  14. Probabilistic 4D blood flow tracking and uncertainty estimation.

    PubMed

    Friman, Ola; Hennemuth, Anja; Harloff, Andreas; Bock, Jelena; Markl, Michael; Peitgen, Heinz-Otto

    2011-10-01

    Phase-Contrast (PC) MRI utilizes signal phase shifts resulting from moving spins to measure tissue motion and blood flow. Time-resolved 4D vector fields representing the motion or flow can be derived from the acquired PC MRI images. In cardiovascular PC MRI applications, visualization techniques such as vector glyphs, streamlines, and particle traces are commonly employed for depicting the blood flow. Whereas these techniques indeed provide useful diagnostic information, uncertainty due to noise in the PC-MRI measurements is ignored, which may lend the results a false sense of precision. In this work, the statistical properties of PC MRI flow measurements are investigated and a probabilistic flow tracking method based on sequential Monte Carlo sampling is devised to calculate flow uncertainty maps. The theoretical derivations are validated using simulated data and a number of real PC MRI data sets of the aorta and carotid arteries are used to demonstrate the flow uncertainty mapping technique.

  15. Biomechanics of DNA structures visualized by 4D electron microscopy

    PubMed Central

    Lorenz, Ulrich J.; Zewail, Ahmed H.

    2013-01-01

    We present a technique for in situ visualization of the biomechanics of DNA structural networks using 4D electron microscopy. Vibrational oscillations of the DNA structure are excited mechanically through a short burst of substrate vibrations triggered by a laser pulse. Subsequently, the motion is probed with electron pulses to observe the impulse response of the specimen in space and time. From the frequency and amplitude of the observed oscillations, we determine the normal modes and eigenfrequencies of the structures involved. Moreover, by selective “nano-cutting” at a given point in the network, it was possible to obtain Young’s modulus, and hence the stiffness, of the DNA filament at that position. This experimental approach enables nanoscale mechanics studies of macromolecules and should find applications in other domains of biological networks such as origamis. PMID:23382239

  16. 4D GPR Experiments--Towards the Virtual Lysimeter

    NASA Astrophysics Data System (ADS)

    Grasmueck, M.; Viggiano, D. A.; Day-Lewis, F. D.; Drasdis, J. B.; Kruse, S. E.; Or, D.

    2006-05-01

    In-situ monitoring of infiltration, water flow and retention in the vadose zone currently rely primarily on invasive methods, which irreversibly disturb original soil structure and alter its hydrologic behavior in the vicinity of the measurement. For example, use of lysimeters requires extraction and repacking of soil samples, and time- domain reflectometry (TDR) requires insertion of probes into the soil profile. This study investigates the use of repeated high-density 3D ground penetrating radar surveys (also known as 4D GPR) as a non-invasive alternative for detailed visualization and quantification of water flow in the vadose zone. Evaluation of the 4D GPR method was based on a series of controlled point-source water injection experiments into undisturbed beach sand deposits at Crandon Park in Miami, Florida. The goal of the GPR surveys was to image the shape and evolution of a wet-bulb as it propagates from the injection points (~0.5 m) towards the water table at 2.2 m depth. The experimental design was guided by predictive modeling using Hydrus 2D and finite-difference GPR waveform codes. Input parameters for the modeling were derived from hydrologic and electromagnetic characterization of representative sand samples. Guided by modeling results, we injected 30 to 40 liters of tap water through plastic-cased boreholes with slotted bottom sections (0.1 m) located 0.4 to 0.6 m below the surface. During and after injection, an area of 25 m2 was surveyed every 20 minutes using 250 and 500 MHz antennas with a grid spacing of 0.05 x 0.025 m. A total of 20 3D GPR surveys were completed over 3 infiltration sites. To confirm wet-bulb shapes measured by GPR, we injected 2 liters of "brilliant blue" dye (~100 mg/l) along with a saline water tracer towards the end of one experiment. After completion of GPR scanning, a trench was excavated to examine the distribution of the saltwater and dye using TDR and visual inspection, respectively. Preliminary analysis of the 4D GPR

  17. 4D fast tracking for experiments at high luminosity LHC

    NASA Astrophysics Data System (ADS)

    Neri, N.; Cardini, A.; Calabrese, R.; Fiorini, M.; Luppi, E.; Marconi, U.; Petruzzo, M.

    2016-11-01

    The full exploitation of the physics potential of the high luminosity LHC is a big challenge that requires new instrumentation and innovative solutions. We present here a conceptual design and simulation studies of a fast timing pixel detector with embedded real-time tracking capabilities. The system is conceived to operate at 40 MHz event rate and to reconstruct tracks in real-time, using precise space and time 4D information of the hit, for fast trigger decisions. This work is part of an R&D project aimed at building an innovative tracking detector with superior time (10 ps) and position (10 μm) resolutions to be used in very harsh radiation environments, for the ultimate flavour physics experiment at the high luminosity phase of the LHC.

  18. Parallel Wavefront Analysis for a 4D Interferometer

    NASA Technical Reports Server (NTRS)

    Rao, Shanti R.

    2011-01-01

    This software provides a programming interface for automating data collection with a PhaseCam interferometer from 4D Technology, and distributing the image-processing algorithm across a cluster of general-purpose computers. Multiple instances of 4Sight (4D Technology s proprietary software) run on a networked cluster of computers. Each connects to a single server (the controller) and waits for instructions. The controller directs the interferometer to several images, then assigns each image to a different computer for processing. When the image processing is finished, the server directs one of the computers to collate and combine the processed images, saving the resulting measurement in a file on a disk. The available software captures approximately 100 images and analyzes them immediately. This software separates the capture and analysis processes, so that analysis can be done at a different time and faster by running the algorithm in parallel across several processors. The PhaseCam family of interferometers can measure an optical system in milliseconds, but it takes many seconds to process the data so that it is usable. In characterizing an adaptive optics system, like the next generation of astronomical observatories, thousands of measurements are required, and the processing time quickly becomes excessive. A programming interface distributes data processing for a PhaseCam interferometer across a Windows computing cluster. A scriptable controller program coordinates data acquisition from the interferometer, storage on networked hard disks, and parallel processing. Idle time of the interferometer is minimized. This architecture is implemented in Python and JavaScript, and may be altered to fit a customer s needs.

  19. An updated version of the Motion4D-library

    NASA Astrophysics Data System (ADS)

    Müller, Thomas; Grave, Frank

    2010-03-01

    We present an updated version of the Motion4D-library that can be used for the newly developed GeodesicViewer application. New version program summaryProgram title: Motion4D-library Catalogue identifier: AEEX_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEEX_v2_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: Standard CPC licence, http://cpc.cs.qub.ac.uk/licence/licence.html No. of lines in distributed program, including test data, etc.: 153 757 No. of bytes in distributed program, including test data, etc.: 5 178 439 Distribution format: tar.gz Programming language: C++ Computer: All platforms with a C++ compiler Operating system: Linux, Unix, Windows RAM: 31 MBytes Catalogue identifier of previous version: AEEX_v1_0 Journal reference of previous version: Comput. Phys. Comm. 180 (2009) 2355 Classification: 1.5 External routines: Gnu Scientific Library (GSL) ( http://www.gnu.org/software/gsl/) Does the new version supersede the previous version?: Yes Nature of problem: Solve geodesic equation, parallel and Fermi-Walker transport in four-dimensional Lorentzian spacetimes. Solution method: Integration of ordinary differential equations. Reasons for new version: To be applicable for the GeodesicViewer (accepted for publication in Comput. Phys. Comm. (COMPHY) 3941, doi:10.1016/j.cpc.2009.10.010 [program AEFP_v1_0]), there were several minor adjustments to be done. Summary of revisions:Calculation of embedding diagrams are improved. Physical units can be used for some metrics. Tests for the constraint equation within the metric classes are slightly modified. New metrics: AlcubierreWarp, GoedelScaled, GoedelScaledCart, Kasner. Running time: The test runs provided with the distribution require only a few seconds to run.

  20. Mapping motion from 4D-MRI to 3D-CT for use in 4D dose calculations: A technical feasibility study

    SciTech Connect

    Boye, Dirk; Lomax, Tony; Knopf, Antje

    2013-06-15

    Purpose: Target sites affected by organ motion require a time resolved (4D) dose calculation. Typical 4D dose calculations use 4D-CT as a basis. Unfortunately, 4D-CT images have the disadvantage of being a 'snap-shot' of the motion during acquisition and of assuming regularity of breathing. In addition, 4D-CT acquisitions involve a substantial additional dose burden to the patient making many, repeated 4D-CT acquisitions undesirable. Here the authors test the feasibility of an alternative approach to generate patient specific 4D-CT data sets. Methods: In this approach motion information is extracted from 4D-MRI. Simulated 4D-CT data sets [which the authors call 4D-CT(MRI)] are created by warping extracted deformation fields to a static 3D-CT data set. The employment of 4D-MRI sequences for this has the advantage that no assumptions on breathing regularity are made, irregularities in breathing can be studied and, if necessary, many repeat imaging studies (and consequently simulated 4D-CT data sets) can be performed on patients and/or volunteers. The accuracy of 4D-CT(MRI)s has been validated by 4D proton dose calculations. Our 4D dose algorithm takes into account displacements as well as deformations on the originating 4D-CT/4D-CT(MRI) by calculating the dose of each pencil beam based on an individual time stamp of when that pencil beam is applied. According to corresponding displacement and density-variation-maps the position and the water equivalent range of the dose grid points is adjusted at each time instance. Results: 4D dose distributions, using 4D-CT(MRI) data sets as input were compared to results based on a reference conventional 4D-CT data set capturing similar motion characteristics. Almost identical 4D dose distributions could be achieved, even though scanned proton beams are very sensitive to small differences in the patient geometry. In addition, 4D dose calculations have been performed on the same patient, but using 4D-CT(MRI) data sets based on

  1. Determinants of the tumor suppressor INPP4B protein and lipid phosphatase activities.

    PubMed

    Lopez, Sandra M; Hodgson, Myles C; Packianathan, Charles; Bingol-Ozakpinar, Ozlem; Uras, Fikriye; Rosen, Barry P; Agoulnik, Irina U

    2013-10-18

    The tumor suppressor INPP4B is an important regulator of phosphatidyl-inositol signaling in the cell. Reduced INPP4B expression is associated with poor outcomes for breast, prostate, and ovarian cancer patients. INPP4B contains a CX5R catalytic motif characteristic of dual-specificity phosphatases, such as PTEN. Lipid phosphatase activity of INPP4B has previously been described. In this report we show that INPP4B can dephosphorylate para-nitrophenyl phosphate (pNPP) and 6,8-difluoro-4-methylumbelliferyl (DiFMUP), synthetic phosphotyrosine analogs, suggesting that INPP4B has protein tyrosine phosphatase (PTP) activity. Using mutagenesis, we examined the functional role of specific amino acids within the INPP4B C842KSAKDR catalytic site. The K843M mutant displayed increased pNPP hydrolysis, the K846M mutant lost lipid phosphatase activity with no effect on PTP activity, and the D847E substitution ablated PTP activity and significantly reduced lipid phosphatase activity. Further, we show that INPP4B but not PTEN is able to reduce tyrosine phosphorylation of Akt1 and both the lipid and PTP activity of INPP4B likely contribute to the reduction of Akt1 phosphorylation. Taken together our data identified key residues in the INPP4B catalytic domain associated with lipid and protein phosphatase activities and found a robust downstream target regulated by INPP4B but not PTEN.

  2. 4D Dynamic RNP Annual Interim Report-Year 1

    NASA Technical Reports Server (NTRS)

    Finkelsztein, Daniel M.; Sturdy, James L.; Alaverdi, Omeed; Chung, William W.; Salvano, Daniel; Klooster, Joel; Hochwarth, Joachim K.

    2010-01-01

    This Annual Interim Report summarizes the activities led by Raytheon, in collaboration with GE Aviation and SAIC, and presents the results obtained during the first year of this research effort to expand the RNP concept to 4 dimensions relative to a dynamic frame of reference. Joint Program Development Office (JPDO)Concepts of Operations for the Next Generation Air Transportation System (NextGen) considers 4 Dimension Trajectory (4DT) procedures a key enabler to Trajectory Based Operations (TBO). The JPDO defines 4DT as a precise description of an aircraft path in space and time . While NextGen assumes that this path is defined within an Earth-reference frame, many 4DT procedure implementations will require an aircraft to precisely navigate relative to a moving reference such as another aircraft to form aggregate flows or a weather cell to allow for flows to shift. Current methods of implementing routes and flight paths rely on aircraft meeting a Required Navigation Performance (RNP) specification and being equipped with a monitoring and alerting capability to annunciate when the aircraft system is unable to meet the performance specification required for the operation. Since all aircraft today operate within the NAS relative to fixed reference points, the current RNP definition is deemed satisfactory. However, it is not well understood how the current RNP construct will support NextGen 4DT procedures where aircraft operate relative to each other or to other dynamic frames of reference. The objective of this research effort is to analyze candidate 4DT procedures from both an Air Navigation Service Provider (ANSP) and aircraft perspective, to identify their specific navigational requirements, assess the shortcomings of the current RNP construct to meet these requirements, to propose an extended 4 Dimensional Dynamic RNP (4D Dynamic RNP) construct that accounts for the dynamic spatial and temporal nature of the selected 4DT procedures, and finally, to design an

  3. Parallel Infrastructure Modeling and Inversion Module for E4D

    SciTech Connect

    2014-10-09

    Electrical resistivity tomography ERT is a method of imaging the electrical conductivity of the subsurface. Electrical conductivity is a useful metric for understanding the subsurface because it is governed by geomechanical and geochemical properties that drive subsurface systems. ERT works by injecting current into the subsurface across a pair of electrodes, and measuring the corresponding electrical potential response across another pair of electrodes. Many such measurements are strategically taken across an array of electrodes to produce an ERT data set. These data are then processed through a computationally demanding process known as inversion to produce an image of the subsurface conductivity structure that gave rise to the measurements. Data can be inverted to provide 2D images, 3D images, or in the case of time-lapse 3D imaging, 4D images. ERT is generally not well suited for environments with buried electrically conductive infrastructure such as pipes, tanks, or well casings, because these features tend to dominate and degrade ERT images. This reduces or eliminates the utility of ERT imaging where it would otherwise be highly useful for, for example, imaging fluid migration from leaking pipes, imaging soil contamination beneath leaking subusurface tanks, and monitoring contaminant migration in locations with dense network of metal cased monitoring wells. The location and dimension of buried metallic infrastructure is often known. If so, then the effects of the infrastructure can be explicitly modeled within the ERT imaging algorithm, and thereby removed from the corresponding ERT image. However,there are a number of obstacles limiting this application. 1) Metallic infrastructure cannot be accurately modeled with standard codes because of the large contrast in conductivity between the metal and host material. 2) Modeling infrastructure in true dimension requires the computational mesh to be highly refined near the metal inclusions, which increases

  4. Respiratory triggered 4D cone-beam computed tomography: A novel method to reduce imaging dose

    SciTech Connect

    Cooper, Benjamin J.; O'Brien, Ricky T.; Keall, Paul J.; Balik, Salim; Hugo, Geoffrey D.

    2013-04-15

    Purpose: A novel method called respiratory triggered 4D cone-beam computed tomography (RT 4D CBCT) is described whereby imaging dose can be reduced without degrading image quality. RT 4D CBCT utilizes a respiratory signal to trigger projections such that only a single projection is assigned to a given respiratory bin for each breathing cycle. In contrast, commercial 4D CBCT does not actively use the respiratory signal to minimize image dose. Methods: To compare RT 4D CBCT with conventional 4D CBCT, 3600 CBCT projections of a thorax phantom were gathered and reconstructed to generate a ground truth CBCT dataset. Simulation pairs of conventional 4D CBCT acquisitions and RT 4D CBCT acquisitions were developed assuming a sinusoidal respiratory signal which governs the selection of projections from the pool of 3600 original projections. The RT 4D CBCT acquisition triggers a single projection when the respiratory signal enters a desired acquisition bin; the conventional acquisition does not use a respiratory trigger and projections are acquired at a constant frequency. Acquisition parameters studied were breathing period, acquisition time, and imager frequency. The performance of RT 4D CBCT using phase based and displacement based sorting was also studied. Image quality was quantified by calculating difference images of the test dataset from the ground truth dataset. Imaging dose was calculated by counting projections. Results: Using phase based sorting RT 4D CBCT results in 47% less imaging dose on average compared to conventional 4D CBCT. Image quality differences were less than 4% at worst. Using displacement based sorting RT 4D CBCT results in 57% less imaging dose on average, than conventional 4D CBCT methods; however, image quality was 26% worse with RT 4D CBCT. Conclusions: Simulation studies have shown that RT 4D CBCT reduces imaging dose while maintaining comparable image quality for phase based 4D CBCT; image quality is degraded for displacement based RT 4D

  5. Androgen Receptor Coactivator ARID4B Is Required for the Function of Sertoli Cells in Spermatogenesis.

    PubMed

    Wu, Ray-Chang; Zeng, Yang; Pan, I-Wen; Wu, Mei-Yi

    2015-09-01

    Defects in spermatogenesis, a process that produces spermatozoa inside seminiferous tubules of the testis, result in male infertility. Spermatogenic progression is highly dependent on a microenvironment provided by Sertoli cells, the only somatic cells and epithelium of seminiferous tubules. However, genes that regulate such an important activity of Sertoli cells are poorly understood. Here, we found that AT-rich interactive domain 4B (ARID4B), is essential for the function of Sertoli cells to regulate spermatogenesis. Specifically, we generated Sertoli cell-specific Arid4b knockout (Arid4bSCKO) mice, and showed that the Arid4bSCKO male mice were completely infertile with impaired testis development and significantly reduced testis size. Importantly, severe structural defects accompanied by loss of germ cells and Sertoli cell-only phenotype were found in many seminiferous tubules of the Arid4bSCKO testes. In addition, maturation of Sertoli cells was significantly delayed in the Arid4bSCKO mice, associated with delayed onset of spermatogenesis. Spermatogenic progression was also defective, showing an arrest at the round spermatid stage in the Arid4bSCKO testes. Interestingly, we showed that ARID4B functions as a "coactivator" of androgen receptor and is required for optimal transcriptional activation of reproductive homeobox 5, an androgen receptor target gene specifically expressed in Sertoli cells and critical for spermatogenesis. Together, our study identified ARID4B to be a key regulator of Sertoli cell function important for male germ cell development.

  6. Multimaterial 4D Printing with Tailorable Shape Memory Polymers

    PubMed Central

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K.; Fang, Nicholas X.; Dunn, Martin L.

    2016-01-01

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures. PMID:27499417

  7. Multimaterial 4D Printing with Tailorable Shape Memory Polymers

    NASA Astrophysics Data System (ADS)

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K.; Fang, Nicholas X.; Dunn, Martin L.

    2016-08-01

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures.

  8. Multimaterial 4D Printing with Tailorable Shape Memory Polymers.

    PubMed

    Ge, Qi; Sakhaei, Amir Hosein; Lee, Howon; Dunn, Conner K; Fang, Nicholas X; Dunn, Martin L

    2016-08-08

    We present a new 4D printing approach that can create high resolution (up to a few microns), multimaterial shape memory polymer (SMP) architectures. The approach is based on high resolution projection microstereolithography (PμSL) and uses a family of photo-curable methacrylate based copolymer networks. We designed the constituents and compositions to exhibit desired thermomechanical behavior (including rubbery modulus, glass transition temperature and failure strain which is more than 300% and larger than any existing printable materials) to enable controlled shape memory behavior. We used a high resolution, high contrast digital micro display to ensure high resolution of photo-curing methacrylate based SMPs that requires higher exposure energy than more common acrylate based polymers. An automated material exchange process enables the manufacture of 3D composite architectures from multiple photo-curable SMPs. In order to understand the behavior of the 3D composite microarchitectures, we carry out high fidelity computational simulations of their complex nonlinear, time-dependent behavior and study important design considerations including local deformation, shape fixity and free recovery rate. Simulations are in good agreement with experiments for a series of single and multimaterial components and can be used to facilitate the design of SMP 3D structures.

  9. Denoising and 4D visualization of OCT images

    PubMed Central

    Gargesha, Madhusudhana; Jenkins, Michael W.; Rollins, Andrew M.; Wilson, David L.

    2009-01-01

    We are using Optical Coherence Tomography (OCT) to image structure and function of the developing embryonic heart in avian models. Fast OCT imaging produces very large 3D (2D + time) and 4D (3D volumes + time) data sets, which greatly challenge ones ability to visualize results. Noise in OCT images poses additional challenges. We created an algorithm with a quick, data set specific optimization for reduction of both shot and speckle noise and applied it to 3D visualization and image segmentation in OCT. When compared to baseline algorithms (median, Wiener, orthogonal wavelet, basic non-orthogonal wavelet), a panel of experts judged the new algorithm to give much improved volume renderings concerning both noise and 3D visualization. Specifically, the algorithm provided a better visualization of the myocardial and endocardial surfaces, and the interaction of the embryonic heart tube with surrounding tissue. Quantitative evaluation using an image quality figure of merit also indicated superiority of the new algorithm. Noise reduction aided semi-automatic 2D image segmentation, as quantitatively evaluated using a contour distance measure with respect to an expert segmented contour. In conclusion, the noise reduction algorithm should be quite useful for visualization and quantitative measurements (e.g., heart volume, stroke volume, contraction velocity, etc.) in OCT embryo images. With its semi-automatic, data set specific optimization, we believe that the algorithm can be applied to OCT images from other applications. PMID:18679509

  10. 4D Cellular Automaton Track Finder in the CBM Experiment

    NASA Astrophysics Data System (ADS)

    Akishina, Valentina; Kisel, Ivan

    2016-11-01

    The CBM experiment (FAIR/GSI, Darmstadt, Germany) will focus on the measurement of rare probes at interaction rates up to 10MHz with data flow of up to 1 TB/s. It requires a novel read-out and data-acquisition concept with self-triggered electronics and free-streaming data. In this case resolving different collisions is a non-trivial task and event building must be performed in software online. That requires full online event reconstruction and selection not only in space, but also in time, so-called 4D event building and selection. This is a task of the First-Level Event Selection (FLES). The FLES reconstruction and selection package consists of several modules: track finding, track fitting, short-lived particles finding, event building and event selection. The Cellular Automaton (CA) track finder algorithm was adapted towards time-based reconstruction. In this article, we describe in detail the modification done to the algorithm, as well as the performance of the developed time-based CA approach.

  11. "4D Biology for health and disease" workshop report.

    PubMed

    Abrahams, Jan-Pieter; Apweiler, Rolf; Balling, Rudi; Bertero, Michela G; Bujnicki, Janusz M; Chayen, Naomi E; Chène, Patrick; Corthals, Gary L; Dyląg, Tomasz; Förster, Friedrich; Heck, Albert J R; Henderson, Peter J F; Herwig, Ralf; Jehenson, Philippe; Kokalj, Sasa Jenko; Laue, Ernest; Legrain, Pierre; Martens, Lennart; Migliorini, Cristiano; Musacchio, Andrea; Podobnik, Marjetka; Schertler, Gebhard F X; Schreiber, Gideon; Sixma, Titia K; Smit, August B; Stuart, David; Svergun, Dmitri I; Taussig, Michael J

    2011-07-01

    The "4D Biology Workshop for Health and Disease", held on 16-17th of March 2010 in Brussels, aimed at finding the best organising principles for large-scale proteomics, interactomics and structural genomics/biology initiatives, and setting the vision for future high-throughput research and large-scale data gathering in biological and medical science. Major conclusions of the workshop include the following. (i) Development of new technologies and approaches to data analysis is crucial. Biophysical methods should be developed that span a broad range of time/spatial resolution and characterise structures and kinetics of interactions. Mathematics, physics, computational and engineering tools need to be used more in biology and new tools need to be developed. (ii) Database efforts need to focus on improved definitions of ontologies and standards so that system-scale data and associated metadata can be understood and shared efficiently. (iii) Research infrastructures should play a key role in fostering multidisciplinary research, maximising knowledge exchange between disciplines and facilitating access to diverse technologies. (iv) Understanding disease on a molecular level is crucial. System approaches may represent a new paradigm in the search for biomarkers and new targets in human disease. (v) Appropriate education and training should be provided to help efficient exchange of knowledge between theoreticians, experimental biologists and clinicians. These conclusions provide a strong basis for creating major possibilities in advancing research and clinical applications towards personalised medicine.

  12. BPO4@B2O3 and (BPO4@B2O3):Eu3+: The novel single-emitting-component phosphors for near UV-white LEDs

    NASA Astrophysics Data System (ADS)

    Cao, Xiyu; Liu, Wei; Jiang, Yu; Cao, Lixin; Su, Ge; Gao, Rongjie

    2016-08-01

    Nowadays much effort has been devoted to exploring novel luminescent materials with low-cost, high stability and excellent luminescent properties. In this paper, a new kind of luminescent material BPO4@B2O3 was prepared by using a facile method. The as-obtained samples contain numerous BPO4 nanoparticles enclosed by amorphous and crystalline B2O3 homogeneously, which exhibits a broad emission band ranging from 380 to 700 nm under near-UV irradiation. More importantly, it is worth noting that the BPO4@B2O3 phosphor exhibits the excellent thermal quenching property, which endows it with a promising prospect as phosphors for high power white LEDs. To further promote its application as white light phosphors, Eu3+ ions were doped into the BPO4@B2O3 samples and prepared the (BPO4@B2O3):Eu3+ phosphors with chromaticity coordinates (0.3022, 0.3122). The corresponding packaging of LEDs indicates that both BPO4@B2O3 and (BPO4@B2O3):Eu3+ can be considered as the promising phosphors for WLEDs.

  13. Digit ratio (2D:4D) and hand preference for writing in the BBC Internet Study.

    PubMed

    Manning, J T; Peters, M

    2009-09-01

    The ratio of the length of the second to the fourth digit (2D:4D) may be negatively correlated with prenatal testosterone. Hand preference has been linked with prenatal testosterone and 2D:4D. Here we show that 2D:4D is associated with hand preference for writing in a large internet sample (n>170,000) in which participants self-reported their finger lengths. We replicated a significant association between right 2D:4D and writing hand preference (low right 2D:4D associated with left hand preference) as well as a significant correlation between writing hand preference and the difference between left and right 2D:4D or Dr-l (low Dr-l associated with left hand preference). A new significant correlation between left 2D:4D and writing hand preference was also shown (high left 2D:4D associated with left hand preference). There was a clear interaction between writing hand preference and 2D:4D: The left 2D:4D was significantly larger than the right 2D:4D in male and female left-handed writers, and the right hand 2D:4D was significantly larger than the left hand 2D:4D in male and female right-handed writers.

  14. 2,4-D and IAA Amino Acid Conjugates Show Distinct Metabolism in Arabidopsis

    PubMed Central

    Eyer, Luděk; Vain, Thomas; Pařízková, Barbora; Oklestkova, Jana; Barbez, Elke; Kozubíková, Hana; Pospíšil, Tomáš; Wierzbicka, Roksana; Kleine-Vehn, Jürgen; Fránek, Milan; Strnad, Miroslav; Robert, Stéphanie

    2016-01-01

    The herbicide 2,4-D exhibits an auxinic activity and therefore can be used as a synthetic and traceable analog to study auxin-related responses. Here we identified that not only exogenous 2,4-D but also its amide-linked metabolite 2,4-D-Glu displayed an inhibitory effect on plant growth via the TIR1/AFB auxin-mediated signaling pathway. To further investigate 2,4-D metabolite conversion, identity and activity, we have developed a novel purification procedure based on the combination of ion exchange and immuno-specific sorbents combined with a sensitive liquid chromatography-mass spectrometry method. In 2,4-D treated samples, 2,4-D-Glu and 2,4-D-Asp were detected at 100-fold lower concentrations compared to 2,4-D levels, showing that 2,4-D can be metabolized in the plant. Moreover, 2,4-D-Asp and 2,4-D-Glu were identified as reversible forms of 2,4-D homeostasis that can be converted to free 2,4-D. This work paves the way to new studies of auxin action in plant development. PMID:27434212

  15. GRAM 88 - 4D GLOBAL REFERENCE ATMOSPHERE MODEL-1988

    NASA Technical Reports Server (NTRS)

    Johnson, D. L.

    1994-01-01

    the Jacchia values. Below 25km the atmospheric parameters are computed by the 4-D worldwide atmospheric model of Spiegler and Fowler (1972). This data set is not included. GRAM-88 incorporates a hydrostatic/gas law check in the 0-30 km altitude range to flag and change any bad data points. Between 5km and 30km, an interpolation scheme is used between the 4-D results and the modified Groves values. The output parameters consist of components for: (1) latitude, longitude, and altitude dependent monthly and annual means, (2) quasi-biennial oscillations (QBO), and (3) random perturbations to partially simulate the variability due to synoptic, diurnal, planetary wave, and gravity wave variations. Quasi-biennial and random variation perturbations are computed from parameters determined by various empirical studies and are added to the monthly mean values. The GRAM-88 program is for batch execution on the IBM 3084. It is written in STANDARD FORTRAN 77 under the MVS/XA operating system. The IBM DISPLA graphics routines are necessary for graphical output. The program was developed in 1988.

  16. Evaluation of a novel 4D in vivo dosimetry system

    SciTech Connect

    Cherpak, A.; Ding, W.; Hallil, A.; Cygler, J. E.

    2009-05-15

    A prototype of a new 4D in vivo dosimetry system capable of simultaneous real-time position monitoring and dose measurement has been developed. The radiation positioning system (RADPOS) is controlled by a computer and combines two technologies: MOSFET radiation detector coupled with an electromagnetic positioning device. Special software has been developed that allows sampling position and dose either manually or automatically in user-defined time intervals. Preliminary tests of the new device include a dosimetric evaluation of the detector in {sup 60}Co, 6 MV, and 18 MV beams and measurements of spatial position stability and accuracy. In addition, the effect of metals and other materials on the performance of the positioning system has been investigated. Results show that the RADPOS system can measure in-air dose profiles that agree, on average, within 3%-5% of diode measurements for the energies tested. The response of the detector is isotropic within 1.6% (1 SD) with a maximum deviation of {+-}4.0% over 360 deg. The maximum variation in the calibration coefficient over field sizes from 6x6 to 25x25 cm{sup 2} was 2.3% for RADPOS probe with the high sensitivity MOSFET and 4.6% for the probe with the standard sensitivity MOSFET. Of the materials tested, only aluminum, lead, and brass caused shifts in the RADPOS read position. The magnitude of the shift varied between materials and size of the material sample. Nonmagnetic stainless steel (Grade 304) caused a distortion of less than 2 mm when placed within 10 mm of the detector; therefore, it can provide a reasonable alternative to other metals if required. The results of the preliminary tests indicate that the device can be used for in vivo dosimetry in {sup 60}Co and high-energy beams from linear accelerators.

  17. Binary 4D seismic history matching, a metric study

    NASA Astrophysics Data System (ADS)

    Chassagne, Romain; Obidegwu, Dennis; Dambrine, Julien; MacBeth, Colin

    2016-11-01

    This paper explores 4D seismic history matching and it specifically focuses on the objective function used during the optimisation with seismic data. The objective function is calculated by using binary maps, where one map is obtained from the observed seismic data and the other is from one realisation of the optimisation algorithm from the simulation model. In order to decide which set of parameters is a relevant update for the simulation model, an efficient way is required to measure how similar these two binary images are, during their evaluation within the objective function. Behind this aspect of quantification of the similarities or dissimilarities lies the metric notion, or the art of measuring distances. Four metrics are proposed with this study, the well-known Hamming distance, two widely used metrics, the Hausdorff distance and Mutual Information and a recent metric, called the Current Measure Metric. These metrics will be tested and compared on different case scenarios, designed in accordance to a real field case (gas exsolution) before being used in the second part of the paper. Despite its simplicity, the Hamming distance gives positive results, but the Current Measure Metric appears to be a more efficient choice to cover a wider range of scenarios, these conclusions remain true when tested on synthetic and real dataset in a history matching exercise. Some practical aspects of binary map processes will be examined through the paper, as it is shown that it is more proper to use a derivative free optimisation algorithm and a proper metric should be more inclined to capture global features than local features.

  18. Infrared PINEM developed by diffraction in 4D UEM.

    PubMed

    Liu, Haihua; Baskin, John Spencer; Zewail, Ahmed H

    2016-02-23

    The development of four-dimensional ultrafast electron microscopy (4D UEM) has enabled not only observations of the ultrafast dynamics of photon-matter interactions at the atomic scale with ultrafast resolution in image, diffraction, and energy space, but photon-electron interactions in the field of nanoplasmonics and nanophotonics also have been captured by the related technique of photon-induced near-field electron microscopy (PINEM) in image and energy space. Here we report a further extension in the ongoing development of PINEM using a focused, nanometer-scale, electron beam in diffraction space for measurements of infrared-light-induced PINEM. The energy resolution in diffraction mode is unprecedented, reaching 0.63 eV under the 200-keV electron beam illumination, and separated peaks of the PINEM electron-energy spectrum induced by infrared light of wavelength 1,038 nm (photon energy 1.2 eV) have been well resolved for the first time, to our knowledge. In a comparison with excitation by green (519-nm) pulses, similar first-order PINEM peak amplitudes were obtained for optical fluence differing by a factor of more than 60 at the interface of copper metal and vacuum. Under high fluence, the nonlinear regime of IR PINEM was observed, and its spatial dependence was studied. In combination with PINEM temporal gating and low-fluence infrared excitation, the PINEM diffraction method paves the way for studies of structural dynamics in reciprocal space and energy space with high temporal resolution.

  19. Fast interactive exploration of 4D MRI flow data

    NASA Astrophysics Data System (ADS)

    Hennemuth, A.; Friman, O.; Schumann, C.; Bock, J.; Drexl, J.; Huellebrand, M.; Markl, M.; Peitgen, H.-O.

    2011-03-01

    1- or 2-directional MRI blood flow mapping sequences are an integral part of standard MR protocols for diagnosis and therapy control in heart diseases. Recent progress in rapid MRI has made it possible to acquire volumetric, 3-directional cine images in reasonable scan time. In addition to flow and velocity measurements relative to arbitrarily oriented image planes, the analysis of 3-dimensional trajectories enables the visualization of flow patterns, local features of flow trajectories or possible paths into specific regions. The anatomical and functional information allows for advanced hemodynamic analysis in different application areas like stroke risk assessment, congenital and acquired heart disease, aneurysms or abdominal collaterals and cranial blood flow. The complexity of the 4D MRI flow datasets and the flow related image analysis tasks makes the development of fast comprehensive data exploration software for advanced flow analysis a challenging task. Most existing tools address only individual aspects of the analysis pipeline such as pre-processing, quantification or visualization, or are difficult to use for clinicians. The goal of the presented work is to provide a software solution that supports the whole image analysis pipeline and enables data exploration with fast intuitive interaction and visualization methods. The implemented methods facilitate the segmentation and inspection of different vascular systems. Arbitrary 2- or 3-dimensional regions for quantitative analysis and particle tracing can be defined interactively. Synchronized views of animated 3D path lines, 2D velocity or flow overlays and flow curves offer a detailed insight into local hemodynamics. The application of the analysis pipeline is shown for 6 cases from clinical practice, illustrating the usefulness for different clinical questions. Initial user tests show that the software is intuitive to learn and even inexperienced users achieve good results within reasonable processing

  20. Infrared PINEM developed by diffraction in 4D UEM

    PubMed Central

    Liu, Haihua; Baskin, John Spencer; Zewail, Ahmed H.

    2016-01-01

    The development of four-dimensional ultrafast electron microscopy (4D UEM) has enabled not only observations of the ultrafast dynamics of photon–matter interactions at the atomic scale with ultrafast resolution in image, diffraction, and energy space, but photon–electron interactions in the field of nanoplasmonics and nanophotonics also have been captured by the related technique of photon-induced near-field electron microscopy (PINEM) in image and energy space. Here we report a further extension in the ongoing development of PINEM using a focused, nanometer-scale, electron beam in diffraction space for measurements of infrared-light-induced PINEM. The energy resolution in diffraction mode is unprecedented, reaching 0.63 eV under the 200-keV electron beam illumination, and separated peaks of the PINEM electron-energy spectrum induced by infrared light of wavelength 1,038 nm (photon energy 1.2 eV) have been well resolved for the first time, to our knowledge. In a comparison with excitation by green (519-nm) pulses, similar first-order PINEM peak amplitudes were obtained for optical fluence differing by a factor of more than 60 at the interface of copper metal and vacuum. Under high fluence, the nonlinear regime of IR PINEM was observed, and its spatial dependence was studied. In combination with PINEM temporal gating and low-fluence infrared excitation, the PINEM diffraction method paves the way for studies of structural dynamics in reciprocal space and energy space with high temporal resolution. PMID:26848135

  1. Polyacrylamide gel electrophoresis of intact bacteriophage T4D particles.

    PubMed Central

    Childs, J D; Birnboim, H C

    1975-01-01

    A method for the electrophoresis of intact bacteriophage T4D particles through polyacrylamide gels has been developed. It was found that phage particles will migrate through dilute polyacrylamide gels (less than 2.1%) in the presence of a low concentration of MgCl2. As few as 5 x 10(9) phage particles can be seen directly as a light-scattering band during the course of electrophoresis. The band can also be detected by scanning gels at 260 to 265 nm or by eluting viable phage particles from gel slices. A new mutant (eph1) has been identified on the basis of its decreased electrophoretic mobility compared with that of the wild type; mutant particles migrated 14% slower than the wild type particles at pH 8.3 and 35% slower at pH 5.0. The isoelectric points of both the wild type and eph1 mutant were found to be between pH 4.0 and 5.0. Particles of T4 with different head lengths were also studied. Petite particles (heads 20% shorter than normal) migrated at the same rate as normal-size particles. Giant particles, heterogenous with respect to head length (two to nine times normal), migrated faster than normal-size particles as a diffuse band. This diffuseness was due to separation within the band of particles having mobilities ranging from 8 to 35% faster than those of normal-size particles. These observations extend the useful range of polyacrylamide gel electrophoresis to include much larger particles than have previously been studied, including most viruses. Images PMID:240037

  2. 4D measurement system for automatic location of anatomical structures

    NASA Astrophysics Data System (ADS)

    Witkowski, Marcin; Sitnik, Robert; Kujawińska, Małgorzata; Rapp, Walter; Kowalski, Marcin; Haex, Bart; Mooshake, Sven

    2006-04-01

    Orthopedics and neurosciences are fields of medicine where the analysis of objective movement parameters is extremely important for clinical diagnosis. Moreover, as there are significant differences between static and dynamic parameters, there is a strong need of analyzing the anatomical structures under functional conditions. In clinical gait analysis the benefits of kinematical methods are undoubted. In this paper we present a 4D (3D + time) measurement system capable of automatic location of selected anatomical structures by locating and tracing the structures' position and orientation in time. The presented system is designed to help a general practitioner in diagnosing selected lower limbs' dysfunctions (e.g. knee injuries) and also determine if a patient should be directed for further examination (e.g. x-ray or MRI). The measurement system components are hardware and software. For the hardware part we adapt the laser triangulation method. In this way we can evaluate functional and dynamic movements in a contact-free, non-invasive way, without the use of potentially harmful radiation. Furthermore, opposite to marker-based video-tracking systems, no preparation time is required. The software part consists of a data acquisition module, an image processing and point clouds (point cloud, set of points described by coordinates (x, y, z)) calculation module, a preliminary processing module, a feature-searching module and an external biomechanical module. The paper briefly presents the modules mentioned above with the focus on the feature-searching module. Also we present some measurement and analysis results. These include: parameters maps, landmarks trajectories in time sequence and animation of a simplified model of lower limbs.

  3. LAPTM4B: an oncogene in various solid tumors and its functions

    PubMed Central

    Meng, Y; Wang, L; Chen, D; Chang, Y; Zhang, M; XU, J-J; Zhou, R; Zhang, Q-Y

    2016-01-01

    The oncogene Lysosome-associated protein transmembrane-4β (LAPTM4B) gene was identified, and the polymorphism region in the 5′-UTR of this gene was certified to be associated with tumor susceptibility. LAPTM4B-35 protein was found to be highly expressed in various solid tumors and could be a poor prognosis marker. The functions of LAPTM4B in solid tumors were also explored. It is suggested that LAPTM4B could promote the proliferation of tumor cells, boost invasion and metastasis, resist apoptosis, initiate autophagy and assist drug resistance. PMID:27212036

  4. The transcription activity of heat shock factor 4b is regulated by FGF2.

    PubMed

    Hu, Yan-Zhong; Zhang, Jun; Li, Shulian; Wang, Chuan; Chu, Liujie; Zhang, Zhi; Ma, Zengyi; Wang, Mingli; Jiang, Qiying; Liu, Guangchao; Qi, Yijun; Ma, Yuanfang

    2013-02-01

    Heat shock factor 4b has been found to be closely associated with postnatal lens development. It expresses in postnatal lens epithelial and secondary fiber cells and controls the expression of small heat shock proteins which are important for lens homeostasis. However, the signal pathways underlying Hsf4b are still not completely understood. Here we present that Hsf4b transcription activity is regulated by FGF2 a key growth factor that is involved in regulating lens development at multiple stages. FGF2 can promote Hsf4b nuclear-translocation and the expression of Hsp25 and αB-crystallin, the key downstream targets of Hsf4b in the Hsf4b-reconstituted mouse hsf4-/- lens epithelial cells. Further study indicates that FGF2 can induce Hsf4b protein stabilization through ERK1/2-mediated posttranslational phosphorylation or sumoylation. Hsf4b can promote FGF2-induced morphology transition from lens epithelial cell to the fiber cell, and this morphology transition can be inhibited by ERK1/2 inhibitor U0126. Taken together, our data demonstrate that Hsf4b is a novel downstream transcription factor of FGF2, and its transcription activity is associated with FGF2-modulated lens epithelial cell-fiber cell transition.

  5. New approach based on tetrahedral-mesh geometry for accurate 4D Monte Carlo patient-dose calculation

    NASA Astrophysics Data System (ADS)

    Han, Min Cheol; Yeom, Yeon Soo; Kim, Chan Hyeong; Kim, Seonghoon; Sohn, Jason W.

    2015-02-01

    In the present study, to achieve accurate 4D Monte Carlo dose calculation in radiation therapy, we devised a new approach that combines (1) modeling of the patient body using tetrahedral-mesh geometry based on the patient’s 4D CT data, (2) continuous movement/deformation of the tetrahedral patient model by interpolation of deformation vector fields acquired through deformable image registration, and (3) direct transportation of radiation particles during the movement and deformation of the tetrahedral patient model. The results of our feasibility study show that it is certainly possible to construct 4D patient models (= phantoms) with sufficient accuracy using the tetrahedral-mesh geometry and to directly transport radiation particles during continuous movement and deformation of the tetrahedral patient model. This new approach not only produces more accurate dose distribution in the patient but also replaces the current practice of using multiple 3D voxel phantoms and combining multiple dose distributions after Monte Carlo simulations. For routine clinical application of our new approach, the use of fast automatic segmentation algorithms is a must. In order to achieve, simultaneously, both dose accuracy and computation speed, the number of tetrahedrons for the lungs should be optimized. Although the current computation speed of our new 4D Monte Carlo simulation approach is slow (i.e. ~40 times slower than that of the conventional dose accumulation approach), this problem is resolvable by developing, in Geant4, a dedicated navigation class optimized for particle transportation in tetrahedral-mesh geometry.

