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  1. The TIMS investigator's guide

    NASA Technical Reports Server (NTRS)

    Palluconi, Frank D.

    1986-01-01

    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 thermal infrared atmospheric window region (8 to 12 microns) with a sensitivity of approximately 0.1 C, TIMS may be used whenever an accurate measurement of spectral radiance or brightness temperature is needed. The purpose of the TIMS Investigator's Guide is to provide in one location, enough information about TIMS that potential investigators can decide whether or not it would provide measurements useful in their research program and to provide a new user of TIMS data sufficient information to begin analysis.

  2. TUBERCULOSIS INFORMATION MANAGEMENT SYSTEM (TIMS)

    EPA Science Inventory

    TIMS is a Windows-based client/server application that assists health departments and other facilities to manage TB patients, to conduct TB surveillance activities, and to manage TB programs overall. TIMS provides for electronic transmission of TB surveillance data (OMB No. 0920-...

  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. Interaction of Tim23 with Tim50 Is essential for protein translocation by the mitochondrial TIM23 complex.

    PubMed

    Gevorkyan-Airapetov, Lada; Zohary, Keren; Popov-Celeketic, Dusan; Mapa, Koyeli; Hell, Kai; Neupert, Walter; Azem, Abdussalam; Mokranjac, Dejana

    2009-02-20

    The TIM23 complex is the major translocase of the mitochondrial inner membrane responsible for the import of essentially all matrix proteins and a number of inner membrane proteins. Tim23 and Tim50, two essential proteins of the complex, expose conserved domains into the intermembrane space that interact with each other. Here, we describe in vitro reconstitution of this interaction using recombinantly expressed and purified intermembrane space domains of Tim50 and Tim23. We established two independent methods, chemical cross-linking and surface plasmon resonance, to track their interaction. In addition, we identified mutations in Tim23 that abolish its interaction with Tim50 in vitro. These mutations also destabilized the interaction between the two proteins in vivo, leading to defective import of preproteins via the TIM23 complex and to cell death at higher temperatures. This is the first study to describe the reconstitution of the Tim50-Tim23 interaction in vitro and to identify specific residues of Tim23 that are vital for the interaction with Tim50. PMID:19017642

  5. 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…

  6. Tim1 and Tim3 are not essential for experimental allergic asthma

    PubMed Central

    Barlow, J L; Wong, S H; Ballantyne, S J; Jolin, H E; McKenzie, A N J

    2011-01-01

    Background Initial studies suggested that polymorphisms in Tim1 and Tim3 contribute to the development of airway hyperreactivity (AHR) in an acute mouse model of asthma. This was also mirrored in human genetic studies where polymorphisms in Tim1 and Tim3 have been associated with atopic populations. Objective Further studies using anti-Tim1 or -Tim3 antibodies, or Tim fusion proteins, have also suggested that these molecules may function as regulators of type-1 and type-2 immunity. However, their role in the development of AHR and airway inflammation remains unclear. Given the proposed roles for Tim1 and Tim3 in type-1 and type-2 responses, we sought to determine whether these molecules were important in regulating antigen-driven lung allergy and inflammation. Method We used Tim1- and Tim3-deficient mice and determined how the development of allergic lung inflammation was affected. Results AHR was induced normally in the absence of both Tim1 and Tim3, although Tim1-deficient mice did show a small but significant decrease in cell infiltration in the lung and blood eosinophilia. Although Tim3 was expressed on CD4+ T cells in the allergic lung, Tim1 expression was restricted to CD86+ B cells. Conclusions and clinical relevance Thus, Tim1 and Tim3 are not essential for the induction of the type-2 response in lung allergy. This is contrary to what was proposed in a number of other studies using neutralizing and activating antibodies and questions the clinical relevance of Tim1 and Tim3 for novel allergy therapies. Cite this as: J. L. Barlow, S. H. Wong, S. J. Ballantyne, H. E. Jolin and A. N. J. McKenzie, Clinical & Experimental Allergy, 2011 (41) 1012–1021. PMID:21470319

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

    PubMed Central

    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. PMID:26211834

  8. Interaction of TIM4 and TIM3 induces T helper 1 cell apoptosis.

    PubMed

    Ge, Rong-Ti; Zeng, Lu; Mo, Li-Hua; Xu, Ling-Zhi; Zhang, Huan-Ping; Yu, Hai-Qiong; Zhang, Min; Liu, Zhi-Gang; Liu, Zhan-Ju; Yang, Ping-Chang

    2016-04-01

    The T helper 1 (Th1) polarization plays a critical role in the pathogenesis of a number of inflammatory disorders in the body; the remedies in the correction of polarized Th1 cells are limited. This study aims to investigate the role of T cell immunoglobulin mucin domain molecule 4 (TIM4) in the induction of Th1 cell apoptosis. In this study, polarized Th1 cells were generated from naive Th1 cells from the mouse spleen. Recombinant TIM4 was added to the culture to stimulate the polarized Th1 cells. The apoptosis of Th1 cells was assessed by flow cytometry. The expression of FasL was analyzed by chromatin immunoprecipitation, real time RT-PCR, and Western blotting. The results showed that the polarized Th1 cells expressed high levels of TIM3. After exposure of the polarized Th1 cells to TIM4 in the culture, a complex of TIM3 and TIM4 was detected on the surface of Th1 cells, which induced the Th1 cell apoptosis. The engagement of TIM3 by TIM4 increased p300 phosphorylation in Th1 cells, which further increased the levels of Fas ligand in the cells and induced Th1 cell apoptosis. In conclusion, TIM4 binds TIM3 on the surface of polarized Th1 cells to induce Th1 cell apoptosis, which may contribute to the development of Th2-dominant immune disorders. PMID:26403707

  9. Mitochondrial presequence translocase: switching between TOM tethering and motor recruitment involves Tim21 and Tim17.

    PubMed

    Chacinska, Agnieszka; Lind, Maria; Frazier, Ann E; Dudek, Jan; Meisinger, Chris; Geissler, Andreas; Sickmann, Albert; Meyer, Helmut E; Truscott, Kaye N; Guiard, Bernard; Pfanner, Nikolaus; Rehling, Peter

    2005-03-25

    The presequence translocase of the inner mitochondrial membrane (TIM23 complex) operates at a central junction of protein import. It accepts preproteins from the outer membrane TOM complex and directs them to inner membrane insertion or, in cooperation with the presequence translocase-associated motor (PAM), to the matrix. Little is known of how the TIM23 complex coordinates these tasks. We have identified Tim21 (YGR033c) that interacts with the TOM complex. Tim21 is specific for a TIM23 form that cooperates with TOM and promotes inner membrane insertion. Protein translocation into the matrix requires a switch to a Tim21-free, PAM bound presequence translocase. Tim17 is crucial for the switch by performing two separable functions: promotion of inner membrane insertion and binding of Pam18 to form the functional TIM-PAM complex. Thus, the presequence translocase is not a static complex but switches between TOM tethering and PAM binding in a reaction cycle involving Tim21 and Tim17. PMID:15797382

  10. 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.

  11. The 1994 laboratory calibration of TIMS

    NASA Technical Reports Server (NTRS)

    Realmuto, Vincent J.; Hajek, Pavel; Sinha, Mahadeva P.; Chrien, Thomas G.

    1995-01-01

    This summary describes the spatial, spectral, and radiometric calibration of Thermal Infrared Multispectral Scanner (TIMS) performed at the Jet Propulsion Laboratory (JPL) Thermal Infrared Calibration Facility (TIRCAL) between May and August, 1994. The 1994 calibration of TIMS was the first to make use of the new EXABYTE (8mm helical-scan tape) recording system. With the new recorder, the TIMS data tapes may be read directly on any computer system that has an EXABYTE tape drive. We analyzed the calibration data sets using image processing procedures written in Interactive Data Language.

  12. TIM-family proteins inhibit HIV-1 release

    PubMed Central

    Li, Minghua; Ablan, Sherimay D.; Miao, Chunhui; Zheng, Yi-Min; Fuller, Matthew S.; Rennert, Paul D.; Maury, Wendy; Johnson, Marc C.; Freed, Eric O.; Liu, Shan-Lu

    2014-01-01

    Accumulating evidence indicates that T-cell immunoglobulin (Ig) and mucin domain (TIM) proteins play critical roles in viral infections. Herein, we report that the TIM-family proteins strongly inhibit HIV-1 release, resulting in diminished viral production and replication. Expression of TIM-1 causes HIV-1 Gag and mature viral particles to accumulate on the plasma membrane. Mutation of the phosphatidylserine (PS) binding sites of TIM-1 abolishes its ability to block HIV-1 release. TIM-1, but to a much lesser extent PS-binding deficient mutants, induces PS flipping onto the cell surface; TIM-1 is also found to be incorporated into HIV-1 virions. Importantly, TIM-1 inhibits HIV-1 replication in CD4-positive Jurkat cells, despite its capability of up-regulating CD4 and promoting HIV-1 entry. In addition to TIM-1, TIM-3 and TIM-4 also block the release of HIV-1, as well as that of murine leukemia virus (MLV) and Ebola virus (EBOV); knockdown of TIM-3 in differentiated monocyte-derived macrophages (MDMs) enhances HIV-1 production. The inhibitory effects of TIM-family proteins on virus release are extended to other PS receptors, such as Axl and RAGE. Overall, our study uncovers a novel ability of TIM-family proteins to block the release of HIV-1 and other viruses by interaction with virion- and cell-associated PS. Our work provides new insights into a virus-cell interaction that is mediated by TIMs and PS receptors. PMID:25136083

  13. 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.

  14. 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

  15. HST PSF simulation using Tiny Tim

    NASA Technical Reports Server (NTRS)

    Krist, J. E.

    1992-01-01

    Tiny Tim is a program which simulates Hubble Space Telescope imaging camera PSF's. It is portable (written and distributed in C) and is reasonably fast. It can model the WFPC, WFPC 2, FOC, and COSTAR corrected FOC cameras. In addition to aberrations such as defocus and spherical, it also includes WFPC obscuration shifting, mirror zonal error maps, and jitter. The program has been used at a number of sites for deconvolving HST images. Tiny Tim is available via anonymous ftp on stsci.edu in the directory software/tinytim.

  16. 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.

  17. Immune Regulation and Antitumor Effect of TIM-1

    PubMed Central

    Du, Peng; Xiong, Ruihua; Li, Xiaodong; Jiang, Jingting

    2016-01-01

    T cells play an important role in antitumor immunity, and the T cell immunoglobulin domain and the mucin domain protein-1 (TIM-1) on its surface, as a costimulatory molecule, has a strong regulatory effect on T cells. TIM-1 can regulate and enhance type 1 immune response of tumor association. Therefore, TIM-1 costimulatory pathways may be a promising therapeutic target in future tumor immunotherapy. This review describes the immune regulation and antitumor effect of TIM-1. PMID:27413764

  18. 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. PMID:27379093

  19. Tim Horton Camps: Spotlight on Onondaga Farms.

    ERIC Educational Resources Information Center

    Evanson, Jason

    2003-01-01

    Tim Horton Children's Foundation operates camps for disadvantaged children that build their self-confidence. The newest camp, Onondaga Farms in Ontario, is also a year-round outdoor education center. Its five program streams--environmental education, creative arts, agriculture, adventure, and recreation--all have direct links to Ontario's…

  20. 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

  1. 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…

  2. 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.

  3. 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.

  4. The phosphatidylserine receptor TIM-4 does not mediate direct signaling.

    PubMed

    Park, Daeho; Hochreiter-Hufford, Amelia; Ravichandran, Kodi S

    2009-02-24

    Engulfment of apoptotic cells is an active process coordinated by receptors on phagocytes and ligands on apoptotic cells [1]. Phosphatidylserine (PtdSer) is a key ligand on apoptotic cells, and recently three PtdSer recognition receptors have been identified, namely, TIM-4, BAI1, and Stabilin-2 [1-6]. Whereas BAI1 is dependent on the ELMO1/Dock180/Rac signaling module, and Stablilin-2 appears to use the intracellular adaptor GULP [2, 3, 7], little is known about how TIM-4 transduces signals downstream of PtdSer recognition [8]. To test the role of known engulfment signaling pathways in TIM-4-mediated engulfment, we used a combination of dominant-negative mutants, knockdown of specific signaling proteins, and knockout cell lines. TIM-4 appears to be largely independent of the two known engulfment signaling pathways [7, 9-17], yet the TIM-4-mediated uptake is inhibited by cytoskeleton disrupting drugs. Remarkably, a version of TIM-4 lacking its cytoplasmic tail promoted corpse uptake via PtdSer recognition. Moreover, replacement of the transmembrane region of TIM-4 with a glycophosphatidylinositol anchor still promoted engulfment comparable to wild-type TIM-4. Thus, the transmembrane region and cytoplasmic tail of TIM-4 are dispensable for apoptotic cell engulfment, and we propose that TIM-4 is a PtdSer tethering receptor without any direct signaling of its own. PMID:19217291

  5. 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

  6. GxxxG motifs hold the TIM23 complex together.

    PubMed

    Demishtein-Zohary, Keren; Marom, Milit; Neupert, Walter; Mokranjac, Dejana; Azem, Abdussalam

    2015-06-01

    Approximately 99% of the mitochondrial proteome is nucleus-encoded, synthesized in the cytosol, and subsequently imported into and sorted to the correct compartment in the organelle. The translocase of the inner mitochondrial membrane 23 (TIM23) complex is the major protein translocase of the inner membrane, and is responsible for translocation of proteins across the inner membrane and their insertion into the inner membrane. Tim23 is the central component of the complex that forms the import channel. A high-resolution structure of the import channel is still missing, and structural elements important for its function are unknown. In the present study, we analyzed the importance of the highly abundant GxxxG motifs in the transmembrane segments of Tim23 for the structural integrity of the TIM23 complex. Of 10 glycines present in the GxxxG motifs in the first, second and third transmembrane segments of Tim23, mutations of three of them in transmembrane segments 1 and 2 resulted in a lethal phenotype, and mutations of three others in a temperature-sensitive phenotype. The remaining four caused no obvious growth phenotype. Importantly, none of the mutations impaired the import and membrane integration of Tim23 precursor into mitochondria. However, the severity of growth impairment correlated with the destabilization of the TIM23 complex. We conclude that the GxxxG motifs found in the first and second transmembrane segments of Tim23 are necessary for the structural integrity of the TIM23 complex. PMID:25765297

  7. 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

  8. 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.

  9. Molecular basis of the dynamic structure of the TIM23 complex in the mitochondrial intermembrane space.

    PubMed

    Bajaj, Rakhi; Jaremko, Łukasz; Jaremko, Mariusz; Becker, Stefan; Zweckstetter, Markus

    2014-10-01

    The presequence translocase TIM23 is a highly dynamic complex in which its subunits can adopt multiple conformations and undergo association-dissociation to facilitate import of proteins into mitochondria. Despite the importance of protein-protein interactions in TIM23, little is known about the molecular details of these processes. Using nuclear magnetic resonance spectroscopy, we characterized the dynamic interaction network of the intermembrane space domains of Tim23, Tim21, Tim50, and Tom22 at single-residue level. We show that Tim23(IMS) contains multiple sites to efficiently interact with the intermembrane space domain of Tim21 and to bind to Tim21, Tim50, and Tom22. In addition, we reveal the atomic details of the dynamic Tim23(IMS)-Tim21(IMS) complex. The combined data support a central role of the intermembrane space domain of Tim23 in the formation and regulation of the presequence translocase. PMID:25263020

  10. 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.

  11. Modeling TSI Variations from SORCE/TIM

    NASA Astrophysics Data System (ADS)

    Chapman, Gary A.; Cookson, A.; Preminger, D.

