Tim-3 is differently expressed in genetically susceptible C57BL/6 and resistant BALB/c mice during oral infection with Toxoplasma gondii.

PubMed

Berrocal Almanza, L C; Muñoz, M; Kühl, A A; Kamradt, T; Heimesaat, M M; Liesenfeld, O

2013-09-01

Tim-3 has opposing roles in innate and adaptive immunities. It not only dampens CD4+ and CD8+ T cells responses but also enhances the ability of macrophages to eliminate intracellular pathogens. After peroral infection with 100 cysts of Toxoplasma gondii genetically susceptible C57BL/6 mice develop an unchecked Th1 response associated with the development of small intestinal immunopathology. Here we report that upon infection with T. gondii, both susceptible C57BL/6 and resistant BALB/c mice exhibit increased frequencies of Tim-3+ cells in spleens and mesenteric lymph nodes. The number of Tim-3+ cells was significantly higher in C57BL/6 than in BALB/c mice. Tim-3 was expressed by macrophages, dendritic, natural killer, as well as CD4+ and CD8+ T cells. Highest frequencies of Tim-3+ cells were observed at the peak of Th1 responses (day 7 post infection) concurrent with the development of ileal immunopathology. Infected Tim-3-deficient BALB/c mice did not develop ileal immunopathology nor did their parasite loads differ from those in wildtype BALB/c mice. Thus, although Tim-3 is markedly upregulated upon infection and differentially regulated in susceptible and resistant mice upon infection with T. gondii, the absence of Tim-3 is not sufficient to overcome the genetic resistance of BALB/c mice to the development of Th1-driven small intestinal immunopathology.

CEACAM1 regulates TIM–3–mediated tolerance and exhaustion

PubMed Central

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

2014-01-01

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers1–5. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition6–10. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity. PMID:25363763

User’s Supplement to MIL-STD-740-2 Modified for Measurements to 20 KHz

DTIC Science & Technology

1989-10-01

Process Compressor Div. 100 Chemung Street 1 AMI Research Painted Post, NY 14870 2 Captain Walk 1 James Seibert New London, CT 06320 1 Mark Clifton 1...CT 06340-4909 942 Memorial Pkwy. 1 Wilf Kalbach Phillipsburg, NJ 08865 1 David Mewha 1 Timothy Luce 1 Ed Miller 1 Kevin Brimmer 2 ITW Linac 1 Robert

Structural effects of protein aging: Terminal marking by deamidation in human triosephosphate isomerase

DOE PAGES

Torres-Larios, Alfredo; Enríquez-Flores, Sergio; Méndez, Sara -Teresa; ...

2015-04-17

Deamidation, the loss of the ammonium group of asparagine and glutamine to form aspartic and glutamic acid, is one of the most commonly occurring post-translational modifications in proteins. Since deamidation rates are encoded in the protein structure, it has been proposed that they can serve as molecular clocks for the timing of biological processes such as protein turnover, development and aging. Despite the importance of this process, there is a lack of detailed structural information explaining the effects of deamidation on the structure of proteins. Here, we studied the effects of deamidation on human triosephosphate isomerase (HsTIM), an enzyme formore » which deamidation of N15 and N71 has been long recognized as the signal for terminal marking of the protein. Deamidation was mimicked by site directed mutagenesis; thus, three mutants of HsTIM (N15D, N71D and N15D/N71D) were characterized. The results show that the N71D mutant resembles, structurally and functionally, the wild type enzyme. In contrast, the N15D mutant displays all the detrimental effects related to deamidation. The N15D/N71D mutant shows only minor additional effects when compared with the N15D mutation, supporting that deamidation of N71 induces negligible effects. The crystal structures show that, in contrast to the N71D mutant, where minimal alterations are observed, the N15D mutation forms new interactions that perturb the structure of loop 1 and loop 3, both critical components of the catalytic site and the interface of HsTIM. Based on a phylogenetic analysis of TIM sequences, we propose the conservation of this mechanism for mammalian TIMs.« less

Structural effects of protein aging: Terminal marking by deamidation in human triosephosphate isomerase

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

Torres-Larios, Alfredo; Enríquez-Flores, Sergio; Méndez, Sara -Teresa

Deamidation, the loss of the ammonium group of asparagine and glutamine to form aspartic and glutamic acid, is one of the most commonly occurring post-translational modifications in proteins. Since deamidation rates are encoded in the protein structure, it has been proposed that they can serve as molecular clocks for the timing of biological processes such as protein turnover, development and aging. Despite the importance of this process, there is a lack of detailed structural information explaining the effects of deamidation on the structure of proteins. Here, we studied the effects of deamidation on human triosephosphate isomerase (HsTIM), an enzyme formore » which deamidation of N15 and N71 has been long recognized as the signal for terminal marking of the protein. Deamidation was mimicked by site directed mutagenesis; thus, three mutants of HsTIM (N15D, N71D and N15D/N71D) were characterized. The results show that the N71D mutant resembles, structurally and functionally, the wild type enzyme. In contrast, the N15D mutant displays all the detrimental effects related to deamidation. The N15D/N71D mutant shows only minor additional effects when compared with the N15D mutation, supporting that deamidation of N71 induces negligible effects. The crystal structures show that, in contrast to the N71D mutant, where minimal alterations are observed, the N15D mutation forms new interactions that perturb the structure of loop 1 and loop 3, both critical components of the catalytic site and the interface of HsTIM. Based on a phylogenetic analysis of TIM sequences, we propose the conservation of this mechanism for mammalian TIMs.« less

Former President George H.W. Bush paid a visit to NASA's Johnson Space Center to speak with Expedition 46 Commander Scott Kelly and Flight Engineer Tim Kopra and take a tour of the Space Vehicle Mockup Facility. Kelly���s twin brother, Mark Kelly and his wife, former Congresswoman Gabrielle Giffords were also present. Photo Date: February 5, 2016. Location: Building 30 - ISS Flight Control Room. Photographer: Robert Markowitz

NASA Image and Video Library

2016-02-05

Former President George H.W. Bush paid a visit to NASA's Johnson Space Center to speak with Expedition 46 Commander Scott Kelly and Flight Engineer Tim Kopra and take a tour of the Space Vehicle Mockup Facility. Kelly’s twin brother, Mark Kelly and his wife, former Congresswoman Gabrielle Giffords were also present. Photo Date: February 5, 2016. Location: Building 30 - ISS Flight Control Room. Photographer: Robert Markowitz

Previsional space during direct laryngoscopy

PubMed Central

Park, Seongjoo; Han, Ji-Won; Cha, Sukwon; Han, Sung-Hee; Kim, Jin-Hee

2017-01-01

Abstract The laryngoscope should displace oral soft tissues forward out of the operator's vision. Therefore, the space in front of the view may be critical for determining the laryngoscopic view. The aim was to investigate the difference in the previsional space during difficult versus easy laryngoscopy (EL). Under general anesthesia, digital photographs of the lateral view of the head and neck were taken in the horizontal sniffing position, after head extension, and during laryngoscopy with a defined force (50 N). Three points (thyroid notch (T), maxillary incisor (I), and mandibular mentum (M)) were marked on the photograph. The previsional space was defined as the TIM triangle. We compared these areas and other variables of the TIM triangle between male patients with difficult laryngoscopy (DL: Cormack–Lehane III–IV, n = 12) versus those of age- and body mass index-matched male patients with EL (Cormack–Lehane I–II, n = 12). When the head was extended, the areas TIM triangle in DL were significantly smaller than in EL. During laryngoscopy, all values of the TIM triangle in DL, including the TIM area (16.4 ± 3.7 vs 22.6 ± 2.8 cm2, P < .01), were significantly smaller than the values in EL. The previsional space was smaller in patients with DL than in those with EL. The TIM triangle could suggest new way to explain the mechanism underlying DL. PMID:28682897

Previsional space during direct laryngoscopy: Implication in the difficult laryngoscopy.

PubMed

Park, Seongjoo; Han, Ji-Won; Cha, Sukwon; Han, Sung-Hee; Kim, Jin-Hee

2017-07-01

The laryngoscope should displace oral soft tissues forward out of the operator's vision. Therefore, the space in front of the view may be critical for determining the laryngoscopic view. The aim was to investigate the difference in the previsional space during difficult versus easy laryngoscopy (EL).Under general anesthesia, digital photographs of the lateral view of the head and neck were taken in the horizontal sniffing position, after head extension, and during laryngoscopy with a defined force (50 N). Three points (thyroid notch (T), maxillary incisor (I), and mandibular mentum (M)) were marked on the photograph. The previsional space was defined as the TIM triangle. We compared these areas and other variables of the TIM triangle between male patients with difficult laryngoscopy (DL: Cormack-Lehane III-IV, n = 12) versus those of age- and body mass index-matched male patients with EL (Cormack-Lehane I-II, n = 12).When the head was extended, the areas TIM triangle in DL were significantly smaller than in EL. During laryngoscopy, all values of the TIM triangle in DL, including the TIM area (16.4 ± 3.7 vs 22.6 ± 2.8 cm, P < .01), were significantly smaller than the values in EL.The previsional space was smaller in patients with DL than in those with EL. The TIM triangle could suggest new way to explain the mechanism underlying DL.

Expedition 44 backup crew ESA (European Space Agency) astronaut Timothy Peake (left), Russian cosmonaut Yuri Malenchenko (ROSCOSMOS) (center), and NASA astronaut Timothy L. Kopra

NASA Image and Video Library

2015-02-19

JSC2015E053686 (04/30/2015) --- Expedition 44 backup crew ESA (European Space Agency) astronaut Timothy Peake (left), Russian cosmonaut Yuri Malenchenko (ROSCOSMOS) (center), and NASA astronaut Timothy L. Kopra .

Timothy-specific IgG antibody levels vary with the pollen seasons.

PubMed

Nordvall, S L; Larsson, P H; Johansson, S G

1986-11-01

Serum samples were collected from eight grass pollen hypersensitive children during a 4-year period. The sera were assayed for contents of timothy-specific IgE antibodies by RAST. Timothy-specific IgG and IgA antibodies were quantified by a refined ELISA in which covalent binding of the antigen to the polystyrene solid phase had been performed. IgG antibodies were also assayed by a Sepharose-protein-A technique with radiolabelled timothy allergens as the antigen. It was possible to register clearcut seasonal variations with postseasonally boosted antibody levels not only of timothy-specific IgE but also of IgG antibody. Both IgG1 and IgG4 antibodies specific for timothy showed seasonal variations of a similar degree. It was not possible to register seasonal variations of the same magnitude of timothy-specific IgA antibodies.

Localized soft elasticity in liquid crystal elastomers (POSTPRINT)

DTIC Science & Technology

2016-02-23

AFRL-RX-WP-JA-2016-0280 LOCALIZED SOFT ELASTICITY IN LIQUID CRYSTAL ELASTOMER (POSTPRINT) Taylor H. Ware, Andreas F. Shick, and...MM-YY) 2. REPORT TYPE 3. DATES COVERED (From - To) 11 August 2015 Interim 31 January 2014 – 11 July 2015 4. TITLE AND SUBTITLE LOCALIZED SOFT ...2016 Localized soft elasticity in liquid crystal elastomers Taylor H. Ware1,2, John S. Biggins3, Andreas F. Shick1, Mark Warner3 & Timothy J. White1

Genetics Home Reference: Timothy syndrome

MedlinePlus

... on PubMed Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, Sanguinetti MC, Keating ... Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz PJ, Joseph ...

76 FR 35052 - Privacy Act of 1974: New System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-15

...: Send written comments to Timothy C. Watkins, Counsel to the Inspector General, U.S. Office of Personnel...: Timothy C. Watkins, Counsel to the Inspector General, 202-606-1200, Timothy.Watkins@opm.gov...

General Matthew B. Ridgway: A Commander’s Maturation of Operational Art

DTIC Science & Technology

2011-05-19

including a review of the reinforced brigade) and army corps, including branches associated therewith; 2) functions of 30 Timothy K . Nenninger...one ‘ K ’ and two ‘D’ rations.”114 However, it did not discuss supply replenishment for where, when, or from whom 82nd troopers received more rations or...marked the successful completion of the initial operation of the XVIII Corps (Airborne).” 143 By the end of December, the 82nd Airborne and the 30th held

A resolution commemorating and celebrating the lives of Deputy Sheriff Stephen Michael Gallagher, Jr., Officer Timothy Q. Brenton, Officer Tina G. Griswold, Officer Ronald Wilbur Owens II, Sergeant Mark Joseph Renninger, Officer Gregory James Richards, and Deputy Sheriff Walter Kent Mundell, Jr. who gave their lives in the service of the people of Washington State in 2009.

THOMAS, 111th Congress

Sen. Murray, Patty [D-WA

2010-05-12

Senate - 05/14/2010 Resolution agreed to in Senate without amendment and with a preamble by Unanimous Consent. (All Actions) Tracker: This bill has the status Agreed to in SenateHere are the steps for Status of Legislation:

In vitro digestion of short-dough biscuits enriched in proteins and/or fibres, using a multi-compartmental and dynamic system (1): viscosity measurement and prediction.

PubMed

Villemejane, C; Wahl, R; Aymard, P; Denis, S; Michon, C

2015-09-01

The effects of biscuit composition on the viscosity generated during digestion were investigated. A control biscuit, one with proteins, one with fibres, and one with both proteins and fibres were digested under the same conditions, using the TNO intestinal model (TIM-1). The TIM-1 is a multi-compartmental and dynamic in vitro system, simulating digestion in the upper tract (stomach and small intestine) of healthy adult humans. Digesta were collected at different times, in the different compartments of the TIM-1 (stomach, duodenum, jejunum and ileum) and viscosity was measured with a dynamic rheometer. Results showed a marked effect of biscuit composition on chyme viscosity. Highest viscosity was obtained with biscuits containing viscous soluble fibres, followed by those enriched in both proteins and fibres, then by protein-enriched and control biscuits. The viscosity was maintained throughout the gut up to the ileal compartment. A prediction of the evolution of the chyme viscosity in each compartment of the TIM-1 was built, based on model curves describing the evolution of the viscosity as a function of biscuit concentration, and on dilution factors measured by spectrophotometry on a blank digestion. Copyright © 2015 Elsevier Ltd. All rights reserved.

Military Bases: Opportunities Exist to Improve Future Base Realignment and Closure Rounds

DTIC Science & Technology

2013-03-01

Operational Army—realigns Fort Bliss , TX; Fort Hood, TX; Fort Riley, KS; Fort Campbell, KY; and Fort Sill, OK to include rebasing of units from overseas to...Committee on Appropriations United States Senate The Honorable Tim Johnson Chairman The Honorable Mark Kirk Ranking Member Subcommittee on Military

Speed Versus Accuracy: A Zero Sum Game

DTIC Science & Technology

2009-05-11

sacrificed to mitigate the risk to credibility. In Ongoing Crisis Communication : Planning, Managing, and Responding, Timothy W. Coombs presents speed in...Carlson and Abelson, 24. 10 Timothy W. Coombs , Crisis Management and Communication , http://www.instituteforpr.org/essential_knowledge/detail...crisi_management_and_communication s (accessed 30 April 2009). 11 Timothy W. Coombs , Ongoing Crisis Communication : Planning, Managing, and Responding, 2nd

Combined Blockade of T Cell Immunoglobulin and Mucin Domain 3 and Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Results in Durable Therapeutic Efficacy in Mice with Intracranial Gliomas.

PubMed

Li, Jinhu; Liu, Xiaodong; Duan, Yijun; Liu, Yueting; Wang, Hongqin; Lian, Shizhong; Zhuang, Guotao; Fan, Yimin

2017-07-24

BACKGROUND Glioblastoma multiforme (GBM) evades immune surveillance by inducing immunosuppression via receptor-ligand interactions between immune checkpoint molecules. T cell immunoglobulin and mucin domain 3 (Tim-3) is a key checkpoint receptor responsible for exhaustion and dysfunction of T cells and plays a critical role in immunosuppression. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) has been recently identified as a heterophilic ligand for Tim-3. MATERIAL AND METHODS We established an intracranial GBM model using C57BL/6 mice and GL261 cells, and treated the mice with single or combined monoclonal antibodies (mAbs) against Tim-3/CEACAM1. The CD4+, CD8+, and regulatory T cells in brain-infiltrating lymphocytes were analyzed using flow cytometry, and the effector function of T cells was assessed using ELISA. We performed a rechallenge by subcutaneous injection of GL261 cells in the "cured" (>90 days post-orthotopic tumor implantation) and naïve mice. RESULTS The mean survival time in the control, anti-Tim-3, anti-CEACAM1, and combined treatment groups was 29.8, 43.4, 42.3, and 86.0 days, respectively, with 80% of the mice in the combined group becoming long-term survivors showing immune memory against glioma cells. Infiltrating CD4+ and CD8+ T cells increased and immunosuppressive Tregs decreased with the combined therapy, which resulted in a markedly elevated ratio of CD4+ and CD8+ cells to Tregs. Additionally, plasma IFN-γ and TGF-β levels were upregulated and downregulated, respectively. CONCLUSIONS Our data indicate that combined blockade of Tim-3 and CEACAM1 generates robust therapeutic efficacy in mice with intracranial tumors, and provides a promising option for GBM immunotherapy.

Applying a Qualitative Modeling Shell to Process Diagnosis: The Caster System.

DTIC Science & Technology

1986-03-01

Process Diagnosis: The Caster System by Timothy F. Thompson and William J. Clancey Department of Computer Science Stanford University Stanford, CA 94303...MODELING SHELL TO PROCESS DIAGNOSIS: THE CASTER SYSTEM 12 PERSONAL AUTHOR(S) TIMOTHY F. THOMPSON. WESTINGHOUSE R&D CENTER, WILLIAM CLANCEY, STANFORD...editions are obsolete. Applying a Qualitative Modeling Shell to Process Diagnosis: The Caster System by Timothy F. Thompson, Westinghouse R&D Center

The 13th Psychological Operations Battalion (EPW) during Mobilization, Desert Shield / Desert Storm and Demobilization

DTIC Science & Technology

1993-05-10

they did not sit, they squatted . They also had a great need for privacy. A modification was made, converting the latrines into a three-hole facility...BRYANT, Cedric SSG FELTON, Mark A. SSG MCQUAID, Daniel A. SSG NUCKLES, Bradley SSG TAYLOR, Ernest K JR SSG GAUL, Robert J. SGT CAIN, William T. SPC ...MCSHANE, Charles A. SPC THOMAS, Timothy L. SPC r Ii rP .I’., . .. ; :; ’, .; ., ., . ’I .If ’’ . Ill TL 5IL LLG •~ ,i:b F--,.,,. ’ 9 1 .... E8~ %F, 4

Semi Quantitative MALDI TOF for Antimicrobial Susceptibility Testing in Staphylococcus aureus

DTIC Science & Technology

2017-08-31

Semi- quantitative MALDI-TOF for antimicrobial susceptibility testing in Staphylococcus 1 aureus 2 3 4 Tucker Maxson,a Cheryl L. Taylor-Howell,a...Timothy D. Minoguea# 5 6 Diagnostic Systems Division, United States Army Medical Research Institute of Infectious 7 Disease, Fort Detrick, MD...USAa 8 9 Running Title: Quantitative MALDI for AST in S. aureus 10 #Address correspondence to Timothy D. Minogue, timothy.d.minogue.civ@mail.mil

DOD Joint Bases: Implementation Challenges Demonstrate Need to Reevaluate the Program

DTIC Science & Technology

2014-09-01

members on Guam regarding available housing options on the island . According to the officials, this effort will result in reducing the need for...The Honorable Tim Johnson Chairman The Honorable Mark Kirk Ranking Member Subcommittee on Military Construction, Veterans Affairs, and...installation management function · to Commander, U aval Forces, Marianas Islands , Guam. SECRETARY OF DEFENSE JUSTIFICATION All installations employ

78 FR 54658 - Allergenic Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-05

... Vernal Grass, Perennial Ryegrass, Timothy Grass, Orchard Grass, and Kentucky Bluegrass Mixed Pollens... Grastek, a Timothy Grass Pollen Allergen Extract tablet for sublingual use, manufactured by Merck. FDA...

Timothy Ley, M.D., Advocates for Personalized Medicine in AML - TCGA

Cancer.gov

Oncologist Dr. Timothy Ley talks about how repurposing of existing drugs based on better understanding of the genetic basis of acute myeloid leukemia (AML) can help patients receive personalized care.

78 FR 66011 - Allergenic Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-11-04

... vernal, orchard, perennial rye, Timothy, and Kentucky bluegrass mixed pollens allergen extract tablet for... to discuss and make recommendations on the safety and efficacy of Grastek, a Timothy grass pollen...

Divergent Small Tim Homologues Are Associated with TbTim17 and Critical for the Biogenesis of TbTim17 Protein Complexes in Trypanosoma brucei

PubMed Central

Smith, Joseph T.; Singha, Ujjal K.; Misra, Smita

2018-01-01

ABSTRACT The small Tim proteins belong to a group of mitochondrial intermembrane space chaperones that aid in the import of mitochondrial inner membrane proteins with internal targeting signals. Trypanosoma brucei, the protozoan parasite that causes African trypanosomiasis, possesses multiple small Tim proteins that include homologues of T. brucei Tim9 (TbTim9) and Tim10 (TbTim10) and a unique small Tim that shares homology with both Tim8 and Tim13 (TbTim8/13). Here, we found that these three small TbTims are expressed as soluble mitochondrial intermembrane space proteins. Coimmunoprecipitation and mass spectrometry analysis showed that the small TbTims stably associated with each other and with TbTim17, the major component of the mitochondrial inner membrane translocase in T. brucei. Yeast two-hybrid analysis indicated direct interactions among the small TbTims; however, their interaction patterns appeared to be different from those of their counterparts in yeast and humans. Knockdown of the small TbTims reduced cell growth and decreased the steady-state level of TbTim17 and T. brucei ADP/ATP carrier (TbAAC), two polytopic mitochondrial inner membrane proteins. Knockdown of small TbTims also reduced the matured complexes of TbTim17 in mitochondria. Depletion of any of the small TbTims reduced TbTim17 import moderately but greatly hampered the stability of the TbTim17 complexes in T. brucei. Altogether, our results revealed that TbTim9, TbTim10, and TbTim8/13 interact with each other, associate with TbTim17, and play a crucial role in the integrity and maintenance of the levels of TbTim17 complexes. IMPORTANCE Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite’s mitochondrion represents a useful source for potential chemotherapeutic targets. Similarly to yeast and humans, mitochondrial functions depend on the import of proteins that are encoded in the nucleus and made in the cytosol. Even though the machinery involved in this mitochondrial protein import process is becoming clearer in T. brucei, a comprehensive picture of protein complex composition and function is still lacking. In this study, we characterized three T. brucei small Tim proteins, TbTim9, TbTim10, and TbTim8/13. Although the parasite does not have the classical TIM22 complex that imports mitochondrial inner membrane proteins containing internal targeting signals in yeast or humans, we found that these small TbTims associate with TbTim17, the major subunit of the TbTIM complex in T. brucei, and play an essential role in the stability of the TbTim17 complexes. Therefore, these divergent proteins are critical for mitochondrial protein biogenesis in T. brucei. PMID:29925672

Divergent Small Tim Homologues Are Associated with TbTim17 and Critical for the Biogenesis of TbTim17 Protein Complexes in Trypanosoma brucei.

PubMed

Smith, Joseph T; Singha, Ujjal K; Misra, Smita; Chaudhuri, Minu

2018-06-27

The small Tim proteins belong to a group of mitochondrial intermembrane space chaperones that aid in the import of mitochondrial inner membrane proteins with internal targeting signals. Trypanosoma brucei , the protozoan parasite that causes African trypanosomiasis, possesses multiple small Tim proteins that include homologues of T. brucei Tim9 (TbTim9) and Tim10 (TbTim10) and a unique small Tim that shares homology with both Tim8 and Tim13 (TbTim8/13). Here, we found that these three small TbTims are expressed as soluble mitochondrial intermembrane space proteins. Coimmunoprecipitation and mass spectrometry analysis showed that the small TbTims stably associated with each other and with TbTim17, the major component of the mitochondrial inner membrane translocase in T. brucei Yeast two-hybrid analysis indicated direct interactions among the small TbTims; however, their interaction patterns appeared to be different from those of their counterparts in yeast and humans. Knockdown of the small TbTims reduced cell growth and decreased the steady-state level of TbTim17 and T. brucei ADP/ATP carrier (TbAAC), two polytopic mitochondrial inner membrane proteins. Knockdown of small TbTims also reduced the matured complexes of TbTim17 in mitochondria. Depletion of any of the small TbTims reduced TbTim17 import moderately but greatly hampered the stability of the TbTim17 complexes in T. brucei Altogether, our results revealed that TbTim9, TbTim10, and TbTim8/13 interact with each other, associate with TbTim17, and play a crucial role in the integrity and maintenance of the levels of TbTim17 complexes. IMPORTANCE Trypanosoma brucei is the causative agent of African sleeping sickness. The parasite's mitochondrion represents a useful source for potential chemotherapeutic targets. Similarly to yeast and humans, mitochondrial functions depend on the import of proteins that are encoded in the nucleus and made in the cytosol. Even though the machinery involved in this mitochondrial protein import process is becoming clearer in T. brucei , a comprehensive picture of protein complex composition and function is still lacking. In this study, we characterized three T. brucei small Tim proteins, TbTim9, TbTim10, and TbTim8/13. Although the parasite does not have the classical TIM22 complex that imports mitochondrial inner membrane proteins containing internal targeting signals in yeast or humans, we found that these small TbTims associate with TbTim17, the major subunit of the TbTIM complex in T. brucei , and play an essential role in the stability of the TbTim17 complexes. Therefore, these divergent proteins are critical for mitochondrial protein biogenesis in T. brucei . Copyright © 2018 Smith et al.

Clinical studies of a purified timothy pollen extract: desensitization therapy with a purified timothy pollen preparation compared to a crude timothy pollen extract. II. Results of the tests in vitro and their relation to symptoms and tests in vivo.

PubMed

Nordvall, S L; Berg, T; Johansson, S G; Lanner, A

1982-01-01

Perennial desensitization therapy was given during a period of 3.5 years to 40 children allergic to grass pollen allergens. 20 patients were treated with a crude and another 20 with a purified timothy pollen extract. 8 children served as untreated controls. The concentration of total and specific IgE in the treated groups covaried with those in the control group. Neither a suppression of the seasonal booster effect nor a suppression of IgE synthesis attributable to the treatment was found. The rise of timothy-specific "blocking' IgG antibodies was more pronounced in the group treated with the purified extract than in the group treated with the crude extract. A significant difference was found only after 3.5 years of treatment. The amplitude of rise of IgG antibodies correlated significantly with the effect of the treatment as judged by repeated conjunctival titration test. The results suggest that a good IgG response is an indication of successful therapy and that a better IgG response may be achieved with purified allergen extracts.

The Tim9p–Tim10p complex binds to the transmembrane domains of the ADP/ATP carrier

PubMed Central

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

2002-01-01

The soluble Tim9p–Tim10p (Tim, translocase of inner membrane) complex of the mitochondrial intermembrane space mediates the import of the carrier proteins and is a component of the TIM22 import system. The mechanism by which the Tim9p–Tim10p complex assembles and binds the carriers is not well understood, but previous studies have proposed that the conserved cysteine residues in the ‘twin CX3C’ motif coordinate zinc and potentially generate a zinc-finger-like structure that binds to the matrix loops of the carrier proteins. Here we have purified the native and recombinant Tim9p–Tim10p complex, and show that both complexes resemble each other and consist of three Tim9p and three Tim10p. Results from inductively coupled plasma–mass spectrometry studies failed to detect zinc in the Tim9p–Tim10p complex. Instead, the cysteine residues seemingly formed disulfide linkages. The Tim9p–Tim10p complex bound specifically to the transmembrane domains of the ADP/ATP carrier, but had no affinity for Tim23p, an inner membrane protein that is inserted via the TIM22 complex. The chaperone-like Tim9p–Tim10p complex thus may prevent aggregation of the unfolded carrier proteins in the aqueous intermembrane space. PMID:11867522

Timothy syndrome-like condition with syndactyly but without prolongation of the QT interval.

PubMed

Kosaki, Rika; Ono, Hiroshi; Terashima, Hiroshi; Kosaki, Kenjiro

2018-05-07

Timothy syndrome is characterized by a unique combination of a prolongation of the corrected QT interval of the electrocardiogram and bilateral cutaneous syndactyly of the fingers and the toes and is caused by heterozygous mutations in CACNA1C, a gene encoding a calcium channel. After the discovery of the CACNA1C gene as the causative gene for Timothy syndrome, patients with CACNA1C mutations with QT prolongation but without syndactyly were described. Here, we report a 5-year-old female patient with cutaneous syndactyly, developmental delay, and pulmonary hypertension. Exome analysis showed a previously undescribed de novo heterozygous mutation in the CACNA1C gene, p.Arg1024Gly. To our knowledge, this patient is the first to exhibit syndactyly and to carry a CACNA1C mutation but to not have QT prolongation, which has long been considered an obligatory feature of Timothy syndrome. © 2018 Wiley Periodicals, Inc.

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

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.

Environmental Assessment (EA): Proposed Rail Spur, Utah Test And Training Range

DTIC Science & Technology

2012-03-19

National Guard, Camp Navajo Tim Cowan, Director of Ammunition Operations, (928) 773-3250 EMAssist, Inc. Mark Kaschmitter, Air Regulatory Analysis, (801...Tribe of Montana, w/o attachments Eastern Shoshone Tribe, w/o attachments Hopi Tribe, w/o attachments Navajo Nation , w/o attachments Northern Arapaho...w/o attachments Navajo Nation , w/o attachments Northern Arapaho Tribe, w/o attachments Northwestern Band of the Shoshone Nation , w/o attachments

Circadian Activators Are Expressed Days before They Initiate Clock Function in Late Pacemaker Neurons from Drosophila.

PubMed

Liu, Tianxin; Mahesh, Guruswamy; Houl, Jerry H; Hardin, Paul E

2015-06-03

Circadian pacemaker neurons in the Drosophila brain control daily rhythms in locomotor activity. These pacemaker neurons can be subdivided into early or late groups depending on whether rhythms in period (per) and timeless (tim) expression are initiated at the first instar (L1) larval stage or during metamorphosis, respectively. Because CLOCK-CYCLE (CLK-CYC) heterodimers initiate circadian oscillator function by activating per and tim transcription, a Clk-GFP transgene was used to mark when late pacemaker neurons begin to develop. We were surprised to see that CLK-GFP was already expressed in four of five clusters of late pacemaker neurons during the third instar (L3) larval stage. CLK-GFP is only detected in postmitotic neurons from L3 larvae, suggesting that these four late pacemaker neuron clusters are formed before the L3 larval stage. A GFP-cyc transgene was used to show that CYC, like CLK, is also expressed exclusively in pacemaker neurons from L3 larval brains, demonstrating that CLK-CYC is not sufficient to activate per and tim in late pacemaker neurons at the L3 larval stage. These results suggest that most late pacemaker neurons develop days before novel factors activate circadian oscillator function during metamorphosis. Copyright © 2015 the authors 0270-6474/15/358662-10$15.00/0.

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.

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

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

Li, Jingzhi; Sha, Bingdong, E-mail: bdsha@uab.edu

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 occurmore » 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.« less

TIM-1 Promotes Hepatitis C Virus Cell Attachment and Infection.

PubMed

Wang, Jing; Qiao, Luhua; Hou, Zhouhua; Luo, Guangxiang

2017-01-15

Human TIM and TAM family proteins were recently found to serve as phosphatidylserine (PS) receptors which promote infections by many different viruses, including dengue virus, West Nile virus, Ebola virus, Marburg virus, and Zika virus. In the present study, we provide substantial evidence demonstrating that TIM-1 is important for efficient infection by hepatitis C virus (HCV). The knockdown of TIM-1 expression significantly reduced HCV infection but not HCV RNA replication. Likewise, TIM-1 knockout in Huh-7.5 cells remarkably lowered HCV cell attachment and subsequent HCV infection. More significantly, the impairment of HCV infection in the TIM-1 knockout cells could be restored completely by ectopic expression of TIM-1 but not TIM-3 or TIM-4. Additionally, HCV infection and cell attachment were inhibited by PS but not by phosphatidylcholine (PC), demonstrating that TIM-1-mediated enhancement of HCV infection is PS dependent. The exposure of PS on the HCV envelope was confirmed by immunoprecipitation of HCV particles with a PS-specific monoclonal antibody. Collectively, these findings demonstrate that TIM-1 promotes HCV infection by serving as an attachment receptor for binding to PS exposed on the HCV envelope. TIM family proteins were recently found to enhance infections by many different viruses, including several members of the Flaviviridae family. However, their importance in HCV infection has not previously been examined experimentally. The TIM family proteins include three members in humans: TIM-1, TIM-3, and TIM-4. The findings derived from our studies demonstrate that TIM-1, but not TIM-3 or TIM-4, promotes HCV infection by functioning as an HCV attachment factor. Knockout of the TIM-1 gene resulted in a remarkable reduction of HCV cell attachment and infection. PS-containing liposomes blocked HCV cell attachment and subsequent HCV infection. HCV particles could also be precipitated with a PS-specific monoclonal antibody. These findings suggest that TIM-1 and its binding ligand, PS, may serve as novel targets for antiviral intervention. Copyright © 2017 American Society for Microbiology.

KSC-2013-1788

NASA Image and Video Library

2013-03-08

CAPE CANAVERAL, Fla. – At Kennedy Space Center's Shuttle Landing Facility, a granite plaque marks the spot where space shuttle Atlantis' nose gear came to a stop at the conclusion of STS-135, the final flight of the Space Shuttle Program. Permanent reminders indicate where on the runway the orbiters Discovery, Endeavour and Atlantis stopped rolling as each finished its last mission in 2011. In addition to the granite markers, which are installed alongside the runway, there are etchings in the grooved concrete along the runway's centerline to mark each wheelstop. The etchings and markers were created and installed by local artist Chad Stout of C Spray Glass Blasting in Cocoa, Fla. Photo credit: NASA/Tim Jacobs

KSC-2013-1790

NASA Image and Video Library

2013-03-08

CAPE CANAVERAL, Fla. – At Kennedy Space Center's Shuttle Landing Facility, a granite plaque marks the spot where space shuttle Discovery's nose gear came to a stop at the conclusion of STS-133, the final flight of the Space Shuttle Program. Permanent reminders indicate where on the runway the orbiters Discovery, Endeavour and Atlantis stopped rolling as each finished its last mission in 2011. In addition to the granite markers, which are installed alongside the runway, there are etchings in the grooved concrete along the runway's centerline to mark each wheelstop. The etchings and markers were created and installed by local artist Chad Stout of C Spray Glass Blasting in Cocoa, Fla. Photo credit: NASA/Tim Jacobs

KSC-2013-1789

NASA Image and Video Library

2013-03-08

CAPE CANAVERAL, Fla. – At Kennedy Space Center's Shuttle Landing Facility, a granite plaque marks the spot where space shuttle Endeavour's nose gear came to a stop at the conclusion of STS-134, the final flight of the Space Shuttle Program. Permanent reminders indicate where on the runway the orbiters Discovery, Endeavour and Atlantis stopped rolling as each finished its last mission in 2011. In addition to the granite markers, which are installed alongside the runway, there are etchings in the grooved concrete along the runway's centerline to mark each wheelstop. The etchings and markers were created and installed by local artist Chad Stout of C Spray Glass Blasting in Cocoa, Fla. Photo credit: NASA/Tim Jacobs

Thresholds, injury, and loss relationships for thrips in Phleum pratense (Poales: Poaceae).

PubMed

Reisig, Dominic D; Godfrey, Larry D; Marcum, Daniel B

2009-12-01

Timothy (Phleum pratense L.) is an important forage crop in many Western U.S. states. Marketing of timothy hay is primarily based on esthetics, and green color is an important attribute. The objective of these studies was to determine a relationship between arthropod populations, yield, and esthetic injury in timothy. Economic injury levels (EILs) and economic thresholds were calculated based on these relationships. Thrips (Thripidae) numbers were manipulated with insecticides in small plot studies in 2006, 2007, and 2008, although tetranychid mite levels were incidentally flared by cyfluthrin in some experiments. Arthropod population densities were determined weekly, and yield and esthetic injury were measured at each harvest. Effects of arthropods on timothy were assessed using multilinear regression. Producers were also surveyed to relate economic loss from leaf color to the injury ratings for use in establishing EILs. Thrips population levels were significantly related to yield loss in only one of nine experiments. Thrips population levels were significantly related to injury once before the first annual harvest and twice before the second. Thrips were the most important pest in these experiments, and they were more often related to esthetic injury rather than yield loss. EILs and economic thresholds for thrips population levels were established using esthetic injury data. These results document the first example of a significant relationship between arthropod pest population levels and economic yield and quality losses in timothy.

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry.

PubMed

Rhein, Bethany A; Brouillette, Rachel B; Schaack, Grace A; Chiorini, John A; Maury, Wendy

2016-07-01

Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVΔG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. With more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Characterization of Human and Murine T-Cell Immunoglobulin Mucin Domain 4 (TIM-4) IgV Domain Residues Critical for Ebola Virus Entry

PubMed Central

Rhein, Bethany A.; Brouillette, Rachel B.; Schaack, Grace A.; Chiorini, John A.

2016-01-01

ABSTRACT Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion–TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVΔG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. IMPORTANCE With more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor. PMID:27122575

An Instructor’s Guide for the Building and Sustaining Foreign Counterpart Organizations Curriculum

DTIC Science & Technology

2016-02-01

best. K-1 AppendixL Problem-centered vs. Strengths-centered Conversation Script Part 1: Problem-centered Conversation OMOLO: Ah. Hello , Timothy B...Strengths-centered conversation OMOLO: Ah. Hello , Timothy Seawright. Please sit down. Seawright: Thank you, Director Omolo. It’s a pleasure to meet

Tim Tetreault | NREL

Science.gov Websites

Tetreault Photo of Tim Tetreault Tim Tetreault Senior Project Leader - DOD Programs Tim.Tetreault @nrel.gov | 303-384-7524 Tim is a senior project lead in the Integrated Applications Center and is currently

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

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

PubMed

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

2010-06-21

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

Fatty acid composition of ruminal digesta and longissimus muscle from lambs fed silage mixtures including red clover, sainfoin, and timothy.

PubMed

Campidonico, L; Toral, P G; Priolo, A; Luciano, G; Valenti, B; Hervás, G; Frutos, P; Copani, G; Ginane, C; Niderkorn, V

2016-04-01

This work investigated the effects of feeding silage mixtures of a plant containing polyphenol oxidase (PPO; red clover [; RC]), a plant containing tannins (sainfoin [; SF]), and a grass species not containing these compounds (timothy [; T]) on ruminal and intramuscular (i.m.) fatty acids of lambs. Forty 4-mo-old castrated male Romane lambs, divided into 5 groups, received 1 of the following silages: 1) T (100%), 2) a binary mixture of timothy and tannin-containing sainfoin ( cv. Perly; 50:50 [T-SF]), 3) a binary mixture of timothy and PPO-containing red clover ( cv. Mervius; 50:50 [T-RC]), 4) a ternary mixture of timothy, sainfoin, and red clover containing both tannins and PPO (50:25:25, respectively [T-SF-RC]), and 5) a binary mixture of tannin-containing sainfoin and PPO-containing red clover (50:50 [SF-RC]). In the rumen digesta, the partial or total replacement of T with forage legumes was associated with greater concentrations of PUFA ( < 0.001) and 1esser concentrations of MUFA ( < 0.001). The inclusion of forage legumes in the silage favored the accumulation of 18:3 -3 ( < 0.001), with the greatest concentrations being observed in SF-RC. This latter diet also led to the greatest percentage of 18:2 -6 ( < 0.001). Forage legumes decreased the -11 18:1 to 30% of T in rumen digesta ( < 0.001). Forage legumes decreased the total concentration of branched-chain fatty acids in the rumen digesta (on average, -28%; < 0.001), this effect being less marked (-17%; = 0.014) in T-RC in comparison with T. The dietary treatment tended to affect the proportion of MUFA ( = 0.081) and of PUFA ( = 0.079) in the i.m. fat of the LM, respectively, at the highest and lowest numerical value in the T group. The sum of -3 fatty acids was less in the T and T-SF groups compared with the mixture of legumes without T (SF-RC; < 0.001 and < 0.008, respectively). The latter group had also a lesser -6-to--3 ratio than the T-SF group ( = 0.01). -11 18:1 was greater ( < 0.03) in lambs given T as the sole silage in comparison with lambs given T-RC, T-SF-RC, and SF-RC. Rumenic acid (-9 -11 CLA) was detected at a greater percentage in the LM from the animals fed the T silage compared with animals fed the T-SF-RC treatment ( = 0.004). Contrarily, -9 -12 -15 18:3 was found at a greater concentration in the muscle from lambs in the SF-RC treatment compared with lambs in the other treatments ( < 0.001). Furthermore, the T-RC group showed a greater proportion of α-linolenic acid than the T group ( = 0.03). In conclusion, the effects of the 2 active compounds (PPO and tannins) appear to be similar and additive. Moreover, a silage composed of a mixture of RC and SF is an excellent forage for growing lambs in terms of i.m. fatty acid composition.

Reconstituted TOM core complex and Tim9/Tim10 complex of mitochondria are sufficient for translocation of the ADP/ATP carrier across membranes.

PubMed

Vasiljev, Andreja; Ahting, Uwe; Nargang, Frank E; Go, Nancy E; Habib, Shukry J; Kozany, Christian; Panneels, Valérie; Sinning, Irmgard; Prokisch, Holger; Neupert, Walter; Nussberger, Stephan; Rapaport, Doron

2004-03-01

Precursor proteins of the solute carrier family and of channel forming Tim components are imported into mitochondria in two main steps. First, they are translocated through the TOM complex in the outer membrane, a process assisted by the Tim9/Tim10 complex. They are passed on to the TIM22 complex, which facilitates their insertion into the inner membrane. In the present study, we have analyzed the function of the Tim9/Tim10 complex in the translocation of substrates across the outer membrane of mitochondria. The purified TOM core complex was reconstituted into lipid vesicles in which purified Tim9/Tim10 complex was entrapped. The precursor of the ADP/ATP carrier (AAC) was found to be translocated across the membrane of such lipid vesicles. Thus, these components are sufficient for translocation of AAC precursor across the outer membrane. Peptide libraries covering various substrate proteins were used to identify segments that are bound by Tim9/Tim10 complex upon translocation through the TOM complex. The patterns of binding sites on the substrate proteins suggest a mechanism by which portions of membrane-spanning segments together with flanking hydrophilic segments are recognized and bound by the Tim9/Tim10 complex as they emerge from the TOM complex into the intermembrane space.

Molecular identification, immunolocalization, and characterization of Clonorchis sinensis triosephosphate isomerase.

PubMed

Zhou, Juanjuan; Liao, Hua; Li, Shan; Zhou, Chenhui; Huang, Yan; Li, Xuerong; Liang, Chi; Yu, Xinbing

2015-08-01

Clonorchis sinensis triosephosphate isomerase (CsTIM) is a key regulatory enzyme of glycolysis and gluconeogenesis, which catalyzes the interconversion of glyceraldehyde 3-phosphate to dihydroxyacetone phosphate. In this study, the biochemical characterizations of CsTIM have been examined. A full-length complementary DNA (cDNA; Cs105350) sequence encoding CsTIM was obtained from our C. sinensis cDNA library. The open reading frame of CsTIM contains 759 bp which encodes 252 amino acids. The amino acid sequence of CsTIM shares 60-65% identity with other species. Western blot analysis displayed that recombinant CsTIM (rCsTIM) can be probed by anti-rCsTIM rat serum and anti-C. sinensis excretory/secretory products (anti-CsESPs) rat serum. Quantitative reverse transcription (RT)-PCR and western blotting analysis revealed that CsTIM messenger RNA (mRNA) and protein were differentially expressed in development cycle stages of the parasite, including adult worm, metacercaria, excysted metacercaria, and egg. In addition, immunolocalization assay showed that CsTIM was located in the seminal vesicle, eggs, and testicle. Moreover, rCsTIM exhibited active enzyme activity in catalytic reactions. The Michaelis constant (K m) of rCsTIM was 0.33 mM, when using glyceraldehyde 3-phosphate as the substrate. The optimal temperature and pH of CsTIM were 37 °C and 7.5-9.5, respectively. Collectively, these results suggest that CsTIM is an important protein involved in glycometabolism, and CsTIM possibly take part in many biological functions in the growth and development of C. sinensis.

The intermembrane space domain of Tim23 is intrinsically disordered with a distinct binding region for presequences

PubMed Central

de la Cruz, Laura; Bajaj, Rakhi; Becker, Stefan; Zweckstetter, Markus

2010-01-01

Proteins targeted to the mitochondrial matrix are translocated through the outer and the inner mitochondrial membranes by two protein complexes, the translocase of the outer membrane (TOM) and one of the translocases of the inner membrane (TIM23). The protein Tim23, the core component of TIM23, consists of an N-terminal, soluble domain in the intermembrane space (IMS) and a C-terminal domain that forms the import pore across the inner membrane. Before translocation proceeds, precursor proteins are recognized by the N-terminal domain of Tim23, Tim23N (residues 1–96). By using NMR spectroscopy, we show that Tim23N is a monomeric protein belonging to the family of intrinsically disordered proteins. Titrations of Tim23N with two presequences revealed a distinct binding region of Tim23N formed by residues 71–84. In a charge-hydropathy plot containing all soluble domains of TOM and TIM23, Tim23N was found to be the only domain with more than 40 residues in the IMS that is predicted to be intrinsically disordered, suggesting that Tim23N might function as hub in the mitochondrial import machinery protein network. PMID:20718036

Distinct forms of mitochondrial TOM-TIM supercomplexes define signal-dependent states of preprotein sorting.

PubMed

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

2010-01-01

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

77 FR 63893 - In the Matter of Timothy M. Goold; IA-12-014; Confirmatory Order (Effective Immediately)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-17

... NUCLEAR REGULATORY COMMISSION [NRC-2012-0242] In the Matter of Timothy M. Goold; IA-12-014... the U.S. Nuclear Regulatory Commission (NRC or Commission's) Materials License No. 21-16560-01 which authorized, at the time, specific activities involving byproduct, source, and/or special nuclear material...

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE ...

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

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE PIPE TRUSS BRIDGE (NO LONGER EXTANT) SPANNING DEEP CREEK, SHACKELFORD COUNTY, TEXAS, CONSTRUCTED BY FLINN-MOYER COMPANY IN 1896. 3/4 VIEW. - Clear Fork of Brazos River Suspension Bridge, Spanning Clear Fork of Brazos River at County Route 179, Albany, Shackelford County, TX

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE ...

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

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE PIPE TRUSS BRIDGE (NO LONGER EXTANT) SPANNING DEEP CREEK, SHACKELFORD COUNTY, TEXAS, CONSTRUCTED BY FLINN-MOYER COMPANY IN 1896. BARREL VIEW. - Clear Fork of Brazos River Suspension Bridge, Spanning Clear Fork of Brazos River at County Route 179, Albany, Shackelford County, TX

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE ...

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

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE PIPE TRUSS BRIDGE (NO LONGER EXTANT) SPANNING DEEP CREEK, SHACKELFORD COUNTY, TEXAS, CONSTRUCTED BY FLINN-MOYER COMPANY IN 1896. ELEVATION VIEW. - Clear Fork of Brazos River Suspension Bridge, Spanning Clear Fork of Brazos River at County Route 179, Albany, Shackelford County, TX

Identifying Local Benefits of Early Childhood Development Programs Using Regional Modeling

ERIC Educational Resources Information Center

Temple, Judy A.; Rolnick, Arthur J.

2012-01-01

This article presents a review of "Investing in Kids: Early Childhood Programs and Local Economic Development" by Timothy J. Bartik. Timothy Bartik's timely book contributes to an important conversation about the role of government in promoting investments in children in the years before traditional public schooling typically begins. Until…

TIM-3 Does Not Act as a Receptor for Galectin-9

PubMed Central

Leitner, Judith; Rieger, Armin; Pickl, Winfried F.; Zlabinger, Gerhard; Grabmeier-Pfistershammer, Katharina; Steinberger, Peter

2013-01-01

T cell immunoglobulin and mucin protein 3 (TIM-3) is a type I cell surface protein that was originally identified as a marker for murine T helper type 1 cells. TIM-3 was found to negatively regulate murine T cell responses and galectin-9 was described as a binding partner that mediates T cell inhibitory effects of TIM-3. Moreover, it was reported that like PD-1 the classical exhaustion marker, TIM-3 is up-regulated in exhausted murine and human T cells and TIM-3 blockade was described to restore the function of these T cells. Here we show that the activation of human T cells is not affected by the presence of galectin-9 or antibodies to TIM-3. Furthermore, extensive studies on the interaction of galectin-9 with human and murine TIM-3 did not yield evidence for specific binding between these molecules. Moreover, profound differences were observed when analysing the expression of TIM-3 and PD-1 on T cells of HIV-1-infected individuals: TIM-3 was expressed on fewer cells and also at much lower levels. Furthermore, whereas PD-1 was preferentially expressed on CD45RA−CD8 T cells, the majority of TIM-3-expressing CD8 T cells were CD45RA+. Importantly, we found that TIM-3 antibodies were ineffective in increasing anti-HIV-1 T cell responses in vitro, whereas PD-L antibodies potently reverted the dysfunctional state of exhausted CD8 T cells. Taken together, our results are not in support of an interaction between TIM-3 and galectin-9 and yield no evidence for a functional role of TIM-3 in human T cell activation. Moreover, our data indicate that PD-1, but not TIM-3, is a promising target to ameliorate T cell exhaustion. PMID:23555261

Architecture of the TIM23 inner mitochondrial translocon and interactions with the matrix import motor.

PubMed

Ting, See-Yeun; Schilke, Brenda A; Hayashi, Masaya; Craig, Elizabeth A

2014-10-10

Translocation of proteins from the cytosol across the mitochondrial inner membrane is driven by action of the matrix-localized multi-subunit import motor, which is associated with the TIM23 translocon. The architecture of the import apparatus is not well understood. Here, we report results of site-specific in vivo photocross-linking along with genetic and coimmunoprecipitation analyses dissecting interactions between import motor subunits and the translocon. The translocon is composed of the two integral membrane proteins Tim23 and Tim17, each containing four membrane-spanning segments. We found that Tim23 having a photoactivatable cross-linker in the matrix exposed loop between transmembrane domains 1 and 2 (loop 1) cross-linked to Tim44. Alterations in this loop destabilized interaction of Tim44 with the translocon. Analogously, Tim17 having a photoactivatable cross-linker in the matrix exposed loop between transmembrane segments 1 and 2 (loop 1) cross-linked to Pam17. Alterations in this loop caused destabilization of the interaction of Pam17 with the translocon. Substitution of individual photoactivatable residues in Tim44 and Pam17 in regions we previously identified as important for translocon association resulted in cross-linking to Tim23 and Tim17, respectively. Our results are consistent with a model in which motor association is achieved via interaction of Tim23 with Tim44, which serves as a scaffold for association of other motor components, and of Tim17 with Pam17. As both Tim44 and Pam17 have been implicated as regulatory subunits of the motor, this positioning is conducive for responding to conformational changes in the translocon upon a translocating polypeptide entering the channel. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Two Brothers, Two Cities: Music Education in Boston and Cincinnati from 1830-1844

ERIC Educational Resources Information Center

Lenzo, Terri Brown; Resta, Craig

2011-01-01

The birth of American music education is often attributed solely to Lowell Mason in Boston. His younger brother Timothy, however, was also active at the same time in Cincinnati. This study traces the roots of music education in both cities, but highlights the rarely cited accomplishments of Timothy Mason and his colleagues. Using historical…

Technique Development Results for the Study of a Novel Dexamethasone Impregnated Bandage Contact Lens in a Rabbit Model After Photorefractive Keratectomy

DTIC Science & Technology

2017-10-22

PRK Inflammation in a Rabbit Model Timothy A. Soekenl, Michael Merkley!, Wesley Brundridgel, Gary Legaultl, Matthew Caldwelll, Joseph Ciolino2...7 .0 Dexamethasone Impregnated Contact Lenses in the Treatment of Post- PRK Inflammation · in a Rabbit Model Timothy A. Soeken 1, Michael Merkley1

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE ...

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

MODEL FROM COLLECTION OF DR. TIMOTHY L. FLINN, OF HOWE PIPE TRUSS BRIDGE (NO LONGER EXTANT) SPANNING DEEP CREEK, SHACKELFORD COUNTY, TEXAS, CONSTRUCTED BY FLINN-MOYER COMPANY IN 1896. 3/4 VIEW FROM ABOVE. - Clear Fork of Brazos River Suspension Bridge, Spanning Clear Fork of Brazos River at County Route 179, Albany, Shackelford County, TX

Multicenter, Randomized, Controlled Study Comparing Tafluprost/Timolol Fixed Combination with Latanoprost/Timolol Fixed Combination in Primary Open-Angle Glaucoma and Ocular Hypertension.

PubMed

Suzuki, Katsuyoshi; Otsuka, Naomi; Hizaki, Hiroko; Hashimoto, Masayo; Kuwayama, Yasuaki

2018-06-05

This was the first exploratory randomized controlled study to compare the efficacy and safety of a preserved tafluprost/timolol fixed combination (TAF/TIM) with a preserved latanoprost/timolol fixed combination (LAT/TIM). This prospective, randomized, open-label study was conducted in Japanese patients with primary open-angle glaucoma, including normal-tension glaucoma or ocular hypertension. Following a 4-week LAT/TIM run-in period, eligible patients entered a 12-week treatment period, during which they received either LAT/TIM or TAF/TIM. The efficacy endpoint was the change in intraocular pressure (IOP) from baseline to week 12 and the safety endpoints included the changes from baseline to week 12 in superficial punctate keratopathy (SPK) score, tear breakup time (TBUT), and hyperemia score, as well as adverse events (AEs). At week 6, ocular symptoms were evaluated using a questionnaire. In total, 131 patients provided informed consent. Of these, 115 completed the run-in period and were assigned to receive TAF/TIM (n = 60) or LAT/TIM (n = 55). At week 12, there were no significant differences between the TAF/TIM and LAT/TIM groups in the change from baseline in trough IOP and IOP at 4-6 h after instillation. There were no significant differences between the two groups in the change from baseline to week 12 in SPK score, TBUT, and hyperemia score. However, only in the TAF/TIM group, the total SPK score and the inferior cornea SPK score were significantly lower at week 12 compared with baseline. Eye irritation and eye pain were significantly decreased in the TAF/TIM group compared with the LAT/TIM group. Two treatment-related AEs were reported in the TAF/TIM group (3.3%) and none in the LAT/TIM group, while no serious AEs were reported in either group. TAF/TIM is as effective as LAT/TIM in terms of IOP-reducing effect, with fewer ocular symptoms. TAF/TIM was associated with a significant improvement in SPK scores. UMIN Clinical Trials Registry Identifier, UMIN000023862. Santen Pharmaceutical Co., Ltd., Osaka, Japan.

Efficacy and tolerability of fixed-combination bimatoprost/timolol versus fixed-combination dorzolamide/brimonidine/timolol in patients with primary open-angle glaucoma or ocular hypertension: a multicenter, prospective, crossover study.

