Ultracompliant Heterogeneous Copper-Tin Nanowire Arrays Making a Supersolder.

PubMed

Gong, Wei; Li, Pengfei; Zhang, Yunheng; Feng, Xuhui; Major, Joshua; DeVoto, Douglas; Paret, Paul; King, Charles; Narumanchi, Sreekant; Shen, Sheng

2018-06-13

Due to the substantial increase in power density, thermal interface resistance that can constitute more than 50% of the total thermal resistance has generally become a bottleneck for thermal management in electronics. However, conventional thermal interface materials (TIMs) such as solder, epoxy, gel, and grease cannot fulfill the requirements of electronics for high-power and long-term operation. Here, we demonstrate a high-performance TIM consisting of a heterogeneous copper-tin nanowire array, which we term "supersolder" to emulate the role of conventional solders in bonding various surfaces. The supersolder is ultracompliant with a shear modulus 2-3 orders of magnitude lower than traditional solders and can reduce the thermal resistance by two times as compared with the state-of-the-art TIMs. This supersolder also exhibits excellent long-term reliability with >1200 thermal cycles over a wide temperature range. By resolving this critical thermal bottleneck, the supersolder enables electronic systems, ranging from microelectronics and portable electronics to massive data centers, to operate at lower temperatures with higher power density and reliability.

Thermal management and prototype testing of Compton scattering X-ray beam position monitor for the Advanced Photon Source Upgrade

NASA Astrophysics Data System (ADS)

Lee, S. H.; Yang, B. X.; Collins, J. T.; Ramanathan, M.

2017-02-01

Accurate and stable x-ray beam position monitors (XBPMs) are key elements in obtaining the desired user beam stability in the Advanced Photon Source Upgrade. In the next-generation XBPMs for the canted-undulator front ends, where two undulator beams are separated by 1.0 mrad, the lower beam power (<10 kW) per undulator allows us to explore lower-cost solutions based on Compton scattering from a diamond placed edge-on to the x-ray beam. Because of the high peak power density of the x-ray beams, this diamond experiences high temperatures and has to be clamped to a water-cooled heat spreader using thermal interface materials (TIMs), which play a key role in reducing the temperature of the diamond. To evaluate temperature changes through the interface via thermal simulations, the thermal contact resistance (TCR) of TIMs at an interface between two solid materials under even contact pressure must be known. This paper addresses the TCR measurements of several TIMs, including gold, silver, pyrolytic graphite sheet, and 3D graphene foam. In addition, a prototype of a Compton-scattering XBPM with diamond blades was installed at APS Beamline 24-ID-A in May 2015 and has been tested. This paper presents the design of the Compton-scattering XBPM, and compares thermal simulation results obtained for the diamond blade of this XBPM by the finite element method with in situ empirical measurements obtained by using reliable infrared technology.

Thermal management and prototype testing of Compton scattering X-ray beam position monitor for the Advanced Photon Source Upgrade.

PubMed

Lee, S H; Yang, B X; Collins, J T; Ramanathan, M

2017-02-01

Accurate and stable x-ray beam position monitors (XBPMs) are key elements in obtaining the desired user beam stability in the Advanced Photon Source Upgrade. In the next-generation XBPMs for the canted-undulator front ends, where two undulator beams are separated by 1.0 mrad, the lower beam power (<10 kW) per undulator allows us to explore lower-cost solutions based on Compton scattering from a diamond placed edge-on to the x-ray beam. Because of the high peak power density of the x-ray beams, this diamond experiences high temperatures and has to be clamped to a water-cooled heat spreader using thermal interface materials (TIMs), which play a key role in reducing the temperature of the diamond. To evaluate temperature changes through the interface via thermal simulations, the thermal contact resistance (TCR) of TIMs at an interface between two solid materials under even contact pressure must be known. This paper addresses the TCR measurements of several TIMs, including gold, silver, pyrolytic graphite sheet, and 3D graphene foam. In addition, a prototype of a Compton-scattering XBPM with diamond blades was installed at APS Beamline 24-ID-A in May 2015 and has been tested. This paper presents the design of the Compton-scattering XBPM, and compares thermal simulation results obtained for the diamond blade of this XBPM by the finite element method with in situ empirical measurements obtained by using reliable infrared technology.

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.

Ultracompliant Heterogeneous Copper-Tin Nanowire Arrays Making a Supersolder

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

Narumanchi, Sreekant V; Feng, Xuhui; Major, Joshua

Due to the substantial increase in power density, thermal interface resistance that can constitute more than 50% of the total thermal resistance has generally become a bottleneck for thermal management in electronics. However, conventional thermal interface materials (TIMs) such as solder, epoxy, gel, and grease cannot fulfill the requirements of electronics for high-power and long-term operation. Here, we demonstrate a high-performance TIM consisting of a heterogeneous copper-tin nanowire array, which we term 'supersolder' to emulate the role of conventional solders in bonding various surfaces. The supersolder is ultracompliant with a shear modulus 2-3 orders of magnitude lower than traditional soldersmore » and can reduce the thermal resistance by two times as compared with the state-of-the-art TIMs. This supersolder also exhibits excellent long-term reliability with >1200 thermal cycles over a wide temperature range. By resolving this critical thermal bottleneck, the supersolder enables electronic systems, ranging from microelectronics and portable electronics to massive data centers, to operate at lower temperatures with higher power density and reliability.« less

Thermal management and prototype testing of Compton scattering X-ray beam position monitor for the Advanced Photon Source Upgrade

DOE PAGES

Lee, S. H.; Yang, B. X.; Collins, J. T.; ...

2017-02-07

Accurate and stable x-ray beam position monitors (XBPMs) are key elements in obtaining the desired user beam stability in the Advanced Photon Source Upgrade. In the next-generation XBPMs for the canted-undulator front ends, where two undulator beams are separated by 1.0 mrad, the lower beam power (<10 kW) per undulator allows us to explore lower-cost solutions based on Compton scattering from a diamond placed edge-on to the x-ray beam. Because of the high peak power density of the x-ray beams, this diamond experiences high temperatures and has to be clamped to a water-cooled heat spreader using thermal interface materials (TIMs),more » which play a key role in reducing the temperature of the diamond. To evaluate temperature changes through the interface via thermal simulations, the thermal contact resistance (TCR) of TIMs at an interface between two solid materials under even contact pressure must be known. This paper addresses the TCR measurements of several TIMs, including gold, silver, pyrolytic graphite sheet, and 3D graphene foam. In addition, a prototype of a Compton-scattering XBPM with diamond blades was installed at APS Beamline 24-ID-A in May 2015 and has been tested. This study presents the design of the Compton-scattering XBPM, and compares thermal simulation results obtained for the diamond blade of this XBPM by the finite element method with in situ empirical measurements obtained by using reliable infrared technology.« less

Remarkably enhanced thermal transport based on a flexible horizontally-aligned carbon nanotube array film

PubMed Central

Qiu, Lin; Wang, Xiaotian; Su, Guoping; Tang, Dawei; Zheng, Xinghua; Zhu, Jie; Wang, Zhiguo; Norris, Pamela M.; Bradford, Philip D.; Zhu, Yuntian

2016-01-01

It has been more than a decade since the thermal conductivity of vertically aligned carbon nanotube (VACNT) arrays was reported possible to exceed that of the best thermal greases or phase change materials by an order of magnitude. Despite tremendous prospects as a thermal interface material (TIM), results were discouraging for practical applications. The primary reason is the large thermal contact resistance between the CNT tips and the heat sink. Here we report a simultaneous sevenfold increase in in-plane thermal conductivity and a fourfold reduction in the thermal contact resistance at the flexible CNT-SiO2 coated heat sink interface by coupling the CNTs with orderly physical overlapping along the horizontal direction through an engineering approach (shear pressing). The removal of empty space rapidly increases the density of transport channels, and the replacement of the fine CNT tips with their cylindrical surface insures intimate contact at CNT-SiO2 interface. Our results suggest horizontally aligned CNT arrays exhibit remarkably enhanced in-plane thermal conductivity and reduced out-of-plane thermal conductivity and thermal contact resistance. This novel structure makes CNT film promising for applications in chip-level heat dissipation. Besides TIM, it also provides for a solution to anisotropic heat spreader which is significant for eliminating hot spots. PMID:26880221

Reliability of emerging bonded interface materials for large-area attachments

DOE PAGES

Paret, Paul P.; DeVoto, Douglas J.; Narumanchi, Sreekant

2015-12-30

In this study, conventional thermal interface materials (TIMs), such as greases, gels, and phase change materials, pose bottlenecks to heat removal and have long caused reliability issues in automotive power electronics packages. Bonded interface materials (BIMs) with superior thermal performance have the potential to be a replacement to the conventional TIMs. However, due to coefficient of thermal expansion mismatches between different components in a package and resultant thermomechanical stresses, fractures or delamination could occur, causing serious reliability concerns. These defects manifest themselves in increased thermal resistance in the package. In this paper, the results of reliability evaluation of emerging BIMsmore » for large-area attachments in power electronics packaging are reported. Thermoplastic (polyamide) adhesive with embedded near-vertical-aligned carbon fibers, sintered silver, and conventional lead solder (Sn 63Pb 37) materials were bonded between 50.8 mm x 50.8 mm cross-sectional footprint silicon nitride substrates and copper base plate samples, and were subjected to accelerated thermal cycling until failure or 2500 cycles. Damage in the BIMs was monitored every 100 cycles by scanning acoustic microscopy. Thermoplastic with embedded carbon fibers performed the best with no defects, whereas sintered silver and lead solder failed at 2300 and 1400 thermal cycles, respectively. Besides thermal cycling, additional lead solder samples were subjected to thermal shock and thermal cycling with extended dwell periods. A finite element method (FEM)-based model was developed to simulate the behavior of lead solder under thermomechanical loading. Strain energy density per cycle results were calculated from the FEM simulations. A predictive lifetime model was formulated for lead solder by correlating strain energy density results extracted from modeling with cycles-to-failure obtained from experimental accelerated tests. A power-law-based approach was used to formulate the - redictive lifetime model.« less

Degradation Characterization of Thermal Interface Greases

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

DeVoto, Douglas J; Major, Joshua; Paret, Paul P

Thermal interface materials (TIMs) are used in power electronics packaging to minimize thermal resistance between the heat generating component and the heat sink. Thermal greases are one such class. The conformability and thin bond line thickness (BLT) of these TIMs can potentially provide low thermal resistance throughout the operation lifetime of a component. However, their performance degrades over time due to pump-out and dry-out during thermal and power cycling. The reliability performance of greases through operational cycling needs to be quantified to develop new materials with superior properties. NREL, in collaboration with DuPont, has performed thermal and reliability characterization ofmore » several commercially available thermal greases. Initial bulk and contact thermal resistance of grease samples were measured, and then the thermal degradation that occurred due to pump-out and dry-out during temperature cycling was monitored. The thermal resistances of five different grease materials were evaluated using NREL's steady-state thermal resistance tester based on the ASTM test method D5470. Greases were then applied, utilizing a 2.5 cm x 2.5 cm stencil, between invar and aluminum plates to compare the thermomechanical performance of the materials in a representative test fixture. Scanning Acoustic microscopy, thermal, and compositional analyses were performed periodically during thermal cycling from -40 degrees Celcius to 125 degrees Celcius. Completion of this characterization has allowed for a comprehensive evaluation of thermal greases both for their initial bulk and contact thermal performance, as well as their degradation mechanisms under accelerated thermal cycling conditions.« less

Degradation Characterization of Thermal Interface Greases: Preprint

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

DeVoto, Douglas J; Major, Joshua; Paret, Paul P

Thermal interface materials (TIMs) are used in power electronics packaging to minimize thermal resistance between the heat generating component and the heat sink. Thermal greases are one such class. The conformability and thin bond line thickness (BLT) of these TIMs can potentially provide low thermal resistance throughout the operation lifetime of a component. However, their performance degrades over time due to pump-out and dry-out during thermal and power cycling. The reliability performance of greases through operational cycling needs to be quantified to develop new materials with superior properties. NREL, in collaboration with DuPont, has performed thermal and reliability characterization ofmore » several commercially available thermal greases. Initial bulk and contact thermal resistance of grease samples were measured, and then the thermal degradation that occurred due to pump-out and dry-out during temperature cycling was monitored. The thermal resistances of five different grease materials were evaluated using NREL's steady-state thermal resistance tester based on the ASTM test method D5470. Greases were then applied, utilizing a 2.5 cm x 2.5 cm stencil, between invar and aluminum plates to compare the thermomechanical performance of the materials in a representative test fixture. Scanning Acoustic microscopy, thermal, and compositional analyses were performed periodically during thermal cycling from -40 degrees Celcius to 125 degrees Celcius. Completion of this characterization has allowed for a comprehensive evaluation of thermal greases both for their initial bulk and contact thermal performance, as well as their degradation mechanisms under accelerated thermal cycling conditions.« less

Degradation Characterization of Thermal Interface Greases

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

Major, Joshua; Narumanchi, Sreekant V; Paret, Paul P

Thermal interface materials (TIMs) are used in power electronics packaging to minimize thermal resistance between the heat generating component and the heat sink. Thermal greases are one such class. The conformability and thin bond line thickness (BLT) of these TIMs can potentially provide low thermal resistance throughout the operation lifetime of a component. However, their performance degrades over time due to pump-out and dry-out during thermal and power cycling. The reliability performance of greases through operational cycling needs to be quantified to develop new materials with superior properties. NREL, in collaboration with DuPont, has performed thermal and reliability characterization ofmore » several commercially available thermal greases. Initial bulk and contact thermal resistance of grease samples were measured, and then the thermal degradation that occurred due to pump-out and dry-out during temperature cycling was monitored. The thermal resistances of five different grease materials were evaluated using NREL's steady-state thermal resistance tester based on the ASTM test method D5470. Greases were then applied, utilizing a 2.5 cm x 2.5 cm stencil, between invar and aluminum plates to compare the thermomechanical performance of the materials in a representative test fixture. Scanning Acoustic microscopy, thermal, and compositional analyses were performed periodically during thermal cycling from -40 degrees C to 125 degrees C. Completion of this characterization has allowed for a comprehensive evaluation of thermal greases both for their initial bulk and contact thermal performance, as well as their degradation mechanisms under accelerated thermal cycling conditions.« less

Metal-Organic-Inorganic Nanocomposite Thermal Interface Materials with Ultralow Thermal Resistances.

PubMed

Yegin, Cengiz; Nagabandi, Nirup; Feng, Xuhui; King, Charles; Catalano, Massimo; Oh, Jun Kyun; Talib, Ansam J; Scholar, Ethan A; Verkhoturov, Stanislav V; Cagin, Tahir; Sokolov, Alexei V; Kim, Moon J; Matin, Kaiser; Narumanchi, Sreekant; Akbulut, Mustafa

2017-03-22

As electronic devices get smaller and more powerful, energy density of energy storage devices increases continuously, and moving components of machinery operate at higher speeds, the need for better thermal management strategies is becoming increasingly important. The removal of heat dissipated during the operation of electronic, electrochemical, and mechanical devices is facilitated by high-performance thermal interface materials (TIMs) which are utilized to couple devices to heat sinks. Herein, we report a new class of TIMs involving the chemical integration of boron nitride nanosheets (BNNS), soft organic linkers, and a copper matrix-which are prepared by the chemisorption-coupled electrodeposition approach. These hybrid nanocomposites demonstrate bulk thermal conductivities ranging from 211 to 277 W/(m K), which are very high considering their relatively low elastic modulus values on the order of 21.2-28.5 GPa. The synergistic combination of these properties led to the ultralow total thermal resistivity values in the range of 0.38-0.56 mm 2 K/W for a typical bond-line thickness of 30-50 μm, advancing the current state-of-art transformatively. Moreover, its coefficient of thermal expansion (CTE) is 11 ppm/K, forming a mediation zone with a low thermally induced axial stress due to its close proximity to the CTE of most coupling surfaces needing thermal management.

Thermal Characterization of Nanostructures and Advanced Engineered Materials

NASA Astrophysics Data System (ADS)

Goyal, Vivek Kumar

Continuous downscaling of Si complementary metal-oxide semiconductor (CMOS) technology and progress in high-power electronics demand more efficient heat removal techniques to handle the increasing power density and rising temperature of hot spots. For this reason, it is important to investigate thermal properties of materials at nanometer scale and identify materials with the extremely large or extremely low thermal conductivity for applications as heat spreaders or heat insulators in the next generation of integrated circuits. The thin films used in microelectronic and photonic devices need to have high thermal conductivity in order to transfer the dissipated power to heat sinks more effectively. On the other hand, thermoelectric devices call for materials or structures with low thermal conductivity because the performance of thermoelectric devices is determined by the figure of merit Z=S2sigma/K, where S is the Seebeck coefficient, K and sigma are the thermal and electrical conductivity, respectively. Nanostructured superlattices can have drastically reduced thermal conductivity as compared to their bulk counterparts making them promising candidates for high-efficiency thermoelectric materials. Other applications calling for thin films with low thermal conductivity value are high-temperature coatings for engines. Thus, materials with both high thermal conductivity and low thermal conductivity are technologically important. The increasing temperature of the hot spots in state-of-the-art chips stimulates the search for innovative methods for heat removal. One promising approach is to incorporate materials, which have high thermal conductivity into the chip design. Two suitable candidates for such applications are diamond and graphene. Another approach is to integrate the high-efficiency thermoelectric elements for on-spot cooling. In addition, there is strong motivation for improved thermal interface materials (TIMs) for heat transfer from the heat-generating chip to heat-sinking units. This dissertation presents results of the experimental investigation and theoretical interpretation of thermal transport in the advanced engineered materials, which include thin films for thermal management of nanoscale devices, nanostructured superlattices as promising candidates for high-efficiency thermoelectric materials, and improved TIMs with graphene and metal particles as fillers providing enhanced thermal conductivity. The advanced engineered materials studied include chemical vapor deposition (CVD) grown ultrananocrystalline diamond (UNCD) and microcrystalline diamond (MCD) films on Si substrates, directly integrated nanocrystalline diamond (NCD) films on GaN, free-standing polycrystalline graphene (PCG) films, graphene oxide (GOx) films, and "pseudo-superlattices" of the mechanically exfoliated Bi2Te3 topological insulator films, and thermal interface materials (TIMs) with graphene fillers.

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.

Synthesis and metrology of conducting carbon nanotube assemblies

NASA Astrophysics Data System (ADS)

Longson, Timothy Jay

Since its discovery, the carbon nanotube (CNT) has been proposed as one of the ultimate materials for its electrical, thermal and mechanical properties due to its incredibly strong sp2 bonds, low defect density, and large aspect ratio. Many experimental results on individual CNTs have confirmed these outstanding theoretically predicted properties. However, scaling these properties to the macroscopic regime has proved to be challenging. This work focused on the synthesis and measurement of highly conducting, macroscopic, CNT assemblies. Scaling up the synthesis of vertically aligned multiwalled CNT (MWNT) forests was investigated through the development of a large, 100mm, wafer scale, cold wall chemical vapor deposition chamber. In addition to the synthesis, two distinct CNT assemblies have been investigated. A linear morphology where CNTs are strung in series for electrical transport (CNT wires) and a massively parallel 2D array of vertically aligned CNTs for Thermal Interface Material (TIM) applications. Poymer-CNT wire composites have been fabricated by developing a coaxial CNT core-polymer shell electrospinning technique. The core-shell interactions in this system have been studied by way of Hansen's solubility parameters. The most well defined CNT core was achieved using a core solvent that is semi-immiscible with the shell solution, yet still a solvent of the shell polymer. Electrical characterization of the resulting CNT core has shown a two orders of magnitude increase in conductivity over traditional, homogeneously mixed, electrospun CNT wires. A number of vertically aligned MWNT assemblies were studied for their thermal interface properties. Double-sided Silicon substrate (MWNT-Si-MWNT) TIM assemblies were characterized using a DC, 1D reference bar, thermal measurement technique. While attempts to control MWNT density via a micelle template technique produced only 'spaghetti like' CNTs, sputter deposited catalyst provided stark variations in array density. Relevant array morphologies such as density, height, and crystallinity were studied in conjunction with their thermal performance. A Euler buckling model was used to identify the transition between increasing and decreasing resistance with density over array height, these two regimes are explained by way of contact analysis. Self catalyzing Fecralloy substrate MWNT TIMs were studied in a similar vein to the Silicon based assemblies. This substrate was investigated because of its malleability, ease of CNT synthesis and increased CNT adhesion. The growth behavior was studied with respect to the array morphologies, i.e. array height, density, crystallinity, and diameter, while the contact resistance was evaluated using a DC, 1D reference bar technique. The best performing samples were found to have a factor of two increase over their Si counterparts. Temperature dependent thermal measurements offer insight into the interfacial phonon conduction physics and are found to agree with other temperature dependent studies, suggesting inelastic scattering at the MWNT-Cu interface. Due to the challenges associated with deliberately controlling a single array morphology, a statistical approach was used for identifying the influences of the multivariate array morphology on contact resistance. Showing the strongest correlation with array height, following a R ~ L-0.5. Several models were investigated to help explain this behavior, although little insight is gained over the empirical relations. To better characterize these MWNT TIM assemblies two experimental techniques were developed. A transient 3o thermal measurement technique was adapted to characterize the thermal performance of CNT TIMs, offering insight into the limiting resistance in a mulilayer material stack. The MWNT-growth substrate interface was found to dominate in the Si samples while the MWNT-opposing substrate interface dominated in the Fecralloy samples. These measurements strongly supported the DC thermal measurements and the qualitative observations of substrate adhesion. Additionally, a new technique for observing nano sized contacts was established by viewing contact loading through an electron transparent membrane, imaged under an SEM. The contrast mechanism is explained by a voltage contrast phenomenon developed by trapped charges at the interface. The resolution limits have been studied by way of electron beam interactions and the use of Monte Carlo simulations, showing nanometer resolution with appropriate experimental conditions. The real MWNT contact area was found to be less than 1/100th the apparent contact area even at moderate pressures and the number of contacting CNTs is approximately 1/10th the total number of CNTs. These results confirm experimental measurement values for van der Waals adhesion strengths and thermal interface resistance.

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…

Metal–Organic–Inorganic Nanocomposite Thermal Interface Materials with Ultralow Thermal Resistances

DOE PAGES

Yegin, Cengiz; Nagabandi, Nirup; Feng, Xuhui; ...

2017-02-27

As electronic devices get smaller and more powerful, energy density of energy storage devices increases continuously, and moving components of machinery operate at higher speeds, the need for better thermal management strategies is becoming increasingly important. The removal of heat dissipated during the operation of electronic, electrochemical, and mechanical devices is facilitated by high-performance thermal interface materials (TIMs) which are utilized to couple devices to heat sinks. Here in this paper, we report a new class of TIMs involving the chemical integration of boron nitride nanosheets (BNNS), soft organic linkers, and a copper matrix -- which are prepared by chemisorption-coupledmore » electrodeposition approach. These hybrid nanocomposites demonstrate bulk thermal conductivities ranging from 211 to 277 W/(m.K), which are very high considering their relatively low elastic modulus values on the order of 21.2 to 28.5 GPa. The synergistic combination of these properties lead to the ultra-low total thermal resistivity values in the range of 0.38 to 0.56 mm 2.K/W for a typical bondline thickness of 30-50 um, advancing the current state-of-art transformatively. Moreover, its coefficient of thermal expansion (CTE) is 11 ppm/K, forming a mediation zone with a low thermally-induced axial stress due to its close proximity to the CTE of most coupling surfaces needing thermal management.« less

Metal–Organic–Inorganic Nanocomposite Thermal Interface Materials with Ultralow Thermal Resistances

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

Yegin, Cengiz; Nagabandi, Nirup; Feng, Xuhui

As electronic devices get smaller and more powerful, energy density of energy storage devices increases continuously, and moving components of machinery operate at higher speeds, the need for better thermal management strategies is becoming increasingly important. The removal of heat dissipated during the operation of electronic, electrochemical, and mechanical devices is facilitated by high-performance thermal interface materials (TIMs) which are utilized to couple devices to heat sinks. Here in this paper, we report a new class of TIMs involving the chemical integration of boron nitride nanosheets (BNNS), soft organic linkers, and a copper matrix -- which are prepared by chemisorption-coupledmore » electrodeposition approach. These hybrid nanocomposites demonstrate bulk thermal conductivities ranging from 211 to 277 W/(m.K), which are very high considering their relatively low elastic modulus values on the order of 21.2 to 28.5 GPa. The synergistic combination of these properties lead to the ultra-low total thermal resistivity values in the range of 0.38 to 0.56 mm 2.K/W for a typical bondline thickness of 30-50 um, advancing the current state-of-art transformatively. Moreover, its coefficient of thermal expansion (CTE) is 11 ppm/K, forming a mediation zone with a low thermally-induced axial stress due to its close proximity to the CTE of most coupling surfaces needing thermal management.« less

Advances in Multicollector ICPMS for precise and accurate isotope ratio measurements of Uranium isotopes

NASA Astrophysics Data System (ADS)

Bouman, C.; Lloyd, N. S.; Schwieters, J.

2011-12-01

The accurate and precise determination of uranium isotopes is challenging, because of the large dynamic range posed by the U isotope abundances and the limited available sample material. Various mass spectrometric techniques are used for the measurement of U isotopes, where TIMS is the most accepted and accurate one. Multicollector inductively coupled plasma mass spectrometry (MC-ICPMS) can offer higher productivity compared to TIMS, but is traditionally limited by low efficiency of sample utilisation. This contribution will discuss progress in MC-ICPMS for detecting 234U, 235U, 236U and 238U in various uranium reference materials from IRMM and NBL. The Thermo Scientific NEPTUNE Plus with Jet Interface offers a modified dry plasma ICP interface using a large interface pump combined with a special set of sample and skimmer cones giving ultimate sensitivity for all elements across the mass range. For uranium, an ion yield of > 3 % was reported previously [1]. The NEPTUNE Plus also offers Multi Ion Counting using discrete dynode electron multipliers as well as two high abundance-sensitivity filters to discriminate against peak tailing effects on 234U and 236U originating from the major uranium beams. These improvements in sensitivity and dynamic range allow accurate measurements of 234U, 235U and 236U abundances on very small samples and at low concentration. In our approach, minor U isotopes 234U and 236U were detected on ion counters with high abundance sensitivity filters, whereas 235U and 238U were detected on Faraday Cups using a high gain current amplifier (10e12 Ohm) for 235U. Precisions and accuracies for 234U and 236U were down to ~1%. For 235U, subpermil levels were reached.