    2011-05-01

    Total Solar Irradiance (TSI) measurements have been available from the TIM instrument on the SORCE spacecraft since 2003. We compare TSI data with photometric indices from red and K-line images obtained on a daily basis at the San Fernando Observatory (SFO). For 1375 days of data from 2003 March 02 to 2010 May 05 we compare the data in linear multiple regression analyses. The best results come from using only two photometric indices, the red and K-line photometric sums, and SORCE TSI 6-hour averages interpolated to the SFO time of observation. For this case, we obtain a coefficient of multiple correlation, R2, of 0.94798 and a quiet-Sun irradiance, So = 1360.778 ± 0.004 W/m2. These results provide tighter contstraints than before on hypotheses linking TSI variations with assumed changes in the quiet Sun. This research has been partially supported by NSF Grant ATM-0848518.

  12. 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.

  13. WFPC2 photometry from subtraction of TinyTim PSFs

    NASA Technical Reports Server (NTRS)

    Remy, M.; Surdej, J.; Baggett, S.; Wiggs, M.

    1997-01-01

    Based upon the subtraction of TinyTim Point Spread Function (PSFs) from Principle Component Image (PC1) point-like objects, a method has been developed to determine the optimal values for the telescope jitter and the Z4 relative focus during calibration or science observations. Using these jitter and focus values, an optimal TinyTim PSF, computed over a resampled grid, is then iteratively fitted to the object, yielding an improvement in the PSF centering, more accurate photometric results and a better detection of underlying structures. Preliminary results seem to indicate that appropriate synthetic TinyTim PSFs perform as well as observed PSFs.

  14. 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.

  15. 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...

  16. 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.

  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. Folding and Biogenesis of Mitochondrial Small Tim Proteins

    PubMed Central

    Ceh-Pavia, Efrain; Spiller, Michael P.; Lu, Hui

    2013-01-01

    Correct and timely folding is critical to the function of all proteins. The importance of this is illustrated in the biogenesis of the mitochondrial intermembrane space (IMS) “small Tim” proteins. Biogenesis of the small Tim proteins is regulated by dedicated systems or pathways, beginning with synthesis in the cytosol and ending with assembly of individually folded proteins into functional complexes in the mitochondrial IMS. The process is mostly centered on regulating the redox states of the conserved cysteine residues: oxidative folding is crucial for protein function in the IMS, but oxidized (disulfide bonded) proteins cannot be imported into mitochondria. How the redox-sensitive small Tim precursor proteins are maintained in a reduced, import-competent form in the cytosol is not well understood. Recent studies suggest that zinc and the cytosolic thioredoxin system play a role in the biogenesis of these proteins. In the IMS, the mitochondrial import and assembly (MIA) pathway catalyzes both import into the IMS and oxidative folding of the small Tim proteins. Finally, assembly of the small Tim complexes is a multistep process driven by electrostatic and hydrophobic interactions; however, the chaperone function of the complex might require destabilization of these interactions to accommodate the substrate. Here, we review how folding of the small Tim proteins is regulated during their biogenesis, from maintenance of the unfolded precursors in the cytosol, to their import, oxidative folding, complex assembly and function in the IMS. PMID:23945562

  19. 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

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

    PubMed Central

    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. PMID:26339368

  1. 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. PMID:26921445

  2. Pursuing the impossible: an interview with Tim Hunt.

    PubMed

    Hunt, Tim

    2015-01-01

    Tim Hunt took an undergraduate degree in Natural Sciences at Cambridge in 1964, and his PhD and subsequent work focussed on the control of protein synthesis until 1982, when his adventitious discovery of the central cell cycle regulator cyclin, while he was teaching at the Marine Biological Laboratory in Woods Hole, redirected him to the study of cell cycle regulation. From 1990 to his retirement Tim worked in the Clare Hall Laboratories of Cancer Research UK. He shared the Nobel Prize in Physiology and Medicine with Lee Hartwell and Paul Nurse in 2001, and talked to us about the series of coincidences that led him to the prizewinning discovery. PMID:26253553

  3. Tim-1-Mediated T Cell Activation Requires Recruitment and Activation of PI 3-Kinase

    PubMed Central

    de Souza, Anjali J.; Oak, Jean S.; Jordanhazy, Ryan; DeKruyff, Rosemarie H.; Fruman, David A.; Kane, Lawrence P.

    2009-01-01

    Ligation of the transmembrane protein Tim-1 can co-stimulate T cell activation. Agonistic antibodies to Tim-1 are also capable of inducing T cell activation without additional stimuli. However, little is known about the biochemical mechanisms underlying T cell stimulation or co-stimulation through Tim-1. We show that a tyrosine in Tim-1 becomes phosphorylated in an lck-dependent manner, whereupon it can directly recruit p85 adaptor subunits of PI 3-kinase. This results in PI3K activation, which is required for Tim-1 function. We also provide genetic evidence that p85 expression is required for optimal Tim-1 function. Thus, we describe a pathway from Tim-1 tyrosine phosphorylation to the PI3K signaling pathway, which appears to be a major effector of Tim-1-mediated T cell activation. PMID:18453570

  4. TIM3 Mediates T Cell Exhaustion during Mycobacterium tuberculosis Infection

    PubMed Central

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

    2016-01-01

    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. PMID:26967901

  5. 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…

  6. 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). PMID:27091308

  7. The mitochondrial protein translocation motor: structural conservation between the human and yeast Tim14/Pam18-Tim16/Pam16 co-chaperones.

    PubMed

    Elsner, Shira; Simian, Dana; Iosefson, Ohad; Marom, Milit; Azem, Abdussalam

    2009-05-01

    Most of our knowledge regarding the process of protein import into mitochondria has come from research employing Saccharomyces cerevisiae as a model system. Recently, several mammalian homologues of the mitochondrial motor proteins were identified. Of particular interest for us is the human Tim14/Pam18-Tim16/Pam16 complex. We chose a structural approach in order to examine the evolutionary conservation between yeast Tim14/Pam18-Tim16/Pam16 proteins and their human homologues. For this purpose, we examined the structural properties of the purified human proteins and their interaction with their yeast homologues, in vitro. Our results show that the soluble domains of the human Tim14/Pam18 and Tim16/Pam16 proteins interact with their yeast counterparts, forming heterodimeric complexes and that these complexes interact with yeast mtHsp70. PMID:19564938

  8. The Mitochondrial Protein Translocation Motor: Structural Conservation between the Human and Yeast Tim14/Pam18-Tim16/Pam16 co-Chaperones

    PubMed Central

    Elsner, Shira; Simian, Dana; Iosefson, Ohad; Marom, Milit; Azem, Abdussalam

    2009-01-01

    Most of our knowledge regarding the process of protein import into mitochondria has come from research employing Saccharomyces cerevisiae as a model system. Recently, several mammalian homologues of the mitochondrial motor proteins were identified. Of particular interest for us is the human Tim14/Pam18-Tim16/Pam16 complex. We chose a structural approach in order to examine the evolutionary conservation between yeast Tim14/Pam18-Tim16/Pam16 proteins and their human homologues. For this purpose, we examined the structural properties of the purified human proteins and their interaction with their yeast homologues, in vitro. Our results show that the soluble domains of the human Tim14/Pam18 and Tim16/Pam16 proteins interact with their yeast counterparts, forming heterodimeric complexes and that these complexes interact with yeast mtHsp70. PMID:19564938

  9. 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.

  10. Direct interaction of mitochondrial targeting presequences with purified components of the TIM23 protein complex.

    PubMed

    Marom, Milit; Dayan, Dana; Demishtein-Zohary, Keren; Mokranjac, Dejana; Neupert, Walter; Azem, Abdussalam

    2011-12-23

    Precursor proteins that are imported from the cytosol into the matrix of mitochondria carry positively charged amphipathic presequences and cross the inner membrane with the help of vital components of the TIM23 complex. It is currently unclear which subunits of the TIM23 complex recognize and directly bind to presequences. Here we analyzed the binding of presequence peptides to purified components of the TIM23 complex. The interaction of three different presequences with purified soluble domains of yeast Tim50 (Tim50IMS), Tim23 (Tim23IMS), and full-length Tim44 was examined. Using chemical cross-linking and surface plasmon resonance we demonstrate, for the first time, the ability of purified Tim50IMS and Tim44 to interact directly with the yeast Hsp60 presequence. We also analyzed their interaction with presequences derived from precursors of yeast mitochondrial 70-kDa heat shock protein (mHsp70) and of bovine cytochrome P450SCC. Moreover, we characterized the nature of the interactions and determined their KDs. On the basis of our results, we suggest a mechanism of translocation where stronger interactions of the presequences on the trans side of the channel support the import of precursor proteins through TIM23 into the matrix. PMID:21969381

  11. Direct Interaction of Mitochondrial Targeting Presequences with Purified Components of the TIM23 Protein Complex*

    PubMed Central

    Marom, Milit; Dayan, Dana; Demishtein-Zohary, Keren; Mokranjac, Dejana; Neupert, Walter; Azem, Abdussalam

    2011-01-01

    Precursor proteins that are imported from the cytosol into the matrix of mitochondria carry positively charged amphipathic presequences and cross the inner membrane with the help of vital components of the TIM23 complex. It is currently unclear which subunits of the TIM23 complex recognize and directly bind to presequences. Here we analyzed the binding of presequence peptides to purified components of the TIM23 complex. The interaction of three different presequences with purified soluble domains of yeast Tim50 (Tim50IMS), Tim23 (Tim23IMS), and full-length Tim44 was examined. Using chemical cross-linking and surface plasmon resonance we demonstrate, for the first time, the ability of purified Tim50IMS and Tim44 to interact directly with the yeast Hsp60 presequence. We also analyzed their interaction with presequences derived from precursors of yeast mitochondrial 70-kDa heat shock protein (mHsp70) and of bovine cytochrome P450SCC. Moreover, we characterized the nature of the interactions and determined their KDs. On the basis of our results, we suggest a mechanism of translocation where stronger interactions of the presequences on the trans side of the channel support the import of precursor proteins through TIM23 into the matrix. PMID:21969381

  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. 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.

  14. Mexican infrared optical new technology telescope (TIM) project

    NASA Astrophysics Data System (ADS)

    Salas, Luis; Ruiz, Elfego; Cruz-Gonzales, Irene; Luna, Esteban; Cuevas, Salvador; Pedrayes, Maria H.; Sierra, Gerardo; Sohn, Erika; Koenigsberger, G.; Valdez, Jorge; Harris, Oswaldo N.; Cobos Duenas, Francisco J.; Tejada, Carlos; Gutierrez, L.; Iriarte, Arturo

    1998-08-01

    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 parabolic Zerodur segments. 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).

  15. Aeration of hydroturbine discharges at TIMS Ford Dam

    SciTech Connect

    Harshbarger, E.D.; Mobley, M.H.; Brock, W.G.

    1995-12-31

    Tims Ford Dam located on the Elk River in middle Tennessee is a multipurpose project of the Tennessee Valley Authority (TVA) which provides flood control, water supply, and hydropower generation. Because of thermal stratification in the reservoir and biochemical processes, the hydroturbine discharges from Tims Ford have been historically low in dissolved oxygen (DO) content during several months of the year. To increase the DO of these discharges to a concentration level of 6 mg/L, a dual aeration system using both air injection into the turbine and oxygen injection through porous hoses in the turbine penstock has been installed. This paper describes the air and oxygen systems and presents the results of aeration system operation on DO and total dissolved gas in the turbine discharge and on hydroturbine efficiency.

  16. 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

  17. 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.

  18. Application of split window technique to TIMS data

    NASA Technical Reports Server (NTRS)

    Matsunaga, Tsuneo; Rokugawa, Shuichi; Ishii, Yoshinori

    1992-01-01

    Absorptions by the atmosphere in thermal infrared region are mainly due to water vapor, carbon dioxide, and ozone. As the content of water vapor in the atmosphere greatly changes according to weather conditions, it is important to know its amount between the sensor and the ground for atmospheric corrections of thermal Infrared Multispectral Scanner (TIMS) data (i.e. radiosonde). On the other hand, various atmospheric correction techniques were already developed for sea surface temperature estimations from satellites. Among such techniques, Split Window technique, now widely used for AVHRR (Advanced Very High Resolution Radiometer), uses no radiosonde or any kind of supplementary data but a difference between observed brightness temperatures in two channels for estimating atmospheric effects. Applications of Split Window technique to TIMS data are discussed because availability of atmospheric profile data is not clear when ASTER operates. After these theoretical discussions, the technique is experimentally applied to TIMS data at three ground targets and results are compared with atmospherically corrected data using LOWTRAN 7 with radiosonde data.

  19. 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.

  20. 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

  1. The Pam18/Tim14-Pam16/Tim16 complex of the mitochondrial translocation motor: the formation of a stable complex from marginally stable proteins.

    PubMed

    Iosefson, Ohad; Levy, Ran; Marom, Milit; Slutsky-Leiderman, Olga; Azem, Abdussalam

    2007-02-01

    The vast majority of mitochondrial proteins are imported from the cytosol. For matrix-localized proteins, the final step of translocation across the inner membrane is mediated by the mitochondrial translocation motor, of which mhsp70 is a key component. The ATP-dependent function of mhsp70 is regulated by a complex, composed of a J-protein (called Pam18 or Tim14) and a J-like protein (called Pam16 or Tim16), and the nucleotide exchange factor Mge1. In this study, we investigated the structural properties of a recombinant purified Pam18/Tim14-Pam16/Tim16 complex using cross-linking with the bifunctional reagent DSS and CD-spectroscopy. The results of the study show that both Pam18/Tim14 and Pam16/Tim16 are thermally unstable proteins that unfold at very low temperatures (T(m) values of 16.5 degrees C and 29 degrees C, respectively). Upon mixing the proteins in vitro, or when both proteins are co-overexpressed in bacteria, Pam18/Tim14 and Pam16/Tim16 form a heterodimer that is thermally more stable than the individual proteins (T(m) = 41 degrees C). Analysis of the properties of the complex in GdnHCl shows that dissociation of the heterodimer is the limiting step in achieving full denaturation. PMID:17242434

  2. The Pam18/Tim14–Pam16/Tim16 complex of the mitochondrial translocation motor: The formation of a stable complex from marginally stable proteins

    PubMed Central

    Iosefson, Ohad; Levy, Ran; Marom, Milit; Slutsky-Leiderman, Olga; Azem, Abdussalam

    2007-01-01

    The vast majority of mitochondrial proteins are imported from the cytosol. For matrix-localized proteins, the final step of translocation across the inner membrane is mediated by the mitochondrial translocation motor, of which mhsp70 is a key component. The ATP-dependent function of mhsp70 is regulated by a complex, composed of a J-protein (called Pam18 or Tim14) and a J-like protein (called Pam16 or Tim16), and the nucleotide exchange factor Mge1. In this study, we investigated the structural properties of a recombinant purified Pam18/Tim14–Pam16/Tim16 complex using cross-linking with the bifunctional reagent DSS and CD-spectroscopy. The results of the study show that both Pam18/Tim14 and Pam16/Tim16 are thermally unstable proteins that unfold at very low temperatures (Tm values of 16.5°C and 29°C, respectively). Upon mixing the proteins in vitro, or when both proteins are co-overexpressed in bacteria, Pam18/Tim14 and Pam16/Tim16 form a heterodimer that is thermally more stable than the individual proteins (Tm = 41°C). Analysis of the properties of the complex in GdnHCl shows that dissociation of the heterodimer is the limiting step in achieving full denaturation. PMID:17242434

  3. 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

  4. 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

  5. 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

  6. Role of Tim50 in the transfer of precursor proteins from the outer to the inner membrane of mitochondria.

    PubMed

    Mokranjac, Dejana; Sichting, Martin; Popov-Celeketić, Dusan; Mapa, Koyeli; Gevorkyan-Airapetov, Lada; Zohary, Keren; Hell, Kai; Azem, Abdussalam; Neupert, Walter

    2009-03-01

    Transport of essentially all matrix and a number of inner membrane proteins is governed, entirely or in part, by N-terminal presequences and requires a coordinated action of the translocases of outer and inner mitochondrial membranes (TOM and TIM23 complexes). Here, we have analyzed Tim50, a subunit of the TIM23 complex that is implicated in transfer of precursors from TOM to TIM23. Tim50 is recruited to the TIM23 complex via Tim23 in an interaction that is essentially independent of the rest of the translocase. We find Tim50 in close proximity to the intermembrane space side of the TOM complex where it recognizes both types of TIM23 substrates, those that are to be transported into the matrix and those destined to the inner membrane, suggesting that Tim50 recognizes presequences. This function of Tim50 depends on its association with TIM23. We conclude that the efficient transfer of precursors between TOM and TIM23 complexes requires the concerted action of Tim50 with Tim23. PMID:19144822