PubMed

García-López, Alfonso; Paczka, José A; Jiménez-Román, Jesús; Hartleben, Curt

2014-12-19

Fixed-combination ocular hypotensives have multiple advantages, but triple-therapy dorzolamide/brimonidine/timolol (dorz/brim/tim) is only available in Latin and South America, and information on its relative efficacy is limited. This study compares the efficacy and tolerability of fixed-combination bimatoprost/timolol (bim/tim) and dorz/brim/tim in Mexican patients with primary open-angle glaucoma or ocular hypertension. In this investigator-masked, crossover study, patients with unmet target intraocular pressure (IOP) on once-daily bim/tim or twice-daily dorz/brim/tim received the opposite medication for 3 months before returning to their pre-baseline medication for 3 months. IOP was evaluated before and after morning instillation at months 2, 3, 5 and 6. Primary endpoints were mean IOP change and Ocular Surface Disease Index© (OSDI) score at each visit. The intent-to-treat population was the a priori analysis population, but due to the number of discontinuations, the per-protocol and intent-to-treat populations were used for the primary efficacy and sensitivity analyses, respectively. Seventy-eight and 56 patients were included in the intent-to-treat and per-protocol populations, respectively. At month 3, statistically significant IOP reductions from baseline were observed in the bim/tim (P < 0.01) and dorz/brim/tim (P < 0.0001) groups, regardless of assessment time. At month 6, patients returned to bim/tim exhibited no significant IOP increase (regardless of assessment time), but patients returned to dorz/brim/tim exhibited a statistically significant IOP increase (P < 0.001) when assessed before instillation of study treatment. Results were similar in both intent-to-treat and per-protocol analysis populations. In the per-protocol analysis, 70% of patients on bim/tim at month 3 had an IOP <14 mm Hg, which declined to 58% (P = 0.0061) at month 6 (ie, after 3 months of dorz/brim/tim treatment). In patients receiving dorz/brim/tim at month 3, 38% had an IOP <14 mm Hg, which remained comparable after return to bim/tim. OSDI scores and incidence of adverse events were similar in both groups. In this first direct comparison of the efficacy of dorz/brim/tim and bim/tim, patients switched from dorz/brim/tim to bim/tim demonstrated improved/lower IOP; when returned to dorz/brim/tim, IOP increased to levels seen at study initiation, suggesting that once-daily bim/tim may have greater IOP-lowering efficacy. Both bim/tim and dorz/brim/tim were well tolerated with minimal ocular surface damage. ClinicalTrials.gov: NCT01737853 (registered October 9, 2012).

Tim-4 inhibition of T-cell activation and T helper type 17 differentiation requires both the immunoglobulin V and mucin domains and occurs via the mitogen-activated protein kinase pathway

PubMed Central

Cao, Wei; Ryan, Michelle; Buckley, Deirdre; O'Connor, Rosemary; Clarkson, Michael R

2011-01-01

Emerging experimental data suggest an important role for the T-cell immunoglobulin mucin 1 (Tim-1):Tim-4 pathway in autoimmune and alloimmune responses in vivo. Using a Tim-4 ectodomain human IgG Fc fusion protein we studied the role of Tim-4 in T-cell activation, signalling and differentiation responses in vitro. We demonstrate that Tim-4Fc can inhibit naive and pre-activated T-cell activation, proliferation and cytokine secretion via a Tim-1-independent pathway. Tim-4 contains immunoglobulin variable (IgV) and mucin domains; to identify which domain accounts for the inhibitory effect novel Tim-4 fusion proteins containing either the IgV or mucin domain were generated. We demonstrate that both IgV and mucin domains are required for the inhibitory effects and that they are mediated at least in part by inhibition of extracellular signal-regulated kinase pathway activity. Given the emerging interest in the role of the Tim family in T helper type 17 (Th17) cells, which play an important role in autoimmune disease and transplantation tolerance, our data show that Tim-4Fc can prevent polarization of CD4+ T cells to the Th17 phenotype. Collectively, our results highlight an inhibitory role for Tim-4Fc in vitro, which we propose is mediated by a receptor other than Tim-1. In addition, this study provides new insights into the role of Tim-4Fc in regulating Th17 immune responses and may open a new avenue for autoimmune therapy. PMID:21463297

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

PubMed

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

2015-02-01

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

Role of the Phosphatidylserine Receptor TIM-1 in Enveloped-Virus Entry

PubMed Central

Moller-Tank, Sven; Kondratowicz, Andrew S.; Davey, Robert A.; Rennert, Paul D.

2013-01-01

The cell surface receptor T cell immunoglobulin mucin domain 1 (TIM-1) dramatically enhances filovirus infection of epithelial cells. Here, we showed that key phosphatidylserine (PtdSer) binding residues of the TIM-1 IgV domain are critical for Ebola virus (EBOV) entry through direct interaction with PtdSer on the viral envelope. PtdSer liposomes but not phosphatidylcholine liposomes competed with TIM-1 for EBOV pseudovirion binding and transduction. Further, annexin V (AnxV) substituted for the TIM-1 IgV domain, supporting a PtdSer-dependent mechanism. Our findings suggest that TIM-1-dependent uptake of EBOV occurs by apoptotic mimicry. Additionally, TIM-1 enhanced infection of a wide range of enveloped viruses, including alphaviruses and a baculovirus. As further evidence of the critical role of enveloped-virion-associated PtdSer in TIM-1-mediated uptake, TIM-1 enhanced internalization of pseudovirions and virus-like proteins (VLPs) lacking a glycoprotein, providing evidence that TIM-1 and PtdSer-binding receptors can mediate virus uptake independent of a glycoprotein. These results provide evidence for a broad role of TIM-1 as a PtdSer-binding receptor that mediates enveloped-virus uptake. Utilization of PtdSer-binding receptors may explain the wide tropism of many of these viruses and provide new avenues for controlling their virulence. PMID:23698310

DoD Science and Engineering Apprenticeship Program for High School Students. 1993-1994 Activities

DTIC Science & Technology

1994-05-01

session on the history of science using the book Coming of Age in the Milky Way by Timothy Ferris. A summary of their activities and projects is...engaged in discussions with Dr. Long on the Coming of Age in the Milky Way, an exciting book on the history of science by Timothy Ferris. A series of

USMC Inventory Control Using Optimization Modeling and Discrete Event Simulation

DTIC Science & Technology

2016-09-01

release. Distribution is unlimited. USMC INVENTORY CONTROL USING OPTIMIZATION MODELING AND DISCRETE EVENT SIMULATION by Timothy A. Curling...USING OPTIMIZATION MODELING AND DISCRETE EVENT SIMULATION 5. FUNDING NUMBERS 6. AUTHOR(S) Timothy A. Curling 7. PERFORMING ORGANIZATION NAME(S...optimization and discrete -event simulation. This construct can potentially provide an effective means in improving order management decisions. However

On Timothy Findley's "The Wars" and Classrooms as Communities of Remembrance

ERIC Educational Resources Information Center

Chinnery, Ann

2014-01-01

In this paper I explore the connection between narrative ethics and the increasing emphasis on historical consciousness as a way to cultivate moral responsibility in history education. I use Timothy Findley's World War I novel, "The Wars," as an example of how teachers might help students to see history neither simply as a…

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

PubMed Central

Veenstra, Rachelle G.; Taylor, Patricia A.; Zhou, Qing; Panoskaltsis-Mortari, Angela; Hirashima, Mitsuomi; Flynn, Ryan; Liu, Derek; Anderson, Ana C.; Strom, Terry B.; Kuchroo, Vijay K.

2012-01-01

T-cell immunoglobulin mucin-3 (Tim-3) is expressed on pathogenic T cells, and its ligand galectin-9 (gal-9) is up-regulated in inflamed tissues. When Tim-3+ T cells encounter high gal-9 levels, they are deleted. Tim-3 is up-regulated on activated T cells during GVHD. Inhibition of Tim-3/gal-9 binding by infusion of a Tim-3-Ig fusion protein or Tim-3−/− donor T cells increased T-cell proliferation and GVHD lethality. When the Tim-3/gal-9 pathway engagement was augmented using gal-9 transgenic recipients, GVHD lethality was slowed. Together, these data indicate a potential for modulating this pathway to reduce disease by increasing Tim-3 or gal-9 engagement. Paradoxically, when Tim-3/gal-9 was inhibited in the absence of donor T-regulatory cells (Tregs), GVHD was inhibited. GVHD reduction was associated with decreased colonic inflammatory cytokines as well as epithelial barrier destruction. CD25-depleted Tim-3−/− donor T cells underwent increased activation-induced cell death because of increased IFN-γ production. To our knowledge, these studies are the first to show that although the absence of Tim-3/gal-9 pathway interactions augments systemic GVHD, concurrent donor Treg depletion paradoxically and surprisingly inhibits GVHD. Thus, although donor Tregs typically inhibit GVHD, under some conditions, such Tregs actually may contribute to GVHD by reducing activation-induced T-cell death. PMID:22677125

Tim18, a component of the mitochondrial translocator, mediates yeast cell death induced by arsenic.

PubMed

Du, Li; Yu, Yong; Li, Zidong; Chen, Jingsi; Liu, Yan; Xia, Yongjing; Liu, Xiangjun

2007-08-01

Evidence is presented that Tim18, a mitochondria translocase, plays a role in the previously described apoptosis induced by arsenite in Saccharomyces cerevisiae. Tim18 deletion mutant exhibited resistance to arsenite. After arsenite treatment, both the wild type and Tim18-deficient cells showed reactive oxygen species (ROS) production. Arsenite induced the higher expression of tim18 in wild type yeast cells. We found that the tim18 deletion mutant also exhibited resistance to other apoptotic stresses such as acetic acid, H2O2, and hyperosmotic stress. These results suggest that Tim18 is important for yeast cell death induced by arsenic, and it may act downstream of ROS production.

Structural and biochemical characterization of a recombinant triosephosphate isomerase from Rhipicephalus (Boophilus) microplus

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

Moraes, Jorge; Arreola, Rodrigo; Cabrera, Nallely

2012-02-06

Triosephosphate isomerase (TIM) is an enzyme with a role in glycolysis and gluconeogenesis by catalyzing the interconversion between glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. This enzyme has been used as a target in endoparasite drug development. In this work we cloned, expressed, purified and studied kinetic and structural characteristics of TIM from tick embryos, Rhipicephalus (Boophilus) microplus (BmTIM). The Km and Vmax of the recombinant BmTIM with glyceraldehyde 3-phosphate as substrate, were 0.47 mM and 6031 {micro}mol min{sup -1} mg protein{sup -1}, respectively. The resolution of the diffracted crystal was estimated to be 2.4 {angstrom} and the overall data showed thatmore » BmTIM is similar to other reported dimeric TIMs. However, we found that, in comparison to other TIMs, BmTIM has the highest content of cysteine residues (nine cysteine residues per monomer). Only two cysteines could make disulfide bonds in monomers of BmTIM. Furthermore, BmTIM was highly sensitive to the action of the thiol reagents dithionitrobenzoic acid and methyl methane thiosulfonate, suggesting that there are five cysteines exposed in each dimer and that these residues could be employed in the development of species-specific inhibitors.« less

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. Copyright © 2014 Elsevier Ltd. All rights reserved.

Tim-3 directly enhances CD8 T cell responses to acute Listeria monocytogenes infection

PubMed Central

Gorman, Jacob V.; Starbeck-Miller, Gabriel; Pham, Nhat-Long L.; Traver, Geri L.; Rothman, Paul B.; Harty, John T.; Colgan, John D.

2014-01-01

Tim-3 is a surface molecule expressed throughout the immune system that can mediate both stimulatory and inhibitory effects. Previous studies have provided evidence that Tim-3 functions to enforce CD8 T cell exhaustion, a dysfunctional state associated with chronic stimulation. In contrast, the role of Tim-3 in the regulation of CD8 T cell responses to acute and transient stimulation remains undefined. To address this knowledge gap, we examined how Tim-3 affects CD8 T cell responses to acute Listeria monocytogenes (LM) infection. Analysis of wild-type (WT) mice infected with LM revealed that Tim-3 was transiently expressed by activated CD8 T cells and was associated primarily with acquisition of an effector phenotype. Comparison of responses to LM by WT and Tim-3 KO mice showed that the absence of Tim-3 significantly reduced the magnitudes of both primary and secondary CD8 T cell responses, which correlated with decreased IFN-γ production and degranulation by Tim-3 KO cells stimulated with peptide antigen ex vivo. To address the T cell-intrinsic role of Tim-3, we analyzed responses to LM infection by WT and Tim-3 KO TCR-transgenic CD8 T cells following adoptive transfer into a shared WT host. In this setting, the accumulation of CD8 T cells and the generation of cytokine-producing cells were significantly reduced by the lack of Tim-3, demonstrating that this molecule has a direct effect on CD8 T cell function. Combined, our results suggest that Tim-3 can mediate a stimulatory effect on CD8 T cell responses to an acute infection. PMID:24567532

Drosophila TIM Binds Importin α1, and Acts as an Adapter to Transport PER to the Nucleus

PubMed Central

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

2015-01-01

Regulated nuclear entry of clock proteins is a conserved feature of eukaryotic circadian clocks and serves to separate the phase of mRNA activation from mRNA repression in the molecular feedback loop. In Drosophila, nuclear entry of the clock proteins, PERIOD (PER) and TIMELESS (TIM), is tightly controlled, and impairments of this process produce profound behavioral phenotypes. We report here that nuclear entry of PER-TIM in clock cells, and consequently behavioral rhythms, require a specific member of a classic nuclear import pathway, Importin α1 (IMPα1). In addition to IMPα1, rhythmic behavior and nuclear expression of PER-TIM require a specific nuclear pore protein, Nup153, and Ran-GTPase. IMPα1 can also drive rapid and efficient nuclear expression of TIM and PER in cultured cells, although the effect on PER is mediated by TIM. Mapping of interaction domains between IMPα1 and TIM/PER suggests that TIM is the primary cargo for the importin machinery. This is supported by attenuated interaction of IMPα1 with TIM carrying a mutation previously shown to prevent nuclear entry of TIM and PER. TIM is detected at the nuclear envelope, and computational modeling suggests that it contains HEAT-ARM repeats typically found in karyopherins, consistent with its role as a co-transporter for PER. These findings suggest that although PER is the major timekeeper of the clock, TIM is the primary target of nuclear import mechanisms. Thus, the circadian clock uses specific components of the importin pathway with a novel twist in that TIM serves a karyopherin-like role for PER. PMID:25674790

Combination Therapy with Anti-PD-1, Anti-TIM-3, and Focal Radiation Results in Regression of Murine Gliomas.

PubMed

Kim, Jennifer E; Patel, Mira A; Mangraviti, Antonella; Kim, Eileen S; Theodros, Debebe; Velarde, Esteban; Liu, Ann; Sankey, Eric W; Tam, Ada; Xu, Haiying; Mathios, Dimitrios; Jackson, Christopher M; Harris-Bookman, Sarah; Garzon-Muvdi, Tomas; Sheu, Mary; Martin, Allison M; Tyler, Betty M; Tran, Phuoc T; Ye, Xiaobu; Olivi, Alessandro; Taube, Janis M; Burger, Peter C; Drake, Charles G; Brem, Henry; Pardoll, Drew M; Lim, Michael

2017-01-01

Checkpoint molecules like programmed death-1 (PD-1) and T-cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme. Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model. However, tumor-infiltrating lymphocytes (TIL) can express multiple checkpoints, and expression of ≥2 checkpoints corresponds to a more exhausted T-cell phenotype. We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (i) control, (ii) SRS, (iii) anti-PD-1 antibody, (iv) anti-TIM-3 antibody, (v) anti-PD-1 + SRS, (vi) anti-TIM-3 + SRS, (vii) anti-PD-1 + anti-TIM-3, and (viii) anti-PD-1 + anti-TIM-3 + SRS. Survival and immune activation were assessed. Dual therapy with anti-TIM-3 antibody + SRS or anti-TIM-3 + anti-PD-1 improved survival compared with anti-TIM-3 antibody alone. Triple therapy resulted in 100% overall survival (P < 0.05), a significant improvement compared with other arms. Long-term survivors demonstrated increased immune cell infiltration and activity and immune memory. Finally, positive staining for TIM-3 was detected in 7 of 8 human GBM samples. This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human glioblastoma multiforme and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of glioblastoma multiforme. Clin Cancer Res; 23(1); 124-36. ©2016 AACR. ©2016 American Association for Cancer Research.

CULLIN-3 Controls TIMELESS Oscillations in the Drosophila Circadian Clock

PubMed Central

Lamouroux, Annie; Chélot, Elisabeth; Rouyer, François

2012-01-01

Eukaryotic circadian clocks rely on transcriptional feedback loops. In Drosophila, the PERIOD (PER) and TIMELESS (TIM) proteins accumulate during the night, inhibit the activity of the CLOCK (CLK)/CYCLE (CYC) transcriptional complex, and are degraded in the early morning. The control of PER and TIM oscillations largely depends on post-translational mechanisms. They involve both light-dependent and light-independent pathways that rely on the phosphorylation, ubiquitination, and proteasomal degradation of the clock proteins. SLMB, which is part of a CULLIN-1-based E3 ubiquitin ligase complex, is required for the circadian degradation of phosphorylated PER. We show here that CULLIN-3 (CUL-3) is required for the circadian control of PER and TIM oscillations. Expression of either Cul-3 RNAi or dominant negative forms of CUL-3 in the clock neurons alters locomotor behavior and dampens PER and TIM oscillations in light-dark cycles. In constant conditions, CUL-3 deregulation induces behavioral arrhythmicity and rapidly abolishes TIM cycling, with slower effects on PER. CUL-3 affects TIM accumulation more strongly in the absence of PER and forms protein complexes with hypo-phosphorylated TIM. In contrast, SLMB affects TIM more strongly in the presence of PER and preferentially associates with phosphorylated TIM. CUL-3 and SLMB show additive effects on TIM and PER, suggesting different roles for the two ubiquitination complexes on PER and TIM cycling. This work thus shows that CUL-3 is a new component of the Drosophila clock, which plays an important role in the control of TIM oscillations. PMID:22879814

Analysis of the Lake Superior Watershed Seasonal Snow Cover

DTIC Science & Technology

2007-05-01

ER D C/ CR R EL T R -0 7 -5 Analysis of the Lake Superior Watershed Seasonal Snow Cover Steven F. Daly, Timothy B. Baldwin, and...unlimited. ERDC/CRREL TR-07-5 May 2007 Analysis of the Lake Superior Watershed Seasonal Snow Cover Steven F. Daly, Timothy B. Baldwin, and...12 5 GIS Analysis of SWE over the Lake Superior Watershed .........................................................15

DoD Science and Engineering Apprenticeship Program for Socially and Economically Disadvantaged High School Students. 1991-1992 Activities

DTIC Science & Technology

1992-04-01

history of science using the book Coming of Age in the Milky hay by Timothy Ferris. A summary of their activities and projects is included in section 3...book on the history of science by Timothy Ferris. A series of scientific films was also selected and shown by Dr. Kung. These covered topics such as

Color-Tunable Mirrors Based on Electrically Regulated Bandwidth Broadening in Polymer-Stabilized Cholesteric Liquid Crystals (Postprint)

DTIC Science & Technology

2014-10-01

DISTRIBUTION STATEMENT. //Signature// //Signature// TIMOTHY J. WHITE CHRISTOPHER D. BREWER, Chief Photonic Materials Branch... Photonic Materials Branch Functional Materials Division Functional Materials Division //Signature// TIMOTHY J. BUNNING, Chief Functional...LIQUID CRYSTALS (POSTPRINT) 5a. CONTRACT NUMBER FA8650-09-D-5434-0009 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 62102F 6. AUTHOR(S

Surveillance of traffic incident management-related occupational fatalities in Kentucky, 2005-2016.

PubMed

Bunn, T L; Slavova, S; Chandler, M; Hanner, N; Singleton, M

2018-05-19

Traffic incidents occurring on roadways require the coordinated effort of multiple responder and recovery entities, including communications, law enforcement, fire and rescue, emergency medical services, hazardous materials, transportation agencies, and towing and recovery. The objectives of this study were to (1) identify and characterize transportation incident management (TIM)-related occupational fatalities; (2) assess concordance of surveillance data sources in identifying TIM occupations, driver vs. pedestrian status, and occupational fatality incident location; and (3) determine and compare U.S. occupational fatality rates for TIM industries. The Kentucky Fatality Assessment and Control Evaluation (FACE) program analyzed 2005-2016 TIM occupational fatality data using multiple data sources: death certificate data, Collision Report Analysis for Safer Highways (CRASH) data, and media reports, among others. Literal text analysis was performed on FACE data, and a multiple linear regression model and SAS proc sgpanel were used to estimate and visualize the U.S. TIM occupational mortality trend lines and confidence bounds. There were 29 TIM fatalities from 2005 to 2015 in Kentucky; 41% of decedents were in the police protection occupation, and 21% each were in the fire protection and motor vehicle towing industries. Over one half of the TIM decedents were performing work activities as pedestrians when they died. Media reports identified the majority of the occupational fatalities as TIM related (28 of 29 TIM-related deaths); the use of death certificates as the sole surveillance data source only identified 17 of the 29 deaths as TIM related, and the use of CRASH data only identified 4 of the 29 deaths as TIM related. Injury scenario text analysis showed that law enforcement vehicle pursuit, towing and recovery vehicle loading, and disabled vehicle response were particular high-risk activities that led to TIM deaths. Using U.S. data, the motor vehicle towing industry had a significantly higher risk for occupational mortality compared to the fire protection and police protection industries. Multiple data sources are needed to comprehensively identify TIM fatalities and to examine the circumstances surrounding TIM fatalities, because no one data source in itself was adequate and undercounted the total number of TIM fatalities. The motor vehicle towing industry, in particular, is at elevated risk for occupational mortality, and targeted mandatory TIM training for the motor vehicle towing industry should be considered. In addition, enhanced law enforcement roadside safety training during vehicle pursuit and apprehension of suspects is recommended.

Dual interaction of scaffold protein Tim44 of mitochondrial import motor with channel-forming translocase subunit Tim23

PubMed Central

Ting, See-Yeun; Yan, Nicholas L; Schilke, Brenda A; Craig, Elizabeth A

2017-01-01

Proteins destined for the mitochondrial matrix are targeted to the inner membrane Tim17/23 translocon by their presequences. Inward movement is driven by the matrix-localized, Hsp70-based motor. The scaffold Tim44, interacting with the matrix face of the translocon, recruits other motor subunits and binds incoming presequence. The basis of these interactions and their functional relationships remains unclear. Using site-specific in vivo crosslinking and genetic approaches in Saccharomyces cerevisiae, we found that both domains of Tim44 interact with the major matrix-exposed loop of Tim23, with the C-terminal domain (CTD) binding Tim17 as well. Results of in vitro experiments showed that the N-terminal domain (NTD) is intrinsically disordered and binds presequence near a region important for interaction with Hsp70 and Tim23. Our data suggest a model in which the CTD serves primarily to anchor Tim44 to the translocon, whereas the NTD is a dynamic arm, interacting with multiple components to drive efficient translocation. DOI: http://dx.doi.org/10.7554/eLife.23609.001 PMID:28440746

A trypanosomal orthologue of an intermembrane space chaperone has a non-canonical function in biogenesis of the single mitochondrial inner membrane protein translocase.

PubMed

Wenger, Christoph; Oeljeklaus, Silke; Warscheid, Bettina; Schneider, André; Harsman, Anke

2017-08-01

Mitochondrial protein import is essential for Trypanosoma brucei across its life cycle and mediated by membrane-embedded heterooligomeric protein complexes, which mainly consist of trypanosomatid-specific subunits. However, trypanosomes contain orthologues of small Tim chaperones that escort hydrophobic proteins across the intermembrane space. Here we have experimentally analyzed three novel trypanosomal small Tim proteins, one of which contains only an incomplete Cx3C motif. RNAi-mediated ablation of TbERV1 shows that their import, as in other organisms, depends on the MIA pathway. Submitochondrial fractionation combined with immunoprecipitation and BN-PAGE reveals two pools of small Tim proteins: a soluble fraction forming 70 kDa complexes, consistent with hexamers and a second fraction that is tightly associated with the single trypanosomal TIM complex. RNAi-mediated ablation of the three proteins leads to a growth arrest and inhibits the formation of the TIM complex. In line with these findings, the changes in the mitochondrial proteome induced by ablation of one small Tim phenocopy the effects observed after ablation of TbTim17. Thus, the trypanosomal small Tims play an unexpected and essential role in the biogenesis of the single TIM complex, which for one of them is not linked to import of TbTim17.

Subdiffractional tracking of internalized molecules reveals heterogeneous motion states of synaptic vesicles

PubMed Central

Morrow, Isabel C.; Harper, Callista B.

2016-01-01

Our understanding of endocytic pathway dynamics is severely restricted by the diffraction limit of light microscopy. To address this, we implemented a novel technique based on the subdiffractional tracking of internalized molecules (sdTIM). This allowed us to image anti–green fluorescent protein Atto647N-tagged nanobodies trapped in synaptic vesicles (SVs) from live hippocampal nerve terminals expressing vesicle-associated membrane protein 2 (VAMP2)–pHluorin with 36-nm localization precision. Our results showed that, once internalized, VAMP2–pHluorin/Atto647N–tagged nanobodies exhibited a markedly lower mobility than on the plasma membrane, an effect that was reversed upon restimulation in presynapses but not in neighboring axons. Using Bayesian model selection applied to hidden Markov modeling, we found that SVs oscillated between diffusive states or a combination of diffusive and transport states with opposite directionality. Importantly, SVs exhibiting diffusive motion were relatively less likely to switch to the transport motion. These results highlight the potential of the sdTIM technique to provide new insights into the dynamics of endocytic pathways in a wide variety of cellular settings. PMID:27810917

Tim2 is expressed in mouse fetal hepatocytes and regulates their differentiation.

PubMed

Watanabe, Natsumi; Tanaka, Minoru; Suzuki, Kaori; Kumanogoh, Atsushi; Kikutani, Hitoshi; Miyajima, Atsushi

2007-05-01

Liver development is regulated by various extracellular molecules such as cytokines and cell surface proteins. Although several such regulators have been identified, additional molecules are likely to be involved in liver development. To identify such molecules, we employed the signal sequence trap (SST) method to screen cDNAs encoding a secreted or membrane protein from fetal liver and obtained a number of clones. Among them, we found that T cell immunoglobulin and mucin domain 2 (Tim2) was expressed specifically on immature hepatocytes in the fetal liver. Tim2 has been shown to regulate immune responses, but its role in liver development had not been studied. We have examined the possible role of Tim2 in hepatocyte differentiation. At first, we prepared a soluble Tim2 fusion protein consisting of its extracellular domain and the Fc domain of human IgG (Tim2-hFc) and found that it bound to fetal and adult hepatocytes, suggesting that there are Tim2-binding molecules on hepatocytes. Second, Tim2-hFc inhibited the differentiation of hepatocytes in fetal liver primary culture, i.e., the expression of mature hepatic enzymes and accumulation of glycogen were severely reduced. Third, Tim2-hFc also inhibited proliferation of fetal hepatocytes. Fourth, down-regulation of Tim2 expression by small interfering RNA (siRNA) enhanced the expression of liver differentiation marker genes. It is strongly suggested that Tim2 is involved in the differentiation of fetal hepatocytes.

Analysis and production of the traffic incident management state self-assessments (TIM SA) national report.

DOT National Transportation Integrated Search

2008-09-29

The Traffic Incident Management Self-Assessment (TIM SA) provides a means for evaluating progress in achievement of individual TIM program components and overall TIM program success in three areas: Program and Institutional Issues; Operational Issues...

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

PubMed

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

2015-09-01

Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC. ©2015 American Association for Cancer Research.

Performance and Operability of a Dual Cavity Flame Holder in a Supersonic Combustor

DTIC Science & Technology

2009-06-01

Mark Gruber, for his mentorship during this work and for the past three years. It has been a pleasure and honor to work with and learn from you...Olmstead, Lt John Heaton, Paul Kennedy, Tim Bulcher, Steve Enneking, and Dr. Skip Williams. I appreciate all of your hard work and dedication through the...months of late run nights. I could not have asked for a better group of people to work with. I am also extremely indebted to Dr. John Tam for the

New Therapeutic Modalities of Retinal Laser Injury.

DTIC Science & Technology

1992-03-31

Clawticarroni New Therapeutic Modalities for Retinal Laser Injury 1 2 . PERSONAL AUTHOR(S) Tim T.Lar. Ph.D., .and Mark Q.M. Tso. M.D. 13a. TYPE OF...Experimental treatment of retinal laser Injury 4 1.3: Clinical therapy 4 1.4: Our hypothesis and approaches 4 Chapter 2 : Accidental laser Injury to the...human retina 7 2.1: Introduction 7 2.2: Case 1 7 2.3: Case 2 8 2.4: General comments 9 2.5: Clinical course 10 2.6: Implications 10 Chapter 3: Sub

ESO 50th Anniversary Gala Dinner

NASA Astrophysics Data System (ADS)

Sirey, R.

2012-12-01

To formally mark the 50th anniversary of the signing of the ESO Convention, a gala dinner was held in the Munich Residenz. A brief report of the event is presented and the speeches are reproduced. The speakers were the President of the Council, Xavier Barcons; the German Minister for Education and Research, Prof. Dr Annette Schavan; the Bavarian State Minister for Science, Research and the Arts, Dr Wolfgang Heubisch; physics Nobel Laureate, Brian Schmidt; the current Director General, Tim de Zeeuw and the Chilean Minister of Foreign Affairs, Alfredo Moreno Charme.

Independent Review of the Defense Logistics Agencys Roles and Missions

DTIC Science & Technology

2014-12-01

3,000 3,500 C-5 F-15 C-130 KC-135 B-1 B-52 E-3 N IIN / N SN s BoM Items Ordered BoM Items Not Ordered Orders Not on BoM Warner- Robbins ALC Tinker... Tony Poleo Fred Pribble Michael Scott BG Steven Shapiro Brig Gen Giovanni Tuck Col Rex Adee Linda Barnett Matthew Beebe CDR Tim Benesh COL...DeVincentis Lt Gen (Ret) Kathleen Gainey RADM (Ret) Mark Heinrich CAPT (Ret) Stuart Jones Eric Peltz Marc Robbins This page is intentionally blank

TIM-1 signaling in B cells regulates antibody production

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

Ma, Juan; Usui, Yoshihiko; Department of Ophthalmology, Tokyo Medical University, 6-7-1 Nishi-shinjuku-ku, Tokyo 160-0023

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 expressedmore » 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.« less

Increased expression of T cell immunoglobulin and mucin domain 3 aggravates brain inflammation via regulation of the function of microglia/macrophages after intracerebral hemorrhage in mice.

PubMed

Xu, ChangJun; Wang, Tao; Cheng, Si; Liu, YuGuang

2013-12-01

Microglia/macrophages are known to play important roles in initiating brain inflammation after spontaneous intracerebral hemorrhage (ICH). T cell immunoglobulin and mucin domain-3 (Tim-3) have been proven to play a critical part in several inflammatory diseases through regulation of both adaptive and innate immune responses. Tim-3 can be expressed by microglia/macrophages and regulates their function in the innate immune response. However, the effect of Tim-3 on inflammatory responses following ICH is unclear. In this study, we investigated Tim-3 expression, the inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and brain water content in peri-hematomal brain tissue at 12 hours and at 1, 3, 5, and 7 days post-ICH in wild type (WT) ICH and Tim-3-/- ICH mice. The numbers of Tim-3 positive cells,astrocytes, neutrophils and microglia/macrophages were detected using immunofluorescence staining. Cytokines were measured by ELISA. Double immunofluorescence labeling was performed to identify the cellular source of Tim-3 expression. Mouse neurological deficit scores were assessed through animal behavior. Expression of Tim-3 increased early in mouse peri-hematomal brain tissue after autologous blood injection, peaked at day 1, and was positively correlated with the concentrations of TNF-α, IL-1β, and brain water content. Tim-3 was predominantly expressed in microglia/macrophages. Compared with WT mice, Tim-3-/- mice had reduced ICH-induced brain inflammation with decreased TNF-α and IL-1β, cerebral edema and neurological deficit scores. Moreover, Tim-/- inhibited activation of microglia/macrophages. The number of activated microglia/macrophages in Tim-3-/- ICH mice was much lower than that in WT ICH mice. Our findings demonstrate that Tim-3 plays an important role in brain inflammation after ICH, and may be a potential treatment target.

Pershing in Mexico: a case study in limited contingency operations

DTIC Science & Technology

2016-05-26

Pershing in Mexico: A Case Study in Limited Contingency Operations A Monograph by MAJ Timothy J. Lawrence United States Army School...DATE (00-MM-YYYY) REPORT TYPE 12. 31-03-2016 SAMS Monograph 4. TITLE AND SUBTITLE Pershing in Mexico: A Case Study in Limited Contingency Operations...Monograph Approval Page Name of Candidate: MAJ Timothy J. Lawrence Monograph Title: Pershing in Mexico: A Case Study in Limited Contingency Operations

Cross-Species Virus-Host Protein-Protein Interactions Inhibiting Innate Immunity

DTIC Science & Technology

2016-07-01

HDTRA1-13-1-0017 Timothy C. Umland Prepared by: Hauptman-Woodward Medical Research Institute DESTRUCTION NOTICE: Destroy this report when it is no...Wayne Schultz (departed project Feb. 2015) and Timothy C. Umland Organization/Institution: Hauptman-Woodward Medical Research Institute Project Title...Figure 1. Zoonotic infectious diseases are a global problem. This project focused upon members of three negative-sense single- stranded RNA (ssRNA

Immune Cells, if Rendered Insensitive to Transforming Growth Factorbeta, Can Cure Prostate Cancer

DTIC Science & Technology

2007-02-01

Robert E. Meyer,2 Shilajit Kundu,1 Michael Pins,2 Borko Javonovic,3 Timothy Kuzel,4 Seong-Jin Kim,5 Luk Van Parijs,6 Norm Smith,1 Larry Wong,1 Norman M...Zhang,1 Ximing Yang,2,5 Shilajit D. Kundu,1 Michael Pins,2,5 Borko Javonovic,3,5 Robert Meryer,2 Seong-Jin Kim,7 Norman M. Greenberg,8 Timothy Kuzel

Detection and Localization of Vibrotactile Signals in Moving Vehicles

DTIC Science & Technology

2008-05-01

Detection and Localization of Vibrotactile Signals in Moving Vehicles by Andrea S . Krausman and Timothy L. White ARL-TR-4463 May 2008...Proving Ground, MD 21005-5425 ARL-TR-4463 May 2008 Detection and Localization of Vibrotactile Signals in Moving Vehicles Andrea S ...5e. TASK NUMBER 6. AUTHOR( S ) Andrea S . Krausman and Timothy L. White (both of ARL) 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION

Tim-3 is a Marker of Plasmacytoid Dendritic Cell Dysfunction during HIV Infection and Is Associated with the Recruitment of IRF7 and p85 into Lysosomes and with the Submembrane Displacement of TLR9.

PubMed

Schwartz, Jordan Ari; Clayton, Kiera L; Mujib, Shariq; Zhang, Hongliang; Rahman, A K M Nur-Ur; Liu, Jun; Yue, Feng Yun; Benko, Erika; Kovacs, Colin; Ostrowski, Mario A

2017-04-15

In chronic diseases, such as HIV infection, plasmacytoid dendritic cells (pDCs) are rendered dysfunctional, as measured by their decreased capacity to produce IFN-α. In this study, we identified elevated levels of T cell Ig and mucin-domain containing molecule-3 (Tim-3)-expressing pDCs in the blood of HIV-infected donors. The frequency of Tim-3-expressing pDCs correlated inversely with CD4 T cell counts and positively with HIV viral loads. A lower frequency of pDCs expressing Tim-3 produced IFN-α or TNF-α in response to the TLR7 agonists imiquimod and Sendai virus and to the TLR9 agonist CpG. Thus, Tim-3 may serve as a biomarker of pDC dysfunction in HIV infection. The source and function of Tim-3 was investigated on enriched pDC populations from donors not infected with HIV. Tim-3 induction was achieved in response to viral and artificial stimuli, as well as exogenous IFN-α, and was PI3K dependent. Potent pDC-activating stimuli, such as CpG, imiquimod, and Sendai virus, induced the most Tim-3 expression and subsequent dysfunction. Small interfering RNA knockdown of Tim-3 increased IFN-α secretion in response to activation. Intracellular Tim-3, as measured by confocal microscopy, was dispersed throughout the cytoplasm prior to activation. Postactivation, Tim-3 accumulated at the plasma membrane and associated with disrupted TLR9 at the submembrane. Tim-3-expressing pDCs had reduced IRF7 levels. Furthermore, intracellular Tim-3 colocalized with p85 and IRF7 within LAMP1 + lysosomes, suggestive of a role in degradation. We conclude that Tim-3 is a biomarker of dysfunctional pDCs and may negatively regulate IFN-α, possibly through interference with TLR signaling and recruitment of IRF7 and p85 into lysosomes, enhancing their degradation. Copyright © 2017 by The American Association of Immunologists, Inc.

Clinical significance of Tim3-positive T cell subsets in patients with multiple sclerosis.

PubMed

Feng, Xuemei; Feng, Juan

2016-12-01

The present study evaluated associations between the percentages of T cell immunoglobulin and mucin domain 3 (Tim3)-positive T cells and related cytokines and multiple sclerosis (MS). We collected peripheral blood samples from 30 MS patients and 30 healthy controls. Flow cytometry was used to determine the proportions of CD3 + Tim3 + , CD4 + Tim3 + , and CD4 + CD25 + Tim3 + in peripheral blood mononuclear cells (PBMCs) and related cell subsets. The serum concentrations of galectin-9, IL-17, and IFN-γ also were determined using enzyme-linked immunosorbent assays (ELISA). The percentages of Tim3-positive T cells in CD4 + and CD4 + CD25 + T cell subsets were significantly lower among MS patients than among controls. This difference was particularly evident in the CD4 + CD25(high) T cell subset. The proportions of CD4 + Tim3 + and CD4 + CD25 + Tim3 + cells in PBMCs were significantly lower in the MS group than in the control group, whereas no significant differences were detected regarding the percentages of CD3 + Tim3 + in PBMCs and T cell subsets. The serum concentrations of galectin-9, IL-17, and IFN-γ all were increased in MS patients compared with healthy controls. Our results support that Tim3 and related cytokines may be involved in the onset of MS. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of a Stable Cell Line, Overexpressing Human T-cell Immunoglobulin Mucin 1

PubMed Central

Ebrahimi, Mina; Kazemi, Tohid; Ganjalikhani-hakemi, Mazdak; Majidi, Jafar; khanahmad, Hossein; Rahimmanesh, Ilnaz; Homayouni, Vida; Kohpayeh, Shirin

2015-01-01

Background Recent researches have demonstrated that human T-cell immunoglobulin mucin 1 (TIM-1) glycoprotein plays important roles in regulation of autoimmune and allergic diseases, as well as in tumor immunity and response to viral infections. Therefore, targeting TIM-1 could be a potential therapeutic approach against such diseases. Objectives In this study, we aimed to express TIM-1 protein on Human Embryonic kidney (HEK) 293T cell line in order to have an available source of the TIM-1 antigen. Materials and Methods The cDNA was synthesized after RNA extraction from peripheral blood mononuclear cells (PBMC) and TIM-1 cDNA was amplified by PCR with specific primers. The PCR product was cloned in pcDNA™3.1/Hygro (+) and transformed in Escherichia coli TOP 10 F’. After cloning, authenticity of DNA sequence was checked and expressed in HEK 293T cells. Finally, expression of TIM-1 was analyzed by flow cytometry and real-time PCR. Results The result of DNA sequencing demonstrated correctness of TIM-1 DNA sequence. The flow cytometry results indicated that TIM-1 was expressed in about 90% of transfected HEK 293T cells. The real-time PCR analysis showed TIM-1 mRNA expression increased 195-fold in transfected cells compared with un-transfected cells. Conclusions Findings of present study demonstrated the successful cloning and expression of TIM-1 on HEK 293T cells. These cells could be used as an immunogenic source for production of specific monoclonal antibodies, nanobodies and aptamers against human TIM-1. PMID:28959306

History of U.S. Military Contributions to the Study of Viral Hemorrhagic Fevers

DTIC Science & Technology

2005-04-01

MILITARY MEDICINE, 170. 4;77, 2005 History of U.S. Military Contributions to the Study of Viral Hemorrhagic Fevers Guarantor: COL Timothy P. Endy, MC...USA Contributors: MAJ Stephen J. Thomas, MC USA*; LCDR James V. Lawler, MC USNf; COL Timothy P, Endv, MC USAI The viral hemorrhagic fever viruses...The viral hemorrhagic fever viruses display a great deal of diversity in their genetic organization, vectors for transmission, and geographic

Developments in Nanoscience: Polyhedral Oligomeric Silsesquioxane (POSS) - Polymers

DTIC Science & Technology

2004-03-08

Approved for public release; distribution is unlimited 1 Developments in Nanoscience: Polyhedral Oligomeric Silsesquioxane (POSS)-Polymers Timothy S ...Polymers 5a. CONTRACT NUMBER F04611-99-C-0025 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) Shawn Phillips; Timothy Haddad...Sandra Tomczak 5d. PROJECT NUMBER 2303 5e. TASK NUMBER M1A3 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) ERC Incorporated

Optical Tuning of the Reflection of Azobenzene Liquid Crystal Doped Cholesterics (Preprint)

DTIC Science & Technology

2007-04-01

RG 6. AUTHOR(S) Uladzimir A . Hrozhyk, Svetlana V . Serak, and Nelson V . Tabiryan (Beam Engineering for Advanced Measurements Corporation) Timothy...Reflection of Azobenzene Liquid Crystal Doped Cholesterics** By Uladzimir A . Hrozhyk, Svetlana V Serak, Nelson V . Tabil)lall * and Timothy 1. Bunning...1249. [5] T. Ikeda, O. Tsutsumi, Science 1995, 268, 1873. [6] T. Ikeda, J Mat. Chern. 2003, 13, 2037. [7] A . Urbas, J. Klosterman, V . Tondiglia, L

LTG Timothy J. Maude: Leader of Change

DTIC Science & Technology

2005-03-18

Reserve, and National Guard - was seriously in question. Army recruiters were struggling to attract sufficient numbers of quality men and women , and...sufficient numbers of quality men and women , and current recruiting initiatives were increasingly ineffective.’• 7 Former Secretary of the Army Louis... number . 1. REPORT DATE 3. DATES COVERED 18 MAR 2005 2. REPORT TYPE 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER LTG Timothy J. Maude Leader of Change 5b

Adaptation of Physiological and Cognitive Workload via Interactive Multi-modal Displays

DTIC Science & Technology

2014-05-28

peer-reviewed journals (N/A for none) 09/07/2013 Received Paper 8.00 James Merlo, Joseph E. Mercado , Jan B.F. Van Erp, Peter A. Hancock. Improving...08, . : , Mr. Joseph Mercado , Mr. Timothy White, Dr. Peter Hancock. Effects of Cross-Modal Sensory Cueing Automation Failurein a Target Detection Task...fields:...... ...... ...... ...... ...... PERCENT_SUPPORTEDNAME FTE Equivalent: Total Number: Discipline Joseph Mercado 0.50 Timothy White 0.50 1.00 2

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

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

PubMed

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

2013-03-01

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.

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.

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

PubMed Central

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

2014-01-01

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

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

PubMed

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

2015-06-12

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

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

PubMed

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

2014-12-12

Filoviruses, including Ebola and Marburg viruses, cause severe hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Human T-cell immunoglobulin and mucin domain 1 (TIM-1) is one of the host proteins that have been shown to promote filovirus entry into cells. In this study, we cloned TIM-1 genes from three different African green monkey kidney cell lines (Vero E6, COS-1, and BSC-1) and found that TIM-1 of Vero E6 had a 23-amino acid deletion and 6 amino acid substitutions compared with those of COS-1 and BSC-1. Interestingly, Vero E6 TIM-1 had a greater ability to promote the infectivity of vesicular stomatitis viruses pseudotyped with filovirus glycoproteins than COS-1-derived TIM-1. We further found that the increased ability of Vero E6 TIM-1 to promote virus infectivity was most likely due to a single amino acid difference between these TIM-1s. These results suggest that a polymorphism of the TIM-1 molecules is one of the factors that influence cell susceptibility to filovirus infection, providing a new insight into the molecular basis for the filovirus host range. Copyright © 2014 Elsevier Inc. All rights reserved.

A fluorescence assay for peptide translocation into mitochondria.

PubMed

Martinez-Caballero, Sonia; Peixoto, Pablo M V; Kinnally, Kathleen W; Campo, María Luisa

2007-03-01

Translocation of the presequence is an early event in import of preproteins across the mitochondrial inner membrane by the TIM23 complex. Import of signal peptides, whose sequences mimic mitochondrial import presequences, was measured using a novel, qualitative, fluorescence assay in about 1h. This peptide assay was used in conjunction with classical protein import analyses and electrophysiological approaches to examine the mechanisms underlying the functional effects of depleting two TIM23 complex components. Tim23p forms, at least in part, the pore of this complex while Tim44p forms part of the translocation motor. Depletion of Tim23p eliminates TIM23 channel activity, which interferes with both peptide and preprotein translocation. In contrast, depletion of Tim44p disrupts preprotein but not peptide translocation, which has no effect on TIM23 channel activity. Two conclusions were made. First, this fluorescence peptide assay was validated as two different mutants were accurately identified. Hence, this assay could provide a rapid means of screening mutants to identify those that fail an initial step in import, i.e., translocation of the presequence. Second, translocation of signal peptides required normal channel activity and disruption of the presequence translocase-associated motor complex did not modify TIM23 channel activity nor prevent presequence translocation.

Temperature-dependent resetting of the molecular circadian oscillator in Drosophila

PubMed Central

Goda, Tadahiro; Sharp, Brandi; Wijnen, Herman

2014-01-01

Circadian clocks responsible for daily time keeping in a wide range of organisms synchronize to daily temperature cycles via pathways that remain poorly understood. To address this problem from the perspective of the molecular oscillator, we monitored temperature-dependent resetting of four of its core components in the fruitfly Drosophila melanogaster: the transcripts and proteins for the clock genes period (per) and timeless (tim). The molecular circadian cycle in adult heads exhibited parallel responses to temperature-mediated resetting at the levels of per transcript, tim transcript and TIM protein. Early phase adjustment specific to per transcript rhythms was explained by clock-independent temperature-driven transcription of per. The cold-induced expression of Drosophila per contrasts with the previously reported heat-induced regulation of mammalian Period 2. An altered and more readily re-entrainable temperature-synchronized circadian oscillator that featured temperature-driven per transcript rhythms and phase-shifted TIM and PER protein rhythms was found for flies of the ‘Tim 4’ genotype, which lacked daily tim transcript oscillations but maintained post-transcriptional temperature entrainment of tim expression. The accelerated molecular and behavioural temperature entrainment observed for Tim 4 flies indicates that clock-controlled tim expression constrains the rate of temperature cycle-mediated circadian resetting. PMID:25165772

Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

PubMed

Du, Xianhong; Wu, Zhuanchang; Xu, Yong; Liu, Yuan; Liu, Wen; Wang, Tixiao; Li, Chunyang; Zhang, Cuijuan; Yi, Fan; Gao, Lifen; Liang, Xiaohong; Ma, Chunhong

2018-05-07

As an immune checkpoint, Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases. However, the precise roles of Tim-3 in nonalcoholic steatohepatitis (NASH) remain unstated. In the current study, we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet (MCD)-induced NASH mice. The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice, including F4/80 + CD11b + , F4/80 + CD68 + , and F4/80 + CD169 + macrophages. Remarkably, Tim-3 knockout (KO) significantly accelerated MCD-induced liver steatosis, displaying higher serum ALT, larger hepatic vacuolation, more liver lipid deposition, and more severe liver fibrosis. Moreover, compared with wild-type C57BL/6 mice, Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2, NLRP3, and caspase-1 p20 together with increased generation of IL-1β and IL-18 in livers. In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species (ROS) and related downstream pro-inflammatory cytokine secretion of IL-1β and IL-18 in macrophages. Exogenous administration of N-Acetyl-L-cysteine (NAC), a small molecular inhibitor of ROS, remarkably suppressed caspase-1 p20 expression and IL-1β and IL-18 production in livers of Tim-3 KO mice, thus significantly reducing the severity of steatohepatitis induced by MCD. In conclusion, Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

Inverse European Latitudinal Cline at the timeless Locus of Drosophila melanogaster Reveals Selection on a Clock Gene: Population Genetics of ls-tim.

PubMed

Zonato, Valeria; Vanin, Stefano; Costa, Rodolfo; Tauber, Eran; Kyriacou, Charalambos P

2018-02-01

The spread of adaptive genetic variants in populations is a cornerstone of evolutionary theory but with relatively few biologically well-understood examples. Previous work on the ls-tim variant of timeless, which encodes the light-sensitive circadian regulator in Drosophila melanogaster, suggests that it may have originated in southeastern Italy. Flies characterized by the new allele show photoperiod-related phenotypes likely to be adaptive in seasonal environments. ls-tim may be spreading from its point of origin in Italy by directional selection, but there are alternative explanations for its observed clinal geographical distribution, including balancing selection and demography. From population analyses of ls-tim frequencies collected on the eastern side of the Iberian Peninsula, we show that ls-tim frequencies are inverted compared with those in Italy. This pattern is consistent with a scenario of directional selection rather than latitude-associated balancing selection. Neutrality tests further reveal the signature of directional selection at the ls-tim site, which is reduced a few kb pairs either side of ls-tim. A reanalysis of allele frequencies from a large number of microsatellite loci do not demonstrate any frequent ls-tim-like spatial patterns, so a general demographic effect or population expansion from southeastern Italy cannot readily explain current ls-tim frequencies. Finally, a revised estimate of the age of ls-tim allele using linkage disequilibrium and coalescent-based approaches reveals that it may be only 300 to 3000 years old, perhaps explaining why it has not yet gone to fixation. ls-tim thus provides a rare temporal snapshot of a new allele that has come under selection before it reaches equilibrium.

Cyclic lipopeptide signature as fingerprinting for the screening of halotolerant Bacillus strains towards microbial enhanced oil recovery.

PubMed

Farias, Bárbara C S; Hissa, Denise C; do Nascimento, Camila T M; Oliveira, Samuel A; Zampieri, Davila; Eberlin, Marcos N; Migueleti, Deivid L S; Martins, Luiz F; Sousa, Maíra P; Moyses, Danuza N; Melo, Vânia M M

2018-02-01

Cyclic lipopeptides (CLPs) are non-ribosomal biosurfactants produced by Bacillus species that exhibit outstanding interfacial activity. The synthesis of CLPs is under genetic and environmental influence, and representatives from different families are generally co-produced, generating isoforms that differ in chemical structure and biological activities. This study to evaluate the effect of low and high NaCl concentrations on the composition and surface activity of CLPs produced by Bacillus strains TIM27, TIM49, TIM68, and ICA13 towards microbial enhanced oil recovery (MEOR). The strains were evaluated in mineral medium containing NaCl 2.7, 66, or 100 g L -1 and growth, surface tension and emulsification activity were monitored. Based on the analysis of 16S rDNA, gyrB and rpoB sequences TIM27 and TIM49 were assigned to Bacillus subtilis, TIM68 to Bacillus vallismortis, and ICA13 to Bacillus amyloliquefaciens. All strains tolerated up to 100-g L -1 NaCl, but only TIM49 and TIM68 were able to reduce surface tension at this concentration. TIM49 also showed emulsification activity at concentrations up to 66-g L -1 NaCl. ESI-MS analysis showed that the strains produced a mixture of CLPs, which presented distinct CLP profiles at low and high NaCl concentrations. High NaCl concentration favored the synthesis of surfactins and/or fengycins that correlated with the surface activities of TIM49 and TIM68, whereas low concentration favored the synthesis of iturins. Taken together, these findings suggest that the determination of CLP signatures under the expected condition of oil reservoirs can be useful in the guidance for choosing well-suited strains to MEOR.

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

Tim-3 Up-regulation in Patients with Gastric Cancer and Peptic Ulcer Disease

PubMed Central

Naghavi-Alhosseini, Mahdieh; Tehrani, Mohsen; Ajami, Abolghasem; Rafiei, Alireza; Taghvaei, Tarang; Vahedi-Larijani, Laleh; Hossein-Nataj, Hadi; Asgarian-Omran, Hossein

2017-01-01

Background: T-cell immunoglobulin and mucin domain protein-3 (Tim-3), an inhibitory immunoregulatory receptor, has been recently implicated in tumor biology and tumor-associated immune suppression. In the present study, expression of Tim-3 was evaluated in gastric cancer (GC) and peptic ulcer disease (PUD) at both mRNA and protein levels. Methods: A total of 133 gastric tissue biopsies, comprising 43 from GC cases, 48 from PUD and 42 from non-ulcer dyspepsia (NUD) serving as controls were collected. Additionally, non-neoplastic adjacent tissue biopsies were also obtained from 6 patients with GC. Infection with Helicobacter pylori was determined by the rapid urease test for all participants and H&E staining was conducted for GC and PUD patients. Tim-3 relative mRNA expression was determined by SYBR Green based Real-Time PCR using β-actin as a reference gene. Tim-3 protein expression was also studied by immunohistochemistry in 7 GC, 7 PUD and 10 NUD tissue samples. Results: Tim-3 was expressed at higher levels in GC (p=0.030) and PUD (p=0.022) cases compared to he NUD group. Among paired samples obtained from gastric cancer patients, tumor tissues showed elevated Tim-3 expression (p=0.019) in comparison with adjacent non-neoplastic biopsies. Tim-3 mRNA findings were supported by detection of more Tim-3 protein in cancerous (p=0.002) and ulcerative (p=0.01) tissues than in controls. Tim-3 was similarly expressed in H. pylori positive and negative cases. Conclusion: Higher Tim-3 expression in patients with gastric cancer and peptic ulcer implies that it might be involved in immune regulation and establishment of these gastrointestinal diseases. Targeted immunotherapy by blocking of inhibitory receptors like Tim-3 could be a promising approach for gastric cancer treatment. PMID:28441784

Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients.

PubMed

Ma, Qiang; Liu, Junning; Wu, Guoliang; Teng, Mujian; Wang, Shaoxuan; Cui, Meng; Li, Yuantao

2018-06-15

Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3 +  Treg accumulation in the tumor was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4 + CD25 +/hi T cells and in the more canonical CD4 + CD25 +/hi Foxp3 + Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into LAG3 - TIM3 - and LAG3 + TIM3 + subsets. In CRC patients, the LAG3 + TIM3 + subset represented approximately half of CD4 + CD25 +/hi T cells and greater than 60% of CD4 + CD25 +/hi Foxp3 + Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3 - TIM3 - CD4 + CD25 +/hi T cells, the LAG3 + TIM3 + CD4 + CD25 +/hi T cells presented considerably higher transforming growth factor (TGF)-β and slightly higher interleukin (IL)-10 secretion, together with higher CTLA-4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3 - TIM3 - CD4 + CD25 +/hi T cells and LAG3 + TIM3 + CD4 + CD25 +/hi T cells displayed different characteristics. Macrophages incubated with LAG3 + TIM3 + CD4 + CD25 +/hi T cells presented lower expression of MHC class II, CD80, CD86, and tumor necrosis factor alpha (TNFα) but higher expression of IL-10, than macrophages incubated with LAG3 - TIM3 - CD4 + CD25 +/hi T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3 + TIM3 + subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3 + TIM3 + Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3 - TIM3 - Treg cells. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Interaction between Galectin-9/TIM-3 pathway and follicular helper CD4+ T cells contributes to viral persistence in chronic hepatitis C.