  6. New approach based on tetrahedral-mesh geometry for accurate 4D Monte Carlo patient-dose calculation.

    PubMed

    Han, Min Cheol; Yeom, Yeon Soo; Kim, Chan Hyeong; Kim, Seonghoon; Sohn, Jason W

    2015-02-21

    In the present study, to achieve accurate 4D Monte Carlo dose calculation in radiation therapy, we devised a new approach that combines (1) modeling of the patient body using tetrahedral-mesh geometry based on the patient's 4D CT data, (2) continuous movement/deformation of the tetrahedral patient model by interpolation of deformation vector fields acquired through deformable image registration, and (3) direct transportation of radiation particles during the movement and deformation of the tetrahedral patient model. The results of our feasibility study show that it is certainly possible to construct 4D patient models (= phantoms) with sufficient accuracy using the tetrahedral-mesh geometry and to directly transport radiation particles during continuous movement and deformation of the tetrahedral patient model. This new approach not only produces more accurate dose distribution in the patient but also replaces the current practice of using multiple 3D voxel phantoms and combining multiple dose distributions after Monte Carlo simulations. For routine clinical application of our new approach, the use of fast automatic segmentation algorithms is a must. In order to achieve, simultaneously, both dose accuracy and computation speed, the number of tetrahedrons for the lungs should be optimized. Although the current computation speed of our new 4D Monte Carlo simulation approach is slow (i.e. ~40 times slower than that of the conventional dose accumulation approach), this problem is resolvable by developing, in Geant4, a dedicated navigation class optimized for particle transportation in tetrahedral-mesh geometry.

  7. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 6 2010-07-01 2010-07-01 false Class 4-D: Minister of religion. 1630.43 Section... CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D who is a: (a) Duly ordained minister of religion; or (b)...

  8. 49 CFR 178.53 - Specification 4D welded steel cylinders for aircraft use.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 3 2014-10-01 2014-10-01 false Specification 4D welded steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.53 Specification 4D welded steel cylinders for aircraft use. (a) Type, size, and service pressure. A DOT 4D cylinder is a welded steel sphere...

  9. 49 CFR 178.53 - Specification 4D welded steel cylinders for aircraft use.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 3 2013-10-01 2013-10-01 false Specification 4D welded steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.53 Specification 4D welded steel cylinders for aircraft use. (a) Type, size, and service pressure. A DOT 4D cylinder is a welded steel sphere...

  10. 49 CFR 178.53 - Specification 4D welded steel cylinders for aircraft use.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 3 2011-10-01 2011-10-01 false Specification 4D welded steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.53 Specification 4D welded steel cylinders for aircraft use. (a) Type, size, and service pressure. A DOT 4D cylinder is a welded steel sphere...

  11. 49 CFR 178.53 - Specification 4D welded steel cylinders for aircraft use.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 3 2012-10-01 2012-10-01 false Specification 4D welded steel cylinders for...) SPECIFICATIONS FOR PACKAGINGS Specifications for Cylinders § 178.53 Specification 4D welded steel cylinders for aircraft use. (a) Type, size, and service pressure. A DOT 4D cylinder is a welded steel sphere...

  12. 40 CFR 180.142 - 2,4-D; tolerances for residues.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...,4-D; tolerances for residues. (a) General. Tolerances are established for residues of the herbicide... § 180.1(l), are established for residues of the herbicide, plant regulator, and fungicide 2,4-D (2,4... established for indirect or inadvertent residues of the herbicide, plant regulator, and fungicide 2,4-D...

  13. 40 CFR 180.142 - 2,4-D; tolerances for residues.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...,4-D; tolerances for residues. (a) General. Tolerances are established for residues of the herbicide... § 180.1(m), are established for residues of the herbicide, plant regulator, and fungicide 2,4-D (2,4... established for indirect or inadvertent residues of the herbicide, plant regulator, and fungicide 2,4-D...

  14. 2,4-D removal via denitrification using volatile fatty acids.

    PubMed

    He, X; Wareham, D G

    2011-01-01

    Many countries have waters contaminated with both herbicides and nitrates; however, information is limited with respect to removal rates for combined nitrate and herbicide elimination. This research investigates the removal of 2,4-D via denitrification, with a particular emphasis on the effect of adding naturally generated volatile fatty acids (VFAs). The acids were produced from an acid-phase anaerobic digester with a mean VFA concentration of 3153±801 mg/L (as acetic acid). Initially, 2,4-D degrading bacteria were developed in an SBR fed with both sewage and 2,4-D (30-100 mg/L). Subsequent denitrification batch tests demonstrated that the specific denitrification rate increased from 0.0119±0.0039 using 2,4-D alone to 0.0192±0.0079 g NO₃-N/g VSS per day, when 2,4-D was combined with natural VFAs from the digester. Similarly, the specific 2,4-D consumption rate increased from 0.0016±0.0009 using 2,4-D alone to 0.0055±0.0021 g 2,4-D/g VSS per day, when using 2,4-D plus natural VFAs. Finally, a parallel increase in the percent 2,4-D removal was observed, rising from 28.33±11.88 using 2,4-D alone to 54.17±21.89 using 2,4-D plus natural VFAs.

  15. Mapping the Interactions between the NS4B and NS3 Proteins of Dengue Virus

    PubMed Central

    Zou, Jing; Lee, Le Tian; Wang, Qing Yin; Xie, Xuping; Lu, Siyan; Yau, Yin Hoe; Yuan, Zhiming; Geifman Shochat, Susana; Kang, Congbao

    2015-01-01

    ABSTRACT Flavivirus RNA synthesis is mediated by a multiprotein complex associated with the endoplasmic reticulum membrane, named the replication complex (RC). Within the flavivirus RC, NS4B, an integral membrane protein with a role in virulence and regulation of the innate immune response, binds to the NS3 protease-helicase. NS4B modulates the RNA helicase activity of NS3, but the molecular details of their interaction remain elusive. Here, we used dengue virus (DENV) to map the determinants for the NS3-NS4B interaction. Coimmunoprecipitation and an in situ proximity ligation assay confirmed that NS3 colocalizes with NS4B in both DENV-infected cells and cells coexpressing both proteins. Surface plasmon resonance demonstrated that subdomains 2 and 3 of the NS3 helicase region and the cytoplasmic loop of NS4B are required for binding. Using nuclear magnetic resonance (NMR), we found that the isolated cytoplasmic loop of NS4B is flexible, with a tendency to form a three-turn α-helix and two short β-strands. Upon binding to the NS3 helicase, 12 amino acids within the cytoplasmic loop of NS4B exhibited line broadening, suggesting a participation in the interaction. Sequence alignment showed that 4 of these 12 residues are strictly conserved across different flaviviruses. Mutagenesis analysis showed that three (Q134, G140, and N144) of the four evolutionarily conserved NS4B residues are essential for DENV replication. The mapping of the NS3/NS4B-interacting regions described here can assist the design of inhibitors that disrupt their interface for antiviral therapy. IMPORTANCE NS3 and NS4B are essential components of the flavivirus RC. Using DENV as a model, we mapped the interaction between the viral NS3 and NS4B proteins. The subdomains 2 and 3 of NS3 helicase as well as the cytoplasmic loop of NS4B are critical for the interaction. Functional analysis delineated residues within the NS4B cytoplasmic loop that are crucial for DENV replication. Our findings reveal

  16. A dose error evaluation study for 4D dose calculations

    NASA Astrophysics Data System (ADS)

    Milz, Stefan; Wilkens, Jan J.; Ullrich, Wolfgang

    2014-10-01

    Previous studies have shown that respiration induced motion is not negligible for Stereotactic Body Radiation Therapy. The intrafractional breathing induced motion influences the delivered dose distribution on the underlying patient geometry such as the lung or the abdomen. If a static geometry is used, a planning process for these indications does not represent the entire dynamic process. The quality of a full 4D dose calculation approach depends on the dose coordinate transformation process between deformable geometries. This article provides an evaluation study that introduces an advanced method to verify the quality of numerical dose transformation generated by four different algorithms. The used transformation metric value is based on the deviation of the dose mass histogram (DMH) and the mean dose throughout dose transformation. The study compares the results of four algorithms. In general, two elementary approaches are used: dose mapping and energy transformation. Dose interpolation (DIM) and an advanced concept, so called divergent dose mapping model (dDMM), are used for dose mapping. The algorithms are compared to the basic energy transformation model (bETM) and the energy mass congruent mapping (EMCM). For evaluation 900 small sample regions of interest (ROI) are generated inside an exemplary lung geometry (4DCT). A homogeneous fluence distribution is assumed for dose calculation inside the ROIs. The dose transformations are performed with the four different algorithms. The study investigates the DMH-metric and the mean dose metric for different scenarios (voxel sizes: 8 mm, 4 mm, 2 mm, 1 mm 9 different breathing phases). dDMM achieves the best transformation accuracy in all measured test cases with 3-5% lower errors than the other models. The results of dDMM are reasonable and most efficient in this study, although the model is simple and easy to implement. The EMCM model also achieved suitable results, but the approach requires a more complex

  17. Experimenting with the GMAO 4D Data Assimilation

    NASA Technical Reports Server (NTRS)

    Todling, R.; El Akkraoui, A.; Errico, R. M.; Guo, J.; Kim, J.; Kliest, D.; Parrish, D. F.; Suarez, M.; Trayanov, A.; Tremolet, Yannick; Whitaker, J.

    2012-01-01

    The Global Modeling and Assimilation Office (GMAO) has been working to promote its prototype four-dimensional variational (4DVAR) system to a version that can be exercised at operationally desirable configurations. Beyond a general circulation model (GeM) and an analysis system, traditional 4DV AR requires availability of tangent linear (TL) and adjoint (AD) models of the corresponding GeM. The GMAO prototype 4DVAR uses the finite-volume-based GEOS GeM and the Grid-point Statistical Interpolation (GSI) system for the first two, and TL and AD models derived ITom an early version of the finite-volume hydrodynamics that is scientifically equivalent to the present GEOS nonlinear GeM but computationally rather outdated. Specifically, the TL and AD models hydrodynamics uses a simple (I-dimensional) latitudinal MPI domain decomposition, which has consequent low scalability and prevents the prototype 4DV AR ITom being used in realistic applications. In the near future, GMAO will be upgrading its operational GEOS GCM (and assimilation system) to use a cubed-sphere-based hydrodynamics. This versions of the dynamics scales to thousands of processes and has led to a decision to re-derive the TL and AD models for this more modern dynamics, thus taking advantage of a two-dimensional MPI decomposition and improved scalability properties. With the aid of the Transformation of Algorithms in FORTRAN (l'AF) automatic adjoint generation tool and some hand-coding, a version of the cubed-sphere-based TL and AD models, with a simplified vertical diffusion scheme, is now available, enabling multiple configurations of standard implementations of 4DV AR in GEOS. Concurrent to this development, collaboration with the National Centers for Environmental Prediction (NCEP) and the Earth System Research Laboratory (ESRL) has allowed GMAO to implement a hybrid-ensemble capability within the GEOS data assimilation system. Both 3Dand 4D-ensemble capabilities are presently available thus allowing

  18. Predicting lower mantle heterogeneity from 4-D Earth models

    NASA Astrophysics Data System (ADS)

    Flament, Nicolas; Williams, Simon; Müller, Dietmar; Gurnis, Michael; Bower, Dan J.

    2016-04-01

    basal layer ˜ 4% denser than ambient mantle. Increasing convective vigour (Ra ≈ 5 x 108) or decreasing the density of the basal layer decreases both the accuracy and sensitivity of the predicted lower mantle structure. References: D. J. Bower, M. Gurnis, N. Flament, Assimilating lithosphere and slab history in 4-D Earth models. Phys. Earth Planet. Inter. 238, 8-22 (2015). V. Lekic, S. Cottaar, A. Dziewonski, B. Romanowicz, Cluster analysis of global lower mantle tomography: A new class of structure and implications for chemical heterogeneity. Earth Planet. Sci. Lett. 357, 68-77 (2012).

  19. 4D motion animation of coronary arteries from rotational angiography

    NASA Astrophysics Data System (ADS)

    Holub, Wolfgang; Rohkohl, Christopher; Schuldhaus, Dominik; Prümmer, Marcus; Lauritsch, Günter; Hornegger, Joachim

    2011-03-01

    Time-resolved 3-D imaging of the heart is a major research topic in the medical imaging community. Recent advances in the interventional cardiac 3-D imaging from rotational angiography (C-arm CT) are now also making 4-D imaging feasible during procedures in the catheter laboratory. State-of-the-art reconstruction algorithms try to estimate the cardiac motion and utilize the motion field to enhance the reconstruction of a stable cardiac phase (diastole). The available data offers a handful of opportunities during interventional procedures, e.g. the ECG-synchronized dynamic roadmapping or the computation and analysis of functional parameters. In this paper we will demonstrate that the motion vector field (MVF) that is output by motion compensated image reconstruction algorithms is in general not directly usable for animation and motion analysis. Dependent on the algorithm different defects are investigated. A primary issue is that the MVF needs to be inverted, i.e. the wrong direction of motion is provided. A second major issue is the non-periodicity of cardiac motion. In algorithms which compute a non-periodic motion field from a single rotation the in depth motion information along viewing direction is missing, since this cannot be measured in the projections. As a result, while the MVF improves reconstruction quality, it is insufficient for motion animation and analysis. We propose an algorithm to solve both problems, i.e. inversion and missing in-depth information in a unified framework. A periodic version of the MVF is approximated. The task is formulated as a linear optimization problem where a parametric smooth motion model based on B-splines is estimated from the MVF. It is shown that the problem can be solved using a sparse QR factorization within a clinical feasible time of less than one minute. In a phantom experiment using the publicly available CAVAREV platform, the average quality of a non-periodic animation could be increased by 39% by applying the

  20. Interactive 4D Visualization of Sediment Transport Models

    NASA Astrophysics Data System (ADS)

    Butkiewicz, T.; Englert, C. M.

    2013-12-01

    Coastal sediment transport models simulate the effects that waves, currents, and tides have on near-shore bathymetry and features such as beaches and barrier islands. Understanding these dynamic processes is integral to the study of coastline stability, beach erosion, and environmental contamination. Furthermore, analyzing the results of these simulations is a critical task in the design, placement, and engineering of coastal structures such as seawalls, jetties, support pilings for wind turbines, etc. Despite the importance of these models, there is a lack of available visualization software that allows users to explore and perform analysis on these datasets in an intuitive and effective manner. Existing visualization interfaces for these datasets often present only one variable at a time, using two dimensional plan or cross-sectional views. These visual restrictions limit the ability to observe the contents in the proper overall context, both in spatial and multi-dimensional terms. To improve upon these limitations, we use 3D rendering and particle system based illustration techniques to show water column/flow data across all depths simultaneously. We can also encode multiple variables across different perceptual channels (color, texture, motion, etc.) to enrich surfaces with multi-dimensional information. Interactive tools are provided, which can be used to explore the dataset and find regions-of-interest for further investigation. Our visualization package provides an intuitive 4D (3D, time-varying) visualization of sediment transport model output. In addition, we are also integrating real world observations with the simulated data to support analysis of the impact from major sediment transport events. In particular, we have been focusing on the effects of Superstorm Sandy on the Redbird Artificial Reef Site, offshore of Delaware Bay. Based on our pre- and post-storm high-resolution sonar surveys, there has significant scour and bedform migration around the

  1. Estrogen-dependent proteolytic cleavage of semaphorin 4D and plexin-B1 enhances semaphorin 4D-induced apoptosis during postnatal vaginal remodeling in pubescent mice.

    PubMed

    Ito, Takuji; Bai, Tao; Tanaka, Tetsuji; Yoshida, Kenji; Ueyama, Takashi; Miyajima, Masayasu; Negishi, Takayuki; Kawasaki, Takahiko; Takamatsu, Hyota; Kikutani, Hitoshi; Kumanogoh, Atsushi; Yukawa, Kazunori

    2014-01-01

    Around the fifth week after birth, the vaginal cavity in female mouse pups opens to the overlaying skin. This postnatal tissue remodeling of the genital tract occurs during puberty, and it largely depends upon hormonally induced apoptosis that mainly occurs in the epithelium at the lower part of the mouse vaginal cavity. Previously, we showed that most BALB/c mice lacking the class IV Semaphorin (Sema4D) develop imperforate vagina and hydrometrocolpos; therefore, we reasoned that the absence of Sema4D-induced apoptosis in vaginal epithelial cells may cause the imperforate vagina. Sema4D signals via the Plexin-B1 receptor; nevertheless detailed mechanisms mediating this hormonally triggered apoptosis are not fully documented. To investigate the estrogen-dependent control of Sema4D signaling during the apoptosis responsible for mouse vaginal opening, we examined structural and functional modulation of Sema4D, Plexin-B1, and signaling molecules by analyzing both wild-type and Sema4D-/- mice with or without ovariectomy. Both the release of soluble Sema4D and the conversion of Plexin-B1 by proteolytic processing in vaginal tissue peaked 5 weeks after birth of wild-type BALB/c mice at the time of vaginal opening. Estrogen supplementation of ovariectomized wild-type mice revealed that both the release of soluble Sema4D and the conversion of Plexin-B1 into an active form were estrogen-dependent and concordant with apoptosis. Estrogen supplementation of ovariectomized Sema4D-/- mice did not induce massive vaginal apoptosis in 5-week-old mice; therefore, Sema4D may be an essential apoptosis-inducing ligand that acts downstream of estrogen action in vaginal epithelium during this postnatal tissue remodeling. Analysis of ovariectomized mice also indicated that Sema4D contributed to estrogen-dependent dephosphorylation of Akt and ERK at the time of vaginal opening. Based on our results, we propose that apoptosis in vaginal epithelium during postnatal vaginal opening is induced

  2. Mutations in classical swine fever virus NS4B affect virulence in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    NS4B is one of the non-structural proteins of Classical Swine Fever Virus (CSFV), a virus causing a severe disease in swine. Protein domain analysis of the predicted amino acid sequence of NS4B in highly pathogenic CSFV strain Brescia (BICv) identified a Toll/Interleukin-1 receptor like domain (TIR...

  3. Mutations in the classical swine fever virus NS4B protein affects virulence in swine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    NS4B is one of the non-structural proteins of Classical Swine Fever Virus (CSFV), the etiological agent of a severe, highly lethal disease of swine. Protein domain analysis of the predicted amino acid sequence of the NS4B protein of highly pathogenic CSFV strain Brescia (BICv) identified a Toll/Inte...

  4. 78 FR 63221 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... availability of a guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the... ICH Q4B evaluation of the Bacterial Endotoxins Test General Chapter harmonized text from each of...

  5. 76 FR 37129 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-24

    ... Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... ] availability of a guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the... published ICH guidance, ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the...

  6. Atypical Listeria monocytogenes Serotype 4b strains harboring a lineage II-specific gene cassette

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Listeria monocytogenes is the etiological agent of listeriosis, a severe foodborne illness. The population of L. monocytogenes is divided into four lineages (I-IV) and serotype 4b in lineage I has been involved in numerous outbreaks. Several serotype 4b epidemic-associated clonal groups (ECI, II, an...

  7. TAF4b Regulates Oocyte-Specific Genes Essential for Meiosis

    PubMed Central

    Grive, Kathryn J.; Gustafson, Eric A.; Seymour, Kimberly A.; Baddoo, Melody; Schorl, Christoph; Golnoski, Kayla; Rajkovic, Aleksandar; Brodsky, Alexander S.; Freiman, Richard N.

    2016-01-01

    TAF4b is a gonadal-enriched subunit of the general transcription factor TFIID that is implicated in promoting healthy ovarian aging and female fertility in mice and humans. To further explore the potential mechanism of TAF4b in promoting ovarian follicle development, we analyzed global gene expression at multiple time points in the human fetal ovary. This computational analysis revealed coordinate expression of human TAF4B and critical regulators and effectors of meiosis I including SYCP3, YBX2, STAG3, and DAZL. To address the functional relevance of this analysis, we turned to the embryonic Taf4b-deficient mouse ovary where, for the first time, we demonstrate, severe deficits in prophase I progression as well as asynapsis in Taf4b-deficient oocytes. Accordingly, TAF4b occupies the proximal promoters of many essential meiosis and oogenesis regulators, including Stra8, Dazl, Figla, and Nobox, and is required for their proper expression. These data reveal a novel TAF4b function in regulating a meiotic gene expression program in early mouse oogenesis, and support the existence of a highly conserved TAF4b-dependent gene regulatory network promoting early oocyte development in both mice and women. PMID:27341508

  8. Identification of breast cancer cell subtypes sensitive to ATG4B inhibition

    PubMed Central

    Bortnik, Svetlana; Choutka, Courtney; Horlings, Hugo M.; Leung, Samuel; Baker, Jennifer H.; Lebovitz, Chandra; Dragowska, Wieslawa H.; Go, Nancy E.; Bally, Marcel B.; Minchinton, Andrew I.; Gelmon, Karen A.; Gorski, Sharon M.

    2016-01-01

    Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target. In this study, we investigated the expression of ATG4B in breast cancer, a heterogeneous disease comprised of several molecular subtypes. We examined a panel of breast cancer cell lines, xenograft tumors, and breast cancer patient specimens for the protein expression of ATG4B, and found a positive association between HER2 and ATG4B protein expression. We showed that HER2-positive cells, but not HER2-negative breast cancer cells, require ATG4B to survive under stress. In HER2-positive cells, cytoprotective autophagy was dependent on ATG4B under both starvation and HER2 inhibition conditions. Combined knockdown of ATG4B and HER2 by siRNA resulted in a significant decrease in cell viability, and the combination of ATG4B knockdown with trastuzumab resulted in a greater reduction in cell viability compared to trastuzumab treatment alone, in both trastuzumab-sensitive and -resistant HER2 overexpressing breast cancer cells. Together these results demonstrate a novel association of ATG4B positive expression with HER2 positive breast cancers and indicate that this subtype is suitable for emerging ATG4B inhibition strategies. PMID:27556700

  9. (4bS,8aS)-1-Isopropyl-4b,8,8-trimethyl-4b,5,6,7,8,8a,9,10-octa­hydro­phenan­thren-2-yl acetate

    PubMed Central

    Oubabi, Radouane; Auhmani, Aziz; Ait Itto, My Youssef; Auhmani, Abdelwahed; Daran, Jean-Claude

    2014-01-01

    The hemisynthesis of the title compound, C22H32O2, was carried out through direct acetyl­ation reaction of the naturally occurring diterpene totarol [systematic name: (4bS,8aS)-4b,8,8-trimethyl-1-propan-2-yl-5,6,7,8a,9,10-hexa­hydro­phen­an­thren-2-ol]. The mol­ecule is built up from three fused six membered rings, one saturated and two unsaturated. The central unsaturated ring has a half-chair conformation, whereas the other unsaturated ring displays a chair conformation. The absolute configuration is deduced from the chemical pathway. The value of the Hooft parameter [−0.10 (6)] allowed this absolute configuration to be confirmed. PMID:24765017

  10. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.

    PubMed

    Smith, Ernest S; Jonason, Alan; Reilly, Christine; Veeraraghavan, Janaki; Fisher, Terrence; Doherty, Michael; Klimatcheva, Ekaterina; Mallow, Crystal; Cornelius, Chad; Leonard, John E; Marchi, Nicola; Janigro, Damir; Argaw, Azeb Tadesse; Pham, Trinh; Seils, Jennifer; Bussler, Holm; Torno, Sebold; Kirk, Renee; Howell, Alan; Evans, Elizabeth E; Paris, Mark; Bowers, William J; John, Gareth; Zauderer, Maurice

    2015-01-01

    Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit.

  11. INPP4B is an oncogenic regulator in human colon cancer

    PubMed Central

    Guo, S T; Chi, M N; Yang, R H; Guo, X Y; Zan, L K; Wang, C Y; Xi, Y F; Jin, L; Croft, A; Tseng, H-Y; Yan, X G; Farrelly, M; Wang, F H; Lai, F; Wang, J F; Li, Y P; Ackland, S; Scott, R; Agoulnik, I U; Hondermarck, H; Thorne, R F; Liu, T; Zhang, X D; Jiang, C C

    2016-01-01

    Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates phosphatidylinositol 3-kinase signaling and is a tumor suppressor in some types of cancers. However, we have found that it is frequently upregulated in human colon cancer cells. Here we show that silencing of INPP4B blocks activation of Akt and serum- and glucocorticoid-regulated kinase 3 (SGK3), inhibits colon cancer cell proliferation and retards colon cancer xenograft growth. Conversely, overexpression of INPP4B increases proliferation and triggers anchorage-independent growth of normal colon epithelial cells. Moreover, we demonstrate that the effect of INPP4B on Akt and SGK3 is associated with inactivation of phosphate and tensin homolog through its protein phosphatase activity and that the increase in INPP4B is due to Ets-1-mediated transcriptional upregulation in colon cancer cells. Collectively, these results suggest that INPP4B may function as an oncogenic driver in colon cancer, with potential implications for targeting INPP4B as a novel approach to treat this disease. PMID:26411369

  12. Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival

    PubMed Central

    Wang, Yubao; Begley, Michael; Li, Qing; Huang, Hai-Tsang; Lako, Ana; Eck, Michael J.; Gray, Nathanael S.; Mitchison, Timothy J.; Cantley, Lewis C.; Zhao, Jean J.

    2016-01-01

    The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MELK–eIF4B signaling axis regulates protein synthesis during mitosis. Specifically, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in cancer cell survival during cell division, depends on the function of MELK-elF4B. Inactivation of MELK or eIF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of cancer cells. Our study thus defines a MELK–eIF4B signaling axis that regulates protein synthesis during mitosis, and consequently influences cancer cell survival. PMID:27528663

  13. ATG4B/autophagin-1 regulates intestinal homeostasis and protects mice from experimental colitis

    PubMed Central

    Cabrera, Sandra; Fernández, Álvaro F.; Mariño, Guillermo; Aguirre, Alina; Suárez, María F.; Español, Yaiza; Vega, José A.; Laurà, Rosaria; Fueyo, Antonio; Fernández-García, M. Soledad; Freije, José M.P.; Kroemer, Guido; López-Otín, Carlos

    2013-01-01

    The identification of inflammatory bowel disease (IBD) susceptibility genes by genome-wide association has linked this pathology to autophagy, a lysosomal degradation pathway that is crucial for cell and tissue homeostasis. Here, we describe autophagy-related 4B, cysteine peptidase/autophagin-1 (ATG4B) as an essential protein in the control of inflammatory response during experimental colitis. In this pathological condition, ATG4B protein levels increase in parallel with the induction of autophagy. Moreover, ATG4B expression is significantly reduced in affected areas of the colon from IBD patients. Consistently, atg4b−/− mice present Paneth cell abnormalities, as well as an increased susceptibility to DSS-induced colitis. atg4b-deficient mice exhibit significant alterations in proinflammatory cytokines and mediators of the immune response to bacterial infections, which are reminiscent of those found in patients with Crohn disease or ulcerative colitis. Additionally, antibiotic treatments and bone marrow transplantation from wild-type mice reduced colitis in atg4b−/− mice. Taken together, these results provided additional evidence for the importance of autophagy in intestinal pathologies and describe ATG4B as a novel protective protein in inflammatory colitis. Finally, we propose that atg4b-null mice are a suitable model for in vivo studies aimed at testing new therapeutic strategies for intestinal diseases associated with autophagy deficiency. PMID:23782979

  14. Heat capacity, resistivity, and angular dependent magnetization studies of single crystal Nd1+ϵFe4B4 for ϵ≈17

    DOE PAGES

    Conner, Benjamin S.; Susner, Michael A.; Lampen-Kelley, Paula; ...

    2017-04-04

    Advances in crystal growth have allowed for synthesis of large single crystals of Nd1+ϵFe4B4, a well-known phase with a modulated structure. As a result we are able to report heat capacity and resistivity measurements on a single crystal Nd1+ϵFe4B4 sample with a distribution of ϵ that skews towards the solubility limit of Nd near ϵ ≈ 17. Heat capacity measurements show evidence of crystal field splitting at temperatures higher than the long-range ferromagnetic Curie temperature. Heat capacity, resistivity, and magnetization measurements all confirm a Curie temperature of 7 K which is lower than previously reported values in the Nd1+ϵFe4B4 system.more » Here, we also perform measurements of the angular dependence of the magnetization and discover behavior associated with the magnetic anisotropy that is inconsistent with the simple description previously proposed.« less

  15. Regulation of semaphorin 4D expression and cell proliferation of ovarian cancer by ERalpha and ERbeta

    PubMed Central

    Liu, Y.; Hou, Y.; Ma, L.; Sun, C.; Pan, J.; Yang, Y.; Zhou, H.; Zhang, J.

    2017-01-01

    Ovarian cancer is one of the most common malignancies in women. Semaphorin 4D (sema 4D) is involved in the progress of multiple cancers. In the presence of estrogen-like ligands, estrogen receptors (ERα and ERβ) participate in the progress of breast and ovarian cancers by transcriptional regulation. The aim of the study was to investigate the role of sema 4D and elucidate the regulatory pattern of ERα and ERβ on sema 4D expression in ovarian cancers. Sema 4D levels were up-regulated in ovarian cancer SKOV-3 cells. Patients with malignant ovarian cancers had significantly higher sema 4D levels than controls, suggesting an oncogene role of sema 4D in ovarian cancer. ERα expressions were up-regulated in SKOV-3 cells compared with normal ovarian IOSE80 epithelial cells. Conversely, down-regulation of ERβ was observed in SKOV-3 cells. Forced over-expression of ERα and ERβ in SKOV-3 cells was manipulated to establish ERα+ and ERβ+ SKOV-3 cell lines. Incubation of ERα+ SKOV-3 cells with ERs agonist 17β-estradiol (E2) significantly enhanced sema 4D expression and rate of cell proliferation. Incubated with E2, ERβ+ SKOV-3 cells showed lower sema 4D expression and cell proliferation. Blocking ERα and ERβ activities with ICI182-780 inhibitor, sema 4D expressions and cell proliferation of ERα+ and ERβ+ SKOV-3 cells were recovered to control levels. Taken together, the data showed that sema 4D expression was positively correlated with the progress of ovarian cancer. ERα positively regulated sema 4D expression and accelerated cell proliferation. ERβ negatively regulated sema 4D expression and inhibited cell multiplication. PMID:28225892

  16. Geometric validation of self-gating k-space-sorted 4D-MRI vs 4D-CT using a respiratory motion phantom

    PubMed Central

    Yue, Yong; Fan, Zhaoyang; Yang, Wensha; Pang, Jianing; Deng, Zixin; McKenzie, Elizabeth; Tuli, Richard; Wallace, Robert; Li, Debiao; Fraass, Benedick

    2015-01-01

    Purpose: MRI is increasingly being used for radiotherapy planning, simulation, and in-treatment-room motion monitoring. To provide more detailed temporal and spatial MR data for these tasks, we have recently developed a novel self-gated (SG) MRI technique with advantage of k-space phase sorting, high isotropic spatial resolution, and high temporal resolution. The current work describes the validation of this 4D-MRI technique using a MRI- and CT-compatible respiratory motion phantom and comparison to 4D-CT. Methods: The 4D-MRI sequence is based on a spoiled gradient echo-based 3D projection reconstruction sequence with self-gating for 4D-MRI at 3 T. Respiratory phase is resolved by using SG k-space lines as the motion surrogate. 4D-MRI images are reconstructed into ten temporal bins with spatial resolution 1.56 × 1.56 × 1.56 mm3. A MRI-CT compatible phantom was designed to validate the performance of the 4D-MRI sequence and 4D-CT imaging. A spherical target (diameter 23 mm, volume 6.37 ml) filled with high-concentration gadolinium (Gd) gel is embedded into a plastic box (35 × 40 × 63 mm3) and stabilized with low-concentration Gd gel. The phantom, driven by an air pump, is able to produce human-type breathing patterns between 4 and 30 respiratory cycles/min. 4D-CT of the phantom has been acquired in cine mode, and reconstructed into ten phases with slice thickness 1.25 mm. The 4D images sets were imported into a treatment planning software for target contouring. The geometrical accuracy of the 4D MRI and CT images has been quantified using target volume, flattening, and eccentricity. The target motion was measured by tracking the centroids of the spheres in each individual phase. Motion ground-truth was obtained from input signals and real-time video recordings. Results: The dynamic phantom has been operated in four respiratory rate (RR) settings, 6, 10, 15, and 20/min, and was scanned with 4D-MRI and 4D-CT. 4D-CT images have target-stretching, partial

  17. Geometric validation of self-gating k-space-sorted 4D-MRI vs 4D-CT using a respiratory motion phantom

    SciTech Connect

    Yue, Yong Yang, Wensha; McKenzie, Elizabeth; Tuli, Richard; Wallace, Robert; Fraass, Benedick; Fan, Zhaoyang; Pang, Jianing; Deng, Zixin; Li, Debiao

    2015-10-15

    Purpose: MRI is increasingly being used for radiotherapy planning, simulation, and in-treatment-room motion monitoring. To provide more detailed temporal and spatial MR data for these tasks, we have recently developed a novel self-gated (SG) MRI technique with advantage of k-space phase sorting, high isotropic spatial resolution, and high temporal resolution. The current work describes the validation of this 4D-MRI technique using a MRI- and CT-compatible respiratory motion phantom and comparison to 4D-CT. Methods: The 4D-MRI sequence is based on a spoiled gradient echo-based 3D projection reconstruction sequence with self-gating for 4D-MRI at 3 T. Respiratory phase is resolved by using SG k-space lines as the motion surrogate. 4D-MRI images are reconstructed into ten temporal bins with spatial resolution 1.56 × 1.56 × 1.56 mm{sup 3}. A MRI-CT compatible phantom was designed to validate the performance of the 4D-MRI sequence and 4D-CT imaging. A spherical target (diameter 23 mm, volume 6.37 ml) filled with high-concentration gadolinium (Gd) gel is embedded into a plastic box (35 × 40 × 63 mm{sup 3}) and stabilized with low-concentration Gd gel. The phantom, driven by an air pump, is able to produce human-type breathing patterns between 4 and 30 respiratory cycles/min. 4D-CT of the phantom has been acquired in cine mode, and reconstructed into ten phases with slice thickness 1.25 mm. The 4D images sets were imported into a treatment planning software for target contouring. The geometrical accuracy of the 4D MRI and CT images has been quantified using target volume, flattening, and eccentricity. The target motion was measured by tracking the centroids of the spheres in each individual phase. Motion ground-truth was obtained from input signals and real-time video recordings. Results: The dynamic phantom has been operated in four respiratory rate (RR) settings, 6, 10, 15, and 20/min, and was scanned with 4D-MRI and 4D-CT. 4D-CT images have target

  18. A C-terminal di-leucine motif controls plasma membrane expression of PMCA4b.

    PubMed

    Antalffy, Géza; Pászty, Katalin; Varga, Karolina; Hegedűs, Luca; Enyedi, Agnes; Padányi, Rita

    2013-12-01

    Recent evidences show that the localization of different plasma membrane Ca(2+) ATPases (PMCAs) is regulated in various complex, cell type-specific ways. Here we show that in low-density epithelial and endothelial cells PMCA4b localized mostly in intracellular compartments and its plasma membrane localization was enhanced upon increasing density of cells. In good correlation with the enhanced plasma membrane localization a significantly more efficient Ca(2+) clearance was observed in confluent versus non-confluent HeLa cell cultures expressing mCherry-PMCA4b. We analyzed the subcellular localization and function of various C-terminally truncated PMCA4b variants and found that a truncated mutant PMCA4b-ct24 was mostly intracellular while another mutant, PMCA4b-ct48, localized more to the plasma membrane, indicating that a protein sequence corresponding to amino acid residues 1158-1181 contained a signal responsible for the intracellular retention of PMCA4b in non-confluent cultures. Alteration of three leucines to alanines at positions 1167-1169 resulted in enhanced cell surface expression and an appropriate Ca(2+) transport activity of both wild type and truncated pumps, suggesting that the di-leucine-like motif (1167)LLL was crucial in targeting PMCA4b. Furthermore, upon loss of cell-cell contact by extracellular Ca(2+) removal, the wild-type pump was translocated to the early endosomal compartment. Targeting PMCA4b to early endosomes was diminished by the L(1167-69)A mutation, and the mutant pump accumulated in long tubular cytosolic structures. In summary, we report a di-leucine-like internalization signal at the C-tail of PMCA4b and suggest an internalization-mediated loss of function of the pump upon low degree of cell-cell contact.

  19. LAPTM4B Gene Expression and Polymorphism as Diagnostic Markers of Breast Cancer in Egyptian Patients

    PubMed Central

    Shaker, Olfat; Taha, Fatma; Salah, Maha; El-Marzouky, Mohamed

    2015-01-01

    Summary Background The aim of this study was to investigate the association between LAPTM4B gene polymorphism and the risk of breast cancer among Egyptian female patients. Also, measurement was done of its serum level to evaluate its significance as a diagnostic marker for breast cancer. Methods This case control study was done on 88 breast cancer patients, 40 with fibroadenoma and 80 healthy subjects. Genotyping of the LAPTM4B polymorphism was determined by PCR. Serum LAPTM4B level was measured using ELISA. Results There was a significant difference in the (*1/2+ *2/2) genotypes in breast cancer patients (59.1) compared to the control subjects (43.8%) (P=0.047; OR=1.86; 95% CI =1.01–3.43). The frequency of the allele 2* of the LAPTM4B gene was significantly higher in breast cancer patients (36.4%) than in the control (25.6%) (p=0.034; OR=1.66; 95% CI =1.04–2.65). Genotypes (*1/2+*2/2) were significantly associated with the differential classification of TNM. Serum level of LAPTM4B was significantly higher in breast cancer patients than in control and fibroadenoma and in fibroadenoma patients than in control. In breast cancer patients, serum LAPTM4B was significantly higher in stage III and in large tumor size. Serum LAPTM4B was significantly higher in the cancer patients’ genotypes (*1/2+*2/2). Conclusions Genetic polymorphism of LAPTM4B is a potential risk factor for the development of breast cancer. Serum LAPTM4B may be used as a diagnostic and prognostic marker for breast cancer. PMID:28356847

  20. Chronic Cognitive Dysfunction after Traumatic Brain Injury Is Improved with a Phosphodiesterase 4B Inhibitor

    PubMed Central

    Titus, David J.; Wilson, Nicole M.; Freund, Julie E.; Carballosa, Melissa M.; Sikah, Kevin E.; Furones, Concepcion; Dietrich, W. Dalton; Gurney, Mark E.

    2016-01-01

    Learning and memory impairments are common in traumatic brain injury (TBI) survivors. However, there are no effective treatments to improve TBI-induced learning and memory impairments. TBI results in decreased cAMP signaling and reduced cAMP-response-element binding protein (CREB) activation, a critical pathway involved in learning and memory. TBI also acutely upregulates phosphodiesterase 4B2 (PDE4B2), which terminates cAMP signaling by hydrolyzing cAMP. We hypothesized that a subtype-selective PDE4B inhibitor could reverse the learning deficits induced by TBI. To test this hypothesis, adult male Sprague-Dawley rats received sham surgery or moderate parasagittal fluid-percussion brain injury. At 3 months postsurgery, animals were administered a selective PDE4B inhibitor or vehicle before cue and contextual fear conditioning, water maze training and a spatial working memory task. Treatment with the PDE4B inhibitor significantly reversed the TBI-induced deficits in cue and contextual fear conditioning and water maze retention. To further understand the underlying mechanisms of these memory impairments, we examined hippocampal long-term potentiation (LTP). TBI resulted in a significant reduction in basal synaptic transmission and impaired expression of LTP. Treatment with the PDE4B inhibitor significantly reduced the deficits in basal synaptic transmission and rescued LTP expression. The PDE4B inhibitor reduced tumor necrosis factor-α levels and increased phosphorylated CREB levels after TBI, suggesting that this drug inhibited molecular pathways in the brain known to be regulated by PDE4B. These results suggest that a subtype-selective PDE4B inhibitor is a potential therapeutic to reverse chronic learning and memory dysfunction and deficits in hippocampal synaptic plasticity following TBI. SIGNIFICANCE STATEMENT Currently, there are an estimated 3.2–5.3 million individuals living with disabilities from traumatic brain injury (TBI) in the United States, and 8 of

  1. The role of semaphorin 4D in tumor development and angiogenesis in human breast cancer

    PubMed Central

    Jiang, Hongchao; Chen, Ceshi; Sun, Qiangming; Wu, Jing; Qiu, Lijuan; Gao, Change; Liu, Weiqing; Yang, Jun; Jun, Nie; Dong, Jian

    2016-01-01

    Background Semaphorin 4D (Sema4D) is highly expressed in certain types of tumors and functions in the regulation of tumor angiogenesis and growth. However, it is still not clear regarding the roles of Sema4D in breast cancer. This study was designed to explore the effects of Sema4D on proliferation, cell cycle progression, apoptosis, invasion, migration, tumor growth, and angiogenesis in breast cancer. Materials and methods The expression level of Sema4D was investigated in MCF10A, 184A1, HCC1937, MDA-MB-468, MDA-MB-231, Hs578T, BT474, MCF-7, and T47D breast cancer cell lines by Western blotting analysis. Sema4D downregulation or overexpression was established by infection with lentiviruses-encoding Sema4D short hairpin RNA (shRNA) or Sema4D. To evaluate the effects of Sema4D on cell proliferation, cell cycle progression, apoptosis, invasion, and migration of MDA-MB-231 and MDA-MB-468 cells, methods including MTT assay, flow cytometry, wound healing assay, and transwell experiments were applied. BALB/c nude mice were injected with MDA-MB-231 cells, which were respectively infected with lentiviruses-encoding Sema4D, Sema4D shRNA, and GFP, followed by tumor angiogenesis assay. Results Sema4D was expressed at higher levels in breast cancer cell lines compared with the normal human breast epithelial cell lines, especially in MDA-MB-231 and MDA-MB-468 cells. Cell proliferation ability was remarkably inhibited in Sema4D downregulated condition, whereas the proportions of cells in the G0/G1 phase and apoptosis increased in MDA-MB-231 and MDA-MB-468 cells. In addition, the invasion and migration abilities of these cells were obviously reduced. Xenograft growth as well as angiogenesis was inhibited when infected with lentiviruses-encoding Sema4D shRNA in vivo. Conclusion Downregulation of Sema4D had notable influence on cell proliferation ability, invasion, migration, and apoptosis of both MDA-MB-231 and MDA-MB-468 cells. Furthermore, infection with lentiviruses

  2. IMRT treatment planning on 4D geometries for the era of dynamic MLC tracking.

    PubMed

    Suh, Yelin; Murray, Walter; Keall, Paul J

    2014-12-01

    The problem addressed here was to obtain optimal and deliverable dynamic multileaf collimator (MLC) leaf sequences from four-dimensional (4D) geometries for dynamic MLC tracking delivery. The envisaged scenario was where respiratory phase and position information of the target was available during treatment, from which the optimal treatment plan could be further adapted in real time. A tool for 4D treatment plan optimization was developed that integrates a commercially available treatment planning system and a general-purpose optimization system. The 4D planning method was applied to the 4D computed tomography planning scans of three lung cancer patients. The optimization variables were MLC leaf positions as a function of monitor units and respiratory phase. The objective function was the deformable dose-summed 4D treatment plan score. MLC leaf motion was constrained by the maximum leaf velocity between control points in terms of monitor units for tumor motion parallel to the leaf travel direction and between phases for tumor motion parallel to the leaf travel direction. For comparison and a starting point for the 4D optimization, three-dimensional (3D) optimization was performed on each of the phases. The output of the 4D IMRT planning process is a leaf sequence which is a function of both monitor unit and phase, which can be delivered to a patient whose breathing may vary between the imaging and treatment sessions. The 4D treatment plan score improved during 4D optimization by 34%, 4%, and 50% for Patients A, B, and C, respectively, indicating 4D optimization generated a better 4D treatment plan than the deformable sum of individually optimized phase plans. The dose-volume histograms for each phase remained similar, indicating robustness of the 4D treatment plan to respiratory variations expected during treatment delivery. In summary, 4D optimization for respiratory phase-dependent treatment planning with dynamic MLC motion tracking improved the 4D treatment plan

  3. 4D MRI for the Localization of Parathyroid Adenoma: A Novel Method in Evolution.