  7. Role of Tim50 in the Transfer of Precursor Proteins from the Outer to the Inner Membrane of Mitochondria

    PubMed Central

    Sichting, Martin; Popov-Čeleketić, Dušan; Mapa, Koyeli; Gevorkyan-Airapetov, Lada; Zohary, Keren; Hell, Kai; Azem, Abdussalam

    2009-01-01

    Transport of essentially all matrix and a number of inner membrane proteins is governed, entirely or in part, by N-terminal presequences and requires a coordinated action of the translocases of outer and inner mitochondrial membranes (TOM and TIM23 complexes). Here, we have analyzed Tim50, a subunit of the TIM23 complex that is implicated in transfer of precursors from TOM to TIM23. Tim50 is recruited to the TIM23 complex via Tim23 in an interaction that is essentially independent of the rest of the translocase. We find Tim50 in close proximity to the intermembrane space side of the TOM complex where it recognizes both types of TIM23 substrates, those that are to be transported into the matrix and those destined to the inner membrane, suggesting that Tim50 recognizes presequences. This function of Tim50 depends on its association with TIM23. We conclude that the efficient transfer of precursors between TOM and TIM23 complexes requires the concerted action of Tim50 with Tim23. PMID:19144822

  8. 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. PMID:27156907

  9. 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. PMID:26598760

  10. Interaction of the Intermembrane Space Domain of Tim23 Protein with Mitochondrial Membranes*

    PubMed Central

    Bajaj, Rakhi; Munari, Francesca; Becker, Stefan; Zweckstetter, Markus

    2014-01-01

    Tim23 mediates protein translocation into mitochondria. Although inserted into the inner membrane, the dynamic association of its intermembrane space (IMS) domain with the outer membrane promotes protein import. However, little is known about the molecular basis of this interaction. Here, we demonstrate that the IMS domain of Tim23 tightly associates with both inner and outer mitochondrial membrane-like membranes through a hydrophobic anchor at its N terminus. The structure of membrane-bound Tim23IMS is highly dynamic, allowing recognition of both the incoming presequence and other translocase components at the translocation contact. Cardiolipin enhances Tim23 membrane attachment, suggesting that cardiolipin can influence preprotein import. PMID:25349212

  11. Cooperation of TOM and TIM23 complexes during translocation of proteins into mitochondria.

    PubMed

    Waegemann, Karin; Popov-Čeleketić, Dušan; Neupert, Walter; Azem, Abdussalam; Mokranjac, Dejana

    2015-03-13

    Translocation of the majority of mitochondrial proteins from the cytosol into mitochondria requires the cooperation of TOM and TIM23 complexes in the outer and inner mitochondrial membranes. The molecular mechanisms underlying this cooperation remain largely unknown. Here, we present biochemical and genetic evidence that at least two contacts from the side of the TIM23 complex play an important role in TOM-TIM23 cooperation in vivo. Tim50, likely through its very C-terminal segment, interacts with Tom22. This interaction is stimulated by translocating proteins and is independent of any other TOM-TIM23 contact known so far. Furthermore, the exposure of Tim23 on the mitochondrial surface depends not only on its interaction with Tim50 but also on the dynamics of the TOM complex. Destabilization of the individual contacts reduces the efficiency of import of proteins into mitochondria and destabilization of both contacts simultaneously is not tolerated by yeast cells. We conclude that an intricate and coordinated network of protein-protein interactions involving primarily Tim50 and also Tim23 is required for efficient translocation of proteins across both mitochondrial membranes. PMID:25083920

  12. 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

  13. 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

  14. Tim-3 polymorphism downregulates gene expression and is involved in the susceptibility to ankylosing spondylitis.

    PubMed

    Wang, Mingfei; Ji, Bin; Wang, Jian; Cheng, Xiangyu; Zhou, Qiang; Zhou, Junjie; Cao, Chengfu; Guo, Qunfeng

    2014-10-01

    Ankylosing spondylitis (AS) is a chronic inflammatory disorder primarily affecting the sacroiliac joints and the spine. T-cell immunoglobulin- and mucin-domain-containing molecule 3 (TIM-3) has been established as a negative regulatory molecule that plays a critical role in controlling inflammation. Studies have shown that polymorphisms in TIM-3 gene may be associated with inflammatory diseases. The current study investigated the association between polymorphisms in the TIM-3 gene and susceptibility to AS, and it examined the effects of these polymorphisms on gene expression. Two polymorphisms in TIM-3 -574G/T and +4259T/G polymorphisms were identified by polymerase chain reaction-restriction fragment length polymorphism in 282 AS patients and 298 healthy controls. Results showed that frequency of the TIM-3 -574GT genotype was significantly increased in cases than in controls (Odd ratio [OR]=2.50, 95% confidence interval [CI]: 1.39-4.48, p=0.002). Similarly, TIM-3 -574T allele revealed a positive association with the disease (OR=2.39, p=0.002). The TIM-3 +4259T/G polymorphism did not show any correlation with AS. We further evaluated TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes from subjects carrying different TIM-3 genotypes. Results revealed that subjects carrying polymorphic -574GT genotype had significantly lower TIM-3 mRNA and protein levels in CD4(+) T cells, CD8(+) T cells, and monocytes than those with wild-type GG genotype. These data suggest that TIM-3 polymorphism is associated with increased susceptibility to AS possibly by downregulating gene expression. PMID:24905803

  15. 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.

  16. Identification of TIM3 2'-fluoro oligonucleotide aptamer by HT-SELEX for cancer immunotherapy.

    PubMed

    Hervas-Stubbs, Sandra; Soldevilla, Mario M; Villanueva, Helena; Mancheño, Uxua; Bendandi, Maurizio; Pastor, Fernando

    2016-01-26

    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

  17. 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.

  18. 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

  19. In-Flight Wavelength Calibration of Thermal Infrared Multispectral Scanner (TIMS) Data Acquired from the ER-2

    NASA Technical Reports Server (NTRS)

    Hook, S.; Okada, K.

    1994-01-01

    In 1991 one flightline of Thermal Infrared Multispectral Scanner (TIMS) data was acquired over Castaic Lake, California and in 1992 four flightlines of TIMS data were acquired over Death Valley, California.

  20. 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

  1. 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

  2. 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

  3. PD-1 and Tim-3 Pathways Regulate CD8+ T Cells Function in Atherosclerosis

    PubMed Central

    Qiu, Ming-Ke; Wang, Song-Cun; Dai, Yu-Xin; Wang, Shu-Qing; Ou, Jing-Min; Quan, Zhi-Wei

    2015-01-01

    T cell-mediated immunity plays a significant role in the development of atherosclerosis (AS). There is increasing evidence that CD8+ T cells are also involved in AS but their exact roles remain unclear. The inhibitory receptors programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) are well known inhibitory molecules that play a crucial role in regulating CD8+ T cell activation or tolerance. Here, we demonstrate that the co-expression of PD-1 and Tim-3 on CD8+ T cells is up-regulated in AS patients. PD-1+ Tim-3+ CD8+ T cells are enriched for within the central T (TCM) cell subset, with high proliferative activity and CD127 expression. Co-expression of PD-1 and Tim-3 on CD8+ T cells is associated with increased anti-atherogenic cytokine production as well as decreased pro-atherogenic cytokine production. Blockade of PD-1 and Tim-3 results in a decrease of anti-atherogenic cytokine production by PD-1+ Tim-3+ CD8+ T cells and in an augmentation of TNF-α and IFN-γ production. These findings highlight the important role of the PD-1 and Tim-3 pathways in regulating CD8+ T cells function in human AS. PMID:26035207

  4. A Novel Soluble Form of Tim-3 Associated with Severe Graft-versus-Host Disease

    PubMed Central

    Hansen, John A.; Hanash, Samir M.; Tabellini, Laura; Baik, Chris; Lawler, Richard L.; Grogan, Bryan M.; Storer, Barry; Chin, Alice; Johnson, Melissa; Wong, Chee-Hong; Zhang, Qing; Martin, Paul J.; McDonald, George B.

    2014-01-01

    The T cell Ig and mucin domain 3 (Tim-3) receptor has been implicated as a negative regulator of adaptive immune responses. We have utilized a proteomic strategy to identify novel proteins associated with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). Mass spectrometry analysis of plasma from subjects with mid-gut and upper-gut GVHD compared with those without GVHD identified increased levels of a protein identified with high confidence as Tim-3. A follow-up validation study using an immunoassay to measure Tim-3 levels in individual plasma samples from 127 patients demonstrated significantly higher plasma Tim-3 concentrations in patients with the more severe mid-gut GVHD, compared with those with upper-gut GVHD (P = .005), patients without GVHD (P = .002), and normal controls (P < .0001). Surface expression of Tim-3 was increased on CD8+ T cells from patients with grade 2 to 4 acute GVHD (P = .01). Mass spectrometry–based profiling of plasma from multiple subjects diagnosed with common diseases provided evidence for restricted release of soluble Tim-3 in the context of GVHD. These findings have mechanistic implications for the development of novel strategies for targeting the Tim-3 immune regulatory pathway as an approach to improving control of GVHD. PMID:23791624

  5. 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.

  6. Mitochondrial protein import: Mia40 facilitates Tim22 translocation into the inner membrane of mitochondria

    PubMed Central

    Wrobel, Lidia; Trojanowska, Agata; Sztolsztener, Malgorzata E.; Chacinska, Agnieszka

    2013-01-01

    The mitochondrial intermembrane space assembly (MIA) pathway is generally considered to be dedicated to the redox-dependent import and biogenesis of proteins localized to the intermembrane space of mitochondria. The oxidoreductase Mia40 is a central component of the pathway responsible for the transfer of disulfide bonds to intermembrane space precursor proteins, causing their oxidative folding. Here we present the first evidence that the function of Mia40 is not restricted to the transport and oxidative folding of intermembrane space proteins. We identify Tim22, a multispanning membrane protein and core component of the TIM22 translocase of inner membrane, as a protein with cysteine residues undergoing oxidation during Tim22 biogenesis. We show that Mia40 is involved in the biogenesis and complex assembly of Tim22. Tim22 forms a disulfide-bonded intermediate with Mia40 upon import into mitochondria. Of interest, Mia40 binds the Tim22 precursor also via noncovalent interactions. We propose that Mia40 not only is responsible for disulfide bond formation, but also assists the Tim22 protein in its integration into the inner membrane of mitochondria. PMID:23283984

  7. Differential requirement for the mitochondrial Hsp70-Tim44 complex in unfolding and translocation of preproteins.

    PubMed Central

    Voos, W; von Ahsen, O; Müller, H; Guiard, B; Rassow, J; Pfanner, N

    1996-01-01

    The mitochondrial heat shock protein Hsp70 is essential for import of nuclear-encoded proteins, involved in both unfolding and membrane translocation of preproteins. mtHsp70 interacts reversibly with Tim44 of the mitochondrial inner membrane, yet the role of this interaction is unknown. We analysed this role by using two yeast mutants of mtHsp70 that differentially influenced its interaction with Tim44. One mutant mtHsp70 (Ssc1-2p) efficiently bound preproteins, but did not show a detectable complex formation with Tim44; the mitochondria imported loosely folded preproteins with wild-type kinetics, yet were impaired in unfolding of preproteins. The other mutant Hsp70 (Ssc1-3p') bound both Tim44 and preproteins, but the mitochondria did not import folded polypeptides and were impaired in import of unfolded preproteins; Ssc1-3p' was defective in its ATPase domain and did not undergo a nucleotide-dependent conformational change, resulting in permanent binding to Tim44. The following conclusions are suggested. (i) The import of loosely folded polypeptides (translocase function of mtHsp70) does not depend on formation of a detectable Hsp70-Tim44 complex. Two explanations are possible: a trapping mechanism by soluble mtHsp70, or a weak/very transient interaction of Ssc1-2p with Tim44 that leads to a weak force generation sufficient for import of loosely folded, but not folded, polypeptides. (ii) Import of folded preproteins (unfoldase function of mtHsp70) involves a reversible nucleotide-dependent interaction of mtHsp70 with Tim44, including a conformational change in mtHsp70. This is consistent with a model that the dynamic interaction of mtHsp70 with Tim44 generates a pulling force on preproteins which supports unfolding during translocation. Images PMID:8654364

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

    PubMed Central

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

    2015-01-01

    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

  9. Topical immune modulation (TIM): a novel approach to the immunotherapy of systemic disease.

    PubMed

    Stricker, R B; Goldberg, B; Epstein, W L

    1997-12-01

    In this article, we present the concept of topical immune modulation, or TIM. TIM is based on the observation that skin contact sensitizing agents such as poison ivy, poison oak and dinitrochlorobenzene (DNCB) are potent stimulants of the cellular immune system that combats viruses and other pathogens. We discuss the evolution of DNCB as a therapeutic modality in the acquired immunodeficiency syndrome (AIDS) and we explore the mechanism by which DNCB directs the immune response. The potential use of topical immune modulators in autoimmune disease and vaccine development is also delineated. TIM represents a novel approach to immunotherapy that should have widespread application for immunologic diseases. PMID:9419021

  10. 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

  11. The Human Tim-Tipin Complex Interacts Directly with DNA Polymerase ϵ and Stimulates Its Synthetic Activity*

    PubMed Central

    Aria, Valentina; De Felice, Mariarita; Di Perna, Roberta; Uno, Shuji; Masai, Hisao; Syväoja, Juhani E.; van Loon, Barbara; Hübscher, Ulrich; Pisani, Francesca M.

    2013-01-01

    The Tim-Tipin complex plays an important role in the S phase checkpoint and replication fork stability in metazoans, but the molecular mechanism underlying its biological function is poorly understood. Here, we present evidence that the recombinant human Tim-Tipin complex (and Tim alone) markedly enhances the synthetic activity of DNA polymerase ϵ. In contrast, no significant effect on the synthetic ability of human DNA polymerase α and δ by Tim-Tipin was observed. Surface plasmon resonance measurements and co-immunoprecipitation experiments revealed that recombinant DNA polymerase ϵ directly interacts with either Tim or Tipin. In addition, the results of DNA band shift assays suggest that the Tim-Tipin complex (or Tim alone) is able to associate with DNA polymerase ϵ bound to a 40-/80-mer DNA ligand. Our results are discussed in view of the molecular dynamics at the human DNA replication fork. PMID:23511638

  12. Biogenesis of Tim proteins of the mitochondrial carrier import pathway: differential targeting mechanisms and crossing over with the main import pathway.

    PubMed

    Kurz, M; Martin, H; Rassow, J; Pfanner, N; Ryan, M T

    1999-07-01

    Two major routes of preprotein targeting into mitochondria are known. Preproteins carrying amino-terminal signals mainly use Tom20, the general import pore (GIP) complex and the Tim23-Tim17 complex. Preproteins with internal signals such as inner membrane carriers use Tom70, the GIP complex, and the special Tim pathway, involving small Tims of the intermembrane space and Tim22-Tim54 of the inner membrane. Little is known about the biogenesis and assembly of the Tim proteins of this carrier pathway. We report that import of the preprotein of Tim22 requires Tom20, although it uses the carrier Tim route. In contrast, the preprotein of Tim54 mainly uses Tom70, yet it follows the Tim23-Tim17 pathway. The positively charged amino-terminal region of Tim54 is required for membrane translocation but not for targeting to Tom70. In addition, we identify two novel homologues of the small Tim proteins and show that targeting of the small Tims follows a third new route where surface receptors are dispensable, yet Tom5 of the GIP complex is crucial. We conclude that the biogenesis of Tim proteins of the carrier pathway cannot be described by either one of the two major import routes, but involves new types of import pathways composed of various features of the hitherto known routes, including crossing over at the level of the GIP. PMID:10397776

  13. 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.