Metallic Nanocomposites as Next-Generation Thermal Interface Materials: Preprint

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

Feng, Xuhui; Narumanchi, Sreekant V; King, Charles C

Thermal interface materials (TIMs) are an integral and important part of thermal management in electronic devices. The electronic devices are becoming more compact and powerful. This increase in power processed or passing through the devices leads to higher heat fluxes and makes it a challenge to maintain temperatures at the optimal level during operation. Herein, we report a free standing nanocomposite TIM in which boron nitride nanosheets (BNNS) are uniformly dispersed in copper matrices via an organic linker, thiosemicarbazide. Integration of these metal-organic-inorganic nanocomposites was made possible by a novel electrodeposition technique where the functionalized BNNS (f-BNNS) experience the Brownianmore » motion and reach the cathode through diffusion, while the nucleation and growth of the copper on the cathode occurs via the electrochemical reduction. Once the f-BNNS bearing carbonothioyl/thiol groups on the terminal edges come into the contact with copper crystals, the chemisorption reaction takes place. We performed thermal, mechanical, and structural characterization of these nanocomposites using scanning electron microcopy (SEM), diffusive laser flash (DLF) analysis, phase-sensitive transient thermoreflectence (PSTTR), and nanoindentation. The nanocomposites exhibited a thermal conductivity ranging from 211 W/mK to 277 W/mK at a filler mass loading of 0-12 wt.percent. The nanocomposites also have about 4 times lower hardness as compared to copper, with values ranging from 0.27 GPa to 0.41 GPa. The structural characterization studies showed that most of the BNNS are localized at grain boundaries - which enable efficient thermal transport while making the material soft. PSTTR measurements revealed that the synergistic combinations of these properties yielded contact resistances on the order of 0.10 to 0.13 mm2K/W, and the total thermal resistance of 0.38 to 0.56 mm2K/W at bondline thicknesses of 30-50 um. The coefficient of thermal expansion (CTE) of the nanocomposite is 11 ppm/K, which lies between the CTEs of aluminum (22 ppm/K) and silicon (3 ppm/K), which are common heat sink and heat source materials, respectively. The nanocomposite can also be deposited directly on to heat sink which will simplify the packaging processes by removing one possible element to assemble. These unique properties and ease of assembly makes the nanocomposite a promising next-generation TIM.« less

Metallic Nanocomposites as Next-Generation Thermal Interface Materials

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

Feng, Xuhui; Narumanchi, Sreekant V; King, Charles C

Thermal interface materials (TIMs) are an integral and important part of thermal management in electronic devices. The electronic devices are becoming more compact and powerful. This increase in power processed or passing through the devices leads to higher heat fluxes and makes it a challenge to maintain temperatures at the optimal level during operation. Herein, we report a free standing nanocomposite TIM in which boron nitride nanosheets (BNNS) are uniformly dispersed in copper matrices via an organic linker, thiosemicarbazide. Integration of these metal-organic-inorganic nanocomposites was made possible by a novel electrodeposition technique where the functionalized BNNS (f-BNNS) experience the Brownianmore » motion and reach the cathode through diffusion, while the nucleation and growth of the copper on the cathode occurs via the electrochemical reduction. Once the f-BNNS bearing carbonothioyl/thiol groups on the terminal edges come into the contact with copper crystals, the chemisorption reaction takes place. We performed thermal, mechanical, and structural characterization of these nanocomposites using scanning electron microcopy (SEM), diffusive laser flash (DLF) analysis, phase-sensitive transient thermoreflectence (PSTTR), and nanoindentation. The nanocomposites exhibited a thermal conductivity ranging from 211 W/mK to 277 W/mK at a filler mass loading of 0-12 wt.percent. The nanocomposites also have about 4 times lower hardness as compared to copper, with values ranging from 0.27 GPa to 0.41 GPa. The structural characterization studies showed that most of the BNNS are localized at grain boundaries - which enable efficient thermal transport while making the material soft. PSTTR measurements revealed that the synergistic combinations of these properties yielded contact resistances on the order of 0.10 to 0.13 mm2K/W, and the total thermal resistance of 0.38 to 0.56 mm2K/W at bondline thicknesses of 30-50 um. The coefficient of thermal expansion (CTE) of the nanocomposite is 11 ppm/K, which lies between the CTEs of aluminum (22 ppm/K) and silicon (3 ppm/K), which are common heat sink and heat source materials, respectively. The nanocomposite can also be deposited directly on to heat sink which will simplify the packaging processes by removing one possible element to assemble. These unique properties and ease of assembly makes the nanocomposite a promising next-generation TIM.« less

Structural analysis on mutation residues and interfacial water molecules for human TIM disease understanding

PubMed Central

2013-01-01

Background Human triosephosphate isomerase (HsTIM) deficiency is a genetic disease caused often by the pathogenic mutation E104D. This mutation, located at the side of an abnormally large cluster of water in the inter-subunit interface, reduces the thermostability of the enzyme. Why and how these water molecules are directly related to the excessive thermolability of the mutant have not been investigated in structural biology. Results This work compares the structure of the E104D mutant with its wild type counterparts. It is found that the water topology in the dimer interface of HsTIM is atypical, having a "wet-core-dry-rim" distribution with 16 water molecules tightly packed in a small deep region surrounded by 22 residues including GLU104. These water molecules are co-conserved with their surrounding residues in non-archaeal TIMs (dimers) but not conserved across archaeal TIMs (tetramers), indicating their importance in preserving the overall quaternary structure. As the structural permutation induced by the mutation is not significant, we hypothesize that the excessive thermolability of the E104D mutant is attributed to the easy propagation of atoms' flexibility from the surface into the core via the large cluster of water. It is indeed found that the B factor increment in the wet region is higher than other regions, and, more importantly, the B factor increment in the wet region is maintained in the deeply buried core. Molecular dynamics simulations revealed that for the mutant structure at normal temperature, a clear increase of the root-mean-square deviation is observed for the wet region contacting with the large cluster of interfacial water. Such increase is not observed for other interfacial regions or the whole protein. This clearly suggests that, in the E104D mutant, the large water cluster is responsible for the subunit interface flexibility and overall thermolability, and it ultimately leads to the deficiency of this enzyme. Conclusions Our study reveals that a large cluster of water buried in protein interfaces is fragile and high-maintenance, closely related to the structure, function and evolution of the whole protein. PMID:24564410

Recurring sequence-structure motifs in (βα)8-barrel proteins and experimental optimization of a chimeric protein designed based on such motifs.

PubMed

Wang, Jichao; Zhang, Tongchuan; Liu, Ruicun; Song, Meilin; Wang, Juncheng; Hong, Jiong; Chen, Quan; Liu, Haiyan

2017-02-01

An interesting way of generating novel artificial proteins is to combine sequence motifs from natural proteins, mimicking the evolutionary path suggested by natural proteins comprising recurring motifs. We analyzed the βα and αβ modules of TIM barrel proteins by structure alignment-based sequence clustering. A number of preferred motifs were identified. A chimeric TIM was designed by using recurring elements as mutually compatible interfaces. The foldability of the designed TIM protein was then significantly improved by six rounds of directed evolution. The melting temperature has been improved by more than 20°C. A variety of characteristics suggested that the resulting protein is well-folded. Our analysis provided a library of peptide motifs that is potentially useful for different protein engineering studies. The protein engineering strategy of using recurring motifs as interfaces to connect partial natural proteins may be applied to other protein folds. Copyright © 2016 Elsevier B.V. All rights reserved.

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.

Nonhomogeneous morphology and the elastic modulus of aligned carbon nanotube films

NASA Astrophysics Data System (ADS)

Won, Yoonjin; Gao, Yuan; Guzman de Villoria, Roberto; Wardle, Brian L.; Xiang, Rong; Maruyama, Shigeo; Kenny, Thomas W.; Goodson, Kenneth E.

2015-11-01

Carbon nanotube (CNT) arrays offer the potential to develop nanostructured materials that leverage their outstanding physical properties. Vertically aligned carbon nanotubes (VACNTs), also named CNT forests, CNT arrays, or CNT turfs, can provide high heat conductivity and sufficient mechanical compliance to accommodate thermal expansion mismatch for use as thermal interface materials (TIMs). This paper reports measurements of the in-plane moduli of vertically aligned, single-walled CNT (SWCNT) and multi-walled CNT (MWCNT) films. The mechanical response of these films is related to the nonhomogeneous morphology of the grown nanotubes, such as entangled nanotubes of a top crust layer, aligned CNTs in the middle region, and CNTs in the bottom layer. To investigate how the entanglements govern the overall mechanical moduli of CNT films, we remove the crust layer consisting of CNT entanglements by etching the CNT films from the top. A microfabricated cantilever technique shows that crust removal reduces the resulting moduli of the etched SWCNT films by as much as 40%, whereas the moduli of the etched MWCNT films do not change significantly, suggesting a minimal crust effect on the film modulus for thick MWCNT films (>90 μm). This improved understanding will allow us to engineer the mechanical moduli of CNT films for TIMs or packaging applications.

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.

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

Design and analysis of multifunctional structures for embedded electronics in unmanned aerial vehicles

NASA Astrophysics Data System (ADS)

Kothari, Rushabh M.

Multifunctional structures are a new trend in the aerospace industry for the next generation structural design. Many future structures are expected to be something in addition to a load bearing structure. The design and analysis of multifunctional structures combining structural, electrical and thermal functionalities are presented here. The sandwich beam is considered as a starting point for the load bearing structure and then it is modified with a cavity to embed avionics and thermal controls. The embedded avionics inside the load bearing structure would allow weight reduction of the aerospace vehicle due to elimination of separate electronics housing, interconnects, cables etc. The cavity reduces strength of the structure so various reinforcements methods are evaluated. The result of various reinforcements and their effectiveness are presented. The current generation of electronics produce massive amount of heat. In the case of embedded electronics, the excessive heat presents a major challenge to the structural and heat transfer engineers. The embedded nature of electronics prevents the use of the classical heat dissipative methods such as fans and high velocity air flows, etc. The integrated thermal control of the electronics has been designed using passive heat transfer device and highly optimized particulate composite thermal interface material (TIM). The TIMs are used to fill the air gaps and reduce contact resistance between two surfaces, such as electronics and heat dissipators. The efficiency of TIM directly affects the overall heat transfer ability of the integrated thermal control system. The effect of the particles at micron and nano scales are studied for the particulate composite TIM. The thermal boundary resistance study for the particulate composite TIM with nano silica particles is presented in this thesis. The FEA analysis is used to model thermal boundary resistance and compared with the theoretical micromechanics model. The heat pipes are chosen as a part of passive heat transfer device due to their durability and excellent thermal conductivities. The multifunctional system consisting of all above components is modeled for unmanned aerial vehicle (UAV) at subsonic air speeds to demonstrate the validity of the design.

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

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

NASA Astrophysics Data System (ADS)

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

2006-08-01

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

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

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.

Some Aspects of Thermal Transport across the Interface between Graphene and Epoxy in Nanocomposites.

PubMed

Wang, Yu; Yang, Chunhui; Pei, Qing-Xiang; Zhang, Yingyan

2016-03-01

Owing to the superior thermal properties of graphene, graphene-reinforced polymer nanocomposites hold great potential as the thermal interface materials (TIMs) dissipating heat for electronic packages. However, this application is greatly hindered by the high thermal resistance at the interface between graphene and polymer. In this paper, some important aspects of the improvement of the thermal transport across the interface between graphene and epoxy in graphene-epoxy nanocomposites, including the effectiveness of covalent and noncovalent functionalization, isotope doping, and acetylenic linkage in graphene are systematically investigated using molecular dynamics (MD) simulations. The simulation results show that the covalent and noncovalent functionalization techniques could considerably reduce the graphene-epoxy interfacial thermal resistance in the nanocomposites. Among different covalent functional groups, butyl is more effective than carboxyl and hydroxyl in reducing the interfacial thermal resistance. Different noncovalent functional molecules, including 1-pyrenebutyl, 1-pyrenebutyric acid, and 1-pyrenebutylamine, yield a similar amount of reductions. Moreover, it is found that the graphene-epoxy interfacial thermal resistance is insensitive to the carbon isotope doping in graphene, while it can be reduced moderately by replacing the sp(2) bonds in graphene with acetylenic linkages.

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.

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.

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.

Controlled High Filler Loading of Functionalized Al2O3-Filled Epoxy Composites for LED Thermal Management

NASA Astrophysics Data System (ADS)

Permal, Anithambigai; Devarajan, Mutharasu; Hung, Huong Ling; Zahner, Thomas; Lacey, David; Ibrahim, Kamarulazizi

2018-03-01

Thermal management in light-emitting diode (LED) has been extensively researched recently. This study is intended to develop an effective thermally conductive epoxy composite as thermal interface material (TIM) for headlamp LEDs. Silane-functionalized aluminum oxide (Al2O3) powder of different average particle sizes (44 and 10 µm) was studied for its feasibility as filler at its maximum loading. A detailed comparison of three different methods of particle dispersions, hand-mix, speed-mix and calendaring process (3-roll mill), has been reported. The dispersion of Al2O3 particles, the thermal conductivity and thermal degradation characteristics of the composites were investigated and explained in detail. At 75 wt.% filler loading, 10 and 44 µm Al2O3 achieved composite thermal conductivities of 1.13 and 2.08 W/mK, respectively, which is approximately 528 and 1055% of enhancement with respect to neat epoxy. The package-level thermal performance of the LED employing the Al2O3-filled TIMs was carried out using thermal transient analysis. The experimental junction-to-ambient thermal resistances ( R thJ-A) achieved were 6.65, 7.24, and 8.63 K/W for Al2O3_44µm, Al2O3_10µm and neat epoxy, respectively. The results revealed that the Al2O3_44µm fillers-filled composite performed better in both material-level and package-level thermal characteristics.

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.

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.

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

Mullite fiber reinforced reaction bonded Si3N4 composites

NASA Technical Reports Server (NTRS)

Saleh, T.; Sayir, A.; Lightfoot, A.; Haggerty, J.

1996-01-01

Fracture toughnesses of brittle ceramic materials have been improved by introducing reinforcements and carefully tailored interface layers. Silicon carbide and Si3N4 have been emphasized as matrices of structural composites intended for high temperature service because they combine excellent mechanical, chemical, thermal and physical properties. Both matrices have been successfully toughened with SiC fibers, whiskers and particles for ceramic matrix composite (CMC) parts made by sintering, hot pressing or reaction forming processes. These SiC reinforced CMCs have exhibited significantly improved toughnesses at low and intermediate temperature levels, as well as retention of properties at high temperatures for selected exposures; however, they are vulnerable to attack from elevated temperature dry and wet oxidizing atmospheres after the matrix has cracked. Property degradation results from oxidation of interface layers and/or reinforcements. The problem is particularly acute for small diameter (-20 tim) polymer derived SiC fibers used for weavable toes. This research explored opportunities for reinforcing Si3N4 matrices with fibers having improved environmental stability; the findings should also be applicable to SiC matrix CMCs.

Contribution of bulk mass spectrometry isotopic analysis to characterization of materials in the framework of CMX-4

DOE PAGES

Kuchkin, A.; Stebelkov, V.; Zhizhin, K.; ...

2018-01-30

Seven laboratories used the results of bulk uranium isotopic analysis by either inductively coupled plasma mass spectrometry (ICP-MS) or thermal ionization mass spectrometry (TIMS) for characterization of the samples in the Nuclear Forensic International Technical Working Group fourth international collaborative material exercise, CMX-4. Comparison of the measured isotopic compositions of uranium in three exercise samples is implemented for identifying any differences or similarities between the samples. The role of isotopic analyses in the context of a real nuclear forensic investigation is discussed. Several limitations in carrying out ICP-MS or TIMS analysis in CMX-4 are noted.

Contribution of bulk mass spectrometry isotopic analysis to characterization of materials in the framework of CMX-4

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

Kuchkin, A.; Stebelkov, V.; Zhizhin, K.

Seven laboratories used the results of bulk uranium isotopic analysis by either inductively coupled plasma mass spectrometry (ICP-MS) or thermal ionization mass spectrometry (TIMS) for characterization of the samples in the Nuclear Forensic International Technical Working Group fourth international collaborative material exercise, CMX-4. Comparison of the measured isotopic compositions of uranium in three exercise samples is implemented for identifying any differences or similarities between the samples. The role of isotopic analyses in the context of a real nuclear forensic investigation is discussed. Several limitations in carrying out ICP-MS or TIMS analysis in CMX-4 are noted.

Synergetic Improvement in Thermal Conductivity and Flame Retardancy of Epoxy/Silver Nanowires Composites by Incorporating "Branch-Like" Flame-Retardant Functionalized Graphene.

PubMed

Feng, Yuezhan; Li, Xiongwei; Zhao, Xiaoyu; Ye, Yunsheng; Zhou, Xingping; Liu, Hu; Liu, Chuntai; Xie, Xiaolin

2018-06-27

The significant fire hazards on the polymer-based thermal interface materials (TIM) used in electronic devices are but often neglected. Also, high filler loading with the incident deterioration of mechanical, thermal, and processing properties limits the further application of the traditional polymer-based TIMs. In this work, a ternary TIMs with epoxy resin (EP) matrix, silver nanowires (AgNWs), and a small amount of flame-retardant functionalized graphene (GP-DOPO) were proposed to address the above questions. Briefly, a facile "branch-like" strategy with a polymer as the backbone and flame-retardant molecule as the branch was first used to functionalize reduced graphene oxide (RGO) toward increasing the flame-retardant grafting ratio and RGO's compatibility in matrix, and the resulted GP-DOPO was then in situ introduced into the EP/AgNW composites. As expected, the incorporation of GP-DOPO (2 wt %) can increase the thermal conductivity to 1.413 W/(m K) at a very low AgNW loading (4 vol %), which is 545 and 56% increments compared to pure EP and EP/AgNW, respectively. The prominent improvement in thermal conductivity was put down to the synergetic effect of AgNW and GP-DOPO, i.e., the improving dispersion and bridging effect for AgNWs by adding GP-DOPO. Moreover, the high flame-retardant grafting amount and the excellent compatibility of GP-DOPO resulted in a strong catalytic charring effect on EP matrix, which further formed a robust protective char layer by combining the AgNW and graphene network. Therefore, the flame retardancy of EP/AgNW was significantly improved by introducing GP-DOPO, i.e., the peak heat release rate, total heat release and total smoke production reduced by 27.0, 32.4, and 30.9% reduction compared to EP/AgNW, respectively.

Mass spectrometry of long-lived radionuclides

NASA Astrophysics Data System (ADS)

Becker, Johanna Sabine

2003-10-01

The capability of determining element concentrations at the trace and ultratrace level and isotope ratios is a main feature of inorganic mass spectrometry. The precise and accurate determination of isotope ratios of long-lived natural and artificial radionuclides is required, e.g. for their environmental monitoring and health control, for studying radionuclide migration, for age dating, for determining isotope ratios of radiogenic elements in the nuclear industry, for quality assurance and determination of the burn-up of fuel material in a nuclear power plant, for reprocessing plants, nuclear material accounting and radioactive waste control. Inorganic mass spectrometry, especially inductively coupled plasma mass spectrometry (ICP-MS) as the most important inorganic mass spectrometric technique today, possesses excellent sensitivity, precision and good accuracy for isotope ratio measurements and practically no restriction with respect to the ionization potential of the element investigated—therefore, thermal ionization mass spectrometry (TIMS), which has been used as the dominant analytical technique for precise isotope ratio measurements of long-lived radionuclides for many decades, is being replaced increasingly by ICP-MS. In the last few years instrumental progress in improving figures of merit for the determination of isotope ratio measurements of long-lived radionuclides in ICP-MS has been achieved by the application of a multiple ion collector device (MC-ICP-MS) and the introduction of the collision cell interface in order to dissociate disturbing argon-based molecular ions, to reduce the kinetic energy of ions and neutralize the disturbing noble gas ions (e.g. of 129Xe + for the determination of 129I). The review describes the state of the art and the progress of different inorganic mass spectrometric techniques such as ICP-MS, laser ablation ICP-MS vs. TIMS, glow discharge mass spectrometry, secondary ion mass spectrometry, resonance ionization mass spectrometry and accelerator mass spectrometry for the determination of long-lived radionuclides in quite different materials.

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.

Controlled growth of vertically aligned carbon nanotubes on metal substrates

NASA Astrophysics Data System (ADS)

Gao, Zhaoli

Carbon nanotube (CNT) is a fascinating material with extraordinary electrical thermal and mechanical properties. Growing vertically aligned CNT (VACNT) arrays on metal substrates is an important step in bringing CNT into practical applications such as thermal interface materials (TIMs) and microelectrodes. However, the growth process is challenging due to the difficulties in preventing catalyst diffusion and controlling catalyst dewetting on metal substrates with physical surface heterogeneity. In this work, the catalyst diffusion mechanism and catalyst dewetting theory were studied for the controlled growth of VACNTs on metal substrates. The diffusion time of the catalyst, the diffusion coefficients for the catalyst in the substrate materials and the number density of catalyst nanoparticles after dewetting are identified as the key parameters, based on which three strategies are developed. Firstly, a fast-heating catalyst pretreatment strategy was used, aiming at preserving the amount of catalyst prior to CNT growth by reducing the catalyst diffusion time. The catalyst lifetime is extended from half an hour to one hour on a patterned Al thin film and a VACNT height of 106 mum, about twenty fold of that reported in the literature, was attained. Secondly, a diffusion barrier layer strategy is employed for a reduction of catalyst diffusion into the substrate materials. Enhancement of VACNT growth on Cu substrates was achieved by adopting a conformal Al2O 3 diffusion barrier layer fabricated by a specially designed atomic layer deposition (ALD) system. Lastly, a novel catalyst glancing angle deposition (GLAD) strategy is performed to manipulate the morphology of a relatively thick catalyst on metal substrates with physical surface heterogeneity, aiming to obtain uniform and dense catalyst nanoparticles after dewetting in the pretreatment process for enhanced VACNT growth. We are able to control the VACNT growth conditions on metal substrates in terms of their distribution, heights and alignments. Catalyst loss is controlled by the catalyst diffusion time and catalyst diffusion coefficients. A shorter catalyst diffusion time and smaller diffusion coefficient enhance VACNT growth on metals due to reduced catalyst loss during the pretreatment process. The dewetting behaviors of the thin film catalysts are influenced by the physical surface heterogeneity of the substrates which leads to non-uniform growth of VACNTs. The GLAD process facilitates the deposition of a relatively thick catalyst layer for the creation of dense and uniform catalyst nanoparticles. Applications of VACNT-metal structures in TIMs and microelectrodes are demonstrated. The VACNT-TIMs fabricated on Al alloy substrates have a typical thermal contact resistivity of 17.1 mm2˙K/W and their effective application in high-brightness LED thermal management was demonstrated. Electrochemical characterization was carried out on VACNT microelectrodes for the development of high resolution retinal prostheses and a satisfactory electrochemical property was again demonstrated.

Multiphase Combustion of Metalized Nanocomposite Energetic Materials

DTIC Science & Technology

2014-12-19

Materials, Energy & Fuels (01 2011) Eric Nixon, Michelle Pantoya, Ganapathy Sivakumar, Ashwin Vijayasai, Tim Dallas. Superhydrophobic Coatings for... Superhydrophobic Coatings for Nanoenergetic Material Combustion, Surface Coatings and Technology205, 5103-5108, 2011. 4. Dikici, B., Shaw, B...A., Dallas, T., Superhydrophobic Coatings for Nanoenergetic Material Combustion, Surface Coatings and Technology 205, 5103-5108, 2011. (3

DockoMatic 2.0: high throughput inverse virtual screening and homology modeling.

PubMed

Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T; McDougal, Owen M; Andersen, Timothy L

2013-08-26

DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly graphical user interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to (1) conduct high throughput inverse virtual screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELER programs and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education.

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

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.

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

Preparation and application of silver nanopaste as thermal interface materials

NASA Astrophysics Data System (ADS)

Zou, Lianfeng

The power densities in electronic devices have increased dramatically; heat dissipation has become a major challenge in high performance electronics applications. We have investigated a new type of resin-free hybrid silver nanopastes, which contain silver micro-flakes with particle sizes of 1 - 10 um and silver nanoparticles with diameters of 3 - 8 nm. The assemble temperature can be as low as 150oC due to the low sintering temperature of silver nanoparticles. The fused silver micro-and nanoparticles in TIM form continuous metallic networks, resulting in good thermal, electrical and mechanical bonding. The steady-state thermal gradient measurement show the bulk thermal conductivity between 20W/ (m*K) and 100 W/ (m*K), which is higher than commercial product in the market. The application specific performance of the nanopaste has been using LED lamp on heat sinks as model test vehicle.

Qualification and initial characterization of a high-purity 233U spike for use in uranium analyses

DOE PAGES

Mathew, K. J.; Canaan, R. D.; Hexel, C.; ...

2015-08-20

Several high-purity 233U items potentially useful as isotope dilution mass spectrometry standards for safeguards, non-proliferation, and nuclear forensics measurements are identified and rescued from downblending. By preserving the supply of 233U materials of different pedigree for use as source materials for certified reference materials (CRMs), it is ensured that the safeguards community has high quality uranium isotopic standards required for calibration of the analytical instruments. One of the items identified as a source material for a high-purity CRM is characterized for the uranium isotope-amount ratios using thermal ionization mass spectrometry (TIMS). Additional verification measurements on this material using quadrupole inductivelymore » coupled plasma mass spectrometry (ICPMS) are also performed. As a result, the comparison of the ICPMS uranium isotope-amount ratios with the TIMS data, with much smaller uncertainties, validated the ICPMS measurement practices. ICPMS is proposed for the initial screening of the purity of items in the rescue campaign.« less

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.

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.

Structures of Bacterial Biosynthetic Arginine Decarboxylases

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

F Forouhar; S Lew; J Seetharaman

2011-12-31

Biosynthetic arginine decarboxylase (ADC; also known as SpeA) plays an important role in the biosynthesis of polyamines from arginine in bacteria and plants. SpeA is a pyridoxal-5'-phosphate (PLP)-dependent enzyme and shares weak sequence homology with several other PLP-dependent decarboxylases. Here, the crystal structure of PLP-bound SpeA from Campylobacter jejuni is reported at 3.0 {angstrom} resolution and that of Escherichia coli SpeA in complex with a sulfate ion is reported at 3.1 {angstrom} resolution. The structure of the SpeA monomer contains two large domains, an N-terminal TIM-barrel domain followed by a {beta}-sandwich domain, as well as two smaller helical domains. Themore » TIM-barrel and {beta}-sandwich domains share structural homology with several other PLP-dependent decarboxylases, even though the sequence conservation among these enzymes is less than 25%. A similar tetramer is observed for both C. jejuni and E. coli SpeA, composed of two dimers of tightly associated monomers. The active site of SpeA is located at the interface of this dimer and is formed by residues from the TIM-barrel domain of one monomer and a highly conserved loop in the {beta}-sandwich domain of the other monomer. The PLP cofactor is recognized by hydrogen-bonding, {pi}-stacking and van der Waals interactions.« less

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra aids in Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

NASA Image and Video Library

2004-02-03

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra aids in Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

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

DockoMatic 2.0: High Throughput Inverse Virtual Screening and Homology Modeling

PubMed Central

Bullock, Casey; Cornia, Nic; Jacob, Reed; Remm, Andrew; Peavey, Thomas; Weekes, Ken; Mallory, Chris; Oxford, Julia T.; McDougal, Owen M.; Andersen, Timothy L.

2013-01-01

DockoMatic is a free and open source application that unifies a suite of software programs within a user-friendly Graphical User Interface (GUI) to facilitate molecular docking experiments. Here we describe the release of DockoMatic 2.0; significant software advances include the ability to: (1) conduct high throughput Inverse Virtual Screening (IVS); (2) construct 3D homology models; and (3) customize the user interface. Users can now efficiently setup, start, and manage IVS experiments through the DockoMatic GUI by specifying a receptor(s), ligand(s), grid parameter file(s), and docking engine (either AutoDock or AutoDock Vina). DockoMatic automatically generates the needed experiment input files and output directories, and allows the user to manage and monitor job progress. Upon job completion, a summary of results is generated by Dockomatic to facilitate interpretation by the user. DockoMatic functionality has also been expanded to facilitate the construction of 3D protein homology models using the Timely Integrated Modeler (TIM) wizard. The wizard TIM provides an interface that accesses the basic local alignment search tool (BLAST) and MODELLER programs, and guides the user through the necessary steps to easily and efficiently create 3D homology models for biomacromolecular structures. The DockoMatic GUI can be customized by the user, and the software design makes it relatively easy to integrate additional docking engines, scoring functions, or third party programs. DockoMatic is a free comprehensive molecular docking software program for all levels of scientists in both research and education. PMID:23808933

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.

Composites Materials and Manufacturing Technologies for Space Applications

NASA Technical Reports Server (NTRS)

Vickers, J. H.; Tate, L. C.; Gaddis, S. W.; Neal, R. E.

2016-01-01

Composite materials offer significant advantages in space applications. Weight reduction is imperative for deep space systems. However, the pathway to deployment of composites alternatives is problematic. Improvements in the materials and processes are needed, and extensive testing is required to validate the performance, qualify the materials and processes, and certify components. Addressing these challenges could lead to the confident adoption of composites in space applications and provide spin-off technical capabilities for the aerospace and other industries. To address the issues associated with composites applications in space systems, NASA sponsored a Technical Interchange Meeting (TIM) entitled, "Composites Materials and Manufacturing Technologies for Space Applications," the proceedings of which are summarized in this Conference Publication. The NASA Space Technology Mission Directorate and the Game Changing Program chartered the meeting. The meeting was hosted by the National Center for Advanced Manufacturing (NCAM)-a public/private partnership between NASA, the State of Louisiana, Louisiana State University, industry, and academia, in association with the American Composites Manufacturers Association. The Louisiana Center for Manufacturing Sciences served as the coordinator for the TIM.

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

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.

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.

How new is the new philosophy of psychiatry?

PubMed

Denys, Damiaan

2007-10-20

In their recent paper, Natalie Banner and Tim Thornton evaluate seven volumes of the Oxford University Press series "International Perspectives in Philosophy and Psychiatry," an international book series begun in 2003 focusing on the emerging interdisciplinary field at the interface of philosophy and psychiatry. According to Natalie Banner and Tim Thornton, the series represents a clear indication that the interdisciplinary field of philosophy of psychiatry has been flourishing lately. Philosophers and psychiatrists face a "new philosophy of psychiatry". However, the optimism which the "new" philosophy of psychiatry celebrates is precisely the exiling of philosophy from the foundations of psychiatry. The 150 year old belief that psychopathology cannot do without philosophical reflection has virtually disappeared from common psychiatric education and daily clinical practice. Though the discipline of psychiatry is particularly suited to contributions from philosophy, the impact of philosophy on psychiatry nowadays remains limited. With some exceptions, philosophical papers are embedded in a philosophical context inscrutable to ordinary psychiatrists. Much current philosophical work is perceived by psychiatrists as negativistic. I would encourage the field of psychiatry to incorporate once again basic philosophical attitudes which render possible true dialogue with philosophy and enrich both disciplines. The views developed here should not discredit the value and importance of Natalie Banner and Tim Thornton's paper and the excellent series "International Perspectives in Philosophy and Psychiatry." As Jaspers said "Everybody inclined to disregard philosophy will be overwhelmed by philosophy in an unperceived way".

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.

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra (facing camera) aids in Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

NASA Image and Video Library

2004-02-03

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra (facing camera) aids in Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra talks to a technician (off-camera) during Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

NASA Image and Video Library

2004-02-03

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra talks to a technician (off-camera) during Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

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.

