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  1. The Tim8-Tim13 complex has multiple substrate binding sites and binds cooperatively to Tim23.

    PubMed

    Beverly, Kristen N; Sawaya, Michael R; Schmid, Einhard; Koehler, Carla M

    2008-10-24

    The Tim8-Tim13 complex, located in the mitochondrial intermembrane space, functions in the TIM22 import pathway that mediates the import of the mitochondrial carriers Tim23, Tim22, and Tim17 into the mitochondrial inner membrane. The Tim8-Tim13 complex assembles as a hexamer and binds to the substrate Tim23 to chaperone the hydrophobic Tim23 across the aqueous intermembrane space. However, both structural features of the Tim8-Tim13 complex and the binding interaction to Tim23 remain poorly defined. The crystal structure of the yeast Tim8-Tim13 complex, reported here at 2.6 A resolution, reveals that the architecture of the Tim8-Tim13 complex is similar to those of other chaperones such as Tim9-Tim10, prefoldin, and Skp, in which long helices extend from a central body like tentacles from a jellyfish. Surface plasmon resonance was applied to investigate interactions between the Tim8-Tim13 complex and Tim23. The Tim8-Tim13 complex contained approximately six binding sites and showed a complex binding interaction indicative of positive cooperativity rather than a simple bimolecular interaction. By combining results from the structural and binding studies, we provide a molecular model of the Tim8-Tim13 complex binding to Tim23. The regions where the tentacle helices attach to the body of the Tim8-Tim13 complex contain six hydrophobic pockets that likely interact with specific sequences of Tim23 and possibly other substrates. Smaller hydrophobic patches on the tentacles themselves likely interact nonspecifically with the substrate's transmembrane helices, shielding it from the aqueous intermembrane space. The central region of Tim23, which enters the intermembrane space first, may serve to nucleate the binding of the Tim8-Tim13 complex, thereby initiating the chaperoned translocation of Tim23 to the mitochondrial inner membrane. PMID:18706423

  2. The TIMS instrument

    NASA Technical Reports Server (NTRS)

    Stanich, Chuck

    1986-01-01

    The scan head and spectrometer of the Thermal Infrared Multispectral Scanner (TIMS) are mounted in the unpressurized tail cone of a NASA/NSTL Learjet and operated through a hole cut through the skin. Design criteria are discussed. The digitized field of view is described. The functions of the scan head and spectrometer are examined.

  3. The TIMS Data User's Workshop

    NASA Technical Reports Server (NTRS)

    Kahle, Anne B. (Editor); Abbott, Elsa (Editor)

    1986-01-01

    A workshop was held to bring together all users of data from NASA's airborne Thermal Infrared Multispectral Scanner (TIMS). The purpose was to allow users to compare results, data processing algorithms, and problems encountered; to update the users on the latest instrument changes and idiosyncracies, including distribution of the TIMS investigation guide; to inform the users of the wide range of problems that are currently being tackled by other TIMS investigators; to explore ways to expand the user community; to discuss current areas where more basic research is required; and to discuss the future directions of NASA's thermal infrared remote sensing programs. Also discussed were: geology, land use, archeology; and data processing and noise research.

  4. Corner Office: EBSCO's Tim Collins

    ERIC Educational Resources Information Center

    Fialkoff, Francine; Oder, Norman

    2008-01-01

    This article presents an interview with Tim Collins, president of EBSCO Publishing. The amiable Collins put EBSCO Publishing (EP) on the map through a combination of first-rate search and user-friendly interfaces, a long list of strategic acquisitions, and a dedicated, stable staff. Now, the company Collins has nurtured for over two decades ranks…

  5. Tim-3 and Tim-4 as the potential targets for antitumor therapy.

    PubMed

    Cheng, Lin; Ruan, Zhihua

    2015-01-01

    Both Tim-3 and Tim-4 belong to the T-cell immunoglobulin and mucin domain (Tim) gene family, which plays a critical role in immunoregulation. Tim-3 has been suggested as a negative regulator of anti-tumor immunity due to its function on inducing T cells exhaustion in cancer. In addition to its expression on exhausted T cells, Tim-3 also has been reported to up-regulate on nature killer (NK) cells and promote NK cells functionally exhausted in cancer. While Tim-3 selectively expression on most types of leukemia stem cells, it promotes the progression of acute myeloid leukemia. Recently, data from experimental models of tumor discovered that Tim-3 and Tim-4 up-regulation on tumor associated dendritic cells and macrophages attenuated the anti-tumor effects of cancer vaccines and chemotherapy. Moreover, co-blockage of Tim-3 and PD-1, Tim-3 and CD137, Tim-3 and carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) could enhance cell-mediated immunity in advanced tumor, and combined treatment with anti-Tim-3 and anti-Tim-4 mAbs further increase the efficacy of cancer vaccines. The therapeutic manipulation of TIM-3 and TIM-4 may provide a novel strategy to improve the clinical efficacy of cancer immunotherapy.

  6. Application of TIMS data in stratigraphic analysis

    NASA Technical Reports Server (NTRS)

    Lang, H. R.

    1986-01-01

    An in-progress study demonstrates the utility of Thermal Infrared Multispectral Scanner (TIMS) data for unraveling the stratigraphic sequence of a western interior, North American foreland basin. The TIMS data can be used to determine the stratigraphic distribution of minerals that are diagnostic of specific depositional distribution. The thematic mapper (TM) and TIMS data were acquired in the Wind River/Bighorn area of central Wyoming in November 1982, and July 1983, respectively. Combined image processing, photogeologic, and spectral analysis methods were used to: map strata; construct stratigraphic columns; correlate data; and identify mineralogical facies.

  7. TIM-3 Regulates Distinct Functions in Macrophages.

    PubMed

    Ocaña-Guzman, Ranferi; Torre-Bouscoulet, Luis; Sada-Ovalle, Isabel

    2016-01-01

    The transmembrane protein TIM-3 is a type I protein expressed by sub-types of lymphoid cells, such as lymphocytes Th1, Th17, Tc1, NK, as well as in myeloid cells. Scientific evidence indicates that this molecule acts as a negative regulator of T lymphocyte activation and that its expression is modified in viral infections or autoimmune diseases. In addition to evidence from lymphoid cells, the function of TIM-3 has been investigated in myeloid cells, such as monocytes, macrophages, and dendritic cells (DC), where studies have demonstrated that it can regulate cytokine production, cell activation, and the capture of apoptotic bodies. Despite these advances, the function of TIM-3 in myeloid cells and the molecular mechanisms that this protein regulates are not yet fully understood. This review examines the most recent evidence concerning the function of TIM-3 when expressed in myeloid cells, primarily macrophages, and the potential impact of that function on the field of basic immunology.

  8. A geologic atlas of TIMS data

    NASA Technical Reports Server (NTRS)

    Abbott, Elsa

    1986-01-01

    In the three years since the first data were taken, it was well demonstrated that the Thermal Infrared Multispectral Scanner (TIMS), properly used, can be a most valuable tool for the geologist. Compilation of the TIMS data into a geological atlas was felt to be useful. Several data sets were extensively studied to establish TIMS as a geologic tool and to explore the optimum enhancement techniques. It was found that a decorrelation stretch of bands 1, 3, and 5 enhance the data to a form that is very useful and this enhancement will be used in the geologic atlas along with an accompanying geologic map and description. Many data sets are well published and familiar to TIMS users, but there are some sets that, for lack of time and funds, were not thoroughly studied or published. A short description of these least studied sets of data is presented. The images presented along with the many previously studied and published TIMS images constitute an enormously useful set of information for the geologist in the 8 to 10 micron range.

  9. Tim29 is a novel subunit of the human TIM22 translocase and is involved in complex assembly and stability.

    PubMed

    Kang, Yilin; Baker, Michael James; Liem, Michael; Louber, Jade; McKenzie, Matthew; Atukorala, Ishara; Ang, Ching-Seng; Keerthikumar, Shivakumar; Mathivanan, Suresh; Stojanovski, Diana

    2016-01-01

    The TIM22 complex mediates the import of hydrophobic carrier proteins into the mitochondrial inner membrane. While the TIM22 machinery has been well characterised in yeast, the human complex remains poorly characterised. Here, we identify Tim29 (C19orf52) as a novel, metazoan-specific subunit of the human TIM22 complex. The protein is integrated into the mitochondrial inner membrane with it's C-terminus exposed to the intermembrane space. Tim29 is required for the stability of the TIM22 complex and functions in the assembly of hTim22. Furthermore, Tim29 contacts the Translocase of the Outer Mitochondrial Membrane, TOM complex, enabling a mechanism for transport of hydrophobic carrier substrates across the aqueous intermembrane space. Identification of Tim29 highlights the significance of analysing mitochondrial import systems across phylogenetic boundaries, which can reveal novel components and mechanisms in higher organisms. PMID:27554484

  10. Essential Roles of TIM-1 and TIM-4 Homologs in Adaptive Humoral Immunity in a Zebrafish Model.

    PubMed

    Xu, Xiao-Gang; Hu, Jing-Fang; Ma, Jun-Xia; Nie, Li; Shao, Tong; Xiang, Li-Xin; Shao, Jian-Zhong

    2016-02-15

    TIM-1 and TIM-4 proteins have become increasingly attractive for their critical functions in immune modulation, particularly in CD4(+) Th2 cell activation. Thus, these proteins were hypothesized to regulate adaptive humoral immunity. However, further evidence is needed to validate this hypothesis. This study describes the molecular and functional characteristics of TIM-1 and TIM-4 homologs from a zebrafish (Danio rerio) model (D. rerio TIM [DrTIM]-1 and DrTIM-4). DrTIM-1 and DrTIM-4 were predominantly expressed in CD4(+) T cells and MHC class II(+) APCs under the induction of Ag stimulation. Blockade or knockdown of both DrTIM-1 and DrTIM-4 significantly decreased Ag-specific CD4(+) T cell activation, B cell proliferation, Ab production, and vaccinated immunoprotection against bacterial infection. This result suggests that DrTIM-1 and DrTIM-4 serve as costimulatory molecules required for the full activation of adaptive humoral immunity. DrTIM-1 was detected to be a trafficking protein located in the cytoplasm of CD4(+) T cells. It can translocate onto the cell surface under stimulation by TIM-4-expressing APCs, which might be a precise regulatory strategy for CD4(+) T cells to avoid self-activation before APCs stimulation. Furthermore, a unique alternatively spliced soluble DrTIM-4 variant was identified to exert a negative regulatory effect on the proliferation of CD4(+) T cells. The above findings highlight a novel costimulatory mechanism underlying adaptive immunity. This study enriches the current knowledge on TIM-mediated immunity and provides a cross-species understanding of the evolutionary history of costimulatory systems throughout vertebrate evolution.

  11. The structure of Tim50(164–361) suggests the mechanism by which Tim50 receives mitochondrial presequences

    SciTech Connect

    Li, Jingzhi; Sha, Bingdong

    2015-08-25

    The Tim50 crystal structure indicates that the IMS domain of Tim50 exhibits significant structural plasticity within the putative presequence-binding groove. Mitochondrial preproteins are transported through the translocase of the outer membrane (TOM) complex. Tim50 and Tim23 then transfer preproteins with N-terminal targeting presequences through the intermembrane space (IMS) across the inner membrane. The crystal structure of the IMS domain of Tim50 [Tim50(164–361)] has previously been determined to 1.83 Å resolution. Here, the crystal structure of Tim50(164–361) at 2.67 Å resolution that was crystallized using a different condition is reported. Compared with the previously determined Tim50(164–361) structure, significant conformational changes occur within the protruding β-hairpin of Tim50 and the nearby helix A2. These findings indicate that the IMS domain of Tim50 exhibits significant structural plasticity within the putative presequence-binding groove, which may play important roles in the function of Tim50 as a receptor protein in the TIM complex that interacts with the presequence and multiple other proteins. More interestingly, the crystal packing indicates that helix A1 from the neighboring monomer docks into the putative presequence-binding groove of Tim50(164–361), which may mimic the scenario of Tim50 and the presequence complex. Tim50 may recognize and bind the presequence helix by utilizing the inner side of the protruding β-hairpin through hydrophobic interactions. Therefore, the protruding β-hairpin of Tim50 may play critical roles in receiving the presequence and recruiting Tim23 for subsequent protein translocations.

  12. Tim Rollins + K.O.S.

    ERIC Educational Resources Information Center

    Klawans, Stuart

    1990-01-01

    Explains how artist, Tim Rollins, worked with Kids of Survival, a group of secondary school students in the South Bronx area of New York City, to create large scale art works inspired by Franz Kafka's book, "Amerika." Describes scale, materials used, use of contrasts, and inspiration for these artworks. Suggests similar art activities for students…

  13. TIM-3 Regulates Distinct Functions in Macrophages

    PubMed Central

    Ocaña-Guzman, Ranferi; Torre-Bouscoulet, Luis; Sada-Ovalle, Isabel

    2016-01-01

    The transmembrane protein TIM-3 is a type I protein expressed by sub-types of lymphoid cells, such as lymphocytes Th1, Th17, Tc1, NK, as well as in myeloid cells. Scientific evidence indicates that this molecule acts as a negative regulator of T lymphocyte activation and that its expression is modified in viral infections or autoimmune diseases. In addition to evidence from lymphoid cells, the function of TIM-3 has been investigated in myeloid cells, such as monocytes, macrophages, and dendritic cells (DC), where studies have demonstrated that it can regulate cytokine production, cell activation, and the capture of apoptotic bodies. Despite these advances, the function of TIM-3 in myeloid cells and the molecular mechanisms that this protein regulates are not yet fully understood. This review examines the most recent evidence concerning the function of TIM-3 when expressed in myeloid cells, primarily macrophages, and the potential impact of that function on the field of basic immunology. PMID:27379093

  14. Thermal Infrared Multispectral Scanner (TIMS): An investigator's guide to TIMS data

    NASA Technical Reports Server (NTRS)

    Palluconi, F. D.; Meeks, G. R.

    1985-01-01

    The Thermal Infrared Multispectral Scanner (TIMS) is a NASA aircraft scanner providing six channel spectral capability in the thermal infrared region of the electromagnetic spectrum. Operating in the atmospheric window region (8 to 12 micrometers) with a channel sensitivity of approximately 0.1 C, TIMS may be used whenever an accurate measure of the Earth's surface is needed. A description of this scanner is provided as well as a discussion of data acquisition and reduction.

  15. Plasma soluble Tim-3 emerges as an inhibitor in sepsis: sepsis contrary to membrane Tim-3 on monocytes.

    PubMed

    Ren, F; Li, J; Jiang, X; Xiao, K; Zhang, D; Zhao, Z; Ai, J; Hou, C; Jia, Y; Han, G; Xie, L

    2015-11-01

    Immune dysfunction is the main characteristic of sepsis. T cell Ig and mucin domain protein 3 (Tim-3) on the monocytes has been reported to promote immune homeostasis during sepsis, but the influences of plasm soluble Tim-3 (sTim-3) on the immune system during sepsis remain unknown. Here, 100 patients with different severities of sepsis (40 sepsis, 42 severe sepsis, and 18 septic shock) were enrolled in this study. The Tim-3 and human leukocyte antigen-DR (HLA-DR) on the circulating monocytes were detected using flow cytometry. Plasma sTim-3 was detected by enzyme-linked immunosorbent assay. Inflammatory factors and two kinds of A disintegrin and metalloprotease (ADAM) - ADAM10 and ADAM17 were assessed. The Tim-3 and HLA-DR on the monocytes decreased with increasing sepsis severity. The sTim-3 was reduced in the sepsis and severe sepsis patients but was elevated in the septic shock patients who exhibited significant immunosuppression as predicted by HLA-DR. sTim-3 levels were negatively correlated with IL-12 and TNF-α. ADAM10 and ADAM17, sheddases of Tim-3, exhibited trends toward elevations in the septic shock group. In conclusion, sTim-3 was involved in the development of sepsis. The homeostasis-promoting role of the Tim-3 on the monocytes was disrupted, while the inhibitory role of sTim-3 emerged during sepsis-induced immunosuppression.

  16. A small Tim homohexamer in the relict mitochondrion of Cryptosporidium.

    PubMed

    Alcock, Felicity; Webb, Chaille T; Dolezal, Pavel; Hewitt, Victoria; Shingu-Vasquez, Miguel; Likić, Vladimir A; Traven, Ana; Lithgow, Trevor

    2012-01-01

    The apicomplexan parasite Cryptosporidium parvum possesses a mitosome, a relict mitochondrion with a greatly reduced metabolic capability. This mitosome houses a mitochondrial-type protein import apparatus, but elements of the protein import pathway have been reduced, and even lost, through evolution. The small Tim protein family is a case in point. The genomes of C. parvum and related species of Cryptosporidium each encode just one small Tim protein, CpTimS. This observation challenged the tenet that small Tim proteins are always found in pairs as α3β3 hexamers. We show that the atypical CpTimS exists as a relatively unstable homohexamer, shedding light both on the early evolution of the small Tim protein family and on small Tim hexamer formation in contemporary eukaryotes.

  17. The crystal structure of triosephosphate isomerase (TIM) from Thermotoga maritima: a comparative thermostability structural analysis of ten different TIM structures.

    PubMed

    Maes, D; Zeelen, J P; Thanki, N; Beaucamp, N; Alvarez, M; Thi, M H; Backmann, J; Martial, J A; Wyns, L; Jaenicke, R; Wierenga, R K

    1999-11-15

    The molecular mechanisms that evolution has been employing to adapt to environmental temperatures are poorly understood. To gain some further insight into this subject we solved the crystal structure of triosephosphate isomerase (TIM) from the hyperthermophilic bacterium Thermotoga maritima (TmTIM). The enzyme is a tetramer, assembled as a dimer of dimers, suggesting that the tetrameric wild-type phosphoglycerate kinase PGK-TIM fusion protein consists of a core of two TIM dimers covalently linked to 4 PGK units. The crystal structure of TmTIM represents the most thermostable TIM presently known in its 3D-structure. It adds to a series of nine known TIM structures from a wide variety of organisms, spanning the range from psychrophiles to hyperthermophiles. Several properties believed to be involved in the adaptation to different temperatures were calculated and compared for all ten structures. No sequence preferences, correlated with thermal stability, were apparent from the amino acid composition or from the analysis of the loops and secondary structure elements of the ten TIMs. A common feature for both psychrophilic and T. maritima TIM is the large number of salt bridges compared with the number found in mesophilic TIMs. In the two thermophilic TIMs, the highest amount of accessible hydrophobic surface is buried during the folding and assembly process.

  18. Lithologic mapping of silicate rocks using TIMS

    NASA Technical Reports Server (NTRS)

    Gillespie, A. R.

    1986-01-01

    Common rock-forming minerals have thermal infrared spectral features that are measured in the laboratory to infer composition. An airborne Daedalus scanner (TIMS) that collects six channels of thermal infrared radiance data (8 to 12 microns), may be used to measure these same features for rock identification. Previously, false-color composite pictures made from channels 1, 3, and 5 and emittance spectra for small areas on these images were used to make lithologic maps. Central wavelength, standard deviation, and amplitude of normal curves regressed on the emittance spectra are related to compositional information for crystalline igneous silicate rocks. As expected, the central wavelength varies systematically with silica content and with modal quartz content. Standard deviation is less sensitive to compositional changes, but large values may result from mixed admixture of vegetation. Compression of the six TIMS channels to three image channels made from the regressed parameters may be effective in improving geologic mapping from TIMS data, and these synthetic images may form a basis for the remote assessment of rock composition.

  19. Novel insights into Tim-4 function in autoimmune diseases.

    PubMed

    Fang, Xin-Yu; Xu, Wang-Dong; Pan, Hai-Feng; Leng, Rui-Xue; Ye, Dong-Qing

    2015-06-01

    T-cell immunoglobulin domain and mucin domain-4 (Tim-4) was first recognized as a costimulatory molecule regulating T-cell activation. Dysregulation of Tim-4 has been found in some autoimmune conditions, particularly in the immune cells. Recently, Tim-4 was found to be critical for regulating T cells, with the ability of inhibiting naïve CD4(+) T cells and Th17 cells, increasing Th2 cell development. Tim-4 can also enhance T cell expansion via linker for activation of T cells, extracellular signal-regulated kinase (ERK) and Protein kinase B (PKB, also known as Akt) signaling pathways. Moreover, the Tim-4 signaling pathway may affect multiple molecular processes in autoimmune diseases. A number of previous studies have demonstrated that Tim-4 influences chronic autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus. In addition, an association between Tim-4 polymorphisms and susceptibility to several autoimmune diseases have been identified, such as RA. Taken together, recent works have indicated that Tim-4 may represent a novel target for the treatment of autoimmune diseases. In this article, we will discuss the Tim-4 function and the therapeutic potential of modulating the Tim-4 in autoimmune diseases.

  20. The Essential Function of the Small Tim Proteins in the TIM22 Import Pathway Does Not Depend on Formation of the Soluble 70-Kilodalton Complex

    PubMed Central

    Murphy, Michael P.; Leuenberger, Danielle; Curran, Sean P.; Oppliger, Wolfgang; Koehler, Carla M.

    2001-01-01

    The TIM22 protein import pathway of the yeast mitochondrion contains several components, including a family of five proteins (Tim8p, -9p, -10p, -12p, and -13p [Tim, for translocase of inner membrane]) that are located in the intermembrane space and are 25% identical. Tim9p and Tim10p have dual roles in mediating the import of inner membrane proteins. Like the Tim8p-Tim13p complex, the Tim9p-Tim10p complex functions as a putative chaperone to guide hydrophobic precursors across the intermembrane space. Like membrane-associated Tim12p, they are members of the Tim18p-Tim22p-Tim54p membrane complex that mediates precursor insertion into the membrane. To understand the role of this family in protein import, we have used a genetic approach to manipulate the complement of the small Tim proteins. A strain has been constructed that lacks the 70-kDa soluble Tim8p-Tim13p and Tim9p-Tim10p complexes in the intermembrane space. Instead, a functional version of Tim9p (Tim9S67Cp), identified as a second-site suppressor of a conditional tim10 mutant, maintains viability. Characterization of this strain revealed that Tim9S67Cp and Tim10p were tightly associated with the inner membrane, the soluble 70-kDa Tim8p-Tim13p and Tim9p-Tim10p complexes were not detectable, and the rate of protein import into isolated mitochondria proceeded at a slower rate. An arrested translocation intermediate bound to Tim9S67Cp was located in the intermembrane space, associated with the inner membrane. We suggest that the 70-kDa complexes facilitate import, similar to the outer membrane receptors of the TOM (hetero-oligomeric translocase of the outer membrane) complex, and the essential role of Tim9p and Tim10p may be to mediate protein insertion in the inner membrane with the TIM22 complex. PMID:11509656

  1. Import of small Tim proteins into the mitochondrial intermembrane space.

    PubMed

    Lutz, Thomas; Neupert, Walter; Herrmann, Johannes M

    2003-09-01

    Proteins of the intermembrane space (IMS) of mitochondria are typically synthesized without presequences. Little is known about their topogenesis. We used Tim13, a member of the 'small Tim protein' family, as model protein to investigate the mechanism of translocation into the IMS. Tim13 contains four conserved cysteine residues that bind a zinc ion as cofactor. Import of Tim13 did not depend on the membrane potential or ATP hydrolysis. Upon import into mitochondria Tim13 adopted a stably folded conformation in the IMS. Mutagenesis of the cysteine residues or pretreatment with metal chelators interfered with folding of Tim13 in vitro and impaired its import into mitochondria. Upon depletion of metal ions or modification of cysteine residues, imported Tim13 diffused back out of the IMS. We propose an import pathway in which (1) Tim13 can pass through the TOM complex into and out of the IMS in an unfolded conformation, and (2) cofactor acquisition stabilizes folding on the trans side of the outer membrane and traps Tim13 in the IMS, and drives unidirectional movement of the protein across the outer membrane of mitochondria.

  2. Import of small Tim proteins into the mitochondrial intermembrane space

    PubMed Central

    Lutz, Thomas; Neupert, Walter; Herrmann, Johannes M.

    2003-01-01

    Proteins of the intermembrane space (IMS) of mitochondria are typically synthesized without presequences. Little is known about their topogenesis. We used Tim13, a member of the ‘small Tim protein’ family, as model protein to investigate the mechanism of translocation into the IMS. Tim13 contains four conserved cysteine residues that bind a zinc ion as cofactor. Import of Tim13 did not depend on the membrane potential or ATP hydrolysis. Upon import into mitochondria Tim13 adopted a stably folded conformation in the IMS. Mutagenesis of the cysteine residues or pretreatment with metal chelators interfered with folding of Tim13 in vitro and impaired its import into mitochondria. Upon depletion of metal ions or modification of cysteine residues, imported Tim13 diffused back out of the IMS. We propose an import pathway in which (1) Tim13 can pass through the TOM complex into and out of the IMS in an unfolded conformation, and (2) cofactor acquisition stabilizes folding on the trans side of the outer membrane and traps Tim13 in the IMS, and drives unidirectional movement of the protein across the outer membrane of mitochondria. PMID:12941692

  3. Tim29 is a novel subunit of the human TIM22 translocase and is involved in complex assembly and stability

    PubMed Central

    Kang, Yilin; Baker, Michael James; Liem, Michael; Louber, Jade; McKenzie, Matthew; Atukorala, Ishara; Ang, Ching-Seng; Keerthikumar, Shivakumar; Mathivanan, Suresh; Stojanovski, Diana

    2016-01-01

    The TIM22 complex mediates the import of hydrophobic carrier proteins into the mitochondrial inner membrane. While the TIM22 machinery has been well characterised in yeast, the human complex remains poorly characterised. Here, we identify Tim29 (C19orf52) as a novel, metazoan-specific subunit of the human TIM22 complex. The protein is integrated into the mitochondrial inner membrane with it’s C-terminus exposed to the intermembrane space. Tim29 is required for the stability of the TIM22 complex and functions in the assembly of hTim22. Furthermore, Tim29 contacts the Translocase of the Outer Mitochondrial Membrane, TOM complex, enabling a mechanism for transport of hydrophobic carrier substrates across the aqueous intermembrane space. Identification of Tim29 highlights the significance of analysing mitochondrial import systems across phylogenetic boundaries, which can reveal novel components and mechanisms in higher organisms. DOI: http://dx.doi.org/10.7554/eLife.17463.001 PMID:27554484

  4. The 1994 TIMS airborne calibration experiment: Castaic Lake, California

    NASA Technical Reports Server (NTRS)

    Realmuto, Vincent J.; Hook, Simon J.; Vandenbosch, Jeannette

    1995-01-01

    This summary describes the 9 March 1994 Thermal Infrared Multispectral Scanner (TIMS) airborne calibration experiment conducted at Castaic Lake, California. This experiment was a collaborative effort between the TIMS and Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) science teams at the Jet Propulsion Laboratory (JPL). TIMS was flown on the NASA/Ames Research Center C130 with the new retractable air fence installed in the TIMS instrument bay. The purpose of this experiment was to determine if the fence would reduce the air turbulence in the TIMS instrument bay, thereby reducing the errors in calibration caused by wind-blast cooling of the blackbody reference sources internal to TIMS. Previous experiments have indicated that the wind blast effect could cause TIMS to over-estimate surface temperatures by more than 10 C. We have examined the TIMS data from twelve lines flown over Castaic Lake. Four of the lines were flown at an altitude of approximately 2.5 km (MSL), four at an altitude of approximately 6.7 km, and four at approximately 8.3 km. At each altitude there were flights with northern and southern headings, with the aircraft level and at a positive pitch (nose-up attitude). The suite of twelve flights was designed to subject the TIMS/air fence system to different wind conditions and air temperatures. The TIMS flights were supported by a ground-truth team, who measured lake surface temperatures from a boat, and an atmosphere characterization team, who launched an airsonde and measured solar irradiance with a Reagan Sun Photometer. The Reagan measurements were used to construct a time-series of estimates of the total abundance of water vapor in the atmospheric column. These estimates were used to constrain modifications of the airsonde water vapor profile measurements made when processing the TIMS data with a customized version of the MODTRAN radiative transfer code.

  5. Conserved motifs reveal details of ancestry and structure in the small TIM chaperones of the mitochondrial intermembrane space.

    PubMed

    Gentle, Ian E; Perry, Andrew J; Alcock, Felicity H; Likić, Vladimir A; Dolezal, Pavel; Ng, Ee Ting; Purcell, Anthony W; McConnville, Malcolm; Naderer, Thomas; Chanez, Anne-Laure; Charrière, Fabien; Aschinger, Caroline; Schneider, André; Tokatlidis, Kostas; Lithgow, Trevor

    2007-05-01

    The mitochondrial inner and outer membranes are composed of a variety of integral membrane proteins, assembled into the membranes posttranslationally. The small translocase of the inner mitochondrial membranes (TIMs) are a group of approximately 10 kDa proteins that function as chaperones to ferry the imported proteins across the mitochondrial intermembrane space to the outer and inner membranes. In yeast, there are 5 small TIM proteins: Tim8, Tim9, Tim10, Tim12, and Tim13, with equivalent proteins reported in humans. Using hidden Markov models, we find that many eukaryotes have proteins equivalent to the Tim8 and Tim13 and the Tim9 and Tim10 subunits. Some eukaryotes provide "snapshots" of evolution, with a single protein showing the features of both Tim8 and Tim13, suggesting that a single progenitor gene has given rise to each of the small TIMs through duplication and modification. We show that no "Tim12" family of proteins exist, but rather that variant forms of the cognate small TIMs have been recently duplicated and modified to provide new functions: the yeast Tim12 is a modified form of Tim10, whereas in humans and some protists variant forms of Tim9, Tim8, and Tim13 are found instead. Sequence motif analysis reveals acidic residues conserved in the Tim10 substrate-binding tentacles, whereas more hydrophobic residues are found in the equivalent substrate-binding region of Tim13. The substrate-binding region of Tim10 and Tim13 represent structurally independent domains: when the acidic domain from Tim10 is attached to Tim13, the Tim8-Tim13(10) complex becomes essential and the Tim9-Tim10 complex becomes dispensable. The conserved features in the Tim10 and Tim13 subunits provide distinct binding surfaces to accommodate the broad range of substrate proteins delivered to the mitochondrial inner and outer membranes.

  6. BOREAS Level-0 TIMS Imagery: Digital Counts in BIL Format

    NASA Technical Reports Server (NTRS)

    Newcomer, Jeffrey A.; Dominquez, Roseanne; Hall, Forrest G. (Editor)

    2000-01-01

    For BOREAS, the TIMS imagery, along with the other remotely sensed images, was collected to provide spatially extensive information over the primary study areas. The level-0 TIMS images cover the time periods of 16-Apr-1994 to 20-Apr-1994 and 06-Sep-1994 to 17-Sep-1994. The images are available in their original uncalibrated format.

  7. CEACAM1 regulates TIM-3-mediated tolerance and exhaustion.

    PubMed

    Huang, Yu-Hwa; Zhu, Chen; Kondo, Yasuyuki; Anderson, Ana C; Gandhi, Amit; Russell, Andrew; Dougan, Stephanie K; Petersen, Britt-Sabina; Melum, Espen; Pertel, Thomas; Clayton, Kiera L; Raab, Monika; Chen, Qiang; Beauchemin, Nicole; Yazaki, Paul J; Pyzik, Michal; Ostrowski, Mario A; Glickman, Jonathan N; Rudd, Christopher E; Ploegh, Hidde L; Franke, Andre; Petsko, Gregory A; Kuchroo, Vijay K; Blumberg, Richard S

    2015-01-15

    T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T

  8. Characterizing Functional Domains for TIM-Mediated Enveloped Virus Entry

    PubMed Central

    Moller-Tank, Sven; Albritton, Lorraine M.; Rennert, Paul D.

    2014-01-01

    ABSTRACT T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members were recently identified as phosphatidylserine (PtdSer)-mediated virus entry-enhancing receptors (PVEERs). These proteins enhance entry of Ebola virus (EBOV) and other viruses by binding PtdSer on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. The PtdSer-binding activity of the immunoglobulin-like variable (IgV) domain is essential for both virus binding and internalization by TIM-1. However, TIM-3, whose IgV domain also binds PtdSer, does not effectively enhance virus entry, indicating that other domains of TIM proteins are functionally important. Here, we investigate the domains supporting enhancement of enveloped virus entry, thereby defining the features necessary for a functional PVEER. Using a variety of chimeras and deletion mutants, we found that in addition to a functional PtdSer-binding domain PVEERs require a stalk domain of sufficient length, containing sequences that promote an extended structure. Neither the cytoplasmic nor the transmembrane domain of TIM-1 is essential for enhancing virus entry, provided the protein is still plasma membrane bound. Based on these defined characteristics, we generated a mimic lacking TIM sequences and composed of annexin V, the mucin-like domain of α-dystroglycan, and a glycophosphatidylinositol anchor that functioned as a PVEER to enhance transduction of virions displaying Ebola, Chikungunya, Ross River, or Sindbis virus glycoproteins. This identification of the key features necessary for PtdSer-mediated enhancement of virus entry provides a basis for more effective recognition of unknown PVEERs. IMPORTANCE T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members are recently identified phosphatidylserine (PtdSer)-mediated virus entry-enhancing receptors (PVEERs). These proteins enhance virus entry by binding the phospholipid, PtdSer, present on the viral

  9. Project TIMS (Teaching Integrated Math/Science)

    NASA Technical Reports Server (NTRS)

    Edwards, Leo, Jr.

    1993-01-01

    The goal of this project is to increase the scientific knowledge and appreciation bases and skills of pre-service and in-service middle school teachers, so as to impact positively on teaching, learning, and student retention. This report lists the objectives and summarizes the progress thus far. Included is the working draft of the TIMS (Teaching Integrated Math/Science) curriculum outline. Seven of the eight instructional subject-oriented modules are also included. The modules include informative materials and corresponding questions and educational activities in a textbook format. The subjects included here are the universe and stars; the sun and its place in the universe; our solar system; astronomical instruments and scientific measurements; the moon and eclipses; the earth's atmosphere: its nature and composition; and the earth: directions, time, and seasons. The module not included regards winds and circulation.

  10. Regulation of the cycling of timeless (tim) RNA.

    PubMed

    Wang, G K; Ousley, A; Darlington, T K; Chen, D; Chen, Y; Fu, W; Hickman, L J; Kay, S A; Sehgal, A

    2001-06-01

    Circadian rhythms in Drosophila depend upon expression of the timeless (tim) and period (per) genes, which encode interacting components of the endogenous clock. These two clock genes show a robust circadian oscillation in transcription rate as well as RNA and protein levels. Transcriptional activation of both genes requires the basic helix-loop-helix (bHLH) PAS transcription factors dCLOCK (dCLK) and CYCLE (CYC), which bind E-box elements. We investigated the role of E-box elements in regulating behavioral rhythmicity and tim gene expression. We show that mutation of the upstream E-box in the tim gene prevents the rescue by tim cDNA sequences of the arrhythmic tim(01) phenotype. RNA encoded by this mutated tim transgene fails to cycle and is expressed at low levels. While a tim transgene carrying a wild-type E-box restores behavioral rhythms, tim RNA levels are intermediate to those of the mutant E-box transgenic lines and wild type, and do not display high amplitude cycling. On the other hand, high-amplitude RNA cycling was consistently obtained with a tim transgene that contains genomic, rather than cDNA, sequences. To identify additional sequences that may be required for tim cycling, we investigated the role of an E-box in the first intron of the tim gene through cell culture experiments. In these experiments, the presence of this intron did not have any effect on the activation of tim transcription by dCLK/CYC. As the upstream E-box was implicated in activation by dCLK/CYC in cell culture, we assayed sequences containing this E-box for association with proteins in fly head extracts. These studies provide the first biochemical evidence for an in vivo complex containing dCLK and CYC that binds the tim upstream sequence and is detected at all times of day. Together, these data highlight molecular mechanisms that are critical for behavioral rhythms.

  11. TIM-1 signaling in B cells regulates antibody production

    SciTech Connect

    Ma, Juan; Usui, Yoshihiko; Takeda, Kazuyoshi; Harada, Norihiro; Yagita, Hideo; Okumura, Ko; Akiba, Hisaya

    2011-03-11

    Highlights: {yields} TIM-1 is highly expressed on anti-IgM + anti-CD40-stimulated B cells. {yields} Anti-TIM-1 mAb enhanced proliferation and Ig production on activated B cell in vitro. {yields} TIM-1 signaling regulates Ab production by response to TI-2 and TD antigens in vivo. -- Abstract: Members of the T cell Ig and mucin (TIM) family have recently been implicated in the control of T cell-mediated immune responses. In this study, we found TIM-1 expression on anti-IgM- or anti-CD40-stimulated splenic B cells, which was further up-regulated by the combination of anti-IgM and anti-CD40 Abs. On the other hand, TIM-1 ligand was constitutively expressed on B cells and inducible on anti-CD3{sup +} anti-CD28-stimulated CD4{sup +} T cells. In vitro stimulation of activated B cells by anti-TIM-1 mAb enhanced proliferation and expression of a plasma cell marker syndecan-1 (CD138). We further examined the effect of TIM-1 signaling on antibody production in vitro and in vivo. Higher levels of IgG2b and IgG3 secretion were detected in the culture supernatants of the anti-TIM-1-stimulated B cells as compared with the control IgG-stimulated B cells. When immunized with T-independent antigen TNP-Ficoll, TNP-specific IgG1, IgG2b, and IgG3 Abs were slightly increased in the anti-TIM-1-treated mice. When immunized with T-dependent antigen OVA, serum levels of OVA-specific IgG2b, IgG3, and IgE Abs were significantly increased in the anti-TIM-1-treated mice as compared with the control IgG-treated mice. These results suggest that TIM-1 signaling in B cells augments antibody production by enhancing B cell proliferation and differentiation.

  12. 27. YCC CREW THAT REBUILT PIMA POINT TRAILS. TIM BEALE, ...

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

    27. YCC CREW THAT REBUILT PIMA POINT TRAILS. TIM BEALE, NPS TRAILS, FRONT ROW RIGHT; BERNIE PONYAH, NPS YCC SUPERVISOR, BACK ROW RIGHT. - West Rim Drive, Between Grand Canyon Village & Hermit Rest, Grand Canyon, Coconino County, AZ

  13. ISS Update: NBL Orion Flight Lead Tim Goddard

    NASA Video Gallery

    NASA Public Affairs Officer Brandi Dean talks with Tim Goddard, Neutral Buoyancy Laboratory (NBL) Orion Flight Lead, about how the NBL is used to train rescue and recovery personnel for future Orio...

  14. TIMS observations of surface emissivity in HAPEX-Sahel

    NASA Technical Reports Server (NTRS)

    Schmugge, Thomas; Hook, Simon; Kahle, Anne

    1995-01-01

    The Thermal Infrared Multispectral Scanner (TIMS) was flown on the NASA C-130 aircraft for a series of 12 flights during HAPEX-Sahel at altitudes ranging from 0.25 to 6 km (0.6 to 15 m resolution). TIMS provides coverage of the 8 to 12 micrometer thermal infrared band in 6 contiguous channels. Thus it is possible to observe the spectral behavior of the surface emissivity over this wavelength interval.

  15. Evidence for carbohydrate recognition and homotypic and heterotypic binding by the TIM family.

    PubMed

    Wilker, Peter R; Sedy, John R; Grigura, Vadim; Murphy, Theresa L; Murphy, Kenneth M

    2007-06-01

    The T cell Ig domain and mucin domain (TIM) proteins form a conserved family of transmembrane cell-surface glycoproteins expressed by a variety of tissues. Each TIM protein contains a single V-type Ig domain, a glycosylated mucin-like domain, a transmembrane domain and a cytoplasmic domain. TIM proteins recognize a diverse array of ligands, including H-ferritin, galectin-9 as well as other TIM family members. In this study, we demonstrate that the Ig domains of murine TIM-1, -3 and -4 display calcium-dependent binding to ligands expressed by murine splenocytes and several non-murine cell lines, indicating non-species-specific ligand recognition. Further, the intrafamilial interaction of various TIM family Ig domains with surface-expressed TIM-1 and TIM-4 requires an intact TIM-1 and TIM-4 glycosylated mucin stalk. Importantly, we also uncovered the previously unrecognized potential for homotypic TIM interactions in forming ligand-receptor pairs. Using a glycan array screen, we identified the novel capacity of the TIM-3 Ig domain to recognize specific carbohydrate moieties, suggesting a role for carbohydrate modification along with protein epitopes in TIM ligand recognition. Identification of the carbohydrate-binding capacity of TIM proteins helps explain the diversity of ligands recognized by this family and adds to our understanding of homotypic and heterotypic interactions between TIM family members.

  16. T cell Immunoglobulin Mucin Protein (TIM)-4 binds phosphatidylserine and mediates uptake of apoptotic cells

    PubMed Central

    Kobayashi, Norimoto; Karisola, Piia; Peña-Cruz, Victor; Dorfman, David M.; Jinushi, Masahisa; Umetsu, Sarah E.; Butte, Manish J.; Nagumo, Haruo; Chernova, Irene; Zhu, Baogong; Sharpe, Arlene H.; Ito, Susumu; Dranoff, Glenn; Kaplan, Gerardo G.; Casasnovas, Jose M.; Umetsu, Dale T.; DeKruyff, Rosemarie H.; Freeman, Gordon J.

    2009-01-01

    Summary The T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance. Both TIM-4, expressed on human and mouse macrophages and dendritic cells, and TIM-1 specifically bind to phosphatidylserine (PS) on the surface of apoptotic cells and do not bind to any other phospholipid tested. TIM-4+ peritoneal macrophages, TIM-1+ kidney cells, as well as TIM-4 or TIM-1 transfected cells efficiently phagocytose apoptotic cells and phagocytosis can be blocked by TIM-4 or TIM-1 mAbs. TIM proteins have a unique binding cavity made by an unusual conformation of the CC′ and FG loops of the TIM IgV domain and mutations in this cavity eliminated PS binding and phagocytosis. TIM-4 mAbs that block PS binding and phagocytosis map to epitopes in this binding cavity. These results show that TIM-4 and TIM-1 are immunologically restricted members of the group of receptors that recognize PS, critical for the efficient clearance of apoptotic cells and prevention of autoimmunity. PMID:18082433

  17. Analysis of TIMS performance subjected to simulated wind blast

    NASA Technical Reports Server (NTRS)

    Jaggi, S.; Kuo, S.

    1992-01-01

    The results of the performance of the Thermal Infrared Multispectral Scanner (TIMS) when it is subjected to various wind conditions in the laboratory are described. Various wind conditions were simulated using a 24 inch fan or combinations of air jet streams blowing toward either or both of the blackbody surfaces. The fan was used to simulate a large volume of air flow at moderate speeds (up to 30 mph). The small diameter air jets were used to probe TIMS system response in reaction to localized wind perturbations. The maximum nozzle speed of the air jet was 60 mph. A range of wind directions and speeds were set up in the laboratory during the test. The majority of the wind tests were conducted under ambient conditions with the room temperature fluctuating no more than 2 C. The temperature of the high speed air jet was determined to be within 1 C of the room temperature. TIMS response was recorded on analog tape. Additional thermistor readouts of the blackbody temperatures and thermocouple readout of the ambient temperature were recorded manually to be compared with the housekeeping data recorded on the tape. Additional tests were conducted under conditions of elevated and cooled room temperatures. The room temperature was varied between 19.5 to 25.5 C in these tests. The calibration parameters needed for quantitative analysis of TIMS data were first plotted on a scanline-by-scanline basis. These parameters are the low and high blackbody temperature readings as recorded by the TIMS and their corresponding digitized count values. Using these values, the system transfer equations were calculated. This equation allows us to compute the flux for any video count by computing the slope and intercept of the straight line that relates the flux to the digital count. The actual video of the target (the lab floor in this case) was then compared with a simulated target. This simulated target was assumed to be a blackbody at emissivity of .95 degrees and the temperature was

  18. Atmospheric corrections for TIMS estimated emittance

    NASA Technical Reports Server (NTRS)

    Warner, T. A.; Levandowski, D. W.

    1992-01-01

    The estimated temperature of the average of 500 lines of Thermal Infrared Multispectral Scanner (TIMS) data of the Pacific Ocean, from flight line 94, collected on 30 Sep. 1988, at 1931 GMT is shown. With no atmospheric corrections, estimated temperature decreases away from nadir (the center of the scan line). A LOWTRAN modeled correction, using local radiosonde data and instrument scan angle information, results in reversed limb darkening effects for most bands, and does not adequately correct all bands to the same temperature. The atmosphere tends to re-radiate energy at the wavelengths at which it most absorbs, and thus the overall difference between corrected and uncorrected temperatures is approximately 40 C, despite the average LOWTRAN calculated transmittance of only 60 percent between 8.1 and 11.6 microns. An alternative approach to atmospheric correction is a black body normalization. This is done by calculating a normalization factor for each pixel position and wavelength, which when applied results in a single calculated temperature, as would be expected for a gray body with near uniform emittance. The black body adjustment is based on the atmospheric conditions over the sea. The ground elevation profile along the remaining 3520 scan lines (approximately 10 km) of flight line 94, up the slopes of Kilauea, determined from aircraft pressure and laser altimeter data is shown. This flight line includes a large amount of vegetation that is clearly discernible on the radiance image, being much cooler than the surrounding rocks. For each of the 3520 scan lines, pixels were classified as vegetation or 'other'. A moving average of 51 lines was applied to the composite vegetation emittance for each scan line, to reduce noise. Assuming vegetation to be like water, and to act as gray body with an emittance of 0.986 across the spectrum, it is shown that that the LOWTRAN induced artifacts are severe, and other than for the 0.9.9 micron channel, not significantly

  19. Random tag insertions by Transposon Integration mediated Mutagenesis (TIM).

    PubMed

    Hoeller, Brigitte M; Reiter, Birgit; Abad, Sandra; Graze, Ina; Glieder, Anton

    2008-10-01

    Transposon Integration mediated Mutagenesis (TIM) is a broadly applicable tool for protein engineering. This method combines random integration of modified bacteriophage Mu transposons with their subsequent defined excision employing type IIS restriction endonuclease AarI. TIM enables deletion or insertion of an arbitrary number of bases at random positions, insertion of functional sequence tags at random positions, replacing randomly selected triplets by a specific codon (e.g. scanning) and site-saturation mutagenesis. As a proof of concept a transposon named GeneOpenerAarIKan was designed and employed to introduce 6xHis tags randomly into the esterase EstC from Burkholderia gladioli. A TIM library was screened with colony based assays for clones with an integrated 6xHis tag and for clones exhibiting esterase activity. The employed strategy enables the isolation of randomly tagged active enzymes in single mutagenesis experiments.

  20. The regulation of TIM-3 transcription in T cells involves c-Jun binding but not CpG methylation at the TIM-3 promoter.

    PubMed

    Yun, Su Jin; Jun, Ka-Jung; Komori, Kuniharu; Lee, Mi Jin; Kwon, Myung-Hee; Chwae, Yong-Joon; Kim, Kyongmin; Shin, Ho-Joon; Park, Sun

    2016-07-01

    Tim-3 is an immunomodulatory protein that is expressed constitutively on monocytes but is induced in activated T cells. The mechanisms involved in the regulation of TIM-3 transcription are poorly understood. In the present study, we investigated whether methylation of the TIM-3 promoter is involved in regulatingTIM-3 transcription in T cells, and identified a transcription factor that regulates TIM-3 transcription by associating with the TIM-3 minimal promoter region. Pyrosequencing of the TIM-3 promoter up to -1440bp revealed 11 hypermethylated CpG sites and 4 hypomethylated CpG sites in human CD4(+) T cells as well as in CD11b(+) cells. Dimethylation of histone H3 lysine 4 (H3K4), a mark of transcriptional activation, was predominantly found in the proximal TIM-3 promoter -954 to -34bp region, whereas trimethylation of H3K9 and H3K27, which are markers of transcriptional suppression, were mostly observed in the distal promoter -1549 to -1048bp region in human CD4(+) T cells and CD11b(+) cells. However, no change in the methylation status of CpG sites and the histone H3 in the TIM-3 promoter was found during induction of TIM-3 transcription in T cells. Finally, AP-1 involvement in TIM-3 transcription was shown in relation with the TIM-3 minimal promoter -146 to +144bp region. The present study defines the minimal TIM-3 promoter region and demonstrates its interaction with c-Jun during TIM-3 transcription in CD4(+) T cells.

  1. Up-regulation of Tim-3 is associated with poor prognosis of patients with colon cancer.

    PubMed

    Zhou, Encheng; Huang, Qing; Wang, Ji; Fang, Chengfeng; Yang, Leilei; Zhu, Min; Chen, Jianhui; Chen, Lihua; Dong, Milian

    2015-01-01

    Tim-3 (T cell immunoglobulin and mucin domain 3), belonging to the member of the novel Tim family, has been confirmed that it plays a critical negative role in regulating the immune responses against viral infection and carcinoma. Recently, it has also been reported that the over-expression of Tim-3 is associated with poor prognosis in solid tumors. However, the role of Tim-3 in colorectal cancer remains largely unknown. In the current study, we aim to investigate the expression of Tim-3 in colorectal carcinoma and discuss the relationship between Tim-3 expression and colon cancer prognosis, thus speculating the possible role of Tim-3 in colon cancer progression. Colon cancer tissues and paired normal tissue were obtained from 201 patients with colon cancer for preparation of tissue microarray. Tim-3 expression was evaluated by immunohistochemical staining. The Tim-3 expression level was evaluated by q-RT-PCR, western blot and immunocytochemistry in four colon cancer cell lines (HT-29, HCT116, LoVo, SW620). Tim-3 was expressed in 92.5% tumor tissue samples and 86.5% corresponding normal tissue samples. Expression of Tim-3 was significantly higher in tumor tissues than in normal tissues (P < 0.0001). Tim-3 expression in colon cancer tissues is in correlation with colon cancer lymphatic metastasis and TNM (P < 0.0001). Multivariate analysis demonstrated that Tim-3 expression could be a potential independent prognostic factor for colon cancer patients (P < 0.0001). Kaplan-Meier survival analysis result showed that patients with higher Tim-3 expression had a significantly shorter survival time than those with lower Tim-3 expression patients. Our results indicated that Tim-3 might participate in the tumorgenesis of colon cancer and Tim-3 expression might be a potential independent prognostic factor for patients with colorectal cancer.

  2. Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer.

    PubMed

    Kang, Chiao-Wen; Dutta, Avijit; Chang, Li-Yuan; Mahalingam, Jayashri; Lin, Yung-Chang; Chiang, Jy-Ming; Hsu, Chen-Yu; Huang, Ching-Tai; Su, Wan-Ting; Chu, Yu-Yi; Lin, Chun-Yen

    2015-01-01

    TIM-3 functions to enforce CD8+ T cell exhaustion, a dysfunctional state associated with the tolerization of tumor microenvironment. Here we report apoptosis of IFN-γ competent TIM-3+ population of tumor-infiltrating CD8+ T cells in colon cancer. In humans suffering from colorectal cancer, TIM-3+ population is higher in cancer tissue-resident relative to peripheral blood CD8+ T cells. Both the TIM-3+ and TIM-3- cancer tissue-resident CD8+ T cells secrete IFN-γ of comparable levels, although apoptotic cells are more in TIM-3+ compared to TIM-3- population. In mouse CT26 colon tumor model, majority of tumor-infiltrating CD8+ T cells express TIM-3 and execute cytolysis function with higher effector cytokine secretion and apoptosis in TIM-3+ compared to TIM-3- population. The tumor cells secrete galectin-9, which increases apoptosis of tumor-infiltrating CD8+ T cells. Galectin-9/TIM-3 signaling blockade with anti-TIM-3 antibody reduces the apoptosis and in addition, inhibits tumor growth in mice. The blockade increases therapeutic efficacy of cyclophosphamide to treat tumor in mice as well. These results reveal a previously unexplored role of TIM-3 on tumor-infiltrating CD8+ T cells in vivo.

  3. Activation of TIM1 induces colon cancer cell apoptosis via modulating Fas ligand expression.

    PubMed

    Wang, Hao; Zhang, Xueyan; Sun, Wenjing; Hu, Xiaocui; Li, Xiaolin; Fu, Songbin; Liu, Chen

    2016-04-29

    The pathogenesis of colon cancer is unclear. It is proposed that TIM1 has an association with human cancer. The present study aims to investigate the role of TIM1 activation in the inhibition of human colon cancer cells. In this study, human colon cancer cell line, HT29 and T84 cells were cultured. The expression of TIM1 was assessed by real time RT-PCR and Western blotting. The TIM1 on the cancer cells was activated in the culture by adding recombinant TIM4. The chromatin structure at the FasL promoter locus was assessed by chromatin immunoprecipitation. The apoptosis of the cancer cells was assessed by flow cytometry. The results showed that human colon cancer cell lines, HT29 cells and T84 cells, expressed TIM1. Activation of TIM1 by exposing the cells to TIM4 significantly increased the frequency of apoptotic colon cancer cells. The expression of FasL was increased in the cancer cells after treating by TIM4. Blocking Fas or FasL abolished the exposure to TIM4-induced T84 cell apoptosis. In conclusion, HT29 cells and T84 cells express TIM1; activation TIM1 can induce the cancer cell apoptosis. TIM1 may be a novel therapeutic target of colon cancer.

  4. Fishery status assessment of Tims Ford Reservoir with management recommendations

    SciTech Connect

    Lowery, D.R.; Taylor, F.H.

    1986-04-01

    Fishery information was collected on Tims Ford Reservoir to determine the status of the fishery resource as an indictor of the biological health of these reservoirs, and to formulate management recommendations for improving the status of the biological resource that can be implemented by TVA and/or cooperating agencies.

  5. TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection.

    PubMed

    Jayaraman, Pushpa; Jacques, Miye K; Zhu, Chen; Steblenko, Katherine M; Stowell, Britni L; Madi, Asaf; Anderson, Ana C; Kuchroo, Vijay K; Behar, Samuel M

    2016-03-01

    While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain-containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis.

  6. Wise Leadership for Student Success: An Interview with Tim White

    ERIC Educational Resources Information Center

    Kezar, Adrianna

    2015-01-01

    Adrianna Kezar recently sat down with Chancellor Tim White of the California State University system to discuss, among many other things, the newly released California State Graduation Initiative and what it will take to enact it. The key commitments of the initiative are: (1) hire more tenure-track faculty; (2) develop engaged advising; (3) solve…

  7. TIM-3 Regulates Innate Immune Cells to Induce Fetomaternal Tolerance

    PubMed Central

    Chabtini, Lola; Mfarrej, Bechara; Mounayar, Marwan; Zhu, Bing; Batal, Ibrahim; Dakle, Pranal J; Smith, Brian D; Boenisch, Olaf; Najafian, Nader; Akiba, Hisaya; Yagita, Hideo; Guleria, Indira

    2012-01-01

    TIM-3 is constitutively expressed on subsets of macrophages and dendritic cells. Its expression on other cells of the innate immune system and its role in fetomaternal tolerance has not yet been explored. Here we investigate the role of TIM-3 expressing innate immune cells in the regulation of tolerance at the fetomaternal interface (FMI) using an allogeneic mouse model of pregnancy. Blockade of TIM-3 results in accumulation of inflammatory granulocytes and macrophages at the utero-placental interface and up regulation of pro-inflammatory cytokines. Furthermore, TIM-3 blockade inhibits the phagocytic potential of uterine macrophages resulting in a build up of apoptotic bodies at the utero-placental interface that elicits a local immune response. In response to inflammatory cytokines, Ly-6ChiGneg M-MDSCs (monocytic myeloid derived suppressor cells) expressing iNOS and arginase 1 are induced. However, these suppressive cells fail to down-regulate the inflammatory cascade induced by inflammatory granulocytes (Ly-6Cint Ghi) and apoptotic cells; the increased production of IFNγ and TNFα by inflammatory granulocytes leads to abrogation of tolerance at the fetomaternal interface and fetal rejection. These data highlight the interplay between cells of the innate immune system at the FMI and their influence on successful pregnancy in mice. PMID:23180822

  8. Association of TIM-1 5383-5397ins/del and TIM-3 -1541C>T polymorphisms with multiple sclerosis in Isfahan population.

    PubMed

    Mazrouei, F; Ganjalikhani-Hakemi, M; Salehi, R; Alesahebfosoul, F; Etemadifar, M; Pouladian, M; Meshkat, R; Nekoueian, Sh; Zarkesh-Esfahani, H; Ziyaee-Ghahnaviyeh, M

    2016-06-01

    Multiple sclerosis (MS) is an organ-specific autoimmune disease in central nervous system, affecting about 2.5 million people around the world. Probable involvement of two newly identified immunoregulator molecules, TIM-1 and TIM-3, has been reported in autoimmune diseases. In this study, for the first time, the association of TIM-1 5383-5397ins/del and TIM-3 -1541C>T polymorphisms with MS in an Iranian population was considered. The results of our study showed that there is no significant association between TIM-1 5383-5397ins/del and MS (P = 0.38); however, the frequency of CT genotype of TIM-3 -1541C>T in patient group was significantly higher than the control group, and there was a significant association between CT genotype and MS (P = 0.009, OR = 4.08).

  9. Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma.

    PubMed

    Xu, Liyun; Huang, Yanyan; Tan, Linlin; Yu, Wei; Chen, Dongdong; Lu, ChangChang; He, Jianying; Wu, Guoqing; Liu, Xiaoguang; Zhang, Yongkui

    2015-12-01

    T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to play an important role in mediating NK-cell function in human diseases. However, the relationship between Tim-3 expression in natural killer (NK) cells and human lung adenocarcinoma remains unclear. We therefore investigated the expression of Tim-3 in NK cells and explored the effect of Tim-3 blockade on NK cell-mediated activity in human lung adenocarcinoma. Upregulated expression of Tim-3 on CD3-CD56+ cells (P<0.05) and CD3-CD56(dim) cells (P<0.05) of patients with lung adenocarcinoma was detected by flow cytometry. Moreover, Tim-3 expression in CD3-CD56+ NK cells was higher in patients with lung adenocarcinoma with lymph node metastasis (LNM) (P<0.05) or with tumor stage T3-T4 (P<0.05). Tim-3 expression in CD56(dim) NK-cell subset was higher in patients with tumor size ≥3cm (P<0.05), or LNM (P<0.05) or with tumor stage T3-T4 (P<0.05). Further analysis showed that higher expressions of Tim-3 on both CD3-CD56+ NK cells and CD56(dim) NK-cell subset were independently correlated with shorter overall survival of patients with lung adenocarcinoma (log-rank test, P=0.0418, 0.0406, respectively). Importantly, blockade of Tim-3 signaling with anti-Tim-3 antibodies resulted in the increased cytotoxicity and IFN-γ production of peripheral NK cells from patients with lung adenocarcinoma. Our data indicate that Tim-3 expression in NK cells can function as a prognostic biomarker in human lung adenocarcinoma and support that Tim-3 could be a new target for an immunotherapeutic strategy.

  10. Interaction of divalent metal ions with human translocase of inner membrane of mitochondria Tim23.

    PubMed

    Feng, Wei; Zhang, Yongqiang; Deng, Honghua; Li, Shu Jie

    2016-06-17

    The preprotein translocase of the inner membrane of mitochondria (TIM23 complex) is the main entry gate for proteins of the matrix and the inner membrane. Tim23p, the core component of TIM23 complex, forms the import pore across the inner membrane and exerts a key function in the protein import. However, the interaction of divalent metal ions with Tim23p and the contribution in the interaction of presequence peptide with Tim23p are still unknown. Herein, we investigated the interaction of divalent metal ions with the intermembrane space domain of Tim23p (Tim23IMS) and the interaction of presequence peptides with Tim23IMS in presence of Ca(2+) ion by fluorescence spectroscopy in vitro. The static fluorescence quenching indicates the existence of strong binding between divalent metal ions and Tim23IMS. The order of the binding strength is Ca(2+), Mg(2+), Cu(2+), Mn(2+), and Co(2+) (from strong to weak). Moreover, the interaction of presequence peptides with Tim23IMS is weakened in presence of Ca(2+) ion, which implicates that Ca(2+) ion may play an important role in the protein import by TIM23 complex.

  11. DNA demethylation of the TIM-3 promoter is critical for its stable expression on T cells.

    PubMed

    Chou, F-C; Kuo, C-C; Chen, H-Y; Chen, H-H; Sytwu, H-K

    2016-04-01

    The T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is selectively expressed on terminally differentiated T helper 1 (Th1) cells and acts as a negative regulator that terminates Th1 responses. The dysregulation of TIM-3 expression on T cells is associated with several autoimmune phenotypes and with chronic viral infections; however, the mechanism of this regulation is unclear. In this study, we investigated the effect of DNA methylation on the expression of TIM-3. By analyzing the sequences of TIM-3 promoter regions in human and mouse, we identified a CpG island within the TIM-3 promoter and demonstrated that the promoter activity was controlled by DNA methylation. Furthermore, treatment with 5-aza-2'-deoxycytidine enhanced TIM-3 expression on mouse primary CD4(+) T cells under Th0-, Th1- or Th2-polarizing conditions. Finally, pyrosequencing analysis revealed that the methylation level of the TIM-3 promoter gradually decreased after each round of T-cell polarization, and this decrease was inversely correlated with TIM-3 expression. These data suggest that the DNA methylation of the TIM-3 promoter cooperates with lineage-specific transcription factors in the control of Th-cell development. In conclusion, DNA methylation-based regulation of TIM-3 may provide novel insights into understanding the dysregulation of TIM-3 expression under pathogenic conditions.

  12. Interaction of divalent metal ions with human translocase of inner membrane of mitochondria Tim23.

    PubMed

    Feng, Wei; Zhang, Yongqiang; Deng, Honghua; Li, Shu Jie

    2016-06-17

    The preprotein translocase of the inner membrane of mitochondria (TIM23 complex) is the main entry gate for proteins of the matrix and the inner membrane. Tim23p, the core component of TIM23 complex, forms the import pore across the inner membrane and exerts a key function in the protein import. However, the interaction of divalent metal ions with Tim23p and the contribution in the interaction of presequence peptide with Tim23p are still unknown. Herein, we investigated the interaction of divalent metal ions with the intermembrane space domain of Tim23p (Tim23IMS) and the interaction of presequence peptides with Tim23IMS in presence of Ca(2+) ion by fluorescence spectroscopy in vitro. The static fluorescence quenching indicates the existence of strong binding between divalent metal ions and Tim23IMS. The order of the binding strength is Ca(2+), Mg(2+), Cu(2+), Mn(2+), and Co(2+) (from strong to weak). Moreover, the interaction of presequence peptides with Tim23IMS is weakened in presence of Ca(2+) ion, which implicates that Ca(2+) ion may play an important role in the protein import by TIM23 complex. PMID:27178215

  13. Distinct Forms of Mitochondrial TOM-TIM Supercomplexes Define Signal-Dependent States of Preprotein Sorting▿

    PubMed Central

    Chacinska, Agnieszka; van der Laan, Martin; Mehnert, Carola S.; Guiard, Bernard; Mick, David U.; Hutu, Dana P.; Truscott, Kaye N.; Wiedemann, Nils; Meisinger, Chris; Pfanner, Nikolaus; Rehling, Peter

    2010-01-01

    Mitochondrial import of cleavable preproteins occurs at translocation contact sites, where the translocase of the outer membrane (TOM) associates with the presequence translocase of the inner membrane (TIM23) in a supercomplex. Different views exist on the mechanism of how TIM23 mediates preprotein sorting to either the matrix or inner membrane. On the one hand, two TIM23 forms were proposed, a matrix transport form containing the presequence translocase-associated motor (PAM; TIM23-PAM) and a sorting form containing Tim21 (TIM23SORT). On the other hand, it was reported that TIM23 and PAM are permanently associated in a single-entity translocase. We have accumulated distinct transport intermediates of preproteins to analyze the translocases in their active, preprotein-carrying state. We identified two different forms of active TOM-TIM23 supercomplexes, TOM-TIM23SORT and TOM-TIM23-PAM. These two supercomplexes do not represent separate pathways but are in dynamic exchange during preprotein translocation and sorting. Depending on the signals of the preproteins, switches between the different forms of supercomplex and TIM23 are required for the completion of preprotein import. PMID:19884344

  14. Preliminary crystallographic studies of yeast mitochondrial peripheral membrane protein Tim44p

    SciTech Connect

    Josyula, Ratnakar; Jin, Zhongmin; McCombs, Deborah; DeLucas, Lawrence; Sha, Bingdong

    2006-02-01

    Tim44p is an essential mitochondrial peripheral membrane protein. To investigate the mechanism by which Tim44p functions in the TIM23 translocon to deliver the mitochondrial protein precursors, the yeast Tim44p has been crystallized. Protein translocations across mitochondrial membranes play critical roles in mitochondrion biogenesis. Protein transport from the cell cytosol to the mitochondrial matrix is carried out by the translocase of the outer membrane (TOM) complex and the translocase of the inner membrane (TIM) complexes. Tim44p is an essential mitochondrial peripheral membrane protein and a major component of the TIM23 translocon. To investigate the mechanism by which Tim44p functions in the TIM23 translocon to deliver the mitochondrial protein precursors, the yeast Tim44p was crystallized. The crystals diffract to 3.2 Å using a synchrotron X-ray source and belong to space group P6{sub 3}22, with unit-cell parameters a = 124.25, c = 77.83 Å. There is one Tim44p molecule in one asymmetric unit, which corresponds to a solvent content of approximately 43%. Structure determination by MAD methods is under way.

  15. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity

    PubMed Central

    Freeman, Gordon J.; Casasnovas, Jose M.; Umetsu, Dale T.; DeKruyff, Rosemarie H.

    2010-01-01

    Summary The TIM (T cell/transmembrane, immunoglobulin, and mucin) gene family plays a critical role in regulating immune responses, including allergy, asthma, transplant tolerance, autoimmunity, and the response to viral infections. The unique structure of TIM immunoglobulin variable region domains allows highly specific recognition of phosphatidylserine (PtdSer), exposed on the surface of apoptotic cells. TIM-1, TIM-3, and TIM-4 all recognize PtdSer but differ in expression, suggesting that they have distinct functions in regulating immune responses. TIM-1, an important susceptibility gene for asthma and allergy, is preferentially expressed on T-helper 2 (Th2) cells and functions as a potent costimulatory molecule for T-cell activation. TIM-3 is preferentially expressed on Th1 and Tc1 cells, and generates an inhibitory signal resulting in apoptosis of Th1 and Tc1 cells. TIM-3 is also expressed on some dendritic cells and can mediate phagocytosis of apoptotic cells and cross-presentation of antigen. In contrast, TIM-4 is exclusively expressed on antigen-presenting cells, where it mediates phagocytosis of apoptotic cells and plays an important role in maintaining tolerance. TIM molecules thus provide a functional repertoire for recognition of apoptotic cells, which determines whether apoptotic cell recognition leads to immune activation or tolerance, depending on the TIM molecule engaged and the cell type on which it is expressed. PMID:20536563

  16. Inspiring pupils in STEM through Tim Peake's Principia Mission

    NASA Astrophysics Data System (ADS)

    Grant, Stephanie

    2016-04-01

    This poster looks at a particular case study of how a science programme with a lot of media attention can be embedded into schools to inspire pupils in STEM subjects. In this case, the UK has become very excited about their first publicly funded British astronaut, Tim Peake, visiting the International Space Station between December 2015 and June 2016. Tim is particularly keen to dedicate a lot of his time to education initiatives including undertaking a live radio contact with a handful of UK schools so that pupils can ask him their questions. A group of schools in Norfolk have won this opportunity and will host a live radio contact in February 2015. As part of this initiative, local schools (primary and secondary) are being encouraged to embed the mission into their curriculum in various ways using many excellent resources developed by a number of agencies. The range of these and our proposed methods for judging their efficacies are explored in this poster.

  17. The new airborne Thermal Infrared Multispectral Scanner (TIMS)

    NASA Technical Reports Server (NTRS)

    Kahle, A. B.

    1983-01-01

    A new airborne Thermal Infrared Multispectral Scanner (TIMS) with six bands between 8 and 12 microns is briefly characterized, and some results of remote sensing experiments are reported. The instrument has an instantaneous field of view of 2.5 milliradians, a total field of view of 80 deg, and a NE Delta T of approximately 0.1-0.3 C depending on the band. In the TIMS image of Death Valley, silica-rich rocks were easily separable from the nonsilicates. The Eureka Quartzite stood out in sharp contrast to other Ordovician and Cambrian metasediments, and Tertiary volcanic rocks were easily separable from both. Also distinguishable were various units in the fan gravels.

  18. GUM Analysis for TIMS and SIMS Isotopic Ratios in Graphite

    SciTech Connect

    Heasler, Patrick G.; Gerlach, David C.; Cliff, John B.; Petersen, Steven L.

    2007-04-01

    This report describes GUM calculations for TIMS and SIMS isotopic ratio measurements of reactor graphite samples. These isotopic ratios are used to estimate reactor burn-up, and currently consist of various ratios of U, Pu, and Boron impurities in the graphite samples. The GUM calculation is a propagation of error methodology that assigns uncertainties (in the form of standard error and confidence bound) to the final estimates.

  19. Techniques for noise removal and registration of TIMS data

    USGS Publications Warehouse

    Hummer-Miller, S.

    1990-01-01

    Extracting subtle differences from highly correlated thermal infrared aircraft data is possible with appropriate noise filters, constructed and applied in the spatial frequency domain. This paper discusses a heuristic approach to designing noise filters for removing high- and low-spatial frequency striping and banding. Techniques for registering thermal infrared aircraft data to a topographic base using Thematic Mapper data are presented. The noise removal and registration techniques are applied to TIMS thermal infrared aircraft data. -Author

  20. The Mexican Infrared-Optical New Technology Telescope: TIM Project

    NASA Astrophysics Data System (ADS)

    Cruz-Gonzalez, I.; Salas, L.; Ruiz, E.; Luna, E.; Pedrayes, M.; Sohn, E.; Si Erra, G.; Sanchez, B.; Valdez, J.; Gutierrez, L.; Hiriart, D.; Iriarte, A.

    2001-07-01

    We present the Mexican Infrared-Optical New Technology Telescope Project (TIM). The design and construction of a 7.8 m telescope, which will operate at the Observatorio Astronomico Nacional in San Pedro Martir, B.C. (Mexico), are described. The site has been selected based on seeing and sky condition measurements taken for several years. The f/1.5 primary mirror consists of 19 hexagonal off-axis hyperbolic segments of 1.8 m in diameter. The telescope structure will be alt-az, lightweight, low cost, and high stiffness. It will be supported by hydrostatic bearings. The single secondary will complement a Ritchey-Chretien f/15 design, delivering to Cassegrain focus instrumentation. The telescope will be infrared optimized to allow observations ranging from 0.3 to 20 microns. The TIM mirror cell provides an independent and full active support system for each segment, in order to achieve both, phasing capability and very high quality imaging (0.25 arcsec). The TIM project is one of the most advanced technological UNAM projects. The participation of technical and scientific professionals of other national institutions is crucial for its success. The project is seeking partners and financing.

  1. TinyTIM Modeling of WFC3/IR Images

    NASA Astrophysics Data System (ADS)

    Biretta, J.

    2012-07-01

    We test the accuracy of TinyTIM version 7.4 for performing PSF modeling and subtraction on WFC3/IR data. These models are based on pre-launch laboratory tests, and have a number of issues when applied to on-orbit data. There are large residuals along the OTA spider diffraction spikes, which appear to be caused by the cold mask spider widths being ~20% too small in the model. There are also weaker patterns of rings which may be related to errors in the cold mask secondary size or centration. Excess coma is present in the models, and appears as a dark feature 2 to 6 pixels to the left of the star images. Finally the residuals show "speckle patterns" of bright and dark pixels at the center of the star which reach a maximum of 2% - 10% error. We have estimated the 5-sigma detection limit for identifying faint companions in TinyTIM subtractions, and it is about 6 magnitudes at 0.5 arcseconds from the star, and falls to about 9 magnitudes at 2 arcseconds, relative to the peak brightness of the star. These limits are several magnitudes poorer than obtained by other methods which subtract on-orbit observed PSFs from the target image. A future report will discuss improvements to the TinyTIM models.

  2. Environmental factors in Tiny Tim's near-fatal illness.

    PubMed

    Chesney, Russell W

    2012-03-01

    Physicians, Dickens scholars, and historians have tried to diagnose the condition that affected Tiny Tim in A Christmas Carol. Leading entities include tuberculosis (TB), rickets, malnutrition, cerebral palsy, spinal dysraphism, and renal tubular acidosis. This article posits that an examination of the environment of London of 1820 to 1843 (when the novella was written) can provide important clues as to his condition. The blackened skies from burning coal, the crowding of people in tenements, the limited diet of the underclass, and the filth of London resulted in a haven for infectious diseases and rickets in children. Sixty percent of children in London had rickets, and nearly 50% had signs of TB. Tiny Tim likely had a combination of both diseases. After Ebenezer Scrooge's transformation, Scrooge could have ensured an improved diet, sunshine exposure, and possibly cod liver oil for Tiny Tim, which could have led to a "cure." Dickens was familiar with both rickets and TB and wrote about cod liver oil as a possible cure for rickets and scrofula. Improved vitamin D status can result in enhanced macrophage synthesis of 1,25-dihydroxyvitamin D, which increases the synthesis of the antimicrobial peptide cathelicidin (LL-37). This component of the innate immune system has strong killing properties for Mycobacterium tuberculosis. The combination of rickets and TB represent a crippling condition that could be reversed by improved vitamin D status.

  3. Dr TIM: Ray-tracer TIM, with additional specialist scientific capabilities

    NASA Astrophysics Data System (ADS)

    Oxburgh, Stephen; Tyc, Tomáš; Courtial, Johannes

    2014-03-01

    We describe several extensions to TIM, a raytracing program for ray-optics research. These include relativistic raytracing; simulation of the external appearance of Eaton lenses, Luneburg lenses and generalised focusing gradient-index lens (GGRIN) lenses, which are types of perfect imaging devices; raytracing through interfaces between spaces with different optical metrics; and refraction with generalised confocal lenslet arrays, which are particularly versatile METATOYs. Catalogue identifier: AEKY_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKY_v2_0.html Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland Licencing provisions: GNU General Public License No. of lines in distributed program, including test data, etc.: 106905 No. of bytes in distributed program, including test data, etc.: 6327715 Distribution format: tar.gz Programming language: Java. Computer: Any computer capable of running the Java Virtual Machine (JVM) 1.6. Operating system: Any, developed under Mac OS X Version 10.6 and 10.8.3. RAM: Typically 130 MB (interactive version running under Mac OS X Version 10.8.3) Classification: 14, 18. Catalogue identifier of previous version: AEKY_v1_0 Journal reference of previous version: Comput. Phys. Comm. 183(2012)711 External routines: JAMA [1] (source code included) Does the new version supersede the previous version?: Yes Nature of problem: Visualisation of scenes that include scene objects that create wave-optically forbidden light-ray fields. Solution method: Ray tracing. Reasons for new version: Significant extension of the capabilities (see Summary of revisions), as demanded by our research. Summary of revisions: Added capabilities include the simulation of different types of camera moving at relativistic speeds relative to the scene; visualisation of the external appearance of generalised focusing gradient-index (GGRIN) lenses, including Maxwell fisheye, Eaton and Luneburg lenses; calculation of

  4. TIM-1 signaling is required for maintenance and induction of regulatory B cells.

    PubMed

    Yeung, M Y; Ding, Q; Brooks, C R; Xiao, S; Workman, C J; Vignali, D A A; Ueno, T; Padera, R F; Kuchroo, V K; Najafian, N; Rothstein, D M

    2015-04-01

    Apart from their role in humoral immunity, B cells can exhibit IL-10-dependent regulatory activity (Bregs). These regulatory subpopulations have been shown to inhibit inflammation and allograft rejection. However, our understanding of Bregs has been hampered by their rarity, lack of a specific marker, and poor insight into their induction and maintenance. We previously demonstrated that T cell immunoglobulin mucin domain-1 (TIM-1) identifies over 70% of IL-10-producing B cells, irrespective of other markers. We now show that TIM-1 is the primary receptor responsible for Breg induction by apoptotic cells (ACs). However, B cells that express a mutant form of TIM-1 lacking the mucin domain (TIM-1(Δmucin) ) exhibit decreased phosphatidylserine binding and are unable to produce IL-10 in response to ACs or by specific ligation with anti-TIM-1. TIM-1(Δmucin) mice also exhibit accelerated allograft rejection, which appears to be due in part to their defect in both baseline and induced IL-10(+) Bregs, since a single transfer of WT TIM-1(+) B cells can restore long-term graft survival. These data suggest that TIM-1 signaling plays a direct role in Breg maintenance and induction both under physiological conditions (in response to ACs) and in response to therapy through TIM-1 ligation. Moreover, they directly demonstrate that the mucin domain regulates TIM-1 signaling.

  5. Histone acetyltransferease p300 modulates TIM4 expression in dendritic cells

    PubMed Central

    Yang, Bo; Li, Lin-Jing; Xu, Ling-Zhi; Liu, Jiang-Qi; Zhang, Huan-Ping; Geng, Xiao-Rui; Liu, Zhi-Gang; Yang, Ping-Chang

    2016-01-01

    TIM4 (T cell immunoglobulin mucin domain molecule-4) plays a critical role in the initiation of skewed T helper (Th) 2 polarization. The factors regulating TIM4 expression are unclear. This study tests a hypothesis that p300 and STAT6 (signal transducer and activator transcription-6) regulates TIM4 expression in dendritic cells (DC). In this study, a food allergy mouse model was developed with ovalbumin (a specific antigen) and cholera toxin (CT; an adjuvant). The chromatin immunoprecipitation assay was performed to evaluate the chromatin changes at TIM4 and STAT6 promoters. The TIM4 expression was evaluated by real time RT-PCR and Western blotting. The results showed that high levels of p300 and TIM4 were detected in the intestinal DCs of mice with intestinal allergy. p300 is involved in the CT-induced TIM4 expression in DCs. p300 interacts with the chromatin at the TIM4 promoter locus in DCs isolated from allergic mice. CT increases p300 expression to regulate STAT6 levels in DCs. STAT6 mediates the CT-induced TIM4 expression in DCs. In conclusion, p300 and STAT6 mediate the microbial product CT-induced TIM4 expression in DCs. PMID:26899911

  6. A highly conserved tyrosine of Tim-3 is phosphorylated upon stimulation by its ligand galectin-9

    SciTech Connect

    Weyer, Philipp S. van de; Muehlfeit, Michael; Klose, Christoph; Bonventre, Joseph V.; Walz, Gerd; Kuehn, E. Wolfgang . E-mail: wolfgang.kuehn@uniklinik-freiburg.de

    2006-12-15

    Tim-3 is a member of the TIM family of proteins (T-cell immunoglobulin mucin) involved in the regulation of CD4+ T-cells. Tim-3 is a T{sub H}1-specific type 1 membrane protein and regulates T{sub H}1 proliferation and the development of tolerance. Binding of galectin-9 to the extracellular domain of Tim-3 results in apoptosis of T{sub H}1 cells, but the intracellular pathways involved in the regulatory function of Tim-3 are unknown. Unlike Tim-1, which is expressed in renal epithelia and cancer, Tim-3 has not been described in cells other than neuronal or T-cells. Using RT-PCR we demonstrate that Tim-3 is expressed in malignant and non-malignant epithelial tissues. We have cloned Tim-3 from an immortalized liver cell carcinoma line and identified a highly conserved tyrosine in the intracellular tail of Tim-3 (Y265). We demonstrate that Y265 is specifically phosphorylated in vivo by the interleukin inducible T cell kinase (ITK), a kinase which is located in close proximity of the TIM genes on the allergy susceptibility locus 5q33.3. Stimulation of Tim-3 by its ligand galectin-9 results in increased phosphorylation of Y265, suggesting that this tyrosine residue plays an important role in downstream signalling events regulating T-cell fate. Given the role of TIM proteins in autoimmunity and cancer, the conserved SH2 binding domain surrounding Y265 could represent a possible target site for pharmacological intervention.

  7. Increased bovine Tim-3 and its ligand expressions during bovine leukemia virus infection

    PubMed Central

    2012-01-01

    The immunoinhibitory receptor T cell immunoglobulin domain and mucin domain-3 (Tim-3) and its ligand, galectin-9 (Gal-9), are involved in the immune evasion mechanisms for several pathogens causing chronic infections. However, there is no report concerning the role of Tim-3 in diseases of domestic animals. In this study, cDNA encoding for bovine Tim-3 and Gal-9 were cloned and sequenced, and their expression and role in immune reactivation were analyzed in bovine leukemia virus (BLV)-infected cattle. Predicted amino acid sequences of Tim-3 and Gal-9 shared high homologies with human and mouse homologues. Functional domains, including tyrosine kinase phosphorylation motif in the intracellular domain of Tim-3 were highly conserved among cattle and other species. Quantitative real-time PCR analysis showed that bovine Tim-3 mRNA is mainly expressed in T cells such as CD4+ and CD8+ cells, while Gal-9 mRNA is mainly expressed in monocyte and T cells. Tim-3 mRNA expression in CD4+ and CD8+ cells was upregulated during disease progression of BLV infection. Interestingly, expression levels for Tim-3 and Gal-9 correlated positively with viral load in infected cattle. Furthermore, Tim-3 expression level closely correlated with up-regulation of IL-10 in infected cattle. The expression of IFN-γ and IL-2 mRNA was upregulated when PBMC from BLV-infected cattle were cultured with Cos-7 cells expressing Tim-3 to inhibit the Tim-3/Gal-9 pathway. Moreover, combined blockade of the Tim-3/Gal-9 and PD-1/PD-L1 pathways significantly promoted IFN-γ mRNA expression compared with blockade of the PD-1/PD-L1 pathway alone. These results suggest that Tim-3 is involved in the suppression of T cell function during BLV infection. PMID:22621175

  8. The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells.

    PubMed

    Gonçalves Silva, Isabel; Rüegg, Laura; Gibbs, Bernhard F; Bardelli, Marco; Fruehwirth, Alexander; Varani, Luca; Berger, Steffen M; Fasler-Kan, Elizaveta; Sumbayev, Vadim V

    2016-07-01

    The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells. We concluded that AML cells might use Tim-3 as a trafficker for the secretion of galectin-9 which can then be possibly used to impair the anticancer activities of cytotoxic T cells and natural killer (NK) cells.