    PubMed

    Merchavy, Shlomo; Luckman, Judith; Guindy, Michal; Segev, Yoram; Khafif, Avi

    2016-03-01

    The sestamibi scan (MIBI) and ultrasound (US) are used for preoperative localization of parathyroid adenoma (PTA), with sensitivity as high as 90%. We developed 4-dimensional magnetic resonance imaging (4D MRI) as a novel tool for identifying PTAs. Eleven patients with PTA were enrolled. 4D MRI from the mandible to the aortic arch was used. Optimization of the timing of image acquisition was obtained by changing dynamic and static sequences. PTAs were identified in all except 1 patient. In 9 patients, there was a complete match between the 4D MRI and the US and MIBI, as well as with the operative finding. In 1 patient, the adenoma was correctly localized by 4D MRI, in contrast to the US and MIBI scan. The sensitivity of the 4D MRI was 90% and after optimization, 100%. Specificity was 100%. We concluded that 4D MRI is a reliable technique for identification of PTAs, although more studies are needed.

  4. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 6 2013-07-01 2013-07-01 false Class 4-D: Minister of religion. 1630.43 Section 1630.43 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D...

  5. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 6 2011-07-01 2011-07-01 false Class 4-D: Minister of religion. 1630.43 Section 1630.43 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D...

  6. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 6 2014-07-01 2014-07-01 false Class 4-D: Minister of religion. 1630.43 Section 1630.43 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D...

  7. 32 CFR 1630.43 - Class 4-D: Minister of religion.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 6 2012-07-01 2012-07-01 false Class 4-D: Minister of religion. 1630.43 Section 1630.43 National Defense Other Regulations Relating to National Defense SELECTIVE SERVICE SYSTEM CLASSIFICATION RULES § 1630.43 Class 4-D: Minister of religion. In accord with part 1645 of this chapter any registrant shall be placed in Class 4-D...

  8. Immunomodulation of the tumor microenvironment by neutralization of Semaphorin 4D

    PubMed Central

    Evans, Elizabeth E; Paris, Mark; Smith, Ernest S; Zauderer, Maurice

    2015-01-01

    Semaphorin 4D is highly expressed at the invasive tumor margin and acts as a guidance molecule, restricting movement of tumoricidal immune cells into the tumor microenvironment. We recently showed that antibody neutralization of SEMA4D augmented activated monocyte and anticancer T-cell tumor penetration and that anti-SEMA4D antibody potentiated other immunomodulatory therapies in murine tumor models. PMID:26587332

  9. Mitotic activation of the DISC1-inducible cyclic AMP phosphodiesterase-4D9 (PDE4D9), through multi-site phosphorylation, influences cell cycle progression.

    PubMed

    Sheppard, Catherine L; Lee, Louisa C Y; Hill, Elaine V; Henderson, David J P; Anthony, Diana F; Houslay, Daniel M; Yalla, Krishna C; Cairns, Lynne S; Dunlop, Allan J; Baillie, George S; Huston, Elaine; Houslay, Miles D

    2014-09-01

    In Rat-1 cells, the dramatic decrease in the levels of both intracellular cyclic 3'5' adenosine monophosphate (cyclic AMP; cAMP) and in the activity of cAMP-activated protein kinase A (PKA) observed in mitosis was paralleled by a profound increase in cAMP hydrolyzing phosphodiesterase-4 (PDE4) activity. The decrease in PKA activity, which occurs during mitosis, was attributable to PDE4 activation as the PDE4 selective inhibitor, rolipram, but not the phosphodiesterase-3 (PDE3) inhibitor, cilostamide, specifically ablated this cell cycle-dependent effect. PDE4 inhibition caused Rat-1 cells to move from S phase into G2/M more rapidly, to transit through G2/M more quickly and to remain in G1 for a longer period. Inhibition of PDE3 elicited no observable effects on cell cycle dynamics. Selective immunopurification of each of the four PDE4 sub-families identified PDE4D as being selectively activated in mitosis. Subsequent analysis uncovered PDE4D9, an isoform whose expression can be regulated by Disrupted-In-Schizophrenia 1 (DISC1)/activating transcription factor 4 (ATF4) complex, as the sole PDE4 species activated during mitosis in Rat-1 cells. PDE4D9 becomes activated in mitosis through dual phosphorylation at Ser585 and Ser245, involving the combined action of ERK and an unidentified 'switch' kinase that has previously been shown to be activated by H2O2. Additionally, in mitosis, PDE4D9 also becomes phosphorylated at Ser67 and Ser81, through the action of MK2 (MAPKAPK2) and AMP kinase (AMPK), respectively. The multisite phosphorylation of PDE4D9 by all four of these protein kinases leads to decreased mobility (band-shift) of PDE4D9 on SDS-PAGE. PDE4D9 is predominantly concentrated in the perinuclear region of Rat-1 cells but with a fraction distributed asymmetrically at the cell margins. Our investigations demonstrate that the diminished levels of cAMP and PKA activity that characterise mitosis are due to enhanced cAMP degradation by PDE4D9. PDE4D9, was found to

  10. Two New Copper Borates with Mesoscale Cubic Supramolecular Cages Assembled from {Cu4 @B20 } Clusters.

    PubMed

    Wang, Jia-Jia; Wei, Qi; Yang, Bai-Feng; Yang, Guo-Yu

    2017-02-24

    Two new copper borates, namely H6 [(μ4 -O)Cu4 @B20 O32 (OH)8 ]⋅25 H2 O (1) and H6 [(μ4 -O)Cu4 @B20 O32 (OH)8 ]⋅34 H2 O⋅8 H3 BO3 (2), with 3D supramolecular framework have been made under solvothermal conditions, which built by novel cubic supramolecular cages with mesoscale cavities via the H-bondings. Interestingly, the cage is assembled by [(μ4 -O)Cu4 @B20 O32 (OH)8 ] ({Cu4 @B20 }) cluster units with different point-group symmetry. Owing to extra H3 BO3 molecules participated in building the supramolecular framework, 2 has a larger cubic cage size and higher non-framework volume, leading to the cage size extended to mesoporous size set as a version of ''1 plus".

  11. A sinogram warping strategy for pre-reconstruction 4D PET optimization.

    PubMed

    Gianoli, Chiara; Riboldi, Marco; Fontana, Giulia; Kurz, Christopher; Parodi, Katia; Baroni, Guido

    2016-03-01

    A novel strategy for 4D PET optimization in the sinogram domain is proposed, aiming at motion model application before image reconstruction ("sinogram warping" strategy). Compared to state-of-the-art 4D-MLEM reconstruction, the proposed strategy is able to optimize the image SNR, avoiding iterative direct and inverse warping procedures, which are typical of the 4D-MLEM algorithm. A full-count statistics sinogram of the motion-compensated 4D PET reference phase is generated by warping the sinograms corresponding to the different PET phases. This is achieved relying on a motion model expressed in the sinogram domain. The strategy was tested on the anthropomorphic 4D PET-CT NCAT phantom in comparison with the 4D-MLEM algorithm, with particular reference to robustness to PET-CT co-registrations artefacts. The MLEM reconstruction of the warped sinogram according to the proposed strategy exhibited better accuracy (up to +40.90 % with respect to the ideal value), whereas images reconstructed according to the 4D-MLEM reconstruction resulted in less noisy (down to -26.90 % with respect to the ideal value) but more blurred. The sinogram warping strategy demonstrates advantages with respect to 4D-MLEM algorithm. These advantages are paid back by introducing approximation of the deformation field, and further efforts are required to mitigate the impact of such an approximation in clinical 4D PET reconstruction.

  12. The Relationship Between Digit Ratio (2D:4D) and Sexual Orientation in Men from China.

    PubMed

    Xu, Yin; Zheng, Yong

    2016-04-01

    We examined the relationship between 2D:4D digit ratio and sexual orientation in men from China and analyzed the influences of the components used to assess sexual orientation and the criteria used to classify individuals as homosexual on this relationship. A total of 309 male and 110 female participants took part in a web-based survey. Our results showed that heterosexual men had a significantly lower 2D:4D than heterosexual women and exclusively homosexual men had a significantly higher left 2D:4D than heterosexual men whereas only exclusively homosexual men had a significantly higher right 2D:4D than heterosexual men when sexual orientation was assessed via sexual attraction. The left 2D:4D showed a significant positive correlation with sexual identity, sexual attraction, and sexual behavior, and the right 2D:4D showed a significant positive correlation with sexual attraction. The effect sizes for differences in 2D:4D between homosexual and heterosexual men varied according to criteria used to classify individuals as homosexual and sexual orientation components; the more stringent the criteria (scores closer to the homosexual category), the larger the effect sizes; further, sexual attraction yielded the largest effect size. There were no significant effects of age and latitude on Chinese 2D:4D. This study contributes to the current understanding of the relationship between 2D:4D and male sexual orientation.

  13. 4D VMAT, gated VMAT, and 3D VMAT for stereotactic body radiation therapy in lung

    NASA Astrophysics Data System (ADS)

    Chin, E.; Loewen, S. K.; Nichol, A.; Otto, K.

    2013-02-01

    Four-dimensional volumetric modulated arc therapy (4D VMAT) is a treatment strategy for lung cancers that aims to exploit relative target and tissue motion to improve organ at risk (OAR) sparing. The algorithm incorporates the entire patient respiratory cycle using 4D CT data into the optimization process. Resulting treatment plans synchronize the delivery of each beam aperture to a specific phase of target motion. Stereotactic body radiation therapy treatment plans for 4D VMAT, gated VMAT, and 3D VMAT were generated on three patients with non-small cell lung cancer. Tumour motion ranged from 1.4-3.4 cm. The dose and fractionation scheme was 48 Gy in four fractions. A B-spline transformation model registered the 4D CT images. 4D dose volume histograms (4D DVH) were calculated from total dose accumulated at the maximum exhalation. For the majority of OARs, gated VMAT achieved the most radiation sparing but treatment times were 77-148% longer than 3D VMAT. 4D VMAT plan qualities were comparable to gated VMAT, but treatment times were only 11-25% longer than 3D VMAT. 4D VMAT's improvement of healthy tissue sparing can allow for further dose escalation. Future study could potentially adapt 4D VMAT to irregular patient breathing patterns.

  14. VizieR Online Data Catalog: XO-4b 3yr observations with DEMONEX (Villanueva+, 2016)

    NASA Astrophysics Data System (ADS)

    Villanueva, S. Jr; Eastman, J. D.; Gaudi, B. S.

    2016-06-01

    New observations of XO-4b were made using DEdicated MONitor of EXotransits (DEMONEX). DEMONEX monitored bright stars hosting known transiting planets over a 3yr period from 2008 to 2011 in order to provide a homogeneous data set of precise relative photometry for over 40 transiting systems. There are 20 nights of data from 2008 November to 2010 May taken during primary transits of XO-4b. All observations were made in the Sloan z band. (1 data file).

  15. Noninvasive 4D pressure difference mapping derived from 4D flow MRI in patients with repaired aortic coarctation: comparison with young healthy volunteers.

    PubMed

    Rengier, Fabian; Delles, Michael; Eichhorn, Joachim; Azad, Yoo-Jin; von Tengg-Kobligk, Hendrik; Ley-Zaporozhan, Julia; Dillmann, Rüdiger; Kauczor, Hans-Ulrich; Unterhinninghofen, Roland; Ley, Sebastian

    2015-04-01

    To assess spatial and temporal pressure characteristics in patients with repaired aortic coarctation compared to young healthy volunteers using time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and derived 4D pressure difference maps. After in vitro validation against invasive catheterization as gold standard, 4D flow MRI of the thoracic aorta was performed at 1.5T in 13 consecutive patients after aortic coarctation repair without recoarctation and 13 healthy volunteers. Using in-house developed processing software, 4D pressure difference maps were computed based on the Navier-Stokes equation. Pressure difference amplitudes, maximum slope of pressure amplitudes and spatial pressure range at mid systole were retrospectively measured by three readers, and twice by one reader to assess inter- and intraobserver agreement. In vitro, pressure differences derived from 4D flow MRI showed excellent agreement to invasive catheter measurements. In vivo, pressure difference amplitudes, maximum slope of pressure difference amplitudes and spatial pressure range at mid systole were significantly increased in patients compared to volunteers in the aortic arch, the proximal descending and the distal descending thoracic aorta (p < 0.05). Greatest differences occurred in the proximal descending aorta with values of the three parameters for patients versus volunteers being 19.7 ± 7.5 versus 10.0 ± 2.0 (p < 0.001), 10.9 ± 10.4 versus 1.9 ± 0.4 (p = 0.002), and 8.7 ± 6.3 versus 1.6 ± 0.9 (p < 0.001). Inter- and intraobserver agreements were excellent (p < 0.001). Noninvasive 4D pressure difference mapping derived from 4D flow MRI enables detection of altered intraluminal aortic pressures and showed significant spatial and temporal changes in patients with repaired aortic coarctation.

  16. Current Drug Discovery for Anti-hepatitis C Virus Targeting NS4B.

    PubMed

    Wang, Zhenya; Chen, Xinli; Wu, Chunli; Xu, Haiwei; Liu, Hongmin

    2016-01-01

    Hepatitis C virus (HCV) infection is a major worldwide epidemic disease. It is estimated that more than 170 million individuals are infected with HCV and with three to four million new cases each year. Many new direct-acting antiviral (DAA) agents that specifically target HCV NS3 protease or NS5B polymerase inhibitors are therefore in development, with a significant effect for the patient and for the market recently. The non-structural 4B (NS4B) protein, is among the least characterized of the HCV proteins. A variety of functions have been recognized for NS4B, such as the ability to induce the membranous web replication platform, RNA binding and NTPase activity. In order to maximize antiviral efficacy and prevent the emergence of resistance, novel NS4B inhibitors have been subjected to pharmacological studies. In this review, we discussed current understanding of the structure and function of NS4B, and novel drug discoveries targeting NS4B as anti-hepatitis C virus such as sulfonamide, piperidine, carboxamide, piperazinone and quinoline derivatives within the last three years.

  17. UBE4B targets phosphorylated p53 at serines 15 and 392 for degradation

    PubMed Central

    Du, Cheng; Wu, Hong; Leng, Roger P.

    2016-01-01

    Phosphorylation of p53 is a key mechanism responsible for the activation of its tumor suppressor functions in response to various stresses. In unstressed cells, p53 is rapidly turned over and is maintained at a low basal level. After DNA damage or other forms of cellular stress, the p53 level increases, and the protein becomes metabolically stable. However, the mechanism of phosphorylated p53 regulation is unclear. In this study, we studied the kinetics of UBE4B, Hdm2, Pirh2, Cop1 and CHIP induction in response to p53 activation. We show that UBE4B coimmunoprecipitates with phosphorylated p53 at serines 15 and 392. Notably, the affinity between UBE4B and Hdm2 is greatly decreased after DNA damage. Furthermore, we observe that UBE4B promotes endogenous phospho-p53(S15) and phospho-p53(S392) degradation in response to IR. We demonstrate that UBE4B and Hdm2 repress p53S15A, p53S392A, and p53-2A(S15A, S392A) functions, including p53-dependent transactivation and growth inhibition. Overall, our results reveal that UBE4B plays an important role in regulating phosphorylated p53 following DNA damage. PMID:26673821

  18. O-GlcNAcylation of ATG4B positively regulates autophagy by increasing its hydroxylase activity.

    PubMed

    Jo, Yoon Kyung; Park, Na Yeon; Park, So Jung; Kim, Byung-Gyu; Shin, Ji Hyun; Jo, Doo Sin; Bae, Dong-Jun; Suh, Young-Ah; Chang, Jeong Ho; Lee, Eun Kyung; Kim, Sang-Yeob; Kim, Jin Cheon; Cho, Dong-Hyung

    2016-08-30

    Autophagy is a catabolic degradation process and maintains cellular homeostasis. And autophagy is activated in response to various stress conditions. Although O-GlcNAcylation functions a sensor for nutrient and stress, the relationship between O-GlcNAcylation and autophagy is largely unknown. Here, we identified that ATG4B is novel target for O-GlcNAcylation under metabolic stress condition. Treatment with PugNAc, an O-GlcNAcase inhibitor increased activation of autophagy in SH-SY5Y cells. Both bimolecular fluorescence complementation and immunoprecipitation assay indicated that OGT directly interacts with ATG4B in SH-SY5Y cells. We also found that the O-GlcNAcylated ATG4B was increased in autophagy activation conditions, and down-regulation of OGT reduces O-GlcNAcylation of ATG4B under low glucose condition. Furthermore, the proteolytic activity of ATG4B for LC3 cleavage was enhanced in PugNAc-treated cells. Taken together, these results imply that O-GlcNAcylation of ATG4B regulates autophagy activation by increasing its proteolytic activity under metabolic stress condition.

  19. O-GlcNAcylation of ATG4B positively regulates autophagy by increasing its hydroxylase activity

    PubMed Central

    Jo, Yoon Kyung; Park, Na Yeon; Park, So Jung; Kim, Byung-Gyu; Shin, Ji Hyun; Jo, Doo Sin; Bae, Dong-Jun; Suh, Young-Ah; Chang, Jeong Ho; Lee, Eun Kyung; Kim, Sang-Yeob; Kim, Jin Cheon; Cho, Dong-Hyung

    2016-01-01

    Autophagy is a catabolic degradation process and maintains cellular homeostasis. And autophagy is activated in response to various stress conditions. Although O-GlcNAcylation functions a sensor for nutrient and stress, the relationship between O-GlcNAcylation and autophagy is largely unknown. Here, we identified that ATG4B is novel target for O-GlcNAcylation under metabolic stress condition. Treatment with PugNAc, an O-GlcNAcase inhibitor increased activation of autophagy in SH-SY5Y cells. Both bimolecular fluorescence complementation and immunoprecipitation assay indicated that OGT directly interacts with ATG4B in SH-SY5Y cells. We also found that the O-GlcNAcylated ATG4B was increased in autophagy activation conditions, and down-regulation of OGT reduces O-GlcNAcylation of ATG4B under low glucose condition. Furthermore, the proteolytic activity of ATG4B for LC3 cleavage was enhanced in PugNAc-treated cells. Taken together, these results imply that O-GlcNAcylation of ATG4B regulates autophagy activation by increasing its proteolytic activity under metabolic stress condition. PMID:27527864

  20. Mechanisms of Membrane Binding of Small GTPase K-Ras4B Farnesylated Hypervariable Region*

    PubMed Central

    Jang, Hyunbum; Abraham, Sherwin J.; Chavan, Tanmay S.; Hitchinson, Ben; Khavrutskii, Lyuba; Tarasova, Nadya I.; Nussinov, Ruth; Gaponenko, Vadim

    2015-01-01

    K-Ras4B belongs to a family of small GTPases that regulates cell growth, differentiation and survival. K-ras is frequently mutated in cancer. K-Ras4B association with the plasma membrane through its farnesylated and positively charged C-terminal hypervariable region (HVR) is critical to its oncogenic function. However, the structural mechanisms of membrane association are not fully understood. Here, using confocal microscopy, surface plasmon resonance, and molecular dynamics simulations, we observed that K-Ras4B can be distributed in rigid and loosely packed membrane domains. Its membrane binding domain interaction with phospholipids is driven by membrane fluidity. The farnesyl group spontaneously inserts into the disordered lipid microdomains, whereas the rigid microdomains restrict the farnesyl group penetration. We speculate that the resulting farnesyl protrusion toward the cell interior allows oligomerization of the K-Ras4B membrane binding domain in rigid microdomains. Unlike other Ras isoforms, K-Ras4B HVR contains a single farnesyl modification and positively charged polylysine sequence. The high positive charge not only modulates specific HVR binding to anionic phospholipids but farnesyl membrane orientation. Phosphorylation of Ser-181 prohibits spontaneous farnesyl membrane insertion. The mechanism illuminates the roles of HVR modifications in K-Ras4B targeting microdomains of the plasma membrane and suggests an additional function for HVR in regulation of Ras signaling. PMID:25713064

  1. KDM4B is a master regulator of the estrogen receptor signalling cascade.

    PubMed

    Gaughan, Luke; Stockley, Jacqueline; Coffey, Kelly; O'Neill, Daniel; Jones, Dominic L; Wade, Mark; Wright, Jamie; Moore, Madeleine; Tse, Sandy; Rogerson, Lynsey; Robson, Craig N

    2013-08-01

    The importance of the estrogen receptor (ER) in breast cancer (BCa) development makes it a prominent target for therapy. Current treatments, however, have limited effectiveness, and hence the definition of new therapeutic targets is vital. The ER is a member of the nuclear hormone receptor superfamily of transcription factors that requires co-regulator proteins for complete regulation. Emerging evidence has implicated a small number of histone methyltransferase (HMT) and histone demethylase (HDM) enzymes as regulators of ER signalling, including the histone H3 lysine 9 tri-/di-methyl HDM enzyme KDM4B. Two recent independent reports have demonstrated that KDM4B is required for ER-mediated transcription and depletion of the enzyme attenuates BCa growth in vitro and in vivo. Here we show that KDM4B has an overarching regulatory role in the ER signalling cascade by controlling expression of the ER and FOXA1 genes, two critical components for maintenance of the estrogen-dependent phenotype. KDM4B interacts with the transcription factor GATA-3 in BCa cell lines and directly co-activates GATA-3 activity in reporter-based experiments. Moreover, we reveal that KDM4B recruitment and demethylation of repressive H3K9me3 marks within upstream regulatory regions of the ER gene permits binding of GATA-3 to drive receptor expression. Ultimately, our findings confirm the importance of KDM4B within the ER signalling cascade and as a potential therapeutic target for BCa treatment.

  2. Neuroblastoma patient outcomes, tumor differentiation, and ERK activation are correlated with expression levels of the ubiquitin ligase UBE4B

    PubMed Central

    Woodfield, Sarah E.; Guo, Rong Jun; Liu, Yin; Major, Angela M.; Hollingsworth, Emporia Faith; Indiviglio, Sandra; Whittle, Sarah B.; Mo, Qianxing; Bean, Andrew J.; Ittmann, Michael; Lopez-Terrada, Dolores; Zage, Peter E.

    2016-01-01

    Background UBE4B is an E3/E4 ubiquitin ligase whose gene is located in chromosome 1p36.22. We analyzed the associations of UBE4B gene and protein expression with neuroblastoma patient outcomes and with tumor prognostic features and histology. Methods We evaluated the association of UBE4B gene expression with neuroblastoma patient outcomes using the R2 Platform. We screened neuroblastoma tumor samples for UBE4B protein expression using immunohistochemistry. FISH for UBE4B and 1p36 deletion was performed on tumor samples. We then evaluated UBE4B expression for associations with prognostic factors and with levels of phosphorylated ERK in neuroblastoma tumors and cell lines. Results Low UBE4B gene expression is associated with poor outcomes in patients with neuroblastoma and with worse outcomes in all patient subgroups. UBE4B protein expression was associated with neuroblastoma tumor differentiation, and decreased UBE4B protein levels were associated with high-risk features. UBE4B protein levels were also associated with levels of phosphorylated ERK. Conclusions We have demonstrated associations between UBE4B gene expression and neuroblastoma patient outcomes and prognostic features. Reduced UBE4B protein expression in neuroblastoma tumors was associated with high-risk features, a lack of differentiation, and with ERK activation. These results suggest UBE4B may contribute to the poor prognosis of neuroblastoma tumors with 1p36 deletions and that UBE4B expression may mediate neuroblastoma differentiation. PMID:27014418

  3. Presentation and Outcomes of C4d-Negative Antibody-Mediated Rejection After Kidney Transplantation.

    PubMed

    Orandi, B J; Alachkar, N; Kraus, E S; Naqvi, F; Lonze, B E; Lees, L; Van Arendonk, K J; Wickliffe, C; Bagnasco, S M; Zachary, A A; Segev, D L; Montgomery, R A

    2016-01-01

    The updated Banff classification allows for the diagnosis of antibody-mediated rejection (AMR) in the absence of peritubular capillary C4d staining. Our objective was to quantify allograft loss risk in patients with consistently C4d-negative AMR (n = 51) compared with C4d-positive AMR patients (n = 156) and matched control subjects without AMR. All first-year posttransplant biopsy results from January 2004 through June 2014 were reviewed and correlated with the presence of donor-specific antibody (DSA). C4d-negative AMR patients were not different from C4d-positive AMR patients on any baseline characteristics, including immunologic risk factors (panel reactive antibody, prior transplant, HLA mismatch, donor type, DSA class, and anti-HLA/ABO-incompatibility). C4d-positive AMR patients were significantly more likely to have a clinical presentation (85.3% vs. 54.9%, p < 0.001), and those patients presented substantially earlier posttransplantation (median 14 [interquartile range 8-32] days vs. 46 [interquartile range 20-191], p < 0.001) and were three times more common (7.8% vs 2.5%). One- and 2-year post-AMR-defining biopsy graft survival in C4d-negative AMR patients was 93.4% and 90.2% versus 86.8% and 82.6% in C4d-positive AMR patients, respectively (p = 0.4). C4d-negative AMR was associated with a 2.56-fold (95% confidence interval, 1.08-6.05, p = 0.033) increased risk of graft loss compared with AMR-free matched controls. No clinical characteristics were identified that reliably distinguished C4d-negative from C4d-positive AMR. However, both phenotypes are associated with increased graft loss and thus warrant consideration for intervention.

  4. Evaluation of single nucleotide polymorphisms in the phosphodiesterase 4D gene (PDE4D) and their association with ischaemic stroke in a large German cohort.

    PubMed

    Kuhlenbäumer, G; Berger, K; Huge, A; Lange, E; Kessler, C; John, U; Funke, H; Nabavi, D G; Stögbauer, F; Ringelstein, E B; Stoll, M

    2006-04-01

    Genetic fine mapping of the first locus identified for genetically complex forms of stroke, STRK1 (which has been mapped to chromosome 5q12 in Icelandic families), has identified the phosphodiesterase 4D gene (PDE4D) gene as a good candidate gene. Association analysis of single nucleotide polymorphisms (SNPs) in the PDE4D gene in an Icelandic stroke cohort demonstrated genetic association between six SNPs in the 5' region of PDE4D and ischaemic stroke. The present study aimed to test whether the same six SNPs in PDE4D were also associated with stroke in a large stroke cohort from northern Germany (stroke patients with acute completed ischaemic stroke: n = 1181; population based controls: n = 1569). None of the six SNPs showed significant association with ischaemic stroke in the whole stroke sample before and after adjustment for conventional stroke risk factors (age, sex, hypertension, diabetes, and hypercholesterolaemia). Haplotype analysis did also not reveal any significant association. Marginally positive statistical measures of association in the subgroup with cardioembolic stroke did not remain significant after correction for multiple testing. In conclusion, this study was unable to demonstrate an association between the six SNPs which had showed significant single marker association with stroke in the Icelandic stroke cohort and ischaemic stroke in a large German cohort.

  5. eIF4B stimulates translation of long mRNAs with structured 5′ UTRs and low closed-loop potential but weak dependence on eIF4G

    PubMed Central

    Sen, Neelam Dabas; Zhou, Fujun; Harris, Michael S.; Ingolia, Nicholas T.

    2016-01-01

    DEAD-box RNA helicases eukaryotic translation initiation factor 4A (eIF4A) and Ded1 promote translation by resolving mRNA secondary structures that impede preinitiation complex (PIC) attachment to mRNA or scanning. Eukaryotic translation initiation factor 4B (eIF4B) is a cofactor for eIF4A but also might function independently of eIF4A. Ribosome profiling of mutants lacking eIF4B or with impaired eIF4A or Ded1 activity revealed that eliminating eIF4B reduces the relative translational efficiencies of many more genes than does inactivation of eIF4A, despite comparable reductions in bulk translation, and few genes display unusually strong requirements for both factors. However, either eliminating eIF4B or inactivating eIF4A preferentially impacts mRNAs with longer, more structured 5′ untranslated regions (UTRs). These findings reveal an eIF4A-independent role for eIF4B in addition to its function as eIF4A cofactor in promoting PIC attachment or scanning on structured mRNAs. eIF4B, eIF4A, and Ded1 mutations also preferentially impair translation of longer mRNAs in a fashion mitigated by the ability to form closed-loop messenger ribonucleoprotein particles (mRNPs) via eIF4F–poly(A)-binding protein 1 (Pab1) association, suggesting cooperation between closed-loop assembly and eIF4B/helicase functions. Remarkably, depleting eukaryotic translation initiation factor 4G (eIF4G), the scaffold subunit of eukaryotic translation initiation factor 4F (eIF4F), preferentially impacts short mRNAs with strong closed-loop potential and unstructured 5′ UTRs, exactly the opposite features associated with hyperdependence on the eIF4B/helicases. We propose that short, highly efficient mRNAs preferentially depend on the stimulatory effects of eIF4G-dependent closed-loop assembly. PMID:27601676

  6. Teaching Tip: Managing Software Engineering Student Teams Using Pellerin's 4-D System

    ERIC Educational Resources Information Center

    Doman, Marguerite; Besmer, Andrew; Olsen, Anne

    2015-01-01

    In this article, we discuss the use of Pellerin's Four Dimension Leadership System (4-D) as a way to manage teams in a classroom setting. Over a 5-year period, we used a modified version of the 4-D model to manage teams within a senior level Software Engineering capstone course. We found that this approach for team management in a classroom…

  7. Helical mode lung 4D-CT reconstruction using Bayesian model.

    PubMed

    He, Tiancheng; Xue, Zhong; Nitsch, Paige L; Teh, Bin S; Wong, Stephen T

    2013-01-01

    4D computed tomography (CT) has been widely used for treatment planning of thoracic and abdominal cancer radiotherapy. Current 4D-CT lung image reconstruction methods rely on respiratory gating to rearrange the large number of axial images into different phases, which may be subject to external surrogate errors due to poor reproducibility of breathing cycles. New image-matching-based reconstruction works better for the cine mode of 4D-CT acquisition than the helical mode because the table position of each axial image is different in helical mode and image matching might suffer from bigger errors. In helical mode, not only the phases but also the un-uniform table positions of images need to be considered. We propose a Bayesian method for automated 4D-CT lung image reconstruction in helical mode 4D scans. Each axial image is assigned to a respiratory phase based on the Bayesian framework that ensures spatial and temporal smoothness of surfaces of anatomical structures. Iterative optimization is used to reconstruct a series of 3D-CT images for subjects undergoing 4D scans. In experiments, we compared visually and quantitatively the results of the proposed Bayesian 4D-CT reconstruction algorithm with the respiratory surrogate and the image matching-based method. The results showed that the proposed algorithm yielded better 4D-CT for helical scans.

  8. Phosphodiesterase 4B negatively regulates endotoxin-activated interleukin-1 receptor antagonist responses in macrophages

    PubMed Central

    Yang, Jing-Xing; Hsieh, Kou-Chou; Chen, Yi-Ling; Lee, Chien-Kuo; Conti, Marco; Chuang, Tsung-Hsien; Wu, Chin-Pyng; Jin, S.-L. Catherine

    2017-01-01

    Activation of TLR4 by lipopolysaccharide (LPS) induces both pro-inflammatory and anti-inflammatory cytokine production in macrophages. Type 4 phosphodiesterases (PDE4) are key cAMP-hydrolyzing enzymes, and PDE4 inhibitors are considered as immunosuppressors to various inflammatory responses. We demonstrate here that PDE4 inhibitors enhance the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) secretion in LPS-activated mouse peritoneal macrophages, and this response was regulated at the transcriptional level rather than an increased IL-1Ra mRNA stability. Studies with PDE4-deficient macrophages revealed that the IL-1Ra upregulation elicited by LPS alone is PKA-independent, whereas the rolipram-enhanced response was mediated by inhibition of only PDE4B, one of the three PDE4 isoforms expressed in macrophages, and it requires PKA but not Epac activity. However, both pathways activate CREB to induce IL-1Ra expression. PDE4B ablation also promoted STAT3 phosphorylation (Tyr705) to LPS stimulation, but this STAT3 activation is not entirely responsible for the IL-1Ra upregulation in PDE4B-deficient macrophages. In a model of LPS-induced sepsis, only PDE4B-deficient mice displayed an increased circulating IL-1Ra, suggesting a protective role of PDE4B inactivation in vivo. These findings demonstrate that PDE4B negatively modulates anti-inflammatory cytokine expression in innate immune cells, and selectively targeting PDE4B should retain the therapeutic benefits of nonselective PDE4 inhibitors. PMID:28383060

  9. The higher level of complexity of K-Ras4B activation at the membrane

    PubMed Central

    Jang, Hyunbum; Banerjee, Avik; Chavan, Tanmay S.; Lu, Shaoyong; Zhang, Jian; Gaponenko, Vadim; Nussinov, Ruth

    2016-01-01

    Is nucleotide exchange sufficient to activate K-Ras4B? To signal, oncogenic rat sarcoma (Ras) anchors in the membrane and recruits effectors by exposing its effector lobe. With the use of NMR and molecular dynamics (MD) simulations, we observed that in solution, farnesylated guanosine 5′-diphosphate (GDP)-bound K-Ras4B is predominantly autoinhibited by its hypervariable region (HVR), whereas the GTP-bound state favors an activated, HVR-released state. On the anionic membrane, the catalytic domain adopts multiple orientations, including parallel (∼180°) and perpendicular (∼90°) alignments of the allosteric helices, with respect to the membrane surface direction. In the autoinhibited state, the HVR is sandwiched between the effector lobe and the membrane; in the active state, with membrane-anchored farnesyl and unrestrained HVR, the catalytic domain fluctuates reinlessly, exposing its effector-binding site. Dimerization and clustering can reduce the fluctuations. This achieves preorganized, productive conformations. Notably, we also observe HVR-autoinhibited K-Ras4B-GTP states, with GDP-bound-like orientations of the helices. Thus, we propose that the GDP/GTP exchange may not be sufficient for activation; instead, our results suggest that the GDP/GTP exchange, HVR sequestration, farnesyl insertion, and orientation/localization of the catalytic domain at the membrane conjointly determine the active or inactive state of K-Ras4B. Importantly, K-Ras4B-GTP can exist in active and inactive states; on its own, GTP binding may not compel K-Ras4B activation.—Jang, H., Banerjee, A., Chavan, T. S, Lu, S., Zhang, J., Gaponenko, V., Nussinov, R. The higher level of complexity of K-Ras4B activation at the membrane. PMID:26718888

  10. The Influence of Facial Characteristics on the Relation between Male 2D:4D and Dominance

    PubMed Central

    Ryckmans, Jan; Millet, Kobe; Warlop, Luk

    2015-01-01

    Although relations between 2D:4D and dominance rank in both baboons and rhesus macaques have been observed, evidence in humans is mixed. Whereas behavioral patterns in humans have been discovered that are consistent with these animal findings, the evidence for a relation between dominance and 2D:4D is weak or inconsistent. The present study provides experimental evidence that male 2D:4D is related to dominance after (fictitious) male-male interaction when the other man has a dominant, but not a submissive or neutral face. This finding provides evidence that the relationship between 2D:4D and dominance emerges in particular, predictable situations and that merely dominant facial characteristics of another person are enough to activate supposed relationships between 2D:4D and dominance. PMID:26600255

  11. TU-C-BRD-01: Image Guided SBRT I: Multi-Modality 4D Imaging

    SciTech Connect

    Cai, J; Mageras, G; Pan, T

    2014-06-15

    Motion management is one of the critical technical challenges for radiation therapy. 4D imaging has been rapidly adopted as essential tool to assess organ motion associated with respiratory breathing. A variety of 4D imaging techniques have been developed and are currently under development based on different imaging modalities such as CT, MRI, PET, and CBCT. Each modality provides specific and complementary information about organ and tumor respiratory motion. Effective use of each different technique or combined use of different techniques can introduce a comprehensive management of tumor motion. Specifically, these techniques have afforded tremendous opportunities to better define and delineate tumor volumes, more accurately perform patient positioning, and effectively apply highly conformal therapy techniques such as IMRT and SBRT. Successful implementation requires good understanding of not only each technique, including unique features, limitations, artifacts, imaging acquisition and process, but also how to systematically apply the information obtained from different imaging modalities using proper tools such as deformable image registration. Furthermore, it is important to understand the differences in the effects of breathing variation between different imaging modalities. A comprehensive motion management strategy using multi-modality 4D imaging has shown promise in improving patient care, but at the same time faces significant challenges. This session will focuses on the current status and advances in imaging respiration-induced organ motion with different imaging modalities: 4D-CT, 4D-MRI, 4D-PET, and 4D-CBCT/DTS. Learning Objectives: Understand the need and role of multimodality 4D imaging in radiation therapy. Understand the underlying physics behind each 4D imaging technique. Recognize the advantages and limitations of each 4D imaging technique.

  12. Weight of the evidence on the human carcinogenicity of 2,4-D*

    PubMed Central

    Ibrahim, M. A.; Bond, G. G.; Burke, T. A.; Cole, P.; Dost, F. N.; Enterline, P. E.; Gough, M.; Greenberg, R. S.; Halperin, W. E.; McConnell, E.; Munro, I. C.; Swenberg, J. A.; Zahm, S. H.; Graham, J. D.

    1991-01-01

    The phenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used to control the growth of weeds and broadleaf plants. We convened a panel of 13 scientists to weigh the evidence on the human carcinogenicity of 2,4-D. The panel based its findings on a review of the toxicological and epidemiological literature on 2,4-D and related phenoxy herbicides. The toxicological data do not provide a strong basis for predicting that 2,4-D is a human carcinogen. Although a cause–effect relationship is far from being established, the epidemiological evidence for an association between exposure to 2,4-D and non–Hodgkin's lymphoma is suggestive and requires further investigation. There is little evidence of an association between use of 2,4-D and soft-tissue sarcoma or Hodgkin's disease, and no evidence of an association between 2,4-D use and any other form of cancer. Scientists on the panel were asked to categorize 2,4-D as a “known,” “probable,” “possible,” or “unlikely” carcinogen or as a noncarcinogen in humans. The predominant opinion among the panel members was that the weight of the evidence indicates that it is possible that exposure to 2,4-D can cause cancer in humans, although not all of the panelists believed the possibility was equally likely: one thought the possibility was strong, leaning toward probable, and five thought the possibility was remote, leaning toward unlikely. Two panelists believed it unlikely that 2,4-D can cause cancer in humans. PMID:1820267

  13. Scientometric analysis and bibliography of digit ratio (2D:4D) research, 1998-2008.

    PubMed

    Voracek, Martin; Loibl, Lisa Mariella

    2009-06-01

    A scientometric analysis of modern research on the second-to-fourth digit ratio (2D:4D), a widely studied putative marker for prenatal androgen action, is presented. In early 2009, this literature totalled more than 300 publications and, since its initiation in 1998, has grown at a rate slightly faster than linear. Key findings included evidence of publication bias and citation bias, incomplete coverage and outdatedness of existing reviews, and a dearth of meta-analyses in this field. 2D:4D research clusters noticeably in terms of researchers, institutions, countries, and journals involved. Although 2D:4D is an anthropometric trait, most of the research has been conducted at psychology departments, not anthropology departments. However, 2D:4D research has not been predominantly published in core and specialized journals of psychology, but rather in more broadly scoped journals of the behavioral sciences, biomedical social sciences, and neurosciences. Total citation numbers of 2D:4D papers for the most part were not larger than their citation counts within 2D:4D research, indicating that until now, only a few 2D:4D studies have attained broader interest outside this specific field. Comparative citation analyses show that 2D:4D research presently is commensurate in size and importance to evolutionary psychological jealousy research, but has grown faster than the latter field. In contrast, it is much smaller and has spread more slowly than research about the Implicit Association Test Fifteen conjectures about anticipated trends in 2D:4D research are outlined, appendixed by a first-time bibliography of the entirety of the published 2D:4D literature.

  14. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis

    PubMed Central

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-01-01

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses. PMID:25906080

  15. Essential role for the ATG4B protease and autophagy in bleomycin-induced pulmonary fibrosis.

    PubMed

    Cabrera, Sandra; Maciel, Mariana; Herrera, Iliana; Nava, Teresa; Vergara, Fabián; Gaxiola, Miguel; López-Otín, Carlos; Selman, Moisés; Pardo, Annie

    2015-04-03

    Autophagy is a critical cellular homeostatic process that controls the turnover of damaged organelles and proteins. Impaired autophagic activity is involved in a number of diseases, including idiopathic pulmonary fibrosis suggesting that altered autophagy may contribute to fibrogenesis. However, the specific role of autophagy in lung fibrosis is still undefined. In this study, we show for the first time, how autophagy disruption contributes to bleomycin-induced lung fibrosis in vivo using an Atg4b-deficient mouse as a model. Atg4b-deficient mice displayed a significantly higher inflammatory response at 7 d after bleomycin treatment associated with increased neutrophilic infiltration and significant alterations in proinflammatory cytokines. Likewise, we found that Atg4b disruption resulted in augmented apoptosis affecting predominantly alveolar and bronchiolar epithelial cells. At 28 d post-bleomycin instillation Atg4b-deficient mice exhibited more extensive and severe fibrosis with increased collagen accumulation and deregulated extracellular matrix-related gene expression. Together, our findings indicate that the ATG4B protease and autophagy play a crucial role protecting epithelial cells against bleomycin-induced stress and apoptosis, and in the regulation of the inflammatory and fibrotic responses.

  16. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors.

    PubMed

    Akin, Debra; Wang, S Keisin; Habibzadegah-Tari, Pouran; Law, Brian; Ostrov, David; Li, Min; Yin, Xiao-Ming; Kim, Jae-Sung; Horenstein, Nicole; Dunn, William A

    2014-01-01

    Autophagy has been implicated in the progression and chemoresistance of various cancers. In this study, we have shown that osteosarcoma Saos-2 cells lacking ATG4B, a cysteine proteinase that activates LC3B, are defective in autophagy and fail to form tumors in mouse models. By combining in silico docking with in vitro and cell-based assays, we identified small compounds that suppressed starvation-induced protein degradation, LC3B lipidation, and formation of autophagic vacuoles. NSC185058 effectively inhibited ATG4B activity in vitro and in cells while having no effect on MTOR and PtdIns3K activities. In addition, this ATG4B antagonist had a negative impact on the development of Saos-2 osteosarcoma tumors in vivo. We concluded that tumor suppression was due to a reduction in ATG4B activity, since we found autophagy suppressed within treated tumors and the compound had no effects on oncogenic protein kinases. Our findings demonstrate that ATG4B is a suitable anti-autophagy target and a promising therapeutic target to treat osteosarcoma.