PubMed

Zhuo, Ya; Zhang, Yi-Fu; Wu, Hong-Jie; Qin, Lei; Wang, Yan-Ping; Liu, A-Min; Wang, Xin-Hong

2017-10-01

Both Galectin 9 (Gal-9)/T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) pathway and follicular helper CD4 + T (Tfh) cells play important roles in persistent hepatitis C virus (HCV) infection. Thus, we aimed to investigate the regulatory role of interaction between Gal-9/TIM-3 pathway and Tfh cells in chronic hepatitis C. A total of 44 chronic hepatitis C patients and 19 normal controls (NCs) were enrolled in this study. Purified CD4 + T cells were cultured by TIM-3 Fc protein, recombinant Gal-9, or IL-21 for 48h. TIM-3 expression, Tfh proportion, and IL-21 production was measured, respectively. The immunomodulatory role of Gal-9/TIM-3 and IL-21 was also investigated in HCV cell culture system in vitro. We found that the percentage corresponding to both TIM-3-positive and CXCR5 + ICOS + Tfh cells within CD4 + T cells, which correlated with HCV RNA replication, was significantly elevated in patients with chronic hepatitis C in comparison with those in NCs. Moreover, blockade of Gal-9/TIM-3 pathway by TIM-3 Fc protein increased Tfh cells proportion, IL-21 mRNA and protein expression within purified CD4 + T cells, while activation of Gal-9/TIM-3 signaling by Gal-9 stimulation decreased IL-21 production in both patients with chronic HCV infection and healthy individuals. Meanwhile, high concentrations (100 and 200ng/mL) of IL-21 stimulation also elevated TIM-3 expression on CD4 + T cells in chronic hepatitis C. Furthermore, TIM-3 blockage and IL-21 stimulation suppressed mRNA expressions of HCV-induced antiviral proteins (myxovirus resistance A and oligoadenylate synthetase) in Huh7.5 cells without affecting viral replication in HCV cell culture system. The interaction between Gal-9/TIM-3 pathway and Tfh cells contributed to viral persistent in chronic HCV infection, which might be pivotal for development of new therapeutic approaches for chronic hepatitis C. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

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 therapeutic approach for CRC patients. PMID:26008981

Peripheral blood TIM-3 positive NK and CD8+ T cells throughout pregnancy: TIM-3/galectin-9 interaction and its possible role during pregnancy.

PubMed

Meggyes, Matyas; Miko, Eva; Polgar, Beata; Bogar, Barbara; Farkas, Balint; Illes, Zsolt; Szereday, Laszlo

2014-01-01

The T-cell immunoglobulin and mucin domain (TIM) family is a relatively newly described group of molecules with a conserved structure and important immunological functions. Identification of Galectin-9 as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important negative regulator of Th1 immunity and tolerance induction. Data about the TIM-3/Gal-9 pathway in the pathogenesis of human diseases is emerging, but their possible role during human pregnancy is not precisely known. The aim of our study was to investigate the number, phenotype and functional activity of TIM-3+ peripheral blood mononuclear cells during healthy human pregnancy. 57 healthy pregnant women [first trimester (n = 16); second trimester (n = 19); third trimester (n = 22)] and 30 non-pregnant controls were enrolled in the study. We measured the surface expression of TIM-3 by cytotoxic T cells, NK cells and NK cell subsets as well as Galectin-9 expression by regulatory T cells by flow cytometry. We analyzed the cytokine production and cytotoxicity of TIM3+ and TIM3- CD8 T and NK cells obtained from non-pregnant and healthy pregnant women at different stages of pregnancy by flow cytometry. Serum Galectin-9 levels were measured by ELISA. Our results show that the numbers of peripheral NK and cytotoxic T cells and their TIM-3 expression do not change between the first, second and third trimesters of pregnancy. Compared to non-pregnant individuals, regulatory T cells show higher level of Galectin-9 expression as pregnancy proceeds, which is in line with the level of Galectin-9 in the patients sera. Cytotoxic T cells, NK cells and NK cell subsets expressing TIM-3 molecule show altered cytokine production and cytotoxicity during pregnancy compared to non-pregnant individuals. Our results indicate that Galectin-9 expressing regulatory T cells, TIM-3+ cytotoxic T cells and NK cells could play an important role in the maintenance of healthy pregnancy.

Characterizing Functional Domains for TIM-Mediated Enveloped Virus Entry

PubMed Central

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

2014-01-01

ABSTRACT T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members were recently identified as phosphatidylserine (PtdSer)-mediated virus entry-enhancing receptors (PVEERs). These proteins enhance entry of Ebola virus (EBOV) and other viruses by binding PtdSer on the viral envelope, concentrating virus on the cell surface, and promoting subsequent internalization. The PtdSer-binding activity of the immunoglobulin-like variable (IgV) domain is essential for both virus binding and internalization by TIM-1. However, TIM-3, whose IgV domain also binds PtdSer, does not effectively enhance virus entry, indicating that other domains of TIM proteins are functionally important. Here, we investigate the domains supporting enhancement of enveloped virus entry, thereby defining the features necessary for a functional PVEER. Using a variety of chimeras and deletion mutants, we found that in addition to a functional PtdSer-binding domain PVEERs require a stalk domain of sufficient length, containing sequences that promote an extended structure. Neither the cytoplasmic nor the transmembrane domain of TIM-1 is essential for enhancing virus entry, provided the protein is still plasma membrane bound. Based on these defined characteristics, we generated a mimic lacking TIM sequences and composed of annexin V, the mucin-like domain of α-dystroglycan, and a glycophosphatidylinositol anchor that functioned as a PVEER to enhance transduction of virions displaying Ebola, Chikungunya, Ross River, or Sindbis virus glycoproteins. This identification of the key features necessary for PtdSer-mediated enhancement of virus entry provides a basis for more effective recognition of unknown PVEERs. IMPORTANCE T-cell immunoglobulin and mucin domain 1 (TIM-1) and other TIM family members are recently identified phosphatidylserine (PtdSer)-mediated virus entry-enhancing receptors (PVEERs). These proteins enhance virus entry by binding the phospholipid, PtdSer, present on the viral membrane. While it is known that the PtdSer binding is essential for the PVEER function of TIM-1, TIM-3 shares this binding activity but does not enhance virus entry. No comprehensive studies have been done to characterize the other domains of TIM-1. In this study, using a variety of chimeric proteins and deletion mutants, we define the features necessary for a functional PVEER. With these features in mind, we generated a TIM-1 mimic using functionally similar domains from other proteins. This mimic, like TIM-1, effectively enhanced transduction. These studies provide insight into the key features necessary for PVEERs and will allow for more effective identification of unknown PVEERs. PMID:24696470

Summary of Awards: FY 1979 and 1980 Program of University Research,

DTIC Science & Technology

1980-12-01

completed. The wind tunnel Timothy M. Barrow, DTS-222 model for correlation of lateral/directional theory is also com- U.S. Department of...of SSOM through generalization and verification MONITOR of the program. The objective is to refine the SSOM to make it Timothy E. Aloney, NRD-12 a...Future Mobility Needs for the Elderly: Development of a Methodology 3. GALLAUDET COLLEGE DOT-OS-501 10 A Study to Identify the Problems that Deaf

Outage management and health physics issue, 2007

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

Agnihotri, Newal

2007-05-15

The focus of the May-June issue is on outage management and health physics. Major articles/reports in this issue include: India: a potential commercial opportunity, a U.S. Department of Commerce Report, by Joe Neuhoff and Justin Rathke; The changing climate for nuclear energy, by Skip Bowman, Nuclear Energy Insitute; Selecting protective clothing, by J. Mark Price, Southern California Edison; and Succssful refurbishment outage, by Sudesh K. Gambhir, Omaha Public Power District. Industry innovation articles in this issue are: Containment radiation monitoring spiking, by Michael W. Lantz and Robert Routolo, Arizona Public Service Company; Improved outage performance, by Michael Powell and Troymore » Wilfong, Arizona Public Service Company, Palo Verde Nuclear Generating Station; Stop repacking valves and achieve leak-free performance, by Kenneth Hart, PPL Susquehanna LLC; and Head assembly upgrade package, by Timothy Petit, Dominion Nuclear.« less

Identification of triosephosphate isomerase as a novel allergen in Octopus fangsiao.

PubMed

Yang, Yang; Chen, Zhong-Wei; Hurlburt, Barry K; Li, Gui-Ling; Zhang, Yong-Xia; Fei, Dan-Xia; Shen, Hai-Wang; Cao, Min-Jie; Liu, Guang-Ming

2017-05-01

Octopus is an important mollusk in human dietary for its nutritional value, however it also causes allergic reactions in humans. Major allergens from octopus have been identified, while the knowledge of novel allergens remains poor. In the present study, a novel allergen with molecular weight of 28kDa protein was purified from octopus (Octopus fangsiao) and identified as triosephosphate isomerase (TIM) by mass spectrometry. TIM aggregated beyond 45°C, and its IgE-binding activity was affected under extreme pH conditions due to the altered secondary structure. In simulated gastric fluid digestion, TIM can be degraded into small fragments, while retaining over 80% of the IgE-binding activity. The full-length cDNA of O. fangsiao TIM (1140bp) was cloned, which encodes 247 amino acid residues, and the entire recombinant TIM was successfully expressed in Escherichia coli BL21, which showed similar immunoreactivity to the native TIM. Different intensity of cross-reactivity among TIM from related species revealed the complexity of its epitopes. Eight linear epitopes of TIM were predicted following bioinformatic analysis. Furthermore, a conformational epitope (A 71 G 74 S 69 D 75 T 73 F 72 V 67 ) was confirmed by the phage display technology. The results revealed the physicochemical and immunological characteristics of TIM, which is significant in the development of hyposensitivity food and allergy diagnosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Taming dendritic cells with TIM-3: another immunosuppressive strategy used by tumors.

PubMed

Patel, Jaina; Bozeman, Erica N; Selvaraj, Periasamy

2012-12-01

Evaluation of: Chiba S, Baghdadi M, Akiba H et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13, 832-842 (2012). The identification of TIM-3 expression on tumor-associated dendritic cells (TADCs) provides insight into another aspect of tumor-mediated immunosuppression. The role of TIM-3 has been well characterized on tumor-infiltrating T cells; however, its role on TADCs was not previously known. The current paper demonstrated that TIM-3 was predominantly expressed by TADCs and its interaction with the nuclear protein HMGB1 suppressed nucleic acid-mediated activation of an effective antitumor immune response. The authors were able to show that TIM-3 interaction with HMGB1 prevented the localization of nucleic acids into endosomal vesicles. Furthermore, chemotherapy was found to be more effective in anti-TIM-3 monoclonal antibody-treated mice or mice depleted of all DCs, which indicated that a significant role is played by TADCs in inhibiting tumor regression. Taken together, these findings identify TIM-3 as a potential target for inducing antitumor immunity in conjunction with DNA vaccines and/or immunogenic chemotherapy in clinical settings.

Architecture and ssDNA interaction of the Timeless-Tipin-RPA complex

PubMed Central

Witosch, Justine; Wolf, Eva; Mizuno, Naoko

2014-01-01

The Timeless-Tipin (Tim-Tipin) complex, also referred to as the fork protection complex, is involved in coordination of DNA replication. Tim-Tipin is suggested to be recruited to replication forks via Replication Protein A (RPA) but details of the interaction are unknown. Here, using cryo-EM and biochemical methods, we characterized complex formation of Tim-Tipin, RPA and single-stranded DNA (ssDNA). Tim-Tipin and RPA form a 258 kDa complex with a 1:1:1 stoichiometry. The cryo-EM 3D reconstruction revealed a globular architecture of the Tim-Tipin-RPA complex with a ring-like and a U-shaped domain covered by a RPA lid. Interestingly, RPA in the complex adopts a horse shoe-like shape resembling its conformation in the presence of long ssDNA (>30 nucleotides). Furthermore, the recruitment of the Tim-Tipin-RPA complex to ssDNA is modulated by the RPA conformation and requires RPA to be in the more compact 30 nt ssDNA binding mode. The dynamic formation and disruption of the Tim-Tipin-RPA-ssDNA complex implicates the RPA-based recruitment of Tim-Tipin to the replication fork. PMID:25348395

Taming dendritic cells with TIM-3: Another immunosuppressive strategy by tumors

PubMed Central

Patel, Jaina; Bozeman, Erica N.; Selvaraj, Periasamy

2013-01-01

The identification of TIM-3 expression on tumor associated dendritic cells (TADCs) provides insight into another aspect of tumor-mediated immunosuppression. The role of TIM-3 has been well characterized on tumor-infiltrating T cells, however its role on TADCs was not previously known. The current paper demonstrated that TIM-3 was predominantly expressed by TADCs and its interaction with the nuclear protein HMGB1 suppressed nucleic acid mediated activation of an effective antitumor immune response. The authors were able to show that TIM-3 interaction with HMGB1 prevented the localization of nucleic acids into endosomal vesicles. Furthermore, chemotherapy was found to be more effective in anti-TIM-3 mAb treated mice or mice depleted of all DCs which indicated that significant role played by TADCs inhibiting tumor regression. Taken together, these findings identify TIM-3 as a potential target for inducing antitumor immunity in conjunction with DNA vaccines and/or immunogenic chemotherapy in clinical settings. PMID:23240746

The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry.

PubMed

Meertens, Laurent; Carnec, Xavier; Lecoin, Manuel Perera; Ramdasi, Rasika; Guivel-Benhassine, Florence; Lew, Erin; Lemke, Greg; Schwartz, Olivier; Amara, Ali

2012-10-18

Dengue viruses (DVs) are responsible for the most medically relevant arboviral diseases. However, the molecular interactions mediating DV entry are poorly understood. We determined that TIM and TAM proteins, two receptor families that mediate the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, serve as DV entry factors. Cells poorly susceptible to DV are robustly infected after ectopic expression of TIM or TAM receptors. Conversely, DV infection of susceptible cells is inhibited by anti-TIM or anti-TAM antibodies or knockdown of TIM and TAM expression. TIM receptors facilitate DV entry by directly interacting with virion-associated PtdSer. TAM-mediated infection relies on indirect DV recognition, in which the TAM ligand Gas6 acts as a bridging molecule by binding to PtdSer within the virion. This dual mode of virus recognition by TIM and TAM receptors reveals how DVs usurp the apoptotic cell clearance pathway for infectious entry. Copyright © 2012 Elsevier Inc. All rights reserved.

Tim Johansson | NREL

Science.gov Websites

performed maintenance, operation, and repair on laboratory support systems, including some minor /electrical technician Chief Engineer, Tim leads the maintenance crew at NWTC. Prior to joining NREL, Tim was

Mapping swamp timothy (Cripsis schenoides) seed productivity using spectral values and vegetation indices in managed wetlands

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

Rahilly, P.J.A.; Li, D.; Guo, Q.

2010-01-15

This work examines the potential to predict the seed productivity of a key wetland plant species using spectral reflectance values and spectral vegetation indices. Specifically, the seed productivity of swamp timothy (Cripsis schenoides) was investigated in two wetland ponds, managed for waterfowl habitat, in California's San Joaquin Valley. Spectral reflectance values were obtained and associated spectral vegetation indices (SVI) calculated from two sets of high resolution aerial images (May 11, 2006 and June 9, 2006) and were compared to the collected vegetation data. Vegetation data were collected and analyzed from 156 plots for total aboveground biomass, total aboveground swamp timothymore » biomass, and total swamp timothy seed biomass. The SVI investigated included the Simple Ratio (SR), Normalized Difference Vegetation Index (NDVI), Soil Adjusted Vegetation Index (SAVI), Transformed Soil Adjusted Vegetation Index (TSAVI), Modified Soil Adjusted Vegetation Index (MSAVI), and Global Environment Monitoring Index (GEMI). We evaluated the correlation of the various SVI with in situ vegetation measurements for linear, quadratic, exponential and power functions. In all cases, the June image provided better predictive capacity relative to May, a result that underscores the importance of timing imagery to coincide with more favorable vegetation maturity. The north pond with the June image using SR and the exponential function (R{sup 2}=0.603) proved to be the best predictor of swamp timothy seed productivity. The June image for the south pond was less predictive, with TSAVI and the exponential function providing the best correlation (R{sup 2}=0.448). This result was attributed to insufficient vegetal cover in the south pond (or a higher percentage of bare soil) due to poor drainage conditions which resulted in a delay in swamp timothy germination. The results of this work suggest that spectral reflectance can be used to estimate seed productivity in managed seasonal wetlands.« less

For geological investigations with airborne thermal infrared multispectral images: Transfer of calibration from laboratory spectrometer to TIMS as alternative for removing atmospheric effects

NASA Technical Reports Server (NTRS)

Edgett, Kenneth S.; Anderson, Donald L.

1995-01-01

This paper describes an empirical method to correct TIMS (Thermal Infrared Multispectral Scanner) data for atmospheric effects by transferring calibration from a laboratory thermal emission spectrometer to the TIMS multispectral image. The method does so by comparing the laboratory spectra of samples gathered in the field with TIMS 6-point spectra for pixels at the location of field sampling sites. The transference of calibration also makes it possible to use spectra from the laboratory as endmembers in unmixing studies of TIMS data.

Hydrographic Data from the Pilot Study of the Coastal Transition Zone (CTZ) Program, 17-26 March 1987

DTIC Science & Technology

1989-01-30

C- o C! -0 0 0 -4i 104 Wz 0 4 P, N. *40 #A -*0 9*4 14 -*40s on f I046.. I 4n in f" *l eq r,4 "I CA 0~ 0 ~ 4 i 0 ~1 0 00 Va 4 n !=4 O .." VV " Ka ...97331 Dr. Robert L. Smith 1 Dr. Adriana Huyer I Dr. P. Michael Kosro 1 Dr. Mark R. Abbott I Dr. John S. Allen 1 Dr. Tim Cowles 1 Dr. David Kadco i Dr. Ted

Hydrographic Data from the Pilot Study of the Coastal Transition Zone (CTZ) Program, 15-28 June 1987

DTIC Science & Technology

1989-04-01

8217i Wi Ui L6 LOlaa to LO to 0 a. ’U ’𔃺I’ N W Oa ON4’𔃺 C40 W4010404 r4 10 r% r - ’ : r a . ) - ’ : - : 0 ’n p 4 44 * t*- Ka 0I 0A I 0A 000)In "i pq m...OR 97331 Dr. Robert L. Smith 1 Dr. Adriana Huyer 1 Dr. P. Michael Kosro I Dr. Mark R. Abbott 1 Dr. John S. Allen I Dr. Tim Cowles 1 Dr. David Kadco

The effect of specific proline residues on the kinetic stability of the triosephosphate isomerases of two trypanosomes.

PubMed

Guzmán-Luna, Valeria; Quezada, Andrea G; Díaz-Salazar, A Jessica; Cabrera, Nallely; Pérez-Montfort, Ruy; Costas, Miguel

2017-04-01

The effect of specific residues on the kinetic stability of two closely related triosephosphate isomerases (from Trypanosoma cruzi, TcTIM and Trypanosoma brucei, TbTIM) has been studied. Based on a comparison of their β-turn occurrence, we engineered two chimerical enzymes where their super secondary β-loop-α motifs 2 ((βα) 2 ) were swapped. Differential scanning calorimetry (DSC) experiments showed that the (βα) 2 motif of TcTIM inserted into TbTIM (2Tc) increases the kinetic stability. On the other hand, the presence of the (βα) 2 motif of TbTIM inserted into TcTIM (2Tb) gave a chimerical protein difficult to purify in soluble form and with a significantly reduced kinetic stability. The comparison of the contact maps of the (βα) 2 of TbTIM and TcTIM showed differences in the contact pattern of residues 43 and 49. In TcTIM these residues are prolines, located at the N-terminal of loop-2 and the C-terminal of α-helix-2. Twelve mutants were engineered involving residues 43 and 49 to study the effect over the unfolding activation energy barrier (E A ). A systematic analysis of DSC data showed a large decrease on the E A of TcTIM (ΔE A ranging from 468 to 678 kJ/mol) when the single and double proline mutations are present. The relevance of Pro43 to the kinetic stability is also revealed by mutation S43P, which increased the free energy of the transition state of TbTIM by 17.7 kJ/mol. Overall, the results indicate that protein kinetic stability can be severely affected by punctual mutations, disturbing the complex network of interactions that, in concerted action, determine protein stability. Proteins 2017; 85:571-579. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Supplemental Enviromnentul Assessment for Control of Common Reed (Phragmites australis) at Joint Base Langley-Eustis, Fort Eustis, Virginia

DTIC Science & Technology

2012-09-01

lo prevent new nests lium that area and a programmutic permit is being discussed with US Fish und Wildlite Service. n1ese nests also have designated...mgular mail lo : Timothy P, Christensen 733 Mission Snpport Group Civil Engineer Division 1407 Washington Blvd Fort Eustis, VA 23604 Timothy .p...have consulted with city .~taff rcgan.llng this project. Based on this review, the proposal appears lo be consistent with local and rogional plans

iss047e135573

NASA Image and Video Library

2016-05-28

ISS047e135573 (05/28/2016) --- Expedition 47 astronauts Jeff Williams (left) and Timothy Kopra (middle) of NASA, along with ESA (European Space Agency) astronaut Timothy Peake (right) pose in front of the entrance to the Bigelow Expandable Activity Module (BEAM) after successful expansion. NASA Astronaut Jeff Williams and the NASA and Bigelow Aerospace teams working at Mission Control Center at NASA’s Johnson Space Center spent more than seven hours on operations to fill the BEAM with air to cause it to expand.

NATO - Standardization of Equipment Now and in the Future.

DTIC Science & Technology

1986-05-14

RD-RI66 472 NATO - STANDRROIZRTION OF EGUI UET MOM AMO IN THE 1/1 FUTUREMU RY MAR COLL CARLISLE SARACKS PA T C SCOBIE 14 NAY SE UNCLASSIFIEP F/O 15/5...FUTURE BY COLONEL TIMOTHY C. SCOBIE D T IC IIELECTE JUN 17 LD DISTRIBUTION STATEMENT A: Approved for public release- distribution is unlimited. Aq14...AUTHOR(*) S. CONTRACT OR GRANT NUMBER(&) COL Timothy C. Scobie 9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT. PROJECT. TASK AREA d WORK

Catalog of Resources for Education in Ada (Trade Name) and Software Engineering (CREASE). Version 5.0.

DTIC Science & Technology

1988-04-01

are eligible to participate in this course. This course is not offered for graduate credit. This course is taught by Timothy J. Fullam. For more...information on this course, contact Timothy J. Fullman at the above address and phone number. University of Alaska Southeast CREASE Version 5.0 13 CS 202...259 DATA STRUCTURES USING Ada University Offeror: Gallaudet University Department of Math/Computer Science Washington, DC 20002 (202) 651-5315 The

Hunting America’s Most Wanted While Saving Money, Lives, and Face: The Rise of RPA

DTIC Science & Technology

2014-06-01

THE RISE OF RPA BY TIMOTHY J. CURRY A THESIS PRESENTED TO THE FACULTY OF THE SCHOOL OF ADVANCED AIR AND SPACE STUDIES FOR...iv ABOUT THE AUTHOR Major Timothy J. Curry is a 1999 graduate of the USAF Academy, where he majored in social sciences. His 15... Curry will become a director of operations at Creech Air Force Base, Nevada. Major Curry is married to his best friend, and they have two children

Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor

DTIC Science & Technology

2013-07-01

Dawen Zhao, Masaya Takahashi, Timothy Dobin, Leah Gandee, Timothy D. Solberg, Amyn A. Habib and Debabrata Saha; International Journal of Oncology, 42...5] Kong Z, Xie D, Boike T, Raghavan P, Burma S, Chen DJ, Habib AA, Chakraborty A, Hsieh JT, and Saha D (2010). Downregulation of human DAB2IP gene...study. Phys Med Biol 56: 1243-1258, 2011. 4. De Crevoisier R, Tucker SL , Dong L, et al: Increased risk of biochemical and local failure in patients

Analysis of the Air Force Logistics Enterprise. Evaluation of Global Repair Network Options for Supporting the F-16 and KC-135

DTIC Science & Technology

2009-01-01

Approved for public release; distribution unlimited PROJECT AIR FORCE Ronald G. McGarvey, Manuel Carrillo, Douglas C. Cato, Jr., John G. Drew, Thomas Lang...Planning Framework, Robert S. Tripp, Lionel A. Galway, Paul Killingsworth, Eric Peltz, Timothy Ramey, and John G. Drew (MR-1056-AF). This report describes...Robert S. Tripp, Timothy Ramey, and John G. Drew (MR-1174-AF). This report examines alternatives for meeting F-15 avionics maintenance requirements

Indigenous Police Forces in Counterinsurgency

DTIC Science & Technology

2010-05-27

A ppr oved for Public R elease; Distr ibution is Unlimited Indigenous P olice F orces in C ounterins urgenc y A Monograph by Major Timothy...Std. Z39.18 iv S C HOOL OF ADV ANC E D MIL IT AR Y S T UDIE S MONOG R AP H AP P R OV AL Major Timothy R. Mungie Title of Monograph...research. T he Organization of Indigenous P olic e in C ounterins urgenc y Operations To explore what makes for indigenous police

Improving Air Force Command and Control Through Enhanced Agile Combat Support Planning, Execution, Monitoring, and Control Processes

DTIC Science & Technology

2012-01-01

Tripp, Lionel A. Galway , Timothy L. Ramey, Mahyar A. Amouzegar, and Eric Peltz (MR-1179-AF), 2000. This report describes a vision for the combat...Postures, Lionel  A. Galway , Robert S. Tripp, Timothy  L. Ramey, and John G. Drew (MR-1075-AF), 2000. This report describes how alternative resourcing of...Aerospace Forces: An Integrated Strate- gic Agile Combat Support Planning Framework, Robert S. Tripp, Lionel  A. Galway , Paul Killingsworth, Eric Peltz

Disruption of T-cell immunoglobulin and mucin domain molecule (TIM)-1/TIM4 interaction as a therapeutic strategy in a dendritic cell-induced peanut allergy model.

PubMed

Feng, Bai-Sui; Chen, Xiao; He, Shao-Heng; Zheng, Peng-Yuan; Foster, Jane; Xing, Zhou; Bienenstock, John; Yang, Ping-Chang

2008-07-01

Recent reports indicate that dendritic cell (DC)-derived T-cell immunoglobulin and mucin domain molecule (TIM)-4 plays an important role in the initiation of T(H)2 polarization. This study aims to elucidate the mechanisms of peanut allergy mediated by microbial products and DCs and the relationship between peanut allergy and TIM4. Mouse bone marrow-derived DCs (BMDCs) were generated and exposed to cholera toxin (CT) or/and peanut extract (PE) for 24 hours and then adoptively transferred to naive mice. After re-exposure to specific antigen PE, the mice were killed; intestinal allergic status was determined. Increased expression of TIM4 and costimulatory molecules was detected in BMDCs after concurrent exposure to CT and PE. Adoptively transferred CT/PE-conditioned BMDCs resulted in the increases in serum PE-specific IgE and skewed T(H)2 polarization in the intestine. Oral challenge with specific antigen PE induced mast cell activation in the intestine. Treating with Toll-like receptor 4 small interfering RNA abolished increased expression of TIM4 and costimulatory molecules by BMDCs. Pretreatment with anti-TIM1 or anti-TIM4 antibody abolished PE-specific T(H)2 polarization and allergy in the intestine. Concurrent exposure to microbial product CT and food antigen PE increases TIM4 expression in DCs and promotes DC maturation, which plays an important role in the initiation of PE-specific T(H)2 polarization and allergy in the intestine. Modulation of TIM4 production in DCs represents a novel therapeutic approach for the treatment of peanut allergy.

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

PubMed Central

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

2015-01-01

CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy. PMID:25950468

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

PubMed

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.

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

Architecture and ssDNA interaction of the Timeless-Tipin-RPA complex.

PubMed

Witosch, Justine; Wolf, Eva; Mizuno, Naoko

2014-11-10

The Timeless-Tipin (Tim-Tipin) complex, also referred to as the fork protection complex, is involved in coordination of DNA replication. Tim-Tipin is suggested to be recruited to replication forks via Replication Protein A (RPA) but details of the interaction are unknown. Here, using cryo-EM and biochemical methods, we characterized complex formation of Tim-Tipin, RPA and single-stranded DNA (ssDNA). Tim-Tipin and RPA form a 258 kDa complex with a 1:1:1 stoichiometry. The cryo-EM 3D reconstruction revealed a globular architecture of the Tim-Tipin-RPA complex with a ring-like and a U-shaped domain covered by a RPA lid. Interestingly, RPA in the complex adopts a horse shoe-like shape resembling its conformation in the presence of long ssDNA (>30 nucleotides). Furthermore, the recruitment of the Tim-Tipin-RPA complex to ssDNA is modulated by the RPA conformation and requires RPA to be in the more compact 30 nt ssDNA binding mode. The dynamic formation and disruption of the Tim-Tipin-RPA-ssDNA complex implicates the RPA-based recruitment of Tim-Tipin to the replication fork. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Identification of a Degradation Signal Sequence within Substrates of the Mitochondrial i-AAA Protease.

PubMed

Rampello, Anthony J; Glynn, Steven E

2017-03-24

The i-AAA protease is a component of the mitochondrial quality control machinery that regulates respiration, mitochondrial dynamics, and protein import. The protease is required to select specific substrates for degradation from among the diverse complement of proteins present in mitochondria, yet the rules that govern this selection are unclear. Here, we reconstruct the yeast i-AAA protease, Yme1p, to examine the in vitro degradation of two intermembrane space chaperone subunits, Tim9 and Tim10. Yme1p degrades Tim10 more rapidly than Tim9 despite high sequence and structural similarity, and loss of Tim10 is accelerated by the disruption of conserved disulfide bonds within the substrate. An unstructured N-terminal region of Tim10 is necessary and sufficient to target the substrate to the protease through recognition of a short phenylalanine-rich motif, and the presence of similar motifs in other small Tim proteins predicts robust degradation by the protease. Together, these results identify the first specific degron sequence within a native i-AAA protease substrate. Copyright © 2017 Elsevier Ltd. All rights reserved.

The plant i-AAA protease controls the turnover of an essential mitochondrial protein import component.

PubMed

Opalińska, Magdalena; Parys, Katarzyna; Murcha, Monika W; Jańska, Hanna

2018-01-29

Mitochondria are multifunctional organelles that play a central role in energy metabolism. Owing to the life-essential functions of these organelles, mitochondrial content, quality and dynamics are tightly controlled. Across the species, highly conserved ATP-dependent proteases prevent malfunction of mitochondria through versatile activities. This study focuses on a molecular function of the plant mitochondrial inner membrane-embedded AAA protease (denoted i -AAA) FTSH4, providing its first bona fide substrate. Here, we report that the abundance of the Tim17-2 protein, an essential component of the TIM17:23 translocase (Tim17-2 together with Tim50 and Tim23), is directly controlled by the proteolytic activity of FTSH4. Plants that are lacking functional FTSH4 protease are characterized by significantly enhanced capacity of preprotein import through the TIM17:23-dependent pathway. Taken together, with the observation that FTSH4 prevents accumulation of Tim17-2, our data point towards the role of this i -AAA protease in the regulation of mitochondrial biogenesis in plants. © 2018. Published by The Company of Biologists Ltd.

TIM Version 3.0 beta - Technical Description and User's Guidance

EPA Pesticide Factsheets

Provides technical information on version 3.0 of the Terrestrial Investigation Model (TIM v.3.0). Describes how TIM derives joint distributions of exposure and toxicity to calculate the risk of mortality to birds.

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm.

PubMed

Younan, Patrick; Iampietro, Mathieu; Nishida, Andrew; Ramanathan, Palaniappan; Santos, Rodrigo I; Dutta, Mukta; Lubaki, Ndongala Michel; Koup, Richard A; Katze, Michael G; Bukreyev, Alexander

2017-09-26

Ebola virus (EBOV) disease (EVD) results from an exacerbated immunological response that is highlighted by a burst in the production of inflammatory mediators known as a "cytokine storm." Previous reports have suggested that nonspecific activation of T lymphocytes may play a central role in this phenomenon. T-cell immunoglobulin and mucin domain-containing protein 1 (Tim-1) has recently been shown to interact with virion-associated phosphatidylserine to promote infection. Here, we demonstrate the central role of Tim-1 in EBOV pathogenesis, as Tim-1 -/- mice exhibited increased survival rates and reduced disease severity; surprisingly, only a limited decrease in viremia was detected. Tim-1 -/- mice exhibited a modified inflammatory response as evidenced by changes in serum cytokines and activation of T helper subsets. A series of in vitro assays based on the Tim-1 expression profile on T cells demonstrated that despite the apparent absence of detectable viral replication in T lymphocytes, EBOV directly binds to isolated T lymphocytes in a phosphatidylserine-Tim-1-dependent manner. Exposure to EBOV resulted in the rapid development of a CD4 Hi CD3 Low population, non-antigen-specific activation, and cytokine production. Transcriptome and Western blot analysis of EBOV-stimulated CD4 + T cells confirmed the induction of the Tim-1 signaling pathway. Furthermore, comparative analysis of transcriptome data and cytokine/chemokine analysis of supernatants highlight the similarities associated with EBOV-stimulated T cells and the onset of a cytokine storm. Flow cytometry revealed virtually exclusive binding and activation of central memory CD4 + T cells. These findings provide evidence for the role of Tim-1 in the induction of a cytokine storm phenomenon and the pathogenesis of EVD. IMPORTANCE Ebola virus infection is characterized by a massive release of inflammatory mediators, which has come to be known as a cytokine storm. The severity of the cytokine storm is consistently linked with fatal disease outcome. Previous findings have demonstrated that specific T-cell subsets are key contributors to the onset of a cytokine storm. In this study, we investigated the role of Tim-1, a T-cell-receptor-independent trigger of T-cell activation. We first demonstrated that Tim-1-knockout (KO) mice survive lethal Ebola virus challenge. We then used a series of in vitro assays to demonstrate that Ebola virus directly binds primary T cells in a Tim-1-phosphatidylserine-dependent manner. We noted that binding induces a cytokine storm-like phenomenon and that blocking Tim-1-phosphatidylserine interactions reduces viral binding, T-cell activation, and cytokine production. These findings highlight a previously unknown role of Tim-1 in the development of a cytokine storm and "immune paralysis." Copyright © 2017 Younan et al.

Quantitative parameters of complexes of tris(1-alkylindol-3-yl)methylium salts with serum albumin: Relevance for the design of drug candidates.

PubMed

Durandin, Nikita A; Tsvetkov, Vladimir B; Bykov, Evgeny E; Kaluzhny, Dmitry N; Lavrenov, Sergey N; Tevyashova, Anna N; Preobrazhenskaya, Maria N

2016-09-01

Triarylmethane derivatives are extensively investigated as antitumor and antibacterial drug candidates alone and as photoactivatable compounds. In the series of tris(1-alkylindol-3-yl)methylium salts (TIMs) these two activities differed depending on the length of N-alkyl chain, with C4-5 derivatives being the most potent compared to the shorter or longer chain analogs and to the natural compound turbomycin A (no N-substituent). Given that the human serum albumin (HSA) is a major transporter protein with which TIMs can form stable complexes, and that the formation of these complexes might be advantageous for phototoxicity of TIMs we determined the quantitative parameters of TIMs-HSA binding using spectroscopic methods and molecular docking. TIMs bound to HSA (1:1 stoichiometry) altered the protein's secondary structure by changing the α-helix/β-turn ratio. The IIa subdomain (Sudlow site I) is the preferred TIM binding site in HSA as determined in competition experiments with reference drugs ibuprofen and warfarin. The values of binding constants increased with the number of CH2 groups from 0 to 6 and then dropped down for C10 compound, a dependence similar to the one observed for cytocidal potency of TIMs. We tend to attribute this non-linear dependence to an interplay between hydrophobicity and steric hindrance, the two key characteristics of TIMs-HSA complexes calculated in the molecular docking procedure. These structure-activity relationships provide evidence for rational design of TIMs-based antitumor and antimicrobial drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

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

PubMed

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

2016-01-01

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

Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma

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

Liu, Yang; Cai, Pengcheng; Wang, Ning

Insights into the role of the mitogen-activated protein kinase (MAPK) pathway and immune checkpoints have led combined targeted therapy and immunotherapy to be a promising regimen. Trametinib, as a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated effectiveness in patients with advanced melanoma. T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3), an immune checkpoint molecule, participates in multiple negative regulation of antitumor immunity. We for the first time to our knowledge reported the combination of trametinib and anti-Tim-3 monoclonal antibody (mAb) in treating B16-F10 melanoma mice. We discovered that trametinib remarkably promoted apoptosis and inhibited cell proliferation while inhibition of MEKmore » improved the expression of Tim-3 and caused the decrease of CD8{sup +} T cells; to the contrary, anti-Tim-3 mAb enhanced antitumor immunity by stimulating CD8{sup +} T cells, thus the combined therapy produced potent antitumor effect cooperatively. Taken together, our study provides compelling evidence for combining trametinib and anti-Tim-3 mAb as a potential valuable regimen in treating melanoma. - Highlights: • The potent antitumor efficacy of combined trametinib and anti-Tim-3 mAb. • MEK inhibitor involves in up-regulation of Tim-3. • The combined medication provides new insights into melanoma treatment.« less

TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions

PubMed Central

Das, Anshuman; Hirai-Yuki, Asuka; González-López, Olga; Rhein, Bethany; Moller-Tank, Sven; Brouillette, Rachel; Hensley, Lucinda; Misumi, Ichiro; Lovell, William; Cullen, John M.; Whitmire, Jason K.; Maury, Wendy

2017-01-01

ABSTRACT Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1−/− Ifnar1−/− and Tim4−/− Ifnar1−/− double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1−/− mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1−/−Ifnar1−/− mice compared to Ifnar1−/− mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice. PMID:28874468

Future sea-level rise in the Mediterranean Sea

NASA Astrophysics Data System (ADS)

Galassi, Gaia; Spada, Giorgio

2014-05-01

Secular sea level variations in the Mediterranean Sea are the result of a number of processes characterized by distinct time scales and spatial patterns. Here we predict the future sea level variations in the Mediterranean Sea to year 2050 combining the contributions from terrestrial ice melt (TIM), glacial isostatic adjustment (GIA), and the ocean response (OR) that includes the thermal expansion and the ocean circulation contributions. The three contributions are characterized by comparable magnitudes but distinctly different sea-level fingerprints across the Mediterranean basin. The TIM component of future sea-level rise is taken from Spada et al. (2013) and it is mainly driven by the melt of small glaciers and ice caps and by the dynamic ice loss from Antarctica. The sea-level fingerprint associated with GIA is studied using two distinct models available from the literature: ICE-5G(VM2) (Peltier, 2004) and the ice model progressively developed at the Research School of Earth Sciences (RSES) of the National Australian University (KL05) (see Fleming and Lambeck, 2004 and references therein). Both the GIA and the TIM sea-level predictions have been obtained with the aid of the SELEN program (Spada and Stocchi, 2007). The spatially-averaged OR component, which includes thermosteric and halosteric sea-level variations, recently obtained using a regional coupled ocean-atmosphere model (Carillo et al., 2012), vary between 2 and 7 cm according to scenarios adopted (EA1B and EA1B2, see Meehl at al., 2007). Since the sea-level variations associated with TIM mainly result from the gravitational interactions between the cryosphere components, the oceans and the solid Earth, and long-wavelength rotational variations, they are characterized by a very smooth global pattern and by a marked zonal symmetry reflecting the dipole geometry of the ice sources. Since the Mediterranean Sea is located in the intermediate far-field of major ice sources, TIM sea-level changes have sub-eustatic values (i.e. they do not exceed the global average) and show little (but still significant) variations across the basin associated with the subsidence driven by the meltwater load. For year 2050, TIM calculations predict a sea-level rise of ~10 and ~30 cm for the mid range and the high end scenarios, respectively. Mainly because of the distinct mantle viscosity profiles adopted in ICE-5G(VM2) and KL05, the GIA patterns differ significantly and, in contrast with the TIM fingerprint, are both characterized by strong variations across the Mediterranean Sea, showing maximum values in the bulk of the basin. For the OR component, a significant geographical variation is observed across the Mediterranean sub-basins, corresponding to different Atlantic boundary conditionsAccording to this study, the total future sea-level rise for year 2050 will reach maximum values for the extreme scenario (hig-hend prediction for TIM, KL05 for GIA and EA1B2 for OR) of ˜ 27 cm in average with peak of ˜ 30 cm in the central sub-basins. Our results show that when these three components of future sea-level rise are simultaneously considered, the spatial variability is enhanced because of the neatly distinct geometry of the three fingerprints. References: Carillo, A., Sannino, G., Artale, V., Ruti, P., Calmanti, S., DellAquila, A., 2012, Clim. Dyn. 39 (9-10), 2167-2184; Fleming, K. and Lambeck, K., 2004, Quat. Sci. Rev. 23 (9-10), 1053-1077; Meehl, G.A., and 11 others, 2007, in Climate Change 2007: The Physical Science Basis, Cambridge University Press; Peltier W.R., 2004, Annu. Rev. Earth Pl. Sc., 32, 111-149; Spada, G. and Stocchi, P., 2007, Comput. and Geosci., 33(4), 538-562; Spada G., Bamber J. L., Hurkmans R. T. W. L., 2013, Geophys. Res. Lett., 1-5, 40.

TIM Barrel Protein Structure Classification Using Alignment Approach and Best Hit Strategy

NASA Astrophysics Data System (ADS)

Chu, Jia-Han; Lin, Chun Yuan; Chang, Cheng-Wen; Lee, Chihan; Yang, Yuh-Shyong; Tang, Chuan Yi

2007-11-01

The classification of protein structures is essential for their function determination in bioinformatics. It has been estimated that around 10% of all known enzymes have TIM barrel domains from the Structural Classification of Proteins (SCOP) database. With its high sequence variation and diverse functionalities, TIM barrel protein becomes to be an attractive target for protein engineering and for the evolution study. Hence, in this paper, an alignment approach with the best hit strategy is proposed to classify the TIM barrel protein structure in terms of superfamily and family levels in the SCOP. This work is also used to do the classification for class level in the Enzyme nomenclature (ENZYME) database. Two testing data sets, TIM40D and TIM95D, both are used to evaluate this approach. The resulting classification has an overall prediction accuracy rate of 90.3% for the superfamily level in the SCOP, 89.5% for the family level in the SCOP and 70.1% for the class level in the ENZYME. These results demonstrate that the alignment approach with the best hit strategy is a simple and viable method for the TIM barrel protein structure classification, even only has the amino acid sequences information.

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

PubMed Central

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

2013-01-01

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

Ebola Virus Binding to Tim-1 on T Lymphocytes Induces a Cytokine Storm

PubMed Central

Younan, Patrick; Iampietro, Mathieu; Nishida, Andrew; Ramanathan, Palaniappan; Santos, Rodrigo I.; Dutta, Mukta; Lubaki, Ndongala Michel; Koup, Richard A.; Katze, Michael G.

2017-01-01

ABSTRACT Ebola virus (EBOV) disease (EVD) results from an exacerbated immunological response that is highlighted by a burst in the production of inflammatory mediators known as a “cytokine storm.” Previous reports have suggested that nonspecific activation of T lymphocytes may play a central role in this phenomenon. T-cell immunoglobulin and mucin domain-containing protein 1 (Tim-1) has recently been shown to interact with virion-associated phosphatidylserine to promote infection. Here, we demonstrate the central role of Tim-1 in EBOV pathogenesis, as Tim-1−/− mice exhibited increased survival rates and reduced disease severity; surprisingly, only a limited decrease in viremia was detected. Tim-1−/− mice exhibited a modified inflammatory response as evidenced by changes in serum cytokines and activation of T helper subsets. A series of in vitro assays based on the Tim-1 expression profile on T cells demonstrated that despite the apparent absence of detectable viral replication in T lymphocytes, EBOV directly binds to isolated T lymphocytes in a phosphatidylserine–Tim-1-dependent manner. Exposure to EBOV resulted in the rapid development of a CD4Hi CD3Low population, non-antigen-specific activation, and cytokine production. Transcriptome and Western blot analysis of EBOV-stimulated CD4+ T cells confirmed the induction of the Tim-1 signaling pathway. Furthermore, comparative analysis of transcriptome data and cytokine/chemokine analysis of supernatants highlight the similarities associated with EBOV-stimulated T cells and the onset of a cytokine storm. Flow cytometry revealed virtually exclusive binding and activation of central memory CD4+ T cells. These findings provide evidence for the role of Tim-1 in the induction of a cytokine storm phenomenon and the pathogenesis of EVD. PMID:28951472

Tim-3 facilitates osteosarcoma proliferation and metastasis through the NF-κB pathway and epithelial-mesenchymal transition.

PubMed

Feng, Z M; Guo, S M

2016-09-02

The aim of this study was to investigate the expression of T-cell immunoglobulin mucin domain molecule-3 (Tim-3) in osteosarcoma tissues, and analyze its effect on cell proliferation and metastasis in an osteosarcoma cell line. Tim-3 mRNA and protein expression in osteosarcoma tissue was detected by reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. Additionally, the cell viability, apoptosis rate, and invasive ability of the osteosarcoma cell line MG-63 were tested using the methyl thiazolyl tetrazolium assay, Annexin V-propidium iodide flow cytometry, and a Transwell assay, respectively, following Tim-3 interference using small interfering RNA (siRNA). We also analyzed the expression of Snail, E-cadherin, vimentin, and nuclear factor (NF)-kB in the cells by western blot. We observed that Tim-3 mRNA and protein was significantly overexpressed in osteosarcoma tissues, compared to the adjacent normal tissue (P < 0.01). Moreover, MG-63 cells transfected with the Tim-3 siRNA presented lower cell viability, a greater number of apoptotic cells, and decreased invasive ability (P < 0.01), compared to control cells. Additionally, we observed a decrease in Snail and vimentin expression, an increase in the E-cadherin level, and an increase in NF-kB p65 phosphorylation (P < 0.01) in Tim-3 siRNA-transfected MG-63 cells. Based on these results, we concluded that Tim-3 is highly expressed in osteosarcoma tissue. Moreover, we speculated that interfering in Tim-3 expression could significantly suppress osteosarcoma cell (MG-63) proliferation and metastasis via the NF-kB/Snail signaling pathway and epithelial-mesenchymal transition.

The Glycolytic Enzyme Triosephosphate Isomerase of Trichomonas vaginalis Is a Surface-Associated Protein Induced by Glucose That Functions as a Laminin- and Fibronectin-Binding Protein

PubMed Central

Miranda-Ozuna, Jesús F. T.; Hernández-García, Mar S.; Brieba, Luis G.; Benítez-Cardoza, Claudia G.; Ortega-López, Jaime; González-Robles, Arturo

2016-01-01

Triosephosphate isomerase of Trichomonas vaginalis (TvTIM) is a 27-kDa cytoplasmic protein encoded by two genes, tvtim1 and tvtim2, that participates in glucose metabolism. TvTIM is also localized to the parasite surface. Thus, the goal of this study was to identify the novel functions of the surface-associated TvTIM in T. vaginalis and to assess the effect of glucose as an environmental factor that regulates its expression and localization. Reverse transcription-PCR (RT-PCR) showed that the tvtim genes were differentially expressed in response to glucose concentration. tvtim1 was overexpressed under glucose-restricted (GR) conditions, whereas tvtim2 was overexpressed under glucose-rich, or high-glucose (HG), conditions. Western blot and indirect immunofluorescence assays also showed that glucose positively affected the amount and surface localization of TvTIM in T. vaginalis. Affinity ligand assays demonstrated that the recombinant TvTIM1 and TvTIM2 proteins bound to laminin (Lm) and fibronectin (Fn) but not to plasminogen. Moreover, higher levels of adherence to Lm and Fn were detected in parasites grown under HG conditions than in those grown under GR conditions. Furthermore, pretreatment of trichomonads with an anti-TvTIMr polyclonal antibody or pretreatment of Lm- or Fn-coated wells with both recombinant proteins (TvTIM1r and TvTIM2r) specifically reduced the binding of live parasites to Lm and Fn in a concentration-dependent manner. Moreover, T. vaginalis was exposed to different glucose concentrations during vaginal infection of women with trichomoniasis. Our data indicate that TvTIM is a surface-associated protein under HG conditions that mediates specific binding to Lm and Fn as a novel virulence factor of T. vaginalis. PMID:27481251

TIM1 (HAVCR1) Is Not Essential for Cellular Entry of Either Quasi-enveloped or Naked Hepatitis A Virions.

PubMed

Das, Anshuman; Hirai-Yuki, Asuka; González-López, Olga; Rhein, Bethany; Moller-Tank, Sven; Brouillette, Rachel; Hensley, Lucinda; Misumi, Ichiro; Lovell, William; Cullen, John M; Whitmire, Jason K; Maury, Wendy; Lemon, Stanley M

2017-09-05

Receptor molecules play key roles in the cellular entry of picornaviruses, and TIM1 (HAVCR1) is widely accepted to be the receptor for hepatitis A virus (HAV), an unusual, hepatotropic human picornavirus. However, its identification as the hepatovirus receptor predated the discovery that hepatoviruses undergo nonlytic release from infected cells as membrane-cloaked, quasi-enveloped HAV (eHAV) virions that enter cells via a pathway distinct from naked, nonenveloped virions. We thus revisited the role of TIM1 in hepatovirus entry, examining both adherence and infection/replication in cells with clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9-engineered TIM1 knockout. Cell culture-derived, gradient-purified eHAV bound Huh-7.5 human hepatoma cells less efficiently than naked HAV at 4°C, but eliminating TIM1 expression caused no difference in adherence of either form of HAV, nor any impact on infection and replication in these cells. In contrast, TIM1-deficient Vero cells showed a modest reduction in quasi-enveloped eHAV (but not naked HAV) attachment and replication. Thus, TIM1 facilitates quasi-enveloped eHAV entry in Vero cells, most likely by binding phosphatidylserine (PtdSer) residues on the eHAV membrane. Both Tim1 -/- Ifnar1 -/- and Tim4 -/- Ifnar1 -/- double-knockout mice were susceptible to infection upon intravenous challenge with infected liver homogenate, with fecal HAV shedding and serum alanine aminotransferase (ALT) elevations similar to those in Ifnar1 -/- mice. However, intrahepatic HAV RNA and ALT elevations were modestly reduced in Tim1 -/- Ifnar1 -/- mice compared to Ifnar1 -/- mice challenged with a lower titer of gradient-purified HAV or eHAV. We conclude that TIM1 is not an essential hepatovirus entry factor, although its PtdSer-binding activity may contribute to the spread of quasi-enveloped virus and liver injury in mice. IMPORTANCE T cell immunoglobulin and mucin-containing domain protein 1 (TIM1) was reported more than 2 decades ago to be an essential cellular receptor for hepatitis A virus (HAV), a picornavirus in the Hepatovirus genus, resulting in its designation as "hepatitis A virus cellular receptor 1" (HAVCR1) by the Human Genome Organization Gene Nomenclature Committee. However, recent studies have shown that HAV exists in nature as both naked, nonenveloped (HAV) virions and membrane-cloaked, quasi-enveloped infectious virus (eHAV), prompting us to revisit the role of TIM1 in viral entry. We show here that TIM1 (HAVCR1) is not an essential cellular receptor for HAV entry into cultured cells or required for viral replication and pathogenesis in permissive strains of mice, although it may facilitate early stages of infection by binding phosphatidylserine on the eHAV surface. This work thus corrects the published record and sets the stage for future efforts to identify specific hepatovirus entry factors. Copyright © 2017 Das et al.

Vertically Aligned and Interconnected Boron Nitride Nanosheets for Advanced Flexible Nanocomposite Thermal Interface Materials.

PubMed

Chen, Jin; Huang, Xingyi; Sun, Bin; Wang, Yuxin; Zhu, Yingke; Jiang, Pingkai

2017-09-13

The continuous evolution toward semiconductor technology in the "more-than-Moore" era and rapidly increasing power density of modern electronic devices call for advanced thermal interface materials (TIMs). Here, we report a novel strategy to construct flexible polymer nanocomposite TIMs for advanced thermal management applications. First, aligned polyvinyl alcohol (PVA) supported and interconnected 2D boron nitride nanosheets (BNNSs) composite fiber membranes were fabricated by electrospinning. Then, the nanocomposite TIMs were constructed by rolling the PVA/BNNS composite fiber membranes to form cylinders and subsequently vacuum-assisted impregnation of polydimethylsiloxane (PDMS) into the porous cylinders. The nanocomposite TIMs not only exhibit a superhigh through-plane thermal conductivity enhancement of about 10 times at a low BNNS loading of 15.6 vol % in comparison with the pristine PDMS but also show excellent electrical insulating property (i.e., high volume electrical resistivity). The outstanding thermal management capability of the nanocomposite TIMs was practically confirmed by capturing the surface temperature variations of a working LED chip integrated with the nanocomposite TIMs.

Kinetics and intrapulmonary disposition of tilmicosin after single and repeated oral bolus administrations to rabbits.

PubMed

Gallina, G; Lucatello, L; Drigo, I; Cocchi, M; Scandurra, S; Agnoletti, F; Montesissa, C

2010-06-01

Tilmicosin (TIM, Pulmotil) was administered to eight rabbits by oral gavage at a dose of 12.5 mg/kg body weight for 2, 5, and 7 days, and its plasma kinetics and intrapulmonary disposition were investigated. TIM concentrations in plasma samples collected after days 1 and 6 of treatment were measured by high-performance liquid chromatography with ultraviolet detection. The pharmacokinetic parameters, obtained by non-compartmental analysis of TIM plasma concentrations, did not show any significant variations between days 1 and 6. From the second day of treatment, TIM concentrations attained in lung tissue and pulmonary alveolar macrophages (PAM) exceeded those in plasma by 7- and 400-fold, respectively, and high levels were maintained in lung tissues during the entire treatment duration. After the first day of withdrawal, a fast decline in TIM levels in both plasma and lung tissue was observed, but in PAM, much higher concentrations were maintained after 3 days of TIM withdrawal.

Traditional Indian medicine (TIM) and traditional Korean medicine (TKM): aconstitutional-based concept and comparison.