  9. The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells

    PubMed Central

    Gonçalves Silva, Isabel; Rüegg, Laura; Gibbs, Bernhard F.; Bardelli, Marco; Fruehwirth, Alexander; Varani, Luca; Berger, Steffen M.; Fasler-Kan, Elizaveta; Sumbayev, Vadim V.

    2016-01-01

    ABSTRACT The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells. We concluded that AML cells might use Tim-3 as a trafficker for the secretion of galectin-9 which can then be possibly used to impair the anticancer activities of cytotoxic T cells and natural killer (NK) cells. PMID:27622049

  10. The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells.

    PubMed

    Gonçalves Silva, Isabel; Rüegg, Laura; Gibbs, Bernhard F; Bardelli, Marco; Fruehwirth, Alexander; Varani, Luca; Berger, Steffen M; Fasler-Kan, Elizaveta; Sumbayev, Vadim V

    2016-07-01

    The immune receptor Tim-3 is often highly expressed in human acute myeloid leukemia (AML) cells where it acts as a growth factor and inflammatory receptor. Recently, it has been demonstrated that Tim-3 forms an autocrine loop with its natural ligand galectin-9 in human AML cells. However, the pathophysiological functions of Tim-3 in human AML cells remain unclear. Here, we report for the first time that Tim-3 is required for galectin-9 secretion in human AML cells. However, this effect is cell-type specific and was found so far to be applicable only to myeloid (and not, for example, lymphoid) leukemia cells. We concluded that AML cells might use Tim-3 as a trafficker for the secretion of galectin-9 which can then be possibly used to impair the anticancer activities of cytotoxic T cells and natural killer (NK) cells. PMID:27622049

  11. TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 gene polymorphisms as possible risk factor for rheumatoid arthritis: relation to activity and severity.

    PubMed

    Mosaad, Y M; El-Bassiony, S R; El-Ghaweet, A E; Elhindawy, M M; El-Deek, B S; Sultan, W A

    2015-08-01

    This study was aimed to evaluate the impact of both TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 polymorphisms on susceptibility to rheumatoid arthritis (RA) in a cohort of Egyptian population and to evaluate for the first time their relation to activity, severity, disease-related disability and erosion. TIM-1 rs41297579 G>A (-1454) and TIM-4 rs7700944 gene polymorphisms were typed by RFLP for 128 patients with RA and 125 healthy controls. The A allele, A-containing genotypes (GA and AA) of the TIM-4 and GA haplotype were present with significant higher frequency in patients with RA than healthy controls (Pc  < 0.001). These findings suggest that the A allele, A-containing genotypes (GA and AA) and GA haplotype may be a susceptibility risk factor for RA [OR = 5.83 (3.6-9.4), OR = 9.41 (5.0-17.6) and OR = 4.21 (1.07-19.2), respectively]. No associations were found between TIM genotypes and disease activity, severity or presence of erosion. However, the RA patients with GA genotype of TIM-4 have higher grade of rheumatoid factor (RF) positivity (P = 0.018), and have worse disease-related disability (P = 0.007) and worse pain (0.025). TIM-4 rs7700944 and not TIM-1 rs41297579 G>A (-1454) is associated with RA in the present cohort of Egyptian and may be a risk factor for development of RA in Egyptian. Both SNPs have no effect on disease activity, severity or erosion. However, TIM-4 GA genotype is associated with higher grade of RF positivity and worse disease-related disability and pain.

  12. Pam17 and Tim44 act sequentially in protein import into the mitochondrial matrix.

    PubMed

    Schiller, Dirk

    2009-11-01

    Import of proteins into the matrix is driven by the Tim23 presequence translocase-associated import motor PAM. The core component of PAM is the mitochondrial chaperone mtHsp70, which ensures efficient translocation of proteins across the inner membrane through interactions with the J-protein complex Pam16-Pam18 (Tim16-Tim14) and its cochaperone Tim44. The recently identified non-essential Pam17 is a further member of PAM. Genetic and biochemical analyses reveal synthetic interactions between PAM17 and TIM44. Pam17 is involved in an early stage of protein translocation whereas Tim44 assists in a later step of transport, suggesting that both proteins can cooperate in a complementary manner in protein import.

  13. TIM-4 structures identify a Metal Ion-dependent Ligand Binding Site where phosphatidylserine binds

    PubMed Central

    Santiago, Cesar; Ballesteros, Angela; Martinez-Muñoz, Laura; Mellado, Mario; Kaplan, Gerardo G.; Freeman, Gordon J.; Casasnovas, José M.

    2008-01-01

    The T-cell immunoglobulin and mucin domain (TIM) proteins are important regulators of T cell responses. They have been linked to autoimmunity and cancer. Structures of the murine TIM-4 identified a Metal Ion-dependent Ligand Binding Site (MILIBS) in the immunoglobulin (Ig) domain of the TIM family. The characteristic CC’ loop of the TIM domain and the hydrophobic FG loop shaped a narrow cavity where acidic compounds penetrate and coordinate to a metal ion bound to conserved residues in the TIM proteins. The structure of phosphatidylserine bound to the Ig domain showed that the hydrophilic head penetrates into the MILIBS and coordinates with the metal ion, while the aromatic residues on the tip of the FG loop interacted with the fatty acid chains and could insert into the lipid bilayer. Our results also revealed a significant role of the MILIBS in trafficking of TIM-1 to the cell surface. PMID:18083575

  14. Tim-3 identifies exhausted follicular helper T cells in breast cancer patients.

    PubMed

    Zhu, Shiguang; Lin, Jun; Qiao, Guangdong; Wang, Xingmiao; Xu, Yanping

    2016-09-01

    Breast cancer is the most common cancer diagnosed in women worldwide. Although a series of treatment options have improved the overall 5-year survival rate to 90%, individual responses still vary from patient to patient. New evidence suggested that the infiltration of CXCL13-expressing CD4(+) follicular helper cells (Tfh) in breast tumor predicted better survival. Here, we examined the regulation of Tfh function in breast cancer patients in depth. We found that the frequencies of circulating Tfh cells were not altered in breast cancer patients compared to healthy controls. However, the expression of PD-1 and Tim-3 in Tfh cells was significantly elevated in breast cancer patients. Interestingly, we observed a preferential upregulation of PD-1 in Tim-3(+) Tfh cells compared to Tim-3(-) Tfh cells. Coexpression of PD-1 and Tim-3 is typically a hallmark of functional exhaustion in chronic virus infections and tumor. To examine whether Tim-3(+) identifies exhausted Tfh cells, we stimulated Tfh cells with anti-CD3/CD28, and found that Tim-3(+) T cells expressed reduced frequencies of chemokine CXCL13 and cytokine interleukin 21 (IL-21), and contained fewer proliferating cells, than Tim-3(-) Tfh cells. Compared to those cocultured with Tim-3(-) Tfh cells, naive B cells cocultured with Tim-3(+) Tfh cells resulted in significantly less IgM, IgG and IgA production after 12 day incubation, demonstrating a reduction in Tim-3(+) Tfh-mediated B cell help. Moreover, the frequencies of Tim-3(+) Tfh cells in resected breast tumor were further upregulated than autologous blood, suggesting a participation of Tim-3(+) Tfh cells in tumor physiology. Overall, the data presented here provided new insight in the regulation of Tfh cells in breast cancer patients.

  15. Phosphotyrosine-dependent coupling of Tim-3 to T-cell receptor signaling pathways.

    PubMed

    Lee, Judong; Su, Ee Wern; Zhu, Chen; Hainline, Sarah; Phuah, Jiayao; Moroco, Jamie A; Smithgall, Thomas E; Kuchroo, Vijay K; Kane, Lawrence P

    2011-10-01

    The transmembrane protein Tim-3 has been shown to negatively regulate T-cell-dependent immune responses and was recently demonstrated to be associated with the phenomenon of immune exhaustion, which can occur as a consequence of chronic viral infection. Unlike other negative regulators of T-cell function (e.g., PD-1), Tim-3 does not contain any obvious inhibitory signaling motifs. We have found that ectopic expression of Tim-3 in T cells leads to enhancement of T-cell receptor (TCR)-dependent signaling pathways, which was observed at the level of transcriptional reporters and endogenous cytokine production. We have exploited this observation to dissect what elements within the cytoplasmic tail of Tim-3 are required for coupling to downstream signaling pathways. Here we have demonstrated that two of the more membrane-proximal cytoplasmic tail tyrosines are required for Tim-3 signaling to T-cell activation pathways in a redundant fashion. Furthermore, we show that Tim-3 can directly bind to the Src family tyrosine kinase Fyn and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor. Thus, at least under conditions of short-term stimulation, Tim-3 can augment T-cell activation, although this effect can be blocked by the inclusion of an agonistic antibody to Tim-3. These findings should help further the study of Tim-3 function in other physiological settings, such as those that lead to immune exhaustion.

  16. Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation.

    PubMed

    Phong, Binh L; Avery, Lyndsay; Sumpter, Tina L; Gorman, Jacob V; Watkins, Simon C; Colgan, John D; Kane, Lawrence P

    2015-12-14

    T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.

  17. Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse.

    PubMed

    Echbarthi, Meriem; Zonca, Manuela; Mellwig, Rachel; Schwab, Yannick; Kaplan, Gerardo; DeKruyff, Rosemarie H; Roda-Navarro, Pedro; Casasnovas, Jose M

    2015-11-01

    The T cell costimulatory molecule TIM-1 (T cell/transmembrane, mucin and immunoglobulin domain protein 1) sorts mainly to endosomes in lymphoid cells. At difference from the cell surface protein, endosomal TIM-1 translocates to the immune synapse (IS), where it can contribute to antigen-dependent T cell costimulation. TIM-1 ligands increase the amount of cell surface protein, preventing its traffic to the IS. The bipolar sorting of TIM-1 observed during IS formation is determined by differences in its subcellular location, and probably modulates antigen-driven immune responses.

  18. Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages.

    PubMed

    Jiang, Xingwei; Yu, Jiahui; Shi, Qingzhu; Xiao, Yan; Wang, Wei; Chen, Guojiang; Zhao, Zhi; Wang, Renxi; Xiao, He; Hou, Chunmei; Feng, Jiannan; Ma, Yuanfang; Shen, Beifen; Wang, Lili; Li, Yan; Han, Gencheng

    2015-10-01

    Tim-3 is involved in the physiopathology of inflammatory bowel disease (IBD), but the underlying mechanism is unknown. Here, we demonstrated that, in mouse with DSS colitis, Tim-3 inhibited the polarization of pathogenic pro-inflammatory M1 macrophages, while Tim-3 downregulation or blockade resulted in an increased M1 response. Adoptive transfer of Tim-3-silenced macrophages worsened DSS colitis and enhanced inflammation, while Tim-3 overexpression attenuated DSS colitis by decreasing the M1 macrophage response. Co-culture of Tim-3-overexpressing macrophages with intestinal lymphocytes decreased the pro-inflammatory response. Tim-3 shaped intestinal macrophage polarization may be TLR-4 dependent since Tim-3 blockade failed to exacerbate colitis or increase M1 macrophage response in the TLR-4 KO model. Finally, Tim-3 signaling inhibited phosphorylation of IRF3, a TLR-4 downstream transcriptional factor regulating macrophage polarization. A better understanding of this pathway may shed new light on colitis pathogenesis and result in a new therapeutic strategy.

  19. Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse.

    PubMed

    Echbarthi, Meriem; Zonca, Manuela; Mellwig, Rachel; Schwab, Yannick; Kaplan, Gerardo; DeKruyff, Rosemarie H; Roda-Navarro, Pedro; Casasnovas, Jose M

    2015-11-01

    The T cell costimulatory molecule TIM-1 (T cell/transmembrane, mucin and immunoglobulin domain protein 1) sorts mainly to endosomes in lymphoid cells. At difference from the cell surface protein, endosomal TIM-1 translocates to the immune synapse (IS), where it can contribute to antigen-dependent T cell costimulation. TIM-1 ligands increase the amount of cell surface protein, preventing its traffic to the IS. The bipolar sorting of TIM-1 observed during IS formation is determined by differences in its subcellular location, and probably modulates antigen-driven immune responses. PMID:26332704

  20. Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

    PubMed Central

    Phong, Binh L.; Avery, Lyndsay; Sumpter, Tina L.; Gorman, Jacob V.; Watkins, Simon C.; Colgan, John D.

    2015-01-01

    T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation. PMID:26598760

  1. Q & A with grower Tim Cullen [interview by Mary Winter].

    PubMed

    Cullen, Tim

    2015-03-01

    Tim Cullen is CEO and founder of the Colorado Harvest Company and Evergreen Apothecary, an expanding business in Denver that grows and sells marijuana. His most lucrative store averages 200 to 300 sales a day, with roughly 80 percent being for recreational purposes. The former high school biology teacher became interested in marijuana when he saw how it helped his father control the pain and nausea of Crohn's Disease, which Cullen himself developed later. He began growing marijuana in his basement in Colorado, where growing medical marijuana for personal use has been legal for 12 years. He now grows his plants in 55,000 square feet in four warehouses. PMID:25946754

  2. Q & A with grower Tim Cullen [interview by Mary Winter].

    PubMed

    Cullen, Tim

    2015-03-01

    Tim Cullen is CEO and founder of the Colorado Harvest Company and Evergreen Apothecary, an expanding business in Denver that grows and sells marijuana. His most lucrative store averages 200 to 300 sales a day, with roughly 80 percent being for recreational purposes. The former high school biology teacher became interested in marijuana when he saw how it helped his father control the pain and nausea of Crohn's Disease, which Cullen himself developed later. He began growing marijuana in his basement in Colorado, where growing medical marijuana for personal use has been legal for 12 years. He now grows his plants in 55,000 square feet in four warehouses.

  3. Tim-3 induces Th2-biased immunity and alternative macrophage activation during Schistosoma japonicum infection.

    PubMed

    Hou, Nan; Piao, Xianyu; Liu, Shuai; Wu, Chuang; Chen, Qijun

    2015-08-01

    T cell immunoglobulin- and mucin-domain-containing molecule 3 (Tim-3) has been regarded as an important regulatory factor in both adaptive and innate immunity. Recently, Tim-3 was reported to be involved in Th2-biased immune responses in mice infected with Schistosoma japonicum, but the exact mechanism behind the involvement of Tim-3 remains unknown. The present study aims to understand the role of Tim-3 in the immune response against S. japonicum infection. Tim-3 expression was determined by flow cytometry, and increased Tim-3 expression was observed on CD4(+) and CD8(+) T cells, NK1.1(+) cells, and CD11b(+) cells from the livers of S. japonicum-infected mice. However, the increased level of Tim-3 was lower in the spleen than in the liver, and no increase in Tim-3 expression was observed on splenic CD8(+) T cells or CD11b(+) cells. The schistosome-induced upregulation of Tim-3 on natural killer (NK) cells was accompanied by reduced NK cell numbers in vitro and in vivo. Tim-3 antibody blockade led to upregulation of inducible nitric oxide synthase and interleukin-12 (IL-12) mRNA in CD11b(+) cells cocultured with soluble egg antigen and downregulation of Arg1 and IL-10, which are markers of M2 macrophages. In summary, we observed schistosome-induced expression of Tim-3 on critical immune cell populations, which may be involved in the Th2-biased immune response and alternative activation of macrophages during infection.

  4. Two distinct mechanisms for TIM barrel prenyltransferases in bacteria.

    PubMed

    Doud, Emma H; Perlstein, Deborah L; Wolpert, Manuel; Cane, David E; Walker, Suzanne

    2011-02-01

    The reactions of two bacterial TIM barrel prenyltransferases (PTs), MoeO5 and PcrB, were explored. MoeO5, the enzyme responsible for the first step in moenomycin biosynthesis, catalyzes the transfer of farnesyl to 3-phosphoglyceric acid (3PG) to give a product containing a cis-allylic double bond. We show that this reaction involves isomerization to a nerolidyl pyrophosphate intermediate followed by bond rotation prior to attack by the nucleophile. This mechanism is unprecedented for a prenyltransferase that catalyzes an intermolecular coupling. We also show that PcrB transfers geranyl and geranylgeranyl groups to glycerol-1-phosphate (G1P), making it the first known bacterial enzyme to use G1P as a substrate. Unlike MoeO5, PcrB catalyzes prenyl transfer without isomerization to give products that retain the trans-allylic bond of the prenyl donors. The TIM barrel family of PTs is unique in including enzymes that catalyze prenyl transfer by distinctly different reaction mechanisms.

  5. Space Solar Power Technical Interchange Meeting 2: SSP TIM 2

    NASA Technical Reports Server (NTRS)

    Sanders, Jim; Hawk, Clark W.

    1998-01-01

    The 2nd Space Solar Power Technical Interchange Meeting (SSP TIM 2) was conducted September 21st through 24th with the first part consisting of a Plenary session. The summary results of this Plenary session are contained in part one of this report. The attendees were then organized into Working Breakout Sessions and Integrated Product Team (IPT) Sessions for the purpose of conducting in-depth discussions in specific topic areas and developing a consensus as to appropriate study plans and actions to be taken. The Second part covers the Plenary Summary Session, which contains the summary results of the Working Breakout Sessions and IPT Sessions. The appendix contains the list of attendees. The ob'jective was to provide an update for the study teams and develop plans for subsequent study activities. This SSP TIM 2 was initiated and the results reported electronically over the Internet. The International Space Station (ISS) could provide the following opportunities for conducting research and technology (R&T) which are applicable to SSP: (1) Automation and Robotics, (2) Advanced Power Generation, (3) Advanced Power Management & Distribution (PMAD), (4) Communications Systems and Networks, (5) Energy Storage, (6) In Space Propulsion (ISP), (7) Structural Dynamics and Control, and Assembly and (8) Wireless Power Transmission.

  6. Iron uptake mediated by binding of H-ferritin to the TIM-2 receptor in mouse cells.

    PubMed

    Han, Jian; Seaman, William E; Di, Xiumin; Wang, Wei; Willingham, Mark; Torti, Frank M; Torti, Suzy V

    2011-01-01

    Ferritin binds specifically and saturably to a variety of cell types, and recently several ferritin receptors have been cloned. TIM-2 is a specific receptor for H ferritin (HFt) in the mouse. TIM-2 is a member of the T cell immunoglobulin and mucin domain containing (TIM) protein family and plays an important role in immunity. The expression of TIM-2 outside of the immune system indicates that this receptor may have broader roles. We tested whether ferritin binding to TIM-2 can serve as an iron delivery mechanism. TIM-2 was transfected into normal (TCMK-1) mouse kidney cells, where it was appropriately expressed on the cell surface. HFt was labeled with (55)Fe and (55)Fe-HFt was incubated with TIM-2 positive cells or controls. (55)Fe-HFt uptake was observed only in TIM-2 positive cells. HFt uptake was also seen in A20 B cells, which express endogenous TIM-2. TIM-2 levels were not increased by iron chelation. Uptake of (55)Fe-HFt was specific and temperature-dependent. HFt taken up by TIM-2 positive cells transited through the endosome and eventually entered a lysosomal compartment, distinguishing the HFt pathway from that of transferrin, the classical vehicle for cellular iron delivery. Iron delivered following binding of HFt to TIM-2 entered the cytosol and became metabolically available, resulting in increased levels of endogenous intracellular ferritin. We conclude that TIM-2 can function as an iron uptake pathway.

  7. Microglia activity modulated by T cell Ig and mucin domain protein 3 (Tim-3).

    PubMed

    Wang, Hong-wei; Zhu, Xin-li; Qin, Li-ming; Qian, Hai-jun; Wang, Yiner

    2015-01-01

    Microglia are the main innate immune cells in the central nervous system that are actively involved in maintaining brain homeostasis and diseases. T cell Ig and mucin domain protein 3 (Tim-3) plays critical roles in both the adaptive and the innate immune system and is an emerging therapeutic target for treatment of various disorders. In the brain Tim-3 is specifically expressed on microglia but its functional role is unclear. Here, we showed that Tim-3 was up-regulated on microglia by ATP or LPS stimulation. Tim-3 activation with antibodies increased microglia expression of TGF-β, TNF-α and IL-1β. Blocking of Tim-3 with antibodies decreased the microglial phagocytosis of apoptotic neurons. Tim-3 blocking alleviated the detrimental effect of microglia on neurons and promoted NG2 cell differentiation in co-cultures. Finally, MAPKs namely ERK1/2 and JNK proteins were phosphorylated upon Tim-3 activation in microglia. Data indicated that Tim-3 modulates microglia activity and regulates the interaction of microglia-neural cells.

  8. GUM Analysis for TIMS Isotopic Ratios in BEP0 Graphite Qualification Samples, Round 2

    SciTech Connect

    Gerlach, David C.; Heasler, Patrick G.; Reid, Bruce D.

    2009-01-01

    In May 2007, one set of three samples from NBL were addressed to Steve Petersen for TIMS analysis, and included BEP0 samples numbered 27008, 30986, and 50846. All cores were trimmed by tooling, and lightly cleaned by CO2 pellet blasting. Small discs were cut from the second set of samples for SIMS analysis, with the remainder of each used for TIMS preparation.

  9. Interaction of the Tim44 C-terminal domain with negatively charged phospholipids.

    PubMed

    Marom, Milit; Safonov, Roman; Amram, Shay; Avneon, Yoav; Nachliel, Esther; Gutman, Menachem; Zohary, Keren; Azem, Abdussalam; Tsfadia, Yossi

    2009-12-01

    The translocation of proteins from the cytosol into the mitochondrial matrix is mediated by the coordinated action of the TOM complex in the outer membrane, as well as the TIM23 complex and its associated protein import motor in the inner membrane. The focus of this work is the peripheral inner membrane protein Tim44. Tim44 is a vital component of the mitochondrial protein translocation motor that anchors components of the motor to the TIM23 complex. For this purpose, Tim44 associates with the import channel by direct interaction with the Tim23 protein. Additionally, it was shown in vitro that Tim44 associates with acidic model membranes, in particular those containing cardiolipin. The latter interaction was shown to be mediated by the carboxy-terminal domain of Tim44 [Weiss, C., et al. (1999) Proc. Natl. Acad. Sci. U.S.A. 96, 8890-8894]. The aim of this study was to determine the precise recognition site for negative lipids in the C-terminal domain of Tim44. In particular, we wanted to examine the recently suggested hypothesis that acidic phospholipids associate with Tim44 via a hydrophobic cavity that is observed in the high-resolution structure of the C-terminal domain of the protein [Josyula, R., et al. (2006) J. Mol. Biol. 359, 798-804]. Molecular dynamics simulations suggest that (i) the hydrophobic tail of lipids may interact with Tim44 via the latter's hydrophobic cavity and (ii) a region, located in the N-terminal alpha-helix of the C-terminal domain (helices A1 and A2), may serve as a membrane attachment site. To validate this assumption, N-terminal truncations of yeast Tim44 were examined for their ability to bind cardiolipin-containing phospholipid vesicles. The results indicate that removal of the N-terminal alpha-helix (helix A1) abolishes the capacity of Tim44 to associate with cardiolipin-containing liposomes. We suggest that helices A1 and A2, in Tim44, jointly promote the association of the protein with acidic phospholipids. PMID:19863062

  10. Biological and chemical assessment of M-Area process discharge to TIM`s Branch, June 1985--December 1986

    SciTech Connect

    Carlton, W.H.; Starkel, W.M.; Giffin, M.; Trapp, K.E.

    1987-03-01

    The production facilities of M-Area process uranium, lithium, and aluminum into fuel and target components for nuclear reactors at the Savannah River Plant (SRP). These processes produce wastewaters that contain dissolved metals, solvents, and nitric acid. Beginning in July 1985, wastewater was diverted to the M-Area Liquid Effluent Treatment Facility (LETF), which treats the waste via precipitation, filtration, and neutralization. Major constituents of the LETF discharge include nitrate (as NaNO{sub 3}), phosphorus, total suspended solids, and trace amounts of aluminum, lead, nickel, iron, and uranium. In addition to the intermittent LETF discharge, the A-014 outfall also has received a continuous discharge of noncontact cooling water (700 to 2500 gpm) since 1982 and effluent from the M-Area Ground Water Recovery Action (MAGWRA) air stripper (375 gpm) since September 1985. These effluents consist of trace amounts of (trichloroethylene, tetrachloroethylene, and 1, 1, 1-trichloroethane) in the MAGWRA effluent. In June 1985, a chemical and biological monitoring program was initiated to determine if M-Area discharges are a significant environmental hazard to Tim`s Branch. The main concerns are whether the discharge is toxic to aquatic life and whether high levels of nitrate in the discharge from the M-Area Liquid Effluent Treatment Facility (LETF) will cause eutrophication of the aquatic system.

  11. The phosphatidylserine receptor TIM4 utilizes integrins as coreceptors to effect phagocytosis.

    PubMed

    Flannagan, Ronald S; Canton, Johnathan; Furuya, Wendy; Glogauer, Michael; Grinstein, Sergio

    2014-05-01

    T-cell immunoglobulin mucin protein 4 (TIM4), a phosphatidylserine (PtdSer)-binding receptor, mediates the phagocytosis of apoptotic cells. How TIM4 exerts its function is unclear, and conflicting data have emerged. To define the mode of action of TIM4, we used two distinct but complementary approaches: 1) we compared bone marrow-derived macrophages from wild-type and TIM4(-/-) mice, and 2) we heterologously expressed TIM4 in epithelioid AD293 cells, which rendered them competent for engulfment of PtdSer-bearing targets. Using these systems, we demonstrate that rather than serving merely as a tether, as proposed earlier by others, TIM4 is an active participant in the phagocytic process. Furthermore, we find that TIM4 operates independently of lactadherin, which had been proposed to act as a bridging molecule. Of interest, TIM4-driven phagocytosis depends on the activation of integrins and involves stimulation of Src-family kinases and focal adhesion kinase, as well as the localized accumulation of phosphatidylinositol 3,4,5-trisphosphate. These mediators promote recruitment of the nucleotide-exchange factor Vav3, which in turn activates small Rho-family GTPases. Gene silencing or ablation experiments demonstrated that RhoA, Rac1, and Rac2 act synergistically to drive the remodeling of actin that underlies phagocytosis. Single-particle detection experiments demonstrated that TIM4 and β1 integrins associate upon receptor clustering. These findings support a model in which TIM4 engages integrins as coreceptors to evoke the signal transduction needed to internalize PtdSer-bearing targets such as apoptotic cells.

  12. Multicollector ICPMS and TIMS as tools for isotopic fingerprinting

    NASA Astrophysics Data System (ADS)

    Bouman, C.; Schwieters, J. B.; Lloyd, N. S.; Trinquier, A.

    2012-04-01

    Elements such as C, N, O and S are essential for chemical and biological processes in nature and very small shifts in the isotopic composition of these elements are important tracers to explore complex processes in nature. During the last few years, stable isotopes of elements as Cl, Ca, Fe, Cu, Zn, Sr, Hg and Pb are getting more and more attention as tracer to study biomedical and environmental processes, as well as forensics and archaeometry. Multi-collector ICPMS and TIMS enable high-precision isotopic analysis of these so-called non-traditional stable isotope systems. MC-ICPMS is a powerful technique for the isotopic analysis of most elements, with the exception of light elements such as H, C, N and O and the noble gases. Various inlet systems can be used to introduce samples into the mass spectrometer, for instance gas chromatography (GC), liquid chromatography (LC) ) for compound-specific isotope analysis, laser ablation for direct analysis of solids, or conventional liquid nebulization for liquid samples. The aerosol is transported by an Ar and/or He gas flow into the ICP source where it is effectively ionized and introduced into the mass analyzer through a differential pumping system. Molecular interferences as carbides, nitrides, oxides, argides or doubly-charged species can show up in the mass spectrum and interfere with the elemental isotope peaks. High mass resolution is needed to effectively discriminate against these interferences. The NEPTUNE Plus is specially designed to meet this requirement and expand the power of isotope ratio measurements even to elements where previously isobaric interferences were the limit. For some specific isotope systems, such as Ca, Sr and Pb, the thermal ionization technique may have advantages, due to the potentially lower backgrounds and higher sensitivity. Prior to the TIMS analysis, the sample is chemically purified, loaded on a filament and introduced into the mass spectrometer. With the introduction of the TRITON

  13. Discrimination of alkalinity in granitoid Rocks: A potential TIMS application

    NASA Technical Reports Server (NTRS)

    Ruff, Steven W.

    1995-01-01

    In mineral exploration, the ability to distinguish and map petrochemical variations of magmatic rocks can be a useful reconnaissance tool. Alkalinity is one such petrochemical parameter and is used in the characterization of granitoid rocks. In quartz normative plutonic rocks, alkalinity is related to the composition and abundance of feldspars. Together with quartz abundance, knowledge of feldspar modes allows the classification of these igneous rocks according to the Streckeisen diagram. Alternative classification schemes rely on whole rock geochemistry instead of mineral identifications. The relative ease of obtaining whole rock analyses means that geochemical classifications tend to be favored in exploration geology. But the technique of thermal infrared spectroscopy of rocks yields information on mineralogy and is one that can be applied remotely. The goal of the current work then is to establish whether data from TIMS can be used to distinguish the mineralogical variations that relate to alkalinity. An ideal opportunity to test this thesis arises from the work presented in a paper by Dewitt (1989). This paper contains the results of mapping and analysis of Proterozoic plutonic rocks in north-central Arizona. The map resulting from this work delineates plutons according to alkalinity in an effort to establish a trend or polarity in the regional magmatism. Also contained within this paper are brief descriptions of the mineralogy of half of the region's plutons. This combination of mineralogical and geochemical information was the rationale behind choosing this area as a site for TIMS over flights. A portion of the region centered on the northern Bradshaw Mountains was selected because it contains plutons of all three alkalinity classifications (alkali-calcic, calc-alkalic, and calic) present on DeWitt's map within a relatively small area. The site was flown in August of 1994 and the data received a few days before the writing of this manuscript. Most of this

  14. Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques.

    PubMed

    Fujita, Tsuyoshi; Burwitz, Benjamin J; Chew, Glen M; Reed, Jason S; Pathak, Reesab; Seger, Elizabeth; Clayton, Kiera L; Rini, James M; Ostrowski, Mario A; Ishii, Naoto; Kuroda, Marcelo J; Hansen, Scott G; Sacha, Jonah B; Ndhlovu, Lishomwa C

    2014-12-01

    The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8(+) T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8(+) T cell responses in vitro and, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3(+)CD8(+) T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3(+)PD-1(+)CD8(+) T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8(+) T cells in all tissues examined. Tim-3(+)CD8(+) T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3(-)CD8(+) T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8(+) T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8(+) T cell responses. PMID:25348621

  15. Tim-3: an emerging target in the cancer immunotherapy landscape.

    PubMed

    Anderson, Ana C

    2014-05-01

    The cancer immunotherapy field has grown exponentially in the past few years, largely driven by the success of immune checkpoint blockade. Therapies targeting the immune checkpoint molecules CTLA-4 and PD-1 have achieved objective responses in melanoma, renal cancer, and lung cancer; however, a large number of patients are still suffering with these cancers that are not benefiting from these therapies. Moreover, several cancers have proved to be largely refractory to therapies that target CTLA-4 and PD-1. This has catalyzed interest in targeting novel immune checkpoint receptors with the goal of realizing the full potential of checkpoint blockade for treating cancer. In this regard, the immune checkpoint receptor Tim-3 exhibits several unique features that make it an intriguing candidate for the next wave of therapies that target immune checkpoints in cancer. PMID:24795351

  16. The TIM Barrel Architecture Facilitated the Early Evolution of Protein-Mediated Metabolism.

    PubMed

    Goldman, Aaron David; Beatty, Joshua T; Landweber, Laura F

    2016-01-01

    The triosephosphate isomerase (TIM) barrel protein fold is a structurally repetitive architecture that is present in approximately 10% of all enzymes. It is generally assumed that this ubiquity in modern proteomes reflects an essential historical role in early protein-mediated metabolism. Here, we provide quantitative and comparative analyses to support several hypotheses about the early importance of the TIM barrel architecture. An information theoretical analysis of protein structures supports the hypothesis that the TIM barrel architecture could arise more easily by duplication and recombination compared to other mixed α/β structures. We show that TIM barrel enzymes corresponding to the most taxonomically broad superfamilies also have the broadest range of functions, often aided by metal and nucleotide-derived cofactors that are thought to reflect an earlier stage of metabolic evolution. By comparison to other putatively ancient protein architectures, we find that the functional diversity of TIM barrel proteins cannot be explained simply by their antiquity. Instead, the breadth of TIM barrel functions can be explained, in part, by the incorporation of a broad range of cofactors, a trend that does not appear to be shared by proteins in general. These results support the hypothesis that the simple and functionally general TIM barrel architecture may have arisen early in the evolution of protein biosynthesis and provided an ideal scaffold to facilitate the metabolic transition from ribozymes, peptides, and geochemical catalysts to modern protein enzymes.

  17. Decreased TIM-3 mRNA expression in peripheral blood mononuclear cells from nephropathy patients.

    PubMed

    Cai, X Z; Liu, N; Qiao, Y; Du, S Y; Chen, Y; Chen, D; Yu, S; Jiang, Y

    2015-01-01

    Increasing evidence shows that TIM-1 and TIM-3 in-fluence chronic autoimmune diseases, and their expression levels in immune cells from nephritic patients are still unknown. Real-time transcription-polymerase chain reaction analysis was used to deter-mine expression levels of TIM-1 and TIM-3 mRNA in peripheral blood mononuclear cells (PBMCs) from 36 patients with minimal change glo-merulopathy (MCG), 65 patients with lupus nephritis (LN), 78 patients with IgA nephropathy (IgAN), 55 patients with membranous nephropa-thy (MN), 22 patients with crescentic glomerulonephritis (CGN), 26 patients with anaphylactoid purpura nephritis (APN), and 63 healthy controls. TIM-3 mRNA expression significantly decreased in PBMCs from nephritic patients (LN, P < 0.0001; MCG, P < 0.0001; MN, P = 0.0031; CGN, P = 0.0464; IgAN, P = 0.0002; APN, P = 0.0392) com-pared with healthy controls. In contrast, there was no significant differ-ence in TIM-1 mRNA expression between the patients and the healthy controls. Our results suggest that insufficient expression of TIM-3 mRNA may be involved in the pathogenesis of nephropathy.

  18. Airborne Thermal Infrared Multispectral Scanner (TIMS) images over disseminated gold deposits, Osgood Mountains, Humboldt County, Nevada

    NASA Technical Reports Server (NTRS)

    Krohn, M. Dennis

    1986-01-01

    The U.S. Geological Survey (USGS) acquired airborne Thermal Infrared Multispectral Scanner (TIMS) images over several disseminated gold deposits in northern Nevada in 1983. The aerial surveys were flown to determine whether TIMS data could depict jasperoids (siliceous replacement bodies) associated with the gold deposits. The TIMS data were collected over the Pinson and Getchell Mines in the Osgood Mountains, the Carlin, Maggie Creek, Bootstrap, and other mines in the Tuscarora Mountains, and the Jerritt Canyon Mine in the Independence Mountains. The TIMS data seem to be a useful supplement to conventional geochemical exploration for disseminated gold deposits in the western United States. Siliceous outcrops are readily separable in the TIMS image from other types of host rocks. Different forms of silicification are not readily separable, yet, due to limitations of spatial resolution and spectral dynamic range. Features associated with the disseminated gold deposits, such as the large intrusive bodies and fault structures, are also resolvable on TIMS data. Inclusion of high-resolution thermal inertia data would be a useful supplement to the TIMS data.

  19. Evaluation of two dynamic in vitro models simulating fasted and fed state conditions in the upper gastrointestinal tract (TIM-1 and tiny-TIM) for investigating the bioaccessibility of pharmaceutical compounds from oral dosage forms.

    PubMed

    Verwei, Miriam; Minekus, Mans; Zeijdner, Evelijn; Schilderink, Ronald; Havenaar, Robert

    2016-02-10

    Pharmaceutical research needs predictive in vitro tools for API bioavailability in humans. We evaluated two dynamic in vitro gastrointestinal models: TIM-1 and tiny-TIM. Four low-soluble APIs in various formulations were investigated in the TIM systems under fasted and fed conditions. API small-intestinal bioaccessibility profiles were evaluated between the two systems and in comparison with human data. Both TIM systems showed a higher bioaccessibility of ciprofloxacin and nifedipine during 3-4h after dosing immediate release (IR) compared to modified release (MR) formulations. Higher bioaccessibility levels from IR formulations were observed under fasted state in the first 30-90 min in tiny-TIM as compared to TIM-1, resulting in a tmax similar to clinical data. Absence (ciprofloxacin) or presence (posaconazole) of a food effect on bioaccessibility was observed in both TIM systems in line with human data. A higher bioaccessibility of fenofibrate from nano- vs micro-particle formulation was found in both TIM systems. This dataset shows the predictive quality of the TIM systems for clinical data on API small-intestinal bioaccessibility from IR and MR formulations and food effects. Tiny-TIM provides higher throughput and better prediction for IR formulations. TIM-1 provides detailed information on site-specific release of APIs, relevant for MR formulations and food effects.

  20. Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) and TIM-3 ligands in peripheral blood from patients with systemic lupus erythematosus.

    PubMed

    Jiao, Qingqing; Qian, Qihong; Zhao, Zuotao; Fang, Fumin; Hu, Xiaohan; An, Jingnan; Wu, Jian; Liu, Cuiping

    2016-10-01

    Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease. The T cell immunoglobulin and mucin domain (TIM) family is associated with autoimmune diseases, but its level of expression in the immune cells of patients with SLE is still uncertain. The aim of this study was to examine whether TIM-3 and Galectin-9 (Gal-9) contribute to the pathogenesis of SLE. In total, 30 patients with SLE and 30 healthy controls were recruited, and their levels of TIM-3 expression in peripheral blood mononuclear cells (PBMCs) were examined via flow cytometry. Meanwhile, the levels of Gal-9 expression in serum and in PBMCs were measured via an enzyme-linked immunosorbent assay (ELISA) kit and immunofluorescence staining, respectively. The relation between the level of TIM-3 or Gal-9 expression and the SLE disease activity index (SLEDAI) was also studied. Finally, the function of the TIM-3 and Gal-9 pathway in the pathogenesis of SLE was explored. Our results showed that the levels of expression of TIM-3 and Gal-9 on CD4(+) T cells, CD8(+) T cells, CD56(+) T cells and in serum in patients with SLE were significantly higher than those of healthy controls. We found that the level of Gal-9 expression was significantly higher in both serum and PMBCs of patients with SLE than in healthy controls. The up-regulation of TIM-3 and Gal-9 expression in patients with SLE was closely related to the SLEDAI scores. In addition, Gal-9 blocking antibody significantly inhibited CD3-stimulated PBMC proliferation and Th1-derived cytokines (IL-2, IFN-γ, and TNF-α), Th2-derived cytokines (IL-4, IL-10), a Th17-derived cytokine (IL-17A), and release of a pro-inflammatory factor (IL-6) in patients with SLE. The results suggest that increased expression of TIM-3 and Gal-9 may be a biomarker for SLE diagnosis and that the TIM-3 pathway may be a target for SLE treatment.

  1. Circulating and tumor-infiltrating Tim-3 in patients with colorectal cancer.

    PubMed

    Xu, Benling; Yuan, Long; Gao, Quanli; Yuan, Peng; Zhao, Peng; Yuan, Huijuan; Fan, Huijie; Li, Tiepeng; Qin, Peng; Han, Lu; Fang, Weijia; Suo, Zhenhe

    2015-08-21

    T-cell exhaustion represents a progressive loss of T-cell function. The inhibitory receptor PD-1 is known to negatively regulate CD8+ T cell responses directed against tumor antigen, but the blockades of PD-1 pathway didn't show the objective responses in patients with colorectal cancer (CRC). Thus, further exploring the molecular mechanism responsible for inducing T-cell dysfunction in CRC patients may reveal effective strategies for immune therapy. This study aims to characterize co-inhibitory receptors on T cells in CRC patients to identify novel targets for immunotherapy. In this study, peripheral blood samples from 20 healthy controls and 54 consented CRC patients, and tumor and matched paraneoplastic tissues from 7 patients with advanced CRC, subjected to multicolor flow cytometric analysis of the expression of PD-1 and Tim-3 receptors on CD8+ T cells. It was found that CRC patients presented with significantly higher levels of circulating Tim-3+PD-1+CD8+ T cells compared to the healthy controls (medians of 3.12% and 1.99%, respectively, p = 0.0403). A similar increase of Tim-3+PD-1+CD8+ T cells was also observed in the tumor tissues compared to paraneoplastic tussues. Tim-3+PD-1+CD8+ T cells in tumor tissues produced even less cytokine than that in paraneoplastic tissues. Functional ex vivo experiments showed that Tim-3+PD-1+CD8+ T cells produced significantly less IFN-γ than Tim-3-PD-1-CD8+ T cells, followed by Tim-3+PD-1-CD8+ T cells, and Tim-3-PD-1+CD8+ T cells, indicating a stronger inhibition of IFN-γ production of Tim-3+CD8+ T cells . It is also found in this study that Tim-3+PD-1+CD8+ T cell increase in circulation was correlated with clinical cancer stage but not histologic grade and serum concentrations of cancer biomarker CEA. Our results indicate that upregulation of the inhibitory receptor Tim-3 may restrict T cell responses in CRC patients, and therefore blockage of Tim-3 and thus restoring T cell responses may be a potential therapeutic

  2. Abnormal expression of Tim-3 antigen on peripheral blood T cells is associated with progressive disease in osteosarcoma patients.

    PubMed

    Liu, Hongliang; Zhi, Liqiang; Duan, Ning; Su, Pengxiao

    2016-08-01

    T-cell immunoglobulin and mucin-domain-3-containing molecule 3 (TIM-3) plays a pivotal role in immune regulation and has been found in various tumors. However, the prevalence and distribution of Tim-3 in osteosarcoma (OS) is still unclear. The aim of this study was to investigate the prevalence and distribution of Tim-3 in OS. Tim-3 on peripheral T cells from 82 OS patients and 60 healthy controls were examined by flow cytometry. Plasma levels of IL-2, IFN-γ, and TNF-α were measured by ELSIA. Tim-3 on both CD4(+) T and CD8(+) T cells were significantly upregulated in OS patients compared with healthy controls, Tim-3(+) CD4(+) T, and Tim-3(+) CD8(+) T cells were both negatively associated with serum levels of IL-2 and IFN-γ and TNF-α. In addition, Tim-3 showed similar levels in patients with different tumor sites. Nevertheless, patients with advanced tumor stage, metastasis, and pathological tumor fracture displayed significantly higher Tim-3 on both CD4(+) T cells and CD8(+) T cells than those with early tumor stage, without metastasis and pathological tumor fracture. Moreover, high Tim-3 on peripheral CD4(+) T cells or CD8(+) T were significantly related to poor overall survival (P = 0.014, P = 0.035, respectively). In conclusion, Tim-3 may be a potential diagnostic and prognostic biomarker for OS progression.

  3. Abnormal expression of Tim-3 antigen on peripheral blood T cells is associated with progressive disease in osteosarcoma patients.

    PubMed

    Liu, Hongliang; Zhi, Liqiang; Duan, Ning; Su, Pengxiao

    2016-08-01

    T-cell immunoglobulin and mucin-domain-3-containing molecule 3 (TIM-3) plays a pivotal role in immune regulation and has been found in various tumors. However, the prevalence and distribution of Tim-3 in osteosarcoma (OS) is still unclear. The aim of this study was to investigate the prevalence and distribution of Tim-3 in OS. Tim-3 on peripheral T cells from 82 OS patients and 60 healthy controls were examined by flow cytometry. Plasma levels of IL-2, IFN-γ, and TNF-α were measured by ELSIA. Tim-3 on both CD4(+) T and CD8(+) T cells were significantly upregulated in OS patients compared with healthy controls, Tim-3(+) CD4(+) T, and Tim-3(+) CD8(+) T cells were both negatively associated with serum levels of IL-2 and IFN-γ and TNF-α. In addition, Tim-3 showed similar levels in patients with different tumor sites. Nevertheless, patients with advanced tumor stage, metastasis, and pathological tumor fracture displayed significantly higher Tim-3 on both CD4(+) T cells and CD8(+) T cells than those with early tumor stage, without metastasis and pathological tumor fracture. Moreover, high Tim-3 on peripheral CD4(+) T cells or CD8(+) T were significantly related to poor overall survival (P = 0.014, P = 0.035, respectively). In conclusion, Tim-3 may be a potential diagnostic and prognostic biomarker for OS progression. PMID:27516959

  4. The small Tim proteins and the twin Cx3C motif.

    PubMed

    Koehler, Carla M

    2004-01-01

    The mitochondrial intermembrane space contains the 'small' Tim (translocase of inner membrane) proteins that are marked by their conserved 'twin Cx(3)C' motif separated by 11-16 residues. Together with the Tim22 complex at the inner membrane, the small Tim proteins form the TIM22 import machinery that mediates the biogenesis of polytopic inner membrane proteins. Upon first investigation, the conserved motif resembles a zinc-finger-like domain, but the spacing between the cysteine residues differs from that a canonical zinc finger. Recent publications present different views about the function of the conserved cysteines: the cysteines form a zinc-finger-like structure to coordinate zinc or, alternatively, they form juxtapositioned disulfide bonds.

  5. Electrodeposition of Technetium on Platinum for Thermal Ionization Mass Spectrometry (TIMS)

    SciTech Connect

    Engelmann, Mark D.; Metz, Lori A.; Delmore, James E.; Engelhard, Mark H.; Ballou, Nathan E.

    2008-05-15

    A novel device has been fabricated for the electrodeposition of technetium metal onto platinum filaments for thermal ionization mass spectrometric (TIMS) measurements. The ability of the device to focus the deposition to diameters of hundreds of micrometers on pre-mounted TIMS filaments coupled with the ease of use and simplicity of design permit for an extremely sensitive yet economical TIMS filament loading technique. Electrodeposition parameters were varied in order to maximize deposition efficiency. X-ray photoelectron spectroscopy (XPS) was used to confirm and characterize the technetium deposit. The technetium is deposited in the metallic state, although surface oxides in the 4+ and 7+ state form readily. Initial TIMS measurements of the electrodeposited technetium in the presence of a barium sulfate ionization enhancer show potential for excellent sensitivity.

  6. Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients

    PubMed Central

    Sada-Ovalle, Isabel; Ocaña-Guzman, Ranferi; Pérez-Patrigeón, Santiago; Chávez-Galán, Leslie; Sierra-Madero, Juan; Torre-Bouscoulet, Luis; Addo, Marylyn M.

    2015-01-01

    Introduction T cell immunoglobulin and mucin domain (Tim) 3 and programmed death 1 (PD-1) are co-inhibitory receptors involved in the so-called T cell exhaustion, and in vivo blockade of these molecules restores T cell dysfunction. High expression of Tim-3 and PD-1 is induced after chronic antigen-specific stimulation of T cells during HIV infection. We have previously demonstrated that the interaction of Tim-3 with its ligand galectin-9 induces macrophage activation and killing of Mycobacterium tuberculosis. Our aim in this study was to analyze the Tim-3 expression profile before and after six months of antiretroviral therapy and the impact of Tim-3 and PD-1 blocking on immunity against M. tuberculosis. Materials and methods HIV+ patients naïve to anti-retroviral therapy (ART) were followed up for six months. Peripheral immune-cell phenotype (CD38/HLA-DR/galectin-9/Tim-3 and PD-1) was assessed by flow cytometry. Supernatants were analyzed with a multiplex cytokine detection system (human Th1/Th2 cytokine Cytometric Bead Array) by flow cytometry. Control of bacterial growth was evaluated by using an in vitro experimental model in which virulent M. tuberculosis-infected macrophages were cultured with T cells in the presence or absence of Tim-3 and PD-1 blocking antibodies. Interleukin-1 beta treatment of infected macrophages was evaluated by enumerating colony-forming units. Results We showed that HIV+ patients had an increased expression of Tim-3 in T cells and were able to control bacterial growth before ART administration. By blocking Tim-3 and PD-1, macrophages and T cells recovered their functionality and had a higher ability to control bacterial growth; this result was partially dependent on the restitution of cytokine production. Conclusions In this study, we demonstrated that increased Tim-3 expression can limit the ability of the immune system to control the infection of intracellular bacteria such as M. tuberculosis. The use of ART and the in vitro

  7. Significant association between TIM1 promoter polymorphisms and protection against cerebral malaria in Thailand.

    PubMed

    Nuchnoi, P; Ohashi, J; Kimura, R; Hananantachai, H; Naka, I; Krudsood, S; Looareesuwan, S; Tokunaga, K; Patarapotikul, J

    2008-05-01

    Although cerebral malaria is a major life-threatening complication of Plasmodium falciparum infection, its pathophysiology is not well understood. Prolonged activation of the T helper type 1 (Th1) response characterized by the production of pro-inflammatory cytokines such as IFN-gamma and TNF-alpha has been suggested to be responsible for immunopathological process leading to cerebral malaria unless they are downregulated by the anti-inflamatory cytokines produced by the Th2 response. The T cell immunoglobulin and mucin domain (TIM) family of proteins are cell surface proteins involved in regulating Th1 and Th2 immune responses. In this study, the possible association between the polymorphisms of TIM1, TIM3, and TIMD4 genes and the severity of malaria was examined in 478 adult Thai patients infected with P. falciparum malaria. The TIM1 promoter haplotype comprising three derived alleles, -1637A (rs7702919), -1549C (rs41297577) and -1454A (rs41297579), which were in complete linkage disequilibrium, was significantly associated with protection against cerebral malaria (OR = 0.41; 95% CI = 0.24-0.71; P= 0.0009). Allele-specific transcription quantification analysis revealed that the level of mRNA transcribed from TIM1 was higher for the protective promoter haplotype than for the other promoter haplotype (P= 0.004). Engagement with TIM1 in combination with T cell receptor stimulation induces anti-inflammatory Th2 cytokine production, which can protect the development of cerebral malaria caused by overproduction of pro-inflammatory Th1 cytokines. The present results suggest that the higher TIM1 expression associated with the protective TIM1 promoter haplotype confers protection against cerebral malaria.

  8. Mechanical property of a TIM-barrel protein.

    PubMed

    Kobayashi, N; Yamato, T; Go, N

    1997-05-01

    The mechanical response of a TIM-barrel protein to an applied pressure has been studied. We generated structures under an applied pressure by assuming the volume change to be a linear function of normal mode variables. By Delaunay tessellation, the space occupied by protein atoms is divided uniquely into tetrahedra, whose four vertices correspond to atomic positions. Based on the atoms that define them, the resulting Delaunay tetrahedra are classified as belonging to various secondary structures in the protein. The compressibility of various regions identified with respect to secondary structural elements in this protein is obtained from volume changes of respective regions in two structures with and without an applied pressure. We found that the beta barrel region located at the core of the protein is quite soft. The interior of the beta barrel, occupied by side chains of beta strands, is the softest. The helix, strand, and loop segments themselves are extremely rigid, while the regions existing between these secondary structural elements are soft. These results suggest that the regions between secondary structural elements play an important role in protein dynamics. Another aspect of tetrahedra, referred to as bond distance, is introduced to account for rigidities of the tetrahedra. Bond distance is a measure of separation of the atoms of a tetrahedron in terms of number of bonds along the polypeptide chain or side chains. Tetrahedra with longer bond distances are found to be softer on average. From this behavior, we derive a simple empirical equation, which well describes the compressibilities of various regions.

  9. International Pyroheliometer Comparison 2010 Results from SORCE/TIM

    NASA Astrophysics Data System (ADS)

    Heuerman, K.; Kopp, G.; Harber, D.

    2010-12-01

    The Eleventh International Pyrheliometer Comparison (IPC-XI), organized by the World Radiation Center (WRC) on behalf of the World Meteorological Organization (WMO), was held 27 September - 15 October 2010 at the Physikalisch-Meteorologisches Observatorium Davos (PMOD/WRC) in Davos Dorf, Switzerland with nearly 100 participants representing approximately 60 countries. This ground-based comparison, held every 5 years, has established a multi-decadal baseline record of solar measurement inter-comparisons with which solar radiometers can be linked to the WRC-maintained World Radiation Reference (WRR) and compared to other current and historical radiometers across the IPC’s multi-decadal time range. A ground-based SOlar Radiation and Climate Experiment (SORCE) Total Irradiance Monitor (TIM) participated in the IPC this year, indirectly linking the on-orbit total solar irradiance (TSI) measurements that NASA’s SORCE mission has been acquiring since 2003 with the IPC record. We report the results of this 3-week inter-comparison and estimate the corrections needed and uncertainties introduced in linking these ground-based relative comparisons to the spaceborne TSI data record.

  10. Sensor 17 Thermal Isolation Mounting Structure (TIMS) Design Improvements

    SciTech Connect

    Enstrom, K.

    2015-09-04

    The SENSOR 17 thermographic camera weighs approximately 0.5lbs, has a fundamental mode of 167 Hz, and experiences 0.75W of heat leakage in through the TIMS. The configuration, shown in Figure 1, is comprised of four 300 Series SST washers paired in tandem with P.E.I (Ultem 100) washers. The SENSOR 17 sensor is mounted to a 300 series stainless plate with A-shaped arms. The Plate can be assumed to be at ambient temperatures (≈293K) and the I.R. Mount needs to be cooled to 45K. It is attached to the tip of a cryocooler by a ‘cold strap’ and is assumed to be at the temperature of the cold-strap (≈45K). During flights SENSOR 17 experiences excitations at frequencies centered around 10-30Hz, 60Hz, and 120Hz from the aircraft flight environment. The temporal progression described below depicts the 1st Modal shape at the systems resonant frequency. This simulation indicates Modal articulation will cause a pitch rate of the camera with respect to the body axis of the airplane. This articulation shows up as flutter in the camera.

  11. Tim-2 is the receptor for H-ferritin on oligodendrocytes.

    PubMed

    Todorich, Bozho; Zhang, Xuesheng; Slagle-Webb, Becky; Seaman, William E; Connor, James R

    2008-12-01

    Oligodendrocytes stain more strongly for iron than any other cell in the CNS, and they require iron for the production of myelin. For most cell types transferrin is the major iron delivery protein, yet neither transferrin receptor protein nor mRNA are detectable in mature oligodendrocytes. Thus an alternative iron delivery mechanism must exist. Given the significant long term consequences of developmental iron deficiency and the iron requirements for normal myelination, identification of the iron delivery mechanism for oligodendrocytes is important. Previously we have reported that oligodendrocytes bind H-ferritin and that H-ferritin binds to white matter tracts in vivo. Recently, T cell immunoglobulin and mucin domain-containing protein-2 (Tim-2) was shown to bind and internalize H-ferritin. In the present study we show that Tim-2 is expressed on oligodendrocytes both in vivo and in vitro. Further, the onset of saturable H-ferritin binding in CG4 oligodendrocyte cell line is accompanied by Tim-2 expression. Application of a blocking antibody to the extracellular domain of Tim-2 significantly reduces H-ferritin binding to the differentiated CG4 cells and primary oligodendrocytes. Tim-2 expression on CG4 cells is responsive to iron; decreasing with iron loading and increasing with iron chelation. Taken together, these data provide compelling evidence that Tim-2 is the H-ferritin receptor on oligodendrocytes suggesting it is the primary mechanism for iron acquisition by these cells.

  12. Tim-3 pathway affects NK cell impairment in patients with active tuberculosis.

    PubMed

    Wang, Feng; Hou, Hongyan; Wu, Shiji; Tang, Qing; Huang, Min; Yin, Botao; Huang, Jing; Liu, Weiyong; Mao, Lie; Lu, Yanfang; Sun, Ziyong

    2015-12-01

    Active tuberculosis (TB) patients show impaired NK cell function, and the underlying mechanism remains largely unknown. In this study, we confirmed the decrease in activation, cytokine secretion, and degranulation potential of NK cells in active TB patients. We further investigated whether coinhibitory receptor Tim-3 was involved with impairment of NK cells. Our results revealed that the expression of Tim-3 on NK cells was increased in active TB patients. Tim-3 expression was inversely correlated with IL-12-stimualted IFN-γ production. Moreover, blocking the Tim-3 pathway restored IFN-γ secretion and degranulation of NK cells. Blocking this pathway also increased NK cell cytotoxicity against K562 target cells, and improved the ability of NK cells to control Mtb growth in monocyte-derived macrophages. The Tim-3 expression on NK cells was also observed to be significantly decreased in TB patients post-treatment. In this study, we have identified that Tim-3 is involved with NK cell impairment in TB patients.

  13. Antagonism of TIM-1 blocks the development of disease in a humanized mouse model of allergic asthma.

    PubMed

    Sonar, Sanchaita Sriwal; Hsu, Yen-Ming; Conrad, Melanie Lynn; Majeau, Gerard R; Kilic, Ayse; Garber, Ellen; Gao, Yan; Nwankwo, Chioma; Willer, Gundi; Dudda, Jan C; Kim, Hellen; Bailly, Véronique; Pagenstecher, Axel; Rennert, Paul D; Renz, Harald

    2010-08-01

    Studies in mice and humans have revealed that the T cell, immunoglobulin, mucin (TIM) genes are associated with several atopic diseases. TIM-1 is a type I membrane protein that is expressed on T cells upon stimulation and has been shown to modulate their activation. In addition to a recently described interaction with dendritic cells, TIM-1 has also been identified as a phosphatidylserine recognition molecule, and several protein ligands have been proposed. Our understanding of its activity is complicated by the possibility that TIM-1 possesses multiple and diverse binding partners. In order to delineate the function of TIM-1, we generated monoclonal antibodies directed to a cleft formed within the IgV domain of TIM-1. We have shown here that antibodies that bind to this defined cleft antagonize TIM-1 binding to specific ligands and cells. Notably, these antibodies exhibited therapeutic activity in a humanized SCID model of experimental asthma, ameliorating inflammation, and airway hyperresponsiveness. Further experiments demonstrated that the effects of the TIM-1-specific antibodies were mediated via suppression of Th2 cell proliferation and cytokine production. These results demonstrate that modulation of the TIM-1 pathway can critically influence activated T cells in a humanized disease model, suggesting that TIM-1 antagonists may provide potent therapeutic benefit in asthma and other immune-mediated disorders.

  14. Expression of Tim-3 in gastric cancer tissue and its relationship with prognosis.

    PubMed

    Cheng, Gui; Li, Min; Wu, Jun; Ji, Mei; Fang, Cheng; Shi, Hongbing; Zhu, Danxia; Chen, Lujun; Zhao, Jiemin; Shi, Liangrong; Xu, Bin; Zheng, Xiao; Wu, Changping; Jiang, Jingting

    2015-01-01

    As a negative regulatory molecule, T-cell immunoglobulin-and mucin domain-3 (Tim-3) plays a crucial role in the tumor immunological tolerance. In the present study, we aimed to determine the Tim-3 expression in gastric cancer tissue and its relationship with clinicopathological parameters and prognosis. The Tim-3 expression was assessed in 52 gastric cancer specimens and 15 gastritis tissues by flow cytometry, and gastritis tissues served as the control. As a result, we found that the Tim-3 expressions on CD4(+)T cells and CD8(+)T cells in gastric cancer tissue was significantly higher than those in gastritis tissue (P=0.022, P=0.047, respectively). The median expression level of Tim-3 on CD4(+)T cells were significantly correlated with clinicopathological parameters, such as tumor size, lymph node metastasis, the depth of tumor invasion and TNM staging (P=0.042, P=0.026, P=0.001, P=0.003, respectively), while it was not correlated with sex, age and histological subtype (all P>0.05). In CD8(+)T cells, the Tim-3 expression was relevant to tumor invasion and TNM staging (P=0.035, P=0.017, respectively), while it was irrelevant to other clinicopathological parameters (all P>0.05). Additionally, Kaplan-Meier survival curves showed that the median overall survival time of patients with lower Tim-3 expression was greater than that of patients with higher Tim-3 expression in CD4(+)T cells and CD8(+)T cells (χ(2)=18.036, P<0.001 and χ(2)=18.036, P<0.001, respectively). Moreover, the multivariate analysis revealed that the Tim-3 expression and TNM stage were independent prognostic factors for gastric cancer patients (P=0.029, P=0.043 and P=0.003, respectively). These results suggest that Tim-3 played an important role in the development and progression of gastric cancer, and it could be used as an independent prognostic factor for gastric cancer patients.

  15. Influence of the redox active ligand on the reactivity and electronic structure of a series of Fe(TIM) complexes.

    PubMed

    Hess, Corinna R; Weyhermüller, Thomas; Bill, Eckhard; Wieghardt, Karl

    2010-06-21

    The redox properties of Fe and Zn complexes coordinated by an alpha-diimine based N(4)-macrocyclic ligand (TIM) have been examined using spectroscopic methods and density functional theory (DFT) computational analysis. DFT results on the redox series of [Zn(TIM*)](n) and [Fe(TIM*)](n) molecules indicate the preferential reduction of the alpha-diimine ligand moiety. In addition to the previously reported [Fe(TIM*)](2) dimer, we have now synthesized and characterized a further series of monomeric and dimeric complexes coordinated by the TIM ligand. This includes the five-coordinate monomeric [Fe(TIM*)I], the neutral and cationic forms of a monomeric phosphite adduct, [Fe(TIM*)(P(OPh)(3))] and [Fe(TIM*)(P(OPh)(3))](PF(6)), as well as a binuclear hydroxy-bridged complex, [{Fe(TIM*)}(2)(mu-OH)](PF(6)). Experimental and computational data for these synthetic compounds denote the presence of ferrous and ferric species, suggesting that the alpha-diimine based macrocycles do not readily support the formation of formally low-valent (M(0) or M(I)) metal complexes as previously speculated. Magnetochemical, Mossbauer, electron paramagnetic resonance (EPR), and electronic spectral data have been employed to experimentally determine the oxidation state of the central metal ion and of the macrocyclic ligand (TIM*) in each compound. The series of compounds is described as follows: [Fe(II)(TIM(0))(CH(3)CN(2))](2+), S(Fe) = S(T) = 0; [Fe(2.5)(TIM(2.5-))](2), S(T) = 1; [{Fe(III)(TIM(2-))}(2)(mu-OH)](+), S(Fe) = 3/2, S(T) = 0; [Fe(III)(TIM(2-))I], S(Fe) = 3/2, S(T) = 1/2; [Fe(II)(TIM(2-))(P(OPh(3)))], S(Fe) = S(T) = 0; and [Fe(II)(TIM(1-))(P(OPh(3)))](1+)/[Fe(I)(TIM(0))(P(OPh(3)))](1+), S(T) = 1/2. The results have been corroborated by DFT calculations.

  16. The Drosophila CLOCK protein undergoes daily rhythms in abundance, phosphorylation, and interactions with the PER-TIM complex.

    PubMed

    Lee, C; Bae, K; Edery, I

    1998-10-01

    We report the in vivo characterization of the Drosophila CLOCK protein (dCLOCK), a transcription factor that is required for the expression of the circadian clock genes period (per) and timeless (tim). dCLOCK undergoes circadian fluctuations in abundance, is phosphorylated throughout a daily cycle, and interacts with PER, TIM, and/or the PER-TIM complex during the night but not during most of the day. Our results suggest that PER and TIM participate in transcriptional autoinhibition by physically interacting with dCLOCK or a dCLOCK-containing complex. Nevertheless, in the absence of PER or TIM, the levels of dCLOCK are constitutively low, indicating that PER and TIM also act as positive elements in the feedback loop by stimulating the production of dCLOCK.

  17. De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy.

    PubMed

    Huang, Po-Ssu; Feldmeier, Kaspar; Parmeggiani, Fabio; Fernandez Velasco, D Alejandro; Höcker, Birte; Baker, David

    2016-01-01

    Despite efforts for over 25 years, de novo protein design has not succeeded in achieving the TIM-barrel fold. Here we describe the computational design of four-fold symmetrical (β/α)8 barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of side chain-backbone hydrogen bonds for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical to that of the designed TIM-barrel model. PSI-BLAST searches do not identify sequence similarities to known TIM-barrel proteins, and sensitive profile-profile searches indicate that the design sequence is distant from other naturally occurring TIM-barrel superfamilies, suggesting that Nature has sampled only a subset of the sequence space available to the TIM-barrel fold. The ability to design TIM barrels de novo opens new possibilities for custom-made enzymes.

  18. Drosophila TIM binds importin α1, and acts as an adapter to transport PER to the nucleus.

    PubMed

    Jang, A Reum; Moravcevic, Katarina; Saez, Lino; Young, Michael W; Sehgal, Amita

    2015-02-01

    Regulated nuclear entry of clock proteins is a conserved feature of eukaryotic circadian clocks and serves to separate the phase of mRNA activation from mRNA repression in the molecular feedback loop. In Drosophila, nuclear entry of the clock proteins, PERIOD (PER) and TIMELESS (TIM), is tightly controlled, and impairments of this process produce profound behavioral phenotypes. We report here that nuclear entry of PER-TIM in clock cells, and consequently behavioral rhythms, require a specific member of a classic nuclear import pathway, Importin α1 (IMPα1). In addition to IMPα1, rhythmic behavior and nuclear expression of PER-TIM require a specific nuclear pore protein, Nup153, and Ran-GTPase. IMPα1 can also drive rapid and efficient nuclear expression of TIM and PER in cultured cells, although the effect on PER is mediated by TIM. Mapping of interaction domains between IMPα1 and TIM/PER suggests that TIM is the primary cargo for the importin machinery. This is supported by attenuated interaction of IMPα1 with TIM carrying a mutation previously shown to prevent nuclear entry of TIM and PER. TIM is detected at the nuclear envelope, and computational modeling suggests that it contains HEAT-ARM repeats typically found in karyopherins, consistent with its role as a co-transporter for PER. These findings suggest that although PER is the major timekeeper of the clock, TIM is the primary target of nuclear import mechanisms. Thus, the circadian clock uses specific components of the importin pathway with a novel twist in that TIM serves a karyopherin-like role for PER.

  19. A disulfide bond in the TIM23 complex is crucial for voltage gating and mitochondrial protein import.

    PubMed

    Ramesh, Ajay; Peleh, Valentina; Martinez-Caballero, Sonia; Wollweber, Florian; Sommer, Frederik; van der Laan, Martin; Schroda, Michael; Alexander, R Todd; Campo, María Luisa; Herrmann, Johannes M

    2016-08-15

    Tim17 is a central, membrane-embedded subunit of the mitochondrial protein import machinery. In this study, we show that Tim17 contains a pair of highly conserved cysteine residues that form a structural disulfide bond exposed to the intermembrane space (IMS). This disulfide bond is critical for efficient protein translocation through the TIM23 complex and for dynamic gating of its preprotein-conducting channel. The disulfide bond in Tim17 is formed during insertion of the protein into the inner membrane. Whereas the import of Tim17 depends on the binding to the IMS protein Mia40, the oxidoreductase activity of Mia40 is surprisingly dispensable for Tim17 oxidation. Our observations suggest that Tim17 can be directly oxidized by the sulfhydryl oxidase Erv1. Thus, import and oxidation of Tim17 are mediated by the mitochondrial disulfide relay, though the mechanism by which the disulfide bond in Tim17 is formed differs considerably from that of soluble IMS proteins. PMID:27502485

  20. Role of Tim-3 in hepatitis B virus infection: An overview.

    PubMed

    Liu, Yuan; Gao, Li-Fen; Liang, Xiao-Hong; Ma, Chun-Hong

    2016-02-21

    Hepatitis B virus (HBV) infection has received increasing public attention. HBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the above-mentioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of HBV-related liver disease and suggest new therapeutic methods for intervention.

  1. Expression of PER, CRY, and TIM genes for the pathological features of colorectal cancer patients.

    PubMed

    Wang, Yong; Cheng, Yunsheng; Yu, Gang; Jia, Benli; Hu, Zhihang; Zhang, Lijiu

    2016-01-01

    As typical clock gene machinery, period (PER1, PER2, and PER3), cryptochrome (CRY1 and CRY2), and timeless (TIM), could control proliferation, cellular metabolism, and many key functions, such as recognition and repair of DNA damage, dysfunction of the circadian clock could result in tumorigenesis of colorectal cancer (CRC). In this study, the expression levels of PER1, PER2, and PER3, as well as CRY1, CRY2, and TIM in the tumor tissue and apparently healthy mucosa from CRC patients were examined and compared via quantitative real-time polymerase chain reaction. Compared with the healthy mucosa from CRC patients, expression levels of PER1, PER2, PER3, and CRY2 in their tumor tissue are much lower, while TIM level was much enhanced. There was no significant difference in the CRY1 expression level. High levels of TIM mRNA were much prevalent in the tumor mucosa with proximal lymph nodes. CRC patients with lower expression of PER1 and PER3 in the tumor tissue showed significantly poorer survival rates. The abnormal expression levels of PER and TIM genes in CRC tissue could be related to the genesis process of the tumor, influencing host-tumor interactions.

  2. Expression of PER, CRY, and TIM genes for the pathological features of colorectal cancer patients

    PubMed Central

    Wang, Yong; Cheng, Yunsheng; Yu, Gang; Jia, Benli; Hu, Zhihang; Zhang, Lijiu

    2016-01-01

    As typical clock gene machinery, period (PER1, PER2, and PER3), cryptochrome (CRY1 and CRY2), and timeless (TIM), could control proliferation, cellular metabolism, and many key functions, such as recognition and repair of DNA damage, dysfunction of the circadian clock could result in tumorigenesis of colorectal cancer (CRC). In this study, the expression levels of PER1, PER2, and PER3, as well as CRY1, CRY2, and TIM in the tumor tissue and apparently healthy mucosa from CRC patients were examined and compared via quantitative real-time polymerase chain reaction. Compared with the healthy mucosa from CRC patients, expression levels of PER1, PER2, PER3, and CRY2 in their tumor tissue are much lower, while TIM level was much enhanced. There was no significant difference in the CRY1 expression level. High levels of TIM mRNA were much prevalent in the tumor mucosa with proximal lymph nodes. CRC patients with lower expression of PER1 and PER3 in the tumor tissue showed significantly poorer survival rates. The abnormal expression levels of PER and TIM genes in CRC tissue could be related to the genesis process of the tumor, influencing host–tumor interactions. PMID:27103825

  3. Role of Tim-3 in hepatitis B virus infection: An overview

    PubMed Central

    Liu, Yuan; Gao, Li-Fen; Liang, Xiao-Hong; Ma, Chun-Hong

    2016-01-01

    Hepatitis B virus (HBV) infection has received increasing public attention. HBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the above-mentioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of HBV-related liver disease and suggest new therapeutic methods for intervention. PMID:26900291

  4. Disruption of TIM-4 in dendritic cell ameliorates hepatic warm IR injury through the induction of regulatory T cells.

    PubMed

    Li, Ji; Zhao, Xin; Liu, Xiaoliang; Liu, Huanqiu

    2015-08-01

    Hepatic ischaemia reperfusion (IR) injury results from the infiltration of multiple immune cells especially dendritic cells (DC). T-cell immunoglobulin-domain and mucin-domain 4 (TIM-4) is a type I cell-surface glycoprotein which is extensively expressed on antigen presenting cells (APC) like DC and macrophages. TIM-4 has been demonstrated to be implicated in mucosal allergy, skin allograft rejection and tumour-immune tolerance. However, the role of TIM-4 expressed on DC in hepatic IR injury remains largely unknown. In the present study, we aimed to investigate whether and how DC expressed TIM-4 was involved in hepatic IR injury. With segmental hepatic warm ischaemia mice models, we demonstrated that promoted DC infiltration and increased TIM-4 expression were induced by hepatic IR. Blockade of TIM-4 by anti-TIM-4 mAb (0.35mg/mouse) markedly ameliorated hepatic injury and reduced inflammatory cytokine secretion. Furthermore, in a DC:CD4+ T cell co-culture system, blockade of TIM-4 on DC significantly inhibited T helper-2 cell differentiation and facilitated induced CD4+ CD25+ Foxp3+ T regulatory cell (iTreg) expansion. Interleukin-4 (IL-4)/signal transducer and activator of transcription 6 (Stat 6) signalling was shown to be impeded by TIM-4 blockade and involved in iTreg generation. Additionally, adoptive transfer of iTreg produced by TIM-4 blockade into hepatic IR mice models remarkably attenuated liver injury. We conclude that TIM-4 on DC play a critical role in hepatic IR injury and may be an efficient target for the prevention of liver or other organ IR injury.

  5. Too much of a good thing? Tim-3 and TCR signaling in T cell exhaustion.

    PubMed

    Ferris, Robert L; Lu, Binfeng; Kane, Lawrence P

    2014-08-15

    T cell exhaustion is thought to be a natural mechanism for limiting immune pathology, although it may be desirable to circumvent this mechanism to help eliminate viral reservoirs or tumors. Although there are no definitive markers, a fingerprint for exhausted T cells has been described that includes the transmembrane proteins PD-1, LAG3, and Tim-3. However, apart from the recruitment of tyrosine phosphatases to PD-1, little is known about the biochemical mechanisms by which these proteins contribute to the development or maintenance of exhaustion. Tim-3 contains no known motifs for the recruitment of inhibitory phosphatases, but it may actually increase signaling downstream of TCR/CD3, at least under acute conditions. Other studies showed that T cell exhaustion results from chronic stimulation that extends the effector phase of T cell activation, at the expense of T cell memory. We suggest that Tim-3 may contribute to T cell exhaustion by enhancing TCR-signaling pathways.

  6. BOREAS Level-1B TIMS Imagery: At-sensor Radiance in BSQ Format

    NASA Technical Reports Server (NTRS)

    Hall, Forrest G. (Editor); Nickeson, Jaime (Editor); Strub, Richard; Newcomer, Jeffrey A.; Chernobieff, Sonia

    2000-01-01

    The Boreal Ecosystem-Atmospheric Study (BOREAS) Staff Science Aircraft Data Acquisition Program focused on providing the research teams with the remotely sensed satellite data products they needed to compare and spatially extend point results. For BOREAS, the Thermal Infrared Multispectral Scanner (TIMS) imagery, along with other aircraft images, was collected to provide spatially extensive information over the primary study areas. The Level-1b TIMS images cover the time periods of 16 to 20 Apr 1994 and 06 to 17 Sep 1994. The system calibrated images are stored in binary image format files. The TIMS images are available from the Earth Observing System Data and Information System (EOSDIS) Oak Ridge National Laboratory (ORNL) Distributed Active Archive Center (DAAC).

  7. Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model.

    PubMed

    Liu, Jinfeng; Xiao, Siyu; Huang, Shiguang; Pei, Fuquan; Lu, Fangli

    2016-02-01

    Malaria is the most relevant parasitic disease worldwide, and severe malaria is characterized by cerebral edema, acute lung injury (ALI), and multiple organ dysfunctions; however, the mechanisms of lung damage need to be better clarified. In this study, we used Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) to elucidate the profiles of T cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of ALI. Mice were injected intraperitoneally with 10(6) PbANKA-infected red blood cells. The lungs and mediastinal lymph nodes (MLNs) were harvested at days 5, 10, 15, and 20 post infections (p.i.). The grade of lung injury was histopathologically evaluated. Tim-3- and Gal-9-positive cells in the lungs and MLNs were stained by immunohistochemistry, and the messenger RNA (mRNA) expressions of Tim-3, Gal-9, and related cytokines were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Bronchoalveolar lavage fluid (BALF) analyses were performed from days 18 to 20 p.i. The results showed that the pathological severities in the lungs were increased with times and the total protein level in the BALFs was significantly elevated in PbANKA-infected mice. The numbers of Gal-9(+) and Tim-3(+) cells in the lungs were significantly increased, and the mRNA levels of both Gal-9 and Tim-3 in the lungs and MLNs were over-expressed in PbANKA-infected mice. In conclusion, our data suggested that Tim-3/Gal-9 may play a role in PbANKA-induced ALI. PMID:26494364

  8. TIM, a ray-tracing program for METATOY research and its dissemination

    NASA Astrophysics Data System (ADS)

    Lambert, Dean; Hamilton, Alasdair C.; Constable, George; Snehanshu, Harsh; Talati, Sharvil; Courtial, Johannes

    2012-03-01

    TIM (The Interactive METATOY) is a ray-tracing program specifically tailored towards our research in METATOYs, which are optical components that appear to be able to create wave-optically forbidden light-ray fields. For this reason, TIM possesses features not found in other ray-tracing programs. TIM can either be used interactively or by modifying the openly available source code; in both cases, it can easily be run as an applet embedded in a web page. Here we describe the basic structure of TIM's source code and how to extend it, and we give examples of how we have used TIM in our own research. Program summaryProgram title: TIM Catalogue identifier: AEKY_v1_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKY_v1_0.html Program obtainable from: CPC Program Library, Queen's University, Belfast, N. Ireland Licensing provisions: GNU General Public License No. of lines in distributed program, including test data, etc.: 124 478 No. of bytes in distributed program, including test data, etc.: 4 120 052 Distribution format: tar.gz Programming language: Java Computer: Any computer capable of running the Java Virtual Machine (JVM) 1.6 Operating system: Any; developed under Mac OS X Version 10.6 RAM: Typically 145 MB (interactive version running under Mac OS X Version 10.6) Classification: 14, 18 External routines: JAMA [1] (source code included) Nature of problem: Visualisation of scenes that include scene objects that create wave-optically forbidden light-ray fields. Solution method: Ray tracing. Unusual features: Specifically designed to visualise wave-optically forbidden light-ray fields; can visualise ray trajectories; can visualise geometric optic transformations; can create anaglyphs (for viewing with coloured "3D glasses") and random-dot autostereograms of the scene; integrable into web pages. Running time: Problem-dependent; typically seconds for a simple scene.

  9. Increased Gal-9 and Tim-3 expressions during liver damage in a murine malarial model.

    PubMed

    Xiao, Siyu; Liu, Jinfeng; Huang, Shiguang; Lu, Fangli

    2016-02-01

    Malaria has been one of the most devastating tropical parasite infectious diseases popular around the world. Severe malaria is characterized by multiple organ dysfunctions, especially liver damage. However, the mechanisms of malarial liver injury remain to be better clarified. In this study, Kunming mice inoculated intraperitoneally (i.p.) with 10(6) Plasmodium berghei ANKA (PbANKA)-infected red blood cells (iRBCs) were investigated at days 5, 10, 15, and 20 post-infection (p.i.) to elucidate the profiles of T-cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of liver injury. The histopathology of livers and spleens from PbANKA-infected mice were observed, the parasite burdens of the livers and spleens using quantitative real-time PCR (qRT-PCR), Tim-3- and Gal-9-positive cells in the livers and spleens using immunohistochemical staining, and the mRNA levels of Tim-3, Gal-9, and cytokines in both the livers and spleens using qRT-PCR were examined. Our results showed that parasite burdens in the livers and spleens were significantly increased with time after PbANKA infection. Histological scores of both the liver and spleen tissues were significantly increased with time; the numbers of Tim-3- and Gal-9-positive cells were significantly increased in both the livers and spleens using immunohistochemical staining, and the mRNA levels of Tim-3 and Gal-9 in the livers and spleens were also significantly increased after infection. Our data suggests that the increase of Tim-3/Gal-9 expressions may play an important role in the liver damage during P. berghei infection.

  10. Upregulated Tim-3/galectin-9 expressions in acute lung injury in a murine malarial model.

    PubMed

    Liu, Jinfeng; Xiao, Siyu; Huang, Shiguang; Pei, Fuquan; Lu, Fangli

    2016-02-01

    Malaria is the most relevant parasitic disease worldwide, and severe malaria is characterized by cerebral edema, acute lung injury (ALI), and multiple organ dysfunctions; however, the mechanisms of lung damage need to be better clarified. In this study, we used Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) to elucidate the profiles of T cell immunoglobulin and mucin domain-3 (Tim-3) and its ligand galecin-9 (Gal-9) in the development of ALI. Mice were injected intraperitoneally with 10(6) PbANKA-infected red blood cells. The lungs and mediastinal lymph nodes (MLNs) were harvested at days 5, 10, 15, and 20 post infections (p.i.). The grade of lung injury was histopathologically evaluated. Tim-3- and Gal-9-positive cells in the lungs and MLNs were stained by immunohistochemistry, and the messenger RNA (mRNA) expressions of Tim-3, Gal-9, and related cytokines were assessed using quantitative real-time polymerase chain reaction (qRT-PCR). Bronchoalveolar lavage fluid (BALF) analyses were performed from days 18 to 20 p.i. The results showed that the pathological severities in the lungs were increased with times and the total protein level in the BALFs was significantly elevated in PbANKA-infected mice. The numbers of Gal-9(+) and Tim-3(+) cells in the lungs were significantly increased, and the mRNA levels of both Gal-9 and Tim-3 in the lungs and MLNs were over-expressed in PbANKA-infected mice. In conclusion, our data suggested that Tim-3/Gal-9 may play a role in PbANKA-induced ALI.

  11. Ultra Fast X-ray Streak Camera for TIM Based Platforms

    SciTech Connect

    Marley, E; Shepherd, R; Fulkerson, E S; James, L; Emig, J; Norman, D

    2012-05-02

    Ultra fast x-ray streak cameras are a staple for time resolved x-ray measurements. There is a need for a ten inch manipulator (TIM) based streak camera that can be fielded in a newer large scale laser facility. The LLNL ultra fast streak camera's drive electronics have been upgraded and redesigned to fit inside a TIM tube. The camera also has a new user interface that allows for remote control and data acquisition. The system has been outfitted with a new sensor package that gives the user more operational awareness and control.