  14. Correction: Reversibility and two state behaviour in the thermal unfolding of oligomeric TIM barrel proteins.

    PubMed

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

    2016-04-21

    Correction for 'Reversibility and two state behaviour in the thermal unfolding of oligomeric TIM barrel proteins' by Sergio Romero-Romero et al., Phys. Chem. Chem. Phys., 2015, 17, 20699-20714. PMID:27010946

  15. Tabulating Ingestion of Mocha Solution (TIMS): a longitudinal prospective cohort study

    PubMed Central

    Staios, Gregory; Khan, Waqas U.; Chiuccariello, Lina; Sellings, Laurie H.; De Sousa, Kim; Wang, Shan; Lo, Steven; Elkader, Alexander K.

    2011-01-01

    The annual “Roll Up the Rim to Win” contest at Tim Hortons restaurants provides customers the opportunity to win prizes. This study investigated win ratios, prize types and patterns of coffee consumption. PMID:22159361

  16. Research of the Holiday kind: Tabulating Ingestion of Mocha Solution (TIMS): a longitudinal prospective cohort study.

    PubMed

    Staios, Gregory; Khan, Waqas U; Chiuccariello, Lina; Sellings, Laurie H; De Sousa, Kim; Wang, Shan; Lo, Steven; Elkader, Alexander K

    2011-12-13

    The annual "Roll Up the Rim to Win" contest at Tim Hortons restaurants provides customers the opportunity to win prizes. This study investigated win ratios, prize types and patterns of coffee consumption. PMID:22159361

  17. 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

  18. 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.

  19. DAS performance analysis

    SciTech Connect

    Bates, G.; Bodine, S.; Carroll, T.; Keller, M.

    1984-02-01

    This report begins with an overview of the Data Acquisition System (DAS), which supports several of PPPL's experimental devices. Performance measurements which were taken on DAS and the tools used to make them are then described.

  20. Stress-Regulated Translational Attenuation Adapts Mitochondrial Protein Import Through Tim17A Degradation

    PubMed Central

    Rainbolt, T. Kelly; Atanassova, Neli; Genereux, Joseph C.; Wiseman, R. Luke

    2014-01-01

    SUMMARY Stress-regulated signaling pathways protect mitochondrial proteostasis, and thus mitochondrial function, from pathologic insults. Despite the importance of stress-regulated signaling pathways in mitochondrial proteome maintenance, the molecular mechanisms by which these pathways maintain mitochondrial proteostasis remain largely unknown. Here, we identify Tim17A as a stress-regulated subunit of the Translocase of the Inner Membrane 23 (TIM23) mitochondrial protein import complex. We show that Tim17A protein levels are decreased downstream of stress-regulated translational attenuation induced by eIF2α phosphorylation through a mechanism dependent on the mitochondrial protease YME1L. Furthermore, we demonstrate that decreasing Tim17A protein levels attenuates TIM23-dependent protein import, promotes the induction of mitochondrial Unfolded Protein Response-associated proteostasis genes, and confers stress-resistance in C. elegans and mammalian cells. Thus, our results indicate that Tim17A degradation is a stress-responsive mechanism by which cells adapt mitochondrial protein import efficiency and promote mitochondrial proteostasis in response to the numerous pathologic insults that induce stress-regulated translation attenuation. PMID:24315374

  1. 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. PMID:20628202

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

    PubMed Central

    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 (χ2=18.036, P<0.001 and χ2=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. PMID:26464703

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

    PubMed Central

    Parmeggiani, Fabio; Velasco, D. Alejandro Fernandez; Höcker, Birte; Baker, David

    2015-01-01

    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 4-fold symmetrical (β/α)8-barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of sidechain-backbone hydrogen bonding for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical with 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 only sampled a subset of the sequence space available to the TIM-barrel fold. The ability to de novo design TIM-barrels opens new possibilities for custom-made enzymes. PMID:26595462

  4. 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

  5. A Terrestrial Integrated Modeling System (TIMS) at a catchment scale - implications for Earth System Modeling

    NASA Astrophysics Data System (ADS)

    Niu, G. Y.; Fang, Y.; Wu, R.; Mathias, A.; Paniconi, C.; Troch, P. A. A.; Zeng, X.; Chorover, J.; Monson, R. K.

    2014-12-01

    To enhance our predictive understandings of the interactions between the soil, plants, and air and their integrated behavior at hillslope and catchment scales, we have been developing a Terrestrial Integrated Modeling System (TIMS). TIMS aims to numerically simulate various physical and chemical processes that occur over the Earth's terrestrial surface, e.g., exchanges and flows of energy, water, carbon and other chemicals between and within the soil, plants, and air. TIMS is being compiled from existing models that have arisen from individual scientific communities, including 1) a surface energy, water, and carbon exchange scheme (NoahMP), 2) a 3-dimensional physically-based hydrological model (CATHY), 3) a reactive transport model (CrunchFlow), and 4) an individual-based vegetation dynamics model (ECOTONE). TIMS also integrates newly developed components, e.g., a microbial enzyme based soil organic carbon decomposition model and a solar radiation correction scheme accounting for the effects of terrain shading and slope angle and aspect. We will present the current state of TIMS development and some validations against measurements at various scales, the challenges for developing and evaluating such a complex modeling system, and implications for scaling-up plot-scale processes (e.g., AmeriFlux) to global-scale land surface models for use in Earth System Models (ESMs).

  6. 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

  7. Mexican Infrared-Optical New Technology Telescope: The TIM project

    NASA Astrophysics Data System (ADS)

    Salas, L.

    1998-11-01

    The scientific goals for TIM are an image quality of 0.25", consistent with the seeing at our site, optimization for the infrared as many scientific programs are going in that region of the spectrum, a M1 diameter in excess of 6.5 meters and a field of view limited to 10 arc minutes. Practical reasons, such as the limited funding available and the requirement of mexican financial agencies that the telescope should be built and installed in Mexico, lead us to decide for a segmented telescope, with a single secondary mirror, a single cassegrain focus and a light high stifness tubular structure. ALthough we are still working on the conceptual design of the telescope, there are some concepts that we are pursuing. The optical desing (M1+M2) is Ritchey-Cretien type with an hyperbolic primary 7.8 m od F/1.5 and a 0.9 m diameter f/15 secondary mirror. This will give a plate scale of 1.7 "/mm. This is 0.03 "/pix in direct mode, enough for AO goals. As for direct imaging, a factor of 5 reduction with 20 cm diam optical components would be able to produce 5' fields on a 2048, 20 microns type detector with 0.17"/pix. This implies that, with the use of auxiliary optics which is a common need for each particular instrument anyway, a wide variety of needs can be accomodated with a single secondary mirror. Choping for infrared observations would however introduce a additional cost in the secondary mirror. Alternatively the use of cold tertiary choping mirror is currently under study. The M1+M2 design currently aquires d80 of 0.17" in a 5' field without correction and 1" in a 10' field, that would require a field correcting lens. The M1 mirror will be segmented into 19 1.8 m diameter segments. There are 4 kinds of segments, the central, which we have kept to provide a reference for phasing, 6 more segments for the first ring and 12 in the outer ring, of two different kinds. The spacing between the segments is 5 mm, enough to reduce the inter-segment thermal background to half a

  8. Precise determination of strontium isotope ratios by TIMS to authenticate tomato geographical origin.

    PubMed

    Trincherini, P R; Baffi, C; Barbero, P; Pizzoglio, E; Spalla, S

    2014-02-15

    Thermal Ionisation Mass Spectrometry (TIMS) was applied to discriminate a total of 118 tomato samples (berries, "passata", tinned tomatoes, sauce, double and triple concentrate) coming from two different countries. The TIMS technique gave significantly different results for the (87)Sr/(86)Sr ratios and δ‰ values between Chinese and Italian tomato samples, irrespective of the treatment type. This technique proved to be a "robust" method, suitable for a precise discrimination of the two geographical origins. TIMS was able, within the Italian samples, to discriminate different geographical production areas, by virtue of different (87)Sr/(86)Sr ratios and δ‰ values. This technique could be employed in the field of food safety and quality, as a profitable tool for authenticating tomato geographical origin. PMID:24128488

  9. Mapping the Piute Mountains, CA with Thermal Infrared Multispectral Scanner (TIMS)

    NASA Technical Reports Server (NTRS)

    Hook, S. J.; Karlstrom, K. E.; Miller, C. F.; McCaffrey, K. J. W.

    1993-01-01

    Thermal Infrared Multispectral Scanner (TIMS) data were acquired in 1990 over the PiuteMountains, California to evaluate their usefulness for lithologic mapping in an area ofmetamorphosed, structurally complex, igneous and sedimentary rocks. The data were calibrated,atmospherically corrected, and emissivity variations extracted from them. There was an excellentvisual correlation between the units revealed in the TIMS data and the recent mapping in the easternside of the area. It was also possible to correct, improve and extend the recent map. For example,several areas of amphibolite were identified in the TIMS data that had been incorrectly mapped asgranodioritic gneiss, and the presence of a swarm of mafic dikes, of which only a few had previouslybeen identified, was revealed...

  10. 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).

  11. 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.

  12. 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

  13. Applications of TIMS data in agricultural areas and related atmospheric considerations

    NASA Technical Reports Server (NTRS)

    Pelletier, R. E.; Ochoa, M. C.

    1986-01-01

    While much of traditional remote sensing in agricultural research was limited to the visible and reflective infrared, advances in thermal infrared remote sensing technology are adding a dimension to digital image analysis of agricultural areas. The Thermal Infrared Multispectral Scanner (TIMS) an airborne sensor having six bands over the nominal 8.2 to 12.2 m range, offers the ability to calculate land surface emissivities unlike most previous singular broadband sensors. Preliminary findings on the utility of the TIMS for several agricultural applications and related atmospheric considerations are discussed.

  14. Analysis of Eocene depositional environments - Preliminary TM and TIMS results, Wind River Basin, Wyoming

    NASA Technical Reports Server (NTRS)

    Stucky, Richard K.; Krishtalka, Leonard; Redline, Andrew D.; Lang, Harold R.

    1987-01-01

    Both Landsat TM and aircraft Thermal IR Multispectral Scanner (TIMS) data have been used to map the lithofacies of the Wind River Basin's Eocene physical and biological environments. Preliminary analyses of these data have furnished maps of a fault contact boundary and a complex network of fluvial ribbon channel sandstones. The synoptic view thereby emerging for Eocene fluvial facies clarifies the relationships of ribbon channel sandstones to fossil-bearing overbank/floodplain facies and certain peleosols. The utility of TM and TIMS data is thereby demonstrated.

  15. 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.

  16. 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

  17. 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…

  18. 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.

  19. 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…

  20. 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)

  1. 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…

  2. 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…

  3. 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

  4. 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.

  5. 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. PMID:14532110

  6. Crystal structure and magnetic properties of Cu(TIM)CuBr 4: An alternating site-alternating exchange chain system

    NASA Astrophysics Data System (ADS)

    Willett, Roger D.; Gomez-Garcia, Carlos J.

    2007-09-01

    The title compound, Cu(TIM)CuBr 4 (where TIM is a macrocycle ligand) is a member of the Cu(TIM)MX 4 family, which contains linear chain structures with ⋯Cu⋯X-M-X⋯Cu⋯X-M-⋯ linkages. This chain structure defines an alternating exchange/alternating site 1d system. For M=Cu, alternating FM/AFM chains are formed with JFM>| JAFM|. Structural and magnetic data are presented, along with an analysis of the exchange pathways.

  7. 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.

  8. Instrument performance for IIP Tropospheric Infrared Mapping Spectrometers (TIMS) for vertically resolved CO

    NASA Astrophysics Data System (ADS)

    Roche, A. E.; Kumer, J. B.; Rairden, R. L.; Jamieson, T. H.; Mergenthaler, J. L.

    2008-12-01

    The NASA Earth Science Technology Office (ESTO) Instrument Incubator Program (IIP) Tropospheric Infrared Mapping Spectrometers (TIMS) have been developed to demonstrate measurement capability, when deployed in space, for multi-layer retrieval of CO from spectral measurements acquired in the solar reflective band ~ 4281 to 4301 cm-1 and in the thermal band ~ 2110 to 2165 cm-1. The presentation will describe [a] the top level designs [b] measured instrument performance parameters including spectral and spatial resolution, spectral quality and noise performance, [c] comparisons of the performance (spectral, spatial, noise) with instrument modeling and [d] calibration procedures and results for spectral registration, spectral response, flat fielding, zero level determination and radiometric. Good comparison with demonstration instrument performance and modeling gives a high level of confidence for instrument performance in the space based case. Lessons learned will be described. These are very valuable for the space deployed application. The TIMS are well suited for either LEO or GEO application.

  9. 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.

  10. TIM-3/Gal-9 interaction induces IFNγ-dependent IDO1 expression in acute myeloid leukemia blast cells.

    PubMed

    Folgiero, Valentina; Cifaldi, Loredana; Li Pira, Giuseppina; Goffredo, Bianca Maria; Vinti, Luciana; Locatelli, Franco

    2015-01-01

    NK cells expressing TIM-3 show a marked increase in IFNγ production in response to acute myeloid leukemia (AML) blast cells that endogenously express Gal-9. Herein, we demonstrate that NK cell-mediated production of IFNγ, induced by TIM-3/Gal-9 interaction and released in bone marrow microenvironment, is responsible for IDO1 expression in AML blasts. IDO1-expressing AML blasts consequently down-regulate NK cell degranulation activity, by sustaining leukemia immune escape. Furthermore, the blocking of TIM-3/Gal-9 interaction strongly down-regulates IFNγ-dependent IDO1 activity. Thus, the inhibition of TIM-3/Gal-9 immune check point, which affects NK cell-dependent IFNγ production and the consequent IDO1 activation, could usefully integrate current chemotherapeutic approaches. PMID:25886742

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine.

    PubMed

    Lee, Mi Jin; Woo, Min-Yeong; Heo, Yoo Mi; Kim, Jung Sik; Kwon, Myung-Hee; Kim, Kyongmin; Park, Sun

    2010-11-01

    T-cell immunoglobulin and mucin domain 3 (Tim3) plays an important role in the Th1-mediated immune response; however, its effect on the efficacy of tumor vaccines has not been fully evaluated. Here, we demonstrate the effect of Tim3 pathway inhibition on tumor growth in mice. Lewis lung carcinoma (3LL) cells expressing a Tim3 pathway inhibitor, when injected into mice, showed suppressed tumor growth and a reduced frequency of CD4(+)CD25(+)Foxp3(+) T-cells. Furthermore, Tim3 pathway inhibition significantly enhanced the efficacy of a prophylactic tumor vaccine and marginally enhanced the efficacy of a therapeutic tumor vaccine. However, when given in combination with the chemotherapeutic agent, 5-fluorouracil, the therapeutic tumor vaccine capable of Tim3 pathway inhibition had no additional anti-tumor effect. Our results show that Tim3 pathway inhibition can enhance tumor vaccine efficacy. PMID:20920468

  17. Synergistic effect of Tim4 and MFG-E8 null mutations on the development of autoimmunity.

    PubMed

    Miyanishi, Masanori; Segawa, Katsumori; Nagata, Shigekazu

    2012-09-01

    Phagocytes, including macrophages, recognize phosphatidylserine exposed on apoptotic cells as an "eat me" signal. Milk Fat Globule EGF Factor VIII (MFG-E8) is secreted by one subset of macrophages, whereas Tim4, a type I membrane protein, is expressed by another. These proteins bind tightly to phosphatidylserine on apoptotic cells and enhance their engulfment by macrophages. To study the contribution of these proteins to the engulfment of apoptotic cells, we established a mouse line that was deficient in the genes encoding MFG-E8 and Tim4. The null mutation of Tim4 impaired the ability of resident peritoneal macrophages, but not thioglycollate-elicited macrophages, to engulf apoptotic cells. Mice deficient in either MFG-E8 or Tim4 on the C57BL/6 background developed hardly any autoantibodies, but aged female mice deficient in both MFG-E8 and Tim4 developed autoantibodies in an age-dependent manner. Tumour necrosis factor (TNF) α is known to protect against systemic lupus erythematosus-type autoimmunity, whereas type I IFN accelerates the disease. Indeed, the administration of an anti-TNFα antibody or a reagent that stimulates the IFN-α production [2,6,10,14-tetramethylpentadecane (TMPD; also known as pristane)] enhanced the production of autoantibodies in the MFG-E8- and Tim4-double-deficient mice. These results suggest that the double deficiency of Tim4 and MFG-E8, phosphatidylserine-binding proteins, can trigger autoimmunity and that TNFα and type I IFN regulate reciprocally the development of autoimmune disease. PMID:22723547

  18. 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.