PubMed

Kang, Young Min; Komakech, Richard; Karigar, Chandrakant Shivappa; Saqib, Asma

2017-06-01

Traditional and complementary medicine (T&CM) plays an integral role in providing health care worldwide. It is based on sound fundamental principles and centuries of practices. This study compared traditional Indian medicine (TIM) and traditional Korean medicine (TKM) basing on data obtained from peer reviewed articles, respective government institutional reports and World Health Organization reports. Despite the fact that TIM and TKM have individual qualities that are unique from each other including different histories of origin, they share a lot in common. Apart from Homeopathy in TIM, both systems are hinged on similar principle of body constitutional-based concept and similar disease diagnosis methods of mainly auscultation, palpation, visual inspection, and interrogation. Similarly, the treatment methods of TIM and TKM follow similar patterns involving use of medicinal herbs, moxibustion, acupuncture, cupping, and manual therapy. Both T&CM are majorly practiced in well-established hospitals by T&CM doctors who have undergone an average of 6-7 years of specialized trainings. However, unlike TIM which has less insurance coverage, the popularity of TKM is majorly due to its wide national insurance coverage. These two medical traditions occupy increasingly greater portion of the global market. However, TIM especially Ayurveda has gained more global recognition than TKM although the emergence of Sasang Constitutional Medicine in TKM is beginning to become more popular. This comparative analysis between TIM and TKM may provide vital and insightful contribution towards constitutional-based concept for further development and future studies in T&CM.

KSC-06pd0622

NASA Image and Video Library

2006-04-03

KENNEDY SPACE CENTER, FLA. -- Astronaut Nicole Stott is one of three astronauts taking part in the 17-day NASA Extreme Environment Mission Operations (NEEMO) project from the National Oceanic and Atmospheric Administration (NOAA) Aquarius Underwater Laboratory. At left is NEEMO instructor "Otter" Mark Rutten. The astronauts are testing space medicine concepts and moon-walking techniques. The 45-foot-long, 13-foot-diameter complex is three miles off Key Largo in the Florida Keys National Marine Sanctuary and anchored 62 feet below the surface. Canadian astronaut Dave Williams is leading the undersea mission, along with Stott and astronaut Ron Garan. Dr. Tim Broderick of the University of Cincinnati rounds out the crew.

User's manual for The TIM benefit-cost (TIM-BC) Tool (Version: 1.0.0)

DOT National Transportation Integrated Search

2015-07-04

This document serves as a users manual for the Traffic Incident Management Benefit-Cost Tool (TIM-BC) Version 1.0.0 - Safety Service Patrol Benefit-Cost (SSP-BC) Tool, which is used to assist State and local engineers and decisionmakers with evalu...

TIM Version 3.0 beta Technical Description and User Guide - Appendix A - User's Guidance for TIM v.3.0(beta)

EPA Pesticide Factsheets

Provides detailed guidance to the user on how to select input parameters for running the Terrestrial Investigation Model (TIM) and recommendations for default values that can be used when no chemical-specific or species-specific information are available.

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.

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.

Effects of vocal training in a musicophile with congenital amusia.

PubMed

Wilbiks, Jonathan M P; Vuvan, Dominique T; Girard, Pier-Yves; Peretz, Isabelle; Russo, Frank A

2016-12-01

Congenital amusia is a condition in which an individual suffers from a deficit of musical pitch perception and production. Individuals suffering from congenital amusia generally tend to abstain from musical activities. Here, we present the unique case of Tim Falconer, a self-described musicophile who also suffers from congenital amusia. We describe and assess Tim's attempts to train himself out of amusia through a self-imposed 18-month program of formal vocal training and practice. We tested Tim with respect to music perception and vocal production across seven sessions including pre- and post-training assessments. We also obtained diffusion-weighted images of his brain to assess connectivity between auditory and motor planning areas via the arcuate fasciculus (AF). Tim's behavioral and brain data were compared to that of normal and amusic controls. While Tim showed temporary gains in his singing ability, he did not reach normal levels, and these gains faded when he was not engaged in regular lessons and practice. Tim did show some sustained gains with respect to the perception of musical rhythm and meter. We propose that Tim's lack of improvement in pitch perception and production tasks is due to long-standing and likely irreversible reduction in connectivity along the AF fiber tract.

Efficacy and tolerability of fixed-combination brinzolamide/timolol in Latin American patients with open-angle glaucoma or ocular hypertension previously on brimonidine/timolol fixed combination.

PubMed

Alezzandrini, Arturo; Hubatsch, Douglas; Alfaro, Rene

2014-09-01

Fixed-combination glaucoma medications are commonly used to achieve target intraocular pressure (IOP) reduction in patients uncontrolled with monotherapy; however, ocular discomfort associated with eye drops can decrease adherence. This study assessed the efficacy and tolerability of twice-daily fixed-combination brinzolamide 1%/timolol 0.5% (BRINZ/TIM-FC) in Latin American patients transitioned from fixed-combination brimonidine 0.2%/timolol 0.5% (BRIM/TIM-FC) because of insufficient IOP control or treatment intolerance. This 8-week, open-label, prospective study was conducted at six sites in Argentina, Chile, and Mexico. Enrolled patients were aged ≥18 years with open-angle glaucoma (including primary, exfoliative, or pigment-dispersion glaucoma) or ocular hypertension with IOP of 19-35 mmHg in ≥1 eye at baseline (on BRIM/TIM-FC). Patients self-administered BRINZ/TIM-FC to both eyes at 8 a.m. and 8 p.m. daily for 8 weeks. The primary and secondary efficacy endpoints were mean IOP change from baseline at week 8 and percentage of patients achieving target IOP (≤18 mmHg) at week 8, respectively. Exploratory endpoints included patient and investigator preference for treatment at week 8. Adverse events (AEs) were assessed as the safety endpoint. Fifty patients (mean ± SD age, 66.7 ± 11.5 years) received BRINZ/TIM-FC, and 49 were included in the intent-to-treat population. Mean ± SD IOP was significantly reduced from baseline after 8 weeks of treatment with BRINZ/TIM-FC (-3.6 ± 3.0 mmHg; P < 0.0001, Wilcoxon signed-rank test; 17.1% reduction). Overall, 55.3% of patients achieved IOP ≤18 mmHg at week 8. Significantly more patients (89.4%) and investigators (95.7%) preferred BRINZ/TIM-FC to BRIM/TIM-FC (both P < 0.0001, exact binomial test). Of the 13 AEs observed, 8 were related to BRINZ/TIM-FC; the most common treatment-related AEs were eye irritation (n = 4) and abnormal sensation in the eye (n = 2). BRINZ/TIM-FC provides an effective and well-tolerated treatment option for patients transitioned from BRIM/TIM-FC.

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

PubMed

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

2015-04-01

The short isoform of Rho guanine nucleotide exchange factor ARHGEF5 is known as TIM, which plays diverse roles in, for example, tumorigenesis, neuronal development and Src-induced podosome formation through the activation of its substrates, the Rho family of GTPases. The activation is auto-inhibited by a putative helix N-terminal to the DH domain of TIM, which is stabilized by the intramolecular interaction of C-terminal SH3 domain with a poly-proline sequence between the putative helix and the DH domain. In this study, we systematically investigated the structural basis, energetic landscape and biological implication underlying TIM auto-inhibition by using atomistic molecular dynamics simulations and binding free energy analysis. The computational study revealed that the binding of SH3 domain to poly-proline sequence is the prerequisite for the stabilization of TIM auto-inhibition. Thus, it is suggested that targeting SH3 domain with competitors of the poly-proline sequence would be a promising strategy to relieve the auto-inhibitory state of TIM. In this consideration, we rationally designed a number of peptide aptamers for competitively inhibiting the SH3 domain based on modeled TIM structure and computationally generated data. Peptide binding test and guanine nucleotide exchange analysis solidified that these designed peptides can both bind to the SH3 domain potently and activate TIM-catalyzed RhoA exchange reaction effectively. Interestingly, a positive correlation between the peptide affinity and induced exchange activity was observed. In addition, separate mutation of three conserved residues Pro49, Pro52 and Lys54 - they are required for peptide recognition by SH3 domain -- in a designed peptide to Ala would completely abolish the capability of this peptide activating TIM. All these come together to suggest an intrinsic relationship between peptide binding to SH3 domain and the activation of TIM. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Identification of triosephosphate isomerase as a novel allergen in octopus fangsiao

USDA-ARS?s Scientific Manuscript database

A 28 kDa-protein was purified from octopus (Octopus fangsiao) and identified to be triosephosphate isomerase (TIM). The purified TIM is a glycoprotein with 1.7% carbohydrates and the isoelectric point is 7.6. TIM aggregated after heating above 45 °C, and the secondary structure was altered in extre...

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.

Tim-3 and PD-1 regulate CD8+ T cell function to maintain early pregnancy in mice

PubMed Central

XU, Yuan-Yuan; WANG, Song-Cun; LIN, Yi-Kong; LI, Da-Jin; DU, Mei-Rong

2017-01-01

During pregnancy, CD8+ T cells are important regulators in the balance of fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are well-recognized negative co-stimulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that CD8+ T cells co-expressing Tim-3 and PD-1 were down-regulated in the deciduae of female mice in abortion-prone matings compared with normal pregnant mice. In addition to their reduced numbers, the Tim-3+PD-1+CD8+ T cells produced lower levels of the anti-inflammatory cytokines interleukin (IL)-4 and IL-10, as well as a higher level of the pro-inflammatory cytokine interferon (IFN)-γ, relative to those from normal pregnancy. Furthermore, normal pregnant CBA/J females challenged with Tim-3- and/or PD-1-blocking antibodies were more susceptible to fetal resorption. These findings indicate that Tim-3 and PD-1 pathways play critical roles in regulating CD8+ T cell function and maintaining normal pregnancy. PMID:28331165

The Glycolytic Enzyme Triosephosphate Isomerase of Trichomonas vaginalis Is a Surface-Associated Protein Induced by Glucose That Functions as a Laminin- and Fibronectin-Binding Protein.

PubMed

Miranda-Ozuna, Jesús F T; Hernández-García, Mar S; Brieba, Luis G; Benítez-Cardoza, Claudia G; Ortega-López, Jaime; González-Robles, Arturo; Arroyo, Rossana

2016-10-01

Triosephosphate isomerase of Trichomonas vaginalis (TvTIM) is a 27-kDa cytoplasmic protein encoded by two genes, tvtim1 and tvtim2, that participates in glucose metabolism. TvTIM is also localized to the parasite surface. Thus, the goal of this study was to identify the novel functions of the surface-associated TvTIM in T. vaginalis and to assess the effect of glucose as an environmental factor that regulates its expression and localization. Reverse transcription-PCR (RT-PCR) showed that the tvtim genes were differentially expressed in response to glucose concentration. tvtim1 was overexpressed under glucose-restricted (GR) conditions, whereas tvtim2 was overexpressed under glucose-rich, or high-glucose (HG), conditions. Western blot and indirect immunofluorescence assays also showed that glucose positively affected the amount and surface localization of TvTIM in T. vaginalis Affinity ligand assays demonstrated that the recombinant TvTIM1 and TvTIM2 proteins bound to laminin (Lm) and fibronectin (Fn) but not to plasminogen. Moreover, higher levels of adherence to Lm and Fn were detected in parasites grown under HG conditions than in those grown under GR conditions. Furthermore, pretreatment of trichomonads with an anti-TvTIMr polyclonal antibody or pretreatment of Lm- or Fn-coated wells with both recombinant proteins (TvTIM1r and TvTIM2r) specifically reduced the binding of live parasites to Lm and Fn in a concentration-dependent manner. Moreover, T. vaginalis was exposed to different glucose concentrations during vaginal infection of women with trichomoniasis. Our data indicate that TvTIM is a surface-associated protein under HG conditions that mediates specific binding to Lm and Fn as a novel virulence factor of T. vaginalis. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Altered Cav1.2 function in the Timothy syndrome mouse model produces ascending serotonergic abnormalities.

PubMed

Ehlinger, Daniel G; Commons, Kathryn G

2017-10-01

Polymorphism in the gene CACNA1C, encoding the pore-forming subunit of Cav1.2 L-type calcium channels, has one of the strongest genetic linkages to schizophrenia, bipolar disorder and major depressive disorder: psychopathologies in which serotonin signaling has been implicated. Additionally, a gain-of-function mutation in CACNA1C is responsible for the neurodevelopmental disorder Timothy syndrome that presents with prominent behavioral features on the autism spectrum. Given an emerging role for serotonin in the etiology of autism spectrum disorders (ASD), we investigate the relationship between Cav1.2 and the ascending serotonin system in the Timothy syndrome type 2 (TS2-neo) mouse, which displays behavioral features consistent with the core triad of ASD. We find that TS2-neo mice exhibit enhanced serotonin tissue content and axon innervation of the dorsal striatum, as well as decreased serotonin turnover in the amygdala. These regionally specific alterations are accompanied by an enhanced active coping response during acute stress (forced swim), serotonin neuron Fos activity in the caudal dorsal raphe, and serotonin type 1A receptor-dependent feedback inhibition of the rostral dorsal raphe nuclei. Collectively, these results suggest that the global gain-of-function Cav1.2 mutation associated with Timothy syndrome has pleiotropic effects on the ascending serotonin system including neuroanatomical changes, regional differences in forebrain serotonin metabolism and feedback regulatory control mechanisms within the dorsal raphe. Altered activity of the ascending serotonin system continues to emerge as a common neural signature across several ASD mouse models, and the capacity for Cav1.2 L-type calcium channels to impact both serotonin structure and function has important implications for several neuropsychiatric conditions. © 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

TIM-1 Mediates Dystroglycan-Independent Entry of Lassa Virus.

PubMed

Brouillette, Rachel B; Phillips, Elisabeth K; Patel, Radhika; Mahauad-Fernandez, Wadie; Moller-Tank, Sven; Rogers, Kai J; Dillard, Jacob A; Cooney, Ashley L; Martinez-Sobrido, Luis; Okeoma, Chioma; Maury, Wendy

2018-06-06

Lassa virus (LASV) is an Old World arenavirus responsible for hundreds of thousands of infections in West Africa every year. LASV entry into a variety of cell types is mediated by interactions with glycosyltransferase LARGE-modified O-linked glycans present on the ubiquitous receptor, α-dystroglycan (αDG). Yet, cells lacking αDG are permissive to LASV infection, suggesting that alternative receptors exist. Previous studies demonstrate that phosphatidylserine (PtdSer)-binding receptors, Axl and Tyro3 along with C-type lectin receptors, mediate αDG-independent entry. Here, we demonstrate that another PtdSer receptor, TIM-1, mediates LASV glycoprotein (GP) pseudotyped virions entry into αDG knocked out HEK 293T and wild-type (WT) Vero which express αDG lacking appropriate glycosylation. To investigate the mechanism by which TIM-1 mediates enhancement of entry, we demonstrate that mutagenesis of the TIM-1 IgV domain PtdSer-binding pocket abrogated transduction. Further, the human TIM-1 IgV domain binding monoclonal antibody, ARD5, blocked transduction of pseudovirions bearing LASV GP in a dose-dependent manner. Finally, as we showed previously for other viruses that use TIM-1 for entry, a chimeric TIM-1 protein that substitutes the proline rich region (PRR) from murine leukemia virus envelope (Env) for the mucin-like domain served as a competent receptor. These studies provide evidence that, in the absence of a functional αDG, TIM-1 mediates entry of LASV pseudoviral particles through interactions of virions with the IgV PtdSer binding pocket of TIM-1. Importance PtdSer receptors, such as TIM-1, are emerging as critical entry factors for many enveloped viruses. Most recently, Hepatitis C virus and Zika virus have been added to a growing list. PtdSer receptors engage with enveloped viruses through binding of PtdSer embedded in the viral envelope, defining them as GP-independent receptors. This GP-independent entry mechanism should effectively mediate entry of all enveloped viruses, yet LASV GP pseudotyped viruses were previously found to be unresponsive to PtdSer receptor enhancement in HEK 293T cells. Here we demonstrate that LASV pseudovirions can utilize the PtdSer receptor TIM-1, but only in the absence of appropriately glycosylated α-dystroglycan (αDG), the high affinity cell surface receptor for LASV. Our studies shed light on LASV receptor utilization and explain why earlier studies performed in α-DG-expressing cells did not find that LASV pseudovirions utilize PtdSer receptors for virus uptake. Copyright © 2018 American Society for Microbiology.

Blocking Tim-3 or/and PD-1 reverses dysfunction of tumor-infiltrating lymphocytes in HBV-related hepatocellular carcinoma.

PubMed

Liu, Furong; Zeng, Gucheng; Zhou, Shaotang; He, Xiaoshun; Sun, Nianfeng; Zhu, Xiaofeng; Hu, Anbin

2018-05-01

The immunosuppression of tumor-infiltrating lymphocytes (TILs) is associated with rapid progression of hepatitis B virus-related hepatocellular carcinoma (HBV-HCC). T cell Ig- and mucin-domain-containing molecule-3 (Tim-3) and programmed cell death 1 (PD-1) are important inhibitory molecules expressed on the surface of T cells, but their roles in the function of TILs in HBV-HCC are poorly understood. We aimed to study the roles of these two markers in HBV-HCC. Ninety patients with pathologically confirmed HBV-associated HCC were enrolled in our study. Blood samples, paired fresh tumor tissues and adjacent tissues were collected, and isolating peripheral blood mononuclear cells, TILs and adjacent-infiltrating lymphocytes were isolated from these samples. The patients were followed-up to allow survival analysis. Tim-3 or/and PD-1 was up-regulated expressed on CD4 + and CD8 + TILs in HBV-HCC patients and a higher proportion of TILs expressed PD-1 alone. Tim-3 + and PD-1 + TILs greatly decreased secretion of IFN-? and TNF-a. Expression of Tim-3 and PD-1 on TILs negatively correlated with disease-free survival of HCC patients. Direct blockade of Tim-3 and PD-1 in vitro significantly enhanced TILs proliferation and secretion of IFN-? and TNF-a. Expression of Tim-3 and/or PD-1 on TILs impairs their function and correlates negatively with disease-free survival in HBV-HCC. Direct blockade of Tim-3 and PD-1 restores anti-tumor effects of TILs, which suggests a potential target for novel immunotherapy in HBV-HCC. Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein.

PubMed

Banerjee, Rupa; Gladkova, Christina; Mapa, Koyeli; Witte, Gregor; Mokranjac, Dejana

2015-12-29

The majority of mitochondrial proteins are targeted to mitochondria by N-terminal presequences and use the TIM23 complex for their translocation across the mitochondrial inner membrane. During import, translocation through the channel in the inner membrane is coupled to the ATP-dependent action of an Hsp70-based import motor at the matrix face. How these two processes are coordinated remained unclear. We show here that the two domain structure of Tim44 plays a central role in this process. The N-terminal domain of Tim44 interacts with the components of the import motor, whereas its C-terminal domain interacts with the translocation channel and is in contact with translocating proteins. Our data suggest that the translocation channel and the import motor of the TIM23 complex communicate through rearrangements of the two domains of Tim44 that are stimulated by translocating proteins.

Dense Vertically Aligned Copper Nanowire Composites as High Performance Thermal Interface Materials.

PubMed

Barako, Michael T; Isaacson, Scott G; Lian, Feifei; Pop, Eric; Dauskardt, Reinhold H; Goodson, Kenneth E; Tice, Jesse

2017-12-06

Thermal interface materials (TIMs) are essential for managing heat in modern electronics, and nanocomposite TIMs can offer critical improvements. Here, we demonstrate thermally conductive, mechanically compliant TIMs based on dense, vertically aligned copper nanowires (CuNWs) embedded into polymer matrices. We evaluate the thermal and mechanical characteristics of 20-25% dense CuNW arrays with and without polydimethylsiloxane infiltration. The thermal resistance achieved is below 5 mm 2 K W -1 , over an order of magnitude lower than commercial heat sink compounds. Nanoindentation reveals that the nonlinear deformation mechanics of this TIM are influenced by both the CuNW morphology and the polymer matrix. We also implement a flip-chip bonding protocol to directly attach CuNW composites to copper surfaces, as required in many thermal architectures. Thus, we demonstrate a rational design strategy for nanocomposite TIMs that simultaneously retain the high thermal conductivity of aligned CuNWs and the mechanical compliance of a polymer.

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.

Tower Illuminance Model

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

Ho, Clifford K.; Sims, Cianan

TIM is a real-time interactive concentrating solar field simulation. TIM models a concentrating tower (receiver), heliostat field, and potential reflected glare based on user-specified parameters such as field capacity, tower height and location. TIM provides a navigable 3D interface, allowing the user to “fly” around the field to determine the potential glare hazard from off-target heliostats. Various heliostat aiming strategies are available for specifying how heliostats behave when in standby mode. Strategies include annulus, point-per-group, up-aiming and single-point-focus. Additionally, TIM includes an avian path feature for approximating the irradiance and feather temperature of a bird flying through the field airspace.

Impact of the introduction of mandatory generic substitution in South Africa: private sector sales of generic and originator medicines for chronic diseases.

PubMed

Gray, Andrew Lofts; Santa-Ana-Tellez, Yared; J Wirtz, Veronika

2016-12-01

To assess the impact of mandatory offer of generic substitution, introduced in South Africa in May 2003, on private sector sales of generic and originator medicines for chronic diseases. Private sector sales data (June 2001 to May 2005) were obtained from IMS Health for proton pump inhibitors (PPIs; ATC code A02BC), HMG-CoA reductase inhibitors (statins; C10AA), dihydropyridine calcium antagonists (C08CA), angiotensin-converting enzyme inhibitors (ACE-I; C09AA) and selective serotonin reuptake inhibitors (SSRIs; N06AB). Monthly sales were expressed as defined daily doses per 1000 insured population per month (DDD/TIM). Interrupted time-series models were used to estimate the changes in slope and level of medicines use after the policy change. ARIMA models were used to correct for autocorrelation and stationarity. Only the SSRIs saw a significant rise in level of generic utilisation (0.2 DDD/TIM; P < 0.001) and a fall in originator usage (-0.1 DDD/TIM; P < 0.001) after the policy change. Utilisation of generic PPIs fell (level 0.06 DDD/TIM, P = 0.048; slope 0.01 DDD/TIM, P = 0.043), but utilisation of originator products also grew (level 0.05 DDD/TIM, P < 0.001; slope 0.003, P = 0.001). Generic calcium antagonists and ACE-I showed an increase in slope (0.01 DDD/TIM, P = 0.016; 0.02 DDD/TIM, P < 0.001), while the originators showed a decrease in slope (-0.003 DDD/TIM, P = 0.046; -0.01 DDD/TIM, P < 0.001). There were insufficient data on generic statin use before the policy change to allow for analysis. The mandatory offer of generic substitution appeared to have had a quantifiable effect on utilisation patterns in the 2 years after May 2003. Managed care interventions that were already in place before the intervention may have blunted the extent of the changes seen in this period. Generic policies are an important enabling provision for cost-containment efforts. However, decisions taken outside of official policy may anticipate or differ from that policy, with important consequences. © 2016 John Wiley & Sons Ltd.

Tim-3 expression on PD-1+ HCV-specific human CTLs is associated with viral persistence, and its blockade restores hepatocyte-directed in vitro cytotoxicity

PubMed Central

McMahan, Rachel H.; Golden-Mason, Lucy; Nishimura, Michael I.; McMahon, Brian J.; Kemper, Michael; Allen, Todd M.; Gretch, David R.; Rosen, Hugo R.

2010-01-01

Having successfully developed mechanisms to evade immune clearance, hepatitis C virus (HCV) establishes persistent infection in approximately 75%–80% of patients. In these individuals, the function of HCV-specific CD8+ T cells is impaired by ligation of inhibitory receptors, the repertoire of which has expanded considerably in the past few years. We hypothesized that the coexpression of the negative regulatory receptors T cell immunoglobulin and mucin domain–containing molecule 3 (Tim-3) and programmed death 1 (PD-1) in HCV infection would identify patients at risk of developing viral persistence during and after acute HCV infection. The frequency of PD-1–Tim-3– HCV-specific CTLs greatly outnumbered PD-1+Tim-3+ CTLs in patients with acute resolving infection. Moreover, the population of PD-1+Tim-3+ T cells was enriched for within the central memory T cell subset and within the liver. Blockade of either PD-1 or Tim-3 enhanced in vitro proliferation of HCV-specific CTLs to a similar extent, whereas cytotoxicity against a hepatocyte cell line that expressed cognate HCV epitopes was increased exclusively by Tim-3 blockade. These results indicate that the coexpression of these inhibitory molecules tracks with defective T cell responses and that anatomical differences might account for lack of immune control of persistent pathogens, which suggests their manipulation may represent a rational target for novel immunotherapeutic approaches. PMID:21084749

Structural insights from a novel invertebrate triosephosphate isomerase from Litopenaeus vannamei

PubMed Central

Lopez-Zavala, Alonso A.; Carrasco-Miranda, Jesus S.; Ramirez-Aguirre, Claudia D.; López-Hidalgo, Marisol; Benitez-Cardoza, Claudia G.; Ochoa-Leyva, Adrian; Cardona-Felix, Cesar S.; Diaz-Quezada, Corina; Rudiño-Piñera, Enrique; Sotelo-Mundo, Rogerio R.; Brieba, Luis G.

2016-01-01

Triosephosphate isomerase (TIM; EC 5.3.1.1) is a key enzyme involved in glycolysis and gluconeogenesis. Glycolysis is one of the most regulated metabolic pathways, however little is known about the structural mechanisms for its regulation in non-model organisms, like crustaceans. To understand the structure and function of this enzyme in invertebrates, we obtained the crystal structure of triosephosphate isomerase from the marine Pacific whiteleg shrimp (Litopenaeus vannamei, LvTIM) in complex with its inhibitor 2-phosphogyceric acid (2-PG) at 1.7 Å resolution. LvTIM assembles as a homodimer with residues 166-176 covering the active site and residue Glu166 interacting with the inhibitor. We found that LvTIM is the least stable TIM characterized to date, with the lowest range of melting temperatures, and with the lowest activation enthalpy associated with the thermal unfolding process reported. In TIMs dimer stabilization is maintained by an interaction of loop 3 by a set of hydrophobic contacts between subunits. Within these contacts, the side chain of a hydrophobic residue of one subunit fits into a cavity created by a set of hydrophobic residues in the neighboring subunit, via a "ball and socket" interaction. LvTIM presents a Cys47 at the "ball" inter-subunit contact indicating that the character of this residue is responsible for the decrease in dimer stability. Mutational studies show that this residue plays a role in dimer stability but is not a solely determinant for dimer formation. PMID:27614148

Reactivation of triosephosphate isomerase from three trypanosomatids and human: effect of suramin.

PubMed Central

Gao, X G; Garza-Ramos, G; Saavedra-Lira, E; Cabrera, N; De Gómez-Puyou, M T; Perez-Montfort, R; Gómez-Puyou, A

1998-01-01

The reactivation of the homodimeric triosephosphate isomerases (TIMs) from Trypanosoma brucei, T. cruzi, Leishmania mexicana and humans was determined after their denaturation with guanidine hydrochloride. In the range of 2-32 microg of T. brucei TIM per ml and 0.2-5 microg of the other enzymes per ml, the rate and extent of TIM reactivation depended on protein concentration, indicating that at these protein concentrations, the rate-limiting step of reactivation is monomer association and not monomer folding. The rate of monomer association was more than one order of magnitude lower in the T. brucei enzyme than in the other three enzymes. Suramin is a drug of choice in the treatment of sleeping sickness, but its mechanism of action is not known. At micromolar concentrations, Suramin inhibited the reactivation of the four enzymes, but the extent of inhibition by Suramin decreased with increasing protein concentration as consequence of a diminution of the life time of the folded monomer. Since the life time of the monomer of T. brucei TIM is longer than that of the other enzymes, Suramin is a more effective inhibitor of the reactivation of TIM from T. brucei, particularly at monomer concentrations above 1 microg of protein per ml (monomer concentration approx. 37 nM). Compounds that are structurally related to Suramin also inhibit TIM reactivation; their effect was about five times more pronounced in the enzyme from T. brucei than in human TIM. PMID:9576855

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.

Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein

PubMed Central

Banerjee, Rupa; Gladkova, Christina; Mapa, Koyeli; Witte, Gregor; Mokranjac, Dejana

2015-01-01

The majority of mitochondrial proteins are targeted to mitochondria by N-terminal presequences and use the TIM23 complex for their translocation across the mitochondrial inner membrane. During import, translocation through the channel in the inner membrane is coupled to the ATP-dependent action of an Hsp70-based import motor at the matrix face. How these two processes are coordinated remained unclear. We show here that the two domain structure of Tim44 plays a central role in this process. The N-terminal domain of Tim44 interacts with the components of the import motor, whereas its C-terminal domain interacts with the translocation channel and is in contact with translocating proteins. Our data suggest that the translocation channel and the import motor of the TIM23 complex communicate through rearrangements of the two domains of Tim44 that are stimulated by translocating proteins. DOI: http://dx.doi.org/10.7554/eLife.11897.001 PMID:26714107

Differential effects on enzyme stability and kinetic parameters of mutants related to human triosephosphate isomerase deficiency.

PubMed

Cabrera, Nallely; Torres-Larios, Alfredo; García-Torres, Itzhel; Enríquez-Flores, Sergio; Perez-Montfort, Ruy

2018-06-01

Human triosephosphate isomerase (TIM) deficiency is a very rare disease, but there are several mutations reported to be causing the illness. In this work, we produced nine recombinant human triosephosphate isomerases which have the mutations reported to produce TIM deficiency. These enzymes were characterized biophysically and biochemically to determine their kinetic and stability parameters, and also to substitute TIM activity in supporting the growth of an Escherichia coli strain lacking the tim gene. Our results allowed us to rate the deleteriousness of the human TIM mutants based on the type and severity of the alterations observed, to classify four "unknown severity mutants" with altered residues in positions 62, 72, 122 and 154 and to explain in structural terms the mutation V231M, the most affected mutant from the kinetic point of view and the only homozygous mutation reported besides E104D. Copyright © 2018 Elsevier B.V. All rights reserved.

Towards Discovery and Targeted Peptide Biomarker Detection Using nanoESI-TIMS-TOF MS

NASA Astrophysics Data System (ADS)

Garabedian, Alyssa; Benigni, Paolo; Ramirez, Cesar E.; Baker, Erin S.; Liu, Tao; Smith, Richard D.; Fernandez-Lima, Francisco

2018-05-01

In the present work, the potential of trapped ion mobility spectrometry coupled to TOF mass spectrometry (TIMS-TOF MS) for discovery and targeted monitoring of peptide biomarkers from human-in-mouse xenograft tumor tissue was evaluated. In particular, a TIMS-MS workflow was developed for the detection and quantification of peptide biomarkers using internal heavy analogs, taking advantage of the high mobility resolution (R = 150-250) prior to mass analysis. Five peptide biomarkers were separated, identified, and quantified using offline nanoESI-TIMS-CID-TOF MS; the results were in good agreement with measurements using a traditional LC-ESI-MS/MS proteomics workflow. The TIMS-TOF MS analysis permitted peptide biomarker detection based on accurate mobility, mass measurements, and high sequence coverage for concentrations in the 10-200 nM range, while simultaneously achieving discovery measurements of not initially targeted peptides as markers from the same proteins and, eventually, other proteins. [Figure not available: see fulltext.

Acoustic Measurement and Model Predictions for the Aural Nondetectability of Two Night-Vision Goggles

DTIC Science & Technology

2013-11-01

Acoustic Measurement and Model Predictions for the Aural Nondetectability of Two Night-Vision Goggles by Jeremy Gaston, Tim Mermagen, and...Goggles Jeremy Gaston, Tim Mermagen, and Kelly Dickerson Human Research and Engineering Directorate, ARL...5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Jeremy Gaston, Tim Mermagen, and Kelly Dickerson 5d. PROJECT NUMBER 74A 5e. TASK NUMBER 5f. WORK

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

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

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

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.

Scientific Evaluation of Edible Fruits and Spices Used for the Treatment of Peptic Ulcer in Traditional Iranian Medicine

PubMed Central

Farzaei, Mohammad Hosein; Shams-Ardekani, Mohammad Reza; Abbasabadi, Zahra; Rahimi, Roja

2013-01-01

In traditional Iranian medicine (TIM), several edible fruits and spices are thought to have protective and healing effects on peptic ulcer (PU). The present study was conducted to verify anti-PU activity of these remedies. For this purpose, edible fruits and spices proposed for the management of PU in TIM were collected from TIM sources, and they were searched in modern medical databases to find studies that confirmed their efficacy. Findings from modern investigations support the claims of TIM about the efficacy of many fruits and spices in PU. The fruit of Phyllanthus emblica as a beneficial remedy for PU in TIM has been demonstrated to have antioxidant, wound healing, angiogenic, anti-H. pylori, cytoprotective, antisecretory, and anti-inflammatory properties. The fruit of Vitis vinifera has been found to be anti-H. pylori, anti-inflammatory, wound healing, angiogenic, cytoprotective, and antioxidant. The fruit and aril of seed from Myristica fragrans exert their beneficial effects in PU by increasing prostaglandin, modulation of nitric oxide and inflammatory mediators, wound healing, antisecretory, antacid, antioxidant, and anti-H. pylori activities, and improving angiogenesis. Pharmacological and clinical studies for evaluation of efficacy of all TIM fruits and spices in PU and their possible mechanisms of action are recommended. PMID:24066235

Species-Specific Inactivation of Triosephosphate Isomerase from Trypanosoma brucei: Kinetic and Molecular Dynamics Studies.

PubMed

Vázquez-Raygoza, Alejandra; Cano-González, Lucia; Velázquez-Martínez, Israel; Trejo-Soto, Pedro Josué; Castillo, Rafael; Hernández-Campos, Alicia; Hernández-Luis, Francisco; Oria-Hernández, Jesús; Castillo-Villanueva, Adriana; Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Valdez-Solana, Mónica; Téllez-Valencia, Alfredo

2017-11-24

Human African Trypanosomiasis (HAT), a disease that provokes 2184 new cases a year in Sub-Saharan Africa, is caused by Trypanosoma brucei . Current treatments are limited, highly toxic, and parasite strains resistant to them are emerging. Therefore, there is an urgency to find new drugs against HAT. In this context, T. brucei depends on glycolysis as the unique source for ATP supply; therefore, the enzyme triosephosphate isomerase (TIM) is an attractive target for drug design. In the present work, three new benzimidazole derivatives were found as TbTIM inactivators (compounds 1 , 2 and 3 ) with an I 50 value of 84, 82 and 73 µM, respectively. Kinetic analyses indicated that the three molecules were selective when tested against human TIM (HsTIM) activity. Additionally, to study their binding mode in TbTIM, we performed a 100 ns molecular dynamics simulation of TbTIM-inactivator complexes. Simulations showed that the binding of compounds disturbs the structure of the protein, affecting the conformations of important domains such as loop 6 and loop 8. In addition, the physicochemical and drug-like parameters showed by the three compounds suggest a good oral absorption. In conclusion, these molecules will serve as a guide to design more potent inactivators that could be used to obtain new drugs against HAT.

Virion-associated phosphatidylethanolamine promotes TIM1-mediated infection by Ebola, dengue, and West Nile viruses.

PubMed

Richard, Audrey Stéphanie; Zhang, Adam; Park, Sun-Jin; Farzan, Michael; Zong, Min; Choe, Hyeryun

2015-11-24

Phosphatidylserine (PS) receptors contribute to two crucial biological processes: apoptotic clearance and entry of many enveloped viruses. In both cases, they recognize PS exposed on the plasma membrane. Here we demonstrate that phosphatidylethanolamine (PE) is also a ligand for PS receptors and that this phospholipid mediates phagocytosis and viral entry. We show that a subset of PS receptors, including T-cell immunoglobulin (Ig) mucin domain protein 1 (TIM1), efficiently bind PE. We further show that PE is present in the virions of flaviviruses and filoviruses, and that the PE-specific cyclic peptide lantibiotic agent Duramycin efficiently inhibits the entry of West Nile, dengue, and Ebola viruses. The inhibitory effect of Duramycin is specific: it inhibits TIM1-mediated, but not L-SIGN-mediated, virus infection, and it does so by blocking virus attachment to TIM1. We further demonstrate that PE is exposed on the surface of apoptotic cells, and promotes their phagocytic uptake by TIM1-expressing cells. Together, our data show that PE plays a key role in TIM1-mediated virus entry, suggest that disrupting PE association with PS receptors is a promising broad-spectrum antiviral strategy, and deepen our understanding of the process by which apoptotic cells are cleared.

The Oligomeric Nature of Triosephosphate Isomerase. Studies of Monomerization

NASA Astrophysics Data System (ADS)

Zárate-Pérez, Francisco; Vázquez-Contreras, Edgar

2008-02-01

In this work, we report the implications of the monomerization of triosephosphate isomerase (TIM) from T. cruzi (TcTIM). A monomeric mutant (monoTcTIM) of this species was constructed by genetic engineering, shortening the main loop of interdigitation, which is fundamental for its dimerization. The properties of monoTcTIM were compared with those of the other TIM monomeric versions: genetically engineered mutants, or equilibrium intermediates obtained by chemical denaturation. The stability for almost all the monomeric variants so far reported appears in the same range, and also presents similar structural characteristics. Regarding the catalytic activity of monomeric mutants, when it is present is in several orders of magnitude lower than those observed in their respective wild-type enzyme. The change in the hydrophobic surface of TcTIM after and before monomerization was also studied and corresponds to an extensive area of the interface region, which becomes exposed when monomers are dissociated. This fact could be related with conformational changes in the local environment of the catalytic amino acids responsible for the isomerization of the substrate and consequently the inactivation of its catalytic properties. Comparison of the structural, folding and unfolding properties, as well as stability studies could give answers on why this enzyme is an obligate oligomer.

T-bet-mediated Tim-3 expression dampens monocyte function during chronic hepatitis C virus infection.

PubMed

Yi, Wenjing; Zhang, Peixin; Liang, Yan; Zhou, Yun; Shen, Huanjun; Fan, Chao; Moorman, Jonathan P; Yao, Zhi Q; Jia, Zhansheng; Zhang, Ying

2017-03-01

Hepatitis C virus (HCV) induces a high rate of chronic infection via dysregulation of host immunity. We have previously shown that T-cell immunoglobulin and mucin domain protein-3 (Tim-3) is up-regulated on monocyte/macrophages (M/Mφ) during chronic HCV infection; little is known, however, about the transcription factor that controls its expression in these cells. In this study, we investigated the role of transcription factor, T-box expressed in T cells (T-bet), in Tim-3 expression in M/Mφ in the setting of HCV infection. We demonstrate that T-bet is constitutively expressed in resting CD14 + M/Mφ in the peripheral blood. M/Mφ from chronically HCV-infected individuals exhibit a significant increase in T-bet expression that positively correlates with an increased level of Tim-3 expression. Up-regulation of T-bet is also observed in CD14 + M/Mφ incubated with HCV + Huh7.5 cells, as well as in primary M/Mφ or monocytic THP-1 cells exposed to HCV core protein in vitro, which is reversible by blocking HCV core/gC1qR interactions. Moreover, the HCV core-induced up-regulation of T-bet and Tim-3 expression in M/Mφ can be abrogated by incubating the cells with SP600125 - an inhibitor for the c-Jun N-terminal kinase (JNK) signalling pathway. Importantly, silencing T-bet gene expression decreases Tim-3 expression and enhances interleukin-12 secretion as well as signal transducer and activator of transcription 1 phosphorylation. These data suggest that T-bet, induced by the HCV core/gC1qR interaction, enhances Tim-3 expression via the JNK pathway, leading to dampened M/Mφ function during HCV infection. These findings reveal a novel mechanism for Tim-3 regulation via T-bet during HCV infection, providing new targets to combat this global epidemic viral disease. © 2016 John Wiley & Sons Ltd.

Travoprost 0.004%/timolol 0.5%-fixed combination with and without benzalkonium chloride: a prospective, randomized, doubled-masked comparison of safety and efficacy

PubMed Central

Kitazawa, Y; Smith, P; Sasaki, N; Kotake, S; Bae, K; Iwamoto, Y

2011-01-01

Purpose The purpose of this study is to compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost/timolol in a benzalkonium chloride (BAK)-free fixed combination preserved with polyquaternium-1 (TRA/TIM BAK-free), with travoprost/timolol-fixed combination preserved with BAK (TRA/TIM), in patients with open-angle glaucoma or ocular hypertension. Methods In this prospective randomized controlled trial, subjects with IOP of at least 22 mm Hg in one or both eyes at 0900 h, and IOP of at least 21 mm Hg in one or both eyes at 1100 h and 1600 h at two eligibility visits were randomly assigned to receive either TRA/TIM BAK-free (n=195) or TRA/TIM (n=193), dosed once daily in the morning (0900 h) for 6 weeks. IOP was assessed at 0900 h, 1100 h, and 1600 h at each scheduled visit (baseline, 2 and 6 weeks after randomization). Results Mean IOP reduction across all visits and time points was 8.0 mm Hg in the TRA/TIM BAK-free group and 8.4 mm Hg in the TRA/TIM group (P=0.0943). The difference in mean IOP between groups ranged from 0.2 to 0.7 mm Hg across visits and time points, with a mean pooled difference of 0.4 mm Hg (95% CI: −0.1 to 0.8), demonstrating equivalence of the two formulations. The most common drug-related adverse event was hyperemia of the eye (ocular hyperemia and conjunctival hyperemia combined), occurring in 11.8% of the TRA/TIM BAK-free group and 13.0% of the TRA/TIM group. Conclusion Travoprost/timolol BAK-free demonstrated equivalence to travoprost/timolol preserved with BAK in efficacy. No clinically relevant differences in the safety profiles of travoprost/timolol BAK-free and travoprost/timolol preserved with BAK were identified. PMID:21701528

Travoprost 0.004%/timolol 0.5%-fixed combination with and without benzalkonium chloride: a prospective, randomized, doubled-masked comparison of safety and efficacy.

PubMed

Kitazawa, Y; Smith, P; Sasaki, N; Kotake, S; Bae, K; Iwamoto, Y

2011-09-01

The purpose of this study is to compare the safety and intraocular pressure (IOP)-lowering efficacy of travoprost/timolol in a benzalkonium chloride (BAK)-free fixed combination preserved with polyquaternium-1 (TRA/TIM BAK-free), with travoprost/timolol-fixed combination preserved with BAK (TRA/TIM), in patients with open-angle glaucoma or ocular hypertension. In this prospective randomized controlled trial, subjects with IOP of at least 22  mm Hg in one or both eyes at 0900  h, and IOP of at least 21  mm Hg in one or both eyes at 1100  h and 1600  h at two eligibility visits were randomly assigned to receive either TRA/TIM BAK-free (n=195) or TRA/TIM (n=193), dosed once daily in the morning (0900  h) for 6 weeks. IOP was assessed at 0900  h, 1100  h, and 1600  h at each scheduled visit (baseline, 2 and 6 weeks after randomization). Mean IOP reduction across all visits and time points was 8.0  mm Hg in the TRA/TIM BAK-free group and 8.4  mm Hg in the TRA/TIM group (P=0.0943). The difference in mean IOP between groups ranged from 0.2 to 0.7  mm Hg across visits and time points, with a mean pooled difference of 0.4  mm Hg (95% CI: -0.1 to 0.8), demonstrating equivalence of the two formulations. The most common drug-related adverse event was hyperemia of the eye (ocular hyperemia and conjunctival hyperemia combined), occurring in 11.8% of the TRA/TIM BAK-free group and 13.0% of the TRA/TIM group. Travoprost/timolol BAK-free demonstrated equivalence to travoprost/timolol preserved with BAK in efficacy. No clinically relevant differences in the safety profiles of travoprost/timolol BAK-free and travoprost/timolol preserved with BAK were identified.

Uranium(iii) complexes supported by hydrobis(mercaptoimidazolyl)borates: synthesis and oxidation chemistry.

PubMed

Maria, Leonor; Santos, Isabel C; Santos, Isabel

2018-05-23

The reaction of [UI3(thf)4] with the sodium or lithium salts of hydrobis(2-mercapto-1-methylimidazolyl)borate ligands ([H(R)B(timMe)2]-) in a 1 : 2 ratio, in tetrahydrofuran, gave the U(iii) complexes [UI{κ3-H,S,S'-H(R)B(timMe)2}2(thf)2] (R = H (1), Ph (2)) in good yields. Crystals of [UI{κ3-H,S,S'-H(Ph)B(timMe)2}2(thf)2] (2) were obtained by recrystallization from a tetrahydrofuran/acetonitrile solution, and the ion-separated uranium complex [U{κ3-H,S,S'-H(Ph)B(timMe)2}2(CH3CN)3][I] (3-I) was obtained by dissolution of 2 in acetonitrile followed by recrystallization. One-electron oxidation of 2 with AgBPh4 or I2 resulted in the formation of the cationic U(iv) complexes [U{κ3-H,S,S'-H(Ph)B(timMe)2}3][X] (X = BPh4 (6-BPh4), I (6-I)), due to a ligand redistribution process. These complexes are the first examples of homoleptic poly(azolyl)borate U(iv) complexes. Treatment of complex 2 with azobenzene led to the isolation of crystals of the U(iv) compound [UI{κ3-H(Ph)B(timMe)2}2(κ2-timMe)] (7). Treatment of 2 with pyridine-N oxide (pyNO) led to the formation of the uranyl complex [UO2{κ2-S,S'-H(Ph)B(timMe)2}2] (8) and of complex 6-I, while from the reaction of [U{κ3-H(Ph)B(timMe)2}2(thf)3][BPh4] (5) with pyNO, the oxo-bridged U(iv) complex [{U{κ3-H(Ph)B(timMe)2}2(pyNO)}2(μ-O)][BPh4]2 (9) was also obtained. In the U(iii) and U(iv) complexes, the bis(azolyl)borate ligands bind to the uranium center in a κ3-H,S,S' coordination mode, while in the U(vi) complex the ligands bind to the metal in a κ2-S,S' mode. The presence of UH-B interactions in the solid-state, for the nine-coordinate complexes 1, 2, 3, 6 and 7 and for the eight-coordinate complex 9, was supported by IR spectroscopy and/or X-ray diffraction analysis.

Smart Mirrors for Photorefractive Control of Light with Tim Bunning, RX - Agile Filters Application

DTIC Science & Technology

2016-11-08

AFRL-AFOSR-UK-TR-2017-0008 Smart Mirrors for photorefractive control of light with Tim Bunning, RX-- Agile filters application Luciano De Sio...photorefractive control of light with Tim Bunning, RX-- Agile filters application 5a.  CONTRACT NUMBER 5b.  GRANT NUMBER FA9550-14-1-0050 5c.  PROGRAM...photorefractive, switchable optical filters , liquide crystalline composite materials, Switchable reflective holographic gratings, polymer-dispersed liquid

Link Correlated Military Data for Better Decision Support

DTIC Science & Technology

2011-06-01

automatically translated into URI based links, thus can greatly reduce man power cost on software development. 3 Linked Data Technique Tim Berners - Lee ...Linked Data - while Linked Data is usually considered as part of Semantic Web, or “the Semantic Web done right” as described by Tim himself - has been...Required data of automatic link construction mechanism on more kinds of correlations. References [1] B. L. Tim , “The next Web of open, linked data

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.

Antimicrobial capacity of the freshwater planarians against S. aureus is under the control of Timeless.

PubMed

Tsoumtsa, Landry Laure; Torre, Cedric; Trouplin, Virginie; Coiffard, Benjamin; Gimenez, Gregory; Mege, Jean-Louis; Ghigo, Eric

2017-10-03

Planarians, which are non-parasitic flatworms, are highly resistant to bacterial infections. To better understand the mechanisms underlying this resistance, we investigated the role of the circadian machinery in the anti-bacterial response of the freshwater planarian Schmidtea mediterranea. We identified Smed-Tim from S. mediterranea as a homolog of the mammalian clock gene Tim. We showed via RNA interference that Smed-Tim is required for the anti-microbial activities of Schmidtea mediterranea against Staphylococcus aureus infection during the light/dark cycle. Indeed, S. aureus infection leads to the expression of Smed-Tim, which in turn promotes Smed-Traf6 and Smed-morn2, but not Smed-p38 MAPK expression, 2 master regulators of planarian anti-microbial responses.

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).

Analysis of PD-1 and Tim-3 expression on CD4+ T cells of patients with rheumatoid arthritis; negative association with DAS28.

PubMed

Koohini, Zohreh; Hossein-Nataj, Hadi; Mobini, Maryam; Hosseinian-Amiri, Aref; Rafiei, Alireza; Asgarian-Omran, Hossein

2018-04-07

Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4 + T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3 + /PD-1 + /CD4 + T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-γ, and TNF-α were measured in culture supernatants by ELISA. The frequency of PD-1 + /CD4 + and Tim-3 + /PD-1 + /CD4 + T cells was significantly higher in patients with RA compared to that in controls (p = 0.0013 and p = 0.050, respectively). The percentage of Tim-3 + /CD4 + T cells was similar in patients and controls (p = 0.4498). The RA patients have produced significant higher levels of TNF-α, IL-17, and IFN-γ than those of healthy controls (p = 0.0121, p = 0.0417, and p = 0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim-3 + /CD4 + cells and DAS28 of RA patients (r = - 0.4696, p = 0.0493). Similarly, the percentage of Tim-3 + /PD-1 + /CD4 + T cells was also revealed an inverse correlation with DAS28 (r = - 0.5268, p = 0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-α (r = 0.6418, p = 0.0023) and IL-17 (r = 0.4683, p = 0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression.

SU-F-BRE-03: Consideration of a Track-Interaction Model for Radiochromic Film Response

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

Rosen, B; DeWerd, L

2014-06-15

Purpose: Conventional methods for characterizing the energy response of radiochromic film (RCF) typically involve assessing changes in response when exposed to various beam qualities and use Monte Carlo to determine absorbed dose. These methods represent RCF as a dose integrator of a homogeneous energy deposition volume. Apparent film saturation, nonlinearity, and intrinsic energy dependence are unpredicted with conventional methods. Recent work has shown significant RCF intrinsic energy dependence, which limits its use in absolute dosimetry. This work introduces a track-interaction model (TIM) for RCF and assesses its ability to predict total energy response. Methods: A TIM based on Katz single-hitmore » theory was developed to accumulate energy flux along particle tracks within active crystals, represented as (1×1×20)um{sup 3} prisms about the Gafchromic™ EBT3 active volume using MCNP5 and Matlab. Energy flux contributed to film response only if near the threshold energy for polymerization in polydiacetylenes (2.5eV/monomer). Energy deposition in excess of maximum efficiency represented crystal saturation and did not contribute to film response. The TIM was applied to RCF exposed in air to various monoenergetic photon beams and Co-60. Geometric distribution of energy flux was found for each beam quality in a (1×1)mm{sup 2} RCF area. RCF response relative to Co-60 absorbed dose-to-water (S-TIM) was determined and compared to published values (S-PUB). Results: TIM successfully predicted that lower energy radiation is less effective at inducing polymerization, though the magnitude of the phenomenon was overpredicted. S-TIM was −29% and +20% for 20 and 40 keV, respectively. This agreed qualitatively with S-PUB of −27% and +16%. TIM-generated sensitometric curves contained the non-linearity and saturation apparent in RCF. Conclusion: This work indicates the possibility for TIMs to predict changes in RCF response to various energies. Future work will refine TIM by considering size distributions of active elements, other RCF formulations, and response in complex treatment fields. Acknowledgements: The authors wish to thank Dr. Christopher Soares at NIST (Gaithersburg, MD) for performing film measurements and Dr. David Lewis of Ashland, Inc. (Wayne, NJ) for making the EBT3 film available to us.« less

Medicinal properties of Peganum harmala L. in traditional Iranian medicine and modern phytotherapy: a review.

PubMed

Mina, Cheraghi Niroumand; Farzaei, Mohammad Hosein; Gholamreza, Amin

2015-02-01

To review the pharmacological activities of Peganum harmala L. (P. harmala, Nitrariaceae) in traditional Iranian medicine (TIM) and modern phytotherapy. Opinions of TIM and modern phytotherapy about safety and acceptable dosage of this plant are discussed. Various medical properties of P. harmala were collected from important TIM references and added to scientific reports derived from modern medical databases like PubMed, Scirus, ScienceDirect and Scopus. The main medicinal part of the plant is the seed. In TIM resources, this plant possesses various Pharmacological activities such as carminative, galactagogue, diuretic, emmenagogue, antithrombotic and analgesic. In modern phytotherapy, P. harmala demonstrated numerous medicinal effects including cardiovascular, neurologic, antimicrobial, insecticidal, antineoplasmic, antiproliferative, gastrointestinal and antidiabetic effects. Adverse events such as neuro-sensorial symptoms, visual hallucination, bradycardia, hypotension, agitation, tremors, ataxia, abortion and vomiting cause people to use this plant cautiously. P. harmala is contraindicated during pregnancy, due to its abortive and mutagenic activities. Because of increasing the expression of CYP1A2, 2C19, and 3A4 and inhibition of monoamine oxidase, the pharmacokinetic parameters of drugs which are mainly metabolized by these enzymes may be affected by P. harmala. The medicinal properties declared for this plant in TIM are compared with those showed in modern phytotherapy. Some of the TIM properties were confirmed in modern phytotherapy like emetic and analgesic activities and some have not been evaluated in modern phytotherapy such as its therapeutic effects on paralysis, epilepsy and numbness. Finally, the current review provides the evidence for other researchers to use TIM properties of P. harmala as an efficacious natural drug. Further preclinical and clinical studies for adequate evaluating safety and therapeutic efficacy are recommended.

Conjugated Bilirubin Upregulates TIM-3 Expression on CD4+CD25+ T Cells: Anti-Inflammatory Implications for Hepatitis A Virus Infection.

PubMed

Trujillo-Ochoa, Jorge L; Corral-Jara, Karla F; Charles-Niño, Claudia L; Panduro, Arturo; Fierro, Nora A

2018-04-01

Bilirubin (BR), a metabolite with increased concentrations in plasma during viral hepatitis, has been recognized as a potential immune-modulator. We recently reported that conjugated BR (CB) augments regulatory T cell (Treg) suppressor activity during acute hepatitis A virus (HAV) infection. However, the mechanisms related to the effects of CB on Treg function in the course of hepatotropic viral diseases have not been elucidated. T cell immunoglobulin domain and mucin domain 3 (TIM-3), via its interactions with galectin-9 (GAL-9), is a receptor associated with enhanced Treg function. Thus, TIM-3 expression may be related to the crosstalk between CB and Tregs during HAV infection. Herein, in vitro treatment with high concentrations of CB upregulated TIM-3 expression on Tregs from healthy donors. CB treatment in vitro did not induce de novo Treg generation, and in vitro stimulation with TGF-β, which shows increased secretion during HAV infection, resulted in a trend toward increased TIM-3 expression on Tregs and CD4 + T lymphocytes (TLs) from healthy donors. Interestingly, an upregulation of TIM-3 expression on CD4 + CD25 + T cells and an increase in the proportion of CD4 + TLs expressing GAL-9 were found in HAV-infected patients with abnormal CB values relative to healthy controls. In addition, a statistically significantly reduction in IL-17F production was observed after treatment of CD4 + TLs from healthy donors with high doses of CB in vitro. In summary, our results suggest that CB might regulate Treg activity via a TIM-3-mediated mechanism, ultimately leading to an anti-inflammatory hepatoprotective effect.

Preparation of bone-implants by coating hydroxyapatite nanoparticles on self-formed titanium dioxide thin-layers on titanium metal surfaces.