Stable Chlorine Isotopes and Elemental Chlorine by Thermal Ionization Mass Spectrometry and Ion Chromatography; Martian Meteorites, Carbonaceous Chondrites and Standard Rocks

NASA Technical Reports Server (NTRS)

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

2011-01-01

Recently significantly large mass fractionation of stable chlorine isotopes has been reported for terrestrial and lunar samples [1,2]. In addition, in view of possible early solar system processes [3] and also potential perchlorate-related fluid/microbial activities on the Martian surface [4,5], a large chlorine isotopic fractionation might be expected for some types of planetary materials. Due to analytical difficulties of isotopic and elemental analyses, however, current chlorine analyses for planetary materials are controversial among different laboratories, particularly between IRMS (gas source mass spectrometry) and TIMS (Thermal Ionization Mass Spectrometry) groups [i.e. 1,6,7] for isotopic analyses, as well as between those doing pyrohydrolysis and other groups [i.e. 6,8]. Additional careful investigations of Cl isotope and elemental abundances are required to confirm real chlorine isotope and elemental variations for planetary materials. We have developed a TIMS technique combined with HF-leaching/ion chromatography at NASA JSC that is applicable to analysis of small amounts of meteoritic and planetary materials. We present here results for several standard rocks and meteorites, including Martian meteorites.

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.

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.

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

A comparative study of 129I content in environmental standard materials IAEA-375, NIST SRM 4354 and NIST SRM 4357 by Thermal Ionization Mass Spectrometry and Accelerator Mass Spectrometry

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

Olson, John; Adamic, Mary; Snyder, Darin

Iodine environmental measurements have consistently been backed up in the literature by standard materials like IAEA-375, Chernobyl Soil. There are not many other sources of a certified reference material for 129I content for mass spectrometry measurements. Some that have been found in the literature include NIST-4354 and NIST-4357. They are still available at the time of this writing. They don’t have certified content or isotopic values. There has been some work in the literature to show that iodine is present, but there hasn’t been enough to establish a consensus value. These materials have been analyzed at INL through two separatemore » mass spectrometry techniques. They involve a combustion method of the starting material in oxygen, followed by TIMS analysis and a leaching preparation analyzed by accelerator mass spectrometry. Combustion/TIMS preparation of NIST SRM-4354 resulted in a 129I/127I ratio of 1.92 x 10-6 which agrees with AMS measurements which measured the 129I/127I ratio to be 1.93 x 10-6.« less

Novel effector phenotype of Tim-3+ regulatory T cells leads to enhanced suppressive function in head and neck cancer patients.

PubMed

Liu, Zhuqing; McMichael, Elizabeth L; Shayan, Gulidanna; Li, Jing; Chen, Kevin; Srivastava, Raghvendra M; Kane, Lawrence P; Lu, Binfeng; Ferris, Robert L

2018-04-30

Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear. CD4+CTLA-4+CD25high Treg were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.  Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naïve T cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39 and IFN-γ receptor. Exogenous IFN-γ treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs. Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T cell proliferation despite high PD-1 expression.  IFN-γ induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim-3+ Treg suppression. Copyright ©2018, American Association for Cancer Research.

Geologic remote sensing - New technology, new information

NASA Technical Reports Server (NTRS)

Kruse, F. A.

1992-01-01

Results of geologic studies using data collected by the NASA/JPL Thermal Infrared Imaging Spectrometer (TIMS), Airborne Visible/Infrared Imaging Spectrometer (AVIRIS), and the Airborne Synthetic Aperture Radar (AIRSAR) are discussed. These instruments represent prototypes for the Earth Observing System (EOS) satellite instruments ASTER, High Resolution Imaging Spectrometer (HIRIS), and EOS SAR. Integrated analysis of this data type is one of the keys to successful geologic research using EOS. TIMS links the physical properties of surface materials in the 8-12-*mm region to their composition. Calibrated aircraft data make direct lithological mapping possible. AVIRIS, an analog for HIRIS, provides quantitative information about the surface composition of materials based on their detailed visible and infrared spectral signatures (0.4-2.45 mm). Calibrated AVIRIS data make direct identification of minerals possible. The AIRSAR provides additional complementary information about the surface morphology of rocks and soils.

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

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

Sm-Nd isotopic compositions of LREE minerals for use as reference materials for in situ analysis by LA-MC-ICPMS

NASA Astrophysics Data System (ADS)

Fisher, C. M.; McFarlane, C. R.; Sylvester, P.; Hanchar, J. M.; Lam, R.; Schmitz, M. D.

2009-12-01

Recent work has demonstrated the possibility of obtaining both accurate and precise in situ Sm-Nd isotopic data in light rare earth enriched (LREE) accessory minerals including apatite, titanite, and monazite, using laser ablation-multicollector-inductively coupled plasma mass spectrometry (LA-MC-ICPMS). A distinct advantage of using LA-MC-ICPMS is that Sm-Nd isotopic data from these minerals can be determined in sub-grain domains potentially avoiding problems of isotopic mixing from inherited or xenocrystic components and allowing both valuable tracer isotope and geochronologic data to be obtained. However, a number of analytical obstacles complicate accurate Sm-Nd determination by LA-MC-ICPMS including mass bias corrections, the 144Sm isobaric interference on 144Nd, and potential offset (ca. 20-40 ppm) from thermal ionization mass spectrometry (TIMS) determination of similar materials. Thus, in order to verify Sm-Nd isotopic determination from unknowns, matrix-matched quality control standards (i.e., reference materials) must be developed to test the data handling protocol. This talk will present new Sm-Nd isotopic data determined by both TIMS as well as LA-MC-ICPMS of a number of natural potential reference minerals including Durango apatite, Fish Canyon titanite, Daibosatsu allanite, Trebilcock monazite, as well as a monazite from the Doi Inthanon core complex in northern Thailand. Our preliminary LA-MC-ICPMS results demonstrate that Durango apatite, Fish Canyon titanite, and Thailand monazite show both inter- and intra-grain homogeneity at current levels of precision (ca. 0.3-0.5 ɛNd) and close agreement with our TIMS data.

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

Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

PubMed Central

Li, Jing; Shayan, Gulidanna; Avery, Lyndsay; Jie, Hyun-Bae; Gildener-Leapman, Neil; Schmitt, Nicole; Lu, Bin Feng; Kane, Lawrence P.; Ferris, Robert L.

2016-01-01

ABSTRACT Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors highly expressed on tumor infiltrating T lymphocytes (TIL). PD-1 inhibits T cell activation and type-1 T cell responses, while Tim-3 is proposed to mark more extensively exhausted cells, although the mechanisms underlying Tim-3 function are not clear. Trials of anti-PD-1 therapy have identified a large subset of non-responder patients, likely due to expression of alternative checkpoint molecules like Tim-3. We investigated the phenotypic and functional characteristics of T cells with differential expression of PD-1 (high/low) and Tim-3 (positive/negative), using TIL directly isolated from head and neck squamous cell carcinomas (HNSCC). Unexpectedly, we found that expression of Tim-3 alone does not necessarily mark TIL as dysfunctional/exhausted. In Tim-3-TIL, PD-1 levels correlate with T cell dysfunction, with a PD-1low/intermed phenotype identifying recently activated and still functional cells, whereas PD-1hiTim-3− T cells are actually exhausted. Nonetheless, PD-1intermed cells are still potently suppressed by PD-L1. PD-1 expression was associated with reduced phosphorylation of ribosomal protein S6 (pS6), whereas Tim-3 expression was associated with increased pS6. Using a novel mouse model for inducible Tim-3 expression, we confirmed that expression of Tim-3 does not necessarily render T cells refractory to further activation. These results suggest the existence of PD-1 and Tim-3 crosstalk in regulating antitumor T cell responses, with important implications for anti-PD-1 immunotherapy. PMID:27853635

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

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.

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.

How new is the new philosophy of psychiatry?

PubMed Central

Denys, Damiaan

2007-01-01

In their recent paper, Natalie Banner and Tim Thornton evaluate seven volumes of the Oxford University Press series “International Perspectives in Philosophy and Psychiatry,” an international book series begun in 2003 focusing on the emerging interdisciplinary field at the interface of philosophy and psychiatry. According to Natalie Banner and Tim Thornton, the series represents a clear indication that the interdisciplinary field of philosophy of psychiatry has been flourishing lately. Philosophers and psychiatrists face a “new philosophy of psychiatry”. However, the optimism which the “new” philosophy of psychiatry celebrates is precisely the exiling of philosophy from the foundations of psychiatry. The 150 year old belief that psychopathology cannot do without philosophical reflection has virtually disappeared from common psychiatric education and daily clinical practice. Though the discipline of psychiatry is particularly suited to contributions from philosophy, the impact of philosophy on psychiatry nowadays remains limited. With some exceptions, philosophical papers are embedded in a philosophical context inscrutable to ordinary psychiatrists. Much current philosophical work is perceived by psychiatrists as negativistic. I would encourage the field of psychiatry to incorporate once again basic philosophical attitudes which render possible true dialogue with philosophy and enrich both disciplines. The views developed here should not discredit the value and importance of Natalie Banner and Tim Thornton’s paper and the excellent series “International Perspectives in Philosophy and Psychiatry.” As Jaspers said “Everybody inclined to disregard philosophy will be overwhelmed by philosophy in an unperceived way”. PMID:17949505

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

Overview of thermal conductivity models of anisotropic thermal insulation materials

NASA Astrophysics Data System (ADS)

Skurikhin, A. V.; Kostanovsky, A. V.

2017-11-01

Currently, the most of existing materials and substances under elaboration are anisotropic. It makes certain difficulties in the study of heat transfer process. Thermal conductivity of the materials can be characterized by tensor of the second order. Also, the parallelism between the temperature gradient vector and the density of heat flow vector is violated in anisotropic thermal insulation materials (TIM). One of the most famous TIM is a family of integrated thermal insulation refractory material («ITIRM»). The main component ensuring its properties is the «inflated» vermiculite. Natural mineral vermiculite is ground into powder state, fired by gas burner for dehydration, and its precipitate is then compressed. The key feature of thus treated batch of vermiculite is a package structure. The properties of the material lead to a slow heating of manufactured products due to low absorption and high radiation reflection. The maximum of reflection function is referred to infrared spectral region. A review of current models of heat propagation in anisotropic thermal insulation materials is carried out, as well as analysis of their thermal and optical properties. A theoretical model, which allows to determine the heat conductivity «ITIRM», can be useful in the study of thermal characteristics such as specific heat capacity, temperature conductivity, and others. Materials as «ITIRM» can be used in the metallurgy industry, thermal energy and nuclear power-engineering.

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

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra (second from right) talks with workers in the Space Station Processing Facility about the Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. . The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

NASA Image and Video Library

2004-02-03

KENNEDY SPACE CENTER, FLA. - Astronaut Tim Kopra (second from right) talks with workers in the Space Station Processing Facility about the Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. . The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

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.

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...

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

NASA Astrophysics Data System (ADS)

Oxburgh, Stephen; Tyc, Tomáš; Courtial, Johannes

2014-03-01

We describe several extensions to TIM, a raytracing program for ray-optics research. These include relativistic raytracing; simulation of the external appearance of Eaton lenses, Luneburg lenses and generalised focusing gradient-index lens (GGRIN) lenses, which are types of perfect imaging devices; raytracing through interfaces between spaces with different optical metrics; and refraction with generalised confocal lenslet arrays, which are particularly versatile METATOYs. Catalogue identifier: AEKY_v2_0 Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEKY_v2_0.html Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland Licencing provisions: GNU General Public License No. of lines in distributed program, including test data, etc.: 106905 No. of bytes in distributed program, including test data, etc.: 6327715 Distribution format: tar.gz Programming language: Java. Computer: Any computer capable of running the Java Virtual Machine (JVM) 1.6. Operating system: Any, developed under Mac OS X Version 10.6 and 10.8.3. RAM: Typically 130 MB (interactive version running under Mac OS X Version 10.8.3) Classification: 14, 18. Catalogue identifier of previous version: AEKY_v1_0 Journal reference of previous version: Comput. Phys. Comm. 183(2012)711 External routines: JAMA [1] (source code included) Does the new version supersede the previous version?: Yes Nature of problem: Visualisation of scenes that include scene objects that create wave-optically forbidden light-ray fields. Solution method: Ray tracing. Reasons for new version: Significant extension of the capabilities (see Summary of revisions), as demanded by our research. Summary of revisions: Added capabilities include the simulation of different types of camera moving at relativistic speeds relative to the scene; visualisation of the external appearance of generalised focusing gradient-index (GGRIN) lenses, including Maxwell fisheye, Eaton and Luneburg lenses; calculation of refraction at the interface between spaces with different optical metrics; and handling of generalised confocal lenslet arrays (gCLAs), a new type of METATOY. Unusual features: Specifically designed to visualise wave-optically forbidden light-ray fields; can visualise ray trajectories and geometric optic transformations; can simulate photos taken with different types of camera moving at relativistic speeds, interfaces between spaces with different optical metrics, the view through METATOYs and generalised focusing gradient-index lenses; can create anaglyphs (for viewing with coloured “3D glasses”), HDMI-1.4a standard 3D images, and random-dot autostereograms of the scene; integrable into web pages. Running time: Problem-dependent; typically seconds for a simple scene. References: [1] JAMA: A Java Matrix Package, http://math.nist.gov/javanumerics/jama/

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.

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.

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.

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

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.

GREAT III Erosion and Sediment Inventory (Saverton, Missouri to Cairo, Illinois).

DTIC Science & Technology

1982-06-01

Berkas (Don Coffin) (Horace Jeffery) Illinois Tim Lazaro (Doug Glysson) University of Missouri at Rolla, 140 (Dr. Glendon Stevens) Dr. Charles Morris...sediment sampling began with periodic particle size samples of suspended material, bedload, and bad material. All data collection at this station has been... Berkas , W.D., Personal Communication, Hydrologist, Water Resources * Division, Missouri, United States Geological Survey, Rolla, Missouri, 1981. 3

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

PubMed Central

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

2015-01-01

Despite efforts for over 25 years, de novo protein design has not succeeded in achieving the TIM-barrel fold. Here we describe the computational design of 4-fold symmetrical (β/α)8-barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of sidechain-backbone hydrogen bonding for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical with the designed TIM-barrel model. PSI-BLAST searches do not identify sequence similarities to known TIM-barrel proteins, and sensitive profile-profile searches indicate that the design sequence is distant from other naturally occurring TIM-barrel superfamilies, suggesting that Nature has only sampled a subset of the sequence space available to the TIM-barrel fold. The ability to de novo design TIM-barrels opens new possibilities for custom-made enzymes. PMID:26595462

A review on the determination of isotope ratios of boron with mass spectrometry.

PubMed

Aggarwal, Suresh Kumar; You, Chen-Feng

2017-07-01

The present review discusses different mass spectrometric techniques-viz, thermal ionization mass spectrometry (TIMS), inductively coupled plasma mass spectrometry (ICPMS), and secondary ion mass spectrometry (SIMS)-used to determine 11 B/ 10 B isotope ratio, and concentration of boron required for various applications in earth sciences, marine geochemistry, nuclear technology, environmental, and agriculture sciences, etc. The details of the techniques-P-TIMS, which uses Cs 2 BO 2 + , N-TIMS, which uses BO 2 - , and MC-ICPMS, which uses B + ions for bulk analysis or B - and B + ions for in situ micro-analysis with SIMS-are highlighted. The capabilities, advantages, limitations, and problems in each mass spectrometric technique are summarized. The results of international interlaboratory comparison experiments conducted at different times are summarized. The certified isotopic reference materials available for boron are also listed. Recent developments in laser ablation (LA) ICPMS and QQQ-ICPMS for solids analysis and MS/MS analysis, respectively, are included. The different aspects of sample preparation and analytical chemistry of boron are summarized. Finally, the future requirements of boron isotope ratios for future applications are also given. Presently, MC-ICPMS provides the best precision and accuracy (0.2-0.4‰) on isotope ratio measurements, whereas N-TIMS holds the potential to analyze smallest amount of boron, but has the issue of bias (+2‰ to 4‰) which needs further investigations. © 2016 Wiley Periodicals, Inc. Mass Spec Rev 36:499-519, 2017. © 2016 Wiley Periodicals, Inc.

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

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

NASA Technical Reports Server (NTRS)

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

2009-01-01

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

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

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.

Determination of low-level (sub-microgram) sulfur concentrations by isotope dilution multi-collector inductively couple plasma mass spectrometry using a 33S spike and internal normalization for mass bias correction.

PubMed

Mann, Jacqueline L; Vocke, Robert D; Kelly, W Robert

2012-05-30

The certification of sulfur (S) in Standard Reference Materials™ by the National Institute of Standards and Technology (NIST) has been exclusively performed using isotope dilution thermal ionization mass spectrometry (ID-TIMS). The ID-TIMS measurement method is limited in its capability for low concentration measurements (<1 µg/g) due to the blank associated with the chemical reduction procedure (≈0.2 S µg). Newly developed materials and applications, such as biofuels made from soy and nanomedicine, pose a challenge to the ID-TIMS technique because of their very low concentrations (<1 µg/g) of S. As described here, a measurement technique with low S blanks is essential for low-level S measurements. An isotope dilution (ID) multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) method combined with an internal normalization approach for mass bias correction has been used to determine low-level S concentrations in synthetically prepared mixtures using a (33)S-enriched spike material. Dilute sulfur solutions (1 µg S/g) were prepared from NIST SRM 3154 (Sulfate Spectrometric Solution) to test the capability of this technique for measuring very low-level S concentrations. The concentration results for each solution were 0.983 ± 0.004 µg/g (95% CI, n = 2, k = 2), 1.006 ± 0.005 µg/g (95% CI, n = 2, k = 2), and 0.999 ± 0.003 µg/g (95% CI, n = 2, k = 2), in excellent agreement with the gravimetric determination, deviating less than 0.35% and suggesting the technique can yield unbiased and accurate results. The blanks averaged 13 ± 0.0017 ng S (1s). The data results provide a clear indication that the ID-MC-ICP-MS method for the determination of low-level S concentrations is feasible. The more than one order of magnitude reduction of the blanks suggests that it is a better alternative to the ID-TIMS method for very low S materials such as are encountered in biofuels and some biochemical species. Published 2012. This article is a US Government work and is in the public domain in the USA. Published 2012. This article is a US Government work and is in the public domain in the USA.

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

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.

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

NASA Astrophysics Data System (ADS)

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

2009-01-01

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

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.

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.

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

PubMed Central

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

2013-01-01

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. PMID:24265941

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.

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

Pixelsex or Cosmic Revelation – how art & science can meet in public space

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

Otto Roth, Tim

2009-10-28

Tim Otto Roth is known for his large projects in public space linking art & science. In his presentation the German artist and media theorist demonstrates some of his latest projects - among others Cosmic Revelation which changed the KASCADE detector field for cosmic rays at the Karlsruhe Institute of Technology into a giant flashing light field. The Pixelsex project leads him to the question if the universe might be digital. In occasion of his one week residency at CERN Tim Otto Roth explores the material culture of particle physics and its ways of finding pictorial representations. Above all hemore » is interested in methods like the Monte Carlo simulation, but also in CERN as giant collaborative institution and consequently as birthplace for the World Wide Web.« less

Pixelsex or Cosmic Revelation – how art & science can meet in public space

ScienceCinema

Otto Roth, Tim

2018-05-18

Tim Otto Roth is known for his large projects in public space linking art & science. In his presentation the German artist and media theorist demonstrates some of his latest projects - among others Cosmic Revelation which changed the KASCADE detector field for cosmic rays at the Karlsruhe Institute of Technology into a giant flashing light field. The Pixelsex project leads him to the question if the universe might be digital. In occasion of his one week residency at CERN Tim Otto Roth explores the material culture of particle physics and its ways of finding pictorial representations. Above all he is interested in methods like the Monte Carlo simulation, but also in CERN as giant collaborative institution and consequently as birthplace for the World Wide Web.

HTLV-1 Tax Specific CD8+ T Cells Express Low Levels of Tim-3 in HTLV-1 Infection: Implications for Progression to Neurological Complications

PubMed Central

Hasenkrug, Aaron M.; Jha, Aashish R.; Carvalho, Karina I.; Eccles-James, Ijeoma G.; Bruno, Fernanda R.; Vieira, Raphaella G. S.; York, Vanessa A.; Chew, Glen M.; Jones, R. Brad; Tanaka, Yuetsu; Neto, Walter K.; Sanabani, Sabri S.; Ostrowski, Mario A.; Segurado, Aluisio C.; Nixon, Douglas F.; Kallas, Esper G.

2011-01-01

The T cell immunoglobulin mucin 3 (Tim-3) receptor is highly expressed on HIV-1-specific T cells, rendering them partially “exhausted” and unable to contribute to the effective immune mediated control of viral replication. To elucidate novel mechanisms contributing to the HTLV-1 neurological complex and its classic neurological presentation called HAM/TSP (HTLV-1 associated myelopathy/tropical spastic paraparesis), we investigated the expression of the Tim-3 receptor on CD8+ T cells from a cohort of HTLV-1 seropositive asymptomatic and symptomatic patients. Patients diagnosed with HAM/TSP down-regulated Tim-3 expression on both CD8+ and CD4+ T cells compared to asymptomatic patients and HTLV-1 seronegative controls. HTLV-1 Tax-specific, HLA-A*02 restricted CD8+ T cells among HAM/TSP individuals expressed markedly lower levels of Tim-3. We observed Tax expressing cells in both Tim-3+ and Tim-3− fractions. Taken together, these data indicate that there is a systematic downregulation of Tim-3 levels on T cells in HTLV-1 infection, sustaining a profoundly highly active population of potentially pathogenic T cells that may allow for the development of HTLV-1 complications. PMID:21541358

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.

Geochemistry, thermometry and isotope ratios on the same zircon crystals: the tandem use of quadrupole LA-ICPMS and CA-TIMS

NASA Astrophysics Data System (ADS)

Olin, P. H.; Schmitz, M. D.; Crowley, J. L.

2011-12-01

Current trends in igneous petrology include the extraction of diverse geochemical information from smaller sample targets by ever more efficient and cost effective means. Igneous zircons are repositories of several types of petrogenetic information, such as magmatic crystallization ages obtained using U-Pb geochronology, magmatic temperatures using Ti-in-zircon geothermometry, and magmatic differentiation and/or mixing trends using trace element contents. Here we demonstrate a tandem quadrupole LA-ICPMS and CA-TIMS approach on single zircon crystals and within domains in single crystals, which extracts all of these data from a single laser spot analysis and then guides the acquisition of CA-TIMS ages at precisions relevant to magmatic histories. We present data from zircon-bearing intrusive and extrusive rocks spanning the compositional spectrum, and highlight results from silicic volcanic rocks with different affinities. The utility of our approach is illustrated in zircons from the Temora diorite, a commonly used standard material which we analysed using 25-μm ablation spots placed on dozens of grains which had been previously annealed and chemically abraded prior to mounting in epoxy. Our LA-ICPMS results illustrate a 3- to 5-fold variation in trace element concentrations and trace element ratios over >150 degrees of cooling as estimated from Ti-in-zircon thermometry. Some geochemical parameters (e.g., Nb/Ta variations and Eu anomalies) are consistent with crystal fractionation during progressive crystallization, while others are bimodal (e.g., Hf and U contents), suggesting the mixing of crystal/magma batches prior to final solidification. LA-ICPMS U-Pb spot ages reproduce the accepted CA-TIMS age within 2% precision and accuracy, while our CA-TIMS results on the same grains constrain the development of the observed geochemical variability to within 100 ka. Other zircon standard materials to be presented include Plesovich syenite, FC1 gabbro, and R33 diorite. Analyses of zircons from selected western Snake River Plain silicic volcanic units further demonstrate the capability of our approach. These units are targeted with the overarching goal of better understanding magmatism in the region and to identify geochemical fingerprints to better distinguish among and to correlate between units. Several rhyolites distributed along the northern margin of the plain have LA-ICPMS ages of ca. 11 Ma, within error of each other and their CA-TIMS ages, and reveal differences in temperatures of crystallization and trace element contents and ratios. Individual units have crystallization temperatures that span 100 degrees or more, and show correlations with whole-rock major and trace element contents and ratios. In many cases, zircon geochemical parameters such as REE and Y contents, and Nb/Ta and Th/U ratios allow units proximal to each other to be distinguished from one another while also providing fingerprints to correlate to distal units on the south side of the plain or elsewhere in the province.

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.

KSC-2013-2909

NASA Image and Video Library

2013-06-25

VANDENBERG AIR FORCE BASE, Calif. – At Vandenberg Air Force Base in California, NASA hosted a prelaunch news conference on the Interface Region Imaging Spectrograph, or IRIS, solar observatory scheduled to launch on a Pegasus XL rocket. Participating in the news conference are George Diller, NASA Public Affairs, Geoffrey Yoder, deputy associate administrator for the Programs, Science Mission Directorate at NASA Headquarters in Washington, D.C., Tim Dunn, NASA launch director/NASA Launch Manager at the Kennedy Space Center in Florida, Bryan Baldwin, Pegasus launch vehicle program director for Orbital Sciences Corp. of Dulles, Va., Gary Kushner, IRIS project manager for Lockheed Martin's Solar and Astrophysics Laboratory in Palo Alto, Calif., and First Lt. Jennifer Kelley, launch weather officer for the U.S. Air Force 30th Operations Support Squadron at Vandenberg. Scheduled for launch from Vandenberg on June 26, 2013, IRIS will open a new window of discovery by tracing the flow of energy and plasma through the chromospheres and transition region into the sun’s corona using spectrometry and imaging. The IRIS mission will observe how solar material moves, gathers energy and heats up as it travels through a largely unexplored region of the solar atmosphere. The interface region, located between the sun's visible surface and upper atmosphere, is where most of the sun's ultraviolet emission is generated. These emissions impact the near-Earth space environment and Earth's climate. For more information, visit http://www.nasa.gov/iris Photo credit: NASA/ Daniel Casper

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

Feet, Footwork, Footwear, and "Being Alive" in the Modern School

ERIC Educational Resources Information Center

Burke, Catherine

2018-01-01

This article considers the theoretical argument of anthropologist Tim Ingold, that the denial and subsequent encasement of bare feet in footwear was a critical characteristic of the development of modern societies, in exploring three aspects of feet, footwork, and footwear in the history of the modern school. First, the material conditions of feet…

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

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

Effects of Different Fabrication Techniques on the Yttrium-Barium-Copper Oxide High Temperature Superconductor

DTIC Science & Technology

1988-12-01

and barium peroxide. The eperimental design includes barium carbonate as a precursor since it is a comronly used starting material for the ccupound...Kerans, Materials Laboratory, for his assistance in designing this project. I would also like to thank Tim Peterson for his patient instructing. I...the design of the devices used for taking measurements was detailed. Chapter IV showed the results of each type of measurement on each individual

Summary Report for the Technical Interchange Meeting on Development of Baseline Material Properties and Design Guidelines for In-Space Manufacturing Activities

NASA Technical Reports Server (NTRS)

Prater, T. J.; Bean, Q. A.; Werkheiser, N. J.; Johnston, M. M.; Ordonez, E. A.; Ledbetter, F. E.; Risdon, D. L.; Stockman, T. J.; Sandridge, S. K. R.; Nelson, G. M.

2016-01-01

NASA Marshall Space Flight Center (MSFC) and the Agency as a whole are currently engaged in a number of in-space manufacturing (ISM) activities that have the potential to reduce launch costs, enhance crew safety, and provide the capabilities needed to undertake long-duration spaceflight. The recent 3D Printing in Zero-G experiment conducted on board the International Space Station (ISS) demonstrated that parts of acrylonitrile butadiene styrene (ABS) plastic can be manufactured in microgravity using fused deposition modeling (FDM). This project represents the beginning of the development of a capability that is critical to future NASA missions. Current and future ISM activities will require the development of baseline material properties to facilitate design, analysis, and certification of materials manufactured using in-space techniques. The purpose of this technical interchange meeting (TIM) was to bring together MSFC practitioners and experts in materials characterization and development of baseline material properties for emerging technologies to advise the ISM team as we progress toward the development of material design values, standards, and acceptance criteria for materials manufactured in space. The overall objective of the TIM was to leverage MSFC's shared experiences and collective knowledge in advanced manufacturing and materials development to construct a path forward for the establishment of baseline material properties, standards development, and certification activities related to ISM. Participants were asked to help identify research and development activities that will (1) accelerate acceptance and adoption of ISM techniques among the aerospace design community; (2) benefit future NASA programs, commercial technology developments, and national needs; and (3) provide opportunities and avenues for further collaboration.

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

Project TIMS (Teaching Integrated Math/Science)

NASA Technical Reports Server (NTRS)

Edwards, Leo, Jr.

1993-01-01

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

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.

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.

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

NASA Astrophysics Data System (ADS)

Hasözbek, Altug; Mathew, Kattathu; Wegener, Michael

2013-04-01

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

A procedural manual for measurement of uranium and thorium isotopes utilizing the USGS-Stanford Finnegan Mat 262

USGS Publications Warehouse

Shamp, Donald D.

