Research Containing: Models

Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude via REV-ERB Loading

by cfynanon 22 August 2016in Biology & Biotechnology No comment

A central mechanism for controlling circadian gene amplitude remains elusive. We present evidence for a "facilitated repression (FR)" model that functions as an amplitude rheostat for circadian gene oscillation. We demonstrate that ROR and/or BMAL1 promote global chromatin decondensation during the activation phase of the circadian cycle to actively facilitate REV-ERB loading for repression of circadian gene expression. Mechanistically, we found that SRC-2 dictates global circadian chromatin remodeling through spatial and temporal recruitment of PBAF members of the SWI/SNF complex to facilitate loading of REV-ERB in the hepatic genome. Mathematical modeling highlights how the FR model sustains proper circadian rhythm despite fluctuations of REV-ERB levels. Our study not only reveals a mechanism for active communication between the positive and negative limbs of the circadian transcriptional loop but also establishes the concept that clock transcription factor binding dynamics is perhaps a central tenet for fine-tuning circadian rhythm.

Three-dimensional structure of carboxypeptidase T from Thermoactinomyces vulgaris in complex with N-BOC-L-leucine

by cfynanon 22 August 2016in Biology & Biotechnology No comment

The 3D structure of recombinant bacterial carboxypeptidase T (CPT) in complex with N-BOC-L-leucine was determined at 1.38 A resolution. Crystals for the X-ray study were grown in microgravity using the counter-diffusion technique. N-BOC-L-leucine and SO4(2-) ion bound in the enzyme active site were localized in the electron density map. Location of the leucine side chain in CPT-N-BOC-L-leucine complex allowed identification of the S1 subsite of the enzyme, and its structure was determined. Superposition of the structures of CPT-N-BOC-L-leucine complex and complexes of pancreatic carboxypeptidases A and B with substrate and inhibitors was carried out, and similarity of the S1 subsites in these three carboxypeptidases was revealed. It was found that SO4(2-) ion occupies the same position in the S1′ subsite as the C-terminal carboxy group of the substrate.

Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

by cfynanon 22 August 2016in Biology & Biotechnology No comment

Huntington’s disease is caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. A structural basis for the apparent transition between normal and disease-causing expanded polyQ repeats of huntingtin is unknown. The "linear lattice" model proposed random-coil structures for both normal and expanded polyQ in the preaggregation state. Consistent with this model, the affinity and stoichiometry of the anti-polyQ antibody MW1 increased with the number of glutamines. An opposing "structural toxic threshold" model proposed a conformational change above the pathogenic polyQ threshold resulting in a specific toxic conformation for expanded polyQ. Support for this model was provided by the anti-polyQ antibody 3B5H10, which was reported to specifically recognize a distinct pathologic conformation of soluble expanded polyQ. To distinguish between these models, we directly compared binding of MW1 and 3B5H10 to normal and expanded polyQ repeats within huntingtin exon 1 fusion proteins. We found similar binding characteristics for both antibodies. First, both antibodies bound to normal, as well as expanded, polyQ in huntingtin exon 1 fusion proteins. Second, an expanded polyQ tract contained multiple epitopes for fragments antigen-binding (Fabs) of both antibodies, demonstrating that 3B5H10 does not recognize a single epitope specific to expanded polyQ. Finally, small-angle X-ray scattering and dynamic light scattering revealed similar binding modes for MW1 and 3B5H10 Fab-huntingtin exon 1 complexes. Together, these results support the linear lattice model for polyQ binding proteins, suggesting that the hypothesized pathologic conformation of soluble expanded polyQ is not a valid target for drug design.

Benchmark studies of the effectiveness of structural and internal materials as radiation shielding for the international space station

by cfynanon 9 June 2015in Technology Development & Demonstration No comment

Accelerator-based measurements and model calculations have been used to study the heavy-ion radiation transport properties of materials in use on the International Space Station (ISS). Samples of the ISS aluminum outer hull were augmented with various configurations of internal wall material and polyethylene. The materials were bombarded with high-energy iron ions characteristic of a significant part of the galactic cosmic-ray (GCR) heavy-ion spectrum. Transmitted primary ions and charged fragments produced in nuclear collisions in the materials were measured near the beam axis, and a model was used to extrapolate from the data to lower beam energies and to a lighter ion. For the materials and ions studied, at incident particle energies from 1037 MeV/nucleon down to at least 600 MeV/nucleon, nuclear fragmentation reduces the average dose and dose equivalent per incident ion. At energies below 400 MeV/nucleon, the calculation predicts that as material is added, increased ionization energy loss produces increases in some dosimetric quantities. These limited results suggest that the addition of modest amounts of polyethylene or similar material to the interior of the ISS will reduce the dose to ISS crews from space radiation; however, the radiation transport properties of ISS materials should be evaluated with a realistic space radiation field.

Dose distribution in the Russian Segment of the International Space Station

by cfynanon 9 June 2015in Technology Development & Demonstration No comment

Absorbed dose and average linear energy transfer (LET) were assessed by means of (7)LiF:Mg,Ti (TLD-700) thermoluminescent (TL) detectors for different panels on-board the Russian Segment of the International Space Station in the timeframe between March and November 2002 (233 d). A technique is presented to correct the measured absorbed dose values for TL efficiency in the radiation climate on-board the spacecraft. Average LET is determined from the high-temperature TL emission in the TLD-700 glow curve and used as a parameter in the TL efficiency correction. Depending on the shielding distribution, the efficiency-corrected absorbed dose varies between 154 +/- 5 microGy d(-1) in panel no. 327 (core block ceiling) and 191 +/- 3 microGy d(-1) in panel no. 110 (core block central axis, floor). The experimental data are compared with the model calculations by using detailed shielding distributions and orbit parameters as inputs.