PubMed

Wijesinghe, W P S L; Mantilaka, M M M G P G; Chathuranga Senarathna, K G; Herath, H M T U; Premachandra, T N; Ranasinghe, C S K; Rajapakse, R P V J; Rajapakse, R M G; Edirisinghe, Mohan; Mahalingam, S; Bandara, I M C C D; Singh, Sanjleena

2016-06-01

Preparation of hydroxyapatite coated custom-made metallic bone-implants is very important for the replacement of injured bones of the body. Furthermore, these bone-implants are more stable under the corrosive environment of the body and biocompatible than bone-implants made up of pure metals and metal alloys. Herein, we describe a novel, simple and low-cost technique to prepare biocompatible hydroxyapatite coated titanium metal (TiM) implants through growth of self-formed TiO2 thin-layer (SFTL) on TiM via a heat treatment process. SFTL acts as a surface binder of HA nanoparticles in order to produce HA coated implants. Colloidal HA nanorods prepared by a novel surfactant-assisted synthesis method, have been coated on SFTL via atomized spray pyrolysis (ASP) technique. The corrosion behavior of the bare and surface-modified TiM (SMTiM) in a simulated body fluid (SBF) medium is also studied. The highest corrosion rate is found to be for the bare TiM plate, but the corrosion rate has been reduced with the heat-treatment of TiM due to the formation of SFTL. The lowest corrosion rate is recorded for the implant prepared by heat treatment of TiM at 700 °C. The HA-coating further assists in the passivation of the TiM in the SBF medium. Both SMTiM and HA coated SMTiM are noncytotoxic against osteoblast-like (HOS) cells and are in high-bioactivity. The overall production process of bone-implant described in this paper is in high economic value. Copyright © 2016 Elsevier B.V. All rights reserved.

Stable isotope ratio mass spectrometry of nanogram quantities of boron and sulfur

NASA Astrophysics Data System (ADS)

Wieser, Michael Eugene

1998-09-01

Instrumentation and analytical techniques were developed to measure isotope abundances from nanograms of sulfur and boron. Sulfur isotope compositions were determined employing continuous flow isotope ratio mass spectroscopy (CF-IRMS) procedures and AsS+ thermal ionization mass spectrometry techniques (AsS+-TIMS). Boron isotope abundances were determined by BO2/sp--TIMS. CF-IRMS measurements realized δ34S values from 10 μg sulfur with precisions of ±0.3/perthous. To extend sulfur isotope measurements to much smaller samples, a TIMS procedure was developed to measure 75As32S+ and 75As34S+ at masses 108 and 109 from 200 ng S on a Finnigan MAT 262 with an ion counter. This is possibly the smallest amount of sulfur which has been successfully analyzed isotopically. The internal precision of 32S/34S ratios measured by AsS+-TIMS was better than ±0.15 percent. δ34S-values calculated relative to the measured 32S/34S value of an IAEA AG2S standard (S-1) agreed with those determined by CF-IRMS to within ±3/perthous. The increasing sensitivity of S-isotope analyses permits hiterto impossible investigations e.g. sulfur in tree rings and ice cores. Boron isotope abundances were measured as BO2/sp- from 50 ng B using an older thermal ionization mass spectrometer which had been extensively upgraded including the addition of computer control electronics, sensitive ion current amplification and fiber optic data bus. The internal precisions of the measured 11B/10B ratios were ±0.15 percent and the precisions of δ11B values calculated relative to the accepted international standard (SRM-951) were ±3/perthous. Two applications of boron isotope abundance variations were initiated (1) ground waters of Northern Alberta and (2) coffee beans in different regions of the world. In the first it was demonstrated that boron isotopes could be used to trace boron released during steam injection of oil sands into the surrounding environment. Data from the second study suggest that boron isotopes can be used to improve cultivation of coffee particularly in regions where 'organically grown' coffee had markedly different δ11B values than beans grown with boron- containing fertilizers in neighbouring regions. A regional dependence on the δ11B values of the coffee allow the sources of commercial coffee blends to be identified.

A polymorphism in TIM1 is associated with susceptibility to severe hepatitis A virus infection in humans

PubMed Central

Kim, Hye Young; Eyheramonho, María Belén; Pichavant, Muriel; Gonzalez Cambaceres, Carlos; Matangkasombut, Ponpan; Cervio, Guillermo; Kuperman, Silvina; Moreiro, Rita; Konduru, Krishnamurthy; Manangeeswaran, Mohanraj; Freeman, Gordon J.; Kaplan, Gerardo G.; DeKruyff, Rosemarie H.; Umetsu, Dale T.; Rosenzweig, Sergio D.

2011-01-01

During infection with the hepatitis A virus (HAV), most patients develop mild or asymptomatic disease. However, a small number of patients develop serious, life-threatening hepatitis. We investigated this variability in disease severity by examining 30 Argentinean patients with HAV-induced acute liver failure in a case-control, cross-sectional, observational study. We found that HAV-induced severe liver disease was associated with a 6-amino-acid insertion in TIM1/HAVCR1 (157insMTTTVP), the gene encoding the HAV receptor. This polymorphism was previously shown to be associated with protection against asthma and allergic diseases and with HIV progression. In binding assays, the TIM-1 protein containing the 157insMTTTVP insertion polymorphism bound HAV more efficiently. When expressed by human natural killer T (NKT) cells, this long form resulted in greater NKT cell cytolytic activity against HAV-infected liver cells, compared with the shorter TIM-1 protein without the polymorphism. To our knowledge, the 157insMTTTVP polymorphism in TIM1 is the first genetic susceptibility factor shown to predispose to HAV-induced acute liver failure. Furthermore, these results suggest that HAV infection has driven the natural selection of shorter forms of the TIM-1 protein, which binds HAV less efficiently, thereby protecting against severe HAV-induced disease, but which may predispose toward inflammation associated with asthma and allergy. PMID:21339644

Enhanced upper genital tract pathologies by blocking Tim-3 and PD-L1 signaling pathways in mice intravaginally infected with Chlamydia muridarum.

PubMed

Peng, Bo; Lu, Chunxue; Tang, Lingli; Yeh, I-Tien; He, Zhimin; Wu, Yimou; Zhong, Guangming

2011-12-14

Although Tim-3 & PD-L1 signaling pathways play important roles in negatively regulating immune responses, their roles in chlamydial infection have not been evaluated. Neutralization antibodies targeting Tim-3 and PD-L1 were used to treat mice. Following an intravaginal infection with C. muridarum organisms, mice with or without the dual antibody treatment were compared for live chlamydial organism shedding from the lower genital tract and inflammatory pathology in the upper genital tract. Mice treated with anti-Tim-3 and anti-PD-L1 antibodies displayed a time course of live organism shedding similar to that of mice treated with equivalent amounts of isotype-matched IgG molecules. The combined antibody blocking failed to alter either the lower genital tract cytokine or systemic humoral and cellular adaptive responses to C. muridarum infection. However, the antibody blocking significantly enhanced C. muridarum-induced pathologies in the upper genital tract, including more significant hydrosalpinx and inflammatory infiltration in uterine horn and oviduct tissues. The Tim-3 and PD-L1-mediated signaling can significantly reduce pathologies in the upper genital tract without suppressing immunity against chlamydial infection, suggesting that Tim-3 and PD-L1-mediated negative regulation may be manipulated to attenuate tubal pathologies in women persistently infected with C. trachomatis organisms.

Isolation and expression of a Bacillus cereus gene encoding benzil reductase.

PubMed

Maruyama, R; Nishizawa, M; Itoi, Y; Ito, S; Inoue, M

2001-12-20

Benzil was reduced stereospecifically to (S)-benzoin by Bacillus cereus strain Tim-r01. To isolate the gene responsible for asymmetric reduction, we constructed a library consisting of Escherichia coli clones that harbored plasmids expressing Bacillus cereus genes. The library was screened using the halo formation assay, and one clone showed benzil reduction to (S)-benzoin. Thus, this clone seemed to carry a plasmid encoding a Bacillus cereus benzil reductase. The deduced amino acid sequence had marked homologies to the Bacillus subtilis yueD protein (41% identity), the yeast open reading frame YIR036C protein (31%), and the mammalian sepiapterin reductases (28% to 30%), suggesting that benzil reductase is a novel short-chain de-hydrogenases/ reductase. Copyright 2001 John Wiley & Sons, Inc.

Heliophysics: Plasma Physics of the Local Cosmos

NASA Astrophysics Data System (ADS)

Schrijver, Carolus J.; Siscoe, George L.

2009-07-01

Preface; 1. Prologue Carolus J. Schrijver and George L. Siscoe; 2. Introduction to heliophysics Thomas J. Bogdan; 3. Creation and destruction of magnetic field Matthias Rempel; 4. Magnetic field topology Dana W. Longcope; 5. Magnetic reconnection Terry G. Forbes; 6. Structures of the magnetic field Mark B. Moldwin, George L. Siscoe and Carolus J. Schrijver; 7. Turbulence in space plasmas Charles W. Smith; 8. The solar atmosphere Viggo H. Hansteen; 9. Stellar winds and magnetic fields Viggo H. Hansteen; 10. Fundamentals of planetary magnetospheres Vytenis M. Vasyliunas; 11. Solar-wind magnetosphere coupling: an MHD perspective Frank R. Toffoletto and George L. Siscoe; 12. On the ionosphere and chromosphere Tim Fuller-Rowell and Carolus J. Schrijver; 13. Comparative planetary environments Frances Bagenal; Bibliography; Index.

Heliophysics: Plasma Physics of the Local Cosmos

NASA Astrophysics Data System (ADS)

Schrijver, Carolus J.; Siscoe, George L.

2011-08-01

Preface; 1. Prologue Carolus J. Schrijver and George L. Siscoe; 2. Introduction to heliophysics Thomas J. Bogdan; 3. Creation and destruction of magnetic field Matthias Rempel; 4. Magnetic field topology Dana W. Longcope; 5. Magnetic reconnection Terry G. Forbes; 6. Structures of the magnetic field Mark B. Moldwin, George L. Siscoe and Carolus J. Schrijver; 7. Turbulence in space plasmas Charles W. Smith; 8. The solar atmosphere Viggo H. Hansteen; 9. Stellar winds and magnetic fields Viggo H. Hansteen; 10. Fundamentals of planetary magnetospheres Vytenis M. Vasyliūnas; 11. Solar-wind magnetosphere coupling: an MHD perspective Frank R. Toffoletto and George L. Siscoe; 12. On the ionosphere and chromosphere Tim Fuller-Rowell and Carolus J. Schrijver; 13. Comparative planetary environments Frances Bagenal; Bibliography; Index.

Secrets of the Dark Universe: Simulating the Sky on the Blue Gene/Q

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

None

An astonishing 99.6% of our Universe is dark. Observations indicate that the Universe consists of 70% of a mysterious dark energy and 25% of a yet unidentified dark matter component, and only 0.4% of the remaining ordinary matter is visible. Understanding the physics of this dark sector is the foremost challenge in cosmology today. Sophisticated simulations of the evolution of the Universe play a crucial task in this endeavor. Credits: Science: Hal Finkel, Salman Habib, Katrin Heitmann, Kalyan Kumaran, Vitali Morozov, Tom Peterka, Adrian Pope, Tim Williams, David Daniel, Patricia Fasel, Nicholas Frontiere and Zarija Lukic Visualization: Mark Herald, Josephmore » A. Insley, Aaron Knoll, Michael E. Papka, Venkatram Vishwanath and Eric C. Olson« less

KSC-2009-3410

NASA Image and Video Library

2009-06-03

CAPE CANAVERAL, Fla. – The STS-127 crew members stand for a final photograph after a question-and-answer session with the media at NASA Kennedy Space Center's Launch Pad 39A. From left are Commander Mark Polansky, Pilot Doug Hurley and Mission Specialists Julie Payette, Tom Marshburn , Tim Kopra, Christopher Cassidy and Dave Wolf. Payette represents the Canadian Space Agency. The crew is at Kennedy for a launch dress rehearsal called the terminal countdown demonstration test, or TCDT, which includes emergency egress training and equipment familiarization. Space shuttle Endeavour's STS-127 mission is the final of three flights dedicated to the assembly of the Japanese Kibo laboratory complex on the International Space Station. Endeavour's launch is targeted for June 13. Photo credit: NASA/Kim Shiflett

KSC-2009-3407

NASA Image and Video Library

2009-06-03

CAPE CANAVERAL, Fla. – Photographers and videographers capture the STS-127 crew during a question-and-answer session with the media at NASA Kennedy Space Center's Launch Pad 39A. Standing behind the pad are, from left, Commander Mark Polansky, , Pilot Doug Hurley and Mission Specialists Julie Payette, Tom Marshburn, Tim Kopra, Christopher Cassidy and Dave Wolf. Payette represents the Canadian Space Agency. The crew is at Kennedy for a launch dress rehearsal called the terminal countdown demonstration test, or TCDT, which includes emergency egress training and equipment familiarization. Space shuttle Endeavour's STS-127 mission is the final of three flights dedicated to the assembly of the Japanese Kibo laboratory complex on the International Space Station. Endeavour's launch is targeted for June 13. Photo credit: NASA/Kim Shiflett

Active remodelling of the TIM23 complex during translocation of preproteins into mitochondria.

PubMed

Popov-Celeketić, Dusan; Mapa, Koyeli; Neupert, Walter; Mokranjac, Dejana

2008-05-21

The TIM23 (translocase of the mitochondrial inner membrane) complex mediates translocation of preproteins across and their insertion into the mitochondrial inner membrane. How the translocase mediates sorting of preproteins into the two different subcompartments is poorly understood. In particular, it is not clear whether association of two operationally defined parts of the translocase, the membrane-integrated part and the import motor, depends on the activity state of the translocase. We established conditions to in vivo trap the TIM23 complex in different translocation modes. Membrane-integrated part of the complex and import motor were always found in one complex irrespective of whether an arrested preprotein was present or not. Instead, we detected different conformations of the complex in response to the presence and, importantly, the type of preprotein being translocated. Two non-essential subunits of the complex, Tim21 and Pam17, modulate its activity in an antagonistic manner. Our data demonstrate that the TIM23 complex acts as a single structural and functional entity that is actively remodelled to sort preproteins into different mitochondrial subcompartments.

Active remodelling of the TIM23 complex during translocation of preproteins into mitochondria

PubMed Central

Popov-Čeleketić, Dus̆an; Mapa, Koyeli; Neupert, Walter; Mokranjac, Dejana

2008-01-01

The TIM23 (translocase of the mitochondrial inner membrane) complex mediates translocation of preproteins across and their insertion into the mitochondrial inner membrane. How the translocase mediates sorting of preproteins into the two different subcompartments is poorly understood. In particular, it is not clear whether association of two operationally defined parts of the translocase, the membrane-integrated part and the import motor, depends on the activity state of the translocase. We established conditions to in vivo trap the TIM23 complex in different translocation modes. Membrane-integrated part of the complex and import motor were always found in one complex irrespective of whether an arrested preprotein was present or not. Instead, we detected different conformations of the complex in response to the presence and, importantly, the type of preprotein being translocated. Two non-essential subunits of the complex, Tim21 and Pam17, modulate its activity in an antagonistic manner. Our data demonstrate that the TIM23 complex acts as a single structural and functional entity that is actively remodelled to sort preproteins into different mitochondrial subcompartments. PMID:18418384

Novel polymer composite having diamond particles and boron nitride platelets for thermal management of electric vehicle motors

NASA Astrophysics Data System (ADS)

Nakajima, Anri; Shoji, Atsushi; Yonemori, Kei; Seo, Nobuhide

2016-02-01

Thermal conductivities of silicone matrix polymers including fillers of diamond particles and/or hexagonal boron nitride (h-BN) platelets were systematically investigated in an attempt to find a thermal interface material (TIM) having high isotropic thermal conductivity and high electrical insulating ability to enable efficient heat dissipation from the motor coil ends of electric vehicles. The TIM with mixed fillers of diamond particles and h-BN platelets had a maximum thermal conductivity of 6.1 W m-1 K-1 that was almost isotropic. This is the highest value among the thermal conductivities of TIMs with silicone matrix polymer reported to date. The mechanism behind the thermal conductivity of the TIMs was also examined from the viewpoint of the change in the number of thermally conductive networks and/or a decrease in the thermal resistivity of junctions of neighboring diamond particles through the incorporation of h-BN platelets. The TIMs developed in this study will make it possible to manage the heat of electric motors and will help to popularize electric vehicles.

Alleviation of Drought Stress and Metabolic Changes in Timothy (Phleum pratense L.) Colonized with Bacillus subtilis B26

PubMed Central

Gagné-Bourque, François; Bertrand, Annick; Claessens, Annie; Aliferis, Konstantinos A.; Jabaji, Suha

2016-01-01

Drought is a major limiting factor of crop productivity worldwide and its incidence is predicted to increase under climate change. Drought adaptation of cool-season grasses is thus a major challenge to secure the agricultural productivity under current and future climate conditions. Endophytes are non-pathogenic plant-associated bacteria that can play an important role in conferring resistance and improving plant tolerance to drought. In this study, the effect of inoculation of the bacterial endophyte Bacillus subtilis strain B26 on growth, water status, photosynthetic activity and metabolism of timothy (Phleum pratense L.) subjected to drought stress was investigated under controlled conditions. Under both drought-stress and non-stressed conditions, strain B26 successfully colonized the internal tissues of timothy and had a positive impact on plant growth. Exposure of inoculated plant to a 8-week drought-stress led to significant increase in shoot and root biomass by 26.6 and 63.8%, and in photosynthesis and stomatal conductance by 55.2 and 214.9% respectively, compared to non-inoculated plants grown under similar conditions. There was a significant effect of the endophyte on plant metabolism; higher levels of several sugars, notably sucrose and fructans and an increase of key amino acids such as, asparagine, glutamic acid and glutamine were recorded in shoots and roots of colonized plants compared to non-colonized ones. The accumulation of the non-protein amino acid GABA in shoots of stressed plants and in roots of stressed and unstressed plants was increased in the presence of the endophyte. Taken together, our results indicate that B. subtilis B26 improves timothy growth under drought stress through the modification of osmolyte accumulation in roots and shoots. These results will contribute to the development of a microbial agent to improve the yield of grass species including forage crops and cereals exposed to environmental stresses. PMID:27200057

Phleum pratense pollen starch granules induce humoral and cell-mediated immune responses in a rat model of allergy.

PubMed

Motta, A; Peltre, G; Dormans, J A M A; Withagen, C E T; Lacroix, G; Bois, F; Steerenberg, P A

2004-02-01

Timothy grass (Phleum pratense) pollen allergens are an important cause of allergic symptoms. However, pollen grains are too large to penetrate the deeper airways. Grass pollen is known to release allergen-bearing starch granules (SG) upon contact with water. These granules can create an inhalable allergenic aerosol capable of triggering an early asthmatic response and are implicated in thunderstorm-associated asthma. We studied the humoral (IgE) and bronchial lymph node cells reactivities to SG from timothy grass pollen in pollen-sensitized rats. Brown-Norway rats were sensitized (day 0) and challenged (day 21) intratracheally with intact pollen and kept immunized by pollen intranasal instillation by 4 weeks intervals during 3 months. Blood and bronchial lymph nodes were collected 7 days after the last intranasal challenge. SG were purified from fresh timothy grass pollen using 5 microm mesh filters. To determine the humoral response (IgE) to SG, we developed an original ELISA inhibition test, based on competition between pollen allergens and purified SG. The cell-mediated response to SG in the bronchial lymph node cells was determined by measuring the uptake of [3H]thymidine in a proliferation assay. An antibody response to SG was induced, and purified SG were able to inhibit the IgE ELISA absorbance by 45%. Pollen extract and intact pollen gave inhibitions of 55% and 52%, respectively. A cell-mediated response was also found, as pollen extract, intact pollen and SG triggered proliferation of bronchial lymph node cells. It was confirmed that timothy grass pollen contains allergen-loaded SG, which are released upon contact with water. These granules were shown to be recognized by pollen-sensitized rats sera and to trigger lymph node cell proliferation in these rats. These data provide new arguments supporting the implication of grass pollen SG in allergic asthma.

Determination of the turbulence integral model parameters for a case of a coolant angular flow in regular rod-bundle

NASA Astrophysics Data System (ADS)

Bayaskhalanov, M. V.; Vlasov, M. N.; Korsun, A. S.; Merinov, I. G.; Philippov, M. Ph

2017-11-01

Research results of “k-ε” turbulence integral model (TIM) parameters dependence on the angle of a coolant flow in regular smooth cylindrical rod-bundle are presented. TIM is intended for the definition of efficient impulse and heat transport coefficients in the averaged equations of a heat and mass transfer in the regular rod structures in an anisotropic porous media approximation. The TIM equations are received by volume-averaging of the “k-ε” turbulence model equations on periodic cell of rod-bundle. The water flow across rod-bundle under angles from 15 to 75 degrees was simulated by means of an ANSYS CFX code. Dependence of the TIM parameters on flow angle was as a result received.

Antimicrobial capacity of the freshwater planarians against S. aureus is under the control of Timeless

PubMed Central

Tsoumtsa, Landry Laure; Torre, Cedric; Trouplin, Virginie; Coiffard, Benjamin; Gimenez, Gregory; Mege, Jean-Louis; Ghigo, Eric

2017-01-01

ABSTRACT Planarians, which are non-parasitic flatworms, are highly resistant to bacterial infections. To better understand the mechanisms underlying this resistance, we investigated the role of the circadian machinery in the anti-bacterial response of the freshwater planarian Schmidtea mediterranea. We identified Smed-Tim from S. mediterranea as a homolog of the mammalian clock gene Tim. We showed via RNA interference that Smed-Tim is required for the anti-microbial activities of Schmidtea mediterranea against Staphylococcus aureus infection during the light/dark cycle. Indeed, S. aureus infection leads to the expression of Smed-Tim, which in turn promotes Smed-Traf6 and Smed-morn2, but not Smed-p38 MAPK expression, 2 master regulators of planarian anti-microbial responses. PMID:28051908

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 analyzed by U-Pb TIMS-TEA. In situ trace element transects are used to model predicted TIMS-TEA trace element concentrations to test whether complicated trace element profiles undermine U-Pb TIMS-TEA data. We find good agreement between predicted and measured TIMS-TEA data, and can argue that the measured ID-TIMS U-Pb date corresponds to the time at which the geochemical signature measured by TIMS-TEA was acquired. Thus, in a hypothetical magma that is differentiating through AFC processes on timescales resolvable by geochronology, U-Pb TIMS-TEA should usually be a robust indicator of magma evolution through time. We present data from two ca. 40-30 Ma alpine intrusions from northern Italy: the southern Adamello batholith and the Bergell intrusion. The relatively young age of these intrusions permits uncertainties on individual zircon or zircon fragments as good as 10 ka, while zircon populations from individual hand samples often record zircon growth of >200 ka. Using the methodologies described above, we explore whether these zircons record in situ magmatic differentiation or introduction of antecrystic zircon to magma batches, and integrate these data to gain a better understanding of magma storage, differentiation and emplacement as a function of pressure, temperature, and time. These methods are a promising step towards interpreting complicated geochronologic data in ashbed samples as well through a better understanding of magmatic processes that precede eruption.

Spirit Rover on 'Husband Hill'

NASA Technical Reports Server (NTRS)

2006-01-01

[figure removed for brevity, see original site] Figure 1: Location of Spirit

Two Earth years ago, NASA's Mars Exploration Rover Spirit touched down in Gusev Crater. The rover marked its first Mars-year (687 Earth days) anniversary in November 2005. Shortly before Spirit's Martian anniversary, the Mars Orbiter Camera on NASA's Mars Global Surveyor acquired an image covering approximately 3 kilometers by 3 kilometers (1.9 miles by 1.9 miles) centered on the rover's location at that time in the 'Columbia Hills.'

'Husband Hill,' the tallest in the range, is just below the center of the image. The image has a resolution of about 50 centimeters (1.6 feet) per pixel. North is up; illumination is from the left. The location is near 14.8 degrees south latitude, 184.6 degrees west longitude.

The image was acquired on Nov. 2, 2005. A white box (see Figure 1) indicates the location of an excerpted portion on which the location of Spirit on that date is marked. Dr. Timothy J. Parker of the Mars Exploration Rover team at the NASA's Jet Propulsion Laboratory, Pasadena, Calif., confirmed the location of the rover in the image. The region toward the bottom of the image shows the area where the rover is currently headed. The large dark patch and other similar dark patches are accumulations of windblown sand and granules.

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 assumed to be at ambient temperature as recorded by the TIMS for each scanline. Using the slope and the intercept the flux corresponding to this target was converted into digital counts. The counts were observed to have a strong correlation with the actual video as recorded by the TIMS. The attached graphs describe the performance of the TIMS when compressed air is blown at each one of the blackbodies at different speeds. The effect of blowing a fan and changing the room temperature is also being analyzed. Results indicate that the TIMS system responds to variation in wind speed in real time and maintains the capability to produce accurate temperatures on a scan line basis.

Isotopic Ratios of Samarium by TIMS for Nuclear Forensic Application

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

Louis Jean, James; Inglis, Jeremy David

The isotopic ratio of Nd, Sm, and Gd can provide important information regarding fissile material (nuclear devices, reactors), neutron environment, and device yield. These studies require precise measurement of Sm isotope ratios, by either TIMS or MC-ICP-MS. There has been an increasing trend to measure smaller and smaller quantities of Sm bearing samples. In nuclear forensics 10-100 ng of Sm are needed for precise measurement. To measure sub-ng Sm samples using TIMS for nuclear forensic analysis.

OCT-based in vivo tissue injury mapping

NASA Astrophysics Data System (ADS)

Baran, Utku; Li, Yuandong; Wang, Ruikang K.

2016-03-01

Tissue injury mapping (TIM) is developed by using a non-invasive in vivo optical coherence tomography to generate optical attenuation coefficient and microvascular map of the injured tissue. Using TIM, the infarct region development in mouse cerebral cortex during stroke is visualized. Moreover, we demonstrate the in vivo human facial skin structure and microvasculature during an acne lesion development. The results indicate that TIM may help in the study and the treatment of various diseases by providing high resolution images of tissue structural and microvascular changes.

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.

The Long-Term U.S. Strategic Implications of Huawei’s Penetration in Latin America

DTIC Science & Technology

2013-03-01

TIM Brasil Picks NSN, Ericsson and Huawei to Deliver LTE 2012, para. 1). This shows a commitment to a long-term relationship between Huawei and...statement of Eliot L. Engel, congressional representative from New York). 1-37. "TIM Brasil Picks NSN, Ericsson and Huawei to Deliver LTE...34 TeleGeography. October 31, 2012. Accessed January 21, 2013. http://www.telegeography.com/products/commsupdate/arti cles/2012/10/31/tim- brasil -picks-nsn

Heliophysics 3 Volume Set

NASA Astrophysics Data System (ADS)

Schrijver, Carolus J.; Siscoe, George L.

2010-11-01

Volume 1: Preface; 1. Prologue Carolus J. Schrijver and George L. Siscoe; 2. Introduction to heliophysics Thomas J. Bogdan; 3. Creation and destruction of magnetic field Matthias Rempel; 4. Magnetic field topology Dana W. Longcope; 5. Magnetic reconnection Terry G. Forbes; 6. Structures of the magnetic field Mark B. Moldwin, George L. Siscoe and Carolus J. Schrijver; 7. Turbulence in space plasmas Charles W. Smith; 8. The solar atmosphere Viggo H. Hansteen; 9. Stellar winds and magnetic fields Viggo H. Hansteen; 10. Fundamentals of planetary magnetospheres Vytenis M. Vasyliūnas; 11. Solar-wind magnetosphere coupling: an MHD perspective Frank R. Toffoletto and George L. Siscoe; 12. On the ionosphere and chromosphere Tim Fuller-Rowell and Carolus J. Schrijver; 13. Comparative planetary environments Frances Bagenal; Bibliography; Index. Volume 2: Preface; 1. Perspective on heliophysics George L. Siscoe and Carolus J. Schrijver; 2. Introduction to space storms and radiation Sten Odenwald; 3. In-situ detection of energetic particles George Gloeckler; 4. Radiative signatures of energetic particles Tim Bastian; 5. Observations of solar and stellar eruptions, flares, and jets Hugh Hudson; 6. Models of coronal mass ejections and flares Terry Forbes; 7. Shocks in heliophysics Merav Opher; 8. Particle acceleration in shocks Dietmar Krauss-Varban; 9. Energetic particle transport Joe Giacalone; 10. Energy conversion in planetary magnetospheres Vytenis Vasyliūnas; 11. Energization of trapped particles Janet Green; 12. Flares, CMEs, and atmospheric responses Tim Fuller-Rowell and Stanley C. Solomon; 13. Energetic particles and manned spaceflight 358 Stephen Guetersloh and Neal Zapp; 14. Energetic particles and technology Alan Tribble; Appendix I. Authors and editors; List of illustrations; List of tables; Bibliography; Index. Volume 3: Preface; 1. Interconnectedness in heliophysics Carolus J. Schrijver and George L. Siscoe; 2. Long-term evolution of magnetic activity of Sun-like stars Carolus J. Schrijver; 3. Formation and early evolution of stars and proto-planetary disks Lee W. Hartmann; 4. Planetary habitability on astronomical time scales Donald E. Brownlee; 5. Solar internal flows and dynamo action Mark S. Miesch; 6. Modeling solar and stellar dynamos Paul Charbonneau; 7. Planetary fields and dynamos Ulrich R. Christensen; 8. The structure and evolution of the 3D solar wind John T. Gosling; 9. The heliosphere and cosmic rays J. Randy Jokipii; 10. Solar spectral irradiance: measurements and models Judith L. Lean and Thomas N. Woods; 11. Astrophysical influences on planetary climate systems Juerg Beer; 12. Evaluating the drivers of Earth's climate system Thomas J. Crowley; 13. Ionospheres of the terrestrial planets Stanley C. Solomon; 14. Long-term evolution of the geospace climate Jan J. Sojka; 15. Waves and transport processes in atmospheres and oceans Richard L. Walterscheid; 16. Solar variability, climate, and atmospheric photochemistry Guy P. Brasseur, Daniel Marsch and Hauke Schmidt; Appendix I. Authors and editors; List of illustrations; List of tables; Bibliography; Index.

Heliophysics 3 Volume Paperback Set

NASA Astrophysics Data System (ADS)

Schrijver, Carolus J.; Siscoe, George L.

2013-03-01

Volume 1: Preface; 1. Prologue Carolus J. Schrijver and George L. Siscoe; 2. Introduction to heliophysics Thomas J. Bogdan; 3. Creation and destruction of magnetic field Matthias Rempel; 4. Magnetic field topology Dana W. Longcope; 5. Magnetic reconnection Terry G. Forbes; 6. Structures of the magnetic field Mark B. Moldwin, George L. Siscoe and Carolus J. Schrijver; 7. Turbulence in space plasmas Charles W. Smith; 8. The solar atmosphere Viggo H. Hansteen; 9. Stellar winds and magnetic fields Viggo H. Hansteen; 10. Fundamentals of planetary magnetospheres Vytenis M. Vasyliunas; 11. Solar-wind magnetosphere coupling: an MHD perspective Frank R. Toffoletto and George L. Siscoe; 12. On the ionosphere and chromosphere Tim Fuller-Rowell and Carolus J. Schrijver; 13. Comparative planetary environments Frances Bagenal; Bibliography; Index. Volume 2: Preface; 1. Perspective on heliophysics George L. Siscoe and Carolus J. Schrijver; 2. Introduction to space storms and radiation Sten Odenwald; 3. In-situ detection of energetic particles George Gloeckler; 4. Radiative signatures of energetic particles Tim Bastian; 5. Observations of solar and stellar eruptions, flares, and jets Hugh Hudson; 6. Models of coronal mass ejections and flares Terry Forbes; 7. Shocks in heliophysics Merav Opher; 8. Particle acceleration in shocks Dietmar Krauss-Varban; 9. Energetic particle transport Joe Giacalone; 10. Energy conversion in planetary magnetospheres Vytenis Vasyliunas; 11. Energization of trapped particles Janet Green; 12. Flares, CMEs, and atmospheric responses Tim Fuller-Rowell and Stanley C. Solomon; 13. Energetic particles and manned spaceflight Stephen Guetersloh and Neal Zapp; 14. Energetic particles and technology Alan Tribble; Appendix I. Authors and editors; List of illustrations; List of tables; Bibliography; Index. Volume 3: Preface; 1. Interconnectedness in heliophysics Carolus J. Schrijver and George L. Siscoe; 2. Long-term evolution of magnetic activity of Sun-like stars Carolus J. Schrijver; 3. Formation and early evolution of stars and proto-planetary disks Lee W. Hartmann; 4. Planetary habitability on astronomical time scales Donald E. Brownlee; 5. Solar internal flows and dynamo action Mark S. Miesch; 6. Modeling solar and stellar dynamos Paul Charbonneau; 7. Planetary fields and dynamos Ulrich R. Christensen; 8. The structure and evolution of the 3D solar wind John T. Gosling; 9. The heliosphere and cosmic rays J. Randy Jokipii; 10. Solar spectral irradiance: measurements and models Judith L. Lean and Thomas N. Woods; 11. Astrophysical influences on planetary climate systems Juerg Beer; 12. Evaluating the drivers of Earth's climate system Thomas J. Crowley; 13. Ionospheres of the terrestrial planets Stanley C. Solomon; 14. Long-term evolution of the geospace climate Jan J. Sojka; 15. Waves and transport processes in atmospheres and oceans Richard L. Walterscheid; 16. Solar variability, climate, and atmospheric photochemistry Guy P. Brasseur, Daniel Marsch and Hauke Schmidt; Appendix I. Authors and editors; List of illustrations; List of tables; Bibliography; Index.

Increased Expression of T Cell Immunoglobulin and Mucin Domain 3 on CD14+ Monocytes Is Associated with Systemic Inflammatory Reaction and Brain Injury in Patients with Spontaneous Intracerebral Hemorrhage.

PubMed

Xu, ChangJun; Ge, HaiTao; Wang, Tao; Qin, JianBing; Liu, De; Liu, YuGuang

2018-05-01

To study the expression of T cell immunoglobulin and mucin domain 3 (Tim-3) on peripheral blood immunocytes, and the relationship between Tim-3 and the systemic inflammatory response or brain injury in patients with intracerebral hemorrhage (ICH). According to the volume of hematoma at 12 hours after onset of ICH, 60 newly diagnosed patients with ICH were divided into the small (volume of hematoma <30 mL, 30 cases) and large (volume of hematoma ≥30 mL, 30 cases) ICH groups. The expression of Tim-3 on peripheral blood immunocytes was analyzed by flow cytometry. Real-time reverse transcriptase polymerase chain reaction was used to detect Tim-3 mRNA on peripheral blood mononuclear cells (PBMCs). Meanwhile, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and S-100B protein were measured by enzyme-linked immunosorbent assay. Glasgow outcome scale (GOS) score at Day 30 was used to estimate prognosis of patients. The leukocyte count, neutrophil count, monocyte count, TNF-α, IL-1β, and S-100B protein increased remarkably after ICH. However, all of them in the large ICH group increased more obviously, and there were significant differences when compared with those in the small ICH group (P < .01). The expression of Tim-3 mRNA on PBMCs in the large ICH group increased remarkably, peaked at Day 3, and was positively associated with the concentrations of TNF-α, IL-1β, and S-100B protein (P < .01). Tim-3 was predominantly expressed itself on CD14 + monocytes. There was a negative correlation between GOS score and Tim-3 mRNA, TNF-α, IL-1β, or S-100B protein. The expression of Tim-3 on CD14 + monocytes involves in systemic inflammatory reaction after ICH and may be a novel treatment target. Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

A novel method for sampling the suspended sediment load in the tidal environment using bi-directional time-integrated mass-flux sediment (TIMS) samplers

NASA Astrophysics Data System (ADS)

Elliott, Emily A.; Monbureau, Elaine; Walters, Glenn W.; Elliott, Mark A.; McKee, Brent A.; Rodriguez, Antonio B.

2017-12-01

Identifying the source and abundance of sediment transported within tidal creeks is essential for studying the connectivity between coastal watersheds and estuaries. The fine-grained suspended sediment load (SSL) makes up a substantial portion of the total sediment load carried within an estuarine system and efficient sampling of the SSL is critical to our understanding of nutrient and contaminant transport, anthropogenic influence, and the effects of climate. Unfortunately, traditional methods of sampling the SSL, including instantaneous measurements and automatic samplers, can be labor intensive, expensive and often yield insufficient mass for comprehensive geochemical analysis. In estuaries this issue is even more pronounced due to bi-directional tidal flow. This study tests the efficacy of a time-integrated mass sediment sampler (TIMS) design, originally developed for uni-directional flow within the fluvial environment, modified in this work for implementation the tidal environment under bi-directional flow conditions. Our new TIMS design utilizes an 'L' shaped outflow tube to prevent backflow, and when deployed in mirrored pairs, each sampler collects sediment uniquely in one direction of tidal flow. Laboratory flume experiments using dye and particle image velocimetry (PIV) were used to characterize the flow within the sampler, specifically, to quantify the settling velocities and identify stagnation points. Further laboratory tests of sediment indicate that bidirectional TIMS capture up to 96% of incoming SSL across a range of flow velocities (0.3-0.6 m s-1). The modified TIMS design was tested in the field at two distinct sampling locations within the tidal zone. Single-time point suspended sediment samples were collected at high and low tide and compared to time-integrated suspended sediment samples collected by the bi-directional TIMS over the same four-day period. Particle-size composition from the bi-directional TIMS were representative of the array of single time point samples, but yielded greater mass, representative of flow and sediment-concentration conditions at the site throughout the deployment period. This work proves the efficacy of the modified bi-directional TIMS design, offering a novel tool for collection of suspended sediment in the tidally-dominated portion of the watershed.

Binding thermodynamics of phosphorylated inhibitors to triosephosphate isomerase and the contribution of electrostatic interactions.

PubMed

Serratos, Iris N; Pérez-Hernández, Gerardo; Garza-Ramos, Georgina; Hernández-Arana, Andrés; González-Mondragón, Edith; Zubillaga, Rafael A

2011-01-07

Electrostatic interactions have a central role in some biological processes, such as recognition of charged ligands by proteins. We characterized the binding energetics of yeast triosephosphate isomerase (TIM) with phosphorylated inhibitors 2-phosphoglycollate (2PG) and phosphoglycolohydroxamate (PGH). We determined the thermodynamic parameters of the binding process (K(b), ΔG(b), ΔH(b), ΔS(b) and ΔC(p)) with different concentrations of NaCl, using fluorimetric and calorimetric titrations in the conventional mode of ITC and a novel method, multithermal titration calorimetry (MTC), which enabled us to measure ΔC(p) in a single experiment. We ruled out specific interactions of Na(+) and Cl(-) with the native enzyme and did not detect significant linked protonation effects upon the binding of inhibitors. Increasing ionic strength (I) caused K(b), ΔG(b) and ΔH(b) to become less favorable, while ΔS(b) became less unfavorable. From the variation of K(b) with I, we determined the electrostatic contribution of TIM-2PG and TIM-PGH to ΔG(b) at I=0.06 M and 25 °C to be 36% and 26%, respectively. The greater affinity of PGH for TIM is due to a more favorable ΔH(b) compared to 2PG (by 19-24 kJ mol(-1) at 25 °C). This difference is compatible with PGH establishing up to five more hydrogen bonds with TIM. Both binding ΔC(p)s were negative, and less negative with increasing ionic strength. ΔC(p)s at I=0.06 M were much more negative than predicted by surface area models. Water molecules trapped in the interface when ligands bind to protein could explain the highly negative ΔCps. Thermodynamic binding functions for TIM-2PG changed more with ionic strength than those for TIM-PGH. This greater dependence is consistent with linked, but compensated, protonation equilibriums yielding the dianionic species of 2PG that binds to TIM, process that is not required for PGH. Copyright © 2010 Elsevier Ltd. All rights reserved.

Timothy Remo | NREL

Science.gov Websites

Analysis Center. Areas of Expertise Photovoltaic and semiconductor manufacturing cost analysis Process , Norcross, GA (2011-2015) Production Engineer, Emcore Photovoltaic Corp, Albuquerque, NM (2008-2010

Effects of irrigation on seed production and vegetative characteristics of four moist-soil plants on impounded wetlands in California

USGS Publications Warehouse

Mushet, D.M.; Euliss, N.H.; Harris, S.W.

1992-01-01

We examined the effects of irrigation on 4 moist-soil plants commonly managed for waterfowl in the Sacramento Valley, California. Irrigation resulted in taller and heavier swamp timothy (Heleochloa schoenoides), pricklegrass (Crypsis niliaca), and sprangletop (Leptochloa fasicularis). Barnyardgrass (Echinochloa crusgalli) grew taller in irrigated wetlands, but no significant difference in weight was detected. Only sprangletop yielded larger seed masses in response to irrigation. Without irrigation, swamp timothy and pricklegrass assumed a typical prostrate growth form, but with irrigation, they assumed a vertical growth form. Irrigation did not significantly affect plant density. Because of rising water costs, wetland managers should consider wildlife management objectives and plant responses before implementing irrigation practices.

Meet EPA Scientist Tim Shafer, Ph.D.

EPA Pesticide Factsheets

Tim Shafer earned his bachelor’s degree in biology and chemistry from Hope College in Holland, MI, in 1986 and his Ph.D. in pharmacology and environmental toxicology from Michigan State University in 1991.

Tim Reber | NREL

Science.gov Websites

also leads the Sustainable Energy for Remote Indonesian Grids program, with the aim to increase deployment of clean energy in small, remote grids across Indonesia. Prior to joining NREL, Tim worked as a

Behind their Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Kopra of NASA (left), Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, center) and Tim Peake of the European Space Agency (right) pose for pictures Dec. 9 after a traditional tree-planting ceremony. The trio will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station...NASA/Victor Zelentsov.

NASA Image and Video Library

2015-12-09

Behind their Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Kopra of NASA (left), Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, center) and Tim Peake of the European Space Agency (right) pose for pictures Dec. 9 after a traditional tree-planting ceremony. The trio will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station. NASA/Victor Zelentsov

Interspecific studies of circadian genes period and timeless in Drosophila.

PubMed

Noreen, Shumaila; Pegoraro, Mirko; Nouroz, Faisal; Tauber, Eran; Kyriacou, Charalambos P

2018-03-30

The level of rescue of clock function in genetically arrhythmic Drosophila melanogaster hosts using interspecific clock gene transformation was used to study the putative intermolecular coevolution between interacting clock proteins. Among them PER and TIM are the two important negative regulators of the circadian clock feedback loop. We transformed either the D. pseudoobscura per or tim transgenes into the corresponding arrhythmic D. melanogaster mutant (per01 or tim01) and observed >50% rhythmicity but the period of activity rhythm was either longer (D. pseudoobscura-per) or shorter than 24 h (D. pseudoobscura-tim) compared to controls. By introducing both transgenes simultaneously into double mutants, we observed that the period of the activity rhythm was rescued by the pair of hemizygous transgenes (~24 h). These flies also showed a more optimal level of temperature compensation for the period. Under LD 12:12 these flies have a D. pseudoobscura like activity profile with the absence of morning anticipation as well as a very prominent earlier evening peak of activity rhythm. These observation are consistent with the view that TIM and PER form a heterospecific coevolved module at least for the circadian period of activity rhythms. However the strength of rhythmicity was reduced by having both transgenes present, so while evidence for a coevolution between PER and TIM is observed for some characters it is not for others. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlates with response in head and neck cancer patients

PubMed Central

Jie, Hyun-Bae; Srivastava, Raghvendra M.; Argiris, Athanassios; Bauman, Julie E.; Kane, Lawrence P.; Ferris, Robert L.

2017-01-01

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients. PMID:28408386

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

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.

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.

A quantitative analysis of TIMS data obtained on the Learjet 23 at various altitudes

NASA Technical Reports Server (NTRS)

Jaggi, S.

1992-01-01

A series of Thermal Infrared Multispectral Scanner (TIMS) data acquisition flights were conducted on the NASA Learjet 23 at different altitudes over a test site. The objective was to monitor the performance of the TIMS (its estimation of the brightness temperatures of the ground scene) with increasing altitude. The results do not show any significant correlation between the brightness temperatures and the altitude. The analysis indicates that the estimation of the temperatures is a function of the accuracy of the atmospheric correction used for each altitude.

Achieving DoD’s Net Centric Vision of Information Sharing While Overcoming Cultural Biases to Control Information

DTIC Science & Technology

2008-05-09

using better technology as a means might be an effective strategy to achieve desired effects and to reduce risk. Tim Berners - Lee , founder of the World...of information disclosure persecution. Tim Berners - Lee advises, “human communication scales up only if we can be tolerant of the differences while we...the government to define intended use Figure 1: Slide by Tim Berners - Lee at http://www.w3.org/2000/Talks/1206-xml2k- tbl.27 The Author added the

Identification and characterization of lactic acid bacteria isolated from mixed pasture of timothy and orchardgrass, and its badly preserved silage.

PubMed

Tohno, Masanori; Kobayashi, Hisami; Nomura, Masaru; Uegaki, Ryuichi; Cai, Yimin

2012-04-01

In order to understand the relationship between lactic acid bacteria (LAB) species and silage fermentation, a total of 65 LAB strains isolated from mixed pasture of timothy (Phleum pratense L.) and orchardgrass (Dactylis glomerata L.), and its badly preserved silages were subjected to phenotypic and genetic analysis. According to these analyses, the isolates were divided into 13 groups, including Enterococcus gallinarum, Lactobacillus acidipiscis, L. coryniformis subsp. coryniformis, L. coryniformis subsp. torquens, L. curvatus, L. paraplantarum, L. plantarum subsp. argentoratensis, L. plantarum subsp. plantarum, L. sakei subsp. carnosus, Lactococcus garvieae, Lactococcus lactis subsp. cremoris, Leuconostoc pseudomesenteroides, Pediococcus acidilactici, Pediococcus pentosaceus, Weissella hellenica, Weissella paramesenteroides and Carnobacterium divergens. This is the first report to document that C. divergens, L. acidipiscis, L. sakei subsp. carnosus, L. garvieae, phenotypically novel L. lactis subsp. cremoris, E. gallinarum and W. hellenica are present in vegetative forage crops. L. plantarum group strains were most frequently isolated from the badly preserved silages. Some isolates showed a wide range of growth preferences for carbohydrate utilization, optimal growth pH and temperature in vitro, indicating that they have a high growth potential. These results are useful in understanding the diversity of LAB associated with decayed silage of timothy and orchardgrass. © 2011 The Authors. Animal Science Journal © 2011 Japanese Society of Animal Science.

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.

Autologous Stem Cell Transplantation in Patients With Multiple Myeloma: An Activity-based Costing Analysis, Comparing a Total Inpatient Model Versus an Early Discharge Model.

PubMed

Martino, Massimo; Console, Giuseppe; Russo, Letteria; Meliado', Antonella; Meliambro, Nicola; Moscato, Tiziana; Irrera, Giuseppe; Messina, Giuseppe; Pontari, Antonella; Morabito, Fortunato

2017-08-01

Activity-based costing (ABC) was developed and advocated as a means of overcoming the systematic distortions of traditional cost accounting. We calculated the cost of high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients with multiple myeloma using the ABC method, through 2 different care models: the total inpatient model (TIM) and the early-discharge outpatient model (EDOM) and compared this with the approved diagnosis related-groups (DRG) Italian tariffs. The TIM and EDOM models involved a total cost of €28,615.15 and €16,499.43, respectively. In the TIM model, the phase with the greatest economic impact was the posttransplant (recovery and hematologic engraftment) with 36.4% of the total cost, whereas in the EDOM model, the phase with the greatest economic impact was the pretransplant (chemo-mobilization, apheresis procedure, cryopreservation, and storage) phase, with 60.4% of total expenses. In an analysis of each episode, the TIM model comprised a higher absorption than the EDOM. In particular, the posttransplant represented 36.4% of the total costs in the TIM and 17.7% in EDOM model, respectively. The estimated reduction in cost per patient using an EDOM model was over €12,115.72. The repayment of the DRG in Calabrian Region for the ASCT procedure is €59,806. Given the real cost of the transplant, the estimated cost saving per patient is €31,190.85 in the TIM model and €43,306.57 in the EDOM model. In conclusion, the actual repayment of the DRG does not correspond to the real cost of the ASCT procedure in Italy. Moreover, using the EDOM, the cost of ASCT is approximately the half of the TIM model. Copyright © 2017 Elsevier Inc. All rights reserved.

Division of Forestry Directory

Science.gov Websites

Regional Regional Forester Tim Dabney tim.dabney@alaska.gov (907) 761-6238 Fairbanks/Delta Area Fairbanks Sanford, Fire Management Officer (907) 451-2634 edward.sanford@alaska.gov Delta Office P.O. Box 1149 Delta

Towards Discovery and Targeted Peptide Biomarker Detection Using nanoESI-TIMS-TOF MS

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

Garabedian, Alyssa; Benigni, Paolo; Ramirez, Cesar E.

Abstract. In the present work, the potential of trapped ion mobility spectrometry coupled to TOF mass spectrometry (TIMS-TOF MS) for discovery and targeted monitoring of peptide biomarkers from human-in-mouse xenograft tumor tissue was evaluated. In particular, a TIMS-MS workflow was developed for the detection and quantification of peptide biomarkers using internal heavy analogs, taking advantage of the high mobility resolution (R = 150–250) prior to mass analysis. Five peptide biomarkers were separated, identified, and quantified using offline nanoESI-TIMSCID- TOF MS; the results were in good agreement with measurements using a traditional LC-ESI-MS/MS proteomics workflow. The TIMS-TOF MS analysis permitted peptidemore » biomarker detection based on accurate mobility, mass measurements, and high sequence coverage for concentrations in the 10–200 nM range, while simultaneously achieving discovery measurements« less

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.

Thermally Conductive-Silicone Composites with Thermally Reversible Cross-links.

PubMed

Wertz, J T; Kuczynski, J P; Boday, D J

2016-06-08

Thermally conductive-silicone composites that contain thermally reversible cross-links were prepared by blending diene- and dienophile-functionalized polydimethylsiloxane (PDMS) with an aluminum oxide conductive filler. This class of thermally conductive-silicones are useful as thermal interface materials (TIMs) within Information Technology (IT) hardware applications to allow rework of valuable components. The composites were rendered reworkable via retro Diels-Alder cross-links when temperatures were elevated above 130 °C and required little mechanical force to remove, making them advantageous over other TIM materials. Results show high thermal conductivity (0.4 W/m·K) at low filler loadings (45 wt %) compared to other TIM solutions (>45 wt %). Additionally, the adhesion of the material was found to be ∼7 times greater at lower temperatures (25 °C) and ∼2 times greater at higher temperatures (120 °C) than commercially available TIMs.

At the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Kopra of NASA took a turn on a tilt table to test his vestibular system Dec. 9 as part of his pre-launch training. Kopra, Tim Peake of the European Space Agency and Yuri Malenchenko of the Russian Federal Space Agency will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station...NASA/Victor Zelentsov.

NASA Image and Video Library

2015-12-09

At the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Kopra of NASA took a turn on a tilt table to test his vestibular system Dec. 9 as part of his pre-launch training. Kopra, Tim Peake of the European Space Agency and Yuri Malenchenko of the Russian Federal Space Agency will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station. NASA/Victor Zelentsov

At the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Peake of the European Space Agency took a turn in a spinning chair to test his vestibular system Dec. 9 as part of his pre-launch training. Peake, Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos) and Tim Kopra of NASA will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station...NASA/Victor Zelentsov.

NASA Image and Video Library

2015-12-09

At the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Peake of the European Space Agency took a turn in a spinning chair to test his vestibular system Dec. 9 as part of his pre-launch training. Peake, Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos) and Tim Kopra of NASA will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station. NASA/Victor Zelentsov

Identification of the critical residues responsible for differential reactivation of the triosephosphate isomerases of two trypanosomes

PubMed Central

Rodríguez-Bolaños, Monica; Cabrera, Nallely

2016-01-01

The reactivation of triosephosphate isomerase (TIM) from unfolded monomers induced by guanidine hydrochloride involves different amino acids of its sequence in different stages of protein refolding. We describe a systematic mutagenesis method to find critical residues for certain physico-chemical properties of a protein. The two similar TIMs of Trypanosoma brucei and Trypanosoma cruzi have different reactivation velocities and efficiencies. We used a small number of chimeric enzymes, additive mutants and planned site-directed mutants to produce an enzyme from T. brucei with 13 mutations in its sequence, which reactivates fast and efficiently like wild-type (WT) TIM from T. cruzi, and another enzyme from T. cruzi, with 13 slightly altered mutations, which reactivated slowly and inefficiently like the WT TIM of T. brucei. Our method is a shorter alternative to random mutagenesis, saturation mutagenesis or directed evolution to find multiple amino acids critical for certain properties of proteins. PMID:27733588

CD8+ T cells of chronic HCV-infected patients express multiple negative immune checkpoints following stimulation with HCV peptides.

PubMed

Barathan, Muttiah; Mohamed, Rosmawati; Vadivelu, Jamuna; Chang, Li Yen; Vignesh, Ramachandran; Krishnan, Jayalakshmi; Sigamani, Panneer; Saeidi, Alireza; Ram, M Ravishankar; Velu, Vijayakumar; Larsson, Marie; Shankar, Esaki M

2017-03-01

Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray™ following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide-stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-β1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-α, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence. Copyright © 2016 Elsevier Inc. All rights reserved.

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 the dunes range from 70% to 90% quartz mainly derived from a source 40 km to the west. The dune field is assumed to have formed in a much more arid climate than present, with the age of the deposit estimated at greater than 100,000 years.

An RNAi Screen To Identify Protein Phosphatases That Function Within the Drosophila Circadian Clock.

PubMed

Agrawal, Parul; Hardin, Paul E

2016-12-07

Circadian clocks in eukaryotes keep time via cell-autonomous transcriptional feedback loops. A well-characterized example of such a transcriptional feedback loop is in Drosophila, where CLOCK-CYCLE (CLK-CYC) complexes activate transcription of period (per) and timeless (tim) genes, rising levels of PER-TIM complexes feed-back to repress CLK-CYC activity, and degradation of PER and TIM permits the next cycle of CLK-CYC transcription. The timing of CLK-CYC activation and PER-TIM repression is regulated posttranslationally, in part through rhythmic phosphorylation of CLK, PER, and TIM. Previous behavioral screens identified several kinases that control CLK, PER, and TIM levels, subcellular localization, and/or activity, but two phosphatases that function within the clock were identified through the analysis of candidate genes from other pathways or model systems. To identify phosphatases that play a role in the clock, we screened clock cell-specific RNA interference (RNAi) knockdowns of all annotated protein phosphatases and protein phosphatase regulators in Drosophila for altered activity rhythms. This screen identified 19 protein phosphatases that lengthened or shortened the circadian period by ≥1 hr (p ≤ 0.05 compared to controls) or were arrhythmic. Additional RNAi lines, transposon inserts, overexpression, and loss-of-function mutants were tested to independently confirm these RNAi phenotypes. Based on genetic validation and molecular analysis, 15 viable protein phosphatases remain for future studies. These candidates are expected to reveal novel features of the circadian timekeeping mechanism in Drosophila that are likely to be conserved in all animals including humans. Copyright © 2016 Agrawal and Hardin.