  12. Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus

    PubMed Central

    Kuroda, Makoto; Fujikura, Daisuke; Nanbo, Asuka; Marzi, Andrea; Noyori, Osamu; Kajihara, Masahiro; Maruyama, Junki; Matsuno, Keita; Miyamoto, Hiroko; Yoshida, Reiko; Feldmann, Heinz

    2015-01-01

    ABSTRACT Multiple host molecules are known to be involved in the cellular entry of filoviruses, including Ebola virus (EBOV); T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) have been identified as attachment and fusion receptors, respectively. However, the molecular mechanisms underlying the entry process have not been fully understood. We found that TIM-1 and NPC1 colocalized and interacted in the intracellular vesicles where EBOV glycoprotein (GP)-mediated membrane fusion occurred. Interestingly, a TIM-1-specific monoclonal antibody (MAb), M224/1, prevented GP-mediated membrane fusion and also interfered with the binding of TIM-1 to NPC1, suggesting that the interaction between TIM-1 and NPC1 is important for filovirus membrane fusion. Moreover, MAb M224/1 efficiently inhibited the cellular entry of viruses from all known filovirus species. These data suggest a novel mechanism underlying filovirus membrane fusion and provide a potential cellular target for antiviral compounds that can be universally used against filovirus infections. IMPORTANCE Filoviruses, including Ebola and Marburg viruses, cause rapidly fatal diseases in humans and nonhuman primates. There are currently no approved vaccines or therapeutics for filovirus diseases. In general, the cellular entry step of viruses is one of the key mechanisms to develop antiviral strategies. However, the molecular mechanisms underlying the entry process of filoviruses have not been fully understood. In this study, we demonstrate that TIM-1 and NPC1, which serve as attachment and fusion receptors for filovirus entry, interact in the intracellular vesicles where Ebola virus GP-mediated membrane fusion occurs and that this interaction is important for filovirus infection. We found that filovirus infection and GP-mediated membrane fusion in cultured cells were remarkably suppressed by treatment with a TIM-1-specific monoclonal antibody that interfered with the interaction between TIM-1 and

  13. A polymorphism of the TIM-1 IgV domain: implications for the susceptibility to filovirus infection.

    PubMed

    Kuroda, Makoto; Fujikura, Daisuke; Noyori, Osamu; Kajihara, Masahiro; Maruyama, Junki; Miyamoto, Hiroko; Yoshida, Reiko; Takada, Ayato

    2014-12-12

    Filoviruses, including Ebola and Marburg viruses, cause severe hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Human T-cell immunoglobulin and mucin domain 1 (TIM-1) is one of the host proteins that have been shown to promote filovirus entry into cells. In this study, we cloned TIM-1 genes from three different African green monkey kidney cell lines (Vero E6, COS-1, and BSC-1) and found that TIM-1 of Vero E6 had a 23-amino acid deletion and 6 amino acid substitutions compared with those of COS-1 and BSC-1. Interestingly, Vero E6 TIM-1 had a greater ability to promote the infectivity of vesicular stomatitis viruses pseudotyped with filovirus glycoproteins than COS-1-derived TIM-1. We further found that the increased ability of Vero E6 TIM-1 to promote virus infectivity was most likely due to a single amino acid difference between these TIM-1s. These results suggest that a polymorphism of the TIM-1 molecules is one of the factors that influence cell susceptibility to filovirus infection, providing a new insight into the molecular basis for the filovirus host range.

  14. Identification of TIM3 2′-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy

    PubMed Central

    Soldevilla, Mario M.; Villanueva, Helena; Mancheño, Uxua; Bendandi, Maurizio

    2016-01-01

    TIM3 belongs to a family of receptors that are involved in T-cell exhaustion and Treg functions. The development of new therapeutic agents to block this type of receptors is opening a new avenue in cancer immunotherapy. There are currently several clinical trials ongoing to combine different immune-checkpoint blockades to improve the outcome of cancer patients. Among these combinations we should underline PD1:PDL1 axis and TIM3 blockade, which have shown very promising results in preclinical settings. Most of these types of therapeutic agents are protein cell-derived products, which, although broadly used in clinical settings, are still subject to important limitations. In this work we identify by HT-SELEX TIM3 non-antigenic oligonucleotide aptamers (TIM3Apt) that bind with high affinity and specificity to the extracellular motives of TIM3 on the cell surface. The TIM3Apt1 in its monomeric form displays a potent antagonist capacity on TIM3-expressing lymphocytes, determining the increase of IFN-γ secretion. In colon carcinoma tumor-bearing mice, the combinatorial treatment of TIM3Apt1 and PDL1-antibody blockade is synergistic with a remarkable antitumor effect. Immunotherapeutic aptamers could represent an attractive alternative to monoclonal antibodies, as they exhibit important advantages; namely, lower antigenicity, being chemically synthesized agents with a lower price of manufacture, providing higher malleability, and antidote availability. PMID:26683225

  15. The correlation of Tim-3 and IFN-γ expressions in mice infected with Toxoplasma gondii during gestation.

    PubMed

    Fu, Xiaoyin; Wu, Bin; Huang, Bo; Zheng, Huanqin; Huang, Shiguang; Gan, Yan; Shen, Jilong; Lun, Zhao-Rong; Lu, Fangli

    2015-01-01

    The immunoinhibitory receptor T cell immunoglobulin domain and mucin domain-1 (Tim-1) and Tim-3 participate in the regulation of Th immune response as well as innate immunity. However, there is no report about the expression of Tim genes in Toxoplasma gondii-infected experimental models during pregnancy. In this study, Kunming outbred pregnant mice were infected with RH strain of T. gondii through vagina at days 10 to 16 of gestation, and the mRNA expressions of Tim-1, Tim-3, interleukin (IL)-4, and interferon (IFN)-γ in the placentas, uteri, and draining lumber aortic lymph nodes (LALNs) at day 18 of gestation were analyzed using quantitative real-time PCR (qRT-PCR). Compared with uninfected pregnant controls, significantly increased levels of IFN-γ and Tim-3 were detected in the placentas (P < 0.001), uteri (P = 0.003 and P = 0.017, respectively), and LALNs (P = 0.003 and P = 0.025, respectively) of T. gondii-infected mice; there were positive and significant correlations between Tim-3 and IFN-γ mRNA expression levels in the placentas (R(2) = 0.6331, P = 0.0011), uteri (R(2) = 0.5658, P = 0.003), and LALNs (R(2) = 0.5583, P = 0.0033) of infected mice. Tim-1 (P = 0.002) and IL-4 (P = 0.003) expressions were significantly increased in the placentas, but Tim-1 were significantly decreased in the uteri (P = 0.013) and LALNs (P < 0.001) of infected pregnant mice in comparison of uninfected pregnant controls. Our data suggested that Tim-3 may play a regulatory role in T. gondii-infected pregnant mouse model.

  16. Differential expression and biochemical activity of the immune receptor Tim-3 in healthy and malignant human myeloid cells.

    PubMed

    Gonçalves Silva, Isabel; Gibbs, Bernhard F; Bardelli, Marco; Varani, Luca; Sumbayev, Vadim V

    2015-10-20

    The T cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated receptor which is involved in a variety of biological responses in human immune cells. It is highly expressed in most acute myeloid leukaemia (AML) cells and therefore may serve as a possible target for AML therapy. However, its biochemical activities in primary human AML cells remain unclear. We therefore analysed the total expression and surface presence of the Tim-3 receptor in primary human AML blasts and healthy primary human leukocytes isolated from human blood. We found that Tim-3 expression was significantly higher in primary AML cells compared to primary healthy leukocytes. Tim-3 receptor molecules were distributed largely on the surface of primary AML cells, whereas in healthy leukocytes Tim-3 protein was mainly expressed intracellularly. In primary human AML blasts, both Tim-3 agonistic antibody and galectin-9 (a Tim-3 natural ligand) significantly upregulated mTOR pathway activity. This was in line with increased accumulation of hypoxia-inducible factor 1 alpha (HIF-1α) and secretion of VEGF and TNF-α. Similar results were obtained in primary human healthy leukocytes. Importantly, in both types of primary cells, Tim-3-mediated effects were compared with those induced by lipopolysaccharide (LPS) and stem cell factor (SCF). Tim-3 induced comparatively moderate responses in both AML cells and healthy leukocytes. However, Tim-3, like LPS, mediated the release of both TNF-α and VEGF, while SCF induced mostly VEGF secretion and did not upregulate TNF-α release.

  17. Zinc can play chaperone-like and inhibitor roles during import of mitochondrial small Tim proteins.

    PubMed

    Morgan, Bruce; Ang, Swee Kim; Yan, Guanhua; Lu, Hui

    2009-03-13

    Zinc is an essential cofactor required for the function of approximately 8% of the yeast and 10% of the human proteome. All of the "small Tim" proteins of the mitochondrial intermembrane space contain a strictly conserved "twin CX(3)C" zinc finger motif, which can bind zinc ions in the Cys-reduced form. We have shown previously that although disulfide bond formation is essential for the function of these proteins in mitochondria, only reduced proteins can be imported into mitochondria (Lu, H., Allen, S., Wardleworth, L., Savory, P., and Tokatlidis, K. (2004) J. Biol. Chem. 279, 18952-18958 and Morgan, B., and Lu, H. (2008) Biochem. J. 411, 115-122). However, the role of zinc during the import of these proteins is unclear. This study shows that the function of zinc is complex. It can play a thiol stabilizer role preventing oxidative folding of the small Tim proteins and maintaining the proteins in an import-competent form. On the other hand, zinc-bound forms cannot be imported into mitochondria efficiently. Furthermore, our results show that zinc is a powerful inhibitor of Erv1, an essential component of the import pathway used by the small Tim proteins. We propose that zinc plays a chaperone-like role in the cytosol during biogenesis of the small Tim proteins and that the proteins are imported into mitochondria through the apo-forms.

  18. A Ghoulish Inconsistency: A Comment on Tim Keller's "The National Implications of "Cain v. Horne""

    ERIC Educational Resources Information Center

    Schoenig, John

    2010-01-01

    Tim Keller's article insightfully explores the flawed legal reasoning behind and potentially pernicious consequences of the Arizona Supreme Court's 2009 "Cain vs. Horne" ruling. He carefully examines the two fundamental flaws in the court's interpretative methodology: a failure to engage in a straightforward textual analysis of Arizona's Blaine…

  19. Reading and Understanding: Tim O'Brien and the Narrative of Failure

    ERIC Educational Resources Information Center

    Buchanan, Jeffrey

    2008-01-01

    Tim O'Brien's "The Things They Carried" is an example of what the author calls a narrative of failure. A narrative of failure is a term for a narrative that both fails in the enactment of its own telling and that takes failure or failing as one of its subjects. This paper discusses how, as a form for telling a teaching story, narratives…

  20. Beyond "Cain v. Horne": Comment on Tim Keller's "The National Implications of 'Cain v. Horne'"

    ERIC Educational Resources Information Center

    Harmon, Corinne

    2010-01-01

    This commentary is in response to Tim Keller's article "The National Implications of 'Cain v. Horne.'" In his analysis, Keller asserts that the Arizona Supreme Court wrongfully struck down a voucher program for students with special needs by characterizing the voucher as aid to schools rather than aid to students. In this response to Keller, I…

  1. Constructing a Writer's Voice: Ethos, Tim Cahill, and the Jonestown Massacre

    ERIC Educational Resources Information Center

    Miller, Rich

    2007-01-01

    For over twenty years, Tim Cahill's writing has appeared in popular publications such as "Outside" and "Rolling Stone," and in many academic contexts, ranging from remedial and freshman composition textbooks to the use of his novels and short story collections in a variety of upper division literary courses. Cahill, then, is a…

  2. The Filmmaker as Humanist: An Interview with Tim Robbins on the Making of "Cradle Will Rock".

    ERIC Educational Resources Information Center

    Mason, Terrence C.

    2000-01-01

    Presents an interview with Tim Robbins that focuses on the making of the film "Cradle Will Rock." Robbins offers his perspectives on issues such as the power of art to convey important social messages and sources of violence in schools. Includes resources for teachers. (CMK)

  3. Identity and Agonism: Tim Miller, Cornerstone, and the Politics of Community-Based Theatre.

    ERIC Educational Resources Information Center

    Fletcher, John

    2003-01-01

    Contends that community-based theatre (CBT) can productively redefine the parameters of what "political performance" can mean. Draws on the work of community-based performance artist Tim Miller and on the author's experience as a dramaturg to suggest that artists and scholars must develop a revised idea of what constitutes activist democratic…

  4. Investigating Enhanced Thorium Ionization in TIMS Using Re/Pt Porous Ion Emitters

    SciTech Connect

    Floyd E. Stanley III; K. J. Spencer; D. S. Schwartz; M. G. Watrous; J. E. Delmore

    2014-03-01

    Thermal ionization mass spectrometry (TIMS) is a widely used, benchmark method in the isotopic analysis of actinides relevant to various nuclear and geological fields. Despite significant previous use and inherent advantages, however, poor sample ionization continues to hamper the use of TIMS in the measurement of trace species; actinide ionization efficiencies frequently fall below 0.1 % using traditional instrument sources. Factors leading to poor ionization are compounded in the measurement of several highly refractory metals (e.g. U and Th) that may provide key signatures data in non-proliferation, safeguards and forensics efforts. Herein, a relatively new TIMS ion source strategy, employing porous ion emitters (PIEs) atop traditional filament assemblies, is investigated for the first time as a straightforward means of enhancing the ionization of Th, which is arguably a worst case scenario for TIMS-based actinide measurements. These sources yielded up to 410% greater Th sample utilization, relative to previously published values and in-house measurements collected using traditional methods. Accompanying scanning electron microscopy (SEM) investigations provide preliminary insight into possible mechanisms of PIE functioning and explore the impacts that extended heating have on the constructed source’s structure and composition.

  5. Consumerism, Activism, Intrinsic Motivation, and Balance: An Interview with Tim Kasser

    ERIC Educational Resources Information Center

    Keeley, Jared

    2010-01-01

    A year after receiving his PhD in psychology from the University of Rochester, Tim Kasser accepted a position at Knox College, in Galesburg, Illinois, where he is currently professor of psychology. He regularly teaches psychology classes on personality, clinical and abnormal psychology, dreaming, and research methods, as well as an…

  6. Reversibility and two state behaviour in the thermal unfolding of oligomeric TIM barrel proteins.

    PubMed

    Romero-Romero, Sergio; Costas, Miguel; Rodríguez-Romero, Adela; Alejandro Fernández-Velasco, D

    2015-08-28

    Temperature is one of the main variables that modulate protein function and stability. Thermodynamic studies of oligomeric proteins, the dominant protein natural form, have been often hampered because irreversible aggregation and/or slow reactions are common. There are no reports on the reversible equilibrium thermal unfolding of proteins composed of (β/α)8 barrel subunits, albeit this "TIM barrel" topology is one of the most abundant and versatile in nature. We studied the eponymous TIM barrel, triosephosphate isomerase (TIM), belonging to five species of different bacterial taxa. All of them were found to be catalytically efficient dimers. The three-dimensional structure of four enzymes was solved at high/medium resolution. Irreversibility and kinetic control were observed in the thermal unfolding of two TIMs, while for the other three the thermal unfolding was found to follow a two-state equilibrium reversible process. Shifts in the global stability curves of these three proteins are related to the organismal temperature range of optimal growth and modulated by variations in maximum stability temperature and in the enthalpy change at that temperature. Reversibility appears to correlate with the low isoelectric point, the absence of a residual structure in the unfolded state, small cavity volume in the native state, low conformational stability and a low melting temperature. Furthermore, the strong coupling between dimer dissociation and monomer unfolding may reduce aggregation and favour reversibility. It is therefore very thought-provoking to find that a common topological ensemble, such as the TIM barrel, can unfold/refold in the Anfinsen way, i.e. without the help of the cellular machinery. PMID:26206330

  7. Ligand-promoted solvent-dependent ionization and conformational equilibria of Re(CO)3Br[CH2(S-tim)2] (tim = 1-methylthioimidazolyl). Crystal structures of Re(CO)3Br[CH2(S-tim)2] and {Re(CO)3(CH3CN)[CH2(S-tim)2]}(PF6).

    PubMed

    Silva, Rosalice M; Liddle, Brendan J; Lindeman, Sergey J; Smith, Mark D; Gardinier, James R

    2006-08-21

    The compounds Re(CO)3Br[CH2(S-tim)2] (1) and {Re(CO)3(CH3CN)[CH2(S-tim)2]}(PF6) (2), where tim is 1-methylthioimidazolyl, were prepared in high yields and characterized both in the solid state and in solution. The solid-state structures show that the ligand acts in a chelating binding mode where the eight-member chelate ring adopts twist-boat conformations in both compounds. A comparison of both solid-state IR data for CO stretching frequencies and the solution-phase voltammetric measurements for the Re(1+/2+) couples between 1, 2, and related N,N-chelates of the rhenium tricarbonyl moiety indicate that the CH2(S-tim)2 ligand is a stronger donor than even the ubiquitous dipyridyl ligands. A combination of NMR spectroscopic studies and voltammetric studies revealed that compound 1 undergoes spontaneous ionization to form {Re(CO)3(CH3CN)[CH2(S-tim)2]+}(Br-) in acetonitrile. Ionization does not occur in solvents such as CH2Cl2 or acetone that are less polar and Lewis basic (less coordinating). The equilibrium constant at 293 K for the ionization of 1 in CH3CN is 4.3 x 10(-3). The eight-member chelate rings in each 1 and 2 were found to be conformationally flexible in all solvents, and boat-chair conformers could be identified. Variable-temperature NMR spectroscopic studies were used to elucidate the various kinetic and thermodynamic parameters associated with the energetically accessible twist-boat to twist-boat and twist-boat to boat-chair interconversions.

  8. Tucumán ionospheric model (TIM): Initial results for STEC predictions

    NASA Astrophysics Data System (ADS)

    Scidá, L. A.; Ezquer, R. G.; Cabrera, M. A.; Jadur, C.; Sfer, A. M.

    2016-09-01

    Most ionospheric models can calculate vertical total electron content (VTEC) predictions, but only a few are suitable for calculating slant total electron content (STEC). This ionospheric magnitude is generally measured for electron content determinations, with VTEC particularly corresponding to an elevation of 90°. This is generally obtained by applying a mapping function to STEC measurements, which leads to important calculation errors. Moreover, the equatorial region has unique characteristics, such as the fountain effect and the equatorial electrojet, which lead to significant errors in the model's calculations. In this paper, the Tucumán ionospheric model (TIM) is presented as a novel alternative for calculating the STEC in low-latitude regions (-24 to 24 dip latitude). The model is based on spatial geometry where the considered trajectory is segmented, and the corresponding electron density calculations for the resulting segment end points are determined using the semi-empirical low-latitude ionospheric model (SLIM) with reference to their corresponding magnetic coordinates and height. Finally, the electron density values are integrated along the path to obtain the STEC. This work describes the TIM and tests their STEC predictions for five ray paths around the world (totaling 16 cases under study), which are compared with experimental data from satellites and with those calculated by the NeQuick model. Moreover, the TIM performance for VTEC predictions is also checked and compared with VTEC data obtained from Global Positioning System (GPS) signals, IRI model, and NeQuick model predictions, for six GPS receiver stations during the equinox and solstice (totaling 12 cases studied). Comparisons of the TIM predictions with experimental data show that 53% of the calculation has, in general, deviations <30%. For the considered cases, TIM reproduces the experimental data better than the other models.

  9. Mitochondrial translocation contact sites: separation of dynamic and stabilizing elements in formation of a TOM-TIM-preprotein supercomplex.

    PubMed

    Chacinska, Agnieszka; Rehling, Peter; Guiard, Bernard; Frazier, Ann E; Schulze-Specking, Agnes; Pfanner, Nikolaus; Voos, Wolfgang; Meisinger, Chris

    2003-10-15

    Preproteins with N-terminal presequences are imported into mitochondria at translocation contact sites that include the translocase of the outer membrane (TOM complex) and the presequence translocase of the inner membrane (TIM23 complex). Little is known about the functional cooperation of these translocases. We have characterized translocation contact sites by a productive TOM-TIM-preprotein supercomplex to address the role of three translocase subunits that expose domains to the intermembrane space (IMS). The IMS domain of the receptor Tom22 is required for stabilization of the translocation contact site supercomplex. Surprisingly, the N-terminal segment of the channel Tim23, which tethers the TIM23 complex to the outer membrane, is dispensable for both protein import and generation of the TOM-TIM supercomplex. Tim50, with its large IMS domain, is crucial for generation but not for stabilization of the supercomplex. Thus, Tim50 functions as a dynamic factor and the IMS domain of Tom22 represents a stabilizing element in formation of a productive translocation contact site supercomplex.

  10. TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity.

    PubMed

    Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara; Dusi, Silvia; Pietronigro, Enrica; Zenaro, Elena; Della Bianca, Vittorina; Toffali, Lara; Piacentino, Gennj; Budui, Simona; Rennert, Paul; Xiao, Sheng; Laudanna, Carlo; Casasnovas, Jose M; Kuchroo, Vijay K; Constantin, Gabriela

    2014-04-17

    Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper 1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but it reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 immunoglobulin variable domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease.

  11. TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity.

    PubMed

    Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara; Dusi, Silvia; Pietronigro, Enrica; Zenaro, Elena; Della Bianca, Vittorina; Toffali, Lara; Piacentino, Gennj; Budui, Simona; Rennert, Paul; Xiao, Sheng; Laudanna, Carlo; Casasnovas, Jose M; Kuchroo, Vijay K; Constantin, Gabriela

    2014-04-17

    Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper 1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but it reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 immunoglobulin variable domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease. PMID:24703780

  12. TIM-1 glycoprotein binds the adhesion receptor P-selectin and mediates T cell trafficking during inflammation and autoimmunity

    PubMed Central

    Angiari, Stefano; Donnarumma, Tiziano; Rossi, Barbara; Dusi, Silvia; Pietronigro, Enrica; Zenaro, Elena; Della Bianca, Vittorina; Toffali, Lara; Piacentino, Gennj; Budui, Simona; Rennert, Paul; Xiao, Sheng; Laudanna, Carlo; Casasnovas, Jose M.; Kuchroo, Vijay K.; Constantin, Gabriela

    2014-01-01

    SUMMARY Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper-1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 IgV domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease. PMID:24703780

  13. Tim-3 Is Upregulated in NK Cells during Early Pregnancy and Inhibits NK Cytotoxicity toward Trophoblast in Galectin-9 Dependent Pathway.

    PubMed

    Sun, Jintang; Yang, Meixiang; Ban, Yanli; Gao, Wenjuan; Song, Bingfeng; Wang, Yang; Zhang, Yun; Shao, Qianqian; Kong, Beihua; Qu, Xun

    2016-01-01

    NK cells accumulate at the maternal-fetal interface (MFI) and play essential roles in maintaining immune tolerance during pregnancy. The mechanisms that facilitate NK cells tolerance to fetal tissue are largely unknown. T cell Ig and mucin domain-containing protein 3 (Tim-3) is a newly defined molecule with essential immunological function in many physiological and pathological processes. Recent study showed that Tim-3 was involved in the regulation of immune tolerance at MFI. However, whether Tim-3 regulates NK cells cytotoxicity toward trophoblasts is unclear. Here, we showed Tim-3 was mainly expressed by decidual NK cells (dNK) and Tim-3 level in dNK was higher than peripheral NK cells (pNK). Tim-3(+) dNK expressed more levels of mature markers CD94 and CD69 than Tim-3- dNK cells and blocking Tim-3 significantly inhibited dNK IFN-γ and TNF-α secretion. Furthermore, we found TGF-β1 may contribute to such up-regulation of Tim-3 in NK cells. Interestingly, blocking Tim-3 enhanced NK cytotoxicity toward trophoblast cell line HTR-8 but not K562. We found HTR-8 expressed Tim-3 ligand Galectin-9, in contrast K562 did not. Small interfering RNA-mediated silencing of Galectin-9 expression enhanced NK cytotoxicity toward HTR-8. We further showed Tim-3/Galecin-9 inhibited NK cytotoxicity toward trophoblast partially via impairing the degranulation process. In addition, clinical data showed that abnormal Tim-3 level on pNK might be associated with recurrent spontaneous abortion (RSA). Thus, our data demonstrate Tim-3/Galectin-9 pathway maintains local tolerance by suppressing NK cytotoxicity toward trophoblasts which may represent a new immunologic tolerance mechanism at MFI.

  14. T-Cell Immunoglobulin and Mucin Domain 4 (TIM-4) Signaling in Innate Immune-Mediated Liver Ischemia-Reperfusion Injury

    PubMed Central

    Zhang, Yu; Shen, Xiu-da; Gao, Feng; Busuttil, Ronald W.; Kuchroo, Vijay K.; Kupiec-Weglinski, Jerzy W.

    2015-01-01

    Hepatic ischemia-reperfusion injury (IRI), an innate immunity-driven inflammation response, occurs in multiple clinical settings including liver resection, transplantation, trauma, and shock. TIM-4, the only TIM protein not expressed on T cells, is found on macrophages and dendritic cells. The regulatory function of macrophage TIM-4 in the engulfment of apoptotic/necrotic bodies in innate immunity-mediated disease states remains unknown. This study focuses on putative role of TIM-4 signaling in a model of liver warm ischemia (90min) and reperfusion. The ischemia insult triggered TIM-4 expression by stressed hepatocellular phosphatidylserine (PS) presentation, peaking at 6h of reperfusion, and coinciding with the maximal hepatocellular damage. TIM-4-deficient or WT mice treated with antagonistic TIM-4 mAb were resistant against liver IRI, evidenced by diminished sALT levels and well-preserved hepatic architecture. Liver hepatoprotection rendered by TIM-4 deficiency was accompanied by diminished macrophage infiltration/chemoattraction, phagocytosis and activation of TLR2/4/9-dependent signaling. Correlating with in vivo kinetics, the peak of TIM-4 induction in LPS-activated bone marrow derived-macrophages (BMM) was detected in 6h cultures. To mimic liver IRI, we employed hydrogen peroxide-necrotic hepatocytes, which readily present PS. Indeed, necrotic hepatocytes were efficiently captured/engulfed by WT (TIM-4+) but not by TIM-4-deficient BMM. Finally, in a newly established model of liver IRI, adoptive transfer of WT but not TIM-4 deficient BMM readily recreated local inflammation response/hepatocellular damage in the CD11b-DTR mouse system. Conclusion: Our novel findings document the importance of macrophage-specific TIM-4 activation in the mechanism of hepatic IRI. Macrophage TIM-4 may represent a therapeutic target to minimize innate inflammatory responses in IR-stressed organs. PMID:25066922

  15. The use of TIMS for mapping different pahoehoe surfaces: Mauna Iki, Kilauea

    NASA Technical Reports Server (NTRS)

    Rowland, Scott K.

    1992-01-01

    S-type and p-type pahoehoe record different mechanisms and vigors of activity within an active flow field. There is some controversy about what these mechanisms are exactly, and this study was undertaken with the idea that an accurate map of the two surfaces within a pahoehoe flow field could be helpful in solving the problem. Thermal Infrared Multispectral Scanner (TIMS) allows discrimination between s-type and p-type pahoehoe, and this ability was used to map the two surface types on the Mauna Iki satellite shield (southwest rift zone, Kilauea Volcano). TIMS was previously used to discriminate a'a from pahoehoe as well as to determine relative age relationships of different flows. Although inter-flow variation was minor in the data published by these authors, a second goal presented is to understand such variations to better constrain intra-flow differences used for age dating.

  16. HHrep: de novo protein repeat detection and the origin of TIM barrels.

    PubMed

    Söding, Johannes; Remmert, Michael; Biegert, Andreas

    2006-07-01

    HHrep is a web server for the de novo identification of repeats in protein sequences, which is based on the pairwise comparison of profile hidden Markov models (HMMs). Its main strength is its sensitivity, allowing it to detect highly divergent repeat units in protein sequences whose repeats could as yet only be detected from their structures. Examples include sequences with beta-propellor fold, ferredoxin-like fold, double psi barrels or (betaalpha)8 (TIM) barrels. We illustrate this with proteins from four superfamilies of TIM barrels by revealing a clear 4- and 8-fold symmetry, which we detect solely from their sequences. This symmetry might be the trace of an ancient origin through duplication of a betaalphabetaalpha or betaalpha unit. HHrep can be accessed at http://hhrep.tuebingen.mpg.de.

  17. A multipurpose TIM-based optical telescope for Omega and the Trident laser facilities

    SciTech Connect

    Oertel, J.A.; Murphy, T.J.; Berggren, R.R.

    1998-12-31

    The authors have recently designed and are building a telescope which acts as an imaging light collector relaying the image to an optical table for experiment dependent analysis and recording. The expected primary use of this instrument is a streaked optical pyrometer for witness plate measurements of Hohlraum drive temperature. The telescope is based on University of Rochester`s Ten-Inch Manipulator (TIM) which allows compatibility between Omega, Trident, and the NIF lasers. The optics capture a f/7 cone of light, have a field of view of 6-mm, have a spatial resolution of 5 to 7-{micro}m per line pair at the object plane, and are optimized for operation at 280-nm. The image is at a magnification of 11.7x, which is convenient for many experiments, but can be changed using additional optics that reside outside the TIM.

  18. Betaalpha-hairpin clamps brace betaalphabeta modules and can make substantive contributions to the stability of TIM barrel proteins.

    PubMed

    Yang, Xiaoyan; Kathuria, Sagar V; Vadrevu, Ramakrishna; Matthews, C Robert

    2009-01-01

    Non-local hydrogen bonding interactions between main chain amide hydrogen atoms and polar side chain acceptors that bracket consecutive betaalpha or alphabeta elements of secondary structure in alphaTS from E. coli, a TIM barrel protein, have previously been found to contribute 4-6 kcal mol(-1) to the stability of the native conformation. Experimental analysis of similar betaalpha-hairpin clamps in a homologous pair of TIM barrel proteins of low sequence identity, IGPS from S. solfataricus and E. coli, reveals that this dramatic enhancement of stability is not unique to alphaTS. A survey of 71 TIM barrel proteins demonstrates a 4-fold symmetry for the placement of betaalpha-hairpin clamps, bracing the fundamental betaalphabeta building block and defining its register in the (betaalpha)(8) motif. The preferred sequences and locations of betaalpha-hairpin clamps will enhance structure prediction algorithms and provide a strategy for engineering stability in TIM barrel proteins.

  19. Insights into the Fold Organization of TIM Barrel from Interaction Energy Based Structure Networks

    PubMed Central

    Vijayabaskar, M. S.; Vishveshwara, Saraswathi

    2012-01-01

    There are many well-known examples of proteins with low sequence similarity, adopting the same structural fold. This aspect of sequence-structure relationship has been extensively studied both experimentally and theoretically, however with limited success. Most of the studies consider remote homology or “sequence conservation” as the basis for their understanding. Recently “interaction energy” based network formalism (Protein Energy Networks (PENs)) was developed to understand the determinants of protein structures. In this paper we have used these PENs to investigate the common non-covalent interactions and their collective features which stabilize the TIM barrel fold. We have also developed a method of aligning PENs in order to understand the spatial conservation of interactions in the fold. We have identified key common interactions responsible for the conservation of the TIM fold, despite high sequence dissimilarity. For instance, the central beta barrel of the TIM fold is stabilized by long-range high energy electrostatic interactions and low-energy contiguous vdW interactions in certain families. The other interfaces like the helix-sheet or the helix-helix seem to be devoid of any high energy conserved interactions. Conserved interactions in the loop regions around the catalytic site of the TIM fold have also been identified, pointing out their significance in both structural and functional evolution. Based on these investigations, we have developed a novel network based phylogenetic analysis for remote homologues, which can perform better than sequence based phylogeny. Such an analysis is more meaningful from both structural and functional evolutionary perspective. We believe that the information obtained through the “interaction conservation” viewpoint and the subsequently developed method of structure network alignment, can shed new light in the fields of fold organization and de novo computational protein design. PMID:22615547

  20. TIM-3 Genetic Variations Affect Susceptibility to Osteoarthritis by Interfering with Interferon Gamma in CD4+ T Cells.

    PubMed

    Li, Shufeng; Ren, Yanjun; Peng, Dayong; Yuan, Zhen; Shan, Shiying; Sun, Huaqiang; Yan, Xinfeng; Xiao, Hong; Li, Guang; Song, Haihan

    2015-10-01

    Osteoarthritis (OA) is the most common type of arthritis, in which T cell responses and cytokines may play critical roles in the development of the disease. TIM-3 may affect immune responses and is correlated with decreased expression of interferon gamma (INF-γ) in CD4+ T cells. In the current study, we investigated the association between polymorphisms in the TIM-3 gene and susceptibility to OA. Two polymorphisms in TIM-3, -574G/T and +4259T/G polymorphisms, were identified in OA cases and healthy donors by polymerase chain reaction-restriction fragment length polymorphism method. Data revealed that the prevalence of TIM-3 +4259T/G genotype was significantly elevated in OA patients than in the healthy donors after adjustment (Odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.32-5.11, P < 0.001). Similarly, the TIM-3 +4259G allele presented a positive association with the risk of OA after adjustment (OR = 2.58, 95% CI 1.29-4.82, P = 0.003). The TIM-3 -574G/T polymorphism did not show any correlation with the disease. We further examined whether the two TIM-3 polymorphisms could affect INF-γ expression in CD4+ T cells. Data revealed that subjects carrying polymorphic +4259TG genotype had significantly higher mRNA and protein levels of INF-γ in CD4+ T cells compared to wild-type GG genotype (P < 0.001 and P < 0.01). These results indicated that TIM-3 polymorphism is associated with increased susceptibility to OA possibly by upregulating INF-γ expression in CD4+ T cells.

  1. TIMS 1.6 micron Measurement of Atmospheric CO2 and CH4

    NASA Astrophysics Data System (ADS)

    Rairden, R. L.; Kumer, J. B.; Roche, A. E.; Palmer, A.

    2013-12-01

    The Tropospheric Infrared Mapping Spectrometers (TIMS) were originally developed with support from the NASA ESTO Instrument Incubator program (IIP). These were designed to operate in the spectral regions of the CO overtone and fundamental bands at about 2.33 and 4.67 microns, respectively. In the IIP it was shown these could provide measurements of CO vertical structure, with area coverage rate and spatial resolution that would satisfy GEO-CAPE requirements as laid out in the NRC Decadal Survey report. Since completion of the IIP there has been further internally supported development discussed by Kumer et al, Aerospace Conference, 2013 IEEE. In this presentation we describe a demonstration of TIMS capability in a third wavelength region with two orders operating from approximately 1602 to 1616 nm, and from 1646 to 1660 nm. We will discuss and illustrate the reversible conversion of the 2.33 TIMS for operation at 1600 - 1660 nm; the high quality of the spectral mages and excellent agreement with models; and automated calibration algorithms. The figures show a wavelength calibrated spectral image and excellent agreement of the data and model on a spectrum extracted from the image. Fig 1. Wavelength-calibrated image of sunlight through atmosphere, with methane lines. Yellow box outlines the rows averaged for profile. Fig 2. Calibrated spectral profile, data fit to modeled atmosphere H2O, CO2, and CH4.

  2. Downregulation of IL-10 secretion by Treg cells in osteoarthritis is associated with a reduction in Tim-3 expression.

    PubMed

    Li, Shufeng; Wan, Jinliang; Anderson, William; Sun, Huaqiang; Zhang, Hu; Peng, Xianbo; Yu, Zhaolong; Wang, Teng; Yan, Xinfeng; Smith, Wendy

    2016-04-01

    Knee osteoarthritis (OA) is the most common cause of musculoskeletal pain and disability in the knee. Though traditionally thought a mechanical wear-and-tear disease, in recent years, knee OA as a low-grade, chronic inflammatory disease has been increasingly recognized. In this study, we examined the Treg responses in non-obese knee OA patients at different stages. Significantly elevated frequencies of CD4(+)CD25(+)Foxp3(+) Tregs were found in OA patients, while on the other hand, lower IL-10 secretion from Tregs in OA patients was observed. Importantly, this decrease in IL-10 was associated with reduced Tim-3 expression on Tregs. Although both Tim-3(-) and Tim3(+) Tregs could secrete IL-10, the majority of IL-10 was observed in Tim-3(+) Tregs. Reduction of Tim-3(+) Tregs in OA patients resulted in less IL-10-producing Tregs. Interestingly, the OA patients in more advanced stages showed further reductions in IL-10 and Tim-3 expression. In conclusion, our results revealed an immunoregulatory disorder in OA independent of obesity, and demonstrated a potential mechanism in establishing the proinflammatory status of OA patients.

  3. TIM-3 expression in lymphoma cells predicts chemoresistance in patients with adult T-cell leukemia/lymphoma

    PubMed Central

    Horlad, Hasita; Ohnishi, Koji; Ma, Chaoya; Fujiwara, Yukio; Niino, Daisuke; Ohshima, Koichi; Jinushi, Masahisa; Matsuoka, Masao; Takeya, Motohiro; Komohara, Yoshihiro

    2016-01-01

    Adult T-cell leukemia/lymphoma (ATLL), an aggressive type of malignant lymphoma, is highly resistant to chemotherapy. However, the detailed mechanisms of the chemoresistance of ATLL have never been elucidated. We previously demonstrated that direct cell-cell interaction between macrophages and lymphoma cells was significantly associated with lymphoma progression in patients with ATLL. The present study aimed to further analyze the effects of cell-cell interaction between macrophages and ATLL cells by means of cell culture studies and immunohistochemical analysis using human ATLL samples. It was found that direct co-culture with macrophages induced chemoresistance in the ATLL ATN-1 cell line, but not in other cell lines, including TL-Mor, ED and ATL-2S. It was also found that expression of the T cell Ig and mucin domain-containing molecule-3 (TIM-3) was induced in ATN-1 cells by their long-term co-culture with macrophages. TIM-3 gene transfection induced chemoresistance in the ATN-1 cells. Immunostaining of ATLL tissues showed TIM-3 expression in 25 out of 58 ATLL cases. Although TIM-3 expression was not associated with overall survival or T classification, it was associated with resistance to chemotherapy. TIM-3 expression is therefore considered to be a marker for predicting the efficacy of chemotherapy, and TIM-3-associated signals may be a therapeutic target for patients with ATLL. PMID:27446463

  4. Cis Association of Galectin-9 with Tim-3 Differentially Regulates IL-12/IL-23 Expressions in Monocytes via TLR Signaling

    PubMed Central

    Ma, Cheng J.; Li, Guang Y.; Cheng, Yong Q.; Wang, Jia M.; Ying, Ruo S.; Shi, Lei; Wu, Xiao Y.; Niki, Toshiro; Hirashima, Mitsumi; Li, Chuan F.; Moorman, Jonathan P.; Yao, Zhi Q.

    2013-01-01

    Human monocytes/macrophages (M/MФ) of the innate immunity sense and respond to microbial products via specific receptor coupling with stimulatory (such as TLR) and inhibitory (such as Tim-3) receptors. Current models imply that Tim-3 expression on M/MØ can deliver negative signaling to TLR-mediated IL-12 expression through trans association with its ligand Galectin-9 (Gal-9) presented by other cells. However, Gal-9 is also expressed within M/MØ, and the effect of intracellular Gal-9 on Tim-3 activities and inflammatory responses in the same M/MØ remains unknown. In this study, our data suggest that Tim-3 and IL-12/IL-23 gene transcriptions are regulated by enhanced or silenced Gal-9 expression within monocytes through synergizing with TLR signaling. Additionally, TLR activation facilitates Gal-9/Tim-3 cis association within the same M/MØ to differentially regulate IL-12/IL-23 expressions through STAT-3 phosphorylation. These results reveal a ligand (Gal-9) compartment-dependent regulatory effect on receptor (Tim-3) activities and inflammatory responses via TLR pathways—a novel mechanism underlying cellular responses to external or internal cues. PMID:23967307

  5. Das DNA-Puzzle

    NASA Astrophysics Data System (ADS)

    Kirchner, Stefan

    Im Jahre 1953 wurde von James Watson und Francis Crick erstmalig der strukturelle Aufbau der sogenannten DNA (Desoxyribonukleinsäure) beschrieben, welche das Erbgut jedes Lebewesens enthält. Der wesentliche Teil des Erbguts wird dabei durch eine sehr lange Folge der vier Basen Adenin (A), Cytosin (C), Guanin (G) und Thymin (T) codiert. Seit einigen Jahren ist es möglich, die Folge der vier Basen zu einer gegebenen DNA zu bestimmen. Biologen bezeichnen diesen Vorgang als Sequenzierung.

  6. Tim-3 protects decidual stromal cells from toll-like receptor-mediated apoptosis and inflammatory reactions and promotes Th2 bias at the maternal-fetal interface.

    PubMed

    Wang, SongCun; Cao, ChunMei; Piao, HaiLan; Li, YanHong; Tao, Yu; Zhang, XiaoMing; Zhang, Di; Sun, Chan; Zhu, Rui; Wang, Yan; Yuan, MinMin; Li, DaJin; Du, MeiRong

    2015-01-01

    Toll-like receptors (TLRs) are important in mediating immune responses against various pathogens during pregnancy. However, uncontrolled TLR-triggered inflammation will endanger normal pregnancy, resulting in pregnancy loss. Therefore, maintenance of a moderate inflammatory response is crucial for successful pregnancy under conditions of infection. Here, we demonstrated significantly lowered expression of T-cell immunoglobulin and mucin domain 3 (Tim-3) in miscarried decidual stromal cells (DSCs), indicating that Tim-3 might play important roles in maintaining successful pregnancies. Activation of TLR signaling induced pro-inflammatory cytokine production and apoptosis of DSCs, which was accompanied by up-regulated Tim-3 expression. Tim-3, in turn, protected DSCs from TLR-mediated apoptosis in an ERK1/2 pathway-dependent manner. In addition, Tim-3 inhibited TLR signaling-induced inflammatory cytokine production by DSCs through suppressing NF-κB activation. Tim-3 increased production of T helper 2 (Th2)-type cytokines by DSCs and reversed the inhibitory effect of LPS on Th2 cytokine generation by up-regulation of interferon regulatory factor 4 expression. Tim-3 blockade abolished the effect of Tim-3 on the inflammatory response to LPS stimulation. Thus, Tim-3 signaling could represent a "self-control" mechanism in TLR-triggered inflammation during pregnancy. These findings identify Tim-3 as a key regulator of DSCs and suggest its potential as a target for the treatment of spontaneous abortion.

  7. TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway.

    PubMed

    Tomkowicz, Brian; Walsh, Eileen; Cotty, Adam; Verona, Raluca; Sabins, Nina; Kaplan, Fred; Santulli-Marotto, Sandy; Chin, Chen-Ni; Mooney, Jill; Lingham, Russell B; Naso, Michael; McCabe, Timothy

    2015-01-01

    TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3) is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion). Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK), the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor protein to positively or negatively regulate IL-2 production via NF-κB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR)-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i) NF-kB/NFAT activation, ii) CD69 expression, and iii) suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-γ with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation.

  8. TIM-3 Suppresses Anti-CD3/CD28-Induced TCR Activation and IL-2 Expression through the NFAT Signaling Pathway

    PubMed Central

    Tomkowicz, Brian; Walsh, Eileen; Cotty, Adam; Verona, Raluca; Sabins, Nina; Kaplan, Fred; Santulli-Marotto, Sandy; Chin, Chen-Ni; Mooney, Jill; Lingham, Russell B.; Naso, Michael; McCabe, Timothy

    2015-01-01

    TIM-3 (T cell immunoglobulin and mucin-domain containing protein 3) is a member of the TIM family of proteins that is preferentially expressed on Th1 polarized CD4+ and CD8+ T cells. Recent studies indicate that TIM-3 serves as a negative regulator of T cell function (i.e. T cell dependent immune responses, proliferation, tolerance, and exhaustion). Despite having no recognizable inhibitory signaling motifs, the intracellular tail of TIM-3 is apparently indispensable for function. Specifically, the conserved residues Y265/Y272 and surrounding amino acids appear to be critical for function. Mechanistically, several studies suggest that TIM-3 can associate with interleukin inducible T cell kinase (ITK), the Src kinases Fyn and Lck, and the p85 phosphatidylinositol 3-kinase (PI3K) adaptor protein to positively or negatively regulate IL-2 production via NF-κB/NFAT signaling pathways. To begin to address this discrepancy, we examined the effect of TIM-3 in two model systems. First, we generated several Jurkat T cell lines stably expressing human TIM-3 or murine CD28-ECD/human TIM-3 intracellular tail chimeras and examined the effects that TIM-3 exerts on T cell Receptor (TCR)-mediated activation, cytokine secretion, promoter activity, and protein kinase association. In this model, our results demonstrate that TIM-3 inhibits several TCR-mediated phenotypes: i) NF-kB/NFAT activation, ii) CD69 expression, and iii) suppression of IL-2 secretion. To confirm our Jurkat cell observations we developed a primary human CD8+ cell system that expresses endogenous levels of TIM-3. Upon TCR ligation, we observed the loss of NFAT reporter activity and IL-2 secretion, and identified the association of Src kinase Lck, and PLC-γ with TIM-3. Taken together, our results support the conclusion that TIM-3 is a negative regulator of TCR-function by attenuating activation signals mediated by CD3/CD28 co-stimulation. PMID:26492563

  9. Space Solar Power Exploratory Research and Technology (SERT) Technical Interchange Meeting 2 (SERT TIM 2)

    NASA Technical Reports Server (NTRS)

    Howell, Joe; Sanders, Clark W.

    2000-01-01

    The University of Alabama in Huntsville's (UAH) Propulsion Research Center hosted the Space Solar Power Exploratory Research & Technology (SERT) Technical Interchange Meeting TIM) 2 in Huntsville, Alabama December 7-10. 1999 with 126 people in attendance. The SERT program includes both competitively procured activities. which are being implemented through a portfolio of focused R&D investments--with the maximum leveraging of existing resources inside and outside NASA. and guided by these system studies. Axel Roth. Director of the Flight Projects Directorate NASA MSFC, welcomed the SERT TIM 2 participants and challenged them to develop the necessary technologies and demonstrations that will lead to Space Solar Power (SSP) International implementation. Joe Howell, NASA MSFC, reiterated the SERT TIM 2 objectives: 1) Refining and modeling systems approaches for the utilization of SSP concepts and technologies, ranging, from the near-term e.g. for space science, exploration and commercial space applications to the far-term (e. g. SSP for terrestrial markets), including systems concepts, technology, infrastructure (i.g., transportation), and economics. 2) Conducting technology research, development and demonstration activities to produce "proof- of-concept" validation of critical SSP elements for both the nearer and farther-term applications. 3) Initiating partnerships Nationality and Internationally that could be expanded, as appropriate, to pursue later SSP technology and applications (e.g., space science. colonization, etc.). Day one began with the NASA Centers presenting their SERT activities summary since SERT TIM 1 and wound up with a presentation by Masahiro Mori, NASDA titled "NASDA In-house Study for SSP". Demonstration for the Near-Term. Day two began with the SERT Systems Studies and Analysis reports resulting from NRA 8-23 followed by presentations of SERT Technology Demonstrations reports resulting from NRA 8-23. Day two closed with John Mankins presentation

  10. Negative CD4 + TIM-3 signaling confers resistance against cold preservation damage in mouse liver transplantation.

    PubMed

    Liu, Y; Ji, H; Zhang, Y; Shen, X-D; Gao, F; Nguyen, T T; Shang, X; Lee, N; Busuttil, R W; Kupiec-Weglinski, J W

    2015-04-01

    Ischemia-reperfusion injury (IRI), an innate immunity-driven local inflammation, remains the major problem in clinical organ transplantation. T cell immunoglobulin and mucin domain (TIM-3)-Galectin-9 (Gal-9) signaling regulates CD4+ Th1 immune responses. Here, we explored TIM-3-Gal-9 function in a clinically relevant murine model of hepatic cold storage and orthotopic liver transplantation (OLT). C57BL/6 livers, preserved for 20 h at 4°C in UW solution, were transplanted to syngeneic mouse recipients. Up-regulation of TIM-3 on OLT-infiltrating activated CD4+ T cells was observed in the early IRI phase (1 h). By 6 h of reperfusion, OLTs in recipients treated with a blocking anti-TIM-3 Ab were characterized by: (1) enhanced hepatocellular damage (sALT levels, liver Suzuki's histological score); (2) polarized cell infiltrate towards Th1/Th17-type phenotype; (3) depressed T cell exhaustion markers (PD-1, LAG3); and (4) elevated neutrophil and macrophage infiltration/activation. In parallel studies, adoptive transfer of CD4+ T cells from naïve WT, but not from TIM-3 Tg donors, readily recreated OLT damage in otherwise IR-resistant RAG(-/-) test recipients. Furthermore, pre-treatment of mice with rGal-9 promoted hepatoprotection against preservation-association liver damage, accompanied by enhanced TIM-3 expression in OLTs. Thus, CD4+ T cell-dependent "negative" TIM-3 costimulation is essential for hepatic homeostasis and resistance against IR stress in OLTs.

  11. Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival.

    PubMed

    Yeung, Melissa Y; McGrath, Martina M; Nakayama, Masafumi; Shimizu, Tetsunosuke; Boenisch, Olaf; Magee, Ciara N; Abdoli, Rozita; Akiba, Hisaya; Ueno, Takuya; Turka, Laurence A; Najafian, Nader

    2013-10-15

    Dendritic cells (DCs) are the central architects of the immune response, inducing inflammatory or tolerogenic immunity, dependent on their activation status. As such, DCs are highly attractive therapeutic targets and may hold the potential to control detrimental immune responses. TIM-4, expressed on APCs, has complex functions in vivo, acting both as a costimulatory molecule and a phosphatidylserine receptor. The effect of TIM-4 costimulation on T cell activation remains unclear. In this study, we demonstrate that Ab blockade of DC-expressed TIM-4 leads to increased induction of induced regulatory T cells (iTregs) from naive CD4(+) T cells, both in vitro and in vivo. iTreg induction occurs through suppression of IL-4/STAT6/Gata3-induced Th2 differentiation. In addition, blockade of TIM-4 on previously activated DCs still leads to increased iTreg induction. iTregs induced under TIM-4 blockade have equivalent potency to control and, upon adoptive transfer, significantly prolong skin allograft survival in vivo. In RAG(-/-) recipients of skin allografts adoptively transferred with CD4(+) T cells, we show that TIM-4 blockade in vivo is associated with a 3-fold prolongation in allograft survival. Furthermore, in this mouse model of skin transplantation, increased induction of allospecific iTregs and a reduction in T effector responses were observed, with decreased Th1 and Th2 responses. This enhanced allograft survival and protolerogenic skewing of the alloresponse is critically dependent on conversion of naive CD4(+) to Tregs in vivo. Collectively, these studies identify blockade of DC-expressed TIM-4 as a novel strategy that holds the capacity to induce regulatory immunity in vivo.

  12. INTERRUPTION OF DENDRITIC CELL-MEDIATED TIM-4 SIGNALING INDUCES REGULATORY T CELLS AND PROMOTES SKIN ALLOGRAFT SURVIVAL

    PubMed Central

    Yeung, Melissa Y.; McGrath, Martina M.; Nakayama, Masafumi; Shimizu, Tetsunosuke; Boenisch, Olaf; Magee, Ciara N.; Abdoli, Rozita; Akiba, Hisaya; Ueno, Takuya; Turka, Laurence A.; Najafian, Nader

    2013-01-01

    Dendritic cells (DCs) are the central architects of the immune response, inducing inflammatory or tolerogenic immunity, dependent upon their activation status. As such, DCs are highly attractive therapeutic targets and may hold the potential to control detrimental immune responses. TIM-4, expressed on antigen presenting cells, has complex functions in vivo, acting both as a costimulatory molecule and a phosphatidylserine (PS) receptor. The effect of TIM-4 costimulation on T cell activation remains unclear. Here, we demonstrate that antibody blockade of DC-expressed TIM-4 leads to increased induction of iTregs from naïve CD4+ T cells, both in vitro and in vivo. iTreg induction occurs through suppression of IL-4/STAT6/Gata3 induced Th2 differentiation. In addition, blockade of TIM-4 on previously activated DCs still leads to increased iTreg induction. iTregs induced under TIM-4 blockade have equivalent potency to control and upon adoptive transfer, significantly prolong skin allograft survival in vivo. In RAG−/− recipients of skin allografts adoptively transferred with CD4+ T cells, we show that TIM-4 blockade in vivo is associated with a three-fold prolongation in allograft survival. Furthermore, in this mouse model of skin transplantation, increased induction of allospecific iTregs and a reduction in T effector responses were observed, with decreased Th1 and Th2 responses. This enhanced allograft survival and pro-tolerogenic skewing of the alloresponse is critically dependent upon conversion of naïve CD4+ to Tregs in vivo. Collectively, these studies identify blockade of DC-expressed TIM-4 as a novel strategy which holds the capacity to induce regulatory immunity in vivo. PMID:24038092

  13. Detection and mapping of volcanic rock assemblages and associated hydrothermal alteration with Thermal Infrared Multiband Scanner (TIMS) data Comstock Lode Mining District, Virginia City, Nevada

    NASA Technical Reports Server (NTRS)

    Taranik, James V.; Hutsinpiller, Amy; Borengasser, Marcus

    1986-01-01

    Thermal Infrared Multispectral Scanner (TIMS) data were acquired over the Virginia City area on September 12, 1984. The data were acquired at approximately 1130 hours local time (1723 IRIG). The TIMS data were analyzed using both photointerpretation and digital processing techniques. Karhuen-Loeve transformations were utilized to display variations in radiant spectral emittance. The TIMS image data were compared with color infrared metric camera photography, LANDSAT Thematic Mapper (TM) data, and key areas were photographed in the field.

  14. [{Fe(tim)}2]: an Fe-Fe dimer containing an unsupported metal-metal bond and redox-active N4 macrocyclic ligands.

    PubMed

    Hess, Corinna R; Weyhermüller, Thomas; Bill, Eckhard; Wieghardt, Karl

    2009-01-01

    Mixed doubles: The dimeric complex [{Fe(tim)}(2)] (see structure, tim = 2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene) represents an unprecedented complex containing an unsupported Fe-Fe bond. The crystal structure confirms the presence of reduced tim units, thus indicating ligand redox activity. Spectroscopic and computational studies establish a triplet ground state for [{Fe(tim)}(2)] and suggest a mixed-valence compound with respect to both the Fe ions and the ligands.

  15. T cell Ig and mucin 1 (TIM-1) is expressed on in vivo-activated T cells and provides a costimulatory signal for T cell activation.

    PubMed

    de Souza, Anjali J; Oriss, Timothy B; O'malley, Katherine J; Ray, Anuradha; Kane, Lawrence P

    2005-11-22

    Polymorphisms in TIM-1, a member of the T cell Ig and mucin (TIM) domain family, are associated with relative susceptibility to the development of T helper 2-dominated immune responses such as in allergic asthma. Recent data have also suggested that ligation of TIM-1 can augment T cell activation. We have found that the TIM-1 protein is expressed on CD4(+) T cells in vivo after intranasal immunization. Ectopic expression of TIM-1 during T cell differentiation results in a significant increase in the number of cells producing IL-4 but not IFN-gamma. Furthermore, TIM-1 expression provides a costimulatory signal that increases transcription from the IL-4 promoter and from isolated nuclear factor of activated T cells/activating protein-1 (NFAT/AP-1) elements. Finally, we provide evidence that TIM-1 can be phosphorylated on tyrosine and that TIM-1 costimulation requires its cytoplasmic tail and the conserved tyrosine within that domain. These results constitute evidence that TIM-1 directly couples to phosphotyrosine-dependent intracellular signaling pathways.

  16. Approaches to vegetation mapping and ecophysiological hypothesis testing using combined information from TIMS, AVIRIS, and AIRSAR

    NASA Technical Reports Server (NTRS)

    Oren, R.; Vane, G.; Zimmermann, R.; Carrere, V.; Realmuto, V.; Zebker, Howard A.; Schoeneberger, P.; Schoeneberger, M.

    1991-01-01

    The Tropical Rainforest Ecology Experiment (TREE) had two primary objectives: (1) to design a method for mapping vegetation in tropical regions using remote sensing and determine whether the result improves on available vegetation maps; and (2) to test a specific hypothesis on plant/water relations. Both objectives were thought achievable with the combined information from the Thermal Infrared Multispectral Scanner (TIMS), Airborne Visible/Infrared Imaging Spectrometer (AVIRIS), and Airborne Synthetic Aperture Radar (AIRSAR). Implicitly, two additional objectives were: (1) to ascertain that the range within each variable potentially measurable with the three instruments is large enough in the site, relative to the sensitivity of the instruments, so that differences between ecological groups may be detectable; and (2) to determine the ability of the three systems to quantify different variables and sensitivities. We found that the ranges in values of foliar nitrogen concentration, water availability, stand structure and species composition, and plant/water relations were large, even within the upland broadleaf vegetation type. The range was larger when other vegetation types were considered. Unfortunately, cloud cover and navigation errors compromised the utility of the TIMS and AVIRIS data. Nevertheless, the AIRSAR data alone appear to have improved on the available vegetation map for the study area. An example from an area converted to a farm is given to demonstrate how the combined information from AIRSAR, TIMS, and AVIRIS can uniquely identify distinct classes of land use. The example alludes to the potential utility of the three instruments for identifying vegetation at an ecological scale finer than vegetation types.

  17. Modulation of TIM-3 expression on NK and T cell subsets in HIV immunological non-responders.

    PubMed

    de Kivit, Sander; Lempsink, Ludwijn J R; Plants, Jill; Martinson, Jeffrey; Keshavarzian, Ali; Landay, Alan L

    2015-01-01

    Highly active antiretroviral therapy (HAART) for the treatment of HIV infection sustains viral suppression and increases CD4(+) T cells in HIV patients. However, in 10-25% of subjects, known as immunological non-responders (INRs), HAART does not increase CD4 count. We investigated a potential role for galectin-9 and TIM-3 in INRs as galectin-9 and TIM-3 have been described to modulate NK and T cell function. PBMCs were isolated from healthy controls, HIV immunological responders (IRs, >350CD4(+) cells/mm(3)) and HIV INRs (<350CD4(+) cells/mm(3)) and TIM-3 and galectin-9 expressions on NK cell subsets and CD4(+) T cells were assessed. HIV INRs and HIV IRs showed increased galectin-9 expression on CD16(-)CD56(bright) and CD16(+)CD56(+) NK cells and CD4(+) T cells. Only HIV INRs showed a reduced frequency of TIM-3-expressing CD16(+)CD56(+), CD16(+)CD56(-) and CD4(+) cells, which correlated with low peripheral CD4 counts. These data suggest that TIM-3 expression may be characteristic for HIV INRs. PMID:25450337

  18. TIM-4, a Receptor for Phosphatidylserine, Controls Adaptive Immunity by Regulating the Removal of Antigen-Specific T Cells

    PubMed Central

    Albacker, Lee A.; Karisola, Piia; Chang, Ya-Jen; Umetsu, Sarah E.; Zhou, Meixia; Akbari, Omid; Kobayashi, Norimoto; Baumgarth, Nicole; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.

    2010-01-01

    Adaptive immunity is characterized by the expansion of an Ag-specific T cell population following Ag exposure. The precise mechanisms, however, that control the expansion and subsequent contraction in the number of Ag-specific T cells are not fully understood. We show that T cell/transmembrane, Ig, and mucin (TIM)-4, a receptor for phosphatidylserine, a marker of apoptotic cells, regulates adaptive immunity in part by mediating the removal of Ag-specific T cells during the contraction phase of the response. During Ag immunization or during infection with influenza A virus, blockade of TIM-4 on APCs increased the expansion of Ag-specific T cells, resulting in an increase in secondary immune responses. Conversely, overexpression of TIM-4 on APCs in transgenic mice reduced the number of Ag-specific T cells that remained after immunization, resulting in reduced secondary T cell responses. There was no change in the total number of cell divisions that T cells completed, no change in the per cell proliferative capacity of the remaining Ag-specific T cells, and no increase in the development of Ag-specific regulatory T cells in TIM-4 transgenic mice. Thus, TIM-4–expressing cells regulate adaptive immunity by mediating the removal of phosphatidylserine-expressing apoptotic, Ag-specific T cells, thereby controlling the number of Ag-specific T cells that remain after the clearance of Ag or infection. PMID:21037090

  19. A field- and laboratory-based quantitative analysis of alluvium: Relating analytical results to TIMS data

    NASA Technical Reports Server (NTRS)

    Wenrich, Melissa L.; Hamilton, Victoria E.; Christensen, Philip R.

    1995-01-01

    Thermal Infrared Multispectral Scanner (TIMS) data were acquired over the McDowell Mountains northeast of Scottsdale, Arizona during August 1994. The raw data were processed to emphasize lithologic differences using a decorrelation stretch and assigning bands 5, 3, and 1 to red, green, and blue, respectively. Processed data of alluvium flanking the mountains exhibit moderate color variation. The objective of this study was to determine, using a quantitative approach, what environmental variable(s), in the absence of bedrock, is/are responsible for influencing the spectral properties of the desert alluvial surface.

  20. Summaries of the 4th Annual JPL Airborne Geoscience Workshop. Volume 2: TIMS Workshop

    NASA Technical Reports Server (NTRS)

    Realmuto, Vincent J. (Editor)

    1993-01-01

    This is volume 2 of a three volume set of publications that contain the summaries for the Fourth Annual JPL Airborne Geoscience Workshop, held in Washington, D.C. on October 25-29, 1993. The main workshop is divided into three smaller workshops as follows: The Airborne Visible/Infrared Imaging Spectrometer (AVIRIS) workshop, on October 25-26. The summaries for this workshop appear in Volume 1. The Thermal Infrared Multispectral Scanner (TIMS) workshop, on October 27. The summaries for this workshop appear in Volume 2. The Airborne Synthetic Aperture Radar (AIRSAR) workshop, on October 28-29. The summaries for this workshop appear in Volume 3.

  1. AVIRIS and TIMS data processing and distribution at the land processes distributed active archive center

    NASA Technical Reports Server (NTRS)

    Mah, G. R.; Myers, J.

    1993-01-01

    The U.S. Government has initiated the Global Change Research program, a systematic study of the Earth as a complete system. NASA's contribution of the Global Change Research Program is the Earth Observing System (EOS), a series of orbital sensor platforms and an associated data processing and distribution system. The EOS Data and Information System (EOSDIS) is the archiving, production, and distribution system for data collected by the EOS space segment and uses a multilayer architecture for processing, archiving, and distributing EOS data. The first layer consists of the spacecraft ground stations and processing facilities that receive the raw data from the orbiting platforms and then separate the data by individual sensors. The second layer consists of Distributed Active Archive Centers (DAAC) that process, distribute, and archive the sensor data. The third layer consists of a user science processing network. The EOSDIS is being developed in a phased implementation. The initial phase, Version 0, is a prototype of the operational system. Version 0 activities are based upon existing systems and are designed to provide an EOSDIS-like capability for information management and distribution. An important science support task is the creation of simulated data sets for EOS instruments from precursor aircraft or satellite data. The Land Processes DAAC, at the EROS Data Center (EDC), is responsible for archiving and processing EOS precursor data from airborne instruments such as the Thermal Infrared Multispectral Scanner (TIMS), the Thematic Mapper Simulator (TMS), and Airborne Visible and Infrared Imaging Spectrometer (AVIRIS). AVIRIS, TIMS, and TMS are flown by the NASA-Ames Research Center ARC) on an ER-2. The ER-2 flies at 65000 feet and can carry up to three sensors simultaneously. Most jointly collected data sets are somewhat boresighted and roughly registered. The instrument data are being used to construct data sets that simulate the spectral and spatial

  2. Tim Folger Receives 2013 Walter Sullivan Award for Excellence in Science Journalism—Features: Citation

    NASA Astrophysics Data System (ADS)

    Kunzig, Robert

    2014-01-01

    A writer needs two distinct qualities to produce an article like "The Calm Before the Wave," the piece on tsunamis for which Tim Folger is being honored with the 2013 Walter Sullivan Award. Like any good science writer, he needs the ability to sort through a large mass of scientific information and transform it into a clear, compelling narrative. But he also needs an empathic eye and ear—the ability to feel his way into the lives of people whose stories are utterly different from his own and to see and hear the telling details that will make those people come alive on the page.

  3. High-precision isotopic characterization of USGS reference materials by TIMS and MC-ICP-MS

    NASA Astrophysics Data System (ADS)

    Weis, Dominique; Kieffer, Bruno; Maerschalk, Claude; Barling, Jane; de Jong, Jeroen; Williams, Gwen A.; Hanano, Diane; Pretorius, Wilma; Mattielli, Nadine; Scoates, James S.; Goolaerts, Arnaud; Friedman, Richard M.; Mahoney, J. Brian

    2006-08-01

    The Pacific Centre for Isotopic and Geochemical Research (PCIGR) at the University of British Columbia has undertaken a systematic analysis of the isotopic (Sr, Nd, and Pb) compositions and concentrations of a broad compositional range of U.S. Geological Survey (USGS) reference materials, including basalt (BCR-1, 2; BHVO-1, 2), andesite (AGV-1, 2), rhyolite (RGM-1, 2), syenite (STM-1, 2), granodiorite (GSP-2), and granite (G-2, 3). USGS rock reference materials are geochemically well characterized, but there is neither a systematic methodology nor a database for radiogenic isotopic compositions, even for the widely used BCR-1. This investigation represents the first comprehensive, systematic analysis of the isotopic composition and concentration of USGS reference materials and provides an important database for the isotopic community. In addition, the range of equipment at the PCIGR, including a Nu Instruments Plasma MC-ICP-MS, a Thermo Finnigan Triton TIMS, and a Thermo Finnigan Element2 HR-ICP-MS, permits an assessment and comparison of the precision and accuracy of isotopic analyses determined by both the TIMS and MC-ICP-MS methods (e.g., Nd isotopic compositions). For each of the reference materials, 5 to 10 complete replicate analyses provide coherent isotopic results, all with external precision below 30 ppm (2 SD) for Sr and Nd isotopic compositions (27 and 24 ppm for TIMS and MC-ICP-MS, respectively). Our results also show that the first- and second-generation USGS reference materials have homogeneous Sr and Nd isotopic compositions. Nd isotopic compositions by MC-ICP-MS and TIMS agree to within 15 ppm for all reference materials. Interlaboratory MC-ICP-MS comparisons show excellent agreement for Pb isotopic compositions; however, the reproducibility is not as good as for Sr and Nd. A careful, sequential leaching experiment of three first- and second-generation reference materials (BCR, BHVO, AGV) indicates that the heterogeneity in Pb isotopic compositions

  4. Summaries of the Third Annual JPL Airborne Geoscience Workshop. Volume 2: TIMS Workshop

    NASA Technical Reports Server (NTRS)

    Realmuto, Vincent J. (Editor)

    1992-01-01

    This publication contains the preliminary agenda and summaries for the Third Annual JPL Airborne Geoscience Workshop, held at the Jet Propulsion Laboratory, Pasadena, California, on 1-5 June 1992. This main workshop is divided into three smaller workshops as follows: (1) the Airborne Visible/Infrared Imaging Spectrometer (AVIRIS) workshop, on June 1 and 2; the summaries for this workshop appear in Volume 1; (2) the Thermal Infrared Multispectral Scanner (TIMS) workshop, on June 3; the summaries for this workshop appear in Volume 2; and (3) the Airborne Synthetic Aperture Radar (AIRSAR) workshop, on June 4 and 5; the summaries for this workshop appear in Volume 3.

  5. Second NASA Technical Interchange Meeting (TIM): Advanced Technology Lifecycle Analysis System (ATLAS) Technology Tool Box (TTB)

    NASA Technical Reports Server (NTRS)

    ONeil, D. A.; Mankins, J. C.; Christensen, C. B.; Gresham, E. C.

    2005-01-01

    The Advanced Technology Lifecycle Analysis System (ATLAS), a spreadsheet analysis tool suite, applies parametric equations for sizing and lifecycle cost estimation. Performance, operation, and programmatic data used by the equations come from a Technology Tool Box (TTB) database. In this second TTB Technical Interchange Meeting (TIM), technologists, system model developers, and architecture analysts discussed methods for modeling technology decisions in spreadsheet models, identified specific technology parameters, and defined detailed development requirements. This Conference Publication captures the consensus of the discussions and provides narrative explanations of the tool suite, the database, and applications of ATLAS within NASA s changing environment.

  6. Summaries of the Fifth Annual JPL Airborne Earth Science Workshop. Volume 2: TIMS Workshop

    NASA Technical Reports Server (NTRS)

    Realmuto, Vincent J. (Editor)

    1995-01-01

    This publication is the second volume of the summaries for the Fifth Annual JPL Airborne Earth Science Workshop, held in Pasadena, California, on January 23-26, 1995. The main workshop is divided into three smaller workshops as follows: (1) The Airborne Visible/Infrared Imaging Spectrometer (AVIRIS) workshop on January 23-24. The summaries for this workshop appear in Volume 1; (2) The Airborne Synthetic Aperture Radar (AIRSAR) workshop on January 25-26. The summaries for this workshop appear in volume 3; and (3) The Thermal Infrared Multispectral Scanner (TIMS) workshop on January 26. The summaries for this workshop appear in this volume.

  7. Tim de Zeeuw to Become the Next Director General of ESO

    NASA Astrophysics Data System (ADS)

    2007-01-01

    The ESO Council has just appointed Tim de Zeeuw, 50, as the next Director General of ESO, effective as of 1 September 2007, when the current Director General, Catherine Cesarsky will complete her mandate. ESO PR Photo 02/07 ESO PR Photo 03/07 Professor Tim de Zeeuw "ESO is Europe's flagship organisation for ground-based astronomy," said, Richard Wade, President of the ESO Council. "The ESO Council is very pleased that Professor de Zeeuw has accepted the task as its next Director General. He has played a key role over the last few years in developing a strategic vision for ESO, and I have every confidence that he will now lead the organisation in the realisation of that exciting vision." Tim de Zeeuw has an excellent record, both as a highly respected scientist and as a leader of an internationally recognised science institute in the Netherlands. He is Scientific Director of the Leiden Observatory, a research institute in the College of Mathematics and Natural Sciences of Leiden University. Tim de Zeeuw also has considerable experience as regards science policy issues. Catherine Cesarsky, ESO's current Director General commented: "Over the recent years, ESO has developed considerably with more activities and new member states, and with its ambitious project portfolio, ESO is clearly facing an exciting future. I shall be delighted to pass the baton to Tim de Zeeuw, who as a recent Council member is very familiar with our Organisation." "It is a great honour and an exciting challenge to lead this world-class organisation in the years to come in support of one of the most dynamic areas of science today," said de Zeeuw. "I look forward to overseeing the continued upgrading of the Very Large Telescope with the second-generation instrumentation and the completion of the ALMA project, and in particular to help developing the future European Extremely Large Telescope." Tim de Zeeuw's main research interests embrace the formation, structure and dynamics of galaxies

  8. The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas.

    PubMed

    Komohara, Yoshihiro; Morita, Tomoko; Annan, Dorcas A; Horlad, Hasita; Ohnishi, Koji; Yamada, Sohsuke; Nakayama, Toshiyuki; Kitada, Shohei; Suzu, Shinya; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Akashi, Koichi; Takeya, Motohiro; Jinushi, Masahisa

    2015-09-01

    Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC.

  9. The amelioration of composite tissue allograft rejection by TIM-3-modified dendritic cell: Regulation of the balance of regulatory and effector T cells.

    PubMed

    Wang, Yaojun; Zheng, Zhao; Zhu, Xiongxiang; Han, Juntao; Dong, Maolong; Tao, Ke; Wang, Hongtao; Wang, Yunchuan; Hu, Dahai

    2016-01-01

    T cell-dependent immune responses play a central role in allograft rejection. Exploring ways to disarm alloreactive T cells represents a potential strategy to promote long-term allograft acceptance and survival. T cell Ig domain and mucin domain 3 (TIM-3) has previously been demonstrated as a central regulator of T helper 1 (Th1) responses and immune tolerance. Hence, TIM-3 may be an important molecule for decreasing immunological rejection during composite tissue allotransplantation (CTA). In this study, BALB/c and C57BL/6 mice were chosen as the experimental animals. The effects of TIM-3 on allograft rejection were explored using TIM-3-modified mature dendritic cells (TIM-3 mDCs). A laser speckle blood flow (LSBF) imager was used to evaluate blood distribution of the BALB/c mice. ELISA, MTT, ELISPOT assays and flow cytometry analysis were carried out for further researches. We found that TIM-3 could obviously prolong the survival time of the transplanted limbs. And TIM-3 could mitigate the immune response and thus enhance immune tolerance after CTA. Also, TIM-3 can induce lymphocyte hyporesponsiveness, including facilitating lymphocyte apoptosis, decreasing lymphocyte proliferation, and influencing the secretion of inflammatory cytokines by CD4(+) T cells. Furthermore, TIM-3 overexpression could induce CD4(+) T cells to differentiate into regulatory T cells (Tregs), which recalibrate the effector and regulatory arms of the alloimmune response. In summary, we concluded that TIM-3 can mitigate allograft rejection and thus enhance immune tolerance by inducing lymphocyte hyporesponsiveness and increasing the number of Tregs of the alloimmune response. TIM-3 may be a potential therapeutic molecule for allograft rejection in CTA.

  10. The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas.

    PubMed

    Komohara, Yoshihiro; Morita, Tomoko; Annan, Dorcas A; Horlad, Hasita; Ohnishi, Koji; Yamada, Sohsuke; Nakayama, Toshiyuki; Kitada, Shohei; Suzu, Shinya; Kinoshita, Ichiro; Dosaka-Akita, Hirotoshi; Akashi, Koichi; Takeya, Motohiro; Jinushi, Masahisa

    2015-09-01

    Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC. PMID:25783986

  11. Simulation modeling and preliminary analysis of TIMS data from the Carlin area and the northern Grapevine Mountains, Nevada

    NASA Technical Reports Server (NTRS)

    Watson, Ken; Hummer-Miller, Susanne; Kruse, Fred A.

    1986-01-01

    A theoretical radiance model was employed together with laboratory data on a suite of igneous rock to evaluate various algorithms for processing Thermal Infrared Multispectral Scanner (TIMS) data. Two aspects of the general problem were examined: extraction of emissivity information from the observed TIMS radiance data, and how to use emissivity data in a way that is geologically meaningful. The four algorithms were evaluated for appropriate band combinations of TIMS data acquired on both day and night overflights of the Tuscarora Mountains, including the Carlin gold deposit, in north-central Nevada. Analysis of a color composited PC decorrelated image (Bands 3, 4, 5--blue/green/red) of the Northern Grapevine Mountains, Nevada, area showed some useful correlation with the regional geology. The thermal infrared region provides fundamental spectral information that can be used to discriminate the major rock types occurring on the Earth's surface.

  12. Earth-Mars Telecommunications and Information Management System (TIMS): Antenna Visibility Determination, Network Simulation, and Management Models

    NASA Technical Reports Server (NTRS)

    Odubiyi, Jide; Kocur, David; Pino, Nino; Chu, Don

    1996-01-01

    This report presents the results of our research on Earth-Mars Telecommunications and Information Management System (TIMS) network modeling and unattended network operations. The primary focus of our research is to investigate the feasibility of the TIMS architecture, which links the Earth-based Mars Operations Control Center, Science Data Processing Facility, Mars Network Management Center, and the Deep Space Network of antennae to the relay satellites and other communication network elements based in the Mars region. The investigation was enhanced by developing Build 3 of the TIMS network modeling and simulation model. The results of several 'what-if' scenarios are reported along with reports on upgraded antenna visibility determination software and unattended network management prototype.

  13. An N-TIMS Br Isotopic Study of Australian Playa Lakes

    NASA Astrophysics Data System (ADS)

    Schaefer, B. F.

    2013-12-01

    Bromine possesses a chemistry broadly comparable to that of Cl and F, however its heavier mass and lower abundance results in slightly different behaviours in geochemical cycling. For example it is disproportionately enriched in sea water with respect to Cl. Br can be considered to be a 'hydrophile' element, and hence its behaviour is in governed by that of water. It possesses two isotopes 79Br (50.686%) and 81Br (49.314%). This study has developed new chemical extraction, and most significantly, new mass spectrometric protocols for Br isotopes for evaporites and waters using N-TIMS methodologies. Existing CF-IRMS methodologies offer internal precision of ~0.3‰ (1SD, [1]), whereas N-TIMS measurements of laboratory HBr and seawater standards produce external reproducibility of <0.05‰ (1SD) over an 24 month period with internal precision typically <0.03‰ (1SD) on single analyses. Australian playa lakes record variations of >5‰, comparable to that of the whole solar system. Regionality is implied on this preliminary data set whereby Lake Gairdner, which is sourced from a single, arid region lithology, is displaced from other, multi lithological sourced lakes from the same climatic zone. [1] Shouaker-Stash et al., Anal. Chem, 77; p4027-4033, 2005.

  14. Improving the prediction of secondary structure of 'TIM-barrel' enzymes.

    PubMed

    Niermann, T; Kirschner, K

    1991-02-01

    The information contained in aligned sets of homologous protein sequences should improve the score of secondary structure prediction. Seven different enzymes having the (beta/alpha)8 or TIM-barrel fold were used to optimize the prediction with regard to this class of enzymes. The alpha-helix, beta-strand and loop propensities of the Garnier-Osguthorpe-Robson method were averaged at aligned residue positions, leading to a significant improvement over the average score obtained from single sequences. The increased accuracy correlates with the average sequence variability of the aligned set. Further improvements were obtained by using the following averaged properties as weights for the averaged state propensities: amphipathic moment and alpha-helix; hydropathy and beta-strand; chain flexibility and loop. The clustering of conserved residues at the C-terminal ends of the beta-strands was used as an additional positive weight for beta-strand propensity and increased the prediction of otherwise unpredicted beta-strands decisively. The automatic weighted prediction method identifies greater than 95% of the secondary structure elements of the set of seven TIM-barrel enzymes.

  15. Radical use of Rossmann and TIM barrel architectures for controlling coenzyme B12 chemistry.

    PubMed

    Dowling, Daniel P; Croft, Anna K; Drennan, Catherine L

    2012-01-01

    The ability of enzymes to harness free-radical chemistry allows for some of the most amazing transformations in nature, including reduction of ribonucleotides and carbon skeleton rearrangements. Enzyme cofactors involved in this chemistry can be large and complex, such as adenosylcobalamin (coenzyme B(12)), simpler, such as S-adenosylmethionine and an iron-sulfur cluster (i.e., poor man's B(12)), or very small, such as one nonheme iron atom coordinated by protein ligands. Although the chemistry catalyzed by these enzyme-bound cofactors is unparalleled, it does come at a price. The enzyme must be able to control these radical reactions, preventing unwanted chemistry and protecting the enzyme active site from damage. Here, we consider a set of radical folds: the (β/α)(8) or TIM barrel, combined with a Rossmann domain for coenzyme B(12)-dependent chemistry. Using specific enzyme examples, we consider how nature employs the common TIM barrel fold and its Rossmann domain partner for radical-based chemistry.

  16. Phlebotomine fauna in the urban area of Timóteo, State of Minas Gerais, Brazil.

    PubMed

    de Souza, Cristian Ferreira; Quaresma, Patrícia Flávia; Andrade Filho, Jose Dilermando; Bevilacqua, Paula Dias

    2014-06-01

    This work is characterized by an entomological research and an investigation on whether seasonal behaviours can be associated to the phlebotomine fauna found in the urban area of Timóteo-MG - an endemic focus of tegumentary leishmaniasis (TL). The analysis of the seasonal behaviour of sand flies has taken into account the following climatic variables: rainfall, relative humidity and temperature. Automatic light traps were installed in households between 2009 and 2010. The sand fly species with the highest number captured was Lutzomyia whitmani (66.5%), a TL vector species, whose abundance has provided strong evidences that this species is the main vector of TL in the municipality of Timóteo, with its cycle of transmission developing in its urban area. Amongst the results observed in the analyses of seasonal behaviour, only temperature conveyed particular association between seasonal occurrence of sand flies and climate variables. The findings of this study may assist the local epidemiological surveillance agency in defining strategies and directing efforts for controlling these insects.

  17. Connecting the Dots in DAS

    ERIC Educational Resources Information Center

    Ford, Tracy

    2012-01-01

    Many institutions implement a distributed antenna system (DAS) as part of a holistic approach to providing better wireless coverage and capacity on campus. A DAS provides wireless service within a particular area or structure via a network of separate antenna nodes that are connected to a common source through fiber or coaxial cable. Because DAS…

  18. Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation.

    PubMed

    Xiao, Sheng; Brooks, Craig R; Sobel, Raymond A; Kuchroo, Vijay K

    2015-02-15

    T cell Ig and mucin domain (Tim)-1 identifies IL-10-producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss-of-function Tim-1 mutant showed progressive loss of IL-10 production in B cells and with age developed severe multiorgan tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production, including IL-1 and IL-6. Tim-1-deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3(+) and IL-10-producing type 1 regulatory T cells) and enhance the severity of experimental autoimmune encephalomyelitis. Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with ACs reduces the severity of experimental autoimmune encephalomyelitis in hosts with wild-type but not Tim-1-deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10-producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.

  19. The Galectin-9/Tim-3 pathway is involved in the regulation of NK cell function at the maternal-fetal interface in early pregnancy.