2001-01-01

Over the past several decades investigators have extensively examined the 238U-234U- 230Th systematics of a variety of geologic materials using alpha spectroscopy. Analytical uncertainty for 230Th by alpha spectroscopy has been limited to about 2% (2σ). The advantage of thermal ionization mass spectroscopy (TIMS), introduced by Edwards and co-workers in the late 1980’s is the increased detectability of these isotopes by a factor of ~200, and decreases in the uncertainty for 230Th to about 5‰ (2σ) error. This report is a procedural manual for using the USGS-Stanford Finnegan-Mat 262 TIMS to collect and isolate Uranium and Thorium isotopic ratio data. Chemical separation of Uranium and Thorium from the sample media is accomplished using acid dissolution and then processed using anion exchange resins. The Finnegan-Mat262 Thermal Ionization Mass Spectrometer (TIMS) utilizes a surface ionization technique in which nitrates of Uranium and Thorium are placed on a source filament. Upon heating, positive ion emission occurs. The ions are then accelerated and focused into a beam which passes through a curved magnetic field dispersing the ions by mass. Faraday cups and/or an ion counter capture the ions and allow for quantitative analysis of the various isotopes.

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.

Optimization Techniques for Improving the Precision of Isotopic Analysis by Thermal Ionization Mass Spectrometry

NASA Astrophysics Data System (ADS)

Wang, G. Q.; Xu, J. F.; Wu-Yang, S. Q.

2016-12-01

Operation of instruments and preparation of samples are also significant factors that can affect the precision of TIMS analyses, in addition to instrument hardware. We have reviewed the isotopic data of several standard materials at our TIMS lab for 5 years. It is suggested that several optimization techniques should be used in order to obtain high-precision isotopic ratio data: (1) It is important to choose a suitable filament material for isotopic measurements. We have established that W filament is likely the most efficient for ionizing Sr when selecting from W, Re, and Ta; meanwhile, Re filament can produce a higher intensity for Nd isotopes than W and Ta filament can. It is concluded that the best TIMS signals are obtained for Sr using W signal-filaments and for Nd using Re double-filaments. (2) The preparation of the activator plays a key role in the analysis of some isotopic ratios. This study indicates that choosing a suitable activator can greatly elevate the precision of 206Pb/204Pb ratios during Pb isotopic measurements. We have suggested a new scheme to make an activator by using a mixture of 10% Si-gel + 7.5% H3PO3 + 82.5% H2O (weight %). (3) It is necessary to re-set the cup configuration to avoid cup degradation when operating for a long period of time (a year or more). We propose a new cup configuration to avoid this disadvantage during Sr isotopic analyses. (4) The contamination of 187Re and 185Re after using Re-filament could be eliminated by cleaning the ion source and baking the source housing.

Essentials of iron, chromium, and calcium isotope analysis of natural materials by thermal ionization mass spectrometry

USGS Publications Warehouse

Fantle, M.S.; Bullen, T.D.

2009-01-01

The use of isotopes to understand the behavior of metals in geological, hydrological, and biological systems has rapidly expanded in recent years. One of the mass spectrometric techniques used to analyze metal isotopes is thermal ionization mass spectrometry, or TIMS. While TIMS has been a useful analytical technique for the measurement of isotopic composition for decades and TIMS instruments are widely distributed, there are significant difficulties associated with using TIMS to analyze isotopes of the lighter alkaline earth elements and transition metals. Overcoming these difficulties to produce relatively long-lived and stable ion beams from microgram-sized samples is a non-trivial task. We focus here on TIMS analysis of three geologically and environmentally important elements (Fe, Cr, and Ca) and present an in-depth look at several key aspects that we feel have the greatest potential to trouble new users. Our discussion includes accessible descriptions of different analytical approaches and issues, including filament loading procedures, collector cup configurations, peak shapes and interferences, and the use of isotopic double spikes and related error estimation. Building on previous work, we present quantitative simulations, applied specifically in this study to Fe and Ca, that explore the effects of (1) time-variable evaporation of isotopically homogeneous spots from a filament and (2) interferences on the isotope ratios derived from a double spike subtraction routine. We discuss how and to what extent interferences at spike masses, as well as at other measured masses, affect the double spike-subtracted isotope ratio of interest (44Ca/40Ca in the case presented, though a similar analysis can be used to evaluate 56Fe/54Fe and 53Cr/52Cr). The conclusions of these simulations are neither intuitive nor immediately obvious, making this examination useful for those who are developing new methodologies. While all simulations are carried out in the context of a specific isotope system, it should be noted that the same methods can be used to evaluate any isotope system of interest. ?? 2008 Elsevier B.V.

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.

Numerical Study of High-Speed Droplet Impact on Surfaces and its Physical Cleaning Effects

NASA Astrophysics Data System (ADS)

Kondo, Tomoki; Ando, Keita

2015-11-01

Spurred by the demand for cleaning techniques of low environmental impact, one favors physical cleaning that does not rely on any chemicals. One of the promising candidates is based on water jets that often involve fission into droplet fragments and collide with target surfaces to which contaminant particles (often micron-sized or even smaller) stick. Hydrodynamic force (e.g., shearing and lifting) arising from the droplet impact will play a role to remove the particles, but its detailed mechanism is still unknown. To explore the role of high-speed droplet impact in physical cleaning, we solve compressible Navier-Stokes equations with a finite volume method that is designed to capture both shocks and material interfaces in accurate and robust manners. Water hammer and shear flow accompanied by high-speed droplet impact at a rigid wall is simulated to evaluate lifting force and rotating torque, which are relevant to the application of particle removal. For the simulation, we use the numerical code recently developed by Computational Flow Group lead by Tim Colonius at Caltech. The first author thanks Jomela Meng for her help in handling the code during his stay at Caltech.

Effects of Solvation on One- and Two-Photon Spectra of Coumarin Derivatives: A Time-Dependent Density Functional Theory Study (Postprint)

DTIC Science & Technology

2007-01-01

2003. 15 A. Barik , S. Nath, and H. Pal, J . Chem. Phys. 119, 10202 2003. 16 A. Fisher, C. Cremer, and E. H. K. Stelzer, Appl. Opt. 34, 1989 1995...Hardened Materials Branch //Signature// TIM J . SCHUMACHER, Chief Survivability and Sensor Materials Division This...coumarin 152, 152A, 522, 153, 307, and 151. 094303-2 Nguyen, Day, and Pachter J . Chem. Phys. 126, 094303 2007 Downloaded 06 Nov 2007 to 134.131.125.49

Real-Time, General-Purpose, High-Speed Signal Processing Systems for Underwater Research. Proceedings of a Working Level Conference held at Supreme Allied Commander, Atlantic, Anti-Submarine Warfare Research Center (SACLANTCEN) on 18-21 September 1979. Part 1. Sessions I to III.

DTIC Science & Technology

1979-12-01

intelligent graphics terminals in real-tim processing S (e) 5-1 to 5-9 MIel ita|ger The application of high-speed processors to propagation e.piriamnts...interface SACLANTCEN CP-25 5-2 M IM M STEIGER: Intelligent graphics terminals The less desirable features of the terminal are listed below. reiatively small...hours. Dismantling of the equipment is normally performed in less than one-half hour and often while waiting to clear customs. Transportation of the

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...

Learning to Grow

ERIC Educational Resources Information Center

Rodia, Becky

2004-01-01

What does the National Football League have in common with a small K-6 school in Iowa City, Iowa? Two things: one is San Diego Chargers wide receiver Tim Dwight, who grew up in Iowa City, where he attended Mark Twain Elementary; the other is Twain third grade teacher Julie Busch, Tim's former teacher and--thanks to Tim's thoughtful…

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.

Compliance and Functional Testing of IEEE 1451.1 for NCAP-to-NCAP Communications in a Sensor Network

NASA Technical Reports Server (NTRS)

Figueroa, Jorge; Gurkan, Deniz; Yuan, X.; Benhaddou, D.; Liu, H.; Singla, A.; Franzl, R.; Ma, H.; Bhatt, S.; Morris, J.;

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.

How Theories of Perception Deploy the Line: Reconfiguring Students' Bodies through Topo-Philosophy

ERIC Educational Resources Information Center

de Freitas, Elizabeth

2014-01-01

In this essay Elizabeth de Freitas follows Tim Ingold's groundbreaking anthropological work on lines and their cultural and material significance to argue that the line is the engine of theory, be it the drawn line of inscription or mathematical measure, the exclusionary line of delineation, or the undulating generative line of flight. De…

Counter-Chemical, Biological, Radiological, and Nuclear Operations

DTIC Science & Technology

2007-01-26

environment. (Page 10) Consequence management activities serve to reduce the effects of a CBRN attack or event, and assist in the restoration of...can be used quite effectively as attack agents. Toxic Industrial Chemicals (TICs), Toxic Industrial Materials (TIMs), and other potentially...CBRN pillars. Consequence Management Consequence management (CM) activities serve to reduce the effects of a CBRN attack or event, and assist in

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.

Mini-DIAL system measurements coupled with multivariate data analysis to identify TIC and TIM simulants: preliminary absorption database analysis.

NASA Astrophysics Data System (ADS)

Gaudio, P.; Malizia, A.; Gelfusa, M.; Martinelli, E.; Di Natale, C.; Poggi, L. A.; Bellecci, C.

2017-01-01

Nowadays Toxic Industrial Components (TICs) and Toxic Industrial Materials (TIMs) are one of the most dangerous and diffuse vehicle of contamination in urban and industrial areas. The academic world together with the industrial and military one are working on innovative solutions to monitor the diffusion in atmosphere of such pollutants. In this phase the most common commercial sensors are based on “point detection” technology but it is clear that such instruments cannot satisfy the needs of the smart cities. The new challenge is developing stand-off systems to continuously monitor the atmosphere. Quantum Electronics and Plasma Physics (QEP) research group has a long experience in laser system development and has built two demonstrators based on DIAL (Differential Absorption of Light) technology could be able to identify chemical agents in atmosphere. In this work the authors will present one of those DIAL system, the miniaturized one, together with the preliminary results of an experimental campaign conducted on TICs and TIMs simulants in cell with aim of use the absorption database for the further atmospheric an analysis using the same DIAL system. The experimental results are analysed with standard multivariate data analysis technique as Principal Component Analysis (PCA) to develop a classification model aimed at identifying organic chemical compound in atmosphere. The preliminary results of absorption coefficients of some chemical compound are shown together pre PCA analysis.

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.

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.

Northeast Regional Planetary Data Center

NASA Technical Reports Server (NTRS)

Schultz, Peter H.; Saunders, Stephen (Technical Monitor)

2005-01-01

In 1980, the Northeast Planetary Data Center (NEPDC) was established with Tim Mutch as its Director. The Center was originally located in the Sciences Library due to space limitations but moved to the Lincoln Field Building in 1983 where it could serve the Planetary Group and outside visitors more effectively. In 1984 Dr. Peter Schultz moved to Brown University and became its Director after serving in a similar capacity at the Lunar and Planetary Institute since 1976. Debbie Glavin has served as the Data Center Coordinator since 1982. Initially the NEPDC was build around Tim Mutch's research collection of Lunar Orbiter and Mariner 9 images with only partial sets of Apollo and Viking materials. Its collection was broadened and deepened as the Director (PHS) searched for materials to fill in gaps. Two important acquisitions included the transfer of a Viking collection from a previous PI in Tucson and the donation of surplused lunar materials (Apollo) from the USGS/Menlo Park prior to its building being torn down. Later additions included the pipeline of distributed materials such as the Viking photomosaic series and certain Magellan products. Not all materials sent to Brown, however, found their way to the Data Center, e.g., Voyager prints and negatives. In addition to the NEPDC, the planetary research collection is separately maintained in conjunction with past and ongoing mission activities. These materials (e.g., Viking, Magellan, Galileo, MGS mission products) are housed elsewhere and maintained independently from the NEPDC. They are unavailable to other researchers, educators, and general public. Consequently, the NEPDC represents the only generally accessible reference collection for use by researchers, students, faculty, educators, and general public in the Northeast corridor.

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

Visible Light Emitting Materials and Injection Devices

DTIC Science & Technology

1993-01-01

view to preventing the occurrence of faceting in these films. (II) MOCVD growth of II-VI materials (Tim Anderson) (11.1) Growth of novel Zn ZCd SSeI ...E.J. Stofko and R.J, Paff, "Synthesis and some properties of BeTe, BeSe, and BeS", J, Phys, Chem. Soiid. 33 (1972) 501. 2. R. Yamamoto, M . Inoue, K...Technology," SID Seminar Lecture Notes, 1988, Vol. 1 7. R.M. Park, M ,B. Troffer, and C.M. Rouleau, "p-type ZnSe by nitrogen atom beam doping during molecular

Kopra at the MSG

NASA Image and Video Library

2016-04-07

ISS047e050514 (04/07/2016) --- Expedition 47 Commander Tim Kopra configures the station’s Microgravity Science Glovebox for upcoming research operations. The glovebox is one of the major dedicated science facilities inside Destiny. It has a large front window and built-in gloves to provide a sealed environment for conducting science and technology experiments. The Glovebox is particularly suited for handling hazardous materials when the crew is present.

Molecular Nanoparks for CWAs, TICs, and TIMs

DTIC Science & Technology

2012-12-11

Symposium on Macrocyclic and Supramolecular Chemistry, June 2010, Nara, Japan (Plenary talk). O. M. Yaghi, Zeolitic imidazolate frameworks, 5th...International Zeolite Membrane Meeting, May 2010, Loutraki, Greece (Plenary talk). O. M. Yaghi, Reticular chemistry and its applications to clean energy...highest uptake capacity (15 mol/kg, 298 K, 1 bar) of any porous material, including zeolite , cation exchange resin, and mesoporous silica. 4. The gas

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.

The plutonic-volcanic connection in porphyry copper deposits: Evidence from zircon geochemistry and high-precision CA-ID-TIMS geochronology

NASA Astrophysics Data System (ADS)

Buret, Y.; Von Quadt, A.; Wotzlaw, J. F.; Heinrich, C. A.

2016-12-01

Porphyry Cu deposits represent the interface between plutonic and volcanic domains of upper crustal magmatic systems. These deposits are typically composed of multiple porphyritic intrusions which constrain the duration of ore formation to a maximum of several 104 years [1] and are commonly intruded into the base of volcanoes. The relationship between volcanic activity and porphyry stocks is often difficult to establish, as they are rarely exposed together unless later faulting and/or tilting occurred [2]. In order to investigate the relationships between extrusive magmatism and porphyry Cu formation we compare zircon petrochronology from late stage volcanic units with the nearby world class Bajo de la Alumbrera porphyry Cu deposit, from the Late Miocene Farallón Negro Volcanic Complex (FNVC) in Northwest Argentina. In this study we texturally characterise zircon crystals by CL-imaging prior to obtaining in-situ geochemical and geochronological information by LA-ICP-MS. Analysed zircon grains were then extracted and analysed by high precision CA-ID-TIMS. This approach has the two-fold benefit of screening for inherited cores, and obtaining texturally defined geochemical information, prior to dissolution of the zircon crystal for CA-ID-TIMS analysis. We use this information to establish temporal and geochemical links between studied volcanic and porphyry units in the FNVC. The results of this study suggest a close temporal and genetic link between the Bajo de la Alumbrera porphyry Cu deposit and the late stage volcanism at the FNVC. Voluminous explosive volcanism immediately following porphyry formation has important implications for the thermal and rheological state of the magma that is parental to the porphyries and fed the eruption. Further work investigating the geochemistry of other accessory and major minerals could shed further light on the evolution of the magmatic body prior to eruption/ emplacement. References: [1] Buret et al. (2016) EPSL 450:120-131; [2] Dilles (1987) Econ Geol 82:1750-1789.

Variable Spaced Grating (VSG) Snout, Rotator and Rails for use at LLE

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

Mukherjee, S K; Emig, J A; Griffith, L V

2010-01-25

The Variable Spaced Grating (VSG) is a spectrometer snout mounted to an X-Ray Framing Camera (XRFC) through the Unimount flange. This equipment already exists and is used at the University of Rochester, Laboratory for Laser Energetics (LLE) facility. The XRFC and the Unimount flange are designed by LLE. The Tilt Rotator fixture that mounts next to the XRFC and the cart rails are designed by LLNL, and are included in this safety note. The other related components, such as the TIM rails and the Unimount flange, are addressed in a separate safety note, EDSN09-500005-AA. The Multipurpose Spectrometer (MSPEC) and VSGmore » are mounted on the TIM Boat through the cart rails that are very similar in design. The tilt rotator combination with the Unimount flange is also a standard mounting procedure. The later mounting system has been included in this safety note. Figure-1 shows the interface components and the VSG snout. Figure-2 shows the VSG assembly mounted on the Unimount flange. The calibration pointer attachment is shown in place of the snout. There are two types of VSG, one made of 6061-T6 aluminum, weighing approximately 3 pounds, and the other made of 304 stainless steel, weighing approximately 5.5 pounds. This safety note examines the VSG steel design. Specific experiments may require orienting the VSG snout in 90 degrees increment with respect to the Unimount flange. This is done by changing the bolts position on the VSG-main body adapter flange to the Unimount adapter plate. There is no hazard involved in handling the VSG during this procedure as it is done outside the target chamber on the cart rail before installing on the TIM. This safety note addresses the mechanical integrity of the VSG structure, the tilt rotating fixture, the cart rails with handle and their connections. Safety Factors are also calculated for the MSPEC in place of the VSG.« less

PD-1+Tim-3+ CD8+ T Lymphocytes Display Varied Degrees of Functional Exhaustion in Patients with Regionally Metastatic Differentiated Thyroid Cancer

PubMed Central

Severson, Jill J.; Serracino, Hilary S.; Mateescu, Valerica; Raeburn, Christopher D.; C.McIntyre, Robert; Sams, Sharon B.; Haugen, Bryan R.; French, Jena D.

2015-01-01

Regional metastatic differentiated thyroid cancer (mDTC) provides a unique model in which to study the tumor-immune interface. These lymph node (LN) metastases persist for years, generally without progression to distant metastases. While the immune system likely impedes disease progression, it is unsuccessful in eliminating disease. Our previous studies revealed that programmed death-1 (PD-1)+ T cells were enriched in tumor-involved lymph nodes (TILN). Tumor-associated leukocytes and tumor cells were collected from grossly involved LNs from 12 patients to further characterize the phenotype and functional potential of mDTC-associated PD-1+ T cells. PD-1+CD4+ and PD-1+CD8+ T cells were enriched in 8/12 TILN samples. PD-1+ T cells co-expressed Tim-3 and CD69 and failed to down-regulate CD27. CD8+ T cells, but not CD4+ T cells, from these samples were variably deficient in their ability to produce effector cytokines when compared to control TILNs that lacked resident PD-1+ T cells. PD-1+CD8+ T cells were capable of exocytosis but lacked intracellular perforin. Surprisingly, T-cell proliferative capacity was largely maintained in all samples. Thus, while PD-1 expression by mDTC-associated CD8+ T cells was associated with dysfunction, exhaustion was not complete. Notably, molecular markers of exhaustion did not translate to dysfunction in all samples or in CD4+ T cells. Regulatory T (Treg) cells, PD-L1, and galectin-9 were commonly found in mDTC and likely contributed to the initiation of T-cell exhaustion and disease progression. Therapies that release the effects of PD-1 and Tim-3 and reduce the suppressive effects of Tregs may encourage tumor elimination in patients with mDTC. PMID:25701326

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.

Precise determination of δ88Sr in rocks, minerals, and waters by double-spike TIMS: A powerful tool in the study of chemical, geologic, hydrologic and biologic processes

USGS Publications Warehouse

Neymark, Leonid A.; Premo, Wayne R.; Mel'nikov, Nikolay N.; Emsbo, Poul

2014-01-01

We present strontium isotopic (88Sr/86Sr and 87Sr/86Sr) results obtained by 87Sr–84Sr double spike thermal ionization mass-spectrometry (DS-TIMS) for several standards as well as natural water samples and mineral samples of abiogenic and biogenic origin. The detailed data reduction algorithm and a user-friendly Sr-specific stand-alone computer program used for the spike calibration and the data reduction are also presented. Accuracy and precision of our δ88Sr measurements, calculated as permil (‰) deviations from the NIST SRM-987 standard, were evaluated by analyzing the NASS-6 seawater standard, which yielded δ88Sr = 0.378 ± 0.009‰. The first DS-TIMS data for the NIST SRM-607 potassium feldspar standard and for several US Geological Survey carbonate, phosphate, and silicate standards (EN-1, MAPS-4, MAPS-5, G-3, BCR-2, and BHVO-2) are also reported. Data obtained during this work for Sr-bearing solids and natural waters show a range of δ88Sr values of about 2.4‰, the widest observed so far in terrestrial materials. This range is easily resolvable analytically because the demonstrated external error (±SD, standard deviation) for measured δ88Sr values is typically ≤0.02‰. It is shown that the “true” 87Sr/86Sr value obtained by the DS-TIMS or any other external normalization method combines radiogenic and mass-dependent mass-fractionation effects, which cannot be separated. Therefore, the “true” 87Sr/86Sr and the δ87Sr parameter derived from it are not useful isotope tracers. Data presented in this paper for a wide range of naturally occurring sample types demonstrate the potential of the δ88Sr isotope tracer in combination with the traditional radiogenic 87Sr/86Sr tracer for studying a variety of biological, hydrological, and geological processes.

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.

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).

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

NASA Astrophysics Data System (ADS)

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

2014-12-01

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

U.S. Tsunami Information technology (TIM) Modernization:Developing a Maintainable and Extensible Open Source Earthquake and Tsunami Warning System

NASA Astrophysics Data System (ADS)

Hellman, S. B.; Lisowski, S.; Baker, B.; Hagerty, M.; Lomax, A.; Leifer, J. M.; Thies, D. A.; Schnackenberg, A.; Barrows, J.

2015-12-01

Tsunami Information technology Modernization (TIM) is a National Oceanic and Atmospheric Administration (NOAA) project to update and standardize the earthquake and tsunami monitoring systems currently employed at the U.S. Tsunami Warning Centers in Ewa Beach, Hawaii (PTWC) and Palmer, Alaska (NTWC). While this project was funded by NOAA to solve a specific problem, the requirements that the delivered system be both open source and easily maintainable have resulted in the creation of a variety of open source (OS) software packages. The open source software is now complete and this is a presentation of the OS Software that has been funded by NOAA for benefit of the entire seismic community. The design architecture comprises three distinct components: (1) The user interface, (2) The real-time data acquisition and processing system and (3) The scientific algorithm library. The system follows a modular design with loose coupling between components. We now identify the major project constituents. The user interface, CAVE, is written in Java and is compatible with the existing National Weather Service (NWS) open source graphical system AWIPS. The selected real-time seismic acquisition and processing system is open source SeisComp3 (sc3). The seismic library (libseismic) contains numerous custom written and wrapped open source seismic algorithms (e.g., ML/mb/Ms/Mwp, mantle magnitude (Mm), w-phase moment tensor, bodywave moment tensor, finite-fault inversion, array processing). The seismic library is organized in a way (function naming and usage) that will be familiar to users of Matlab. The seismic library extends sc3 so that it can be called by the real-time system, but it can also be driven and tested outside of sc3, for example, by ObsPy or Earthworm. To unify the three principal components we have developed a flexible and lightweight communication layer called SeismoEdex.

Physicochemical characterization of titanium dioxide pigments using various techniques for size determination and asymmetric flow field flow fractionation hyphenated with inductively coupled plasma mass spectrometry.

PubMed

Helsper, Johannes P F G; Peters, Ruud J B; van Bemmel, Margaretha E M; Rivera, Zahira E Herrera; Wagner, Stephan; von der Kammer, Frank; Tromp, Peter C; Hofmann, Thilo; Weigel, Stefan

2016-09-01

Seven commercial titanium dioxide pigments and two other well-defined TiO2 materials (TiMs) were physicochemically characterised using asymmetric flow field flow fractionation (aF4) for separation, various techniques to determine size distribution and inductively coupled plasma mass spectrometry (ICPMS) for chemical characterization. The aF4-ICPMS conditions were optimised and validated for linearity, limit of detection, recovery, repeatability and reproducibility, all indicating good performance. Multi-element detection with aF4-ICPMS showed that some commercial pigments contained zirconium co-eluting with titanium in aF4. The other two TiMs, NM103 and NM104, contained aluminium as integral part of the titanium peak eluting in aF4. The materials were characterised using various size determination techniques: retention time in aF4, aF4 hyphenated with multi-angle laser light spectrometry (MALS), single particle ICPMS (spICPMS), scanning electron microscopy (SEM) and particle tracking analysis (PTA). PTA appeared inappropriate. For the other techniques, size distribution patterns were quite similar, i.e. high polydispersity with diameters from 20 to >700 nm, a modal peak between 200 and 500 nm and a shoulder at 600 nm. Number-based size distribution techniques as spICPMS and SEM showed smaller modal diameters than aF4-UV, from which mass-based diameters are calculated. With aF4-MALS calculated, light-scattering-based "diameters of gyration" (Øg) are similar to hydrodynamic diameters (Øh) from aF4-UV analyses and diameters observed with SEM, but much larger than with spICPMS. A Øg/Øh ratio of about 1 indicates that the TiMs are oblate spheres or fractal aggregates. SEM observations confirm the latter structure. The rationale for differences in modal peak diameter is discussed.

Measurement and Analysis of Thermal Energy Responses from Discrete Urban Surfaces Using Remote Sensing Data

NASA Technical Reports Server (NTRS)

Quattrochi, D. A.; Ridd, M. K.

1993-01-01

This study employs data from the airborne Thermal Infrared Multispectral Scanner (TIMS) to measure thermal (i.e., longwave) energy responses, emitted or upwelling, from discrete surfaces that are typical of the city landscape within Salt Lake City, Utah, over a single diurnal time period (i.e., a single day, night-time sequence). These data are used to quantify the disposition of thermal energy for selected urban surfaces during the daytime and night-time, and the amount of change in thermal response or flux recorded between day and night. An analysis is presented on the thermal interrelationships observed for common urban materials for day, night, and flux, as identified from the TIMS data through the delineation of discrete surface type polygons. The results from the study illustrate that such factors as heat capacity, thermal conductivity, and the amount of soil moisture available have a profound impact on the magnitude of thermal energy emanating from a specific surface and on the dynamics of longwave energy response between day and night.

Multispectral thermal infrared mapping of the 1 October 1988 Kupaianaha flow field, Kilauea volcano, Hawaii

NASA Technical Reports Server (NTRS)

Realmuto, Vincent J.; Hon, Ken; Kahle, Anne B.; Abbott, Elsa A.; Pieri, David C.

1992-01-01

Multispectral thermal infrared radiance measurements of the Kupaianaha flow field were acquired with the NASA airborne Thermal Infrared Multispectral Scanner (TIMS) on the morning of 1 October 1988. The TIMS data were used to map both the temperature and emissivity of the surface of the flow field. The temperature map depicted the underground storage and transport of lava. The presence of molten lava in a tube or tumulus resulted in surface temperatures that were at least 10 C above ambient. The temperature map also clearly defined the boundaries of hydrothermal plumes which resulted from the entry of lava into the ocean. The emissivity map revealed the boundaries between individual flow units within the Kupaianaha field. Distinct spectral anomalies, indicative of silica-rich surface materials, were mapped near fumaroles and ocean entry sites. This apparent enrichment in silica may have resulted from an acid-induced leaching of cations from the surfaces of glassy flows.

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

JALT98 Proceedings. The Proceedings of the JALT Annual International Conference on Language Teaching/Learning & Educational Materials Expo. Focus on the Classroom: Interpretations (24th, Omiya, Saitama, Japan, November 20-23, 1998).

ERIC Educational Resources Information Center

Barfield, Andrew, Ed.; Betts, Robert, Ed.; Cunningham, Joyce, Ed.; Dunn, Neil, Ed.; Katsura, Haruko, Ed.; Kobayashi, Kunihiko, Ed.; Padden, Nina, Ed.; Parry, Neil, Ed.; Watanabe, Mayumi, Ed.

This volume includes papers presented at the 1998 Japan Association for Language Teaching Conference. Section 1, "Voices of Experience," includes: "Towards More Use of English in Class by JTEs" (Midori Iwano); "Paperless Portfolios" (Tim Stewart); "Textbook Creation in Reverse Order for Chinese" (Chou Jine…

GSD-1G and MPI-DING Reference Glasses for In Situ and Bulk Isotopic Determination

USGS Publications Warehouse

Jochum, K.P.; Wilson, S.A.; Abouchami, W.; Amini, M.; Chmeleff, J.; Eisenhauer, A.; Hegner, E.; Iaccheri, L.M.; Kieffer, B.; Krause, J.; McDonough, W.F.; Mertz-Kraus, R.; Raczek, I.; Rudnick, R.L.; Scholz, Donna K.; Steinhoefel, G.; Stoll, B.; Stracke, A.; Tonarini, S.; Weis, D.; Weis, U.; Woodhead, J.D.