Efficacy and Safety of Switching Prostaglandin Analog Monotherapy to Tafluprost/Timolol Fixed-Combination Therapy

PubMed Central

Kitamura, Kazuyoshi; Chiba, Tatsuya; Mabuchi, Fumihiko; Ishijima, Kiyotaka; Omoto, Shu; Kashiwagi, Fumiko; Godo, Takashi; Kogure, Satoshi; Goto, Teruhiko; Shibuya, Takashi; Tanabe, Jhoji; Tsukahara, Shigeo; Tsuchiya, Tadaharu; Tokunaga, Takaharu; Hosaka, Osamu; Saito, Tetsunori

2018-01-01

Purpose To assess the efficacy and safety of switching from prostaglandin analog (PGA) monotherapy to tafluprost/timolol fixed-combination (Taf/Tim) therapy. Subjects and Methods Patients with primary open-angle glaucoma, normal-tension glaucoma, or ocular hypertension who had received PGA monotherapy for at least 3 months were enrolled. Patients were examined at 1, 2, and 3 months after changing therapies. Subsequently, the patients were returned to PGA monotherapy. The examined parameters included intraocular pressure (IOP) and adverse events. A questionnaire survey was conducted after the switch to Taf/Tim therapy. Results Forty patients with a mean age of 66.5 ± 10.3 years were enrolled; 39 of these patients completed the study protocol. Switching to Taf/Tim significantly reduced the IOP from 18.2 ± 2.6 mmHg at baseline to 14.8 ± 2.5 mmHg at 1 month, 15.2 ± 2.8 mmHg at 2 months, and 14.9 ± 2.5 mmHg at 3 months (P < 0.001). Switching back to the original PGA monotherapy returned the IOP values to baseline levels. Taf/Tim reduced the pulse rate insignificantly. No significant differences were observed in blood pressure, conjunctival hyperemia, or corneal adverse events. A questionnaire showed that the introduction of Taf/Tim did not significantly influence symptoms. Conclusions Compared with PGA monotherapy, Taf/Tim fixed-combination therapy significantly reduced IOP without severe adverse events. PMID:29675274

Timolol LA: a double-masked, active-controlled, randomized, crossover, comfort, ocular safety, and systemic bioavailability study in healthy volunteers.

PubMed

Mundorf, Thomas K; Ogawa, Takahiro; Inui, Noritsugu; Naka, Hiroaki; Novack, Gary D; Crockett, R Stephens

2005-03-01

A new formulation of timolol with sorbic acid, timolol-LA (TLA) (Istaloldagger), has been developed which increases its ocular bioavailability. In the present study, we desired to evaluate the ocular comfort and systemic bioavailability of TLA in healthy volunteers in comparison to standard timolol maleate ophthalmic solution (TIM). This study was a randomized, double-masked, active-controlled, crossover evaluation of 0.5% TLA and 0.5% TIM, bid, in 12 normal healthy volunteers. Visits were at Days 0, 1, 2, 4 and 8 in each period, and there was a minimum 7 day interperiod washout. At all three post-dosing evaluation times (Day 1: Peak, Day 8: Trough, and Day 8: Peak), the 95% confidence interval for the difference between TLA and TIM was not more than 0.37 ng/mL. After administration of TLA, there was a greater incidence of burning/stinging and tearing, but not foreign body sensation, relative to TIM. In general, most symptoms were mild in intensity, and no subject discontinued treatment due to ocular discomfort. Both treatments decreased IOP to a similar level. TLA was relatively comfortable, with a safety profile consistent with further clinical development, and, with bid dosing (exaggerated [2X] that anticipated for clinical use), had a systemic bioavailability similar to that of TIM 0.5%, bid. The incidence of burning and stinging was higher with TLA than with TIM, although reports were mild in severity and did not result in any patient discontin uations. Although the results are of interest, further evaluation in a larger trial may be warranted.

Making the connection: advancing traffic incident management in transportation planning : a primer.

DOT National Transportation Integrated Search

2013-07-01

"The intent of this primer is to inform and guide traffic incident management (TIM) professionals and transportation planners to initiate and develop collaborative relationships and advance TIM programs through the metropolitan planning process. The ...

Demonstration of Unmanned Aircraft Systems Use for Traffic Incident Management (UAS-TIM)

DOT National Transportation Integrated Search

2017-12-01

Previous investigations into technologies that can improve incident response, monitoring, and clearance resulted in the potential application of Unmanned Aerial System (UAS) for use in Traffic Incident Management (TIM). An initial investigation of UA...

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

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

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

Structure–Function Studies of Hydrophobic Residues That Clamp a Basic Glutamate Side Chain during Catalysis by Triosephosphate Isomerase

PubMed Central

2016-01-01

Kinetic parameters are reported for the reactions of whole substrates (kcat/Km, M–1 s–1) (R)-glyceraldehyde 3-phosphate (GAP) and dihydroxyacetone phosphate (DHAP) and for the substrate pieces [(kcat/Km)E·HPi/Kd, M–2 s–1] glycolaldehyde (GA) and phosphite dianion (HPi) catalyzed by the I172A/L232A mutant of triosephosphate isomerase from Trypanosoma brucei brucei (TbbTIM). A comparison with the corresponding parameters for wild-type, I172A, and L232A TbbTIM-catalyzed reactions shows that the effect of I172A and L232A mutations on ΔG⧧ for the wild-type TbbTIM-catalyzed reactions of the substrate pieces is nearly the same as the effect of the same mutations on TbbTIM previously mutated at the second side chain. This provides strong evidence that mutation of the first hydrophobic side chain does not affect the functioning of the second side chain in catalysis of the reactions of the substrate pieces. By contrast, the effects of I172A and L232A mutations on ΔG⧧ for wild-type TbbTIM-catalyzed reactions of the whole substrate are different from the effect of the same mutations on TbbTIM previously mutated at the second side chain. This is due to the change in the rate-determining step that determines the barrier to the isomerization reaction. X-ray crystal structures are reported for I172A, L232A, and I172A/L232A TIMs and for the complexes of these mutants to the intermediate analogue phosphoglycolate (PGA). The structures of the PGA complexes with wild-type and mutant enzymes are nearly superimposable, except that the space opened by replacement of the hydrophobic side chain is occupied by a water molecule that lies ∼3.5 Å from the basic side chain of Glu167. The new water at I172A mutant TbbTIM provides a simple rationalization for the increase in the activation barrier ΔG⧧ observed for mutant enzyme-catalyzed reactions of the whole substrate and substrate pieces. By contrast, the new water at the L232A mutant does not predict the decrease in ΔG⧧ observed for the mutant enzyme-catalyzed reactions of the substrate piece GA. PMID:27149328

Tumor vs. Cyst: What's the Difference?

MedlinePlus

... biopsy. With Timothy J. Moynihan, M.D. NCI Dictionary of cancer terms: Cyst. National Cancer Institute. http://www.cancer.gov/publications/dictionaries/cancer-terms?CdrID=46461. Accessed June 8, 2016. ...

76 FR 64382 - Agency Information Collection Activities: Proposed Collection; Comments Requested

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-18

... Collection Under Review: Office for Victims of Crime Trafficking Information Management System (TIMS). The... following information collection request to the Office of Management and Budget (OMB) for review and... Trafficking Information Management System (TIMS) Online. [[Page 64383

Reconstitution of the protein insertion machinery of the mitochondrial inner membrane.

PubMed Central

Haucke, V; Schatz, G

1997-01-01

We have reconstituted the protein insertion machinery of the yeast mitochondrial inner membrane into proteoliposomes. The reconstituted proteoliposomes have a distinct morphology and protein composition and correctly insert the ADP/ATP carrier (AAC) and Tim23p, two multi-spanning integral proteins of the mitochondrial inner membrane. The reconstituted system requires a membrane potential, but not Tim44p or mhsp70, both of which are required for the ATP-driven translocation of proteins into the matrix. The protein insertion machinery can thus operate independently of the energy-transducing Tim44p-mhsp70 complex. PMID:9303300

The Mitochondrial Protein Import Component, TRANSLOCASE OF THE INNER MEMBRANE17-1, Plays a Role in Defining the Timing of Germination in Arabidopsis1[W][OPEN

PubMed Central

Wang, Yan; Law, Simon R.; Ivanova, Aneta; van Aken, Olivier; Kubiszewski-Jakubiak, Szymon; Uggalla, Vindya; van der Merwe, Margaretha; Duncan, Owen; Narsai, Reena; Whelan, James; Murcha, Monika W.

2014-01-01

In Arabidopsis (Arabidopsis thaliana), small gene families encode multiple isoforms for many of the components of the mitochondrial protein import apparatus. There are three isoforms of the TRANSLOCASE OF THE INNER MEMBRANE17 (Tim17). Transcriptome analysis indicates that AtTim17-1 is only detectable in dry seed. In this study, two independent transfer DNA insertional mutant lines of tim17-1 exhibited a germination-specific phenotype, showing a significant increase in the rate of germination. Microarray analyses revealed that Attim17-1 displayed alterations in the temporal sequence of transcriptomic events during germination, peaking earlier compared with the wild type. Promoter analysis of AtTim17-1 further identified an abscisic acid (ABA)-responsive element, which binds ABA-responsive transcription factors, acting to repress the expression of AtTim17-1. Attim17-1 dry seeds contained significantly increased levels of ABA and gibberellin, 2- and 5-fold, respectively. These results support the model that mitochondrial biogenesis is regulated in a tight temporal sequence of events during germination and that altering mitochondrial biogenesis feeds back to alter the germination rate, as evidenced by the altered levels of the master regulatory hormones that define germination. PMID:25253887

Spirit on 'Husband Hill,' with 2004 Comparison

NASA Technical Reports Server (NTRS)

2006-01-01

Two Earth years ago, NASA's Mars Exploration Rover Spirit touched down in Gusev Crater. The rover marked its first Mars-year (687 Earth days) anniversary in November 2005. On Nov. 2, 2005, shortly before Spirit's Martian anniversary, the Mars Orbiter Camera on NASA's Mars Global Surveyor acquired an image centered on the rover's location in the 'Columbia Hills.' The location of Spirit on that date is circled on the image on the right. On the left, for comparison, is an image from Jan. 10, 2004, when few dreamed that the Spirit would ever reach the hills from its landing site about three kilometers (two miles) away.

The newer image has a resolution of about 50 centimeters (1.6 feet) per pixel. North is up; illumination is from the left. The location is near 14.8 degrees south latitude, 184.6 degrees west longitude. Dr. Timothy J. Parker of the Mars Exploration Rover team at NASA's Jet Propulsion Laboratory, Pasadena, Calif., confirmed the location of the rover in the 2005 image. The scale bar is 50 meters (164 feet).

78 FR 5196 - Meeting of the California Desert District Advisory Council

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-24

... BLM California Desert District manager, five field office managers, and council subgroups. Final...) 697-5220. Dated: January 3, 2013. Timothy J. Wakefield, Associate District Manager, California Desert...

Carbon nanotube thermal interfaces and related applications

NASA Astrophysics Data System (ADS)

Hodson, Stephen L.

The development of thermal interface materials (TIMs) is necessitated by the temperature drop across interfacing materials arising from macro and microscopic irregularities of their surfaces that constricts heat through small contact regions as well as mismatches in their thermal properties. Similar to other types of TIMs, CNT TIMs alleviate the thermal resistance across the interface by thermally bridging two materials together with cylindrical, high-aspect ratio, and nominally vertical conducting elements. Within the community of TIM engineers, the vision driving the development of CNT TIMs was born from measurements that revealed impressively high thermal conductivities of individual CNTs. This vision was then projected to efforts focused on packing many individual CNTs on a single substrate that efficiently conduct heat in parallel and ultimately through many contact regions at CNT-to-substrate contacts. This thesis encompasses a comprehensive investigation of the viability of carbon nanotube based thermal interface materials (CNT TIMs) to efficiently conduct heat across two contacting materials. The efforts in this work were initially devoted to engaging CNT TIMs with an opposing substrate using two bonding techniques. Using palladium hexadecanethiolate, Pd(SC16H35)2 the CNT ends were bonded to an opposing substrate (one-sided interface) or opposing CNT array (two-sided interface) to enhance contact conductance while maintaining a compliant joint. The palladium weld is particularly attractive for its mechanical stability at high temperatures. The engagement of CNT TIMs with an opposing substrate was also achieved by inserting a solder foil between the CNT TIM and opposing substrate and subsequently raising the temperature of the interface above the eutectic point of the solder foil. This bonding technique creates a strong weld that not only reduces the thermal resistance significantly but also minimizes the change in thermal resistance with an applied compressive load. The thermal performance was further improved by infiltrating the CNT TIM with paraffin wax, which serves as an alternate pathway for heat conduction across the interface that ultimately reduces the bulk thermal resistance of the CNT TIM. For CNT TIMs synthesized at the Birck Nanotechnology Center at Purdue University, the thermal resistance was shown to scale linearly with their aggregate, as-grown height. Thus, the bulk thermal resistance can alternatively be tuned by adjusting the as-grown height. The linear relationship between thermal resistance and CNT TIM height provides a simple and efficient methodology to estimate the contact resistance and effective thermal conductivity of CNT TIMs. In this work, the contact resistance and effective thermal conductivity were estimated using two measurement techniques: (i) one-dimensional, steady-state reference bar and (ii) photoacoustic technique. A discrepancy in the estimated contact resistance exists between the two measurement techniques, which is due to the difficulty in measuring the true contact area. In contrast, the effective thermal conductivities estimated from both measurement techniques moderately agreed and were estimated to be on the order of O(1 W/mK). The final chapter is in collaboration with Sandia National Laboratories and focuses on the development of an apparatus to measure the thermal conductivity of insulation materials critical for the operation of molten salt batteries. Molten salt batteries are particularly useful power sources for radar and guidance systems in military applications such as guided missiles, ordinance, and other weapons. Molten salt batteries are activated by raising the temperature of the electrolyte above its melting temperature using pyrotechnic heat pellets. The battery will remain active as long as the electrolyte is molten. As a result, the thermal processes within the components and interactions between them are critical to the overall performance of molten salt batteries. A molten salt battery is typically thermally insulated using wrappable and board-like insulation materials such as Fiberfrax wrap, Fiberfrax board, and Min-K insulation. The Fiberfrax board and Min-K insulation are composites of alumino-silicate and fumed silica-titania, respectively. In Chapter 9, the thermal conductivities of the Fiberfrax board and Min-K insulation were measured under different uniaxial compressive states and ambient environments. The thermal conductivity of the mixed separator pellets (LiCl/MgO/KCl) was also measured along with its contact resistances with interfacing members. To measure the thermal quantities, a steady-state reference bar with thermocouples was employed. The resulting values serve as inputs to a thermal model that aims to predict lifetimes of the batteries. (Abstract shortened by ProQuest.).

User-friendly traffic incident management (TIM) program benefit-cost estimation tool, Version 1.2

DOT National Transportation Integrated Search

2016-01-01

Traffic incidents contribute significantly to the deterioration of the level of service of both freeways and arterials. Traffic Incident Management (TIM) programs have been introduced worldwide with the aim of mitigating the impact of traffic inciden...

System integration case study : FAST-TRAC : preliminary IV deliverable : #2-systems integration case study

DOT National Transportation Integrated Search

1999-02-12

This report focuses on the system integration aspect of the Transportation Information Management System (TIMS), a component of the FAST-TRAC project. The TIMS functions as the center of a communications network which integrates advanced traffic cont...

77 FR 27817 - Self-Regulatory Organizations; NYSE Arca, Inc.; Order Approving a Proposed Rule Change To List...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-11

... its parent company or its affiliates. See id. \\9\\ See email from Tim Malinowski, Senior Director, NYSE... IIV is no longer calculated or available as required. \\17\\ See email from Tim Malinowski, Senior...

75 FR 72843 - National Science Board; Sunshine Act Meetings; Notice

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-26

.... Electronic Distribution of Initial Chapter Drafts for Board Review. Update on Graphic Design Review of State... Education for Sustainability (SEES), Dr. Timothy Killeen. Approval of Minutes. Chairman's Report. Director's...

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

Realmuto, V.J.; Abrams, M.J.; Buongiorno, M.F.

The authors have found that image data acquired with NASA's airborne Thermal Infrared Multispectral Scanner (TIMS) can be used to make estimates of the SO[sub 2] content of volcanic plumes. TIMS image data are most applicable to the study of partially transparent SO[sub 2] plumes, such as those released during quiescent periods or nonexplosive eruptions. The estimation procedure is based on the LOWTRAN 7 radiative transfer code, which the authors use to model the radiance perceived by TIMS as it views the ground through an SO[sub 2] plume. The input to the procedure includes the altitudes of the aircraft andmore » ground, the altitude and thickness of the SO[sub 2] plume, the emissivity of the ground, and altitude profiles of the atmospheric pressure, temperature, and relative humidity. They use the TIMS data to estimate both ground temperatures beneath a plume and SO[sub 2] concentrations within a plume. Applying this procedure to TIMS data acquired over Mount Etna, Sicily, on July 29, 1986, the authors estimate that the SO[sub 2] flux from the volcano was approximately 6700 t d[sup [minus]1]. The use of TIMS to study SO[sub 2] plumes represents a bridge between highly localized methods, such as correlation spectroscopy or direct sampling, and small-scale mapping techniques involving satellite instruments such as the Total Ozone Mapping Spectrometer or Microwave Limb Sounder. The authors require further airborne experiments to refine their estimation procedure. This refinement is a necessary preparation for the scheduled 1998 launch of the Advanced Spaceborne Thermal Emission and Reflectance Radiometer, which will allow large-scale multispectral thermal infrared image data to be collected over virtually any volcano on Earth at least once every 16 days.« less

TIM Version 3.0 beta Technical Description and User Guide - Appendix B - Example input file for TIMv3.0

EPA Pesticide Factsheets

Terrestrial Investigation Model, TIM, has several appendices to its user guide. This is the appendix that includes an example input file in its preserved format. Both parameters and comments defining them are included.

TIM Version 3.0 beta Technical Description and User Guide - Appendix D - Avian Data to Support Generic and Custom Species

EPA Pesticide Factsheets

TIM Appendix D summarizes avian census studies from pesticide registrant submissions and literature. The purpose of this review is to identify avian species that are representative of those that commonly visit agricultural fields.

Using the thermal infrared multispectral scanner (TIMS) to estimate surface thermal responses

NASA Technical Reports Server (NTRS)

Luvall, J. C.; Holbo, H. R.

1987-01-01

A series of measurements was conducted over the H.J. Andrews, Oregon, experimental coniferous forest, using airborne thermal infrared multispectral scanner (TIMS). Flight lines overlapped, with a 28-min time difference between flight lines. Concurrent radiosonde measurements of atmospheric profiles of air temperature and moisture were used for atmospheric radiance corrections of the TIMS data. Surface temperature differences over time between flight lines were used to develop thermal response numbers (TRNs) which characterized the thermal response (in KJ/sq m/C, where K is the measured incoming solar radiation) of the different surface types. The surface types included a mature forest (canopy dominated by dense crowns of Pseudosuga menziesii, with a secondary canopy of dense Tsuga heterophylla, and also a tall shrub layer of Acer circinatum) and a two-year-old clear-cut. The temperature distribution, within TIMS thermal images was found to reflect the surface type examined. The clear-cut surface had the lowest TRN, while mature Douglas fir the highest.

Behind the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Kopra of NASA (left) plants a tree at a site bearing his name Dec. 9 in a traditional pre-launch ceremony. Looking on are his crewmates, Tim Peake of the European Space Agency (center) and Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, right). The trio will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station...NASA/Victor Zelentsov.

NASA Image and Video Library

2015-12-09

Behind the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Kopra of NASA (left) plants a tree at a site bearing his name Dec. 9 in a traditional pre-launch ceremony. Looking on are his crewmates, Tim Peake of the European Space Agency (center) and Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, right). The trio will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station. NASA/Victor Zelentsov

Behind the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Peake of the European Space Agency (center) plants a tree at a site bearing his name Dec. 9 in a traditional pre-launch ceremony. Looking on are his crewmates, Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, left, and Tim Kopra of NASA (right). The trio will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station...NASA/Victor Zelentsov.

NASA Image and Video Library

2015-12-09

Behind the Cosmonaut Hotel crew quarters in Baikonur, Kazakhstan, Expedition 46-47 crewmember Tim Peake of the European Space Agency (center) plants a tree at a site bearing his name Dec. 9 in a traditional pre-launch ceremony. Looking on are his crewmates, Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, left, and Tim Kopra of NASA (right). The trio will launch Dec. 15 on their Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station. NASA/Victor Zelentsov

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.

Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

PubMed Central

Sims, Brian; Farrow, Anitra L; Williams, Sparkle D; Bansal, Anju; Krendelchtchikov, Alexandre; Gu, Linlin; Matthews, Qiana L

2017-01-01

Exosomes, 30–200 nm nanostructures secreted from donor cells and internalized by recipient cells, can play an important role in the cellular entry of some viruses. These microvesicles are actively secreted into various body fluids, including blood, urine, saliva, cerebrospinal fluid, and breast milk. We successfully isolated exosomes from human breast milk and plasma. The size and concentration of purified exosomes were measured by nanoparticle tracking, while Western blotting confirmed the presence of the exosomal-associated proteins CD9 and CD63, clathrin, and T cell immunoglobulin and mucin proteins (TIMs). Through viral infection assays, we determined that HIV-1 utilizes an exosome-dependent mechanism for entry into human immune cells. The virus contains high amounts of phosphatidylserine (PtdSer) and may bind PtdSer receptors, such as TIMs. This mechanism is supported by our findings that exosomes from multiple sources increased HIV-1 entry into T cells and macrophages, and viral entry was potently blocked with anti-TIM-4 antibodies. PMID:28740388

CK1/Doubletime activity delays transcription activation in the circadian clock

PubMed Central

O'Neil, Jenna L; Merz, Gregory E; Dusad, Kritika; Crane, Brian R; Young, Michael W

2018-01-01

In the Drosophila circadian clock, Period (PER) and Timeless (TIM) proteins inhibit Clock-mediated transcription of per and tim genes until PER is degraded by Doubletime/CK1 (DBT)-mediated phosphorylation, establishing a negative feedback loop. Multiple regulatory delays within this feedback loop ensure ~24 hr periodicity. Of these delays, the mechanisms that regulate delayed PER degradation (and Clock reactivation) remain unclear. Here we show that phosphorylation of certain DBT target sites within a central region of PER affect PER inhibition of Clock and the stability of the PER/TIM complex. Our results indicate that phosphorylation of PER residue S589 stabilizes and activates PER inhibitory function in the presence of TIM, but promotes PER degradation in its absence. The role of DBT in regulating PER activity, stabilization and degradation ensures that these events are chronologically and biochemically linked, and contributes to the timing of an essential delay that influences the period of the circadian clock. PMID:29611807

Expression of immune checkpoints in T cells of esophageal cancer patients.

PubMed

Xie, Jinhua; Wang, Ji; Cheng, Shouliang; Zheng, Liangfeng; Ji, Feiyue; Yang, Lin; Zhang, Yan; Ji, Haoming

2016-09-27

Inhibition of immune checkpoint proteins (checkpoints) has become a promising anti-esophageal cancer strategy. We here tested expressions of immune checkpoints in human esophageal cancers. Our results showed the expressions of many immune checkpoints, including CD28, CD27, CD137L, programmed death 1 (PD-1), T cell immunoglobulin mucin-3 (TIM-3), T cell Ig and ITIM domain (TIGIT), CD160, cytotoxic T lymphocyte antigen 4 (CTLA-4), CD200, CD137 and CD158, were dysregulated in peripheral T cells of esophageal cancer patients. Further, the expressions of PD-1, TIM-3 and TIGIT were upregulated in tumor infiltrating lymphocytes (TILs), which might be associated with TILs exhaustion. Meanwhile, the expressions of PD-1 and TIM-3 on CD4+ T cells were closely associated with clinic pathological features of esophageal cancer patients. These results indicate that co-inhibitory receptors PD-1, TIM-3 and TIGIT may be potential therapeutic oncotargets for esophageal cancer.

The Expedition 46-47 crewmembers arrive in Baikonur, Kazakhstan Nov. 30 for final pre-launch training following a flight from their training base at the Gagarin Cosmonaut Training Center in Star City, Russia and are greeted by school children. Tim Peake of the European Space Agency (left), Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, center) and Tim Kopra of NASA (right), will launch Dec. 15 on the Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station...NASA / Victor Zelentsov .

NASA Image and Video Library

2015-11-30

The Expedition 46-47 crewmembers arrive in Baikonur, Kazakhstan Nov. 30 for final pre-launch training following a flight from their training base at the Gagarin Cosmonaut Training Center in Star City, Russia and are greeted by school children. Tim Peake of the European Space Agency (left), Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, center) and Tim Kopra of NASA (right), will launch Dec. 15 on the Soyuz TMA-19M spacecraft for a six-month mission on the International Space Station. NASA / Victor Zelentsov

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. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

System Study: Technology Assessment and Prioritizing

NASA Technical Reports Server (NTRS)

2005-01-01

The objective of this NASA funded project is to assess and prioritize advanced technologies required to achieve the goals for an "Intelligent Propulsion System" through collaboration among GEAE, NASA, and Georgia Tech. Key GEAE deliverables are parametric response surface equations (RSE's) relating technology features to system benefits (sfc, weight, fuel burn, design range, acoustics, emission, etc...) and listings of Technology Impact Matrix (TIM) with benefits, debits, and approximate readiness status. TIM has been completed for GEAE and NASA proposed technologies. The combined GEAE and NASA TIM input requirement is shown in Table.1. In the course of building the RSE's and TIM, significant parametric technology modeling and RSE accuracy improvements were accomplished. GEAE has also done preliminary ranking of the technologies using Georgia Tech/GEAE USA developed technology evaluation tools. System level impact was performed by combining beneficial technologies with minimum conflict among various system figures of merits to assess their overall benefits to the system. The shortfalls and issues with modeling the proposed technologies are identified, and recommendations for future work are also proposed.

David Young | NREL

Science.gov Websites

(HVPE) growth of III-V materials for high-efficiency 1-sun to low-concentration solar cell applications growth, 2011. Timothy, J.C., D.L. Young, and T.A. Gessert, Modeling, Characterization, and Properties of

jsc2014e079941

NASA Image and Video Library

2014-09-08

PHOTO DATE: 09-08-14 LOCATION: Building 16N/1040 - SES Alpha-Cupola SUBJECT: ESA Astronaut Timothy Peake on behalf of ESA prior to FF RNDZ ADV 3 training with Kopra and Wilmore. PHOTOGRAPHER: BILL STAFFORD

jsc2014e079942

NASA Image and Video Library

2014-09-08

PHOTO DATE: 09-08-14 LOCATION: Building 16N/1040 - SES Alpha-Cupola SUBJECT: ESA Astronaut Timothy Peake on behalf of ESA prior to FF RNDZ ADV 3 training with Kopra and Wilmore. PHOTOGRAPHER: BILL STAFFORD

Tim-3-expressing macrophages are functionally suppressed and expanded in oral squamous cell carcinoma due to virus-induced Gal-9 expression.

PubMed

Dong, Jianfeng; Cheng, Lijun; Zhao, Minchao; Pan, Xiangfeng; Feng, Zhiqiang; Wang, Dawei

2017-05-01

Oropharyngeal head and neck squamous cell carcinoma is a common malignant tumor in the oral cavity. High-risk human papillomavirus 16 infection is a major cause of oropharyngeal head and neck squamous cell carcinoma development. Strong antitumor immune responses, especially CD8 + T cell responses, are thought to be essential to effective cancer treatment and are associated with better prognosis in oropharyngeal head and neck squamous cell carcinoma. In this study, we examined the role of the Tim-3/Gal-9 pathway in oropharyngeal head and neck squamous cell carcinoma patients. We found that Gal-9 expression by CD4 + T cells was increased in human papillomavirus-positive oropharyngeal head and neck squamous cell carcinoma patients, but not in human papillomavirus-negative oropharyngeal head and neck squamous cell carcinoma patients. Increased Gal-9 secretion by CD4 + T cells presented multiple immunosuppressive effects. Coculturing monocytes with high Gal-9-expressing CD4 + T cells resulted in the expansion of Tim-3 + monocytes, which suppressed interferon gamma production by activated CD8 + T cells. Subsequently, total monocytes incubated with exogenous Gal-9, or high Gal-9-expressing CD4 + T cells, suppressed the expression of interferon gamma by CD8 + T cells. Exogenous Gal-9 and high Gal-9-expressing CD4 + T cells also suppressed the secretion of both interleukin 10 and interleukin 12 by monocytes. These effects are Tim-3/Gal-9-dependent because blocking Tim-3 and/or Gal-9 could enhance the support of CD8 + T cell interferon gamma production and the interleukin 10 and interleukin 12 secretion by monocytes. Together, these data suggest that the high Tim-3 expression in monocytes could be utilized by tumor-promoting Gal-9 expression on CD4 + T cells. Immunotherapy in human papillomavirus-positive oropharyngeal head and neck squamous cell carcinoma patients therefore faces an additional challenge posed by Tim-3 and Gal-9 and likely requires the blockade of these molecules.

Characterization of the heat transfer properties of thermal interface materials

NASA Astrophysics Data System (ADS)

Fullem, Travis Z.

Physicists have studied the thermal conductivity of solids for decades. As a result of these efforts, thermal conduction in crystalline solids is well understood; there are detailed theories describing thermal conduction due to electrons and phonons. Phonon scattering and transmission at solid/solid interfaces, particularly above cryogenic temperatures, is not well understood and more work is needed in this area. The desire to solve engineering problems which require good thermal contact between mating surfaces has provided enhanced motivation for furthering the state of the art on this topic. Effective thermal management is an important design consideration in microelectronic systems. A common technique for removing excess heat from an electronic device is to attach a heatsink to the device; it is desirable to minimize the thermal resistance between the device and the heatsink. This can be accomplished by placing a thermal interface material (TIM) between the two surfaces. Due to the ever-increasing power densities found in electronic components, there is a desire to design better TIMs, which necessitates the ability to characterize TIM bondlines and to better understand the physics of heat conduction through TIM bondlines. A micro Fourier apparatus which employs Pt thin film thermometers of our design has been built and is capable of precisely quantifying the thermal resistance of thermal interface materials. In the present work several types of commercially available TIMs have been studied using this apparatus, including: greases, filled epoxies, and thermally conductive pads. In the case of filled epoxies, bondlines of various thicknesses, ranging from thirty microns to several hundred microns, have been measured. The microstructure of these bondlines has been investigated using optical microscopy and acoustic microscopy. Measured values of thermal conductivity are considered in terms of microstructural features such as percolation networks and filler particle depleted regions at the interface between the TIM and the substrate. The extent to which depleted regions contribute to the interfacial resistance is examined. The relationship between electrical and thermal resistance of the TIM bondline is considered in the context of comparing the relative contribution of electron and phonon heat conduction and how this correlates to microstructural features.

Virtual Airspace Modeling and Simulation (VAMS) Project First Technical Interchange Meeting

NASA Technical Reports Server (NTRS)

Beard, Robert; Kille, Robert; Kirsten, Richard; Rigterink, Paul; Sielski, Henry; Gratteau, Melinda F. (Editor)

2002-01-01

A three-day NASA Virtual Airspace and Modeling Project (VAMS) Technical Interchange Meeting (TIM) was held at the NASA Ames Research Center in Mountain View, CA. on May 21 through May 23,2002. The purpose of this meeting was to share initial concept information sponsored by the VAMS Project. An overall goal of the VAMS Project is to develop validated, blended, robust and transition-able air transportation system concepts over the next five years that will achieve NASA's long-term Enterprise Aviation Capacity goals. This document describes the presentations at the TIM, their related questions and answers, and presents the TIM recommendations.

Up-regulated expression of Tim-3/Gal-9 at maternal-fetal interface in pregnant woman with recurrent spontaneous abortion.

PubMed

Li, Jing; Li, Fan-fan; Zuo, Wei; Zhou, Yuan; Hao, Hai-yan; Dang, Jing; Jiang, Min; He, Meng-zhou; Deng, Dong-rui

2014-08-01

The relationship between T cell immunoglobulin domain and mucin domain protein 3 (Tim-3)/Galectin (Gal)-9 pathway and recurrent spontaneous abortion (RSA) was studied. Thirty-one pregnant women with RSA and 27 normal early gravidas were investigated to detect the levels of Tim-3 and Gal-9 in villi and deciduas by Western blotting. Meanwhile, the concentration of interleukin (IL)-4 and IL-12 in peripheral blood plasma was determined by ELISA in 25 healthy fertile non-pregnant controls, the normal early gravidas and pregnant women with RSA mentioned above, respectively. It was found that the relative expression levels of Tim-3 and Gal-9 in villi and deciduas were significantly increased in pregnant women with RSA as compared with those in the normal early gravidas. The concentration of IL-4 in peripheral blood plasma of pregnant women with RSA was lower than that of the normal early gravidas (P<0.05) and healthy fertile non-pregnant controls (P<0.05), but that of IL-2 in pregnant women with RSA was significantly higher than that of the normal early gravidas (P<0.05) and healthy fertile non-pregnant controls (P<0.05). It was suggested that the overexpression of Tim-3/Gal-9 pathway may be related to the pathogenesis of RSA.

Suppression of TIM-1 predicates clinical efficacy of sublingual immunotherapy for allergic rhinitis in children.

PubMed

Lin, Zhibin; Zhou, Lifeng; Luo, Xi; Xia, Wentong; Chen, Dehua; Xu, Rui; Wang, Jie; Luo, Renzhong; Xu, Geng; Li, Huabin

2013-08-01

To evaluate the clinical efficacy of sublingual immunotherapy (SLIT) with house-dust mite (HDM) extract and to examine the change of biomarkers (TIM-1, IL-5 and IL-10) after 6-month SLIT in children with allergic rhinitis (AR). One hundred and sixteen HDM-sensitized children with persistent AR were enrolled to assess the clinical efficacy of SLIT by determining the individual nasal symptom score (INSS) and total nasal symptom scores (TNSS) after 6-month SLIT. Moreover, the mRNA expression of TIM-1, IL-5 and IL-10 in peripheral blood mononuclear cells (PBMCs) was examined in 16 well-controlled and 12 uncontrolled AR patients using quantitative reverse transcription polymerase chain reaction (qRT-PCR). After 6-month SLIT, both TNSS and INSS scores were significantly decreased compared with the baseline value (p < 0.01). The rates for well-controlled, partly controlled and uncontrolled children were 43.1%, 32.8% and 24.1%, respectively. Accordingly, the mRNA levels of TIM-1 and IL-5 decreased significantly and IL-10 mRNA level increased significantly compared with the baseline value in well-controlled children (p < 0.05). Our findings suggest SLIT with HDM extract is effective and safe for AR children and TIM-1 may be considered as an indicator for evaluating the clinical efficacy of SLIT. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

CD163(+) M2-type tumor-associated macrophage support the suppression of tumor-infiltrating T cells in osteosarcoma.

PubMed

Han, Qinglin; Shi, Hongguang; Liu, Fan

2016-05-01

Osteosarcoma is one of the most common childhood cancers with high numbers of cancer-related deaths. Progress in conventional therapies is showing limited improvement. An adaptive T cell-based immunotherapy represents a promising new therapeutic option, but to improve its efficacy, regulatory mechanisms in osteosarcoma need further elucidation. Here, to evaluate the regulatory effect of tumor microenvironment of T cells in osteosarcoma, we examined the peripheral blood (PB) and tumor infiltrating (TI) T cells, and their correlations with PB and tumor immune characteristics. We found that TI T cells contained significantly higher levels of TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) cells than their PB counterparts. Similar to that in chronic HIV and HCV infections, these TIM-3(+)PD-1(-) and TIM-3(+)PD-1(+) T cells presented reduced proliferation and proinflammatory cytokine secretion in response to stimulation. Presence of M2-type (CD163(+)) macrophages exacerbated T cell immunosuppression, since frequencies of CD163(+) tumor-associated macrophages were directly correlated with the frequencies of suppressed TIM-3(+)PD-1(+) T cells. Moreover, depletion of CD163(+) macrophages significantly improved T cell proliferation and proinflammatory cytokine production. Overall, our data presented an intratumoral T cell-specific immunosuppression that was amplified by M2-type tumor-associated macrophages. Copyright © 2016. Published by Elsevier B.V.

KSC-2009-3402

NASA Image and Video Library

2009-06-03

CAPE CANAVERAL, Fla. – STS-127 crew members gather at NASA Kennedy Space Center's Launch Pad 39A for a question-and-answer session with the media. From left are Mission Specialist Christopher Cassidy, Tim Kopra, Julie Payette and Dave Wolf, Commander Mark Polansky, Pilot Doug Hurley and Mission Specialist Tom Marshburn. Payette represents the Canadian Space Agency. In the background is the fixed service structure with the solid rocket boosters and external fuel tank attached to space shuttle Endeavour. The crew is at Kennedy for a launch dress rehearsal called the terminal countdown demonstration test, or TCDT, which includes emergency egress training and equipment familiarization. Space shuttle Endeavour's STS-127 mission is the final of three flights dedicated to the assembly of the Japanese Kibo laboratory complex on the International Space Station. Endeavour's launch is targeted for June 13. Photo credit: NASA/Kim Shiflett

Chemotherapy Side Effects: A Cause of Heart Disease?

MedlinePlus

... Can chemotherapy side effects increase the risk of heart disease? Answers from Timothy J. Moynihan, M.D. Chemotherapy side effects may increase the risk of heart disease, including weakening of the heart muscle (cardiomyopathy) and ...

EVA Skills training in the NBL

NASA Image and Video Library

2012-11-27

ESA astronaut and first astronaut from the United Kingdom, Timothy Peake, with NASA astronaut Scott Tingle (unassigned) during EVA Skills training in the NBL. Photo Date: November 27, 2012. Location: NBL - Pool Topside. Photographer: Robert Markowitz

76 FR 50499 - Agency Information Collection Activities: Proposed Collection; Comments Requested; Office for...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-15

... Information Management System (TIMS) ACTION: 60-Day Notice of Information Collection Under Review. The... information collection request to the Office of Management and Budget (OMB) for review and approval in...: Trafficking Information Management System (TIMS) Online. (3) The Agency form number, if any, and the...

Coordinated Traffic Incident and Congestion Management (TIM-CM) : Mitigating Regional Impacts of Major Traffic Incidents in the Seattle I-5 Corridor

DOT National Transportation Integrated Search

2018-02-02

Within the Seattle metropolitan area, traffic incident management (TIM) operations provide a multi-jurisdictional and coordinated strategy to detect, respond to, and clear traffic incidents so that traffic flow can be restored quickly and safely. The...

Shaping the Air Force Operational Environment in Cyberspace

DTIC Science & Technology

2009-02-12

the Internet. The World Wide Web was created in 1989 by English scientist Tim Berners - Lee , working at the European Organization for Nuclear Research...www.af.mil/news/story.asp?id=123013440 Goldsmith, Jack L. and Wu, Tim . Who Controls the Internet?: Illusions of a Borderless World. New York

77 FR 58405 - Endangered Species; Marine Mammals; Receipt of Applications for Permit

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-20

..., Portola Valley, CA; PRT-83520A Applicant: Kevin Dunworth, Austin, TX; PRT-84493A Applicant: Timothy... scientific research. The specimens would be obtained opportunistically from sea otters taken from the wild in...

77 FR 74273 - Qualification of Drivers; Exemption Applications; Vision

Federal Register 2010, 2011, 2012, 2013, 2014

2012-12-13

... (SD) Terry L. Anderson (PA) Sammy J. Barada (NE) Timothy Bradford (TN) Cody W. Cook (OK) Marvin R...) Thomas L. Oglesby (GA) Garrick Pitts (AR) Jonathan C. Rollings (IA) Preston S. Salisbury (MT) Victor M...

Book review: Black bass diversity: Multidisciplinary science for conservation

USGS Publications Warehouse

Jelks, Howard L.

2016-01-01

Review info: Black bass diversity: Multidisciplinary science for conservation. Edited by Michael D. Tringali, James M. Long, Timothy W. Birdsong, and Michael S. Allen, 2015. ISBN: 978-1-934874-40-0, 685 pp.

7 CFR 5.4 - Commodities for which parity prices shall be calculated.

Code of Federal Regulations, 2011 CFR

2011-01-01

... the provisions of subsections (g) and (h) of section 359 of the Agricultural Adjustment Act of 1938 as..., Ladino clover, lespedeza, orchard grass, red clover, timothy, and hairy vetch. sugar crops Sugar beets...

7 CFR 5.4 - Commodities for which parity prices shall be calculated.

Code of Federal Regulations, 2010 CFR

2010-01-01

... the provisions of subsections (g) and (h) of section 359 of the Agricultural Adjustment Act of 1938 as..., Ladino clover, lespedeza, orchard grass, red clover, timothy, and hairy vetch. sugar crops Sugar beets...

Timothy Syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons

PubMed Central

Krey, Jocelyn F.; Pasca, Sergiu P.; Shcheglovitov, Aleksandr; Yazawa, Masayuki; Schwemberger, Rachel; Rasmusson, Randall; Dolmetsch, Ricardo E.

2012-01-01

L-type voltage gated calcium channels (LTCs) play an important role in neuronal development by promoting dendritic growth and arborization1–3. A point mutation in CaV1.2 causes Timothy Syndrome (TS)4, a neurodevelopmental disorder associated with autism spectrum disorders (ASD). We report that channels with the TS mutation cause activity-dependent dendrite retraction in rodent neurons and in induced pluripotent stem cell (iPSCs)– derived neurons from individuals with TS. Dendrite retraction is independent of calcium permeation through the mutant channel, is associated with ectopic activation of RhoA and is inhibited by over-expression of the channel associated GTPase Gem. These results suggest that CaV1.2 can activate RhoA signaling independently of Ca2+ and provide novel insights into the cellular basis of TS and other ASDs. PMID:23313911

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)

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…

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…

UPA Fill Drain Valve Modification kit installation

NASA Image and Video Library

2016-01-25

ISS046e023885 (01/25/2016) --- NASA astronaut Tim Kopra performs regular maintenance on the Urine Processing Assembly (UPA) aboard the International Space Station. The UPA is used by the crew to recycle water for use on the station. The image shows Tim replacing the brine filter from the UPA Fill Drain Valve enclosure.

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

ERIC Educational Resources Information Center

Miller, Rich

2007-01-01

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

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.

Calculation of day and night emittance values

NASA Technical Reports Server (NTRS)

Kahle, Anne B.

1986-01-01

In July 1983, the Thermal Infrared Multispectral Scanner (TIMS) was flown over Death Valley, California on both a midday and predawn flight within a two-day period. The availability of calibrated digital data permitted the calculation of day and night surface temperature and surface spectral emittance. Image processing of the data included panorama correction and calibration to radiance using the on-board black bodies and the measured spectral response of each channel. Scene-dependent isolated-point noise due to bit drops, was located by its relatively discontinuous values and replaced by the average of the surrounding data values. A method was developed in order to separate the spectral and temperature information contained in the TIMS data. Night and day data sets were processed. The TIMS is unique in allowing collection of both spectral emittance and thermal information in digital format with the same airborne scanner. For the first time it was possible to produce day and night emittance images of the same area, coregistered. These data add to an understanding of the physical basis for the discrimination of difference in surface materials afforded by TIMS.

Laser-Induced Ionization Efficiency Enhancement On A Filament For Thermal Ionization Mass Spectrometry

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

Siegfried, M.

2015-10-14

The evaluation of trace Uranium and Plutonium isotope ratios for nanogram to femtogram material quantities is a vital tool for nuclear counter-proliferation and safeguard activities. Thermal Ionization Mass Spectrometry (TIMS) is generally accepted as the state of the art technology for highly accurate and ultra-trace measurements of these actinide ratios. However, the very low TIMS ionization yield (typically less than 1%) leaves much room for improvement. Enhanced ionization of Nd and Sm from a TIMS filament was demonstrated using wavelength resonance with a nanosecond (pulse width) laser operating at 10 Hz when light was directed toward the filament.1 For thismore » study, femtosecond and picosecond laser capabilities were to be employed to study the dissociation and ionization mechanisms of actinides/lanthanides and measure the enhanced ionization of the metal of interest. Since the underlying chemistry of the actinide/lanthanide carbides produced and dissociated on a TIMS filament is not well understood, the experimental parameters affecting the photodissociation and photoionization with one and two laser beams were to be investigated.« less

With St. Basil���s Cathedral in Red Square in Moscow serving as a backdrop, Expedition 46-47 crewmembers Tim Kopra of NASA (left), Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, center) and Tim Peake of the European Space Agency (right) pose for pictures Nov. 23 after laying flowers at the Kremlin Wall where Russian space icons are interred. Peake, Malenchenko and Kopra will launch on Dec. 15 on the Soyuz TMA-19M spacecraft from the Baikonur Cosmodrome in Kazakhstan for a six-month mission on the International Space Station..NASA/Seth Marcantel

NASA Image and Video Library

2015-11-23

With St. Basil’s Cathedral in Red Square in Moscow serving as a backdrop, Expedition 46-47 crewmembers Tim Kopra of NASA (left), Yuri Malenchenko of the Russian Federal Space Agency (Roscosmos, center) and Tim Peake of the European Space Agency (right) pose for pictures Nov. 23 after laying flowers at the Kremlin Wall where Russian space icons are interred. Peake, Malenchenko and Kopra will launch on Dec. 15 on the Soyuz TMA-19M spacecraft from the Baikonur Cosmodrome in Kazakhstan for a six-month mission on the International Space Station. NASA/Seth Marcantel

Estimating Thruster Impulses From IMU and Doppler Data

NASA Technical Reports Server (NTRS)

Lisano, Michael E.; Kruizinga, Gerhard L.

2009-01-01

A computer program implements a thrust impulse measurement (TIM) filter, which processes data on changes in velocity and attitude of a spacecraft to estimate the small impulsive forces and torques exerted by the thrusters of the spacecraft reaction control system (RCS). The velocity-change data are obtained from line-of-sight-velocity data from Doppler measurements made from the Earth. The attitude-change data are the telemetered from an inertial measurement unit (IMU) aboard the spacecraft. The TIM filter estimates the threeaxis thrust vector for each RCS thruster, thereby enabling reduction of cumulative navigation error attributable to inaccurate prediction of thrust vectors. The filter has been augmented with a simple mathematical model to compensate for large temperature fluctuations in the spacecraft thruster catalyst bed in order to estimate thrust more accurately at deadbanding cold-firing levels. Also, rigorous consider-covariance estimation is applied in the TIM to account for the expected uncertainty in the moment of inertia and the location of the center of gravity of the spacecraft. The TIM filter was built with, and depends upon, a sigma-point consider-filter algorithm implemented in a Python-language computer program.

Isotope ratios of trace elements in samples from human nutrition studies determined by TIMS and ICP-MS: precision and accuracy compared.

PubMed

Turnlund, Judith R; Keyes, William R

2002-09-01

Stable isotopes are used with increasing frequency to trace the metabolic fate of minerals in human nutrition studies. The precision of the analytical methods used must be sufficient to permit reliable measurement of low enrichments and the accuracy should permit comparisons between studies. Two methods most frequently used today are thermal ionization mass spectrometry (TIMS) and inductively coupled plasma mass spectrometry (ICP-MS). This study was conducted to compare the two methods. Multiple natural samples of copper, zinc, molybdenum, and magnesium were analyzed by both methods to compare their internal and external precision. Samples with a range of isotopic enrichments that were collected from human studies or prepared from standards were analyzed to compare their accuracy. TIMS was more precise and accurate than ICP-MS. However, the cost, ease, and speed of analysis were better for ICP-MS. Therefore, for most purposes, ICP-MS is the method of choice, but when the highest degrees of precision and accuracy are required and when enrichments are very low, TIMS is the method of choice.

Adaptive NKG2C+CD57+ Natural Killer Cell and Tim-3 Expression During Viral Infections

PubMed Central

Kared, Hassen; Martelli, Serena; Tan, Shu Wen; Simoni, Yannick; Chong, Meng Li; Yap, Siew Hwei; Newell, Evan W.; Pender, Sylvia L. F.; Kamarulzaman, Adeeba; Rajasuriar, Reena; Larbi, Anis

2018-01-01

Repetitive stimulation by persistent pathogens such as human cytomegalovirus (HCMV) or human immunodeficiency virus (HIV) induces the differentiation of natural killer (NK) cells. This maturation pathway is characterized by the acquisition of phenotypic markers, CD2, CD57, and NKG2C, and effector functions—a process regulated by Tim-3 and orchestrated by a complex network of transcriptional factors, involving T-bet, Eomes, Zeb2, promyelocytic leukemia zinc finger protein, and Foxo3. Here, we show that persistent immune activation during chronic viral co-infections (HCMV, hepatitis C virus, and HIV) interferes with the functional phenotype of NK cells by modulating the Tim-3 pathway; a decrease in Tim-3 expression combined with the acquisition of inhibitory receptors skewed NK cells toward an exhausted and cytotoxic phenotype in an inflammatory environment during chronic HIV infection. A better understanding of the mechanisms underlying NK cell differentiation could aid the identification of new immunological targets for checkpoint blockade therapies in a manner that is relevant to chronic infection and cancer. PMID:29731749

Qualification of heavy water based irradiation device in the JSI TRIGA reactor for irradiations of FT-TIMS samples for nuclear safeguards

NASA Astrophysics Data System (ADS)

Radulović, Vladimir; Kolšek, Aljaž; Fauré, Anne-Laure; Pottin, Anne-Claire; Pointurier, Fabien; Snoj, Luka

2018-03-01

The Fission Track Thermal Ionization Mass Spectrometry (FT-TIMS) method is considered as the reference method for particle analysis in the field of nuclear Safeguards for measurements of isotopic compositions (fissile material enrichment levels) in micrometer-sized uranium particles collected in nuclear facilities. An integral phase in the method is the irradiation of samples in a very well thermalized neutron spectrum. A bilateral collaboration project was carried out between the Jožef Stefan Institute (JSI, Slovenia) and the Commissariat à l'Énergie Atomique et aux Énergies Alternatives (CEA, France) to determine whether the JSI TRIGA reactor could be used for irradiations of samples for the FT-TIMS method. This paper describes Monte Carlo simulations, experimental activation measurements and test irradiations performed in the JSI TRIGA reactor, firstly to determine the feasibility, and secondly to design and qualify a purpose-built heavy water based irradiation device for FT-TIMS samples. The final device design has been shown experimentally to meet all the required performance specifications.

Conjugated Bilirubin Differentially Regulates CD4+ T Effector Cells and T Regulatory Cell Function through Outside-In and Inside-Out Mechanisms: The Effects of HAV Cell Surface Receptor and Intracellular Signaling

PubMed Central

Corral-Jara, Karla F.; Gómez-Leyva, Juan F.; Rosenstein, Yvonne; Jose-Abrego, Alexis; Roman, Sonia

2016-01-01

We recently reported an immune-modulatory role of conjugated bilirubin (CB) in hepatitis A virus (HAV) infection. During this infection the immune response relies on CD4+ T lymphocytes (TLs) and it may be affected by the interaction of HAV with its cellular receptor (HAVCR1/TIM-1) on T cell surface. How CB might affect T cell function during HAV infection remains to be elucidated. Herein, in vitro stimulation of CD4+ TLs from healthy donors with CB resulted in a decrease in the degree of intracellular tyrosine phosphorylation and an increase in the activity of T regulatory cells (Tregs) expressing HAVCR1/TIM-1. A comparison between CD4+ TLs from healthy donors and HAV-infected patients revealed changes in the TCR signaling pathway relative to changes in CB levels. The proportion of CD4+CD25+ TLs increased in patients with low CB serum levels and an increase in the percentage of Tregs expressing HAVCR1/TIM-1 was found in HAV-infected patients relative to controls. A low frequency of 157insMTTTVP insertion in the viral receptor gene HAVCR1/TIM-1 was found in patients and controls. Our data revealed that, during HAV infection, CB differentially regulates CD4+ TLs and Tregs functions by modulating intracellular pathways and by inducing changes in the proportion of Tregs expressing HAVCR1/TIM-1. PMID:27578921

Effects of different sweet preloads on incretin hormone secretion, gastric emptying, and postprandial glycemia in healthy humans.

PubMed

Wu, Tongzhi; Zhao, Beiyi R; Bound, Michelle J; Checklin, Helen L; Bellon, Max; Little, Tanya J; Young, Richard L; Jones, Karen L; Horowitz, Michael; Rayner, Christopher K

2012-01-01

Macronutrient "preloads" can stimulate glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), slow gastric emptying, and reduce postprandial glycemic excursions. After sweet preloads, these effects may be signaled by sodium-glucose cotransporter-1 (SGLT1), sweet taste receptors, or both. We determined the effects of 4 sweet preloads on GIP and GLP-1 release, gastric emptying, and postprandial glycemia. Ten healthy subjects were studied on 4 separate occasions each. A preload drink containing 40 g glucose, 40 g tagatose/isomalt mixture (TIM), 40 g 3-O-methylglucose (3OMG; a nonmetabolized substrate of SGLT1), or 60 mg sucralose was consumed 15 min before a (13)C-octanoic acid-labeled mashed potato meal. Blood glucose, plasma total GLP-1 and GIP, serum insulin, and gastric emptying were determined. Both glucose and 3OMG stimulated GLP-1 and GIP release in advance of the meal (each P < 0.05), whereas TIM and sucralose did not. The overall postprandial GLP-1 response was greater after glucose, 3OMG, and TIM than after sucralose (P < 0.05), albeit later after TIM than the other preloads. The blood glucose and insulin responses in the first 30 min after the meal were greatest after glucose (each P < 0.05). Gastric emptying was slower after both 3OMG and TIM than after sucralose (each P < 0.05). In healthy humans, SGLT1 substrates stimulate GLP-1 and GIP and slow gastric emptying, regardless of whether they are metabolized, whereas the artificial sweetener sucralose does not. Poorly absorbed sweet tastants (TIM), which probably expose a greater length of gut to nutrients, result in delayed GLP-1 secretion but not in delayed GIP release. These observations have the potential to optimize the use of preloads for glycemic control. This trial was registered at www.actr.org.au as ACTRN12611000775910.

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 Branch watershed at Savannah River Site.

Investigation of T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) polymorphisms in essential thrombocythaemia (ET).

PubMed

Han, Fuyan; Wang, Guanghai; Li, Yuantang; Tian, Wenjun; Dong, Zhenfang; Cheng, Shiqing; Liu, Yiqing; Qu, Teng; Wang, Xiaoying; Wang, Yong; Zhang, Bingchang; Ju, Ying

2017-07-01

T-cell immunoglobulin- and mucin-domain-containing molecule-3 (TIM-3) is preferentially expressed on terminally differentiated Th1 cells and inhibits their IFN-γ production. It has been reported that chronic inflammation may be an important driving force for myeloproliferative neoplasms (MPNs). Therefore, we hypothesized that as an important inflammation regulator, TIM-3 may be involved in essential thrombocythaemia (ET). The goal of this study was to investigate whether the -1516G > T, -574G > T and +4259T > G single-nucleotide polymorphisms (SNPs) within the TIM-3 gene contribute to the genetic susceptibility of individuals to ET. Genotyping of the TIM-3 -1516G > T, -574G > T and + 4259T > G SNPs was performed in 175 patients with ET and in 151 controls via a polymerase chain reaction-restriction fragment length polymorphism assay. We also investigated the relationships between the genotypes of each SNP and the risk factors of ET such as routine blood indexes, age and JAK2 V617F mutation. The genotype and allele frequencies of the -1516G > T SNP (p = 0.016 and 0.019, respectively), the -574G > T SNP (p = 0.035 and 0.038, respectively) and the +4259T > G SNP (p = 0.036 and 0.038, respectively) of the ET patients and the controls were significantly different. A haplotype analysis found that the GGT and TGT haplotypes had significantly different distributions between ET and controls (p = 0.041 and 0.041, respectively). However, no significant differences were detected between the genotypes of all SNPs and routine blood indexes, age and JAK2V617F mutation. The -1516G > T, -574G > T and +4259T > G SNPs within TIM-3 gene might play an important role as a genetic risk factor in the pathogenesis of ET.