  17. A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors

    PubMed Central

    Akin, Debra; Wang, S Keisin; Habibzadegah-Tari, Pouran; Law, Brian; Ostrov, David; Li, Min; Yin, Xiao-Ming; Kim, Jae-Sung; Horenstein, Nicole; Dunn, William A

    2014-01-01

    Autophagy has been implicated in the progression and chemoresistance of various cancers. In this study, we have shown that osteosarcoma Saos-2 cells lacking ATG4B, a cysteine proteinase that activates LC3B, are defective in autophagy and fail to form tumors in mouse models. By combining in silico docking with in vitro and cell-based assays, we identified small compounds that suppressed starvation-induced protein degradation, LC3B lipidation, and formation of autophagic vacuoles. NSC185058 effectively inhibited ATG4B activity in vitro and in cells while having no effect on MTOR and PtdIns3K activities. In addition, this ATG4B antagonist had a negative impact on the development of Saos-2 osteosarcoma tumors in vivo. We concluded that tumor suppression was due to a reduction in ATG4B activity, since we found autophagy suppressed within treated tumors and the compound had no effects on oncogenic protein kinases. Our findings demonstrate that ATG4B is a suitable anti-autophagy target and a promising therapeutic target to treat osteosarcoma. PMID:25483883

  18. 4D dose simulation in volumetric arc therapy: Accuracy and affecting parameters.

    PubMed

    Sothmann, Thilo; Gauer, Tobias; Werner, René

    2017-01-01

    Radiotherapy of lung and liver lesions has changed from normofractioned 3D-CRT to stereotactic treatment in a single or few fractions, often employing volumetric arc therapy (VMAT)-based techniques. Potential unintended interference of respiratory target motion and dynamically changing beam parameters during VMAT dose delivery motivates establishing 4D quality assurance (4D QA) procedures to assess appropriateness of generated VMAT treatment plans when taking into account patient-specific motion characteristics. Current approaches are motion phantom-based 4D QA and image-based 4D VMAT dose simulation. Whereas phantom-based 4D QA is usually restricted to a small number of measurements, the computational approaches allow simulating many motion scenarios. However, 4D VMAT dose simulation depends on various input parameters, influencing estimated doses along with mitigating simulation reliability. Thus, aiming at routine use of simulation-based 4D VMAT QA, the impact of such parameters as well as the overall accuracy of the 4D VMAT dose simulation has to be studied in detail-which is the topic of the present work. In detail, we introduce the principles of 4D VMAT dose simulation, identify influencing parameters and assess their impact on 4D dose simulation accuracy by comparison of simulated motion-affected dose distributions to corresponding dosimetric motion phantom measurements. Exploiting an ITV-based treatment planning approach, VMAT treatment plans were generated for a motion phantom and different motion scenarios (sinusoidal motion of different period/direction; regular/irregular motion). 4D VMAT dose simulation results and dose measurements were compared by local 3% / 3 mm γ-evaluation, with the measured dose distributions serving as ground truth. Overall γ-passing rates of simulations and dynamic measurements ranged from 97% to 100% (mean across all motion scenarios: 98% ± 1%); corresponding values for comparison of different day repeat measurements were

  19. 4D dose simulation in volumetric arc therapy: Accuracy and affecting parameters

    PubMed Central

    Werner, René

    2017-01-01

    Radiotherapy of lung and liver lesions has changed from normofractioned 3D-CRT to stereotactic treatment in a single or few fractions, often employing volumetric arc therapy (VMAT)-based techniques. Potential unintended interference of respiratory target motion and dynamically changing beam parameters during VMAT dose delivery motivates establishing 4D quality assurance (4D QA) procedures to assess appropriateness of generated VMAT treatment plans when taking into account patient-specific motion characteristics. Current approaches are motion phantom-based 4D QA and image-based 4D VMAT dose simulation. Whereas phantom-based 4D QA is usually restricted to a small number of measurements, the computational approaches allow simulating many motion scenarios. However, 4D VMAT dose simulation depends on various input parameters, influencing estimated doses along with mitigating simulation reliability. Thus, aiming at routine use of simulation-based 4D VMAT QA, the impact of such parameters as well as the overall accuracy of the 4D VMAT dose simulation has to be studied in detail–which is the topic of the present work. In detail, we introduce the principles of 4D VMAT dose simulation, identify influencing parameters and assess their impact on 4D dose simulation accuracy by comparison of simulated motion-affected dose distributions to corresponding dosimetric motion phantom measurements. Exploiting an ITV-based treatment planning approach, VMAT treatment plans were generated for a motion phantom and different motion scenarios (sinusoidal motion of different period/direction; regular/irregular motion). 4D VMAT dose simulation results and dose measurements were compared by local 3% / 3 mm γ-evaluation, with the measured dose distributions serving as ground truth. Overall γ-passing rates of simulations and dynamic measurements ranged from 97% to 100% (mean across all motion scenarios: 98% ± 1%); corresponding values for comparison of different day repeat measurements were

  20. Wetting of microstructured alumina fabricated by epitaxial growth of Al4B2O9 whiskers

    NASA Astrophysics Data System (ADS)

    Wang, Yifeng; Feng, Jicai; Chen, Zhe; Song, Xiaoguo; Cao, Jian

    2015-12-01

    Topographical microstructures were fabricated on alumina by epitaxial growth of Al4B2O9 whiskers in air. The products were characterized via scanning electron microscopy, transmission electron microscopy, and X-ray diffraction. The whiskers were found to grow along the [0 0 1] crystallographic direction, and the lattice mismatch between Al2O3 and Al4B2O9 was determined to be 0.03%. The wetting of the Al4B2O9-whisker-coated surfaces by Ag-36.7Cu-8.0Ti at.% alloy was studied. The time needed to reach the equilibrium stage reduced as the temperature increased, and the final contact angle for liquid alloy on the rough surface was 27° at 880 °C. The wetting dynamics of the whiskers coated surfaces was investigated. After wetting, a whisker-interconnected region was formed between alumina and the alloy.

  1. Alternative pathways for association and dissociation of the calmodulin-binding domain of plasma membrane Ca(2+)-ATPase isoform 4b (PMCA4b).

    PubMed

    Penniston, John T; Caride, Ariel J; Strehler, Emanuel E

    2012-08-24

    The calmodulin (CaM)-binding domain of isoform 4b of the plasma membrane Ca(2+) -ATPase (PMCA) pump is represented by peptide C28. CaM binds to either PMCA or C28 by a mechanism in which the primary anchor residue Trp-1093 binds to the C-terminal lobe of the extended CaM molecule, followed by collapse of CaM with the N-terminal lobe binding to the secondary anchor Phe-1110 (Juranic, N., Atanasova, E., Filoteo, A. G., Macura, S., Prendergast, F. G., Penniston, J. T., and Strehler, E. E. (2010) J. Biol. Chem. 285, 4015-4024). This is a relatively rapid reaction, with an apparent half-time of ~1 s. The dissociation of CaM from PMCA4b or C28 is much slower, with an overall half-time of ~10 min. Using targeted molecular dynamics, we now show that dissociation of Ca(2+)-CaM from C28 may occur by a pathway in which Trp-1093, although deeply embedded in a pocket in the C-terminal lobe of CaM, leaves first. The dissociation begins by relatively rapid release of Trp-1093, followed by very slow release of Phe-1110, removal of C28, and return of CaM to its conformation in the free state. Fluorescence measurements and molecular dynamics calculations concur in showing that this alternative path of release of the PMCA4b CaM-binding domain is quite different from that of binding. The intermediate of dissociation with exposed Trp-1093 has a long lifetime (minutes) and may keep the PMCA primed for activation.

  2. Mineralization of 2,4-Dichlorophenoxyacetic Acid (2,4-D) and Mixtures of 2,4-D and 2,4,5-Trichlorophenoxyacetic Acid by Phanerochaete chrysosporium

    PubMed Central

    Yadav, J. S.; Reddy, C. A.

    1993-01-01

    Evidence is presented for mineralization of 2,4-dichlorophenoxyacetic acid (2,4-D) in nutrient-rich media (high-nitrogen and malt extract media) by wild-type Phanerochaete chrysosporium and by a peroxidase-negative mutant of this organism. Mass balance analysis of [U-ring-14C]2,4-D mineralization in malt extract cultures showed 82.7% recovery of radioactivity. Of this, 38.6% was released as 14CO2 and 27.0, 11.2, and 5.9% were present in the aqueous, methylene chloride, and mycelial fractions, respectively. 2,4-D and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) were simultaneously mineralized when presented as a mixture, and mutual inhibition of degradation was not observed. In contrast, a relatively higher rate of mineralization of 2,4-D and 2,4,5-T was observed when these compounds were tested as mixtures than when they were tested alone. PMID:16349039

  3. 2,4-D resistance in wild radish: reduced herbicide translocation via inhibition of cellular transport

    PubMed Central

    Goggin, Danica E.; Cawthray, Gregory R.; Powles, Stephen B.

    2016-01-01

    Resistance to auxinic herbicides is increasing in a range of dicotyledonous weed species, but in most cases the biochemical mechanism of resistance is unknown. Using 14C-labelled herbicide, the mechanism of resistance to 2,4-dichlorophenoxyacetic acid (2,4-D) in two wild radish (Raphanus raphanistrum L.) populations was identified as an inability to translocate 2,4-D out of the treated leaf. Although 2,4-D was metabolized in wild radish, and in a different manner to the well-characterized crop species wheat and bean, there was no difference in metabolism between the susceptible and resistant populations. Reduced translocation of 2,4-D in the latter was also not due to sequestration of the herbicide, or to reduced uptake by the leaf epidermis or mesophyll cells. Application of auxin efflux or ABCB transporter inhibitors to 2,4-D-susceptible plants caused a mimicking of the reduced-translocation resistance phenotype, suggesting that 2,4-D resistance in the populations under investigation could be due to an alteration in the activity of a plasma membrane ABCB-type auxin transporter responsible for facilitating long-distance transport of 2,4-D. PMID:26994475

  4. Identification of New ATG4B Inhibitors Based on a Novel High-Throughput Screening Platform.

    PubMed

    Xu, Danqing; Xu, Zhiheng; Han, Li; Liu, Cheng; Zhou, Zheng; Qiu, Zongxing; Lin, Xianfeng; Tang, Guozhi; Shen, Hong; Aebi, Johannes; Riemer, Claus; Kuhn, Bernd; Stahl, Martin; Mark, David; Qin, Ning; Ding, Haiyuan

    2017-04-01

    Autophagy is an evolutionarily conserved homeostasis process through which aggregated proteins or damaged organelles are enveloped in a double-membrane structure called an autophagosome and then digested in a lysosome-dependent manner. Growing evidence suggests that malfunction of autophagy contributes to the pathogenesis of a variety of diseases, including cancer, viral infection, and neurodegeneration. However, autophagy is a complicated process, and understanding of the relevance of autophagy to disease is limited by lack of specific and potent autophagy modulators. ATG4B, a Cys-protease that cleaves ATG8 family proteins, such as LC3B, is a key protein in autophagosome formation and maturation process. A novel time-resolved fluorescence resonance energy transfer (TR-FRET) assay measuring protease activity of ATG4B was developed, validated, and adapted into a high-throughput screening (HTS) format. HTS was then conducted with a Roche focus library of 57,000 compounds. After hit confirmation and a counterscreen to filter out fluorescence interference compounds, 267 hits were confirmed, constituting a hit rate of 0.49%. Furthermore, among 65 hits with an IC50 < 50 µM, one compound mimics the LC3 peptide substrate (-TFG-). Chemistry modification based on this particular hit gave preliminary structure activity relationship (SAR) resulting in a compound with a 10-fold increase in potency. This compound forms a stable covalent bond with Cys74 of ATG4B in a 1:1 ratio as demonstrated by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Furthermore, this compound displayed cellular ATG4B inhibition activity. Overall, the novel TR-FRET ATG4B protease assay plus counterscreen assay provides a robust platform to identify ATG4B inhibitors, which would help to elucidate the mechanism of the autophagy pathway and offer opportunities for drug discovery.

  5. Clinical evaluation of 4D PET motion compensation strategies for treatment verification in ion beam therapy

    NASA Astrophysics Data System (ADS)

    Gianoli, Chiara; Kurz, Christopher; Riboldi, Marco; Bauer, Julia; Fontana, Giulia; Baroni, Guido; Debus, Jürgen; Parodi, Katia

    2016-06-01

    A clinical trial named PROMETHEUS is currently ongoing for inoperable hepatocellular carcinoma (HCC) at the Heidelberg Ion Beam Therapy Center (HIT, Germany). In this framework, 4D PET-CT datasets are acquired shortly after the therapeutic treatment to compare the irradiation induced PET image with a Monte Carlo PET prediction resulting from the simulation of treatment delivery. The extremely low count statistics of this measured PET image represents a major limitation of this technique, especially in presence of target motion. The purpose of the study is to investigate two different 4D PET motion compensation strategies towards the recovery of the whole count statistics for improved image quality of the 4D PET-CT datasets for PET-based treatment verification. The well-known 4D-MLEM reconstruction algorithm, embedding the motion compensation in the reconstruction process of 4D PET sinograms, was compared to a recently proposed pre-reconstruction motion compensation strategy, which operates in sinogram domain by applying the motion compensation to the 4D PET sinograms. With reference to phantom and patient datasets, advantages and drawbacks of the two 4D PET motion compensation strategies were identified. The 4D-MLEM algorithm was strongly affected by inverse inconsistency of the motion model but demonstrated the capability to mitigate the noise-break-up effects. Conversely, the pre-reconstruction warping showed less sensitivity to inverse inconsistency but also more noise in the reconstructed images. The comparison was performed by relying on quantification of PET activity and ion range difference, typically yielding similar results. The study demonstrated that treatment verification of moving targets could be accomplished by relying on the whole count statistics image quality, as obtained from the application of 4D PET motion compensation strategies. In particular, the pre-reconstruction warping was shown to represent a promising choice when combined with intra

  6. Comparing Dislodgeable 2,4-D Residues across Athletic Field Turfgrass Species and Time

    PubMed Central

    Brosnan, James T.; Breeden, Gregory K.

    2016-01-01

    2,4-dimethylamine salt (2,4-D) is an herbicide commonly applied on athletic fields for broadleaf weed control that can dislodge from treated turfgrass. Dislodge potential is affected by numerous factors, including turfgrass canopy conditions. Building on previous research confirming herbicide-turfgrass dynamics can vary widely between species, field research was initiated in 2014 and 2015 in Raleigh, NC, USA to quantify dislodgeable 2,4-D residues from dormant hybrid bermudagrass (Cynodon dactylon L. x C. transvaalensis) and hybrid bermudagrass overseeded with perennial ryegrass (Lolium perenne L.), which are common athletic field playing surfaces in subtropical climates. Additionally, dislodgeable 2,4-D was compared at AM (7:00 eastern standard time) and PM (14:00) sample timings within a day. Samples collected from perennial ryegrass consistently resulted in greater 2,4-D dislodgment immediately after application (9.4 to 9.9% of applied) compared to dormant hybrid bermudagrass (2.3 to 2.9%), as well as at all AM compared to PM timings from 1 to 3 d after treatment (DAT; 0.4 to 6.3% compared to 0.1 to 0.8%). Dislodgeable 2,4-D did not differ across turfgrass species at PM sample collections, with ≤ 0.1% of the 2,4-D applied dislodged from 1 to 6 DAT, and 2,4-D detection did not occur at 12 and 24 DAT. In conclusion, dislodgeable 2,4-D from treated turfgrass can vary between species and over short time-scales within a day. This information should be taken into account in human exposure risk assessments, as well as by turfgrass managers and athletic field event coordinators to minimize 2,4-D exposure. PMID:27936174

  7. Clinical evaluation of 4D PET motion compensation strategies for treatment verification in ion beam therapy.

    PubMed

    Gianoli, Chiara; Kurz, Christopher; Riboldi, Marco; Bauer, Julia; Fontana, Giulia; Baroni, Guido; Debus, Jürgen; Parodi, Katia

    2016-06-07

    A clinical trial named PROMETHEUS is currently ongoing for inoperable hepatocellular carcinoma (HCC) at the Heidelberg Ion Beam Therapy Center (HIT, Germany). In this framework, 4D PET-CT datasets are acquired shortly after the therapeutic treatment to compare the irradiation induced PET image with a Monte Carlo PET prediction resulting from the simulation of treatment delivery. The extremely low count statistics of this measured PET image represents a major limitation of this technique, especially in presence of target motion. The purpose of the study is to investigate two different 4D PET motion compensation strategies towards the recovery of the whole count statistics for improved image quality of the 4D PET-CT datasets for PET-based treatment verification. The well-known 4D-MLEM reconstruction algorithm, embedding the motion compensation in the reconstruction process of 4D PET sinograms, was compared to a recently proposed pre-reconstruction motion compensation strategy, which operates in sinogram domain by applying the motion compensation to the 4D PET sinograms. With reference to phantom and patient datasets, advantages and drawbacks of the two 4D PET motion compensation strategies were identified. The 4D-MLEM algorithm was strongly affected by inverse inconsistency of the motion model but demonstrated the capability to mitigate the noise-break-up effects. Conversely, the pre-reconstruction warping showed less sensitivity to inverse inconsistency but also more noise in the reconstructed images. The comparison was performed by relying on quantification of PET activity and ion range difference, typically yielding similar results. The study demonstrated that treatment verification of moving targets could be accomplished by relying on the whole count statistics image quality, as obtained from the application of 4D PET motion compensation strategies. In particular, the pre-reconstruction warping was shown to represent a promising choice when combined with intra

  8. Hepatitis C Virus NS4B Can Suppress STING Accumulation To Evade Innate Immune Responses

    PubMed Central

    Wen, Yahong; Shu, Chang; Han, Qingxia; Konan, Kouacou V.; Li, Pingwei; Kao, C. Cheng

    2015-01-01

    ABSTRACT The cyclic dinucleotide 2′,3′-cGAMP can bind the adaptor protein STING (stimulator of interferon [IFN] genes) to activate the production of type I IFNs and proinflammatory cytokines. We found that cGAMP added to the culture medium could suppress the replication of the hepatitis C virus (HCV) genotype 1b strain Con1 subgenomic replicon in human hepatoma cells. Knockdown of STING expression diminished the inhibitory effect on replicon replication, while overexpression of STING enhanced the inhibitory effects of cGAMP. The addition of cGAMP into 1b/Con1 replicon cells significantly increased the expression of type I IFNs and antiviral interferon-stimulated genes. Unexpectedly, replication of the genotype 2a JFH1 replicon and infectious JFH1 virus was less sensitive to the inhibitory effect of cGAMP than was that of 1b/Con1 replicon. Using chimeric replicons, 2a NS4B was identified to confer resistance to cGAMP. Transient expression of 2a NS4B resulted in a pronounced inhibitory effect on STING-mediated beta IFN (IFN-β) reporter activation compared to that of 1b NS4B. 2a NS4B was found to suppress STING accumulation in a dose-dependent manner. The predicted transmembrane domain of 2a NS4B was required to inhibit STING accumulation. These results demonstrate a novel genotype-specific inhibition of the STING-mediated host antiviral immune response. IMPORTANCE The cyclic dinucleotide cGAMP was found to potently inhibit the replication of HCV genotype 1b Con1 replicon but was less effective for the 2a/JFH1 replicon and infectious JFH1 virus. The predicted transmembrane domain in 2a NS4B was shown to be responsible for the decreased sensitivity to cGAMP. The N terminus of NS4B has been reported to suppress STING-mediated signaling by disrupting the interaction of STING and TBK1 and/or MAVS. We show that 2a/JFH1 NS4B has an additional mechanism to evade STING signaling through suppressing STING accumulation. PMID:26468527

  9. Genome-first approach diagnosed Cabezas syndrome via novel CUL4B mutation detection.

    PubMed

    Okamoto, Nobuhiko; Watanabe, Miki; Naruto, Takuya; Matsuda, Keiko; Kohmoto, Tomohiro; Saito, Masako; Masuda, Kiyoshi; Imoto, Issei

    2017-01-01

    Cabezas syndrome is a syndromic form of X-linked intellectual disability primarily characterized by a short stature, hypogonadism and abnormal gait, with other variable features resulting from mutations in the CUL4B gene. Here, we report a clinically undiagnosed 5-year-old male with severe intellectual disability. A genome-first approach using targeted exome sequencing identified a novel nonsense mutation [NM_003588.3:c.2698G>T, p.(Glu900*)] in the last coding exon of CUL4B, thus diagnosing this patient with Cabezas syndrome.

  10. Genome-first approach diagnosed Cabezas syndrome via novel CUL4B mutation detection

    PubMed Central

    Okamoto, Nobuhiko; Watanabe, Miki; Naruto, Takuya; Matsuda, Keiko; Kohmoto, Tomohiro; Saito, Masako; Masuda, Kiyoshi; Imoto, Issei

    2017-01-01

    Cabezas syndrome is a syndromic form of X-linked intellectual disability primarily characterized by a short stature, hypogonadism and abnormal gait, with other variable features resulting from mutations in the CUL4B gene. Here, we report a clinically undiagnosed 5-year-old male with severe intellectual disability. A genome-first approach using targeted exome sequencing identified a novel nonsense mutation [NM_003588.3:c.2698G>T, p.(Glu900*)] in the last coding exon of CUL4B, thus diagnosing this patient with Cabezas syndrome. PMID:28144446

  11. Mutation in the AP4B1 gene cause hereditary spastic paraplegia type 47 (SPG47) .

    PubMed

    Bauer, Peter; Leshinsky-Silver, Esther; Blumkin, Lubov; Schlipf, Nina; Schröder, Christopher; Schicks, Julia; Lev, Dorit; Riess, Olaf; Lerman-Sagie, Tally; Schöls, Ludger

    2012-02-01

    We recently identified a new locus for spastic paraplegia type 47 (SPG47) in a consanguineous Arabic family with two affected siblings with progressive spastic paraparesis,intellectual disability, seizures, periventricular white matter changes and thin corpus callosum. Using exome sequencing, we now identified a novel AP4B1 frameshift mutation (c.664delC) in this family. This mutation was homozygous in both affected siblings and heterozygous in both parents. The mutant allele was absent in 316 Caucasian and 200 ethnically matched control chromosomes. We propose that AP4B1 mutations cause SPG47 and should be considered in early onset spastic paraplegia with intellectual disability.

  12. Overview of the Lockheed Martin Compact Fusion Reactor (CFR) T4B Experiment

    NASA Astrophysics Data System (ADS)

    McGuire, Thomas

    2016-10-01

    The Lockheed Martin Compact Fusion Reactor (CFR) Program endeavors to quickly develop a compact fusion power plant with favorable commercial economics and military utility. The CFR uses a diamagnetic, high beta, magnetically encapsulated, linear ring cusp plasma confinement scheme. The goal of the T4B experiment is to demonstrate a suitable plasma target for heating experiments and to characterize the behavior of plasma sources in the CFR configuration. The design of the T4B experiment will be presented, including discussion of predicted behavior, plasma sources, heating mechanisms, diagnostics suite and relevant numerical modeling. ©2016 Lockheed Martin Corporation. All Rights Reserved.

  13. Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks

    PubMed Central

    Camacho, Cristel V.; Mukherjee, Bipasha; McEllin, Brian; Ding, Liang-Hao; Hu, Burong; Habib, Amyn A.; Xie, Xian-Jin; Nirodi, Chaitanya S.; Saha, Debabrata; Story, Michael D.; Balajee, Adayabalam S.; Bachoo, Robert M.; Boothman, David A.; Burma, Sandeep

    2010-01-01

    DNA double-strand breaks (DSBs) are the most deleterious lesion inflicted by ionizing radiation. Although DSBs are potentially carcinogenic, it is not clear whether complex DSBs that are refractory to repair are more potently tumorigenic compared with simple breaks that can be rapidly repaired, correctly or incorrectly, by mammalian cells. We previously demonstrated that complex DSBs induced by high-linear energy transfer (LET) Fe ions are repaired slowly and incompletely, whereas those induced by low-LET gamma rays are repaired efficiently by mammalian cells. To determine whether Fe-induced DSBs are more potently tumorigenic than gamma ray-induced breaks, we irradiated ‘sensitized’ murine astrocytes that were deficient in Ink4a and Arf tumor suppressors and injected the surviving cells subcutaneously into nude mice. Using this model system, we find that Fe ions are potently tumorigenic, generating tumors with significantly higher frequency and shorter latency compared with tumors generated by gamma rays. Tumor formation by Fe-irradiated cells is accompanied by rampant genomic instability and multiple genomic changes, the most interesting of which is loss of the p15/Ink4b tumor suppressor due to deletion of a chromosomal region harboring the CDKN2A and CDKN2B loci. The additional loss of p15/Ink4b in tumors derived from cells that are already deficient in p16/Ink4a bolsters the hypothesis that p15 plays an important role in tumor suppression, especially in the absence of p16. Indeed, we find that reexpression of p15 in tumor-derived cells significantly attenuates the tumorigenic potential of these cells, indicating that p15 loss may be a critical event in tumorigenesis triggered by complex DSBs. PMID:20663777

  14. SU-E-J-241: Creation of Ventilation CT From Daily 4D CTs Or 4D Conebeam CTs Acquired During IGRT for Thoracic Cancers

    SciTech Connect

    Tai, A; Ahunbay, E; Li, X

    2014-06-01

    Purpose: To develop a method to create ventilation CTs from daily 4D CTs or 4D KV conebeam CTs (4DCBCT) acquired during image-guided radiation therapy (IGRT) for thoracic tumors, and to explore the potential for using the ventilation CTs as a means for early detection of lung injury during radiation treatment. Methods: 4DCT acquired using an in-room CT (CTVision, Siemens) and 4DCBCT acquired using the X-ray Volume Imaging (XVI) system (Infinity, Elekta) for representative lung cancer patients were analyzed. These 4D data sets were sorted into 10 phase images. A newly-available deformable image registration tool (ADMIRE, Elekta) is used to deform the phase images at the end of exhale (EE) to the phase images at the end of inhale (EI). The lung volumes at EI and EE were carefully contoured using an intensity-based auto-contour tool and then manually edited. The ventilation images were calculated from the variations of CT numbers of those voxels masked by the lung contour at EI between the registered phase images. The deformable image registration is also performed between the daily 4D images and planning 4DCT, and the resulting deformable field vector (DFV) is used to deform the planning doses to the daily images by an in-house Matlab program. Results: The ventilation images were successfully created. The tide volumes calculated using the ventilation images agree with those measured through volume difference of contours at EE and EI, indicating the accuracy of ventilation images. The association between the delivered doses and the change of lung ventilation from the daily ventilation CTs is identified. Conclusions: A method to create the ventilation CT using daily 4DCTs or 4D KV conebeam CTs was developed and demonstrated.

  15. Reducing the 4d index to the S 3 partition function

    NASA Astrophysics Data System (ADS)

    Gadde, Abhijit; Yan, Wenbin

    2012-12-01

    The superconformal index of a 4 d gauge theory is computed by a matrix integral arising from localization of the supersymmetric path integral on S 3 × S 1. As the radius of the circle goes to zero, it is natural to expect that the 4 d path integral becomes the partition function of dimensionally reduced gauge theory on S 3. We show that this is indeed the case and recover the matrix integral of Kapustin, Willett and Yaakov from the matrix integral that computes the superconformal index. Remarkably, the superconformal index of the "parent" 4 d theory can be thought of as the q-deformation of the 3 d partition function.

  16. Inheritance of 2,4-D resistance traits in multiple herbicide- resistant Raphanus raphanistrum populations.

    PubMed

    Busi, Roberto; Powles, Stephen B

    2017-04-01

    A relatively low number of weed species have evolved resistance to auxinic herbicides despite their use for almost 70 years. This inheritance study with two Raphanus raphanistrum populations multiple-resistant 2,4-D and the ALS-inhibiting herbicide chlorsulfuron determined the number of genes and genetic dominance of 2,4-D resistance and investigated the association between traits conferring resistance to the two herbicide modes of action. Levels of 2,4-D phenotypic resistance and resistance segregation patterns were assessed in parental populations, F1 and F2 families.

  17. Bacterial degradation of phenoxy herbicide mixtures 2,4-D and MCPP

    SciTech Connect

    Kyeheon Oh; Tuovinen, O.H. )

    1991-08-01

    The phenoxy herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and 2-(2-methyl-4-chlorophenoxy)propionic acid (MCPP) have auxin-like growth regulating properties and are extensively used for the control of broad-leaf angiosperm weeds. The microbiological degradation of 2,4-D by pure and mixed cultures has been examined in a number of studies. The authors have previously evaluated the concurrent microbiological degradation of 2,4-D and MCPP in stirred tank reactors. For the present paper, they examined the utilization of the two substrates by three mixed cultures that had a previous history of growth with the respective single phenoxy herbicide.

  18. [Knockdown of Larp4b in Lin(-) cells does not affect the colony forming ability of mouse hematopoietic cells].

    PubMed

    Wang, Xiao-Juan; Pang, Ya-Kun; Cheng, Hui; Dong, Fang; Liang, Hao-Yue; Zhang, Ying-Chi; Wang, Xiao-Min; Xu, Jing; Cheng, Tao; Yuan, Wei-Ping

    2013-06-01

    Larp4b is a member of the LARP family, which can interact with RNA and generally stimulate the translation of mRNA. Abnormal expression of Larp4b can be found in leukemia patients in our previous study. This study was purposed to detect the relative expression of Larp4b mRNA in different subpopulations of mouse hematopoietic cells, to construct lentivirus vector containing shLarp4b targeting mouse gene Larp4b and to explore its effects on mouse Lin(-) cells infected with shLarp4b by lentivirus. SF-LV-shLarP4b-EGFP and control vectors were constructed and two-plasmid lentivirus packing system was used to transfect 293T cells. After 48 h and 72 h, lentivirus SF-LV-shLarp4b-EGFP was harvested and was used to infect Lin(-) cells. After 48 h, EGFP(+) cells was sorted by flow cytometry (FCM). Meanwhile, semi-quantitative real time-PCR, AnnexinV-PE/7-AAD staining, PI staining and colony forming cell assay (CFC) were performed to determine the expression of Larp4b and its effect on the proliferation of hematopoietic progenitor cells. The results showed that Larp4b was highly expressed in myeloid cells. SF-LV-shLarp4b-EGFP was successfully constructed according to the restriction endonuclease digestion assay. RT-PCR confirmed that Larp4b was efficiently knockdown in mouse Lin(-) cells. The low expression of Larp4b did not affect the colony forming number, the apoptosis and cell cycle of Lin(-) cells. It is concluded that knockdown of Larp4b in mouse Lin(-) cells do not contribute to the colony forming ability and the growth of Lin(-) cells in vitro. This useful knockdown system will be used to study in vivo Larp4b in future.

  19. The calculated magnetic, electronic and thermodynamic properties of Ce{sub 3}Co{sub 29}Si{sub 4}B{sub 10} compound

    SciTech Connect

    Huo, Jin-Rong; Wang, Xiao-Xu; Hu, Yao-Wen; Zhang, Guo-Hua; Cheng, Hai-Xia; Li, Lu; Qian, Ping

    2016-05-15

    The magnetic moment, lattice parameter and atom fraction coordinates for Ce{sub 3}Co{sub 29}Si{sub 4}B{sub 10} are calculated by the first-principles GGA+U method, and the results indicate that the calculated and experimental values are basically accordant when U=2.6 eV. We study the interaction effect and orbital hybridization between Co and Ce atoms. The projected density of states at U=2.6 eV which provided by Co-2c, Ce-2b and Ce-4d sites are contrasted with else U values. Meanwhile the electron density of states for different sites and the distance between various atoms are exhibited. In addition, the thermodynamic properties of Ce{sub 3}Co{sub 29}Si{sub 4}B{sub 10} are evaluated by using a series of interatomic pair potentials. - Graphical abstract: Change of the total magnetic moment for Ce{sub 3}Co{sub 29}Si{sub 4}B{sub 10} along with the value of U. There is a sharply decline of the curve at U=2.6 eV and, at the moment, the total magnetic moment of the compound have a good agreement with the experimental data. - Highlights: • We research of quaternary rare earth and transition metal compounds. • We perform the calculation of magnetic moment and electronic structure by GGA+U method. • The orbital hybridization between Co and Ce atoms is displayed and analyzed. • Show the plot of projected density of states for different sites more clearly. • Calculate the thermodynamic property of rare-earth transition metal compound.

  20. Low 2D:4D Values Are Associated with Video Game Addiction

    PubMed Central

    Kornhuber, Johannes; Zenses, Eva-Maria; Lenz, Bernd; Stoessel, Christina; Bouna-Pyrrou, Polyxeni; Rehbein, Florian; Kliem, Sören; Mößle, Thomas

    2013-01-01

    Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction. PMID:24236143

  1. Dissipation and residue of 2,4-D in citrus under field condition.

    PubMed

    Chen, Weijun; Jiao, Bining; Su, Xuesu; Zhao, Qiyang; Sun, Dali

    2015-05-01

    The dissipation, residues, and risks of 2,4-dicholrophenoxyacetic acid (2,4-D) in citrus under field condition were investigated based on a simple ultra-performance LC (UPLC)-MS/MS method. The results indicated that the residue level of 2,4-D in citrus did not degrade gradually with sampling time under field condition. At pre-harvest intervals (PHI) of 20-40 days, 2,4-D residues were 0.021-0.269 mg/kg in citrus flesh, 0.028-0.337 mg/kg in whole citrus, and 0.028-0.376 mg/kg in citrus peel, all bellow the China maximum residue limit in citrus (1 mg/kg). Risks of 2,4-D were assessed by calculation of risk quotient, and the results revealed no significant health risks after consumption of citrus.

  2. Low 2D:4D values are associated with video game addiction.

    PubMed

    Kornhuber, Johannes; Zenses, Eva-Maria; Lenz, Bernd; Stoessel, Christina; Bouna-Pyrrou, Polyxeni; Rehbein, Florian; Kliem, Sören; Mößle, Thomas

    2013-01-01

    Androgen-dependent signaling regulates the growth of the fingers on the human hand during embryogenesis. A higher androgen load results in lower 2D:4D (second digit to fourth digit) ratio values. Prenatal androgen exposure also impacts brain development. 2D:4D values are usually lower in males and are viewed as a proxy of male brain organization. Here, we quantified video gaming behavior in young males. We found lower mean 2D:4D values in subjects who were classified according to the CSAS-II as having at-risk/addicted behavior (n = 27) compared with individuals with unproblematic video gaming behavior (n = 27). Thus, prenatal androgen exposure and a hyper-male brain organization, as represented by low 2D:4D values, are associated with problematic video gaming behavior. These results may be used to improve the diagnosis, prediction, and prevention of video game addiction.

  3. Identification of an NTPase motif in classical swine fever virus NS4B protein

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Classical swine fever (CSF) is a highly contagious and often fatal disease of swine caused by CSF virus (CSFV), a positive sense single-stranded RNA virus in the genus Pestivirus of the Flaviviridae family. Here, we have identified, within CSFV non-structural (NS) protein NS4B, conserved sequence el...

  4. Identification of immunogenic MAGED4B peptides for vaccine development in oral cancer immunotherapy.

    PubMed

    Lim, Kue Peng; Chun, Nicole Ai Leng; Gan, Chai Phei; Teo, Soo-Hwang; Rahman, Zainal Ariff Abdul; Abraham, Mannil Thomas; Zain, Rosnah Binti; Ponniah, Sathibalan; Cheong, Sok Ching

    2014-01-01

    The ever-increasing number of tumor-associated antigens has provided a major stimulus for the development of therapeutic peptides vaccines. Tumor-associated peptides can induce high immune response rates and have been developed as vaccines for several types of solid tumors, and many are at various stages of clinical testing. MAGED4B, a melanoma antigen, is overexpressed in oral squamous cell carcinoma (OSCC) and this expression promotes proliferation and cell migration. In this study, we have identified 9 short peptides derived from MAGED4B protein that are restricted in binding to the HLA subtypes common in the Asian population (HLA-A2, A11, and A24). The peptides had good binding affinity with the MHC-Class I molecules and stimulated ex-vivo IFN-gamma and Granzyme-B production in blood samples from OSCC patients, suggesting that they are immunogenic. Further, T cells stimulated with peptide-pulsed dendritic cells showed enhanced T-cell cytotoxic activity against MAGED4B-overexpressing OSCC cell lines. In summary, we have identified MAGED4B peptides that induce anti-tumor immune responses advocating that they could be further developed as vaccine candidates for the treatment of OSCC.

  5. 16 CFR 1508.5 - Component spacing test method for § 1508.4(b).

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 2 2011-01-01 2011-01-01 false Component spacing test method for § 1508.4(b). 1508.5 Section 1508.5 Commercial Practices CONSUMER PRODUCT SAFETY COMMISSION FEDERAL HAZARDOUS SUBSTANCES ACT REGULATIONS REQUIREMENTS FOR FULL-SIZE BABY CRIBS § 1508.5 Component spacing test method...

  6. 20. FOUR 4B17Gs BEING CONVERTED TO F9Cs. Photographic copy of ...

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

    20. FOUR 4B-17Gs BEING CONVERTED TO F-9Cs. Photographic copy of historic photograph. Jan.-June 1947 OAMA (original print located at Ogden Air Logistics Center, Hill Air Force Base, Utah). Photographer unknown. - Hill Field, Airplane Repair Hangars No. 1-No. 4, 5875 Southgate Avenue, Layton, Davis County, UT

  7. PSD-95 mediates membrane clustering of the human plasma membrane Ca2+ pump isoform 4b.

    PubMed

    Padányi, Rita; Pászty, Katalin; Strehler, Emanuel E; Enyedi, Agnes

    2009-06-01

    Besides the control of global calcium changes, specific plasma membrane calcium ATPase (PMCA) isoforms are involved in the regulation of local calcium signals. Although local calcium signaling requires the confinement of signaling molecules into microdomains, little is known about the specific organization of PMCA molecules within the plasma membrane. Here we show that co-expression with the postsynaptic density-95 (PSD-95) scaffolding protein increased the plasma membrane expression of PMCA4b and redistributed the pump into clusters. The clustering of PMCA4b was fully dependent on the presence of its PDZ-binding sequence. Using the fluorescence recovery after photobleaching (FRAP) technique, we show that the lateral membrane mobility of the clustered PMCA4b is significantly lower than that of the non-clustered molecules. Disruption of the actin-based cytoskeleton by cytochalasin D resulted in increased cluster size. Our results suggest that PSD-95 promotes the formation of high-density PMCA4b microdomains in the plasma membrane and that the membrane cytoskeleton plays an important role in the regulation of this process.

  8. 75 FR 54153 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-03

    ... Recommendation of Pharmacopoeial Texts for Use in the International Conference on Harmonisation Regions; Annex 11... guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions... Electrophoresis General Chapter harmonized text from each of the three pharmacopoeias (United States,...

  9. 75 FR 18509 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-12

    ... Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... Texts for Use in the ICH Regions; Annex 10: Polyacrylamide Gel Electrophoresis General Chapter.'' The... ICH Q4B evaluation of the Polyacrylamide Gel Electrophoresis General Chapter harmonized text from...

  10. 75 FR 17148 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-05

    ... Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... availability of a guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the... Dissolution Test General Chapter harmonized text from each of the three pharmacopoeias (United...

  11. 75 FR 53973 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-02

    ... Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... availability of a guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the... Sieving General Chapter harmonized text from each of the three pharmacopoeias (United States,...

  12. 75 FR 17147 - International Conference on Harmonisation; Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-04-05

    ... Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... availability of a guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the... Friability General Chapter harmonized text from each of the three pharmacopoeias (United States,...

  13. Planning 4D intensity-modulated arc therapy for tumor tracking with a multileaf collimator

    NASA Astrophysics Data System (ADS)

    Niu, Ying; Betzel, Gregory T.; Yang, Xiaocheng; Gui, Minzhi; Parke, William C.; Yi, Byongyong; Yu, Cedric X.

    2017-02-01

    This study introduces a practical four-dimensional (4D) planning scheme of IMAT using 4D computed tomography (4D CT) for planning tumor tracking with dynamic multileaf beam collimation. We assume that patients can breathe regularly, i.e. the same way as during 4D CT with an unchanged period and amplitude, and that the start of 4D-IMAT delivery can be synchronized with a designated respiratory phase. Each control point of the IMAT-delivery process can be associated with an image set of 4D CT at a specified respiratory phase. Target is contoured at each respiratory phase without a motion-induced margin. A 3D-IMAT plan is first optimized on a reference-phase image set of 4D CT. Then, based on the projections of the planning target volume in the beam’s eye view at different respiratory phases, a 4D-IMAT plan is generated by transforming the segments of the optimized 3D plan by using a direct aperture deformation method. Compensation for both translational and deformable tumor motion is accomplished, and the smooth delivery of the transformed plan is ensured by forcing connectivity between adjacent angles (control points). It is envisioned that the resultant plans can be delivered accurately using the dose rate regulated tracking method which handles breathing irregularities (Yi et al 2008 Med. Phys. 35 3955–62).This planning process is straightforward and only adds a small step to current clinical 3D planning practice. Our 4D planning scheme was tested on three cases to evaluate dosimetric benefits. The created 4D-IMAT plans showed similar dose distributions as compared with the 3D-IMAT plans on a single static phase, indicating that our method is capable of eliminating the dosimetric effects of breathing induced target motion. Compared to the 3D-IMAT plans with large treatment margins encompassing respiratory motion, our 4D-IMAT plans reduced radiation doses to surrounding normal organs and tissues.

  14. Pregnancy monitoring in dogs and cats using 3D and 4D ultrasonography.

    PubMed

    Hildebrandt, T B; Drews, B; Kurz, J; Hermes, R; Yang, S; Göritz, F

    2009-07-01

    Three-dimensional (3D)/four-dimensional (4D) volume ultrasound is an established method in human medicine that offers various options for analysing and presenting ultrasound volume data. However, the successful application of the different 3D/4D imaging modalities in pregnant dogs and cats has not yet been reported in the literature. The main reasons for this are: (1) the high costs of 3D/4D ultrasound systems, (2) operation difficulties due to high breathing frequency in non-sedated animals and (3) the missing specific knowledge in veterinary medicine concerning how to perform high-quality volume scans. Automatically acquired ultrasound volume data sets were generated with two different ultrasound systems: the portable Voluson i and the stationary Voluson Expert 730. Different 3D/4D imaging modalities were tested in regard of their practicability in pregnancy monitoring in dogs and cats. Nine different volume imaging modalities were applied using the saved files. For the presentation of the static 3D volume data sets, we used the multiplanar, niche, surface, transparency, glass body, inversion, volume calculation and tomographic ultrasound imaging modes. For the dynamic 4D data, the surface and glass body modes were applied. By changing the human standard settings to the requirements of small animal anatomy, it was found that 3D/4D ultrasound has great potential for the characterization of pregnancy in queens and bitches. The 3D/4D technology offered advanced information about pregnancy status and birth prediction and improved the diagnostic confidence. By using standardized examination protocols, 3D/4D ultrasound will allow a reduction in examination time by generating even more relevant information. These benefits, combined with possible future cost reduction of commercial ultrasound systems, might lead to frequent utilization in routine pregnancy diagnostic and birth management in small animal practice.

  15. A standardized method for 4D ultrasound-guided peripheral nerve blockade and catheter placement.

    PubMed

    Clendenen, N J; Robards, C B; Clendenen, S R

    2014-01-01

    We present a standardized method for using four-dimensional ultrasound (4D US) guidance for peripheral nerve blocks. 4D US allows for needle tracking in multiple planes simultaneously and accurate measurement of the local anesthetic volume surrounding the nerve following injection. Additionally, the morphology and proximity of local anesthetic spread around the target nerve is clearly seen with the described technique. This method provides additional spatial information in real time compared to standard two-dimensional ultrasound.