2011-01-01

This paper contains the results of an extensive isotopic study of United States Geological Survey GSD-1G and MPI-DING reference glasses. Thirteen different laboratories were involved using high-precision bulk (TIMS, MC-ICP-MS) and microanalytical (LA-MC-ICP-MS, LA-ICP-MS) techniques. Detailed studies were performed to demonstrate the large-scale and small-scale homogeneity of the reference glasses. Together with previously published isotopic data from ten other laboratories, preliminary reference and information values as well as their uncertainties at the 95% confidence level were determined for H, O, Li, B, Si, Ca, Sr, Nd, Hf, Pb, Th and U isotopes using the recommendations of the International Association of Geoanalysts for certification of reference materials. Our results indicate that GSD-1G and the MPI-DING glasses are suitable reference materials for microanalytical and bulk analytical purposes. Ce document contient les r??sultats d'une importante ??tude isotopique des verres de r??f??rence USGS GSD-1G et MPI-DING. Treize laboratoires diff??rents ont particip?? au travers de techniques analytiques de haute pr??cision travaillant soit sur ??chantillon total (TIMS, MC-ICP-MS) soit par microanalyse ??in situ?? (LA-MC-ICP-MS, LA-ICP-MS). ?? 2010 The Authors. Geostandards and Geoanalytical Research ?? 2010 International Association of Geoanalysts.

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.

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

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

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.

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.

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

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

A comparative study of 129I content in environmental standard materials IAEA-375, NIST SRM 4354 and NIST SRM 4357 by Thermal Ionization Mass Spectrometry and Accelerator Mass Spectrometry.

PubMed

Olson, John; Adamic, Mary; Snyder, Darin; Brookhart, Jacob; Hahn, Paula; Watrous, Matthew

2017-08-01

Iodine environmental measurements have consistently been validated in the literature using the standard material IAEA-375, soil collected approximately 160 miles northeast of Chernobyl, which is currently the only soil/sediment material with a certified 129 I activity. IAEA-375 has not been available for purchase since approximately 2010. Two other standard materials that are available (NIST SRM 4354, freshwater lake sediment and NIST SRM 4357, ocean sediment) have certified activities for a variety of radionuclides but not for 129 I. This paper reports a comparison of TIMS and AMS data for all three standards. Copyright © 2017. Published by Elsevier Ltd.

New Insights on the Recrystallization and New Growth of Extensively Radiation-damaged Zircon

NASA Astrophysics Data System (ADS)

Hanchar, J. M.; Schmitz, M. D.; Wirth, R.

2012-12-01

Approximately 10 grams of cm-sized nearly metamict zircon crystals from the Saranac Prospect in the Bancroft District of Ontario were combined by breaking into small pieces and then ground under ethanol to a fine powder with an agate mortar and pestle in order to make enough homogeneously mixed material for multiple powder X-Ray and diffraction scans, high-resolution transmission electron microscopy (HR-TEM) measurements, and chemical abrasion isotope dilution thermal ionization mass spectrometry (CA-TIMS). While these large zircon crystals ground to a powder have a larger surface area and not in the same physical state (i.e., brown and metamict) as what is typically analyzed in single zircon CA-ID-TIMS U-Pb analysis (clear euhedral grains), the physical and chemical changes that occur during the heat treatment used in CA-TIMS are thought to be similar processes. Aliquots of the ground zircon powder were annealed in situ using a Pt furnace in a powder diffractometer during which time simultaneous powder diffraction patterns were acquired starting at 25°C, at elevated temperature (from 500°C to 1400°C) at selected time intervals, and then again at 25°C. The powder X-ray diffraction results indicate that below ~900°C the recrystallization of the zircon powder commences but is incomplete, even after 36 hours, with diffuse low intensity diffraction peaks. At 1150°C the zircon powder shows significant recrystallization. At 1150°C, the recrystallization is essentially complete in less than one hour. Before heating the zircon powder samples consisted of clear, transparent to brown, translucent, complexly zoned fragments. After heating at 900°C the zircon powder retained a smaller percentage of clear or brown complexly zoned fragments, while the majority of material had transformed to oscillatory or irregularly zoned, dominantly white opaque microcrystalline fragments. The clear fragments were hypothesized to be preexisting original crystalline zircon, the brown complexly zoned fragments preexisting metamict zircon, and the white opaque fragment new recrystallized zircon and other oxides. At 1150°C all that remained after heating were dominantly white opaque fragments and extremely rare clear fragments. A variety of fragment types from unannealed, 900°C and 1150°C anneals were chemically abraded in concentrated hydrofluoric acid at 190°C for 12 hours. Upon treatment with chemical abrasion, all unannealed material, nearly all material from the 900°C anneal, and all white opaque microcrystalline material from the 1150°C anneal dissolved; only the rare residual clear, transparent fragments from the 1150°C anneal were robust to chemical abrasion at these conditions. Residual clear fragments yielded concordant U-Pb ID-TIMS dates of 1064 Ma (considering updated U decay constant ratio), confirming the hypothesis that low-U closed system domains are preserved through annealing up to 1150°C and can be extracted via chemical abrasion from even dominantly metamict zircon crystals. By contrast, newly formed crystallites resulting from metamict zircon breakdown during annealing appear to be quite soluble during chemical abrasion. Further experiments are underway to refine minimum threshold chemical abrasion conditions necessary to eliminate open-system domains in the Saranac zircon.

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.

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

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.

KSC-04PD-0148

NASA Technical Reports Server (NTRS)

2004-01-01

KENNEDY SPACE CENTER, FLA. Astronaut Tim Kopra (second from right) talks with workers in the Space Station Processing Facility about the Intravehicular Activity (IVA) constraints testing on the Italian-built Node 2, a future element of the International Space Station. . The second of three Station connecting modules, the Node 2 attaches to the end of the U.S. Lab and provides attach locations for several other elements. Kopra is currently assigned technical duties in the Space Station Branch of the Astronaut Office, where his primary focus involves the testing of crew interfaces for two future ISS modules as well as the implementation of support computers and operational Local Area Network on ISS. Node 2 is scheduled to launch on mission STS-120, Station assembly flight 10A.

Irondequoit Creek Watershed New York, Final Feasibility Report and Environmental Impact Statement.

DTIC Science & Technology

1982-03-01

National Flood Insurance Program 58 8 System of Accounts 95 9 Summary of Benefits and Costs 96 10 Summary of Average Annual Benefits - Selected Plan 112...material, velocity distribution, vegetation, soil type, topography, and especially rainfall regime, where a few intense storms can account for severe...Alternative B is described later in this report. Flood Insurance - Flood insurance provides some financial protection to vic- tims of flood related

Stabile Chlorine Isotope Study of Martian Shergottites and Nakhlites; Whole Rock and Acid Leachates and Residues

NASA Technical Reports Server (NTRS)

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

2011-01-01

We have established a precise analytical technique for stable chlorine isotope measurements of tiny planetary materials by TIMS (Thermal Ionization Mass Spectrometry) [1], for which the results are basically consistent with the IRMS tech-nique (gas source mass spectrometry) [2,3,4]. We present here results for Martian shergottites and nakhlites; whole rocks, HNO3-leachates and residues, and discuss the chlorine isotope evolution of planetary Mars.

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

Crystallisation ages in coeval silicic magma bodies: 238U-230Th disequilibrium evidence from the Rotoiti and earthquake flat eruption deposits, Taupo volcanic zone, New Zealand

USGS Publications Warehouse

Charlier, B.L.A.; Peate, D.W.; Wilson, C.J.N.; Lowenstern, J. B.; Storey, M.; Brown, S.J.A.

2003-01-01

The timescales over which moderate to large bodies of silicic magma are generated and stored are addressed here by studies of two geographically adjacent, successive eruption deposits in the Taupo Volcanic Zone, New Zealand. The earlier, caldera-forming Rotoiti eruption (>100 km3 magma) at Okataina volcano was followed, within months at most, by the Earthquake Flat eruption (??? 10 km3 magma) from nearby Kapenga volcano; both generated nonwelded ignimbrite and coeval widespread fall deposits. The Rotoiti and Earthquake Flat deposits are both crystal-rich high-silica rhyolites, with sparse glass-bearing granitoid fragments also occurring in Rotoiti lag breccias generated during caldera collapse. Here we report 238U-230Th disequilibrium data on whole rocks and mineral separates from representative Rotoiti and Earthquake Flat pumices and the co-eruptive Rotoiti granitoid fragments using TIMS and in situ zircon analyses by SIMS. Multiple-grain zircon-controlled crystallisation ages measured by TIMS from the Rotoiti pumice range from 69??3 ka ( 350 ka, with a pronounced peak at 70-90 ka. The weighted mean of isochrons is 83??14 ka, in accord with the TIMS data. One glass-bearing Rotoiti granitoid clast yielded an age of 57??8 ka by TIMS (controlled by Th-rich phases that, however, are not apparently present in the juvenile pumices). Another glass-bearing Rotoiti granitoid yielded SIMS zircon model ages peaking at 60-90 ka, having a similar age distribution to the pumice. Age data from pumices are consistent with a published 64??4 ka eruptive age (now modified to 62??2 ka), but chemical and/or mineralogical data imply that the granitoid lithics are not largely crystalline Rotoiti rhyolite, but instead represent contemporaneous partly molten intrusions reflecting different sources in their chemistries and mineralogies. Similarly, although the Earthquake Flat eruption immediately followed (and probably was triggered by) the Rotoiti event, age data from juvenile material are significantly different. A multiple-grain zircon-controlled crystallisation age measured by TIMS from a representative pumice is 173??5 ka, while SIMS model ages range from 70-26+34 ka to >350 ka, with a peak at 105 ka. These age data coupled with previously published geochemical and isotopic data show that the Rotoiti and Earthquake Flat deposits were erupted from independent, unconnected magma bodies. Published by Elsevier Science B.V.

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

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.

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

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.

Improving the Efficacy of Department of the Army Title 10 Forces Performing Defense Support of Civil Authorities

DTIC Science & Technology

2013-06-13

Standing Rules for the Use of Force ix TACON Tactical Control TF Task Force TIC Toxic Industrial Chemical TIM Toxic Industrial Material UCMJ...The sole maneuver entity under TF-Ops was the Military Police Battalion stationed at Fort Bliss , Texas. The MP battalion had a garrison requirement...at Fort Bliss having conflicting ideas of what the CCMRF requirements were. This resulted in multiple higher headquarters with differing

Nanosecond and Picosecond Spectroscopy and Kinetics of Dynamic Absorbing Materials.

DTIC Science & Technology

1981-10-08

pS i~n antenna ]"lti ’Ri" 4. Artit’r corctiption of ibactf.ria I rac’tirr (n’i htr owing chlracteristic tims’ of the carl c% entis in lite prinury...pliytin a. poor ovvrlap wt,4d overlai) Fi(; vRF ’ Ili, Franck ( tm~im di;tgram, loW mal stiapt’ channg’s Amo tc’nap and large shiape i’(langes goo(d

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

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

KSC-08pd2999

NASA Image and Video Library

2008-10-01

CAPE CANAVERAL, Fla. - In the Space Station Processing Facility at NASA's Kennedy Space Center in Florida, STS-127 crew members watch as Japanese Aerospace Exploration Agency, or JAXA, technicians maneuver the antenna in the Inter Orbit Communication System Extended Facility, or ICS-EF. Standing at right are Mission Specialists Dave Wolf, Christopher Cassidy, Tim Kopra and Tom Marshburn. Equipment familiarization is part of a Crew Equipment Interface Test. The antenna and a pointing mechanism will be used to communicate with JAXA’s Data Relay Test Satellite, or DRTS. The ICS-EF will be launched, along with the Extended Facility and Experiment Logistics Module-Exposed Section, to the International Space Station aboard the space shuttle Endeavour on the STS-127 mission targeted for launch on May 15, 2009. Photo credit: NASA/Kim Shiflett

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...

238U/235U determinations of some commonly used reference materials and U-bearing accessory minerals (Invited)

NASA Astrophysics Data System (ADS)

Condon, D.; Noble, S.; McLean, N.; Bowring, S. A.

2009-12-01

We have determined 238U/235U ratios for a suite of commonly used natural (CRM 112a, SRM 950a, HU-1) and synthetic (IRMM 184 and CRM U500) uranium reference materials in addition to several U-bearing accessory phases (zircon and monazite) by thermal ionisation mass-spectrometry (TIMS) using the IRMM 3636 233U-236U double spike to accurately correct for mass fractionation. The 238U/235U values for the natural uranium reference materials differ, by up to 0.1%, from the widely used ‘consensus’ value (137.88) with all having 238U/235U values less than 137.88. Similarly, initial 238U/235U data from zircon and monazite yield 238U/235U values that are lower than the ‘consensus’ value. The data obtained from U-bearing minerals is used to assess how the uncertainty in the 238U/235U ratio contributes to the systematic discordance observed in 238U/206Pb and 235U/207Pb dates (Mattinson, 2000; Schoene et al., 2006) which has traditionally been wholly attributed to error in the U decay constants. The 238U/235U determinations made on the synthetic reference materials yield results that are considerably more precise and accurate than the certified values (0.02% vs. 0.1% for CRM U500). The calibration of isotopic tracers used for U-daughter geochronology that are partially based upon these reference materials, and the resultant age determinations, will benefit from increased accuracy and precision. Mattinson, J.M., 2000. Revising the “gold standard”—the uranium decay constants of Jaffey et al., 1971. Eos Trans. AGU, Spring Meet. Suppl., Abstract V61A-02. Schoene B., Crowley J.L., Condon D.C., Schmitz M.D., Bowring S.A., 2006, Reassessing the uranium decay constants for geochronology using ID-TIMS U-Pb data. Geochimica et Cosmochimica Acta 70: 426-445

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

Development of Silicone Rubbers for Use at Temperatures Down to -100 deg F

DTIC Science & Technology

1950-05-01

The properties of the cured stocks vary greatly, the tensile strength range being about ten-fold. The effective - ness of the pigments does not...the pigments (such as degassing at 1000°C. and 0.0001 .Tim. Hg, coating with a silicone film, etc.) has little effect on the results, leads to a...charges on the pigments and qn the gum. £ f The effect of variable volume loading has been determined for some of the most promising materials. Stocks

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.

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.

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.

Approximate static condensation algorithm for solving multi-material diffusion problems on meshes non-aligned with material interfaces

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

Kikinzon, Evgeny; Kuznetsov, Yuri; Lipnikov, Konstatin

In this study, we describe a new algorithm for solving multi-material diffusion problem when material interfaces are not aligned with the mesh. In this case interface reconstruction methods are used to construct approximate representation of interfaces between materials. They produce so-called multi-material cells, in which materials are represented by material polygons that contain only one material. The reconstructed interface is not continuous between cells. Finally, we suggest the new method for solving multi-material diffusion problems on such meshes and compare its performance with known homogenization methods.

Approximate static condensation algorithm for solving multi-material diffusion problems on meshes non-aligned with material interfaces

DOE PAGES

Kikinzon, Evgeny; Kuznetsov, Yuri; Lipnikov, Konstatin; ...

2017-07-08

In this study, we describe a new algorithm for solving multi-material diffusion problem when material interfaces are not aligned with the mesh. In this case interface reconstruction methods are used to construct approximate representation of interfaces between materials. They produce so-called multi-material cells, in which materials are represented by material polygons that contain only one material. The reconstructed interface is not continuous between cells. Finally, we suggest the new method for solving multi-material diffusion problems on such meshes and compare its performance with known homogenization methods.

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.

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

Embodied labour in music work.

PubMed

Pettinger, Lynne

2015-06-01

This paper frames the work of performance as embodied labour in order to understand the contingent production of particular music performances. It is an interdisciplinary account that sits at the intersection of the sociology of work, culture and the body. The concept of embodied labour is developed with reference to the complex account of materiality - of bodies and things - present in Tim Ingold's account of skill. This material account of skill is used to inform use to develop already of well established conceptualizations of body labour: craft, emotional and aesthetic labour through a reading of how these dimensions of embodied labour make possible the work of performance. © London School of Economics and Political Science 2015.

Precise and accurate isotope ratio measurements by ICP-MS.

PubMed

Becker, J S; Dietze, H J

2000-09-01

The precise and accurate determination of isotope ratios by inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation ICP-MS (LA-ICP-MS) is important for quite different application fields (e.g. for isotope ratio measurements of stable isotopes in nature, especially for the investigation of isotope variation in nature or age dating, for determining isotope ratios of radiogenic elements in the nuclear industry, quality assurance of fuel material, for reprocessing plants, nuclear material accounting and radioactive waste control, for tracer experiments using stable isotopes or long-lived radionuclides in biological or medical studies). Thermal ionization mass spectrometry (TIMS), which used to be the dominant analytical technique for precise isotope ratio measurements, is being increasingly replaced for isotope ratio measurements by ICP-MS due to its excellent sensitivity, precision and good accuracy. Instrumental progress in ICP-MS was achieved by the introduction of the collision cell interface in order to dissociate many disturbing argon-based molecular ions, thermalize the ions and neutralize the disturbing argon ions of plasma gas (Ar+). The application of the collision cell in ICP-QMS results in a higher ion transmission, improved sensitivity and better precision of isotope ratio measurements compared to quadrupole ICP-MS without the collision cell [e.g., for 235U/238U approximately 1 (10 microg x L(-1) uranium) 0.07% relative standard deviation (RSD) vs. 0.2% RSD in short-term measurements (n = 5)]. A significant instrumental improvement for ICP-MS is the multicollector device (MC-ICP-MS) in order to obtain a better precision of isotope ratio measurements (with a precision of up to 0.002%, RSD). CE- and HPLC-ICP-MS are used for the separation of isobaric interferences of long-lived radionuclides and stable isotopes by determination of spallation nuclide abundances in an irradiated tantalum target.

Conducting polymer nanocomposites loaded with nanotubes and fibers for electrical and thermal applications

NASA Astrophysics Data System (ADS)

Chiguma, Jasper

The design, fabrication and measurement of electrical and thermal properties of polymers loaded with nanotubes and fibers are the foci of the work presented in this dissertation. The resulting products of blending polymers with nanomaterials are called nanocomposites and are already finding applications in many areas of human endeavour. Among some of the most recent envisioned applications of nanocomposites is in electronic devices as thermal interface materials (TIMs). This potential application as TIMs, has been made more real by the realization that carbon nanotubes, could potentially transfer their high electrical, thermal and mechanical properties to polymers in the nanocomposites. In Chapter 1, the events leading to the discovery of carbon nanotubes are reviewed followed by an elaborate discussion of their structure and properties. The discussion of the structure and properties of carbon nanotubes help in understanding the envisaged applications. Chapter 2 focuses on the fabrication of insulating polymer nanocomposites, their electrical and mechanical properties. Poly (methyl methacrylate) (PMMA) and a polyimide formed by reacting pyromellitic dianhydride (PMDA) and 4, 4'-oxydianiline (ODA) (PMDA-ODA) nanocomposites with carbon nanotubes were prepared by in-situ polymerization. Poly (1-methyl-4-pentene) (TPX), Polycarbonate (PC), Poly (vinyl chloride) (PVC), Poly (acrylonitrile-butadiene-styrene) (ABS), the alloys ABS-PC, ABS-PVC, and ABS-PC-PVC nanocomposites were prepared from the respective polymers and carbon nanotubes and their mechanical and electrical properties measured. Chapter 3 covers the nanocomposites that were prepared by the in-situ polymerization of the conducting polymers Polyaniline (PANi), Polypyrrole (PPy) and Poly (3, 4-ethylenedioxythiophene) (PEDOT) by in-situ polymerization. These are evaluated for electrical conductivity. The use of surfactants in facilitating carbon nanotube dispersion is discussed and applied in the preparation of conducting polymer nanocomposites. In Chapter 4 epoxy nanocomposites are prepared. MWCNTs, Graphite Fibers and Boron Nitride are used as filler materials. There thermal conductivity is determined by using the Flash Technique as well as Differential Scanning Calorimetry (DSC). The thermal conductivity of graphite and BN loaded epoxy was found to be much higher than for the MWCNTs filled. Chapter 5 covers the synthesis and electrical conductivity of PANi nanotubes and nanorods without the use of templates. Also covered in this Chapter is the template free synthesis of Cu (II) hydroxide and Copper nanorods. In Chapter 6, Organic Solderability Preservatives (OSPs) are evaluated for integrity after thermal stress. The two types of OSPs that are evaluated in this chapter are a benzimidazole derivative known as WPF207 and an imidazole derivative called F2LX. The OSP WPF was found to be more robust. In Chapter 7, two encapsulants are evaluated after thermal stress. The encapsulants are Sumitomo type 6730B and type 6730B-LX. No significant differences were found after analysis.

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)

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.

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

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.

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.

Effects of Solvation On One- and Two-Photon Spectra of Coumarin Derivatives: A TDDFT Study (Preprint)

DTIC Science & Technology

2006-10-01

1999,103,9614. (14) Pal, H.; Nad, S.; Kumbhakar, M. J Chern. Phys. 2003, 119,443. (15) Barik , A.; Nath, S.; Pal, H. J Chern. Phys. 2003, 119, 10202...Signature// TIM J . SCHUMACHER, Chief Survivability and Sensor Materials Division This report is published in the interest of...6-311 ++G(d,p) and the aug-cc-pVTZ basis sets. Theory Expt System/Method E(S])f Jlo]Energy (JlO]) [ j ]Solvent C120 CAMB3LYP 4.29 (4.24)0.373 (0.368

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.

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.

Precise and accurate in situ Pb-Pb dating of apatite, monazite, and sphene by laser ablation multiple-collector ICP-MS

NASA Astrophysics Data System (ADS)

Willigers, B. J. A.; Baker, J. A.; Krogstad, E. J.; Peate, D. W.

2002-03-01

To evaluate in situ Pb dating by laser ablation multiple-collector inductively coupled plasma mass spectrometry (LA-MC-ICP-MS), we analysed apatite, sphene, and monazite from Paleoproterozoic metamorphic rocks from West Greenland. Pb isotope ratios were also determined in the National Institute of Standards and Technology (NIST) 610 glass standard and were corrected for mass fractionation by reference to the measured thallium isotope ratio. The NIST 610 glass was used to monitor Pb isotope mass fractionation in the low Tl/Pb accessory minerals. Replicate analyses of the glass (1 to 2 min) yielded ratios with an external reproducibility comparable to conventional analyses of standard reference material 981 by thermal ionisation mass spectrometry (TIMS). Mineral grains were generally analysed with a 100-μm laser beam, although some monazite crystals were analysed at smaller spot sizes (10 and 25 μm). The common Pb isotope ratios required for age calculations were either measured on coexisting plagioclase by LA-MC-ICP-MS or could be ignored, as individual crystals exhibit sufficient Pb isotopic heterogeneity to perform isochron calculations on replicate analyses of single crystals. Mean mineral ages with the 204Pb ion beam measured in the multiplier were as follows: apatite, 1715 ± 23 m.y.; sphene, 1789 ± 11 m.y.; and monazite, 1783 to 1888 m.y., with relative uncertainties on individual monazite ages of <0.2% but highly reproducible age determinations on single monazite crystals (≪1%). Isochron ages calculated from several mineral analyses without assumption of common Pb also yield precise age determinations. Apatite and monazite Pb ages determined by in situ Pb isotope analysis are identical to those determined by conventional TIMS analysis of bulk mineral separates, and the analytical uncertainties of these short laser analyses with no prior mechanical or chemical separation are comparable to those obtained by TIMS. Detailed examination of the sphene in situ age data does, however, show a small discrepancy between the LA-MC-ICP-MS and TIMS ages (˜1% younger). High-resolution mass scans of the sphene during ablation clearly showed several small and as yet unidentified isobaric interferences that overlap with the 207Pb peak at the resolution conditions for measurement of isotope ratios. These might account for the age discrepancy between the LA-MC-ICP-MS and TIMS sphene ages. LA-MC-ICP-MS is a rapid, accurate, and precise method for in situ determination of Pb isotope ratios that can be used for geochronological studies in a manner similar to an ion microprobe, albeit currently at a somewhat degraded spatial resolution. Further modifications to the LA-MC-ICP-MS system, such as improved sensitivity, ion transmission, and LA methodology, may lead to this type of instrument becoming the method of choice for many types of in situ Pb isotope dating.

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.

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.

230Th-U dating of surficial deposits using the ion microprobe (SHRIMP-RG): A microstratigraphic perspective

USGS Publications Warehouse

Maher, K.; Wooden, J.L.; Paces, J.B.; Miller, D.M.

2007-01-01

We used the sensitive high-resolution ion microprobe reverse-geometry (SHRIMP-RG) to date pedogenic opal using the 230Th-U system. Due to the high-spatial resolution of an ion microprobe (typically 30 ??m), regions of pure opal within a sample can be targeted and detrital material can be avoided. In addition, because the technique is non-destructive, the sample can be preserved for other types of analyses including electron microprobe or other stable isotope or trace element ion microprobe measurements. The technique is limited to material with U concentrations greater than ???50 ppm. However, the high spatial resolution, small sample requirements, and the ability to avoid detrital material make this technique a suitable technique for dating many Pleistocene deposits formed in semi-arid environments. To determine the versatility of the method, samples from several different deposits were analyzed, including silica-rich pebble coatings from pedogenic carbonate horizons, a siliceous sinter deposit, and opaline silica deposited as a spring mound. U concentrations for 30-??m-diameter spots ranged from 50 to 1000 ppm in these types of materials. The 230Th/232Th activity ratios also ranged from ???100 to 106, eliminating the need for detrital Th corrections that reduce the precision of traditional U-Th ages for many milligram- and larger-sized samples. In pedogenic material, layers of high-U opal (ca. 500 ppm) are commonly juxtaposed next to layers of calcite with much lower U concentrations (1-2 ppm). If these types of samples are not analyzed using a technique with the appropriate spatial resolution, the ages may be strongly biased towards the age of the opal. Comparison with standard TIMS (Thermal Ionization Mass Spectrometry) measurements from separate microdrilled samples suggests that although the analytical precision of the ion microprobe (SHRIMP-RG) measurements is less than TIMS, the high spatial resolution results in better accuracy in the age determination for finely layered or complex deposits. The ion microprobe approach also may be useful for pre-screening samples to determine the age and degree of post-depositional alteration, analyzing finely layered samples or samples with complex growth histories, and obtaining simultaneous measurements of trace elements.

Thermal Stir Welder

NASA Technical Reports Server (NTRS)

Ding, R. Jeffrey (Inventor)

2012-01-01

A welding apparatus is provided for forming a weld joint between first and second elements of a workpiece. The apparatus heats the first and second elements to form an interface of material in a plasticized or melted state interface between the elements. The interface material is then allowed to cool to a plasticized state if previously in a melted state. The interface material, while in the plasticized state, is then mixed, for example, using a grinding/extruding mixer, to remove any dendritic-type weld microstructures introduced into the interface material during heating.

Simulations of Chemical Reactions with the Frozen Domain Formulation of the Fragment Molecular Orbital Method.

PubMed

Nakata, Hiroya; Fedorov, Dmitri G; Nagata, Takeshi; Kitaura, Kazuo; Nakamura, Shinichiro

2015-07-14

The fully analytic first and second derivatives of the energy in the frozen domain formulation of the fragment molecular orbital (FMO) were developed and applied to locate transition states and determine vibrational contributions to free energies. The development is focused on the frozen domain with dimers (FDD) model. The intrinsic reaction coordinate method was interfaced with FMO. Simulations of IR and Raman spectra were enabled using FMO/FDD by developing the calculation of intensities. The accuracy is evaluated for S(N)2 reactions in explicit solvent, and for the free binding energies of a protein-ligand complex of the Trp cage protein (PDB: 1L2Y ). FMO/FDD is applied to study the keto-enol tautomeric reaction of phosphoglycolohydroxamic acid and the triosephosphate isomerase (PDB: 7TIM ), and the role of amino acid residue fragments in the reaction is discussed.

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.

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

Utility of remotely sensed data for identification of soil conservation practices

NASA Technical Reports Server (NTRS)

Pelletier, R. E.; Griffin, R. H.

1986-01-01

Discussed are a variety of remotely sensed data sources that may have utility in the identification of conservation practices and related linear features. Test sites were evaluated in Alabama, Kansas, Mississippi, and Oklahoma using one or more of a variety of remotely sensed data sources, including color infrared photography (CIR), LANDSAT Thematic Mapper (TM) data, and aircraft-acquired Thermal Infrared Multispectral Scanner (TIMS) data. Both visual examination and computer-implemented enhancement procedures were used to identify conservation practices and other linear features. For the Kansas, Mississippi, and Oklahoma test sites, photo interpretations of CIR identified up to 24 of the 109 conservation practices from a matrix derived from the SCS National Handbook of Conservation Practices. The conservation practice matrix was modified to predict the possibility of identifying the 109 practices at various photographic scales based on the observed results as well as photo interpreter experience. Some practices were successfully identified in TM data through visual identification, but a number of existing practices were of such size and shape that the resolution of the TM could not detect them accurately. A series of computer-automated decorrelation and filtering procedures served to enhance the conservation practices in TM data with only fair success. However, features such as field boundaries, roads, water bodies, and the Urban/Ag interface were easily differentiated. Similar enhancement techniques applied to 5 and 10 meter TIMS data proved much more useful in delineating terraces, grass waterways, and drainage ditches as well as the features mentioned above, due partly to improved resolution and partly to thermally influenced moisture conditions. Spatially oriented data such as those derived from remotely sensed data offer some promise in the inventory and monitoring of conservation practices as well as in supplying parameter data for a variety of computer-implemented agricultural models.