    PubMed

    Li, Yan-Hong; Zhou, Wen-Hui; Tao, Yu; Wang, Song-Cun; Jiang, Yun-Lan; Zhang, Di; Piao, Hai-Lan; Fu, Qiang; Li, Da-Jin; Du, Mei-Rong

    2016-01-01

    Decidual natural killer (dNK) cells actively participate in the establishment and maintenance of maternal-fetal immune tolerance and act as local guardians against infection. However, how dNK cells maintain the immune balance between tolerance and anti-infection immune responses during pregnancy remains unknown. Here, we demonstrated that the inhibitory molecule T-cell immunoglobulin domain and mucin domain-containing molecule-3 (Tim-3) are expressed on over 60% of dNK cells. Tim-3(+) dNK cells display higher interleukin (IL)-4 and lower tumor necrosis factor (TNF)-α and perforin production. Human trophoblast cells can induce the transformation of peripheral NK cells into a dNK-like phenotype via the secretion of galectin-9 (Gal-9) and the interaction between Gal-9 and Tim-3. In addition, trophoblasts inhibit lipopolysaccharide (LPS)-induced pro-inflammatory cytokine and perforin production by dNK cells, which can be attenuated by Tim-3 neutralizing antibodies. Interestingly, a decreased percentage of Tim-3-expressing dNK cells were observed in human miscarriages and murine abortion-prone models. Moreover, T helper (Th)2-type cytokines were decreased and Th1-type cytokines were increased in Tim-3(+) but not Tim-3(-) dNK cells from human and mouse miscarriages. Therefore, our results suggest that the Gal-9/Tim-3 signal is important for the regulation of dNK cell function, which is beneficial for the maintenance of a normal pregnancy.

  20. PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy.

    PubMed

    Wang, S-C; Li, Y-H; Piao, H-L; Hong, X-W; Zhang, D; Xu, Y-Y; Tao, Y; Wang, Y; Yuan, M-M; Li, D-J; Du, M-R

    2015-01-01

    CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.

  1. [A TIM-3/galectin-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemia progression].

    PubMed

    Kikushige, Yoshikane

    2016-04-01

    Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We previously reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the LCS surface in most types of AML. Since only the TIM-3(+), i.e. not the TIM-3(-), fraction of human AML cells can reconstitute human AML in immunodeficient mice, we hypothesized that the TIM-3 has an essential function in maintaining AML LSCs. Herein, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, as well as Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were found to be involved in the progressive transformation of a variety of pre-leukemic disorders into myeloid leukemia. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop are potential therapeutic targets applicable to most types of myeloid leukemia.

  2. [A TIM-3/galectin-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemia progression].

    PubMed

    Kikushige, Yoshikane

    2016-04-01

    Acute myeloid leukemia (AML) originates from self-renewing leukemic stem cells (LSCs), an ultimate therapeutic target for AML. We previously reported that the T-cell immunoglobulin mucin-3 (TIM-3) is expressed on the LCS surface in most types of AML. Since only the TIM-3(+), i.e. not the TIM-3(-), fraction of human AML cells can reconstitute human AML in immunodeficient mice, we hypothesized that the TIM-3 has an essential function in maintaining AML LSCs. Herein, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for human AML LSC development. Serum Gal-9 was significantly elevated in primary AML patients and in mice xenografted with human AML. Neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML, as well as Gal-9 ligation of TIM-3 co-activated NF-κB and β-catenin signaling, suggesting that TIM-3 signaling is necessary for LSC self-renewal. Interestingly, identical changes were found to be involved in the progressive transformation of a variety of pre-leukemic disorders into myeloid leukemia. Thus, molecules constituting the TIM-3/Gal-9 autocrine loop are potential therapeutic targets applicable to most types of myeloid leukemia. PMID:27169443

  3. Progress integrating ID-TIMS U-Pb geochronology with accessory mineral geochemistry: towards better accuracy and higher precision time

    NASA Astrophysics Data System (ADS)

    Schoene, B.; Samperton, K. M.; Crowley, J. L.; Cottle, J. M.

    2012-12-01

    It is increasingly common that hand samples of plutonic and volcanic rocks contain zircon with dates that span between zero and >100 ka. This recognition comes from the increased application of U-series geochronology on young volcanic rocks and the increased precision to better than 0.1% on single zircons by the U-Pb ID-TIMS method. It has thus become more difficult to interpret such complicated datasets in terms of ashbed eruption or magma emplacement, which are critical constraints for geochronologic applications ranging from biotic evolution and the stratigraphic record to magmatic and metamorphic processes in orogenic belts. It is important, therefore, to develop methods that aid in interpreting which minerals, if any, date the targeted process. One promising tactic is to better integrate accessory mineral geochemistry with high-precision ID-TIMS U-Pb geochronology. These dual constraints can 1) identify cogenetic populations of minerals, and 2) record magmatic or metamorphic fluid evolution through time. Goal (1) has been widely sought with in situ geochronology and geochemical analysis but is limited by low-precision dates. Recent work has attempted to bridge this gap by retrieving the typically discarded elution from ion exchange chemistry that precedes ID-TIMS U-Pb geochronology and analyzing it by ICP-MS (U-Pb TIMS-TEA). The result integrates geochemistry and high-precision geochronology from the exact same volume of material. The limitation of this method is the relatively coarse spatial resolution compared to in situ techniques, and thus averages potentially complicated trace element profiles through single minerals or mineral fragments. In continued work, we test the effect of this on zircon by beginning with CL imaging to reveal internal zonation and growth histories. This is followed by in situ LA-ICPMS trace element transects of imaged grains to reveal internal geochemical zonation. The same grains are then removed from grain-mount, fragmented, and

  4. Use of New 1013 Ohm Current Amplifiers in U and Pb Isotope Ratio Analysis by TIMS

    NASA Astrophysics Data System (ADS)

    Bouman, C.; Trinquier, A.; Lloyd, N. S.; Schwieters, J. B.

    2014-12-01

    For U-Pb dating of small zircon grains as well as for nuclear forensics, sample volume is limited and the ion beam currents in TIMS analyses are typically down to the fA range. For some samples, all ion beams are measured sequentially in a peak jumping experiment using a single collector ion counting detector, i.e. a Daly or a secondary electron multiplier. Such analyses do not take advantage of multicollection and require reasonable ion beam stability. Because of the sequential measurement sample utilization is a concern. With respect to the attainable precision and accuracy, there are at least two major ion counter characteristics to be dealt with: 1) linearity effects related to the dead time of the ion counter and 2) the mass-dependent detection efficiency of the ion counter inducing an instrumental mass bias effect. Both effects need proper calibration and monitoring otherwise could lead to systematic errors. For instance, the accurate measurement of a 1 Mcps signal down to 0.01% would require an accuracy of the dead time correction to <100 ps, which in itself is a challenge. Also proper calibration of detector-induced mass bias effects to the required precision of 0.01% is difficult. For demanding applications like high-precision U-Pb geochronology TIMS measurements, the goal is even to get precision and accuracy down to 100 ppm. In this paper, we present our latest developments on low noise Faraday cup amplifier technology, that completely avoids the dead time calibration as well as instrumental mass bias effects introduced by ion counters. Faraday cup detectors have proven accuracy down to the ppm range, but have a limitation due to the Johnson noise involved in classical current 1011 Ohm amplifiers. We have developed new current amplifiers using 100 times larger resistor values of 1013 Ohm, giving a signal-to-noise improvement of a factor of 10 over the classical 1011Ohm current amplifiers. As such the final precision of very small sample measurements on

  5. Making Sense of Instruction on Fractions when a Student Lacks Necessary Fractional Schemes: The Case of Tim

    ERIC Educational Resources Information Center

    Olive, John; Vomvoridi, Eugenia

    2006-01-01

    This paper critically examines the discrepancies among the pre-requisite fractional concepts assumed by a curricular unit on operations with fractions, the teacher's assumptions about those concepts and a particular student's understanding of fractions. The paper focuses on the case of one student (Tim) in the teacher's 6th grade class who was…

  6. Operations Manager Tim Miller checks out software for the Airborne Synthetic Aperature Radar (AIRSAR

    NASA Technical Reports Server (NTRS)

    1998-01-01

    Tim Miller checks out software for the Airborne Synthetic Aperture Radar (AIRSAR). He was the AIRSAR operations manager for NASA's Jet Propulsion Laboratory. The AIRSAR produces imaging data for a range of studies conducted by the DC-8. NASA is using a DC-8 aircraft as a flying science laboratory. The platform aircraft, based at NASA's Dryden Flight Research Center, Edwards, Calif., collects data for many experiments in support of scientific projects serving the world scientific community. Included in this community are NASA, federal, state, academic and foreign investigators. Data gathered by the DC-8 at flight altitude and by remote sensing have been used for scientific studies in archeology, ecology, geography, hydrology, meteorology, oceanography, volcanology, atmospheric chemistry, soil science and biology.

  7. Comparison of preliminary results from Airborne Aster Simulator (AAS) with TIMS data

    NASA Technical Reports Server (NTRS)

    Kannari, Yoshiaki; Mills, Franklin; Watanabe, Hiroshi; Ezaka, Teruya; Narita, Tatsuhiko; Chang, Sheng-Huei

    1992-01-01

    The Japanese Advanced Spaceborne Thermal Emission and Reflection radiometer (ASTER), being developed for a NASA EOS-A satellite, will have 3 VNIR, 6 SWIR, and 5 TIR (8-12 micron) bands. An Airborne ASTER Simulator (AAS) was developed for Japan Resources Observation System Organization (JAROS) by the Geophysical Environmental Research Group (GER) Corp. to research surface temperature and emission features in the MWIR/TIR, to simulate ASTER's TIR bands, and to study further possibility of MWIR/TIR bands. ASTER Simulator has 1 VNIR, 3 MWIR (3-5 microns), and 20 (currently 24) TIR bands. Data was collected over 3 sites - Cuprite, Nevada; Long Valley/Mono Lake, California; and Death Valley, California - with simultaneous ground truth measurements. Preliminary data collected by AAS for Cuprite, Nevada is presented and AAS data is compared with Thermal Infrared Multispectral Scanner (TIMS) data.

  8. Optimizing separation of iodine from halogen interferences in preparation for TIMS analysis

    SciTech Connect

    Metz, Lori A.; Payne, Rosara F.; Engelmann, Mark D.

    2011-11-28

    Low-level analysis of radioiodine performed by TIMS requires an initial chemical separation from interfering higher electron-affinity halogens. Experiments using 125I and 36Cl tracers have shown that iodide can be selectively oxidized and purged from solution while the chloride remains in the solution. A systematic investigation of the experimental factors that affect the oxidation and transfer of iodine along with the separation of iodide from chloride has been completed. Experimental design was used to determine the optimum experimental conditions by obtaining a better understanding of factor affects and interactions. Factors such as gas purge rate, experiment run time, and oxidant concentration were simultaneously studied in a central composite design of experiments and response surfaces were generated from results. Optimizing experimental factors resulted in improved iodide oxidation and transfer efficiencies, halogen separation, and shorter analysis times.

  9. TIM23-mediated insertion of transmembrane α-helices into the mitochondrial inner membrane.

    PubMed

    Botelho, Salomé Calado; Osterberg, Marie; Reichert, Andreas S; Yamano, Koji; Björkholm, Patrik; Endo, Toshiya; von Heijne, Gunnar; Kim, Hyun

    2011-03-16

    While overall hydrophobicity is generally recognized as the main characteristic of transmembrane (TM) α-helices, the only membrane system for which there are detailed quantitative data on how different amino acids contribute to the overall efficiency of membrane insertion is the endoplasmic reticulum (ER) of eukaryotic cells. Here, we provide comparable data for TIM23-mediated membrane protein insertion into the inner mitochondrial membrane of yeast cells. We find that hydrophobicity and the location of polar and aromatic residues are strong determinants of membrane insertion. These results parallel what has been found previously for the ER. However, we see striking differences between the effects elicited by charged residues flanking the TM segments when comparing the mitochondrial inner membrane and the ER, pointing to an unanticipated difference between the two insertion systems.

  10. Development of an improved method to perform single particle analysis by TIMS for nuclear safeguards.

    PubMed

    Kraiem, M; Richter, S; Kühn, H; Aregbe, Y

    2011-02-28

    A method is described that allows measuring the isotopic composition of small uranium oxide particles (less than 1μm in diameter) for nuclear safeguards purposes. In support to the development of reliable tools for the identification of uranium and plutonium signatures in trace amounts of nuclear materials, improvements in scanning electron microscopy (SEM) and thermal ionization mass spectrometry (TIMS) in combination with filament carburization and multiple ion counting (MIC) detection were investigated. The method that has been set up enables the analysis of single particles by a combination of analytical tools, thus yielding morphological, elemental and isotopic information. Hereby individual particles of certified reference materials (CRMs) containing uranium at femtogram levels were analysed. The results showed that the combination of techniques proposed in this work is suitable for the accurate determination of uranium isotope ratios in single particles with improved capabilities for the minor abundant isotopes. PMID:21296200

  11. SIMS and TIMS U-Th-Pb Geochronology of Zircon From the Bishop Tuff

    NASA Astrophysics Data System (ADS)

    Ickert, R. B.; Magee, C. W.; Mundil, R.

    2013-12-01

    The mid-Pleistocene Bishop Tuff (Long Valley, California) is one of the largest volume Quaternary volcanic eruptions and has been extensively studied for its physical and chemical characteristics. These data sets have resulted in the Bishop Tuff being described as an 'archetypal' magmatic system. It has also been the subject of multiple geochronological investigations, in particular due to its occurrence just above the Bruhnes-Matuyama geomagnetic reversal, but also for geochemical investigations of the longevity of magmatic systems and the determination of crystal residence times. Published ages for the BT using different isotopic systems and techniques are difficult to reconcile; for example SIMS Pb/U data sets have been interpreted to reflect zircon crystallization over a timescale of 105 years, with a mean crystallization date around 820 Ka, suggesting a protracted magmatic evolution. In contrast, TIMS Pb/U data suggests zircon crystallization over a much shorter period of time, interpreted to be less than 104 years, with the bulk of zircon crystallization occurring in the last few thousand years before eruption. Augmenting these problems are that some new 40Ar/39Ar sanidine dates are >10% older than the youngest population of zircon, yielding a physically impossible reversal of cooling (eruption) and crystallization ages. Here, we present new SHRIMP II U-Th-Pb data and TIMS single-grain and sub-grain analyses of zircon from the Bishop Tuff. Cathodoluminescence imaging reveals similar features described by others - featureless central regions bounded by sector and oscillatory zoned rims. For young zircon such as these, with radiogenic 206Pb concentrations below 0.5ppm, analyses are very sensitive to corrections to common Pb (either introduced in the lab or present as initial Pb in the zircon). The results of 37 single spot SHRIMP analyses, in which central portions of grains were targeted in order to capture the onset of zircon crytsallization, show a range of

  12. Improving Functional Annotation in the DRE-TIM Metallolyase Superfamily through Identification of Active Site Fingerprints.

    PubMed

    Kumar, Garima; Johnson, Jordyn L; Frantom, Patrick A

    2016-03-29

    Within the DRE-TIM metallolyase superfamily, members of the Claisen-like condensation (CC-like) subgroup catalyze C-C bond-forming reactions between various α-ketoacids and acetyl-coenzyme A. These reactions are important in the metabolic pathways of many bacterial pathogens and serve as engineering scaffolds for the production of long-chain alcohol biofuels. To improve functional annotation and identify sequences that might use novel substrates in the CC-like subgroup, a combination of structural modeling and multiple-sequence alignments identified active site residues on the third, fourth, and fifth β-strands of the TIM-barrel catalytic domain that are differentially conserved within the substrate-diverse enzyme families. Using α-isopropylmalate synthase and citramalate synthase from Methanococcus jannaschii (MjIPMS and MjCMS), site-directed mutagenesis was used to test the role of each identified position in substrate selectivity. Kinetic data suggest that residues at the β3-5 and β4-7 positions play a significant role in the selection of α-ketoisovalerate over pyruvate in MjIPMS. However, complementary substitutions in MjCMS fail to alter substrate specificity, suggesting residues in these positions do not contribute to substrate selectivity in this enzyme. Analysis of the kinetic data with respect to a protein similarity network for the CC-like subgroup suggests that evolutionarily distinct forms of IPMS utilize residues at the β3-5 and β4-7 positions to affect substrate selectivity while the different versions of CMS use unique architectures. Importantly, mapping the identities of residues at the β3-5 and β4-7 positions onto the protein similarity network allows for rapid annotation of probable IPMS enzymes as well as several outlier sequences that may represent novel functions in the subgroup. PMID:26935545

  13. Urban remote sensing applications: TIMS observations of the City of Scottsdale

    NASA Technical Reports Server (NTRS)

    Christensen, Philip R.; Melendrez, David E.; Anderson, Donald L.; Hamilton, Victoria E.; Wenrich, Melissa L.; Howard, Douglas

    1995-01-01

    A research program has been initiated between Arizona State University and the City of Scottsdale, Arizona to study the potential applications of TIMS (Thermal Infrared Multispectral Scanner) data for urban scene classification, desert environmental assessment, and change detection. This program is part of a long-term effort to integrate remote sensing observations into state and local planning activities to improve decision making and future planning. Specific test sites include a section of the downtown Scottsdale region that has been mapped in very high detail as part of a pilot program to develop an extensive GIS database. This area thus provides excellent time history of the evolution of the city infrastructure, such as the timing and composition of street repavement. A second area of study includes the McDowell intensive study by state and local agencies to assess potential sites for urban development as well as preservation. These activities are of particular relevance as the Phoenix metropolitan area undergoes major expansion into the surrounding desert areas. The objectives of this study in urban areas are aimed at determining potential applications of TIMS data for classifying and assessing land use and surface temperatures. Land use centers on surface impermeability studies for storm runoff assessment and pollution control. These studies focus on determining the areal abundance of urban vegetation and undeveloped soil. Highly experimental applications include assessment and monitoring of pavement condition. Temperature studies focus on determining swimming pool area and temperature for use in monitoring evaporating and urban water consumption. These activities are of particular relevance as the Phoenix metropolitan area undergoes major expansion into the surrounding desert area.

  14. Integrated Modeling System for Analysis of Watershed Water Balance: A Case Study in the Tims Branch Watershed, South Carolina

    NASA Astrophysics Data System (ADS)

    Setegn, S. G.; Mahmoudi, M.; Lawrence, A.; Duque, N.

    2015-12-01

    The Applied Research Center at Florida International University (ARC-FIU) is supporting the soil and groundwater remediation efforts of the U.S. Department of Energy (DOE) Savannah River Site (SRS) by developing a surface water model to simulate the hydrology and the fate and transport of contaminants and sediment in the Tims Branch watershed. Hydrological models are useful tool in water and land resource development and decision-making for watershed management. Moreover, simulation of hydrological processes improves understanding of the environmental dynamics and helps to manage and protect water resources and the environment. MIKE SHE, an advanced integrated modeling system is used to simulate the hydrological processes of the Tim Branch watershed with the objective of developing an integrated modeling system to improve understanding of the physical, chemical and biological processes within the Tims Branch watershed. MIKE SHE simulates water flow in the entire land based phase of the hydrological cycle from rainfall to river flow, via various flow processes such as, overland flow, infiltration, evapotranspiration, and groundwater flow. In this study a MIKE SHE model is developed and applied to the Tim branch watershed to study the watershed response to storm events and understand the water balance of the watershed under different climatic and catchment characteristics. The preliminary result of the integrated model indicated that variation in the depth of overland flow highly depend on the amount and distribution of rainfall in the watershed. The ultimate goal of this project is to couple the MIKE SHE and MIKE 11 models to integrate the hydrological component in the land phase of hydrological cycle and stream flow process. The coupled MIKE SHE/MIKE 11 model will further be integrated with an Ecolab module to represent a range of water quality, contaminant transport, and ecological processes with respect to the stream, surface water and groundwater in the Tims

  15. Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway.

    PubMed

    Calì, Federica; Bharti, Sanjay Kumar; Di Perna, Roberta; Brosh, Robert M; Pisani, Francesca M

    2016-01-29

    We present evidence that Tim establishes a physical and functional interaction with DDX11, a super-family 2 iron-sulfur cluster DNA helicase genetically linked to the chromosomal instability disorder Warsaw breakage syndrome. Tim stimulates DDX11 unwinding activity on forked DNA substrates up to 10-fold and on bimolecular anti-parallel G-quadruplex DNA structures and three-stranded D-loop approximately 4-5-fold. Electrophoretic mobility shift assays revealed that Tim enhances DDX11 binding to DNA, suggesting that the observed stimulation derives from an improved ability of DDX11 to interact with the nucleic acid substrate. Surface plasmon resonance measurements indicate that DDX11 directly interacts with Tim. DNA fiber track assays with HeLa cells exposed to hydroxyurea demonstrated that Tim or DDX11 depletion significantly reduced replication fork progression compared to control cells; whereas no additive effect was observed by co-depletion of both proteins. Moreover, Tim and DDX11 are epistatic in promoting efficient resumption of stalled DNA replication forks in hydroxyurea-treated cells. This is consistent with the finding that association of the two endogenous proteins in the cell extract chromatin fraction is considerably increased following hydroxyurea exposure. Overall, our studies provide evidence that Tim and DDX11 physically and functionally interact and act in concert to preserve replication fork progression in perturbed conditions.

  16. The use of TIMS data to estimate the SO2 concentrations of volcanic plumes: A case study at Mount Etna, Sicily

    NASA Technical Reports Server (NTRS)

    Realmuto, Vincent J.

    1992-01-01

    Thermal Infrared Multispectral Scanner (TIMS) data were acquired over Mount Etna, Sicily, on 29 July 1986. The volcanic activity at that time was characterized by the steady effusion of gas from the Bocca Nuova (BN), Chasm, and Southeast craters. The Northeast crater, quiet at the time of the TIMS overflight, was the site of Strombolian eruptive activity between 31 July and 24 Sep. 1986. In aerial photographs of the Etna summit region acquired during the TIMS overflight, the SO2-rich plume is visible due to the scattering of sunlight by the entrained aerosols. In the TIMS imagery, the plume is revealed by the strong absorption of SO2 between 8 and 9 microns. This absorption feature falls within the first three channels of TIMS, with the strongest absorption falling within Channel 2. Following decorrelation processing, the plume is visible in color-composites of TIMS channels 2, 3, and 5. To estimate the concentration of SO2 within the plume, the LOWTRAN 7 radiative transfer code was used to model the radiance spectra measured by TIMS.

  17. The auto-inhibitory state of Rho guanine nucleotide exchange factor ARHGEF5/TIM can be relieved by targeting its SH3 domain with rationally designed peptide aptamers.

    PubMed

    He, Ping; Tan, De-Li; Liu, Hong-Xiang; Lv, Feng-Lin; Wu, Wei

    2015-04-01

    The short isoform of Rho guanine nucleotide exchange factor ARHGEF5 is known as TIM, which plays diverse roles in, for example, tumorigenesis, neuronal development and Src-induced podosome formation through the activation of its substrates, the Rho family of GTPases. The activation is auto-inhibited by a putative helix N-terminal to the DH domain of TIM, which is stabilized by the intramolecular interaction of C-terminal SH3 domain with a poly-proline sequence between the putative helix and the DH domain. In this study, we systematically investigated the structural basis, energetic landscape and biological implication underlying TIM auto-inhibition by using atomistic molecular dynamics simulations and binding free energy analysis. The computational study revealed that the binding of SH3 domain to poly-proline sequence is the prerequisite for the stabilization of TIM auto-inhibition. Thus, it is suggested that targeting SH3 domain with competitors of the poly-proline sequence would be a promising strategy to relieve the auto-inhibitory state of TIM. In this consideration, we rationally designed a number of peptide aptamers for competitively inhibiting the SH3 domain based on modeled TIM structure and computationally generated data. Peptide binding test and guanine nucleotide exchange analysis solidified that these designed peptides can both bind to the SH3 domain potently and activate TIM-catalyzed RhoA exchange reaction effectively. Interestingly, a positive correlation between the peptide affinity and induced exchange activity was observed. In addition, separate mutation of three conserved residues Pro49, Pro52 and Lys54 - they are required for peptide recognition by SH3 domain -- in a designed peptide to Ala would completely abolish the capability of this peptide activating TIM. All these come together to suggest an intrinsic relationship between peptide binding to SH3 domain and the activation of TIM.

  18. Preferential Tim-3 expression on Treg and CD8(+) T cells, supported by tumor-associated macrophages, is associated with worse prognosis in gastric cancer.

    PubMed

    Shen, Pinying; Yue, Rongxi; Tang, Jiahong; Si, Haige; Shen, Liqun; Guo, Changsheng; Zhang, Lixin; Han, Huaizhong; Song, Haihan K; Zhao, Pengfei; Wang, Ning; Song, Zongchang; Guo, Chunliang

    2016-01-01

    While infection with H. pylori is a strong risk factor for gastric cancer, most H. pylori-colonized individuals, even those with the high-risk CagA(+)VacA(+) strain, remain asymptomatic over their lifetime. We hypothesized that the discordant outcomes were due to differences in the host immune responses. Previously, Tim-3-mediated immune modulation was observed in H. pylori-challenged mice. In this study, we compared Tim-3-related responses in CagA(+)VacA(+) H. pylori-infected asymptomatic individuals and H. pylori-associated gastric adenocarcinoma patients. We showed that compared to H. pylori-uninfected individuals, both H. pylori-infected asymptomatic and gastric cancer patients upregulated Tim-3 overall. However, the Tim-3 upregulation was enriched on Th1 cells in asymptomatic patients and on Treg and CD8(+) T cells in gastric cancer patients, with respective differences in T cell subset functions. In gastric cancer patients, high Tim-3 expression on Treg and CD8(+) T cells, but not on Th1 cells, was associated with worse prognosis. H. pylori-antigen presentation by tumor-associated macrophages upregulated Tim-3 expression more effectively than by blood monocyte-derived macrophages in vitro. The upregulation of Tim-3 in vitro depended on the concentration of H. pylori antigen but not on whether the cells were from asymptomatic or cancer patients. These data suggest that the discrepancy in Tim-3 upregulation in asymptomatic and cancer subjects is induced by cancer but not the other way around. Once gastric cancer is developed, Tim-3 expression is associated with worse prognosis.

  19. Preferential Tim-3 expression on Treg and CD8+ T cells, supported by tumor-associated macrophages, is associated with worse prognosis in gastric cancer

    PubMed Central

    Shen, Pinying; Yue, Rongxi; Tang, Jiahong; Si, Haige; Shen, Liqun; Guo, Changsheng; Zhang, Lixin; Han, Huaizhong; Song, Haihan K; Zhao, Pengfei; Wang, Ning; Song, Zongchang; Guo, Chunliang

    2016-01-01

    While infection with H. pylori is a strong risk factor for gastric cancer, most H. pylori-colonized individuals, even those with the high-risk CagA+VacA+ strain, remain asymptomatic over their lifetime. We hypothesized that the discordant outcomes were due to differences in the host immune responses. Previously, Tim-3-mediated immune modulation was observed in H. pylori-challenged mice. In this study, we compared Tim-3-related responses in CagA+VacA+ H. pylori-infected asymptomatic individuals and H. pylori-associated gastric adenocarcinoma patients. We showed that compared to H. pylori-uninfected individuals, both H. pylori-infected asymptomatic and gastric cancer patients upregulated Tim-3 overall. However, the Tim-3 upregulation was enriched on Th1 cells in asymptomatic patients and on Treg and CD8+ T cells in gastric cancer patients, with respective differences in T cell subset functions. In gastric cancer patients, high Tim-3 expression on Treg and CD8+ T cells, but not on Th1 cells, was associated with worse prognosis. H. pylori-antigen presentation by tumor-associated macrophages upregulated Tim-3 expression more effectively than by blood monocyte-derived macrophages in vitro. The upregulation of Tim-3 in vitro depended on the concentration of H. pylori antigen but not on whether the cells were from asymptomatic or cancer patients. These data suggest that the discrepancy in Tim-3 upregulation in asymptomatic and cancer subjects is induced by cancer but not the other way around. Once gastric cancer is developed, Tim-3 expression is associated with worse prognosis. PMID:27648132

  20. Preferential Tim-3 expression on Treg and CD8+ T cells, supported by tumor-associated macrophages, is associated with worse prognosis in gastric cancer

    PubMed Central

    Shen, Pinying; Yue, Rongxi; Tang, Jiahong; Si, Haige; Shen, Liqun; Guo, Changsheng; Zhang, Lixin; Han, Huaizhong; Song, Haihan K; Zhao, Pengfei; Wang, Ning; Song, Zongchang; Guo, Chunliang

    2016-01-01

    While infection with H. pylori is a strong risk factor for gastric cancer, most H. pylori-colonized individuals, even those with the high-risk CagA+VacA+ strain, remain asymptomatic over their lifetime. We hypothesized that the discordant outcomes were due to differences in the host immune responses. Previously, Tim-3-mediated immune modulation was observed in H. pylori-challenged mice. In this study, we compared Tim-3-related responses in CagA+VacA+ H. pylori-infected asymptomatic individuals and H. pylori-associated gastric adenocarcinoma patients. We showed that compared to H. pylori-uninfected individuals, both H. pylori-infected asymptomatic and gastric cancer patients upregulated Tim-3 overall. However, the Tim-3 upregulation was enriched on Th1 cells in asymptomatic patients and on Treg and CD8+ T cells in gastric cancer patients, with respective differences in T cell subset functions. In gastric cancer patients, high Tim-3 expression on Treg and CD8+ T cells, but not on Th1 cells, was associated with worse prognosis. H. pylori-antigen presentation by tumor-associated macrophages upregulated Tim-3 expression more effectively than by blood monocyte-derived macrophages in vitro. The upregulation of Tim-3 in vitro depended on the concentration of H. pylori antigen but not on whether the cells were from asymptomatic or cancer patients. These data suggest that the discrepancy in Tim-3 upregulation in asymptomatic and cancer subjects is induced by cancer but not the other way around. Once gastric cancer is developed, Tim-3 expression is associated with worse prognosis.

  1. Preferential Tim-3 expression on Treg and CD8(+) T cells, supported by tumor-associated macrophages, is associated with worse prognosis in gastric cancer.

    PubMed

    Shen, Pinying; Yue, Rongxi; Tang, Jiahong; Si, Haige; Shen, Liqun; Guo, Changsheng; Zhang, Lixin; Han, Huaizhong; Song, Haihan K; Zhao, Pengfei; Wang, Ning; Song, Zongchang; Guo, Chunliang

    2016-01-01

    While infection with H. pylori is a strong risk factor for gastric cancer, most H. pylori-colonized individuals, even those with the high-risk CagA(+)VacA(+) strain, remain asymptomatic over their lifetime. We hypothesized that the discordant outcomes were due to differences in the host immune responses. Previously, Tim-3-mediated immune modulation was observed in H. pylori-challenged mice. In this study, we compared Tim-3-related responses in CagA(+)VacA(+) H. pylori-infected asymptomatic individuals and H. pylori-associated gastric adenocarcinoma patients. We showed that compared to H. pylori-uninfected individuals, both H. pylori-infected asymptomatic and gastric cancer patients upregulated Tim-3 overall. However, the Tim-3 upregulation was enriched on Th1 cells in asymptomatic patients and on Treg and CD8(+) T cells in gastric cancer patients, with respective differences in T cell subset functions. In gastric cancer patients, high Tim-3 expression on Treg and CD8(+) T cells, but not on Th1 cells, was associated with worse prognosis. H. pylori-antigen presentation by tumor-associated macrophages upregulated Tim-3 expression more effectively than by blood monocyte-derived macrophages in vitro. The upregulation of Tim-3 in vitro depended on the concentration of H. pylori antigen but not on whether the cells were from asymptomatic or cancer patients. These data suggest that the discrepancy in Tim-3 upregulation in asymptomatic and cancer subjects is induced by cancer but not the other way around. Once gastric cancer is developed, Tim-3 expression is associated with worse prognosis. PMID:27648132

  2. Upregulation of Tim-3 on CD4(+) T cells is associated with Th1/Th2 imbalance in patients with allergic asthma.

    PubMed

    Tang, Fei; Wang, Fukun; An, Liyun; Wang, Xianling

    2015-01-01

    T cell Ig and mucin domain-containing molecule-3 (Tim-3) is a negative regulator preferentially expressed on Th1 cells. Allergic asthma is a clinical syndrome well characterized by Th1/Th2 imbalance. To investigate the role of Tim-3 in the pathogenesis of asthma and its relationship with Th1/Th2 imbalance, a total of 40 patients with allergic asthma and 40 healthy controls were enrolled. Expression of Tim-3 and Th1/Th2 imbalance as well as the relationship between them was analyzed by flow cytometry and real-time PCR. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro and anti-Tim-3 was used to block Tim-3 signaling; Th1/Th2 cytokines in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA). CD4(+) T cells and B cells were sorted and co-cultured in vitro, and anti-Tim-3 was used to block Tim-3 signaling; Total IgG/IgE in the culture supernatant was detected by ELISA. The mRNA level of T-bet and IFN-γ were significantly decreased in allergic asthma patients, while GATA-3 and IL-4 were significantly increased. Expression of Tim-3 on CD4(+) T cells was much higher in allergic asthma patients and it was negatively correlated with T-bet/GATA-3 ratio or IFN-γ/IL-4 ratio. Blocking of Tim-3 significantly increased Th1 cytokines (TNF-α and IFN-γ) and decreased Th2 cytokines (IL-4, IL-5, IL-13) in the culture supernatant of PBMCs. Blocking of Tim-3 dramatically reduced the production of IgG and IgE in the co-culture supernatant of CD4(+) T cells and B cells. In conclusion, Tim-3 was up-regulated in allergic asthma patients and related with the Th1/Th2 imbalance. Blocking of Tim-3 may be of therapeutic benefit by enhancing the Th1 cytokines response, down-regulating the Th2 cytokines response, and reducing IgG/IgE production.

  3. Upregulation of Tim-3 on CD4(+) T cells is associated with Th1/Th2 imbalance in patients with allergic asthma.

    PubMed

    Tang, Fei; Wang, Fukun; An, Liyun; Wang, Xianling

    2015-01-01

    T cell Ig and mucin domain-containing molecule-3 (Tim-3) is a negative regulator preferentially expressed on Th1 cells. Allergic asthma is a clinical syndrome well characterized by Th1/Th2 imbalance. To investigate the role of Tim-3 in the pathogenesis of asthma and its relationship with Th1/Th2 imbalance, a total of 40 patients with allergic asthma and 40 healthy controls were enrolled. Expression of Tim-3 and Th1/Th2 imbalance as well as the relationship between them was analyzed by flow cytometry and real-time PCR. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro and anti-Tim-3 was used to block Tim-3 signaling; Th1/Th2 cytokines in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA). CD4(+) T cells and B cells were sorted and co-cultured in vitro, and anti-Tim-3 was used to block Tim-3 signaling; Total IgG/IgE in the culture supernatant was detected by ELISA. The mRNA level of T-bet and IFN-γ were significantly decreased in allergic asthma patients, while GATA-3 and IL-4 were significantly increased. Expression of Tim-3 on CD4(+) T cells was much higher in allergic asthma patients and it was negatively correlated with T-bet/GATA-3 ratio or IFN-γ/IL-4 ratio. Blocking of Tim-3 significantly increased Th1 cytokines (TNF-α and IFN-γ) and decreased Th2 cytokines (IL-4, IL-5, IL-13) in the culture supernatant of PBMCs. Blocking of Tim-3 dramatically reduced the production of IgG and IgE in the co-culture supernatant of CD4(+) T cells and B cells. In conclusion, Tim-3 was up-regulated in allergic asthma patients and related with the Th1/Th2 imbalance. Blocking of Tim-3 may be of therapeutic benefit by enhancing the Th1 cytokines response, down-regulating the Th2 cytokines response, and reducing IgG/IgE production. PMID:26064278

  4. Least destructive sampling of human remains using laser drilling for Sr isotope analysis by TIMS

    NASA Astrophysics Data System (ADS)

    Willmes, Malte; Moffat, Ian; Grün, Rainer; Armstrong, Richard; Kinsley, Les; McMorrow, Linda

    2013-04-01

    Strontium isotope ratios (87Sr/86Sr) measured in ancient human remains can be used to reconstruct migration patterns of ancient human populations. This application is based on the fact that different geologic regions have distinct Sr isotope signatures that are cycled through the soils, plants and rivers, and eventually enter the food cycle. Sr isotope ratios measured in skeletal remains (bones and teeth) reflect the average of dietary Sr that was consumed when the tissue was formed, allowing the investigation of human migration between geologically distinct terrains. The analysis of human remains is always a sensitive topic requiring minimal damage to the sample, while at the same time providing highly precise and accurate results. Samples can be analysed either by solution methods like thermal ionisation mass spectrometry (TIMS), or by in-situ laser ablation MC-ICP-MS. For TIMS a drill is used to extract a small amount of sample, which is then digested in acid and Sr is separated out using ion exchange chromatography. This technique provides highly precise and accurate results, because any isobaric interferences are removed during chemical separation. The drawback is that drilling may cause visible damage to the sample, restricting access to precious human remains. LA-MC-ICP-MS analysis is very fast and nearly destruction free. However, the accuracy and precision of LA-MC-ICP-MS is limited by a number of factors including large instrumental mass discrimination, laser-induced isotopic and elemental fractionations and molecular interferences on 87Sr. Its application thus requires rigorous data reduction, which can introduce significant uncertainties into the analysis. This is especially true for samples with relatively low Sr concentrations such as human teeth (e.g., Woodhead et al., 2005; Horstwood et al., 2008; Vroon et al., 2008). In addition, LA-MC-ICP-MS has traditionally required a flat sample surface, thus an unbroken tooth needs to be cut, which is rather

  5. Dating Intrusions in the Salinian Block Using Single Zircon U-PB CA-TIMS Analysis

    NASA Astrophysics Data System (ADS)

    DeNicola, S.; Mundil, R.; Wang, C. Y.; Sprain, C. J.; Manga, M.

    2015-12-01

    The Salinian block (SB) consists largely of metasedimentary basement intruded by suites of compositionally heterogeneous Early to Late Cretaceous rocks. Exposed throughout Central and Northern California, it is bordered to the northwest by the Naciemiento fault, to the southwest by the Big Pine fault and to the east by the San Andreas Fault. These faults are thought to have caused a dextral offset of the SB; however, its original position is still debated. Published radioisotopic ages from various techniques on SB intrusives suggest that the initial magmatic activity of the Salinian arc began at around 100 Ma and concluded some 40 myr later, but the timing of individual magmatic pulses are yet to be fully understood because arguably most of the available geochronological data are compromised with respect to precision and accuracy. Previous studies include U-Pb zircon ages from different lithologies and areas using multi-crystal TIMS as well as ICPMS, and SIMS techniques. Whereas the former technique is now known to be prone to producing inaccurate, although precise, ages due to averaging effects from older inheritance and open system behavior, the latter are often associated with analytical uncertainty at the several percent level as well as unrecognized open system behavior, making the interpretation of age data notoriously difficult. Complementary geochemical, petrological and structural studies have been conducted, but are also difficult to interpret in absence of precise and accurate geochronological data because geochemical trends and intrusion rates cannot be reconstructed. Here, we examine a group of intrusive rocks from the Northern California SB that include a biotite-hornblende granodiorite host rock which is intruded by a complex array of igneous dikes of varying lithology ranging from ~5% to ~50% mafic components. We perform closed system single zircon U-Pb CA-TIMS analysis and obtain 206Pb/238U ages of ~98 Ma and ~92 Ma (with permil level resolution

  6. Thrombolytic-Related Asymptomatic Hemorrhagic Transformation Does Not Deteriorate Clinical Outcome: Data from TIMS in China

    PubMed Central

    Jia, Weihua; Liao, Xiaoling; Pan, Yuesong; Wang, Yilong; Cui, Tao; Zhou, Lichun; Wang, Yongjun

    2015-01-01

    Objective It has been unclear whether thrombolytic-related asymptomatic hemorrhagic transformation (AHT) affects the clinical outcome. To answer this question, we examined whether thrombolytic-related AHT affect short-term and long-term clinical outcome. Methods All data were collected from the Thrombolysis Implementation and Monitor of Acute Ischemic Stroke in China (TIMS-China) registry. The patients were diagnosed as having AHT group and non- hemorrhagic transformation (HT) group based on clinical and imaging data. The patients with symptomatic hemorrhagic transformation were excluded from this study. Thrombolytic-related AHT was defined according to European-Australasian Acute Stroke Study (ECASS) II criteria. 90-day functional outcome, 7-day National Institutes of Health Stroke Scale (NIHSS) score, 7-day and 90-day mortalities were compared between two groups. Logistic regression analysis was used to evaluate the effects of AHT on a short-term and long-term clinical outcome. Results 904 of all 1440 patients in TIMS-China registry were enrolled. 89 (9.6%) patients presented with AHT after thrombolysis within 24-36h. These patients with AHT were more likely to be elder age, cardioembolic subtype, and to have higher National Institutes of Health Stroke Scale score before thrombolysis than patients without AHT. No significant difference was found on the odds of 7-day (95% CI:0.692 (0.218–2.195), (P = 0.532) or 90-day mortalities (95% CI:0.548 (0.237–1.268), P = 0.160) and modified Rankin Score(0–1) at 90-day (95% CI:0.798 (0.460–1.386), P = 0.423) or modified Rankin Score(0–2) at 90-day (95% CI:0.732 (0.429–1.253), P = 0.116) or modified Rankin Score(5–6) at 90-day (95% CI:0.375 (0.169–1.830), P = 0.116) between two groups. Conclusions Thrombolytic-related AHT does not deteriorate short-term and long-term clinical outcome. PMID:26619008

  7. High precision calcium isotope analysis using 42Ca-48Ca double-spike TIMS technique

    NASA Astrophysics Data System (ADS)

    Feng, L.; Zhou, L.; Gao, S.; Tong, S. Y.; Zhou, M. L.

    2014-12-01

    Double spike techniques are widely used for determining calcium isotopic compositions of natural samples. The most important factor controlling precision of the double spike technique is the choice of appropriate spike isotope pair, the composition of double spikes and the ratio of spike to sample(CSp/CN). We propose an optimal 42Ca-48Ca double spike protocol which yields the best internal precision for calcium isotopic composition determinations among all kinds of spike pairs and various spike compositions and ratios of spike to sample, as predicted by linear error propagation method. It is suggested to use spike composition of 42Ca/(42Ca+48Ca) = 0.44 mol/mol and CSp/(CN+ CSp)= 0.12mol/mol because it takes both advantages of the largest mass dispersion between 42Ca and 48Ca (14%) and lowest spike cost. Spiked samples were purified by pass through homemade micro-column filled with Ca special resin. K, Ti and other interference elements were completely separated, while 100% calcium was recovered with negligible blank. Data collection includes integration time, idle time, focus and peakcenter frequency, which were all carefully designed for the highest internal precision and lowest analysis time. All beams were automatically measured in a sequence by Triton TIMS so as to eliminate difference of analytical conditions between samples and standards, and also to increase the analytical throughputs. The typical internal precision of 100 duty cycles for one beam is 0.012‒0.015 ‰ (2δSEM), which agrees well with the predicted internal precision of 0.0124 ‰ (2δSEM). Our methods improve internal precisions by a factor of 2‒10 compared to previous methods of determination of calcium isotopic compositions by double spike TIMS. We analyzed NIST SRM 915a, NIST SRM 915b and Pacific Seawater as well as interspersed geological samples during two months. The obtained average δ44/40Ca (all relative to NIST SRM 915a) is 0.02 ± 0.02 ‰ (n=28), 0.72±0.04 ‰ (n=10) and 1

  8. Biological and chemical assessment of M-Area process discharge to Tim's Branch: June 1985-December 1986

    SciTech Connect

    Specht, W.L.; Pickett, J.B.; Muska, C.F.; Starkel, W.M.; Giffin, M.; Trapp, K.E.

    1987-05-01

    This study addresses the effects of the A-014 outfall on the chemistry and biota of Tim's Branch and Upper Three Runs Creek from June 1985 through December 1986. In addition to analyses for chemical parameters, the periphyton and macroinvertebrate communities on each site were sampled to assess the impact of the M-Area discharges on the overall condition of these communities. Acute laboratory toxicity tests were conducted on noncontact cooling water/air stripper water and noncontact cooling water/air stripper water/Liquid Effluent Treatment Facility (LETF) effluent using bluegill sunfish and Daphnia pulex. The data indicate no adverse impact on the water chemistry, water quality, or aquatic communities of the Tim's Branch/Upper Three Runs system due to discharges from the A-014 outfall after startup of the M-Area Project Air Stripper and the M-Area Liquid Effluent Treatment Facility.

  9. When the CA-TIMS therapy fails: the over-enthusiastic, the mixed-up, and the stubborn zircon

    NASA Astrophysics Data System (ADS)

    Corfu, F.

    2009-12-01

    Mattinson’s CA-TIMS technique has proven to be highly successful in efficiently removing disturbed domains of zircon, thus enabling the determination of precise and accurate ages in a variety of geological situations. The method generally produces equal or better results than mechanical abrasion. There are, however, cases where CA-TIMS fails to achieve perfect concordance, and occasionally actually increases the degree of discordance. Such a behaviour (the over-reaction) is observed for example in U-rich (>1000 ppm) but texturally homogeneous zircon, a type quite common in highly differentiated portions of mafic intrusions, in granitic pegmatites, and in some metamorphic rocks. Because of their internal uniformity, such zircons do not exhibit large contrasts in crystallinity and solubility and after the baking stage of the CA-TIMS procedure they will either totally dissolve in the first HF attack, or produce discordant results. By contrast, mechanical abrasion of this type of zircon can isolate alteration-free zircon domains that yield concordant and reproducible data. This is due to the homogeneity of the crystals, the lack of zoning limiting contrasts in the degrees of metamictization and brittleness and preventing fracturing. The absence of fractures helps to confine alteration of zircon to the marginal domains, and these can be removed very efficiently by mechanical abrasion. This behaviour is exemplified by zircon populations from 252.0 Ma and 182.5 Ma mafic sills in Siberia and the Karoo basin. Another class of zircons that in general does not, or only partially comply with CA-TIMS includes populations from metamorphic and poly-orogenic rocks, typical of many Proterozoic orogens. The metamorphic reprocessing of zircon into low-U domains can freeze-in old Pb-loss patterns that cannot be undone by any technique. New metamorphic zircon growth can also create mixtures of different aged domains that cannot be resolved by CA-TIMS. In favourable circumstances

  10. Quantitative estimation of granitoid composition from thermal infrared multispectral scanner (TIMS) data, Desolation Wilderness, northern Sierra Nevada, California

    NASA Technical Reports Server (NTRS)

    Sabine, Charles; Realmuto, Vincent J.; Taranik, James V.

    1994-01-01

    We have produced images that quantitatively depict modal and chemical parameters of granitoids using an image processing algorithm called MINMAP that fits Gaussian curves to normalized emittance spectra recovered from thermal infrared multispectral scanner (TIMS) radiance data. We applied the algorithm to TIMS data from the Desolation Wilderness, an extensively glaciated area near the northern end of the Sierra Nevada batholith that is underlain by Jurassic and Cretaceous plutons that range from diorite and anorthosite to leucogranite. The wavelength corresponding to the calculated emittance minimum lambda(sub min) varies linearly with quartz content, SiO2, and other modal and chemical parameters. Thematic maps of quartz and silica content derived from lambda(sub min) values distinguish bodies of diorite from surrounding granite, identify outcrops of anorthosite, and separate felsic, intermediate, and mafic rocks.

  11. Characterization of age-associated exhausted CD8⁺ T cells defined by increased expression of Tim-3 and PD-1.

    PubMed

    Lee, Kyoo-A; Shin, Kwang-Soo; Kim, Ga-Young; Song, You Chan; Bae, Eun-Ah; Kim, Il-Kyu; Koh, Choong-Hyun; Kang, Chang-Yuil

    2016-04-01

    Aging is accompanied by altered T-cell responses that result in susceptibility to various diseases. Previous findings on the increased expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1), in the T cells of aged mice emphasize the importance of investigations into the relationship between T-cell exhaustion and aging-associated immune dysfunction. In this study, we demonstrate that T-cell immunoglobulin mucin domain-3 (Tim-3), another exhaustion marker, is up-regulated on aged T cells, especially CD8(+) T cells. Tim-3-expressing cells also produced PD-1, but Tim-3(+) PD-1(+) CD8(+) T cells had a distinct phenotype that included the expression of CD44 and CD62L, from Tim-3(-) PD-1(+) cells. Tim-3(+) PD-1(+) CD8(+) T cells showed more evident properties associated with exhaustion than Tim-3(-) PD-1(+) CD8(+) T cells: an exhaustion-related marker expression profile, proliferative defects following homeostatic or TCR stimulation, and altered production of cytokines. Interestingly, these cells produced a high level of IL-10 and induced normal CD8(+) T cells to produce IL-10, which might contribute to immune dysregulation in aged mice. The generation of Tim-3-expressing CD8(+) T cells in aged mice seems to be mediated by encounters with antigens but not by specific infection, based on their high expression of CD49d and their unbiased TCR Vβ usage. In conclusion, we found that a CD8(+) T-cell population with age-associated exhaustion was distinguishable by its expression of Tim-3. These results provide clues for understanding the alterations that occur in T-cell populations with age and for improving dysfunctions related to the aging of the immune system.

  12. GroEL/ES chaperonin modulates the mechanism and accelerates the rate of TIM-barrel domain folding.

    PubMed

    Georgescauld, Florian; Popova, Kristina; Gupta, Amit J; Bracher, Andreas; Engen, John R; Hayer-Hartl, Manajit; Hartl, F Ulrich

    2014-05-01

    The GroEL/ES chaperonin system functions as a protein folding cage. Many obligate substrates of GroEL share the (βα)8 TIM-barrel fold, but how the chaperonin promotes folding of these proteins is not known. Here, we analyzed the folding of DapA at peptide resolution using hydrogen/deuterium exchange and mass spectrometry. During spontaneous folding, all elements of the DapA TIM barrel acquire structure simultaneously in a process associated with a long search time. In contrast, GroEL/ES accelerates folding more than 30-fold by catalyzing segmental structure formation in the TIM barrel. Segmental structure formation is also observed during the fast spontaneous folding of a structural homolog of DapA from a bacterium that lacks GroEL/ES. Thus, chaperonin independence correlates with folding properties otherwise enforced by protein confinement in the GroEL/ES cage. We suggest that folding catalysis by GroEL/ES is required by a set of proteins to reach native state at a biologically relevant timescale, avoiding aggregation or degradation.

  13. Structure of the human Tim44 C-terminal domain in complex with pentaethylene glycol: ligand-bound form

    SciTech Connect

    Handa, N.; Kishishita, S.; Morita, S.; Akasaka, R.; Jin, Z.; Chrzas, J.; Chen, L.; Liu, Z.-J.; Wang, B.-C.; Sugano, S.; Tanaka, A.; Terada, T.; Shirouzu, M.; Yokoyama, S.

    2008-06-23

    Familial oncocytic thyroid carcinoma is associated with a missense mutation, P308Q, in the C-terminal domain of Tim44. Tim44 is the mitochondrial inner-membrane translocase subunit and it functions as a membrane anchor for the mitochondrial heat-shock protein 70 (mtHsp70). Here, the crystal structure of the human Tim44 C-terminal domain complexed with pentaethylene glycol has been determined at 1.9 {angstrom} resolution. The overall structure resembles that of the nuclear transport factor 2-like domain. In the crystal structure, pentaethylene glycol molecules are associated at two potential membrane-binding sites: the large hydrophobic cavity and the highly conserved loop between the {alpha} 1 and {alpha} 2 helices near Pro308. A comparison with the yeast homolog revealed that lipid binding induces conformational changes around the {alpha} 1-{alpha} 2 loop, leading to slippage of the {alpha} 1 helix along the large {beta}-sheet. These changes may play important roles in the translocation of polypeptides across the mitochondrial inner membrane.

  14. Activation-Induced TIM-4 Expression Identifies Differential Responsiveness of Intestinal CD103+ CD11b+ Dendritic Cells to a Mucosal Adjuvant.

    PubMed

    Hilligan, Kerry L; Connor, Lisa M; Schmidt, Alfonso J; Ronchese, Franca

    2016-01-01

    Macrophage and dendritic cell (DC) populations residing in the intestinal lamina propria (LP) are highly heterogeneous and have disparate yet collaborative roles in the promotion of adaptive immune responses towards intestinal antigen. Under steady-state conditions, macrophages are efficient at acquiring antigen but are non-migratory. In comparison, intestinal DC are inefficient at antigen uptake but migrate to the mesenteric lymph nodes (mLN) where they present antigen to T cells. Whether such distinction in the roles of DC and macrophages in the uptake and transport of antigen is maintained under immunostimulatory conditions is less clear. Here we show that the scavenger and phosphatidylserine receptor T cell Immunoglobulin and Mucin (TIM)-4 is expressed by the majority of LP macrophages at steady-state, whereas DC are TIM-4 negative. Oral treatment with the mucosal adjuvant cholera toxin (CT) induces expression of TIM-4 on a proportion of CD103+ CD11b+ DC in the LP. TIM-4+ DC selectively express high levels of co-stimulatory molecules after CT treatment and are detected in the mLN a short time after appearing in the LP. Importantly, intestinal macrophages and DC expressing TIM-4 are more efficient than their TIM-4 negative counterparts at taking up apoptotic cells and soluble antigen ex vivo. Taken together, our results show that CT induces phenotypic changes to migratory intestinal DC that may impact their ability to take up local antigens and in turn promote the priming of mucosal immunity.

  15. Participation of T cell immunoglobulin and mucin domain-3 (TIM-3) and its ligand (galectin-9) in the pathogenesis of active generalized vitiligo.

    PubMed

    Tembhre, Manoj Kumar; Parihar, Anita Singh; Sharma, Alpana; Gupta, Somesh; Chattopadhyay, Parthaprasad; Sharma, Vinod Kumar

    2015-05-01

    Vitiligo is a depigmentary disease where melanocytes of the basal layer of epidermis are selectively destroyed by immune-cell-mediated cytotoxicity. The T cell immunoglobulin- and mucin-domain-containing molecules (TIMs) are involved in immune regulation, and their participation is not known in vitiligo. The present study revealed significant increase in the percentage of CD3+CD4+TIM3+ T cells (P < 0.05) in peripheral blood and was positively correlated with percentage body surface area involvement in aGV group. Further, increased expression of TIM-3 and its ligand galectin-9 (Gal-9) mRNA was found in peripheral blood and lesional/perilesional skin of active generalized vitiligo (aGV) compared with controls. Characteristic migration pattern of TIM-3-positive immune cells in lesional (near/in the epidermis) and perilesional (towards epidermis) skin section suggested that TIM-3+ immune cells may be involved in melanocyte destruction. Further, investigation is required to understand the role of TIM-3/Gal-9 signalling pathways in aGV and it can be targeted in the management of vitiligo.

  16. Activation-Induced TIM-4 Expression Identifies Differential Responsiveness of Intestinal CD103+ CD11b+ Dendritic Cells to a Mucosal Adjuvant

    PubMed Central

    Schmidt, Alfonso J.; Ronchese, Franca

    2016-01-01

    Macrophage and dendritic cell (DC) populations residing in the intestinal lamina propria (LP) are highly heterogeneous and have disparate yet collaborative roles in the promotion of adaptive immune responses towards intestinal antigen. Under steady-state conditions, macrophages are efficient at acquiring antigen but are non-migratory. In comparison, intestinal DC are inefficient at antigen uptake but migrate to the mesenteric lymph nodes (mLN) where they present antigen to T cells. Whether such distinction in the roles of DC and macrophages in the uptake and transport of antigen is maintained under immunostimulatory conditions is less clear. Here we show that the scavenger and phosphatidylserine receptor T cell Immunoglobulin and Mucin (TIM)-4 is expressed by the majority of LP macrophages at steady-state, whereas DC are TIM-4 negative. Oral treatment with the mucosal adjuvant cholera toxin (CT) induces expression of TIM-4 on a proportion of CD103+ CD11b+ DC in the LP. TIM-4+ DC selectively express high levels of co-stimulatory molecules after CT treatment and are detected in the mLN a short time after appearing in the LP. Importantly, intestinal macrophages and DC expressing TIM-4 are more efficient than their TIM-4 negative counterparts at taking up apoptotic cells and soluble antigen ex vivo. Taken together, our results show that CT induces phenotypic changes to migratory intestinal DC that may impact their ability to take up local antigens and in turn promote the priming of mucosal immunity. PMID:27379516

  17. MicroRNA-155 regulates interferon-γ production in natural killer cells via Tim-3 signalling in chronic hepatitis C virus infection.

    PubMed

    Cheng, Yong Q; Ren, Jun P; Zhao, Juan; Wang, Jia M; Zhou, Yun; Li, Guang Y; Moorman, Jonathan P; Yao, Zhi Q

    2015-08-01

    Host immune responses must be tightly regulated by an intricate balance between positive and negative signals while fighting pathogens; persistent pathogens may usurp these regulatory mechanisms to dampen host immunity to facilitate survival in vivo. Here we report that Tim-3, a negative signalling molecule expressed on monocytes and T cells, is up-regulated on natural killer (NK) cells in individuals chronically infected with hepatitis C virus (HCV). Additionally, the transcription factor T-bet was also found to be up-regulated and associated with Tim-3 expression in NK cells during chronic HCV infection. MicroRNA-155 (miR-155), an miRNA that inhibits signalling proteins involved in immune responses, was down-regulated in NK cells by HCV infection. This Tim-3/T-bet over-expression and miR-155 inhibition were recapitulated in vitro by incubating primary NK cells or NK92 cell line with Huh-7 hepatocytes expressing HCV. Reconstitution of miR-155 in NK cells from HCV-infected patients led to a decrease in T-bet/Tim-3 expression and an increase in interferon-γ production. Blocking Tim-3 signalling also enhanced interferon-γ production in NK cells by improving signal transducer and activator of transcription-5 phosphorylation. These data indicate that HCV-induced, miR-155-regulated Tim-3 expression regulates NK cell function, suggesting a novel mechanism for balancing immune clearance and immune injury during chronic viral infection.

  18. Comprehensive and systematic MC-ICP-MS/TIMS isotopic characterization of USGS Standards

    NASA Astrophysics Data System (ADS)

    Mahoney, J. B.; Weis, D.; Keiffer, B.; Hanano, D.; Williams, G.; Pretorius, W.; Barling, J.; Scoates, J.; Friedman, R.; Goolaerts, A.; Mattielli, N.; Maerschalk, C.

    2003-12-01

    The Pacific Centre for Isotopic and Geochemical Research (PCIGR) at the University of British Columbia has undertaken a systematic analysis of isotopic (Nd, Sr, Hf, Pb) composition and concentration of a broad compositional range of United States Geological Survey standards, including basalt (BCR-1, 2; BHVO-1, 2; BIR-1), dunite (DNC-1), andesite (AGV-1, 2), rhyolite (RGM-1, 2), syenite (STM-1, 2) and granite (G-2). USGS rock standards are geochemically well-characterized, but there is no systematic methodology nor database for radiogenic isotopic analyses, even for the widely used BCR-I. This investigation represents the first comprehensive, systematic analysis of the isotopic concentration and composition of USGS standards, and will provide an important database for the isotopic community. The wide range of equipment at PCIGR, including a Nu MC-ICPMS, a Triton TIMS, and an ElementII HR-ICPMS, permits a rigorous assessment and comparison of precision and accuracy in isotopic analyses. Our separation technique involves an HF/HNO3 dissolution in Teflon bombs, standard cation exchange elutriation for Sr and REE separation, and HDEHP Teflon columns for Nd separation. Samples are unspiked, and elemental concentration is determined by HR-ICPMS. Isotopic composition is determined by both thermal ionization mass spectrometry (Sr, Nd) and by multi-collector inductively coupled plasma mass spectrometry (Nd, Hf, Pb). Replicate runs of La Jolla Nd standard demonstrate excellent agreement between MC-ICPMS (143Nd/144Nd=0.511846+/-14 [n=100]) and TIMS (0.511850+/-16 [n=67]). Replicate analyses of strontium standard NBS987 yield 86Sr/87Sr values of 0.710256+/-15 [n=130]. Neodymium isotopic analyses (143Nd/144Nd values and Sm/Nd ratios) of previously characterized standards, such as BCR-1 (143Nd/144Nd=0.512623+/-2 [Nu; n=2]; 0.512627+/-8 [Triton; n=8]; Sm/Nd=0.1389) and BHVO-1 (0.512972+/-5 [Nu; n=2]; 0.512973+/-6 [Triton; n=14]; 0.1522-0.1532) are within error of published values

  19. U.S. Tsunami Information technology (TIM) Modernization: Performance Assessment of Tsunamigenic Earthquake Discrimination System

    NASA Astrophysics Data System (ADS)

    Hagerty, M. T.; Lomax, A.; Hellman, S. B.; Whitmore, P.; Weinstein, S.; Hirshorn, B. F.; Knight, W. R.

    2015-12-01

    Tsunami warning centers must rapidly decide whether an earthquake is likely to generate a destructive tsunami in order to issue a tsunami warning quickly after a large event. For very large events (Mw > 8 or so), magnitude and location alone are sufficient to warrant an alert. However, for events of smaller magnitude (e.g., Mw ~ 7.5), particularly for so-called "tsunami earthquakes", magnitude alone is insufficient to issue an alert and other measurements must be rapidly made and used to assess tsunamigenic potential. The Tsunami Information technology Modernization (TIM) is a National Oceanic and Atmospheric Administration (NOAA) project to update and standardize the earthquake and tsunami monitoring systems currently employed at the U.S. Tsunami Warning Centers in Ewa Beach, Hawaii (PTWC) and Palmer, Alaska (NTWC). We (ISTI) are responsible for implementing the seismic monitoring components in this new system, including real-time seismic data collection and seismic processing. The seismic data processor includes a variety of methods aimed at real-time discrimination of tsunamigenic events, including: Mwp, Me, slowness (Theta), W-phase, mantle magnitude (Mm), array processing and finite-fault inversion. In addition, it contains the ability to designate earthquake scenarios and play the resulting synthetic seismograms through the processing system. Thus, it is also a convenient tool that integrates research and monitoring and may be used to calibrate and tune the real-time monitoring system. Here we show results of the automated processing system for a large dataset of subduction zone earthquakes containing recent tsunami earthquakes and we examine the accuracy of the various discrimation methods and discuss issues related to their successful real-time application.

  20. Absence of association between two insertion/deletion coding genetic polymorphisms of TIM-1 gene and asthma in Chinese Han population.

    PubMed

    Li, J S; Liu, Q J; Wang, P; Li, H C; Wei, C H; Guo, C H; Gong, Y Q

    2006-12-01

    TIM-1, a member of T-cell immunoglobulin domain and mucin domain (TIM) gene family, was implicated as an asthma susceptibility gene in previous studies. TIM-1 was expressed on CD4(+) T cells after activation and its expression was sustained preferentially in T-helper type 2 (T(H)2) but not in T(H)1 cells, therefore TIM-1 became a good candidate gene for atopic diseases. Recent studies indicated that two insertion/deletion (ins/del) coding genetic polymorphisms in exon 4 of TIM-1 were associated with asthma susceptibility in some but not in all populations. In order to investigate the relationship between TIM-1 genetic polymorphisms and asthma in Chinese Han population, we performed a case-control study for two insertion/deletion polymorphisms in TIM-1 exon 4 (5383_5397ins/del and 5509_5511delCAA) and a single nucleotide polymorphism (SNP) in intron 8 (IVS 8+9 G/A) between a healthy control group of 309 people and an asthma patient group of 352 people recruited from Chinese Han population. The polymorphisms were genotyped and the allele and genotype frequencies were analysed, but none of the three polymorphisms showed association with asthma susceptibility in single-locus association analyses. Linkage disequilibrium (LD) analyses demonstrated that the two insertion/deletion polymorphisms were in strong LD but the haplotypes constructed from these two polymorphisms showed no significant association with asthma. In conclusion, our findings suggest that 5383_5397ins/del, 5509_5511delCAA and SNP IVS 8+9 G/A polymorphisms are not associated with asthma susceptibility in Chinese Han population.

  1. Genetic polymorphisms of immune checkpoint proteins PD-1 and TIM-3 are associated with survival of patients with hepatitis B virus-related hepatocellular carcinoma

    PubMed Central

    Li, Zhu; Li, Na; Li, Fang; Zhou, Zhihua; Sang, Jiao; Jin, Zhao; Liu, Huihui; Han, Qunying; Lv, Yi; Liu, Zhengwen

    2016-01-01

    Programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule 3 (TIM-3) are involved in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study examined the associations of PD1 and TIM3 polymorphisms with the overall survival (OS) of a prospective cohort of 258 HBV-related HCC patients. Results showed that PD1 +8669 G allele-containing genotypes or TIM3 −1516 genotype GG were significantly associated with longer OS (P < 0.001 and P = 0.001, respectively). In multivariate analysis, PD1 +8669 G allele-containing genotypes and TIM3 −1516 genotype GG were independently associated with longer OS (hazard ratio (HR), 1.835; 95% confidence interval (CI), 1.342–2.509; P < 0.001 and HR, 2.070; 95%CI, 1.428–3.002; P < 0.001, respectively). PD1 +8669 G allele-containing genotypes were significantly associated with longer OS in patients receiving surgical (resection or radiofrequency) treatment, transcatheter arterial chemoembolization (TACE) or supportive and symptomatic treatment. TIM3 −1516 genotype GG was significantly associated with longer OS in TACE patients. In multivariate analysis, PD1 +8669 G allele-containing genotypes were independently associated with longer OS in each treatment population. TIM3 −1516 genotype GG was independently associated with longer OS in patients receiving surgical treatment or TACE. These findings suggest that PD1 +8669 A/G and TIM3 −1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients. PMID:27034168

  2. On the Use of 233U-236U Double-Spike for TIMS Measurements of Uranium Isotopes: A Simulation Study

    SciTech Connect

    Williams, R W

    2004-03-17

    Synthetic ion beams with instantaneous and temporal characteristics appropriate to thermal ionization mass spectrometry (TIMS) were mathematically generated and analyzed to determine the effects of using a mixed {sup 233}U-{sup 236}U spike (double-spike) in the analysis of uranium isotopes. The instantaneous beam characteristics are the intensities (e.g., counts per second) modeled with a Poisson distribution plus a component of random noise that simulates the detection processes. Several beam intensity and mass fractionation vs. time functions were modeled to simulate a range of sample sizes and the commonly employed methods of data collection. These beam profiles were also generated with different noise levels, and signal-to-noise vs. analytical precision diagrams are presented. Modeling focused on natural uranium, where {sup 238}U/{sup 235}U = 137.88, and on the ability of a given method to determine precisely and accurately small variations in this ratio. Practical limits on precision were determined to be 20-30 ppm, which is consistent with precision seen for other elements by state-of-the-art TIMS. The TIMS total evaporation method was compared directly with the double-spike method. While similar analytical precisions are obtained with either method, the double-spike method of correcting for analytical bias gives more accurate results. The results of a total evaporation analysis will deviate from true by more than the analytical precision if as little as 0.05% of the signal is not integrated, whereas the accuracy and precision of the double-spiked analyses are always linked.

  3. A new approach on measuring calcium isotopic compositions using 42Ca-43Ca double spike on Triton-TIMS

    NASA Astrophysics Data System (ADS)

    Zhang, Z.; Zhu, H.; Liu, Y.; Zhu, J.; Kang, J.; Tan, D.; Liu, F.; Wang, G.

    2013-12-01

    Geochemical investigations on non-traditional stable calcium isotopic compositions of natural samples would greatly provide useful information on understanding the details in all kinds of geological processes, such as to trace the geological reservoirs, to reconstruct the calcium isotopic compositions of paleo sea water and to discover paleoclimate changes, etc. With the development of modern instruments and new chemical separation procedures, it is possible to accurately measure δ44Ca using double spike technique on TIMS/MC-ICP-MS nowadays; however, robust methods are quite few in China. Here we gave an evaluation on selecting the double spike pairs, the best mixture ratio of the two single spikes and made our own 42Ca-43Ca double spike; we also developed and improved new chemical procedures for separating Ca from different kinds of natural sample matrixes, and set up a method for running Ca on the Triton TIMS. Our results confirmed that the calcium fractionation during TIMS runs follows the exponential law. The best sample/spike mixture ratio range was also carefully calculated based on the double spike information and samples were spiked strictly to make it fall in this range. Based on our new approach, a set of standards including 915a, seawater and a couple of USGS standards were measured in our laboratory in China. Recent results show that δ44Ca of 915a, seawater, BHVO-1, BIR-1 and Nod-P-1 yield an average value -0.04×0.13 (2 std. dev.) (n=19), 1.88×0.10 (n=10), 0.82×0.06 (n=10), 0.81×0.13 (n=10) and 0.77×0.10 (n=10) respectively with a whole procedure blank usually ranges from 50-150ng. The data are similar to those in literatures. In addition, our chemical procedures could also be highly employed for separating Mg, Sr and Ba simultaneously from sample matrixes.

  4. High-Precision Th-Pb Dating by Isotope-Dilution TIMS+MC-ICPMS - Preliminary Results

    NASA Astrophysics Data System (ADS)

    Ickert, R. B.; Mundil, R.; Sharp, W. D.

    2014-12-01

    Relative to the U-Pb decay series, the Th-Pb decay series has received relatively little attention for geochronology although it offers promising applications in both high-resolution geochronology as well as thermochronology. The limitations are partly because Th measurements by thermal ionization have proven notoriously difficult, and for many geochronological applications, the additional information provided by Th-Pb has not been worth the effort required. However, the current generation of MC-ICPMS instruments provides nearly two orders of magnitude better sensitivity of Th than TIMS, eliminating this barrier to measurement and opening up this chronometer for new use. We have developed a method to measure relative abundances of Th, U and Pb by isotope dilution for high-precision geochronology. This method leverages the strengths of two instruments, the high sensitivity and stable mass fractionation of MC-ICPMS instruments for Th and U, and the low background, lack of isobaric interference, and signal stability of TIMS instruments for Pb. To make these measurements, we have calibrated a new synthetic isotope tracer that comprises a mixture of 229Th-233U-236U-202Pb-205Pb. The analytical strategy developed for accessory minerals is a hybrid of techniques previously developed for U-Pb ID-TIMS and U/230Th ID-MC-ICPMS, with a two-column HCl-HNO3 anion exchange procedure (one to separate U and Pb from matrix+Th, and the other to separate Th from matrix), followed by a recombination of the U and Th fractions for MC-ICPMS analysis while the Pb fraction is measured by TIMS. Th-Pb measurements are complementary to, and potentially as precise as the U-Pb gold standard, and the method will find application in certain geological problems, including (1) precisely determining the relative decay rates of 232Th and 238U, (2) dating materials that are young enough to be substantially affected by 230Th or 231Pa disequilibria, and (3) dating small quantities of high-Th minerals like

  5. K-feldspar megacrysts growth and their link to the granitic mush: insight from high precision U-Pb dates (ID-TIMS) and trace elements (TIMS-TEA) on zircon

    NASA Astrophysics Data System (ADS)

    Barboni, M.; Schoene, B.

    2012-12-01

    K-feldspar megacrysts are common in granitic to granodioritic rocks though their origin and evolution is still poorly understood. Their occurrence seems to reflect a low nucleation rate relative to growth rate at low degrees of supersaturation. Though K-feldspar has been argued to be one of the last minerals to saturate in felsic magma, crystal mush may still contain 60-70% liquid at the initiation of crystallization. Therefore, abundant liquid might be available for development of large crystals early in the magma cooling process. The recent recognition that many granitoid plutons are built incrementally by many magma injections open new perspectives for K-feldspar megacrysts formation. Repeated replenishment, reheating and reinvigoration of the mush might play a significant role in making and preserving K-feldspar megacrysts. The Miocene Elba island intrusives (Italy) are famous for having some of the largest K-feldspar megacrysts ever found (up to 25 cm.). This young plutonic body emplaced incrementally at shallow crustal level (ca. 3km) and displays extensive evidence of interactions between magmas of contrasting compositions. We have sampled three different families of K-feldspar megacrysts occurring in different host rock and have combined U/Pb high precision dates (ID-TIMS) with trace elements (TIMS-TEA) and Hf isotopes of zircons that are included within the K-feldspar megacrysts and compared them to zircons from the host rock. Ages of zircon included in the megacrysts could document whether the crystals grew early in the magmatic system (inclusions older than the host rock) or late during the cooling history (similar ages within inclusions and host rock). Ti-in zircon thermometer combined with trace-elements signature could record slight differences between megacrysts and host rock zircons, documenting the development of the megacrysts in comparison with the one of the host granite. Strong field evidence support a magmatic/ phenocrystic origin for the Elba

  6. Simultaneous determination of the quantity and isotopic ratios of uranium in individual micro-particles by isotope dilution thermal ionization mass spectrometry (ID-TIMS).

    PubMed

    Park, Jong-Ho; Choi, Eun-Ju

    2016-11-01

    A method to determine the quantity and isotopic ratios of uranium in individual micro-particles simultaneously by isotope dilution thermal ionization mass spectrometry (ID-TIMS) has been developed. This method consists of sequential sample and spike loading, ID-TIMS for isotopic measurement, and application of a series of mathematical procedures to remove the contribution of uranium in the spike. The homogeneity of evaporation and ionization of uranium content was confirmed by the consistent ratio of n((233)U)/n((238)U) determined by TIMS measurements. Verification of the method was performed using U030 solution droplets and U030 particles. Good agreements of resulting uranium quantity, n((235)U)/n((238)U), and n((236)U)/n((238)U) with the estimated or certified values showed the validity of this newly developed method for particle analysis when simultaneous determination of the quantity and isotopic ratios of uranium is required.

  7. Simultaneous determination of the quantity and isotopic ratios of uranium in individual micro-particles by isotope dilution thermal ionization mass spectrometry (ID-TIMS).

    PubMed

    Park, Jong-Ho; Choi, Eun-Ju

    2016-11-01

    A method to determine the quantity and isotopic ratios of uranium in individual micro-particles simultaneously by isotope dilution thermal ionization mass spectrometry (ID-TIMS) has been developed. This method consists of sequential sample and spike loading, ID-TIMS for isotopic measurement, and application of a series of mathematical procedures to remove the contribution of uranium in the spike. The homogeneity of evaporation and ionization of uranium content was confirmed by the consistent ratio of n((233)U)/n((238)U) determined by TIMS measurements. Verification of the method was performed using U030 solution droplets and U030 particles. Good agreements of resulting uranium quantity, n((235)U)/n((238)U), and n((236)U)/n((238)U) with the estimated or certified values showed the validity of this newly developed method for particle analysis when simultaneous determination of the quantity and isotopic ratios of uranium is required. PMID:27591656

  8. Optimized Chemical Separation and Measurement by TE TIMS Using Carburized Filaments for Uranium Isotope Ratio Measurements Applied to Plutonium Chronometry.

    PubMed

    Sturm, Monika; Richter, Stephan; Aregbe, Yetunde; Wellum, Roger; Prohaska, Thomas

    2016-06-21

    An optimized method is described for U/Pu separation and subsequent measurement of the amount contents of uranium isotopes by total evaporation (TE) TIMS with a double filament setup combined with filament carburization for age determination of plutonium samples. The use of carburized filaments improved the signal behavior for total evaporation TIMS measurements of uranium. Elevated uranium ion formation by passive heating during rhenium signal optimization at the start of the total evaporation measurement procedure was found to be a result from byproducts of the separation procedure deposited on the filament. This was avoided using carburized filaments. Hence, loss of sample before the actual TE data acquisition was prevented, and automated measurement sequences could be accomplished. Furthermore, separation of residual plutonium in the separated uranium fraction was achieved directly on the filament by use of the carburized filaments. Although the analytical approach was originally tailored to achieve reliable results only for the (238)Pu/(234)U, (239)Pu/(235)U, and (240)Pu/(236)U chronometers, the optimization of the procedure additionally allowed the use of the (242)Pu/(238)U isotope amount ratio as a highly sensitive indicator for residual uranium present in the sample, which is not of radiogenic origin. The sample preparation method described in this article has been successfully applied for the age determination of CRM NBS 947 and other sulfate and oxide plutonium samples. PMID:27240571

  9. Optimized Chemical Separation and Measurement by TE TIMS Using Carburized Filaments for Uranium Isotope Ratio Measurements Applied to Plutonium Chronometry.

    PubMed

    Sturm, Monika; Richter, Stephan; Aregbe, Yetunde; Wellum, Roger; Prohaska, Thomas

    2016-06-21

    An optimized method is described for U/Pu separation and subsequent measurement of the amount contents of uranium isotopes by total evaporation (TE) TIMS with a double filament setup combined with filament carburization for age determination of plutonium samples. The use of carburized filaments improved the signal behavior for total evaporation TIMS measurements of uranium. Elevated uranium ion formation by passive heating during rhenium signal optimization at the start of the total evaporation measurement procedure was found to be a result from byproducts of the separation procedure deposited on the filament. This was avoided using carburized filaments. Hence, loss of sample before the actual TE data acquisition was prevented, and automated measurement sequences could be accomplished. Furthermore, separation of residual plutonium in the separated uranium fraction was achieved directly on the filament by use of the carburized filaments. Although the analytical approach was originally tailored to achieve reliable results only for the (238)Pu/(234)U, (239)Pu/(235)U, and (240)Pu/(236)U chronometers, the optimization of the procedure additionally allowed the use of the (242)Pu/(238)U isotope amount ratio as a highly sensitive indicator for residual uranium present in the sample, which is not of radiogenic origin. The sample preparation method described in this article has been successfully applied for the age determination of CRM NBS 947 and other sulfate and oxide plutonium samples.

  10. Aerolian erosion, transport, and deposition of volcaniclastic sands among the shifting sand dunes, Christmas Lake Valley, Oregon: TIMS image analysis

    NASA Technical Reports Server (NTRS)

    Edgett, Kenneth S.; Ramsey, Michael S.; Christensen, Philip R.

    1995-01-01

    Remote sensing is a tool that, in the context of aeolian studies, offers a synoptic view of a dune field, sand sea, or entire desert region. Blount et al. (1990) presented one of the first studies demonstrating the power of multispectral images for interpreting the dynamic history of an aeolian sand sea. Blount's work on the Gran Desierto of Mexico used a Landsat TM scene and a linear spectral mixing model to show where different sand populations occur and along what paths these sands may have traveled before becoming incorporated into dunes. Interpretation of sand transport paths and sources in the Gran Desierto led to an improved understanding of the origin and Holocene history of the dunes. With the anticipated advent of the EOS-A platform and ASTER thermal infrared capability in 1998, it will become possible to look at continental sand seas and map sand transport paths using 8-12 mu m bands that are well-suited to tracking silicate sediments. A logical extension of Blount's work is to attempt a similar study using thermal infrared images. One such study has already begun by looking at feldspar, quartz, magnetite, and clay distributions in the Kelso Dunes of southern California. This paper describes the geology and application of TIMS image analysis of a less-well known Holocene dune field in south central Oregon using TIMS data obtained in 1991.

  11. DAS Writeback: A Collaborative Annotation System

    PubMed Central

    2011-01-01

    Background Centralised resources such as GenBank and UniProt are perfect examples of the major international efforts that have been made to integrate and share biological information. However, additional data that adds value to these resources needs a simple and rapid route to public access. The Distributed Annotation System (DAS) provides an adequate environment to integrate genomic and proteomic information from multiple sources, making this information accessible to the community. DAS offers a way to distribute and access information but it does not provide domain experts with the mechanisms to participate in the curation process of the available biological entities and their annotations. Results We designed and developed a Collaborative Annotation System for proteins called DAS Writeback. DAS writeback is a protocol extension of DAS to provide the functionalities of adding, editing and deleting annotations. We implemented this new specification as extensions of both a DAS server and a DAS client. The architecture was designed with the involvement of the DAS community and it was improved after performing usability experiments emulating a real annotation task. Conclusions We demonstrate that DAS Writeback is effective, usable and will provide the appropriate environment for the creation and evolution of community protein annotation. PMID:21569281

  12. PER and TIM inhibit the DNA binding activity of a Drosophila CLOCK-CYC/dBMAL1 heterodimer without disrupting formation of the heterodimer: a basis for circadian transcription.

    PubMed

    Lee, C; Bae, K; Edery, I

    1999-08-01

    The Drosophila CLOCK (dCLOCK) and CYCLE (CYC) (also referred to as dBMAL1) proteins are members of the basic helix-loop-helix PAS (PER-ARNT-SIM) superfamily of transcription factors and are required for high-level expression of the circadian clock genes period (per) and timeless (tim). Several lines of evidence indicate that PER, TIM, or a PER-TIM heterodimer somehow inhibit the transcriptional activity of a putative dCLOCK-CYC complex, generating a negative-feedback loop that is a core element of the Drosophila circadian oscillator. In this report we show that PER and/or TIM inhibits the binding of a dCLOCK-CYC heterodimer to an E-box-containing DNA fragment that is present in the 5' nontranscribed region of per and acts as a circadian enhancer element. Surprisingly, inhibition of this DNA binding activity by PER, TIM, or both is not accompanied by disruption of the association between dCLOCK and CYC. The results suggest that the interaction of PER, TIM, or both with the dCLOCK-CYC heterodimer induces a conformational change or masks protein regions in the heterodimer, leading to a reduction in DNA binding activity. Together with other findings, our results strongly suggest that daily cycles in the association of PER and TIM with the dCLOCK-CYC complex probably contribute to rhythmic expression of per and tim.