  16. Digit ratio (2D:4D), lateral preferences, and performance in fencing.

    PubMed

    Voracek, Martin; Reimer, Barbara; Ertl, Clara; Dressler, Stefan G

    2006-10-01

    The second to fourth digit ratio (2D:4D) is a sexually dimorphic trait (men tend to have lower values than women) and a likely biomarker for the organizational (permanent) effects of prenatal androgens on the human brain and body. Prenatal testosterone, as reflected by 2D:4D, has many extragenital effects, including its relevance for the formation of an efficient cardiovascular system. Previous research, reviewed here, has therefore investigated possible associations of 2D:4D with sport performance. Several studies found more masculinized digit ratio patterns (low 2D:4D values or a negative right-minus-left difference in 2D:4D) to be related to high performance in running, soccer, and skiing. The present research tested this hypothesis in a sample of 54 tournament fencers, predominantly from Austria. For men, negative right-left differences in 2D:4D corresponded significantly to better current as well as highest national fencing rankings, independent of training intensity and fencing experience. The mean 2D:4D values of these fencers were significantly lower and the proportion of left-handers was elevated relative to the local general population. For the right hand, the ratio was somewhat lower in male sabre fencers than in male epée and foil fencers combined and significantly lower in left-handed compared to right-handed fencers. Although nonsignificant due to low statistical power, effect sizes suggested that crossed versus congruent hand-eye and hand-foot preferences might also be related to fencing performance. The present findings add to the evidence that 2D:4D might be a performance indicator for men across a variety of sports.

  17. Evaluation of 2, 4-D Ester and Triclopyr Amine Against Waterlily and Spatterdock

    DTIC Science & Technology

    2008-03-01

    cause un-intended damage to non-target, floating-leaved plant stands. Both 2,4-D and triclopyr are auxin -type herbicides effective on dicotyledons...stem, petioles and leaves) typical of auxin -type herbicides. Both herbicides are rapidly translocated in plant tissues via the symplastic pathway...curling and petiole elongation are common to auxin -type herbicides such as 2,4-D and triclopyr (WSSA 2002). These symptoms are indicators of herbicide

  18. 3D and 4D atlas system of living human body structure.

    PubMed

    Suzuki, N; Takatsu, A; Hattori, A; Ezumi, T; Oda, S; Yanai, T; Tominaga, H

    1998-01-01

    A reference system for accessing anatomical information from a complete 3D structure of the whole body "living human", including 4D cardiac dynamics, was reconstructed with 3D and 4D data sets obtained from normal volunteers. With this system, we were able to produce a human atlas in which sectional images can be accessed from any part of the human body interactively by real-time image generation.

  19. Low Digit Ratio 2D∶4D in Alcohol Dependent Patients

    PubMed Central

    Lenz, Bernd; Kraus, Thomas; Sperling, Wolfgang; Bayerlein, Kristina; Biermann, Teresa; Stoessel, Christina

    2011-01-01

    The ratio of the lengths of the second and fourth finger (2D∶4D) has been described as reflecting the degree of prenatal androgen exposure in humans. 2D∶4D is smaller for males than females and is associated with traits such as left-handedness, physical aggression, attention-deficit-hyperactivity disorder and a genetic polymorphism of the androgen receptor. All of these traits are known to be correlated to the vulnerability for alcohol dependency. We therefore hypothesized low 2D∶4D in patients with alcohol dependency. In the present study on 131 patients suffering from alcohol dependency and 185 healthy volunteers, we found that alcohol dependent patients had smaller 2D∶4D ratios compared to controls with preserved sexual dimorphism but with reduced right-left differences. The detection of alcohol dependency based on 2D∶4D ratios was most accurate using the right hand of males (ROC-analysis: AUC 0.725, sensitivity 0.667, specificity 0.723). These findings provide novel insights into the role of prenatal androgen exposure in the development of alcohol dependency and for the use of 2D∶4D as a possible trait marker in identifying patients with alcohol dependency. PMID:21547078

  20. A hybrid space approach for ensemble-based 4-D variational data assimilation

    NASA Astrophysics Data System (ADS)

    Shao, Aimei; Xi, Shuang; Qiu, Chongjian; Xu, Qin

    2009-09-01

    A new scheme is developed to improve the ensemble-based 4-D variational data assimilation (En4DVar). In this scheme, leading singular vectors are extracted from 4-D ensemble perturbations in a hybrid space and then used to construct the analysis increment to fit the 4-D innovation (observation minus background) data. The hybrid space combines the 4-D observation space with only a gridded 3-D subspace at the end of each assimilation cycle, so its dimension can be much smaller than the dimension of the fully gridded 4-D space used in the original En4DVar. This improves the computational efficiency. With this hybrid space approach, the analysis increment can fit the 4-D innovation data in the observation space directly and also provide the necessary initial condition in the gridded 3-D subspace exclusively for the model integration into the next assimilation cycle, so the background covariance matrix can be and only needs to be constructed by the ensemble perturbations in the 3-D subspace. This reduces the rank deficiency of the ensemble-constructed covariance matrix and improves analysis accuracy as long as the observations are not too sparse. The potential merits of the new scheme are demonstrated by assimilation experiments performed with an imperfect shallow-water equation model and simulated observations.

  1. 4D MR and attenuation map generation in PET/MR imaging using 4D PET derived deformation matrices: a feasibility study for lung cancer applications.

    PubMed

    Fayad, Hadi; Schmidt, Holger; Kuestner, Thomas; Visvikis, Dimitris

    2016-10-13

    Respiratory motion may reduce accuracy in fusion of functional and anatomical images using combined Positron emission tomography / Magnetic resonance (PET/MR) systems. Methodologies for the correction of respiratory motion in PET acquisitions using such systems are mostly based on the use of respiratory synchronized MR acquisitions to derive motion fields. Existing approaches based on tagging acquisitions may introduce artifacts in the MR images, while motion model approaches require the acquisition of training datasets. The objective of this work was to investigate the possibility of generating 4D MR images and associated attenuation maps (AMs) from a single static MR image combined with motion fields obtained from simultaneously acquired 4D non-attenuation corrected (NAC) PET images.

  2. Low external pH replaces 2,4-D in maintaining and multiplying 2,4-D-initiated embryogenic cells of carrot

    NASA Technical Reports Server (NTRS)

    Smith, D. L.; Krikorian, A. D.

    1990-01-01

    A mixed culture comprised of both embryonic globules and nonembryogenic callus was derived from seedling hypocotyls of Daucus carota cv. Scarlet Nantes on 2,4-D- containing medium using well-established methods. Then the mixed cultures were transferred to, and serially subcultured on, a hormone-free medium near pH 4. The medium contained 1 mM NH4+ as the sole nitrogen source. When cultured in this way, embryonic globules were able to multiply without development into later embryo stages. Nonembryogenic callus did not survive. Continuous culture of embryonic globules on this low pH hormone-free medium yielded cultures consisting entirely of preglobular stage proembryos (PGSPs). PGSP cultures have been maintained as such with continuous multiplication for nearly 2 years without loss of embryogenic potential. These hormone-free-maintained PGSPs continue their development to later embryo stages when cultured on the same hormone-free medium buffered at pH 5.8. We show that hormone-free medium near pH 4 can replace 2,4-D in its ability to sustain multiplication of 2,4-D-initiated embryogenic cells of carrot at an acceptable growth rate without their development into later embryo stages. This procedure provides selective conditions that do not permit the growth of non-embryogenic cells while providing an adequate environment for embryogenic cell proliferation and should prove invaluable in studying habituation.

  3. Directional sinogram interpolation for motion weighted 4D cone-beam CT reconstruction

    NASA Astrophysics Data System (ADS)

    Zhang, Hua; Kruis, Matthijs; Sonke, Jan-Jakob

    2017-03-01

    The image quality of respiratory sorted four-dimensional (4D) cone-beam (CB) computed tomography (CT) is often limited by streak artifacts due to insufficient projections. A motion weighted reconstruction (MWR) method is proposed to decrease streak artifacts and improve image quality. Firstly, respiratory correlated CBCT projections were interpolated by directional sinogram interpolation (DSI) to generate additional CB projections for each phase and subsequently reconstructed. Secondly, local motion was estimated by deformable image registration of the interpolated 4D CBCT. Thirdly, a regular 3D FDK CBCT was reconstructed from the non-interpolated projections. Finally, weights were assigned to each voxel, based on the local motion, and then were used to combine the 3D FDK CBCT and interpolated 4D CBCT to generate the final 4D image. MWR method was compared with regular 4D CBCT scans as well as McKinnon and Bates (MKB) based reconstructions. Comparisons were made in terms of (1) comparing the steepness of an extracted profile from the boundary of the region-of-interest (ROI), (2) contrast-to-noise ratio (CNR) inside certain ROIs, and (3) the root-mean-square-error (RMSE) between the planning CT and CBCT inside a homogeneous moving region. Comparisons were made for both a phantom and four patient scans. In a 4D phantom, RMSE were reduced by 24.7% and 38.7% for MKB and MWR respectively, compared to conventional 4D CBCT. Meanwhile, interpolation induced blur was minimal in static regions for MWR based reconstructions. In regions with considerable respiratory motion, image blur using MWR is less than the MKB and 3D Feldkamp (FDK) methods. In the lung cancer patients, average CNRs of MKB, DSI and MWR improved by a factor 1.7, 2.8 and 3.5 respectively relative to 4D FDK. MWR effectively reduces RMSE in 4D cone-beam CT and improves the image quality in both the static and respiratory moving regions compared to 4D FDK and MKB methods.

  4. Dynamically accumulated dose and 4D accumulated dose for moving tumors

    SciTech Connect

    Li Heng; Li Yupeng; Zhang Xiaodong; Li Xiaoqiang; Liu Wei; Gillin, Michael T.; Zhu, X. Ronald

    2012-12-15

    Purpose: The purpose of this work was to investigate the relationship between dynamically accumulated dose (dynamic dose) and 4D accumulated dose (4D dose) for irradiation of moving tumors, and to quantify the dose uncertainty induced by tumor motion. Methods: The authors established that regardless of treatment modality and delivery properties, the dynamic dose will converge to the 4D dose, instead of the 3D static dose, after multiple deliveries. The bounds of dynamic dose, or the maximum estimation error using 4D or static dose, were established for the 4D and static doses, respectively. Numerical simulations were performed (1) to prove the principle that for each phase, after multiple deliveries, the average number of deliveries for any given time converges to the total number of fractions (K) over the number of phases (N); (2) to investigate the dose difference between the 4D and dynamic doses as a function of the number of deliveries for deliveries of a 'pulsed beam'; and (3) to investigate the dose difference between 4D dose and dynamic doses as a function of delivery time for deliveries of a 'continuous beam.' A Poisson model was developed to estimate the mean dose error as a function of number of deliveries or delivered time for both pulsed beam and continuous beam. Results: The numerical simulations confirmed that the number of deliveries for each phase converges to K/N, assuming a random starting phase. Simulations for the pulsed beam and continuous beam also suggested that the dose error is a strong function of the number of deliveries and/or total deliver time and could be a function of the breathing cycle, depending on the mode of delivery. The Poisson model agrees well with the simulation. Conclusions: Dynamically accumulated dose will converge to the 4D accumulated dose after multiple deliveries, regardless of treatment modality. Bounds of the dynamic dose could be determined using quantities derived from 4D doses, and the mean dose difference

  5. The Crystal Structure of Cytochrome P450 4B1 (CYP4B1) Monoxygenase Complexed with Octane Discloses Several Structural Adaptations for ω-Hydroxylation.

    PubMed

    Hsu, Mei-Hui; Baer, Brian R; Rettie, Allan E; Johnson, Eric F

    2017-02-06

    P450 family 4 fatty acid ω-hydroxylases preferentially oxygenate primary C-H bonds over adjacent, energetically favored secondary C-H bonds, but the mechanism explaining this intriguing preference is unclear. To this end, the structure of rabbit P450 4B1 complexed with its substrate octane was determined by X-ray crystallography to define features of the active site that contribute to a preference for ω-hydroxylation. The structure indicated that octane is bound in a narrow active site cavity that limits access of the secondary C-H bond to the reactive intermediate. A highly conserved sequence motif on helix I contributes to positioning the terminal carbon of octane for ω-hydroxylation. Glu-310 of this motif auto-catalytically forms an ester bond with the heme 5-methyl, and the immobilized E310 contributes to substrate positioning. The preference for ω-hydroxylation was decreased in a E310A mutant having a shorter side-chain, but overall rates of metabolism were retained. E310D and E310Q substitutions having longer side-chains exhibit lower overall rates, likely due to higher conformational entropy for these residues, but they retained high preferences for octane ω-hydroxylation. Sequence comparisons indicated that active-site residues constraining octane for ω-hydroxylation are conserved in family 4 P450s. Moreover, the heme 7-propionate is positioned in the active site and provides additional restraints on substrate binding. In conclusion, P450 4B1 exhibits structural adaptations for ω-hydroxylation that include changes in the conformation of the heme and changes in a highly conserved helix I motif that is associated with selective oxygenation of un-activated primary C-H bonds.

  6. Oxford classification of IgA nephropathy and C4d deposition; correlation and its implication.

    PubMed

    Rath, Ashutosh; Tewari, Rohit; Mendonca, Satish; Badwal, Sonia; Nijhawan, Vijay Shrawan

    2016-01-01

    Introduction: IgA nephropathy (IgAN) is well known to be the most common form of primary glomerulonephritis throughout the world. The histopathological changes are wide and varied as brought out by the various classification systems like the Haas and Oxford systems. C4d is a well-known biomarker of the complement cascade and has recently been implicated in certain native renal diseases. We attempted to characterize C4d deposition in IgAN and correlate this with histopathology by the Oxford classification system. Patients and Methods: This retrospective study included renal biopsies of 15 cases of IgAN diagnosed on histopathology and immunofluorescence over a period of 2 years. Demographic parameters of age and sex were reviewed. The Oxford classification system was applied to score the cases and immunohistochemistry for C4d was done on all cases to characterize staining pattern and intensity and was correlated with Oxford classification. Results: On histological examination, the cases showed various combinations of lesions ranging from M0E0S0T0 to M1E1S1T1. C4d deposition was found to be occurring mainly in mesangial location (12/15 cases, 80%). Forty percent cases showed C4d deposition in the glomerular capillary walls in a segmental fashion and 26.67% showed global pattern. Other patterns of deposition were arteriolar (53.33%), in peritubular capillaries (26.67%) and in tubular epithelium (20%). Conclusion: On comparing the various patterns of deposition of C4d with the four variables of the Oxford classification system, we found that segmental and global deposition of C4d correlated best with endocapillary proliferation.

  7. Evaluation of 4D CT acquisition methods designed to reduce artifacts.

    PubMed

    Castillo, Sarah J; Castillo, Richard; Castillo, Edward; Pan, Tinsu; Ibbott, Geoffrey; Balter, Peter; Hobbs, Brian; Guerrero, Thomas

    2015-03-08

    Four-dimensional computed tomography (4D CT) is used to account for respiratory motion in radiation treatment planning, but artifacts resulting from the acquisition and postprocessing limit its accuracy. We investigated the efficacy of three experimental 4D CT acquisition methods to reduce artifacts in a prospective institutional review board approved study. Eighteen thoracic patients scheduled to undergo radiation therapy received standard clinical 4D CT scans followed by each of the alternative 4D CT acquisitions: 1) data oversampling, 2) beam gating with breathing irregularities, and 3) rescanning the clinical acquisition acquired during irregular breathing. Relative values of a validated correlation-based artifact metric (CM) determined the best acquisition method per patient. Each 4D CT was processed by an extended phase sorting approach that optimizes the quantitative artifact metric (CM sorting). The clinical acquisitions were also postprocessed by phase sorting for artifact comparison of our current clinical implementation with the experimental methods. The oversampling acquisition achieved the lowest artifact presence among all acquisitions, achieving a 27% reduction from the current clinical 4D CT implementation (95% confidence interval = 34-20). The rescan method presented a significantly higher artifact presence from the clinical acquisition (37%; p < 0.002), the gating acquisition (26%; p < 0.005), and the oversampling acquisition (31%; p < 0.001), while the data lacked evidence of a significant difference between the clinical, gating, and oversampling methods. The oversampling acquisition reduced artifact presence from the current clinical 4D CT implementation to the largest degree and provided the simplest and most reproducible implementation. The rescan acquisition increased artifact presence significantly, compared to all acquisitions, and suffered from combination of data from independent scans over which large internal anatomic shifts occurred.

  8. 4D scattering amplitudes and asymptotic symmetries from 2D CFT

    NASA Astrophysics Data System (ADS)

    Cheung, Clifford; de la Fuente, Anton; Sundrum, Raman

    2017-01-01

    We reformulate the scattering amplitudes of 4D flat space gauge theory and gravity in the language of a 2D CFT on the celestial sphere. The resulting CFT structure exhibits an OPE constructed from 4D collinear singularities, as well as infinite-dimensional Kac-Moody and Virasoro algebras encoding the asymptotic symmetries of 4D flat space. We derive these results by recasting 4D dynamics in terms of a convenient foliation of flat space into 3D Euclidean AdS and Lorentzian dS geometries. Tree-level scattering amplitudes take the form of Witten diagrams for a continuum of (A)dS modes, which are in turn equivalent to CFT correlators via the (A)dS/CFT dictionary. The Ward identities for the 2D conserved currents are dual to 4D soft theorems, while the bulk-boundary propagators of massless (A)dS modes are superpositions of the leading and subleading Weinberg soft factors of gauge theory and gravity. In general, the massless (A)dS modes are 3D Chern-Simons gauge fields describing the soft, single helicity sectors of 4D gauge theory and gravity. Consistent with the topological nature of Chern-Simons theory, Aharonov-Bohm effects record the "tracks" of hard particles in the soft radiation, leading to a simple characterization of gauge and gravitational memories. Soft particle exchanges between hard processes define the Kac-Moody level and Virasoro central charge, which are thereby related to the 4D gauge coupling and gravitational strength in units of an infrared cutoff. Finally, we discuss a toy model for black hole horizons via a restriction to the Rindler region.

  9. Development and characterization of a replicon-based phenotypic assay for assessing HCV NS4B from clinical isolates.

    PubMed

    Rajyaguru, Sonal; Yang, Huiling; Martin, Ross; Miller, Michael D; Mo, Hongmei

    2013-11-01

    The hepatitis C virus (HCV) NS4B inhibitors have shown potent inhibition of HCV replication in vitro. To assess the effect of viral diversity on the susceptibility to NS4B inhibitors, genotype (GT)-specific GT1a and GT1b replicon shuttle vectors were designed and created for cloning HCV NS4B genes from clinical isolates. For the GT1b NS4B shuttle vector, the S2204I adaptive mutation was introduced in NS5A to improve replication due to the replacement of the K1846T adaptive mutation in NS4B with NS4B from the clinical isolates. In addition to the adaptive mutations, a newly identified Huh-7 cell line, Huh-7-1C, which is highly permissive for both GT1a and GT1b replication, was used to further enhance the replication levels. HCV NS4B gene from clinical isolates was amplified and inserted into the corresponding GT1a and GT1b modified lab strain chimeric replicons. GT1a and GT1b chimeric replicons expressing diverse NS4B genes from corresponding subtypes of clinical isolates replicated at highly efficient levels for phenotypic analysis. Due to natural variation in their amino acid residues in NS4B, these isolates displayed varying drug susceptibilities to an NS4B inhibitor. In mixed populations with wild-type, the sensitivity of resistance detection of NS4B resistant mutants H94R and V105M was between 20% and 80%. The chimeric shuttle vectors can be used to characterize the activity of antiviral drugs targeting NS4B from diverse natural clinical isolates and aid in the development of novel compounds against HCV NS4B.

  10. Expression of human inducible nitric oxide synthase in a tetrahydrobiopterin (H4B)-deficient cell line: H4B promotes assembly of enzyme subunits into an active dimer.

    PubMed Central

    Tzeng, E; Billiar, T R; Robbins, P D; Loftus, M; Stuehr, D J

    1995-01-01

    Murine inducible nitric oxide (NO) synthase (iNOS) is catalytically active only in dimeric form. Assembly of its purified subunits into a dimer requires H4B. To understand the structure-activity relationships of human iNOS, we constitutively expressed recombinant human iNOS in NIH 3T3 cells by using a retroviral vector. These cells are deficient in de novo H4B biosynthesis and the role of H4B in the expression and assembly of active iNOS in an intact cell system could be studied. In the absence of added H4B, NO synthesis by the cells was minimal, whereas cells grown with supplemental H4B or the H4B precursor sepiapterin generated NO (74.1 and 63.3 nmol of nitrite per 10(6) cells per 24 h, respectively). NO synthesis correlated with an increase in intracellular H4B but no increase in iNOS protein. Instead, an increased percentage of dimeric iNOS was observed, rising from 20% in cytosols from unsupplemented cells to 66% in H4B-supplemented cell cytosols. In all cases, only dimeric iNOS displayed catalytic activity. Cytosols prepared from H4B-deficient cells exhibited little iNOS activity but acquired activity during a 60- to 120-min incubation with H4B, reaching final activities of 60-72 pmol of citrulline per mg of protein per min. Reconstitution of cytosolic NO synthesis activity was associated with conversion of monomers into dimeric iNOS during the incubation. Thus, human iNOS subunits dimerize to form an active enzyme, and H4B plays a critical role in promoting dimerization in intact cells. This reveals a post-translational mechanism by which intracellular H4B can regulate iNOS expression. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:8524846

  11. Semaphorin 4D induces vaginal epithelial cell apoptosis to control mouse postnatal vaginal tissue remodeling.

    PubMed

    Ito, Takuji; Bai, Tao; Tanaka, Tetsuji; Yoshida, Kenji; Ueyama, Takashi; Miyajima, Masayasu; Negishi, Takayuki; Kawasaki, Takahiko; Takamatsu, Hyota; Kikutani, Hitoshi; Kumanogoh, Atsushi; Yukawa, Kazunori

    2015-02-01

    The opening of the mouse vaginal cavity to the skin is a postnatal tissue remodeling process that occurs at approximately five weeks of age for the completion of female genital tract maturation at puberty. The tissue remodeling process is primarily composed of a hormonally triggered apoptotic process predominantly occurring in the epithelium of the distal section of the vaginal cavity. However, the detailed mechanism underlying the apoptotic induction remains to be elucidated. In the present study, it was observed that the majority of BALB/c mice lacking the class 4 semaphorin, semaphorin 4D (Sema4D), developed imperforate vagina and hydrometrocolpos resulting in a perpetually unopened vaginal cavity regardless of a normal estrogen level comparable with that in wild‑type (WT) mice. Administration of β‑estradiol to infant Sema4D‑deficient (Sema4D‑/‑) mice did not induce precocious vaginal opening, which was observed in WT mice subjected to the same β‑estradiol administration, excluding the possibility that the closed vaginal phenotype was due to insufficient estrogen secretion at the time of vaginal opening. In order to assess the role of Sema4D in the postnatal vaginal tissue remodeling process, the expression of Sema4D and its receptor, plexin‑B1, was examined as well as the level of apoptosis in the vaginal epithelia of five‑week‑old WT and Sema4D‑/‑ mice. Immunohistochemical analyses confirmed the localization of Sema4D and plexin‑B1 in the mouse vaginal epithelia. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and immunohistochemistry detecting activated caspase‑3 revealed significantly fewer apoptotic cells in situ in the vaginal mucosa of five‑week‑old Sema4D‑/‑ mice compared with WT mice. The addition of recombinant Sema4D to Sema4D‑/‑ vaginal epithelial cells in culture significantly enhanced apoptosis of the vaginal epithelial cells, demonstrating the apoptosis‑inducing activity of Sema4D. The

  12. Optical and Near-UV Observations of the Transiting Extrasolar Planet TrES-4b

    NASA Astrophysics Data System (ADS)

    Smith, Carter-Thaxton; Turner, J.; Carleton, T.; Crawford, B.; Guvenen, B.; Hardegree-Ullman, K.; Small, L.; Towner, A. P.; Walker-LaFollette, A.; Henz, T.

    2013-01-01

    Using the Steward Observatory 61” Kuiper Telescope, The University of Arizona Astronomy Club conducted photometric observations of the transiting extrasolar planet TrES-4b as part of the Exoplanet Observation Project. Observations were made in the Bessell U, Harris B, and Harris R filters. Initial observations were made in 2009, with follow up observations in 2011. Basic data reduction and photometry was done using IRAF and determination of transit parameters was done using Transit Analysis Package (TAP) and JKTEBOP transit modeling code. We present an updated planetary mass, radius, density, surface gravity, Safronov number, equilibrium temperature, orbital distance, and orbital inclination for TrES-4b. In addition, we also searched for asymmetries between the near-UV and optical light curves. This project, started in spring 2009, has introduced many undergraduate students to research and given them valuable experience with data reduction and observation techniques.

  13. Hydrophobic metabolites of 2,4-dichlorophenoxyacetic acid (2,4-D) in cultured coconut tissue.

    PubMed

    López-Villalobos, Arturo; Hornung, Roland; Dodds, Peter F

    2004-10-01

    Cultures of inflorescence and plumular tissues of coconut palm (Cocos nucifera L.) were maintained in the presence of the auxin, [14C]2,4-dichlorophenoxyacetic acid (2,4-D), so that its metabolic fate could be studied. Thin layer chromatography of methanol extracts of the plumular tissue showed that four classes of metabolites, as well as the unchanged acid, were recovered in the extract. In inflorescence tissue, only the unchanged acid and the most polar class of metabolites (metabolite I) were recovered. Metabolite I was shown to consist mostly of a mixture of sugar conjugates and metabolite II (the next most polar) was an unidentified basic metabolite. Metabolites III and IV were both novel triacylglycerol analogues in which one of the natural fatty acids was replaced with a chain-elongated form of 2,4-D. Reversed-phase thin layer chromatography was used to identify the 2,4-D-derived acids and it was found that metabolite III contained the 2,4-dichlorophenoxy-moiety attached to a chain-length of between 2 and 12 carbons, whereas metabolite IV contained 12, 14 and 16 carbon chain lengths. In inflorescence tissue, and in plumular tissue at low sucrose or 2,4-D concentrations and after short periods in culture, metabolite I predominated. The other metabolites increased as a percentage when plumular culture was prolonged or when sucrose or 2,4-D concentrations were raised. These changes correlated with better development of the explant.

  14. Trauma-related altered states of consciousness: exploring the 4-D model.

    PubMed

    Frewen, Paul A; Lanius, Ruth A

    2014-01-01

    Frewen and Lanius (in press) recently articulated a 4-D model as a framework for classifying symptoms of posttraumatic stress into those that potentially occur within normal waking consciousness (NWC) versus those that intrinsically represent dissociative experiences of trauma-related altered states of consciousness (TRASC). Four dimensions were specified: time-memory, thought, body, and emotion. The 4-D model further hypothesizes that in traumatized persons, symptoms of TRASC, compared with NWC forms of distress, will be (a) observed less frequently; (b) less intercorrelated, especially as measured as moment-to-moment states; (c) observed more frequently in people with high dissociative symptomatology as measured independently; and (d) observed more often in people who have experienced repeated traumatization, particularly early developmental trauma. The aim of the present research was to begin to evaluate these 4 predictions of the 4-D model. Within a sample of 74 women with posttraumatic stress disorder (PTSD) primarily due to histories of childhood trauma, as well as within a 2nd sample of 504 undergraduates (384 females), the 1st 2 hypotheses of the 4-D model were supported. In addition, within the PTSD sample, the 3rd hypothesis was supported. However, inconsistent with the 4th hypothesis, severity of childhood trauma history was not strongly associated with TRASC. We conclude that the hypotheses articulated by the 4-D model were generally supported, although further research in different trauma-related disorders is needed, and the role of childhood trauma history in the etiology of TRASC requires further research.

  15. Inter- and Intrarater Reliability Using Different Software Versions of E4D Compare in Dental Education.

    PubMed

    Callan, Richard S; Cooper, Jeril R; Young, Nancy B; Mollica, Anthony G; Furness, Alan R; Looney, Stephen W

    2015-06-01

    The problems associated with intra- and interexaminer reliability when assessing preclinical performance continue to hinder dental educators' ability to provide accurate and meaningful feedback to students. Many studies have been conducted to evaluate the validity of utilizing various technologies to assist educators in achieving that goal. The purpose of this study was to compare two different versions of E4D Compare software to determine if either could be expected to deliver consistent and reliable comparative results, independent of the individual utilizing the technology. Five faculty members obtained E4D digital images of students' attempts (sample model) at ideal gold crown preparations for tooth #30 performed on typodont teeth. These images were compared to an ideal (master model) preparation utilizing two versions of E4D Compare software. The percent correlations between and within these faculty members were recorded and averaged. The intraclass correlation coefficient was used to measure both inter- and intrarater agreement among the examiners. The study found that using the older version of E4D Compare did not result in acceptable intra- or interrater agreement among the examiners. However, the newer version of E4D Compare, when combined with the Nevo scanner, resulted in a remarkable degree of agreement both between and within the examiners. These results suggest that consistent and reliable results can be expected when utilizing this technology under the protocol described in this study.

  16. Allowing for model error in strong constraint 4D-Var

    NASA Astrophysics Data System (ADS)

    Howes, Katherine; Lawless, Amos; Fowler, Alison

    2016-04-01

    Four dimensional variational data assimilation (4D-Var) can be used to obtain the best estimate of the initial conditions of an environmental forecasting model, namely the analysis. In practice, when the forecasting model contains errors, the analysis from the 4D-Var algorithm will be degraded to allow for errors later in the forecast window. This work focusses on improving the analysis at the initial time by allowing for the fact that the model contains error, within the context of strong constraint 4D-Var. The 4D-Var method developed acknowledges the presence of random error in the model at each time step by replacing the observation error covariance matrix with an error covariance matrix that includes both observation error and model error statistics. It is shown that this new matrix represents the correct error statistics of the innovations in the presence of model error. A method for estimating this matrix using innovation statistics, without requiring prior knowledge of the model error statistics, is presented. The method is demonstrated numerically using a non-linear chaotic system with erroneous parameter values. We show that that the new method works to reduce the analysis error covariance when compared with a standard strong constraint 4D-Var scheme. We discuss the fact that an improved analysis will not necessarily provide a better forecast.

  17. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) biomonitoring and epidemiology

    PubMed Central

    Burns, Carol J.; Swaen, Gerard M. H.

    2012-01-01

    A qualitative review of the epidemiological literature on the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and health after 2001 is presented. In order to compare the exposure of the general population, bystanders and occupational groups, their urinary levels were also reviewed. In the general population, 2,4-D exposure is at or near the level of detection (LOD). Among individuals with indirect exposure, i.e. bystanders, the urinary 2,4-D levels were also very low except in individuals with opportunity for direct contact with the herbicide. Occupational exposure, where exposure was highest, was positively correlated with behaviors related to the mixing, loading and applying process and use of personal protection. Information from biomonitoring studies increases our understanding of the validity of the exposure estimates used in epidemiology studies. The 2,4-D epidemiology literature after 2001 is broad and includes studies of cancer, reproductive toxicity, genotoxicity, and neurotoxicity. In general, a few publications have reported statistically significant associations. However, most lack precision and the results are not replicated in other independent studies. In the context of biomonitoring, the epidemiology data give no convincing or consistent evidence for any chronic adverse effect of 2,4-D in humans. PMID:22876750

  18. 4D cone-beam CT reconstruction using multi-organ meshes for sliding motion modeling

    NASA Astrophysics Data System (ADS)

    Zhong, Zichun; Gu, Xuejun; Mao, Weihua; Wang, Jing

    2016-02-01

    A simultaneous motion estimation and image reconstruction (SMEIR) strategy was proposed for 4D cone-beam CT (4D-CBCT) reconstruction and showed excellent results in both phantom and lung cancer patient studies. In the original SMEIR algorithm, the deformation vector field (DVF) was defined on voxel grid and estimated by enforcing a global smoothness regularization term on the motion fields. The objective of this work is to improve the computation efficiency and motion estimation accuracy of SMEIR for 4D-CBCT through developing a multi-organ meshing model. Feature-based adaptive meshes were generated to reduce the number of unknowns in the DVF estimation and accurately capture the organ shapes and motion. Additionally, the discontinuity in the motion fields between different organs during respiration was explicitly considered in the multi-organ mesh model. This will help with the accurate visualization and motion estimation of the tumor on the organ boundaries in 4D-CBCT. To further improve the computational efficiency, a GPU-based parallel implementation was designed. The performance of the proposed algorithm was evaluated on a synthetic sliding motion phantom, a 4D NCAT phantom, and four lung cancer patients. The proposed multi-organ mesh based strategy outperformed the conventional Feldkamp-Davis-Kress, iterative total variation minimization, original SMEIR and single meshing method based on both qualitative and quantitative evaluations.

  19. 4D cone-beam CT reconstruction using multi-organ meshes for sliding motion modeling

    PubMed Central

    Zhong, Zichun; Gu, Xuejun; Mao, Weihua; Wang, Jing

    2016-01-01

    A simultaneous motion estimation and image reconstruction (SMEIR) strategy was proposed for 4D cone-beam CT (4D-CBCT) reconstruction and showed excellent results in both phantom and lung cancer patient studies. In the original SMEIR algorithm, the deformation vector field (DVF) was defined on voxel grid and estimated by enforcing a global smoothness regularization term on the motion fields. The objective of this work is to improve the computation efficiency and motion estimation accuracy of SMEIR for 4D-CBCT through developing a multi-organ meshing model. Feature-based adaptive meshes were generated to reduce the number of unknowns in the DVF estimation and accurately capture the organ shapes and motion. Additionally, the discontinuity in the motion fields between different organs during respiration was explicitly considered in the multi-organ mesh model. This will help with the accurate visualization and motion estimation of the tumor on the organ boundaries in 4D-CBCT. To further improve the computational efficiency, a GPU-based parallel implementation was designed. The performance of the proposed algorithm was evaluated on a synthetic sliding motion phantom, a 4D NCAT phantom, and four lung cancer patients. The proposed multi-organ mesh based strategy outperformed the conventional Feldkamp–Davis–Kress, iterative total variation minimization, original SMEIR and single meshing method based on both qualitative and quantitative evaluations. PMID:26758496

  20. Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression

    PubMed Central

    Binmadi, Nada O.; Yang, Ying-Hua; Proia, Patrizia

    2013-01-01

    The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some neoplasms producing SEMA4D in a manner analogous to vascular endothelial growth factor (VEGF) in order to attract Plexin-B1-expressing endothelial cells into the tumor for the purpose of promoting growth and vascularity. While anti-VEGF strategies have been the focus of most angiogenesis inhibition research, such treatment can lead to upregulation of pro-angiogenic factors that can compensate for the loss of VEGF, eventually leading to failure of therapy. Here, we demonstrate that SEMA4D cooperates with VEGF to promote angiogenesis in malignancies and can perform the same function in a setting of VEGF blockade. We also show the potential value of inhibiting SEMA4D/Plexin-B1 signaling as a complementary mechanism to anti-VEGF treatment, particularly in VEGF inhibitor–resistant tumors, suggesting that this may represent a novel treatment for some cancers. PMID:22476930

  1. Phosphodiesterase 4D and 5-Lipoxygenase Activating Protein in Ischemic Stroke

    PubMed Central

    Meschia, James F.; Brott, Thomas G.; Brown, Robert D.; Crook, Richard; Worrall, Bradford B.; Kissela, Brett; Brown, W. Mark; Rich, Stephen S.; Case, L. Douglas; Evans, E. Whitney; Hague, Stephen; Singleton, Andrew; Hardy, John

    2006-01-01

    Risk for ischemic stroke is mediated by both environmental and genetic factors. Although several environmental exposures have been implicated, relatively little is known about the genetic basis of predisposition to this disease. Recent studies in Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP). A collection of North American sibling pairs concordant for ischemic stroke and two cohorts of prospectively ascertained North American ischemic stroke cases and control subjects were used for evaluation of PDE4D and ALOX5AP. Although no evidence supported linkage of ischemic stroke with either of the two candidate genes, single-nucleotide polymorphisms and haplotypic associations were observed between PDE4D and ischemic stroke. There was no evidence of association between variants of ALOX5AP and ischemic stroke. These data suggest that common variants in PDE4D may contribute to the genetic risk for ischemic stroke in multiple populations. PMID:16130105

  2. Qatar Exoplanet Survey : Qatar-3b, Qatar-4b, and Qatar-5b

    NASA Astrophysics Data System (ADS)

    Alsubai, Khalid; Mislis, Dimitris; Tsvetanov, Zlatan I.; Latham, David W.; Bieryla, Allyson; Buchhave, Lars A.; Esquerdo, Gilbert A.; Bramich, D. M.; Pyrzas, Stylianos; Vilchez, Nicolas P. E.; Mancini, Luigi; Southworth, John; Evans, Daniel F.; Henning, Thomas; Ciceri, Simona

    2017-04-01

    We report the discovery of Qatar-3b, Qatar-4b, and Qatar-5b, three new transiting planets identified by the Qatar Exoplanet Survey. The three planets belong to the hot Jupiter family, with orbital periods of {P}{{Q}3{{b}}} = 2.50792 days, {P}{{Q}4{{b}}} = 1.80539 days, and {P}{{Q}5{{b}}} = 2.87923 days. Follow-up spectroscopic observations reveal the masses of the planets to be {M}{{Q}3{{b}}} = 4.31 ± 0.47 {M}{{J}}, {M}{{Q}4{{b}}} = 6.10 ± 0.54 {M}{{J}}, and {M}{{Q}5{{b}}} = 4.32 ± 0.18 {M}{{J}}, while model fits to the transit light curves yield radii of {R}{{Q}3{{b}}} = 1.096 ± 0.14 {R}{{J}}, {R}{{Q}4{{b}}} = 1.135 ± 0.11 {R}{{J}}, and {R}{{Q}5{{b}}} = 1.107 ± 0.064 {R}{{J}}. The host stars are low-mass main sequence stars with masses and radii M Q3 = 1.145 ± 0.064 M ⊙, M Q4 = 0.896 ± 0.048 M ⊙, M Q5 = 1.128 ± 0.056 M ⊙ and R Q3 = 1.272 ± 0.14 R ⊙, R Q4 = 0.849 ± 0.063 R ⊙, and R Q5 = 1.076 ± 0.051 R ⊙ for Qatar-3, 4, and 5 respectively. The V magnitudes of the three host stars are V Q3 = 12.88, V Q4 = 13.60, and V Q5 = 12.82. All three new planets can be classified as heavy hot Jupiters (M > 4 M J).

  3. A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein.

    PubMed

    Guo, Fang; Wu, Shuo; Julander, Justin; Ma, Julia; Zhang, Xuexiang; Kulp, John; Cuconati, Andrea; Block, Timothy M; Du, Yanming; Guo, Ju-Tao; Chang, Jinhong

    2016-09-21

    Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past two decades, which highlights the pressing need for antiviral therapeutics. In a high throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound, which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV infected cultures with 2 μM of BDAA reduced the virion production by greater than 2 logs, the compound is not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug resistant viruses revealed that substitution of proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine or alanine confers YFV resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, substitution of P219 with glycine confers BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 localizes at the endoplasmic reticulum lumen side of the fifth putative trans-membrane domain of NS4B and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed important role and structural basis for NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs and attenuated viral infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever.

  4. Molecular docking NS4B of DENV 1-4 with known bioactive phyto-chemicals

    PubMed Central

    Paul, Anubrata; Vibhuti, Arpana; Raj, Samuel

    2016-01-01

    Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS4B is a target for designing specific antivirals due to its importance in viral replication. Medicinal plants have been a savior for dengue virus as they consist of a class of phytochemicals having anti-viral activity and can pose a new approach ofstrong drug against viruses. The present study analyzes the activity of compounds against NS4B of DENV (1-4) serotypes. In this study Catechin, Cianidanol, Epicatechin, Eupatoretin, Glabranin, Laurifolin, DL-Catechin, astherapeutic agents were filtered by using Lipinski rule’s five and the drug-likeness property of these agents were used for assessment of pharmacological properties. The molecular docking results presented the 2-D structures of bioactive complex, which interacted with especially conserved residues of target domains. Interestingly, we find the Catechin, Laurifolin, Cianidanol have highest binding energy against NS4B in DENV-1,2,4 which is evident by the formation of more hydrogen bonds with the amino acid residues at the binding site of the receptor. Our results revealed that the bioactive compound, especially Catechin has significant anti-dengue activities. In addition, this study may be helpful in further experimental investigations. PMID:28149049

  5. DISTRIBUTION OF CH{sub 3}OH IN NGC 1333 IRAS4B

    SciTech Connect

    Sakai, Nami; Yamamoto, Satoshi; Ceccarelli, Cecilia; Bottinelli, Sandrine; Sakai, Takeshi

    2012-07-20

    Distribution of the CH{sub 3}OH (J{sub K} = 2{sub K}-1{sub K}, 96.7 GHz) emission has been investigated toward NGC 1333 IRAS4B, a low-mass Class 0 protostar which harbors a hot corino, with Nobeyama Millimeter Array. The CH{sub 3}OH emission is found to be prominent in the shocked region caused by an impact of the molecular outflow from the protostars. The direction of the outflow which is responsible for the shock seems to be opposite to that of a compact outflow known previously in the CO (J = 2-1), HCN (J = 1-0), H{sub 2}CO (3{sub 12}-2{sub 11}), and CH{sub 3}OH (J{sub K} = 7{sub K}-6{sub K}) emissions, whereas it is the same as that of the faint second outflow found in the H{sub 2}CO emission. This double outflow structure can be interpreted most naturally by the existence of more than two protostars in IRAS4B. On the other hand, a centrally condensed component associated apparently with IRAS4B cannot be recognized in our CH{sub 3}OH observation. Our observation suggests that, in this source, the CH{sub 3}OH (J{sub K} 2{sub K}-1{sub K}) emission preferentially traces the shocked regions rather than the hot corino around the protostar.

  6. HATS-4b: A dense hot Jupiter transiting a super metal-rich G star

    SciTech Connect

    Jordán, Andrés; Brahm, Rafael; Rabus, M.; Suc, V.; Espinoza, N.; Bakos, G. Á.; Penev, K.; Hartman, J. D.; Csubry, Z.; Bhatti, W.; De Val Borro, M.; Bayliss, D.; Zhou, G.; Mancini, L.; Mohler-Fischer, M.; Ciceri, S.; Csák, B.; Henning, T.; Sato, B.; Buchhave, L.; and others

    2014-08-01

    We report the discovery by the HATSouth survey of HATS-4b, an extrasolar planet transiting a V = 13.46 mag G star. HATS-4b has a period of P ≈ 2.5167 days, mass of M{sub p} ≈ 1.32 M {sub Jup}, radius of R{sub p} ≈ 1.02 R {sub Jup}, and density of ρ {sub p} = 1.55 ± 0.16 g cm{sup –3} ≈1.24 ρ{sub Jup}. The host star has a mass of 1.00 M {sub ☉}, a radius of 0.92 R {sub ☉}, and a very high metallicity [Fe/H]=0.43 ± 0.08. HATS-4b is among the densest known planets with masses between 1 and 2 M {sub J} and is thus likely to have a significant content of heavy elements of the order of 75 M {sub ⊕}. In this paper we present the data reduction, radial velocity measurements, and stellar classification techniques adopted by the HATSouth survey for the CORALIE spectrograph. We also detail a technique for simultaneously estimating vsin i and macroturbulence using high resolution spectra.