Thermal stir welding process

NASA Technical Reports Server (NTRS)

Ding, R. Jeffrey (Inventor)

2012-01-01

A welding method is provided for forming a weld joint between first and second elements of a workpiece. The method includes heating the first and second elements to form an interface of material in a plasticized or melted state interface between the elements. The interface material is then allowed to cool to a plasticized state if previously in a melted state. The interface material, while in the plasticized state, is then mixed, for example, using a grinding/extruding process, to remove any dendritic-type weld microstructures introduced into the interface material during the heating process.

Thermal stir welding apparatus

NASA Technical Reports Server (NTRS)

Ding, R. Jeffrey (Inventor)

2011-01-01

A welding method and apparatus are provided for forming a weld joint between first and second elements of a workpiece. The method includes heating the first and second elements to form an interface of material in a plasticized or melted state interface between the elements. The interface material is then allowed to cool to a plasticized state if previously in a melted state. The interface material, while in the plasticized state, is then mixed, for example, using a grinding/extruding process, to remove any dendritic-type weld microstructures introduced into the interface material during the heating process.

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.

Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1.

PubMed

Darwish, Noureldien H E; Sudha, Thangirala; Godugu, Kavitha; Elbaz, Osama; Abdelghaffar, Hasan A; Hassan, Emad E A; Mousa, Shaker A

2016-09-06

Acute myeloid leukemia (AML) patients show high relapse rates and some develop conventional chemotherapy resistance. Leukemia Stem Cells (LSCs) are the main player for AML relapses and drug resistance. LSCs might rely on the B-cell-specific Moloney murine leukemia virus integration site-1 (BMI-1) in promoting cellular proliferation and survival. Growth of LSCs in microenvironments that are deprived of nutrients leads to up-regulation of the signaling pathways during the progression of the disease, which may illustrate the sensitivity of LSCs to inhibitors of those signaling pathways as compared to normal cells. We analyzed the expression of LSC markers (CD34, CLL-1, TIM-3 and BMI-1) using quantitative RT-PCR in bone marrow samples of 40 AML patients of different FAB types (M1, M2, M3, M4, M5, and M7). We also studied the expression of these markers in 2 AML cell lines (Kasumi-1 and KG-1a) using flow cytometry and quantitative RT-PCR. The overexpression of TIM-3, CLL-1, and BMI-1 was markedly correlated with poor prognosis in these patients. Our in vitro findings demonstrate that targeting BMI-1, which markedly increased in the leukemic cells, was associated with marked decrease in leukemic burden. This study also presents results for blocking LSCs' surface markers CD44, CLL-1, and TIM-3. These markers may play an important role in elimination of AML. Our study indicates a correlation between the expression of markers TIM-3, CLL-1, and especially of BMI-1 and the aggressiveness of AML and thus the potential impact of prognosis and therapies that target LSCs on improving the cure rates.

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.

Multispectral thermal infrared mapping of the 1 October 1988 Kupaianaha flow field, Kilauea volcano, Hawaii

USGS Publications Warehouse

Realmuto, V.J.; Hon, K.; Kahle, A.B.; Abbott, E.A.; Pieri, D.C.

1992-01-01

Multispectral thermal infrared radiance measurements of the Kupaianaha flow field were acquired with the NASA airborne Thermal Infrared Multispectral Scanner (TIMS) on the morning of 1 October 1988. The TIMS data were used to map both the temperature and emissivity of the surface of the flow field. The temperature map depicted the underground storage and transport of lava. The presence of molten lava in a tube or tumulus resulted in surface temperatures that were at least 10?? C above ambient. The temperature map also clearly defined the boundaries of hydrothermal plumes which resulted from the entry of lava into the ocean. The emissivity map revealed the boundaries between individual flow units within the Kupaianaha field. In general, the emissivity of the flows varied systematically with age but the relationship between age and emissivity was not unique. Distinct spectral anomalies, indicative of silica-rich surface materials, were mapped near fumaroles and ocean entry sites. This apparent enrichment in silica may have resulted from an acid-induced leaching of cations from the surfaces of glassy flows. Such incipient alteration may have been the cause for virtually all of the emissivity variations observed on the flow field, the spectral anomalies representing areas where the acid attack was most intense. ?? 1992 Springer-Verlag.

KSC-2009-1358

NASA Image and Video Library

2009-01-26

CAPE CANAVERAL, Fla. – In the Vehicle Assembly Building at NASA's Kennedy Space Center in Florida, workers begin removing the protective material wrapping the fifth segment simulator of the Ares I-X. Ares I-X is the test vehicle for the Ares I, which is part of the Constellation Program to return men to the moon and beyond. Ares I is the essential core of a safe, reliable, cost-effective space transportation system that eventually will carry crewed missions back to the moon, on to Mars and out into the solar system. Ares I-X is targeted for launch in July 2009. Photo credit: NASA/Tim Jacobs

Relaxation, Structure and Properties of Semi-coherent Interfaces

DOE PAGES

Shao, Shuai; Wang, Jian

2015-11-05

Materials containing high density of interfaces are promising candidates for future energy technologies, because interfaces acting as sources, sinks, and barriers for defects can improve mechanical and irradiation properties of materials. Semi-coherent interface widely occurring in various materials is composed of a network of misfit dislocations and coherent regions separated by misfit dislocations. Lastly, in this article, we review relaxation mechanisms, structure and properties of (111) semi-coherent interfaces in face centered cubic structures.

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.

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.

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.

Isotope dilution inductively coupled plasma mass spectrometry (ID ICP-MS) for the certification of lead and cadmium in environmental standard reference materials.

PubMed

Murphy, K E; Beary, E S; Rearick, M S; Vocke, R D

2000-10-01

Lead (Pb) and cadmium (Cd) have been determined in six new environmental standard reference materials (SRMs) using isotope dilution inductively coupled plasma mass spectrometry (ID ICP-MS). The SRMs are the following: SRM 1944, New York-New Jersey Waterway Sediment, SRMs 2583 and 2584, Trace Elements in Indoor Dust, Nominal 90 mg/kg and 10,000 mg/kg Lead, respectively, SRMs 2586 and 2587, Trace Elements in Soil Containing Lead from Paint, Nominal 500 mg/kg and 3,000 mg/kg Lead, respectively, and SRM 2782, Industrial Sludge. The capabilities of ID ICP-MS for the certification of Pb and Cd in these materials are assessed. Sample preparation and ratio measurement uncertainties have been evaluated. Reproducibility and accuracy of the established procedures are demonstrated by determination of gravimetrically prepared primary standard solutions and by comparison with isotope dilution thermal ionization mass spectrometry (ID TIMS). Material heterogeneity was readily demonstrated to be the dominant source of uncertainty in the certified values.

Lithological and textural controls on radar and diurnal thermal signatures of weathered volcanic deposits, Lunar Crater region, Nevada

NASA Technical Reports Server (NTRS)

Plaut, Jeffrey J.; Rivard, Benoit

1992-01-01

Radar backscatter intensity as measured by calibrated synthetic aperture radar (SAR) systems is primarily controlled by three factors: local incidence angle, wavelength-scale roughness, and dielectric permittivity of surface materials. Radar observations may be of limited use for geological investigations of surface composition, unless the relationships between lithology and the above characteristics can be adequately understood. In arid terrains, such as the Southwest U.S., weathering signatures (e.g. soil development, fracturing, debris grain size and shape, and hill slope characteristics) are controlled to some extent by lithologic characteristics of the parent bedrock. These textural features of outcrops and their associated debris will affect radar backscatter to varying degrees, and the multiple-wavelength capability of the JPL Airborne SAR (AIRSAR) system allows sampling of textures at three distinct scales. Diurnal temperature excursions of geologic surfaces are controlled primarily by the thermal inertia of surface materials, which is a measure of the resistance of a material to a change in temperature. Other influences include albedo, surface slopes affecting insolation, local meteorological conditions and surface emissivity at the relevant thermal wavelengths. To first order, thermal inertia variations on arid terrain surfaces result from grain size distribution and porosity differences, at scales ranging from micrometers to tens of meters. Diurnal thermal emission observations, such as those made by the JPL Thermal Infrared Multispectral Scanner (TIMS) airborne instrument, are thus influenced by geometric surface characteristics at scales comparable to those controlling radar backscatter. A preliminary report on a project involving a combination of field, laboratory and remote sensing observations of weathered felsic-to basaltic volcanic rock units exposed in the southern part of the Lunar Crater Volcanic Field, in the Pancake Range of central Nevada is presented. Focus is on the relationship of radar backscatter cross sections at multiple wavelengths, apparent diurnal temperature excursions identified in multi-temporal TIMS images, surface geometries related to weathering style, and parent bedrock lithology.

Recent work on material interface reconstruction

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

Mosso, S.J.; Swartz, B.K.

1997-12-31

For the last 15 years, many Eulerian codes have relied on a series of piecewise linear interface reconstruction algorithms developed by David Youngs. In a typical Youngs` method, the material interfaces were reconstructed based upon nearly cell values of volume fractions of each material. The interfaces were locally represented by linear segments in two dimensions and by pieces of planes in three dimensions. The first step in such reconstruction was to locally approximate an interface normal. In Youngs` 3D method, a local gradient of a cell-volume-fraction function was estimated and taken to be the local interface normal. A linear interfacemore » was moved perpendicular to the now known normal until the mass behind it matched the material volume fraction for the cell in question. But for distorted or nonorthogonal meshes, the gradient normal estimate didn`t accurately match that of linear material interfaces. Moreover, curved material interfaces were also poorly represented. The authors will present some recent work in the computation of more accurate interface normals, without necessarily increasing stencil size. Their estimate of the normal is made using an iterative process that, given mass fractions for nearby cells of known but arbitrary variable density, converges in 3 or 4 passes in practice (and quadratically--like Newton`s method--in principle). The method reproduces a linear interface in both orthogonal and nonorthogonal meshes. The local linear approximation is generally 2nd-order accurate, with a 1st-order accurate normal for curved interfaces in both two and three dimensional polyhedral meshes. Recent work demonstrating the interface reconstruction for curved surfaces will /be discussed.« less

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

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.

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.

Computational Modeling of Interfacial Behaviors in Nanocomposite Materials

PubMed Central

Lin, Liqiang; Wang, Xiaodu; Zeng, Xiaowei

2017-01-01

Towards understanding the bulk material response in nanocomposites, an interfacial zone model was proposed to define a variety of material interface behaviors (e.g. brittle, ductile, rubber-like, elastic-perfectly plastic behavior etc.). It also has the capability to predict bulk material response though independently control of the interface properties (e.g. stiffness, strength, toughness). The mechanical response of granular nanocomposite (i.e. nacre) was investigated through modeling the “relatively soft” organic interface as an interfacial zone among “hard” mineral tablets and simulation results were compared with experimental measurements of stress-strain curves in tension and compression tests. Through modeling varies material interfaces, we found out that the bulk material response of granular nanocomposite was regulated by the interfacial behaviors. This interfacial zone model provides a possible numerical tool for qualitatively understanding of structure-property relationships through material interface design. PMID:28983123

Second order Method for Solving 3D Elasticity Equations with Complex Interfaces

PubMed Central

Wang, Bao; Xia, Kelin; Wei, Guo-Wei

2015-01-01

Elastic materials are ubiquitous in nature and indispensable components in man-made devices and equipments. When a device or equipment involves composite or multiple elastic materials, elasticity interface problems come into play. The solution of three dimensional (3D) elasticity interface problems is significantly more difficult than that of elliptic counterparts due to the coupled vector components and cross derivatives in the governing elasticity equation. This work introduces the matched interface and boundary (MIB) method for solving 3D elasticity interface problems. The proposed MIB elasticity interface scheme utilizes fictitious values on irregular grid points near the material interface to replace function values in the discretization so that the elasticity equation can be discretized using the standard finite difference schemes as if there were no material interface. The interface jump conditions are rigorously enforced on the intersecting points between the interface and the mesh lines. Such an enforcement determines the fictitious values. A number of new techniques has been developed to construct efficient MIB elasticity interface schemes for dealing with cross derivative in coupled governing equations. The proposed method is extensively validated over both weak and strong discontinuity of the solution, both piecewise constant and position-dependent material parameters, both smooth and nonsmooth interface geometries, and both small and large contrasts in the Poisson’s ratio and shear modulus across the interface. Numerical experiments indicate that the present MIB method is of second order convergence in both L∞ and L2 error norms for handling arbitrarily complex interfaces, including biomolecular surfaces. To our best knowledge, this is the first elasticity interface method that is able to deliver the second convergence for the molecular surfaces of proteins.. PMID:25914422

Controlling the electronic and geometric structures of 2D insertions to realize high performance metal/insertion-MoS2 sandwich interfaces.

PubMed

Su, Jie; Feng, Liping; Zeng, Wei; Liu, Zhengtang

2017-06-08

Metal/insertion-MoS 2 sandwich interfaces are designed to reduce the Schottky barriers at metal-MoS 2 interfaces. The effects of geometric and electronic structures of two-dimensional (2D) insertion materials on the contact properties of metal/insertion-MoS 2 interfaces are comparatively studied by first-principles calculations. Regardless of the geometric and electronic structures of 2D insertion materials, Fermi level pinning effects and charge scattering at the metal/insertion-MoS 2 interface are weakened due to weak interactions between the insertion and MoS 2 layers, no gap states and negligible structural deformations for MoS 2 layers. The Schottky barriers at metal/insertion-MoS 2 interfaces are induced by three interface dipoles and four potential steps that are determined by the charge transfers and structural deformations of 2D insertion materials. The lower the electron affinities of 2D insertion materials, the more are the electrons lost from the Sc surface, resulting in lower n-type Schottky barriers at Sc/insertion-MoS 2 interfaces. The larger the ionization potentials and the thinner the thicknesses of 2D insertion materials, the fewer are the electrons that accumulate at the Pt surface, leading to lower p-type Schottky barriers at Pt/insertion-MoS 2 interfaces. All Sc/insertion-MoS 2 interfaces exhibited ohmic characters. The Pt/BN-MoS 2 interface exhibits the lowest p-type Schottky barrier of 0.52 eV due to the largest ionization potential (∼6.88 eV) and the thinnest thickness (single atomic layer thickness) of BN. These results in this work are beneficial to understand and design high performance metal/insertion-MoS 2 interfaces through 2D insertion materials.

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

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.

Thermal interface material characterization for cryogenic electronic packaging solutions

NASA Astrophysics Data System (ADS)

Dillon, A.; McCusker, K.; Van Dyke, J.; Isler, B.; Christiansen, M.

2017-12-01

As applications of superconducting logic technologies continue to grow, the need for efficient and reliable cryogenic packaging becomes crucial to development and testing. A trade study of materials was done to develop a practical understanding of the properties of interface materials around 4 K. While literature exists for varying interface tests, discrepancies are found in the reported performance of different materials and in the ranges of applied force in which they are optimal. In considering applications extending from top cooling a silicon chip to clamping a heat sink, a range of forces from approximately 44 N to approximately 445 N was chosen for testing different interface materials. For each range of forces a single material was identified to optimize the thermal conductance of the joint. Of the tested interfaces, indium foil clamped at approximately 445 N showed the highest thermal conductance. Results are presented from these characterizations and useful methodologies for efficient testing are defined.

Simultaneous in situ determination of both U-Th-Pb and Sm-Nd isotopes in monazite by laser ablation using a magnetic sector ICP-MS and a multicollector ICP-MS

NASA Astrophysics Data System (ADS)

Goudie, D. J.; Fisher, C. M.; Hanchar, J. M.; Davis, W. J.; Crowley, J. L.; Ayers, J. C.

2012-12-01

We present a method for the simultaneous in situ determination of U-Th-Pb and Sm-Nd isotopes in monazite, using a laser ablation (LA) system coupled to both a magnetic sector inductively coupled plasma mass spectrometer (HR) ICP-MS and a multicollector (MC) ICP-MS. The ablated material is split using a glass Y-connector and transported simultaneously to both mass spectrometers via helium carrier gas. The MC-ICP-MS is configured to provide relative Ce, Gd, and Eu contents, in addition to Sm and Nd. This approach obtains both age (U-Pb), tracer isotope (Sm-Nd), and REE element data (Ce, Gd, and Eu), in the same ablation volume, thus reducing sampling problems associated with fine-scale zoning and other internal structures. The accuracy and precision of the U-Pb data are demonstrated using six well characterized monazite reference materials from the Geological Survey of Canada (three of which are currently used as SHRIMP standards) and agree well with previously determined ID-TIMS ages. The accuracy of the Sm-Nd isotopic data was assessed by comparison to TIMS measurements on a well-characterized in-house monazite standard. The dual LA-ICP-MS method was applied to the Birch Creek Pluton (BCP) in the White Mountains, California in a case study to test the utility of U-Th-Pb dating coupled with Sm-Nd (and Ce, Gd, Eu) isotopic data for solving geologic problems. Previous work on the Cretaceous BCP [1] used Th-Pb ages coupled with O isotopic data to constrain hydrothermal fluid events, as recorded in monazite. The original study suggested that the high delta 18O monazite in Paleozoic country rocks adjacent to the BCP grew in response to fluid alternation associated with the intrusion of the BCP, based on overlapping age with the BCP. New monazite split-stream U-Pb and Sm-Nd data show that monazite from the BCP pluton and monazite from altered country rock have homogenous and overlapping initial Nd isotopic composition, further strengthening the proposal that monazite in altered country rock can be a tracer of fluid alternation events. The split-stream U-Pb ages agrees with new high precision ID-TIMS U-Pb ages from the same monazite grains. These results demonstrate how monazite age and Sm-Nd isotopic data, coupled with delta 18O, can identify hydrothermal monazite and constrain the timing and potential sources of fluid events. [1] Ayers et al., Geology 34 (2006) 653-656.

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.

Effect of Interface Structure on Mechanical Properties of Advanced Composite Materials

PubMed Central

Gan, Yong X.

2009-01-01

This paper deals with the effect of interface structures on the mechanical properties of fiber reinforced composite materials. First, the background of research, development and applications on hybrid composite materials is introduced. Second, metal/polymer composite bonded structures are discussed. Then, the rationale is given for nanostructuring the interface in composite materials and structures by introducing nanoscale features such as nanopores and nanofibers. The effects of modifying matrices and nano-architecturing interfaces on the mechanical properties of nanocomposite materials are examined. A nonlinear damage model for characterizing the deformation behavior of polymeric nanocomposites is presented and the application of this model to carbon nanotube-reinforced and reactive graphite nanotube-reinforced epoxy composite materials is shown. PMID:20054466

Evaluation of Temporary Wound Dressings for Adherence, Durability and Autografting on Sulfur Mustard-Induced Lesions in Weanling Swine

DTIC Science & Technology

2000-12-01

interpretation of the May 7, 1996 meeting with Carl Olson, Tim Hayes, Tom Dreier, Dave Stitcher , and Frances Reid. This procedure of decontamination and proof...with Carl Olson, Tim Hayes, Tom Dreier, Dave Stitcher , and Frances Reid. TASK 33 DECONTAMINATION PROCEDURE AND PROOF OF DECONTAMINATION Decontamination...two of you, Mr. Stitcher and Dr. Estep to share our results and resolve any safety issues. Thanks, and M-3 have a good weekend! John S. Graham John S

The Effects of Dual Career Households and Family Responsibilities on Surface Warfare Officer’s Career Intent.

DTIC Science & Technology

1982-12-01

wide Family Awareness Conference recommended the creation of a special office to provide leadership and coordination for the Navy’s expanding efforts...aqproodmately 8,000 Surfae. Marfare Of ficers over a period of tim . You baoe been selected at random to reaeive enclsure (1) so your participation in...Very (2) (3) (4) (5) Very Tims " Used imfIfectiv. Ineffect V-e SO-SO Iffective Effect ive a. PrefereceuCad( ) ( ) ( ) ( ) ( ) b. Letter( ) ) C

The Loss Cone Imager (LCI)

DTIC Science & Technology

2006-07-24

at this time that the PMO provided the current LCI configuration (integrated DPU/HST on the PM, the RSH units on a composite tube , later to become...approximated by parallel planes of 1000 A of aluminum on a 0.5 mil mylar foil in front of a 1000 tim (or 1500 tim) silicon detector, detector A...above manufacturers form these alloys in tube form. In order to produce a tube , a rod would be formed and then a hold bored through the center. Some of

Expedition 47 Soyuz TMA-19M Landing

NASA Image and Video Library

2016-06-18

Expedition 47 astronaut Tim Kopra of NASA, center, arrives at the Karaganda Airport in Kazakhstan a few hours after he, Yuri Malenchenko of Roscosmos, and Tim Peake of the European Space Agency landed in their Soyuz TMA-19M spacecraft near the town of Zhezkazgan, Kazakhstan on Saturday, June 18, 2016. Kopra, Peake, and Malenchenko are returning after six months in space where they served as members of the Expedition 46 and 47 crews onboard the International Space Station. Photo Credit: (NASA/Bill Ingalls)

JPL Researcher Tim Miller at the primary AirSAR station aboard NASA's DC-8 flying laboratory during the AirSAR 2004 campaign

NASA Image and Video Library

2004-03-03

JPL Researcher Tim Miller at the primary AirSAR station aboard NASA's DC-8 flying laboratory during the AirSAR 2004 campaign. AirSAR 2004 is a three-week expedition by an international team of scientists that will use an all-weather imaging tool, called the Airborne Synthetic Aperture Radar (AirSAR), in a mission ranging from the tropical rain forests of Central America to frigid Antarctica.

Proceedings of Joint RL/AFOSR Workshop on Intelligent Information Systems Held at Griffiss AFB, New York on October 22-23, 1991

DTIC Science & Technology

1992-04-01

AND SCHEDULING" TIM FINN, UNIVERSITY OF MARYLAND, BALTIMORE COUNTY E. " EXTRACTING RULES FROM SOFTWARE FOR KNOWLEDGE-BASES" NOAH S. PRYWES, UNIVERSITY...Databases for Planning and Scheduling" Tim Finin, Unisys Corporation 8:30 - 9:00 " Extracting Rules from Software for Knowledge Baseso Noah Prywes, U. of...Space Requirements are Tractable E.G.: FEM, Multiplication Routines, Sorting Programs Lebmwmy fo Al Roseew d. The Ohio Male Unlversity A-2 Type 2

Bi-material plane with interface crack for the model of semi-linear material

NASA Astrophysics Data System (ADS)

Domanskaya, T. O.; Malkov, V. M.; Malkova, Yu. V.

2018-05-01

The singular plane problems of nonlinear elasticity (plane strain and plane stress) are considered for bi-material infinite plane with interface crack. The plane is formed of two half-planes. Mechanical properties of half-planes are described by the model of semi-linear material. Using model of this harmonic material has allowed to apply the theory of complex functions and to obtain exact analytical global solutions of some nonlinear problems. Among them the problem of bi-material plane with the stresses and strains jumps at an interface is considered. As an application of the problem of jumps, the problem of interface crack is solved. The values of nominal (Piola) and Cauchy stresses and displacements are founded. Based on the global solutions the asymptotic expansions are constructed for stresses and displacements in a vicinity of crack tip. As an example the case of a free crack in bi-material plane subjected to constant stresses at infinity is studied. As a special case, the analytical solution of the problem of a crack in a homogeneous plane is obtained from the problem for bi-material plane with interface crack.

Thermal Protection Supplement for Reducing Interface Thermal Mismatch

NASA Technical Reports Server (NTRS)

Stewart, David A. (Inventor); Leiser, Daniel B. (Inventor)

2017-01-01

A thermal protection system that reduces a mismatch of thermal expansion coefficients CTE between a first material layer (CTE1) and a second material layer (CTE2) at a first layer-second layer interface. A portion of aluminum borosilicate (abs) or another suitable additive (add), whose CTE value, CTE(add), satisfies (CTE(add)-CTE1)(CTE(add)-CTE2)<0, is distributed with variable additive density,.rho.(z;add), in the first material layer and/or in the second material layer, with.rho.(z;add) near the materials interface being relatively high (alternatively, relatively low) and.rho.(z;add) in a region spaced apart from the interface being relatively low (alternatively, relatively high).

Surface polaritons in grating composed of left-handed materials

NASA Astrophysics Data System (ADS)

Tiwari, D. C.; Premlal, P. L.; Chaturvedi, Vandana

2018-01-01

In this work, we developed a unique mathematical model to solve dispersion relation for surface polaritons (SPs) in artificial composite materials grating. Here, we have taken two types of materials for analysis. In the first case, the grating composed of epsilon-negative (ENG) material and air interface. In second case, grating composed of left-handed materials (LHMs) and ENG medium interface is considered. The dispersion curves of both p and s polarized SPs modes are obtained analytically. In the case of ENG grating and air interface, polaritons dispersion curves exist for p-polarization only, whereas for LHM grating and ENG medium interface, the polaritons dispersion curves for both p and s polarization are observed.

Measurements and Modeling of Total Solar Irradiance in X-class Solar Flares

NASA Technical Reports Server (NTRS)

Moore, Christopher S.; Chamberlin, Phillip Clyde; Hock, Rachel

2014-01-01

The Total Irradiance Monitor (TIM) from NASA's SOlar Radiation and Climate Experiment can detect changes in the total solar irradiance (TSI) to a precision of 2 ppm, allowing observations of variations due to the largest X-class solar flares for the first time. Presented here is a robust algorithm for determining the radiative output in the TIM TSI measurements, in both the impulsive and gradual phases, for the four solar flares presented in Woods et al., as well as an additional flare measured on 2006 December 6. The radiative outputs for both phases of these five flares are then compared to the vacuum ultraviolet (VUV) irradiance output from the Flare Irradiance Spectral Model (FISM) in order to derive an empirical relationship between the FISM VUV model and the TIM TSI data output to estimate the TSI radiative output for eight other X-class flares. This model provides the basis for the bolometric energy estimates for the solar flares analyzed in the Emslie et al. study.

A 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 confers protections against HIV-1 infection.

PubMed

Biasin, Mara; Sironi, Manuela; Saulle, Irma; Pontremoli, Chiara; Garziano, Micaela; Cagliani, Rachele; Trabattoni, Daria; Lo Caputo, Sergio; Vichi, Francesca; Mazzotta, Francesco; Forni, Diego; Riva, Stefania; Aguilar-Jimenez, Wbeimar; Cedeño, Samandhy; Sanchez, Jorge; Brander, Christian; Zapata, Wildeman; Rugeles, Maria Teresa; Clerici, Mario

2017-01-01

We investigated whether a 6-amino acid insertion/deletion polymorphism in the mucin domain of TIM-1 (T-cell immunoglobulin and mucin domain 1), modulates susceptibility to HIV-1 infection. The polymorphism was genotyped in three case/control cohorts of HIV-1 exposed seronegative individuals (HESN) and HIV-1 infected subjects from Italy, Peru, and Colombia; data from a Thai population were retrieved from the literature. Across all cohorts, homozygosity for the short TIM-1 allele was more common in HESNs than in HIV-1 infected subjects. A meta-analysis of the four association analyses yielded a p value of 0.005. In vitro infection assays of CD4+ T lymphocytes indicated that homozygosity for the short allele is associated with lower rate of HIV-1 replication. These results suggest that the deletion allele protects from HIV-1 infection with a recessive effect. Copyright © 2016 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

FY02 Final Report on Phytoremediation of Chlorinated Ethenes in Southern Sector Sediments of the Savannah River Site

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

Brigmon, R..L.