  13. Constructing and Deconstructing Giftedness: A Reflective Conversation between Tim Dracup, Architect of England's National Gifted and Talented Education Programme from 1996 to 2009, and Barry Hymer, Professor of Psychology in Education, University of Cumbria, UK

    ERIC Educational Resources Information Center

    Hymer, Barry

    2014-01-01

    This conversation was prompted by a blog entry posted by Tim Dracup in January 2012. The subsequent e-exchange between Tim and Barry Hymer explored a number of issues central to the nature and aetiology of giftedness, confronting these issues from contrasting ontological and epistemological stances. As a result, their conversation includes…

  14. PD-1(hi)TIM-3(+) T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation.

    PubMed

    Kong, Y; Zhang, J; Claxton, D F; Ehmann, W C; Rybka, W B; Zhu, L; Zeng, H; Schell, T D; Zheng, H

    2015-07-31

    Prognosis of leukemia relapse post allogeneic stem cell transplantation (alloSCT) is poor and effective new treatments are urgently needed. T cells are pivotal in eradicating leukemia through a graft versus leukemia (GVL) effect and leukemia relapse is considered a failure of GVL. T-cell exhaustion is a state of T-cell dysfunction mediated by inhibitory molecules including programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3). To evaluate whether T-cell exhaustion and inhibitory pathways are involved in leukemia relapse post alloSCT, we performed phenotypic and functional studies on T cells from peripheral blood of acute myeloid leukemia patients receiving alloSCT. Here we report that PD-1(hi)TIM-3(+) cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1(hi)TIM-3(+) T cells are functionally deficient manifested by reduced production of interleukin 2 (IL-2), tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In addition, these cells demonstrate a phenotype consistent with exhausted antigen-experienced T cells by losing TN and TEMRA subsets. Importantly, increase of PD-1(hi)TIM-3(+) cells occurs before clinical diagnosis of leukemia relapse, suggesting their predictive value. Results of our study provide an early diagnostic approach and a therapeutic target for leukemia relapse post transplantation.

  15. The immune receptor Tim-3 mediates activation of PI3 kinase/mTOR and HIF-1 pathways in human myeloid leukaemia cells.

    PubMed

    Prokhorov, Alexandr; Gibbs, Bernhard F; Bardelli, Marco; Rüegg, Laura; Fasler-Kan, Elizaveta; Varani, Luca; Sumbayev, Vadim V

    2015-02-01

    The T-cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated protein that is highly expressed in human acute myeloid leukaemia cells. As an acute myeloid leukaemia antigen, it could therefore be considered as a potential target for immune therapy and highly-specific drug delivery. However, a conceptual understanding of its biological role is required before consideration of this protein for therapeutic settings. Here, we reveal the detailed mechanism of action underlying the biological responses mediated by the Tim-3 receptor in myeloid cells. Our studies demonstrate that Tim-3 triggers growth factor type responses in acute myeloid leukaemia cells by activating a phosphatidylinositol-3 kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. In addition, the receptor activates hypoxic signalling pathways upregulating glycolysis and pro-angiogenic responses. These findings suggest that Tim-3 could be used as a potential therapeutic target for immune therapy and drug delivery in human acute myeloid leukaemia cells.

  16. The nucleotide exchange factor MGE exerts a key function in the ATP-dependent cycle of mt-Hsp70-Tim44 interaction driving mitochondrial protein import.

    PubMed Central

    Schneider, H C; Westermann, B; Neupert, W; Brunner, M

    1996-01-01

    Import of preproteins into the mitochondrial matrix is driven by the ATP-dependent interaction of mt-Hsp70 with the peripheral inner membrane import protein Tim44 and the preprotein in transit. We show that Mge1p, a co-chaperone of mt-Hsp70, plays a key role in the ATP-dependent import reaction cycle in yeast. Our data suggest a cycle in which the mt-Hsp70-Tim44 complex forms with ATP: Mge1p promotes assembly of the complex in the presence of ATP. Hydrolysis of ATP by mt-Hsp70 occurs in complex with Tim44. Mge1p is then required for the dissociation of the ADP form of mt-Hsp70 from Tim44 after release of inorganic phosphate but before release of ADP. ATP hydrolysis and complex dissociation are accompanied by tight binding of mt-Hsp70 to the preprotein in transit. Subsequently, the release of mt-Hsp70 from the polypeptide chain is triggered by Mge1p which promotes release of ADP from mt-Hsp70. Rebinding of ATP to mt-Hsp70 completes the reaction cycle. Images PMID:8918457

  17. A TIM-3/Gal-9 Autocrine Stimulatory Loop Drives Self-Renewal of Human Myeloid Leukemia Stem Cells and Leukemic Progression.

    PubMed

    Kikushige, Yoshikane; Miyamoto, Toshihiro; Yuda, Junichiro; Jabbarzadeh-Tabrizi, Siamak; Shima, Takahiro; Takayanagi, Shin-ichiro; Niiro, Hiroaki; Yurino, Ayano; Miyawaki, Kohta; Takenaka, Katsuto; Iwasaki, Hiromi; Akashi, Koichi

    2015-09-01

    Signaling mechanisms underlying self-renewal of leukemic stem cells (LSCs) are poorly understood, and identifying pathways specifically active in LSCs could provide opportunities for therapeutic intervention. T-cell immunoglobin mucin-3 (TIM-3) is expressed on the surface of LSCs in many types of human acute myeloid leukemia (AML), but not on hematopoietic stem cells (HSCs). Here, we show that TIM-3 and its ligand, galectin-9 (Gal-9), constitute an autocrine loop critical for LSC self-renewal and development of human AML. Serum Gal-9 levels were significantly elevated in AML patients and in mice xenografted with primary human AML samples, and neutralization of Gal-9 inhibited xenogeneic reconstitution of human AML. Gal-9-mediated stimulation of TIM-3 co-activated NF-κB and β-catenin signaling, pathways known to promote LSC self-renewal. These changes were further associated with leukemic transformation of a variety of pre-leukemic disorders and together highlight that targeting the TIM-3/Gal-9 autocrine loop could be a useful strategy for treating myeloid leukemias. PMID:26279267

  18. IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer

    SciTech Connect

    Heon, Elise K.; Wulan, Hasi; Macdonald, Loch P.; Malek, Adel O.; Braunstein, Glenn H.; Eaves, Connie G.; Schattner, Mark D.; Allen, Peter M.; Alexander, Michael O.; Hawkins, Cynthia A.; McGovern, Dermot W.; Freeman, Richard L.; Amir, Eitan P.; Huse, Jason D.; Zaltzman, Jeffrey S.; Kauff, Noah P.; Meyers, Paul G.; Gleason, Michelle H.; Overholtzer, Michael G.; Wiseman, Sam S.; and others

    2015-08-14

    IL-15 has pivotal roles in the control of CD8{sup +} memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy. - Highlights: • We explored the effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells of breast cancer. • IL-15

  19. A new method integrating high-precision U-Pb geochronology with zircon trace element analysis (U-Pb TIMS-TEA)

    NASA Astrophysics Data System (ADS)

    Schoene, B.; Latkoczy, C.; Schaltegger, U.; Günther, D.

    2010-12-01

    Increased precision in isotope-dilution thermal ionization mass spectrometry (ID-TIMS) U-Pb geochronology has revealed age complexities in zircon populations that require new tools for understanding how the growth of zircon is related to geologic processes. U and Pb are routinely separated from other elements in dated minerals by ion exchange separation prior to TIMS isotope measurement. We develop a method in which trace elements in the exact same volume of zircon are redissolved and analyzed using solution nebulization inductively coupled plasma sector-field mass spectrometry with matrix-matched external liquid calibration. Using <0.5 ml solution, resulting concentrations are between <1 ppt for elements such as Ti, Nb and Ta and tens of ppb for Zr. By analyzing a series of standard solutions, zircons and procedural blanks, we show that accurate measurements are performed on Zr, Hf, Y, Sc, and the HREE while low-concentration elements can be measured accurately to <5 ppt. We performed combined U-Pb ID-TIMS geochronology with trace element analysis (here called U-Pb TIMS-TEA) on zircons from eight volcanic rocks comprising several volcanic systems and one metamorphic sample. Similar to previous in situ trace element analyses, zircon geochemistry is distinct between different samples and records petrogenetic processes such as fractional crystallization, assimilation and/or magma mixing. Unique from in situ analysis, U-Pb TIMS-TEA can trace geochemical evolution in accessory minerals with adequate age precision to resolve magmatic processes in rocks at least 200 million years old. This provides a means to identify auto-, ante- and xenocrystic zircon and lead to more robust age interpretations in ID-TIMS U-Pb geochronology. One suite of Cretaceous andesitic zircons shows correlations in geochemistry and absolute time that record evolution of a magmatic system over ˜250 ka prior to eruption. Future work will combine U-Pb TIMS-TEA with solution isotopic analysis of Nd

  20. KIM-1-/TIM-1-mediated phagocytosis links ATG5-/ULK1-dependent clearance of apoptotic cells to antigen presentation.

    PubMed

    Brooks, Craig R; Yeung, Melissa Y; Brooks, Yang S; Chen, Hui; Ichimura, Takaharu; Henderson, Joel M; Bonventre, Joseph V

    2015-10-01

    Phagocytosis of apoptotic cells by both professional and semi-professional phagocytes is required for resolution of organ damage and maintenance of immune tolerance. KIM-1/TIM-1 is a phosphatidylserine receptor that is expressed on epithelial cells and can transform the cells into phagocytes. Here, we demonstrate that KIM-1 phosphorylation and association with p85 results in encapsulation of phagosomes by lipidated LC3 in multi-membrane organelles. KIM-1-mediated phagocytosis is not associated with increased ROS production, and NOX inhibition does not block LC3 lipidation. Autophagy gene expression is required for efficient clearance of apoptotic cells and phagosome maturation. KIM-1-mediated phagocytosis leads to pro-tolerogenic antigen presentation, which suppresses CD4 T-cell proliferation and increases the percentage of regulatory T cells in an autophagy gene-dependent manner. Taken together, these data reveal a novel mechanism of epithelial biology linking phagocytosis, autophagy and antigen presentation to regulation of the inflammatory response.

  1. dCLOCK is present in limiting amounts and likely mediates daily interactions between the dCLOCK-CYC transcription factor and the PER-TIM complex.

    PubMed

    Bae, K; Lee, C; Hardin, P E; Edery, I

    2000-03-01

    In Drosophila melanogaster four circadian clock proteins termed PERIOD (PER), TIMELESS (TIM), dCLOCK (dCLK), and CYCLE (CYC/dBMAL1) function in a transcriptional feedback loop that is a core element of the oscillator mechanism. dCLK and CYC are members of the basic helix-loop-helix (bHLH)/PAS (PER-ARNT-SIM) superfamily of transcription factors and are required for high-level expression of per and tim and repression of dClk, whereas PER and TIM inhibit dCLK-CYC-mediated transcription and lead to the activation of dClk. To understand further the dynamic regulation within the circadian oscillator mechanism, we biochemically characterized in vivo-produced CYC, determined the interactions of the four clock proteins, and calculated their absolute levels as a function of time. Our results indicate that throughout a daily cycle the majority of the dCLK present in adult heads stably interacts with CYC, indicating that CYC is the primary in vivo partner of dCLK. dCLK-CYC dimers are bound by PER and TIM during the late evening and early morning, suggesting the formation of a tetrameric complex with impaired transcriptional activity. Although dCLK is present in limiting amounts and CYC is by far the most abundant of the four clock proteins that have been examined, PER and TIM appear to interact preferentially with dCLK. Our results suggest that dCLK is the main component regulating the daily abundance of transcriptionally active dCLK-CYC complexes.

  2. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines.

    PubMed

    Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella; Chauvin, Joe-Marc; Sander, Cindy; Janjic, Bratislav; Tarhini, Ahmad A; Tawbi, Hussein A; Kirkwood, John M; Moschos, Stergios; Wang, Hong; Guillaume, Philippe; Luescher, Immanuel F; Krieg, Arthur; Anderson, Ana C; Kuchroo, Vijay K; Zarour, Hassane M

    2014-02-15

    Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid tumor antigen-specific CD8(+) T-cell responses detected ex vivo, however, tumor antigen-specific CD8(+) T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma. PMID:24343228

  3. Isotopic analysis of small Pb samples using MC-ICPMS: The limits of precision and comparison to TIMS

    NASA Astrophysics Data System (ADS)

    Amelin, Y.; Janney, P.; Chakrabarti, R.; Wadhwa, M.; Jacobsen, S. B.

    2008-12-01

    Multicollector ICP-MS is a mainstream method for precise isotopic analyses of large (over 10-8 g) quantities of Pb, and is becoming increasingly popular for very rapid, even if relatively imprecise, U-Pb dating of U-bearing minerals using laser ablation. At the same time, high precision U-Pb geo- and cosmo- chronology mainly utilizes isotope dilution thermal ionization mass spectrometry, recently enhanced by application of double spikes for both Pb and U. Here we explore the suitability of MC-ICPMS for analysis of 10-11-10-9 g quantities of radiogenic Pb, contained in small single grains of zircon and other U- bearing minerals, and in chondrules, refractory inclusions and mineral fractions from meteorites. Analyses were performed at the Geological Survey of Canada using a Nu Plasma with DSN-100 desolvating nebulizer, at Arizona State University using a Neptune with Apex nebulizer, and at Harvard University using an Isoprobe P with Apex nebulizer. A total ion yield of 0.4-0.5% was achieved in all three instruments in 2.5-4 minute analyses. The fractions of SRM-981 and SRM-983 standards, spiked with 202Pb-205Pb- 233U-235U [1], containing between 3*10-11 and 10-9 Pb, were analyzed in all three labs. Precision of 207Pb/206Pb ratios in SRM-981 was 0.1-0.3% for 3*10-11 g fractions, 0.03-0.1% for 10-10 g fractions, and 0.006-0.013% for 10-9 g fractions. Precision of the best MC-ICPMS analyses was similar to precision of average TIMS analyses from the same quantities of Pb. Reproducibility of analyses depends on accurate blank and background subtraction as much as on the counting statistics. A series of analyses of the same solution run within a short period of time (i.e. with constant background) yielded a reproducibility similar to that of TIMS, whereas the analyses of a series of separately prepared aliquots were less reproducible. Our data demonstrate that the quality of analyses of 10^11 - 10^9 g Pb fractions by modern MC-ICPMS approaches the quality of TIMS analyses

  4. Mineralogic variability of the Kelso Dunes, Mojave Desert, California derived from Thermal Infrared Multispectral Scanner (TIMS) data

    NASA Technical Reports Server (NTRS)

    Ramsey, Michael S.; Howard, Douglas A.; Christensen, Philip R.; Lancaster, Nicholas

    1993-01-01

    Mineral identification and mapping of alluvial material using thermal infrared (TIR) remote sensing is extremely useful for tracking sediment transport, assessing the degree of weathering and locating sediment sources. As a result of the linear relation between a mineral's percentage in a given area (image pixel) and the depth of its diagnostic spectral features, TIR spectra can be deconvolved in order to ascertain mineralogic percentages. Typical complications such as vegetation, particle size and thermal shadowing are minimized upon examination of dunes. Actively saltating dunes contain little to no vegetation, are very well sorted and lack the thermal shadows that arise from rocky terrain. The primary focus of this work was to use the Kelso Dunes as a test location for an accuracy analysis of temperature/emissivity separation and linear unmixing algorithms. Accurate determination of ground temperature and component discrimination will become key products of future ASTER data. A decorrelation stretch of the TIMS image showed clear color variations within the active dunes. Samples collected from these color units were analyzed for mineralogy, grain size, and separated into endmembers. This analysis not only revealed that the dunes contained significant mineralogic variation, but were more immature (low quartz percentage) than previously reported. Unmixing of the TIMS data using the primary mineral endmembers produced unique variations within the dunes and may indicate near, rather than far, source locales for the dunes. The Kelso Dunes lie in the eastern Mojave Desert, California, approximately 95 km west of the Colorado River. The primary dune field is contained within a topographic basin bounded by the Providence, Granite Mountains, with the active region marked by three northeast trending linear ridges. Although active, the dunes appear to lie at an opposing regional wind boundary which produces little net movement of the crests. Previous studies have estimated

  5. The Southern Urals Large Igneous Province with an age of approximately 1380 Ma: Precision U-Pb ID-TIMS constraints

    NASA Astrophysics Data System (ADS)

    Ronkin, Yu. L.; Tichomirowa, M.; Maslov, A. V.

    2016-06-01

    The formation of the Large Igneous Province (LIP) approximately 1380 Ma old in the South Urals was related to the Mashak riftogenic event in the Bashkir meganticlinorium, which was synchronous with the emplacement of different magmatic bodies (the Berdyaush pluton of rapakivi granites and associated rocks, the Main dike of the Bakal ore field, and the Medvedev, Guben, and Kusa massifs, among others) localized among sedimentary deposits of the Burzyan and Yurmatin Groups representing Lower and Middle Riphean type units of northern Eurasia. The U-Pb ID-TIMS age of 1379.6 Ma (MSWD = 1.3) obtained with an accuracy of ±2.9 Ma (confidence interval 95%) combined with the available published U-Pb ID-TIMS data constrain the age and duration of the Early-Middle Riphean pulse in the LIP formation in the Southern Urals.

  6. Biological and chemical assessment of M-Area process discharge to TIM's Branch, June 1985--December 1986

    SciTech Connect

    Carlton, W.H. ); Starkel, W.M.; Giffin, M.; Trapp, K.E. )

    1987-03-01

    The production facilities of M-Area process uranium, lithium, and aluminum into fuel and target components for nuclear reactors at the Savannah River Plant (SRP). These processes produce wastewaters that contain dissolved metals, solvents, and nitric acid. Beginning in July 1985, wastewater was diverted to the M-Area Liquid Effluent Treatment Facility (LETF), which treats the waste via precipitation, filtration, and neutralization. Major constituents of the LETF discharge include nitrate (as NaNO{sub 3}), phosphorus, total suspended solids, and trace amounts of aluminum, lead, nickel, iron, and uranium. In addition to the intermittent LETF discharge, the A-014 outfall also has received a continuous discharge of noncontact cooling water (700 to 2500 gpm) since 1982 and effluent from the M-Area Ground Water Recovery Action (MAGWRA) air stripper (375 gpm) since September 1985. These effluents consist of trace amounts of (trichloroethylene, tetrachloroethylene, and 1, 1, 1-trichloroethane) in the MAGWRA effluent. In June 1985, a chemical and biological monitoring program was initiated to determine if M-Area discharges are a significant environmental hazard to Tim's Branch. The main concerns are whether the discharge is toxic to aquatic life and whether high levels of nitrate in the discharge from the M-Area Liquid Effluent Treatment Facility (LETF) will cause eutrophication of the aquatic system.

  7. Evaluation of GO_CONS_GCF_2_TIM and GOCO01S Geopotential Models in Venezuela and Caribbean Region

    NASA Astrophysics Data System (ADS)

    Orihuela, N. D.; Garcia, A. D.; Tabare, T.; Scientific Team Of Venezuelan; Caribbean Crustal Study From Satellital Data

    2010-12-01

    This paper shows two maps of the magnitude of the surface gravity vector (MSGV) of Venezuela and Caribbean region at 1:500.000 scale in the geographic window between the 0-20 north latitude and 74-58 western longitude (Fig. 1 and Fig. 2), that were generated from GOCE gravity gradients data provided by the European Space Agency (ESA). The maps that are showed come from the combined global gravity field model GOCO01s [GOCO Consortium., 2010] and from the satellite-only global gravity field model GO_CONS_GCF_2_TIM [Pail et al., 2010], both of 224 degree. The DEMs used for the evaluation of the MSGV are: Etopo2v2 [NGDC., 2006] and Etopo1 [Amante and Eakins, 2009] respectively. The data processing was done using: Shm2func [ICGEM., 2007]; Goce User Toolbox [ESA., 2009]; Gravsoft package [Tscherning et al., 1992] and Oasis Montaj (Geosoft). This research shows a review of observed gravity in the main geological provinces of the Venezuela and Caribbean region geography, revealing gravitational features important of the geological structures that are in Venezuelan and Caribbean subsurface.

  8. Effects of a high fat meal matrix and protein complexation on the bioaccessibility of blueberry anthocyanins using the TNO gastrointestinal model (TIM-1)

    PubMed Central

    Ribnicky, David M.; Roopchand, Diana E.; Oren, Andrew; Grace, Mary; Poulev, Alexander; Lila, Mary Ann; Havenaar, Robert; Raskin, Ilya

    2014-01-01

    The TNO intestinal model (TIM-1) of the human upper gastrointestinal tract was used to compare intestinal absorption/bioaccessibility of blueberry anthocyanins under different digestive conditions. Blueberry polyphenol-rich extract was delivered to TIM-1 in the absence or presence of a high-fat meal. HPLC analysis of seventeen anthocyanins showed that delphinidin-3-glucoside, delphinidin-3-galactoside, delphinidin-3-arabinoside and petunidin-3-arabinoside were twice as bioaccessible in fed state, whilst delphinidin-3-(6″-acetoyl)-glucoside and malvidin-3-arabinoside were twice as bioaccessible under fasted conditions, suggesting lipid-rich matrices selectively effect anthocyanin bioaccessibility. TIM-1 was fed blueberry juice (BBJ) or blueberry polyphenol-enriched defatted soybean flour (BB-DSF) containing equivalent amounts of free or DSF-sorbed anthocyanins, respectively. Anthocyanin bioaccessibility from BB-DSF (36.0 ± 10.4) was numerically, but not significantly, greater than that from BBJ (26.3 ± 10.3). Ileal efflux samples collected after digestion of BB-DSF contained 2.8-fold more anthocyanins than same from BBJ, suggesting that protein-rich DSF protects anthocyanins during transit through upper digestive tract for subsequent colonic delivery/metabolism. PMID:24001852

  9. Application of Thermal Infrared Multiband Scanner (TIMS) data to mapping of Plutonic and stratified rock and assemblages in accreted terrains of the Northern Sierra, California

    NASA Technical Reports Server (NTRS)

    Taranik, James V.; Davis, David; Borengasser, Marcus

    1986-01-01

    The Thermal Infrared Multispectral Scanner (TIMS) data were acquired over the Donner Pass area in California on September 12, 1985. The higher peaks in the area approach 9,200 feet in elevation, while the canyon of the north fork of the American River is only 3000 feet in elevation. The vegetation is dominated by conifers, although manzanita and other shrubs are present in areas where soils have developed. The data contain noise patterns which cut across scan lines diagonally. The TIMS data were analyzed using both photointerpretative and digital processing techniques. Preliminary image interpretation and field analysis confirmed that TIMS image data displays the chert units and silicic volcanics as bright red. The imagery appears to display zoning in the batholithic and hypabyssal intrusive rocks, although this was not field checked at this time. Rocks which appear to be more dioritic in composition appear purple on the imagery, while rocks more granitic in composition appear shades of red and pink. Areas that have more than 40% vegetative cover appear green on the imagery.

  10. IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

    PubMed

    Heon, Elise K; Wulan, Hasi; Macdonald, Loch P; Malek, Adel O; Braunstein, Glenn H; Eaves, Connie G; Schattner, Mark D; Allen, Peter M; Alexander, Michael O; Hawkins, Cynthia A; McGovern, Dermot W; Freeman, Richard L; Amir, Eitan P; Huse, Jason D; Zaltzman, Jeffrey S; Kauff, Noah P; Meyers, Paul G; Gleason, Michelle H; Overholtzer, Michael G; Wiseman, Sam S; Streutker, Catherine D; Asa, Sylvia W; McAlindon, Timothy P; Newcomb, Polly O; Sorensen, Poul M; Press, Oliver A

    2015-08-14

    IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.

  11. A Multi-Method Approach to Improving Monazite Geochronology: TIMS, LA-ICP-MS, SIMS and EPMA

    NASA Astrophysics Data System (ADS)

    Peterman, E. M.; Hacker, B. R.; Grove, M.; Gehrels, G. E.; Mattinson, J. M.

    2006-12-01

    A challenging aspect of monazite U-Th-Pb analysis by LA-ICPMS or other `in situ' methods relates to how to appropriately standardize measured inter-element ratios in this compositionally variable phase. A major impediment is the lack of widely available and compositionally appropriate standards. At UCSB, we have characterized three monazite samples: `Madagascar' (B. Schultz), `Jefferson County' (M. Bersch), and `Smithsonian' (Smithsonian Institution). Grains were analyzed by multicollector ID-TIMS in the static multi- collection mode to establish precise U-Pb ages. Inclusion free grains from each sample were fully digested in HCl and loaded onto filaments using silica gel. We obtained 206Pb/238U ages of 363.98 ± 0.74 Ma for the Jefferson County monazite, 511.25 ± 4.91 Ma for the Madagascar sample and 274.58 ± 0.58 Ma for the Smithsonian sample. Jefferson County and Madagascar are reversely discordant, which is partly attributed to `excess' 206Pb from the decay of 230Th. U, Th, and Pb isotopic measurements were undertaken by multicollector LA-ICPMS at UA. The He carrier gases have sufficiently low Hg abundance that any Hg in the 204 mass position was subtracted by measuring on-peak backgrounds prior to sample analysis. Using the well-characterized monazite sample `44069' (J. Aleinikoff) as a primary standard, we obtained 206Pb/238U of 365.5 ± 2.6 Ma for Jefferson County, 1416 ± 29 Ma for Madagascar, and 357.1 ± 4.9 Ma for Smithsonian. Measured Th-Pb ages were 360.0 ± 4.6 Ma, 1345 ± 39 Ma, and 262.1 ± 4.1 Ma respectively. Ion microprobe Th-Pb ages obtained at UCLA from the same materials were 411 ± 12 Ma, 571 ± 18 Ma, and 327 ± 16 Ma using 44069 as a standard. The discrepancies among U-Pb and Th-Pb ages measured with the three methods clearly indicates that we have much to learn regarding standard-based in situ analysis of monazite. To quantify polyatomic species interference on targeted masses, we analyzed a synthetic CePO4 on the LA-ICPMS at UA. Data

  12. GHRSST-14 DAS-TAG Report

    NASA Technical Reports Server (NTRS)

    Armstrong, Edward; Piolle, Jean Francois

    2013-01-01

    The DAS-TAG provides the informatics and data management expertise in emerging information technologies for the GHRSST community. It provides expertise in data and metadata formats and standards, fosters improvements for GHRSST data curation, experiments with new data processing paradigms, and evaluates services and tools for data usage. It provides a forum for producer and distributor data management issues and coordination.

  13. Physik gestern und heute Das Eiskalorimeter

    NASA Astrophysics Data System (ADS)

    Heering, P.

    2003-07-01

    Kalorimetrische Messungen gehören heute zum experimentellen Standardrepertoire im Bereich der Thermodynamik und der physikalischen Chemie. Das erste Gerät für derartige Messungen entwickelten Ende des 18. Jahrhunderts die französischen Wissenschaftler Antoine Laurent Lavoisier und Pierre Simon de Laplace.

  14. The intramolecular mechanism for the second proton transfer in triosephosphate isomerase (TIM): a QM/FE approach.

    PubMed

    Alagona, Giuliano; Ghio, Caterina; Kollman, Peter A

    2003-01-15

    The intramolecular mechanism we earlier proposed [Alagona, G.; Desmeules, P.; Ghio, C.; Kollman, P. A. J Am Chem Soc 1984, 106, 3623] for the second proton transfer of the reaction catalyzed by triosephosphate isomerase (TIM) is examined ab initio at the HF and MP2/6-31+G** levels in vacuo for two conformers of the enediolate phosphate (ENEP), with the ethereal oxygen of the phosphate group either syn (X), as in the crystal structure, or anti (Y) with respect to the enediolate carbonyl O. The barrier height for the intramolecular proton transfer occurring in enediolate is very sensitive to electron correlation corrections. The MP2 internal energy barrier is much lower than the HF one, while the free energy (FE) barrier is even more favorable, indicating that the enzyme presence is not requested to speed up that step. An investigation of the dynamical aspects of the mechanism, along the pathway from ENEP A (with H on O(1)) to TS and from TS to ENEP B (with H on O(2)), was, however, carried out in the presence of the enzyme field while using a neutral His-95 with its proton on Ndelta. To perform the FE simulations, it was necessary to parametrize in the AMBER force-field the ENEP A, TS and B species, whose partial charges have been determined with the RESP procedure, with the X and Y arrangements of the phosphate head. Actually, the FE/QM approach produced a low barrier and a substantial balance between A and B, especially at the MP2 level. The trajectories, analyzed paying a particular attention to the positions assumed by His-95 and by the other active site residues, put forward somewhat different H-bond patterns around the X or Y enediolate phosphate.

  15. Relationship between Blood Pressure and Outcomes in Acute Ischemic Stroke Patients Administered Lytic Medication in the TIMS-China Study

    PubMed Central

    Zhao, Xingquan; Liao, Xiaoling; Wang, Chunjuan; Pan, Yuesong; Wang, Yilong; Wang, Yongjun

    2016-01-01

    Objective Increased blood pressure (BP) management following acute ischemic stroke (AIS) remains controversial. This study aimed to identify the association between BP and clinical outcomes in AIS patients administered lytic medication in the TIMS-China (thrombolysis implementation and monitor of acute ischemic stroke in China) database. Methods The sample comprised 1128 patients hospitalized within 4.5 hours (h) of AIS for intravenous recombinant tissue plasminogen activator (i.v. rt-PA) thrombolysis. Systolic BP (SBP) and diastolic BP (DBP) at baseline, 2 h and 24 h after treatment, and changes from baseline were analyzed. The study outcomes comprised a favorable outcome (modified Rankin Scale 0–1 at 90 days) and symptomatic intracerebral hemorrhage (SICH), analyzed using logistic regression, with low BP as the reference group. Results Lower BP (baseline, 2 h, and 24 h) was beneficial in AIS patients and significantly related to a favorable outcome (P<0.05). A substantial BP decrease at 24 h after rt-PA thrombolysis was significantly associated with a favorable outcome compared with a moderate BP decrease (P = 0.0298). A SBP >160 mmHg 2 h after rt-PA thrombolysis was significantly associated with SICH compared with a SBP <140 mmHg (P = 0.0238). An increase or no change (>25 mmHg) in SBP was significantly associated with SICH (P = 0.002) compared with a small SBP decrease (1–9 mmHg). Conclusions This study provides novel evidence that lower BP within the first 24 h is associated with a more favorable outcome and less frequent SICH in AIS patients administered lytic medication. Routine BP-lowering treatment should be considered in AIS patients following lytic medication. PMID:26828609

  16. New Ca-Tims and La-Icp Analyses of GJ-1, Plesovice, and FC1 Reference Materials

    NASA Astrophysics Data System (ADS)

    Feldman, J. D.; Möller, A.; Walker, J. D.

    2014-12-01

    Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) U-Pb zircon geochronology relies on external reference standards to monitor and correct for different mass fractionation effects and instrument drift. Common zircon reference materials used within the community, including the KU Isotope Geochemistry Laboratory, are GJ-1 (207Pb/206Pb age: 608.53 +/- 0.37Ma; Jackson et al., 2004), Plesovice (337.13 +/- 0.37 Ma; Slama et al., 2008), and FC-1 (1099.0 +/-0.6 Ma; Paces and Miller, 1993). The age distribution of zircon reference material varies slightly from sample fraction to sample fraction, and the published results for GJ-1 are slightly discordant. As a result, using the published data for the distributed standard splits can lead to small systematic variations when comparing datasets from different labs, and more high precision data are needed to evaluate potential inhomogeneity of sample splits used in different laboratories. Here we characterize these reference materials with cathodoluminescence, LA-ICP-MS traverses across grains, and high precision CA-TIMS to better constrain the ages and assess zoning of these standards, and present the data for comparison with other laboratories. Reducing systematic error by dating our own reference material lends confidence to our analyses and allows for inter-laboratory age reproducibility of unknowns. Additionally, the reduction in propagated uncertainties (especially in GJ-1, for which both the red and yellow variety will be analyzed) will be used to improve long-term reproducibility, comparisons between samples of similar age, detrital populations and composite pluton zircons. Jackson, S.E., et al., 2004, Chemical Geology, v. 211, p. 47-69. Paces, J.B. & Miller, J.D., 1993, Journal of Geophysical Research, v. 80, p. 13997-14013. Slama, J., et al., 2008, Chemical Geology, v. 249. p. 1-35.

  17. Targeting PD-1 and Tim-3 Pathways to Reverse CD8 T-Cell Exhaustion and Enhance Ex Vivo T-Cell Responses to Autologous Dendritic/Tumor Vaccines.

    PubMed

    Liu, Jingwei; Zhang, Shurong; Hu, Yuefeng; Yang, Zhaomin; Li, Jingpo; Liu, Xuesong; Deng, Lijuan; Wang, Yue; Zhang, Xiaoyan; Jiang, Ting; Lu, Xu

    2016-05-01

    The paradoxical coexistence of spontaneous tumor antigen-specific immune response with progressive disease in cancer patients need to dissect the molecular pathways involved in tumor-induced T-cell dysfunction or exhaustion. Programmed cell death 1 (PD-1) has been identified as a marker of exhausted T cells in chronic disease states, and blockade of PD-1-PD-L1 interactions has been shown to partially restore T-cell function. We have found that T-cell immunoglobulin mucin (Tim) 3 is expressed on CD8+ tumor-infiltrating lymphocytes (TILs) isolated from patients with colorectal cancer. All T-cell immunoglobulin mucin 3 (Tim-3+) TILs coexpress PD-1, and Tim-3+ PD-1+ CD8+ TILs represent the predominant fraction of Tcells infiltrating tumors. Tim-3+PD-1+ CD8+ TILs exhibit the most severe exhausted phenotype as defined by failure to produce cytokines, such as interferon-γ, tumor necrosis factor-α, and interleukin-2. We further find that combined targeting of the Tim-3 and PD-1 pathways increased the frequencies of not only interferon-γ and tumor necrosis factor-α but also frequencies of proliferating tumor antigen-specific CD8+ T cells than targeting either pathway alone. A concomitant decrease in regulatory T cells and enhanced killing in a cytotoxicity assay was observed. Collectively, our findings support the use of Tim-3-Tim-3L blockade together with PD-1-PD-L1 blockade to reverse tumor-induced T-cell exhaustion/dysfunction in patients with colorectal cancer.

  18. High-Resolution Zircon U-Pb CA-TIMS Dating of the Carboniferous—Permian Successions, Paraná Basin, Brazil

    NASA Astrophysics Data System (ADS)

    Griffis, N. P.; Mundil, R.; Montanez, I. P.; Isbell, J.; Fedorchuk, N.; Lopes, R.; Vesely, F.; Iannuzzi, R.

    2015-12-01

    The late Paleozoic Ice Age (LPIA) is Earth's only record of a CO2-forced climatic transition from an icehouse to greenhouse state in a vegetated world. Despite a refined framework of Gondwanan ice distribution, questions remain about the timing, volume, and synchronicity of high-latitude continental ice and the subsequent deglaciation. These questions ultimately preclude our understanding of linkages between ice volume, sea level, and high- and low-latitude climate. Poor constraints on the timing and synchronicity of glacial and interglacial transitions reflect a lack of high-resolution radioisotopic dates from high-latitude, ice-proximal Carboniferous-Permian successions. The Rio Bonito Fm in Rio Grande do Sul State of southern Brazil hosts the oldest non-glaciogenic Carboniferous- Permian deposits of the Paraná Basin, thus recording the icehouse-to-greenhouse transition. Despite a widespread effort over the last two decades to constrain these deposits in time by means of U-Pb zircon geochronology, published data sets of the Candiota and Faxinal coals of the Rio Bonito Fm host discrepancies that may reflect post- eruptive open system behavior of zircon and analytical artifacts. These discrepancies have hindered the correlation of the Candiota and Faxinal sediments within the larger Gondwanan framework. Here we present the first U-Pb ages on closed system single zircons using CA-TIMS techniques on Permo-Carboniferous ash deposits of the Paraná Basin. Preliminary results indicate two major and distinct coal-forming periods that are separated by ca 10 Ma. Our results and conclusions are not in agreement with multi- crystal U-Pb TIMS and SIMS ages that suggest coeval deposition of the Candiota and Faxinal coals. CA-TIMS analyses applied to zircons from additional ash deposits are aimed at constructing a robust chronostratigraphic framework for the Carboniferous- Permian succession of the Paraná Basin, which will facilitate a better understanding of the timing and

  19. Moisture Forecast Bias Correction in GEOS DAS

    NASA Technical Reports Server (NTRS)

    Dee, D.

    1999-01-01

    Data assimilation methods rely on numerous assumptions about the errors involved in measuring and forecasting atmospheric fields. One of the more disturbing of these is that short-term model forecasts are assumed to be unbiased. In case of atmospheric moisture, for example, observational evidence shows that the systematic component of errors in forecasts and analyses is often of the same order of magnitude as the random component. we have implemented a sequential algorithm for estimating forecast moisture bias from rawinsonde data in the Goddard Earth Observing System Data Assimilation System (GEOS DAS). The algorithm is designed to remove the systematic component of analysis errors and can be easily incorporated in an existing statistical data assimilation system. We will present results of initial experiments that show a significant reduction of bias in the GEOS DAS moisture analyses.

  20. Uncle Tim's Dilemma

    ERIC Educational Resources Information Center

    DiBiase, Warren

    2009-01-01

    In this investigation, students make predictions and observations of a counterintuitive phenomenon. Given the scenario of a boat filled with a set of large rocks placed in a swimming pool, the students investigate what happens to both the water level in the pool and the level at which the boat floats when the rocks are taken out of the boat and…

  1. Mechanistic and bioinformatic investigation of a conserved active site helix in α-isopropylmalate synthase from Mycobacterium tuberculosis, a member of the DRE-TIM metallolyase superfamily.

    PubMed

    Casey, Ashley K; Hicks, Michael A; Johnson, Jordyn L; Babbitt, Patricia C; Frantom, Patrick A

    2014-05-13

    The characterization of functionally diverse enzyme superfamilies provides the opportunity to identify evolutionarily conserved catalytic strategies, as well as amino acid substitutions responsible for the evolution of new functions or specificities. Isopropylmalate synthase (IPMS) belongs to the DRE-TIM metallolyase superfamily. Members of this superfamily share common active site elements, including a conserved active site helix and an HXH divalent metal binding motif, associated with stabilization of a common enolate anion intermediate. These common elements are overlaid by variations in active site architecture resulting in the evolution of a diverse set of reactions that include condensation, lyase/aldolase, and carboxyl transfer activities. Here, using IPMS, an integrated biochemical and bioinformatics approach has been utilized to investigate the catalytic role of residues on an active site helix that is conserved across the superfamily. The construction of a sequence similarity network for the DRE-TIM metallolyase superfamily allows for the biochemical results obtained with IPMS variants to be compared across superfamily members and within other condensation-catalyzing enzymes related to IPMS. A comparison of our results with previous biochemical data indicates an active site arginine residue (R80 in IPMS) is strictly required for activity across the superfamily, suggesting that it plays a key role in catalysis, most likely through enolate stabilization. In contrast, differential results obtained from substitution of the C-terminal residue of the helix (Q84 in IPMS) suggest that this residue plays a role in reaction specificity within the superfamily.

  2. Digestion of cooked meat proteins is slightly affected by age as assessed using the dynamic gastrointestinal TIM model and mass spectrometry.

    PubMed

    Denis, S; Sayd, T; Georges, A; Chambon, C; Chalancon, S; Santé-Lhoutellier, V; Blanquet-Diot, S

    2016-06-15

    In humans, meat ensures the supply of proteins with high nutritional value and indispensable amino acids. The main goal of the present study was to compare the degradation of meat proteins in adult and elderly digestive conditions. Cooked meat was subjected to in vitro digestion in the dynamic multi-compartmental TIM (TNO gastroIntestinal Model) system. Digestibility and bioaccessibility were determined using nitrogen balance and digestion products were identified using mass spectrometry. The TIM model was adapted according to in vivo data to mimic the specific digestive conditions of elderly people. Meat protein digestibility and bioaccessibility were around 96 and 60% respectively and were not influenced by age (P > 0.05). As much as 800 peptides were identified in the duodenal and jejunal compartments issued from 50 meat proteins with a percentage of coverage varying from 13 to 69%. Six proteins, mainly from the cytosol, were differentially hydrolyzed under the adult and elderly digestive conditions. Pyruvate kinase was the only protein clearly showing a delay in its degradation under elderly digestive conditions. This study provides significant insights into the understanding of meat protein dynamic digestion. Such data will be helpful to design in vivo studies aiming to evaluate dietary strategies that can attenuate muscle mass loss and more generally maintain a better quality of life in the elderly population.

  3. Das CARNOTsche Paradigma und seine erkenntnistheoretischen Implikationen

    NASA Astrophysics Data System (ADS)

    Schöpf, Hans-Georg

    Der vorliegende historisch-kritische Essay führt die Eigentümlichkeiten der klassischen phänomenologischen Thermodynamik auf das von CARNOT geschaffene Paradigma zurück und greift einige damit zusammenhängende Fragen auf.Translated AbstractCARNOT's Paradigm and its Epistemological ImplicationsThe present historic-critical essay traces the pecularities of classical phenomenological thermodynamics back to the paradigm, created by CARNOT, and takes up some questions to which this paradigm gives rise.

  4. U-Pb Dating of CA/non-CA Treated Zircons Obtained by LA-ICP-MS and CA-TIMS Techniques: Impact for their Geological Interpretation

    NASA Astrophysics Data System (ADS)

    Von Quadt, A.; Gallhofer, D.; Guillong, M.; Peytcheva, I.

    2014-12-01

    Chemical Abrasion Isotope-Dilution Thermal Ionization Mass Spectrometry (CA-ID-TIMS) is known as a high precision technique for resolving lead loss and improving the interpretation of U-Pb zircon age data. We argue that combining CA with the widely applied Laser Ablation-Inductively Coupled Plasma-Mass Spectrometry (LA-ICP-MS) improves the precision and accuracy of zircon dates, while removing the substantial parts with lead loss, reducing data scatter, and providing meaningful geological interpretations. The samples are magmatic rocks chosen from different geological time periods (Paleozoic, Mesozoic and Cenozoic time). All zircon separates are analysed by LA-ICP-MS before and after CA, and all age data are compared with CA-ID-TIMS 206Pb/238U dates that are considered as the most accurately age. All CA-treated zircon crystals show up to 50% less data scatter compared to the non-CA treated zircon grains and thus a reduction of the calculated uncertainties is apparent. The obtained wt average LA-ICP-MS 206Pb/238U ages of the CA-treated zircon grains are up to 4-6% higher than those of the non-CA treated crystals, exceeding the analytical uncertainties of the LA-ICP-MS dating technique of 1-2%. The damaged crystal parts, caused by U-decay, with lead loss are removed, so that we can exclude younging from the possible geological scenarios. CA-LA-ICP-MS age data are in good agreement with the CA-ID-TIMS dates and suggest advantages of using CA-LA-ICP-MS in order to define accurate ages. The use of the CA technique for very young zircons (~0.2 Ma, Kos rhyolitic tuff, Greece) seems optional; as the obtained mean 206Pb/238U ages of non-CA and CA treated zircons coincide within the uncertainty. The negligible time to produce the lattice damage (based on alpha decay or spontaneous fission) makes lead loss less important for age dating and data interpretation of very young zircons (<1 Ma). Von Quadt, A. et al., 2014, JAAS, doi: 10.1039/c4ja00102h.

  5. Rates of magma differentiation and emplacement in a ballooning pluton recorded by U-Pb TIMS-TEA, Adamello batholith, Italy

    NASA Astrophysics Data System (ADS)

    Schoene, Blair; Schaltegger, Urs; Brack, Peter; Latkoczy, Christopher; Stracke, Andreas; Günther, Detlef

    2012-11-01

    Geochemical, structural, field, and geochronological data have been used to arrive at very different models for the construction of upper crustal batholiths. Models for pulsed intrusion of small magma batches over long timescales (>1 Ma) versus transfer of larger magma bodies on shorter timescales predict a different thermal, metamorphic, and rheological state of the crust, highlighting the importance of robust time constraints. This study focuses on a well-characterized upper crustal intrusion, the 15 km2 Lago della Vacca complex (LVC), Adamello batholith, N. Italy. Previous studies used structural and petrologic data to argue that the LVC was emplaced through pulsed magma injection and in situ expansion (or, ballooning) of a short lived (˜ 105 yr) magma chamber. We test this model using a dense sampling strategy and high-precision ID-TIMS U-Pb geochronology of zircon and titanite combined with hafnium isotope and trace element analyses of the same volume of dated mineral (U-Pb TIMS-TEA). These data show that the marginal mafic pulses of magma crystallized zircon with primitive Hf isotopes and negligible Eu anomalies during fractional crystallization and ascent through the crust on 10-30 ka timescales. Subsequent, more felsic pulses yield individual zircon dates spanning as much as 200 ka within single handsamples and restrict the total construction time of the LVC to <300 ka. Rim to core solidification of the LVC, as recorded by titanite U-Pb thermochronology, occurred in ≥300 ka. U-Pb TIMS-TEA data from these complicated zircon populations limit the sources of antecrystic zircon, constrain AFC processes within host magmas, and illustrate the difficulty in interpreting zircon dates as magma emplacement ages. These data are supportive of growth of the LVC by a pulsed ballooning-type process over ˜300 ka, with the restriction that the rims of the LVC had solidified prior to the center-most injection, providing important constraints for thermomechanial models

  6. Chlorine Isotopes: As a Possible Tracer of Fluid/Bio-Activities on Mars and a Progress Report on Chlorine Isotope Analysis by TIMs

    NASA Technical Reports Server (NTRS)

    Nakamura, N.; Nyquist, L.E.; Reese, Y.; Shih, C-Y.; Numata, M.; Fujitani, T.; Okano, O.

    2009-01-01

    Significantly large mass fractionations between chlorine isotopes (Cl-35, Cl-37) have been reported for terrestrial materials including both geological samples and laboratory materials. Also, the chlorine isotopic composition can be used as a tracer for early solar system processes. Moreover, chlorine is ubiquitous on the Martian surface. Typical chlorine abundances in Gusev soils are approx.0.5 %. The global surface average chlorine abundance also is approx.0.5 %. Striking variations among outcrop rocks at Meridiani were reported with some chlorine abundances as high as approx.2%. Characterizing conditions under which chlorine isotopic fractionation may occur is clearly of interest to planetary science. Thus, we have initiated development of a chlorine isotopic analysis technique using TIMS at NASA-JSC. We present here a progress report on the current status of development at JSC and discuss the possible application of chlorine isotopic analysis to Martian meteorites in a search for fluid- and possibly biological activity on Mars.

  7. Evaluation of changes in the element content and biomass of invaded with Meloidogyne arenaria Tiny Tim tomato plants under NH4VO3 treatment.

    PubMed

    Damianova, Anna; Baicheva, Olga; Salkova, Delka; Sivriev, I; Lihareva, Nadejda

    2003-01-01

    The parasite-host system Meloidogyne arenaria--Tiny Tim tomato plants has been studied in order to investigate the influence of the process of invasion on the chemical composition and biomass of plants. The concentrations of seven chemical elements Cu, Zn, Mg, K, Na, Mn and Fe have been determined using AAS in controls and invaded plants, and their changes have been evaluated under treatment with NH4VO3 in three different concentrations 0.01, 0.1 and 0.13 mg/100 ml H2O. The process of treatment with NH4VO3 disbalances significantly the trace element content of plants. The lowest concentration (0.01 mg NH4VO3) causes bigger changes in the concentrations of Mn, Fe and Na in non-invaded plants. The highest concentration (0.13 mg NH4VO3) balances the content of the elements back to their levels in the control plants for the elements Zn, Fe and Na. The pure effect of the process of invasion with Meloidogyne arenaria on the biomass (leaves, stems, roots and total biomass) of Tiny Tim plants is expressed in a significant increasing, mainly due to the development of the parasites. After treatment with different concentrations of NH4VO3 the decreasing in the biomass of leaves, stems and roots is observed which reflects on the total biomass of plants. The concentration of NH4VO3 eliminates the unfavourable changes not only in the chemical content of plants but also in their biomass. It could be taken into consideration as an alternative method used instead of treatment with nematocides.

  8. Clusters of branched aliphatic side chains serve as cores of stability in the native state of the HisF TIM barrel protein.

    PubMed

    Gangadhara, Basavanapura N; Laine, Jennifer M; Kathuria, Sagar V; Massi, Francesca; Matthews, C Robert

    2013-03-25

    Imidazole-3-glycerol phosphate synthase is a heterodimeric allosteric enzyme that catalyzes consecutive reactions in imidazole biosynthesis through its HisF and HisH subunits. The unusually slow unfolding reaction of the isolated HisF TIM barrel domain from the thermophilic bacteria, Thermotoga maritima, enabled an NMR-based site-specific analysis of the main-chain hydrogen bonds that stabilize its native conformation. Very strong protection against exchange with solvent deuterium in the native state was found in a subset of buried positions in α-helices and pervasively in the underlying β-strands associated with a pair of large clusters of isoleucine, leucine and valine (ILV) side chains located in the α7(βα)8(βα)1-2 and α2(βα)3-6β7 segments of the (βα)8 barrel. The most densely packed region of the large cluster, α3(βα)4-6β7, correlates closely with the core of stability previously observed in computational, protein engineering and NMR dynamics studies, demonstrating a key role for this cluster in determining the thermodynamic and structural properties of the native state of HisF. When considered with the results of previous studies where ILV clusters were found to stabilize the hydrogen-bonded networks in folding intermediates for other TIM barrel proteins, it appears that clusters of branched aliphatic side chains can serve as cores of stability across the entire folding reaction coordinate of one of the most common motifs in biology.

  9. Radiogenic Isotopes As Paleoceanographic Tracers in Deep-Sea Corals: Advances in TIMS Measurements of Pb Isotopes and Application to Southern Ocean Corals

    NASA Astrophysics Data System (ADS)

    Wilson, D. J.; van de Flierdt, T.; Bridgestock, L. J.; Paul, M.; Rehkamper, M.; Robinson, L. F.; Adkins, J. F.

    2014-12-01

    Deep-sea corals have emerged as a valuable archive of deep ocean paleoceanographic change, with uranium-series dating providing absolute ages and the potential for centennial resolution. In combination with measurements of radiocarbon, neodymium isotopes and clumped isotopes, this archive has recently been exploited to reconstruct changes in ventilation, water mass sourcing and temperature in relation to millennial climate change. Lead (Pb) isotopes in both corals and seawater have also been used to track anthropogenic inputs through space and time and to trace transport pathways within the oceans. Better understanding of the oceanic Pb cycle is emerging from the GEOTRACES programme. However, while Pb isotopes have been widely used in environmental studies, their full potential as a (pre-anthropogenic) paleoceanographic tracer remains to be exploited. In deep-sea corals, challenges exist from low Pb concentrations in aragonite in comparison to secondary coatings, the potential for contamination, and the efficient elemental separation required for measurement by thermal ionisation mass spectrometry (TIMS). Here we discuss progress in measuring Pb isotopes in coral aragonite using a 207Pb-204Pb double spike on a ThermoFinnigan Triton TIMS. For a 2 ng NIST-981 Pb standard, the long term reproducibility (using 1011 Ω resistors) is ~1000 ppm (2 s.d.) on 206Pb/204Pb, 207Pb/204Pb and 208Pb/204Pb ratios. We now show that using a new 1012 Ω resistor to measure the small 204Pb beam improves the internal precision on these ratios from ~500 ppm (2 s.e.) to ~250 ppm (2 s.e.) and we envisage a potential improvement in the long term reproducibility as a consequence. We further assess the internal precision and external reproducibility of our method using a BCR-2 rock standard and an in-house coral standard. Preliminary evidence on the application of this method to natural samples is derived from cleaning experiments and replication tests on deep-sea corals from the Southern

  10. Details of assessing information content of the Tropospheric Infrared Mapping Spectrometers (TIMS) GEO-CAPE instrument concept when applied for several infrared ozone bands

    NASA Astrophysics Data System (ADS)

    Rairden, R. L.; Kumer, J. B.; Roche, A. E.; Desouza-Machado, S. G.; Chatfield, R. B.; Blatherwick, R.

    2009-12-01

    With support of NASA ESTO Instrument Incubator Program (IIP) Tropospheric Infrared Mapping Spectrometers (TIMS) have been demonstrated for multi-layer retrieval of Atmospheric CO. Two TIMS units operating in spectral regions centered at 2.33 and 4.68 µm were developed for this demonstration. Here we present the details of scaling the characteristics of the demonstration measurements including spectral range, sample spacing and resolution, and noise per sample to the scenario of GEO-CAPE mission and to several additional wave length regions. This includes the detail of expanding to more than two spectral regions. It includes an example of scaling the noise as demonstrated by the demonstration measurements to the space case, and to other spectral regions. Common with our oral presentation, methods based on these scaled instrument characteristics for estimating vertical information content are reviewed. The methods are applied and estimated vertical information content of measurements in ozone bands near 9.4, 4.7, 3.6 and 3.3 µm and in various combinations of these bands is presented. A simple simultaneous retrieval of humidity and ozone from atmospheric spectral absorption data in the 3.3 and 3.6 µm regions that was obtained by a solar viewing FTS is briefly presented. This is partially analogous to the retrieval of ozone from the earth’s surface diffuse reflection of sunlight as viewed from space. It supports the premise that these space borne measurements can contribute to the quality of the GEO-CAPE ozone measurements.

  11. "Das Konkrete ist das Abstrakte, an das man sich schließlich gewöhnt hat." (Laurent Schwartz) Über den Ablauf des mathematischen Verstehens

    NASA Astrophysics Data System (ADS)

    Lowsky, Martin

    Die im Titel genannte Aussage findet sich in den Lebenserinnerungen von Laurent Schwartz (1915-2002), einem der fruchtbarsten Mathematiker, Mitglied der Gruppe Bourbaki. Im Original lautet die Aussage: "un objet concret est un objet abstrait auquel on a fini par s'habituer." Schwartz erläutert sie am Beispiel des Integrals über {e^{-1/2{x^2}}} , das den Wert Wurzel aus 2π hat und in dem sich also die Zahlen e und π verknüpfen. Was Schwartz aber vor allem ausdrücken will, ist dies: Das mathematische Verständnisd geht langsam vor sich und es bedarf der Anstrengung. "Es ist eine Frage der Zeit und der Energie", sagt Schwartz, und gerade dies mache es so schwer, die höhere Mathematik unter das Volk zu bringen. Das Lernen und Lehren von Mathematik laufe eben mühevoll und langsam ab.

  12. Evidence of Motor Programming Deficits in Children Diagnosed with DAS.

    ERIC Educational Resources Information Center

    Nijland, Lian; Maassen, Ben; van der Meulen, Sjoeke

    2003-01-01

    Five children with developmental apraxia of speech (DAS), 5 controls (ages 5-6), and 6 adults produced utterances in a normal condition and in a bite-block condition in which the mandible was in a fixed position. In children with DAS, the bite-block had large effects on coarticulatory patterns and vowel quality. (Contains references.) (Author/CR)

  13. Pedagogical Basis of DAS Formalism in Engineering Education

    ERIC Educational Resources Information Center

    Hiltunen, J.; Heikkinen, E.-P.; Jaako, J.; Ahola, J.

    2011-01-01

    The paper presents a new approach for a bachelor-level curriculum structure in engineering. The approach is called DAS formalism according to its three phases: description, analysis and synthesis. Although developed specifically for process and environmental engineering, DAS formalism has a generic nature and it could also be used in other…

  14. Comparing pre- and post-chemical abrasion ages for Miocene Peach Springs Tuff zircon from ID-TIMS and SIMS analyses

    NASA Astrophysics Data System (ADS)

    Lidzbarski, M. I.; Mundil, R.; Miller, J. S.; Vazquez, J. A.

    2012-12-01

    removes micro-inclusions that typically contain common Pb. Thermal annealing followed by CA techniques were used for ID-TIMS dating of a sub-set of zircon crystals previously analyzed by SIMS. Prior to TIMS analyses, zircon crystals were imaged by scanning electron microscopy (SEM) to evaluate the effects of CA on crystal domains sampled by SIMS. SEM images reveal that whole portions of crystals were removed by the CA technique, and a heterogeneous pattern of etching that was not confined to specific compositional zones visible in cathodoluminescence. Most of the SIMS sputter pits that yield spurious ages, are associated with etching and/or preferential annealing by the combined annealing and CA technique, suggesting that the young ages relative to the 40Ar/39Ar age may be due to Pb loss. ID-TIMS yields a coherent U-Pb age population of 18.8 Ma, with several older and younger crystals that might reflect xenocrysts, Pb-loss, and/or younger crystallization. In order to maintain spatial resolution and further evaluate the effects of Pb-loss in PST zircon, the annealing and CA-technique will be applied to zircon prior to SIMS dating. References: Reid and Coath, 2000, Geology 28: 443 Renne et al., 2010, GCA 78: 5349

  15. Amplifying Earth history: Zircon U-Pb geochronology by ID-TIMS at the 0.1 ‰ level using new 1013 ohm resistors

    NASA Astrophysics Data System (ADS)

    Wotzlaw, Jörn-Frederik; von Quadt, Albrecht

    2016-04-01

    Precise and accurate radiometric dating of volcanic ash beds in sedimentary successions is the backbone of the numerical calibration of Earth history. Uranium-lead geochronology by isotope dilution thermal ionization mass spectrometry (ID-TIMS) is the most precise and accurate dating technique and is applicable to most of Earth history from the Hadean to the Pleistocene. The accessory mineral zircon is the prime target material due to its commonly high U concentration, virtually no initial Pb and high daughter-product retentivity. However, complex crystallization histories as well as magmatic and sedimentary recycling of zircons require the analysis of single crystals resulting in small amounts of radiogenic Pb (Pb* usually <100 pg) available for mass spectrometry. Precise and accurate isotope ratio determinations on such small samples require highly sensitive ion detection systems making ion counting detectors such as secondary electron multipliers and Daly photomultipliers the most commonly employed detectors for the analysis of small Pb* ion beams. While these detector systems are highly sensitive they are limited by their restricted linear dynamic range and require dynamic peak hopping to collect multiple isotopes. We recently demonstrated the applicability of new 1013 ohm resistors in the Faraday cup amplifier feedback loop for the static multi-collection of all tracer and sample Pb isotopes with 202,205,206,207,208Pb measured on Faraday cups and 204Pb measured in the axial SEM of a Thermo Scientific TRITON Plus TIMS instrument [1]. These measurements take advantage of the superior stability of Faraday detectors, their significantly larger dynamic range and the multiple advantages of static multi collector analyses (longer counting on peak, simultaneous collection of all isotopes etc.). Here, we document recent advances in our analytical protocols that further improve the precision, accuracy and reproducibility of U and Pb isotope ratio measurements of small

  16. Structural analysis of kinetic folding intermediates for a TIM barrel protein, indole-3-glycerol phosphate synthase, by hydrogen exchange mass spectrometry and Gō model simulation.

    PubMed

    Gu, Zhenyu; Rao, Maithreyi K; Forsyth, William R; Finke, John M; Matthews, C Robert

    2007-11-23

    The structures of partially folded states appearing during the folding of a (betaalpha)(8) TIM barrel protein, the indole-3-glycerol phosphate synthase from Sulfolobus solfataricus (sIGPS), was assessed by hydrogen exchange mass spectrometry (HX-MS) and Gō model simulations. HX-MS analysis of the peptic peptides derived from the pulse-labeled product of the sub-millisecond folding reaction from the urea-denatured state revealed strong protection in the (betaalpha)(4) region, modest protection in the neighboring (betaalpha)(1-3) and (betaalpha)(5)beta(6) segments and no significant protection in the remaining N and C-terminal segments. These results demonstrate that this species is not a collapsed form of the unfolded state under native-favoring conditions nor is it the native state formed via fast-track folding. However, the striking contrast of these results with the strong protection observed in the (betaalpha)(2-5)beta(6) region after 5 s of folding demonstrates that these species represent kinetically distinct folding intermediates that are not identical as previously thought. A re-examination of the kinetic folding mechanism by chevron analysis of fluorescence data confirmed distinct roles for these two species: the burst-phase intermediate is predicted to be a misfolded, off-pathway intermediate, while the subsequent 5 s intermediate corresponds to an on-pathway equilibrium intermediate. Comparison with the predictions using a C(alpha) Gō model simulation of the kinetic folding reaction for sIGPS shows good agreement with the core of the structure offering protection against exchange in the on-pathway intermediate(s). Because the native-centric Gō model simulations do not explicitly include sequence-specific information, the simulation results support the hypothesis that the topology of TIM barrel proteins is a primary determinant of the folding free energy surface for the productive folding reaction. The early misfolding reaction must involve aspects of

  17. An Improved Method for TIMS High Precision Nd Isotopic Analysis of Very Small Aliquots (1- 10ng) With Example Application in Garnet Sm/Nd Geochronology

    NASA Astrophysics Data System (ADS)

    Baxter, E. F.; Harvey, J.; Mehl, L. Y.; Peterman, E. M.

    2007-12-01

    Technological and scientific developments have demonstrated both the attainability and the utility of very high precision (i.e. 5-20ppm 2 σ) Nd isotopic measurements with TIMS. However such high precision has been limited to relatively large aliquots of Nd, on the order of several hundred nanograms. Several potential applications of precise Nd isotopic measurements, including garnet Sm/Nd geochronology, do not always permit such large samples, instead yielding only a few nanograms of Nd. We have explored and tested an improved method for Nd isotopic analysis of such small (1-10ng) aliquots of Nd using the NdO+ method with a Triton TIMS at Boston University. Analyzing Nd isotopes as the oxide is a well known technique, frequently involving an oxygen bleed valve. Instead, we forego the bleed valve and load samples with a TaO slurry which provides the oxygen source. Using an in-house Nd isotopic standard solution, 4ng loads easily yield stable 2.0-2.5 volt beams resulting in internal precisions of 10ppm 2 σ RSE. Within barrel external precision of 4ng loads of the Nd standard is 13ppm 2 σ RSD (n=20). Long term (6 months, six analysts) external precision of 4ng loads of the standard is currently 23ppm 2 σ RSD (n=55) suggesting that further improvements are possible. As a further test of this method, we dissolved a natural rock sample (a metapelite), separated the Nd using TRU- spec and MLA column chemistry, and loaded nineteen 4ng loads in one barrel. Within barrel external precision was 21ppm 2 σ RSD (n=18). This precision represents a significant advance over previous NdO+ analyses of small samples using an oxygen bleed valve. The TaO loading method for small Nd aliquots is useful in Sm/Nd garnet geochronology as exemplified by two case studies. Garnets from eclogite facies gneisses from Norway ran very well with 2.4-18ng loads and yielded age precision as good as 0.8 million years 2 σ. Conversely, garnets from blueschist facies rocks from Sifnos, Greece, ran

  18. TIM-3 promotes the metastasis of esophageal squamous cell carcinoma by targeting epithelial-mesenchymal transition via the Akt/GSK-3β/Snail signaling pathway.

    PubMed

    Shan, Baoen; Man, Hongwei; Liu, Junfeng; Wang, Ling; Zhu, Tienian; Ma, Ming; Xv, Zhili; Chen, Xinran; Yang, Xingxiao; Li, Pengfei

    2016-09-01

    T-cell immunoglobulin and mucin domain-con-taining protein-3 (TIM-3), a negative regulator of antitumor immune response, has been demonstrated to be involved in the onset and progression of several types of malignancies. The present study aimed to determine whether and how TIM‑3 plays such a role in esophageal squamous cell carcinoma (ESCC). TIM-3 expression was analyzed by immunohistochemistry and real‑time fluorescence quantitative PCR (qRT‑PCR) in ESCC and matched adjacent normal tissues. Functional experiments in vitro were performed to elucidate the effect of TIM‑3 knockdown on the proliferation, apoptosis, migration, invasion and epithelial-mesenchymal transition (EMT) in Eca109 and TE‑1 cell lines. Our data revealed that TIM‑3 expression was significantly elevated at both the mRNA and protein levels in ESCC tissues compared with the levels in the matched adjacent normal tissues (both P<0.001). TIM‑3 expression was significantly associated with lymph node metastasis (P=0.008), tumor‑node‑metastasis (TNM) stage (P=0.042) and depth of tumor invasion (P=0.042). In addition, we observed a strong correlation between high TIM‑3 expression and a worse overall survival of ESCC patients (P=0.001). Functional study demonstrated that TIM‑3 knockdown markedly inhibited proliferation, migration and invasion of ESCC cell lines without affecting apoptosis. In addition, TIM‑3 depletion was associated with downregulation of matrix metalloproteinase (MMP)-9 and upregulation of tissue inhibitor of metalloproteinase (TIMP)-1, and with reversion of EMT, as reflected by higher levels of the epithelial marker E‑cadherin and lower levels of the mesenchymal markers N‑cadherin and vimentin. Further study found that TIM‑3 depletion suppressed the signaling pathway involving p‑Akt, p‑GSK‑3β and Snail. Taken together, these results suggest that TIM‑3 is a novel therapeutic target and prognostic biomarker for ESCC and promotes metastasis of

  19. Twenty‐eight‐joint counts invalidate the DAS28 remission definition owing to the omission of the lower extremity joints: a comparison with the original DAS remission

    PubMed Central

    Landewé, R; van der Heijde, D; van der Linden, S; Boers, M

    2006-01-01

    Objective To compare 28 joint disease activity score (DAS28) remission with comprehensive joint count DAS remission in rheumatoid arthritis. Methods 620 actually measured paired observations of DAS28 and DAS were analysed in 155 patients. Discordant observations (either DAS or DAS28 below remission cut off level: 1.6 for DAS and 2.6 for DAS28) and concordant observations (both DAS and DAS28 below their remission cut off level) were analysed separately. Results 91 of 620 paired DAS observations (15%) were discordant; 87 (in 53 patients) comprised observations in which the DAS28 remission criterion, but not the DAS remission criterion, was met. The reverse was found in only four observations, which were therefore omitted. With the original DAS as standard, DAS28 sensitivity was 95% and specificity 84%. Probability plots showed a swollen joint count >0 in 75% of discordant pairs v 48% of concordant pairs. The same was found for total joint count (TJC >0 in 90% v 40%; median TJC, 0 v 6) and patient global assessment, but not for ESR. Individual joint analysis showed that 51% of discordant v 18% of concordant observations (p<0.0005) had involvement of lower extremity joints that are not included in the DAS28. Conclusions DAS remission is more conservative than DAS28 remission. Activity (tenderness and swelling) in joints not included in the reduced joint counts (ankles, feet) mainly account for the discrepancy between the two assessments. DAS28 remission at a cut off level of 2.6 has insufficient construct validity and should be used with caution in clinical practice and clinical trials. PMID:16219709

  20. CA-TIMS zircon U-Pb dating of felsic ignimbrite from the Binchuan section: Implications for the termination age of Emeishan large igneous province

    NASA Astrophysics Data System (ADS)

    Zhong, Yu-Ting; He, Bin; Mundil, Roland; Xu, Yi-Gang

    2014-09-01

    The age of the Emeishan lavas in SW China remains poorly constrained because the extrusive rocks are (1) thermally overprinted and so represent an open system unsuitable for 40Ar/39Ar geochronology and (2) in most cases devoid of zircon so that it is impossible for the application of U-Pb geochronology. Existing radiometric age constraints of Emeishan large igneous province are mainly from the application of SIMS and LA-ICP-MS U-Pb techniques to zircons from mafic and felsic intrusions, which represent indirect constraints for the lavas. In an attempt to directly determine the age of the Emeishan lava succession, high-resolution chemical abrasion-thermal ionization mass spectrometry (CA-TIMS) zircon U-Pb techniques have been used on the felsic ignimbrite at the uppermost part of the Emeishan lava succession. These techniques have yielded a weighted mean 206Pb/238U age of 259.1 ± 0.5 Ma (n = 6; MSWD = 0.7). We interpret this age as the termination age of the Emeishan flood basalts. The age of the Guadalupian-Lopingian boundary is still unconstrained by high-resolution geochronology but is likely to be close to our new age for this felsic ignimbrite.

  1. Use of the dynamic gastro-intestinal model TIM to explore the survival of the yogurt bacterium Streptococcus thermophilus and the metabolic activities induced in the simulated human gut.

    PubMed

    Uriot, Ophélie; Galia, Wessam; Awussi, Ahoefa Ablavi; Perrin, Clarisse; Denis, Sylvain; Chalancon, Sandrine; Lorson, Emilie; Poirson, Chantal; Junjua, Maira; Le Roux, Yves; Alric, Monique; Dary, Annie; Blanquet-Diot, Stéphanie; Roussel, Yvonne

    2016-02-01

    Streptococcus thermophilus, a lactic acid bacterium used to produce yogurts and cheeses is more and more considered for its potential probiotic properties. This implies that additional information should be obtained regarding its survival and metabolic activity in the human Gastro-Intestinal Tract (GIT). In this study, we screened 30 S. thermophilus strains for urease, small heat shock protein, and amino-acid decarboxylase functions which may play a role in survival in the upper part of the GIT. The survival kinetics of 4 strains was investigated using the TIM, a physiologically relevant in vitro dynamic gastric and small intestinal model. The three strains LMD9, PB18O and EBLST20 showed significantly higher survival than CNRZ21 in all digestive compartments of the TIM, which may be related to the presence of urease and heat shock protein functions. When LMD9 bacterial cells were delivered in a fermented milk formula, a significant improvement of survival in the TIM was observed compared to non-fermented milk. With the RIVET (Recombinase In Vivo Expression Technology) method applied to the LMD9 strain, a promoter located upstream of hisS, responsible for the histidyl-transfer RNA synthesis, was found to be specifically activated in the artificial stomach. The data generated on S. thermophilus survival and its adaptation capacities to the digestive tract are essential to establish a list of biomarkers useful for the selection of probiotic strains. PMID:26611166

  2. Use of the dynamic gastro-intestinal model TIM to explore the survival of the yogurt bacterium Streptococcus thermophilus and the metabolic activities induced in the simulated human gut.

    PubMed

    Uriot, Ophélie; Galia, Wessam; Awussi, Ahoefa Ablavi; Perrin, Clarisse; Denis, Sylvain; Chalancon, Sandrine; Lorson, Emilie; Poirson, Chantal; Junjua, Maira; Le Roux, Yves; Alric, Monique; Dary, Annie; Blanquet-Diot, Stéphanie; Roussel, Yvonne

    2016-02-01

    Streptococcus thermophilus, a lactic acid bacterium used to produce yogurts and cheeses is more and more considered for its potential probiotic properties. This implies that additional information should be obtained regarding its survival and metabolic activity in the human Gastro-Intestinal Tract (GIT). In this study, we screened 30 S. thermophilus strains for urease, small heat shock protein, and amino-acid decarboxylase functions which may play a role in survival in the upper part of the GIT. The survival kinetics of 4 strains was investigated using the TIM, a physiologically relevant in vitro dynamic gastric and small intestinal model. The three strains LMD9, PB18O and EBLST20 showed significantly higher survival than CNRZ21 in all digestive compartments of the TIM, which may be related to the presence of urease and heat shock protein functions. When LMD9 bacterial cells were delivered in a fermented milk formula, a significant improvement of survival in the TIM was observed compared to non-fermented milk. With the RIVET (Recombinase In Vivo Expression Technology) method applied to the LMD9 strain, a promoter located upstream of hisS, responsible for the histidyl-transfer RNA synthesis, was found to be specifically activated in the artificial stomach. The data generated on S. thermophilus survival and its adaptation capacities to the digestive tract are essential to establish a list of biomarkers useful for the selection of probiotic strains.

  3. DAS: A Data Management System for Instrument Tests and Operations

    NASA Astrophysics Data System (ADS)

    Frailis, M.; Sartor, S.; Zacchei, A.; Lodi, M.; Cirami, R.; Pasian, F.; Trifoglio, M.; Bulgarelli, A.; Gianotti, F.; Franceschi, E.; Nicastro, L.; Conforti, V.; Zoli, A.; Smart, R.; Morbidelli, R.; Dadina, M.

    2014-05-01

    The Data Access System (DAS) is a and data management software system, providing a reusable solution for the storage of data acquired both from telescopes and auxiliary data sources during the instrument development phases and operations. It is part of the Customizable Instrument WorkStation system (CIWS-FW), a framework for the storage, processing and quick-look at the data acquired from scientific instruments. The DAS provides a data access layer mainly targeted to software applications: quick-look displays, pre-processing pipelines and scientific workflows. It is logically organized in three main components: an intuitive and compact Data Definition Language (DAS DDL) in XML format, aimed for user-defined data types; an Application Programming Interface (DAS API), automatically adding classes and methods supporting the DDL data types, and providing an object-oriented query language; a data management component, which maps the metadata of the DDL data types in a relational Data Base Management System (DBMS), and stores the data in a shared (network) file system. With the DAS DDL, developers define the data model for a particular project, specifying for each data type the metadata attributes, the data format and layout (if applicable), and named references to related or aggregated data types. Together with the DDL user-defined data types, the DAS API acts as the only interface to store, query and retrieve the metadata and data in the DAS system, providing both an abstract interface and a data model specific one in C, C++ and Python. The mapping of metadata in the back-end database is automatic and supports several relational DBMSs, including MySQL, Oracle and PostgreSQL.

  4. High-precision TIMS U-Pb dating and SHRIMP trace element analyses of zircons from plutonic crust from ODP Hole 735B, Atlantis Bank, Southwest Indian Ridge

    NASA Astrophysics Data System (ADS)

    Rioux, M. E.; Cheadle, M. J.; John, B. E.; Bowring, S. A.; Wooden, J. L.; Baines, G.

    2012-12-01

    Ocean Drilling Program Hole 735B at Atlantis Bank on the Southwest Indian Ridge is the deepest drill hole (1508m) into plutonic oceanic crust. The recovered core provides the opportunity to study both the processes and timescales of lower crustal accretion at a slow-spreading mid-ocean ridge. Major element chemistry suggests that the crust is made up of three 200-1000m thick igneous series (Natland and Dick, 2002). Previous SHRIMP U/Pb dating of zircons from oxide gabbro and felsic/dioritic dikes/veins from the length of the core found no resolvable age differences, suggesting rapid crustal growth; SHRIMP Th-corrected weighted mean 206Pb/238U dates ranged from 11.86 ± 0.20 to 12.13 ± 0.21 Ma (Baines et al., 2009). Here we report combined SHRIMP chemical analyses and high precision TIMS U-Pb geochronology on zircons from a suite of fifteen samples from depths of 26-1430 mbsf. The samples are from each of the three main intrusive series and range from oxide gabbro to diorite and granodiorite dikes/veins. Single grain TIMS 206Pb/238U date uncertainties for most analyses range from ~0.01-0.2 Ma and weighted mean 206Pb/238U date uncertainties range from ~0.004-0.07 Ma, providing precise constraints on the timing and duration of magmatism. Zircon chemistry is variable between samples (John et al., this meeting). Ti and Hf from spot analyses within individual samples range from tight clusters of data to linear trends of decreasing Ti with increasing Hf. Apparent Ti-in-zircon temperature variations within samples range from ~60-230°C, and variations within single grains are as large as 160°C. For zircons with significant chemical zoning, the cores are typically higher in Ti and lower in Hf than the rims. Th-corrected single grain 206Pb/238U dates from individual samples typically overlap within uncertainty, consistent with crystallization of a single batch of magma with no evidence for assimilation of older crust or protracted crystallization, as has been seen in high

  5. Partial melting and rapid exhumation of a Pliocene UHP terrane: CA-TIMS zircon results from Normanby Island, Papau New Guinea

    NASA Astrophysics Data System (ADS)

    DesOrmeau, J. W.; Gordon, S. M.; Little, T. A.; Bowring, S. A.

    2012-12-01

    Some ultra-high pressure (UHP) terranes contain eclogite embedded within migmatitic gneisses that preserve evidence for multiple episodes of partial melting. Understanding the mechanisms by which crustal rocks are subducted to mantle depths and subsequently exhumed requires understanding the timing of metamorphism and the timing and role of partial melting. The D'Entrecasteaux Islands of southeastern Papua New Guinea (PNG) expose Pliocene UHP eclogites contained within migmatitic host gneisses. Garnet-whole rock Lu-Hf geochronology suggests UHP metamorphism may have begun by ca. 7 Ma, and Ar-Ar thermochronology indicates that the rocks were exhumed to the surface by ca. 2 Ma; the history between 7 and 2 Ma is crucial for tectonic models of PNG. We have applied U-Pb chemical-abrasion thermal-ionization mass spectrometry (CA-TIMS) geochronology to zircons separated from granitoid intrusions within the host gneisses to better understand the timing and role of melting in the exhumation of the PNG UHP rocks. Three granodiorite intrusions were collected from Normanby Island as it has received far less study in previous investigations than the other D'Entrecasteaux Islands (Goodenough and Fergusson) and exposes the contact of the UHP-HP rocks against the structurally overlying, weakly metamorphosed rocks of the Papuan ultramafic belt (PUB). From the west side of Normanby dome in contact with the PUB, zircons from a foliated protomylonitic granodiorite sill yielded 206Pb/238U dates of ca. 4.1 Ma. In comparison, on the eastern side of Normanby dome, zircons from a weakly foliated, discordant pegmatitic dike yielded a complex array of zircon analyses and the youngest dates are ca. 4.1 Ma. The zircons extracted from these deformed intrusions are interpreted to date melt emplacement, crystallization, and zircon growth, which may be coeval with amphibolite facies (570-730 °C and ~7-12 Kbar) metamorphism recorded from Goodenough and Fergusson Islands. Zircons from a non

  6. U-Pb geochronology of zircon and polygenetic titanite from the Glastonbury Complex, Connecticut, USA: An integrated SEM, EMPA, TIMS, and SHRIMP study

    USGS Publications Warehouse

    Aleinikoff, J.N.; Wintsch, R.P.; Fanning, C.M.; Dorais, M.J.

    2002-01-01

    U-Pb ages for zircon and titanite from a granodioritic gneiss in the Glastonbury Complex, Connecticut, have been determined using both isotope dilution thermal ionization mass spectrometry (TIMS) and the sensitive high resolution ion microprobe (SHRIMP). Zircons occur in three morphologic populations: (1) equant to stubby, multifaceted, colorless, (2) prismatic, dark brown, with numerous cracks, and (3) elongate, prismatic, light tan to colorless. Cathodoluminescence (CL) imaging of the three populations shows simple concentric oscillatory zoning. The zircon TIMS age [weighted average of 207Pb/206Pb ages from Group 3 grains-450.5 ?? 1.6 Ma (MSWD=1.11)] and SHRIMP age [composite of 206Pb/238 U age data from all three groups-448.2 ?? 2.7 Ma (MSWD = 1.3)], are interpreted to suggest a relatively simple crystallization history. Titanite from the granodioritic gneiss occurs as both brown and colorless varieties. Scanning electron microscope backscatter (BSE) images of brown grains show multiple cross-cutting oscillatory zones of variable brightness and dark overgrowths. Colorless grains are unzoned or contain subtle wispy or very faint oscillatory zoning. Electron microprobe analysis (EMPA) clearly distinguishes the two populations. Brown grains contain relatively high concentrations of Fe2O3, Ce2O3 (up to ~ 1.5 wt.%), Nb2O5, and Zr. Cerium concentration is positively correlated with total REE + Y concentration, which together can exceed 3.5 wt.%. Oscillatory zoning in brown titanite is correlated with variations in REE concentrations. In contrast, colorless titanite (both as discrete grains and overgrowths on brown titanite) contains lower concentrations of Y, REE, Fe2O3, and Zr, but somewhat higher Al2O3 and Nb2O5. Uranium concentrations and Th/U discriminate between brown grains (typically 200-400 ppm U; all analyses but one have Th/U between about 0.8 and 2) and colorless grains (10-60 ppm U; Th/U of 0-0.17). In contrast to the zircon U-Pb age results, SHRIMP U

  7. Lead Isotope Measurement by Lead Double Spike and Thallium Spike Using MC-ICP-MS and TIMS - a Comparison Using Basaltic Samples

    NASA Astrophysics Data System (ADS)

    Taylor, R. N.; Ishizuka, O.

    2001-12-01

    Multi-collector ICP-MS has provided a new level of precision to lead isotope analysis using Thallium addition as an internal mass bias monitor. Further enhancement of precision has been achieved by the application of double lead spike to measurement procedures. In this study, we directly compare results using thallium addition and the new SBL74 double lead spike on both TIMS and MC-ICP-MS (Micromass IsoProbe). The comparisons are performed using standard Pb solutions and basaltic matrix-bearing solutions. Analyses of standards measured over 8 analytical sessions using the thallium spike method are reproducible to within 100 ppm for 206Pb/204Pb, 130 ppm for 207Pb/204Pb and 220 ppm (2sd) for 208Pb/204Pb. If the ratios for individual analytical sessions are normalised to the SRM981{day average}/SRM981true the increasing error with greater mass difference of the ratio is eliminated and all ratios are less than ±85 ppm. This implies that variability between the Tl and Pb mass bias factors on a day-to-day basis is the cause of increasing imprecision with mass difference. Double spike MC-ICP-MS is found to produce similar levels of precision to the Tl method for standards. However, the decreasing precision with increasing mass difference is greatly reduced, indicating that the correlation is due to Tl and Pb differences. With basaltic matrix samples with a single anion exchange separation, the effects of Tl-Pb differential mass bias are slightly exaggerated. We present the results from mixtures of SRM981 with Pb-free Fe measured using MC-ICP-MS using Tl and double spike mass bias correction, to replicate the basaltic matrix analyses.

  8. U.S. Tsunami Information technology (TIM) Modernization:Developing a Maintainable and Extensible Open Source Earthquake and Tsunami Warning System

    NASA Astrophysics Data System (ADS)

    Hellman, S. B.; Lisowski, S.; Baker, B.; Hagerty, M.; Lomax, A.; Leifer, J. M.; Thies, D. A.; Schnackenberg, A.; Barrows, J.