  7. Inhibition of HCV replication by humanized-single domain transbodies to NS4B.

    PubMed

    Glab-Ampai, Kittirat; Malik, Aijaz Ahmad; Chulanetra, Monrat; Thanongsaksrikul, Jeeraphong; Thueng-In, Kanyarat; Srimanote, Potjanee; Tongtawe, Pongsri; Chaicumpa, Wanpen

    2016-08-05

    NS4B of hepatitis C virus (HCV) initiates membrane web formation, binds RNA and other HCV proteins for viral replication complex (RC) formation, hydrolyses NTP, and inhibits innate anti-viral immunity. Thus, NS4B is an attractive target of a novel anti-HCV agent. In this study, humanized-nanobodies (VHs/VHHs) that bound to recombinant NS4B were produced by means of phage display technology. The nanobodies were linked molecularly to a cell penetrating peptide, penetratin (PEN), for making them cell penetrable (become transbodies). Human hepatic (Huh7) cells transfected with HCV JFH1-RNA that were treated with transbodies from four Escherichia coli clones (PEN-VHH7, PEN-VHH9, PEN-VH33, and PEN-VH43) had significant reduction of HCV RNA amounts in their culture fluids and intracellularly when compared to the transfected cells treated with control transbody and medium alone. The results were supported by the HCV foci assay. The transbody treated-transfected cells also had upregulation of the studied innate cytokine genes, IRF3, IFNβ and IL-28b. The transbodies have high potential for testing further as a novel anti-HCV agent, either alone, adjunct of existing anti-HCV agents/remedies, or in combination with their cognates specific to other HCV enzymes/proteins.

  8. (4R,4aS,4bS,7R,10aR)-4-Hy­droxy-4a,7-dimethyl-2-(propan-2-yl)-1,4,4a,4b,5,6,7,8,10,10a-deca­hydro­phenanthren-1-one

    PubMed Central

    Caracelli, Ignez; Zukerman-Schpector, Julio; Machado, André T. Lousada; Brocksom, Timothy J.; Ferreira, M. Lúcia; Tiekink, Edward R. T.

    2011-01-01

    In the title compound, C19H28O2, the A ring adopts a chair conformation, and each of the B and C rings adopts a distorted half-chair conformation with the methine C atom in the CH2C(H)C(=O) residue, common to both rings, lying 0.6397 (19) and 0.6328 (18) Å out of the approximate plane defined by the remaining five C atoms (r.m.s. deviations = 0.0791 and 0.0901 Å for rings B and C, respectively). Helical supra­molecular chains along the a axis mediated by hy­droxy–carbonyl O—H⋯O hydrogen bonds feature in the crystal packing. PMID:22220138

  9. (4R*,4aS*,4bS*,5R*,10aR*)-4-Hy­droxy-4a,5-dimethyl-2-(propan-2-yl)-1,4,4a,4b,5,6,7,8,10,10a-deca­hydro­phenan­thren-1-one

    PubMed Central

    Caracelli, Ignez; Zukerman-Schpector, Julio; Machado, André T. Lousada; Brocksom, Timothy J.; Ferreira, M. Lúcia; Tiekink, Edward R. T.

    2011-01-01

    In the title compound, C19H28O2, the A ring adopts a chair conformation. Both the B and C rings adopt envelope conformations with the C atoms common to both rings and adjacent to the carbonyl and hydroxyl groups, respectively, lying 0.604 (3) and 0.634 (3) Å out of the mean planes defined by the remaining five C atoms of rings B and C, respectively (r.m.s. deviations = 0.0100 and 0.0157 Å, respectively). The formation of linear supra­molecular C(7) chains along the a axis mediated by hy­droxy-O—H⋯O(carbon­yl) hydrogen bonds is the most prominent feature of the crystal packing. PMID:22199834

  10. Chlorinated pesticides (2,4-D and DDT) biodegradation at high concentrations using immobilized Pseudomonas fluorescens.

    PubMed

    Santacruz, Germán; Bandala, Erick R; Torres, Luis G

    2005-01-01

    Degradation of two chlorinated pesticides (2,4-D and DDT) using a 54-mL glass column packed with tezontle (a low-cost basaltic scoria) was tested. Bacteria were cultured in YPG (yeast, peptone, and glucose) liquid medium at 32 degrees C. The rich medium was pumped during 24 h through the column to inoculate it. Later, the wasted medium was discharged and the pesticide added. Optical densities, TOC, and pesticide concentration were determined. Pesticide removals for 2,4-D (with initial concentration between 100 and 500 mg/L) were about 99%. DDT removal (at initial concentration of up to 150 mg/L) was as high as 55-99%. TOC removals for 2,4-D was in the 36-87% interval, whereas for DDT they were as high as 36-78%.

  11. Live 4D optical coherence tomography for early embryonic mouse cardiac phenotyping

    NASA Astrophysics Data System (ADS)

    Lopez, Andrew L.; Wang, Shang; Larin, Kirill V.; Overbeek, Paul A.; Larina, Irina V.

    2016-03-01

    Studying embryonic mouse development is important for our understanding of normal human embryogenesis and the underlying causes of congenital defects. Our research focuses on imaging early development in the mouse embryo to specifically understand cardiovascular development using optical coherence tomography (OCT). We have previously developed imaging approaches that combine static embryo culture, OCT imaging and advanced image processing to visualize the whole live mouse embryos and obtain 4D (3D+time) cardiodynamic datasets with cellular resolution. Here, we present the study of using 4D OCT for dynamic imaging of early embryonic heart in live mouse embryos to assess mutant cardiac phenotypes during development, including a cardiac looping defect. Our results indicate that the live 4D OCT imaging approach is an efficient phenotyping tool that can reveal structural and functional cardiac defects at very early stages. Further studies integrating live embryonic cardiodynamic phenotyping with molecular and genetic approaches in mouse mutants will help to elucidate the underlying signaling defects.

  12. A practical introduction to the hemodynamic analysis of the cardiovascular system with 4D Flow MRI.

    PubMed

    Pineda Zapata, J A; Delgado de Bedout, J A; Rascovsky Ramírez, S; Bustamante, C; Mesa, S; Calvo Betancur, V D

    2014-01-01

    The 4D Flow MRI technique provides a three-dimensional representation of blood flow over time, making it possible to evaluate the hemodynamics of the cardiovascular system both qualitatively and quantitatively. In this article, we describe the application of the 4D Flow technique in a 3T scanner; in addition to the technical parameters, we discuss the advantages and limitations of the technique and its possible clinical applications. We used 4D Flow MRI to study different body areas (chest, abdomen, neck, and head) in 10 volunteers. We obtained 3D representations of the patterns of flow and quantitative hemodynamic measurements. The technique makes it possible to evaluate the pattern of blood flow in large and midsize vessels without the need for exogenous contrast agents.

  13. Proximal femoral focal deficiency of the fetus - early 3D/4D prenatal ultrasound diagnosis.

    PubMed

    Kudla, Marek J; Beczkowska-Kielek, Aleksandra; Kutta, Katarzyna; Partyka-Lasota, Justyna

    2016-09-01

    Proximal Femoral Focal Deficiency (PFFD) is a rare congenital syndrome of unknown etiology. Additional disorders can be present up to 70% of PFFD cases. Management (including termination) depends on the severity of the malformation. We present a case of a 32-year-old woman referred for routine ultrasound examination in the 12th week of pregnancy. Detailed 3D/4D evaluation revealed asymmetry of lower limbs and diagnosis of isolated PFFD was established. Parents were fully informed and decided to continue the pregnancy. We stress here the importance of early 3D/4D ultrasound diagnosis. Our paper presents the earliest case where the diagnosis of PFFD was established with 3D/4D ultrasound.

  14. X-ray emissions in 3d, 4d, and 5d ranges for uranium ions

    SciTech Connect

    Bonnelle, C.; Jonnard, P.; Barre, C.; Giorgi, G.; Bruneau, J.

    1997-05-01

    Radiative decay of nd{sup {minus}1}5f{sup m+1} excited states in UO{sub 2} induced by electron collisions is studied theoretically and experimentally. Energies, transition probabilities, and photoexcitation cross sections for the relevant configurations of U{sup 4+} are calculated by using the multiconfiguration Dirac-Fock method. Experimental observations are made in the 4d range. Direct recombination of the excited 5f electron to the 4d hole and 4d-6p emission in the presence of the spectator excited 5f electron are observed. From the theoretical results, the spectra are simulated and compared to the observed spectra in the three nd regions. The agreement is correct and describes the evolution of the coupling scheme in the nd{sup {minus}1}5f{sup 3} excited states from n=3 to n=5. {copyright} {ital 1997} {ital The American Physical Society}

  15. Magnetic dipole transitions in 4d{sup N} configurations of tungsten ions

    SciTech Connect

    Jonauskas, V.; Kisielius, R.; Kyniene, A.; Kucas, S.; Norrington, P. H.

    2010-01-15

    Magnetic dipole transitions between the levels of ground 4d{sup N} configurations of tungsten ions were analyzed by employing a large basis of interacting configurations. Previously introduced configuration interaction strength between two configurations was used to determine the configurations with the largest contribution to wave functions of atomic states for the considered configurations. Collisional-radiative modeling was performed for the levels of the ground configuration coupled through electric dipole transitions with 4p{sup 5}4d{sup N+1} and 4d{sup N-1}4f configurations. New identification of some lines observed in the electron-beam ion trap plasma was proposed based on calculations in which wavelength convergence was reached.

  16. SU-E-T-300: Dosimetric Comparision of 4D Radiation Therapy and 3D Radiation Therapy for the Liver Tumor Based On 4D Medical Image

    SciTech Connect

    Ma, C; Yin, Y

    2015-06-15

    Purpose: The purpose of this work was to determine the dosimetric benefit to normal tissues by tracking liver tumor dose in four dimensional radiation therapy (4DRT) on ten phases of four dimensional computer tomagraphy(4DCT) images. Methods: Target tracking each phase with the beam aperture for ten liver cancer patients were converted to cumulative plan and compared to the 3D plan with a merged target volume based on 4DCT image in radiation treatment planning system (TPS). The change in normal tissue dose was evaluated in the plan by using the parameters V5, V10, V15, V20,V25, V30, V35 and V40 (volumes receiving 5, 10, 15, 20, 25, 30, 35 and 40Gy, respectively) in the dose-volume histogram for the liver; mean dose for the following structures: liver, left kidney and right kidney; and maximum dose for the following structures: bowel, duodenum, esophagus, stomach and heart. Results: There was significant difference between 4D PTV(average 115.71cm3 )and ITV(169.86 cm3). When the planning objective is 95% volume of PTV covered by the prescription dose, the mean dose for the liver, left kidney and right kidney have an average decrease 23.13%, 49.51%, and 54.38%, respectively. The maximum dose for bowel, duodenum,esophagus, stomach and heart have an average decrease 16.77%, 28.07%, 24.28%, 4.89%, and 4.45%, respectively. Compared to 3D RT, radiation volume for the liver V5, V10, V15, V20, V25, V30, V35 and V40 by using the 4D plans have a significant decrease(P≤0.05). Conclusion: The 4D plan method creates plans that permit better sparing of the normal structures than the commonly used ITV method, which delivers the same dosimetric effects to the target.

  17. Vacuolar protein sorting 4B regulates apoptosis of intestinal epithelial cells via p38 MAPK in Crohn's disease.

    PubMed

    Zhang, Dongmei; Wang, Liang; Yan, Lijun; Miao, Xianjing; Gong, Chen; Xiao, Min; Ni, Runzhou; Tang, Qiyun

    2015-02-01

    Vacuolar protein sorting 4B (VPS4B), a member of ATPase family proteins, reportedly possesses multiple biological functions, such as regulating the development of breast cancer and non-small-cell lung cancer, participating in Parkinson's disease, and modulating neuronal apoptosis after cerebral ischemia. However, its expression and potential functions in Crohn's disease (CD) has not been understood. In this study, we reported for the first time that VPS4B was over-expressed in intestinal epithelial cell (IECs) of patients with CD. In TNBS-induced mouse colitis models, we observed the up-regulation of VPS4B was accompanied with the elevated levels of IEC apoptotic markers (active caspase-3 and cleaved PARP) and phosphorylated p38 in colitis IECs. Co-localization of VPS4B and active caspase-3 in IECs of the TNBS group further indicated the possible involvement of VPS4B in IEC apoptosis. Employing the TNF-α-treated HT29 cells as an in vitro IEC apoptosis model, we confirmed the positive correlation of VPS4B with caspase-dependent cellular apoptosis. Knocking VPS4B down by siRNA significantly alleviated TNF-α-induced p38 phosphorylation and cellular apoptosis in HT29 cells. Taken together, our findings suggested that VPS4B may facilitate the IEC apoptosis in CD via p38 MAPK signaling pathway.

  18. The 2D:4D-Ratio and Neuroticism Revisited: Empirical Evidence from Germany and China

    PubMed Central

    Sindermann, Cornelia; Li, Mei; Sariyska, Rayna; Lachmann, Bernd; Duke, Éilish; Cooper, Andrew; Warneck, Lidia; Montag, Christian

    2016-01-01

    The 2D:4D-Ratio, as an indirect measure of the fetal testosterone to estradiol ratio, is potentially very important for understanding and explaining different personality traits. It was the aim of the present study to replicate the findings from Fink et al. (2004) about the relation between individual differences in 2D:4D-Ratios and the Five Factor Model in different cultural groups. Therefore a sample of n = 78 Chinese and n = 370 German participants was recruited. Every participant provided hand scans of both hands, from which 2D:4D-Ratios were computed. Moreover, all participants filled in the NEO Five Factor Inventory (NEO-FFI). Significant sex differences were found for ratios of both hands in the expected direction, with females showing higher ratios than males. With respect to links between personality and the digit ratio, a positive association was observed between 2D:4D-Ratio and Neuroticism in females, as shown in the earlier study. These findings were observed in both female subsamples from China and Germany, as well as in the full sample of participants. But in contrast to the results for the whole and the German female sample, where 2D:4D-Ratio of both hands were related to Neuroticism, in the Chinese female sample only left hand 2D:4D-Ratio was significantly and positively related to Neuroticism. There were no significant correlations found in any of the male samples. Thus, prenatal exposure to sex steroids appears to influence the personality factor Neuroticism in females specifically. This finding potentially has implications for mental health, as Neuroticism has been shown to be a risk factor for various forms of psychopathology. PMID:27375513

  19. Advances in 4D Treatment Planning for Scanned Particle Beam Therapy — Report of Dedicated Workshops

    PubMed Central

    Bert, Christoph; Graeff, Christian; Riboldi, Marco; Nill, Simeon; Baroni, Guido; Knopf, Antje-Christin

    2014-01-01

    We report on recent progress in the field of mobile tumor treatment with scanned particle beams, as discussed in the latest editions of the 4D treatment planning workshop. The workshop series started in 2009, with about 20 people from 4 research institutes involved, all actively working on particle therapy delivery and development. The first workshop resulted in a summary of recommendations for the treatment of mobile targets, along with a list of requirements to apply these guidelines clinically. The increased interest in the treatment of mobile tumors led to a continuously growing number of attendees: the 2012 edition counted more than 60 participants from 20 institutions and commercial vendors. The focus of research discussions among workshop participants progressively moved from 4D treatment planning to complete 4D treatments, aiming at effective and safe treatment delivery. Current research perspectives on 4D treatments include all critical aspects of time resolved delivery, such as in-room imaging, motion detection, beam application, and quality assurance techniques. This was motivated by the start of first clinical treatments of hepato cellular tumors with a scanned particle beam, relying on gating or abdominal compression for motion mitigation. Up to date research activities emphasize significant efforts in investigating advanced motion mitigation techniques, with a specific interest in the development of dedicated tools for experimental validation. Potential improvements will be made possible in the near future through 4D optimized treatment plans that require upgrades of the currently established therapy control systems for time resolved delivery. But since also these novel optimization techniques rely on the validity of the 4DCT, research focusing on alternative 4D imaging technique, such as MRI based 4DCT generation will continue. PMID:24354749

  20. The 2D:4D-Ratio and Neuroticism Revisited: Empirical Evidence from Germany and China.

    PubMed

    Sindermann, Cornelia; Li, Mei; Sariyska, Rayna; Lachmann, Bernd; Duke, Éilish; Cooper, Andrew; Warneck, Lidia; Montag, Christian

    2016-01-01

    The 2D:4D-Ratio, as an indirect measure of the fetal testosterone to estradiol ratio, is potentially very important for understanding and explaining different personality traits. It was the aim of the present study to replicate the findings from Fink et al. (2004) about the relation between individual differences in 2D:4D-Ratios and the Five Factor Model in different cultural groups. Therefore a sample of n = 78 Chinese and n = 370 German participants was recruited. Every participant provided hand scans of both hands, from which 2D:4D-Ratios were computed. Moreover, all participants filled in the NEO Five Factor Inventory (NEO-FFI). Significant sex differences were found for ratios of both hands in the expected direction, with females showing higher ratios than males. With respect to links between personality and the digit ratio, a positive association was observed between 2D:4D-Ratio and Neuroticism in females, as shown in the earlier study. These findings were observed in both female subsamples from China and Germany, as well as in the full sample of participants. But in contrast to the results for the whole and the German female sample, where 2D:4D-Ratio of both hands were related to Neuroticism, in the Chinese female sample only left hand 2D:4D-Ratio was significantly and positively related to Neuroticism. There were no significant correlations found in any of the male samples. Thus, prenatal exposure to sex steroids appears to influence the personality factor Neuroticism in females specifically. This finding potentially has implications for mental health, as Neuroticism has been shown to be a risk factor for various forms of psychopathology.

  1. Prevention of alveolar bone loss in an osteoporotic animal model via interference of semaphorin 4d.

    PubMed

    Zhang, Y; Wei, L; Miron, R J; Zhang, Q; Bian, Z

    2014-11-01

    Semaphorin 4d (Sema4d) has been proposed as a novel target gene for the treatment of osteoporosis. Recently, we fabricated a site-specific bone-targeting system from polymeric nanoparticles that demonstrates an ability to prevent bone loss in an osteoporotic model by interfering with Sema4d gene expression using small interference RNA (siRNA) molecules. The aim of the present investigation was to determine the effects of this targeting system on the periodontium, an area of high bone turnover. We demonstrated, by single photon emission computed tomography, that intravenous injection of this molecule in ovariectomized Balb/C mice is able to target alveolar bone peaking 4 hr post-injection. We then compared, by histological analysis, the bone volume/total volume (BV/TV), alveolar bone height loss, immunohistochemical expression of Sema4d, and total number of osteoclasts in mandibular alveolar bone. Four treatment modalities were compared as follows: (1) sham-operated, (2) OVX-operated, (3) OVX+estrogen replacement therapy, and (4) OVX+siRNA-Sema4d animals. The results from the present study demonstrate that an osteoporotic condition significantly increases alveolar bone height loss, and that the therapeutic effects via bone-targeting systems featuring interference of Sema4d are able to partly counteract alveolar bone loss caused by osteoporosis. While the future therapeutic demand for the large number of patients suffering from osteoporosis faces many challenges, we demonstrate within the present study an effective drug-delivery moiety with anabolic effects on the bone remodeling cycle able to locate and target alveolar bone regeneration.

  2. Genome-wide Association Analysis Identifies PDE4D as an Asthma-Susceptibility Gene

    PubMed Central

    Himes, Blanca E.; Hunninghake, Gary M.; Baurley, James W.; Rafaels, Nicholas M.; Sleiman, Patrick; Strachan, David P.; Wilk, Jemma B.; Willis-Owen, Saffron A.G.; Klanderman, Barbara; Lasky-Su, Jessica; Lazarus, Ross; Murphy, Amy J.; Soto-Quiros, Manuel E.; Avila, Lydiana; Beaty, Terri; Mathias, Rasika A.; Ruczinski, Ingo; Barnes, Kathleen C.; Celedón, Juan C.; Cookson, William O.C.; Gauderman, W. James; Gilliland, Frank D.; Hakonarson, Hakon; Lange, Christoph; Moffatt, Miriam F.; O'Connor, George T.; Raby, Benjamin A.; Silverman, Edwin K.; Weiss, Scott T.

    2009-01-01

    Asthma, a chronic airway disease with known heritability, affects more than 300 million people around the world. A genome-wide association (GWA) study of asthma with 359 cases from the Childhood Asthma Management Program (CAMP) and 846 genetically matched controls from the Illumina ICONdb public resource was performed. The strongest region of association seen was on chromosome 5q12 in PDE4D. The phosphodiesterase 4D, cAMP-specific (phosphodiesterase E3 dunce homolog, Drosophila) gene (PDE4D) is a regulator of airway smooth-muscle contractility, and PDE4 inhibitors have been developed as medications for asthma. Allelic p values for top SNPs in this region were 4.3 × 10−07 for rs1588265 and 9.7 × 10−07 for rs1544791. Replications were investigated in ten independent populations with different ethnicities, study designs, and definitions of asthma. In seven white and Hispanic replication populations, two PDE4D SNPs had significant results with p values less than 0.05, and five had results in the same direction as the original population but had p values greater than 0.05. Combined p values for 18,891 white and Hispanic individuals (4,342 cases) in our replication populations were 4.1 × 10−04 for rs1588265 and 9.2 × 10−04 for rs1544791. In three black replication populations, which had different linkage disequilibrium patterns than the other populations, original findings were not replicated. Further study of PDE4D variants might lead to improved understanding of the role of PDE4D in asthma pathophysiology and the efficacy of PDE4 inhibitor medications. PMID:19426955

  3. Respiratory motion correction in 4D-PET by simultaneous motion estimation and image reconstruction (SMEIR)

    NASA Astrophysics Data System (ADS)

    Kalantari, Faraz; Li, Tianfang; Jin, Mingwu; Wang, Jing

    2016-08-01

    In conventional 4D positron emission tomography (4D-PET), images from different frames are reconstructed individually and aligned by registration methods. Two issues that arise with this approach are as follows: (1) the reconstruction algorithms do not make full use of projection statistics; and (2) the registration between noisy images can result in poor alignment. In this study, we investigated the use of simultaneous motion estimation and image reconstruction (SMEIR) methods for motion estimation/correction in 4D-PET. A modified ordered-subset expectation maximization algorithm coupled with total variation minimization (OSEM-TV) was used to obtain a primary motion-compensated PET (pmc-PET) from all projection data, using Demons derived deformation vector fields (DVFs) as initial motion vectors. A motion model update was performed to obtain an optimal set of DVFs in the pmc-PET and other phases, by matching the forward projection of the deformed pmc-PET with measured projections from other phases. The OSEM-TV image reconstruction was repeated using updated DVFs, and new DVFs were estimated based on updated images. A 4D-XCAT phantom with typical FDG biodistribution was generated to evaluate the performance of the SMEIR algorithm in lung and liver tumors with different contrasts and different diameters (10-40 mm). The image quality of the 4D-PET was greatly improved by the SMEIR algorithm. When all projections were used to reconstruct 3D-PET without motion compensation, motion blurring artifacts were present, leading up to 150% tumor size overestimation and significant quantitative errors, including 50% underestimation of tumor contrast and 59% underestimation of tumor uptake. Errors were reduced to less than 10% in most images by using the SMEIR algorithm, showing its potential in motion estimation/correction in 4D-PET.

  4. Clinical Utility of 4D FDG-PET/CT Scans in Radiation Treatment Planning

    SciTech Connect

    Aristophanous, Michalis; Sher, David J.; Allen, Aaron M.; Larson, Elysia; Chen, Aileen B.

    2012-01-01

    Purpose: The potential role of four-dimensional (4D) positron emission tomography (PET)/computed tomography (CT) in radiation treatment planning, relative to standard three-dimensional (3D) PET/CT, was examined. Methods and Materials: Ten patients with non-small-cell lung cancer had sequential 3D and 4D [{sup 18}F]fluorodeoxyglucose PET/CT scans in the treatment position prior to radiation therapy. The gross tumor volume and involved lymph nodes were contoured on the PET scan by use of three different techniques: manual contouring by an experienced radiation oncologist using a predetermined protocol; a technique with a constant threshold of standardized uptake value (SUV) greater than 2.5; and an automatic segmentation technique. For each technique, the tumor volume was defined on the 3D scan (VOL3D) and on the 4D scan (VOL4D) by combining the volume defined on each of the five breathing phases individually. The range of tumor motion and the location of each lesion were also recorded, and their influence on the differences observed between VOL3D and VOL4D was investigated. Results: We identified and analyzed 22 distinct lesions, including 9 primary tumors and 13 mediastinal lymph nodes. Mean VOL4D was larger than mean VOL3D with all three techniques, and the difference was statistically significant (p < 0.01). The range of tumor motion and the location of the tumor affected the magnitude of the difference. For one case, all three tumor definition techniques identified volume of moderate uptake of approximately 1 mL in the hilar region on the 4D scan (SUV maximum, 3.3) but not on the 3D scan (SUV maximum, 2.3). Conclusions: In comparison to 3D PET, 4D PET may better define the full physiologic extent of moving tumors and improve radiation treatment planning for lung tumors. In addition, reduction of blurring from free-breathing images may reveal additional information regarding regional disease.

  5. Impact of Petrophysical Experiments on Quantitative Interpretation of 4D Seismic Data at Ketzin, Germany

    NASA Astrophysics Data System (ADS)

    Ivanova, A.; Lueth, S.

    2015-12-01

    Petrophysical investigations for CCS concern relationships between physical properties of rocks and geophysical observations for understanding behavior of injected CO2 in a geological formation. In turn 4D seismic surveying is a proven tool for CO2 monitoring. At the Ketzin pilot site (Germany) 4D seismic data have been acquired by means of a baseline (pre-injection) survey in 2005 and monitor surveys in 2009 and 2012. At Ketzin CO2 was injected in supercritical state from 2008 to 2013 in a sandstone saline aquifer (Stuttgart Formation) at a depth of about 650 m. The 4D seismic data from Ketzin reflected a pronounced effect of this injection. Seismic forward modeling using results of petrophysical experiments on two core samples fromthe target reservoir confirmed that effects of the injected CO2 on the 4D seismic data are significant. The petrophysical data were used in that modeling in order to reflect changes due to the CO2 injection in acoustic parameters of the reservoir. These petrophysical data were further used for a successful quantitative interpretation of the 4D seismic data at Ketzin. Now logs from a well (drilled in 2012) penetrating the reservoir containing information about changes in the acoustic parameters of the reservoir due to the CO2 injection are available. These logs were used to estimate impact of the petrophysical data on the qualitative and quantitative interpretation of the 4D seismic data at Ketzin. New synthetic seismograms were computed using the same software and the same wavelet as the old ones apart from the only difference and namely the changes in the input acoustic parameters would not be affected with any petrophysical experiments anymore. Now these changes were put in computing directly from the logs. In turn the new modelled changes due to the injection in the newly computed seismograms do not include any effects of the petrophysical data anymore. Key steps of the quantitative and qualitative interpretation of the 4D seismic

  6. A hybrid reconstruction algorithm for fast and accurate 4D cone-beam CT imaging

    SciTech Connect

    Yan, Hao; Folkerts, Michael; Jiang, Steve B. E-mail: steve.jiang@UTSouthwestern.edu; Jia, Xun E-mail: steve.jiang@UTSouthwestern.edu; Zhen, Xin; Li, Yongbao; Pan, Tinsu; Cervino, Laura

    2014-07-15

    Purpose: 4D cone beam CT (4D-CBCT) has been utilized in radiation therapy to provide 4D image guidance in lung and upper abdomen area. However, clinical application of 4D-CBCT is currently limited due to the long scan time and low image quality. The purpose of this paper is to develop a new 4D-CBCT reconstruction method that restores volumetric images based on the 1-min scan data acquired with a standard 3D-CBCT protocol. Methods: The model optimizes a deformation vector field that deforms a patient-specific planning CT (p-CT), so that the calculated 4D-CBCT projections match measurements. A forward-backward splitting (FBS) method is invented to solve the optimization problem. It splits the original problem into two well-studied subproblems, i.e., image reconstruction and deformable image registration. By iteratively solving the two subproblems, FBS gradually yields correct deformation information, while maintaining high image quality. The whole workflow is implemented on a graphic-processing-unit to improve efficiency. Comprehensive evaluations have been conducted on a moving phantom and three real patient cases regarding the accuracy and quality of the reconstructed images, as well as the algorithm robustness and efficiency. Results: The proposed algorithm reconstructs 4D-CBCT images from highly under-sampled projection data acquired with 1-min scans. Regarding the anatomical structure location accuracy, 0.204 mm average differences and 0.484 mm maximum difference are found for the phantom case, and the maximum differences of 0.3–0.5 mm for patients 1–3 are observed. As for the image quality, intensity errors below 5 and 20 HU compared to the planning CT are achieved for the phantom and the patient cases, respectively. Signal-noise-ratio values are improved by 12.74 and 5.12 times compared to results from FDK algorithm using the 1-min data and 4-min data, respectively. The computation time of the algorithm on a NVIDIA GTX590 card is 1–1.5 min per phase

  7. Use of 4-D atmospheric models in the simulation of radiometric measurements

    NASA Technical Reports Server (NTRS)

    Chang, D. T.; Fowler, M. G.

    1973-01-01

    Atmospheric moisture data contained in the Global 4-D Atmospheric Models developed in previous studies were analyzed to establish regional differences. The regional values of precipitable water along latitudinal belts were compared with values derived from the corresponding atmospheric models defined in the U.S Standard Atmosphere Supplement. The effects of the differences between the 4-D Models and the Standard Atmosphere Models on radiometric computations in the infrared window and water vapor absorption band regions were evaluated using a standard computation model of radiation transfer through a cloudless atmosphere. The significance of these differences in simulation is discussed.

  8. Fast X-ray micro-CT for real-time 4D observation

    NASA Astrophysics Data System (ADS)

    Takano, H.; Yoshida, K.; Tsuji, T.; Koyama, T.; Tsusaka, Y.; Kagoshima, Y.

    2009-09-01

    Fast X-ray computed tomography (CT) system with sub-second order measurement for single CT acquisition has been developed. The system, consisting of a high-speed sample rotation stage and a high-speed X-ray camera, is constructed at synchrotron radiation beamline in order to utilize fully intense X-rays. A time-resolving CT movie (i.e. 4D CT) can be available by operating the fast CT system continuously. Real-time observation of water absorbing process of super-absorbent polymer (SAP) has been successfully performed with the 4D CT operation.

  9. [Free hand acquisition, reconstruction and visualization of 3D and 4D ultrasound].

    PubMed

    Sakas, G; Walter, S; Grimm, M; Richtscheid, M

    2000-03-01

    3D Ultrasound will find in the next years a wide popularity under the medical imaging applications. The method expands the well-known sonography on the third dimension, therefore it becomes possible to generate spatial 3D views of internal organs. It is further possible to display static (3D) as well as dynamic organs (4D, e.g. pulsating heart). The clarity of the three-dimensional presentation supports very effectively the navigation. In this article we review the upgrading of conventional ultrasound devices on 3D and 4D capabilities, as well as the display of the datasets by corresponding visualisation and filtering approaches.

  10. Exploring the relation between 4D and 5D BPS solutions

    NASA Astrophysics Data System (ADS)

    Behrndt, Klaus; Lopes Cardoso, Gabriel; Mahapatra, Swapna

    2006-01-01

    Based on recent proposals linking four and five-dimensional BPS solutions, we discuss the explicit dictionary between general stationary 4D and 5D supersymmetric solutions in N=2 supergravity theories with cubic prepotentials. All these solutions are completely determined in terms of the same set of harmonic functions and the same set of attractor equations. As an example, we discuss black holes and black rings in Gödel-Taub-NUT spacetime. Then we consider corrections to the 4D solutions associated with more general prepotentials and comment on analogous corrections on the 5D side.

  11. Four-dimensional (4D) tracking of high-temperature microparticles

    NASA Astrophysics Data System (ADS)

    Wang, Zhehui; Liu, Q.; Waganaar, W.; Fontanese, J.; James, D.; Munsat, T.

    2016-11-01

    High-speed tracking of hot and molten microparticles in motion provides rich information about burning plasmas in magnetic fusion. An exploding-wire apparatus is used to produce moving high-temperature metallic microparticles and to develop four-dimensional (4D) or time-resolved 3D particle tracking techniques. The pinhole camera model and algorithms developed for computer vision are used for scene calibration and 4D reconstructions. 3D positions and velocities are then derived for different microparticles. Velocity resolution approaches 0.1 m/s by using the local constant velocity approximation.

  12. Four-dimensional (4D) tracking of high-temperature microparticles

    SciTech Connect

    Wang, Zhehui; Liu, Qiuguang; Waganaar, Bill; Fontanese, John; James, David; Munsat, Tobin

    2016-07-08

    High-speed tracking of hot and molten microparticles in motion provides rich information about burning plasmas in magnetic fusion. An exploding-wire apparatus is used to produce moving high-temperature metallic microparticles and to develop four-dimensional (4D) or time-resolved 3D particle tracking techniques. The pinhole camera model and algorithms developed for computer vision are used for scene calibration and 4D reconstructions. 3D positions and velocities are then derived for different microparticles. As a result, velocity resolution approaches 0.1 m/s by using the local constant velocity approximation.

  13. Biomarker correlations of urinary 2,4-D levels in foresters: genomic instability and endocrine disruption.

    PubMed Central

    Garry, V F; Tarone, R E; Kirsch, I R; Abdallah, J M; Lombardi, D P; Long, L K; Burroughs, B L; Barr, D B; Kesner, J S

    2001-01-01

    Forest pesticide applicators constitute a unique pesticide use group. Aerial, mechanical-ground, and focal weed control by application of herbicides, in particular chlorophenoxy herbicides, yield diverse exposure scenarios. In the present work, we analyzed aberrations in G-banded chromosomes, reproductive hormone levels, and polymerase chain reaction-based V(D)J rearrangement frequencies in applicators whose exposures were mostly limited to chlorophenoxy herbicides. Data from appliers where chlorophenoxy use was less frequent were also examined. The biomarker outcome data were compared to urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) obtained at the time of maximum 2,4-D use. Further comparisons of outcome data were made to the total volume of herbicides applied during the entire pesticide-use season.Twenty-four applicators and 15 minimally exposed foresters (control) subjects were studied. Categorized by applicator method, men who used a hand-held, backpack sprayer in their applications showed the highest average level (453.6 ppb) of 2,4-D in urine. Serum luteinizing hormone (LH) values were correlated with urinary 2,4-D levels, but follicle-stimulating hormone and free and total testosterone were not. At the height of the application season; 6/7 backpack sprayers, 3/4 applicators who used multinozzle mechanical (boom) sprayers, 4/8 aerial applicators, and 2/5 skidder-radiarc (closed cab) appliers had two or more V(D)J region rearrangements per microgram of DNA. Only 5 of 15 minimally exposed (control) foresters had two or more rearrangements, and 3 of these 5 subjects demonstrated detectable levels of 2,4-D in the urine. Only 8/24 DNA samples obtained from the exposed group 10 months or more after their last chlorophenoxy use had two rearrangements per microgram of DNA, suggesting that the exposure-related effects observed were reversible and temporary. Although urinary 2,4-D levels were not correlated with chromosome aberration frequency, chromosome

  14. A method for deriving a 4D-interpolated balanced planning target for mobile tumor radiotherapy

    SciTech Connect

    Roland, Teboh; Hales, Russell; McNutt, Todd; Wong, John; Simari, Patricio; Tryggestad, Erik

    2012-01-15

    Purpose: Tumor control and normal tissue toxicity are strongly correlated to the tumor and normal tissue volumes receiving high prescribed dose levels in the course of radiotherapy. Planning target definition is, therefore, crucial to ensure favorable clinical outcomes. This is especially important for stereotactic body radiation therapy of lung cancers, characterized by high fractional doses and steep dose gradients. The shift in recent years from population-based to patient-specific treatment margins, as facilitated by the emergence of 4D medical imaging capabilities, is a major improvement. The commonly used motion-encompassing, or internal-target volume (ITV), target definition approach provides a high likelihood of coverage for the mobile tumor but inevitably exposes healthy tissue to high prescribed dose levels. The goal of this work was to generate an interpolated balanced planning target that takes into account both tumor coverage and normal tissue sparing from high prescribed dose levels, thereby improving on the ITV approach. Methods: For each 4DCT dataset, 4D deformable image registration was used to derive two bounding targets, namely, a 4D-intersection and a 4D-composite target which minimized normal tissue exposure to high prescribed dose levels and maximized tumor coverage, respectively. Through definition of an ''effective overlap volume histogram'' the authors derived an ''interpolated balanced planning target'' intended to balance normal tissue sparing from prescribed doses with tumor coverage. To demonstrate the dosimetric efficacy of the interpolated balanced planning target, the authors performed 4D treatment planning based on deformable image registration of 4D-CT data for five previously treated lung cancer patients. Two 4D plans were generated per patient, one based on the interpolated balanced planning target and the other based on the conventional ITV target. Plans were compared for tumor coverage and the degree of normal tissue sparing

  15. INPP4B is upregulated and functions as an oncogenic driver through SGK3 in a subset of melanomas

    PubMed Central

    Wilmott, James S.; Guo, Xiang Yun; Yan, Xu Guang; Wang, Chun Yan; Liu, Xiao Ying; Jin, Lei; Tseng, Hsin-Yi; Liu, Tao; Croft, Amanda; Hondermarck, Hubert; Scolyer, Richard A.; Jiang, Chen Chen; Zhang, Xu Dong

    2015-01-01

    Inositol polyphosphate 4-phosphatase type II (INPP4B) negatively regulates PI3K/Akt signalling and has a tumour suppressive role in some types of cancers. However, we have found that it is upregulated in a subset of melanomas. Here we report that INPP4B can function as an oncogenic driver through activation of serum- and glucocorticoid-regulated kinase 3 (SGK3) in melanoma. While INPP4B knockdown inhibited melanoma cell proliferation and retarded melanoma xenograft growth, overexpression of INPP4B enhanced melanoma cell and melanocyte proliferation and triggered anchorage-independent growth of melanocytes. Noticeably, INPP4B-mediated melanoma cell proliferation was not related to activation of Akt, but was mediated by SGK3. Upregulation of INPP4B in melanoma cells was associated with loss of miRNA (miR)-494 and/or miR-599 due to gene copy number reduction. Indeed, overexpression of miR-494 or miR-599 downregulated INPP4B, reduced SGK3 activation, and inhibited melanoma cell proliferation, whereas introduction of anti-miR-494 or anti-miR-599 upregulated INPP4B, enhanced SGK3 activation, and promoted melanoma cell proliferation. Collectively, these results identify upregulation of INPP4B as an oncogenic mechanism through activation of SGK3 in a subset of melanomas, with implications for targeting INPP4B and restoring miR-494 and miR-599 as novel approaches in the treatment of melanomas with high INPP4B expression. PMID:26573229

  16. 16 CFR 300.35 - Hearings under section 4(d) of the act.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Hearings under section 4(d) of the act. 300.35 Section 300.35 Commercial Practices FEDERAL TRADE COMMISSION REGULATIONS UNDER SPECIFIC ACTS OF CONGRESS RULES AND REGULATIONS UNDER THE WOOL PRODUCTS LABELING ACT OF 1939 General § 300.35 Hearings...

  17. Experimental investigation of irregular motion impact on 4D PET-based particle therapy monitoring

    NASA Astrophysics Data System (ADS)

    Tian, Y.; Stützer, K.; Enghardt, W.; Priegnitz, M.; Helmbrecht, S.; Bert, C.; Fiedler, F.

    2016-01-01

    Particle therapy positron emission tomography (PT-PET) is an in vivo and non-invasive imaging technique to monitor treatment delivery in particle therapy. The inevitable patient respiratory motion during irradiation causes artefacts and inaccurate activity distribution in PET images. Four-dimensional (4D) maximum likelihood expectation maximisation (4D MLEM) allows for a compensation of these effects, but has up to now been restricted to regular motion for PT-PET investigations. However, intra-fractional motion during treatment might differ from that during acquisition of the 4D-planning CT (e.g. amplitude variation, baseline drift) and therefore might induce inaccurate 4D PET reconstruction results. This study investigates the impact of different irregular analytical one-dimensional (1D) motion patterns on PT-PET imaging by means of experiments with a radioactive source and irradiated moving phantoms. Three sorting methods, namely phase sorting, equal amplitude sorting and event-based amplitude sorting, were applied to manage the PET list-mode data. The influence of these sorting methods on the motion compensating algorithm has been analysed. The event-based amplitude sorting showed a superior performance and it is applicable for irregular motions with  ⩽4 mm amplitude elongation and drift. For motion with 10 mm baseline drift, the normalised root mean square error was as high as 10.5% and a 10 mm range deviation was observed.

  18. Preoperative localization of hyperfunctioning parathyroid glands with 4D-CT.

    PubMed

    Lundstroem, Anke Katrin; Trolle, Waldemar; Soerensen, Christian Hjort; Myschetzky, Peter Sand

    2016-05-01

    Primary hyperparathyroidism (pHPT) is almost exclusively the result of a solitary parathyroid adenoma. In most cases, the affected gland can be surgically removed, but precise preoperative imaging is essential for adenoma localization prior to surgical intervention. In this study, we evaluated the diagnostic value of four-dimensional computed tomography (4D-CT) as a preoperative imaging tool in relation to the localization of pathologic parathyroid glands in patients with pHPT and negative sestamibi scans. This study included 43 consecutive patients with pHPT referred for parathyroidectomy at the Department of Head and Neck Surgery of Copenhagen University Hospital Rigshospitalet in 2011 and 2012. All patients had a 4D-CT performed prior to parathyroidectomy. CT localization of the suspected adenoma was correlated to the actual surgical findings and subsequent histological diagnosis was also available as references for the accuracy of this imaging tool. Hyperfunctioning parathyroid glands were found in 40 patients. 4D-CT identified 32 solitary hyperfunctioning parathyroid glands located on the correct side of the neck (PPV 76 %) and 21 located within the correct quadrant (PPV 49 %). Unilateral resection was performed in 72 % of patients due to the localization findings of preoperative imaging. 4D-CT can, therefore, be considered an effective method for the preoperative localization of parathyroid adenomas and is an important tool in surgical intervention for patients referred to parathyroidectomy.

  19. Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

    PubMed Central

    Yun, Sanguk; Budatha, Madhusudhan; Dahlman, James E.; Coon, Brian G.; Cameron, Ryan T.; Langer, Robert; Anderson, Daniel G.; Baillie, George; Schwartz, Martin A.

    2016-01-01

    Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin–collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets. PMID:27595237

  20. A design of a DICOM-RT-based tool box for nonrigid 4D dose calculation.

    PubMed

    Wong, Victy Y W; Baker, Colin R; Leung, T W; Tung, Stewart Y

    2016-03-08

    The study was aimed to introduce a design of a DICOM-RT-based tool box to facilitate 4D dose calculation based on deformable voxel-dose registration. The computational structure and the calculation algorithm of the tool box were explicitly discussed in the study. The tool box was written in MATLAB in conjunction with CERR. It consists of five main functions which allow a) importation of DICOM-RT-based 3D dose plan, b) deformable image registration, c) tracking voxel doses along breathing cycle, d) presentation of temporal dose distribution at different time phase, and e) derivation of 4D dose. The efficacy of using the tool box for clinical application had been verified with nine clinical cases on retrospective-study basis. The logistic and the robustness of the tool box were tested with 27 applications and the results were shown successful with no computational errors encountered. In the study, the accumulated dose coverage as a function of planning CT taken at end-inhale, end-exhale, and mean tumor position were assessed. The results indicated that the majority of the cases (67%) achieved maximum target coverage, while the planning CT was taken at the temporal mean tumor position and 56% at the end-exhale position. The comparable results to the literature imply that the studied tool box can be reliable for 4D dose calculation. The authors suggest that, with proper application, 4D dose calculation using deformable registration can provide better dose evaluation for treatment with moving target.

  1. ADULT AND CHILDREN'S EXPOSURE TO 2,4-D FROM MULTIPLE SOURCES AND PATHWAYS

    EPA Science Inventory

    In this study, we investigated the 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide exposures of 135 preschool-aged children and their adult caregivers at 135 homes in North Carolina (NC) and Ohio (OH). Participants were randomly recruited from six NC and six OH counties. Monito...