This final report details the operations and results of a 3-year Seepline Phytoremediation Project performed adjacent to Tims Branch, which is located in the Southern Sector of the Savannah River Site (SRS) A/M Area. Phytoremediation is a process where interactions between vegetation, associated microorganisms, and the host substrate combine to effectively degrade contaminated soils, sediments, and groundwater. Phytoremediation is a rapidly developing technology that shows promise for the effective and safe cleanup of certain hazardous wastes. It has the potential to remediate numerous volatile organic compounds (VOCs). Extensive characterization work has demonstrated that two VOCs, tetrachloroethylene (PCE) and trichloroethylene (TCE)more » are the major components of the VOC-contaminated groundwater that is migrating through the Southern Sector and Tims Branch seepline area (WSRC, 1999). The PCE and TCE are chlorinated ethenes (CE), and have been detected in seepline soils and ground water adjacent to the ecologically-sensitive Tims Branch seepline area.« less

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

NASA Astrophysics Data System (ADS)

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

2010-12-01

A new version of the "modified total evaporation" (MTE) method for isotopic analysis by multi-collector thermal ionization mass spectrometry (TIMS), with high analytical performance and designed in a more user-friendly and routinely applicable way, is described in detail. It is mainly being used for nuclear safeguards measurements of U and Pu and nuclear metrology, but can readily be applied to other scientific tasks in geochemistry, e.g. for Sr, Nd and Ca, as well. The development of the MTE method was organized in collaboration of several "key nuclear mass spectrometry laboratories", namely the New Brunswick Laboratory (NBL), the Institute for Transuranium Elements (ITU), the Safeguards Analytical Laboratory (now Safeguards Analytical Services, SGAS) of the International Atomic Energy Agency (IAEA) and the Institute for Reference Materials and Measurements (IRMM), with IRMM taking the leading role. The manufacturer of the TRITON TIMS instrument, Thermo Fisher Scientific, integrated this method into the software of the instrument. The development has now reached its goal to become a user-friendly and routinely useable method for uranium isotope ratio measurements with high precision and accuracy. Due to the use of the “total evaporation” (TE) method the measurement of the "major" uranium isotope ratio 235U/238U is routinely being performed with a precision of 0.01% to 0.02%. The use of a (certified) reference material measured under comparable conditions is emphasized to achieve an accuracy at a level of 0.02% - depending on the stated uncertainty of the certified value of the reference material. In contrast to the total evaporation method (TE), in the MTE method the total evaporation sequence is interrupted on a regular basis to allow for correction for background from peak tailing, internal calibration of a secondary electron multiplier (SEM) detector versus the Faraday cups, and ion source re-focusing. Therefore, the most significant improvement using the MTE method is in the analytical performance achieved for the "minor" ratios 234U/238U and 236U/238U. The MTE method is now routinely used at all collaborating laboratories and possibly more in the future. Additional applications for the MTE method, e.g. to take advantage of the good external precision in combination with the possibilities of internal background and detector calibrations or mass jumps between different cup configurations, are presented as well. One interesting application concerns new absolute isotope ratio measurements for Ca with an unprecedented level of accuracy. This is important because up to now most reported Ca isotope data are only calculated as relative deviations from a standard like NIST-SRM 915. Using the MTE method measurements on new gravimetrically prepared Ca isotope mixtures were performed. A significantly improved level of accuracy at the level of about 0.02% for both the 42Ca/40Ca and 44Ca/40Ca ratios was obtained.

Facet‐Engineered Surface and Interface Design of Photocatalytic Materials

PubMed Central

Wang, Lili; Li, Zhengquan

2016-01-01

The facet‐engineered surface and interface design for photocatalytic materials has been proven as a versatile approach to enhance their photocatalytic performance. This review article encompasses some recent advances in the facet engineering that has been performed to control the surface of mono‐component semiconductor systems and to design the surface and interface structures of multi‐component heterostructures toward photocatalytic applications. The review begins with some key points which should receive attention in the facet engineering on photocatalytic materials. We then discuss the synthetic approaches to achieve the facet control associated with the surface and interface design. In the following section, the facet‐engineered surface design on mono‐component photocatalytic materials is introduced, which forms a basis for the discussion on more complex systems. Subsequently, we elucidate the facet‐engineered surface and interface design of multi‐component photocatalytic materials. Finally, the existing challenges and future prospects are discussed. PMID:28105398

Manipulating Ferroelectrics through Changes in Surface and Interface Properties

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

Balke, Nina; Ramesh, Ramamoorthy; Yu, Pu

Ferroelectric materials are used in many applications of modern technologies including information storage, transducers, sensors, tunable capacitors, and other novel device concepts. In many of these applications, the ferroelectric properties, such as switching voltages, piezoelectric constants, or stability of nanodomains, are crucial. For any application, even for material characterization, the material itself needs to be interfaced with electrodes. On the basis of the structural, chemical, and electronic properties of the interfaces, the measured material properties can be determined by the interface. This is also true for surfaces. However, the importance of interfaces and surfaces and their effect on experiments aremore » often neglected, which results in many dramatically different experimental results for nominally identical samples. Therefore, it is crucial to understand the role of the interface and surface properties on internal bias fields and the domain switching process. Here, the nanoscale ferroelectric switching process and the stability of nanodomains for Pb(Zr,Ti)O 3 thin films are investigated by using scanning probe microscopy. Interface and surface properties are modulated through the selection/redesign of electrode materials as well as tuning the surface-near oxygen vacancies, which both can result in changes of the electric fields acting across the sample, and consequently this controls the measured ferroelectric and domain retention properties. By understanding the role of surfaces and interfaces, ferroelectric properties can be tuned to eliminate the problem of asymmetric domain stability by combining the effects of different electrode materials. Lastly, this study forms an important step toward integrating ferroelectric materials in electronic devices.« less

Manipulating Ferroelectrics through Changes in Surface and Interface Properties

DOE PAGES

Balke, Nina; Ramesh, Ramamoorthy; Yu, Pu

2017-10-23

Ferroelectric materials are used in many applications of modern technologies including information storage, transducers, sensors, tunable capacitors, and other novel device concepts. In many of these applications, the ferroelectric properties, such as switching voltages, piezoelectric constants, or stability of nanodomains, are crucial. For any application, even for material characterization, the material itself needs to be interfaced with electrodes. On the basis of the structural, chemical, and electronic properties of the interfaces, the measured material properties can be determined by the interface. This is also true for surfaces. However, the importance of interfaces and surfaces and their effect on experiments aremore » often neglected, which results in many dramatically different experimental results for nominally identical samples. Therefore, it is crucial to understand the role of the interface and surface properties on internal bias fields and the domain switching process. Here, the nanoscale ferroelectric switching process and the stability of nanodomains for Pb(Zr,Ti)O 3 thin films are investigated by using scanning probe microscopy. Interface and surface properties are modulated through the selection/redesign of electrode materials as well as tuning the surface-near oxygen vacancies, which both can result in changes of the electric fields acting across the sample, and consequently this controls the measured ferroelectric and domain retention properties. By understanding the role of surfaces and interfaces, ferroelectric properties can be tuned to eliminate the problem of asymmetric domain stability by combining the effects of different electrode materials. Lastly, this study forms an important step toward integrating ferroelectric materials in electronic devices.« less

Geographical analysis of diapause inducibility in European Drosophila melanogaster populations.

PubMed

Pegoraro, Mirko; Zonato, Valeria; Tyler, Elizabeth R; Fedele, Giorgio; Kyriacou, Charalambos P; Tauber, Eran

2017-04-01

Seasonal overwintering in insects represents an adaptation to stressful environments and in European Drosophila melanogaster females, low temperatures and short photoperiods can induce an ovarian diapause. Diapause may represent a recent (<15Ky) adaptation to the colonisation of temperate Europe by D. melanogaster from tropical sub-Saharan Africa, because African D. melanogaster and the sibling species D. simulans, have been reported to fail to undergo diapause. Over the past few centuries, D. melanogaster have also invaded North America and Australia, and eastern populations on both continents show a predictable latitudinal cline in diapause induction. In Europe however, a new diapause-enhancing timeless allele, ls-tim, is observed at high levels in southern Italy (∼80%), where it appears to have arisen and has spread throughout the continent with a frequency of ∼20% in Scandinavia. Given the phenotype of ls-tim and its geographical distribution, we might predict that it would work against any latitudinal cline in diapause induction within Europe. Indeed we reveal that any latitudinal cline for diapause in Europe is very weak, as predicted by ls-tim frequencies. In contrast, we determine ls-tim frequencies in North America and observe that they would be expected to strengthen the latitudinal pattern of diapause. Our results reveal how a newly arisen mutation, can, via the stochastic nature of where it initially arose, blur an otherwise adaptive geographical pattern. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

A novel lineage of myoviruses infecting cyanobacteria is widespread in the oceans.

PubMed

Sabehi, Gazalah; Shaulov, Lihi; Silver, David H; Yanai, Itai; Harel, Amnon; Lindell, Debbie

2012-02-07

Viruses infecting bacteria (phages) are thought to greatly impact microbial population dynamics as well as the genome diversity and evolution of their hosts. Here we report on the discovery of a novel lineage of tailed dsDNA phages belonging to the family Myoviridae and describe its first representative, S-TIM5, that infects the ubiquitous marine cyanobacterium, Synechococcus. The genome of this phage encodes an entirely unique set of structural proteins not found in any currently known phage, indicating that it uses lineage-specific genes for virion morphogenesis and represents a previously unknown lineage of myoviruses. Furthermore, among its distinctive collection of replication and DNA metabolism genes, it carries a mitochondrial-like DNA polymerase gene, providing strong evidence for the bacteriophage origin of the mitochondrial DNA polymerase. S-TIM5 also encodes an array of bacterial-like metabolism genes commonly found in phages infecting cyanobacteria including photosynthesis, carbon metabolism and phosphorus acquisition genes. This suggests a common gene pool and gene swapping of cyanophage-specific genes among different phage lineages despite distinct sets of structural and replication genes. All cytosines following purine nucleotides are methylated in the S-TIM5 genome, constituting a unique methylation pattern that likely protects the genome from nuclease degradation. This phage is abundant in the Red Sea and S-TIM5 gene homologs are widespread in the oceans. This unusual phage type is thus likely to be an important player in the oceans, impacting the population dynamics and evolution of their primary producing cyanobacterial hosts.

Improved sample utilization in thermal ionization mass spectrometry isotope ratio measurements: refined development of porous ion emitters for nuclear forensic applications

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

Baruzzini, Matthew Louis

The precise and accurate determination of isotopic composition in nuclear forensic samples is vital for assessing origin, intended use and process history. Thermal ionization mass spectrometry (TIMS) is widely accepted as the gold standard for high performance isotopic measurements and has long served as the workhorse in the isotopic ratio determination of nuclear materials. Nuclear forensic and safeguard specialists have relied heavily on such methods for both routine and atypical e orts. Despite widespread use, TIMS methods for the assay of actinide systems continue to be hindered by poor ionization e ciency, often less than tenths of a percent; themore » majority of a sample is not measured. This represents a growing challenge in addressing nextgeneration nuclear detection needs by limiting the ability to analyze ultratrace quantities of high priority elements that could potentially provide critical nuclear forensic signatures. Porous ion emitter (PIE) thermal ion sources were developed in response to the growing need for new TIMS ion source strategies for improved ionization e ciency, PIEs have proven to be simple to implement, straightforward approach to boosting ion yield. This work serves to expand the use of PIE techniques for the analysis of trace quantities of plutonium and americium. PIEs exhibited superior plutonium and americium ion yields when compared to direct lament loading and the resin bead technique, one of the most e cient methods for actinide analysis, at similar mass loading levels. Initial attempts at altering PIE composition for the analysis of plutonium proved to enhance sample utilization even further. Preliminary investigations of the instrumental fractionation behavior of plutonium and uranium analyzed via PIE methods were conducted. Data collected during these initial trial indicate that PIEs fractionate in a consistent, reproducible manner; a necessity for high precision isotope ratio measurements. Ultimately, PIEs methods were applied for the age determination of various uranium isotopic standards. PIEs did not exhibit signi cant advantages for the determination of model ages when compared to traditional laments; however, this trial was able to provide valuable insight for guiding future investigations.« less

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.

Nanoscale deformation measurements for reliability assessment of material interfaces

NASA Astrophysics Data System (ADS)

Keller, Jürgen; Gollhardt, Astrid; Vogel, Dietmar; Michel, Bernd

2006-03-01

With the development and application of micro/nano electronic mechanical systems (MEMS, NEMS) for a variety of market segments new reliability issues will arise. The understanding of material interfaces is the key for a successful design for reliability of MEMS/NEMS and sensor systems. Furthermore in the field of BIOMEMS newly developed advanced materials and well known engineering materials are combined despite of fully developed reliability concepts for such devices and components. In addition the increasing interface-to volume ratio in highly integrated systems and nanoparticle filled materials are challenges for experimental reliability evaluation. New strategies for reliability assessment on the submicron scale are essential to fulfil the needs of future devices. In this paper a nanoscale resolution experimental method for the measurement of thermo-mechanical deformation at material interfaces is introduced. The determination of displacement fields is based on scanning probe microscopy (SPM) data. In-situ SPM scans of the analyzed object (i.e. material interface) are carried out at different thermo-mechanical load states. The obtained images are compared by grayscale cross correlation algorithms. This allows the tracking of local image patterns of the analyzed surface structure. The measurement results are full-field displacement fields with nanometer resolution. With the obtained data the mixed mode type of loading at material interfaces can be analyzed with highest resolution for future needs in micro system and nanotechnology.

A comparative study of interface reconstruction methods for multi-material ALE simulations

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

Kucharik, Milan; Garimalla, Rao; Schofield, Samuel

2009-01-01

In this paper we compare the performance of different methods for reconstructing interfaces in multi-material compressible flow simulations. The methods compared are a material-order-dependent Volume-of-Fluid (VOF) method, a material-order-independent VOF method based on power diagram partitioning of cells and the Moment-of-Fluid method (MOF). We demonstrate that the MOF method provides the most accurate tracking of interfaces, followed by the VOF method with the right material ordering. The material-order-independent VOF method performs some-what worse than the above two while the solutions with VOF using the wrong material order are considerably worse.

Uncertainty propagation for the coulometric measurement of the plutonium concentration in MOX-PU4.

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

None, None

This GUM WorkbenchTM propagation of uncertainty is for the coulometric measurement of the plutonium concentration in a Pu standard material (C126) supplied as individual aliquots that were prepared by mass. The C126 solution had been prepared and as aliquoted as standard material. Samples are aliquoted into glass vials and heated to dryness for distribution as dried nitrate. The individual plutonium aliquots were not separated chemically or otherwise purified prior to measurement by coulometry in the F/H Laboratory. Hydrogen peroxide was used for valence adjustment. The Pu assay measurement results were corrected for the interference from trace iron in the solutionmore » measured for assay. Aliquot mass measurements were corrected for air buoyancy. The relative atomic mass (atomic weight) of the plutonium from X126 certoficate was used. The isotopic composition was determined by thermal ionization mass spectrometry (TIMS) for comparison but not used in calculations.« less

Strength evaluation of butt joint by stress intensity factor of small edge crack near interface edge

NASA Astrophysics Data System (ADS)

Sato, T.; Oda, K.; Tsutsumi, N.

2018-06-01

Failure of the bonded dissimilar materials generally initiates near the interface, or just from the interface edge due to the stress singularity at the interface edge. In this study, the stress intensity factor of an edge crack close to the interface between the dissimilar materials is analyzed. The small edge crack is strongly dominated by the singular stress field near the interface edge. The analysis of stress intensity factor of small edge crack near the interface in bi-material and butt joint plates is carried out by changing the length and the location of the crack and the region dominated by the interface edge is examined. It is found that the dimensionless stress intensity factor of small crack, normalized by the singular stress at the crack tip point in the bonded plate without the crack, is equal to 1.12, independent of the material combination and adhesive layer thickness, when the relative crack length with respect to the crack location is less than 0.01. The adhesive strength of the bonded plate with various adhesive layer thicknesses can be expressed as the constant critical stress intensity factor of the small edge crack.

Research to Quantify the Effect of Permanent Change of Station Moves on Wives’ Wages and Labor Supply.

DTIC Science & Technology

1983-01-01

psychic costs and reduces incomes of family members. Spouses and other dependents mast give up jobs and take time to make the move. The Navy...tine only find, wanted, slack, unable 8. why no work hone, school, can’t find, other 9. weeks worked 10. weeks worked part-time 11. weeks unemployed ...Status March 1976 15. full-tim 16. part-tim T-7-1 i 17. unemployed /looking:I 18. keeping house 19. other Demographic Characteristics 20. wife living

Strategy Planning Visualization Tool (SPVT) for the Air Operations Center (AOC) Volume I: SPVT Summary and COA Sketch

DTIC Science & Technology

2009-12-01

Limitations of Real Time Battle Damage Assessment. [Thesis.] Maxwell AFB, AL: Air University. Shadbolt, N., Hall, W., Berners - Lee , T. (2006, May-June... Tim ) COA Development Use Case 3.7: User creates a new Course of Action (COA) User Story / Context of Use:  The JFACC may issue clear and...default, the timing of a Mission Analysis object will be r elative to the Operation’s Default tim ing (D-Day). If Use Case 3.24 is implem ented, then

Signing of ESO-Poland Accession Agreement

NASA Astrophysics Data System (ADS)

2014-12-01

An agreement was signed by Professor Lena Kolarska-Bobińska, the Polish Minister of Science and Higher Education, and the ESO Director General Tim de Zeeuw in Warsaw on 28 October 2014 that will lead to the country joining ESO. The signing of the agreement followed its unanimous approval by the ESO Council during an extraordinary meeting on 8 October 2014. Poland will be welcomed as a new Member State, following subsequent ratification of the accession agreement by the Polish Parliament. Tim de Zeeuw’s speech at this ceremony is reproduced below.

Interface Reactions and Synthetic Reaction of Composite Systems

PubMed Central

Park, Joon Sik; Kim, Jeong Min

2010-01-01

Interface reactions in composite systems often determine their overall properties, since product phases usually formed at interfaces during composite fabrication processing make up a large portion of the composites. Since most composite materials represent a ternary or higher order materials system, many studies have focused on analyses of diffusion phenomena and kinetics in multicomponent systems. However, the understanding of the kinetic behavior increases the complexity, since the kinetics of each component during interdiffusion reactions need to be defined for interpreting composite behaviors. From this standpoint, it is important to clarify the interface reactions for producing compatible interfaces with desired product phases. A thermodynamic evaluation such as a chemical potential of involving components can provide an understanding of the diffusion reactions, which govern diffusion pathways and product phase formation. A strategic approach for designing compatible interfaces is discussed in terms of chemical potential diagrams and interface morphology, with some material examples.

Flexible neural interfaces with integrated stiffening shank

DOEpatents

Tooker, Angela C.; Felix, Sarah H.; Pannu, Satinderpall S.; Shah, Kedar G.; Sheth, Heeral; Tolosa, Vanessa

2016-07-26

A neural interface includes a first dielectric material having at least one first opening for a first electrical conducting material, a first electrical conducting material in the first opening, and at least one first interconnection trace electrical conducting material connected to the first electrical conducting material. A stiffening shank material is located adjacent the first dielectric material, the first electrical conducting material, and the first interconnection trace electrical conducting material.

Reduction of Residual Stresses and Distortion in Girth Welded Pipes.

DTIC Science & Technology

1987-06-01

a material that is otherwise ductile. [7] * Generally, it is believed that pure metals do not crack as a result of stress corrosion. Some alloys are...N:AMEFNAME FE-:: ’ NI iW C S 1ŘC - iL’I-N T L-_ IFORMz=’FORMATTED’) 0026 TYPE ’ DOI Yt0U WANT AN INF0RMA-T[ 1 I C 1) N -IE (:I,: F B C! V N "’" 0027... SI3 -S0)*lO.+( ITI-ITO)/6. 0072 IF(TIII.LT.T(JJ)) GO TO 1 0074 CALL GTIM(ITMl) 0075 CALL CVTTIi1(IrFMIPI~il1lIIITl) 0076 TIM=( Ill-IHO)*36000.+( IM

Frontiers for geological remote sensing from space; Geosat Workshop, 4th, Flagstaff, AZ, June 12-17, 1983, Report

NASA Technical Reports Server (NTRS)

Henderson, F. B. (Editor); Rock, B. N. (Editor)

1983-01-01

Consideration is given to: the applications of near-infrared spectroscopy to geological reconnaissance and exploration from space; imaging systems for identifying the spectral properties of geological materials in the visible and near-infrared; and Thematic Mapper (TM) data analysis. Consideration is also given to descriptions of individual geological remote sensing systems, including: GEO-SPAS; SPOT; the Thermal Infrared Multispectral Scanner (TIMS); and the Shuttle Imaging Radars A and B (SIR-A and SIR-B). Additional topics include: the importance of geobotany in geological remote sensing; achromatic holographic stereograms from Landsat MSS data; and the availability and applications of NOAA's non-Landsat satellite data archive.

Using thermal-infrared imagery to delineate ground-water discharge

USGS Publications Warehouse

Banks, W.S.L.; Paylor, R.L.; Hughes, W.B.

1996-01-01

On March 8 and 9, 1992, a thermal-infrared-multispectral scanner (TIMS) was flown over two military ordnance disposal facilities at the Edgewood Area of Aberdeen Proving Ground, Maryland. The data, collected bythe National Aeronautics and Space Administration, in cooperation with the U.S. Army and the U.S. Geological Survey, were used to locate ground-water discharge zones in surface water. The images from the flight show areas where ground-water discharge is concentrated, as well as areas of diffuse discharge. Concentrated discharge is predominant in isolated or nearly isolated ponds and creeks in the study area. Diffuse dicharge is found near parts of the shoreline where the study area meets the surrounding estuaries of the Chesapeake Bay and the Gunpowder River. The average temperature for surface water, measured directly in the field, and the average temperature, calculated from atmospherically corrected TIMS images, was 10.6??C (Celsius) at the first of two sites. Potentiometric surface maps of both field sites show discharge toward the nontidal marshes, the estuaries which surround the field sites, and creeks which drain into the estuaries. The average measured temperature of ground water at both sites was 10.7??C. The calculated temperature from the TIMS imagery at both sites where ground-water discharge is concentrated within a surface-water body is 10.4??C. In the estuaries which surround the field sites, field measurements of temperature were made resulting in an average temperature of 9.0??C. The average calculated TIMS temperature from the estuaries was 9.3??C. Along the shoreline at the first site and within 40 to 80 meters of the western and southern shores of the second site, water was 1?? to 2??C warmer than water more than 80 meters away. The pattern of warmer water grading to cooler water in an offshore direction could result from diffuse ground-water discharge. Tonal differences in the TIMS imagery could indicate changes in surface-water temperatures. These tonal differences can be interpreted to delineate the location and extent of ground-water discharge to bodies of surface water.

Crystal Structures of Two Bacterial 3-Hydroxy-3-methylglutaryl-CoA Lyases Suggest a Common Catalytic Mechanism among a Family of TIM Barrel Metalloenzymes Cleaving Carbon-Carbon Bonds

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

Forouhar,F.; Hussain, M.; Farid, R.

The enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase catalyzes the terminal steps in ketone body generation and leucine degradation. Mutations in this enzyme cause a human autosomal recessive disorder called primary metabolic aciduria, which typically kills victims because of an inability to tolerate hypoglycemia. Here we present crystal structures of the HMG-CoA lyases from Bacillus subtilis and Brucella melitensis at 2.7 and 2.3 {angstrom} resolution, respectively. These enzymes share greater than 45% sequence identity with the human orthologue. Although the enzyme has the anticipated triose-phosphate isomerase (TIM) barrel fold, the catalytic center contains a divalent cation-binding site formed by a cluster ofmore » invariant residues that cap the core of the barrel, contrary to the predictions of homology models. Surprisingly, the residues forming this cation-binding site and most of their interaction partners are shared with three other TIM barrel enzymes that catalyze diverse carbon-carbon bond cleavage reactions believed to proceed through enolate intermediates (4-hydroxy-2-ketovalerate aldolase, 2-isopropylmalate synthase, and transcarboxylase 5S). We propose the name 'DRE-TIM metallolyases' for this newly identified enzyme family likely to employ a common catalytic reaction mechanism involving an invariant Asp-Arg-Glu (DRE) triplet. The Asp ligates the divalent cation, while the Arg probably stabilizes charge accumulation in the enolate intermediate, and the Glu maintains the precise structural alignment of the Asp and Arg. We propose a detailed model for the catalytic reaction mechanism of HMG-CoA lyase based on the examination of previously reported product complexes of other DRE-TIM metallolyases and induced fit substrate docking studies conducted using the crystal structure of human HMG-CoA lyase (reported in the accompanying paper by Fu, et al. (2006) J. Biol. Chem. 281, 7526-7532). Our model is consistent with extensive mutagenesis results and can guide subsequent studies directed at definitive experimental elucidation of this enzyme's reaction mechanism.« less

The effect of cassia fistula emulsion on pediatric functional constipation in comparison with mineral oil: a randomized, clinical trial

PubMed Central

2012-01-01

Background The prevalence of Pediatric Functional Constipation (FC) has been reported between 0.7% to 29.6%. This study was conducted to compare the laxative effect of cassia fistula emulsion (CFE) with mineral oil (MO) on FC. Cassia fistula is named in Traditional Iranian Medicine (TIM) as “Folus”. Materials and methods A randomized clinical trial was carried on 81 children (age range: 4–13 years) with FC, according to Rome III criteria in Amirkola Children’s Hospital, Babol, Iran. They received CFE or MO randomly for three weeks. CFE was produced according to the order of TIM references. Children were counted as improved when they exited from Rome III criteria of FC. Frequency of defecation, fecal incontinence, retentive posturing, severity of pain, consistency of stool and anal leakage of oily material were compared between the two groups and with baselines. An intent-to-treat analysis was used. Safety of drugs was assessed with the evaluation of clinical adverse effects. Results 41 children were assigned randomly to receive CFE and 40 children received MO. After three weeks of medication, 84% of children in CFE group and 50% in MO group (p = 0.002) exited from the criteria of FC, so called improved. All measurable criteria improved in both groups. The frequency of defecation in CFE group improved from 1.7 per week (before the study) to 10.6 per week (at the third week) while this parameter differed in MO group from 2 to 6.1 (p < 0.001). The severity of pain during defecation and consistency of stool improved significantly better in CFE group than MO group (p < 0.05), but there were not any significant differences between the two groups in fecal incontinence and retentive posturing. Anal leakage of oily material occurred as an important complication in MO group while the children in CFE group did not complaint it. Drug’s compliances were not significantly different in the two groups. CFE and MO did not cause clinically significant side effects. Conclusions CFE was most effective than MO in the 3-week treatment of children with FC. PMID:23351337

Performance Testing of Thermal Interface Filler Materials in a Bolted Aluminum Interface Under Thermal/Vacuum Conditions

NASA Technical Reports Server (NTRS)

Glasgow, S. D.; Kittredge, K. B.

2003-01-01

A thermal interface material is one of the many tools often used as part of the thermal control scheme for space-based applications. Historically, at Marshall Space Flight Center, CHO-THERM 1671 has primarily been used for applications where an interface material was deemed necessary. However, numerous alternatives have come on the market in recent years. It was decided that a number of these materials should be tested against each other to see if there were better performing alternatives. The tests were done strictly to compare the thermal performance of the materials relative to each other under repeatable conditions and do not take into consideration other design issues, such as off-gassing, electrical conduction, isolation, etc. The purpose of this Technical Memorandum is to detail the materials tested, test apparatus, procedures, and results of these tests. The results show that there are a number of better performing alternatives now available.

Method to separate and determine the amount of ejecta produced in a second-shock material-fragmentation event

NASA Astrophysics Data System (ADS)

Buttler, W. T.; Hixson, R. S.; King, N. S. P.; Olson, R. T.; Rigg, P. A.; Zellner, M. B.; Routley, N.; Rimmer, A.

2007-04-01

The authors consider a mathematical method to separate and determine the amount of ejecta produced in a second-shock material-fragmentation process. The technique is theoretical and assumes that a material undergoing a shock release at a vacuum interface ejects particulate material or fragments as the initial shock unloads and reflects at the vacuum-surface interface. In this case it is thought that the reflected shock may reflect again at the source of the shock and return to the vacuum-surface interface and eject another amount of fragments or particulate material.

Interface Management for a NASA Flight Project Using Model-Based Systems Engineering (MBSE)

NASA Technical Reports Server (NTRS)

Vipavetz, Kevin; Shull, Thomas A.; Infeld, Samatha; Price, Jim

2016-01-01

The goal of interface management is to identify, define, control, and verify interfaces; ensure compatibility; provide an efficient system development; be on time and within budget; while meeting stakeholder requirements. This paper will present a successful seven-step approach to interface management used in several NASA flight projects. The seven-step approach using Model Based Systems Engineering will be illustrated by interface examples from the Materials International Space Station Experiment-X (MISSE-X) project. The MISSE-X was being developed as an International Space Station (ISS) external platform for space environmental studies, designed to advance the technology readiness of materials and devices critical for future space exploration. Emphasis will be given to best practices covering key areas such as interface definition, writing good interface requirements, utilizing interface working groups, developing and controlling interface documents, handling interface agreements, the use of shadow documents, the importance of interface requirement ownership, interface verification, and product transition.

The effects of a stannous chloride-based water treatment system in a mercury contaminated stream

DOE PAGES

Mathews, Teresa J.; Looney, Brian B.; Smith, John G.; ...