  19. 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.

  20. 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

  1. Advanced atmospheric measurements demonstrated by the 2.33 µm IIP Tropospheric Infrared Mapping Spectrometers (TIMS)

    NASA Astrophysics Data System (ADS)

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

    2010-12-01

    Introduction: 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 near 2.33 µm and 4.68 µm were developed for this demonstration. The project was completed in Dec. 2008. It was possible to scale ground based measurements to show that the design would support a measurement from geostationary orbit of CO that would satisfy all the CO measurements requirements as listed for the Decadal Survey National Research Council Report for the Geostationary Coastal and Air Pollution Events (GEO-CAPE) Mission. This includes better than 10% total column precision, vertical retrieval in 3 or more independent layers, on contiguous coverage from 45S to 50N on the American Continents and coasts, with footprints < 7 km on a side, and with one hour revisit time. The measurements also indicated this design would collaterally provide measurement of total CH4 column of about 1% precision, O3 with vertical resolution of the troposphere and H2O profile with unprecedented vertical resolution in the lower troposphere. Advanced 2.33 µm TIMS measurements: The shortfall at the end of the project was that the demonstrated data were obtained from the ground, and in the community there was perceived a need to acquire air borne nadir looking measurements in order to reinforce the predictions for the GEO-CAPE application. Since the end of the project we have had some internal support towards this goal for at least one of the TIMS, the 2.33 µm unit. As a first small step we have recently obtained ground based data looking at the moon that illustrate not only the retrieval of earth atmospheric CO, CH4 and H2O, but also the spatial variation of lunar albedo. This latter measurement improves on the original IIP ground based demonstrations. The next nearly ultimate step is to acquire data in the nadir viewing mode from an air craft. Significant effort

  2. 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.

  3. 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

  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. 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

  7. 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.

  8. 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.

  9. [Changes of Tim-3 and PD-1 on peripheral blood monocyte subsets in patients with chronic hepatitis C].

    PubMed

    Liang, Yan; Zhang, Peixin; Yi, Wenjing; Zhou, Yun; Jia, Zhansheng; Zhang, Ying

    2016-05-01

    Objective To investigate the distribution of peripheral blood monocyte subsets of chronic hepatitis C (CHC) patients and observe the expression of negative regulators T cell immunoglobulin and mucin domain-3 (Tim-3) and programmed cell death-1 (PD-1) on the monocyte subsets. Methods Flow cytometry was employed to determine the distribution of three monocyte subsets as well as Tim-3 and PD-1 expression on the three monocyte subsets. Their correlations with the clinical parameters were analyzed by Spearman test. Results Compared with healthy controls, an increased distribution of CD14(+)CD16(+) monocytes, especially CD14(++)CD16(+) monocyte subset, was observed in CHC patients. Tim-3 expression was significantly elevated on CD14(++)CD16(-) and CD14(+)CD16(++) subsets in CHC patients. Obviously increased PD-1 expression was found mainly on CD14(++)CD16(-) and CD14(++)CD16(+) subsets. There were no significant correlations between monocyte subsets, PD-1, Tim-3 and the clinical parameters. Conclusion The levels Tim-3 and PD-1 are different in three monocyte subsets. PMID:27126947

  10. 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.

  11. 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.

  12. analysis of data from upgraded 2.33 micron TIMS: Example of GEO-CAPE application

    NASA Astrophysics Data System (ADS)

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

    2011-12-01

    The Tropospheric Infrared Mapping Spectrometers (TIMS) were originally developed with support from the NASA ESTO Instrument Incubator program (IIP). These were developed 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 internal supported development including but not limited to; (a) deployment of the 2.33 unit on an airship that further developed the case for GEO-CAPE application(see HISE 2011 reference below), and (B) a recent upgrade in the 2.33 micron TIMS performance. In this presentation we describe the upgrade and preliminary data (improved spectral resolution). We describe a retrieval procedure that starts with a trial model that is considerably different than the "truth" atmosphere for which the data were acquired, and modifies the trial model to produce a best fit to the data. The result is a best estimate retrieval of the CO, CH4 and H2O columns. Differences in the trial model temperature vs the truth are accounted for. HISE 2011 reference, click on http://www.opticsinfobase.org/abstract.cfm?URI=HISE-2011-HTuD2 and then click on "View Full Text" .

  13. Application of circuit simulation method for differential modeling of TIM-2 iron uptake and metabolism in mouse kidney cells.

    PubMed

    Xie, Zhijian; Harrison, Scott H; Torti, Suzy V; Torti, Frank M; Han, Jian

    2013-01-01

    Circuit simulation is a powerful methodology to generate differential mathematical models. Due to its highly accurate modeling capability, circuit simulation can be used to investigate interactions between the parts and processes of a cellular system. Circuit simulation has become a core technology for the field of electrical engineering, but its application in biology has not yet been fully realized. As a case study for evaluating the more advanced features of a circuit simulation tool called Advanced Design System (ADS), we collected and modeled laboratory data for iron metabolism in mouse kidney cells for a H ferritin (HFt) receptor, T cell immunoglobulin and mucin domain-2 (TIM-2). The internal controlling parameters of TIM-2 associated iron metabolism were extracted and the ratios of iron movement among cellular compartments were quantified by ADS. The differential model processed by circuit simulation demonstrated a capability to identify variables and predict outcomes that could not be readily measured by in vitro experiments. For example, an initial rate of uptake of iron-loaded HFt (Fe-HFt) was 2.17 pmol per million cells. TIM-2 binding probability with Fe-HFt was 16.6%. An average of 8.5 min was required for the complex of TIM-2 and Fe-HFt to form an endosome. The endosome containing HFt lasted roughly 2 h. At the end of endocytosis, about 28% HFt remained intact and the rest was degraded. Iron released from degraded HFt was in the labile iron pool (LIP) and stimulated the generation of endogenous HFt for new storage. Both experimental data and the model showed that TIM-2 was not involved in the process of iron export. The extracted internal controlling parameters successfully captured the complexity of TIM-2 pathway and the use of circuit simulation-based modeling across a wider range of cellular systems is the next step for validating the significance and utility of this method. PMID:23761763

  14. TIM-3 Rs10515746 (A/C) and Rs10053538 (C/A) Gene Polymorphisms and Risk of Multiple Sclerosis

    PubMed Central

    YAGHOOBI, Esmat; ABEDIAN, Saeed; BABANI, Omid; IZAD, Maryam

    2016-01-01

    Background: Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) caused by auto-reactive T cells against myelin antigens. T-cell immunoglobulin mucin -3 (TIM-3) is a negative regulator glycoprotein expressed by a range of immune cells, including, Th1 cells, activated CD8+ T cells and in a lower level on Th17 cells. A defect in TIM-3 regulation has been shown in multiple sclerosis patients. In humans, several single nucleotide polymorphisms (SNPs) have been identified in the TIM-3 gene and are associated with inflammatory diseases. The aim of this study was to analyze the association between TIM-3 -574A>C and -1516 C>A SNPs in the promoter region, and susceptibility to MS. Methods: DNA samples from 102 patients and 102 healthy controls were genotyped using RFLP-PCR method. Results: In this case-control study, analysis of the alleles and genotypes revealed a significant higher frequency of C/C and lower frequency of A/C genotypes for -574 locus of TIM-3 gene in MS patients (P=0.0002). We also found that C/C genotype for locus of -1516 increased in MS patients, while A/C genotype decreased (P=0.012). Allele C of -574C/C and -1516 C>A SNPs were also more frequent in MS patients (P=0.036 and 0.0027 respectively). Conclusion: -574 A>C and -1516 C>A SNPs in the promoter region of TIM3 gene may affect the disease susceptibility. PMID:27398337

  15. Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

    PubMed Central

    Ju, Ying; Hou, Nan; Zhang, Xiaoning; Zhao, Di; Liu, Ying; Wang, Jinjin; Luan, Fang; Shi, Wei; Zhu, Faliang; Sun, Wensheng; Zhang, Lining; Gao, Chengjiang; Gao, Lifen; Liang, Xiaohong; Ma, Chunhong

    2009-01-01

    T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been reported to participate in the pathogenesis of inflammatory diseases. However, whether Tim-3 is involved in hepatitis B virus (HBV) infection remains unknown. Here, we studied the expression and function of Tim-3 in a hydrodynamics-based mouse model of HBV infection. A significant increase of Tim-3 expression on hepatic T lymphocytes, especially on CD8+ T cells, was demonstrated in HBV model mice from day 7 to day 18. After Tim-3 knockdown by specific shRNAs, significantly increased IFN-γ production from hepatic CD8+ T cells in HBV model mice was observed. Very interestingly, we found Tim-3 expression on CD8+ T cells was higher in HBV model mice with higher serum anti-HBs production. Moreover, Tim-3 knockdown influenced anti-HBs production in vivo. Collectively, our data suggested that Tim-3 might act as a potent regulator of antiviral T-cell responses in HBV infection. PMID:19254478

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

    PubMed Central

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

    2015-01-01

    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 multi-organ 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 (Tr1) cells) and enhance the severity of experimental autoimmune encephalomyelitis (EAE). 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 AC reduces EAE severity in wildtype (WT) 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. PMID:25582854

  17. 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

  18. 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

  19. Galectin-9 Signaling through TIM-3 Is Involved in Neutrophil-Mediated Gram-Negative Bacterial Killing: An Effect Abrogated within the Cystic Fibrosis Lung

    PubMed Central

    Vega-Carrascal, Isabel; Bergin, David A.; McElvaney, Oliver J.; McCarthy, Cormac; Banville, Nessa; Pohl, Kerstin; Hirashima, Mitsuomi; Kuchroo, Vijay K.; Reeves, Emer P.; McElvaney, Noel G.

    2016-01-01

    The T cell Ig and mucin domain–containing molecule (TIM) family of receptors have emerged as potential therapeutic targets to correct abnormal immune function in chronic inflammatory conditions. TIM-3 serves as a functional receptor in structural cells of the airways and via the ligand galectin-9 (Gal-9) can modulate the inflammatory response. The aim of this study was to investigate TIM-3 expression and function in neutrophils, focusing on its potential role in cystic fibrosis (CF) lung disease. Results revealed that TIM-3 mRNA and protein expression values of circulating neutrophils were equal between healthy controls (n = 20) and people with CF (n = 26). TIM-3 was detected on resting neutrophil membranes by FACS analysis, and expression levels significantly increased post IL-8 or TNF-α exposure (p < 0.05). Our data suggest a novel role for TIM-3/Gal-9 signaling involving modulation of cytosolic calcium levels. Via TIM-3 interaction, Gal-9 induced neutrophil degranulation and primed the cell for enhanced NADPH oxidase activity. Killing of Pseudomonas aeruginosa was significantly increased upon bacterial opsonization with Gal-9 (p < 0.05), an effect abrogated by blockade of TIM-3 receptors. This mechanism appeared to be Gram-negative bacteria specific and mediated via Gal-9/ LPS binding. Additionally, we have demonstrated that neutrophil TIM-3/Gal-9 signaling is perturbed in the CF airways due to proteolytic degradation of the receptor. In conclusion, results suggest a novel neutrophil defect potentially contributing to the defective bacterial clearance observed in the CF airways and suggest that manipulation of the TIM-3 signaling pathway may be of therapeutic value in CF, preferably in conjunction with antiprotease treatment. PMID:24477913

  20. 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…

  1. Tim-3-Galectin-9 pathway involves the suppression induced by CD4+CD25+ regulatory T cells.

    PubMed

    Wang, Feng; Wan, Lagen; Zhang, Caicheng; Zheng, Xiaofeng; Li, Junming; Chen, Zhonghua Klaus

    2009-01-01

    CD4(+)CD25(+) regulatory T cells (Tregs) are considered to play a key role as suppressors of immune-mediated reactions. The mechanisms of this suppression in animals and patients with autoimmune, allergic or oncogenic diseases have been investigated under various conditions. However, the precise mode of suppression by CD4(+)CD25(+) Tregs is still not clear. In this report, Tim-3-Galectin-9 pathway was explored as one of the mechanisms for the suppression and cytotoxicity induced by Tregs. Here, we demonstrated that Galectin-9 was expressed on CD4(+)CD25(+) Tregs by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Interestingly, blocking Tim-3-Galectin-9 pathway resulted in an obvious decreased suppression activity of Tregs and enhanced Th1 cytokine level in vitro. Furthermore, blocking Tim-3-Galectin-9 pathway negated prolonged survival of allogeneic skin grafts induced by CD4(+)CD25(+) Tregs in vivo. Our results suggest that Tim-3-Galectin-9 pathway involves the function of CD4(+)CD25(+) Tregs. PMID:19362679

  2. Comparison of TSI from SORCE TIM with SFO Ground-Based Photometry

    NASA Astrophysics Data System (ADS)

    Chapman, G. A.; Cookson, A. M.; Preminger, D. G.

    2012-02-01

    Total solar irradiance (TSI) measurements have been available from the TIM instrument on the SORCE spacecraft since 2003. We compare TSI data, both 24-h and 6-h averages, with photometric indices from red and K-line images obtained on a daily basis at the San Fernando Observatory (SFO). For 1253 days of data from 2 March 2003 to 5 May 2010 we compare the data in linear multiple regression analyses. The best results come from using two photometric indices, the red and K-line photometric sums, and SORCE TSI 6-h averages interpolated to the SFO time of observation. For this case, we obtain a coefficient of multiple determination, R 2, of 0.9495 and a quiet-Sun irradiance S 0 = 1360.810 ± 0.004 W m-2. These results provide further support for the hypothesis that the quiet Sun is constant over time.

  3. 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.

  4. 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.

  5. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.

    PubMed

    Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K

    2016-05-17

    Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors, although they belong to the same class of receptors as PD-1 and CTLA-4, exhibit unique functions, especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic. PMID:27192565

  6. Interpretation of TIMS imagery using laboratory thermal emission spectroscopy: Application to geological mapping

    SciTech Connect

    Ruff, S.W.

    1996-11-01

    A portion of the southern Granite Wash Mountains in west-central Arizona has been mapped with the benefit of image data from the Thermal Infrared Multi-spectral Scanner and laboratory spectroscopy. Data from the TIMS instrument have provided a dramatic view of the well exposed Paleozoic section. One of the units within the section, the Supai Formation, displays significant color heterogeneity in the image. Examination in the field did not identify all of the minerals responsible for the various colors. A suite of rock samples from the area was examined in the lab using high spectral resolution thermal emission spectroscopy. The results establish the identity of the minerals and their relationship to image colors, thus demonstrating the power of combining laboratory analysis with remote sensing. 3 refs., 6 figs.

  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. 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

  9. 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

  10. 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.

  11. 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

  12. 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.