  2. Statistical 4D graphs for multi-organ abdominal segmentation from multiphase CT.

    PubMed

    Linguraru, Marius George; Pura, John A; Pamulapati, Vivek; Summers, Ronald M

    2012-05-01

    The interpretation of medical images benefits from anatomical and physiological priors to optimize computer-aided diagnosis applications. Diagnosis also relies on the comprehensive analysis of multiple organs and quantitative measures of soft tissue. An automated method optimized for medical image data is presented for the simultaneous segmentation of four abdominal organs from 4D CT data using graph cuts. Contrast-enhanced CT scans were obtained at two phases: non-contrast and portal venous. Intra-patient data were spatially normalized by non-linear registration. Then 4D convolution using population training information of contrast-enhanced liver, spleen and kidneys was applied to multiphase data to initialize the 4D graph and adapt to patient-specific data. CT enhancement information and constraints on shape, from Parzen windows, and location, from a probabilistic atlas, were input into a new formulation of a 4D graph. Comparative results demonstrate the effects of appearance, enhancement, shape and location on organ segmentation. All four abdominal organs were segmented robustly and accurately with volume overlaps over 93.6% and average surface distances below 1.1mm.

  3. 4D Ultrasound Tracking of Liver and its Verification for TIPS Guidance.

    PubMed

    Banerjee, Jyotirmoy; Klink, Camiel; Niessen, Wiro J; Moelker, Adriaan; van Walsum, Theo

    2016-01-01

    In this work we describe a 4D registration method for on the fly stabilization of ultrasound volumes for improving image guidance for transjugular intrahepatic portosystemic shunt (TIPS) interventions. The purpose of the method is to enable a continuous visualization of the relevant anatomical planes (determined in a planning stage) in a free breathing patient during the intervention. This requires registration of the planning information to the interventional images, which is achieved in two steps. In the first step tracking is performed across the streaming input. An approximate transformation between the reference image and the incoming image is estimated by composing the intermediate transformations obtained from the tracking. In the second step a subsequent registration is performed between the reference image and the approximately transformed incoming image to account for the accumulation of error. The two step approach helps in reducing the search range and is robust under rotation. We additionally present an approach to initialize and verify the registration. Verification is required when the reference image (containing planning information) is acquired in the past and is not part of the (interventional) 4D ultrasound sequence. The verification score will help in invalidating the registration outcome, for instance, in the case of insufficient overlap or information between the registering images due to probe motion or loss of contact, respectively. We evaluate the method over thirteen 4D US sequences acquired from eight subjects. A graphics processing unit implementation runs the 4D tracking at 9 Hz with a mean registration error of 1.7 mm.

  4. 4D numerical observer for lesion detection in respiratory-gated PET

    SciTech Connect

    Lorsakul, Auranuch; Li, Quanzheng; Ouyang, Jinsong; El Fakhri, Georges; Trott, Cathryn M.; Hoog, Christopher; Petibon, Yoann; Laine, Andrew F.

    2014-10-15

    Purpose: Respiratory-gated positron emission tomography (PET)/computed tomography protocols reduce lesion smearing and improve lesion detection through a synchronized acquisition of emission data. However, an objective assessment of image quality of the improvement gained from respiratory-gated PET is mainly limited to a three-dimensional (3D) approach. This work proposes a 4D numerical observer that incorporates both spatial and temporal informations for detection tasks in pulmonary oncology. Methods: The authors propose a 4D numerical observer constructed with a 3D channelized Hotelling observer for the spatial domain followed by a Hotelling observer for the temporal domain. Realistic {sup 18}F-fluorodeoxyglucose activity distributions were simulated using a 4D extended cardiac torso anthropomorphic phantom including 12 spherical lesions at different anatomical locations (lower, upper, anterior, and posterior) within the lungs. Simulated data based on Monte Carlo simulation were obtained using GEANT4 application for tomographic emission (GATE). Fifty noise realizations of six respiratory-gated PET frames were simulated by GATE using a model of the Siemens Biograph mMR scanner geometry. PET sinograms of the thorax background and pulmonary lesions that were simulated separately were merged to generate different conditions of the lesions to the background (e.g., lesion contrast and motion). A conventional ordered subset expectation maximization (OSEM) reconstruction (5 iterations and 6 subsets) was used to obtain: (1) gated, (2) nongated, and (3) motion-corrected image volumes (a total of 3200 subimage volumes: 2400 gated, 400 nongated, and 400 motion-corrected). Lesion-detection signal-to-noise ratios (SNRs) were measured in different lesion-to-background contrast levels (3.5, 8.0, 9.0, and 20.0), lesion diameters (10.0, 13.0, and 16.0 mm), and respiratory motion displacements (17.6–31.3 mm). The proposed 4D numerical observer applied on multiple-gated images was

  5. Can exposure to prenatal sex hormones (2D:4D) predict cognitive reflection?

    PubMed

    Bosch-Domènech, Antoni; Brañas-Garza, Pablo; Espín, Antonio M

    2014-05-01

    The Cognitive Reflection Test (CRT) is a test introduced by Frederick (2005). The task is designed to measure the tendency to override an intuitive response that is incorrect and to engage in further reflection that leads to the correct response. The consistent sex differences in CRT performance may suggest a role for prenatal sex hormones. A now widely studied putative marker for relative prenatal testosterone is the second-to-fourth digit ratio (2D:4D). This paper tests to what extent 2D:4D, as a proxy for the prenatal ratio of testosterone/estrogens, can predict CRT scores in a sample of 623 students. After controlling for sex, we observe that a lower 2D:4D (reflecting a relative higher exposure to testosterone) is significantly associated with a higher number of correct answers. The result holds for both hands' 2D:4Ds. In addition, the effect appears to be stronger for females than for males. We also control for patience and math proficiency, which are significantly related to performance in the CRT. But the effect of 2D:4D on performance in CRT is not reduced with these controls, implying that these variables are not mediating the relationship between digit ratio and CRT.

  6. Five cycles of selection for 2,4-D resistance in red clover

    Technology Transfer Automated Retrieval System (TEKTRAN)

    2,4-D and other auxin-like mode of action herbicides are used to control broadleaf weeds in pastures. Unfortunately such herbicides also kill beneficial forage legumes in pastures. Although transgene-conferred herbicide-resistance is utilized in some crops, it is unlikely that transgenic breeding ap...

  7. 4-D Cardiac MR Image Analysis: Left and Right Ventricular Morphology and Function

    PubMed Central

    Wahle, Andreas; Johnson, Ryan K.; Scholz, Thomas D.; Sonka, Milan

    2010-01-01

    In this study, a combination of active shape model (ASM) and active appearance model (AAM) was used to segment the left and right ventricles of normal and Tetralogy of Fallot (TOF) hearts on 4-D (3-D+time) MR images. For each ventricle, a 4-D model was first used to achieve robust preliminary segmentation on all cardiac phases simultaneously and a 3-D model was then applied to each phase to improve local accuracy while maintaining the overall robustness of the 4-D segmentation. On 25 normal and 25 TOF hearts, in comparison to the expert traced independent standard, our comprehensive performance assessment showed subvoxel segmentation accuracy, high overlap ratios, good ventricular volume correlations, and small percent volume differences. Following 4-D segmentation, novel quantitative shape and motion features were extracted using shape information, volume-time and dV/dt curves, analyzed and used for disease status classification. Automated discrimination between normal/TOF subjects achieved 90%–100% sensitivity and specificity. The features obtained from TOF hearts show higher variability compared to normal subjects, suggesting their potential use as disease progression indicators. The abnormal shape and motion variations of the TOF hearts were accurately captured by both the segmentation and feature characterization. PMID:19709962

  8. The Cry4B toxin of Bacillus thuringiensis subsp. israelensis kills Permethrin-resistant Anopheles gambiae, the principal vector of malaria.

    PubMed

    Ibrahim, Mohamed A; Griko, Natalya B; Bulla, Lee A

    2013-04-01

    Resurgence of malaria has been attributed, in part, to the development of resistance by Anopheles gambiae, a principal vector of the disease, to various insecticidal compounds such as Permethrin. Permethrin, a neurotoxicant, is widely used to impregnate mosquito nets. An alternative strategy to control mosquitoes is the use of Bacillus thuringiensis subsp. israelensis (Bti) because there is no observable resistance in the field to the bacterium. Bti kills mosquitoes by targeting cadherin molecules residing in the midgut epithelium of larvae of the insect. Cry proteins (Cry4A, Cry4B, Cry10A and Cry11A) produced by the bacterium during the sporulation phase of its life cycle bind to the cadherin molecules, which serve as receptors for the proteins. These Cry proteins have variable specificity to a variety of mosquitoes, including Culex and Aedes as well as Anopheles. Importantly, selective mosquitocidal action is occasioned by binding of the respective Cry toxins to cadherins distinctive to individual mosquito species. Differential fractionation of the four Cry proteins from a novel Bti isolate (M1) and cloning and expression of their genes in Escherichia coli revealed that Cry4B is the only Cry protein that exerts insecticidal action against An. gambiae. Indeed, it does so against a Permethrin-resistant strain of the mosquito. The other three Cry proteins are ineffective. Multiple sequence alignments of the four Cry proteins revealed a divergent sequence motif in the Cry4B toxin, which most likely determines binding of the toxin to its cognate receptor, BT-R3, in An. gambiae and to its specific toxicity. A model showing Cry4B toxin binding to BT-R3 is presented.

  9. New AP4B1 mutation in an African-American child associated with intellectual disability.

    PubMed

    Lamichhane, Dronacharya

    2013-12-01

    Prevalence of intellectual disability (ID) varies from 1-3%. Genetic causes of ID are being increasingly recognized. Although multiple mutations have been identified as a cause of syndromic ID, the genetic etiology of non-syndromic ID is poorly understood. However, more than 100 loci have been mapped that are associated with non-syndromic ID. There have been a couple of reports of AP4B1 gene mutation causing severe intellectual disability, absent speech, shy character, stereotypic laughter, muscular hypotonia that progressed to spastic paraplegia, microcephaly, foot deformity, decreased muscle mass of the lower limbs, inability to walk, and growth retardation. They had structural brain abnormalities and seizures. The reported cases were from Arab families where consanguineous marriage is common. We encountered an African-American child who presented first at the age of 24 mo with language difficulties and was subsequently found to have moderate to severe intellectual disability by standardized tests. Shortly, he started to have seizures and problems with ambulation. Although he was hypotonic at the time of presentation, legs slowly became spastic at the age of 4 yr. After a thorough work up, he was found to have heterozygous mutation in the AP4B1 gene along with another missense mutation in the same gene. There has been no report of mutation in this gene in the North American population. Although AP4B1 typically is said to be an autosomal recessive disease-causing gene, our case is different in the sense that there are two mutations in the same gene one of which has never been reported before and co-exists with a known disease causing mutation. Yet, the phenotype of the case closely resembles those published previously.

  10. Evaluation of the Elekta Symmetry ™ 4D IGRT system by using a moving lung phantom

    NASA Astrophysics Data System (ADS)

    Shin, Hun-Joo; Kim, Shin-Wook; Kay, Chul Seung; Seo, Jae-Hyuk; Lee, Gi-Woong; Kang, Ki-Mun; Jang, Hong Seok; Kang, Young-nam

    2015-07-01

    Purpose: 4D cone-beam computed tomography (CBCT) is a beneficial tool for the treatment of movable tumors because it can help us to understand where the tumors are actually located and it has a precise treatment plan. However, general CBCT images have a limitation in that they cannot perfectly perform a sophisticated registration. On the other hand, the Symmetry TM 4D image-guided radiation therapy (IGRT) system of Elekta offers a 4D CBCT registration option. In this study, we evaluated the usefulness of Symmetry TM . Method and Materials: Planning CT images of the CIRS moving lung phantom were acquired 4D multi-detector CT (MDCT), and the images were sorted as 10 phases from 0% phase to 90% phase. The thickness of the CT images was 1 mm. Acquired MDCT images were transferred to the contouring software, and a virtual target was generated. A one-arc volumetric-modulated arc therapy (VMAT) plan was performed by using the treatment planning system on the virtual target. Finally, the movement of the phantom was verified by using the XVI Symmetry TM system. Results: The physical movement of the CIRS moving lung phantom was ±10.0 mm in the superiorinferior direction, ±1.0 mm in the lateral direction, and ±2.5 mm in the anterior-posterior direction. The movement of the phantom was measured from the 4D MDCT registration as ±10.2 mm in the superior-inferior direction, ±0.9 mm in the lateral direction, and ±2.45 mm in the anterior-posterior direction. The movement of the phantom was measured from the SymmetryTM registration as ±10.1 mm in the superior-inferior direction, ±0.9 mm in the lateral direction, and ±2.4 mm in the anterior-posterior direction. Conclusion: We confirmed that 4D CBCT is a beneficial tool for the treatment of movable tumors, and that the 4D registration of SymmetryTM can increase the precision of the registration when a movable tumor is the target of radiation treatment.

  11. Erythrocyte C3d and C4d for Monitoring Disease Activity in Systemic Lupus Erythematosus

    PubMed Central

    Kao, Amy H.; Navratil, Jeannine S.; Ruffing, Margie J.; Liu, Chau-Ching; Hawkins, Douglas; McKinnon, Kathleen M.; Danchenko, Natalya; Ahearn, Joseph M.; Manzi, Susan

    2010-01-01

    Objective Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE. Methods The levels of E-C3d and E-C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Results At baseline, patients with SLE had higher median levels of E-C3d and E-C4d (P < 0.0001) in addition to higher within-patient and between-patient variability in both E-C3d and E-C4d when compared with the 2 non-SLE groups. In a longitudinal analysis of patients with SLE, E-C3d, E-C4d, serum C3, and anti–double-stranded DNA (anti-dsDNA) antibodies were each significantly associated with the SLAM and SELENA–SLEDAI. In a multivariable analysis, E-C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti-dsDNA antibodies; however, E-C3d was associated with the SLAM but not with the SELENA–SLEDAI. Conclusion Determining the levels of the erythrocyte-bound complement activation products, especially E-C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE. PMID:20187154

  12. Volumetric limiting spatial resolution analysis of four dimensional digital subtraction angiography (4D-DSA)

    NASA Astrophysics Data System (ADS)

    Davis, Brian; Oberstar, Erick; Royalty, Kevin; Schafer, Sebastian; Strother, Charles; Mistretta, Charles

    2015-03-01

    Static C-Arm CT 3D FDK baseline reconstructions (3D-DSA) are unable to provide temporal information to radiologists. 4D-DSA provides a time series of 3D volumes implementing a constrained image, thresholded 3D-DSA, reconstruction utilizing temporal dynamics in the 2D projections. Volumetric limiting spatial resolution (VLSR) of 4DDSA is quantified and compared to a 3D-DSA reconstruction using the same 3D-DSA parameters. Investigated were the effects of varying over significant ranges the 4D-DSA parameters of 2D blurring kernel size applied to the projection and threshold applied to the 3D-DSA when generating the constraining image of a scanned phantom (SPH) and an electronic phantom (EPH). The SPH consisted of a 76 micron tungsten wire encased in a 47 mm O.D. plastic radially concentric thin walled support structure. An 8-second/248-frame/198° scan protocol acquired the raw projection data. VLSR was determined from averaged MTF curves generated from each 2D transverse slice of every (248) 4D temporal frame (3D). 4D results for SPH and EPH were compared to the 3D-DSA. Analysis of the 3D-DSA resulted in a VLSR of 2.28 and 1.69 lp/mm for the EPH and SPH respectively. Kernel (2D) sizes of either 10x10 or 20x20 pixels with a threshold of 10% of the 3D-DSA as a constraining image provided 4D-DSA VLSR nearest to the 3D-DSA. 4D-DSA algorithms yielded 2.21 and 1.67 lp/mm with a percent error of 3.1% and 1.2% for the EPH and SPH respectively as compared to the 3D-DSA. This research indicates 4D-DSA is capable of retaining the resolution of the 3D-DSA.

  13. VMAT QA: Measurement-guided 4D dose reconstruction on a patient

    SciTech Connect

    Nelms, Benjamin E.; Opp, Daniel; Robinson, Joshua; Wolf, Theresa K.; Zhang, Geoffrey; Moros, Eduardo; Feygelman, Vladimir

    2012-07-15

    Purpose: To develop and validate a volume-modulated arc therapy (VMAT) quality assurance (QA) tool that takes as input a time-resolved, low-density ({approx}10 mm) cylindrical surface dose map from a commercial helical diode array, and outputs a high density, volumetric, time-resolved dose matrix on an arbitrary patient dataset. This first validation study is limited to a homogeneous 'patient.'Methods: A VMAT treatment is delivered to a diode array phantom (ARCCHECK, Sun Nuclear Corp., Melbourne, FL). 3DVH software (Sun Nuclear) derives the high-density volumetric dose using measurement-guided dose reconstruction (MGDR). MGDR cylindrical phantom results are then used to perturb the three-dimensional (3D) treatment planning dose on the patient dataset, producing a semiempirical volumetric dose grid. Four-dimensional (4D) dose reconstruction on the patient is also possible by morphing individual sub-beam doses instead of the composite. For conventional (3D) dose comparison two methods were developed, using the four plans (Multi-Target, C-shape, Mock Prostate, and Head and Neck), including their structures and objectives, from the AAPM TG-119 report. First, 3DVH and treatment planning system (TPS) cumulative point doses were compared to ion chamber in a cube water-equivalent phantom ('patient'). The shape of the phantom is different from the ARCCHECK and furthermore the targets were placed asymmetrically. Second, coronal and sagittal absolute film dose distributions in the cube were compared with 3DVH and TPS. For time-resolved (4D) comparisons, three tests were performed. First, volumetric dose differences were calculated between the 3D MGDR and cumulative time-resolved patient (4D MGDR) dose at the end of delivery, where they ideally should be identical. Second, time-resolved (10 Hz sampling rate) ion chamber doses were compared to cumulative point dose vs time curves from 4D MGDR. Finally, accelerator output was varied to assess the linearity of the 4D MGDR with

  14. Yersiniosis due to infection by Yersinia pseudotuberculosis 4b in captive meerkats (Suricata suricatta) in Japan.

    PubMed

    Nakamura, Shin-Ichi; Hayashidani, Hideki; Yonezawa, Aya; Suzuki, Isao; Une, Yumi

    2015-09-01

    Two meerkats (Suricata suricatta) housed in the same zoological garden in Japan died due to Yersinia pseudotuberculosis serotype 4b infection. Gross and microscopic lesions included necrotizing enteritis and enlargement of the spleen and liver with multifocal necrosis. Inflammatory cells, primarily neutrophils, and nuclear debris were associated with clusters of Gram-negative bacilli. Additionally, there were aberrant organism forms that were larger than bacilli and appeared as basophilic globular bodies. Immunohistochemical examination showed that the bacilli and globular bodies were strongly positive for Y. pseudotuberculosis O4 antigen. The globular bodies were considered a shape-changed form of Y. pseudotuberculosis, and these morphologically abnormal bacteria could present a diagnostic challenge.

  15. Input files with ORNL—mathematical phantoms of the human body for MCNP-4B

    NASA Astrophysics Data System (ADS)

    Krstić, D.; Nikezić, D.

    2007-01-01

    Protection against ionizing radiation requires information on the absorbed doses in organs of the human body. Implantation of many dosimeters in the human body is undesirable (or impossible), so the doses in organs are not measurable and some kind of dose calculation has to be applied. Calculation of doses in organs requests: (a) an exact description of the geometry of organs, (b) the chemical constitution of tissues, and (c) appropriate computer programs. The first two items, (a) and (b), make a so-called "phantom". In another words, the "phantom of a human body" is a mathematical representation of the human body including all other relevant information. All organs are represented with geometrical bodies (like cylinders, ellipsoids, tori, cones etc.), which are described with suitable mathematical equations. A corresponding chemical constitution for various types of organ tissues is also defined. MCNP-4B ( Monte Carlo N- Particle) is often used as transport code. Users of this software prepare an "input file" providing all necessary information for program execution. This information includes: (a) source definition—type of ionizing radiation, energy spectrum, and geometry of the source; (b) target definition—material constitution, geometry, location in respect to the source etc.; (c) characterization of absorbing media between the source and target; (d) output tally, etc. This paper presents input files with "human phantoms" for the MCNP-4B code. The input files with "phantoms" were prepared based on publications issued by the Oak Ridge National Laboratory (ORNL). Seven input files relating to different age groups (newborn, 1, 5, 10, 15 years, as well as, male and female adults) are presented here. A test example and comparison with other data found in literature are also given. Program summaryTitle of program: INPUT FILES, AMALE, AFEMALE, AGE15, AGE10, AGE5, AGE01, NEWB Catalogue identifier:ADYF_v1_0 Program summary URL

  16. Synergistic interactions between PDE4B and GSK-3: DISC1 mutant mice.

    PubMed

    Lipina, Tatiana V; Wang, Min; Liu, Fang; Roder, John C

    2012-03-01

    Disrupted-In-Schizophrenia-1 (DISC1) is a strong genetic risk factor associated with psychiatric disorders. Two distinct mutations in the second exon of the DISC1 gene (Q31L and L100P) lead to either depression- or schizophrenia-like behavior in mice. Both phosphodiesterase-4B (PDE4B) and glycogen synthase kinase-3 (GSK-3) have common binding sites on N-terminal region of DISC1 and are implicated into etiology of schizophrenia and depression. It is not known if PDE4B and GSK-3 could converge signals in the cell via DISC1 at the same time. The purpose of the present study was to assess whether rolipram (PDE4 inhibitor) might synergize with TDZD-8 (GSK-3 blocker) to produce antipsychotic effects at low doses on the DISC1-L100P genetic model. Indeed, combined treatment of DISC1-L100P mice with rolipram (0.1 mg/kg) and TDZD-8 (2.5 mg/kg) in sub-threshold doses corrected their Pre-Pulse Inhibition (PPI) deficit and hyperactivity, without any side effects at these doses. We have suggested that rolipram-induced increase of cAMP level might influence GSK-3 function and, hence the efficacy of TDZD-8. Our second goal was to estimate how DISC1-Q31L with reduced PDE4B activity, and therefore mimicking rolipram-induced conditions, could alter pharmacological response to TDZD-8, GSK-3 activity and its interaction with DISC1. DISC1-Q31L mutants showed increased sensitivity to GSK-3 inhibitor compare to DISC1-L100P mice. TDZD-8 (2.5 mg/kg) was able to correct PPI deficit, reduce immobility in the forced swim test (FST) and increased social motivation/novelty. In parallel, biochemical analysis revealed significantly reduced binding of GSK-3 to the mutated DISC1-Q31L and increased enzymatic activity of GSK-3. Taken together, genetic variations in DISC1 influence formation of biochemical complex with PDE4 and GSK-3 and strength the possibility of synergistic interactions between these proteins.

  17. Crystal structure features in a new compound C4B25Mg1.42

    NASA Astrophysics Data System (ADS)

    Konovalikhin, S. V.; Ponomarev, V. I.

    2015-09-01

    The composition of C4B25Mg1.42 crystal obtained by self-propagating high-temperature synthesis was determined using X-ray diffraction. This is the first crystalline structure where all boron atoms in the В12 icosahedron occupy crystallographically independent positions; this circumstance allowed us to analyze the effect of substituents on bond lengths in the icosahedron. The crystal structure features, including the channels filled with disordered Mg atoms and the spread of В—В endo- and exo-bond lengths in the icosahedra, are described. A crystallochemical analysis of pair bonds has been performed for the first time.

  18. Complete Genome Sequence of the Larvicidal Bacterium Lysinibacillus sphaericus Strain OT4b.25

    PubMed Central

    Rey, Andrés; Silva-Quintero, Laura

    2016-01-01

    Lysinibacillus sphaericus OT4b.25 is a native Colombian strain isolated from coleopteran larvae in an oak forest near Bogotá D.C.; this strain has shown high levels of pathogenic activity against Culex quinquefasciatus larvae in laboratory assays compared to that of other members of the same species. Using Pacific Biosciences sequencing technology, we propose a chromosomal contig of 4,665,775 bp that, according to comparative analysis, is highly similar to that of reference strain L. sphaericus C3-41. PMID:27151786

  19. Population Structure of Listeria monocytogenes Serotype 4b Isolates from Sporadic Human Listeriosis in the United States, 2003-2008

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Listeria monocytogenes can cause severe foodborne disease (listeriosis). Serotype 4b strains have resulted in numerous outbreaks, repeatedly involving three epidemic clones (ECI, ECII, and ECIa). Little is known about population structure of L. monocytogenes serotype 4b from sporadic listeriosis, ev...

  20. 75 FR 41871 - International Conference on Harmonisation; Draft Guidance on Q4B Evaluation and Recommendation of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-19

    ... Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use in the International Conference on... availability of a draft guidance entitled ``Q4B Evaluation and Recommendation of Pharmacopoeial Texts for Use... evaluation of the Bacterial Endotoxins Test General Chapter harmonized text from each of the...

  1. Formation of 2,4-D bound residues in soils: New insights into microbial metabolism.

    PubMed

    Botero, Liliana Rocío; Mougin, Chistian; Peñuela, Gustavo; Barriuso, Enrique

    2017-04-15

    The microbial contribution to the formation of bound residues in soils is studied by characterizing the metabolic activity of three microorganisms (Trametes versicolor, Fusarium solani and Ralstonia eutropha) on (14)C-2,4-dichlorophenoxyacetic acid (2,4-D) during incubation in synthetic liquid media and soil. A fractionation protocol was applied to quantify the (14)C-2,4-D that was incorporated into the biomass among biomolecular-like fractions. Successive fractionation of microbial biomass was implemented to break up and quantify the methanol/dichloromethane fraction (corresponding to the (14)C-lipid-like fraction), the trichloroacetic acid fraction (or hydrolysed (14)C-polysaccharide-like fraction) and the acid hydrolysable fraction (or the hydrolysed (14)C-protein-like fraction). Relevant differences in the 2,4-D degradation and biomass radioactivity distribution among the three microorganisms were found. The (14)C-protein-like fraction was the most consistent biomass fraction for reflecting the pesticide use capacity of the microorganisms under liquid and soil conditions. 2,4-D and its metabolite 4-chlorophenol were detected in methanol/dichloromethane and trichloroacetic acid fractions of the biomass of microorganisms exhibiting a low capacity to mineralize 2,4-D, thus proving that the microbial participation in the formation of bound residues while conserving the initial pesticide structure under natural soil conditions may be intimately associated with the lipid- and polysaccharide-like constituents. The fractionation protocol differentiates between (14)C that is incorporated into biomass as a biomolecular constituent and the pesticide or its metabolites that accumulate in the biomass and thus correspond to the stricto sensu definition of bound residues.

  2. Phosphodiesterase 4D polymorphisms associate with the short-term outcome in ischemic stroke

    PubMed Central

    Song, Yan-li; Wang, Chun-juan; Wu, Yi-ping; Lin, Jie; Wang, Peng-lian; Du, Wan-liang; Liu, Li; Lin, Jin-xi; Wang, Yi-long; Wang, Yong-jun; Liu, Gai-fen

    2017-01-01

    It has been demonstrated that phosphodiesterase 4D (PDE4D) genetic polymorphism is associated with ischemic stroke. However, the association between PDE4D gene and prognosis after ischemic stroke remains unknown. We consecutively enrolled ischemic stroke patients admitted to Beijing Tiantan Hospital from October 2009 to December 2013. Clinical, laboratory and imaging data upon admission were collected. All patients were followed up 3 months after stroke onset. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the associations of genetic polymorphisms with 3-month outcome after ischemic stroke and different subtypes, under various genetic models. A total of 1447 patients were enrolled, and 3-month follow-up data were obtained from 1388 (95.92%). Multivariate regression analysis showed that SNP87 of PDE4D gene was associated with increased risk of unfavorable outcome after total ischemic stroke (OR = 1.47, 95%CI 1.12–1.93), as well as stroke due to large-artery atherosclerosis (OR = 1.49, 95%CI 1.04–2.11) and small-artery occlusion (OR = 1.76, 95%CI 1.05–2.96) under a recessive model. No association between SNP83 genotype and poor outcome was found. Overall, this study demonstrated that the TT genotype of SNP87 in PDE4D was associated with increased risk of poor outcome after total ischemic stroke, large-artery atherosclerosis and small-artery occlusion, in a Chinese population. PMID:28225001

  3. Constructing 4D infant cortical surface atlases based on dynamic developmental trajectories of the cortex.

    PubMed

    Li, Gang; Wang, Li; Shi, Feng; Lin, Weili; Shen, Dinggang

    2014-01-01

    Cortical surface atlases play an increasingly important role for analysis, visualization, and comparison of results across different neuroimaging studies. As the first two years of life is the most dynamic period of postnatal structural and functional development of the highly-folded cerebral cortex, longitudinal (4D) cortical surface atlases for the infant brains during this period is highly desired yet still lacking for early brain development studies. In this paper, we construct the first longitudinal (4D) cortical surface atlases for the dynamic developing infant cortical structures at 1, 3, 6, 9, 12, 18 and 24 months of age, based on 202 serial MRI scans from 35 healthy infants. To ensure longitudinal consistency and unbiasedness of the 4D infant cortical surface atlases, we first compute the within-subject mean cortical folding geometries by groupwise registration of longitudinal surfaces of each infant. Then we establish intersubject cortical correspondences by groupwise registration of the within-subject mean cortical folding geometries of all infants. More importantly, for the first time, we further parcellate the 4D infant surface atlases into developmentally and functionally distinctive regions based solely on the dynamic developmental trajectories of the cortical thickness, by using the spectral clustering method. Specifically, to deal with the problem that each infant has different number of scans, we first compute the within-subject affinity matrix of vertices' cortical thickness trajectories of each infant, and then we use the averaged affinity matrix of all infants for parcellation. Our constructed 4D infant cortical surface atlases with developmental trajectories based parcellation will greatly facilitate the surface-based analysis of dynamic brain development in infants.

  4. Radiolucent 4D Ultrasound Imaging: System Design and Application to Radiotherapy Guidance.

    PubMed

    Schlosser, Jeffrey; Hristov, Dimitre

    2016-04-27

    Four-dimensional (4D) ultrasound (US) is an attractive modality for image guidance due to its real-time, non-ionizing, volumetric imaging capability with high soft tissue contrast. However, existing 4D US imaging systems contain large volumes of metal which interfere with diagnostic and therapeutic ionizing radiation in procedures such as CT imaging and radiation therapy. This study aimed to design and characterize a novel 4D Radiolucent Remotely-Actuated UltraSound Scanning (RRUSS) device that overcomes this limitation. In a phantom, we evaluated the imaging performance of the RRUSS device including frame rate, resolution, spatial integrity, and motion tracking accuracy. To evaluate compatibility with radiation therapy workflow, we evaluated device-induced CT imaging artifacts, US tracking performance during beam delivery, and device compatibility with commercial radiotherapy planning software. The RRUSS device produced 4D volumes at 0.1-3.0 Hz with 60⁰ lateral field of view (FOV), 50⁰ maximum elevational FOV, and 200 mm maximum depth. Imaging resolution (-3 dB point spread width) was 1.2-7.9 mm at depths up to 100 mm and motion tracking accuracy was ≤0.3±0.5 mm. No significant effect of the RRUSS device on CT image integrity was found, and RRUSS device performance was not affected by radiotherapy beam exposure. Agreement within ±3.0% / 2.0 mm was achieved between computed and measured radiotherapy dose delivered directly through the RRUSS device at 6 MV and 15 MV. In-vivo liver, kidney, and prostate images were successfully acquired. Our investigations suggest that a RRUSS device can offer non-interfering 4D guidance for radiation therapy and other diagnostic and therapeutic procedures.

  5. Radiolucent 4D Ultrasound Imaging: System Design and Application to Radiotherapy Guidance.

    PubMed

    Schlosser, Jeffrey; Hristov, Dimitre

    2016-10-01

    Four-dimensional (4D) ultrasound (US) is an attractive modality for image guidance due to its real-time, non-ionizing, volumetric imaging capability with high soft tissue contrast. However, existing 4D US imaging systems contain large volumes of metal which interfere with diagnostic and therapeutic ionizing radiation in procedures such as CT imaging and radiation therapy. This study aimed to design and characterize a novel 4D Radiolucent Remotely-Actuated UltraSound Scanning (RRUSS) device that overcomes this limitation. In a phantom, we evaluated the imaging performance of the RRUSS device including frame rate, resolution, spatial integrity, and motion tracking accuracy. To evaluate compatibility with radiation therapy workflow, we evaluated device-induced CT imaging artifacts, US tracking performance during beam delivery, and device compatibility with commercial radiotherapy planning software. The RRUSS device produced 4D volumes at 0.1-3.0 Hz with 60° lateral field of view (FOV), 50° maximum elevational FOV, and 200 mm maximum depth. Imaging resolution (-3 dB point spread width) was 1.2-7.9 mm at depths up to 100 mm and motion tracking accuracy was ≤ 0.3±0.5 mm. No significant effect of the RRUSS device on CT image integrity was found, and RRUSS device performance was not affected by radiotherapy beam exposure. Agreement within ±3.0% / 2.0 mm was achieved between computed and measured radiotherapy dose delivered directly through the RRUSS device at 6 MV and 15 MV. In vivo liver, kidney, and prostate images were successfully acquired. Our investigations suggest that a RRUSS device can offer non-interfering 4D guidance for radiation therapy and other diagnostic and therapeutic procedures.

  6. Fully 4D list-mode reconstruction applied to respiratory-gated PET scans

    NASA Astrophysics Data System (ADS)

    Grotus, N; Reader, A J; Stute, S; Rosenwald, J C; Giraud, P; Buvat, I

    2009-03-01

    18F-fluoro-deoxy-glucose (18F-FDG) positron emission tomography (PET) is one of the most sensitive and specific imaging modalities for the diagnosis of non-small cell lung cancer. A drawback of PET is that it requires several minutes of acquisition per bed position, which results in images being affected by respiratory blur. Respiratory gating techniques have been developed to deal with respiratory motion in the PET images. However, these techniques considerably increase the level of noise in the reconstructed images unless the acquisition time is increased. The aim of this paper is to evaluate a four-dimensional (4D) image reconstruction algorithm that combines the acquired events in all the gates whilst preserving the motion deblurring. This algorithm was compared to classic ordered subset expectation maximization (OSEM) reconstruction of gated and non-gated images, and to temporal filtering of gated images reconstructed with OSEM. Two datasets were used for comparing the different reconstruction approaches: one involving the NEMA IEC/2001 body phantom in motion, the other obtained using Monte-Carlo simulations of the NCAT breathing phantom. Results show that 4D reconstruction reaches a similar performance in terms of the signal-to-noise ratio (SNR) as non-gated reconstruction whilst preserving the motion deblurring. In particular, 4D reconstruction improves the SNR compared to respiratory-gated images reconstructed with the OSEM algorithm. Temporal filtering of the OSEM-reconstructed images helps improve the SNR, but does not achieve the same performance as 4D reconstruction. 4D reconstruction of respiratory-gated images thus appears as a promising tool to reach the same performance in terms of the SNR as non-gated acquisitions while reducing the motion blur, without increasing the acquisition time.

  7. Graph-based retrospective 4D image construction from free-breathing MRI slice acquisitions

    NASA Astrophysics Data System (ADS)

    Tong, Yubing; Udupa, Jayaram K.; Ciesielski, Krzysztof C.; McDonough, Joseph M.; Mong, Andrew; Campbell, Robert M.

    2014-03-01

    4D or dynamic imaging of the thorax has many potential applications [1, 2]. CT and MRI offer sufficient speed to acquire motion information via 4D imaging. However they have different constraints and requirements. For both modalities both prospective and retrospective respiratory gating and tracking techniques have been developed [3, 4]. For pediatric imaging, x-ray radiation becomes a primary concern and MRI remains as the de facto choice. The pediatric subjects we deal with often suffer from extreme malformations of their chest wall, diaphragm, and/or spine, as such patient cooperation needed by some of the gating and tracking techniques are difficult to realize without causing patient discomfort. Moreover, we are interested in the mechanical function of their thorax in its natural form in tidal breathing. Therefore free-breathing MRI acquisition is the ideal modality of imaging for these patients. In our set up, for each coronal (or sagittal) slice position, slice images are acquired at a rate of about 200-300 ms/slice over several natural breathing cycles. This produces typically several thousands of slices which contain both the anatomic and dynamic information. However, it is not trivial to form a consistent and well defined 4D volume from these data. In this paper, we present a novel graph-based combinatorial optimization solution for constructing the best possible 4D scene from such data entirely in the digital domain. Our proposed method is purely image-based and does not need breath holding or any external surrogates or instruments to record respiratory motion or tidal volume. Both adult and children patients' data are used to illustrate the performance of the proposed method. Experimental results show that the reconstructed 4D scenes are smooth and consistent spatially and temporally, agreeing with known shape and motion of the lungs.

  8. [Effects of EDTA on the Reductive Dechlorination of 2,4-D by Pd/Fe].

    PubMed

    Zhou, Hong-yi; Nie, Ya-zhong; Chen, Yong; Lei, Shuang-jian

    2016-02-15

    In Pd/Fe system, zero-valent iron (ZVI) passivation layer is easily formed on the particle surface during the catalytic reductive dechlorination of chlorinated organics, hindering further dechlorination of target contaminants. In this paper, the passivation layer on the Pd/Fe particle surfaces could be eliminated by the chelation of disodium edetate (EDTA) with Fe2+, Fe3+, making the reductive dechlorination continue. The experiment investigated the effects of EDTA addition manner and dosage, pH, Pd loading and temperature on dechlorination of 2,4-dichlorophenoxyacetic acid (2,4-D) by Pd/Fe. The conclusions can be summarized as follows: (1) Phenoxyacetic acid (PA) generation ratio reached 90. 7% within 20 min with EDTA concentration of 25.0 mmol x L(-1) and flow rate of 20 mL x h(-1), while it was only 74.5% after 210 min in the system without EDTA. (2) The EDTA could chelate the Fe2+ and Fe3+ generated from the process of 2,4-D dechlorination by Pd/Fe, preventing or slowing down the formation of passivation layer, and accelerating the reduction efficiency. (3) The appropriate experimental parameters for 2,4-D removal were as follows: EDTA flow rate of 20 mL x h(-1), CEDTA of 25.0 mmol x L(-1), Pd loading of 0.050%, 200 r x min(-1), pH 4.2 and 30.0 degrees C. The removal percentage of 20.0 mg x L(-1) 2,4-D reached nearly up to 100% within 210 min under these conditions. (4) The intermediates of 2, 4-D catalytic dechlorination included 2-chlorophenoxvacetic acid (2-CPA) and trace 4-chloronhenoxyacetic acid (4-CPA), and the end product was PA.

  9. Influence of preformed donor-specific antibodies and C4d on early liver allograft function.

    PubMed

    Perera, M T; Silva, M A; Murphy, N; Briggs, D; Mirza, D F; Neil, D A H

    2013-12-01

    INTRODUCTION. The impact of preformed donor-specific antibodies (DSA) is incompletely understood in liver transplantation. The incidence and impact of preformed DSA on early post liver transplant were assessed and these were correlated with compliment fragment C4d on allograft biopsy. METHODS. Pretransplant serum from 41 consecutive liver transplant recipients (brain dead donors; DBD = 27 and cardiac death donors; DCD = 14) were tested for class-specific anti-human leukocyte antigen (HLA) and compared against donor HLA types. Liver biopsies were taken during cold storage (t-1) and post-reperfusion (t0) stained with C4d and graded for preservation-reperfusion injury (PRI). RESULTS. Of the 41 recipients, 8 (20%) had anti-HLA class I/II antibodies pretransplant, 3 (7%) were confirmed preformed DSA; classes I and II (n=1) and class I only (n=2). No biopsies showed definite evidence of antibody-mediated rejection. Graft biopsies in overall showed only mild PRI with ischemic hepatocyte C4d pattern similar in both positive and negative DSA patients. One DSA-positive (33%) compared with four DSA-negative patients (10%) had significant early graft dysfunction; severe PRI causing graft loss from primary nonfunction was seen only in DSA-negative group. Allograft biopsy of preformed DSA-positive patient demonstrated only minimal PRI; however, no identifiable cause could be attributed to graft dysfunction other than preformed DSA. CONCLUSION. Preformed DSA are present in 5-10% liver transplant recipients. There is no association between anti-HLA DSA and PRI and C4d, but preformed DSA may cause early morbidity. Larger studies on the impact of DSA with optimization of C4d techniques are required.

  10. Combining C(4) D and MS as a dual detection approach for capillary electrophoresis.

    PubMed

    Beutner, Andrea; Cunha, Rafael Rodrigues; Richter, Eduardo Mathias; Matysik, Frank-Michael

    2016-04-01

    The hyphenation of two detectors in combination with separation techniques is a powerful tool to enhance the analytical information. In this work, we present for the first time the coupling of two important detectors for capillary electrophoresis (CE), namely capacitively coupled contactless conductivity detection (C(4) D) and electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS). The elaborated experimental protocol took into account the requirements of separation aspects and the compatibility with both detectors. ESI-TOF-MS requires background electrolytes (BGE) containing only volatile components such as ammonium acetate or formate. These, however, exhibit a rather high conductivity, which is disadvantageous for C(4) D. Thus, the selection of the BGE in an appropriate concentration was undertaken for the determination of various phenolic compounds serving as a model system. The chosen BGE was a 10 mM ammonium acetate/ammonia buffer with a pH of 9. This BGE was a compromise concerning the detection performance of both detectors. The LODs for m-cresol, m- and p-nitrophenol, and 2,4-dinitrophenol were 3.1 μM (C(4) D), 0.8 μM (MS), 0.8 μM (MS), and 1.5 μM (MS), respectively. Moreover, the overall separation efficiency was excellent illustrating that detector-induced band broadening can be neglected in the CE-C(4) D/MS system. The analytical characteristics for the determination of phenolic compounds show the suitability of this dual detection approach and demonstrate the complementary use of C(4) D and MS detection.

  11. Trauma-Related Altered States of Consciousness: Exploring the 4-D Model

    PubMed Central

    Frewen, Paul A.; Lanius, Ruth A.

    2014-01-01

    Frewen and Lanius (in press) recently articulated a 4-D model as a framework for classifying symptoms of posttraumatic stress into those that potentially occur within normal waking consciousness (NWC) versus those that intrinsically represent dissociative experiences of trauma-related altered states of consciousness (TRASC). Four dimensions were specified: time-memory, thought, body, and emotion. The 4-D model further hypothesizes that in traumatized persons, symptoms of TRASC, compared with NWC forms of distress, will be (a) observed less frequently; (b) less intercorrelated, especially as measured as moment-to-moment states; (c) observed more frequently in people with high dissociative symptomatology as measured independently; and (d) observed more often in people who have experienced repeated traumatization, particularly early developmental trauma. The aim of the present research was to begin to evaluate these 4 predictions of the 4-D model. Within a sample of 74 women with posttraumatic stress disorder (PTSD) primarily due to histories of childhood trauma, as well as within a 2nd sample of 504 undergraduates (384 females), the 1st 2 hypotheses of the 4-D model were supported. In addition, within the PTSD sample, the 3rd hypothesis was supported. However, inconsistent with the 4th hypothesis, severity of childhood trauma history was not strongly associated with TRASC. We conclude that the hypotheses articulated by the 4-D model were generally supported, although further research in different trauma-related disorders is needed, and the role of childhood trauma history in the etiology of TRASC requires further research. PMID:24650122

  12. Development of an immunoassay for determination of 2,4-dichlorophenoxyacetic acid (2,4-D) based upon the recombinant Fab fragment of 2,4-D specific antibody

    NASA Astrophysics Data System (ADS)

    Nguyen, Van C.; Nguyen, Thi D. T.; Dau, Hung A.; Tham, Thu N.; Quyen, Dinh T.; Bachmman, Till; Schmid, Rolf D.