2015-06-09

Remediation of mercury (Hg)-contaminated watersheds is often challenging because of the complex nature of Hg biogeochemistry. Stream ecosystems have been shown to be particularly susceptible to Hg contamination and bioaccumulation in fish. Decreasing total Hg loading to stream systems, however, has shown variable performance in decreasing Hg concentrations in fish tissues. In this study, we assess the impacts of an innovative treatment system in reducing releases of Hg to a small stream system in the southeastern United States. The treatment system, installed in 2007, removes Hg from water using tin (Sn) (II) chloride followed by air stripping. Mercury concentrations inmore » the receiving stream, Tims Branch, decreased from > 100 to ~10 ng/L in the four years following treatment, and Hg body burdens in redfin pickerel ( Esox americanus) decreased by 70 % at the most contaminated site. Tin concentrations in water and fish increased significantly in the tributary leading to Tims Branch, but concentrations remain below levels of concern for human health or ecological risks. While other studies have shown that Sn may be environmentally methylated and methyltin can transfer its methyl group to Hg, results from our field studies and sediment incubation experiments suggest that the added Sn to the Tims Branch watershed is not contributing to MeHg production and bioaccumulation. The stannous chloride treatment system installed at Tims Branch was effective at removing Hg inputs and reducing Hg bioaccumulation in the stream with minimal impacts on the environment due to the increased Sn in the system.« less

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

NASA Technical Reports Server (NTRS)

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

1991-01-01

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

Herbal Remedies for Functional Dyspepsia and Traditional Iranian Medicine Perspective

PubMed Central

Babaeian, Mahmoud; Naseri, Mohsen; Kamalinejad, Mohammad; Ghaffari, Farzaneh; Emadi, Fatemeh; Feizi, Awat; Hosseini Yekta, Nafiseh; Adibi, Peyman

2015-01-01

Context: Functional dyspepsia (FD) is a functional gastro-intestinal disorder with high prevalence. Among various treatment options, treatment by complementary and alternative medicines especially herbal remedies also practiced. Traditional Iranian medicine (TIM), a valuable resource of valid applied studies of ancient Iranian scholars, recommends numerous medicinal plants to treat dyspepsia symptoms. In this study, through investigation of TIM references, we aimed to identify medicinal plants for treatment of digestion insufficiency. Evidence Acquisition: In this qualitative study, dyspepsia symptoms including fullness, early satiety, bloating, nausea, and belching were checked under reliable sources of traditional medicine. Then medicinal plants recommended for the treatment of the symptoms were extracted from the books. Likewise, for investigating the pharmacological properties of medicinal plants used for the relieving of dyspepsia symptoms, electronic databases such as PubMed, Scopus, Google Scholar and some Iranian databases like SID and IranMedex were employed. Results: The study yielded 105 plants from 37 families which could treat various dyspepsia symptoms; fifty-seven plants, mainly from Apiaceae, Lamiaceae, Amaryllidaceae and Zingiberaceae had digestive effects. In this research, based on the information in TIM reference texts, we obtained 58 plants effective for bloating, 40 for nausea, 37 for appetite loss and 7 for belching. In human clinical trials conducted on medicinal plants effective for FD symptoms, 7 single plants were used. Conclusions: Finding the medicinal plants effective on digestion insufficiency based on TIM could suggest a better strategy for the relieving of dyspepsia symptoms. Traditional Iranian medicine prescribes medicinal plants based on each patient’s personal characteristics and practices multiple target therapies. PMID:26734483

Herbal Remedies for Functional Dyspepsia and Traditional Iranian Medicine Perspective.

PubMed

Babaeian, Mahmoud; Naseri, Mohsen; Kamalinejad, Mohammad; Ghaffari, Farzaneh; Emadi, Fatemeh; Feizi, Awat; Hosseini Yekta, Nafiseh; Adibi, Peyman

2015-11-01

Functional dyspepsia (FD) is a functional gastro-intestinal disorder with high prevalence. Among various treatment options, treatment by complementary and alternative medicines especially herbal remedies also practiced. Traditional Iranian medicine (TIM), a valuable resource of valid applied studies of ancient Iranian scholars, recommends numerous medicinal plants to treat dyspepsia symptoms. In this study, through investigation of TIM references, we aimed to identify medicinal plants for treatment of digestion insufficiency. In this qualitative study, dyspepsia symptoms including fullness, early satiety, bloating, nausea, and belching were checked under reliable sources of traditional medicine. Then medicinal plants recommended for the treatment of the symptoms were extracted from the books. Likewise, for investigating the pharmacological properties of medicinal plants used for the relieving of dyspepsia symptoms, electronic databases such as PubMed, Scopus, Google Scholar and some Iranian databases like SID and IranMedex were employed. The study yielded 105 plants from 37 families which could treat various dyspepsia symptoms; fifty-seven plants, mainly from Apiaceae, Lamiaceae, Amaryllidaceae and Zingiberaceae had digestive effects. In this research, based on the information in TIM reference texts, we obtained 58 plants effective for bloating, 40 for nausea, 37 for appetite loss and 7 for belching. In human clinical trials conducted on medicinal plants effective for FD symptoms, 7 single plants were used. Finding the medicinal plants effective on digestion insufficiency based on TIM could suggest a better strategy for the relieving of dyspepsia symptoms. Traditional Iranian medicine prescribes medicinal plants based on each patient's personal characteristics and practices multiple target therapies.

Initial oral biofilm formation on titanium implants with different surface treatments: An in vivo study.

PubMed

Ferreira Ribeiro, Cyntia; Cogo-Müller, Karina; Franco, Gilson Cesar; Silva-Concílio, Laís Regiane; Sampaio Campos, Márcia; de Mello Rode, Sigmar; Claro Neves, Ana Christina

2016-09-01

The aim of this study was to examine in vivo the initial bacterial adhesion on titanium implants with different surface treatments. Ten subjects wore oral splints containing machined pure titanium disks (Ti-M), acid-etched titanium (Ti-AE) and anodized and laser irradiated disks (Ti-AL) for 24h. After this period, disks were removed from the splints and adherent bacteria were quantified by an enzymatic assay to assess total viable bacteria and by Real Time PCR to evaluate total bacteria and Streptococcus oralis levels. Additionally, the initial adherent microorganisms were visualized by scanning electron microscopy (SEM). Titanium surface morphology was verified using SEM, and roughness was evaluated by profilometer analysis. Regarding titanium surface roughness, Ti-AL (1.423±0.397) showed significantly higher Ra values than did Ti-M (0.771±0.182) and Ti-AE (0.735±0.196) (p<0.05, ANOVA - Tahame). Ti-AE and Ti-AL presented roughened micro-structure surfaces characterized by open pores, whereas Ti-M showed long grooves alternating with planed areas. Comparing the Ti-M, Ti-AE and Ti-AL groups for viable bacteria (MTT assay), total bacteria and S. oralis quantification (qPCR), no significant differences were observed among these three groups (p>0.05, ANOVA - Tahame). SEM images showed similar bacterial adhesion on the three titanium surfaces, predominantly characterized by cocci and several bacilli, indicating an initial colonization of the oral biofilm. In conclusion, roughness and microtopography did not stimulate initial biofilm formation on titanium surfaces with different surface treatments. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dietary iron intake and iron status of German female vegans: results of the German vegan study.

PubMed

Waldmann, Annika; Koschizke, Jochen W; Leitzmann, Claus; Hahn, Andreas

2004-01-01

As shown in previous studies vegetarians and especially vegans are at risk for iron deficiency. Our study evaluated the iron status of German female vegans. In this cross-sectional study, the dietary intakes of 75 vegan women were assessed by two 9-day food frequency questionnaires. The iron status was analyzed on the basis of blood parameters. Mean daily iron intake was higher than recommended by the German Nutrition Society. Still 42% of the female vegans < 50 years (young women, YW) had a daily iron intake of < 18 mg/day, which is the recommended allowance by the US Food and Nutrition Board. The main dietary sources of iron were vegetables, fruits, cereals and cereal products. Median serum ferritin concentrations were 14 ng/ml for YW and 28 ng/ml for women > or = 50 years (old women, OW). In all, 40% (tri-index model (TIM) 20%) of the YW and 12% (TIM 12%) of the OW were considered iron-deficient based on either serum ferritin levels of < 12 ng/ml or a TIM. Only 3 women had blood parameters which are defined as iron deficiency anemia. Correlations between serum ferritin levels and dietary factors were not found. Although the mean iron intake was above the recommended level, 40% (TIM 20%) of the YW were considered iron-deficient. It is suggested that especially YM on a vegan diet should have their iron status monitored and should consider taking iron supplements in case of a marginal status. Copyright 2004 S. Karger AG, Basel

Fundamentals of lateral and vertical heterojunctions of atomically thin materials.

PubMed

Pant, Anupum; Mutlu, Zafer; Wickramaratne, Darshana; Cai, Hui; Lake, Roger K; Ozkan, Cengiz; Tongay, Sefaattin

2016-02-21

At the turn of this century, Herbert Kroemer, the 2000 Nobel Prize winner in Physics, famously commented that "the interface is the device". This statement has since opened up unparalleled opportunities at the interface of conventional three-dimensional (3D) materials (H. Kroemer, Quasi-Electric and Quasi-Magnetic Fields in Non-Uniform Semiconductors, RCA Rev., 1957, 18, 332-342). More than a decade later, Sir Andre Geim and Irina Grigorieva presented their views on 2D heterojunctions which further cultivated broad interests in the 2D materials field. Currently, advances in two-dimensional (2D) materials enable us to deposit layered materials that are only one or few unit-cells in thickness to construct sharp in-plane and out-of-plane interfaces between dissimilar materials, and to be able to fabricate novel devices using these cutting-edge techniques. The interface alone, which traditionally dominated overall device performance, thus has now become the device itself. Fueled by recent progress in atomically thin materials, we are now at the ultimate limit of interface physics, which brings to us new and exciting opportunities, with equally demanding challenges. This paper endeavors to provide stalwarts and newcomers a perspective on recent advances in synthesis, fundamentals, applications, and future prospects of a large variety of heterojunctions of atomically thin materials.

Analysis of interface crack branching

NASA Technical Reports Server (NTRS)

Ballarini, R.; Mukai, D. J.; Miller, G. R.

1989-01-01

A solution is presented for the problem of a finite length crack branching off the interface between two bonded dissimilar isotropic materials. Results are presented in terms of the ratio of the energy release rate of a branched interface crack to the energy release rate of a straight interface crack with the same total length. It is found that this ratio reaches a maximum when the interface crack branches into the softer material. Longer branches tend to have smaller maximum energy release rate ratio angles indicating that all else being equal, a branch crack will tend to turn back parallel to the interface as it grows.

Identification of Lasso Peptide Topologies Using Native Nanoelectrospray Ionization-Trapped Ion Mobility Spectrometry-Mass Spectrometry.

PubMed

Dit Fouque, Kevin Jeanne; Moreno, Javier; Hegemann, Julian D; Zirah, Séverine; Rebuffat, Sylvie; Fernandez-Lima, Francisco

2018-04-17

Lasso peptides are a fascinating class of bioactive ribosomal natural products characterized by a mechanically interlocked topology. In contrast to their branched-cyclic forms, lasso peptides have higher stability and have become a scaffold for drug development. However, the identification and separation of lasso peptides from their unthreaded topoisomers (branched-cyclic peptides) is analytically challenging since the higher stability is based solely on differences in their tertiary structures. In the present work, a fast and effective workflow is proposed for the separation and identification of lasso from branched cyclic peptides based on differences in their mobility space under native nanoelectrospray ionization-trapped ion mobility spectrometry-mass spectrometry (nESI-TIMS-MS). The high mobility resolving power ( R) of TIMS resulted in the separation of lasso and branched-cyclic topoisomers ( R up to 250, 150 needed on average). The advantages of alkali metalation reagents (e.g., Na, K, and Cs salts) as a way to increase the analytical power of TIMS is demonstrated for topoisomers with similar mobilities as protonated species, efficiently turning the metal ion adduction into additional separation dimensions.

Risk Assessment Update: Russian Segment

NASA Technical Reports Server (NTRS)

Christiansen, Eric; Lear, Dana; Hyde, James; Bjorkman, Michael; Hoffman, Kevin

2012-01-01

BUMPER-II version 1.95j source code was provided to RSC-E- and Khrunichev at January 2012 MMOD TIM in Moscow. MEMCxP and ORDEM 3.0 environments implemented as external data files. NASA provided a sample ORDEM 3.0 g."key" & "daf" environment file set for demonstration and benchmarking BUMPER -II v1.95j installation at the Jan-12 TIM. ORDEM 3.0 has been completed and is currently in beta testing. NASA will provide a preliminary set of ORDEM 3.0 ".key" & ".daf" environment files for the years 2012 through 2028. Bumper output files produced using the new ORDEM 3.0 data files are intended for internal use only, not for requirements verification. Output files will contain these words ORDEM FILE DESCRIPTION = PRELIMINARY VERSION: not for production. The projectile density term in many BUMPER-II ballistic limit equations will need to be updated. Cube demo scripts and output files delivered at the Jan-12 TIM have been updated for the new ORDEM 3.0 data files. Risk assessment results based on ORDEM 3.0 and MEM will be presented for the Russian Segment (RS) of ISS.

Enhanced ionization efficiency in TIMS analyses of plutonium and americium using porous ion emitters

DOE PAGES

Baruzzini, Matthew L.; Hall, Howard L.; Watrous, Matthew G.; ...

2016-12-05

Investigations of enhanced sample utilization in thermal ionization mass spectrometry (TIMS) using porous ion emitter (PIE) techniques for the analyses of trace quantities of americium and plutonium were performed. Repeat ionization efficiency (i.e., the ratio of ions detected to atoms loaded on the filament) measurements were conducted on sample sizes ranging from 10–100 pg for americium and 1–100 pg for plutonium using PIE and traditional (i.e., a single, zone-refined rhenium, flat filament ribbon with a carbon ionization enhancer) TIMS filament sources. When compared to traditional filaments, PIEs exhibited an average boost in ionization efficiency of ~550% for plutonium and ~1100%more » for americium. A maximum average efficiency of 1.09% was observed at a 1 pg plutonium sample loading using PIEs. Supplementary trials were conducted using newly developed platinum PIEs to analyze 10 pg mass loadings of plutonium. As a result, platinum PIEs exhibited an additional ~134% boost in ion yield over standard PIEs and ~736% over traditional filaments at the same sample loading level.« less

A monomeric TIM-barrel structure from Pyrococcus furiosus is optimized for extreme temperatures.

PubMed

Repo, Heidi; Oeemig, Jesper S; Djupsjöbacka, Janica; Iwaï, Hideo; Heikinheimo, Pirkko

2012-11-01

The structure of phosphoribosyl anthranilate isomerase (TrpF) from the hyperthermophilic archaeon Pyrococcus furiosus (PfTrpF) has been determined at 1.75 Å resolution. The PfTrpF structure has a monomeric TIM-barrel fold which differs from the dimeric structures of two other known thermophilic TrpF proteins. A comparison of the PfTrpF structure with the two known bacterial thermophilic TrpF structures and the structure of a related mesophilic protein from Escherichia coli (EcTrpF) is presented. The thermophilic TrpF structures contain a higher proportion of ion pairs and charged residues compared with the mesophilic EcTrpF. These residues contribute to the closure of the central barrel and the stabilization of the barrel and the surrounding α-helices. In the monomeric PfTrpF conserved structural water molecules are mostly absent; instead, the structural waters are replaced by direct side-chain-main-chain interactions. As a consequence of these combined mechanisms, the P. furiosus enzyme is a thermodynamically stable and entropically optimized monomeric TIM-barrel enzyme which defines a good framework for further protein engineering for industrial applications.

The CK2 Kinase Stabilizes CLOCK and Represses Its Activity in the Drosophila Circadian Oscillator

PubMed Central

Szabó, Áron; Papin, Christian; Zorn, Daniela; Ponien, Prishila; Weber, Frank; Raabe, Thomas; Rouyer, François

2013-01-01

Phosphorylation is a pivotal regulatory mechanism for protein stability and activity in circadian clocks regardless of their evolutionary origin. It determines the speed and strength of molecular oscillations by acting on transcriptional activators and their repressors, which form negative feedback loops. In Drosophila, the CK2 kinase phosphorylates and destabilizes the PERIOD (PER) and TIMELESS (TIM) proteins, which inhibit CLOCK (CLK) transcriptional activity. Here we show that CK2 also targets the CLK activator directly. Downregulating the activity of the catalytic α subunit of CK2 induces CLK degradation, even in the absence of PER and TIM. Unexpectedly, the regulatory β subunit of the CK2 holoenzyme is not required for the regulation of CLK stability. In addition, downregulation of CK2α activity decreases CLK phosphorylation and increases per and tim transcription. These results indicate that CK2 inhibits CLK degradation while reducing its activity. Since the CK1 kinase promotes CLK degradation, we suggest that CLK stability and transcriptional activity result from counteracting effects of CK1 and CK2. PMID:24013921

Remote detection of canopy water stress in coniferous forests using the NS001 Thematic Mapper Simulator and the thermal infrared multispectral scanner

NASA Technical Reports Server (NTRS)

Pierce, Lars L.; Running, Steven W.; Riggs, George A.

1990-01-01

Water stress was induced in two coniferous forest stands in West Germany by severing tree sapwood. Leaf water potential, Psi(L), measurements indicated that maximum, naturally occurring levels of water stress developed in the stressed plots while control plots exhibited natural diurnal trends. Images of each site were obtained with the Thematic Mapper Simulator (NS001) and the Thermal Infrared Multispectral Scanner (TIMS) 12 to 15 days after stress induction. NS001 bands 2 to 6, NS001 indices combining bands 4 and 6, and NS001 and TIMS thermal bands showed significant radiance differences between stressed and control plots when large differences in Psi(L) and relative water content (RWC) existed during the morning overflights at Munich. However, the NS001 and TIMS sensors could not detect the slightly smaller differences in Psi(L) and RWC during the Munich afternoon and Frankfurt overflights. The results suggest that routine detection of canopy water stress under operational conditions is difficult utilizing current sensor technology.

Mapping the distribution of vesicular textures on silicic lavas using the Thermal Infrared Multispectral Scanner

NASA Technical Reports Server (NTRS)

Ondrusek, Jaime; Christensen, Philip R.; Fink, Jonathan H.

1993-01-01

To investigate the effect of vesicularity on TIMS (Thermal Infrared Multispectral Scanner) imagery independent of chemical variations, we studied a large rhyolitic flow of uniform composition but textural heterogeneity. The imagery was recalibrated so that the digital number values for a lake in the scene matched a calculated ideal spectrum for water. TIMS spectra for the lava show useful differences in coarsely and finely vesicular pumice data, particularly in TIMS bands 3 and 4. Images generated by ratioing these bands accurately map out those areas known from field studies to be coarsely vesicular pumice. These texture-related emissivity variations are probably due to the larger vesicles being relatively deeper and separated by smaller septa leaving less smooth glass available to give the characteristic emission of the lava. In studies of inaccessible lava flows (as on Mars) areas of coarsely vesicular pumice must be identified and avoided before chemical variations can be interpreted. Remotely determined distributions of vesicular and glassy textures can also be related to the volatile contents and potential hazards associated with the emplacement of silicic lava flows on Earth.

Study program for encapsulation materials interface for low-cost solar array

NASA Technical Reports Server (NTRS)

Kaelble, D. H.; Mansfeld, F. B.; Kendig, M.; Leung, C.

1981-01-01

The service integrity of the bonded interface in solar cell modules used in solar arrays is addressed. The development of AC impedance as a nondestructive evaluation (NDE) methodology for solar arrays is reported along with development of corrosion models and materials selection criteria for corrosion resistant interfaces.

Performance Testing of Thermal Interface Filler Materials in a Bolted Aluminum Interface Under Thermal/Vacuum Conditions

NASA Technical Reports Server (NTRS)

Glasgow, Shaun; Kittredge, Ken

2003-01-01

A thermal interface material is one of the many tools that are often used as part of the thermal control scheme for space-based applications. These materials are placed between, for example, an avionics box and a cold plate, in order to improve the conduction heat transfer so that proper temperatures can be maintained. Historically at Marshall Space Flight Center, CHO-THERM@ 1671 has primarily been used for applications where an interface material was deemed necessary. However, there have been numerous alternatives come on the market in recent years. It was decided that a number of these materials should be tested against each other to see if there were better performing alternatives. The tests were done strictly to compare the thermal performance of the materials relative to each other under repeatable conditions and they do not take into consideration other design issues such as off-gassing, electrical conduction or isolation, etc. This paper details the materials tested, test apparatus, procedures, and results of these tests.

Selenium Interlayer for High-Efficiency Multijunction Solar Cell

NASA Technical Reports Server (NTRS)

Landis, Geoffrey A (Inventor)

2015-01-01

A multi junction solar cell is provided and includes multiple semiconducting layers and an interface layer disposed between the multiple semiconducting layers. The interface layer is made from an interface bonding material that has a refractive index such that a ratio of a refractive index of each of the multiple semiconducting layers to the refractive index of the interface bonding material is less than or equal to 1.5.

Selenium Interlayer for High-Efficiency Multijunction Solar Cell

NASA Technical Reports Server (NTRS)

Landis, Geoffrey A. (Inventor)

2016-01-01

A multi-junction solar cell is provided and includes multiple semiconducting layers and an interface layer disposed between the multiple semiconducting layers. The interface layer is made from an interface bonding material that has a refractive index such that a ratio of a refractive index of each of the multiple semiconducting layers to the refractive index of the interface bonding material is less than or equal to 1.5.

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.

Early Career. Harnessing nanotechnology for fusion plasma-material interface research in an in-situ particle-surface interaction facility

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

Allain, Jean Paul

2014-08-08

This project consisted of fundamental and applied research of advanced in-situ particle-beam interactions with surfaces/interfaces to discover novel materials able to tolerate intense conditions at the plasma-material interface (PMI) in future fusion burning plasma devices. The project established a novel facility that is capable of not only characterizing new fusion nanomaterials but, more importantly probing and manipulating materials at the nanoscale while performing subsequent single-effect in-situ testing of their performance under simulated environments in fusion PMI.

Cutting Modeling of Hybrid CFRP/Ti Composite with Induced Damage Analysis

PubMed Central

Xu, Jinyang; El Mansori, Mohamed

2016-01-01

In hybrid carbon fiber reinforced polymer (CFRP)/Ti machining, the bi-material interface is the weakest region vulnerable to severe damage formation when the tool cutting from one phase to another phase and vice versa. The interface delamination as well as the composite-phase damage is the most serious failure dominating the bi-material machining. In this paper, an original finite element (FE) model was developed to inspect the key mechanisms governing the induced damage formation when cutting this multi-phase material. The hybrid composite model was constructed by establishing three disparate physical constituents, i.e., the Ti phase, the interface, and the CFRP phase. Different constitutive laws and damage criteria were implemented to build up the entire cutting behavior of the bi-material system. The developed orthogonal cutting (OC) model aims to characterize the dynamic mechanisms of interface delamination formation and the affected interface zone (AIZ). Special focus was made on the quantitative analyses of the parametric effects on the interface delamination and composite-phase damage. The numerical results highlighted the pivotal role of AIZ in affecting the formation of interface delamination, and the significant impacts of feed rate and cutting speed on delamination extent and fiber/matrix failure. PMID:28787824

Geologic mapping of Argyre Planitia

NASA Technical Reports Server (NTRS)

Gorsline, Donn S.; Parker, Timothy J.

1995-01-01

This report describes the results from the geologic mapping of the central and southern Argyre basin of Mars. At the Mars Geologic Mapper's Meeting in Flagstaff during July, 1993, Dave Scott (United States Geological Survey, Mars Geologic Mapping Steering Committee Chair) recommended that all four quadrangles be combined into a single 1:1,000,000 scale map for publication. It was agreed that this would be cost-effective and that the decrease in scale would not compromise the original science goals of the mapping. Tim Parker completed mapping on the 1:500,000 scale base maps, for which all the necessary materials had already been produced, and included the work as a chapter in his dissertation, which was completed in the fall of 1994. Geologic mapping of the two southernmost quadrangles (MTM -55036 and MTM -55043; MTM=Mars Transverse Mercator) was completed as planned during the first year of work. These maps and a detailed draft of the map text were given a preliminary review by Dave Scott during summer, 1993. Geologic mapping of the remaining two quadrangles (MTM -50036 and MTM -50043) was completed by summer, 1994. Results were described at the Mars Geologic Mappers Meeting, held in Pocatello, Idaho, during July, 1994. Funds for the third and final year of the project have been transferred to the Jet Propulsion Laboratory, where Tim Parker will revise and finalize all maps and map text for publication by the United States Geological Survey at the 1:1,000,000 map scale.

Isotopic age of the Black Forest Bed, Petrified Forest Member, Chinle Formation, Arizona: An example of dating a continental sandstone

USGS Publications Warehouse

Riggs, N.R.; Ash, S.R.; Barth, A.P.; Gehrels, G.E.; Wooden, J.L.

2003-01-01

Zircons from the Black Forest Bed, Petrified Forest Member, Chinle Formation, in Petrified Forest National Park, yield ages that range from Late Triassic to Late Archean. Grains were analyzed by multigrain TIMS (thermal-ionization mass spectrometry), single-crystal TIMS, and SHRIMP (sensitive, high-resolution ion-microprobe). Multiple-grain analysis yielded a discordia trajectory with a lower intercept of 207 ?? 2 Ma, which because of the nature of multiple-grain sampling of a detrital bed, is not considered conclusive. Analysis of 29 detrital-zircon grains by TIMS yielded U-PB ages of 2706 ?? 6 Ma to 206 ?? 6 Ma. Eleven of these ages lie between 211 and 216 ?? 6.8 Ma. Our statistical analysis of these grains indicates that the mean of the ages, 213 ?? 1.7 Ma, reflects more analytical error than geologic variability in sources of the grains. Grains with ages of ca. 1400 Ma were derived from the widespread plutons of that age exposed throughout the southwestern Cordillera and central United States. Twelve grains analyzed by SHRIMP provide 206Pb*/238U ages from 214 ?? 2 Ma to 200 ?? 4 Ma. We use these data to infer that cores of inherited material were present in many zircons and that single-crystal analysis provides an accurate estimation of the age of the bed. We further propose that, even if some degree of reworking has occurred, the very strong concentration of ages at ca. 213 Ma provides a maximum age for the Black Forest Bed of 213 ?? 1.7 Ma. The actual age of the bed may be closer to 209 Ma. Dating continental successions is very difficult when distinct ash beds are not clearly identified, as is the case in the Chinle Formation. Detrital zircons in the Black Forest Bed, however, are dominated by an acicular morphology with preserved delicate terminations. The shape of these crystals and their inferred environment of deposition in slow-water settings suggest that the crystals were not far removed from their site of deposition in space and likely not far in time. Plinian ash clouds derived from explosive eruptions along the early Mesozoic Cordilleran margin provided the crystals to the Chinle basin, where local conditions insured their preservation. In the case of the Black Forest Bed, the products of one major eruption may dominate the volcanic contribution to the unit. Volcanic detritus in the Chinle Formation was derived from multiple, distinct sources. Coarse pebble- to cobble-size material may have originated in eastern California and/or western Arizona, where Triassic plutons are exposed. Fine-grained detritus, in contrast, was carried in ash clouds that derived from caldera eruptions in east-central California or western Nevada.

Total and Spectral Solar Irradiance Sensor (TSIS) Project Overview

NASA Technical Reports Server (NTRS)

Carlisle, Candace; Wedge, Ronnice; Wu, Dong; Stello, Harry; Robinson, Renee

2015-01-01

The main objective of the Total and Spectral solar Irradiance Sensor (TSIS) is to acquire measurements to determine the direct and indirect effects of solar radiation on climate. TSIS total solar irradiance measurements will extend a 37-year long uninterrupted measurement record of incoming solar radiation, the dominant energy source driving the Earths climate and the most precise indicator of changes in the Suns energy output. TSIS solar spectral irradiance measurements will determine the regions of the Earths multi-layered atmosphere that are affected by solar variability, from which the solar forcing mechanisms causing changes in climate can be quantified. TSIS includes two instruments: the Total Irradiance Monitor (TIM) and the Spectral Irradiance Monitor (SIM), integrated into a single payload. The TSIS TIM and SIM instruments are upgraded versions of the two instruments that are flying on the Solar Radiation and Climate Experiment (SORCE) mission launched in January 2003. TSIS was originally planned for the nadir-pointing National Polar-orbiting Operational Environmental Satellite System (NPOESS) spacecraft. The TSIS instrument passed a Critical Design Review (CDR) for NPOESS in December 2009. In 2010, TSIS was re-planned for the Joint Polar Satellite System (JPSS) Polar Free Flyer (PFF). The TSIS TIM, SIM, and associated electronics were built, tested, and successfully completed pre-ship review as of December 2013.In early 2014, NOAA and NASA agreed to fly TSIS on the International Space Station (ISS). In the FY16 Presidents Budget, NASA assumes responsibility for the TSIS mission on ISS. The TSIS project includes requirements, interface, design, build and test of the TSIS payload, including an updated pointing system, for accommodation on the ISS. It takes advantage of the prior development of the TSIS sensors and electronics. The International Space Station (ISS) program contributions include launch services and robotic installation of the TSIS payload onto an ISS Express Logistics Carrier, mission operations, and communications. Total and Spectral solar irradiance data products will be produced, calibrated, and made publically available through the Goddard Earth Science Data and Information Services Center (GES DISC).The NASA GSFC TSIS project at GSFC is responsible for project management, system engineering, safety and mission assurance, and engineering oversight for the TSIS payload. The TSIS project has contracted with the University of Colorado Laboratory for Atmospheric and Space Physics (LASP) for the design, development and testing of TSIS, support for ISS integration, science operations of the TSIS instrument, data processing, data evaluation and delivery to the GES DISC. TSIS will be delivered to Kennedy Space Center for integration in 2017, with launch and installation onto ISS planned for late 2017-early 2018. After a 90-day check-out period, NASA plans five years of TSIS operations.