Absorbed dose of secondary neutrons from galactic cosmic rays inside the International Space Station

by cfynanon 9 June 2015in Technology Development & Demonstration No comment

In this paper, we present the results of Monte-Carlo simulations of the flux and energy spectra of neutrons generated as a result of galactic cosmic ray proton interactions with the material of International Space Station (ISS) inside Zvezda Service Module, the Airlock between Russian and USA segments and one of Russian Research Modules for a full configuration of ISS. Calculations were made for ISS orbit for the energy ranges <10 and >10 MeV for both maximum and minimum of solar activity. To test the accuracy of the calculations the same simulations were made for MIR orbital station and for CORONAS-I satellite and compared with the results of measurements. Calculated and measured fluxes are in reasonable agreement.

Colloidal aggregation in microgravity by critical Casimir forces

by cfynanon 9 June 2015in Physical Sciences No comment

By using the critical Casimir force, we study the attractive strength dependent aggregation of colloids with and without gravity by means of near field scattering. Significant differences were seen between microgravity and ground experiments, both in the structure of the formed fractal aggregates as well as in the kinetics of growth. In microgravity purely diffusive aggregation is observed. By using the continuously variable particle interaction potential we can for the first time experimentally relate the strength of attraction between the particles and the structure of the aggregates.

Investigation of dose and flux dynamics in the Liulin-5 dosimeter of the tissue-equivalent phantom onboard the Russian segment of the international space station

by cfynanon 9 June 2015in Physical Sciences No comment

Described is the Liulin-5 active dosimetric telescope designed for measurement of the space radiation dose depth-distribution in a human phantom on the Russian Segment of the International Space Station (ISS). The Liulin-5 experiment is a part of the international project MATROSHKA-R on ISS. The MATROSHKA-R project is aimed to study the depth- dose distribution at the sites of critical organs of the human body, using models of human body-anthropomorphic ant spherical tissue-equivalent phantoms. The aim of Liulin-5 experiment is a long term (4–5 years) investigation of the radiation environment dynamics inside the spherical tissue-equivalent phantom, mounted in different compartments. Energy deposition spectra, linear energy transfer spectra, and flux and dose rates for charged particles will be measured simultaneously with near real time resolution at different depths of the phantom by means of three silicon detectors. Data obtained together with data from other active and passive dosimeters will be used to estimate the radiation risk to the crewmembers, which verify the models of radiation environment in low Earth orbit. Presented are the test results of the prototype unit. Liulin-5 will be flown on the ISS in the year 2003.

Astronaut's organ doses inferred from measurements in a human phantom outside the international space station

by cfynanon 9 June 2015in Physical Sciences No comment

Space radiation hazards are recognized as a key concern for human space flight. For long-term interplanetary missions, they constitute a potentially limiting factor since current protection limits for low-Earth orbit missions may be approached or even exceeded. In such a situation, an accurate risk assessment requires knowledge of equivalent doses in critical radiosensitive organs rather than only skin doses or ambient doses from area monitoring. To achieve this, the MATROSHKA experiment uses a human phantom torso equipped with dedicated detector systems. We measured for the first time the doses from the diverse components of ionizing space radiation at the surface and at different locations inside the phantom positioned outside the International Space Station, thereby simulating an extravehicular activity of an astronaut. The relationships between the skin and organ absorbed doses obtained in such an exposure show a steep gradient between the doses in the uppermost layer of the skin and the deep organs with a ratio close to 20. This decrease due to the body self-shielding and a concomitant increase of the radiation quality factor by 1.7 highlight the complexities of an adequate dosimetry of space radiation. The depth-dose distributions established by MATROSHKA serve as benchmarks for space radiation models and radiation transport calculations that are needed for mission planning.

Limits to gelation in colloidal aggregation

by cfynanon 9 June 2015in Physical Sciences No comment

We show that the dynamics of large fractal colloid aggregates are well described by a combination of translational and rotational diffusion and internal elastic fluctuations, allowing both the aggregate size and internal elasticity to be determined by dynamic light scattering. The comparison of results obtained in microgravity and on Earth demonstrates that cluster growth is limited by gravity-induced restructuring. In the absence of gravity, thermal fluctuations ultimately inhibit fractal growth and set the fundamental limitation to the lowest volume fraction which will gel.

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Research Containing: Models

Three-dimensional structure of carboxypeptidase T from Thermoactinomyces vulgaris in complex with N-BOC-L-leucine

Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1

Benchmark studies of the effectiveness of structural and internal materials as radiation shielding for the international space station

Dose distribution in the Russian Segment of the International Space Station

Absorbed dose of secondary neutrons from galactic cosmic rays inside the International Space Station

Colloidal aggregation in microgravity by critical Casimir forces

Investigation of dose and flux dynamics in the Liulin-5 dosimeter of the tissue-equivalent phantom onboard the Russian segment of the international space station

Astronaut's organ doses inferred from measurements in a human phantom outside the international space station

Limits to gelation in colloidal aggregation