  13. 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; Perna, Roberta Di; 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. PMID:26503245

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

    PubMed Central

    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

  15. The relevance of Tim-3 polymorphisms and F protein to the outcomes of HCV infection.

    PubMed

    Pei, J P; Jiang, L F; Ji, X W; Xiao, W; Deng, X Z; Zhou, Z X; Zhu, D Y; Ding, W L; Zhang, J H; Wang, C J; Jing, K

    2016-08-01

    Hepatitis C virus (HCV) is one of the major causes of liver inflammation. The aim of this study was to investigate the associations of T-cell immunoglobulin and mucin domain-3 (Tim-3) polymorphisms and the alternate reading frame protein (F protein) with the outcomes of HCV infection. Three single-nucleotide polymorphisms (SNPs; rs10053538, rs12186731, and rs13170556) of Tim-3 were genotyped in this study, which included 203 healthy controls, 558 hepatitis C anti-F-positive patients, and 163 hepatitis C anti-F-negative patients. The results revealed that the rs12186731 CT and rs13170556 TC and CC genotypes were significantly less frequent in the anti-F-positive patients [odds ratio (OR) = 0.54, 95 % confidence interval (CI) = 0.35-0.83, p = 0.005; OR = 0.26, 95 % CI = 0.18-0.39, p < 0.001; and OR = 0.19, 95 % CI = 0.10-0.35, p < 0.001, respectively), and the rs13170556 TC genotype was more frequent in the chronic HCV (CHC) patients (OR = 1.70, 95 % CI = 1.20-2.40, p = 0.002). The combined analysis of the rs12186731 CT and rs13170556 TC/CC genotypes revealed a locus-dosage protective effect in the anti-F-positive patients (OR = 0.22, 95 % CI = 0.14-0.33, p trend < 0.001). Stratified analyses revealed that the frequencies of the rs12186731 (CT + TT) genotypes were significantly lower in the older (OR = 0.31, 95 % CI = 0.15-0.65, p = 0.002) and female (OR = 0.30, 95 % CI = 0.17-0.52, p < 0.001) subgroups, and rs13170556 (TC + CC) genotypes exhibited the same effect in all subgroups (all p < 0.001) in the anti-F antibody generations. Moreover, the rs13170556 (TC + CC) genotypes were significantly more frequent in the younger (OR = 1.86, 95 % CI = 1.18-2.94, p = 0.007) and female (OR = 2.38, 95 % CI = 1.48-3.83, p < 0.001) subgroups of CHC patients. These findings suggest that the rs12186731 CT and rs13170556 TC/CC genotypes of Tim-3

  16. 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

  17. 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

  18. 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

  19. 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.

  20. A novel import route for an N-anchor mitochondrial outer membrane protein aided by the TIM23 complex.

    PubMed

    Song, Jiyao; Tamura, Yasushi; Yoshihisa, Tohru; Endo, Toshiya

    2014-06-01

    The membrane topology of Om45 in the yeast mitochondrial outer membrane (OM) is under debate. Here, we confirm that Om45 is anchored to the OM from the intermembrane space (IMS) by its N-terminal hydrophobic segment. We show that import of Om45 requires the presequence receptors, Tom20 and Tom22, and the import channel of Tom40. Unlike any of the known OM proteins, Om45 import requires the TIM23 complex in the inner membrane, a translocator for presequence-containing proteins, and the membrane potential (ΔΨ). Therefore, Om45 is anchored to the OM via the IMS by a novel import pathway involving the TIM23 complex. PMID:24781694

  1. 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.

  2. The use of aircraft-based Thermal Infrared Multispectral Scanner (TIMS) data to measure surface energy budgets on a landscape scale

    NASA Technical Reports Server (NTRS)

    Luvall, Jeffrey C.

    1991-01-01

    A series of Thermal Infrared Multispectral Scanner Data (TIMS) was collected over the H. J. Andrews experimental forest in western Oregon and at the Coweeta Hydrologic Laboratory in North Carolina. Flight lines were overlapped with an 8 to 28 minute time difference between flight lines. Concurrent radiosonde measurements of atmospheric profiles of air and dew point temperatures provided inputs to LOWTRAN6 for atmospheric radiance corrections of the TIMS data. Surface temperature differences over time between flight lines allowed the development of thermal response numbers (TRN) which characterized the thermal response of the different surface types. The polygons containing mostly soil and bare rock had the lowest TRN whereas the forested polygons were the highest. Results indicate that forest canopy temperatures measured by the TIMS are comparable to needle thermocouples temperatures. ET models developed from the TIMS data obtained similar ET rates as those using energy balance techniques.

  3. Effects of inhomogeneity on triglyceride digestion of emulsions using an in vitro digestion model (Tiny TIM).

    PubMed

    Oosterveld, Alexander; Minekus, Mans; Bomhof, Esther; Zoet, Franklin D; van Aken, George A

    2016-07-13

    The colloidal behaviour and extent of lipolysis of various emulsions stabilized by whey protein and Tween were studied using the TNO Intestinal Model (TIM) extended with a purposely designed gastric compartment. The in vitro results suggest that creaming of a fatty layer in the gastric region causes a delay in fat entering the small intestinal region, delays and reduces the free fatty acid content in the small intestinal lumen and delays fat absorption. It was shown that controlling the pH with pig gastric juice instead of simulated gastric juice delayed creaming of the emulsions significantly, which resulted in faster gastric lipolysis. However, because the digestive conditions are not adjusted by physiological regulation mechanisms such as the regulation of gastric emptying by the detection of nutrients in the small intestine, care must be taken to translate these results to the in vivo reality. It is expected that the differences between the systems will be tempered by the physiological feedback regulation mechanisms of digestion. PMID:27264678

  4. Cockroach allergen Bla g 7 promotes TIM4 expression in dendritic cells leading to Th2 polarization.

    PubMed

    Xu, Lingxiao; Zhang, Miaojia; Ma, Wenjing; Jin, Shanshan; Song, Weijuan; He, Shaoheng

    2013-01-01

    As one of the most common sources of indoor aeroallergens worldwide, cockroach is important in causing rhinitis and asthma while the mechanisms underlying remain obscure. Since T helper (Th) type 2 polarization plays an important role in the pathogenesis of allergic diseases, we investigated the effect of Bla g 7, a pan-allergen from Blattella germanica (B. germanica), on Th polarization which is controlled by monocyte-derived dendritic cells (DCs). Challenged by recombinant Bla g 7 (rBla g 7), immature DCs obtained from human exhibited upregulated levels of TIM4, CD80, and CD86 and increased IL-13 secretion. Cocultured with CD4+ T cells, challenged DCs increased the ratio of IL-4+ versus IFN-γ+ of CD4+ T cells, suggesting a balance shift from Th1 to Th2. Moreover, antibodies against TIM4, CD80, and CD86 reversed the enhancement of IL-4+/IFN-γ+ ratio and alleviated the IL-13 release induced by rBla g 7, indicating that the Th2 polarization provoked by rBla g 7 challenged DCs is via TIM4-, CD80-, and CD86-dependent mechanisms. In conclusion, the present findings implied a crucial role of Bla g 7 in the development of cockroach allergy and highlighted an involvement of DCs-induced Th2 polarization in cockroach allergy. PMID:24204099

  5. GroEL/ES Chaperonin Modulates the Mechanism and Accelerates the Rate of TIM-Barrel Domain Folding

    PubMed Central

    Bracher, Andreas; Engen, John R.; Hayer-Hartl, Manajit; Hartl, F. Ulrich

    2014-01-01

    SUMMARY 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 time-scale, avoiding aggregation or degradation. PMID:24813614

  6. 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.

  7. Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells.

    PubMed

    Dardalhon, Valerie; Anderson, Ana C; Karman, Jozsef; Apetoh, Lionel; Chandwaskar, Rucha; Lee, David H; Cornejo, Melanie; Nishi, Nozomu; Yamauchi, Akira; Quintana, Francisco J; Sobel, Raymond A; Hirashima, Mitsuomi; Kuchroo, Vijay K

    2010-08-01

    IFN-gamma plays a central role in antitumor immunity. T cell Ig and mucin domain (Tim-3) is expressed on IFN-gamma-producing Th1 cells; on interaction with its ligand, galectin-9, Th1 immunity is terminated. In this study, we show that transgenic overexpression of Tim-3 on T cells results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses. Molecular characterization of CD11b(+)Ly-6G(+) cells reveals a phenotype consistent with granulocytic myeloid-derived suppressor cells. Accordingly, we find that modulation of the Tim-3/galectin-9 (Gal-9) pathway impacts on tumor growth. Similarly, overexpression of Tim-3 ligand, Gal-9, results in an increase in CD11b(+)Ly-6G(+) cells and inhibition of immune responses. Loss of Tim-3 restores normal levels of CD11b(+)Ly-6G(+) cells and normal immune responses in Gal-9 transgenic mice. Our data uncover a novel mechanism by which the Tim-3/Gal-9 pathway regulates immune responses and identifies this pathway as a therapeutic target in diseases where myeloid-derived suppressor cells are disadvantageous. PMID:20574007

  8. 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

  9. Uranium and Calcium Isotope Ratio Measurements using the Modified Total Evaporation Method in TIMS

    NASA Astrophysics Data System (ADS)

    Richter, S.; Kuehn, H.; Berglund, M.; Hennessy, C.

    2010-12-01

    A new version of the "modified total evaporation" (MTE) method for isotopic analysis by multi-collector thermal ionization mass spectrometry (TIMS), with high analytical performance and designed in a more user-friendly and routinely applicable way, is described in detail. It is mainly being used for nuclear safeguards measurements of U and Pu and nuclear metrology, but can readily be applied to other scientific tasks in geochemistry, e.g. for Sr, Nd and Ca, as well. The development of the MTE method was organized in collaboration of several "key nuclear mass spectrometry laboratories", namely the New Brunswick Laboratory (NBL), the Institute for Transuranium Elements (ITU), the Safeguards Analytical Laboratory (now Safeguards Analytical Services, SGAS) of the International Atomic Energy Agency (IAEA) and the Institute for Reference Materials and Measurements (IRMM), with IRMM taking the leading role. The manufacturer of the TRITON TIMS instrument, Thermo Fisher Scientific, integrated this method into the software of the instrument. The development has now reached its goal to become a user-friendly and routinely useable method for uranium isotope ratio measurements with high precision and accuracy. Due to the use of the “total evaporation” (TE) method the measurement of the "major" uranium isotope ratio 235U/238U is routinely being performed with a precision of 0.01% to 0.02%. The use of a (certified) reference material measured under comparable conditions is emphasized to achieve an accuracy at a level of 0.02% - depending on the stated uncertainty of the certified value of the reference material. In contrast to the total evaporation method (TE), in the MTE method the total evaporation sequence is interrupted on a regular basis to allow for correction for background from peak tailing, internal calibration of a secondary electron multiplier (SEM) detector versus the Faraday cups, and ion source re-focusing. Therefore, the most significant improvement using the

  10. 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.

  11. Roles of PD-1, Tim-3 and CTLA-4 in immunoregulation in regulatory T cells among patients with sepsis

    PubMed Central

    Gao, Dong-Na; Yang, Zhi-Xiang; Qi, Qing-Hui

    2015-01-01

    Objective: This study aims to elucidate the roles of PD-1, Tim-3 and CTLA-4 in sepsis. Methods: Sepsis patients (n = 182) were selected as sepsis group and divided into three subgroups: mild sepsis group, severe sepsis group and septic shock group; 185 healthy volunteers were enrolled as control group. Flow cytometry and blood routine examination were performed for T lymphocytes and surface co-stimulatory molecules expressions. Pearson correlation test was applied for the correlation of co-stimulatory molecules expressions on T lymphocytes with critical illness in sepsis. Logistic regression analysis was conducted for risk factors in sepsis. Results: Heart rate and WBC in subgroups were higher than control group (P < 0.05). The differences in APACHE II, SAP II and SOFA score among subgroups were statistically significant (P < 0.05). Compared with control group, lymphocyte ratio and percentage of CD4+ T cells reduced in subgroups (P < 0.05). The differences in expression levels of CD4+PD-1+, CD8+PD-1+, and CD8+CTLA-4+ showed statistical significances (P < 0.05). Apparently, expression levels of CD4+TIM-3+, CD8+TIM-3+, CD4+PD-1+, CD8+PD-1+, and CD4+CTLA-4+ were positively correlated with APACHE II score (all P < 0.05). Logistic regression analysis showed that heart rate and expression level of CD4+PD-1+ might be risk factors while the percentage of CD4+ T cells might be a protective factor for sepsis (P < 0.05). Conclusion: PD-1 aggravates immune responses consistent with promotion of T cell exhaustion in sepsis. Expression level of CD4+PD-1+ and heart rate are potential risk factors while percentage of CD4+ T cells is a possible protective factor for sepsis. PMID:26770525

  12. Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer

    PubMed Central

    2013-01-01

    Background T-cell immunoglobulin and mucin domain 3 (TIM-3) is known as a negative immune regulator and emerging data have implicated TIM-3 a pivotal role in suppressing antitumor immunity. The co-stimulatory receptor CD137 is transiently upregulated on T-cells following activation and increases their proliferation and survival when engaged. Although antagonistic anti-TIM-3 or agonistic anti-CD137 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In this study, we sought to evaluate whether combined TIM-3 blockade and CD137 activation would significantly improve the immunotherapy in the murine ID8 ovarian cancer model. Methods Mice with established ID8 tumor were intraperitoneally injected with single or combined anti-TIM-3/CD137 monoclonal antibody (mAb); mice survival was recorded, the composition and gene expression of tumor-infiltrating immune cells in these mice was analyzed by flow cytometry and quantitative RT-PCR respectively, and the function of CD8+ cells was evaluated by ELISA and cytotoxicity assay. Results Either anti-TIM-3 or CD137 mAb alone, although effective in 3 days established tumor, was unable to prevent tumor progression in mice bearing 10 days established tumor, however, combined anti-TIM-3/CD137 mAb significantly inhibited the growth of these tumors with 60% of mice tumor free 90 days after tumor inoculation. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4+ cells and CD8+ cells. The 2 mAb combination increased CD4+ and CD8+ cells and decreased immunosuppressive CD4+FoxP3+ regulatory T (Treg) cells and CD11b+Gr-1+ myeloid suppressor cells (MDSC) at tumor sites, giving rise to significantly elevated ratios of CD4+ and CD8+ cells to Treg and MDSC; This is consistent with biasing local immune response towards an immunostimulatory Th1 type and is further supported by quantitative RT-PCR data

  13. 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

  14. 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

  15. 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

  16. 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

  17. Comparison of Total Evaporation (TE) and Direct Total Evaporation (DTE) methods in TIMS by using NBL CRMs

    NASA Astrophysics Data System (ADS)

    Hasözbek, Altug; Mathew, Kattathu; Wegener, Michael

    2013-04-01

    The total evaporation (TE) is a well-established analytical method for safeguards measurement of uranium and plutonium isotope-amount ratios using the thermal ionization mass spectrometry (TIMS). High accuracy and precision isotopic measurements find many applications in nuclear safeguards, for e.g. assay measurements using isotope dilution mass spectrometry. To achieve high accuracy and precision in TIMS measurements, mass dependent fractionation effects are minimized by either the measurement technique or changes in the hardware components that are used to control sample heating and evaporation process. At NBL, direct total evaporation (DTE) method on the modified MAT261 instrument, uses the data system to read the ion signal intensity and its difference from a pre-determined target intensity, is used to control the incremental step at which the evaporation filament is heated. The feedback and control is achieved by proprietary hardware from SPECTROMAT that uses an analog regulator in the filament power supply with direct feedback of the detector intensity. Compared to traditional TE method on this instrument, DTE provides better precision (relative standard deviation, expressed as a percent) and accuracy (relative difference, expressed as a percent) of 0.05 to 0.08 % for low enriched and high enriched NBL uranium certified reference materials.

  18. Isotope ratio measurements of pg-size plutonium samples using TIMS in combination with "multiple ion counting" and filament carburization

    NASA Astrophysics Data System (ADS)

    Jakopic, Rozle; Richter, Stephan; Kühn, Heinz; Benedik, Ljudmila; Pihlar, Boris; Aregbe, Yetunde

    2009-01-01

    A sample preparation procedure for isotopic measurements using thermal ionization mass spectrometry (TIMS) was developed which employs the technique of carburization of rhenium filaments. Carburized filaments were prepared in a special vacuum chamber in which the filaments were exposed to benzene vapour as a carbon supply and carburized electrothermally. To find the optimal conditions for the carburization and isotopic measurements using TIMS, the influence of various parameters such as benzene pressure, carburization current and the exposure time were tested. As a result, carburization of the filaments improved the overall efficiency by one order of magnitude. Additionally, a new "multi-dynamic" measurement technique was developed for Pu isotope ratio measurements using a "multiple ion counting" (MIC) system. This technique was combined with filament carburization and applied to the NBL-137 isotopic standard and samples of the NUSIMEP 5 inter-laboratory comparison campaign, which included certified plutonium materials at the ppt-level. The multi-dynamic measurement technique for plutonium, in combination with filament carburization, has been shown to significantly improve the precision and accuracy for isotopic analysis of environmental samples with low-levels of plutonium.