    2015-12-01

    Tsunami Information technology Modernization (TIM) is a National Oceanic and Atmospheric Administration (NOAA) project to update and standardize the earthquake and tsunami monitoring systems currently employed at the U.S. Tsunami Warning Centers in Ewa Beach, Hawaii (PTWC) and Palmer, Alaska (NTWC). While this project was funded by NOAA to solve a specific problem, the requirements that the delivered system be both open source and easily maintainable have resulted in the creation of a variety of open source (OS) software packages. The open source software is now complete and this is a presentation of the OS Software that has been funded by NOAA for benefit of the entire seismic community. The design architecture comprises three distinct components: (1) The user interface, (2) The real-time data acquisition and processing system and (3) The scientific algorithm library. The system follows a modular design with loose coupling between components. We now identify the major project constituents. The user interface, CAVE, is written in Java and is compatible with the existing National Weather Service (NWS) open source graphical system AWIPS. The selected real-time seismic acquisition and processing system is open source SeisComp3 (sc3). The seismic library (libseismic) contains numerous custom written and wrapped open source seismic algorithms (e.g., ML/mb/Ms/Mwp, mantle magnitude (Mm), w-phase moment tensor, bodywave moment tensor, finite-fault inversion, array processing). The seismic library is organized in a way (function naming and usage) that will be familiar to users of Matlab. The seismic library extends sc3 so that it can be called by the real-time system, but it can also be driven and tested outside of sc3, for example, by ObsPy or Earthworm. To unify the three principal components we have developed a flexible and lightweight communication layer called SeismoEdex.

  9. Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

    PubMed Central

    Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.; Engelke, Udo F.; Boekhorst, Jos; Keegan, Kevin P.; Nielsen, Fiona G. G.; Betley, Jason; Weir, Jacqueline C.; Kingsbury, Zoya; Kluijtmans, Leo A. J.; Swinkels, Dorine W.; Venema, Koen; Tjalsma, Harold

    2016-01-01

    Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessed by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. Our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer. PMID:26779139

  10. Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

    DOE PAGES

    Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.; Engelke, Udo F.; Boekhorst, Jos; Keegan, Kevin P.; Nielsen, Fiona G. G.; Betley, Jason; Weir, Jacqueline C.; Kingsbury, Zoya; et al

    2016-01-06

    Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessedmore » by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. In conclusion, our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer.« less

  11. Pedagogical basis of DAS formalism in engineering education

    NASA Astrophysics Data System (ADS)

    Hiltunen, J.; Heikkinen, E.-P.; Jaako, J.; Ahola, J.

    2011-03-01

    The paper presents a new approach for a bachelor-level curriculum structure in engineering. The approach is called DAS formalism according to its three phases: description, analysis and synthesis. Although developed specifically for process and environmental engineering, DAS formalism has a generic nature and it could also be used in other engineering fields. The motivation for this new curriculum structure originates from the urge to solve the problems that engineering education has faced during the past decades, e.g. student recruitment problems and dissatisfactory learning outcomes. The focus of this paper is on the structure of the curriculum but the content is also discussed when it has an effect on the structure and its implementation. The presented structure, i.e. DAS formalism, builds upon the ideas of some classical pedagogical theories, which have regularly been applied at course level but seldom used to solve curriculum-level issues.

  12. The development of the disease activity score (DAS) and the disease activity score using 28 joint counts (DAS28).

    PubMed

    van Riel, P L C M

    2014-01-01

    In rheumatoid arthritis, disease activity cannot be measured using a single variable. The Disease Activity Score (DAS) has been developed as a quantitative index to be able to measure, study and manage disease activity in RA in daily clinical practice, clinical trials, and long term observational studies. The DAS is a continuous measure of RA disease activity that combines information from swollen joints, tender joints, acute phase response and patient self-report of general health. Cut points were developed to classify patients in remission, as well as low, moderate, and severe disease activity in the 1990s. DAS-based EULAR response criteria were primarily developed to be used in clinical trials to classify individual patients as non-, moderate, or good responders, depending on the magnitude of change and absolute level of disease activity at the conclusion of the test.

  13. Precise determination of δ88Sr in rocks, minerals, and waters by double-spike TIMS: A powerful tool in the study of chemical, geologic, hydrologic and biologic processes

    USGS Publications Warehouse

    Neymark, Leonid A.; Premo, Wayne R.; Mel'nikov, Nikolay N.; Emsbo, Poul

    2014-01-01

    We present strontium isotopic (88Sr/86Sr and 87Sr/86Sr) results obtained by 87Sr–84Sr double spike thermal ionization mass-spectrometry (DS-TIMS) for several standards as well as natural water samples and mineral samples of abiogenic and biogenic origin. The detailed data reduction algorithm and a user-friendly Sr-specific stand-alone computer program used for the spike calibration and the data reduction are also presented. Accuracy and precision of our δ88Sr measurements, calculated as permil (‰) deviations from the NIST SRM-987 standard, were evaluated by analyzing the NASS-6 seawater standard, which yielded δ88Sr = 0.378 ± 0.009‰. The first DS-TIMS data for the NIST SRM-607 potassium feldspar standard and for several US Geological Survey carbonate, phosphate, and silicate standards (EN-1, MAPS-4, MAPS-5, G-3, BCR-2, and BHVO-2) are also reported. Data obtained during this work for Sr-bearing solids and natural waters show a range of δ88Sr values of about 2.4‰, the widest observed so far in terrestrial materials. This range is easily resolvable analytically because the demonstrated external error (±SD, standard deviation) for measured δ88Sr values is typically ≤0.02‰. It is shown that the “true” 87Sr/86Sr value obtained by the DS-TIMS or any other external normalization method combines radiogenic and mass-dependent mass-fractionation effects, which cannot be separated. Therefore, the “true” 87Sr/86Sr and the δ87Sr parameter derived from it are not useful isotope tracers. Data presented in this paper for a wide range of naturally occurring sample types demonstrate the potential of the δ88Sr isotope tracer in combination with the traditional radiogenic 87Sr/86Sr tracer for studying a variety of biological, hydrological, and geological processes.

  14. Crystal structures of two bacterial 3-hydroxy-3-methylglutaryl-CoA lyases suggest a common catalytic mechanism among a family of TIM barrel metalloenzymes cleaving carbon-carbon bonds.

    PubMed

    Forouhar, Farhad; Hussain, Munif; Farid, Ramy; Benach, Jordi; Abashidze, Mariam; Edstrom, William C; Vorobiev, Sergey M; Xiao, Rong; Acton, Thomas B; Fu, Zhuji; Kim, Jung-Ja P; Miziorko, Henry M; Montelione, Gaetano T; Hunt, John F

    2006-03-17

    The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the terminal steps in ketone body generation and leucine degradation. Mutations in this enzyme cause a human autosomal recessive disorder called primary metabolic aciduria, which typically kills victims because of an inability to tolerate hypoglycemia. Here we present crystal structures of the HMG-CoA lyases from Bacillus subtilis and Brucella melitensis at 2.7 and 2.3 A resolution, respectively. These enzymes share greater than 45% sequence identity with the human orthologue. Although the enzyme has the anticipated triose-phosphate isomerase (TIM) barrel fold, the catalytic center contains a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel, contrary to the predictions of homology models. Surprisingly, the residues forming this cation-binding site and most of their interaction partners are shared with three other TIM barrel enzymes that catalyze diverse carbon-carbon bond cleavage reactions believed to proceed through enolate intermediates (4-hydroxy-2-ketovalerate aldolase, 2-isopropylmalate synthase, and transcarboxylase 5S). We propose the name "DRE-TIM metallolyases" for this newly identified enzyme family likely to employ a common catalytic reaction mechanism involving an invariant Asp-Arg-Glu (DRE) triplet. The Asp ligates the divalent cation, while the Arg probably stabilizes charge accumulation in the enolate intermediate, and the Glu maintains the precise structural alignment of the Asp and Arg. We propose a detailed model for the catalytic reaction mechanism of HMG-CoA lyase based on the examination of previously reported product complexes of other DRE-TIM metallolyases and induced fit substrate docking studies conducted using the crystal structure of human HMG-CoA lyase (reported in the accompanying paper by Fu, et al. (2006) J. Biol. Chem. 281, 7526-7532). Our model is consistent with extensive mutagenesis results and can

  15. Crystal Structures of Two Bacterial 3-Hydroxy-3-methylglutaryl-CoA Lyases Suggest a Common Catalytic Mechanism among a Family of TIM Barrel Metalloenzymes Cleaving Carbon-Carbon Bonds

    SciTech Connect

    Forouhar,F.; Hussain, M.; Farid, R.; Benach, J.; Abashidze, M.; Edstrom, W.; Vorobiev, S.; Montelione, G.; Hunt, J.; et al.

    2006-01-01

    The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the terminal steps in ketone body generation and leucine degradation. Mutations in this enzyme cause a human autosomal recessive disorder called primary metabolic aciduria, which typically kills victims because of an inability to tolerate hypoglycemia. Here we present crystal structures of the HMG-CoA lyases from Bacillus subtilis and Brucella melitensis at 2.7 and 2.3 {angstrom} resolution, respectively. These enzymes share greater than 45% sequence identity with the human orthologue. Although the enzyme has the anticipated triose-phosphate isomerase (TIM) barrel fold, the catalytic center contains a divalent cation-binding site formed by a cluster of invariant residues that cap the core of the barrel, contrary to the predictions of homology models. Surprisingly, the residues forming this cation-binding site and most of their interaction partners are shared with three other TIM barrel enzymes that catalyze diverse carbon-carbon bond cleavage reactions believed to proceed through enolate intermediates (4-hydroxy-2-ketovalerate aldolase, 2-isopropylmalate synthase, and transcarboxylase 5S). We propose the name 'DRE-TIM metallolyases' for this newly identified enzyme family likely to employ a common catalytic reaction mechanism involving an invariant Asp-Arg-Glu (DRE) triplet. The Asp ligates the divalent cation, while the Arg probably stabilizes charge accumulation in the enolate intermediate, and the Glu maintains the precise structural alignment of the Asp and Arg. We propose a detailed model for the catalytic reaction mechanism of HMG-CoA lyase based on the examination of previously reported product complexes of other DRE-TIM metallolyases and induced fit substrate docking studies conducted using the crystal structure of human HMG-CoA lyase (reported in the accompanying paper by Fu, et al. (2006) J. Biol. Chem. 281, 7526-7532). Our model is consistent with extensive mutagenesis results and

  16. Titanocene-phosphine derivatives as precursors to cytotoxic heterometallic TiAu2 and TiM (M = Pd, Pt) compounds. Studies of their interactions with DNA.

    PubMed

    González-Pantoja, Jose F; Stern, Michael; Jarzecki, Andrzej A; Royo, Eva; Robles-Escajeda, Elisa; Varela-Ramírez, Armando; Aguilera, Renato J; Contel, María

    2011-11-01

    A series of tri- and bimetallic titanium-gold, titanium-palladium, and titanium-platinum derivatives of the general formulas [Ti{η(5)-C(5)H(4)(CH(2))(n)PPh(2)(AuCl)}(2)]·2THF [n = 0 (1); n = 2 (2); n = 3 (3)] and [TiCl(2){η(5)-C(5)H(4)κ-(CH(2))(n)PPh(2)}(2)(MCl(2))]·2THF [M = Pd, n = 0 (4); n = 2 (5); n = 3 (6) ; M = Pt, n = 0 (7); n = 2 (8); n = 3 (9)] have been synthesized and characterized by different spectroscopic techniques and mass spectrometry. The molecular structures of compounds 1-9 have been investigated by means of density functional theory calculations. The calculated IR spectra of the optimized structures fit well with the experimental IR data obtained for 1-9. The stability of the heterometallic compounds in deuterated solvents [CDCl(3), dimethyl sulfoxide (DMSO)-d(6), and mixtures 50:50 DMSO-d(6)/D(2)O and 1:99 DMSO-d(6)/D(2)O at acidic and neutral pH] has been evaluated by (31)P and (1)H NMR spectroscopy showing a higher stability for these compounds than for Cp(2)TiCl(2) or precursors [Ti{η(5)-C(5)H(4)(CH(2))(n)PPh(2)}(2)]. The new compounds display a lower acidity (1-2 units) than Cp(2)TiCl(2). The decomposition products have been identified over time. Complexes 1-9 have been tested as potential anticancer agents, and their cytotoxicity properties were evaluated in vitro against HeLa human cervical carcinoma and DU-145 human prostate cancer cells. TiAu(2) and TiPd compounds were highly cytotoxic for these two cell lines. The interactions of the compounds with calf thymus DNA have been evaluated by thermal denaturation (1-9) and by circular dichroism (1, 3, 4, and 7) spectroscopic methods. All of these complexes show a stronger interaction with DNA than that displayed by Cp(2)TiCl(2) at neutral pH. The data are consistent with electrostatic interactions with DNA for TiAu(2) compounds and for a covalent binding mode for TiM (M = Pd, Pt) complexes.

  17. Levels of CD56+TIM-3- effector CD8 T cells distinguish HIV natural virus suppressors from patients receiving antiretroviral therapy.

    PubMed

    Poonia, Bhawna; Pauza, C David

    2014-01-01

    Prolonged antiretroviral therapy (ART) with effective HIV suppression and reconstitution of CD4 T cells, fails to restore CD8 T cell lytic effector function that is needed to eradicate the viral reservoir. Better understanding of the phenotype and function of circulating CD8 cells in HIV patients will contribute to new targeted therapies directed at increasing CD8 T cell lytic effector function and destruction of the viral reservoir. We show that CD8 T cells from ART treated patients had sharply reduced expression of CD56 (neural cell adhesion molecule-1), a marker associated with cytolytic function whereas elite patients who control HIV in the absence of ART had CD56+ CD8 T cell levels similar to uninfected controls. The CD56+ CD8 T cells had higher perforin upregulation as well as degranulation following stimulation with HIV gag peptides compared with CD56 negative CD8 T cells. Elite patients had the highest frequencies of perforin producing CD56+ CD8 T cells among all HIV+ groups. In patients receiving ART we noted high levels of the exhaustion marker TIM-3 on CD56+ CD8 T cells, implying that defective effector function was related to immune exhaustion. CD56+ CD8 T cells from elite or treated HIV patients responded to PMA plus ionomycin stimulation, and expressed transcription factors T-bet and EOMES at levels similar to uninfected controls. Consequently, the lytic effector defect in chronic HIV disease is due to immune exhaustion and quantitative loss of CD56+ CD8 T cells and this defect is not repaired in patients where viremia is suppressed and CD4 T cells are recovered after ART. Reconstituting the cytotoxic CD56+ subset of CD8+ T cells through new interventions might improve the lytic effector capacity and contribute to reducing the viral reservoir. Our initial studies indicate that IL-15 treatment partly reverses the CD56 defect, implying that myeloid cell defects could be targeted for immune therapy during chronic HIV disease.

  18. Interim Results from a Study of the Impacts of Tin (II) Based Mercury Treatment in a Small Stream Ecosystem: Tims Branch, Savannah River Site

    SciTech Connect

    Looney, Brian; BryanJr., Larry; Mathews, Teresa J; Peterson, Mark J; Roy, W Kelly; Jett, Robert T; Smith, John G

    2012-03-01

    A research team is assessing the impacts of an innovative mercury treatment system in Tims Branch, a small southeastern stream. The treatment system, installed in 2007, reduces and removes inorganic mercury from water using tin(II) (stannous) chloride addition followed by air stripping. The system results in discharge of inorganic tin to the ecosystem. This screening study is based on historical information combined with measurements of contaminant concentrations in water, fish, sediment, biofilms and invertebrates. Initial mercury data indicate that first few years of mercury treatment resulted in a significant decrease in mercury concentration in an upper trophic level fish, redfin pickerel, at all sampling locations in the impacted reach. For example, the whole body mercury concentration in redfin pickerel collected from the most impacted pond decreased approximately 72% between 2006 (pre-treatment) and 2010 (post-treatment). Over this same period, mercury concentrations in the fillet of redfin pickerel in this pond were estimated to have decreased from approximately 1.45 {micro}g/g (wet weight basis) to 0.45 {micro}g/g - a decrease from 4.8x to 1.5x the current EPA guideline concentration for mercury in fillet (0.3 {micro}g/g). Thermodynamic modeling, scanning electron microscopy, and other sampling data for tin suggest that particulate tin (IV) oxides are a significant geochemical species entering the ecosystem with elevated levels of tin measured in surficial sediments and biofilms. Detectable increases in tin in sediments and biofilms extended approximately 3km from the discharge location. Tin oxides are recalcitrant solids that are relatively non-toxic and resistant to dissolution. Work continues to develop and validate methods to analyze total tin in the collected biota samples. In general, the interim results of this screening study suggest that the treatment process has performed as predicted and that the concentration of mercury in upper trophic level

  19. Use of 1012 and 1013 Ohm resistors in TIMS analysis of Sr and Nd isotopes in sub-nanogram geological and environmental samples

    NASA Astrophysics Data System (ADS)

    Koornneef, J.; Bouman, C.; Schwieters, J.; Davies, G. R.

    2012-12-01

    Analysis of isotope ratios in small geological and environmental samples such as inclusions in diamonds or individual human hairs is ultimately limited by the detection system of the mass spectrometer. We report a technique using a TRITON Thermal Ionisation Mass-Spectrometer (TIMS) equipped with nine Faraday cups to measure sample sizes up to 10 times smaller than currently feasible. Use of current amplifiers with 1012 Ohm and 1013 Ohm resistors instead of the standard 1011 Ohm resistors promises a 2-3 fold and 4-5 fold improvement in signal to noise ratios, respectively. This improvement results in higher precision on analyses of small ion beams. The precision of measurements of 100 pg Nd and Sr standards is found to be a factor of ~2 better for the 1012 ohm resistors compared to 1011 Ohm resistors (i.e., 2RSE of 64 ppm instead of 110 ppm for a Nd analysis). The reproducibility of the 143Nd/144Nd and 87Sr/86Sr ratios for 100 pg standards using 1012 Ohm resistors is 201 ppm for Nd (2RSD, n=20) and 116 ppm for Sr (2RSD, n=10). Thus, variability in Nd and Sr isotope ratios in the 4th decimal place, e.g. 143Nd/144Nd 0.5110 - 0.5119 or 87Sr/86Sr 0.7100-0.7109, can be resolved in such small samples provided that the procedural blanks and chemical separation are optimal. A miniaturised low-blank chemical separation procedure is currently developed at the Vrije Universiteit Amsterdam. Preliminary data using current amplifiers with 1013 Ohm resistors show that the precision (2SE) on Nd isotope ratios for 143Nd sizes of 40 μV (~2,500 cps) is 1%, whereas for 1.5 mV (~ 90,000 cps) the 2SE is 480 ppm. The high gain amplifiers can thus potentially be used instead of multi ion counting and/or in the range between ion counting and Faraday cups equipped with the standard 1011 Ohm resistors. Use of the 1013 Ohm resistors is preferred over multiple ion counting systems as potential problems with non-linearity, instability, or the limited dynamic range of the ion counters are

  20. Ejecta patterns of Meteor Crater, Arizona derived from the linear un-mixing of TIMS data and laboratory thermal emission spectra

    NASA Technical Reports Server (NTRS)

    Ramsey, Michael S.; Christensen, Philip R.

    1992-01-01

    Accurate interpretation of thermal infrared data depends upon the understanding and removal of complicating effects. These effects may include physical mixing of various mineralogies and particle sizes, atmospheric absorption and emission, surficial coatings, geometry effects, and differential surface temperatures. The focus is the examination of the linear spectral mixing of individual mineral or endmember spectra. Linear addition of spectra, for particles larger than the wavelength, allows for a straight-forward method of deconvolving the observed spectra, predicting a volume percent of each endmember. The 'forward analysis' of linear mixing (comparing the spectra of physical mixtures to numerical mixtures) has received much attention. The reverse approach of un-mixing thermal emission spectra was examined with remotely sensed data, but no laboratory verification exists. Understanding of the effects of spectral mixing on high resolution laboratory spectra allows for the extrapolation to lower resolution, and often more complicated, remotely gathered data. Thermal Infrared Multispectral Scanner (TIMS) data for Meteor Crater, Arizona were acquired in Sep. 1987. The spectral un-mixing of these data gives a unique test of the laboratory results. Meteor Crater (1.2 km in diameter and 180 m deep) is located in north-central Arizona, west of Canyon Diablo. The arid environment, paucity of vegetation, and low relief make the region ideal for remote data acquisition. Within the horizontal sedimentary sequence that forms the upper Colorado Plateau, the oldest unit sampled by the impact crater was the Permian Coconino Sandstone. A thin bed of the Toroweap Formation, also of Permian age, conformably overlays the Coconino. Above the Toroweap lies the Permian Kiabab Limestone which, in turn, is covered by a thin veneer of the Moenkopi Formation. The Moenkopi is Triassic in age and has two distinct sub-units in the vicinity of the crater. The lower Wupatki member is a fine

  1. Tim Becomes an Eagle Scout.

    ERIC Educational Resources Information Center

    Fredericks, Bud

    1987-01-01

    A parent recounts his Downs Syndrome son's integration into a regular Boy Scout troop and subsequent earning of the Eagle rank. His Eagle project involved speaking about his disability in local elementary, junior high, and senior high schools. Policies of the Boy and Girl Scout organizations concerning disabled members are summarized. (CB)

  2. INTERIM RESULTS FROM A STUDY OF THE IMPACTS OF TIN(II) BASED MERCURY TREATMENT IN A SMALL STREAM ECOSYSTEM: TIMS BRANCH, SAVANNAH RIVER SITE

    SciTech Connect

    Looney, B.; Bryan, L.; Mathews, T.

    2012-03-30

    control measures have resulted in rapid responses in lake or reservoir fisheries (Joslin 1994, Turner and Southworth 1999; Orihel et al., 2007), but examples of similar responses in Hg-contaminated stream ecosystems are less common. Recent work suggests that stream systems may actually be more susceptible to mercury bioaccumulation than lakes, highlighting the need to better understand the ecological drivers of mercury bioaccumulation in stream-dwelling fish (Chasar et al. 2009, Ward et al. 2010). In the present study we examine the response of fish to remedial actions in Tims Branch, a point-source contaminated stream on the Department of Energy's (DOE) Savannah River Site in Aiken, South Carolina. This second order stream received inorganic mercury inputs at its headwaters from the 1950s-2000s which contaminated the water, sediments, and biota downstream. In 2007, an innovative mercury removal system using tin (II) chloride (stannous chloride, SnCl{sub 2}) was implemented at a pre-existing air stripper. Tin(II) reduces dissolved Hg (II) to Hg (0), which is removed by the air stripper. During this process, tin(II) is oxidized to tin (IV) which is expected to precipitate as colloidal tin(IV) oxides and hydroxides, particulate materials with relatively low toxicity (Hallas and Cooney, 1981, EPA 2002, ATSDR, 2005). The objectives of the present research are to provide an initial assessment of the net impacts of the tin(II) based mercury treatment on key biota and to document the distribution and fate of inorganic tin in this small stream ecosystem after the first several years of operating a full scale system. To support these objectives, we collected fish, sediment, water, invertebrates, and biofilm samples from Tims Branch to quantify the general behavior and accumulation patterns for mercury and tin in the ecosystem and to determine if the treatment process has resulted in: (1) a measurable beneficial impact on (i.e., decrease of) mercury concentration in upper trophic

  3. Insights into the role of the (alpha+beta) insertion in the TIM-barrel catalytic domain, regarding the stability and the enzymatic activity of chitinase A from Serratia marcescens.

    PubMed

    Zees, Athanassios C; Pyrpassopoulos, Serapion; Vorgias, Constantinos E

    2009-01-01

    Chitinase A (ChiA) from Serratia marcescens is a mesophilic enzyme with high catalytic activity and high stability. The crystal structure of ChiA has revealed a TIM-barrel fold of the catalytic domain, an (alpha+beta) insertion between the B7 beta-strand and A7 alpha-helix of the TIM-barrel, an FnIII domain at the N-terminus of the molecule and a hinge region that connects the latter to the catalytic domain. In this study, the role of the (alpha+beta) domain on the stability, catalytic activity and specificity of the enzyme was investigated by deleting this domain and studying the enzymatic and structural properties of the resulting truncated enzyme. The obtained data clearly show that by removing the (alpha+beta) domain, the thermal stability of the enzyme is substantially reduced, with an apparent T(m) of 42.0+/-1.0 degrees C, compared to the apparent T(m) of 58.1+/-1.0 degrees C of ChiA at pH 9.0. The specific activity of ChiADelta(alpha+beta) was substantially decreased, the pH optimum was shifted from 6.5 to 5.0 and the substrate and product specificities were altered.

  4. On the Law of Inertia. Translation of: Ueber das Beharrungsgesetz

    NASA Astrophysics Data System (ADS)

    Lange, Ludwig

    2014-04-01

    This article is a translation of Ludwig Lange: "Ueber das Beharrungsgesetz" in: Berichte ueber Verhandlungen der Koenigl. Saechsischen Gesellschaft der Wissenschaften, math.-physik. Klasse (Leipzig, 1885), SS. 333-351. Translated by Herbert Pfister, Institut für Theoretische Physik, Universität Tübingen, Auf der Morgenstelle 14, 72076 Tübingen, Germany; herbert.pfister@uni-tuebingen.de. Kind assistance by Julian Barbour is acknowledged.

  5. Mapping the structure of folding cores in TIM barrel proteins by hydrogen exchange mass spectrometry: the roles of motif and sequence for the indole-3-glycerol phosphate synthase from Sulfolobus solfataricus.

    PubMed

    Gu, Zhenyu; Zitzewitz, Jill A; Matthews, C Robert

    2007-04-27

    To test the roles of motif and amino acid sequence in the folding mechanisms of TIM barrel proteins, hydrogen-deuterium exchange was used to explore the structure of the stable folding intermediates for the of indole-3-glycerol phosphate synthase from Sulfolobus solfataricus (sIGPS). Previous studies of the urea denaturation of sIGPS revealed the presence of an intermediate that is highly populated at approximately 4.5 M urea and contains approximately 50% of the secondary structure of the native (N) state. Kinetic studies showed that this apparent equilibrium intermediate is actually comprised of two thermodynamically distinct species, I(a) and I(b). To probe the location of the secondary structure in this pair of stable on-pathway intermediates, the equilibrium unfolding process of sIGPS was monitored by hydrogen-deuterium exchange mass spectrometry. The intact protein and pepsin-digested fragments were studied at various concentrations of urea by electrospray and matrix-assisted laser desorption ionization time-of-flight mass spectrometry, respectively. Intact sIGPS strongly protects at least 54 amide protons from hydrogen-deuterium exchange in the intermediate states, demonstrating the presence of stable folded cores. When the protection patterns and the exchange mechanisms for the peptides are considered with the proposed folding mechanism, the results can be interpreted to define the structural boundaries of I(a) and I(b). Comparison of these results with previous hydrogen-deuterium exchange studies on another TIM barrel protein of low sequence identify, alpha-tryptophan synthase (alphaTS), indicates that the thermodynamic states corresponding to the folding intermediates are better conserved than their structures. Although the TIM barrel motif appears to define the basic features of the folding free energy surface, the structures of the partially folded states that appear during the folding reaction depend on the amino acid sequence. Markedly, the good

  6. Das menschliche Gehör und Grundlagen der Psychoakustik

    NASA Astrophysics Data System (ADS)

    Genuit, Klaus; Sottek, Roland

    Das menschliche Gehör ist ein äußerst komplexes Empfangs- und Signalverarbeitungssystem. Es ist als Schallanalysator in Leistungsfähigkeit und Vielseitigkeit von technisch-analytischen Verfahren nach wie vor unerreicht. Die Signalverarbeitung läuft auf Grundlage komplexer Prozesse ab, die in ihrer Gesamtheit bislang nicht vollständig erfasst sind. Verschiedene Modelle zur gehörgerechten Zeit- und Frequenzanalyse ahmen jene komplexen Prozesse und Verarbeitungsmechanismen nach, die im menschlichen Gehör vollzogen werden.

  7. Discrepancies in assessment of patients with rheumatoid arthritis and secondary Sjögren's syndrome by DAS28-ESR and DAS28-CRP

    PubMed Central

    Olesińska, Marzena; Paradowska-Gorycka, Agnieszka; Mańczak, Małgorzata; Felis-Giemza, Anna; Wojdasiewicz, Piotr; Szukiewicz, Dariusz

    2016-01-01

    Objectives To investigate whether a difference exists between DAS28 from CRP and DAS28 from ESR in patients with rheumatoid arthritis (RA) and secondary Sjögren's syndrome (sSS). Material and methods One group comprised patients with RA and sSS, the control group comprised patients with RA. The inclusion criteria for the RA and sSS group have been specified as follows: presence of at least one symptom of dryness, and also presence of anti-SS-A and anti-SS-B or at least focus score of one in biopsy. Results The disease activity score 28 (DAS28) was assessed using both ESR and CRP in 60 patients with RA and sSS and 59 patients with RA alone. However, concordance between these two methods was good (Cohen's κ coefficient κ = 0.60, 95% CI: 0.45-0.75 in the first group and κ = 0.71, 95% CI: 0.56-0.86 in the control group). In the group with RA and sSS, the mean value of DAS28-ESR = 5.2, whereas the mean value of DAS28-CRP = 4.7 (p < 0.0001). In the group with RA alone, mean DAS28-ESR = 4.7 while mean DAS28-CRP = 4.6; no significant difference was identified. Moreover, in RA patients with sSS, mean ESR = 39 mm/h compared with mean CRP at 25 mg/l. 79% of all patients demonstrated dysproteinaemia. There were connections between higher ESR and dysproteinaemia. In the control group there was no statistically significant difference between CRP and ESR. Conclusions Both DAS28-ESR and DAS28-CRP are useful outcome measures in RA. However, in patients with RA and sSS, DAS28 should be evaluated based on CRP. PMID:27536205

  8. Improved 206Pb/238U microprobe geochronology by the monitoring of a trace-element-related matrix effect; SHRIMP, ID-TIMS, ELA-ICP-MS and oxygen isotope documentation for a series of zircon standards

    USGS Publications Warehouse

    Black, L.P.; Kamo, S.L.; Allen, C.M.; Davis, D.W.; Aleinikoff, J.N.; Valley, J.W.; Mundil, R.; Campbell, I.H.; Korsch, R.J.; Williams, I.S.; Foudoulis, C.

    2004-01-01

    Precise isotope dilution-thermal ionisation mass spectrometry (ID-TIMS) documentation is given for two new Palaeozoic zircon standards (TEMORA 2 and R33). These data, in combination with results for previously documented standards (AS3, SL13, QGNG and TEMORA 1), provide the basis for a detailed investigation of inconsistencies in 206Pb/238U ages measured by microprobe. Although these ages are normally consistent between any two standards, their relative age offsets are often different from those established by ID-TIMS. This is true for both sensitive high-resolution ion-microprobe (SHRIMP) and excimer laser ablation-inductively coupled plasma-mass spectrometry (ELA-ICP-MS) dating, although the age offsets are in the opposite sense for the two techniques. Various factors have been investigated for possible correlations with age bias, in an attempt to resolve why the accuracy of the method is worse than the indicated precision. Crystallographic orientation, position on the grain-mount and oxygen isotopic composition are unrelated to the bias. There are, however, striking correlations between the 206Pb/238U age offsets and P, Sm and, most particularly, Nd abundances in the zircons. Although these are not believed to be the primary cause of this apparent matrix effect, they indicate that ionisation of 206Pb/238U is influenced, at least in part, by a combination of trace elements. Nd is sufficiently representative of the controlling trace elements that it provides a quantitative means of correcting for the microprobe age bias. This approach has the potential to reduce age biases associated with different techniques, different instrumentation and different standards within and between laboratories. Crown Copyright ?? 2004 Published by Elsevier B.V. All rights reserved.

  9. Structure of L-xylulose-5-Phosphate 3-epimerase (UlaE) from the anaerobic L-ascorbate utilization pathway of Escherichia coli: identification of a novel phosphate binding motif within a TIM barrel fold.

    PubMed

    Shi, Rong; Pineda, Marco; Ajamian, Eunice; Cui, Qizhi; Matte, Allan; Cygler, Miroslaw

    2008-12-01

    Three catabolic enzymes, UlaD, UlaE, and UlaF, are involved in a pathway leading to fermentation of l-ascorbate under anaerobic conditions. UlaD catalyzes a beta-keto acid decarboxylation reaction to produce L-xylulose-5-phosphate, which undergoes successive epimerization reactions with UlaE (L-xylulose-5-phosphate 3-epimerase) and UlaF (L-ribulose-5-phosphate 4-epimerase), yielding D-xylulose-5-phosphate, an intermediate in the pentose phosphate pathway. We describe here crystallographic studies of UlaE from Escherichia coli O157:H7 that complete the structural characterization of this pathway. UlaE has a triosephosphate isomerase (TIM) barrel fold and forms dimers. The active site is located at the C-terminal ends of the parallel beta-strands. The enzyme binds Zn(2+), which is coordinated by Glu155, Asp185, His211, and Glu251. We identified a phosphate-binding site formed by residues from the beta1/alpha1 loop and alpha3' helix in the N-terminal region. This site differs from the well-characterized phosphate-binding motif found in several TIM barrel superfamilies that is located at strands beta7 and beta8. The intrinsic flexibility of the active site region is reflected by two different conformations of loops forming part of the substrate-binding site. Based on computational docking of the L-xylulose 5-phosphate substrate to UlaE and structural similarities of the active site of this enzyme to the active sites of other epimerases, a metal-dependent epimerization mechanism for UlaE is proposed, and Glu155 and Glu251 are implicated as catalytic residues. Mutation and activity measurements for structurally equivalent residues in related epimerases supported this mechanistic proposal.

  10. Structure of L-Xylulose-5-Phosphate 3-Epimerase (UlaE) from the Anaerobic L-Ascorbate Utilization Pathway of Escherichia coli: Identification of a Novel Phosphate Binding Motif within a TIM Barrel Fold

    SciTech Connect

    Shi, Rong; Pineda, Marco; Ajamian, Eunice; Cui, Qizhi; Matte, Allan; Cygler, Miroslaw

    2009-01-15

    Three catabolic enzymes, UlaD, UlaE, and UlaF, are involved in a pathway leading to fermentation of L-ascorbate under anaerobic conditions. UlaD catalyzes a {beta}-keto acid decarboxylation reaction to produce L-xylulose-5-phosphate, which undergoes successive epimerization reactions with UlaE (L-xylulose-5-phosphate 3-epimerase) and UlaF (L-ribulose-5-phosphate 4-epimerase), yielding D-xylulose-5-phosphate, an intermediate in the pentose phosphate pathway. We describe here crystallographic studies of UlaE from Escherichia coli O157:H7 that complete the structural characterization of this pathway. UlaE has a triosephosphate isomerase (TIM) barrel fold and forms dimers. The active site is located at the C-terminal ends of the parallel {beta}-strands. The enzyme binds Zn{sup 2+}, which is coordinated by Glu155, Asp185, His211, and Glu251. We identified a phosphate-binding site formed by residues from the {beta}1/{alpha}1 loop and {alpha}3' helix in the N-terminal region. This site differs from the well-characterized phosphate-binding motif found in several TIM barrel superfamilies that is located at strands {beta}7 and {beta}8. The intrinsic flexibility of the active site region is reflected by two different conformations of loops forming part of the substrate-binding site. Based on computational docking of the L-xylulose 5-phosphate substrate to UlaE and structural similarities of the active site of this enzyme to the active sites of other epimerases, a metal-dependent epimerization mechanism for UlaE is proposed, and Glu155 and Glu251 are implicated as catalytic residues. Mutation and activity measurements for structurally equivalent residues in related epimerases supported this mechanistic proposal.

  11. A Cinnamon-Derived Procyanidin Compound Displays Anti-HIV-1 Activity by Blocking Heparan Sulfate- and Co-Receptor- Binding Sites on gp120 and Reverses T Cell Exhaustion via Impeding Tim-3 and PD-1 Upregulation

    PubMed Central

    Connell, Bridgette Janine; Chang, Sui-Yuan; Prakash, Ekambaranellore; Yousfi, Rahima; Mohan, Viswaraman; Posch, Wilfried; Wilflingseder, Doris; Moog, Christiane; Kodama, Eiichi N.; Clayette, Pascal; Lortat-Jacob, Hugues

    2016-01-01

    Amongst the many strategies aiming at inhibiting HIV-1 infection, blocking viral entry has been recently recognized as a very promising approach. Using diverse in vitro models and a broad range of HIV-1 primary patient isolates, we report here that IND02, a type A procyanidin polyphenol extracted from cinnamon, that features trimeric and pentameric forms displays an anti-HIV-1 activity against CXCR4 and CCR5 viruses with 1–7 μM ED50 for the trimer. Competition experiments, using a surface plasmon resonance-based binding assay, revealed that IND02 inhibited envelope binding to CD4 and heparan sulphate (HS) as well as to an antibody (mAb 17b) directed against the gp120 co-receptor binding site with an IC50 in the low μM range. IND02 has thus the remarkable property of simultaneously blocking gp120 binding to its major host cell surface counterparts. Additionally, the IND02-trimer impeded up-regulation of the inhibitory receptors Tim-3 and PD-1 on CD4+ and CD8+ cells, thereby demonstrating its beneficial effect by limiting T cell exhaustion. Among naturally derived products significantly inhibiting HIV-1, the IND02-trimer is the first component demonstrating an entry inhibition property through binding to the viral envelope glycoprotein. These data suggest that cinnamon, a widely consumed spice, could represent a novel and promising candidate for a cost-effective, natural entry inhibitor for HIV-1 which can also down-modulate T cell exhaustion markers Tim-3 and PD-1. PMID:27788205

  12. Time evolution of a rifted continental arc: Integrated ID-TIMS and LA-ICPMS study of magmatic zircons from the Eastern Srednogorie, Bulgaria

    NASA Astrophysics Data System (ADS)

    Georgiev, S.; von Quadt, A.; Heinrich, C. A.; Peytcheva, I.; Marchev, P.

    2012-12-01

    Eastern Srednogorie in Bulgaria is the widest segment of an extensive magmatic arc that formed by convergence of Africa and Europe during Mesozoic to Tertiary times. Northward subduction of the Tethys Ocean beneath Europe in the Late Cretaceous gave rise to a broad range of basaltic to more evolved magmas with locally associated Cu-Au mineralization along this arc. We used U-Pb geochronology of single zircons to constrain the temporal evolution of the Upper Cretaceous magmatism and the age of basement rocks through which the magmas were emplaced in this arc segment. High precision isotope dilution-thermal ionization mass spectrometry (ID-TIMS) was combined with laser ablation-inductively coupled plasma mass spectrometry (LA-ICPMS) for spatial resolution within single zircon grains. Three tectono-magmatic regions are distinguished from north to south within Eastern Srednogorie: East Balkan, Yambol-Burgas and Strandzha. Late Cretaceous magmatic activity started at ~ 92 Ma in the northernmost East Balkan region, based on stratigraphic evidence and limited geochronology, with the emplacement of minor shallow intrusions and volcanic rocks onto pre-Cretaceous basement. In the southernmost Strandzha region, magmatism was initiated at ~ 86 Ma with emplacement of gabbroic to dioritic intrusions and related dikes into metamorphic basement rocks that have previously been overprinted by Jurassic-Lower Cretaceous metamorphism. The Yambol-Burgas region is an extensional basin between the East Balkan and the Strandzha regions, which broadens and deepens toward the Black Sea further east and is filled with a thick pile of marine sediments and submarine extrusive volcanic rocks accompanied by coeval intrusions. This dominantly mafic magmatism in the intermediate Yambol-Burgas region commenced at ~ 81 Ma and produced large volumes of potassium-rich magma until ~ 78 Ma. These shoshonitic to ultrapotassic basaltic to intermediate magmas formed by differentiation of ankaramitic (high

  13. Next-Generation DAS for the Russian VLBI-Network

    NASA Astrophysics Data System (ADS)

    Nosov, E.

    2011-07-01

    The digital DAS R1002M was developed by Institute of Applied Astronomy. The system consists of 16 Base Band Converters (BBC) with digital signals processing on video frequencies and provides the total data recording rate up to 2048 Mbps. The data format is VSI-H. Input frequency range is 100-1000 MHz. Selectable bandwidths of BBC's are from 0.5 to 32 MHz. The sample rate of ADC is 64 Msps. R1002M system is compatible to analog systems and is intended for their replacement. Two R1002M systems have been installed in Svetloe and Zelenchukskaya observatories. The results of Svetloe-Zelenchukskaya observation with use of R1002M are considered. In 2011 the same system will be established in Badary.

  14. U-Pb (ID-TIMS) baddeleyite ages and paleomagnetism of 1.79 and 1.59 Ga tholeiitic dyke swarms, and position of the Rio de la Plata Craton within the Columbia supercontinent

    NASA Astrophysics Data System (ADS)

    Teixeira, Wilson; D'Agrella-Filho, Manoel S.; Hamilton, Mike A.; Ernst, Richard E.; Girardi, Vicente A. V.; Mazzucchelli, Maurizio; Bettencourt, Jorge S.

    2013-08-01

    The Tandilia Terrane (southernmost fringe of the Rio de la Plata Craton) is an igneous and metamorphic complex produced by an accretionary orogeny (2.25-2.02 Ga). Calc-alkaline acidic dykes with E-W strike and a major shear zone with similar orientation are related with the late orogeny stage, as supported by field relations. In a previous study the acid dykes gave 40A-39Ar ages of 2007 ± 24 Ma to 2020 ± 24 Ma. A N and NW trending tholeiitic dyke swarm (Tandil swarm) is also present in the Tandilia Terrane. One sample from the NW-trending subset previously gave a U-Pb (ID-TIMS) baddeleyite age of 1588 ± 11 Ma. New precise U-Pb (ID-TIMS) baddeleyite dating of both N- and NW-trending Tandil dykes yielded crystallization ages of 1589 ± 3 Ma, 1588 ± 3 Ma and 1588 ± 3 Ma. Significantly older tholeiitic dykes known as the Florida swarm occur in the Northern Rio de la Plata Craton, for which a U-Pb (ID-TIMS) baddeleyite age of 1790 ± 5 Ma was previously reported. Consequently intermittent rifting (1.79, 1.59 Ga) took place after tectonic stabilization of the late Paleoproterozoic lithosphere (proto-Rio de la Plata Craton). The available geochemical data for the 1.59 Ga Tandil dykes define low- and high-TiO2 trends, although, only the low-TiO2 subgroup is firmly dated. Both the Tandil and Florida dykes have geochemical and Nd-Sr characteristics consistent with derivation from heterogeneous mantle sources that underwent metasomatic effects. The Tandil dykes may be linked with the 1.57 ± 0.02 Ga Capivarita anorthosite which occurs to the east of the northern part of the craton. Correlatives on other crustal blocks may include those in Baltica such as bimodal rock association (including the Breven-Hällefors and Åland-Åboland diabase dykes) and in the reconstructed Gawler Craton/NW Laurentia dolerites, bimodal magmatism and IOCG deposits. Contemporary within-plate bimodal associations are also present in the SW Amazonian Craton. Paleomagnetic data for the 1790 Ma

  15. Psychometric Properties of the Disability Assessment Schedule (DAS) for Behavior Problems: An Independent Investigation

    ERIC Educational Resources Information Center

    Tsakanikos, Elias; Underwood, Lisa; Sturmey, Peter; Bouras, Nick; McCarthy, Jane

    2011-01-01

    The present study employed the Disability Assessment Schedule (DAS) to assess problem behaviors in a large sample of adults with ID (N = 568) and evaluate the psychometric properties of this instrument. Although the DAS problem behaviors were found to be internally consistent (Cronbach's [alpha] = 0.87), item analysis revealed one weak item…

  16. Detecting Changes Following the Provision of Assistive Devices: Utility of the WHO-DAS II

    ERIC Educational Resources Information Center

    Raggi, Alberto

    2010-01-01

    The World Health Organization Disability Assessment Schedule II (WHO-DAS II) is a non-disease-specific International Classification of Functioning, Disability, and Health-based disability assessment instrument developed to measure activity limitations and restrictions to participation. The aim of this pilot study is to evaluate WHO-DAS II…

  17. 50 CFR 648.10 - VMS and DAS requirements for vessel owners/operators.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 50 Wildlife and Fisheries 12 2012-10-01 2012-10-01 false VMS and DAS requirements for vessel... UNITED STATES General Provisions § 648.10 VMS and DAS requirements for vessel owners/operators. (a) VMS Demarcation Line. The VMS Demarcation Line is defined by straight lines connecting the following...

  18. 50 CFR 648.10 - VMS and DAS requirements for vessel owners/operators.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 50 Wildlife and Fisheries 8 2010-10-01 2010-10-01 false VMS and DAS requirements for vessel owners... General Provisions § 648.10 VMS and DAS requirements for vessel owners/operators. (a) VMS Demarcation Line. The VMS Demarcation Line is defined by straight lines connecting the following coordinates in...

  19. 50 CFR 648.10 - VMS and DAS requirements for vessel owners/operators.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 50 Wildlife and Fisheries 10 2011-10-01 2011-10-01 false VMS and DAS requirements for vessel... UNITED STATES General Provisions § 648.10 VMS and DAS requirements for vessel owners/operators. (a) VMS Demarcation Line. The VMS Demarcation Line is defined by straight lines connecting the following...

  20. 50 CFR 648.10 - VMS and DAS requirements for vessel owners/operators.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 50 Wildlife and Fisheries 12 2013-10-01 2013-10-01 false VMS and DAS requirements for vessel... UNITED STATES General Provisions § 648.10 VMS and DAS requirements for vessel owners/operators. (a) VMS Demarcation Line. The VMS Demarcation Line is defined by straight lines connecting the following...

  1. A tightly packed hydrophobic cluster directs the formation of an off-pathway sub-millisecond folding intermediate in the alpha subunit of tryptophan synthase, a TIM barrel protein.

    PubMed

    Wu, Ying; Vadrevu, Ramakrishna; Kathuria, Sagar; Yang, Xiaoyan; Matthews, C Robert

    2007-03-01

    Protein misfolding is now recognized as playing a crucial role in both normal and pathogenic folding reactions. An interesting example of misfolding at the earliest state of a natural folding reaction is provided by the alpha-subunit of tryptophan synthase, a (beta/alpha)(8) TIM barrel protein. The molecular basis for the formation of this off-pathway misfolded intermediate, I(BP), and a subsequent on-pathway intermediate, I1, was probed by mutational analysis of 20 branched aliphatic side-chains distributed throughout the sequence. The elimination of I(BP) and the substantial destabilization of I1 by replacement of a selective set of the isoleucine, leucine or valine residues (ILV) with alanine in a large ILV cluster external-to-the-barrel and spanning the N and C termini (cluster 2) implies tight-packing at most sites in both intermediates. Differential effects on I(BP) and I1 for replacements in alpha3, beta4 and alpha8 at the boundaries of cluster 2 suggest that their incorporation into I1 but not I(BP) reflects non-native folds at the edges of the crucial (beta/alpha)(1-2)beta(3) core in I(BP). The retention of I(BP) and the smaller and consistent destabilization of both I(BP) and I1 by similar replacements in an internal-to-the-barrel ILV cluster (cluster 1) and a second external-to-the-barrel ILV cluster (cluster 3) imply molten globule-like packing. The tight packing inferred, in part, for I(BP) or for all of I1 in cluster 2, but not in clusters 1 and 3, may reflect the larger size of cluster 2 and/or the enhanced number of isoleucine, leucine and valine self-contacts in and between contiguous elements of secondary structure. Tightly packed ILV-dominated hydrophobic clusters could serve as an important driving force for the earliest events in the folding and misfolding of the TIM barrel and other members of the (beta/alpha)(n) class of proteins.

  2. Das Programm Oder 2006. Hochwasserschutz in Polen im Zuge der EU-Osterweiterung

    NASA Astrophysics Data System (ADS)

    Kühne, Olaf

    Hochwasser ist ein natürliches Ereignis: Seit jeher sind die Menschen mit Hochwasser und seinen Auswirkungen konfrontiert. Das Ausmaß von Hochwasser reicht dabei von Straßenüberschwemmungen bis zur Überflutung ganzer Landesteile. Auch im Oderflußsystem waren und sind Überschwemmungen keine Seltenheit, in den letzten 200 Jahren ereigneten sie sich in den Jahren 1813, 1838, 1854, 1870, 1903, 1958, 1965, 1970, 1972, 1977, 1981, 1985 und 1997. Das Hochwasser von 1997 war jedoch das schwerste im genannten Zeitraum. Als Reaktion auf das Hochwasser von 1997 wurde in der betroffenen Region das Programm 〝Oder 2006`` entwickelt. Mit seiner Hilfe sollen die Auswirkungen künftiger Hochwasserereignisse abgeschwächt werden.

  3. Crosslinking effect of dialdehyde starch (DAS) on decellularized porcine aortas for tissue engineering.

    PubMed

    Wang, Xu; Gu, Zhipeng; Qin, Huanhuan; Li, Li; Yang, Xu; Yu, Xixun

    2015-08-01

    Biological tissue-derived biomaterials must be chemically modified to avoid immediate degradation and immune response before being implanted in human body to replace malfunctioning organs. DAS with active aldehyde groups was employed to replace glutaraldehyde (GA), a most common synthetic crosslinking reagent in clinical practice, to fix bioprostheses for lower cytotoxicity. The aim of this research was to evaluate fixation effect of DAS. The tensile strength, crosslinking stability, cytotoxicity especially the anti-calcification capability of DAS-fixed tissues were investigated. The tensile strength and resistance to enzymatic degradation of samples were increased after DAS fixation, the values maintained stably in D-Hanks solution for several days. Meanwhile, ultrastructure of samples preserved well and the anti-calcification capability of samples were improved, the amount of positive staining points in the whole visual field of 15% DAS-fixed samples was only 0.576 times to GA-fixed ones. Moreover, both unreacted DAS and its hydrolytic products were nontoxic in cytotoxicity study. The results demonstrated DAS might be an effective crosslinking reagent to fix biological tissue-derived biomaterials in tissue engineering. PMID:26038106

  4. Compositional safety of herbicide-tolerant DAS-81910-7 cotton.

    PubMed

    Herman, Rod A; Fast, Brandon J; Johnson, Tempest Y; Sabbatini, Jane; Rudgers, Gary W

    2013-11-27

    DAS-81910-7 cotton is a transgenic event that was transformed to contain the aad-12 and pat genes. These genes code for the AAD-12 and PAT proteins, which confer tolerance to the herbicides 2,4-D and glufosinate, respectively. Crop composition studies were conducted with DAS-81910-7 cotton (both nonsprayed and sprayed with 2,4-D and glufosinate) to comply with requirements of regulatory authorities responsible for evaluating crop safety. Results indicate compositional equivalence between DAS-81910-7 cottonseed and nontransgenic cottonseed and between sprayed and nonsprayed DAS-81910-7 cottonseed. This study builds on the results from many prior studies which support the conclusion that transgenesis is less likely to unexpectedly alter the composition of crops as compared with traditional breeding.

  5. NMR analysis of partially folded states and persistent structure in the alpha subunit of tryptophan synthase: implications for the equilibrium folding mechanism of a 29-kDa TIM barrel protein.

    PubMed

    Vadrevu, Ramakrishna; Wu, Ying; Matthews, C Robert

    2008-03-14

    Structural insights into the equilibrium folding mechanism of the alpha subunit of tryptophan synthase (alpha TS) from Escherichia coli, a (beta alpha)(8) TIM barrel protein, were obtained with a pair of complementary nuclear magnetic resonance (NMR) spectroscopic techniques. The secondary structures of rare high-energy partially folded states were probed by native-state hydrogen-exchange NMR analysis of main-chain amide hydrogens. 2D heteronuclear single quantum coherence NMR analysis of several (15)N-labeled nonpolar amino acids was used to probe the side chains involved in stabilizing a highly denatured intermediate that is devoid of secondary structure. The dynamic broadening of a subset of isoleucine and leucine side chains and the absence of protection against exchange showed that the highest energy folded state on the free-energy landscape is stabilized by a hydrophobic cluster lacking stable secondary structure. The core of this cluster, centered near the N-terminus of alpha TS, serves as a nucleus for the stabilization of what appears to be nonnative secondary structure in a marginally stable intermediate. The progressive decrease in protection against exchange from this nucleus toward both termini and from the N-termini to the C-termini of several beta-strands is best described by an ensemble of weakly coupled conformers. Comparison with previous data strongly suggests that this ensemble corresponds to a marginally stable off-pathway intermediate that arises in the first few milliseconds of folding and persists under equilibrium conditions. A second, more stable intermediate, which has an intact beta-barrel and a frayed alpha-helical shell, coexists with this marginally stable species. The conversion of the more stable intermediate to the native state of alpha TS entails the formation of a stable helical shell and completes the acquisition of the tertiary structure.

  6. Highlighting young investigators: guest editor Ramanuj DasGupta. Ram DasGupta: pushing the boundaries of β-catenin signaling and drug development.

    PubMed

    Cowin, Pamela

    2013-12-01

    From generating the TOP-GAL mouse to pioneering high-throughput RNAi, and small molecule chemical genetic screens in Drosophila and mammalian cells, Ram DasGupta has consistently developed innovative technological tools of immense value to the fields in which he has chosen to work.

  7. The WHO-DAS II: Measuring Outcomes of Hearing Aid Intervention for Adults

    PubMed Central

    McArdle, Rachel; Chisolm, Theresa H.; Abrams, Harvey B.; Wilson, Richard H.; Doyle, Patrick J.

    2005-01-01

    The World Health Organization's Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument that provides six domain scores and a total, aggregate score. Two of the domain scores, communication and participation, and the total score, have good validity, internal-consistency reliability, and test-retest stability in individuals with adult-onset hearing loss. As such, these two domain scores and the total WHO-DAS II score may be useful as generic outcome measures to assess the effectiveness of hearing aid intervention for this population. Before the use of the WHO-DAS II in hearing aid clinical trials, however, the responsiveness of the instrument and the short- and long-term outcomes to hearing aid intervention had to be determined. Responsiveness and outcomes were assessed in 380 veterans (approximately half received hearing aids and half served as controls) by examining group differences, effect-size estimates, and individual differences as a function of hearing aid intervention. For comparison, data also were obtained on two disease-specific measures, the APHAB and the HHIE. The WHO-DAS II communication domain and total scores were sufficiently responsive to hearing aid intervention for use in future studies in which group differences are to be detected. The WHO-DAS II participation domain was not sufficiently responsive to hearing aid intervention. The APHAB and HHIE, both disease-specific measures, were more sensitive to hearing aid intervention than the generic measure. The short- and long-term outcomes of hearing aid intervention were also examined in the present study. Group outcomes for hearing aid intervention can be expected to be stable for at least 6 months when measured by WHO-DAS II total score and for at least 12 months when measured by the WHO-DAS II communication domain scores. Effect-size estimates and examination of the number of individuals exhibiting change scores exceeding 90% critical differences for true changes in

  8. BOOK REVIEW: Geheimnisvolles Universum - Europas Astronomen entschleiern das Weltall

    NASA Astrophysics Data System (ADS)

    Duerbeck, H. W.; Lorenzen, D. H.

    2002-12-01

    The 25th birthday of ESO, in 1987, was celebrated by the publication of an illustrated popular book, "Exploring the Southern Sky" (Springer-Verlag 1987), which also saw editions in Danish, English, French, German, and Spanish. Written and illustrated by the ESO staff members Svend Laustsen, Claus Madsen and Richard M. West, its many pictures were mainly taken with the ESO 3.6m and Schmidt telescopes. The structure of the book - perhaps at that time somewhat unusual - started with things far away (Universe and galaxies), zoomed in to the Milky Way, and finally reached the Solar System (with a concluding chapter dealing with the La Silla observatory). Now, with the 4 units of the Very Large Telescope in full operation, and on the occasion of ESO's 40th birthday, another jubilee book has appeared: "Geheimnisvolles Universum: Europas Astronomen entschleiern das Weltall", written by the science journalist Dirk H. Lorenzen, of Hamburg, Germany, and prefaced by Catherine Cesarsky, Director General of ESO. Presumably, this book will also soon become available in more languages spoken in ESO member countries. Thus it may be worthwhile to review the first edition, although some readers may like to wait for more easily accessible editions. Before going into details, let me first mention that I find this a very impressing book, great to look at and refreshing to read. With ESO seen through the eyes of a visitor, things gain a perspective that is quite different from that of the previous book, and at least as attractive. It comes as no surprise that the book starts with a visit of ESO's showcase, the Paranal Observatory, and the writer not only notes down his own impressions, but also cites statements of some of the many people that keep Paranal going - technicians and staff astronomers. This mixture of texts provides a good impression of the operations at a large observatory for the general reader. The two more 'astronomical' parts that follow deal with star and planet

  9. Characterization of depositional age and structure of sedimentary successions by U-Pb TIMS and LA-ICP-MS dating of volcanic horizons and detrital zircons: an example from the western Trondheim Nappe Complex, Scandinavian Caledonides

    NASA Astrophysics Data System (ADS)

    Gasser, Deta; Grenne, Tor; Corfu, Fernando; Eivind Augland, Lars

    2016-04-01

    Revealing the absolute depositional age of non-fossiliferous sedimentary successions represents a long-lasting challenge in Earth Sciences. Lacking age control hampers the correct interpretation of the temporal evolution of depositional systems, and, if deformed, of the architecture of fold-and-thrust belts. Dating of detrital zircons within clastic sedimentary successions has over the past decades become a popular method to approximate the absolute depositional age and to characterize the source areas of such rocks. If combined with other geochronological information, such as dating of contemporaneous volcanic horizons, a much better resolution of the stratigraphy and structure of non-fossiliferous sedimentary successions can be achieved. The western Trondheim nappe complex in the central Scandinavian Caledonides is a classical area in this respect. On top of Late Cambrian to Early Ordovician ophiolitic fragments, various volcanic, volcano-clastic and clastic successions tell a complex story of island-arc formation, ocean closure and continent collision. Several famous fossil horizons indicate deposition during the Middle to Upper Ordovician (ca. 470-445 Ma), but large areas lack an absolute age control and several contrasting stratigraphic schemes and structural interpretations have been presented in the past. In this contribution we present the results of LA-ICP-MS detrital U-Pb zircon dating of clastic horizons as well as U-Pb TIMS zircon dating of volcanic horizons and magmatic clasts in conglomerates in order to characterize the depositional age and structure of the western Trondheim nappe complex in more detail. Together with field observations, including way up criteria, the zircon data enable significant revisions of existing stratigraphic and structural models. At least four (volcano-)sedimentary successions can be distinguished above the ca. 480-485 Ma greenstones: (1) ca. 470-463 Ma shales, limestones and andesitic porphyrites (Hølonda and Fanabekken

  10. The Temporal Relationship Between Alkaline and Tholeiitic Magmatism in the Paraná-Etendeka Igneous Province: ID-TIMS U-Pb Ages of the José Fernandes Gabbro and Dykes of the Ponta Grossa Arch, Brazil

    NASA Astrophysics Data System (ADS)

    de Almeida, V. V.; Heaman, L. M.; Shaulis, B.; Janasi, V. A.; Faleiros, F. M.

    2015-12-01

    The Ponta Grossa Arch (PGA) region in S-SE Brazil hosts prominent NW-oriented lineaments with hundreds of tholeiitic dykes of the Ponta Grossa Dyke Swarm (PGDS) and also alkaline intrusions concentrated between the Guapiara and São Jerônimo-Curiúva lineaments. Many of these intrusions lack more robust geochronological data; the alkaline intrusions appear to be both coeval with (e.g. Jacupiranga, Juquiá with ~130 Ma) and much younger than (e.g. Tunas, Cananéia with ~85 Ma) the adjacent Paraná basaltic lavas. We present in this work the first ID-TIMS U-Pb baddeleyite-zircon ages for diabase dykes of the Guapiara Lineament and for an alkaline intrusion (José Fernandes Gabbro) in order to determine more precisely the space-time relation between alkaline and tholeiitic magmatism in the PGA. The dated diabase dykes show high TiO2 (up to 4.5 wt%) and variable Sr (405-890 ppm). Baddeleyite-zircon concordia ages are 130.3 ± 0.5 Ma (all uncertainties reported at 2σ) and 131.3 ± 0.7 Ma, within the range of previously reported step-heating 40Ar/39Ar ages (133.1 ± 0.5 to 130.8 ± 0.4 Ma), confirming a good coherency between crystallization and cooling ages. Three distinct samples of the José Fernandes Gabbro were investigated (melagabbro, banded gabbro and quartz monzogabbro). Preliminary baddeleyite U-Pb ages obtained for a crust-contaminated quartz monzogabbro (52-56% SiO2; ~4% K2O; δ18O= +6.7 to +7.5‰; eNd(T)= -10) yielded a weighted mean 206Pb/238U data of 133.56 ± 0.31 Ma as the age for the intrusion. The age is about 2 m.y. older than the U-Pb ages obtained for the diabase dykes of the PGA. FAPESP proc. 2012/06082-6; CNPq 202043/2014-2

  11. Bottom characterization of Lagoa das Furnas on São Miguel, Azores archipelago

    NASA Astrophysics Data System (ADS)

    Andersson, Tommy; Hermelin, Otto; Skelton, Alasdair; Jakobsson, Martin

    2016-07-01

    Lagoa das Furnas is a crater lake located in an area exposed to geohazards from earthquakes and volcanic activity on the island of São Miguel in the Azores Archipelago. Geophysical mapping of Lagoa das Furnas reveals a previously undiscovered volcanic dome. This dome is comprised largely of subaquatic pyroclastic debris of trachytic composition. Sedimentological, petrological, geochemical and geochronological studies of pyroclastic deposits from the dome link it to the historically documented "Furnas 1630" eruption. The chemistry of glass and crystal fragments sampled from the dome suggests that it is comprised of more evolved magma than that of the main Furnas 1630 dome located 1400 m away. This suggests that the dome was formed during a final phase of the 1630 eruption in the Lagoa das Furnas area.

  12. Amerikas Einschätzung der deutschen Atomforschung: Das deutsche Uranprojekt

    NASA Astrophysics Data System (ADS)

    Walker, Mark

    2002-07-01

    Die amerikanischen Wissenschaftler und ihre emigrierten Kollegen, die am Bau der Atombombe beteiligt waren, verfügten über sehr widersprüchliche und großteils falsche Informationen über den Fortschritt des deutschen Uranprogramms. Noch nach Kriegsende lässt sich dies an Aussagen des Leiters der amerikanischen Alsos-Mission, Samuel Goudsmit, festmachen. Tatsächlich war das deutsche Programm hinsichtlich seiner wissenschaftlichen Grundlagen und des Managements nicht so unterlegen, wie vielfach behauptet wurde. Aber die deutschen Behörden waren nicht in der Lage, Geld und Ressourcen in gleichem Maße in das Uranprojekt zu investieren, wie etwa in das Peenemünder Raketenprojekt.

  13. Visualization of DAS28, SDAI, and CDAI: the magic carpets of rheumatoid arthritis.

    PubMed

    Futó, Gábor; Somogyi, Attila; Szekanecz, Zoltán

    2014-05-01

    There has been continuous debate regarding the applicability of various composite measures for the assessment of disease activity in rheumatoid arthritis (RA). In order to further dissect this issue, we numerically and graphically modeled 28-joint disease activity scale (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI) by three-dimensional (3D) plotting. We wished to graphically visualize the relative contribution of various elements in the three activity indices to each other. We calculated DAS28 (3 variables), SDAI, and CDAI by the standard equations. We plotted 3D "carpets" showing all combinations of the corresponding variables yielding to DAS28 = 5.1, DAS28 = 3.2, DAS28 = 2.6, SDAI = 26, SDAI = 11, and SDAI = 3.3. We also plotted the 3D carpet for CDAI. In patients with high or moderate disease activity, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) was not a major confounding factor when calculating DAS28 and SDAI, respectively. In contrast, ESR and CRP highly overshadowed changes in joint counts and global assessments in patients with low disease activity (LDA) or those in remission. No reliable assessment of LDA can be performed in cases where ESR >54 mm/h or CRP >20 mg/dl. Similarly, remission cannot be determined if ESR >19 mm/h or CRP >5 mg/dl. As CDAI does not include acute phase reactants, CDAI may be a useful tool even in states of remission or LDA. Our results suggest that acute phase reactants are indeed major confounding factors and should be omitted when assessing RA disease activity at least in special cases. PMID:24599677

  14. A Waterman's Journey: Tim Junkin's Bloodsworth

    ERIC Educational Resources Information Center

    Ward, Nathan

    2004-01-01

    Before he was wrongly sent to death row for the rape and murder of a nine-year-old girl in 1984, Kirk Bloodsworth enjoyed the life of a Chesapeake Bay waterman. Convicted largely on the testimony of a seven- and a ten-year-old eyewitness, by 1989 Johnson had exhausted almost every legal option available--after winning a new trial, he was convicted…

  15. Hydrostatic shoe bearing system for the TIM

    NASA Astrophysics Data System (ADS)

    Ruiz Schneider, Elfego; Sohn, Erika; Quiros-Pacheco, Fernando; Godoy, Javier; Farah Simon, Alejandro; Quintanilla, R.; Soto, P.; Salas, Luis; Cruz-Gonzales, Irene

    2000-08-01

    We present an active, low cost hydrostatic shoe bearing system for the Mexican Infrared Telescope which solves the suspension and motion of a 100 ton, 7.8 m telescope. Different geometries are analyzed to optimize the shoe's pressure print. These designs offer a self-adjusting action between the shoe's sliding path and the girth track. Different parameters such as pressure, temperature and proximity are measured and implemented into a control system in order to stabilize the bearing from the fluid's thermal viscosity effects. A simple method for fluid injection is discussed.

  16. Learning to Teach--Tim's Story

    ERIC Educational Resources Information Center

    Rowland, Tim

    2006-01-01

    This article is both a sequel and a companion to the account by Gill Hatch, published in "MT196," of her experience in her first teaching post--as a College of Education Assistant Lecturer. A chance remark by Gill in 2001 made the author aware that their careers as mathematics teachers had begun in similar environments. They set about compiling a…

  17. Consumer Feedback: Tiny Tim Is Dead!

    ERIC Educational Resources Information Center

    Remmes, Harold

    1974-01-01

    In a paper delivered (June, 1974) at the Nationwide Staff Meeting of the National Easter Seal Society for Crippled Children and Adults, the author stresses the need for consumer involvement in agencies providing services to the handicapped. (LS)

  18. Knaurs moderne Astronomie. Das Standardwerk völlig neu bearbeitet.

    NASA Astrophysics Data System (ADS)

    Störig, H. J.

    This elementary textbook covers the following topics: cosmic dimensions, the sun as a star, the solar system, basic knowledge about stars, binary and variable stars, the cosmic windows, birth and death of stars, the Milky Way, extragalactic systems and cosmology. Contents: 1. Weißt du, wieviel Sterne stehen... 2. Die Sonne als Durchschnittsstern. 3. Das Sonnensystem im Überblick. 4. Grundwissen über Sterne. 5. Doppelsterne und Veränderliche. 6. Fenster zum Weltall. 7. Geburt und Tod der Sterne. 8. Die Milchstraße. 9. Extragalaktische Systeme. 10. Das Weltganze in Raum und Zeit.

  19. Anbindung des SISIS-SunRise-Bibliothekssystems an das zentrale Identitätsmanagement

    NASA Astrophysics Data System (ADS)

    Ebner, Ralf; Pretz, Edwin

    Wir berichten über Konzepte und Implementierungen zur Datenprovisionierung aus den Personenverwaltungssystemen der Technischen Universität München (TUM) über das zentrale Metadirectory am Leibniz-Rechenzentrum (LRZ) in das SISIS-SunRise-Bibliothekssystem der Universitätsbibliothek der TUM (TUB). Es werden drei Implementierungsvarianten diskutiert, angefangen von der Generierung und Übertragung einfacher CSV-Dateien über ein OpenLDAP-basiertes Konzept als Backend für die SISIS-Datenbank bis zur endgültigen Implementierung mit dem OCLC IDM Connector.

  20. An exploratory analysis of the factor structure of the Dysfunctional Attitude Scale-Form A (DAS).

    PubMed

    Moore, Michael T; Fresco, David M; Segal, Zindel V; Brown, Timothy A

    2014-10-01

    A number of studies have attempted to identify the factor structure of the Dysfunctional Attitude Scale (DAS). However, no studies have done so using a clinical sample of outpatients likely to generalize to the clinical trials in which the DAS is commonly used. The current investigation utilized exploratory structural equation modeling in an outpatient sample (N = 982) and found support for a one-factor solution (composed of 19 items). This solution was largely confirmed in a second outpatient sample (N = 301). Construct validity was demonstrated in correlations with measures of depression, social interaction anxiety, and symptoms of obsessive-compulsive disorder.

  1. An exploratory analysis of the factor structure of the Dysfunctional Attitude Scale-Form A (DAS).

    PubMed

    Moore, Michael T; Fresco, David M; Segal, Zindel V; Brown, Timothy A

    2014-10-01

    A number of studies have attempted to identify the factor structure of the Dysfunctional Attitude Scale (DAS). However, no studies have done so using a clinical sample of outpatients likely to generalize to the clinical trials in which the DAS is commonly used. The current investigation utilized exploratory structural equation modeling in an outpatient sample (N = 982) and found support for a one-factor solution (composed of 19 items). This solution was largely confirmed in a second outpatient sample (N = 301). Construct validity was demonstrated in correlations with measures of depression, social interaction anxiety, and symptoms of obsessive-compulsive disorder. PMID:24577308

  2. The Deaf Acculturation Scale (DAS): Development and Validation of a 58-Item Measure

    PubMed Central

    Maxwell-McCaw, Deborah; Zea, Maria Cecilia

    2011-01-01

    This study involved the development and validation of the Deaf Acculturation Scale (DAS), a new measure of cultural identity for Deaf and hard-of-hearing (hh) populations. Data for this study were collected online and involved a nation-wide sample of 3,070 deaf/hh individuals. Results indicated strong internal reliabilities for all the subscales, and construct validity was established by demonstrating that the DAS could discriminate groups based on parental hearing status, school background, and use of self-labels. Construct validity was further demonstrated through factorial analyses, and findings resulted in a final 58-item measure. Directions for future research are discussed. PMID:21263041

  3. Das Prinzip Bewegung - Herz und Gehirn als Metaphern des menschlichen Lebens

    NASA Astrophysics Data System (ADS)

    Otis, Laura

    In diesem Jahr, in dem wir Charles Darwins gedenken, möchte ich etwas riskieren und eine Frage erörtern, die für die Literatur ebenso wie für die Biologie zentral ist: Was ist das Leben? Die Antwort auf diese Frage finden wir nicht in der Bibliothek und nicht im Labor, zumindest nicht an diesen erkenntnisproduzierenden Stellen allein. Als Literaturwissenschaftlerin und ehemalige Naturwissenschaftlerin glaube ich, dass wir das Leben nur verstehen werden, wenn wir seinen Wirkungen überall nachforschen, inklusive in der Literatur.

  4. MiDAS: the field guide to the microbes of activated sludge.

    PubMed

    McIlroy, Simon Jon; Saunders, Aaron Marc; Albertsen, Mads; Nierychlo, Marta; McIlroy, Bianca; Hansen, Aviaja Anna; Karst, Søren Michael; Nielsen, Jeppe Lund; Nielsen, Per Halkjær

    2015-01-01

    The Microbial Database for Activated Sludge (MiDAS) field guide is a freely available online resource linking the identity of abundant and process critical microorganisms in activated sludge wastewater treatment systems to available data related to their functional importance. Phenotypic properties of some of these genera are described, but most are known only from sequence data. The MiDAS taxonomy is a manual curation of the SILVA taxonomy that proposes a name for all genus-level taxa observed to be abundant by large-scale 16 S rRNA gene amplicon sequencing of full-scale activated sludge communities. The taxonomy can be used to classify unknown sequences, and the online MiDAS field guide links the identity to the available information about their morphology, diversity, physiology and distribution. The use of a common taxonomy across the field will provide a solid foundation for the study of microbial ecology of the activated sludge process and related treatment processes. The online MiDAS field guide is a collaborative workspace intended to facilitate a better understanding of the ecology of activated sludge and related treatment processes--knowledge that will be an invaluable resource for the optimal design and operation of these systems. PMID:26120139

  5. A Brief History of the J.P. Das Developmental Disabilities Centre

    ERIC Educational Resources Information Center

    Sobsey, Dick

    2008-01-01

    The J.P. Das Developmental Disabilities Centre celebrated its 40th anniversary on September 1, 2007, followed by The University of Alberta's 100th anniversary in 2008. The year 2008 also brought the appointment of a new Director for the Centre. As the immediate past Director of the Centre, the author recounts some of the history of the J.P. Das…

  6. MiDAS: the field guide to the microbes of activated sludge

    PubMed Central

    McIlroy, Simon Jon; Saunders, Aaron Marc; Albertsen, Mads; Nierychlo, Marta; McIlroy, Bianca; Hansen, Aviaja Anna; Karst, Søren Michael; Nielsen, Jeppe Lund; Nielsen, Per Halkjær

    2015-01-01

    The Microbial Database for Activated Sludge (MiDAS) field guide is a freely available online resource linking the identity of abundant and process critical microorganisms in activated sludge wastewater treatment systems to available data related to their functional importance. Phenotypic properties of some of these genera are described, but most are known only from sequence data. The MiDAS taxonomy is a manual curation of the SILVA taxonomy that proposes a name for all genus-level taxa observed to be abundant by large-scale 16 S rRNA gene amplicon sequencing of full-scale activated sludge communities. The taxonomy can be used to classify unknown sequences, and the online MiDAS field guide links the identity to the available information about their morphology, diversity, physiology and distribution. The use of a common taxonomy across the field will provide a solid foundation for the study of microbial ecology of the activated sludge process and related treatment processes. The online MiDAS field guide is a collaborative workspace intended to facilitate a better understanding of the ecology of activated sludge and related treatment processes—knowledge that will be an invaluable resource for the optimal design and operation of these systems. Database URL: http://www.midasfieldguide.org PMID:26120139

  7. The Deaf Acculturation Scale (DAS): Development and Validation of a 58-Item Measure

    ERIC Educational Resources Information Center

    Maxwell-McCaw, Deborah; Zea, Maria Cecilia

    2011-01-01

    This study involved the development and validation of the Deaf Acculturation Scale (DAS), a new measure of cultural identity for Deaf and hard-of-hearing (hh) populations. Data for this study were collected online and involved a nation-wide sample of 3,070 deaf/hh individuals. Results indicated strong internal reliabilities for all the subscales,…

  8. The Great War and Remembrance in Jose Leon Machado's "Memoria das Estrelas sem Brilho"

    ERIC Educational Resources Information Center

    Azevedo, Milton M.

    2011-01-01

    This article analyzes Jose Leon Machado's novel, "Memoria das Estrelas sem Brilho," as a multilayered historical novel in which a war story provides a background for comments on aspects of early twentieth-century Portuguese society, such as male bonding, religion, sexual mores, and social stratification. (Contains 11 notes.)

  9. PoroTomo Project - Subatask 6.2: Deploy and Operate DAS and DTS arrays

    DOE Data Explorer

    Dante Fratta

    2016-03-31

    This metadata submission includes the coordinates of the DAS and DTS surface and borehole arrays, the list of file names, and the list of recorded files during testing at the PoroTomo Natural Laboratory at Brady Hot Spring in Nevada. Testing was completed during March 2016.

  10. National Study of Postsecondary Faculty. NSOPF:88/93: Public Access Data Analysis System (DAS).[CD-ROM].

    ERIC Educational Resources Information Center

    National Center for Education Statistics (ED), Washington, DC.

    This CD-ROM (for both MS-DOS and Windows) contains data from the 1993 National Study of Postsecondary Faculty (NSOPF) and all other available National Center for Education Statistics data analysis systems (DAS). The DAS is a menu-driven system that allows the user to produce frequencies, cross tabulations, and correlation matrices without access…

  11. A 90 day chronic toxicity study of Nigerian herbal preparation DAS-77 in rats

    PubMed Central

    2012-01-01

    Background The herbal preparation DAS-77, used for the treatment of various ailments in Nigeria, contains the milled bark of Mangifera indica L. and root of Carica papaya L. Toxicological assessment of the preparation was carried out in this study. Methods In the acute toxicity study, DAS-77 was administered to mice p.o. up to 20 g/kg in divided doses and i.p. at 250–3000 mg/kg. Mortality within 24 h was recorded. In the chronic toxicity study, rats were treated p.o. for 90 days at doses of 80, 400 (therapeutic dose, TD) and 2000 mg/kg. By 90 days, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination, antioxidants and histopathological assessments. Results DAS-77 did not produce any lethality administered p.o. up to 20 g/kg in divided doses but the i.p. LD50 was 1122.0 mg/kg. At TD, DAS-77 produced significant (p < 0.05) reductions in body weight, food intake and K+, and increases in ovary weight, neutrophils and HDL, which were reversible. Histopathological presentations were generally normal. Effects at the other doses were comparable to those at TD except for reversible increases in antioxidants in the liver, kidney and testes, and sperm abnormality, and reductions in liver enzymes, sperm motility and count. Conclusions Findings in this study revealed that DAS-77 is relatively safe with the potential for enhancing in vivo antioxidant activity. However, possibly reversible side-effects include electrolyte imbalance and sterility in males. PMID:22892317

  12. Performance of broiler chickens fed diets containing DAS-68416-4 soybean meal.

    PubMed

    Herman, Rod A; Dunville, Christina M; Juberg, Daland R; Fletcher, Dale W; Cromwell, Gary L

    2011-01-01

    Broiler chickens are a fast growing monogastric animal commonly used to evaluate the equivalence between transgenic and non-transgenic grains as part of the human safety assessment process. While commonly viewed like other livestock feeding trials, such studies are performed with transgenic crops with input traits (that are not designed to improve nutrition) to aid regulatory authorities in evaluating safety. Studies of this type are actually more similar to toxicology studies in purpose, with sensitive endpoints like growth used to detect metabolic perturbations. DAS-68416-4 soybean expresses the aryloxyalkanoate dioxygenase-12 (AAD-12) enzyme which inactivates 2,4-diclorophenoxyacetic acid (2,4-D) and provides DAS-68416-4 soybeans tolerance to this herbicide. DAS-68416-4 also expresses the phosphinothricin acetyltransferase (PAT) enzyme from Streptomyces viridochromogenes which confers tolerance to glufosinate-ammonium herbicides. A 6-week broiler study was conducted with diets containing toasted DAS-68416-4 soybean meal (40, 36, and 32% in starter, grower and finisher diets, respectively) to evaluate nutritional wholesomeness and safety compared with conventional comparators. Toasting soybean meal is required to inactivate endogenous antinutrients making soybean suitable for consumption by monogastric animals like broiler chickens. Toasting was found to denature both the AAD-12 and PAT proteins rendering them non-detectable by enzyme linked immunosorbent assays. Broiler growth and performance parameters were measured over a 6-week period of exposure to diets containing different sources of toasted soybean meal, and results indicate that DAS-68416-4 soybean is nutritionally equivalent to non-transgenic soybean.

  13. Isotope age of the rare metal pegmatite formation in the Kolmozero-Voron'ya greenstone belt (Kola region of the Fennoscandian shield): U-Pb (TIMS) microlite and tourmaline dating

    NASA Astrophysics Data System (ADS)

    Kudryashov, Nikolay; Lyalina, Ludmila; Mokrushin, Artem; Zozulya, Dmitry; Groshev, Nikolay; Steshenko, Ekaterina; Kunakkuzin, Evgeniy

    2016-04-01

    The Kolmozero-Voron'ya greenstone belt is located in the central suture zone, which separates the Murmansk block from the Central-Kola and the Keivy blocks. The belt is represented by volcano-sedimentary rocks of Archaean age of 2.9-2.5 Ga. Rare metal pegmatites (Li, Cs with accessory Nb, Ta, and Be) occur among amphibolite and gabbroid intrusions in the northwestern and southeastern parts of the belt. According to the Rb-Sr data, the age of pegmatites was considered to be 2.7 Ga. Until recently there was no generally accepted point of view on the origin of pegmatites. Now we have isotopic data for a range of rock complexes that could pretend to be parental granites for the rare metal pegmatites. These are granodiorites with the zircon age of 2733±Ma, and microcline and tourmaline granites, which Pb-Pb isochronal age on tourmaline from the tourmaline granite located near the deposit is estimated to be 2520±70 Ma. The pegmatite field of the Vasin Myl'k deposit with the lepidolite--albite--microcline--spodumene--pollucite association is located among amphibolites in the northwestern part of the belt. The deposit is represented by subparallel low-angle zoned veins up to 220 m long and 5 m thick dipping in the southeastern direction at an angle of 10° too 30°. The minerals of the columbite--tonalite group from Vasin Myl'k deposit include microlite, simpsonite, and torolite, and are the oldest among different minerals represented by several generations in pegmatites under consideration. Zircons from the pegmatites are mostly represented by crystals with the structure affected by the action of fluids that put certain restrictions on its use as a geochronometer of the crystallization process. Microlite from the pegmatite taken from the dump of a prospecting drill hole was used for U--Pb (TIMS). The mineral is represented by 0.5--1.0 mm long euhedral octahedral crystals. It is brown in color, and transparent. The microlite crystals were preliminarily cleaned from

  14. Annotation and visualization of endogenous retroviral sequences using the Distributed Annotation System (DAS) and eBioX

    PubMed Central

    Martínez Barrio, Álvaro; Lagercrantz, Erik; Sperber, Göran O; Blomberg, Jonas; Bongcam-Rudloff, Erik

    2009-01-01

    Background The Distributed Annotation System (DAS) is a widely used network protocol for sharing biological information. The distributed aspects of the protocol enable the use of various reference and annotation servers for connecting biological sequence data to pertinent annotations in order to depict an integrated view of the data for the final user. Results An annotation server has been devised to provide information about the endogenous retroviruses detected and annotated by a specialized in silico tool called RetroTector. We describe the procedure to implement the DAS 1.5 protocol commands necessary for constructing the DAS annotation server. We use our server to exemplify those steps. Data distribution is kept separated from visualization which is carried out by eBioX, an easy to use open source program incorporating multiple bioinformatics utilities. Some well characterized endogenous retroviruses are shown in two different DAS clients. A rapid analysis of areas free from retroviral insertions could be facilitated by our annotations. Conclusion The DAS protocol has shown to be advantageous in the distribution of endogenous retrovirus data. The distributed nature of the protocol is also found to aid in combining annotation and visualization along a genome in order to enhance the understanding of ERV contribution to its evolution. Reference and annotation servers are conjointly used by eBioX to provide visualization of ERV annotations as well as other data sources. Our DAS data source can be found in the central public DAS service repository, , or at . PMID:19534743

  15. DAS Boot!

    ERIC Educational Resources Information Center

    Chretien, Wendy

    2007-01-01

    The residential services group is lobbying to dump its aging hard-wired phone system because students don't use it. The town and campus public safety officials are demanding that their portable two-way radios operate well not only outdoors, but within campus buildings. Students are now expecting text messaging and WiFi service to work everywhere…

  16. Proposal of adaptive wireless cell configuration for RoF-DAS over WDM-PON system

    NASA Astrophysics Data System (ADS)

    Iwakuni, Tatsuhiko; Miyamoto, Kenji; Higashino, Takeshi; Tsukamoto, Katsutoshi; Komaki, Shozo; Tashiro, Takayoshi; Fukada, Youichi; Kani, Jun-ichi; Yoshimoto, Naoto; Iwatsuki, Katsumi

    2013-01-01

    Radio on fiber (RoF) - distributed antenna system (DAS) over wavelength division multiplexing - passive optical network (WDM-PON) with multiple - input multiple - output (MIMO) has been proposed as a next generation radio access network (RAN). This system employs optical time division multiplexing (OTDM) over one WDM channel to multiplex and transmit various types of wireless interfaces such as 3.9G, Wireless LAN and WiMAX. A combination of star and bus topologies has employed to cover a wider service area. The optical transmission loss is caused notably at remote base stations (RBSs) quipped on a WDM bus link. The loss is relatively small, but at the RBS far from the center station (CS), the RBS suffers the large accumulated loss, so the reduction of cell size provides the increasing of the number of RBSs, causes the degradation of the SNR of RoF link. This paper addresses this trade-off problem, and considers the application to the actual service area by the channel capacity investigation of RoF-DAS over WDM-PON with computer simulation. Then, this paper focuses on the flexibility of RoF-DAS over WDM-PON, considers the adaptive wireless cell configuration according to population fluctuations of day and night, or densely populated areas and sparsely populated areas, respectively.