    2001-09-01

    To develop an immunoassay and further an immunosensor for 2,4-D based upon recombinant antibody, the Fab fragments of 2,4-D specific antibody were expressed in E. coli. Western blotting analysis of the periplasmic cell fractions shown that under the non-reducing condition only a single protein band at a molecular mass of 45-kDa, corresponding to the whole Fab fragment was detected. Antigen binding activity for 2,4-D was found only in the extract of cells bearing the 2,4-D plasmid. An immunoassay based on the competitive reaction of 2,4-D and enzyme tracer with 2,4-D Fab fragments immobilized on micro titer plates via rabbit anti-mouse IgC was developed. Using this assay, 2,4-D could be detected at concentration range of 0.5 (mu) g/1 to 10(mu) g/1. The center point of the 2,4-D test was found at a concentration of 5 (mu) g/l. The assay was applied for detection of 2,4-D in spiked orange samples, resulting in recovery rate of 90 percent. The immunoassay could be applied to monitor human exposure to 2,4-D from contamination in fruit samples.

  13. Identification of Amino Acid Determinants in CYP4B1 for Optimal Catalytic Processing of 4-Ipomeanol

    PubMed Central

    Wiek, Constanze; Schmidt, Eva M; Roellecke, Katharina; Freund, Marcel; Nakano, Mariko; Kelly, Edward J; Kaisers, Wolfgang; Yarov-Yarovoy, Vladimir; Kramm, Christof M; Rettie, Allan E; Hanenberg, Helmut

    2014-01-01

    Mammalian CYP4B1 enzymes are cytochrome P450 monooxygenases that are responsible for the bioactivation of several exogenous pro-toxins including 4-ipomeanol (4-IPO). In contrast to the orthologous rabbit enzyme, we show here that native human CYP4B1 with a serine at position 427 is unable to bio-activate 4-IPO and does not cause cytotoxicity in HepG2 cells and primary human T-cells that overexpress these enzymes. We also demonstrate that a proline residue in the meander region at position 427 in human CYB4B1 and 422 in rabbit CYP4B1 is important for protein stability and rescues the 4-IPO bioactivation of the human enzyme, but is not essential for the catalytic activity of the rabbit CYP4B1 protein. Systematic substitution of native and p.S427P human CYP4B1 with peptide regions from the highly active rabbit enzyme reveals that 18 amino acids in the wild-type rabbit CYP4B1 protein are key for conferring high 4-IPO metabolizing activity. Introduction of 12 of the 18 amino acids that are also present at corresponding positions in other human CYP4 family members into the p.S427P human CYP4B1 protein results in a mutant human enzyme (P+12) that is as stable and as active as the rabbit wild-type CYP4B1 protein. These 12 mutations cluster in the predicted B–C loop through F-helix regions and reveal new amino acid regions important to P450 enzyme stability. Finally, by minimally re-engineering the human CYP4B1 enzyme for efficient activation of 4-IPO, we have developed a novel human suicide gene system that is a candidate for adoptive cellular therapies in humans. PMID:25247810

  14. The plasma membrane Ca(2+) pump PMCA4b inhibits the migratory and metastatic activity of BRAF mutant melanoma cells.

    PubMed

    Hegedũs, Luca; Garay, Tamás; Molnár, Eszter; Varga, Karolina; Bilecz, Ágnes; Török, Szilvia; Padányi, Rita; Pászty, Katalin; Wolf, Matthias; Grusch, Michael; Kállay, Enikõ; Döme, Balázs; Berger, Walter; Hegedũs, Balázs; Enyedi, Agnes

    2016-11-04

    Oncogenic mutations of BRAF lead to constitutive ERK activity that supports melanoma cell growth and survival. While Ca(2+) signaling is a well-known regulator of tumor progression, the crosstalk between Ca(2+) signaling and the Ras-BRAF-MEK-ERK pathway is much less explored. Here we show that in BRAF mutant melanoma cells the abundance of the plasma membrane Ca(2+) ATPase isoform 4b (PMCA4b, ATP2B4) is low at baseline but markedly elevated by treatment with the mutant BRAF specific inhibitor vemurafenib. In line with these findings gene expression microarray data also shows decreased PMCA4b expression in cutaneous melanoma when compared to benign nevi. The MEK inhibitor selumetinib-similarly to that of the BRAF-specific inhibitor-also increases PMCA4b levels in both BRAF and NRAS mutant melanoma cells suggesting that the MAPK pathway is involved in the regulation of PMCA4b expression. The increased abundance of PMCA4b in the plasma membrane enhances [Ca(2+) ]i clearance from cells after Ca(2+) entry. Moreover we show that both vemurafenib treatment and PMCA4b overexpression induce marked inhibition of migration of BRAF mutant melanoma cells. Importantly, reduced migration of PMCA4b expressing BRAF mutant cells is associated with a marked decrease in their metastatic potential in vivo. Taken together, our data reveal an important crosstalk between Ca(2+) signaling and the MAPK pathway through the regulation of PMCA4b expression and suggest that PMCA4b is a previously unrecognized metastasis suppressor.

  15. LARP4B is an AU-rich sequence associated factor that promotes mRNA accumulation and translation.

    PubMed

    Küspert, Maritta; Murakawa, Yasuhiro; Schäffler, Katrin; Vanselow, Jens T; Wolf, Elmar; Juranek, Stefan; Schlosser, Andreas; Landthaler, Markus; Fischer, Utz

    2015-07-01

    mRNAs are key molecules in gene expression and subject to diverse regulatory events. Regulation is accomplished by distinct sets of trans-acting factors that interact with mRNAs and form defined mRNA-protein complexes (mRNPs). The resulting "mRNP code" determines the fate of any given mRNA and thus controlling gene expression at the post-transcriptional level. The La-related protein 4B (LARP4B) belongs to an evolutionarily conserved family of RNA-binding proteins characterized by the presence of a La-module implicated in direct RNA binding. Biochemical experiments have shown previously direct interactions of LARP4B with factors of the translation machinery. This finding along with the observation of an association with actively translating ribosomes suggested that LARP4B is a factor contributing to the mRNP code. To gain insight into the function of LARP4B in vivo we tested its mRNA association at the transcriptome level and its impact on the proteome. PAR-CLIP analyses allowed us to identify the in vivo RNA targets of LARP4B. We show that LARP4B binds to a distinct set of cellular mRNAs by contacting their 3' UTRs. Biocomputational analysis combined with in vitro binding assays identified the LARP4B-binding motif on mRNA targets. The reduction of cellular LARP4B levels leads to a marked destabilization of its mRNA targets and consequently their reduced translation. Our data identify LARP4B as a component of the mRNP code that influences the expression of its mRNA targets by affecting their stability.

  16. The electron and energy transfer between oligothiophenes and thieno[3,4-b]thiophene units

    NASA Astrophysics Data System (ADS)

    Szarko, Jodi; Guo, Jianchang; Liang, Yongye; Rolczynski, Brian; Yu, Luping; Chen, Lin X.

    2008-08-01

    In a recent study, it has been shown that organic photovoltaic (OPV) solar cells consisting of polymers with certain stoichiometric ratios of alkyl thiophene:thieno[3,4-b]thiophene monomeric units in random sequences, when combined with [6,6]-phenyl-C61-butyric acid methyl ester (PCBM), may have potentials for creating more efficient devices. Such a potential enhancement is mainly due to the light harvesting in most of the visible and near infrared region by these low band-gap polymers. However, very little is known about the photoinduced energy/electron transfer and transport within these copolymers. It is important to understand both the ultrafast interactions between these two monomeric units when they are linked in the copolymers and their interactions with the electron acceptor PCBM in order to determine the transport mechanisms in these systems, and then to create the architectures that optimize electronic transport properties. Therefore, three oligomer molecules have been synthesized to model the local interactions in the copolymers, each of which consists of a thieno[3,4-b] thiophene derivative at its center linked with two alkyl oligothiophene side units. The alkyl oligothiophene units for the three molecules are 2, 4, or 8 units in length. By performing transient absorption and fluorescence upconversion measurements, the nature of the early exciton diffusion and energy transfer between these different units is elucidated.

  17. Geopotential Model Improvement Using POCM_4B Dynamic Ocean Topography Information: PGM2000A

    NASA Technical Reports Server (NTRS)

    Pavlis, N. K.; Chinn, D. S.; Cox, C. M.; Lemoine, Frank G.; Smith, David E. (Technical Monitor)

    2000-01-01

    The two-year mean (1993-1994) Dynamic Ocean Topography (DOT) field implied by the POCM_4B circulation model was used to develop normal equations for DOT, in a surface spherical harmonic representation. These normal equations were combined with normal equations from satellite tracking data, surface gravity data, and altimeter data from TOPEX/Poseidon and ERS-1. Several least-squares combination solutions were developed in this fashion, by varying parameters such as the maximum degree of the estimated DOT and the relative weights of the different data. The solutions were evaluated in terms of orbit fit residuals, GPS/Leveling-derived undulations, and independent DOT information from in situ WOCE hydrographic data. An optimal solution was developed in this fashion which was originally presented at the 1998 EGS meeting in Nice, France. This model, designated here PGM2000A, maintains the orbit and land geoid modeling performance of EGM96, while improving its marine geoid modeling capability. In addition, PGM2000A's error spectrum is considerably more realistic than those of other contemporary gravitational models and agrees well with the error spectrum of EGM96. We will present the development and evaluation of PGM2000A, with particular emphasis on the weighting of the DOT information implied by POCM_4B. We will also present an inter-comparison of PGM2000A with the GRIM5-C1 and TEG-4 models. Directions for future work and problematic areas will be identified.

  18. Prolactin Regulatory Element Binding Protein Is Involved in Hepatitis C Virus Replication by Interaction with NS4B

    PubMed Central

    Kong, Lingbao; Fujimoto, Akira; Nakamura, Mariko; Aoyagi, Haruyo; Matsuda, Mami; Watashi, Koichi; Suzuki, Ryosuke; Arita, Minetaro; Yamagoe, Satoshi; Dohmae, Naoshi; Suzuki, Takehiro; Sakamaki, Yuriko; Ichinose, Shizuko; Suzuki, Tetsuro; Wakita, Takaji

    2016-01-01

    ABSTRACT It has been proposed that the hepatitis C virus (HCV) NS4B protein triggers the membranous HCV replication compartment, but the underlying molecular mechanism is not fully understood. Here, we screened for NS4B-associated membrane proteins by tandem affinity purification and proteome analysis and identified 202 host proteins. Subsequent screening of replicon cells with small interfering RNA identified prolactin regulatory element binding (PREB) to be a novel HCV host cofactor. The interaction between PREB and NS4B was confirmed by immunoprecipitation, immunofluorescence, and proximity ligation assays. PREB colocalized with double-stranded RNA and the newly synthesized HCV RNA labeled with bromouridine triphosphate in HCV replicon cells. Furthermore, PREB shifted to detergent-resistant membranes (DRMs), where HCV replication complexes reside, in the presence of NS4B expression in Huh7 cells. However, a PREB mutant lacking the NS4B-binding region (PREBd3) could not colocalize with double-stranded RNA and did not shift to the DRM in the presence of NS4B. These results indicate that PREB locates at the HCV replication complex by interacting with NS4B. PREB silencing inhibited the formation of the membranous HCV replication compartment and increased the protease and nuclease sensitivity of HCV replicase proteins and RNA in DRMs, respectively. Collectively, these data indicate that PREB promotes HCV RNA replication by participating in the formation of the membranous replication compartment and by maintaining its proper structure by interacting with NS4B. Furthermore, PREB was induced by HCV infection in vitro and in vivo. Our findings provide new insights into HCV host cofactors. IMPORTANCE The hepatitis C virus (HCV) protein NS4B can induce alteration of the endoplasmic reticulum and the formation of a membranous web structure, which provides a platform for the HCV replication complex. The molecular mechanism by which NS4B induces the membranous HCV replication

  19. 4D Near Real-Time Environmental Monitoring Using Highly Temporal LiDAR

    NASA Astrophysics Data System (ADS)

    Höfle, Bernhard; Canli, Ekrem; Schmitz, Evelyn; Crommelinck, Sophie; Hoffmeister, Dirk; Glade, Thomas

    2016-04-01

    The last decade has witnessed extensive applications of 3D environmental monitoring with the LiDAR technology, also referred to as laser scanning. Although several automatic methods were developed to extract environmental parameters from LiDAR point clouds, only little research has focused on highly multitemporal near real-time LiDAR (4D-LiDAR) for environmental monitoring. Large potential of applying 4D-LiDAR is given for landscape objects with high and varying rates of change (e.g. plant growth) and also for phenomena with sudden unpredictable changes (e.g. geomorphological processes). In this presentation we will report on the most recent findings of the research projects 4DEMON (http://uni-heidelberg.de/4demon) and NoeSLIDE (https://geomorph.univie.ac.at/forschung/projekte/aktuell/noeslide/). The method development in both projects is based on two real-world use cases: i) Surface parameter derivation of agricultural crops (e.g. crop height) and ii) change detection of landslides. Both projects exploit the "full history" contained in the LiDAR point cloud time series. One crucial initial step of 4D-LiDAR analysis is the co-registration over time, 3D-georeferencing and time-dependent quality assessment of the LiDAR point cloud time series. Due to the high amount of datasets (e.g. one full LiDAR scan per day), the procedure needs to be performed fully automatically. Furthermore, the online near real-time 4D monitoring system requires to set triggers that can detect removal or moving of tie reflectors (used for co-registration) or the scanner itself. This guarantees long-term data acquisition with high quality. We will present results from a georeferencing experiment for 4D-LiDAR monitoring, which performs benchmarking of co-registration, 3D-georeferencing and also fully automatic detection of events (e.g. removal/moving of reflectors or scanner). Secondly, we will show our empirical findings of an ongoing permanent LiDAR observation of a landslide (Gresten

  20. Population of anatomically variable 4D XCAT adult phantoms for imaging research and optimization

    SciTech Connect

    Segars, W. P.; Bond, Jason; Frush, Jack; Hon, Sylvia; Eckersley, Chris; Samei, E.; Williams, Cameron H.; Frush, D.; Feng Jianqiao; Tward, Daniel J.; Ratnanather, J. T.; Miller, M. I.

    2013-04-15

    Purpose: The authors previously developed the 4D extended cardiac-torso (XCAT) phantom for multimodality imaging research. The XCAT consisted of highly detailed whole-body models for the standard male and female adult, including the cardiac and respiratory motions. In this work, the authors extend the XCAT beyond these reference anatomies by developing a series of anatomically variable 4D XCAT adult phantoms for imaging research, the first library of 4D computational phantoms. Methods: The initial anatomy of each phantom was based on chest-abdomen-pelvis computed tomography data from normal patients obtained from the Duke University database. The major organs and structures for each phantom were segmented from the corresponding data and defined using nonuniform rational B-spline surfaces. To complete the body, the authors manually added on the head, arms, and legs using the original XCAT adult male and female anatomies. The structures were scaled to best match the age and anatomy of the patient. A multichannel large deformation diffeomorphic metric mapping algorithm was then used to calculate the transform from the template XCAT phantom (male or female) to the target patient model. The transform was applied to the template XCAT to fill in any unsegmented structures within the target phantom and to implement the 4D cardiac and respiratory models in the new anatomy. Each new phantom was refined by checking for anatomical accuracy via inspection of the models. Results: Using these methods, the authors created a series of computerized phantoms with thousands of anatomical structures and modeling cardiac and respiratory motions. The database consists of 58 (35 male and 23 female) anatomically variable phantoms in total. Like the original XCAT, these phantoms can be combined with existing simulation packages to simulate realistic imaging data. Each new phantom contains parameterized models for the anatomy and the cardiac and respiratory motions and can, therefore, serve

  1. Resolution enhancement of lung 4D-CT via group-sparsity

    SciTech Connect

    Bhavsar, Arnav; Wu, Guorong; Shen, Dinggang; Lian, Jun

    2013-12-15

    Purpose: 4D-CT typically delivers more accurate information about anatomical structures in the lung, over 3D-CT, due to its ability to capture visual information of the lung motion across different respiratory phases. This helps to better determine the dose during radiation therapy for lung cancer. However, a critical concern with 4D-CT that substantially compromises this advantage is the low superior-inferior resolution due to less number of acquired slices, in order to control the CT radiation dose. To address this limitation, the authors propose an approach to reconstruct missing intermediate slices, so as to improve the superior-inferior resolution.Methods: In this method the authors exploit the observation that sampling information across respiratory phases in 4D-CT can be complimentary due to lung motion. The authors’ approach uses this locally complimentary information across phases in a patch-based sparse-representation framework. Moreover, unlike some recent approaches that treat local patches independently, the authors’ approach employs the group-sparsity framework that imposes neighborhood and similarity constraints between patches. This helps in mitigating the trade-off between noise robustness and structure preservation, which is an important consideration in resolution enhancement. The authors discuss the regularizing ability of group-sparsity, which helps in reducing the effect of noise and enables better structural localization and enhancement.Results: The authors perform extensive experiments on the publicly available DIR-Lab Lung 4D-CT dataset [R. Castillo, E. Castillo, R. Guerra, V. Johnson, T. McPhail, A. Garg, and T. Guerrero, “A framework for evaluation of deformable image registration spatial accuracy using large landmark point sets,” Phys. Med. Biol. 54, 1849–1870 (2009)]. First, the authors carry out empirical parametric analysis of some important parameters in their approach. The authors then demonstrate, qualitatively as well as

  2. A phantom for testing of 4D-CT for radiotherapy of small lesions

    SciTech Connect

    Dunn, L.; Kron, T.; Taylor, M. L.; Callahan, J.; Franich, R. D.

    2012-09-15

    Purpose: The use of time-resolved four-dimensional computed tomography (4D-CT) in radiotherapy requires strict quality assurance to ensure the accuracy of motion management protocols. The aim of this work was to design and test a phantom capable of large amplitude motion for use in 4D-CT, with particular interest in small lesions typical for stereotactic body radiotherapy. Methods: The phantom of 'see-saw' design is light weight, capable of including various sample materials and compatible with several surrogate marker signal acquisition systems. It is constructed of polymethylmethacrylate (Perspex) and its movement is controlled via a dc motor and drive wheel. It was tested using two CT scanners with different 4D acquisition methods: the Philips Brilliance Big Bore CT (helical scan, pressure belt) and a General Electric Discovery STE PET/CT (axial scan, infrared marker). Amplitudes ranging from 1.5 to 6.0 cm and frequencies of up to 40 cycles per minute were used to study the effect of motion on image quality. Maximum intensity projections (MIPs), as well as average intensity projections (AIPs) of moving objects were investigated and their quality dependence on the number of phase reconstruction bins assessed. Results: CT number discrepancies between moving and stationary objects were found to have no systematic dependence on amplitude, frequency, or specific interphase variability. MIP-delineated amplitudes of motion were found to match physical phantom amplitudes to within 2 mm for all motion scenarios tested. Objects undergoing large amplitude motions (>3.0 cm) were shown to cause artefacts in MIP and AIP projections when ten phase bins were assigned. This problem can be mitigated by increasing the number of phase bins in a 4D-CT scan. Conclusions: The phantom was found to be a suitable tool for evaluating the image quality of 4D-CT motion management technology, as well as providing a quality assurance tool for intercenter/intervendor testing of commercial 4D

  3. Inhibitor screening and enzymatic activity determination for autophagy target Atg4B using a gel electrophoresis-based assay.

    PubMed

    Cleenewerck, Matthias; Grootaert, Mandy O J; Gladysz, Rafaela; Adriaenssens, Yves; Roelandt, Ria; Joossens, Jurgen; Lambeir, Anne-Marie; De Meyer, Guido R Y; Declercq, Wim; Augustyns, Koen; Martinet, Wim; Van der Veken, Pieter

    2016-11-10

    Atg4B is a cysteine hydrolase that plays a key role in autophagy. Although it has been proposed as an attractive drug target, inhibitor discovery has proven highly challenging. The absence of a standardized, easily implementable enzyme activity/inhibition assay for Atg4B most likely contributes to this situation. Therefore, three different assay types for Atg4B activity/inhibition quantification were first compared: (1) an approach using fluorogenic Atg4B-substrates, (2) an in-gel densitometric quantification assay and (3) a thermal shift protocol. The gel-based approach showed the most promising results and was validated for screening of potential Atg4B inhibitors. A set of 8 literature inhibitors was included. Remarkably, in our hands only 2 literature references were found to have measurable Atg4B affinity. Furthermore, a fragment library (n = 182) was tested for Atg4B inhibition. One library member showed inhibition at high micromolar concentration and was found fit for further, fragment-based inhibitor design.

  4. The LARK/RBM4a protein is highly expressed in cerebellum as compared to cerebrum.

    PubMed

    Pfuhl, Thorsten; Mamiani, Alfredo; Dürr, Matthias; Welter, Susanne; Stieber, Johanna; Ankara, Jasmin; Liss, Michael; Dobner, Thomas; Schmitt, Andrea; Falkai, Peter; Kremmer, Elisabeth; Jung, Volker; Barth, Stephanie; Grässer, Friedrich A

    2008-10-17

    The RNA binding motif protein 4 genes RBM4a and RBM4b are located on human chromosome 11q13.2 and encode highly similar proteins of 363 and 359 amino acids, respectively. They contain two RNA recognition motifs (RRMs) and a retroviral-type Zn-finger. RBM4a binds RNA, is involved in alternative splicing and is also a part of the microRNA-processing RISC complex. In particular, RBM4a is involved in exon 10 inclusion of the tau protein. The function of RBM4b is unknown. With new monoclonal antibodies we show that RBM4a is detectable in virtually all tissues and cell lines tested while RBM4b was only found in kidney and liver. Both RBM4a and RBM4b are nuclear phosphoproteins with half-lives of 2.5h and 4.5h, respectively. To our knowledge, this is the first description of RBM4b protein in human tissue. In human brain, expression of RBM4a was strongly up-regulated in cerebellum as compared to forebrain.

  5. Chern-Simons actions and their gaugings in 4D, N =1 superspace

    NASA Astrophysics Data System (ADS)

    Becker, Katrin; Becker, Melanie; Linch, William D.; Robbins, Daniel

    2016-06-01

    We gauge the abelian hierarchy of tensor fields in 4D by a Lie algebra mathfrak{g} . The resulting non-abelian tensor hierarchy can be interpreted via a mathfrak{g} -equivariant chain complex. We lift this structure to N = 1 superspace by constructing superfield analogs for the tensor fields, along with covariant superfield strengths. Next we construct Chern-Simons actions, for both the bosonic and N = 1 cases, and note that the condition of gauge invariance can be presented cohomologically. Finally, we provide an explicit realization of these structures by dimensional reduction, for example by reducing the three-form of eleven-dimensional supergravity into a superspace with manifest 4D, N = 1 supersymmetry.

  6. Unusual molecular material formed through irreversible transformation and revealed by 4D electron microscopy.

    PubMed

    van der Veen, Renske M; Tissot, Antoine; Hauser, Andreas; Zewail, Ahmed H

    2013-05-28

    Four-dimensional (4D) electron microscopy (EM) uniquely combines the high spatial resolution to pinpoint individual nano-objects, with the high temporal resolution necessary to address the dynamics of their laser-induced transformation. Here, using 4D-EM, we demonstrate the in situ irreversible transformation of individual nanoparticles of the molecular framework Fe(pyrazine)Pt(CN)4. The newly formed material exhibits an unusually large negative thermal expansion (i.e. contraction), which is revealed by time-resolved imaging and diffraction. Negative thermal expansion is a unique property exhibited by only few materials. Here we show that the increased flexibility of the metal-cyanide framework after the removal of the bridging pyrazine ligands is responsible for the negative thermal expansion behavior of the new material. This in situ visualization of single nanostructures during reactions should be extendable to other classes of reactive systems.

  7. Imaging rotational dynamics of nanoparticles in liquid by 4D electron microscopy

    NASA Astrophysics Data System (ADS)

    Fu, Xuewen; Chen, Bin; Tang, Jau; Hassan, Mohammed Th.; Zewail, Ahmed H.

    2017-02-01

    In real time and space, four-dimensional electron microscopy (4D EM) has enabled observation of transient structures and morphologies of inorganic and organic materials. We have extended 4D EM to include liquid cells without the time resolution being limited by the response of the detector. Our approach permits the imaging of the motion and morphological dynamics of a single, same particle on nanometer and ultrashort time scales. As a first application, we studied the rotational dynamics of gold nanoparticles in aqueous solution. A full transition from the conventional diffusive rotation to superdiffusive rotation and further to a ballistic rotation was observed with increasing asymmetry of the nanoparticle morphology. We explored the underlying physics both experimentally and theoretically according to the morphological asymmetry of the nanoparticles.

  8. Is digit ratio (2D:4D) a reliable pointer to speech laterality?

    PubMed

    Hudson, John M; Hodgson, Jessica C

    2016-03-15

    The relative length of the second and fourth digits (2D:4D ratio) is sexually dimorphic and a retrospective biomarker of prenatal hormonal exposure. Low ratios indicate higher prenatal testosterone (pT) and lower estrogen exposure, whereas the reverse pattern is associated with high ratios. Elevated levels of pT exposure have long been thought to modulate hemispheric specialisation; subsequently many studies use the 2D:4D ratio as a proxy index for pT to examine the effects of prenatal hormonal exposure on lateralised cognitive abilities. Here we used Transcranial Doppler ultrasonography and digit ratio to investigate whether pT has an influence on speech laterality. We tested 34 right and 14 left handed adults. Our results indicate that speech representation is unrelated to digit characteristics and therefore purportedly pT. We discuss these findings in relation to androgen theories of lateralisation.

  9. From Wheatstone to Cameron and beyond: overview in 3-D and 4-D imaging technology

    NASA Astrophysics Data System (ADS)

    Gilbreath, G. Charmaine

    2012-02-01

    This paper reviews three-dimensional (3-D) and four-dimensional (4-D) imaging technology, from Wheatstone through today, with some prognostications for near future applications. This field is rich in variety, subject specialty, and applications. A major trend, multi-view stereoscopy, is moving the field forward to real-time wide-angle 3-D reconstruction as breakthroughs in parallel processing and multi-processor computers enable very fast processing. Real-time holography meets 4-D imaging reconstruction at the goal of achieving real-time, interactive, 3-D imaging. Applications to telesurgery and telemedicine as well as to the needs of the defense and intelligence communities are also discussed.

  10. Coupled Ocean-Atmosphere 4D-Var: Formulation and Sensitivity Analysis Results

    NASA Astrophysics Data System (ADS)

    Ngodock, Hans; Carrier, Matthew; Xu, Liang; Amerault, Clark; Campbell, Tim; Rowley, Clark

    2016-04-01

    The US Navy is currently developing the first coupled ocean-atmosphere four-dimensional variational (4D-Var) data assimilation system to be used for short-term regional forecasting. This project merges the 4D-Var capabilities of the atmospheric component of the Coupled Ocean/Atmospheric Mesoscale Prediction System (COAMPS©) with the Navy Coastal Ocean Model (NCOM) through the Earth System Modeling Framework (ESMF). This will provide the coupled ocean-atmosphere forecast with a fully balanced analysis that accounts for all combined observations in both primary fluids (i.e. ocean and atmosphere). In this present work, the formulation of the system is presented in detail along with a series of adjoint sensitivity analysis results using the coupled ocean-atmosphere adjoint model. The sensitivity of the atmosphere (ocean) to each ocean (atmosphere) model variable is analyzed in detail in order to illustrate the usefulness of this approach in the coupled data assimilation system.

  11. Development and applications of 4-D ultrasound (dynamic 3-D) in neurosonology.

    PubMed

    Delcker, A; Schürks, M; Polz, H

    1999-10-01

    The development and application of color-coded data in three-dimensional (3-D) reconstruction or four-dimensional (4-D) imaging (equal to dynamic 3-D) are demonstrated. In 4-D imaging, electrocardiography-triggered data acquisition of consecutive phases during the heart cycle are stored to form a multiphase 3-D data set. The option of color-coded data gives a new insight into such hemodynamic information. In the past, 3-D reconstructions were simple unicolor images, as in power mode, and the color-coded hemodynamic information was lost. These new options are presented here, along with color-coded data in examples of angiographically controlled pathologic results in extracranial and intracranial vessels.

  12. HATS-4b: A Dense Hot Jupiter Transiting a Super Metal-rich G star

    NASA Astrophysics Data System (ADS)

    Jordán, Andrés; Brahm, Rafael; Bakos, G. Á.; Bayliss, D.; Penev, K.; Hartman, J. D.; Zhou, G.; Mancini, L.; Mohler-Fischer, M.; Ciceri, S.; Sato, B.; Csubry, Z.; Rabus, M.; Suc, V.; Espinoza, N.; Bhatti, W.; de Val-Borro, M.; Buchhave, L.; Csák, B.; Henning, T.; Schmidt, B.; Tan, T. G.; Noyes, R. W.; Béky, B.; Butler, R. P.; Shectman, S.; Crane, J.; Thompson, I.; Williams, A.; Martin, R.; Contreras, C.; Lázár, J.; Papp, I.; Sári, P.

    2014-08-01

    We report the discovery by the HATSouth survey of HATS-4b, an extrasolar planet transiting a V = 13.46 mag G star. HATS-4b has a period of P ≈ 2.5167 days, mass of Mp ≈ 1.32 M Jup, radius of Rp ≈ 1.02 R Jup, and density of ρ p = 1.55 ± 0.16 g cm-3 ≈1.24 ρJup. The host star has a mass of 1.00 M ⊙, a radius of 0.92 R ⊙, and a very high metallicity [Fe/H]=0.43 ± 0.08. HATS-4b is among the densest known planets with masses between 1 and 2 M J and is thus likely to have a significant content of heavy elements of the order of 75 M ⊕. In this paper we present the data reduction, radial velocity measurements, and stellar classification techniques adopted by the HATSouth survey for the CORALIE spectrograph. We also detail a technique for simultaneously estimating vsin i and macroturbulence using high resolution spectra. The HATSouth network is operated by a collaboration consisting of Princeton University (PU), the Max Planck Institut für Astronomie (MPIA), and the Australian National University (ANU). The station at Las Campanas Observatory (LCO) of the Carnegie Institution is operated by PU in conjunction with collaborators at the Pontificia Universidad Católica de Chile, the station at the High Energy Spectroscopic Survey site is operated in conjunction with MPIA, and the station at Siding Spring Observatory (SSO) is operated jointly with ANU. This paper includes data gathered with the 6.5 m Magellan Telescopes located at LCO, Chile. Based in part on data collected at Subaru Telescope, which is operated by the National Astronomical Observatory of Japan, and on observations made with the MPG/ESO 2.2 m Telescope at the ESO Observatory in La Silla. This paper uses observations obtained with facilities of the Las Cumbres Observatory Global Telescope.

  13. SU-E-J-187: Individually Optimized Contrast-Enhancement 4D-CT for Pancreatic Adenocarcinoma in Radiotherapy Simulation

    SciTech Connect

    Xue, M; Patel, K; Regine, W; Lane, B; D'Souza, W; Lu, W; Klahr, P

    2014-06-01

    Purpose: To study the feasibility of individually optimized contrastenhancement (CE) 4D-CT for pancreatic adenocarcinoma (PDA) in radiotherapy simulation. To evaluate the image quality and contrast enhancement of tumor in the CE 4D-CT, compared to the clinical standard of CE 3D-CT and 4D-CT. Methods: In this IRB-approved study, each of the 7 PDA patients enrolled underwent 3 CT scans: a free-breathing 3D-CT with contrast (CE 3D-CT) followed by a 4D-CT without contrast (4D-CT) in the first study session, and a 4D-CT with individually synchronized contrast injection (CE 4D-CT) in the second study session. In CE 4D-CT, the time of full contrast injection was determined based on the time of peak enhancement for the test injection, injection rate, table speed, and longitudinal location and span of the pancreatic region. Physicians contoured both the tumor (T) and the normal pancreatic parenchyma (P) on the three CTs (end-of-exhalation for 4D-CT). The contrast between the tumor and normal pancreatic tissue was computed as the difference of the mean enhancement level of three 1 cm3 regions of interests in T and P, respectively. Wilcoxon rank sum test was used to statistically compare the scores and contrasts. Results: In qualitative evaluations, both CE 3D-CT and CE 4D-CT scored significantly better than 4D-CT (4.0 and 3.6 vs. 2.6). There was no significant difference between CE 3D-CT and CE 4D-CT. In quantitative evaluations, the contrasts between the tumor and the normal pancreatic parenchyma were 0.6±23.4, −2.1±8.0, and −19.6±28.8 HU, in CE 3D-CT, 4D-CT, and CE 4D-CT, respectively. Although not statistically significant, CE 4D-CT achieved better contrast enhancement between the tumor and the normal pancreatic parenchyma than both CE 3D-CT and 4DCT. Conclusion: CE 4D-CT achieved equivalent image quality and better contrast enhancement between tumor and normal pancreatic parenchyma than the clinical standard of CE 3D-CT and 4D-CT. This study was supported in part

  14. Characterization of an Additional Splice Acceptor Site Introduced into CYP4B1 in Hominoidae during Evolution.

    PubMed

    Schmidt, Eva M; Wiek, Constanze; Parkinson, Oliver T; Roellecke, Katharina; Freund, Marcel; Gombert, Michael; Lottmann, Nadine; Steward, Charles A; Kramm, Christof M; Yarov-Yarovoy, Vladimir; Rettie, Allan E; Hanenberg, Helmut

    2015-01-01

    CYP4B1 belongs to the cytochrome P450 family 4, one of the oldest P450 families whose members have been highly conserved throughout evolution. The CYP4 monooxygenases typically oxidize fatty acids to both inactive and active lipid mediators, although the endogenous ligand(s) is largely unknown. During evolution, at the transition of great apes to humanoids, the CYP4B1 protein acquired a serine instead of a proline at the canonical position 427 in the meander region. Although this alteration impairs P450 function related to the processing of naturally occurring lung toxins, a study in transgenic mice suggested that an additional serine insertion at position 207 in human CYP4B1 can rescue the enzyme stability and activity. Here, we report that the genomic insertion of a CAG triplet at the intron 5-exon 6 boundary in human CYP4B1 introduced an additional splice acceptor site in frame. During evolution, this change occurred presumably at the stage of Hominoidae and leads to two major isoforms of the CYP4B1 enzymes of humans and great apes, either with or without a serine 207 insertion (insSer207). We further demonstrated that the CYP4B1 enzyme with insSer207 is the dominant isoform (76%) in humans. Importantly, this amino acid insertion did not affect the 4-ipomeanol metabolizing activities or stabilities of the native rabbit or human CYP4B1 enzymes, when introduced as transgenes in human primary cells and cell lines. In our 3D modeling, this functional neutrality of insSer207 is compatible with its predicted location on the exterior surface of CYP4B1 in a flexible side chain. Therefore, the Ser207 insertion does not rescue the P450 functional activity of human CYP4B1 that has been lost during evolution.

  15. 4D atlas of the mouse embryo for precise morphological staging.

    PubMed

    Wong, Michael D; van Eede, Matthijs C; Spring, Shoshana; Jevtic, Stefan; Boughner, Julia C; Lerch, Jason P; Henkelman, R Mark

    2015-10-15

    After more than a century of research, the mouse remains the gold-standard model system, for it recapitulates human development and disease and is quickly and highly tractable to genetic manipulations. Fundamental to the power and success of using a mouse model is the ability to stage embryonic mouse development accurately. Past staging systems were limited by the technologies of the day, such that only surface features, visible with a light microscope, could be recognized and used to define stages. With the advent of high-throughput 3D imaging tools that capture embryo morphology in microscopic detail, we now present the first 4D atlas staging system for mouse embryonic development using optical projection tomography and image registration methods. By tracking 3D trajectories of every anatomical point in the mouse embryo from E11.5 to E14.0, we established the first 4D atlas compiled from ex vivo 3D mouse embryo reference images. The resulting 4D atlas comprises 51 interpolated 3D images in this gestational range, resulting in a temporal resolution of 72 min. From this 4D atlas, any mouse embryo image can be subsequently compared and staged at the global, voxel and/or structural level. Assigning an embryonic stage to each point in anatomy allows for unprecedented quantitative analysis of developmental asynchrony among different anatomical structures in the same mouse embryo. This comprehensive developmental data set offers developmental biologists a new, powerful staging system that can identify and compare differences in developmental timing in wild-type embryos and shows promise for localizing deviations in mutant development.

  16. In-treatment 4D cone-beam CT with image-based respiratory phase recognition.

    PubMed

    Kida, Satoshi; Masutani, Yoshitaka; Yamashita, Hideomi; Imae, Toshikazu; Matsuura, Taeko; Saotome, Naoya; Ohtomo, Kuni; Nakagawa, Keiichi; Haga, Akihiro

    2012-07-01

    The use of respiration-correlated cone-beam computed tomography (4D-CBCT) appears to be crucial for implementing precise radiation therapy of lung cancer patients. The reconstruction of 4D-CBCT images requires a respiratory phase. In this paper, we propose a novel method based on an image-based phase recognition technique using normalized cross correlation (NCC). We constructed the respiratory phase by searching for a region in an adjacent projection that achieves the maximum correlation with a region in a reference projection along the cranio-caudal direction. The data on 12 lung cancer patients acquired just prior to treatment and on 3 lung cancer patients acquired during volumetric modulated arc therapy treatment were analyzed in the search for the effective area of cone-beam projection images for performing NCC with 12 combinations of registration area and segment size. The evaluation was done by a "recognition rate" defined as the ratio of the number of peak inhales detected with our method to that detected by eye (manual tracking). The average recognition rate of peak inhale with the most efficient area in the present method was 96.4%. The present method was feasible even when the diaphragm was outside the field of view. With the most efficient area, we reconstructed in-treatment 4D-CBCT by dividing the breathing signal into four phase bins; peak exhale, peak inhale, and two intermediate phases. With in-treatment 4D-CBCT images, it was possible to identify the tumor position and the tumor size in moments of inspiration and expiration, in contrast to in-treatment CBCT reconstructed with all projections.

  17. Combined C4d and CD3 immunostaining predicts immunoglobulin (Ig)A nephropathy progression

    PubMed Central

    Faria, B; Henriques, C; Matos, A C; Daha, M R; Pestana, M; Seelen, M

    2015-01-01

    A number of molecules have been shown recently to be involved in the pathogenesis and progression of immunoglobulin (Ig)A nephropathy (IgAN). Among these, we have selected C4d (complement lectin pathway involvement), CD3 (T cell marker, traducing interstitial inflammation), transglutaminase 2 (TGase-2, involved in tissue fibrosis development) and p-extracelluar-regulated kinase (ERK)1/2 (protein kinase intracellular signaling molecule) to perform a panel of immunohistological biomarkers and assess its predictive value for disease progression. Immunohistochemical staining of these biomarkers was performed in paraffin sections from 74 renal biopsy cases with the clinical diagnosis of IgAN. Association between score analysis of these parameters and disease course was assessed through univariate and multivariate analysis, including baseline clinical and histological data. Univariate analysis showed that glomerular C4d, tubulointerstitial TGase2 and CD3 scores were associated with baseline proteinuria and disease progression. Multivariate analysis showed that only baseline estimated glomerular filtration rate (eGFR), C4d and CD3 were associated independently with progressive kidney disease (decline of at least 50% in the eGFR or progression to end-stage renal disease (ESRD) during the follow-up period). Establishing an accurate prediction model for IgAN progression is still a matter of research in clinical nephrology. The complement system, particularly lectin pathway activation, and T cell activation, have been shown previously to be potential modifiers of the disease course. Here we show that the combination of two histological biomarkers (C4d and CD3) can be a powerful predictor of IgAN progression and a potential useful tool for the clinical approach of this disease. PMID:25267249

  18. Model-driven physiological assessment of the mitral valve from 4D TEE

    NASA Astrophysics Data System (ADS)

    Voigt, Ingmar; Ionasec, Razvan Ioan; Georgescu, Bogdan; Houle, Helene; Huber, Martin; Hornegger, Joachim; Comaniciu, Dorin

    2009-02-01

    Disorders of the mitral valve are second most frequent, cumulating 14 percent of total number of deaths caused by Valvular Heart Disease each year in the United States and require elaborate clinical management. Visual and quantitative evaluation of the valve is an important step in the clinical workflow according to experts as knowledge about mitral morphology and dynamics is crucial for interventional planning. Traditionally this involves examination and metric analysis of 2D images comprising potential errors being intrinsic to the method. Recent commercial solutions are limited to specific anatomic components, pathologies and a single phase of cardiac 4D acquisitions only. This paper introduces a novel approach for morphological and functional quantification of the mitral valve based on a 4D model estimated from ultrasound data. A physiological model of the mitral valve, covering the complete anatomy and eventual shape variations, is generated utilizing parametric spline surfaces constrained by topological and geometrical prior knowledge. The 4D model's parameters are estimated for each patient using the latest discriminative learning and incremental searching techniques. Precise evaluation of the anatomy using model-based dynamic measurements and advanced visualization are enabled through the proposed approach in a reliable, repeatable and reproducible manner. The efficiency and accuracy of the method is demonstrated through experiments and an initial validation based on clinical research results. To the best of our knowledge this is the first time such a patient specific 4D mitral valve model is proposed, covering all of the relevant anatomies and enabling to model the common pathologies at once.

  19. 4D Traction Force Microscopy Reveals Asymmetric Cortical Forces in Migrating Dictyostelium Cells

    NASA Astrophysics Data System (ADS)

    Delanoë-Ayari, H.; Rieu, J. P.; Sano, M.

    2010-12-01

    We present a 4D (x; y; z; t) force map of Dictyostelium cells crawling on a soft gel substrate. Vertical forces are of the same order as the tangential ones. The cells pull the substratum upward along the cell, medium, or substratum contact line and push it downward under the cell except for the pseudopods. We demonstrate quantitatively that the variations in the asymmetry in cortical forces correlates with the variations of the direction and speed of cell displacement.

  20. A design of a DICOM-RT-based tool box for nonrigid 4D dose calculation.

    PubMed

    Wong, Victy Y W; Baker, Colin R; Leung, T W; Tung, Stewart Y

    2016-03-01

    The study was aimed to introduce a design of a DICOM-RT-based tool box to facilitate 4D dose calculation based on deformable voxel-dose registration. The computational structure and the calculation algorithm of the tool box were explicitly discussed in the study. The tool box was written in MATLAB in conjunction with CERR. It consists of five main functions which allow a) importation of DICOM-RT-based 3D dose plan, b) deformable image registration, c) tracking voxel doses along breathing cycle, d) presentation of temporal dose distribution at different time phase, and e) derivation of 4D dose. The efficacy of using the tool box for clinical application had been verified with nine clinical cases on retrospective-study basis. The logistic and the robustness of the tool box were tested with 27 applications and the results were shown successful with no computational errors encountered. In the study, the accumulated dose coverage as a function of planning CT taken at end-inhale, end-exhale, and mean tumor position were assessed. The results indicated that the majority of the cases (67%) achieved maximum target coverage, while the planning CT was taken at the temporal mean tumor position and 56% at the end-exhale position. The comparable results to the literature imply that the studied tool box can be reliable for 4D dose calculation. The authors suggest that, with proper application, 4D dose calculation using deformable registration can provide better dose evaluation for treatment with moving target. PACS number(s): 87.55.kh.