  19. Kinetic Intermediates of Holo- and Apo-Myoglobin Studied Using HDX-TIMS-MS and Molecular Dynamic Simulations

    NASA Astrophysics Data System (ADS)

    Schenk, Emily R.; Almeida, Raybel; Miksovska, Jaroslava; Ridgeway, Mark E.; Park, Melvin A.; Fernandez-Lima, Francisco

    2015-04-01

    In the present work, the kinetic intermediates of holo- and apo-myoglobin were studied by correlating the ion-neutral collision cross section and time resolved H/D back exchange rate simultaneously in a trapped ion mobility spectrometer coupled to a mass spectrometer (HDX-TIMS-MS). The high mobility resolution of the TIMS cell permitted the observation of multiple IMS bands and complementary molecular dynamics simulations resulted in the assignment of candidate structures for each experimental condition studied (e.g., holo [M + 8H]+8-[M + 9H]+9 and apo [M + 9H]+9-[M + 19H]+19). Inspection of the kinetic intermediates suggests that the tertiary structure of apomyoglobin unfolds quickly upon the loss of the Fe protoporphyrin IX that stabilizes the interactions between the A, G, and H helices. In the absence of the porphyrin heme, the apomyoglobin unfolds to Xn kinetic intermediates that vary in the extent of unfolding as a result of the observed charge state.

  20. Kinetic Intermediates of Holo- and Apo-Myoglobin Studied Using HDX-TIMS-MS and Molecular Dynamic Simulations

    PubMed Central

    Schenk, Emily R.; Almeida, Raybel; Miksovska, Jaroslava; Ridgeway, Mark E.; Park, Melvin A.; Fernandez-Lima, Francisco

    2015-01-01

    In the present work, the kinetic intermediates of holo- and apomyoglobin were studied by correlating the ion-neutral collision cross section and time resolved H/D back exchange rate simultaneously in a trapped ion mobility spectrometer coupled to a mass spectrometer (HDX-TIMS-MS). The high mobility resolution of the TIMS cell permitted the observation of multiple IMS bands and complementary molecular dynamics simulations resulted in the assignment of candidate structures for each experimental condition studied (e.g., holo [M+8H]+8–[M+9H]+9 and apo [M+9H]+9–[M+19H]+19). Inspection of the kinetic intermediates suggests that the tertiary structure of apomyoglobin unfolds quickly upon the loss of the Fe protoporphyrin IX that stabilizes the interactions between the A, G, and H helices. In the absence of the porphyrin heme, the apomyoglobin unfolds to Xn kinetic intermediates that vary in the extent of unfolding as a result of the observed charge state. PMID:25690175

  1. 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.

  2. Galectin-9 suppresses Th17 cell development in an IL-2-dependent but Tim-3-independent manner.

    PubMed

    Oomizu, Souichi; Arikawa, Tomohiro; Niki, Toshiro; Kadowaki, Takeshi; Ueno, Masaki; Nishi, Nozomu; Yamauchi, Akira; Hirashima, Mitsuomi

    2012-04-01

    Galectin-9 (Gal-9) ameliorates autoimmune reactions by suppressing Th17 cells while augmenting Foxp3(+) regulatory T cells (Tregs). However, the exact mechanism of Gal-9-mediated immune modulation has been elusive. In a MOG-induced experimental allergic encephalomyelitis model using Gal-9(-/-) mice, we observed exacerbated inflammation and an increase in IL-17-producing Th17 cells balanced by a decrease in Foxp3+ Tregs. During in vitro Th17 skewing using TGF-β1 and IL-6, exogenous Gal-9 suppressed Th17 cell development and expanded Foxp3(+) Tregs from naïve CD4 T cells in an IL-2-dependent manner. Although Gal-9 induced cell death in Tim3-expressing differentiated Th17 cells, Gal-9 suppressed Th17 development in a Tim-3-independent. Benzyl-α-GalNAc (an O-glycan biosynthesis inhibitor), but not swainsonine (a complex-type N-glycan biosynthesis inhibitor) abrogated Gal-9-mediated inhibition of Th17 development indicating that there is a linkage between Gal-9 and an unidentified glycoprotein(s) with O-linked β-galactosides that suppress Th17 development. PMID:22341088

  3. 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. PMID:25772938

  4. Recent advances in airborne terrestrial remote sensing with the NASA airborne visible/infrared imaging spectrometer (AVIRIS), airborne synthetic aperture radar (SAR), and thermal infrared multispectral scanner (TIMS)

    NASA Technical Reports Server (NTRS)

    Vane, Gregg; Evans, Diane L.; Kahle, Anne B.

    1989-01-01

    Significant progress in terrestrial remote sensing from the air has been made with three NASA-developed sensors that collectively cover the solar-reflected, thermal infrared, and microwave regions of the electromagnetic spectrum. These sensors are the airborne visible/infrared imaging spectrometer (AVIRIS), the thermal infrared mapping spectrometer (TIMS) and the airborne synthetic aperture radar (SAR), respectively. AVIRIS and SAR underwent extensive in-flight engineering testing in 1987 and 1988 and are scheduled to become operational in 1989. TIMS has been in operation for several years. These sensors are described.

  5. High-Precision Isotope Analysis of Uranium and Thorium by TIMS

    NASA Astrophysics Data System (ADS)

    Neymark, L. A.; Paces, J. B.

    2006-12-01

    The U.S. Geological Survey (USGS) Yucca Mountain Project Branch laboratory in Denver, Colorado, conducts routine high-precision isotope analyses of uranium (U) and thorium (Th) using thermal ionization mass- spectrometry (TIMS). The measurements are conducted by a ThermoFinnigan Triton\\texttrademark equipped with a Faraday multi-collector system and an energy filter in front of an active-film-type secondary electron multiplier (SEM). The abundance sensitivity of the instrument (signal at mass 237 over 238U in natural U) with the energy filter is about 15 ppb and peak tails are reduced by a factor of about 100 relative to the Faraday cup measurements. Since instrument installation in April 2004, more than 500 rock and water samples have been analyzed in support of isotope-geochemical studies for the U.S. Department of Energy`s Yucca Mountain Project. Isotope ratios of sub-nanogram to microgram U and Th samples are measured on graphite-coated single- filament and double-filament assemblies using zone-refined rhenium filaments. Ion beams less than 5 mV are measured with the SEM, which is corrected for non-linearity on the basis of measurements of NIST U-500 and 4321B standards with ion beams ranging from 0.01 to 8 mV. Inter-calibration between the SEM and the Faraday multi-collector is performed for every mass cycle using a 5 mV beam switched between Faraday cup and SEM (bridging technique), because SEM-Faraday inter-calibrations prior to the measurement failed to produce acceptable results. Either natural (^{235}U) or artificial (^{236}U, ^{229}Th) isotopes were used for the bridging. Separate runs are conducted for minor isotopes using SEM only. These techniques result in high within-run precisions of less than 0.1 to 0.2 percent for 234U/238U and 0.2 to 0.5 percent for 230Th/238U. The performance of the instrument is monitored using several U and Th isotope standards. The mean measured 234U/238U in NIST SRM 4321B is (52.879±0.004)×10-6 (95 percent confidence, n

  6. 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…

  7. Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: role in hepatitis B vaccine failure during hepatitis C infection.

    PubMed

    Wang, Jia M; Ma, Cheng J; Li, Guang Y; Wu, Xiao Y; Thayer, Penny; Greer, Pamela; Smith, Ashley M; High, Kevin P; Moorman, Jonathan P; Yao, Zhi Q

    2013-04-26

    Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production which in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection. PMID:23499521

  8. 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

  9. 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

  10. PD-1hiTIM-3+ T cells associate with and predict leukemia relapse in AML patients post allogeneic stem cell transplantation

    PubMed Central

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

    2015-01-01

    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-1hiTIM-3+ cells are strongly associated with leukemia relapse post transplantation. Consistent with exhaustion, PD-1hiTIM-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-1hiTIM-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. PMID:26230954

  11. 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

    2015-01-01

    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. PMID:26230954

  12. Tim-3 alters the balance of IL-12/IL-23 and drives TH17 cells: role in hepatitis B vaccine failure during hepatitis C infection

    PubMed Central

    Wang, Jia M.; Ma, Cheng J.; Li, Guang Y.; Wu, Xiao Y.; Thayer, Penny; Greer, Pamela; Smith, Ashley M.; High, Kevin P.; Moorman, Jonathan P; Yao, Zhi Q.

    2013-01-01

    Hepatitis B virus (HBV) vaccination is recommended for individuals with hepatitis C virus (HCV) infection given their shared risk factors and increased liver-related morbidity and mortality upon super-infection. Vaccine responses in this setting are often blunted, with poor response rates to HBV vaccinations in chronically HCV-infected individuals compared to healthy subjects. In this study, we investigated the role of T cell immunoglobulin mucin domain-3 (Tim-3)-mediated immune regulation in HBV vaccine responses during HCV infection. We found that Tim-3, a marker for T cell exhaustion, was over-expressed on monocytes, leading to a differential regulation of IL-12/IL-23 production with in turn TH17 cell accumulation, in HCV-infected HBV vaccine non-responders compared to HCV-infected HBV vaccine responders or healthy subjects (HS). Importantly, ex vivo blockade of Tim-3 signaling corrected the imbalance of IL-12/IL-23 as well as the IL-17 bias observed in HBV vaccine non-responders during HCV infection. These results suggest that Tim-3-mediated dysregulation of innate to adaptive immune responses is involved in HBV vaccine failure in individuals with chronic HCV infection, raising the possibility that blocking this negative signaling pathway might improve the success rate of HBV immunization in the setting of chronic viral infection. PMID:23499521

  13. Apatite U-Pb Thermochronology: A combined ID-TIMS and LA-ICP-MS study from southern Ecuador

    NASA Astrophysics Data System (ADS)

    Cochrane, R.; Spikings, R.; Chew, D.; Wotzlaw, J.

    2012-04-01

    A combination of U-Pb LA-ICP-MS and ID-TIMS analyses of apatite has been used to investigate the high temperature (>450° C) thermal history of the Ecuadorian Andean margin. The rocks of the Eastern Cordillera of Ecuador evolved via terrane collision and accretion events, and active margin magmatism since the Early Jurassic. Low temperature (0.5) reveal periods of: i) rapid cooling (~240-220 Ma) through the Pb Partial Retention Zone (PRZ) shortly after crystallization, ii) residence at temperatures lower than the PRZ throughout the Jurassic, iii) reheating during 140-90 Ma, and iv) rapid cooling starting at 80-70 Ma. These findings corroborate conclusions based on geochronological and sedimentological data. Additional in-situ age transects and age-depth profiling of apatite are scheduled to determine the concentration distribution of radiogenic lead in the apatites, which will be used to constrain further the mechanisms of lead loss.

  14. 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

  15. Analysis of Mammalian Sphingolipids by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) and Tissue Imaging Mass Spectrometry (TIMS)

    PubMed Central

    Sullards, M. Cameron; Liu, Ying; Chen, Yanfeng; Merrill, Alfred H.

    2011-01-01

    Sphingolipids are a highly diverse category of molecules that serve not only as components of biological structures but also as regulators of numerous cell functions. Because so many of the structural features of sphingolipids give rise to their biological activity, there is a need for comprehensive or “sphingolipidomic” methods for identification and quantitation of as many individual subspecies as possible. This review defines sphingolipids as a class, briefly discusses classical methods for their analysis, and focuses primarily on liquid chromatography tandem mass spectrometry (LC-MS/MS) and tissue imaging mass spectrometry (TIMS). Recently, a set of evolving and expanding methods have been developed and rigorously validated for the extraction, identification, separation, and quantitation of sphingolipids by LC-MS/MS. Quantitation of these biomolecules is made possible via the use of an internal standard cocktail. The compounds that can be readily analyzed are free long-chain (sphingoid) bases, sphingoid base 1-phosphates, and more complex species such as ceramides, ceramide 1-phosphates, sphingomyelins, mono- and di-hexosylceramides sulfatides, and novel compounds such as the 1-deoxy- and 1-(deoxymethyl)-sphingoid bases and their N-acyl-derivatives. These methods can be altered slightly to separate and quantitate isomeric species such as glucosyl/galactosylceramide. Because these techniques require the extraction of sphingolipids from their native environment, any information regarding their localization in histological slices is lost. Therefore, this review also describes methods for TIMS. This technique has been shown to be a powerful tool to determine the localization of individual molecular species of sphingolipids directly from tissue slices. PMID:21749933

  16. 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

  17. Separation of structural and dynamic functions of the mitochondrial translocase: Tim44 is crucial for the inner membrane import sites in translocation of tightly folded domains, but not of loosely folded preproteins.

    PubMed

    Bömer, U; Maarse, A C; Martin, F; Geissler, A; Merlin, A; Schönfisch, B; Meijer, M; Pfanner, N; Rassow, J

    1998-08-01

    The essential gene TIM44 encodes a subunit of the inner mitochondrial membrane preprotein translocase that forms a complex with the matrix heat-shock protein Hsp70. The specific role of Tim44 in protein import has not yet been defined because of the lack of means to block its function. Here we report on a Saccharomyces cerevisiae mutant allele of TIM44 that allows selective and efficient inactivation of Tim44 in organello. Surprisingly, the mutant mitochondria are still able to import preproteins. The import rate is only reduced by approximately 30% compared with wild-type as long as the preproteins do not carry stably folded domains. Moreover, the number of import sites is not reduced. However, the mutant mitochondria are strongly impaired in pulling folded domains of preproteins close to the outer membrane and in promoting their unfolding. Our results demonstrate that Tim44 is not an essential structural component of the import channel, but is crucial for import of folded domains. We suggest that the concerted action of Tim44 and mtHsp70 drives unfolding of preproteins and accelerates translocation of loosely folded preproteins. While mtHsp70 is essential for import of both tightly and loosly folded preproteins, Tim44 plays a more specialized role in translocation of tightly folded domains. PMID:9687491

  18. Quantitative bedrock characterization using multispectral TIR data: pushing the limits of TIMS and ASTER in a desertic environment

    NASA Astrophysics Data System (ADS)

    Smekens, J.; Christensen, P. R.