  17. Assimilation of SBUV Version 8 Radiances into the GEOS Ozone DAS

    NASA Technical Reports Server (NTRS)

    Mueller, Martin D.; Stajner, Ivanka; Bhartia, Pawan K.

    2004-01-01

    In operational weather forecasting, the assimilation of brightness temperatures from satellite sounders, instead of assimilation of 1D-retrievals has become increasingly common practice over the last two decades. Compared to these systems, assimilation of trace gases is still at a relatively early stage of development, and efforts to directly assimilate radiances instead of retrieved products have just begun a few years ago, partially because it requires much more computation power due to the employment of a radiative transport forward model (FM). This paper will focus on a method to assimilate SBUV/2 radiances (albedos) into the Global Earth Observation System Ozone Data Assimilation Scheme (GEOS-03DAS). While SBUV-type instruments cannot compete with newer sensors in terms of spectral and horizontal resolution, they feature a continuous data record back to 1978, which makes them very valuable for trend studies. Assimilation can help spreading their ground coverage over the whole globe, as has been previously demonstrated with the GEOS-03DAS using SBUV Version 6 ozone profiles. Now, the DAS has been updated to use the newly released SBUV Version 8 data. We will compare pre]lmlnarv results of SBUV radiance assimilation with the assimilation of retrieved ozone profiles, discuss methods to deal with the increased computational load, and try to assess the error characteristics and future potential of the new approach.

  18. pH modulates arsenic toxicity in Bacillus licheniformis DAS-2.

    PubMed

    Tripti, K; Shardendu

    2016-08-01

    The toxic characteristics of arsenic species, As(V) and As(III) result in ecological risks. Arsenic tolerant bacterium was isolated and identified as the Bacillus licheniformis DAS-2 through 16SrDNA sequencing. B. licheniformis DAS-2 was efficient to tolerate and remove both the As(V)[MIC 8mM] and As(III)[MIC 6mM] from the growth medium. The potential for the removal/uptake of arsenic from the 3, 5 and 7mM As(V) enriched growth media was 100%, 60% and 35% respectively and from the 1, 3 and 5mM As(III) enrichment it was 100%, 99% and 58% respectively at neutral pH. 80% of uptake As(V) was reduced to As(III) in 3mM As(V) enrichment which was gradually decreased to only 17% at 7mM As(V) enrichment at neutral pH. The arsenic toxicity in B. licheniformis DAS-2 was found modulated by pH and was examined through alteration in growth, uptake/removal, reduction and measurement of chemical toxicity. PMID:27135959

  19. Performance of broiler chickens fed event DAS-40278-9 maize containing the aryloxyalkanoate dioxygenase-1 protein.

    PubMed

    Herman, Rod A; Dunville, Christina M; Juberg, Daland R; Fletcher, Dale W; Cromwell, Gary L

    2011-08-01

    Event DAS-40278-9 maize grain (containing the aryloxyalkanoate dioxygenase-1 protein), a non-transgenic near-isogenic maize grain, or one of three commercial maize grains were included in the diets of broiler chickens for six weeks. Growth, feed conversion, and carcass measurements indicated no significant difference between the groups fed the diets containing the DAS-40278-9 maize grain and those fed diets containing the matched control grain. The absence of adverse effects in this study supports the dietary safety of the AAD-1 protein expressed in event DAS-40278-9 maize.

  20. A Letter to the Parent(s) of a Child with Developmental Apraxia of Speech. Part II: The Nature and Causes of DAS.

    ERIC Educational Resources Information Center

    Hall, Penelope K.

    2000-01-01

    One of a series of letters to parents of children with developmental apraxia of speech (DAS), this letter discusses issues and current thinking about the nature and causes of the disorder. These include the idea that DAS is a disorder of overall language development or that DAS is a problem of the "motor-programming" system for speech. An…

  1. The S2 VLBI Systems: DAS, RT/PT and Correlator

    NASA Technical Reports Server (NTRS)

    Petrachenko, William T.; Bujold, Marc; Cannon, Wayne H.; Carlson, Brent R.; Dewdney, Peter E.; Feil, Georg H.; Newby, Paul; Novikov, Alexander; Popelar, Josef; Wietfeldt, Richard D.

    2000-01-01

    The S2 VLBI system synthesizes wide IF bandwidths by rapidly switching the local oscillator (LO) frequency in a small (1-4) number of baseband converters (BBC's). Data are recorded on video cassettes using an array of 8 VHS transports. Characteristics of the S2 Data Acquisition System (DAS), the S2 Record and Playback Terminals (RT and PT) and the S2 Correlator are summarized. The bandwidth synthesis (BWS) frequency switching sequence used in a series of system validation experiments is presented.

  2. Ländliche Entwicklung durch erneuerbare Energien - Das Beispiel Photovoltaik in Niederbayern

    NASA Astrophysics Data System (ADS)

    Zink, Roland

    2013-09-01

    Der Ausbau erneuerbarer Energien ist in Deutschland eine zentrale und politisch konsensfähige Forderung, um die Energieversorgung klimafreundlich und nachhaltig zu gestalten. Speziell ländliche Regionen rücken dabei in den Fokus, bieten sie doch aufgrund ihrer hohen Flächenverfügbarkeit große Potenziale für die flächenintensiven dezentralen Energieformen. Folglich erkennen Kommunen zunehmend das Entwicklungspotenzial dieser Technologien und sehen sie auch als Chance, neue wirtschaftliche Impulse vor Ort zu setzen. Der Beitrag skizziert die rasante Entwicklung der Photovoltaik im Regierungsbezirk Niederbayern und diskutiert anhand des Beispiels die Folgen für eine nachhaltige Regionalentwicklung.

  3. Hermann Cohen's Das Princip der Infinitesimal-Methode: The history of an unsuccessful book.

    PubMed

    Giovanelli, Marco

    2016-08-01

    This paper offers an introduction to Hermann Cohen's Das Princip der Infinitesimal-Methode (1883), and recounts the history of its controversial reception by Cohen's early sympathizers, who would become the so-called 'Marburg school' of Neo-Kantianism, as well as the reactions it provoked outside this group. By dissecting the ambiguous attitudes of the best-known representatives of the school (Paul Natorp and Ernst Cassirer), as well as those of several minor figures (August Stadler, Kurd Lasswitz, Dimitry Gawronsky, etc.), this paper shows that Das Princip der Infinitesimal-Methode is a unicum in the history of philosophy: it represents a strange case of an unsuccessful book's enduring influence. The "puzzle of Cohen's Infinitesimalmethode," as we will call it, can be solved by looking beyond the scholarly results of the book, and instead focusing on the style of philosophy it exemplified. Moreover, the paper shows that Cohen never supported, but instead explicitly opposed, the doctrine of the centrality of the 'concept of function', with which Marburg Neo-Kantianism is usually associated. PMID:27474182

  4. The development of Music in Dementia Assessment Scales (MiDAS)

    PubMed Central

    McDermott, Orii; Orrell, Martin; Ridder, Hanne Mette

    2015-01-01

    There is a need to develop an outcome measure specific to music therapy in dementia that reflects a holistic picture of the therapy process and outcome. This study aimed to develop a clinically relevant and scientifically robust music therapy outcome measure incorporating the values and views of people with dementia. Focus groups and interviews were conducted to obtain qualitative data on what music meant to people with dementia and the observed effects of music. Expert and peer consultations were conducted at each stage of the measure development to maximise its content validity. The new measure was field-tested by clinicians in a care home. Feedback from the clinicians and music therapy experts were incorporated during the review and refinement process of the measure. A review of the existing literature, the experiential results and the consensus process enabled the development of the new outcome measure “Music in Dementia Assessment Scales (MiDAS)”. Analysis of the qualitative data identified five key areas of the impact of music on people with dementia and they were transformed as the five Visual Analogue Scale (VAS) items: levels of Interest, Response, Initiation, Involvement and Enjoyment. MiDAS comprises the five VAS items and a supplementary checklist of notable positive and negative reactions from the individual. This study demonstrates that it is possible to design and develop an easy to apply and rigorous quantitative outcome measure which has a high level of clinical relevance for people with dementia, care home staff and music therapists. PMID:26246670

  5. Ocean Color Measurements from Landsat-8 OLI using SeaDAS

    NASA Technical Reports Server (NTRS)

    Franz, Bryan Alden; Bailey, Sean W.; Kuring, Norman; Werdell, P. Jeremy

    2014-01-01

    The Operational Land Imager (OLI) is a multi-spectral radiometer hosted on the recently launched Landsat-8 satellite. OLI includes a suite of relatively narrow spectral bands at 30-meter spatial resolution in the visible to shortwave infrared that make it a potential tool for ocean color radiometry: measurement of the reflected spectral radiance upwelling from beneath the ocean surface that carries information on the biogeochemical constituents of the upper ocean euphotic zone. To evaluate the potential of OLI to measure ocean color, processing support was implemented in SeaDAS, which is an open-source software package distributed by NASA for processing, analysis, and display of ocean remote sensing measurements from a variety of satellite-based multi-spectral radiometers. Here we describe the implementation of OLI processing capabilities within SeaDAS, including support for various methods of atmospheric correction to remove the effects of atmospheric scattering and absorption and retrieve the spectral remote-sensing reflectance (Rrs; sr exp 1). The quality of the retrieved Rrs imagery will be assessed, as will the derived water column constituents such as the concentration of the phytoplankton pigment chlorophyll a.

  6. A causa das estações do ano: modelos mentais

    NASA Astrophysics Data System (ADS)

    de Campos, J. A. S.; de Araujo, J. F. S.

    2003-08-01

    A década de 70 do século passado foi marcada pelo estudo das concepções alternativas que os alunos trazem para a sala de aula. A identificação destas concepções foi o ponto de partida para promover a mudança conceitual, onde as pré-concepções seriam trocadas pelas concepções científicas. Na década seguinte, surgiram muitas propostas de estratégias educacionais para facilitar esta troca, na sua maioria baseadas na idéia do conflito cognitivo, proposta por Piaget. Entretanto, os resultados pouco animadores conduziram à percepção de que a mudança conceitual é um processo mais complexo. Pelas idéias da Ciência Cognitiva, a mudança conceitual é uma mudança progressiva dos modelos mentais que o aluno tem sobre o mundo físico, através de enriquecimento e revisão. A causa das Estações do Ano é um tópico sobre o qual a maioria dos estudantes apresenta concepções alternativas. Os autores fizeram um levantamento sobre as pré-concepções encontradas em trabalhos sobre o tema (16 referências), procurando encontrar elementos comuns que indicassem a presença de modelos mentais específicos. As pré-concepções encontradas na literatura foram obtidas usando-se diversas metodologias (desde entrevistas clínicas até questionários de múltipla escolha) e envolvendo alunos e professores de diferentes regiões geográficas. A partir de uma análise aprofundada de cada trabalho, e utilizando-se a técnica das Redes Sistêmicas, chegou-se a conclusão que as diversas pré-concepções identificadas (em torno de 50), poderiam ser representadas por 6 modelos mentais, onde a explicação da causa das estações do ano tem um mecanismo causal responsável. Os mecanismos causais identificados foram: a dependência da distância, a dependência da orientação, a dependência conjunta da distância e orientação, a dependência da obstrução, a dependência da velocidade e a dependência da inclinação dos raios solares. Foram ainda identificadas

  7. Establishment of feeder-free culture system for human induced pluripotent stem cell on DAS nanocrystalline graphene

    PubMed Central

    Lee, Hyunah; Nam, Donggyu; Choi, Jae-Kyung; Araúzo-Bravo, Marcos J.; Kwon, Soon-Yong; Zaehres, Holm; Lee, Taehee; Park, Chan Young; Kang, Hyun-Wook; Schöler, Hans R.; Kim, Jeong Beom

    2016-01-01

    The maintenance of undifferentiated human pluripotent stem cells (hPSC) under xeno-free condition requires the use of human feeder cells or extracellular matrix (ECM) coating. However, human-derived sources may cause human pathogen contamination by viral or non-viral agents to the patients. Here we demonstrate feeder-free and xeno-free culture system for hPSC expansion using diffusion assisted synthesis-grown nanocrystalline graphene (DAS-NG), a synthetic non-biological nanomaterial which completely rule out the concern of human pathogen contamination. DAS-NG exhibited advanced biocompatibilities including surface nanoroughness, oxygen containing functional groups and hydrophilicity. hPSC cultured on DAS-NG could maintain pluripotency in vitro and in vivo, and especially cell adhesion-related gene expression profile was comparable to those of cultured on feeders, while hPSC cultured without DAS-NG differentiated spontaneously with high expression of somatic cell-enriched adhesion genes. This feeder-free and xeno-free culture method using DAS-NG will facilitate the generation of clinical-grade hPSC. PMID:26846167

  8. Establishment of feeder-free culture system for human induced pluripotent stem cell on DAS nanocrystalline graphene.

    PubMed

    Lee, Hyunah; Nam, Donggyu; Choi, Jae-Kyung; Araúzo-Bravo, Marcos J; Kwon, Soon-Yong; Zaehres, Holm; Lee, Taehee; Park, Chan Young; Kang, Hyun-Wook; Schöler, Hans R; Kim, Jeong Beom

    2016-02-05

    The maintenance of undifferentiated human pluripotent stem cells (hPSC) under xeno-free condition requires the use of human feeder cells or extracellular matrix (ECM) coating. However, human-derived sources may cause human pathogen contamination by viral or non-viral agents to the patients. Here we demonstrate feeder-free and xeno-free culture system for hPSC expansion using diffusion assisted synthesis-grown nanocrystalline graphene (DAS-NG), a synthetic non-biological nanomaterial which completely rule out the concern of human pathogen contamination. DAS-NG exhibited advanced biocompatibilities including surface nanoroughness, oxygen containing functional groups and hydrophilicity. hPSC cultured on DAS-NG could maintain pluripotency in vitro and in vivo, and especially cell adhesion-related gene expression profile was comparable to those of cultured on feeders, while hPSC cultured without DAS-NG differentiated spontaneously with high expression of somatic cell-enriched adhesion genes. This feeder-free and xeno-free culture method using DAS-NG will facilitate the generation of clinical-grade hPSC.

  9. Establishment of feeder-free culture system for human induced pluripotent stem cell on DAS nanocrystalline graphene

    NASA Astrophysics Data System (ADS)

    Lee, Hyunah; Nam, Donggyu; Choi, Jae-Kyung; Araúzo-Bravo, Marcos J.; Kwon, Soon-Yong; Zaehres, Holm; Lee, Taehee; Park, Chan Young; Kang, Hyun-Wook; Schöler, Hans R.; Kim, Jeong Beom

    2016-02-01

    The maintenance of undifferentiated human pluripotent stem cells (hPSC) under xeno-free condition requires the use of human feeder cells or extracellular matrix (ECM) coating. However, human-derived sources may cause human pathogen contamination by viral or non-viral agents to the patients. Here we demonstrate feeder-free and xeno-free culture system for hPSC expansion using diffusion assisted synthesis-grown nanocrystalline graphene (DAS-NG), a synthetic non-biological nanomaterial which completely rule out the concern of human pathogen contamination. DAS-NG exhibited advanced biocompatibilities including surface nanoroughness, oxygen containing functional groups and hydrophilicity. hPSC cultured on DAS-NG could maintain pluripotency in vitro and in vivo, and especially cell adhesion-related gene expression profile was comparable to those of cultured on feeders, while hPSC cultured without DAS-NG differentiated spontaneously with high expression of somatic cell-enriched adhesion genes. This feeder-free and xeno-free culture method using DAS-NG will facilitate the generation of clinical-grade hPSC.

  10. Measuring Primary Teachers' Attitudes Toward Teaching Science: Development of the Dimensions of Attitude Toward Science (DAS) Instrument

    NASA Astrophysics Data System (ADS)

    van Aalderen-Smeets, Sandra; Walma van der Molen, Juliette

    2013-03-01

    In this article, we present a valid and reliable instrument which measures the attitude of in-service and pre-service primary teachers toward teaching science, called the Dimensions of Attitude Toward Science (DAS) Instrument. Attention to the attitudes of primary teachers toward teaching science is of fundamental importance to the professionalization of these teachers in the field of primary science education. With the development of this instrument, we sought to fulfill the need for a statistically and theoretically valid and reliable instrument to measure pre-service and in-service teachers' attitudes. The DAS Instrument is based on a comprehensive theoretical framework for attitude toward (teaching) science. After pilot testing, the DAS was revised and subsequently validated using a large group of respondents (pre-service and in-service primary teachers) (N = 556). The theoretical underpinning of the DAS combined with the statistical data indicate that the DAS possesses good construct validity and that it proves to be a promising instrument that can be utilized for research purposes, and also as a teacher training and coaching tool. This instrument can therefore make a valuable contribution to progress within the field of science education.

  11. Establishment of feeder-free culture system for human induced pluripotent stem cell on DAS nanocrystalline graphene.

    PubMed

    Lee, Hyunah; Nam, Donggyu; Choi, Jae-Kyung; Araúzo-Bravo, Marcos J; Kwon, Soon-Yong; Zaehres, Holm; Lee, Taehee; Park, Chan Young; Kang, Hyun-Wook; Schöler, Hans R; Kim, Jeong Beom

    2016-01-01

    The maintenance of undifferentiated human pluripotent stem cells (hPSC) under xeno-free condition requires the use of human feeder cells or extracellular matrix (ECM) coating. However, human-derived sources may cause human pathogen contamination by viral or non-viral agents to the patients. Here we demonstrate feeder-free and xeno-free culture system for hPSC expansion using diffusion assisted synthesis-grown nanocrystalline graphene (DAS-NG), a synthetic non-biological nanomaterial which completely rule out the concern of human pathogen contamination. DAS-NG exhibited advanced biocompatibilities including surface nanoroughness, oxygen containing functional groups and hydrophilicity. hPSC cultured on DAS-NG could maintain pluripotency in vitro and in vivo, and especially cell adhesion-related gene expression profile was comparable to those of cultured on feeders, while hPSC cultured without DAS-NG differentiated spontaneously with high expression of somatic cell-enriched adhesion genes. This feeder-free and xeno-free culture method using DAS-NG will facilitate the generation of clinical-grade hPSC. PMID:26846167

  12. DasPy – Open Source Multivariate Land Data Assimilation Framework with High Performance Computing

    NASA Astrophysics Data System (ADS)

    Han, Xujun; Li, Xin; Montzka, Carsten; Kollet, Stefan; Vereecken, Harry; Hendricks Franssen, Harrie-Jan

    2015-04-01

    Data assimilation has become a popular method to integrate observations from multiple sources with land surface models to improve predictions of the water and energy cycles of the soil-vegetation-atmosphere continuum. In recent years, several land data assimilation systems have been developed in different research agencies. Because of the software availability or adaptability, these systems are not easy to apply for the purpose of multivariate land data assimilation research. Multivariate data assimilation refers to the simultaneous assimilation of observation data for multiple model state variables into a simulation model. Our main motivation was to develop an open source multivariate land data assimilation framework (DasPy) which is implemented using the Python script language mixed with C++ and Fortran language. This system has been evaluated in several soil moisture, L-band brightness temperature and land surface temperature assimilation studies. The implementation allows also parameter estimation (soil properties and/or leaf area index) on the basis of the joint state and parameter estimation approach. LETKF (Local Ensemble Transform Kalman Filter) is implemented as the main data assimilation algorithm, and uncertainties in the data assimilation can be represented by perturbed atmospheric forcings, perturbed soil and vegetation properties and model initial conditions. The CLM4.5 (Community Land Model) was integrated as the model operator. The CMEM (Community Microwave Emission Modelling Platform), COSMIC (COsmic-ray Soil Moisture Interaction Code) and the two source formulation were integrated as observation operators for assimilation of L-band passive microwave, cosmic-ray soil moisture probe and land surface temperature measurements, respectively. DasPy is parallelized using the hybrid MPI (Message Passing Interface) and OpenMP (Open Multi-Processing) techniques. All the input and output data flow is organized efficiently using the commonly used NetCDF file

  13. Taxonomic notes and distribution extension of Durga Das's leaf-nosed bat Hipposiderosdurgadasi Khajuria, 1970 (Chiroptera: Hipposideridae) from south India.

    PubMed

    Kaur, Harpreet; Chelmala, Srinivasulu; Srinivasulu, Bhargavi; Shah, Tariq Ahmed; Devender, Gundena; Srinivasulu, Aditya

    2014-01-01

    Durga Das's leaf-nosed bat Hipposiderosdurgadasi Khajuria, 1970 is endemic to India, and was known only from Katanga, Katangi, and Richhai villages, in Jabalpur district, Madhya Pradesh. During surveys conducted in Kolar district, Karnataka, India, we successfully mist-netted a few individuals belonging to the bicolor species group which, upon detailed external, craniodental and bacular studies were identified as Durga Das's leaf-nosed bat. This paper reports the presence of this species in southern India, extending its distribution range by almost 1300 km. We also provide a detailed morphological description for this species. PMID:25535483

  14. Event DAS-444Ø6-6 soybean grown in Brazil is compositionally equivalent to non-transgenic soybean.

    PubMed

    Fast, Brandon J; Galan, Maria P; Schafer, Ariane C

    2016-04-01

    Soybean event DAS-444Ø6-6 is tolerant to the herbicides 2,4-D, glyphosate, and glufosinate. An investigation of potential unintended adverse compositional changes in a genetically modified crop is required to meet government regulatory requirements in various geographies. A study to meet these requirements in Brazil was completed demonstrating compositional equivalency between DAS-444Ø6-6 and non-transgenic soybean. This study supplements the extensive literature supporting transgenesis as less disruptive of crop composition compared with traditional breeding methods. PMID:27248569

  15. Software strategies and hardware upgrades to the PPL data acquisition system (DAS)

    SciTech Connect

    Davis, W.M.; Roney, P.; Gibney, T.; Funk, P.; Keller, M.; Sauthoff, N.; Davis, S.; Bates, G.; Corneliussen, M.; Fishman, H.

    1987-08-01

    This paper describes upgrades to the Data Acquisition System for the Experimental Projects Department at PPL, especially in support of the PBX-M upgrade to be completed this year. Hardware and software maintenance problems with the old configuration, consisting of a DEC KL-10 and eight PDP-11's, are described. The real-time software and hardware performance requirements and projections for CAMAC I/O and data analysis and display are presented. Described are three applications that have realtime requirements and are located on separate processors, connected to PPPL's VAX Cluster by an Ethernet link. Building upon a previous large software base, general-purpose subroutine libraries and utilities are being emphasized. The most useful of these are described. The use of software packages from DEC, third-party vendors, and the fusion community, is also described. The new approaches to software development that are being incorporated into the DAS efforts are discussed. Specific future challenges are also described.

  16. Sobre o uso das séries de Puiseux em mecanica celeste

    NASA Astrophysics Data System (ADS)

    Miloni, O. I.

    2003-08-01

    Neste trabalho é apresentada uma demonstração do uso dos diferentes desenvolvimentos em séries para as equações de perturbação em Mecânica Celeste no marco Hamiltoniano. Em trabalhos clássicos como os de Poincaré (Poincaré, 1893) por exemplo, já esta planteado o uso de potências não inteiras no pequeno parâmetro, o que evidencia a não analiticidade das funções quando uma ressonância ocorre. Nestes trabalhos os desenvolvimentos são na raíz quadrada da massa de Júpiter (o pequeno parâmetro). Mais recentemente (Ferraz-Mello, 1985) outros tipos de desenvolvimentos foram aplicados modificando substancialmente as ordens de grandeza e a velocidade de convergência das séries. Com esta abordagem, os desenvolvimentos foram expressados em termos da raíz cúbica do pequeno parâmetro. Neste trabalho apresentamos um enfoque geral, onde os diferentes tipos de desenvolvimentos em séries de Puiseux (Valiron, 1950) são obtidos a partir da aplicação de Teorema de Preparação de Weierstrass (Goursat, 1916) considerando a equação de Hamilton-Jacobi como uma equação algébrica. Os resultados são aplicados ao problema restrito dos três corpos em ressonância de primeira ordem e, dependendo da grandeza da excentricidade do asteróide em relação à de Júpiter, obtemos os diferentes desenvolvimentos, em raíz quadrada ou raíz cúbica da massa de Júpiter.

  17. Latent Factor Structure of the Das-Naglieri Cognitive Assessment System: A Confirmatory Factor Analysis in a Chinese Setting

    ERIC Educational Resources Information Center

    Deng, Ci-ping; Liu, Ming; Wei, Wei; Chan, Raymond C. K.; Das, J. P.

    2011-01-01

    This study aims to measure the psychometric properties of the Das-Naglieri Cognitive Assessment System (D-N CAS) and to determine its clinical utility in a Chinese context. Confirmatory factor analysis (CFA) was conducted to examine the construct validity of the Chinese version of the D-N CAS among a group of 567, normally developed children.…

  18. Test Review: Naglieri, J. A., Das, J. P., & Goldstein, S. (2014). Cognitive Assessment System-Second Edition (2nd Ed.)

    ERIC Educational Resources Information Center

    McGill, Ryan J.

    2015-01-01

    The Cognitive Assessment System-Second Edition (CAS2) is an individually administered measure of cognitive ability designed for children and adolescents ages 5 through 18 years. The measure, authored by Jack A. Naglieri, J. P. Das, and Sam Goldstein, was published by Pro-Ed in 2014 and is the first revision of the Cognitive Assessment System (CAS;…

  19. Planning Ability across Ranges of Intellectual Ability: An Examination of the Luria-Das Information-Processing Model.

    ERIC Educational Resources Information Center

    McCallum, R. Steve; And Others

    1988-01-01

    Based on Luria-Das information processing theory, hypothesized that 26 educable mentally retarded children would score significantly less well on relatively pure measures of planning ability than would 13 younger average ability students after students were matched on cognitive processing ability. Hypothesis was not supported by study. (Author/NB)

  20. Measuring Primary Teachers' Attitudes toward Teaching Science: Development of the Dimensions of Attitude toward Science (DAS) Instrument

    ERIC Educational Resources Information Center

    van Aalderen-Smeets, Sandra; Walma van der Molen, Juliette

    2013-01-01

    In this article, we present a valid and reliable instrument which measures the attitude of in-service and pre-service primary teachers toward teaching science, called the Dimensions of Attitude Toward Science (DAS) Instrument. Attention to the attitudes of primary teachers toward teaching science is of fundamental importance to the…

  1. Concurrent Validity of the WISC-IV and DAS-II in Children with Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Kuriakose, Sarah

    2014-01-01

    Cognitive assessments are used for a variety of research and clinical purposes in children with autism spectrum disorder (ASD). This study establishes concurrent validity of the Wechsler Intelligence Scales for Children-fourth edition (WISC-IV) and Differential Ability Scales-second edition (DAS-II) in a sample of children with ASD with a broad…

  2. Phase Velocity and Full-Waveform Analysis of Co-located Distributed Acoustic Sensing (DAS) Channels and Geophone Sensor

    NASA Astrophysics Data System (ADS)

    Parker, L.; Mellors, R. J.; Thurber, C. H.; Wang, H. F.; Zeng, X.

    2015-12-01

    A 762-meter Distributed Acoustic Sensing (DAS) array with a channel spacing of one meter was deployed at the Garner Valley Downhole Array in Southern California. The array was approximately rectangular with dimensions of 180 meters by 80 meters. The array also included two subdiagonals within the rectangle along which three-component geophones were co-located. Several active sources were deployed, including a 45-kN, swept-frequency, shear-mass shaker, which produced strong Rayleigh waves across the array. Both DAS and geophone traces were filtered in 2-Hz steps between 4 and 20 Hz to obtain phase velocities as a function of frequency from fitting the moveout of travel times over distances of 35 meters or longer. As an alternative to this traditional means of finding phase velocity, it is theoretically possible to find the Rayleigh-wave phase velocity at each point of co-location as the ratio of DAS and geophone responses, because DAS is sensitive to ground strain and geophones are sensitive to ground velocity, after suitable corrections for instrument response (Mikumo & Aki, 1964). The concept was tested in WPP, a seismic wave propagation program, by first validating and then using a 3D synthetic, full-waveform seismic model to simulate the effect of increased levels of noise and uncertainty as data go from ideal to more realistic. The results obtained from this study provide a better understanding of the DAS response and its potential for being combined with traditional seismometers for obtaining phase velocity at a single location. This analysis is part of the PoroTomo project (Poroelastic Tomography by Adjoint Inverse Modeling of Data from Seismology, Geodesy, and Hydrology, http://geoscience.wisc.edu/feigl/porotomo).

  3. Crystal Structures of the Global Regulator DasR from Streptomyces coelicolor: Implications for the Allosteric Regulation of GntR/HutC Repressors

    PubMed Central

    Fillenberg, Simon B.; Friess, Mario D.; Körner, Samuel; Böckmann, Rainer A.; Muller, Yves A.

    2016-01-01

    Small molecule effectors regulate gene transcription in bacteria by altering the DNA-binding affinities of specific repressor proteins. Although the GntR proteins represent a large family of bacterial repressors, only little is known about the allosteric mechanism that enables their function. DasR from Streptomyces coelicolor belongs to the GntR/HutC subfamily and specifically recognises operators termed DasR-responsive elements (dre-sites). Its DNA-binding properties are modulated by phosphorylated sugars. Here, we present several crystal structures of DasR, namely of dimeric full-length DasR in the absence of any effector and of only the effector-binding domain (EBD) of DasR without effector or in complex with glucosamine-6-phosphate (GlcN-6-P) and N-acetylglucosamine-6-phosphate (GlcNAc-6-P). Together with molecular dynamics (MD) simulations and a comparison with other GntR/HutC family members these data allowed for a structural characterisation of the different functional states of DasR. Allostery in DasR and possibly in many other GntR/HutC family members is best described by a conformational selection model. In ligand-free DasR, an increased flexibility in the EBDs enables the attached DNA-binding domains (DBD) to sample a variety of different orientations and among these also a DNA-binding competent conformation. Effector binding to the EBDs of DasR significantly reorganises the atomic structure of the latter. However, rather than locking the orientation of the DBDs, the effector-induced formation of β-strand β* in the DBD-EBD-linker segment merely appears to take the DBDs ‘on a shorter leash’ thereby impeding the ‘downwards’ positioning of the DBDs that is necessary for a concerted binding of two DBDs of DasR to operator DNA. PMID:27337024

  4. Using Distributed Acoustic Sensing (DAS) for Multichannel Analysis of Surface Waves (MASW) to Evaluate Ground Stiffness

    NASA Astrophysics Data System (ADS)

    Baldwin, J. A.; Fratta, D.; Wang, H. F.; Lord, N. E.; Chalari, A.; Karaulanov, R.; Nigbor, R. L.; Lancelle, C.; Castongia, E.

    2014-12-01

    Since its introduction by Park, et al. (1999), Multichannel Analysis of Surface Waves (MASW) has become an invaluable geophysical technique for geotechnical site investigation. The technique is primarily focused on developing 2-D and 3-D shear stiffness vs. depth images of the near surface. MASW involves measuring surfaces waves of various frequencies produced by a seismic source, such as a sledgehammer or vibroseis source, which is evaluated to determine the velocity of the shear waves propagating through the subsurface at shallow depths. Traditionally, this technique relies on a long string of geophones as receivers. However, our study utilized a Distributed Acoustic Sensor array to detect ground motion caused by passing surface waves at a spatial resolution of one meter. The purpose of this investigation is to compare the effectiveness of using a DAS array for MASW data collection instead of traditional geophones. Data were collected at the Network for Earthquake Engineering Simulation's Garner Valley Downhole Array site (NEES's GVDA). Various time-frequency filtering and moving window cross correlation (MWCC) techniques were examined for extracting the surface wave dispersion. The results were found to be in good agreement with those previously obtained by Stokoe et al. (2004).

  5. Das Universum der Sterne. Himmelsbeobachtungen und Streifzüge durch die moderne Astronomie.

    NASA Astrophysics Data System (ADS)

    Rowan-Robinson, M.

    This book is a German translation, by M. Röser, of the English original published in 1990 (see 52.003.046). Contents: 1. Der Halleysche Komet. 2. Alpha Centauri - Der sonnennächste Stern. 3. Sirius und sein Begleiter, ein Weißer Zwerg. 4. Polaris - Der Polarstern. 5. Wega - Ein Planetensystem im Entstehen? 6. Mira - Der erste bekannte veränderliche Stern. 7. Der Ring-Nebel - "Todeskampf" eines sonnenähnlichen Sterns. 8. Der Orion-Nebel - Die Geburt neuer Sterne. 9. Delta Cephei - Die Meßlatte des Weltalls. 10. Algol - Der Teufelsstern. 11. Nova Aquilae - Der neue Stern von 1918. 12. Der Krebs-Nebel - Die Supernova des Jahres 1054. 13. Die Hyaden und Plejaden - Sternhaufen. 14. Die Milchstraße - Unsere Galaxis. 15. Die Magellanschen Wolken - Unsere Nachbarn im Weltall. 16. Der Andromeda-Nebel - Zwilling unserer Galaxis. 17. Messier 87 - Eine Radiogalaxie. 18. 3C 273 - Rätselhafter Quasar. 19. Messier 82 - Eine "Starburst"-Galaxie. 20. Der Virgo-Haufen - Ein reicher Galaxienhaufen. 21. Das Universum.

  6. Common Data Acquisition Systems (DAS) Software Development for Rocket Propulsion Test (RPT) Test Facilities

    NASA Technical Reports Server (NTRS)

    Hebert, Phillip W., Sr.; Davis, Dawn M.; Turowski, Mark P.; Holladay, Wendy T.; Hughes, Mark S.

    2012-01-01

    The advent of the commercial space launch industry and NASA's more recent resumption of operation of Stennis Space Center's large test facilities after thirty years of contractor control resulted in a need for a non-proprietary data acquisition systems (DAS) software to support government and commercial testing. The software is designed for modularity and adaptability to minimize the software development effort for current and future data systems. An additional benefit of the software's architecture is its ability to easily migrate to other testing facilities thus providing future commonality across Stennis. Adapting the software to other Rocket Propulsion Test (RPT) Centers such as MSFC, White Sands, and Plumbrook Station would provide additional commonality and help reduce testing costs for NASA. Ultimately, the software provides the government with unlimited rights and guarantees privacy of data to commercial entities. The project engaged all RPT Centers and NASA's Independent Verification & Validation facility to enhance product quality. The design consists of a translation layer which provides the transparency of the software application layers to underlying hardware regardless of test facility location and a flexible and easily accessible database. This presentation addresses system technical design, issues encountered, and the status of Stennis development and deployment.

  7. Sensitivity of Global Modeling Initiative CTM predictions of Antarctic ozone recovery to GCM and DAS generated meteorological fields

    SciTech Connect

    Rotman, D; Bergmann, D

    2003-12-04

    We use the Global Modeling Initiative chemistry and transport model to simulate the evolution of stratospheric ozone between 1995 and 2030, using boundary conditions consistent with the recent World Meteorological Organization ozone assessment. We compare the Antarctic ozone recovery predictions of two simulations, one driven by meteorological data from a general circulation model (GCM), the other using the output of a data assimilation system (DAS), to examine the sensitivity of Antarctic ozone recovery predictions to the characteristic dynamical differences between GCM and DAS-generated meteorological data. Although the age of air in the Antarctic lower stratosphere differs by a factor of 2 between the simulations, we find little sensitivity of the 1995-2030 Antarctic ozone recovery between 350 K and 650 K to the differing meteorological fields, particularly when the recovery is specified in mixing ratio units. Relative changes are smaller in the DAS-driven simulation compared to the GCM-driven simulation due to a surplus of Antarctic ozone in the DAS-driven simulation which is not consistent with observations. The peak ozone change between 1995 and 2030 in both simulations is {approx}20% lower than photochemical expectations, indicating that changes in ozone transport at 450 K between 1995 and 2030 constitute a small negative feedback. Total winter/spring ozone loss during the base year (1995) of both simulations and the rate of ozone loss during August and September is somewhat weaker than observed. This appears to be due to underestimates of Antarctic Cl{sub y} at the 450 K potential temperature level.

  8. Alice Vance ("Das Bärenweib"): a historical case of Nievergelt syndrome.

    PubMed

    Urban, M; Krüger, S

    1998-03-01

    Several malformed individuals were presented at the World Exhibition in Antwerp in 1894. Among them was Mrs. Alice Vance from Mount Pleasant, Texas, with congenital limb defects, and Mr. Eugen Berry, who had asymmetrical, monstrous enlargement and macrodactyly of the feet, i.e., Proteus syndrome. After the World Exhibition Mrs. Vance presented herself to the public in Castan's Panopticon imitating a bear. She became famous under the stage name "Das Bärenweib" ("the bear-like woman") and was examined by several German clinicians, and her malformations were considered to be of high scientific interest. Mrs. Vance had mesomelic dwarfism and her mother was known to have similar malformations. Her limb deficiencies were generally considered a unique congenital condition those days, and the diagnosis of "a maternally inherited malformation of the forearms and the shanks" [Daffner 1898: Munch Med Wochenschr 25:782] was made. Virchow [1897: Verh Berl Ges Ethnol Urgeschichte 29:624], feeling attacked by a daily newspaper stating that the physicians as well as the police of Berlin had missed the diagnosis of an "English disease," eventually exercised his authority and diagnosed Alice Vance as a "phocomelic." Clearly, she was not a phocomelic according to past and current definition of this term. Thus, from a historical point of view, the story illustrates how pressure from the daily press altered the definition of an up-to-then precisely defined medical term for decades. According to the clinical data and an X-ray report available from the literature, Alice Vance had a dominantly inherited type of mesomelic dwarfism. We propose the diagnosis of Nievergelt syndrome. PMID:9511977

  9. Natural convection in a wavy open porous cavity filled with a nanofluid: Tiwari and Das' nanofluid model

    NASA Astrophysics Data System (ADS)

    Sheremet, M. A.; Pop, I.; Shenoy, A.

    2016-03-01

    Natural convective heat transfer and fluid flow in an open porous cavity filled with a nanofluid is studied numerically using the Tiwari and Das nanofluid model. The transport equations for mass, momentum and energy formulated in dimensionless stream function and temperature are solved numerically using a second-order accurate finite difference method. Particular efforts are focused on the effects of the governing parameters on the heat and fluid flow. It is found that an increase in undulation number of the wavy vertical wall leads to an attenuation of convective flow and a decrease in the heat transfer rate.

  10. The Independent School Admissions Director as Tim Wakefield's Catcher

    ERIC Educational Resources Information Center

    Vachow, Mike

    2012-01-01

    Bob Uecker, the Milwaukee Brewers' quipping radio broadcaster, makes his brief and lackluster career as a major league catcher the subject of much of his humor. About catching the knuckleball, Uecker famously said, "I always thought the knuckleball was the easiest pitch to catch." Of course, there is an even better way to catch a knuckleball, and…

  11. Tim Wirth: playing a leading role. Newsmaker interview.

    PubMed

    Pickett, S

    1995-01-01

    An interview with Timothy Wirth, who has been Under Secretary of State for Global Affairs, is presented. The US played a new role as a partner at several recent UN conferences that focused on a multiplicity of issues that harbinger the 21st century. The 4th World Conference on Women in Beijing in September 1995 underscored the importance of women as agents of change, confirmed the importance of nongovernmental organizations in affecting global change in governance, and revealed the strength of women's groups in developing countries. The US made some pledges at the 1994 UN Population and Development Conference in Cairo as laid down in the program of action. US financial commitment to population stabilization increased as did the commitment from Japan and other developed countries. Egypt, Indonesia, Tunisia, and Mexico with effective family planning programs are also sharing their experiences with other developing countries. The US has an interest in investing in foreign assistance in view of runaway population growth in countries like Haiti. Haiti's excess population would be heading for Florida. The President's Council on Sustainable Development's task force on population and consumption concluded that the US should commit itself to population stabilization because of the high consumption rate of the average American, the number of unplanned and unwanted pregnancies, and the problem of teenage pregnancies. Consumption rather than investment should taxed, subsidies should be removed from the use of natural resources and agriculture, and environmental degradation should be priced properly. Poverty is at the root of economic deprivation and environmental destruction. Micro-enterprises have been successful in Asia, Africa, and Latin America, which experiences could be used by the US as well. The broader empowerment of women could also encourage political change, which, in turn could bring about full access to family planning and support to women and their families.

  12. GOES-R with Dr. Kathy Sullivan and Tim Samaras

    NASA Video Gallery

    This short video features highlights from a live Nationwide broadcast that took place on April 3, 2012, from the studio of NASA Goddard TV. NOAA’s Deputy Administrator and Chief Scientist Dr. Ka...

  13. Tim Wirth: playing a leading role. Newsmaker interview.

    PubMed

    Pickett, S

    1995-01-01

    An interview with Timothy Wirth, who has been Under Secretary of State for Global Affairs, is presented. The US played a new role as a partner at several recent UN conferences that focused on a multiplicity of issues that harbinger the 21st century. The 4th World Conference on Women in Beijing in September 1995 underscored the importance of women as agents of change, confirmed the importance of nongovernmental organizations in affecting global change in governance, and revealed the strength of women's groups in developing countries. The US made some pledges at the 1994 UN Population and Development Conference in Cairo as laid down in the program of action. US financial commitment to population stabilization increased as did the commitment from Japan and other developed countries. Egypt, Indonesia, Tunisia, and Mexico with effective family planning programs are also sharing their experiences with other developing countries. The US has an interest in investing in foreign assistance in view of runaway population growth in countries like Haiti. Haiti's excess population would be heading for Florida. The President's Council on Sustainable Development's task force on population and consumption concluded that the US should commit itself to population stabilization because of the high consumption rate of the average American, the number of unplanned and unwanted pregnancies, and the problem of teenage pregnancies. Consumption rather than investment should taxed, subsidies should be removed from the use of natural resources and agriculture, and environmental degradation should be priced properly. Poverty is at the root of economic deprivation and environmental destruction. Micro-enterprises have been successful in Asia, Africa, and Latin America, which experiences could be used by the US as well. The broader empowerment of women could also encourage political change, which, in turn could bring about full access to family planning and support to women and their families. PMID:12320283

  14. iLIDS Simulations and Videos for Docking TIM

    NASA Technical Reports Server (NTRS)

    Lewis, James L.

    2010-01-01

    The video shows various aspects of the International Low Impact Docking System, including team members, some production, configuration, mated androgynous iLIDS, SCS Lockdown system, thermal analysis, electrical engineering aspects, the iLIDS control box and emulator, radiation testing at BNL, component environmental testing, component vibration testing, 3G processor board delivery system, GTA vibe test, EMA testbed, hook and hook disassembly, flex shaftdrive assembly, GSE cradle MISSE-6 Columbus, MISSE 6 and 7 seal experiments, actuated full scale seal test rig, LIDS on Hubble, dynamics test prep, EDU 54 mass emulation and SCS, load ring characterization, 6DOF proof test, SCS at 6DOF, machining EEMS and inner ring assembly, APAS assembly, inner ring fitting, rotation stand assembly, EEMS mating, and EEMS proof of concept demonstration.

  15. Using the TIMS to estimate evapotranspiration from a forest

    NASA Technical Reports Server (NTRS)

    Teskey, Robert

    1991-01-01

    The main goals were: (1) to characterize the evapotranspiration (Et) of two forested watersheds using direct measurement techniques, and (2) to evaluate if remotely sensed surface temperatures could be used to estimate Et from the same watersheds. Two independent approaches for estimating the Et from watersheds were used. The first was derived using the Penman-Monteith Equation. This model requires the direct measurement of the microclimate of the site as well as biological measurements, i.e., stomatal conductance to water vapor and the leaf area of the stand. The primary limitation of this approach is that the measurement of stomatal conductance is time consuming, and in large trees, access to the foliage is difficult so the sample must be limited to the small number of trees. In the study, the sample was limited to the trees which could be measured from a single tower in each stand.

  16. Stable Isotope Characterization of TICs/TIMs: Analytical Progress Report

    SciTech Connect

    Volpe, A M; Singleton, M J

    2009-06-05

    We measured twelve alkali cyanide samples that were also sent to ORNL and PNNL collaborators. While results indicate distinct {delta}{sup 13}C and {delta}{sup 15}N values that would be useful to signature studies, the alkali cyanides, especially NaCN, show chemical breakdown during storage that will influence forensic analysis. Carbon and nitrogen stable isotopic compositions of raw materials used to synthesis TETS were measured. Results indicate wide ranges in {delta}{sup 13}C and {delta}{sup 15}N values. Using these raw materials, LLNL scientists synthesized three batches of TETS following published procedures. Stable isotopic measurements of TETS synthesis products indicates nitrogen ({var_epsilon} {sup 15}N = -1.7 to -0.8) and carbon ({var_epsilon} {sup 13}C = -1.0 to -0.1) fractionation during production.

  17. Design study for Thermal Infrared Multispectral Scanner (TIMS)

    NASA Technical Reports Server (NTRS)

    Stanich, C. G.; Osterwisch, F. G.; Szeles, D. M.; Houtman, W. H.

    1981-01-01

    The feasibility of dividing the 8-12 micrometer thermal infrared wavelength region into six spectral bands by an airborne line scanner system was investigated. By combining an existing scanner design with a 6 band spectrometer, a system for the remote sensing of Earth resources was developed. The elements in the spectrometer include an off axis reflective collimator, a reflective diffraction grating, a triplet germanium imaging lens, a photoconductive mercury cadmium telluride sensor array, and the mechanical assembly to hold these parts and maintain their optical alignment across a broad temperature range. The existing scanner design was modified to accept the new spectrometer and two field filling thermal reference sources.

  18. Efficacy of Soybean's Event DAS-81419-2 Expressing Cry1F and Cry1Ac to Manage Key Tropical Lepidopteran Pests Under Field Conditions in Brazil.

    PubMed

    Marques, L H; Castro, B A; Rossetto, J; Silva, O A B N; Moscardini, V F; Zobiole, L H S; Santos, A C; Valverde-Garcia, P; Babcock, J M; Rule, D M; Fernandes, O A

    2016-08-01

    Bacillus thuringiensis (Bt) event DAS-81419-2 (Conkesta technology) in soybean, Glycine max (L.) Merrill, expresses Cry1F and Cry1Ac proteins to provide protection from feeding by several lepidopteran pests. A total of 27 field experiments across nine locations were conducted from 2011 to 2015 in southern and central Brazil to characterize the efficacy of DAS-81419-2 soybean infested with Anticarsia gemmatalis Hübner (Lepidoptera: Erebidae), Chrysodeixis includens (Walker) (Lepidoptera: Noctuidae), Heliothis virescens (F.) (Lepidoptera: Noctuidae), and Spodoptera cosmioides (Walker) (Lepidoptera: Noctuidae) during vegetative (V4) and reproductive (R2 and R4) crop developmental stages. The efficacy of DAS-81419-2 was compared to that of a non-Bt isogenic variety managed with or without applications of commercial foliar insecticides for lepidopteran control. DAS-81419-2 soybean consistently experienced defoliation levels of 0.5% or less (compared with 20.05-56.74% in the non-Bt, nonsprayed treatment) and larval survival of < 0.1% in all four species across the vegetative and reproductive plant stages evaluated. The efficacy of DAS-81419-2 was significantly higher than commercial foliar insecticides applied to the non-Bt variety. DAS-81419-2 soybeans containing two highly effective Bt proteins are expected to be a more robust IRM tool compared to single-trait Bt technologies. The consistent efficacy of DAS-81419-2 soybeans across years, locations, and crop stages suggests that it will be a valuable product for management of hard-to-control key lepidopteran pests in South American soybean production. PMID:27401112

  19. Predictors of European League Against Rheumatism (EULAR) good response, DAS-28 remission and sustained responses to TNF-inhibitors in rheumatoid arthritis: a prospective study in refractory disease.

    PubMed

    Mohammed, Reem Hamdy A; Farahat, Faisal; Kewan, Hanady H; Bukhari, Mohammed A

    2015-01-01

    The aim of this study was to survey factors related to EULAR good response, the DAS-28 definition of remission, ACR 50 response, sustained response to tumor necrosis factor inhibitors (TNF-I) therapy in biologic naïve patients with refractory rheumatoid arthritis. This was a single center observational clinical prospective 2 years' study, EULAR response criteria, DAS 28, HAQ and radiographic changes were recorded. Eighty patients included (64 females and 16 males, mean age was 48.4 + -17.9 years, mean disease duration 7.3 + -5.9 years). At 6 months 70% achieved EULAR good response, 51.8% achieved DAS-28 remission. Good response/sustained responses inversely correlated with baseline DAS-28 and radiographic erosions P <0.05. EULAR good response/remission by 6 months, sustained response at 2 years positively correlated with the decline in RF titers (r = 0.33, P < 0.05 & r = 0.30, P < 0.03 respectively), negatively correlated with the baseline HAQ. Regression analysis identified higher serum hemoglobin concentration, lower baseline HAQ scores, and the absence of radiographic erosions as significant predictors of good as well as sustained responses after adjustment for potential covariates. Methotrexate was associated with favorable responses and remission at 6 months (ORs = 1.13, 1.30 respectively). The study concluded that a lower baseline DAS-28 and HAQ scores, the lack of radiographic erosions favored EULAR good response and were significant predictors of sustained response to TNF-I.

  20. Properties of Noise Cross Correlation Functions Obtained from a Distributed Acoustic Sensing (DAS) Array at Garner Valley, California

    NASA Astrophysics Data System (ADS)

    Zeng, X.; Lancelle, C.; Thurber, C. H.; Fratta, D.; Wang, H. F.; Chalari, A.; Clarke, A.

    2015-12-01

    The field test of Distributed Acoustic Sensing (DAS) conducted at Garner Valley, California on September 11-12, 2013 provided a continuous overnight record of ambient noise. The DAS array recorded ground motions every one meter of optical cable that was arranged approximately in the shape of a rectangle with dimensions of 160 m by 80 m. The long dimension of the array was adjacent to a state highway. Three hours of record were used to compute noise cross-correlation functions (NCFs) in one-minute windows. The trace from each sensor channel was pre-processed by downsampling to 200 Hz, followed by normalization in the time-domain and bandpass filtering between 2 and 20 Hz (Bensen et al., 2007). The one-minute NCFs were then stacked using the time-frequency domain phase-weighted stacking method (Schimmel & Gallart, 2007). The NCFs between channels were asymmetrical reflecting the direction of traffic noise. The group velocities were found using the frequency-time analysis method. The energy was concentrated between 5 and 15 Hz, which falls into the typical traffic noise frequency band. The resulting velocities were between 100 and 300 m/s for frequencies between 10 and 20 Hz, which are in the same range as described in the results for surface-wave dispersion obtained using an active source for the same site (Lancelle et al., 2015). The group velocity starts to decrease for frequencies greater than ~10 Hz, which was expected on the basis of a previous shear-wave velocity model (Steidl et al., 1996). Then, the phase velocity was calculated using the multichannel analysis of surface wave technique (MASW - Park et al., 1999) with 114 NCFs spaced one meter apart. The resulting dispersion curve between 5 and 15 Hz gave phase velocities that ranged from approximately 170 m/s at 15 Hz to 250 m/s at 5 Hz. These results are consistent with other results of active-source DAS and seismometer records obtained at the Garner Valley site (e.g., Stokoe et al. 2004). This analysis is

  1. Insect-Protected Event DAS-81419-2 Soybean (Glycine max L.) Grown in the United States and Brazil Is Compositionally Equivalent to Nontransgenic Soybean

    PubMed Central

    2015-01-01

    The transgenic soybean event DAS-81419-2 contains genes that encode the Cry1F, Cry1Ac, and PAT proteins. Cry1F and Cry1Ac provide protection against key lepidopteran insect pests, while PAT confers tolerance to the herbicide glufosinate. To satisfy regulatory requirements for the safety evaluation of transgenic crops, studies were conducted in the United States and Brazil to evaluate the nutrient and antinutrient composition of event DAS-81419-2 soybean. On the basis of the results of these studies, event DAS-81419-2 soybean is compositionally equivalent to nontransgenic soybean. This conclusion concurs with numerous other published studies in soybean and other crops where compositional equivalence between the transgenic crop and its nontransgenic comparator has been demonstrated. PMID:25641393

  2. Insect-protected event DAS-81419-2 soybean (Glycine max L.) grown in the United States and Brazil is compositionally equivalent to nontransgenic soybean.

    PubMed

    Fast, Brandon J; Schafer, Ariane C; Johnson, Tempest Y; Potts, Brian L; Herman, Rod A

    2015-02-25

    The transgenic soybean event DAS-81419-2 contains genes that encode the Cry1F, Cry1Ac, and PAT proteins. Cry1F and Cry1Ac provide protection against key lepidopteran insect pests, while PAT confers tolerance to the herbicide glufosinate. To satisfy regulatory requirements for the safety evaluation of transgenic crops, studies were conducted in the United States and Brazil to evaluate the nutrient and antinutrient composition of event DAS-81419-2 soybean. On the basis of the results of these studies, event DAS-81419-2 soybean is compositionally equivalent to nontransgenic soybean. This conclusion concurs with numerous other published studies in soybean and other crops where compositional equivalence between the transgenic crop and its nontransgenic comparator has been demonstrated.

  3. Der vollständige Brief Brahes an Sørensen über das Erscheinen des Kometen von 1577

    NASA Astrophysics Data System (ADS)

    Kirschner, Stefan

    Es ist erstaunlich, daß sowohl Friis als auch Dreyer in ihrer Ausgabe der Briefe Tycho Brahes den Brief vom 14. November 1577 an Peter Sørensen, die erste bekannte Nachricht Brahes von seiner Entdeckung des Kometen von 1577, nur unvollständig, und zwar ohne den astronomischen Inhalt, ediert haben. Der Brief, dessen Original sehr wahrscheinlich nicht mehr existiert, wurde von dem Kieler Arzt und Medizinprofessor Johann Daniel Major (1634 - 1693) in Kopenhagen in sein Reisetagebuch kopiert. Das Original des Majorschen Reisetagebuches ist verschollen, doch es existieren zwei Abschriften davon (Kopenhagen, Königl. Bibl., Ny Kgl. Sml., 365, Fol. u. Ledreborg, 410, Fol.). Im folgenden wird nach einer kurzen Beschreibung des Stellenwerts, den der Komet von 1577 für Brahe besaß, der Brief nach diesen beiden Abschriften kritisch ediert, mit einer deutschen Übersetzung versehen und kurz kommentiert.

  4. Development of a surface-wave imaging system for geotechnical applications based on distributed acoustic sensing (DAS) and ambient noise interferometry

    NASA Astrophysics Data System (ADS)

    Ajo Franklin, J. B.; Daley, T. M.; Freifeld, B. M.; Tang, D. G.; Zhang, R.; Wagner, A. M.; Dou, S.; Lindsey, N.; Bjella, K.; Pevzner, R.

    2014-12-01

    Distributed fiber-optic sensing methods have been used since the 1980's for continuous monitoring of near-surface soil properties, typically exploiting Raman scattering to measure temperature (DTS) or stimulated Brillouin scattering to measure strain (DSS). Recent advances in high speed measurement of Rayleigh scattering has enabled distributed recording of seismic waves over long sections of fiber; this approach, referred to as distributed acoustic sensing (DAS) has the potential to allow nearly continuous monitoring of near-surface mechanical properties, a crucial target for geotechnical management of infrastructure dependent on soil strength. We present initial results from our effort to build a real-time soil property monitoring system based on DAS; our approach employs seismic interferometry and dispersion analysis of ambient noise generated by infrastructure to provide a continuously updated model of shear modulus. Our preliminary results include an in-depth investigation of DAS fiber response in the context of active sources; this component of our study verifies classical models for the azimuthal response of straight fibers to propagating surface waves. We also explore the "noisescape" of linear infrastructure and show a usable seismic signal band of 8-40 hz at a series of sites, primarily consisting of Rayleigh waves. Finally, we present preliminary results from a DAS monitoring array installed at the Richmond Field Station near a heavily used road and compare interferometric processing of the acquired data to that generated by surface deployment of geophones.

  5. Novas determinações dos parâmetros atmosféricos das estrelas anãs brancas DA

    NASA Astrophysics Data System (ADS)

    Giovannini, O.; Costa, A. F. M.; Kepler, S. O.

    2003-08-01

    Nós temos selecionado uma amostra de estrelas anãs brancas DA (atmosfera de hidrogênio) a partir dos índices de Strömgren cujos valores estão próximos a região de instabilidade das estrelas anãs brancas DA variáveis, as chamadas estrelas DAV ou ZZ Ceti. O objetivo é determinar os parâmetros fundamentais (temperatura efetiva, Teff, aceleração da gravidade, log g, e massa) destas estrelas para verificar quais os parâmetros estelares estão envolvidos com o mecanismo de pulsação das estrelas DAV. Nós obtemos, até agora, mais de 120 espectros óticos de estrelas DA. Entre as estrelas selecionadas há 20 estrelas variáveis (DAV). Assim, podemos verificar se existem ou não estrelas não variáveis dentro da faixa de instabilidade das estrelas ZZ Ceti. Neste trabalho nós apresentamos a determinação dos parâmetros atmosféricos (temperatura efetiva, Teff, e aceleração da gravidade, log g) das estrelas anãs brancas DA usando os novos modelos de atmosfera ML2/a = 0.6. Estes modelos têm sido utilizados recentemente por fornecerem uma excelente consistência interna na determinação das temperaturas nas regiões do ultra-violeta e ótico. Os parâmetros atmosféricos são determinados espectroscopicamente através da comparação do fluxo de energia das linhas de Balmer (Hb à H9) entre os espectros observados e sintéticos (gerados pelos modelos de atmosfera). As temperaturas obtidas com os novos modelos são, em geral, menores (~ 1000 K menos) que as temperaturas determinadas anteriormente, com modelos ML1. Os valores de log g não mudaram significativamente (menos de 10%). A faixa de instabilidade das DAVs está entre 11000 e 13000 K, consistente com dados de outros autores.

  6. Development and evaluation of a DAS-ELISA for rapid detection of Tembusu virus using monoclonal antibodies against the envelope protein.

    PubMed

    Chen, Hao; Ou, Quanbin; Tang, Yi; Gao, Xuhui; Wu, Lili; Xue, Cong; Yu, Chunmei; Cui, Jingteng; Diao, Youxiang

    2014-01-01

    Since April 2010, Tembusu virus (TMUV) which is a contagious pathogen of waterfowls, causing symptoms of high fever, loss of appetite and fall in egg production, has been reported in east of China. A double antibody sandwich enzyme-linked immunosorbent assay (DAS-ELISA) which detects for TMUV was developed, using two monoclonal antibodies (mAbs) against the TMUV envelope (E) protein. BALB/c mice were immunized with purified recombinant E protein expressed in E. coli. Three hybridoma cell lines designated as 12B1, 10C6 and 2D2, were screened by cell fusion and indirect ELISA for their ability to recognize different linear epitopes on the E protein, and were characterized subsequently. High-affinity mAbs 12B1 and 2D2 were used as capture and detection antibodies, respectively. The reaction conditions for the DAS-ELISA were optimized for TMUV detection. The cross-reactivity of the DAS-ELISA was determined using TMUV, duck plague virus, avian influenza virus subtype H9, Newcastle disease virus, duck hepatitis A virus type 1 and duck reovirus samples. A total of 191 homogenized tissues of field samples were simultaneously detected by DAS-ELISA and by RT-PCR. The former was found to have a high specificity of 99.1% and a sensitivity of 93.1%. These results reveal a positive coincidence between DAS-ELISA and RT-PCR at a coincidence rate of 95.8%. The method developed in this study can be used for the diagnosis of TMUV infection of duck origin. PMID:24797141

  7. Simulation of the single-vibronic-level emission spectra of HAsO and DAsO

    NASA Astrophysics Data System (ADS)

    Mok, Daniel K. W.; Lee, Edmond P. F.; Dyke, John M.

    2016-05-01

    The single-vibronic-level (SVL) emission spectra of HAsO and DAsO have been simulated by electronic structure/Franck-Condon factor calculations to confirm the spectral molecular carrier and to investigate the electronic states involved. Various multi-reference (MR) methods, namely, NEVPT2 (n-electron valence state second order perturbation theory), RSPT2-F12 (explicitly correlated Rayleigh-Schrodinger second order perturbation theory), and MRCI-F12 (explicitly correlated multi-reference configuration interaction) were employed to compute the geometries and relative electronic energies for the X ˜ 1 A ' and A ˜ 1 A ″ states of HAsO. These are the highest level calculations on these states yet reported. The MRCI-F12 method gives computed T0 (adiabatic transition energy including zero-point energy correction) values, which agree well with the available experimental T0 value much better than previously computed values and values computed with other MR methods in this work. In addition, the potential energy surfaces of the X ˜ 1 A ' and A ˜ 1 A ″ states of HAsO were computed using the MRCI-F12 method. Franck-Condon factors between the two states, which include anharmonicity and Duschinsky rotation, were then computed and used to simulate the recently reported SVL emission spectra of HAsO and DAsO [R. Grimminger and D. J. Clouthier, J. Chem. Phys. 135, 184308 (2011)]. Our simulated SVL emission spectra confirm the assignments of the molecular carrier, the electronic states involved, and the vibrational structures observed in the SVL emission spectra but suggest a loss of intensity in the reported experimental spectra at the low emission energy region almost certainly due to a loss of responsivity near the cutoff region (˜800 nm) of the detector used. Computed and experimentally derived re (equilibrium) and/or r0 {the (0,0,0) vibrational level} geometries of the two states of HAsO are discussed.

  8. Entomological fauna from Reserva Biológica do Atol das Rocas, RN, Brazil: I. Morphospecies composition.

    PubMed

    Almeida; Marchon-Silva; Ribeiro; Serpa-Filho; Almeida; Costa

    2000-05-01

    Atol das Rocas, the unique atoll in the South-western Atlantic, is located 144 nautical miles (266 Km) northeast from the city of Natal, NE Brazil and 80 nautical miles from Arquipélago de Fernando de Noronha, with geographic co-ordinates 3 masculine51'S and 33 masculine49"W. It's of volcanic origin and coralline formation. The reef is ellipsoid, its largest axis (E-W) is approximately 3.7 km long, and the shortest (N-S) is 2.5 km. Inside the lagoon, there are two islands: the Ilha do Farol and Ilha do Cemitério, which comprehend 7.2 Km2 of emerged area. The Atol das Rocas lodges 143,000 birds, mainly by Sula dactilatra, S. leucogaster, Anous stolidus, A. minuta and Sterna fuscata. Due to their remote location, the islands remain largely undisturbed by the human activities. Aiming to a first characterization of the entomological diversity and the general trophic niches of atoll's entomofauna, three collects were made (1994, 1995 and 1996) utilizing several methods for a wide sample. One thousand six hundred and six insect specimens were collected belonging to eight orders: 1. Coleoptera - 333 individuals of Dermestidae (Dermestes cadaverinus); Tenebrionidae (Phaleria testacea and morphospecies) and Curculionidae (one morphospecies); 2. Dermaptera - 50 individuals of Carcinophoridae (Anisolabis maritima); 3. Diptera - 281 individuals of Ephydridae (Scatella sp. and Hecamede sp.) and Hippoboscidae (one morphospecies); 4. Hymenoptera - 45 individuals of Formicidae (Brachymyrmex sp.); 5. Lepidoptera - 111 individuals of Microlepidoptera (one morphospecies); 6. Mallophaga - 18 individuals in birds (two morphospecies); 7. Orthoptera - 237 individuals of Acrididae (Schistocerca cancellata), Tridactylidae (one morphospecies) and Blattidae (three morphospecies); 8. Thysanoptera -531 individuals (one morphospecies). Also were collected 112 individuals of Arachnida. The taxa of the Order Araneae were represented by the families: 1. Miturgidae (Cheiracanthium inclusum); 2

  9. Common Data Acquisition Systems (DAS) Software Development for Rocket Propulsion Test (RPT) Test Facilities - A General Overview

    NASA Technical Reports Server (NTRS)

    Hebert, Phillip W., Sr.; Hughes, Mark S.; Davis, Dawn M.; Turowski, Mark P.; Holladay, Wendy T.; Marshall, PeggL.; Duncan, Michael E.; Morris, Jon A.; Franzl, Richard W.

    2012-01-01

    The advent of the commercial space launch industry and NASA's more recent resumption of operation of Stennis Space Center's large test facilities after thirty years of contractor control resulted in a need for a non-proprietary data acquisition system (DAS) software to support government and commercial testing. The software is designed for modularity and adaptability to minimize the software development effort for current and future data systems. An additional benefit of the software's architecture is its ability to easily migrate to other testing facilities thus providing future commonality across Stennis. Adapting the software to other Rocket Propulsion Test (RPT) Centers such as MSFC, White Sands, and Plumbrook Station would provide additional commonality and help reduce testing costs for NASA. Ultimately, the software provides the government with unlimited rights and guarantees privacy of data to commercial entities. The project engaged all RPT Centers and NASA's Independent Verification & Validation facility to enhance product quality. The design consists of a translation layer which provides the transparency of the software application layers to underlying hardware regardless of test facility location and a flexible and easily accessible database. This presentation addresses system technical design, issues encountered, and the status of Stennis' development and deployment.

  10. Das Lektin aus der Erbse Pisum sativum : Bindungsstudien, Monomer-Dimer-Gleichgewicht und Rückfaltung aus Fragmenten

    NASA Astrophysics Data System (ADS)

    Küster, Frank

    2002-11-01

    Das Lektin aus Pisum sativum, der Gartenerbse, ist Teil der Familie der Leguminosenlektine. Diese Proteine haben untereinander eine hohe Sequenzhomologie, und die Struktur ihrer Monomere, ein all-ß-Motiv, ist hoch konserviert. Dagegen gibt es innerhalb der Familie eine große Vielfalt an unterschiedlichen Quartärstrukturen, die Gegenstand kristallographischer und theoretischer Arbeiten waren. Das Erbsenlektin ist ein dimeres Leguminosenlektin mit einer Besonderheit in seiner Struktur: Nach der Faltung in der Zelle wird aus einem Loop eine kurze Aminosäuresequenz herausgeschnitten, so dass sich in jeder Untereinheit zwei unabhängige Polypeptidketten befinden. Beide Ketten sind aber stark miteinander verschränkt und bilden eine gemeinsame strukturelle Domäne. Wie alle Lektine bindet Erbsenlektin komplexe Oligosaccharide, doch sind seine physiologische Rolle und der natürliche Ligand unbekannt. In dieser Arbeit wurden Versuche zur Entwicklung eines Funktionstests für Erbsenlektin durchgeführt und seine Faltung, Stabilität und Monomer-Dimer-Gleichgewicht charakterisiert. Um die spezifische Rolle der Prozessierung für Stabilität und Faltung zu untersuchen, wurde ein unprozessiertes Konstrukt in E. coli exprimiert und mit der prozessierten Form verglichen. Beide Proteine zeigen die gleiche kinetische Stabilität gegenüber chemischer Denaturierung. Sie denaturieren extrem langsam, weil nur die isolierten Untereinheiten entfalten können und das Monomer-Dimer-Gleichgewicht bei mittleren Konzentrationen an Denaturierungsmittel auf der Seite der Dimere liegt. Durch die extrem langsame Entfaltung zeigen beide Proteine eine apparente Hysterese im Gleichgewichtsübergang, und es ist nicht möglich, die thermodynamische Stabilität zu bestimmen. Die Stabilität und die Geschwindigkeit der Assoziation und Dissoziation in die prozessierten bzw. nichtprozessierten Untereinheiten sind für beide Proteine gleich. Darüber hinaus konnte gezeigt werden, dass auch unter

  11. Free convection in a parallelogrammic porous cavity filled with a nanofluid using Tiwari and Das' nanofluid model.

    PubMed

    Ghalambaz, Mohammad; Sheremet, Mikhail A; Pop, Ioan

    2015-01-01

    The free convection heat transfer of Cu-water nanofluids in a parallelogrammic enclosure filled with porous media is numerically analyzed. The bottom and top of the enclosure are insulated while the sidewalls are subject to limited temperature difference. The Darcy flow and the Tiwari and Das' nanofluid models are considered. The governing dimensionless partial differential equations are numerically solved using a finite difference code. The results are reported for isotherms and streamlines as well as Nusselt number as a function of the volume fraction of nanoparticles, porosity, types of the porous matrix, inclination angle, aspect ratio and different Rayleigh numbers. It is found that the presence of the nanoparticles inside the enclosure deteriorates the heat transfer rate, which is caused due to the increase of dynamic viscosity by the presence of nanoparticles. Therefore, in applications in which the nanofluids are used for their advantages, such as enhanced dielectric properties or antibacterial properties, more caution for the heat transfer design of the enclosure is necessary. PMID:25993540

  12. Variation of the anthropic vulnerability in Ribeirão das Pedras watershed in Campinas/SP - Brazil.

    NASA Astrophysics Data System (ADS)

    Damame, Desirée; Longo, Regina; Ribeiro, Admilson; Fengler, Felipe

    2015-04-01

    The human actions has caused over the years profound changes in environmental quality in urban ecosystems suffering losses in the quality of air, soil , water and vegetation also the quality of life of the population that inhabit these areas . The study area is characterized by being a highly urbanized watershed, with about 43 % of its area covered by buildings, houses , and commercial and industrial establishments . Called the Ribeirão das Pedras Basin, located in Campinas / SP - Brazil and is bounded by coordinates 22˚47'10 '' and 22˚52'20 '' S , and 47˚ 07'15 '' and 46˚ 02 ' 15' ' . Has an average temperature of 22.4 ° C and average annual rainfall of 1424.5 mm . It has an area of about 42 km² . This is located two universities and a large mall. It also demands a strong agriculture , which occupies about 30 % of the area . It has also been part of two major forest reserves of the municipality, the Forest Santa Geneva and the Forest of Quilombo , both added to other small fragments overlying only about 6% of the total basin area . Avalição to environmental quality , the analysis of the vulnerability of urban watershed becomes an important environmental management tool. The vulnerability can be defined by susceptibility to changes of environment in its initial state , a current tax status by human intervention , and is almost always associated with risk , and the intensity at which such projects in one place, person or structure. In this context , this study aimed to assess environmental vulnerability in an urban watershed coming under increasing human pressures , especially in recent years . For this analysis were prepared soil graphics, slope , elevation and land use and land cover for the years 2009 and 2014 , generating with these , comparative anthropic vulnerability maps of the past five years. Crafting vulnerability maps is a sensitivity in order to enable appropriate management of biotic systems. With the results can be seen that the variation of

  13. Ventos em supergigantes B[e] das nuvens de Magalhães e da Galáxia

    NASA Astrophysics Data System (ADS)

    de Araújo, F. X.; Pilling, D. A.; Pereira, C. B.; Fernandes, M. B.

    2003-08-01

    As Supergigantes B[e] apresentam as seguintes características: (i) alta luminosidade; (ii) espectro típico de estrelas de tipo B; (iii) linhas permitidas e proibidas em emissão de metais de baixa ionização, especialmente FeII; (iv) linhas de Balmer, e por vêzes também dos ions HeI e FeII, com perfis tipo P Cygni indicativos de altas taxas de perda de massa. Atualmente estamos desenvolvendo um projeto que visa comparar as propriedades fisicas (principalmente e v¥) dos ventos destes objetos nas Nuvens de Magalhães e na Galaxia. O objetivo é estudar a influência da metalicidade. No presente painel apresentamos uma determinação das velocidades terminais de 11 estrelas, sendo 4 na GNM (Hen S111, 66, R126 e Hen S93), 4 na PNM (Hen S18, S23, S65 e R4) e 3 na Galaxia (CPD-529243, MWC 300 e GG Car). Nossos dados são espectros de alta resolução obtidos no telescópio 1.52m do ESO com o espectrógrafo FEROS. Para determinar as velocidades terminais usamos as linhas Hd e HeI 3888 Å cujas componentes em absorção costumam estar livres de "blends" e estruturas. Nossos resultados sugerem que as velocidades de expansão na GNM são maiores (ainda que apenas ligeiramente) do que aquelas da PNM, como esperado. No entanto, os objetos da Galaxia não parecem seguir a mesma tendência.

  14. Latent factor structure of the Das-Naglieri Cognitive Assessment System: a confirmatory factor analysis in a Chinese setting.

    PubMed

    Deng, Ci-ping; Liu, Ming; Wei, Wei; Chan, Raymond C K; Das, J P

    2011-01-01

    This study aims to measure the psychometric properties of the Das-Naglieri Cognitive Assessment System (D-N CAS) and to determine its clinical utility in a Chinese context. Confirmatory factor analysis (CFA) was conducted to examine the construct validity of the Chinese version of the D-N CAS among a group of 567, normally developed children. Test-retest reliability was examined in a random subsample of 30 children at a five-week interval. The clinical discrimination of the D-N CAS was also examined by comparing children with and without ADHD (18 children in each group) and by comparing children with and without Chinese reading disabilities (18 children in each group). The current Chinese sample demonstrated a four-factor solution for cognitive performance among children with normal development: Planning, Attention, Simultaneous processing and Successive processing (χ2(48)=91.90, p=.000; χ2/df=1.92, RMSEA=.050, GFI=.966, CFI=.954). Moreover, all subtests of the battery demonstrated acceptable test-retest reliability (r=.72-.90, p<.01) at a five-week interval among the subjects of the small subsample. Children with ADHD performed significantly worse than normal children on the Attention factor (p<.001) and the Planning factor (p<.05) of the D-N CAS, and children with Chinese reading disabilities performed significantly worse than normal children on the Simultaneous processing factor (p<.01), the Successive processing factor (p<.001) and the Planning factor (p<.05) of the D-N CAS. These findings suggested that the current four-factor structure of the D-N CAS was similar to the original factor structure of the test. The latent factor of the D-N CAS was fairly stable across the cultures. Moreover, the D-N CAS can distinguish between children with ADHD or Chinese reading disabilities and normally developed children. PMID:21571501

  15. Kernfusion und das Energieproblem

    NASA Astrophysics Data System (ADS)

    Schlüter, Arnulf

    1982-05-01

    The present understanding of the physics and technology problems of confining a hot plasma ring by magnetic fields and of heating it to such temperatures that thermonuclear fusions between deuterium and tritium nuclei provide the energy required to maintain this temperature seems to allow to predict the possibility of a self-sustaining thermonuclear reactor. Imbedding this chance into world energy scenarios for the next fifty years, it is shown that fusion reactors of a type of which each may supply about ten slow fission reactors with fissionable material may play a critical rôle by drastically reducing the number of required fast fission breeder reactors.

  16. Das motorische Intentionspotential

    NASA Astrophysics Data System (ADS)

    Keidel, Matthias

    1983-04-01

    Autocorrelation of the EEG was used to registrate a potential from the intact human scalp during intended, but not executed movements (dorsalflexion of the right hallux, imaginated in equal time intervals). This “Motor Intention Potential” (MIP) is a possible electrophysiological sign of the otherwise purely introspectively experienced intention of a voluntary movement and the cortex of the frontal lobes is suspected to be its origin. The average maximum amplitude height is 6 μV, and the potential shows a continuous decrease from the frontal to occipital region. The duration of MIP is in the range of seconds. Methodological questions are discussed, and the MIP is differentiated from other event-, movement- and imagination-related potentials. An attempt is made to place the motor intention potential in the context of existing movement theories.

  17. Desenvolvimento das câmeras de raios-X duros do satélite MIRAX

    NASA Astrophysics Data System (ADS)

    Braga, J.; Rothschild, R.; Staubert, R.; Heise, J.; Remillard, R.; D'Amico, F.; Jablonski, F.; Mejía, J.; Carvalho, H.; Heindl, B.; Matteson, J.; Kendziorra, E.; Wilms, J.; in't Zand, J.; Kuulkers, E.

    2003-08-01

    O MIRAX (Monitor e Imageador de RAios-X) é um projeto de desenvolvimento de um pequeno satélite astronômico de raios-X (~200 kg, ~240 W). A estratégia básica da missão será observar continuamente (~9 meses por ano) a região central (~1000 graus2) do plano Galáctico e realizar estudos espectroscópicos de banda larga (2-200 keV) e alta sensibilidade de um grande conjunto de fontes através de imagens com resolução de ~6'. Isso proporcionará uma cobertura inédita do "espaço de descobertas" através da detecção, localização, identificação e estudo detalhado de fenômenos imprevisíveis, tais como transientes fracos de raios-X, novas rápidas de raios-X e bursts de raios gama, assim como o estudo de fontes com emissão persistente. Neste trabalho apresentamos o projeto das duas câmeras de raios-X duros (CXDs) do MIRAX, que irão operar na faixa de 10 a 200 keV. Cada CXD consistirá de um plano de detectores CZT (Cd0,9Zn0,1Te) de 0,5 mm de resolução espacial e 370 cm2 de área total, e de uma máscara codificada com elementos quadrados de 1,3 mm de lado e 0,5 cm de espessura. A máscara terá dimensões de 315 cm ´ 275 cm e será montada a 700 cm de distância dos detectores. Com essa configuração as CXDs terão 6' de resolução angular e, quando colocadas a um ângulo de 29° entre si, as duas câmeras propiciam um campo totalmente codificado de 39° ´ 6°12' e um campo total de 76° ´ 44°. Serão apresentadas simulações de observações da região do plano Galáctico com o conjunto formado pelas duas CXDs.

  18. Soil gas Rn monitoring at Chã das Caldeiras prior the 2014-15 Fogo eruption, Cape Verde

    NASA Astrophysics Data System (ADS)

    Padilla, Germán; Barrancos, José; Dionis, Samara; Fernandes, Paulo; Pérez, Nemesio M.; Sagiya, Takeshi; Padrón, Eleazar; Melián, Gladys V.; Hernández, Pedro A.; Silva, Sónia; Pereira, José Manuel; Rodríguez, Fátima; Asensio-Ramos, María; Calvo, David; Semedo, Helio

    2015-04-01

    Since 2007 the ITER-INVOLCAN/UNICV-OVCV/SNPC research team has implemented a geochemical program for the volcanic surveillance of Fogo volcano by means of applying different geochemical methods in a regularly basis (diffuse degassing surveys, fumarole gas sampling, etc.). This program was improved by setting up a geochemical permanent station (CHA01) to perform continuous measurements of soil gas radon (222Rn) and thoron (220Rn) activities at Chã das Caldeiras, more specific in Portela village, since April 20, 2013. Both gases are characterized to ascend towards the surface mainly through cracks or faults via diffusion and/or advection mechanisms dependent of both soil porosity and permeability, which in turn vary as a function of the stress/strain changes at depth. Measurements of 222Rn and 220Rn activities were performed by an alpha-spectrometer after pumping the soil gas from a thermally isolated PVC pipe inserted 1m in the ground. Even though during the study period the recorded data did not show high 222Rn activity values, a change in the temporal evolution of soil gas 222Rn activity was observed. During the first six months, from April to October, 2013, recorded time series of 222Rn and 220Rn activities showed normal background levels with values of 80.5 and 55.2 Bqm-3, respectively. However, from October, 2013, to February, 2014, 222Rn time series showed an increase trend reaching peak values of 396 Bqm-3 and having an average activity of 134 Bqm-3 until the removal of the station on November 25, 2014 due to the potential danger of being destroyed by the lava flows. The observed increase in the soil gas 222Rn activity from October 2013 to February 2014 occurs almost at the same time of slight observed changes in the vertical displacements detected by the geodetic network installed at the Fogo Island by the ITER-INVOLCAN/UNICV-OVCV/SNPC/Nagoya University research team. Since seismic data are not available, we cannot conclude if the observed changes in soil

  19. Challenges for bathing in rivers in terms of compliance with coliform standards. Case study in a large urbanized basin (das Velhas River, Brazil).