Incomplete Timothy syndrome secondary to a mosaic mutation of the CACNA1C gene diagnosed using next-generation sequencing.

PubMed

Baurand, Amandine; Falcon-Eicher, Sylvie; Laurent, Gabriel; Villain, Elisabeth; Bonnet, Caroline; Thauvin-Robinet, Christel; Jacquot, Caroline; Eicher, Jean-Christophe; Gourraud, Jean-Baptiste; Schmitt, Sébastien; Bézieau, Stéphane; Giraud, Mathilde; Dumont, Solenne; Kuentz, Paul; Probst, Vincent; Burguet, Antoine; Kyndt, Florence; Faivre, Laurence

2017-02-01

Autosomal dominant genetic diseases can occur de novo and in the form of somatic mosaicism, which can give rise to a less severe phenotype, and make diagnosis more difficult given the sensitivity limits of the methods used. We report the case of female child with a history of surgery for syndactyly of the hands and feet, who was admitted at 6 years of age to a pediatric intensive care unit following cardiac arrest. The electrocardiogram (ECG) showed a long QT interval that on occasions reached 500 ms. Despite the absence of facial dysmorphism and the presence of normal psychomotor development, a diagnosis of Timothy syndrome was made given the association of syndactyly and the ECG features. Sanger sequencing of the CACNA1C gene, followed by sequencing of the genes KCNQ1, KCNH2, KCNE1, KCNE2, were negative. The subsequent analysis of a panel of genes responsible for hereditary cardiac rhythm disorders using Haloplex technology revealed a recurrent mosaic p.Gly406Arg missense mutation of the CACNA1C gene in 18% of the cells. This mosaicism can explain the negative Sanger analysis and the less complete phenotype in this patient. Given the other cases in the literature, mosaic mutations in Timothy syndrome appear more common than previously thought. This case demonstrates the importance of using next-generation sequencing to identify mosaic mutations when the clinical picture supports a specific mutation that is not identified using conventional testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Lessons from Queer Bioethics: A Response to Timothy F. Murphy.

PubMed

Richie, Cristina

2016-06-01

'Bioethics still has important work to do in helping to secure status equality for LGBT people' writes Timothy F. Murphy in a recent Bioethics editorial. The focus of his piece, however, is much narrower than human rights, medical care for LGBT people, or ending the HIV/AIDS pandemic. Rather, he is primarily concerned with sexuality and gender identity, and the medical intersections thereof (i.e. DSM diagnosis; access to SrS or ARTs). It is the objective of this response to provide an alternate account of bioethics from a Queer perspective. I will situate Queer bioethics within Queer studies, and offer three 'lessons' that bioethics can derive from this perspective. These are not definitive rules for Queer bioethics, since it is a field which fundamentally opposes categorizations, favoring pastiche over principles. These lessons are exploratory examples, which both complement and contradict LGBT bioethics. My latter two lessons - on environmental bioethics and disability - overlap with some of Murphy's concerns, as well as other conceptions of LGBT bioethics. However, the first lesson takes an antithetical stance to Murphy's primary focus by resisting all forms of heteroconformity and disavowing reproduction as consonant with Queer objectives and theory. The first lesson, which doubles as a primer in Queer theory, does heavy philosophical lifting for the remainder of the essay. This response to Timothy F. Murphy, whose work is certainly a legacy in bioethics, reveals the multiplicity of discourses in LGBT/Queer studies, many of which are advantageous - even essential - to other disciplines like bioethics. © 2016 John Wiley & Sons Ltd.

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

NASA Astrophysics Data System (ADS)

Corfu, F.

2009-12-01

Mattinson’s CA-TIMS technique has proven to be highly successful in efficiently removing disturbed domains of zircon, thus enabling the determination of precise and accurate ages in a variety of geological situations. The method generally produces equal or better results than mechanical abrasion. There are, however, cases where CA-TIMS fails to achieve perfect concordance, and occasionally actually increases the degree of discordance. Such a behaviour (the over-reaction) is observed for example in U-rich (>1000 ppm) but texturally homogeneous zircon, a type quite common in highly differentiated portions of mafic intrusions, in granitic pegmatites, and in some metamorphic rocks. Because of their internal uniformity, such zircons do not exhibit large contrasts in crystallinity and solubility and after the baking stage of the CA-TIMS procedure they will either totally dissolve in the first HF attack, or produce discordant results. By contrast, mechanical abrasion of this type of zircon can isolate alteration-free zircon domains that yield concordant and reproducible data. This is due to the homogeneity of the crystals, the lack of zoning limiting contrasts in the degrees of metamictization and brittleness and preventing fracturing. The absence of fractures helps to confine alteration of zircon to the marginal domains, and these can be removed very efficiently by mechanical abrasion. This behaviour is exemplified by zircon populations from 252.0 Ma and 182.5 Ma mafic sills in Siberia and the Karoo basin. Another class of zircons that in general does not, or only partially comply with CA-TIMS includes populations from metamorphic and poly-orogenic rocks, typical of many Proterozoic orogens. The metamorphic reprocessing of zircon into low-U domains can freeze-in old Pb-loss patterns that cannot be undone by any technique. New metamorphic zircon growth can also create mixtures of different aged domains that cannot be resolved by CA-TIMS. In favourable circumstances, however, CA-TIMS could provide elegant ways to isolate the metamorphic components. A third category includes zircon populations that fail to achieve consistent ages, or concordant plateaus in multi-step partial dissolutions, even though they may have all the attributes of ideal CA-TIMS objects. The category is exemplified by a 62 Ma magmatic suite with a simple geological history and good quality zircon populations. The zircons have moderate U contents, regular growth zoning and few visible imperfections, yet the data reveal very extensive Pb loss requiring the almost total dissolution of the zircon before reaching the concordant residues. Baking of some of these zircon populations turns the colourless crystals brick-red (but still transparent), the red colour persisting long into the partial dissolution procedure. These features suggest that Pb loss may be related to a submicroscopic network of impurities and primary defects in the crystal structures which form pathways for the diffusion of Pb. Subsequent annealing appears to make the discordant domains impervious to partial dissolution. In conclusion, it is evident that CA-TIMS is a very helpful new technique for U-Pb geochronology, but some limitations must be considered that require case-by-case judgment and good Krogh-type abraders in reserve.

HER2-Positive Breast Cancer: What Is It?

MedlinePlus

... it? A friend of mine has HER2-positive breast cancer. Can you tell me what this means? Answers from Timothy J. Moynihan, M.D. HER2-positive breast cancer is a breast cancer that tests positive for ...

Portable Body Temperature Conditioner

DTIC Science & Technology

2012-10-01

TITLE: Portable Body Temperature Conditioner PRINCIPAL INVESTIGATOR...Body Temperature Conditioner 5b. GRANT NUMBER W81XWH-11-1-0792 5c... Conditioner Principal Investigator: Timothy D. Browder, MD Co-Investigator: Deborah Kuhls, MD Co-Investigator: John Fildes, MD Table of Contents

76 FR 27175 - Quarterly Publication of Individuals Who Have Chosen To Expatriate, as Required by Section 6039G

Federal Register 2010, 2011, 2012, 2013, 2014

2011-05-10

... CHAK KIE HOFFMANN HERBERT HOLT MICHAEL LAWRENCE HOLTER KARL GUNNAR HOLTERMANN UTE CHRISTIANE HOOLEY... TIMOTHY SPENCER CAITLIN SARAH SPERLING JOERG JACQUES SRINIVASAN VENKATRAMAN ST-CHARLES CAROLE STEPHANS SIN...

Gravitational Lens: Deep Space Probe Design

DTIC Science & Technology

2012-03-01

Lieutenant, USAF Approved: Timothy Lawrence, Col, USAF (Chairman) Date Carl Hartsfield, Lt Col, USAF (Member) Date Marc G. Millis (Member) Date Abstract A...23 RTG Radioisotope Thermoelectric Generators . . . . . . . . . . . . . . . . . 26 EOL End of Life...26 ASRG Advanced Stirling Radioisotope Generator . . . . . . . . . . . . . . . . 26 GPHS

The Radio Sky and the Echo of Creation.

ERIC Educational Resources Information Center

Ferris, Timothy

1984-01-01

Presents a selection from a revised and updated version of "The Red Limit" by Timothy Ferris. The book is a completely nontechnical introduction to 20th century cosmology, the study of the large-scale properties of the universe. (JN)

Obituary: Timothy P. McCullough, Jr., 1910-2004

NASA Astrophysics Data System (ADS)

McCullough, Charles

2007-12-01

Timothy Pendleton McCullough Jr., 93, a retired research physicist who was a pioneer in the measurement of microwave radiation from planetary surfaces, died of cardiac arrest on 19 November 2004, at Inova Fairfax Hospital. He lived in Springfield, VA. McCullough, who was principally a radio astronomer, published 22 scientific research papers while working in the Atmosphere and Astrophysics Division of NRL, from 1946 until his retirement in 1975. He spent the early part of his career in planetary observation and was among the first in his field to use radio astronomy to measure the surface temperature of Venus. He also studied Mars and Jupiter. Later, his interest turned to supernovas, galaxies and solar flares. He was an emeritus member of the American Astronomical Society and a member of the Sigma Xi Scientific Research Society. McCullough was born on 9 December 1910 in Vardaman, Mississippi. His father, Timothy P. McCullough, was a farmer and bookkeeper. His mother, Annie W. McCullough, was a homemaker. Timothy McCullough, Jr.'s parents, as well as two sisters and a brother, are deceased. McCullough graduated from the University of Mississippi in Oxford in 1936 and received a master's degree in physics from North Carolina State University in Raleigh. He taught physics and aviation navigation before entering the Navy during World War II. He instructed Russian sailors on anti-submarine warfare. McCullough left the Navy at the end of the war, but continued to serve in the Naval Reserve. He was recalled to active duty during the Korean War and was stationed at Potomac River Naval Command, where he wrote technical documents on electronic warfare systems. McCullough retired from the Naval Reserve in 1969 with the rank of commander. He was a charter member of First Baptist Church in Springfield and a former deacon and Sunday school teacher at First Baptist Church in Alexandria. Survivors include his wife of 63 years, Virginia Ball McCullough of Springfield; three children, Robert E. "Gene" McCullough of Denver, Jane Ball Phillips of St. Matthews, S.C., and Charles E. McCullough of Clifton; seven grandchildren and four great-grandchildren. [The preceding article expands upon one published in the NRL Labstracts of 18 April 2005 and is used with permission.)

Doing Literary Criticism: Helping Students Engage with Challenging Texts

ERIC Educational Resources Information Center

Gillespie, Tim

2010-01-01

One of the greatest challenges for English language arts teachers today is the call to engage students in more complex texts. Tim Gillespie, who has taught in public schools for almost four decades, has found the lenses of literary criticism a powerful tool for helping students tackle challenging literary texts. Tim breaks down the dense language…

Norfolk Schools Talked to Astronaut Tim Peake

ERIC Educational Resources Information Center

Grant, Stephanie

2016-01-01

Tim Peake's mission to the International Space Station captured the imagination of the UK and this article describes a live radio link with him, to help him to reach out to pupils across the country and inspire them in STEM subjects. It describes the project, from bidding for the opportunity to host it, to the planning and realisation of the…

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…

Triosephosphate isomerase and filamin C share common epitopes as novel allergens of Procambarus clarkii

USDA-ARS?s Scientific Manuscript database

Triosephosphate isomerase (TIM) is a key enzyme in glycolysis and has been identified as an allergen in saltwater products. In this study, TIM with a molecular mass of 28 kDa was purified from the freshwater crayfish (Procambarus clarkii) muscle. A 90-kDa protein that showed IgG/IgE cross-reactivity...

Cross-Domain Information Exchange Framework (CIEF): Road Map to Web 2.0

DTIC Science & Technology

2007-06-22

open to debate, and some technology experts, notably Tim Berners - Lee , have questioned whether the term has meaning. developerWorks Interviews So the...better the more people use them." Tim O’Reilly (2006-12-10). Web 2.0 Compact Definition: Trying Again Problem: Its (Web 2.0) exact meaning remains

A comparison of lead-isotope measurements on exploration-type samples using inductively coupled plasma and thermal ionization mass spectrometry

USGS Publications Warehouse

Gulson, B.L.; Meier, A.L.; Church, S.E.; Mizon, K.J.

1989-01-01

Thermal ionization mass spectrometry (TI-MS) has long been the method of choice for Pb-isotope determinations. More recently, however, inductively coupled plasma mass spectrometry (ICP-MS) has been used to determine Pb-isotope ratios for mineral exploration. The ICP-MS technique, although not as precise as TI-MS, may promote a wider application of Ph-isotope ratio methods because it allows individual isotopes to be determined more rapidly, generally without need for chemical separation (e.g., Smith et al., 1984; Hinners et al., 1987). To demonstrate the utility of the ICP-MS method, we have conducted a series of Pb-isotope measurements on several suites of samples using both TI-MS and ICP-MS. ?? 1989.

Cancer Prevention in the Precision Medicine Era | Division of Cancer Prevention

Cancer.gov

Speaker | Timothy R. Rebbeck, PhD will present "Cancer Prevention in the Precision Medicine Era" on March 20, 2018, from 11:00 am - 12:00 pm at the NCI Shady Grove Campus. Learn more about this lecture.

Should the Air Force Teach Running Technique

DTIC Science & Technology

2012-02-15

accessed 30 September 2011). Arendse, Regan, Timothy Noakes, Liane Azevedo, Nicholas Romanov, Martin Schwellnus, and Graham Fletcher. “Reduced...Patikas, Waltraud Schuster, Petra Armbrust, and Leonhard Doderlein. “Foot Motion in Shoes- A Comparison of Barefoot Walking with Shod Walking in

ARC-2009-ACD09-0150-007

NASA Image and Video Library

2009-07-22

NASA Research Park (NRP) Timothy Collins, President and Chairman, KleenSpeed Technologies, Inc. and Captain Andrew Butte, rescue helicopter pilot and former Army Aviator, with Butte's 1999 SWIFT. ChampCar Butte has given his racecar to KleenSpeed for conversion to electric.

Foreign Aid: Are We Increasing Stability

DTIC Science & Technology

2016-12-01

ARE WE INCREASING STABILITY ? by Jeffrey Chenard Chad Thibodeau December 2016 Thesis Co-Advisors: Robert Burks Timothy Warren THIS PAGE......to determine the probability of internal conflict. The results of the research show that the USG is not increasing stability through reducing

KSC-2009-3403

NASA Image and Video Library

2009-06-03

CAPE CANAVERAL, Fla. – STS-127 crew members gather at NASA Kennedy Space Center's Launch Pad 39A for a question-and-answer session with the media. At left is Commander Mark Polansky, introducing the other astronauts, who are, from left, Pilot Doug Hurley and Mission Specialists Julie Payette, Tom Marshburn, Tim Kopra, Chris Cassidy and Dave Wolf. Payette represents the Canadian Space Agency. In the background is the fixed service structure with the solid rocket boosters and external fuel tank attached to space shuttle Endeavour. The crew is at Kennedy for a launch dress rehearsal called the terminal countdown demonstration test, or TCDT, which includes emergency egress training and equipment familiarization. Space shuttle Endeavour's STS-127 mission is the final of three flights dedicated to the assembly of the Japanese Kibo laboratory complex on the International Space Station. Endeavour's launch is targeted for June 13. Photo credit: NASA/Kim Shiflett

A competent catalytic active site is necessary for substrate induced dimer assembly in triosephosphate isomerase.

PubMed

Jimenez-Sandoval, Pedro; Vique-Sanchez, Jose Luis; Hidalgo, Marisol López; Velazquez-Juarez, Gilberto; Diaz-Quezada, Corina; Arroyo-Navarro, Luis Fernando; Moran, Gabriela Montero; Fattori, Juliana; Jessica Diaz-Salazar, A; Rudiño-Pinera, Enrique; Sotelo-Mundo, Rogerio; Figueira, Ana Carolina Migliorini; Lara-Gonzalez, Samuel; Benítez-Cardoza, Claudia G; Brieba, Luis G

2017-11-01

The protozoan parasite Trichomonas vaginalis contains two nearly identical triosephosphate isomerases (TvTIMs) that dissociate into stable monomers and dimerize upon substrate binding. Herein, we compare the role of the "ball and socket" and loop 3 interactions in substrate assisted dimer assembly in both TvTIMs. We found that point mutants at the "ball" are only 39 and 29-fold less catalytically active than their corresponding wild-type counterparts, whereas Δloop 3 deletions are 1502 and 9400-fold less active. Point and deletion mutants dissociate into stable monomers. However, point mutants assemble as catalytic competent dimers upon binding of the transition state substrate analog PGH, whereas loop 3 deletions remain monomeric. A comparison between crystal structures of point and loop 3 deletion monomeric mutants illustrates that the catalytic residues in point mutants and wild-type TvTIMs are maintained in the same orientation, whereas the catalytic residues in deletion mutants show an increase in thermal mobility and present structural disorder that may hamper their catalytic role. The high enzymatic activity present in monomeric point mutants correlates with the formation of dimeric TvTIMs upon substrate binding. In contrast, the low activity and lack of dimer assembly in deletion mutants suggests a role of loop 3 in promoting the formation of the active site as well as dimer assembly. Our results suggest that in TvTIMs the active site is assembled during dimerization and that the integrity of loop 3 and ball and socket residues is crucial to stabilize the dimer. Copyright © 2017 Elsevier B.V. All rights reserved.

Equilibrium and kinetic folding of rabbit muscle triosephosphate isomerase by hydrogen exchange mass spectrometry.

PubMed

Pan, Hai; Raza, Ashraf S; Smith, David L

2004-03-05

Unfolding and refolding of rabbit muscle triosephosphate isomerase (TIM), a model for (betaalpha)8-barrel proteins, has been studied by amide hydrogen exchange/mass spectrometry. Unfolding was studied by destabilizing the protein in guanidine hydrochloride (GdHCl) or urea, pulse-labeling with 2H2O and analyzing the intact protein by HPLC electrospray ionization mass spectrometry. Bimodal isotope patterns were found in the mass spectra of the labeled protein, indicating two-state unfolding behavior. Refolding experiments were performed by diluting solutions of TIM unfolded in GdHCl or urea and pulse-labeling with 2H2O at different times. Mass spectra of the intact protein labeled after one to two minutes had three envelopes of isotope peaks, indicating population of an intermediate. Kinetic modeling indicates that the stability of the folding intermediate in water is only 1.5 kcal/mol. Failure to detect the intermediate in the unfolding experiments was attributed to its low stability and the high concentrations of denaturant required for unfolding experiments. The folding status of each segment of the polypeptide backbone was determined from the deuterium levels found in peptic fragments of the labeled protein. Analysis of these spectra showed that the C-terminal half folds to form the intermediate, which then forms native TIM with folding of the N-terminal half. These results show that TIM folding fits the (4+4) model for folding of (betaalpha)8-barrel proteins. Results of a double-jump experiment indicate that proline isomerization does not contribute to the rate-limiting step in the folding of TIM.

Vertically aligned carbon nanotube arrays as thermal interface material for vibrational structure of piezoelectric transformer

NASA Astrophysics Data System (ADS)

Chen, Lie; Ju, Bin; Feng, Zhihua; Zhao, Yang

2018-07-01

The application and characterization of thermal interface material (TIM) for vibrational structures is investigated in this paper. The vibrating feature during the operation requires unique solution for its thermal management, since the connection between the device and heat dissipater should be able to conduct heat efficiently and impose minimum constraint onto the vibration simultaneously. As a typical vibrational device, piezoelectric transformers (PTs) are discussed in this paper. The PTs have urgent demands for thermal dissipation since their power conversion efficiency decrease rapidly with the rising temperature. A novel method by applying vertically aligned carbon nanotube (VACNT) arrays to the interface between PT and heat dissipater is presented to enhance the performance of piezoelectric transformers. VACNT arrays are one of the excellent TIMs. It can directly establish thermal contact between two surfaces by van der Waals’ forces. In addition, the unique anisotropic character of CNT arrays provides enough flexibility to accommodate the vibration during the operation. Different configurations of TIMs are compared with each other in this work, including CNT arrays, tape of polypropylene (PP) membrane and without heat transfer structure (HTS). The results indicate that the temperature rise is lowest and the efficiency is highest at the same power density while CNT arrays served as the TIM. Almost no significant fretting and wearing damage occurred on PT electrode surface with CNT arrays TIM even after working continuously for 120 days. Meanwhile, the thermo-physical properties of CNT arrays at contact interface are measured by optical transient thermo-reflectance technique.

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

ERIC Educational Resources Information Center

Olive, John; Vomvoridi, Eugenia

2006-01-01

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

Astro Academy: Principia--Using Tracker to Analyse Experiments Undertaken by Tim Peake on the International Space Station

ERIC Educational Resources Information Center

Mobbs, Robin

2016-01-01

While on the International Space Station, Tim Peake undertook and recorded video files of experiments suitable for physics teaching coordinated by the National Space Academy. This article describes how the video of these experiments was prepared for use with tracking software. The tracking files of the videos are suitable for use by teachers or…

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

Multispectral thermal infrared mapping of sulfur dioxide plumes: A case study from the East Rift Zone of Kilauea Volcano, Hawaii

NASA Astrophysics Data System (ADS)

Realmuto, V. J.; Sutton, A. J.; Elias, T.

1997-07-01

The synoptic perspective and rapid mode of data acquisition provided by remote sensing are well suited for the study of volcanic SO2 plumes. In this paper we describe a plume-mapping procedure that is based on image data acquired with NASA's airborne thermal infrared multispectral scanner (TIMS) and apply the procedure to TIMS data collected over the East Rift Zone of Kilauea Volcano, Hawaii, on September 30, 1988. These image data covered the Pu`u `O `o and Kupaianaha vents and a skylight in the lava tube that was draining the Kupaianaha lava pond. Our estimate of the SO2 emission rate from Pu`u `O `o (17-20 kg s-1) is roughly twice the average of estimates derived from correlation spectrometer (COSPEC) measurements collected 10 days prior to the TIMS overflight (10 kg s-1). The agreement between the TIMS and COSPEC results improves when we compare SO2 burden estimates, which are relatively independent of wind speed. We demonstrate the feasibility of mapping Pu`u `O `o - scale SO2 plumes from space in anticipation of the 1998 launch of the advanced spaceborne thermal emission and reflectance radiometer (ASTER).

Connecting Active-Site Loop Conformations and Catalysis in Triosephosphate Isomerase: Insights from a Rare Variation at Residue 96 in the Plasmodial Enzyme.

PubMed

Pareek, Vidhi; Samanta, Moumita; Joshi, Niranjan V; Balaram, Hemalatha; Murthy, Mathur R N; Balaram, Padmanabhan

2016-04-01

Despite extensive research into triosephosphate isomerases (TIMs), there exists a gap in understanding of the remarkable conjunction between catalytic loop-6 (residues 166-176) movement and the conformational flip of Glu165 (catalytic base) upon substrate binding that primes the active site for efficient catalysis. The overwhelming occurrence of serine at position 96 (98% of the 6277 unique TIM sequences), spatially proximal to E165 and the loop-6 residues, raises questions about its role in catalysis. Notably, Plasmodium falciparum TIM has an extremely rare residue--phenylalanine--at this position whereas, curiously, the mutant F96S was catalytically defective. We have obtained insights into the influence of residue 96 on the loop-6 conformational flip and E165 positioning by combining kinetic and structural studies on the PfTIM F96 mutants F96Y, F96A, F96S/S73A, and F96S/L167V with sequence conservation analysis and comparative analysis of the available apo and holo structures of the enzyme from diverse organisms. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

At the Kremlin Wall in Red Square in Moscow, Expedition 46-47 crewmember Tim Kopra of NASA lays flowers at the site where Russian space icons are interred in a ceremony Nov. 23. Looking on from left to right are backup crewmember Anatoly Ivanishin of the Russian Federal Space Agency (Roscosmos) and prime crewmembers Tim Peake of the European Space Agency and Yuri Malenchenko of Roscosmos. Peake, Malenchenko and Kopra will launch on Dec. 15 on the Soyuz TMA-19M spacecraft from the Baikonur Cosmodrome in Kazakhstan for a six-month mission on the International Space Station..NASA/Seth Marcantel

NASA Image and Video Library

2015-11-23

At the Kremlin Wall in Red Square in Moscow, Expedition 46-47 crewmember Tim Kopra of NASA lays flowers at the site where Russian space icons are interred in a ceremony Nov. 23. Looking on from left to right are backup crewmember Anatoly Ivanishin of the Russian Federal Space Agency (Roscosmos) and prime crewmembers Tim Peake of the European Space Agency and Yuri Malenchenko of Roscosmos. Peake, Malenchenko and Kopra will launch on Dec. 15 on the Soyuz TMA-19M spacecraft from the Baikonur Cosmodrome in Kazakhstan for a six-month mission on the International Space Station. NASA/Seth Marcantel

Is the catalytic activity of triosephosphate isomerase fully optimized? An investigation based on maximization of entropy production.

PubMed

Bonačić Lošić, Željana; Donđivić, Tomislav; Juretić, Davor

2017-03-01

Triosephosphate isomerase (TIM) is often described as a fully evolved housekeeping enzyme with near-maximal possible reaction rate. The assumption that an enzyme is perfectly evolved has not been easy to confirm or refute. In this paper, we use maximization of entropy production within known constraints to examine this assumption by calculating steady-state cyclic flux, corresponding entropy production, and catalytic activity in a reversible four-state scheme of TIM functional states. The maximal entropy production (MaxEP) requirement for any of the first three transitions between TIM functional states leads to decreased total entropy production. Only the MaxEP requirement for the product (R-glyceraldehyde-3-phosphate) release step led to a 30% increase in enzyme activity, specificity constant k cat /K M , and overall entropy production. The product release step, due to the TIM molecular machine working in the physiological direction of glycolysis, has not been identified before as the rate-limiting step by using irreversible thermodynamics. Together with structural studies, our results open the possibility for finding amino acid substitutions leading to an increased frequency of loop six opening and product release.

Graphene-enhanced thermal interface materials for heat removal from photovoltaic solar cells

NASA Astrophysics Data System (ADS)

Saadah, M.; Gamalath, D.; Hernandez, E.; Balandin, A. A.

2016-09-01

The increase in the temperature of photovoltaic (PV) solar cells affects negatively their power conversion efficiency and decreases their lifetime. The negative effects are particularly pronounced in concentrator solar cells. Therefore, it is crucial to limit the PV cell temperature by effectively removing the excess heat. Conventional thermal phase change materials (PCMs) and thermal interface materials (TIMs) do not possess the thermal conductivity values sufficient for thermal management of the next generation of PV cells. In this paper, we report the results of investigation of the increased efficiency of PV cells with the use of graphene-enhanced TIMs. Graphene reveals the highest values of the intrinsic thermal conductivity. It was also shown that the thermal conductivity of composites can be increased via utilization of graphene fillers. We prepared TIMs with up to 6% of graphene designed specifically for PV cell application. The solar cells were tested using the solar simulation module. It was found that the drop in the output voltage of the solar panel under two-sun concentrated illumination can be reduced from 19% to 6% when grapheneenhanced TIMs are used. The proposed method can recover up to 75% of the power loss in solar cells.

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, including our own Galaxy, the Milky Way. A second area of research is the study of the origin, structure, and evolution of associations of young, massive stars in the Solar Neighbourhood. He obtained his PhD from the University of Leiden in 1980, moving on to work at the Institute for Advanced Study in Princeton, and subsequently at Caltech in Pasadena. He has received several honours and awards and is the author of a large number of research papers. In the 1990's, Tim de Zeeuw was involved in the development of an advanced panoramic integral-field spectrograph for the 4.2-m William Herschel Telescope, while also working as the Principal Investigator of a major research project using the Hipparcos database to conduct a comprehensive census of nearby young stellar groups. In 1993, he became the founding director of NOVA, the Netherlands Research School for Astronomy, which coordinates the graduate education and astronomical research at the five university astronomy institutes in the Netherlands. Today, NOVA supports 25% of the university astronomy positions in The Netherlands and, by reinvigorating the university groups, it has contributed to strongly increasing the international visibility of Dutch astronomy and enabled an intensified Dutch participation in the ESO activities. He is also the co-founder of the Lorentz Center, an international centre for Astronomy, Mathematics and Physics in Leiden. Tim de Zeeuw regularly advises NWO, the Netherlands Organisation for Scientific Research. During the years he has served on the Time Allocation Committee for the NASA/ESA Hubble Space Telescope, and, since 2003, as the Chairman of the Space Telescope Institute Council in Baltimore. He also serves on the AURA Board of Directors, and on the ESA Space Science Advisory Committee, and leads the development of a Science Vision for European Astronomy as part of the EU ASTRONET initiative. Tim de Zeeuw has also served for three years as the Dutch national astronomy delegate to the ESO Council. As a member of the ESO Council he participated in the work of the Council Scientific Strategy Working Group, which resulted in the Council resolution of December 2004 outlining ESO's strategic goals. More recently, as new Chair of this Working Group, he has been elaborating various scenarios for ESO's future role in European astronomy. Tim de Zeeuw is married to Dutch astronomer Ewine van Dishoeck.

Metallized compliant 3D microstructures for dry contact thermal conductance enhancement

NASA Astrophysics Data System (ADS)

Cui, Jin; Wang, Jicheng; Zhong, Yang; Pan, Liang; Weibel, Justin A.

2018-05-01

Microstructured three-dimensional (3D) materials can be engineered to enable new capabilities for various engineering applications; however, microfabrication of large 3D structures is typically expensive due to the conventional top-down fabrication scheme. Herein we demonstrated the use of projection micro-stereolithography and electrodeposition as cost-effective and high-throughput methods to fabricate compliant 3D microstructures as a thermal interface material (TIM). This novel TIM structure consists of an array of metallized micro-springs designed to enhance the dry contact thermal conductance between nonflat surfaces under low interface pressures (10s-100s kPa). Mechanical compliance and thermal resistance measurements confirm that this dry contact TIM can achieve conformal contact between mating surfaces with a nonflatness of approximately 5 µm under low interface pressures.

What web browsing reveals about your health.

PubMed

Libert, Timothy; Grande, David; Asch, David A

2015-11-16

Advertisers can learn a lot from our digital footprints, including about our health. Timothy Libert and colleagues argue that we need to tighten restrictions on such data for marketing purposes while looking at their potential to improve health. © BMJ Publishing Group Ltd 2015.

Overview of Recent Marine and Freshwater Recreational Epidemiology Studies and Their Findings

EPA Science Inventory

Overview of Recent Marine and Freshwater Recreational Epidemiology Studies and Their Findings Timothy J. Wade, Elizabeth A. Sams, Rich Haugland, Alfred P. Dufour The National Epidemiologic and Environmental Assessment of Recreational Water Study was conducted to address aspects...

Silver Nanoparticles and Ionic Silver Have Opposite Effects on Spontaneous Activity and Pharmacological Responses in Neuronal Networks In Vitro

EPA Science Inventory

CONTROL ID: 1850472 CONTACT (NAME ONLY): Timothy Shafer Abstract Details PRESENTATION TYPE: Platform or Poster CURRENT CATEGORY: Nanotoxicology, In Vitro | Neurotoxicity, General | Neurotoxicity, Metals KEYWORDS: Nanoparticle, Neurotoxicity, microelectrode array. DATE/TIME LAST...

Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

DOE PAGES

Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.; ...

2016-01-06

Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessedmore » by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. In conclusion, our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer.« less

Microbial Metabolism Shifts Towards an Adverse Profile with Supplementary Iron in the TIM-2 In vitro Model of the Human Colon

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

Kortman, Guus A. M.; Dutilh, Bas E.; Maathuis, Annet J. H.

Oral iron administration in African children can increase the risk for infections. However, it remains unclear to what extent supplementary iron affects the intestinal microbiome. We here explored the impact of iron preparations on microbial growth and metabolism in the well-controlled TNO's in vitro model of the large intestine (TIM-2). The model was inoculated with a human microbiota, without supplementary iron, or with 50 or 250 μmol/L ferrous sulfate, 50 or 250 μmol/L ferric citrate, or 50 μmol/L hemin. High resolution responses of the microbiota were examined by 16S rDNA pyrosequencing, microarray analysis, and metagenomic sequencing. The metabolome was assessedmore » by fatty acid quantification, gas chromatography-mass spectrometry (GC-MS), and 1H-NMR spectroscopy. Cultured intestinal epithelial Caco-2 cells were used to assess fecal water toxicity. Microbiome analysis showed, among others, that supplementary iron induced decreased levels of Bifidobacteriaceae and Lactobacillaceae, while it caused higher levels of Roseburia and Prevotella. Metagenomic analyses showed an enrichment of microbial motility-chemotaxis systems, while the metabolome markedly changed from a saccharolytic to a proteolytic profile in response to iron. Branched chain fatty acids and ammonia levels increased significantly, in particular with ferrous sulfate. Importantly, the metabolite-containing effluent from iron-rich conditions showed increased cytotoxicity to Caco-2 cells. In conclusion, our explorations indicate that in the absence of host influences, iron induces a more hostile environment characterized by a reduction of microbes that are generally beneficial, and increased levels of bacterial metabolites that can impair the barrier function of a cultured intestinal epithelial monolayer.« less

Antibodies Against Immune Checkpoint Molecules Restore Functions of Tumor-Infiltrating T Cells in Hepatocellular Carcinomas.

PubMed

Zhou, Guoying; Sprengers, Dave; Boor, Patrick P C; Doukas, Michail; Schutz, Hannah; Mancham, Shanta; Pedroza-Gonzalez, Alexander; Polak, Wojciech G; de Jonge, Jeroen; Gaspersz, Marcia; Dong, Haidong; Thielemans, Kris; Pan, Qiuwei; IJzermans, Jan N M; Bruno, Marco J; Kwekkeboom, Jaap

2017-10-01

Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell-mediated immune response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non-small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4 + and CD8 + T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions. We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8 + and CD4 + T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays. Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8 + and CD4 + T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8 + TIL, compared with other CD8 + TIL. Compared with TIL that did not express these inhibitory receptors, CD8 + and CD4 + TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 [PD-L1]), TIM3, or LAG3 increased proliferation of CD8 + and CD4 + TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions. The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Small subunit of a cold-resistant plant, Timothy, does not significantly alter the catalytic properties of Rubisco in transgenic rice.

PubMed

Fukayama, Hiroshi; Koga, Atsushi; Hatanaka, Tomoko; Misoo, Shuji

2015-04-01

Effects of overexpression of high activity-type Rubisco small subunit (RbcS) from a cold-resistant plant, timothy (Phleum pratense), on kinetic properties of Rubisco were studied in rice (Oryza sativa). The full-length mRNA sequence of timothy RbcS (PpRbcS1) was determined by 5'RACE and 3'RACE. The coding sequence of PpRbcS1 was fused to the chlorophyll a/b-binding protein promoter and introduced into rice. PpRbcS was highly expressed in leaf blade and accounted for approximately 30 % of total RbcS in homozygous transgenic lines. However, the catalytic turnover rate and K m for CO2 of Rubisco did not significantly change in these transgenic lines compared to non-transgenic rice, suggesting that PpRbcS1 is not effective for improvement of catalytic efficiency of rice Rubisco. The photosynthetic rate and growth were essentially unchanged, whereas the photosynthetic rate at low CO2 condition was marginally increased in transgenic lines. Rubisco content was significantly increased, whereas soluble protein, nitrogen, and chlorophyll contents were unchanged in transgenic lines compared to non-transgenic rice. Because the kinetic properties were similar, observed slight increase in photosynthetic rate at low CO2 is considered to be large due to increase in Rubisco content in transgenic lines. Introduction of foreign RbcS is an effective approach for the improvement of Rubisco kinetics and photosynthesis. However, in this study, it was suggested that RbcS of high activity-type Rubisco, even showing higher amino acid identity with rice RbcS, did not always enhance the catalytic turnover rate of Rubisco in rice. Thus, we should carefully select RbcS to be overexpressed before introduction.

Allergen extracts and recombinant proteins: comparison of efficiency of in vitro allergy diagnostics using multiplex assay on a biological microchip.

PubMed

Smoldovskaya, Olga; Feyzkhanova, Guzel; Arefieva, Alla; Voloshin, Sergei; Ivashkina, Olga; Reznikov, Yuriy; Rubina, Alla

2016-01-01

Immunological test systems for diagnostics of type I hypersensitivity involve the following types of antigens: whole allergen extracts, individual highly purified proteins and their recombinant analogues. The goal of this study was to compare the results obtained with whole allergen extracts (birch pollen, cat dander, and timothy grass pollen) and their respective recombinant proteins in biochip-based immunoassay. Multiplex fluorescent immunoassay of 139 patients' blood serum samples was carried out using biological microchips (biochips). sIgE concentrations for the chosen allergens and their recombinant components were measured. ROC analysis was used for comparison of the results and determination of diagnostic accuracy. The results for the birch pollen extract and its recombinant allergens have shown that the diagnostic accuracy of the methods utilizing the whole allergen extract, its major component Bet v 1 and the combination of major and minor components (Bet v 1 and Bet v 2) was the same. Values for diagnostic accuracy for the cat dander extract and its major recombinant component Fel d 1 were equal. In contrast with birch pollen and cat dander allergens, using of recombinant components of timothy grass pollen (Phl p 1, Phl p 5, Phl p 7 and Phl p 12) did not allow reaching the diagnostic accuracy of using natural extract. Multiplex analysis of samples obtained from patients with allergy to birch pollen and cat dander using biological microchips has shown that comparable accuracy was observed for the assay with natural extracts and recombinant allergens. In the case of timothy grass allergen, using the recombinant components may be insufficient.

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

Heon, Elise K.; Wulan, Hasi; Macdonald, Loch P.

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 duringmore » 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 and IL-2 had different kinetics in inducing TI CD8 T cell responses. • IL-15 induced stronger but shorter-lived TI CD8 T cell responses than IL-2. • IL-15, but not IL-2, caused upregulation of Tim-3 on TI CD8 T cells. • Blocking Tim-3 resulted in increased IL-15-induced proliferation and IFN-γ production in TI CD8 T cells.« less

16TH Annual Review of Progress in Applied Computational Electromagnetics of the Naval Postgraduate School, Monterey, CA. Volume I

DTIC Science & Technology

2000-03-24

Element Method for Designing Plasma Reactors" Leo Kempel, Paul Rummel, Tim Grotjohn and John Amrhein ............................................ 28...34Finite Element Method for Designing Plasma Reactors" Leo Kempel, Paul Rummel, Tim Grotjohn and John Amrhein...548 "lime-Domain Simulation of Electromagnetic Wave Propagation in a Magnetized Plasma" J. Paul , C. Christopoulos, and

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…

Counterinsurgency in West Africa: Non Lethal Activities

DTIC Science & Technology

2009-06-01

Michael S. Lewis Beck, Alan Bryman , Tim Futing Liao, The SAGE Encyclopedia of Social Science Research Methods , SAGE, 2004, California, USA.p.894. 11...Publishing, 1966. Michael S. Lewis Beck, Alan Bryman , Tim Futing Liao, The SAGE Encyclopedia of Social Science Research Methods , SAGE, 2004...conduct the research . Research Design The methodology that will be used in this thesis is a qualitative method using case studies. Qualitative research

Effect of preservative removal from fixed-combination bimatoprost/timolol on intraocular pressure lowering: a potential timolol dose–response phenomenon

PubMed Central

Shen, Jie; Bejanian, Marina

2016-01-01

Purpose Many patients with glaucoma require combination therapies to achieve target intraocular pressure (IOP) and preserve visual function. Ocular hypotensives often contain a preservative (eg, benzalkonium chloride [BAK]), but preservative-free (PF) formulations have been developed for patients with sensitivity. A Phase III study found the efficacy of bimatoprost 0.03%/timolol 0.5% (bim/tim, Ganfort®) PF to be equivalent to that of preserved bim/tim, although a trend favoring bim/tim PF was observed. As BAK is a corneal penetration enhancer, this literature review aims to explain these findings by exploring the relationship between timolol concentration and its IOP-lowering effect. Methods Systematic searches were performed in Scopus and PubMed for clinical trials published in English between 1960 and July 2014 using the keywords “timolol”, “intraocular pressure”, and the concentrations “1%, 0.5%, OR 0.25%”. Articles that directly compared IOP-lowering effects of ≥2 concentrations of timolol were identified by manual screening, and cross-checked for duplication. Results Seventeen studies that included 10–371 patients were evaluated; the majority were randomized (16/17), double-masked (14/17), and enrolled patients with open-angle glaucoma or ocular hypertension (12/17). All studies investigated timolol in preserved formulations. Timolol concentrations tested ranged from 0.008% to 1.5%. Of 13 studies comparing timolol 0.25% versus 0.5%, two found the 0.25% dose to have greater IOP-lowering effects, and three reported the opposite; eight reported similar IOP lowering. Results also indicate that timolol 0.5% may be more effective than higher concentrations. Conclusion The evidence suggests that timolol may have an inverted U-shaped dose–response curve, and that its optimal IOP-lowering concentration is between 0.25% and 0.5%. Compared with bim/tim, removal of the permeability enhancer BAK in bim/tim PF could have resulted in a lower timolol concentration at the target site, bringing the effective concentration within the 0.25%–0.5% range and enhancing the efficacy of bim/tim PF. PMID:27041984

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 on "Technology Roadmapping" and the delivery of the charge to the Work Breakout Sessions. Day three began with the eleven Work Breakout Session which was the major function of this TIM 2 and day three ended with reports by the Chairs of the eleven Work Breakdown Sessions. Day four began with the six Integrated Product Team OPT) meetings and ended with closing plenary panel sessions.

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. Copyright © 2015 Elsevier Inc. All rights reserved.

Alternative Splice Variants in TIM Barrel Proteins from Human Genome Correlate with the Structural and Evolutionary Modularity of this Versatile Protein Fold

PubMed Central

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 proteins encoded in the human genome. PMID:23950966

Flexible Learning Strategies in Higher and Further Education.

ERIC Educational Resources Information Center

Thomas, Diana, Ed.

This book contains 15 papers written by contributors from all areas of Great Britain in further and higher education. The following papers are included: "Learning to Be Flexible" (Diana Thomas); "Managing Change: Towards a New Paradigm?" (Mac Stephenson, Timothy Lehmann); "Open Learning: Educational Opportunity or…

ARC-2008-ACD08-0265-214

NASA Image and Video Library

2008-11-02

Airship Ventures Zeppelin Dedication during the Moffett Field Diamond Jubilee. New NRP Partner KleenSpeed Chairman Timothy Collins (l) with THRUXAR electric race car at the Nov. 21 Diamond Jubilee exhibits. KleenSpeed is an advanced R&D firm focusing on scalable electric propulsion systems for transportation

Community College Journal for Research and Planning.

ERIC Educational Resources Information Center

Carter, Edith H., Ed.

1981-01-01

This journal, designed as a forum for the exchange of ideas among research and planning professionals, offers articles of research studies and practices. After Timothy Lightfield highlights upcoming professional association events, Janice S. Ancarrow's article, "The National Vocational Education Data Reporting and Accounting System (VEDS): Its…

Scripps Ocean Modeling and Remote Sensing (SOMARS)

DTIC Science & Technology

1990-04-10

1990: Satellite derived estimates of the normal and tangential components of near-surface flow. Internat. J. Rem. Sens., submitted. Mr. Timothy ... Gallaudet - M.S,. in Oceanography/Applied Ocean Sciences (Naval student; not a terminal M.S. degree) Thesis Advisor: Topic will relate to AVIIRR analyses of

ASSESSING CONTAMINANT SENSITIVITY OF ENDANGERED AND THREATENED SPECIES: 3. EFFLUENT TOXICITY TESTS

EPA Science Inventory

Dwyer, F. James, Douglas K. Hardesty, Christopher E. Henke, Christopher G. Ingersoll, David W. Whites, Tom Augspurger, Timothy J. Canfield, David R. Mount and Foster L. Mayer. Submitted. Assessing Contaminant Sensitivity of Endangered and Threatened Species: 3. Effluent Tests. Ar...

Knowledge-Driven Design of Virtual Patient Simulations

ERIC Educational Resources Information Center

Vergara, Victor; Caudell, Thomas; Goldsmith, Timothy; Panaiotis; Alverson, Dale

2009-01-01

Virtual worlds provide unique opportunities for instructors to promote, study, and evaluate student learning and comprehension. In this article, Victor Vergara, Thomas Caudell, Timothy Goldsmith, Panaiotis, and Dale Alverson explore the advantages of using virtual reality environments to create simulations for medical students. Virtual simulations…

78 FR 41867 - Appliance Standards and Rulemaking Federal Advisory Committee: Notice of Open Teleconference/Webinar

Federal Register 2010, 2011, 2012, 2013, 2014

2013-07-12

...), Water Heating (WH), and Refrigeration Certification Working Group (Commercial Certification Group). The... possible, reach consensus on proposed certification requirements for commercial HVAC, WH, and refrigeration...-Conditioning, Heating and Refrigeration Institute) Timothy Ballo (EarthJustice) Jeff Bauman (National...

Canadian Association for University Continuing Education Conference Proceedings (Regina, Saskatchewan, Canada, June 10-13, 1992).

ERIC Educational Resources Information Center

Canadian Association for University Continuing Education, Ottawa (Ontario).

This document contains the following papers: "University Continuing Educators: Entrepreneurs or Social Activists" (Phyllis Cunningham); "Ambivalent Activists, Uneasy Enterprisers--and the Search for Truth" (Milton Stern); "Our Role as Change Agents" (Timothy Pyrch, Albert A. Einsiedel); "Entrepreneurial…

78 FR 72892 - Findings of Research Misconduct

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-04

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Office of the Secretary Findings of Research Misconduct... Research Integrity (ORI) has taken final action in the following case: Timothy Sheehy, B.A., BSc., SAIC-Frederick, Inc. FOR FURTHER INFORMATION CONTACT: David E. Wright, Ph.D., Director, Office of Research...

7 CFR 1436.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

... security interest in personal property when properly filed or recorded. Hay means a grass or legume that has been cut and stored. Commonly used grass mixtures include rye grass, timothy, brome, fescue, coastal Bermuda, orchard grass, and other native species, depending on the region. Forage legumes include...

7 CFR 1436.3 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

... security interest in personal property when properly filed or recorded. Hay means a grass or legume that has been cut and stored. Commonly used grass mixtures include rye grass, timothy, brome, fescue, coastal Bermuda, orchard grass, and other native species, depending on the region. Forage legumes include...

New Equipping Strategies for Combat Support Hospitals

DTIC Science & Technology

2010-01-01

Combat and Doctrine Development and COL Timothy Lamb , supported by MAJ Gary Cooper, included members of our team in visits to Sierra Army Depot and...aspect of improving materiel stew - ardship is improving the quality of data related to the procurement, maintenance, and upgrading of equipment

Counter Piracy: A Repeated Game with Asymmetric Information

DTIC Science & Technology

2009-09-01

Christopher D. Marsh Approved by: Kyle Y. Lin Thesis Advisor Timothy H. Chung Second Reader Robert F. Dell Chairman, Department of...encourage Malaysia and Indonesia to work with the Singapore Navy in coordinated patrols of the region. Increased cooperation in the region includes the

Effect of lignin content and subunit composition on digestibility in clones of timothy (Phleum pratense L.).

PubMed

Kärkönen, Anna; Tapanila, Tarja; Laakso, Tapio; Seppänen, Mervi M; Isolahti, Mika; Hyrkäs, Maarit; Virkajärvi, Perttu; Saranpää, Pekka

2014-07-02

Lignin amount and subunit composition were analyzed from stems and leaf sheaths of timothy (Phleum pratense L.) clones of different in vitro digestibility. Lignin concentration in stems and leaf sheaths was higher in clones of low digestibility than those of high digestibility. No change in lignin concentration occurred in stems as digestibility decreased. Intriguingly, the lignin concentration was lower and the syringyl/guaiacyl (S/G) ratio was higher in stems compared to leaf sheaths at all developmental stages studied. The developmental-associated decrease in digestibility correlated with the increase in S units in lignin in stems and leaf sheaths and in the amounts of p-coumaric acid and ferulic acid residues in the cell wall of stems. Yields of copper oxidation products increased in stems during maturation indicating qualitative changes in the lignin structure. This correlated strongly with the developmentally linked decrease in digestibility. The information obtained is valuable for breeding and for DNA marker development.

Chemically linked metal-matrix nanocomposites of boron nitride nanosheets and silver as thermal interface materials

DOE PAGES

Nagabandi, N.; Yegin, C.; Feng, X.; ...

2018-01-31

Herein, novel hybrid nanocomposite thermal interface materials (TIMs) relying on the chemical linkage of silver, boron nitride nanosheets (BNNSs), and organic ligands are reported. These TIMs were prepared using a co-electrodeposition/chemisorption approach where the electrolytic reduction of silver ions into silver nano-/micro-crystals was coupled with the conjugation of ligand-coated nanosheets onto silver crystals. Furthermore, the influence of bond strength of silver/nanosheet links on the thermal, mechanical, and structural properties is investigated using a combination of techniques; including laser flash analysis, phase-sensitive transient thermoreflectance, nanoindentation, and electron microscopy. Internal nanostructure was found to be strongly dependent on the linker chemistry. Whilemore » the chemical grafting of 4-cyano-benzoyl chloride (CBC) and 2-mercapto-5-benzimidazole carboxylic acid (MBCA) on BNNSs led to the uniform distribution of functionalized-nanosheets in the silver crystal matrix, the physical binding of 4-bromo-benzoyl chloride (BBC) linkers on nanosheets caused the aggregation and phase separation. The thermal conductivity was 236-258 W/m-K and 306-321 W/m-K for physically and chemically conjugated TIMs, respectively, while their hardness varied from 495 to 400 MPa and from 240 to 360 MPa, respectively. The corresponding ratio of thermal conductivity to hardness, which is a critical parameter controlling the performance of TIMs, was ultrahigh for the chemically conjugated TIMs: 1.3x10-6 m2/K-s for MBCA-BNNS and 8.5x10-7 m2/K-s for CBC-BNNS. We anticipate that these materials can satisfy some of the emerging thermal management needs arising from the improved performance and efficiency, miniaturization, and/or high throughput of electronic devices, energy storage devices, energy conversion systems, light-emitting diodes, and telecommunication components.« less

Elevated frequencies of CD8 T cells expressing PD-1, CTLA-4 and Tim-3 within tumour from perineural squamous cell carcinoma patients.

PubMed

Linedale, Richard; Schmidt, Campbell; King, Brigid T; Ganko, Annabelle G; Simpson, Fiona; Panizza, Benedict J; Leggatt, Graham R

2017-01-01

Perineural spread of tumour cells along cranial nerves is a severe complication of primary cutaneous squamous cell carcinomas of the head and neck region. While surgical excision of the tumour is the treatment of choice, removal of all the tumour is often complicated by the neural location and recurrence is frequent. Non-invasive immune treatments such as checkpoint inhibitor blockade may be useful in this set of tumours although little is understood about the immune response to perineural spread of squamous cell carcinomas. Immunohistochemistry studies suggest that perineural tumour contains a lymphocyte infiltrate but it is difficult to quantitate the different proportions of immune cell subsets and expression of checkpoint molecules such as PD-1, Tim-3 and CTLA-4. Using flow cytometry of excised perineural tumour tissue, we show that a T cell infiltrate is prominent in addition to less frequent B cell, NK cell and NKT cell infiltrates. CD8 T cells are more frequent than other T cells in the tumour tissue. Amongst CD8 T cells, the frequency of Tim-3, CTLA-4 and PD-1 expressing cells was significantly greater in the tumour relative to the blood, a pattern that was repeated for Tim-3, CTLA-4 and PD-1 amongst non-CD8 T cells. Using immunohistochemistry, PD-1 and PD-L1-expression could be detected in close proximity amongst perineural tumour tissue. The data suggest that perineural SCC contains a mixture of immune cells with a predominant T cell infiltrate containing CD8 T cells. Elevated frequencies of tumour-associated Tim-3+, CTLA-4+ and PD-1+ CD8 T cells suggests that a subset of patients may benefit from local antibody blockade of these checkpoint inhibitors.

Insights into the fold organization of TIM barrel from interaction energy based structure networks.

PubMed

Vijayabaskar, M S; Vishveshwara, Saraswathi

2012-01-01

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

Chemically linked metal-matrix nanocomposites of boron nitride nanosheets and silver as thermal interface materials.

PubMed

Nagabandi, N; Yegin, C; Feng, X; King, C; Oh, J K; Scholar, E A; Narumanchi, S; Akbulut, M

2018-03-09

Herein, novel hybrid nanocomposite thermal interface materials (TIMs) relying on the chemical linkage of silver, boron nitride nanosheets (BNNSs), and organic ligands are reported. These TIMs were prepared using a co-electrodeposition/chemisorption approach where the electrolytic reduction of silver ions into silver nano-/micro-crystals was coupled with the conjugation of ligand-coated nanosheets onto silver crystals. Furthermore, the influence of the bond strength of silver/nanosheet links on the thermal, mechanical, and structural properties is investigated using a combination of techniques including laser flash analysis, phase-sensitive transient thermoreflectance, nanoindentation, and electron microscopy. The internal nanostructure was found to be strongly dependent on the linker chemistry. While the chemical grafting of 4-cyano-benzoyl chloride (CBC) and 2-mercapto-5-benzimidazole carboxylic acid (MBCA) on BNNSs led to the uniform distribution of functionalized-nanosheets in the silver crystal matrix, the physical binding of 4-bromo-benzoyl chloride linkers on nanosheets caused the aggregation and phase separation. The thermal conductivity was 236-258 W m -1 K and 306-321 W m -1 K for physically and chemically conjugated TIMs, respectively, while their hardness varied from 400-495 MPa and from 240 to 360 MPa, respectively. The corresponding ratio of thermal conductivity to hardness, which is a critical parameter controlling the performance of TIMs, was ultrahigh for the chemically conjugated TIMs: 1.3 × 10 -6 m 2 K -1 s for MBCA-BNNS and 8.5 × 10 -7 m 2 K -1 s for CBC-BNNS. We anticipate that these materials can satisfy some of the emerging thermal management needs arising from the improved performance and efficiency, miniaturization, and/or high throughput of electronic devices, energy storage devices, energy conversion systems, light-emitting diodes, and telecommunication components.

Chemically linked metal-matrix nanocomposites of boron nitride nanosheets and silver as thermal interface materials

NASA Astrophysics Data System (ADS)

Nagabandi, N.; Yegin, C.; Feng, X.; King, C.; Oh, J. K.; Scholar, E. A.; Narumanchi, S.; Akbulut, M.