    2011-12-01

    Thermal Infrared (TIR) spectroscopy constitutes a powerful diagnostic tool for compositional analysis of geological materials. Numerous studies have made use of that tool to investigate geologic problems. However quantitative interpretation is complicated by the trade-off that exists in remote sensing data between spectral and spatial resolutions. The pixel size of hyperspectral datasets usually prevents detailed geologic interpretation while instruments with higher spatial resolution offer limited spectral resolution. We collected natural samples of two types of igneous lithologies (basalt and rhyolite) in the Gila Bend region in an attempt to compare TIR spectra at 3 different levels of resolution: a) laboratory spectra taken on individual samples with hyperspectral resolution (~2 wavenumbers); b) 6-point spectra from Thermal Infrared Multispectral Scanner (TIMS) imagery taken at meter-scale spatial resolution; and c) 5-point spectra from Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) imagery taken with a 90x90 m2/pixel spatial resolution. Identification of each lithology is straightforward in image datasets, using qualitative processing (such as decorrelation stretches). Quantification of the proportion of caliche however - a relatively simple process on hyperspectral laboratory data - proved to be much more challenging, and yielded contrasting results with changing spatial and spectral resolutions. Moreover we observed a mismatch between remotely sensed spectra and the expected spectra derived from laboratory spectra of natural samples. This can only partially be attributed to atmospheric effects, and other factors need to be considered when comparing the datasets. The laboratory spectrometer offers the most ideal conditions, sampling individual and uniform rock surfaces and minimizing the effects of atmospheric CO2 and H2O. However it fails to incorporate the diversity that can be observed in a natural outcrop. TIMS, with a pixel size

  19. 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

  20. 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

  1. A new method fingerprinting magmatic processes using combined U/Pb ID-TIMS geochronology and accessory mineral geochemistry

    NASA Astrophysics Data System (ADS)

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

    2009-12-01

    Zircon is commonly used as a recorder of magmatic processes because of its utility in geochronology and ability to retain primary growth information at prolonged magmatic conditions. Recent applications of U-Pb ID-TIMS geochronology have shown that precision on dates of single zircons are often far smaller than the time-scales of magmatic systems. The result is that dates on such grains record various processes occurring over an interval of time during the production, mobilisation, and emplacement of magmas. Combining age information with geochemical data from the same zircons has proved a useful tool, but thus far has been restricted to low-precision in situ dating techniques. Furthermore, these techniques have been unable to combine age data with trace element geochemistry on the same volume of zircon. We have developed a new technique that combines high-precision ID-TIMS dating with geochemical characterization on the exact same material. U and Pb are commonly separated from the other chemical constituents by ion exchange chemistry during sample preparation. We retain this fraction and analyse it using solution nebulization ICP-SFMS with matrix-matched external liquid calibration. We measured elements such as Zr, Hf, Y, Sc, and the REE, which are present in solution at between 10 and >105 ppt; Hf isotopes are subsequently measured on the same solution. Data obtained using this approach allow us to distinguish between models for melt generation, transport, and assembly of the ca. 40 Ma composite mafic to felsic Re di Castello pluton, Adamello batholith, northern Italy. Coupled with age uncertainties on single zircons as low as 10,000 years, zircon geochemistry preserves a rich record of fractional crystallization, crustal assimilation and magma mixing over timescales of <20,000 to >400,000 years. These data can also be used to distinguish between auto-, xeno-, and antecrystic zircon. Combined with field observation and U-Pb sphene thermochronology, we show that

  2. Assessing the 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)

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

    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 scale 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. A method for estimating vertical information content that is based on these scaled instrument characteristics is reviewed. The method is 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. IIP Tropospheric Infrared Mapping Spectrometers (TIMS) demonstration of CO retrieval, including multi-layer, from atmospheric data acquired simultaneously in the solar reflective region near 2.3 um and the thermal emissive region near 4.7 um

    NASA Astrophysics Data System (ADS)

    Mergenthaler, J. L.; Kumer, J.; Roche, A. E.; Rairden, R. L.; Blatherwick, R.; Hawat, T.; Desouza-Machado, S.; Hannon, S.; Chatfield, R. B.

    2008-12-01

    The NASA Earth Science Technology Office (ESTO) Instrument Incubator Program (IIP) Tropospheric Infrared Mapping Spectrometers (TIMS) have been developed to demonstrate measurement capability, when deployed in space, for multi-layer retrieval of CO from spectral measurements acquired in the solar reflective (SR) region ~ 4281 to 4301 cm-1 and in the thermal InfraRed (TIR) region ~ 2110 to 2165 cm-1. We describe joint deployment at Denver University (DU) with co-investigators there of the TIMS, and of the DU colleagues FTS, to acquire simultaneous measurements of atmospheric spectra in the SR and the TIR. The FTS provided validation radiance data for the TIMS. The TIMS retrievals of CO, H2O and CH4 agreed well with validation vs these as retrieved from the DU data, AIRS retrieval, standard models and ECMWF. The TIMS CO retrievals included column retrieved from the just the SR data, column retrieved from just the TIR data, and a simple two-layer retrieval from the combined data sets. The data were acquired in an operational mode that mimicked the operations in a conceptual application that would provide footprints, coverage, refresh time as in the Decadal Survey GEO-CAPE mission statement. Very encouraging CO precisions were achieved, e.g., the TIMS CO column retrieval from the SR data demonstrated better than the 10% precision requirement as listed on slide 32 of the GEO-CAPE Reference document http://geo- cape.larc.nasa.gov/docs/GEOMAC_FinalReport_no_costs.ppt

  9. Alternative splice variants in TIM barrel proteins from human genome correlate with the structural and evolutionary modularity of this versatile protein fold.

    PubMed

    Ochoa-Leyva, Adrián; Montero-Morán, Gabriela; Saab-Rincón, Gloria; Brieba, Luis G; Soberón, Xavier

    2013-01-01

    After the surprisingly low number of genes identified in the human genome, alternative splicing emerged as a major mechanism to generate protein diversity in higher eukaryotes. However, it is still not known if its prevalence along the genome evolution has contributed to the overall functional protein diversity or if it simply reflects splicing noise. The (βα)8 barrel or TIM barrel is one of the most frequent, versatile, and ancient fold encountered among enzymes. Here, we analyze the structural modifications present in TIM barrel proteins from the human genome product of alternative splicing events. We found that 87% of all splicing events involved deletions; most of these events resulted in protein fragments that corresponded to the (βα)2, (βα)4, (βα)5, (βα)6, and (βα)7 subdomains of TIM barrels. Because approximately 7% of all the splicing events involved internal β-strand substitutions, we decided, based on the genomic data, to design β-strand and α-helix substitutions in a well-studied TIM barrel enzyme. The biochemical characterization of one of the chimeric variants suggests that some of the splice variants in the human genome with β-strand substitutions may be evolving novel functions via either the oligomeric state or substrate specificity. We provide results of how the splice variants represent subdomains that correlate with the independently folding and evolving structural units previously reported. This work is the first to observe a link between the structural features of the barrel and a recurrent genetic mechanism. Our results suggest that it is reasonable to expect that a sizeable fraction of splice variants found in the human genome represent structurally viable functional proteins. Our data provide additional support for the hypothesis of the origin of the TIM barrel fold through the assembly of smaller subdomains. We suggest a model of how nature explores new proteins through alternative splicing as a mechanism to diversify the

  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. PMID:26141233

  11. 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

  12. 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.

  13. Dasty3, a WEB framework for DAS

    PubMed Central

    Villaveces, Jose M.; Jimenez, Rafael C.; Garcia, Leyla J.; Salazar, Gustavo A.; Gel, Bernat; Mulder, Nicola; Martin, Maria; Garcia, Alexander; Hermjakob, Henning

    2011-01-01

    Motivation: Dasty3 is a highly interactive and extensible Web-based framework. It provides a rich Application Programming Interface upon which it is possible to develop specialized clients capable of retrieving information from DAS sources as well as from data providers not using the DAS protocol. Dasty3 provides significant improvements on previous Web-based frameworks and is implemented using the 1.6 DAS specification. Availability: Dasty3 is an open-source tool freely available at http://www.ebi.ac.uk/dasty/ under the terms of the GNU General public license. Source and documentation can be found at http://code.google.com/p/dasty/. Contact: hhe@ebi.ac.uk PMID:21798964

  14. 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.

  15. 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.

  16. The 27-day rotational variations in total solar irradiance observations: From SORCE/TIM, ACRIMSAT/ACRIM III, and SOHO/VIRGO

    NASA Astrophysics Data System (ADS)

    Lee, Jae N.; Cahalan, Robert F.; Wu, Dong L.

    2015-09-01

    During the last decade, observations from SORCE (Solar Radiation and Climate Experiment)/TIM (Total Irradiance Monitor), ACRIMSAT (Active Cavity Radiometer Irradiance Monitor Satellite)/ACRIM III, and SOHO (Solar and Heliospheric Observatory)/VIRGO (Variability of IRradiance and Gravity Oscillations Sun PhotoMeter) provided Total Solar Irradiance (TSI) measurements with unprecedented accuracy and stability to determine the amount of solar irradiance reaching the top of the atmosphere and how solar irradiance varies on different time scales. These three independent measurements are analyzed using the EEMD (Ensemble Empirical Mode Decomposition) method to characterize the phase and amplitude of the 27-day solar rotational variation in TSI. The mode decomposition clearly identifies a 27-day solar rotational signature on TSI measurements. The rotational variations of TSI from the three independent observations are generally consistent with each other, despite different mean TSI values. During the declining phase of solar cycle 23, the amplitude of TSI 27-day variations is as high as 0.8 W/m2 (~0.05%), while during the rising phase of solar cycle 24, the amplitude is up to 0.4 W/m2 (~0.04%). During the minimum phase (2008-2009), the amplitude of the rotational mode is only ~0.1 W/m2. The correlation of this rotational mode between TIM and ACRIM III is ~0.92 and the slope of the local peak values is ~0.98. The correlation between TIM and VIRGO is ~0.96 and the slope of the local peak values is ~0.98, very similar to the slope with ACRIM III.

  17. 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

  18. Characterization Activities to Evaluate Chlorinated Solvent Discharges to Tims Branch from the A/M Area of the Savannah River Site

    SciTech Connect

    Jackson, D.G.

    2001-02-23

    The objective of this investigation was to identify those regions of plume outcrop along Tims Branch southeast of A/M Area and to establish fixed monitoring points along the seepline to evaluate proposed remediation needs and to support long-term monitoring activities in the vicinity of the seepline. The characterization approach employed in completing these tasks was dynamic and graded. Three stages of characterization were used to evaluate the outcrop region, with the results from each of the previous activities used to direct subsequent characterization.

  19. 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…

  20. 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.

  1. Das morgendliche Brückenritual

    NASA Astrophysics Data System (ADS)

    Sander, Oliver

    Es wäre für Mediziner sehr interessant zu wissen, was für Kräfte genau in den menschlichen Knien wirken. Klar ist, dass sie recht groß sein müssen. Das Gewicht eines erwachsenen Mannes beträgt ca. 80 kg. Wenn davon je die Hälfte auf einem Bein ruht hat man schon mindestens 400 Newton pro Knie, beim Laufen, Springen, oder Treppensteigen noch viel mehr. Man will es aber noch viel genauer wissen. Die Kondylen, das sind die Kontaktflächen in den Knien, sind nicht eben. Es gibt dort Unregelmäßigkeiten, und die Kräfte konzentrieren sich dort. An einzelnen Stellen können die Kräfte dann noch viel höher sein.

  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. PMID:27185090

  3. 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 Central

    2015-01-01

    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. PMID:24720347

  4. Long-Term Performance of Pb Isotopic Analysis by TIMS with 202Pb-205Pb Double Spike

    NASA Astrophysics Data System (ADS)

    Amelin, Y.; Connelly, J. N.

    2008-05-01

    The 202Pb-205Pb-233U-235U spike (Pb DS), prepared at the Geological Survey of Canada in 2005 [1], and the 202Pb-205Pb-235U spike, prepared at the Department of Geosciences, University of Oslo [2], have been used for more than two years. Both spikes are routinely used for TIMS analysis of Pb with internal fractionation correction for U-Pb dating of various rocks and minerals, including dating perovskite [2] and meteorites and their components [1, 4-7]. A few hundred standard and sample Pb DS analyses were acquired with these two spikes using Triton TI mass spectrometers at the Geological Survey of Canada, US Geological Survey and the Australian National University, a Finnigan-MAT 261 mass spectrometer at The University of Texas at Austin and a Finnigan-MAT 262 mass spectrometer at the University of Oslo. All analyses were performed using high efficiency silicic acid emitter [8] and a static multicollector mode if the samples were sufficiently large to produce an ion beam greater than ca. 2-5×10-14 A on 206Pb and 207Pb. These data allow us to evaluate long - term performance of the Pb DS procedure for sub-nanogram samples of Pb. The performance of this procedure is evaluated on the basis of the long-term reproducibility of analyses of isotopic standards, and from improving quality of linear fits in Pb-Pb isochron diagrams (and, hence, improved precision of ages) compared to the same data reduced using external normalization. The data for 0.3 ng loads of SRM-981, analyzed with the batches of samples in 2006 and 2007 at the GSC, yield the mean 204Pb/206Pb of 0.05904±0.00013 (0.226% 2σ), #207Pb/206Pb of 0.91483±0.00018 (0.020% 2σ)), and 208Pb/206Pb of 2.16771±0.00054 (0.025% 2σ)). These values and errors are similar to those reported in [1] for the loads of the same size, and to the values obtained for similar loads at the USGS and at ANU over shorter periods of time. The precision and reproducibility of sample analysis and standard analyses is similar, and

  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. 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.

  7. Application of U-Pb ID-TIMS dating to the end-Triassic global crisis: testing the limits on precision and accuracy in a multidisciplinary whodunnit (Invited)

    NASA Astrophysics Data System (ADS)

    Schoene, B.; Schaltegger, U.; Guex, J.; Bartolini, A.

    2010-12-01

    The ca. 201.4 Ma Triassic-Jurassic boundary is characterized by one of the most devastating mass-extinctions in Earth history, subsequent biologic radiation, rapid carbon cycle disturbances and enormous flood basalt volcanism (Central Atlantic Magmatic Province - CAMP). Considerable uncertainty remains regarding the temporal and causal relationship between these events though this link is important for understanding global environmental change under extreme stresses. We present ID-TIMS U-Pb zircon geochronology on volcanic ash beds from two marine sections that span the Triassic-Jurassic boundary and from the CAMP in North America. To compare the timing of the extinction with the onset of the CAMP, we assess the precision and accuracy of ID-TIMS U-Pb zircon geochronology by exploring random and systematic uncertainties, reproducibility, open-system behavior, and pre-eruptive crystallization of zircon. We find that U-Pb ID-TIMS dates on single zircons can be internally and externally reproducible at 0.05% of the age, consistent with recent experiments coordinated through the EARTHTIME network. Increased precision combined with methods alleviating Pb-loss in zircon reveals that these ash beds contain zircon that crystallized between 10^5 and 10^6 years prior to eruption. Mineral dates older than eruption ages are prone to affect all geochronologic methods and therefore new tools exploring this form of “geologic uncertainty” will lead to better time constraints for ash bed deposition. In an effort to understand zircon dates within the framework of a magmatic system, we analyzed zircon trace elements by solution ICPMS for the same volume of zircon dated by ID-TIMS. In one example we argue that zircon trace element patterns as a function of time result from a mix of xeno-, ante-, and autocrystic zircons in the ash bed, and approximate eruption age with the youngest zircon date. In a contrasting example from a suite of Cretaceous andesites, zircon trace elements

  8. 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.

  9. Merkel polyomavirus-specific T cells fluctuate with Merkel cell carcinoma burden and express therapeutically targetable PD-1 and Tim-3 exhaustion markers

    PubMed Central

    Afanasiev, Olga K.; Yelistratova, Lola; Miller, Natalie; Nagase, Kotaro; Paulson, Kelly; Iyer, Jayasri; Ibrani, Dafina; Koelle, David M.; Nghiem, Paul

    2013-01-01

    Purpose The persistent expression of Merkel cell polyomavirus (MCPyV) oncoproteins in Merkel cell carcinoma (MCC) provides a unique opportunity to characterize immune evasion mechanisms in human cancer. We isolated MCPyV-specific T cells and determined their frequency and functional status. Experimental Design Multi-parameter flow cytometry panels and HLA/peptide tetramers were used to identify and characterize T cells from tumors (n=7) and blood (n=18) of MCC patients and control subjects (n=10). PD-1 ligand (PD-L1) and CD8 expression within tumors were determined using mRNA profiling (n=35) and immunohistochemistry (n=13). Results MCPyV-specific CD8 T cells were detected directly ex vivo from the blood of 7 of 11 (64%) patients with MCPyV-positive tumors. In contrast, 0 of 10 control subjects had detectable levels of these cells in their blood (p<0.01). MCPyV-specific T cells in serial blood specimens increased with MCC disease progression and decreased with effective therapy. MCPyV-specific CD8 T cells and MCC-infiltrating lymphocytes expressed higher levels of therapeutically targetable PD-1 and Tim-3 inhibitory receptors compared to T cells specific to other human viruses (p<0.01). PD-L1 was present in 9 of 13 (69%) MCCs and its expression was correlated with CD8 lymphocyte infiltration. Conclusions MCC-targeting T cells expand with tumor burden and express high levels of immune checkpoint receptors PD-1 and Tim-3. Reversal of these inhibitory pathways is therefore a promising therapeutic approach for this virus-driven cancer. PMID:23922299

  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.