    PubMed

    von Sperling, Marcos; von Sperling, Eduardo

    2013-01-01

    This paper presents a case study on the prospects of bathing in a large water course (das Velhas River, Brazil), which crosses the important metropolitan region of Belo Horizonte (25 municipalities), receiving several point and diffuse discharges. The studies were carried out based on a mathematical simulation of thermotolerant coliforms over 227 km of the river, using an adaptation of the Qual2E model (model Qual-UFMG). Simulations of intervention scenarios were made for the current conditions, with three reference flows for the das Velhas River, tributaries and direct contribution: Q7,10 (representative of low-flow conditions), Q50 (average conditions) and Q10 (rainy season). The intervention scenarios simulated were: (a) current conditions without intervention; (b) scenario with effluent disinfection in the two largest wastewater treatment plants in the basin (around 2.4 million inhabitants); (c) scenario with 95% sewage collection and treatment, with disinfection in all municipalities of the study area; (d) scenario with the calculation of values required for the coverage of sewage treatment and coliform removal efficiencies based on a mathematical optimization process. The monitoring data and results of all simulations indicated improvement in coliform concentration as the river flows downstream. However, results suggested that disinfection per se is not enough. Even under hypothetical conditions of excellent sanitary infrastructure for a developing country, coverage of collection and treatment of 95% of the generated sewage, and treatment with disinfection at all wastewater treatment plants, concentrations of thermotolerant coliforms in das Velhas River are likely to be above the maximum allowable of 1,000 MPN/100 mL for bathing purposes. The mathematical optimization indicated the need for very high percentages of sewage treatment coverage (near 100%, i.e. universality of collection and treatment) and implementation of disinfection in most treatment plants

  20. Data Integration Acquired from Micro-Uav and Terrestrial Laser Scanner for the 3d Mapping of Jesuit Ruins of São Miguel das Missões

    NASA Astrophysics Data System (ADS)

    Reiss, M. L. L.; da Rocha, R. S.; Ferraz, R. S.; Cruz, V. C.; Morador, L. Q.; Yamawaki, M. K.; Rodrigues, E. L. S.; Cole, J. O.; Mezzomo, W.

    2016-06-01

    The Jesuit Missions the Guaranis were one of the great examples of cultural, social, and scientific of the eighteenth century, which had its decline from successive wars that followed the exchange of territories domain occupied by Portugal and Spain with the Madrid Treaty of January 13, 1750. One of the great examples of this development is materialized in the ruins of 30 churches and villages that remain in a territory that now comprises part of Brazil, Argentina and Paraguay. These Churches, São Miguel das Missões is among the Brazilian ruins, the best preserved. The ruins of São Miguel das Missões were declared a UNESCO World Cultural Heritage in 1983 and the Institute of National Historical Heritage (IPHAN) is the Brazilian Federal agency that manages and maintains this heritage. In order to produce a geographic database to assist the IPHAN in the management of the Ruins of São Miguel das Missões it was proposed a three-dimensional mapping of these ruins never performed in this location before. The proposal is integrated data acquired from multiple sensors: two micro-UAV, an Asctec Falcon 8 (rotary wing) and a Sensefly e-Bee (fixed wing); photos from terrestrial cameras; two terrestrial LIDAR sensors, one Faro Focus 3D S-120 and Optec 3D-HD ILRIS. With this abundance of sensors has been possible to perform comparisons and integration of the acquired data, and produce a 3D reconstruction of the church with high completeness and accuracy (better than 25 mm), as can be seen in the presentation of this work.

  1. Challenges for bathing in rivers in terms of compliance with coliform standards. Case study in a large urbanized basin (das Velhas River, Brazil).

    PubMed

    von Sperling, Marcos; von Sperling, Eduardo

    2013-01-01

    This paper presents a case study on the prospects of bathing in a large water course (das Velhas River, Brazil), which crosses the important metropolitan region of Belo Horizonte (25 municipalities), receiving several point and diffuse discharges. The studies were carried out based on a mathematical simulation of thermotolerant coliforms over 227 km of the river, using an adaptation of the Qual2E model (model Qual-UFMG). Simulations of intervention scenarios were made for the current conditions, with three reference flows for the das Velhas River, tributaries and direct contribution: Q7,10 (representative of low-flow conditions), Q50 (average conditions) and Q10 (rainy season). The intervention scenarios simulated were: (a) current conditions without intervention; (b) scenario with effluent disinfection in the two largest wastewater treatment plants in the basin (around 2.4 million inhabitants); (c) scenario with 95% sewage collection and treatment, with disinfection in all municipalities of the study area; (d) scenario with the calculation of values required for the coverage of sewage treatment and coliform removal efficiencies based on a mathematical optimization process. The monitoring data and results of all simulations indicated improvement in coliform concentration as the river flows downstream. However, results suggested that disinfection per se is not enough. Even under hypothetical conditions of excellent sanitary infrastructure for a developing country, coverage of collection and treatment of 95% of the generated sewage, and treatment with disinfection at all wastewater treatment plants, concentrations of thermotolerant coliforms in das Velhas River are likely to be above the maximum allowable of 1,000 MPN/100 mL for bathing purposes. The mathematical optimization indicated the need for very high percentages of sewage treatment coverage (near 100%, i.e. universality of collection and treatment) and implementation of disinfection in most treatment plants

  2. DasPy 1.0 - the Open Source Multivariate Land Data Assimilation Framework in combination with the Community Land Model 4.5

    NASA Astrophysics Data System (ADS)

    Han, X.; Li, X.; He, G.; Kumbhar, P.; Montzka, C.; Kollet, S.; Miyoshi, T.; Rosolem, R.; Zhang, Y.; Vereecken, H.; Franssen, H.-J. H.

    2015-08-01

    Data assimilation has become a popular method to integrate observations from multiple sources with land surface models to improve predictions of the water and energy cycles of the soil-vegetation-atmosphere continuum. Multivariate data assimilation refers to the simultaneous assimilation of observation data from multiple model state variables into a simulation model. In recent years, several land data assimilation systems have been developed in different research agencies. Because of the software availability or adaptability, these systems are not easy to apply for the purpose of multivariate land data assimilation research. We developed an open source multivariate land data assimilation framework (DasPy) which is implemented using the Python script language mixed with the C++ and Fortran programming languages. LETKF (Local Ensemble Transform Kalman Filter) is implemented as the main data assimilation algorithm, and uncertainties in the data assimilation can be introduced by perturbed atmospheric forcing data, and represented by perturbed soil and vegetation parameters and model initial conditions. The Community Land Model (CLM) was integrated as the model operator. The implementation allows also parameter estimation (soil properties and/or leaf area index) on the basis of the joint state and parameter estimation approach. The Community Microwave Emission Modelling platform (CMEM), COsmic-ray Soil Moisture Interaction Code (COSMIC) and the Two-Source Formulation (TSF) were integrated as observation operators for the assimilation of L-band passive microwave, cosmic-ray soil moisture probe and land surface temperature measurements, respectively. DasPy has been evaluated in several assimilation studies of neutron count intensity (soil moisture), L-band brightness temperature and land surface temperature. DasPy is parallelized using the hybrid Message Passing Interface and Open Multi-Processing techniques. All the input and output data flows are organized efficiently

  3. Development of multiplex PCR method for simultaneous detection of four events of genetically modified maize: DAS-59122-7, MIR604, MON863 and MON88017.

    PubMed

    Oguchi, Taichi; Onishi, Mari; Mano, Junichi; Akiyama, Hiroshi; Teshima, Reiko; Futo, Satoshi; Furui, Satoshi; Kitta, Kazumi

    2010-01-01

    A novel multiplex PCR method was developed for simultaneous event-specific detection of four events of GM maize, i.e., DAS-59122-7, MIR604, MON88017, and MON863. The single laboratory examination of analytical performance using simulated DNA mixtures containing GM DNA at various concentrations in non-GM DNA suggested that the limits of detection (LOD) of the multiplex PCR method were 0.16% for MON863, MIR604, and MON88017, and 0.078% for DAS-59122-7. We previously developed a nonaplex (9plex) PCR method for eight events of GM maize, i.e., Bt11, Bt176, GA21, MON810, MON863, NK603, T25, and TC1507. Together with the nonaplex PCR method, the newly developed method enabled the detection and identification of eleven GM maize events that are frequently included in commercial GM seed used in Japan. In addition, this combinational analysis may be useful for the identification of combined event products of GM maize. PMID:20595789

  4. Development of multiplex PCR method for simultaneous detection of four events of genetically modified maize: DAS-59122-7, MIR604, MON863 and MON88017.

    PubMed

    Oguchi, Taichi; Onishi, Mari; Mano, Junichi; Akiyama, Hiroshi; Teshima, Reiko; Futo, Satoshi; Furui, Satoshi; Kitta, Kazumi

    2010-01-01

    A novel multiplex PCR method was developed for simultaneous event-specific detection of four events of GM maize, i.e., DAS-59122-7, MIR604, MON88017, and MON863. The single laboratory examination of analytical performance using simulated DNA mixtures containing GM DNA at various concentrations in non-GM DNA suggested that the limits of detection (LOD) of the multiplex PCR method were 0.16% for MON863, MIR604, and MON88017, and 0.078% for DAS-59122-7. We previously developed a nonaplex (9plex) PCR method for eight events of GM maize, i.e., Bt11, Bt176, GA21, MON810, MON863, NK603, T25, and TC1507. Together with the nonaplex PCR method, the newly developed method enabled the detection and identification of eleven GM maize events that are frequently included in commercial GM seed used in Japan. In addition, this combinational analysis may be useful for the identification of combined event products of GM maize.

  5. Feeling Normal? Long-Term Follow-up of Patients with a Cleft Lip-Palate after Rhinoplasty with the Derriford Appearance Scale (DAS-59).

    PubMed

    Albers, Andreas E; Reichelt, Andreas C; Nolst-Trenité, Gilbert J; Menger, Dirk Jan

    2016-04-01

    The stigma of nasal deformity due to a congenital cleft lip-palate has an undeniable influence on the affected patient's life. It is therefore of interest to investigate if efforts to reduce esthetic and functional impairments by rhinoplasty (single or multiple) can result in an increased satisfaction with appearance and a self-perception similar to the noncleft population. Retrospective scoring before and after rhinoplasty using the validated Derriford Appearance Scale (DAS-59) and subsequent statistical evaluation and comparison to datasets available in the literature for further classification was used. Of the 61 patients who underwent at least one rhinoplasty, 26 responded to all questions. The mean age of responders was approximately 30 years of age and the male:female ratio was 1:1.2. The scale showed a significant overall improvement after surgery. The full scale and all subscale scores of the DAS-59 were significantly reduced after surgery demonstrating an improvement in the respective categories. Most importantly, if postoperative results were compared with a population concerned and unconcerned about appearance, no difference "facial self-consciousness" of appearance was apparent. Also postoperative subscores for "general self-consciousness" (GSC) and "social self-consciousness" of appearance (SSC) showed no difference from those obtained from the population concerned about appearance. The postoperative subscore for "sexual and bodily self-consciousness" of appearance (SBSC) indicated improvement beyond the level found in the concerned control population. Due to only a low improvement in the difference compared with the subscore representing a "negative self-concept," a statistically significant difference to the concerned population remained, possibly indicating that therapy beyond surgery is needed for improvement. After rhinoplasty, the investigated group of cleft lip-palate patients with nasal deformities showed an improvement in their self

  6. Dating human occupation at Toca do Serrote das Moendas, São Raimundo Nonato, Piauí-Brasil by electron spin resonance and optically stimulated luminescence.

    PubMed

    Kinoshita, Angela; Skinner, Anne R; Guidon, Niede; Ignacio, Elaine; Felice, Gisele Daltrini; Buco, Cristiane de A; Tatumi, Sonia; Yee, Márcio; Figueiredo, Ana Maria Graciano; Baffa, Oswaldo

    2014-12-01

    Excavation of Toca do Serrote das Moendas, in Piauí state, Brazil revealed a great quantity of fossil wild fauna associated with human remains. In particular, fossils of a cervid (Blastocerus dichotomus) were found, an animal frequently pictured in ancient rock wall paintings. In a well-defined stratum, two loose teeth of this species were found in close proximity to human bones. The teeth were independently dated by electron spin resonance (ESR) in two laboratories. The ages obtained for the teeth were 29 ± 3 ka (thousands of years) and 24 ± 1 ka. The concretion layer capping this stratum was dated by optically stimulated luminescence (OSL) of the quartz grains to 21 ± 3 ka. As these values were derived independently in three different laboratories, using different methods and equipment, these results are compelling evidence of early habitation in this area.

  7. Short-term monitoring of a gas seep field in the Katakolo bay (Western Greece) using Raman spectra DTS and DAS fibre-optic methods

    NASA Astrophysics Data System (ADS)

    Chalari, A.; Mondanos, M.; Finfer, D.; Christodoulou, D.; Kordella, S.; Papatheodorou, G.; Geraga, M.; Ferentinos, G.

    2012-12-01

    A wide submarine seep of thermogenic gas in the Katakolo bay, Western Greece, was monitored passively using the intelligent Distributed Acoustic Sensor (iDAS) and Ultima Raman spectra Distributed Temperature Sensor (DTS), in order to study the thermal and noise signal of the bubble plumes released from the seafloor. Katakolo is one one of the most prolific thermogenic gas seepage zones in Europe and the biggest methane seep ever reported in Greece. Very detailed repetitive offshore gas surveys, including marine remote sensing (sub-bottom profiling, side scan sonar), underwater exploration by a towed instrumented system (MEDUSA), long-term monitoring benthic station (GMM), compositional and isotopic analyses, and flux measurements of gas, showed that: (a) gas seepage takes place over an extended area in the Katakolo harbour and along two main normal faults off the harbour; (b) at least 823 gas bubble ( 10-20 cm in diameter) plumes escaping over an area of 94,200 m2, at depths ranging from 5.5 to 16 m; (c) the gas consists mainly of methane and has H2S levels of hundreds to thousands ppmv, and shows significant amounts of other light hydrocarbons like ethane, propane, iso-butane and C6 alkanes, (d) offshore and onshore seeps release the same type of thermogenic gas; (e) due to the shallow depth, more than 90 % of CH4 released at the seabed enters the atmosphere, and (f) the gas seeps may produce severe geohazards for people, buildings and construction facilities due to the explosive and toxicological properties of methane and hydrogen sulfide, respectively. For the short-term monitoring, the deployment took place on a site located inside the harbour of Katakolo within a thermogenic gas seepage area where active faults are intersected. The iDAS system makes it possible to observe the acoustical signal along the entire length of an unmodified optical cable without introducing any form of point sensors such as Bragg gratings. When the bubble plumes are released by the

  8. Dating human occupation at Toca do Serrote das Moendas, São Raimundo Nonato, Piauí-Brasil by electron spin resonance and optically stimulated luminescence.

    PubMed

    Kinoshita, Angela; Skinner, Anne R; Guidon, Niede; Ignacio, Elaine; Felice, Gisele Daltrini; Buco, Cristiane de A; Tatumi, Sonia; Yee, Márcio; Figueiredo, Ana Maria Graciano; Baffa, Oswaldo

    2014-12-01

    Excavation of Toca do Serrote das Moendas, in Piauí state, Brazil revealed a great quantity of fossil wild fauna associated with human remains. In particular, fossils of a cervid (Blastocerus dichotomus) were found, an animal frequently pictured in ancient rock wall paintings. In a well-defined stratum, two loose teeth of this species were found in close proximity to human bones. The teeth were independently dated by electron spin resonance (ESR) in two laboratories. The ages obtained for the teeth were 29 ± 3 ka (thousands of years) and 24 ± 1 ka. The concretion layer capping this stratum was dated by optically stimulated luminescence (OSL) of the quartz grains to 21 ± 3 ka. As these values were derived independently in three different laboratories, using different methods and equipment, these results are compelling evidence of early habitation in this area. PMID:25456825

  9. Effect of thermal stratification on free convection in a square porous cavity filled with a nanofluid using Tiwari and Das' nanofluid model

    NASA Astrophysics Data System (ADS)

    Sheremet, M. A.; Dinarvand, S.; Pop, I.

    2015-05-01

    Natural convection in a square porous cavity filled with a nanofluid in conditions of thermal stratification has been numerically studied. The mathematical model has been formulated in terms of the dimensionless stream function and temperature using the Darcy-Boussinesq approximation and Tiwari and Das' nanofluid model with new more realistic empirical correlations for the physical properties of the nanofluids. Formulated partial differential equations along with the corresponding boundary conditions have been solved by the finite difference method. Particular efforts have been focused on the effects of the Rayleigh number, thermal stratification parameter, porosity of the porous medium, solid volume fraction parameter of nanoparticles, and the solid matrix of the porous medium (glass balls and aluminum foam) on the local and average Nusselt numbers, streamlines and isotherms. It has been observed an essential effect of thermal stratification parameter on heat and fluid flow fields.

  10. Application of a Fibre Optic Distributed Acoustic Sensor (DAS) for Shallow Seismic Investigations of a Fractured Dolostone Aquifer in Guelph, Ontario.

    NASA Astrophysics Data System (ADS)

    Munn, J. D.; Parker, B. L.; Coleman, T. I.; Mondanos, M.; Chalari, A.

    2014-12-01

    Understanding groundwater flow and contaminant transport in fractured bedrock aquifers requires detailed characterization of the discrete features that control flow, as well as the properties of the rock matrix. This requires multiple, high-resolution, depth discrete datasets that provide different, but complementary information. Distributed fibre optic sensing is a relatively new technology used to continuously monitor properties along the entire length of an optical fibre. Technological advances over the past few years have brought the sensitivity and spatial resolution to the point where shallow (<200m) borehole applications are practicable. Recent studies using fibre optic distributed temperature sensors (DTS) have shown excellent application of DTS for characterizing groundwater flow in both continuously sealed and open boreholes. This presentation highlights the results of a field trial at the Bedrock Aquifer Research Station on the University of Guelph campus (Ontario, Canada) where a single fibre optic cable was interrogated by both a DTS (Ultima-DTS) and a Distributed Acoustic Sensor (iDAS). DAS is a relatively recent development that allows an optical fibre to be used as a receiver for seismic imaging. These seismic images are produced by sending an optical pulse down the fibre and analyzing the effects of seismic waves on the propagating light. Numerous vertical seismic profiles were collected and the effects of different fibre optic cable structures and coupling techniques were examined. The seismic profiles will help delineate structural features and lithological contacts away from the borehole wall, and will assist in correlating other geophysical, hydraulic, or geological logs collected in the boreholes across the site. Preliminary results show promise for shallow seismic imaging and continued field trials will allow refinement of the technique.

  11. Simultaneous functions of the installed DAS/DAK formaldehyde-assimilation pathway and the original formaldehyde metabolic pathways enhance the ability of transgenic geranium to purify gaseous formaldehyde polluted environment.

    PubMed

    Zhou, Shengen; Xiao, Sunqin; Xuan, Xiuxia; Sun, Zhen; Li, Kunzhi; Chen, Limei

    2015-04-01

    The overexpression of dihydroxyacetone synthase (DAS) and dihydroxyacetone kinase (DAK) from methylotrophic yeasts in chloroplasts created a photosynthetic formaldehyde (HCHO)-assimilation pathway (DAS/DAK pathway) in transgenic tobacco. Geranium has abilities to absorb and metabolize HCHO. Results of this study showed that the installed DAS/DAK pathway functioning in chloroplasts greatly enhanced the role of the Calvin cycle in transgenic geranium under high concentrations of gaseous HCHO stress. Consequently, the yield of sugars from HCHO-assimilation increased approximately 6-fold in transgenic geranium leaves, and concomitantly, the role of three original HCHO metabolic pathways reduced, leading to a significant decrease in formic acid, citrate and glycine production from HCHO metabolism. Although the role of three metabolic pathways reduced in transgenic plants under high concentrations of gaseous HCHO stress, the installed DAS/DAK pathway could still function together with the original HCHO metabolic pathways. Consequently, the gaseous HCHO-resistance of transgenic plants was significantly improved, and the generation of H2O2 in the transgenic geranium leaves was significantly less than that in the wild type (WT) leaves. Under environmental-polluted gaseous HCHO stress for a long duration, the stomata conductance of transgenic plants remained approximately 2-fold higher than that of the WT, thereby increasing its ability to purify gaseous HCHO polluted environment.

  12. Simultaneous functions of the installed DAS/DAK formaldehyde-assimilation pathway and the original formaldehyde metabolic pathways enhance the ability of transgenic geranium to purify gaseous formaldehyde polluted environment.

    PubMed

    Zhou, Shengen; Xiao, Sunqin; Xuan, Xiuxia; Sun, Zhen; Li, Kunzhi; Chen, Limei

    2015-04-01

    The overexpression of dihydroxyacetone synthase (DAS) and dihydroxyacetone kinase (DAK) from methylotrophic yeasts in chloroplasts created a photosynthetic formaldehyde (HCHO)-assimilation pathway (DAS/DAK pathway) in transgenic tobacco. Geranium has abilities to absorb and metabolize HCHO. Results of this study showed that the installed DAS/DAK pathway functioning in chloroplasts greatly enhanced the role of the Calvin cycle in transgenic geranium under high concentrations of gaseous HCHO stress. Consequently, the yield of sugars from HCHO-assimilation increased approximately 6-fold in transgenic geranium leaves, and concomitantly, the role of three original HCHO metabolic pathways reduced, leading to a significant decrease in formic acid, citrate and glycine production from HCHO metabolism. Although the role of three metabolic pathways reduced in transgenic plants under high concentrations of gaseous HCHO stress, the installed DAS/DAK pathway could still function together with the original HCHO metabolic pathways. Consequently, the gaseous HCHO-resistance of transgenic plants was significantly improved, and the generation of H2O2 in the transgenic geranium leaves was significantly less than that in the wild type (WT) leaves. Under environmental-polluted gaseous HCHO stress for a long duration, the stomata conductance of transgenic plants remained approximately 2-fold higher than that of the WT, thereby increasing its ability to purify gaseous HCHO polluted environment. PMID:25698666

  13. Further evidence of 777 Ma subduction-related continental arc magmatism in Eastern Dom Feliciano Belt, southern Brazil: The Chácara das Pedras Orthogneiss

    NASA Astrophysics Data System (ADS)

    Koester, E.; Porcher, C. C.; Pimentel, M. M.; Fernandes, L. A. D.; Vignol-Lelarge, M. L.; Oliveira, L. D.; Ramos, R. C.

    2016-07-01

    In this study new SHRIMP U-Pb zircon data for the Chácara das Pedras Gneiss in Porto Alegre, southern Brazil are presented. They represent a small exposure of the crust which was intruded by a large volume of orogenic to anorogenic granitoids at ca. 618-562 m.y. in the Eastern Domain of the Dom Feliciano Belt. The Chácara das Pedras tonalitic orthogneiss has geochemical similarities with subduction-related magmatic rocks of continental arcs. They present high Sr initial ratios (∼0.712), negative ɛNd(t = 777) values (∼-6), TDM varying from 1.8 to 2.0 Ga. The igneous protoliths of these orthogneisses were previously considered to be Paleoproterozoic based on an upper intercept age of discordant zircon analyses. In the present study these orthogneisses were re-sampled and re-analyzed in an attempt to obtain more concordant analytical data. The U-Pb zircon analyses were carried out using the SHRIMP IIe at the Laboratório de Geocronologia de Alta Resolução of the Universidade de São Paulo. The U-Pb concordia age obtained for igneous textural domains of the zircon grains is 777 ± 4 Ma. A few analyses on zircon overgrowths give poorly defined late Cryogenian ages of ca. 650 Ma. Older ages, mostly discordant, were obtained in a few zircon cores, showing an upper intercept age of ca. 1.9 Ga. One sample of the Três Figueiras Granodiorite, which crosscut the orthogneiss in the same outcrop, was also investigated. The zircons of this granodiorite are, however, mostly metamitic, preventing the determination of a reliable age. Some concordant analyses from a few grains define ages ranging in the interval between ca. 603 and 1022 Ma. The youngest (ca. 603 Ma) may represent a maximum age for the granodiorite crystallization. Older ages, with discordance <10%, are of 745, 777, 836 and 1022 Ma. The 777 ± 4 Ma age obtained for the Chácara das Pedras orthogneiss is the first Early Cryogenian magmatic age determined for granitoids in the Porto Alegre region, although

  14. Massa do gás e das estrelas em aglomerados: eficiência da formação estelar

    NASA Astrophysics Data System (ADS)

    Laganá, T. F.; Lima Neto, G. B.

    2003-08-01

    Os aglomerados de galáxias apresentam um interesse especial para a cosmologia observacional. Eles são as maiores estruturas ligadas pela gravitação no Universo e relaxadas na região central. A comparação entre a massa do gás intra-aglomerado (responsável por ~25% da massa total, inferida a partir de observações em raios-X), a massa contida nas estrelas (i.e., nas galáxias) e a massa total (incluindo a matéria escura não bariônica), nos dá informações importantes sobre os processos de formação e evolução de aglomerados. Por exemplo, a razão entre a massa do gás e a massa total é uma medida da fração de bárions no Universo (razão entre a matéria bariônica e matéria escura) e, utilizando a densidade de bárions predita pela nucleosíntese primordial, podemos deduzir a densidade de matéria escura no Universo (cf. White et al. 1993). O objetivo deste trabalho é obter as razões entre as massas do gás, estelar (contida nas galáxias), e a total (massa dinâmica). As massas do gás e total são obtidas a partir das análises fotométrica e espectroscópica em raios-X enquanto que a massa estelar é obtida pela análise fotométrica das galáxias. Esta análise foi aplicada ao aglomerado Abell 496 observado pelo satélite XMM-Newton. A massa contida nas galáxias foi estimada a partir da função de luminosidade obtida por Durret et al. (2002). Para determinar as massas dinâmica e do gás nos precisamos determinar os perfis radiais de densidade e temperatura. Nós apresentaremos aqui estes resultados e suas implicações na eficiência da formação estelar em Abell 496.

  15. Water Quality-Quantity Evaluation of the Ribeirão das Posses Watershed, Brazil, applying the AgES-W model.

    NASA Astrophysics Data System (ADS)

    Green, T. R.; Cruz, P. P. N. D.; Figueiredo, R. D. O.; Camargo, P. B. D.; Santos, C. P.

    2015-12-01

    Southeastern Brazil is under a period of drought that has impacted the conservation of watersheds and the management of water quality and quantity for agricultural and urban demands. In this context agro-hydrological modeling tools can generate information of water response over time in response to climate and landuse changes. A 12-km2 watershed which has suffered from anthropogenic activities is the Ribeirão das Posses watershed that is located in the extreme south of Minas Gerais State and is a headwater catchment of the Jaguari river, one of the contributing rivers of the Cantareira Reservoir Complex in the state of São Paulo. This watershed had its landscape changed over the last century from native forests to more homogeneous vegetation for pastures and small crops and some forest plantations fragments with eucalyptus. Currently, the Conservative Waters project has planted some small areas with vegetation of native species, especially where there are springs and at the top of the hills, in order to recover degraded areas and improve the hydrogeochemistry in this study basin. In this context, the AgroEcoSystem-Watershed (AgES-W) model is presented to simulate the water movement and storage in agricultural watersheds with different spatial resolutions of land areas or hydrological responses units. The objectives are to evaluate the quality and quantity of water in Ribeirão das Posses Basin using measured data, then simulate these responses in space and time to test the AgES-W model. The period chosen for research was from 2011 to 2015, because the water quality data were collected during this period. The answers that we hope to find out are: How well does the AgES-W model simulate this Brazilian watershed in the tropics? What are the future prospects of the quality and quantity of water in this basin? The results will help to guide hydrological simulations in similar tropical environments in Brazil in this and other agricultural watersheds with AgES-W.

  16. Migration of inorganic ions from the leachate of the Rio das Ostras landfill: a comparison of three different configurations of protective barriers.

    PubMed

    Lacerda, Cláudia Virgínia; Ritter, Elisabeth; Pires, João Antônio da Costa; de Castro, José Adilson

    2014-11-01

    Batch tests and diffusion tests were performed to analyze the efficiency of a protective barrier in a landfill consisting of compacted soil with 10% bentonite compared to the results obtained for only compacted soil and for compacted soil covered with a 1-mm-thick HDPE geomembrane; the soil and leachate were collected from the Rio das Ostras Landfill in Rio de Janeiro, Brazil. The diffusion tests were performed for periods of 3, 10 and 60 days. After the test period, the soil pore water was analyzed and the profiles for chloride, potassium and ammonium were determined along a 6-cm soil depth. The results of the batch tests performed to define sorption parameters were used to adjust the profiles obtained in the diffusion cell experiment by applying an ion transfer model between the interstitial solution and the soil particles. The MPHMTP model (Multi Phase Heat and Mass Transfer Program), which is based upon the solution of the transport equations of the ionic contaminants, was used to solve the inverse problem of simultaneously determining the effective diffusion coefficients. The results of the experimental tests and of the model simulation confirmed that the compacted soil with 10% bentonite was moderately efficient in the retention of chloride, potassium and ammonium ions compared to the configurations of compacted soil with a geomembrane and compacted soil alone, representing a solution that is technically feasible and requires potentially lower costs for implementation in landfills. PMID:25042116

  17. Prevalence of juvenile idiopathic arthritis in children aged 6 to 12 years in Embu das Artes, state of Sao Paulo, Brazil.

    PubMed

    Yamashita, Edson; Terreri, Maria Teresa R A; Hilário, Maria Odete E; Len, Claudio A

    2013-01-01

    The aim of the study was to study the prevalence of juvenile idiopathic arthritis (JIA) in school children in the city of Embu das Artes in São Paulo State. 2880 school children from seven public schools, aged between 6 and 12 years, were evaluated (clinical findings) by a pediatric rheumatologist. A board certified Pediatric Rheumatologist evaluated the subjects with suspected inflammatory arthropathy. Children with higher suspicion were referred to a specialized service. One hundred and forty-one children have presented abnormalities on examination of musculoskeletal system, with isolated pain on palpation the most common finding in the first evaluation (60.9%), with improvement in almost all cases in the second examination. Most of the abnormalities were related to recent injuries or congenital malformations. Six children have clinical findings suggestive of chronic arthropathy and were referred to a specialized pediatric rheumatology clinic. Of these, a 12 year-old girl fulfilled the criteria for JIA. The other diagnoses were aseptic necrosis of the hip (P = 1) of and post-trauma synovitis (P = 4). The prevalence of JIA in children aged between 6 and 12 years was 1/2.880 (or 0.34/1.000).

  18. Pollen analysis of Holocene sediments from the Poço das Antas National Biological Reserve, Silva Jardim, Rio de Janeiro, Brazil.

    PubMed

    Coelho, Luciane G; Barth, Ortrud M; Araujo, Dorothy S Dde

    2008-09-01

    The Poço das Antas National Biological Reserve is located in Rio de Janeiro State, southeast Brazil. This paper presents information on past environmental characteristics of the area through pollen analysis. Two sedimentary columns were collected and five samples were selected for radiocarbon dating. The following ages of the columns from bottom to top were detected: column 1 - 1.20-1.16 m: 6080 +/-40 years BP, 0.775-0.735 m: 4090 +/-40 years BP, 0.385-0.345 m: 1880 +/-80 years BP; column 2 - 1.22-1.18 m: 3520 +/-40 years BP, 0.23-0.19 m: 1810 +/-40 years BP. Three samples from column 1 and two samples from column 2 were selected for pollen analysis: 1.20 m, 0.77 m and 0.37 m of column 1 and 1.22 m and 0.21 m of column 2. Chemical treatment followed standard methodology. The palynological analysis shows that around 6080 years BP the study area was dominated by a rain forest and from around 4090 years BP the vegetation changed to a fragmented forest, restricted to low hills and surrounded by an open area of grassland and pioneer plants, swamps and peat areas. The pollen assemblage of the samples 3520, 1880 and 1810 years BP suggest the permanence of this kind of vegetation between 4000 years BP and the actual.

  19. Dating of fossil human teeth and shells from Toca do Enoque site at Serra das Confusões National Park, Brazil.

    PubMed

    Kinoshita, Angela; Sullasi, Henry L; Asfora, Viviane K; Azevedo, Renata L; Guzzo, Pedro; Guidon, Niede; Figueiredo, Ana Maria G; Khoury, Helen; Pessis, Anne-Marie; Baffa, Oswaldo

    2016-06-01

    This work reports the dating of a fossil human tooth and shell found at the archaeological site Toca do Enoque located in Serra das Confusões National Park (Piauí, Brazil). Many prehistoric paintings have been found at this site. An archaeological excavation unearthed three sepulchers with human skeletons and some shells. Two Brazilian laboratories, in Ribeirão Preto (USP) and Recife (UFPE), independently performed Electron Spin Resonance (ESR) measurements to date the tooth and the shell and obtain the equivalent dose received by each sample. The laboratories determined similar ages for the tooth and the shell (~4.8 kyBP). The results agreed with C-14 dating of the shell and other samples (charcoal) collected in the same sepulcher. Therefore, this work provides a valid inter-comparison of results by two independent ESR-dating laboratories and between two dating methods; i.e., C-14 and ESR, showing the validity of ESR dating for this range of ages. PMID:27276381

  20. Dating of fossil human teeth and shells from Toca do Enoque site at Serra das Confusões National Park, Brazil.

    PubMed

    Kinoshita, Angela; Sullasi, Henry L; Asfora, Viviane K; Azevedo, Renata L; Guzzo, Pedro; Guidon, Niede; Figueiredo, Ana Maria G; Khoury, Helen; Pessis, Anne-Marie; Baffa, Oswaldo

    2016-06-01

    This work reports the dating of a fossil human tooth and shell found at the archaeological site Toca do Enoque located in Serra das Confusões National Park (Piauí, Brazil). Many prehistoric paintings have been found at this site. An archaeological excavation unearthed three sepulchers with human skeletons and some shells. Two Brazilian laboratories, in Ribeirão Preto (USP) and Recife (UFPE), independently performed Electron Spin Resonance (ESR) measurements to date the tooth and the shell and obtain the equivalent dose received by each sample. The laboratories determined similar ages for the tooth and the shell (~4.8 kyBP). The results agreed with C-14 dating of the shell and other samples (charcoal) collected in the same sepulcher. Therefore, this work provides a valid inter-comparison of results by two independent ESR-dating laboratories and between two dating methods; i.e., C-14 and ESR, showing the validity of ESR dating for this range of ages.

  1. Guidelines on Management of Human Infection with the Novel Virus Influenza A (H1N1) – A Report from the Hospital das Clínicas of the University of São Paulo

    PubMed Central

    Hajjar, Ludhmila Abrahao; Schout, Denise; Galas, Filomena Regina Barbosa Gomes; Uip, David Everson; Levin, Anna Sara Shafferman; Filho, Helio Hehl Caiaffa; Sakane, Pedro Takanori; Suslik, Carlos Alberto; de Camargo Teixeira, Jose Manoel; Bonfa, Eloisa; Barone, Antonio Alci; de Arruda Martins, Milton; Boulos, Marcos; Auler, Jose Otavio Costa

    2009-01-01

    The pandemic novel influenza A (H1N1) infection was considered widespread in Brazil on July, 2009. Since then, 9.249 cases were confirmed in Brazil, most of them concentrated in São Paulo. The Hospital das Clínicas of the University of São Paulo is a reference center for H1N1 cases in São Paulo. The purpose of this review is to analyze the evidence concerning diagnosis, prevention, and treatment of novel influenza A (H1N1) infection. In addition, we propose guidelines for the management of this pandemic emphasizing Hospital das Clínicas “bundles” for the control of the pandemic novel influenza A (H1N1). PMID:19841710

  2. Observações das explosões cósmicas de raios gama GRB021004 e GRB021211 com o satélite HETE

    NASA Astrophysics Data System (ADS)

    Braga, J.; Ricker, G.; Hurley, K.; Lamb, D.; Grew, G.; et al.

    2003-08-01

    O High Energy Transient Explorer (HETE) é o primeiro satélite inteiramente dedicado ao estudo das explosões cósmicas de raios gama (ECRGs). Lançado em 9 de outubro de 2000, o HETE possui instrumentação capaz de observar as ECRGs desde o UV até raios gama e localizá-las com precisão de ~ 1-10 minutos de arco. As localizações das ECRGs detectadas são disseminadas rapidamente (em alguns segundos) pela Internet através de uma rede de estações de recepção ao longo do equador. A participação brasileira nesse projeto se dá através da montagem e operação de uma estação de recepção em Natal, RN, e da participação na equipe científica da missão. Neste trabalho são apresentados resultados da observação pelo HETE de duas ECRGs: GRB 021004 e GRB 021211. A GRB021004 foi detectada em raios gama pelo HETE em 4 de outubro de 2002 e localizada em raios-X em apenas 48 s, quando a emissão de raios gama ainda estava se processando. A explosão, relativamente brilhante e longa, durou aproximadamente 100 s. Um transiente óptico de magnitude 15 foi detectado no local da explosão nove minutos após o evento, e observações realizadas após 7 horas determinaram um desvio para o vermelho de absorção de 1,6. O GRB021004 foi o burst mais bem observado até o momento e suas observações em vários comprimentos de onda têm sido fundamentais para o aprimoramento dos modelos de ECRGs. O GRB21211, um burst brilhante e rico em raios-X, foi detectado em 11 de dezembro de 2002 e localizado em raios-X em 22 s após o início do evento. A duração do burst foi de 2,3 s em altas energias (85 a 400 keV) e de 8,5 s em baixas energias (2 a 10 keV). Caso essa explosão não tivesse sido rapidamente localizada pelo HETE, ela teria sido classificada como "opticamente escura", já que o transiente óptico decaiu rapidamente de R < 14 a R»19 dentro dos primeiros 20 minutos e já estava mais fraco do que R»23 depois de 24 horas da ocorrência do burst. Ser

  3. The geology of the Morro Velho gold deposit in the Archean Rio das Velhas greenstone belt, Quadrilátero Ferrífero, Brazil

    USGS Publications Warehouse

    Vial, Diogenes Scipioni; DeWitt, Ed; Lobato, Lydia Maria; Thorman, Charles H.

    2007-01-01

    The Morro Velho gold deposit, Quadrilátero Ferrífero region, Minas Gerais, Brazil, is hosted by rocks at the base of the Archean Rio das Velhas greenstone belt. The deposit occurs within a thick carbonaceous phyllite package, containing intercalations of felsic and intermediate volcaniclastic rocks and dolomites. Considering the temporal and spatial association of the deposit with the Rio das Velhas orogeny, and location in close proximity to a major NNW-trending fault zone, it can be classified as an orogenic gold deposit. Hydrothermal activity was characterized by intense enrichment in alteration zones of carbonates, sulfides, chlorite, white mica±biotite, albite and quartz, as described in other Archean lode-type gold ores. Two types of ore occur in the deposit: dark gray quartz veins and sulfide-rich gold orebodies. The sulfide-rich orebodies range from disseminated concentrations of sulfide minerals to massive sulfide bodies. The sulfide assemblage comprises (by volume), on average, 74% pyrrhotite, 17% arsenopyrite, 8% pyrite and 1% chalcopyrite. The orebodies have a long axis parallel to the local stretching lineation, with continuity down the plunge of fold axis for at least 4.8 km. The group of rocks hosting the Morro Velho gold mineralization is locally referred to as lapa seca. These were isoclinally folded and metamorphosed prior to gold mineralization. The lapa seca and the orebodies it hosts are distributed in five main tight folds related to F1 (the best examples are the X, Main and South orebodies, in level 25), which are disrupted by NE- to E-striking shear zones. Textural features indicate that the sulfide mineralization postdated regional peak metamorphism, and that the massive sulfide ore has subsequently been neither metamorphosed nor deformed. Lead isotope ratios indicate a model age of 2.82 ± 0.05 Ga for both sulfide and gold mineralization. The lapa seca are interpreted as the results of a pre-gold alteration process and may be

  4. Das singuläre Modell der über der Oberfläche von Kryodielektrikas lokalisierten Elektronenzustände

    NASA Astrophysics Data System (ADS)

    Dorofeyev, O. F.; Lysov, B. A.; Pavlova, O. S.; Ternov, I. M.

    Wir schlagen ein neues Modell zur Beschreibung der in der Nähe der Oberfläche von Kryodielektrika lokalisierten Elektronenzustände vor. Dabei wird die Nichteindeutigkeit der selbstadjungierten Erweiterung des Hamilton-Operators der elektrostatischen Bildkräfte an der flachen Grenze Dielektrikum-Vakuum benutzt. Im Unterschied zum bekannten Modell von Grimes enthält das von uns vorgeschlagene Modell nur einen einzigen phänomenologischen Parameter, den Vermischungswinkel. Es zeigt sich, daß die entsprechende Wahl des Vermischungswinkels es erlaubt, die spektroskopischen Daten von elektrischen Dipolübergängen zwischen den Einteilchen-Elektronenzuständen, die über der Oberfläche flüssigen 4He und 3He sowie festen Wasserstoffe lokalisiert sind, vollständig zu beschreiben.Translated AbstractA Singular Model of Electronic States, Localized over the Surface of Cryogenized DielectricA new model for the description of localized electronic states near the surface of a cryogenized dielectric is proposed. In this model an ambiguity of the self-adjoined extention of the Hamiltonian for the problem of the motion of an electron in the field of the electrostatic image at flat boundary dielectric-vacuum is used. The proposed model, in contrast with the well known model of Grimes, contains as only phenomenological parameter the mixing angle. It is shown that the proper choise of the mixing angle makes it possible to completely account for the spectroscopic data on electric dipole transitions between singleparticle electronic states localized over the surfaces of 4He, 3He and also solid hydrogen.

  5. Using the DAS-ELISA Test to Establish an Effective Distance Between Bait Stations for Control of Linepithema humile (Hymenoptera: Formicidae) in Natural Areas.

    PubMed

    Song, Jinbo; Benson, Eric P; Zungoli, Patricia A; Gerard, Patrick; Scott, Simon W

    2015-08-01

    Linepithema humile (Mayr), the Argentine ant, is an invasive pest that has spread throughout the United States and is a problem in natural and managed habitats in South Carolina. Foraging patterns and the effectiveness of liquid baits for control of this pest have been studied in urban areas. However, similar studies have not been conducted in natural areas such as parks, picnic grounds, or campsites. L. humile populations can be large and widespread, making them a major nuisance pest for visitors to these natural areas. The primary objective of this study was to determine an effective distance between bait stations for control of L. humile in a natural area. A double antibody-sandwich enzyme-linked immunosorbent assay (DAS-ELISA) procedure was used to detect individual ants that consumed rabbit immunoglobin (IgG) protein for marking and tracking. In both lab and field conditions, there was a significant difference in the detection of IgG in ants fed protein marker mixed with sugar water compared with ants only fed sugar water. Additional field studies revealed that an individual ant could retain detectable levels of protein marker for 3 d and that an ant feeding on IgG containing bait could be detected over 15 m from the original bait source. Overall, we found that using liquid ant baits, with a placement of 20 m between stations, was effective in reducing L. humile numbers between April to October, 2012 in a natural park area of Lake Greenwood State Park, SC.

  6. Das sprachliche Register (Speech Registers)

    ERIC Educational Resources Information Center

    Hess-Luttich, Ernest W. B.

    1974-01-01

    The linguistic behavior of a given individual varies; he will on different occasions speak (or write) differently according to what may be roughly described as different social situations: he will use a number of different registers. The application of such registers both in the field of text analysis and in the preparation of teaching materials…

  7. Similarity in Shape Dictates Signature Intrinsic Dynamics Despite No Functional Conservation in TIM Barrel Enzymes.

    PubMed

    Tiwari, Sandhya P; Reuter, Nathalie

    2016-03-01

    The conservation of the intrinsic dynamics of proteins emerges as we attempt to understand the relationship between sequence, structure and functional conservation. We characterise the conservation of such dynamics in a case where the structure is conserved but function differs greatly. The triosephosphate isomerase barrel fold (TBF), renowned for its 8 β-strand-α-helix repeats that close to form a barrel, is one of the most diverse and abundant folds found in known protein structures. Proteins with this fold have diverse enzymatic functions spanning five of six Enzyme Commission classes, and we have picked five different superfamily candidates for our analysis using elastic network models. We find that the overall shape is a large determinant in the similarity of the intrinsic dynamics, regardless of function. In particular, the β-barrel core is highly rigid, while the α-helices that flank the β-strands have greater relative mobility, allowing for the many possibilities for placement of catalytic residues. We find that these elements correlate with each other via the loops that link them, as opposed to being directly correlated. We are also able to analyse the types of motions encoded by the normal mode vectors of the α-helices. We suggest that the global conservation of the intrinsic dynamics in the TBF contributes greatly to its success as an enzymatic scaffold both through evolution and enzyme design.

  8. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim.

    PubMed

    Darlington, T K; Wager-Smith, K; Ceriani, M F; Staknis, D; Gekakis, N; Steeves, T D; Weitz, C J; Takahashi, J S; Kay, S A

    1998-06-01

    The circadian oscillator generates a rhythmic output with a period of about 24 hours. Despite extensive studies in several model systems, the biochemical mode of action has not yet been demonstrated for any of its components. Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless. dCLOCK functioned as a heterodimer with a Drosophila homolog of BMAL1. These proteins acted through an E-box sequence in the period promoter. The timeless promoter contains an 18-base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene. PERIOD and TIMELESS proteins blocked dCLOCK's ability to transactivate their promoters via the E-box. Thus, dCLOCK drives expression of period and timeless, which in turn inhibit dCLOCK's activity and close the circadian loop.

  9. Understanding the importance of protein structure to nature's routes for divergent evolution in TIM barrel enzymes.

    PubMed

    Wise, Eric L; Rayment, Ivan

    2004-03-01

    It is widely agreed that new enzymes evolve from existing ones through the duplication of genes encoding existing enzymes followed by sequence divergence. While evolution is an inherently random process, studies of divergently related enzymes have shown that the evolution of new enzymes follows one of three general routes in which the substrate specificity, reaction mechanism, or active site architecture of the progenitor enzyme is reused in the new enzyme. Recent developments in structural biology relating to divergently related (beta/alpha)8 enzymes have brought new insight into these processes and have revealed that conserved structural elements play an important role in divergent evolution. These studies have shown that, although evolution occurs as a series of random mutations, stable folds such as the (beta/alpha)8 barrel and structural features of the active sites of enzymes are frequently reused in evolution and adapted for new catalytic purposes.

  10. Sanitizing, Domesticating, Demystifying AIDS: MaryKate Jordan's "Losing Uncle Tim."

    ERIC Educational Resources Information Center

    de Manuel, Dolores

    While the AIDS epidemic has wrought radical changes in the consciousness of culture and society over the past decade, it has been relatively slow to make a significant impact on children's literature. Many children's books on the subject have already been published--a recent survey/search yielded about 15 titles. However, many of these books do…

  11. Stimulated zonal flow generation in the case of TEM and TIM microturbulence

    NASA Astrophysics Data System (ADS)

    Gravier, E.; Lesur, M.; Reveille, T.; Drouot, T.

    2016-09-01

    In this paper, we show that in some parameter range in gyrokinetic simulations, it is possible to apply a control method to stimulate the appearance of zonal flows while minimizing the duration of the control process and the impact on plasma parameters. For this purpose, a gyrokinetic code considering only trapped particles is used. The starting point of our work is a situation where zonal flows transiently appear after the nonlinear phase of saturation of trapped electron modes or trapped ion modes' micro-instabilities. These are observed to be strongly reduced in a later phase, permitting streamers to govern the plasma behavior in the steady-state. By intervening during this latter state (after this transient growth and decay of zonal flow), i.e., by increasing the ion/electron temperature ratio for a short time, it is found to be possible to bifurcate to a new steady-state, in which zonal flows are strongly present and are maintained indefinitely, thereby allowing a significant reduction in radial heat fluxes.

  12. Tim Folger Receives 2013 Walter Sullivan Award for Excellence in Science Journalism—Features: Response

    NASA Astrophysics Data System (ADS)

    Folger, Tim

    2014-01-01

    Few publications have the resources to send journalists halfway around world in pursuit of a story. National Geographic gave me the opportunity to see firsthand the horrific aftermath of a tsunami and to meet with survivors. I'm very grateful to National Geographic for funding nearly a month of costly travel in four different countries. It's a privilege to write for such a remarkable magazine.

  13. Single Chondrule K/Ar ages of Mexican Meteorites Using ID-TIMS.

    NASA Astrophysics Data System (ADS)

    Hernandez, M.; Sole, J.

    2007-05-01

    We have determined the K/Ar ages of two H5 ordinary meteorites: Cosina and Nuevo Mercurio, neither dated until this study. We analyzed several single chondrules - weighing few milligrams - of each meteorite. Ages were obtained by using very precise K content determined by isotope dilution mass spectrometry. The K content in chondrules ranges between 650 and 1400 ppm. The 40Ar was measured by static vacuum noble gas mass spectrometry. Samples were fused with an infrared CO2 laser. Chondrule ages vary from 3.66 to 4.59 Ga for Cosina and from 4.20 to 4.87 Ga for Nuevo Mercurio. A comparison between our data and the published K/Ar ages of H and L whole rocks shows that dates obtained from single chondrules are older than those obtained from whole rocks and seem to preserve older events not evidenced in the WR ages. This implies that chondrules can preserve K/Ar ages very close to U-Pb crystallization ages.

  14. Microsecond acquisition of heterogeneous structure in the folding of a TIM barrel protein

    PubMed Central

    Wu, Ying; Kondrashkina, Elena; Kayatekin, Can; Matthews, C. Robert; Bilsel, Osman

    2008-01-01

    The earliest kinetic folding events for (βα)8 barrels reflect the appearance of off-pathway intermediates. Continuous-flow microchannel mixing methods interfaced to small-angle x-ray scattering (SAXS), circular dichroism (CD), time-resolved Förster resonant energy transfer (trFRET), and time-resolved fluorescence anisotropy (trFLAN) have been used to directly monitor global and specific dimensional properties of the partially folded state in the microsecond time range for a representative (βα)8 barrel protein. Within 150 μs, the α-subunit of Trp synthase (αTS) experiences a global collapse and the partial formation of secondary structure. The time resolution of the folding reaction was enhanced with trFRET and trFLAN to show that, within 30 μs, a distinct and autonomous partially collapsed structure has already formed in the N-terminal and central regions but not in the C-terminal region. A distance distribution analysis of the trFRET data confirmed the presence of a heterogeneous ensemble that persists for several hundreds of microseconds. Ready access to locally folded, stable substructures may be a hallmark of repeat-module proteins and the source of early kinetic traps in these very common motifs. Their folding free-energy landscapes should be elaborated to capture this source of frustration. PMID:18757725

  15. NASA Technical Interchange Meeting (TIM): Advanced Technology Lifecycle Analysis System (ATLAS) Technology Tool Box

    NASA Technical Reports Server (NTRS)

    ONeil, D. A.; Craig, D. A.; Christensen, C. B.; Gresham, E. C.

    2005-01-01

    The objective of this Technical Interchange Meeting was to increase the quantity and quality of technical, cost, and programmatic data used to model the impact of investing in different technologies. The focus of this meeting was the Technology Tool Box (TTB), a database of performance, operations, and programmatic parameters provided by technologists and used by systems engineers. The TTB is the data repository used by a system of models known as the Advanced Technology Lifecycle Analysis System (ATLAS). This report describes the result of the November meeting, and also provides background information on ATLAS and the TTB.

  16. APPLICATION OF MULTI-DATE LANDSAT 5 TIM IMAGERY FOR WETLAND IDENTIFICATION

    EPA Science Inventory

    Multi-temporal Landsat 5 Thematic Mapper (TM) imagery was evaluated for the identification and monitoring of potential jurisdictional wetlands located in the states of Maryland and Delaware. A wetland map prepared from single-date TM imagery was compared to a hybrid map develope...

  17. Teaching Identity Performance through Tim O'Brien's "The Things They Carried"

    ERIC Educational Resources Information Center

    Gratch, Ariel

    2015-01-01

    People express part of their identity through their style, gestures, speech patterns, and language use. Other people read these displays as presentations of ourself, an insight into who we are. It is important, therefore, for students to recognize their own performance of identity and be able to express that identity in a clear way. By focusing on…

  18. Conformational dynamics of xylanase a from Streptomyces lividans: Implications for TIM-barrel enzyme thermostability.

    PubMed

    Ding, Yanrui; Cai, Yujie

    2013-09-01

    The conformational dynamics of xylanase A from Streptomyces lividans (Sl-XlnA) were studied using Molecular Dynamics (MD) simulation to identify the thermally sensitive regions. Sl-XlnA begins to unfold at loop4 and this unfolding expands to the loops near the N-terminus. The high flexibility of loop6 during the 300 K simulation is related to its function. The intense movements of the 310 -helices also affect the structural stability. The interaction between the α4β5-loop and the neighboring α5β6-loop plays a crucial role in stabilizing the region from the α4β5-loop to α6. The most thermally sensitive region is from β3 to loop4. The high mobility of the long loop4 easily transfers to the adjacent β4 and α4 and causes β4 and α4 to fluctuate. And, salt bridges ASP124-ARG79, ASP200-ARG159, and ASP231-LYS166 formed a "clamp" to stabilize the region including α4, β4, β5, β6, and β7.

  19. Emeishan volcanism and the end-Guadalupian extinction: New U-Pb TIMS ages

    NASA Astrophysics Data System (ADS)

    Mundil, Roland; Denyszyn, Steve; He, Bin; Metcalfe, Ian; Yigang, Xu

    2010-05-01

    High-resolution geochronology with an age resolution at the permil level is instrumental in testing proposed causal links between continental-scale, short-term volcanic events and environmental crises that affect life globally. Synchroneity with large-scale volcanic events has been shown for three of the five most severe extinctions, namely the end-Permian extinction coinciding with Siberian Trapp volcanism, the end-Triassic extinction with Central Atlantic Magmatic Province) volcanism and the end-Cretaceous with Deccan Trapp volcanism. Recent studies also show that the magnitude of the extinction is not solely a function of the size (volume) of the volcanic event but more importantly of the eruption rate and also the nature of the host rock that is intruded, and the resulting reactions and release of gases that can affect climate. The end-Guadalupian (end Middle Permian, ca 260 Ma) biotic crisis has traditionally not been included in the 'big five' mass extinctions, possibly because of its close proximity in time to the end-Permian event, although its magnitude (in terms of total extinction rate) is comparable to the three most severe extinctions (end-Ordovician, end-Permian, end-Cretaceous). As a result, research of the end-Guadalupian event has so far been neglected and its timing as well as the temporal relation to the Emeishan volcanic province in western China is as yet not fully studied. Geochronological data are so far mostly based on ambiguous 40Ar/39Ar analyses of commonly altered basaltic products and U-Pb zircon analyses on felsic products using micro-beam techniques that typically result in radio-isotopic ages with percent-level uncertainty, and thus insufficient for high-resolution correlations of events. In addition, no precise and accurate radio-isotopic data exist from this time period so that evolutionary events (extinction and recovery) on land and in the ocean are notoriously difficult to correlate though biostratigraphic records are available from numerous sedimentary archives. A further complication arises from the severe tectonic (and resulting thermal) overprint, due to the closure of the Tethys and the collision of the Indian plate with Asia, of most of the area where Emeishan volcanic products are exposed. Also, currently existing paleo-environmental data are scarce and insufficient for testing this hypothesis with confidence, because studies using stable isotopes as proxies are restricted to short profiles from only a few sites. Therefore, fundamental questions remain unanswered. We present new data U-Pb IDTIMS ages with permil-level resolution that constrain the timing of Emeishan volcanism and the timing of biotic events recorded in sediments. In detail, U-Pb results are from felsic intercalations within late stage Emeishan products and biostratigaphically calibrated marine sedimentary sections in southwestern and central China as well as thick tuffs within terrestrial sections from the Bowen Basin in eastern Australia. There is also great potential for obtaining precise U-Pb age results on volcanic products with basaltic composition using the accessory mineral baddeleyite the occurrence of which we have already confirmed. Geochronological and geochemical research is complemented with paleo-enviromental studies and biostratigraphy. We expect that through integration of U-Pb and 40Ar/39Ar geochronology with chemo- and biostratigraphy, the time scale of the Middle through Late Permian will be greatly improved and will lead to a more realistic evaluation of potential causes for the biotic crisis and its aftermath.

  20. Brazil's premier gold province. Part II: geology and genesis of gold deposits in the Archean Rio das Velhas greenstone belt, Quadrilátero Ferrífero

    NASA Astrophysics Data System (ADS)

    Lobato, Lydia; Ribeiro-Rodrigues, Luiz; Vieira, Frederico

    2001-07-01

    Orogenic, gold deposits are hosted by rocks of the Archean Rio das Velhas greenstone belt in the Quadrilátero Ferrífero region, Minas Gerais state, Brazil, one of the major gold provinces in the world. The gold deposits occur at the base of the mafic-ultramafic succession, with the most important orebodies controlled by E-W-striking, strike-slip faults. The main mineralization styles are (1) structurally controlled, sulfide replacement zones in banded iron formation (BIF); (2) disseminated sulfide minerals and gold in hydrothermally altered rocks along shear zones; and (3) auriferous quartz-carbonate-sulfide veins and veinlets in mafic, ultramafic, and felsic volcanic rocks, and also in clastic sedimentary rocks. The most common host rocks for ore are metamorphosed oxide- and carbonate-facies banded iron (± iron-rich metachert) formations (e.g., the Cuiabá, São Bento and Raposos deposits) and the lapa seca unit, which is a local term for intensely carbonatized rock (e.g., the giant Morro Velho mine with >450 t of contained gold). Metabasalts host most of the remaining gold deposits. Mineralogical characteristics and fluid inclusion studies suggest variations in the H2O/CO2 ratio of a low-salinity, near-neutral, reducing, sulfur-bearing, ore fluid. The presence of abundant CH4-rich inclusions is related to reduction of the original H2O-CO2 fluid via interaction with carbonaceous matter in the wallrocks. Oxygen fugacity was close to that of graphite saturation, with variations likely to have been influenced by reaction with the carbonaceous matter. Carbon-rich phyllites and schists, which commonly bound ore-bearing horizons, seem to have played both a physical and chemical role in localizing hydrothermal mineral deposition. Microtextural studies indicate that gold deposition was mainly related to desulfidation reactions, and was paragenetically coeval with precipitation of arsenic-rich iron sulfide minerals. Carbon isotope data are compatible with dissolution of

  1. Entwicklung von umwelt- und naturschutzgerechten Verfahren der landwirtschaftlichen Landnutzung für das Biosphärenreservat Schorfheide-Chorin

    NASA Astrophysics Data System (ADS)

    Meyer-Aurich, Andreas

    1999-11-01

    Mit der vorliegenden Arbeit werden exemplarisch Chancen und Grenzen der Integration von Umwelt- und Naturschutz in Verfahren der ackerbaulichen Landnutzung aufgezeigt. Die Umsetzung von Zielen des Umwelt- und Naturschutzes in Verfahren der Landnutzung ist mit verschiedenen Schwierigkeiten verbunden. Diese liegen zum einen in der Konkretisierung der Ziele, um diese umsetzen zu können, zum anderen in vielfach unzulänglichem Wissen über den Zusammenhang zwischen unterschiedlichen Formen der Landnutzung und insbesondere den biotischen Naturschutzzielen. Zunächst wird die Problematik der Zielfestlegung und Konkretisierung erörtert. Das Umweltqualitätszielkonzept von Fürst et al. (1992) stellt einen Versuch dar, Ziele des Umwelt- und Naturschutzes zu konkretisieren. Dieses Konzept haben Heidt et al. (1997) auf einen Landschaftsausschnitt von ca. 6000 ha im Biosphärenreservat Schorfheide-Chorin im Nordosten Brandenburgs angewendet. Eine Auswahl der von Heidt et al. (1997) formulierten Umweltqualitätsziele bildet die Basis dieser Arbeit. Für die ausgewählten Umweltqualitätsziele wurden wesentliche Einflussfaktoren der Landnutzung identifiziert und ein Bewertungssystem entwickelt, mit dem die Auswirkungen von landwirtschaftlichen Anbauverfahren auf diese Umweltqualitätsziele abgebildet werden können. Die praktizierte Landnutzung von 20 Betrieben im Biosphärenreservat Schorfheide-Chorin wurde von 1994 bis 1997 hinsichtlich ihrer Auswirkungen auf die Umweltqualitätsziele analysiert. Die Analyse ergab ein sehr differenziertes Bild, das zum Teil Unterschiede in der Auswirkung auf die Umweltqualitätsziele für den Anbau einzelner Kulturen oder für bestimmte Betriebstypen zeigte. Es zeigte sich aber auch, dass es bei der Gestaltung des Anbaus einzelner Kulturarten große Unterschiede gab, die für Umweltqualitätsziele Bedeutung haben. Neben der Analyse der Landnutzung im Biosphärenreservat Schorfheide-Chorin wurde ein System entwickelt, mit dem die modellhafte

  2. Epidemiology of Human Infection with the Novel Virus Influenza A (H1H1) in the Hospital das Clínicas, São Paulo, Brazil – June–September 2009

    PubMed Central

    Schout, Denise; Hajjar, Ludhmila Abrahao; Galas, Filomena Regina Barbosa Gomes; Uip, David Everson; Levin, Anna Sara Shafferman; Filho, Helio Hehl Caiaffa; Sakane, Pedro Takanori; Suslik, Carlos Alberto; de Camargo Teixeira, Jose Manoel; Bonfa, Eloisa; Barone, Antonio Alci; de Arruda Martins, Milton; Boulos, Marcos; Auler, Jose Otavio Costa

    2009-01-01

    The pandemic novel influenza A (H1N1) infection was considered widespread in Brazil on July 16, 2009. Since then, 46,810 cases of acute respiratory syndrome have been reported in Brazil, most of them concentrated in São Paulo. Through September 16, we have confirmed 9,249 cases of novel influenza A H1N1in Brazil, including 699 deaths. The mortality rate observed in Brazil is 0.47/100,000 inhabitants and varies according to region. In this period, São Paulo registered 3733 cases (40.3% of the total) of novel influenza A (H1N1) infection and 327 deaths, reflecting a mortality rate of 0.79/100,000 inhabitants. The Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HC) is a reference center for H1N1 cases in São Paulo. During the winter of 2009, 472 patients in this hospital were diagnosed with H1N1 infection; of these, 210 were admitted, and 16 died. To control this pandemic and to provide adequate care for these patients, the Hospital das Clínicas implemented “bundles” including prevention strategies, an epidemiologic surveillance service, availability of fast diagnosis, antiviral treatment and training of staff. The purpose of this manuscript is to describe the epidemiologic features of novel human influenza A (H1N1) infection in the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo during the winter period of the 2009 pandemic. PMID:19841711

  3. Método numérico das diferenças finitas no domínio do tempo aplicado a ondas Alfvén em plasma astrofísico

    NASA Astrophysics Data System (ADS)

    Dos Santos, L. C.; Kintopp, J. A.; Jatenco-Pereira, V.; Opher, R.

    2003-08-01

    Ondas Alfvén em plasma astrofísico têm sido objeto de intenso estudo nas últimas décadas pelo fato de apresentarem papel importante em muitas áreas de pesquisa na astrofísica. Particularmente são importantes no mecanismo de aquecimento da coroa solar; em ventos estelares; em jatos galácticos e extragalácticos; em discos protoestelares, etc. A formulação para diferenças finitas no domínio do tempo (FDTD), aplicada a plasma magnetizado é desenvolvida para estudo das propriedades de ondas Alfvén em três dimensões (3D-FDTD). O método é aplicado inicialmente a um plasma homogêneo e isotérmico imerso em uma região com campo magnético externo B0, que sofre uma pequena perturbação. Uma vez gerada a onda, esta perturbação é retirada e, então analisamos a evolução temporal das ondas, bem como a forma de seu amortecimento.

  4. Vernetztes Lernen: Eine Unterrichtseinheit mit Heinrich von Kleists Erzahlung "Das Erdbeben in Chili" und Crista Wolfs Roman "Kein Ort. Nirgends" (Networked Learning: An Instructional Unit with Heinrich von Kleist's Story "The Earthquake in Chile" and Christa Wolf's Novel "No Place, No Where").

    ERIC Educational Resources Information Center

    Eidecker, Martina Elisabeth

    1999-01-01

    Presents an instructional model, using Kleist's story "Das Erdbeben in Chili" and Christa Wolf's novel Kei Ort. Nirgends" as a basis. The model clearly distinguishes itself from quantitative models and mediates solid literary knowledge through an inductive approach. Learning takes place in a multidimensional space that makes possible multiple…

  5. Cometa Hyakutake (C/1996 B2): análise do gás e características físicas das partículas de poeira

    NASA Astrophysics Data System (ADS)

    Sanzovo, G. C.; de Almeida, A. A.; Boczko, R.

    2003-08-01

    A completa caracterização e compreensão do núcleo de um cometa novo é de fundamental importância para a elucidação dos processos físicos e químicos atuantes na época da formação do Sistema Solar. O Cometa Hyakutake, conjuntamente com o Cometa Hale-Bopp representam os objetos mais brilhantes que visitaram o Sistema Solar Interno nos últimos 20 anos. Neste Trabalho, nós aplicamos o Método Semi-Empírico das Magnitudes Visuais (MSEMV) à aproximadamente 4000 dados observacionais que correlacionam a magnitude visual absoluta com a distância heliocêntrica para o Cometa Hyakutake nas fases pré- e pós-periélicas. Como produto da aplicação desse método, conseguimos caracterizar dimensionalmente seu núcleo e área ativa efetiva. As taxas de produção dos radicais CN, C2 e C3, obtidos a partir de dados disponíveis na literatura, revelam que, além de muito brilhante, o Hyakutake é um cometa "normal" no sentido de Cochran (1986). Desse modo, deduzimos as taxas de perdas de água (em moléculas/s) a partir da análise de sua magnitude visual aparente, e as convertemos em taxas de perdas de gás (em g/s), despreendido pelo nucleo cometário. Com o auxílio do modelo fotométrico clássico da poeira, realizamos uma análise sistemática e uniforme dessa componente cometária, a partir dos fluxos observacionais no contínuo, para os comprimentos de onda 365,0 e 484,5 nm, assumindo que esses fluxos são o resultado da radiação solar espalhada por grãos de partículas micrométricos presentes na coma. Com isso, pudemos obter as taxas de produção (em g/s), cores (relativas à cor neutra solar), e as dimensões efetivas médias das partículas de poeira, bem como as razões poeira-gás.

  6. Composition of grain and forage from insect-protected and herbicide-tolerant corn, MON 89034 × TC1507 × MON 88017 × DAS-59122-7 (SmartStax), is equivalent to that of conventional corn (Zea mays L.).

    PubMed

    Lundry, Denise R; Burns, J Austin; Nemeth, Margaret A; Riordan, Susan G

    2013-02-27

    Monsanto Company and Dow AgroSciences LLC have developed the combined-trait corn product MON 89034 × TC1507 × MON 88017 × DAS-59122-7 (SmartStax, a registered trademark of Monsanto Technology LLC). The combination of four biotechnology-derived events into a single corn product (stacking) through conventional breeding provides broad protection against lepidopteran and corn rootworm insect pests as well as tolerance to the glyphosate and glufosinate-ammonium herbicide families. The purpose of the work described here was to assess whether the nutrient, antinutrient, and secondary metabolite levels in grain and forage tissues of the combined-trait product are comparable to those in conventional corn. Compositional analyses were conducted on grain and forage from SmartStax, a near-isogenic conventional corn hybrid (XE6001), and 14 conventional reference hybrids, grown at multiple locations across the United States. No statistically significant differences between SmartStax and conventional corn were observed for the 8 components analyzed in forage and for 46 of the 52 components analyzed in grain. The six significant differences observed in grain components (p < 0.05) were assessed in context of the natural variability for that component. These results demonstrate that the stacked product, SmartStax, produced through conventional breeding of four single-event products containing eight proteins, is compositionally equivalent to conventional corn, as previously demonstrated for the single-event products.

  7. Lactic acid microbiota identification in water, raw milk, endogenous starter culture, and fresh Minas artisanal cheese from the Campo das Vertentes region of Brazil during the dry and rainy seasons.

    PubMed

    Castro, R D; Oliveira, L G; Sant'Anna, F M; Luiz, L M P; Sandes, S H C; Silva, C I F; Silva, A M; Nunes, A C; Penna, C F A M; Souza, M R

    2016-08-01

    Minas artisanal cheese, produced in the Campo das Vertentes region of Brazil, is made from raw milk and endogenous starter cultures. Although this cheese is of great historical and socioeconomic importance, little information is available about its microbiological and physical-chemical qualities, or about its beneficial microbiota. This work was aimed at evaluating the qualities of the cheese and the components used for its production, comparing samples collected during the dry and rainy seasons. We also conducted molecular identification and isolated 50 samples of lactic acid bacteria from cheese (n=21), water (n=3), raw milk (n=9), and endogenous starter culture (n=17). The microbiological quality of the cheese, water, raw milk, and endogenous starter culture was lower during the rainy period, given the higher counts of coagulase-positive Staphylococcus and total and thermotolerant coliforms. Enterococcus faecalis was the lactic acid bacteria isolated most frequently (42.86%) in cheese samples, followed by Lactococcus lactis (28.57%) and Lactobacillus plantarum (14.29%). Lactobacillus brevis (5.88%), Enterococcus pseudoavium (5.88%), Enterococcus durans (5.88%), and Aerococcus viridans (5.88%) were isolated from endogenous starter cultures and are described for the first time in the literature. The lactic acid bacteria identified in the analyzed cheeses may inhibit undesirable microbiota and contribute to the safety and flavor of the cheese, but this needs to be evaluated in future research.

  8. Lactic acid microbiota identification in water, raw milk, endogenous starter culture, and fresh Minas artisanal cheese from the Campo das Vertentes region of Brazil during the dry and rainy seasons.

    PubMed

    Castro, R D; Oliveira, L G; Sant'Anna, F M; Luiz, L M P; Sandes, S H C; Silva, C I F; Silva, A M; Nunes, A C; Penna, C F A M; Souza, M R

    2016-08-01

    Minas artisanal cheese, produced in the Campo das Vertentes region of Brazil, is made from raw milk and endogenous starter cultures. Although this cheese is of great historical and socioeconomic importance, little information is available about its microbiological and physical-chemical qualities, or about its beneficial microbiota. This work was aimed at evaluating the qualities of the cheese and the components used for its production, comparing samples collected during the dry and rainy seasons. We also conducted molecular identification and isolated 50 samples of lactic acid bacteria from cheese (n=21), water (n=3), raw milk (n=9), and endogenous starter culture (n=17). The microbiological quality of the cheese, water, raw milk, and endogenous starter culture was lower during the rainy period, given the higher counts of coagulase-positive Staphylococcus and total and thermotolerant coliforms. Enterococcus faecalis was the lactic acid bacteria isolated most frequently (42.86%) in cheese samples, followed by Lactococcus lactis (28.57%) and Lactobacillus plantarum (14.29%). Lactobacillus brevis (5.88%), Enterococcus pseudoavium (5.88%), Enterococcus durans (5.88%), and Aerococcus viridans (5.88%) were isolated from endogenous starter cultures and are described for the first time in the literature. The lactic acid bacteria identified in the analyzed cheeses may inhibit undesirable microbiota and contribute to the safety and flavor of the cheese, but this needs to be evaluated in future research. PMID:27289151

  9. On the self-assembly of a highly selective benzothiazole-based TIM inhibitor in aqueous solution.

    PubMed

    Hassan, Natalia; Gárate, M Pilar; Sandoval, Tania; Espinoza, Luis; Piñeiro, Ángel; Ruso, Juan M

    2010-11-16

    Benzothiazole is a common scaffold on which many bioactive structures, including protein inhibitors and biosensors, are based. The potential self-aggregation of such molecules to form nanoparticles is relevant for a number of practical applications. 3-(2-Benzothiazolylthio)-propanesulfonic acid (BTS) has been reported as a powerful and selective inhibitor of triosephosphate isomerase from Trypanosoma cruzi, the parasite that causes the Chagas' disease. Electrical conductivity, sound velocity, density, and nuclear magnetic resonance experiments as a function of temperature and of NaCl concentration have been performed in the present work to provide a comprehensive physicochemical description of this compound in aqueous solution. Molecular dynamics simulations of the same system were also performed to characterize the structure and dynamic behavior of the corresponding aggregates at several concentrations of BTS.

  10. Structural comparisons of TIM barrel proteins suggest functional and evolutionary relationships between beta-galactosidase and other glycohydrolases.

    PubMed

    Juers, D H; Huber, R E; Matthews, B W

    1999-01-01

    Beta-galactosidase (lacZ) from Escherichia coli is a 464 kDa homotetramer. Each subunit consists of five domains, the third being an alpha/beta barrel that contains most of the active site residues. A comparison is made between each of the domains and a large set of proteins representative of all structures from the protein data bank. Many structures include an alpha/beta barrel. Those that are most similar to the alpha/beta barrel of E. coli beta-galactosidase have similar catalytic residues and belong to the so-called "4/7 superfamily" of glycosyl hydrolases. The structure comparison suggests that beta-amylase should also be included in this family. Of three structure comparison methods tested, the "ProSup" procedure of Zu-Kang and Sippl and the "Superimpose" procedure of Diederichs were slightly superior in discriminating the members of this superfamily, although all procedures were very powerful in identifying related protein structures. Domains 1, 2, and 4 of E. coli beta-galactosidase have topologies related to "jelly-roll barrels" and "immunoglobulin constant" domains. This fold also occurs in the cellulose binding domains (CBDs) of a number of glycosyl hydrolases. The fold of domain 1 of E. coli beta-galactosidase is closely related to some CBDs, and the domain contributes to substrate binding, but in a manner unrelated to cellulose binding by the CBDs. This is typical of domains 1, 2, 4, and 5, which appear to have been recruited to play roles in beta-galactosidase that are unrelated to the functions that such domains provide in other contexts. It is proposed that beta-galactosidase arose from a prototypical single domain alpha/beta barrel with an extended active site cleft. The subsequent incorporation of elements from other domains could then have reduced the size of the active site from a cleft to a pocket to better hydrolyze the disaccharide lactose and, at the same time, to facilitate the production of inducer, allolactose.

  11. Structure analysis of the primary mirror support for the TIM using computer-aided finite element method

    NASA Astrophysics Data System (ADS)

    Farah Simon, Alejandro; Pedrayes, Maria H.; Ruiz Schneider, Elfego; Sierra, Gerardo; Quiros-Pacheco, Fernando; Godoy, Javier; Sohn, Erika

    2000-08-01

    The Mexican Infrared Telescope is one of the most important projects in the Institute for Astronomy of the National University of Mexico. As part of the design we pretend to simulate different components of the telescope by the Finite Element Method (FEM). One of the most important parts of the structure is the primary mirror support. This structure is under stress, causing deformations in the primary mirror; these deformations shouldn't be over 40 nanometers, which is the maximum permissible tolerance. One of the most interesting subjects to develop in this project is to make the segmented primary mirror to work like if it were a monolithic one. Each segment has six degrees of freedom, whose control needs actuators and sensors with stiff mechanical structures. Our purpose is to achieve these levels of design using FEM aided by computer and we pretend to study several models of the structure array using the Conceptual Design Method, in an effort to optimize the design.

  12. Evaluation of the relative risk to birds of alternative pesticides using EPA’s TIM/MCnest Model

    EPA Science Inventory

    Agricultural producers today have many choices of active ingredients for crop protection. These products come with different active ingredients, different modes of action, and that initiate different adverse outcome pathways. Use patterns also differ considerably among products...

  13. Boiling eXperiment Facility (BXF) Fluid Toxicity Technical Interchange Meeting (TIM) with the Payload Safety Review Panel (PSRP)

    NASA Technical Reports Server (NTRS)

    Sheredy, William A.

    2012-01-01

    A Technical Interchange meeting was held between the payload developers for the Boiling eXperiment Facility (BXF) and the NASA Safety Review Panel concerning operational anomaly that resulted in overheating one of the fluid heaters, shorted a 24VDC power supply and generated Perfluoroisobutylene (PFiB) from Perfluorohexane.

  14. U-Pb ID-TIMS zircon ages of TTG gneisses of the Aravalli Craton of India

    NASA Astrophysics Data System (ADS)

    Chauhan, Hiredya; Saikia, Ashima; Kaulina, Tatiana; Bayanova, Tamara; Ahmad, Talat

    2015-04-01

    The crystalline basement of the Aravalli Craton is a heterogeneous assemblage dominated by granitic gneisses and granites with sporadic occurrences of amphibolites and dismembered sedimentary enclaves (Upadhyaya et al., 1992). This assemblage is known to have experienced multiple deformation and metamorphic events followed by emplacement of voluminous granites and basaltic dykes. Based on Sm-Nd whole rock data on the basement Mewar orthogneisses of Jhamarkotra region (Gopalan et al., 1990) and Pb/Pb ages of zircon from Gingla Granites which intrudes the basement (Wiedenbeck et al., 1996), it has been inferred that the whole magmatic episode leading to the formation of the basement spanned from 3300 to 2400 Ma and that the Aravalli cratonic block had broadly stabilized by 2500 Ma on which the younger Aravalli and Delhi Supergroup unconformably deposited. However, no comprehensive age data on the basement gneisses from the study area spanning the entire magmatic episode is available. This work attempts to provide a time frame work for evolution of the basement gneisses of the Aravalli Craton. We present here U-Pb zircon ages from the Precambrian basement TTG gneisses of the Aravalli Craton of north western India. Pb and U were measured on multicollector Finnigan-MAT 262 mass spectrometer. The temperatures of measurements were 1300°C for Pb and 1500°C for U. Pb isotope ratios were corrected for mass fractionation with a factor of 0.10% per amu, based on repeat analyses of the standard NBS SRM 982. The U analyses were corrected for mass fractionation with a factor of 0.003% per amu, based on repeat analyses of the NBS U 500 standard. Reproducibility of the U-Pb ratios was determined from the repeated analysis of standard zircon IGFM-87 (Ukraine) and taken as 0.5% for 207Pb/235U and 206Pb/238U ratios, respectively, at 95% confidence level. All calculations were done using the programs PBDAT and ISOPLOT (Ludwig 1991, 2008). Four zircon fractions corresponding to four zircon types from UD-16 sample yield a U-Pb discordant age of 2680±30 Ma. Two zircon fractions from UD-17 sample show discordant 207Pb/206Pb ages of 2506 and 2577 Ma. Zircons in our samples have moderate to high U contents (180-770 ppm) with low Th/U ratios (0.2-0.5) in the sample UD-16, characteristic for magmatic zircons from TTG rocks. Thus the obtained age of 2680±30 Ma is interpreted as an age of magmatic crystallization of tonalites. Gopalan, K. et al., (1990): Precambrian Res., 48, 287-297. Ludwig, K.R. (1991): PBDAT program. US. Geol. Surv. Open-file report 88-542, 38 p. Ludwig, K. R. (2008): Isoplot/Ex, version 3.6, Berkeley Geochronology Center, Special Publication no. 4. Upadhyaya, R. et al., (1992): Current Sci., 62(2): 87-92. Wiedenbeck, M. et al., (1996): Chem Geol. 129: 325-340.

  15. The Virtual Consortium: Tim Bucknall Describes How a Group of Carolina Libraries Came Together to Expand Dramatically Their Journal Content

    ERIC Educational Resources Information Center

    Bucknall, Tim

    2005-01-01

    The Carolina Consortium came into being for one purpose: to conclude deals that would allow the sharing of both the costs and the content of a large number of academic journals from three major publishers--Wiley, Springer, and Blackwell. In just a few months--and without any central authority, funding, or administrative overhead--librarians from…

  16. T.I.M.S: TaqMan Information Management System, tools to organize data flow in a genotyping laboratory

    PubMed Central

    Monnier, Stéphanie; Cox, David G; Albion, Tim; Canzian, Federico

    2005-01-01

    Background Single Nucleotide Polymorphism (SNP) genotyping is a major activity in biomedical research. The Taqman technology is one of the most commonly used approaches. It produces large amounts of data that are difficult to process by hand. Laboratories not equipped with a Laboratory Information Management System (LIMS) need tools to organize the data flow. Results We propose a package of Visual Basic programs focused on sample management and on the parsing of input and output TaqMan files. The code is written in Visual Basic, embedded in the Microsoft Office package, and it allows anyone to have access to those tools, without any programming skills and with basic computer requirements. Conclusion We have created useful tools focused on management of TaqMan genotyping data, a critical issue in genotyping laboratories whithout a more sophisticated and expensive system, such as a LIMS. PMID:16221298

  17. Physikgeschichte Das Rätsel bleibt

    NASA Astrophysics Data System (ADS)

    Hoffmann, Dieter

    2002-05-01

    Die jüngst erfolgte Veröffentlichung von Dokumenten aus dem Privatarchiv der Familie Bohr [1] über den geheimnisumwitterten Besuch von Werner Heisenberg in Kopenhagen im September 1941 hat in den deutschen Medien große Resonanz gefunden [2]. Tatsächlich verraten uns die jetzt veröffentlichten Dokumente sehr viel mehr über die Zeit ihres Entstehens als über den Besuch selbst.

  18. Internationale Schulreformtendenzen und das Problem der Lehrerausbildung

    NASA Astrophysics Data System (ADS)

    Kupisiewicz, Czeslaw

    1982-09-01

    The main theme of this article is that the socio-economic and educational changes which have occurred in industrialized countries in the past 20 to 25 years necessitate a thorough reform of the present system of teacher education. The first group of such changes includes the information explosion, greater occupational mobility, the growing significance and increasing role of the sciences, the development of the mass media, higher educational aspirations, technical development, the acceleration of the psycho-physical development of children and youth, and the injurious effects of the uncontrolled development of the constantly changing civilisation (deterioration of the human environment, diseases caused by the effects of civilisation, etc.). In the face of these changes, teachers must not remain in