2018-03-01

Herein, novel hybrid nanocomposite thermal interface materials (TIMs) relying on the chemical linkage of silver, boron nitride nanosheets (BNNSs), and organic ligands are reported. These TIMs were prepared using a co-electrodeposition/chemisorption approach where the electrolytic reduction of silver ions into silver nano-/micro-crystals was coupled with the conjugation of ligand-coated nanosheets onto silver crystals. Furthermore, the influence of the bond strength of silver/nanosheet links on the thermal, mechanical, and structural properties is investigated using a combination of techniques including laser flash analysis, phase-sensitive transient thermoreflectance, nanoindentation, and electron microscopy. The internal nanostructure was found to be strongly dependent on the linker chemistry. While the chemical grafting of 4-cyano-benzoyl chloride (CBC) and 2-mercapto-5-benzimidazole carboxylic acid (MBCA) on BNNSs led to the uniform distribution of functionalized-nanosheets in the silver crystal matrix, the physical binding of 4-bromo-benzoyl chloride linkers on nanosheets caused the aggregation and phase separation. The thermal conductivity was 236-258 W m-1 K and 306-321 W m-1 K for physically and chemically conjugated TIMs, respectively, while their hardness varied from 400-495 MPa and from 240 to 360 MPa, respectively. The corresponding ratio of thermal conductivity to hardness, which is a critical parameter controlling the performance of TIMs, was ultrahigh for the chemically conjugated TIMs: 1.3 × 10-6 m2 K-1 s for MBCA-BNNS and 8.5 × 10-7 m2 K-1 s for CBC-BNNS. We anticipate that these materials can satisfy some of the emerging thermal management needs arising from the improved performance and efficiency, miniaturization, and/or high throughput of electronic devices, energy storage devices, energy conversion systems, light-emitting diodes, and telecommunication components.

HPTLC Fingerprint Analysis: A Quality Control for Authentication of Herbal Phytochemicals

NASA Astrophysics Data System (ADS)

Ram, Mauji; Abdin, M. Z.; Khan, M. A.; Jha, Prabhakar

Authentication and consistent quality are the basic requirement for Indian traditional medicine (TIM), Chinese traditional herbal medicine (TCHM), and their commercial products, regardless of the kind of research conducted to modernize the TIM and TCHM. The complexities of TIM and TCHM challenge the current official quality control mode, for which only a few biochemical markers were selected for identification and quantitative assay. Referring too many unknown factors existed in TIM and TCHM, it is impossible and unnecessary to pinpoint qualitatively and quantitatively every single component contained in the herbal drug. Chromatographic fingerprint is a rational option to meet the need for more effective and powerful quality assessment to TIM and TCHM. The optimized chromatographic fingerprint is not only an alternative analytical tool for authentication, but also an approach to express the various pattern of chemical ingredients distribution in the herbal drugs and preserve such "database" for further multifaced sustainable studies. Analytical separation techniques, for example, high-performance liquid chromatography (HPLC), gas chromatography (GC) and mass spectrometry (MS) were among the most popular methods of choice used for quality control of raw material and finished herbal product. Fingerprint analysis approach using high-performance thin-layer chromatography (HPTLC) has become the most potent tool for quality control of herbal medicines because of its simplicity and reliability. It can serve as a tool for identification, authentication, and quality control of herbal drugs. In this chapter, attempts are being made to expand the use of HPTLC and at the same time create interest among prospective researcher in herbal analysis. The developed method can be used as a quality control tool for rapid authentication from a wide variety of herbal samples. Some examples demonstrated the role of fingerprinting in quality control and assessment.

Chemically linked metal-matrix nanocomposites of boron nitride nanosheets and silver as thermal interface materials

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

Nagabandi, N.; Yegin, C.; Feng, X.

Herein, novel hybrid nanocomposite thermal interface materials (TIMs) relying on the chemical linkage of silver, boron nitride nanosheets (BNNSs), and organic ligands are reported. These TIMs were prepared using a co-electrodeposition/chemisorption approach where the electrolytic reduction of silver ions into silver nano-/micro-crystals was coupled with the conjugation of ligand-coated nanosheets onto silver crystals. Furthermore, the influence of bond strength of silver/nanosheet links on the thermal, mechanical, and structural properties is investigated using a combination of techniques; including laser flash analysis, phase-sensitive transient thermoreflectance, nanoindentation, and electron microscopy. Internal nanostructure was found to be strongly dependent on the linker chemistry. Whilemore » the chemical grafting of 4-cyano-benzoyl chloride (CBC) and 2-mercapto-5-benzimidazole carboxylic acid (MBCA) on BNNSs led to the uniform distribution of functionalized-nanosheets in the silver crystal matrix, the physical binding of 4-bromo-benzoyl chloride (BBC) linkers on nanosheets caused the aggregation and phase separation. The thermal conductivity was 236-258 W/m-K and 306-321 W/m-K for physically and chemically conjugated TIMs, respectively, while their hardness varied from 495 to 400 MPa and from 240 to 360 MPa, respectively. The corresponding ratio of thermal conductivity to hardness, which is a critical parameter controlling the performance of TIMs, was ultrahigh for the chemically conjugated TIMs: 1.3x10-6 m2/K-s for MBCA-BNNS and 8.5x10-7 m2/K-s for CBC-BNNS. We anticipate that these materials can satisfy some of the emerging thermal management needs arising from the improved performance and efficiency, miniaturization, and/or high throughput of electronic devices, energy storage devices, energy conversion systems, light-emitting diodes, and telecommunication components.« less

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.

GOES-S Prelaunch News Conference

NASA Image and Video Library

2018-02-27

GOES-S Prelaunch News Conference hosted by NASA Communications' Tori Mclendon, with Stephen Volz, Director for Satellite and Information Services, NOAA; Tim Walsh, GOES-R system program director (acting), NOAA; Sandra Smalley, Director, NASA Joint Agency Satellite Division; Tim Dunn, NASA Launch Director, Kennedy Space Center, Florida; Scott Messer, Program Manager, NASA Missions, United Launch Alliance; and Kathy Winters, Launch Weather Officer, 45th Weather Squadron, Cape Canaveral Air Force Station, Florida.

GUM Analysis for TIMS and SIMS Isotopic Ratios in Graphite

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

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

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.

An Ontological Approach to Developing Information Operations Applications for Use on the Semantic Web

DTIC Science & Technology

2008-09-01

IWPC 21 Berners - Lee , Tim . (1999). Weaving the Web. New York: HarperCollins Publishers, Inc. 22... Berners - Lee , Tim . (1999). Weaving the Web. New York: HarperCollins Publishers, Inc. Berners - Lee , T., Hendler, J., & Lassila, O. (2001). The Semantic...environment where software agents roaming from page to page can readily carry out sophisticated tasks for users. T. Berners - Lee , J. Hendler, and O

Multispectral thermal infrared mapping of sulfur dioxide plumes: A case study from the East Rift Zone of Kilauea Volcano, Hawaii

USGS Publications Warehouse

Realmuto, V.J.; Sutton, A.J.; Elias, T.

1997-01-01

The synoptic perspective and rapid mode of data acquisition provided by remote sensing are well suited for the study of volcanic SO2 plumes. In this paper we describe a plume-mapping procedure that is based on image data acquired with NASA's airborne thermal infrared multispectral scanner (TIMS) and apply the procedure to TIMS data collected over the East Rift Zone of Kilauea Volcano, Hawaii, on September 30, 1988. These image data covered the Pu'u 'O'o and Kupaianaha vents and a skylight in the lava tube that was draining the Kupaianaha lava pond. Our estimate of the SO2 emission rate from Pu'u 'O'o (17 - 20 kg s-1) is roughly twice the average of estimates derived from correlation spectrometer (COSPEC) measurements collected 10 days prior to the TIMS overflight (10 kg s-1). The agreement between the TIMS and COSPEC results improves when we compare SO2 burden estimates, which are relatively independent of wind speed. We demonstrate the feasibility of mapping Pu'u 'O'o - scale SO2 plumes from space in anticipation of the 1998 launch of the advanced spaceborne thermal emission and reflectance radiometer (ASTER). Copyright 1997 by the American Geophysical Union.

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

PubMed

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. Copyright © 2013 Elsevier Ltd. All rights reserved.

An AVHRR Cloud Classification Database Typed by Experts

DTIC Science & Technology

1993-10-01

analysis. Naval Research Laboratory, Monterey, CA. 110 pp. Gallaudet , Timothy C. and James J. Simpson, 1991: Automated cloud screening of AVHRR imagery...1987) and Saunders and Kriebel (1988a,b) have used threshold techniques to classify clouds. Gallaudet and Simpson (1991) have used split-and-merge

Workforce Diversity. Symposium 14. [Concurrent Symposium Session at AHRD Annual Conference, 2000.

ERIC Educational Resources Information Center

2000

Three presentations are provided from Symposium 14, Workforce Diversity, of the Academy of Human Resource Development (HRD) 2000 Conference Proceedings. "Cross-Organizational vs. Localized Participation: A Case Study on Workplace Diversity Dialogues Implementation" (Martin B. Kormanik, Daniel A. Krieger, Timothy E. Tilghman) compares…

DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS

EPA Science Inventory

DEVELOPMENT OF ADME DATA IN AGRICULTURAL CHEMICAL SAFETY ASSESSMENTS
Pastoor, Timothy1, Barton, Hugh2
1 Syngenta Crop Protection, Greensboro, NC, USA.
2 EPA, Office of Research and Development-NHEERL, RTP, NC, USA.

A multi-stakeholder series of discussions d...

76 FR 69793 - Qualification of Drivers; Exemption Applications; Vision

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-09

... Carlos R. Gonzalez Jerard David Menyhart Danny Michael Harris Kevin Palmer Moises P. Ibarra Jeffery O... Roscoe Brittain III Jerry M. Puckett Larry Dexter Georgia Marcum John Darr Kevin Menard Christopher Jax Charles Ray Brittain Kevin Robert Cowger Clifford Blaine Thompson Timothy Garland Kevin Barker The...

Self-reported acute health symptoms and exposure to companion animals#

EPA Science Inventory

Self-reported acute health symptoms and exposure to companion animalsWhitney S. Krueger1,2, Elizabeth D. Hilborn2, Timothy J. Wade21Oak Ridge Institute for Science and Education, Oak Ridge, Tennessee, USA2Environmental Public Health Division, Office of Research and Development, U...

The relationship between microbial DNA concentrations and swimming associated health effects at a tropical environment bathing beach

EPA Science Inventory

The relationship between microbial DNA concentrations and swimming associated health effects at a tropical environment bathing beach. Timothy 1. Wade, presenter. Co-authors: Alfred P. Dufour, Kristen Brenner, Rich Haugland, Larry Wymer, Elizabeth Sams Fecal indicator bacteria (F...

Astronaut Jack R. Lousma and family

NASA Image and Video Library

1971-12-01

S72-31432 (November 1972) --- Astronaut Jack R. Lousma poses for a family portrait with his wife, Gratia Kay, and their three children, left to right, Mary 4; Timothy, 9; and Matthew, 7. Lousma is the pilot for the Skylab 3 or second manned Skylab mission. Photo credit: NASA

40 CFR 180.34 - Tests on the amount of residue remaining.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., barley, oats, rice, rye (each in grain form). (25) Alfalfa, Bermuda grass, bluegrass, brome grass, clovers, cowpea hay, fescue, lespedeza, lupines, orchard grass, peanut hay, peavine hay, rye grass, soybean hay, sudan grass, timothy, and vetch. (26) Corn forage, sorghum forage. (27) Sugarcane, cane...

40 CFR 180.34 - Tests on the amount of residue remaining.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., barley, oats, rice, rye (each in grain form). (25) Alfalfa, Bermuda grass, bluegrass, brome grass, clovers, cowpea hay, fescue, lespedeza, lupines, orchard grass, peanut hay, peavine hay, rye grass, soybean hay, sudan grass, timothy, and vetch. (26) Corn forage, sorghum forage. (27) Sugarcane, cane...

403. Delineator Unknown May 2, 1933 STUDY FOR SUSPENSION TOWERS; ...

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

403. Delineator Unknown May 2, 1933 STUDY FOR SUSPENSION TOWERS; SAN FRANCISCO - OAKLAND BAY BRIDGE; TIMOTHY L. PFLUEGER, ARTHUR BROWN JR., JOHN J. DONOVAN; BOARD OF CONSULTING ARCHITECTS; SCHEME 2 - San Francisco Oakland Bay Bridge, Spanning San Francisco Bay, San Francisco, San Francisco County, CA

Gastrointestinal symptoms among swimmers following rain events at a beach impacted by urban runoff

EPA Science Inventory

Gastrointestinal symptoms among swimmers following rain events at a beach impacted by urban runoff Timothy J. Wade, Reagan R. Converse, Elizabeth A. Sams, Ann H. Williams, Edward Hudgens, Alfred P. Dufour Gastrointestinal symptoms among swimmers have been associated with fecal ...

Real-World Vehicle Emissions: A Summary of the Sixth Coordinating Research Council On-Road Vehicle Emissions Workshop.

PubMed

Cadle, Steven H; Gorse, Robert A; Belian, Timothy C; Lawson, Douglas R

1997-03-01

The Coordinating Research Council (CRC) has conducted a series of workshops on real-world vehicle emissions. This article summarizes findings from the most recent research regarding on-road emissions from mobile sources, presented at the CRC workshop held in March 1996. Among the topics discussed were efforts to improve and update emission models, results from field studies designed to understand the contribution of mobile sources to emission inventories, results from gas-and particle-phase emissions studies from in-use motor vehicles, and areas of future research. The Sixth Coordinating Research Council (CRC) On-Road Vehicle Emissions Workshop was held March 18-20, 1996, in San Diego, CA. More than 160 representatives from academia, industry, government, and consulting firms in the United States, Canada, and Europe participated in the three-day meeting. The objective of the Workshop was to present the most recent information from research programs on: mobile source contributions to the emission inventory emission factor models and activity data model comparison and development emission reduction programs new developments in remote sensing studies of on-road vehicle exhaust and non-tailpipe emissions off-cycle Federal Test Procedure (FTP) studies and revisions to the FTP particle emissions from the light- and heavy-duty fleets future research needs Nine sessions were devoted to vehicle emissions models, improvements to the emission inventory, on-road and tunnel studies, off-cycle emissions, non-tailpipe and diesel emissions, emission reduction programs, and remote sensing. Overall workshop coordination was provided by Timothy Belian and the CRC staff, with Steven Cadle and Robert Gorse serving as cochairmen. Individual session chairmen were Brent Bailey (National Renewable Energy Laboratory), Mark Carlock (California Air Resources Board), Harold Haskew (General Motors), Kenneth Knapp and Philip Lorang (U.S. Environmental Protection Agency), Douglas Lawson (Colorado State University), Alan Lloyd (Desert Research Institute), Robert Slott (Shell Oil), and Timothy Truex (University of California, Riverside). In addition, during the Workshop, Lesha Hrynchuk of the California Air Resources Board (CARB) presented a hands-on demonstration using the Internet to obtain motor vehicle emissions information from groups throughout the world. The complete Workshop proceedings are available from the Coordinating Research Council, 219 Perimeter Center Parkway, Atlanta, GA 30346; phone: (770) 396-3400; fax: (770) 396-3404. The following summarizes each session and includes a short synopsis of all the papers that were presented.

Induced pluripotent stem cell-derived neuron as a human model for testing environmentally induced developmental neurotoxicity

EPA Science Inventory

Induced pluripotent stem cell-derived neurons as a human model for testing environmentally induced developmental neurotoxicity Ingrid L. Druwe1, Timothy J. Shafer2, Kathleen Wallace2, Pablo Valdivia3 ,and William R. Mundy2. 1University of North Carolina, Curriculum in Toxicology...

78 FR 73898 - Operator Licensing Examination Standards for Power Reactors

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-09

... Reactors AGENCY: Nuclear Regulatory Commission. ACTION: Draft NUREG; request for comment. SUMMARY: The U.S..., Revision 10, ``Operator Licensing Examination Standards for Power Reactors.'' DATES: Submit comments [email protected] . Both of the Office of New Reactors; or Timothy Kolb, Office of Nuclear Reactor Regulation, U...

Installation Guidance for Centerline and Edgeline Rumble Strips in Narrow Pavements

DOT National Transportation Integrated Search

2017-09-01

Peter T. Savolainen (orcid.org/0000-0001-5767-9104); Anuj Sharma (orcid.org/0000-0001-5929-5120); Timothy P. Barrette (orcid.org/0000-0002- 7656-3454); Bijan Vafaei (orcid.org/0000-0002-9362-399X); and Trevor J. Kirsch (orcid.org/0000-0002-8163-1570)...

Timothy Silverman | NREL

Science.gov Websites

physical phenomena, PV package reliability, and outdoor PV performance. At NREL, he performs research in advanced concept PV modules. Dr. Silverman studies the performance and reliability of PV modules, including previously studied the degradation of solder joints in high-concentration PV and the outdoor performance of

ITTALKS: A Case Study in the Semantic Web and DAML

DTIC Science & Technology

2005-01-01

For example, a Centaurus room manager agent [26] could watch ITTALKS for events happening in a room for which it is responsible in order to enable...01), Montreal, Quebec, Canada, May 29 2001. [26] Lalana Kagal, Vlad Korolev, Harry Chen, Anupam Joshi, and Timothy Finin. Centaurus : A framework for

75 FR 19676 - Qualification of Drivers; Exemption Renewals; Vision

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-15

... exemptions for Lee A. Burke, Barton C. Caldara, Allan Darley, Robin S. England, Charles D. Grady, Richard Hailey, Jr., Robert V. Hodges, George R. Knavel, John R. Knott III, Timothy S. Miller, Roger D. Mollak... commercial motor vehicle (CMV) drivers. FOR FURTHER INFORMATION CONTACT: Dr. Mary D. Gunnels, Director...

75 FR 8184 - Qualification of Drivers; Exemption Applications; Vision

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-23

.... Burke, Barton C. Caldara, Allan Darley, Robin S. England, Charles D. Grady, Richard Hailey, Jr., Robert V. Hodges, George R. Knavel, John R. Knott, III, Timothy S. Miller, Roger D. Mollak, Edward D....regulations.gov . FOR FURTHER INFORMATION CONTACT: Dr. Mary D. Gunnels, Director, Medical Programs, (202) 366...

Integrating Reading and Language Arts.

ERIC Educational Resources Information Center

French, Michael P., Ed.; Elford, Shirley J., Ed.

1986-01-01

Integrating reading and language arts at all levels is the focus of this journal issue. The articles and their authors are as follows: "Reading and Writing: Close Relatives or Distant Cousins" (Kathryn A. Koch); "The Reading-Writing Relationship: Myths and Realities" (Timothy Shanahan); "The Classroom Teacher as an Action Researcher: Beginning…

Disciplinary Literacy: Just the FAQs

ERIC Educational Resources Information Center

Shanahan, Timothy; Shanahan, Cynthia

2017-01-01

One of the most misunderstood parts of the Common Core State Standards is the section on literacy standards for history/social studies, science, and technical subjects. To help reduce some of the lingering confusion about these disciplinary literacy standards, Timothy and Cynthia Shanahan offer responses to a number of Frequently Asked Questions.…

THE NATIONAL EPIDEMIOLOGICAL AND ENVIRONMENTAL ASSESSMENT OF RECREATIONAL WATERS: RESULTS FROM THE FIRST SUMMER OF FULL-SCALE STUDIES

EPA Science Inventory

The National Epidemiological and Environmental Assessment of Recreational Waters: Results from the first summer of full-scale studies. Timothy J. Wade, Rebecca L. Calderon, Elizabeth Sams, Kristen Brenner, Michael Beach, Ann H. Williams, Al Dufour.

Abstract

Introduc...

75 FR 27768 - Current Connection, LLC; Notice of Preliminary Permit Application Accepted for Filing and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-18

..., Motions To Intervene, and Competing Applications May 11, 2010. On March 30, 2010, Current Connection, LLC.... Applicant Contact: Timothy D. Smith, CEO, Current Connection, LLC, 1300 Rankin Drive, Troy, MI 48083; phone... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Project No. 13694-000] Current...

Institute for the Study of Human Capabilities: Summary Descriptions of Research for the Period December 1989 through September 1990

DTIC Science & Technology

1991-05-30

Gallaudet Univesity Hearing & Communication W. Neil Charman. Ph.D. University of Manchester Visual Sciences Institute of Science & Technology Paul M...Capabilities, Indiana University, Bloomington, IN. Formal properties of cognitive representations. Port, van Gelder Since September, 1990, Timothy van

Representing Control Knowledge as Abstract Task and Metarules.

DTIC Science & Technology

1985-04-01

Timothy Beckett, MD. Reed spent a year extending the original metarules and knowledge base as part of his MSAI practicum. The program was first presented...McGuinness 33 Kirkland St. University of Illinois Gallaudet College Cambridge, MA 02138 Champaign, IL 61801 800 Florida Avenue, N.E. . Washington, DC

A Contested Institutional Culture

ERIC Educational Resources Information Center

Morin, Stephanie A.

2010-01-01

The College of William and Mary (Williamsburg, Virginia) found itself at a crossroads in 2005. Their long-popular president Timothy J. Sullivan was retiring after 13 years at the helm of the world's second oldest institution of higher education (Petkofsky, 2004). Long known as a bastion of conservatism, William and Mary could now change their…

Cliché, Gossip, and Anecdote as Supervision Training

ERIC Educational Resources Information Center

Grealy, Liam

2016-01-01

This article expands on a co-authored project with Timothy Laurie on the practices and ethics of higher degree research (HDR) supervision (or advising): "What does good HDR supervision look like?" in contemporary universities. It connects that project with scholarship on the relevance of "common sense" to questions of…

Tapping the Power of Poetry

ERIC Educational Resources Information Center

Rasinski, Timothy

2014-01-01

"I have become increasingly convinced that poetry offers one of the best-and often most underused--resources for developing literacy foundations," writes Timothy Rasinski. Poetry and songs are typically short and easy to learn, provide opportunities for students to play with the sounds of language, and offer an engaging way to learn…

75 FR 49551 - Petition for Waiver of Compliance

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-13

... below. Docket Number FRA-1998-4821 Applicant: Mr. Timothy R. Luhm, Canadian National, Manager S&C, 17641 South Ashland Avenue, Homewood, Illinois 60430. The Canadian National (CN) seeks an extension for an... expire on April 25, 2011. In addition to the extension, CN requests that the allowable maximum authorized...

76 FR 37126 - Timothy J. Rosio: Debarment Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-24

..., in the Eastern District of California, Dr. Rosio received Botulinum Toxin Type A (TRI-toxin) from Toxin Research International (TRI), which had been shipped in interstate commerce, from Arizona to his clinic in the Eastern District of California. The TRI-toxin that he received was misbranded in that it...

AN UPDATE ON SOME ARSENIC PROGRAMS AT THE US EPA

EPA Science Inventory

An Update on Some Arsenic Projects at the United States

Environmental Protection Agency*

Charles O. Abernathy1, Michael Beringer2, Rebecca L Calderon3,

Timothy McMahon4 and Erik Winchester3

Offices of Science and Technology1, Solid Waste...

77 FR 18862 - Zhiwei Lin, M.D.; Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-28

... DEPARTMENT OF JUSTICE Drug Enforcement Administration [Docket No. 10-54] Zhiwei Lin, M.D.; Decision and Order On September 19, 2011, Administrative Law Judge (ALJ) Timothy D. Wing issued the....C. 824, of the CSA. Calvin Ramsey, 76 FR 20034, 20036 (2011) (other citations omitted); Brenton D...

76 FR 48897 - Sheryl Lavender, D.O. Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-09

... DEPARTMENT OF JUSTICE Drug Enforcement Administration [Docket No. 10-70] Sheryl Lavender, D.O. Decision and Order On October 28, 2010, Administrative Law Judge (ALJ) Timothy D. Wing, issued the attached..., I order that DEA Certificate of Registration, BL1667596, issued to Sheryl Lavender, D.O., be, and it...

76 FR 71370 - Silviu Ziscovici, M.D.; Decision and Order

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-17

... DEPARTMENT OF JUSTICE Drug Enforcement Administration [Docket No. 11-3] Silviu Ziscovici, M.D.; Decision and Order On December 10, 2010, Administrative Law Judge (ALJ) Timothy D. Wing, issued the... Certificate of Registration, BZ4692756, issued to Silviu Ziscovici, M.D., be, and it hereby is, revoked. I...

402. Delineator Unknown May 2, 1933 STUDY FOR SUSPENSION TOWERS; ...

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

402. Delineator Unknown May 2, 1933 STUDY FOR SUSPENSION TOWERS; SAN FRANCISCO - OAKLAND BAY BRIDGE; TIMOTHY L. PFLUEGER, ARTHUR BROWN JR., JOHN J. DONOVAN; BOARD OF CONSULTING ARCHITECTS; SCHEME 1A - San Francisco Oakland Bay Bridge, Spanning San Francisco Bay, San Francisco, San Francisco County, CA

School Law in Review, 2002.

ERIC Educational Resources Information Center

National School Boards Association, Alexandria, VA. Council of School Attorneys.

This is a compilation of presentations delivered at the National School Boards Association Council of School Attorneys' Annual School Law Seminar: (1) "Environmental Hazards for Urban Schools Facing the New Challenge" (Kelly Frels, Kevin A. Ewing, Timothy A. Wilkins, Jason B. Hutt); (2) "How Accommodating? High-Stakes Testing and Federal Laws That…

404. Delineator Unknown June 1, 1933 STUDY FOR TOP OF ...

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

404. Delineator Unknown June 1, 1933 STUDY FOR TOP OF SUSPENSION TOWERS; SAN FRANCISCO OAKLAND BAY BRIDGE; TIMOTHY L. PFLUEGER, ARTHUR BROWN JR., JOHN J. DONOVAN; BOARD OF CONSULTING ARCHITECTS; SCHEME 7-A - San Francisco Oakland Bay Bridge, Spanning San Francisco Bay, San Francisco, San Francisco County, CA

Design, Culture, and Aesthetics Come Together

ERIC Educational Resources Information Center

Crockett, Pamela

2007-01-01

In this article, the author talks about an international art fashion show at St. Timothy's School in Stevenson, Maryland, which provided opportunities for students to showcase what they did best, from design to research, to creative production, to modeling. According to Randy Stevens, Head of School, the project helped students think more deeply…

Validation of Biomarkers for Prostate Cancer Prognosis

DTIC Science & Technology

2013-10-01

mechanism at Stanford University of collating and shipping TMAs to participating sites, We have found shortcomings with the BLISS system and STMAD...quantitated. We have used this system for Ki67 (MIB1) staining and are about to adapt it for p27 staining. Dr. Tim Randolph in our team, in...results included in this Progress Report were generated at MDACC. 8) Dr. Tim Randolph has led the efforts on adjustments to the TACOMA scoring

Development of an Integrated Toxicity Assessment System for use in Operational Deployment and Materials Development

DTIC Science & Technology

2006-05-01

In addition to NBC concerns, there are issues in many current military settings for exposures to toxic industrial chemicals or materials (TICs or TIMs...Significant health issues caused by use of legacy chemicals have emphasized the need for more effective predication of chemical toxicity . This paper...current military settings for exposures to toxic industrial chemicals or materials (TICs or TIMs). Significant health issues caused by use of legacy

Prospects for TIM3-Targeted Antitumor Immunotherapy.

PubMed

Ngiow, Shin Foong; Teng, Michele W L; Smyth, Mark J

2011-11-01

New insights into the control of T-cell activation and proliferation have led to the identification of checkpoint proteins that either up- or downmodulate T-cell reactivity. Monoclonal antibody immunotherapies that are reactive with cytotoxic T lymphocyte antigen 4 or programmed death receptor 1 have shown promising therapeutic outcomes in mice and humans with established cancer, highlighting the fact that cancer immunotherapy using T-cell checkpoint inhibitors is one of the most promising new therapeutic approaches. T-cell immunoglobulin and mucin domain 3 (TIM3) is one of many similar inhibitory molecules that are gaining attention as targets, but it remains relatively poorly studied in oncology. This review discusses our recent probing of the mechanism of action of anti-TIM3 antibody against established spontaneous and experimental tumors in mice, in the context of the exciting possibility of rationally combining agents that promote tumor-specific T-cell activation, proliferation, effector function, and survival. ©2011 AACR.

Correlation of fitness landscapes from three orthologous TIM barrels originates from sequence and structure constraints

PubMed Central

Chan, Yvonne H.; Venev, Sergey V.; Zeldovich, Konstantin B.; Matthews, C. Robert

2017-01-01

Sequence divergence of orthologous proteins enables adaptation to environmental stresses and promotes evolution of novel functions. Limits on evolution imposed by constraints on sequence and structure were explored using a model TIM barrel protein, indole-3-glycerol phosphate synthase (IGPS). Fitness effects of point mutations in three phylogenetically divergent IGPS proteins during adaptation to temperature stress were probed by auxotrophic complementation of yeast with prokaryotic, thermophilic IGPS. Analysis of beneficial mutations pointed to an unexpected, long-range allosteric pathway towards the active site of the protein. Significant correlations between the fitness landscapes of distant orthologues implicate both sequence and structure as primary forces in defining the TIM barrel fitness landscape and suggest that fitness landscapes can be translocated in sequence space. Exploration of fitness landscapes in the context of a protein fold provides a strategy for elucidating the sequence-structure-fitness relationships in other common motifs. PMID:28262665

Theoretical predictor for candidate structure assignment from IMS data of biomolecule-related conformational space.

PubMed

Schenk, Emily R; Nau, Frederic; Fernandez-Lima, Francisco

2015-06-01

The ability to correlate experimental ion mobility data with candidate structures from theoretical modeling provides a powerful analytical and structural tool for the characterization of biomolecules. In the present paper, a theoretical workflow is described to generate and assign candidate structures for experimental trapped ion mobility and H/D exchange (HDX-TIMS-MS) data following molecular dynamics simulations and statistical filtering. The applicability of the theoretical predictor is illustrated for a peptide and protein example with multiple conformations and kinetic intermediates. The described methodology yields a low computational cost and a simple workflow by incorporating statistical filtering and molecular dynamics simulations. The workflow can be adapted to different IMS scenarios and CCS calculators for a more accurate description of the IMS experimental conditions. For the case of the HDX-TIMS-MS experiments, molecular dynamics in the "TIMS box" accounts for a better sampling of the molecular intermediates and local energy minima.

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.

Stable Chlorine Isotope Study: Application to Early Solar System Materials

NASA Technical Reports Server (NTRS)

Mala,ira. M/; Nyquist, L. E.; Reese, Y.; Shih, C-Y; Fujitani, T.; Okano, O.

2010-01-01

A significantly large mass fractionation between two stable chlorine isotopes is expected during planetary processes In addition, in view of the isotopic heterogeneity of other light elements, the chlorine isotopes can potentially be used as a tracer for the origins and evolutionary processes of early solar system materials. Due to analytical difficulties, however, current chlorine isotope studies on planetary materials are quite controversial among IRMS (gas source mass spectrometry) and/or TIMS (Thermal Ionization Mass Spectrometry) groups [i.e. 1-3]. Although a cross-calibration of IRMS and TIMS indicates that both techniques are sufficiently consistent with each other [4], some authors have claimed that the Cl-37/Cl-35 ratio of geological samples obtained by TIMS technique are, in general, misleadingly too high and variable compared to those of IRMS [3]. For example, almost no differences of Cl isotope composition were observed among mantle materials and carbonaceous meteorites by [3]. On the other hand, according to more recent IRMS work [2], significant Cl isotope variations are confirmed for mantle materials. Therefore, additional careful investigation of Cl isotope analyses are now required to confirm real chlorine isotope variations for planetary materials including carbonaceous chondrites [5]. A significantly large mass fractionation between two stable chlorine isotopes is expected during planetary processes In addition, in view of the isotopic heterogeneity of other light elements, the chlorine isotopes can potentially be used as a tracer for the origins and evolutionary processes of early solar system materials. Due to analytical difficulties, however, current chlorine isotope studies on planetary materials are quite controversial among IRMS (gas source mass spectrometry) and/or TIMS (Thermal Ionization Mass Spectrometry) groups [i.e. 1-3]. Although a cross-calibration of IRMS and TIMS indicates that both techniques are sufficiently consistent with each other [4], some authors have claimed that the 37Cl/35Cl ratio of geological samples obtained by TIMS technique are, in general, misleadingly too high and variable compared to those of IRMS [3]. For eample, almost no differences of Cl isotope composition were observed among mantle materials and carbonaceous meteorites by [3]. On the other hand, according to more recent IRMS work [2], significant Cl isotope variations are confirmed for mantle materials. Therefore, additional careful investigation of Cl isotope analyses are now required to confirm real chlorine isotope variations for planetary materials including carbonaceous chondrites [5]. In order to clarify the stable chlorine isotope features of early solar system materials, we have initiated development of the TIMS technique at NASA JSC applicable to analysis of small amounts of meteoritic and planetary materials. We report here the current status of chlorine isotope analysis at NASA JSC.

Enzyme architecture: the effect of replacement and deletion mutations of loop 6 on catalysis by triosephosphate isomerase.

PubMed

Zhai, Xiang; Go, Maybelle K; O'Donoghue, AnnMarie C; Amyes, Tina L; Pegan, Scott D; Wang, Yan; Loria, J Patrick; Mesecar, Andrew D; Richard, John P

2014-06-03

Two mutations of the phosphodianion gripper loop in chicken muscle triosephosphate isomerase (cTIM) were examined: (1) the loop deletion mutant (LDM) formed by removal of residues 170-173 [Pompliano, D. L., et al. (1990) Biochemistry 29, 3186-3194] and (2) the loop 6 replacement mutant (L6RM), in which the N-terminal hinge sequence of TIM from eukaryotes, 166-PXW-168 (X = L or V), is replaced by the sequence from archaea, 166-PPE-168. The X-ray crystal structure of the L6RM shows a large displacement of the side chain of E168 from that for W168 in wild-type cTIM. Solution nuclear magnetic resonance data show that the L6RM results in significant chemical shift changes in loop 6 and surrounding regions, and that the binding of glycerol 3-phosphate (G3P) results in chemical shift changes for nuclei at the active site of the L6RM that are smaller than those of wild-type cTIM. Interactions with loop 6 of the L6RM stabilize the enediolate intermediate toward the elimination reaction catalyzed by the LDM. The LDM and L6RM result in 800000- and 23000-fold decreases, respectively, in kcat/Km for isomerization of GAP. Saturation of the LDM, but not the L6RM, by substrate and inhibitor phosphoglycolate is detected by steady-state kinetic analyses. We propose, on the basis of a comparison of X-ray crystal structures for wild-type TIM and the L6RM, that ligands bind weakly to the L6RM because a large fraction of the ligand binding energy is utilized to overcome destabilizing electrostatic interactions between the side chains of E168 and E129 that are predicted to develop in the loop-closed enzyme. Similar normalized yields of DHAP, d-DHAP, and d-GAP are formed in LDM- and L6RM-catalyzed reactions of GAP in D2O. The smaller normalized 12-13% yield of DHAP and d-DHAP observed for the mutant cTIM-catalyzed reactions compared with the 79% yield of these products for wild-type cTIM suggests that these mutations impair the transfer of a proton from O-2 to O-1 at the initial enediolate phosphate intermediate. No products are detected for the LDM-catalyzed isomerization reactions in D2O of [1-(13)C]GA and HPi, but the L6RM-catalyzed reaction in the presence of 0.020 M dianion gives a 2% yield of the isomerization product [2-(13)C,2-(2)H]GA.

Real-Time Identification of Wheel Terrain Interaction Models for Enhanced Autonomous Vehicle Mobility

DTIC Science & Technology

2014-04-24

tim at io n Er ro r ( cm ) 0 2 4 6 8 10 Color Statistics Angelova...Color_Statistics_Error) / Average_Slip_Error Position Estimation Error: Global Pose Po si tio n Es tim at io n Er ro r ( cm ) 0 2 4 6 8 10 12 Color...get some kind of clearance for releasing pose and odometry data) collected at the following sites – Taylor, Gascola, Somerset, Fort Bliss and

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

Targeting Tim-1 to Circumvent Immune Tolerance in Prostate Cancer

DTIC Science & Technology

2012-09-01

findings that SIM2 is selectively expressed in PCa, that human HLA- A2.1–restricted SIM2 epitopes induce specific T cells in vivo, and that anti -SIM2...TAA, would include a vaccine in conjunction with biologic agents that are known to simultaneously augment antigen presentation by DCs and inhibit...such agents is the agonist antibody that targets TIM-1, a receptor expressed on lymphocytes and dendritic cells that enhances cytotoxic lymphocyte

Genetic control of hepatitis A severity and susceptibility to allergy

PubMed Central

Chatenoud, Lucienne; Bach, Jean-François

2011-01-01

Hepatitis A virus (HAV) usually results in asymptomatic infection or mild disease, but in a small subset of patients it can lead to severe disease and even liver failure. In this issue of the JCI, Kim et al. identify a polymorphism associated with this increased disease risk in the gene that encodes the HAV receptor — TIM1. Importantly, this TIM1 gene polymorphism protects from the development of atopic diseases in HAV-seropositive individuals. PMID:21339636

The Osmium Isotopic Composition of Tagish Lake and Other Chondrites, Implications for Late Terrestrial Planetary Accretion

NASA Technical Reports Server (NTRS)

Brandon, A. D.

2003-01-01

The goals of this investigation are twofold. First, obtain high-precision Os isotope measurements of Tagish Lake and other chondrites by TIMS. Second, measure Re, Os, Pt, and other HSE concentrations by isotope dilution using TIMS and ICPMS. These measurements will determine whether this meteorite does in fact represent C-chondrite material with timeintegrated elevated Re/Os and Pt/Os with the implications to late accretion material characteristics.

A Decision Framework for Enhancing Mobile Ad Hoc Network Stability and Security

DTIC Science & Technology

2008-06-01

www.selfless-security.org/papers/addendum.php#ivt, accessed: March 2008. [10] Berners - Lee , T., Hendler, J., and O. Lassila, "The Semantic Web," in...study under her mentorship. Professor Tim Levin consistently offered his time and expertise throughout my time at NPS. Watching and listening to...Senge, "Tests for Building Confidence in System Dynamics Models," in TIMS Studies in the Management Sciences, Vol. 14, pp. 209-228, 1980. [40

An Evidence-Based Review on Medicinal Plants Used as Insecticide and Insect Repellent in Traditional Iranian Medicine

PubMed Central

Cheraghi Niroumand, Mina; Farzaei, Mohammad Hosein; Karimpour Razkenari, Elahe; Amin, Gholamreza; Khanavi, Mahnaz; Akbarzadeh, Tahmineh; Shams-Ardekani, Mohammad Reza

2016-01-01

Context Insects can be the cause of major ecological problems; they can transmit microbes and parasites that affect humans, and damage food crops, trees, and homes. The total economic cost of insect-related damage and disease is immeasurable. In traditional Iranian medicine (TIM), several medicinal plants have been identified as insecticides or insect repellents, but many of them are still unknown. Therefore, the aim of this study was to review the insecticidal or insect repellent activity of certain medicinal plants described in TIM. Evidence Acquisition Information about medicinal plants proposed as insecticides and insect repellents in the TIM was collected from the TIM literature, and searched in modern medical databases to find studies that confirmed their efficacy. Results Modern investigations have supported the claims of the insecticidal activity of several plants, including Allium sativum, Artemisia absinthium, Citrullus colocynthis, Laurus nobilis, Mentha pulegium, Myrtus communis, Nerium oleander, Ocimum basilicum, and Origanum majorana. However, in the cases of plants like Iris florentina and Malva sylvestris, there is not enough evidence in modern medicine to prove their effectiveness with regard to their insecticidal and insect repellent activities. Conclusions This study confirmed the Iranian traditional medicine claims of the insecticidal and insect repellent activity of certain plants. Further pharmacological and clinical studies are recommended to evaluate the overall efficacy and possible mechanisms underlying these herbs. PMID:27186389

An Evidence-Based Review on Medicinal Plants Used as Insecticide and Insect Repellent in Traditional Iranian Medicine.

PubMed

Cheraghi Niroumand, Mina; Farzaei, Mohammad Hosein; Karimpour Razkenari, Elahe; Amin, Gholamreza; Khanavi, Mahnaz; Akbarzadeh, Tahmineh; Shams-Ardekani, Mohammad Reza

2016-02-01

Insects can be the cause of major ecological problems; they can transmit microbes and parasites that affect humans, and damage food crops, trees, and homes. The total economic cost of insect-related damage and disease is immeasurable. In traditional Iranian medicine (TIM), several medicinal plants have been identified as insecticides or insect repellents, but many of them are still unknown. Therefore, the aim of this study was to review the insecticidal or insect repellent activity of certain medicinal plants described in TIM. Information about medicinal plants proposed as insecticides and insect repellents in the TIM was collected from the TIM literature, and searched in modern medical databases to find studies that confirmed their efficacy. Modern investigations have supported the claims of the insecticidal activity of several plants, including Allium sativum, Artemisia absinthium, Citrullus colocynthis, Laurus nobilis, Mentha pulegium, Myrtus communis, Nerium oleander, Ocimum basilicum, and Origanum majorana. However, in the cases of plants like Iris florentina and Malva sylvestris, there is not enough evidence in modern medicine to prove their effectiveness with regard to their insecticidal and insect repellent activities. This study confirmed the Iranian traditional medicine claims of the insecticidal and insect repellent activity of certain plants. Further pharmacological and clinical studies are recommended to evaluate the overall efficacy and possible mechanisms underlying these herbs.

The expression patterns of the clock genes period and timeless are affected by photoperiod in the Mediterranean corn stalk borer, Sesamia nonagrioides.

PubMed

Kontogiannatos, Dimitrios; Gkouvitsas, Theodoros; Kourti, Anna

2017-01-01

To obtain clues to the link between the molecular mechanism of circadian and photoperiod clocks, we cloned two circadian clock genes, period (per) and timeless (tim) from the moth Sesamia nonagrioides, which undergoes facultative diapause controlled by photoperiod. Sequence analysis revealed a high degree of conservation among the compared insects fοr both genes. We also investigated the expression patterns of per and tim in brains of larvae growing under 16L:8D (long days), constant darkness (DD) and 10L:14D (short days) conditions by qPCR assays. The results showed that mRNA accumulations encoding both genes exhibited diel oscillations under different photoperiods. The oscillation of per and tim mRNA, under short-day photoperiod differed from long-day. The difference between long-day and short-day conditions in the pattern of mRNA levels of per and tim appears to distinguish photoperiodic conditions clearly and both genes were influenced by photoperiod in different ways. We infer that not all photoperiodic clocks of insects interact with circadian clocks in the same fashion. Our results suggest that transcriptional regulations of the both clock genes act in the diapause programing in S. nonagrioides. The expression patterns of these genes are affected by photoperiod but runs with 24 h by entrainment to daily environmental cues. © 2016 Wiley Periodicals, Inc.

A 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% versus each of its individual preservative-free components.

PubMed

Pfeiffer, Norbert; Traverso, Carlo E; Lorenz, Katrin; Saarela, Ville; Liinamaa, Johanna; Uusitalo, Hannu; Astakhov, Yury; Boiko, Ernest; Ropo, Auli

2014-12-01

The efficacy, safety and tolerability of the preservative-free (PF) fixed combination (FC) of tafluprost 0.0015% and timolol 0.5% (once daily) were compared to those of the individual components (PF tafluprost 0.0015% once daily and PF timolol 0.5% twice daily) in patients with open-angle glaucoma or ocular hypertension inadequately controlled on prior timolol or prostaglandin monotherapy for 6 months. A stratified, double-masked, randomized, multicenter phase III study was conducted. A total of 189 prior timolol users were randomized within the timolol stratum (TS) to receive either FC (n = 95) or timolol 0.5% (TIM; n = 94). Furthermore, a total of 375 prior prostaglandin analog (PGA) users were randomized within the prostaglandin stratum (PS) to receive either FC (n = 188) or tafluprost 0.0015% (TAF; n = 187). To be eligible for participation in the study, the patients were required to have an intraocular pressure (IOP) of ≥22 mmHg when on timolol (TIM) or of ≥20 mmHg when on PGA in either treated eye at the screening and end-of-run-in visits. In addition to these, the study included visits at baseline, 2 and 6 weeks, 3 and 6 months and at a post-study visit. IOP was measured at 8 a.m., 10 a.m., 4 p.m., and 8 p.m. In the TS, a significant reduction from baseline IOP was seen with FC and TIM throughout the study. Average diurnal IOP change from baseline at month 3 was -8.55 mmHg (32%) for FC and -7.35 mmHg (28%) for TIM. The model-based treatment difference (FC-TIM) was -0.885 mmHg [95% confidence interval (CI) -1.745 to -0.024; p = 0.044] demonstrating the superiority of FC over TIM. In the PS, a significant reduction in IOP was seen with both FC and TAF throughout the study. The average diurnal IOP change from baseline at month 3 was -8.61 mmHg (33%) for FC and -7.23 mmHg (28%) for TAF. The model-based treatment difference (FC-TAF) was -1.516 mmHg (95% CI -2.044 to -0.988; p < 0.001) demonstrating the superiority of FC over TAF. In the TS, related ocular adverse events (AEs) were more frequent for patients treated with FC compared to TIM (16.8% versus 6.4%), whereas related non-ocular AEs were more frequent with TIM compared to FC (2.1% versus 0.0%). In the PS, AEs were similarly distributed between FC and TAF. The frequency of conjunctival hyperemia of FC was low (6.4%). The preservative-free fixed combination of tafluprost and timolol provided a substantial and significant IOP reduction in both strata. The IOP reduction was superior to both tafluprost 0.0015% and timolol 0.5% when given as monotherapies. Overall, the study treatments were safe and well tolerated. Santen Oy, Tampere, Finland.

Professor Tim de Zeeuw Takes Up Duty as New ESO Director General

NASA Astrophysics Data System (ADS)

2007-09-01

On 1 September, Tim de Zeeuw became the new ESO Director General, succeeding Catherine Cesarsky. In his first day in office, he kindly agreed to answer a few questions. ESO PR Photo 38/07 ESO PR Video 38/07 Watch the Video! How would you describe the current period for astronomy? Tim de Zeeuw: We are in an extremely exciting time for astronomy and I think this is understood worldwide and not just by astronomers. The technology is now available to look not only at the farthest objects in the Universe, where the light left a long time ago, allowing us to see how the Universe evolved and developed, but we can even detect signatures of planets around other stars, and that answers an age-old question which is a fundamental question in all of science, and really excites the general public. How do you see the role of ESO in this context? Tim de Zeeuw: ESO has a very important role in the context of European and worldwide astronomy because it is one of the leading organisations for ground-based astronomy. You may even say it is the pre-eminent organisation. Therefore, we have both an opportunity and a responsibility to lead the further developments in astronomy. Where do you see ESO developing in the coming years? Tim de Zeeuw: I see three main goals for ESO in the coming years. The first one is to get the best possible science out of the Very Large Telescope, the interferometer and the survey telescopes, all of them on Paranal. The second is to build ALMA, the new observatory at 5 000 metres in the high Andes. Together with our North American and East Asian partners, we need to deliver this on budget and on time, and prepare the European astronomers for leading the science. The third main goal is to design a world-leading Extremely Large Telescope (ELT), which may have a main mirror with a diameter larger than 40 metres and will enable wonderful science. And of course, we don't only want to design it, we also want to construct it. And what about La Silla? Tim de Zeeuw: La Silla is the cornerstone of the existence of ESO in Chile, and it is home to some wonderful telescopes, including the one that is discovering so many exoplanets. I see no reason why this could not continue for many years into the future. And on top of that, La Silla is one of the potential sites for the future ELT. What made you take up this position? Tim de Zeeuw: I took up this position because ESO is the most exciting astronomy organisation in the world, with highly qualified staff and long-term and stable support by the member countries. It will be a pleasure and a privilege to come and work here. What will you do in your first days in office? Tim de Zeeuw: First, I will further familiarise myself with the organisation but then I will very quickly travel to Chile. After all, the crown jewels of ESO are in Chile and it is very important that I meet not only the ESO staff in Chile, but also the Chilean astronomers and authorities.

The Role of LAT in Increased CD8+ T Cell Exhaustion in Trigeminal Ganglia of Mice Latently Infected with Herpes Simplex Virus 1▿

PubMed Central

Allen, Sariah J.; Hamrah, Pedram; Gate, David; Mott, Kevin R.; Mantopoulos, Dimosthenis; Zheng, Lixin; Town, Terrence; Jones, Clinton; von Andrian, Ulrich H.; Freeman, Gordon J.; Sharpe, Arlene H.; BenMohamed, Lbachir; Ahmed, Rafi; Wechsler, Steven L.; Ghiasi, Homayon

2011-01-01

Herpes simplex virus (HSV) infection is a classic example of latent viral infection in humans and experimental animal models. The HSV-1 latency-associated transcript (LAT) plays a major role in the HSV-1 latency reactivation cycle and thus in recurrent disease. Whether the presence of LAT leads to generation of dysfunctional T cell responses in the trigeminal ganglia (TG) of latently infected mice is not known. To address this issue, we used LAT-positive [LAT(+)] and LAT-deficient [LAT(−)] viruses to evaluate the effect of LAT on CD8 T cell exhaustion in TG of latently infected mice. The amount of latency as determined by quantitative reverse transcription-PCR (qRT-PCR) of viral DNA in total TG extracts was 3-fold higher with LAT(+) than with LAT(−) virus. LAT expression and increased latency correlated with increased mRNA levels of CD8, PD-1, and Tim-3. PD-1 is both a marker for exhaustion and a primary factor leading to exhaustion, and Tim-3 can also contribute to exhaustion. These results suggested that LAT(+) TG contain both more CD8+ T cells and more CD8+ T cells expressing the exhaustion markers PD-1 and Tim-3. This was confirmed by flow cytometry analyses of expression of CD3/CD8/PD-1/Tim-3, HSV-1, CD8+ T cell pentamer (specific for a peptide derived from residues 498 to 505 of glycoprotein B [gB498–505]), interleukin-2 (IL-2), and tumor necrosis factor alpha (TNF-α). The functional significance of PD-1 and its ligands in HSV-1 latency was demonstrated by the significantly reduced amount of HSV-1 latency in PD-1- and PD-L1-deficient mice. Together, these results may suggest that both PD-1 and Tim-3 are mediators of CD8+ T cell exhaustion and latency in HSV-1 infection. PMID:21307196

Creation of active TIM barrel enzymes through genetic fusion of half-barrel domain constructs derived from two distantly related glycosyl hydrolases.

PubMed

Sharma, Prerna; Kaila, Pallavi; Guptasarma, Purnananda

2016-12-01

Diverse unrelated enzymes that adopt the beta/alpha (or TIM) barrel topology display similar arrangements of beta/alpha units placed in a radial eight-fold symmetry around the barrel's axis. The TIM barrel was originally thought to be a single structural domain; however, it is now thought that TIM barrels arose from duplication and fusion of smaller half-barrels consisting of four beta/alpha units. We describe here the design, expression and purification, as well as characterization of folding, activity and stability, of chimeras of two TIM barrel glycosyl hydrolases, made by fusing different half-barrel domains derived from an endoglucanase from Clostridium cellulolyticum, CelCCA and a beta-glucosidase from Pyrococcus furiosus, CelB. We show that after refolding following purification from inclusion bodies, the two half-barrel fusion chimeras (CelCCACelB and CelBCelCCA) display catalytic activity although they assemble into large soluble oligomeric aggregated species containing chains of mixed beta and alpha structure. CelBCelCCA displays hyperthermophile-like structural stability as well as significant stability to chemical denaturation (C m of 2.6 m guanidinium hydrochloride), whereas CelCCACelB displays mesophile-like stability (T m of ~ 71 °C). The endoglucanase activities of both chimeras are an order of magnitude lower than those of CelB or CelCCA, whereas the beta-glucosidase activity of CelBCelCCA is about two orders of magnitude lower than that of CelB. The chimera CelCCACelB shows no beta-glucosidase activity. Our results demonstrate that half-barrel domains from unrelated sources can fold, assemble and function, with scope for improvement. Pyrococcus furiosus beta-glucosidase (CelB, EC: 3.2.1.21). Clostridium cellulolyticum endoglucanase A (CelCCA, EC: 3.2.1.4). © 2016 Federation of European Biochemical Societies.

Role of Loop-Clamping Side Chains in Catalysis by Triosephosphate Isomerase.

PubMed

Zhai, Xiang; Amyes, Tina L; Richard, John P

2015-12-09

The side chains of Y208 and S211 from loop 7 of triosephosphate isomerase (TIM) form hydrogen bonds to backbone amides and carbonyls from loop 6 to stabilize the caged enzyme-substrate complex. The effect of seven mutations [Y208T, Y208S, Y208A, Y208F, S211G, S211A, Y208T/S211G] on the kinetic parameters for TIM catalyzed reactions of the whole substrates dihydroxyacetone phosphate and d-glyceraldehyde 3-phosphate [(k(cat)/K(m))(GAP) and (k(cat)/K(m))DHAP] and of the substrate pieces glycolaldehyde and phosphite dianion (k(cat)/K(HPi)K(GA)) are reported. The linear logarithmic correlation between these kinetic parameters, with slope of 1.04 ± 0.03, shows that most mutations of TIM result in an identical change in the activation barriers for the catalyzed reactions of whole substrate and substrate pieces, so that the transition states for these reactions are stabilized by similar interactions with the protein catalyst. The second linear logarithmic correlation [slope = 0.53 ± 0.16] between k(cat) for isomerization of GAP and K(d)(⧧) for phosphite dianion binding to the transition state for wildtype and many mutant TIM-catalyzed reactions of substrate pieces shows that ca. 50% of the wildtype TIM dianion binding energy, eliminated by these mutations, is expressed at the wildtype Michaelis complex, and ca. 50% is only expressed at the wildtype transition state. Negative deviations from this correlation are observed when the mutation results in a decrease in enzyme reactivity at the catalytic site. The main effect of Y208T, Y208S, and Y208A mutations is to cause a reduction in the total intrinsic dianion binding energy, but the effect of Y208F extends to the catalytic site.

Coalition Warfare Program Tactile Situation Awareness System for Aviation Applications: Simulator Flight Test

DTIC Science & Technology

2015-12-01

David Myers1 Timothy Gowen2 Angus Rupert3 Ben Lawson3 Justin Dailey3,4 1Chesapeake Technology International 2Naval Aviation Center for... Angus Rupert of the USAARL. The algorithm is described in “Configuration Parameters for the Tactile Situation Awareness System (TSAS)” dated July 2010

Commentary: Reflecting on and Navigating Projects in Humanization

ERIC Educational Resources Information Center

Lee, Carol D.

2017-01-01

Timothy San Pedro and Valerie Kinloch are among a powerful cohort of scholars who are pushing the ontological boundaries surrounding how we think about the conduct of educational research. A longstanding tension in the history of educational research has been conceptualizations of the goal of such work as discovering foundational principles about…

77 FR 1019 - Renewable Energy Alternate Uses of Existing Facilities on the Outer Continental Shelf-Acquire a...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-09

...-0045] RIN 1010-AD79 Renewable Energy Alternate Uses of Existing Facilities on the Outer Continental... rule related to acquiring a lease non-competitively for offshore renewable energy projects. DATES... or Timothy Redding, Renewable Energy, BOEM, at (703) 787-1219 or email [email protected