Understanding conformational transitions in RAS proteins using all-atom and coarse-grained molecular dynamics

RAS subfamily proteins regulates cell growth and differentiation by cycling between active (GTP-bound) and inactive (GDP-bound) states. Mutations intervening normal Ras functioning are associated with several human cancers and developmental disorders. The three RAS isoforms in human HRAS, KRAS, and NRAS are the most common oncogene found in human cancers. Despite considerable experimental and computational efforts, it has remained difficult to achieve a therapeutic grip on RAS proteins mainly due to the incomplete understanding of the intermediate structures in RAS GDP-GTP transitions. Identifying the distinct features of intermediate states in RAS signaling processes is thus highly desirable for the design of small molecule inhibitors. The primary focus of this work was to develop a generic coarse-grained model of proteins, use it to study conformational transitions in RAS proteins with the goal to identify the critical structural features controlling the intrinsic conformational transitions, and complement the results using all-atom simulations. Knowledge of such critical features is bound to provide invaluable understanding of the ways in which these processes would be catalyzed by regulatory proteins. Thus, the present work also lays the foundation for future works involving coarse-grained modeling of RAS conformational switch mechanisms in the presence of regulatory proteins. In the first part of the thesis, we developed a coarse-grained model that successfully folded nineteen different proteins into their native states (containing β-sheet, α-helix, and mixed α/β) starting from completely random configurations. The model is sensitive to small changes in protein sequence, and more importantly, the results obtained from the coarse-grained model were shown to complement very well with results from all-atom molecular dynamics. Using coarse-grained simulations in combination with all-atom simulations (total of 3.02µs) of HRAS, we identified the structural features that regulate the intrinsic nucleotide (GDP) exchange reaction. Our results suggests that dissociation of GDP/Mg from the nucleotide binding pocket is initiated by a loss of interaction between GDP and the base binding region of RAS. Further, we provide the first simulation study showing displacement of GDP/Mg away from the nucleotide pocket in both mutant and wild-type RAS. Both SwitchI and SwitchII, the known critical elements in RAS signaling, delay the escape of displaced GDP/Mg in the absence of guanine nucleotide exchange factors (GEFs). A model for the mechanism of GEF in accelerating the exchange process is presented. We also provided a comprehensive comparison of the dynamics of all the three RAS isoforms using extensive molecular dynamics simulations in both the GDP- (total of 3.06µs) and GTP-bound (total of 2.4µs) states. We identified a new pocket on RAS structure, which opens transiently during MD simulations, and can be targeted to regulate the nucleotide exchange reaction or possibly interfere with membrane localization. Furthermore, we have identified a new cluster of wild-type GTP-bound structures that potentially represents an intermediate conformation in the GTP hydrolysis process

Microelectronic bioinstrumentation systems

The possibility of using RF fields to power biologically implanted transmitters used in biomedical experiments was investigated. This approach would be especially useful when animal subjects are strapped in chairs or confined in cages. A telemetry system using an external source of energy has the additional advantage of not being limited in operation by battery lifetime and can therefore operate for virtually infinite lengths of time. A description of a system based on this principle is given. Progress in the development of battery-driven transmitters is also reported, including an ingestible temperature telemetry system and a resistance-to-pulse frequency convertor for implantable temperature telemetry systems

Critical Perspectives Sustainability of the on South African Civil Society Sector

This report presents the findings of a research and advocacy process that included consultative workshops with CSOs in all nine of South Africa's provinces, interviews with CSOs, politicians, government departments, the NLB, NDA and local funders. The report highlights the successes and ongoing problems associated with the NLB and the NDA. It locates them within a broader context of government unevenness, inefficiency and corruption

Condensation and T-dependent mobility of different vdW adsorbates within and across quantum confinements

In this thesis a number of important and fundamental surface phenomena have been investigated in an unprecedented way: These involve the condensation of atomic (Xe, Ar) and molecular (cycloalkanes C5H10 to C8H16) gases within surface supported network architectures; the observation of surface phase transitions for the condensates in confinements and the diffusion of adsorbates across a complex nanostructured surface. Uniquely, all these phenomena are investigated under the Scanning Tunneling Microscope and with different adsorbates which predominantly interact by non-directional van der Waals interactions. The substrate for all these investigations is provided by a complex surface architecture formed by a regular porous metal-coordinated network of perylene-derived molecules self-assembled on Cu(111). Each pore contains a characteristic confined state derived from substrate electrons, thus constituting a quantum confinement. Condensation of Xe is observed in the larger pores and on the smaller nodes of the network, as well as next to the network on the free metal Cu(111) surface. Xe, the first ‘van der Waals’ gas forms condensates comprising a different number of Xe atoms in different pores. The structural transitions of these condensates containing 1-9 Xe atoms in their hosting confinements have been investigated first (Chapter [[1]]). These transitions e.g. between the ‘solid’ condensed and the ‘fluid’ phase of a minimal amount of matter are attributed to different ‘phase transition temperatures’ and have been also induced locally by electric field excitation. In the second part of the thesis the unique and complex hierarchy of the Xe atoms’ diffusion pathways within and across the surface nano-architecture is revealed with respect to their temperature dependent activation. The inter-pore diffusion at higher temperatures leads to a ‘coarsening’ of the condensates in that the lower populated ones disappear to the benefit of the larger condensates, in particular the 12 fold occupied ‘full’ pore (Chapter [[2]]). A unique chemical object has been identified in the form of a linear trimer which we attribute to the Xe3 or the Xe3+ condensate (Chapter [[3]]). The last chapter discusses the condensation of the significantly larger cyclo-alkanes as they form aggregates with sizes incrementing from one to a max value which depends both on the size and also on the different possibilities for the stacking of the cycloalkanes in the nanopore confinements (Chapter [[4]]). This work establishes a radically new approach to induce phase transition in minimal amount of matter in confinements embedded in on-surface porous networks. Moreover, it is shown that the quantum confinements can be used as nano-traps, offering real-space access to the phase transition and condensation proceeding under the influence of van der walls forces in an atom-by-atom and molecule-by-molecule way

Reliability Abstracts and Technical Reviews January-December 1968

No abstract availabl

Exploration of new superconductors and functional materials and fabrication of superconducting tapes and wires of iron pnictides

This paper reviews the highlights of a 4-years-long research project supported by the Japanese Government to explore new superconducting materials and relevant functional materials. The project found several tens of new superconductors by examining ~1000 materials, each of which was chosen by Japanese team member experts with a background in solid state chemistry. This review summarizes the major achievements of the project in newly found superconducting materials, and the wire and tape fabrication of iron-based superconductors. It is a unique feature of this review to incorporate a list of ~700 unsuccessful materials examined for superconductivity in the project. In addition, described are new functional materials and functionalities discovered during the project.Comment: 141 pages, 127 Figures, 14 Tables, 535 Refrence

Properties of Transition Metals and Their Compounds at Extreme Conditions

The characterization of the physical and chemical properties of transition metals and their compounds under extreme conditions of pressure and temperature has always attracted the interest of a wide scientific community. Their properties have numerous implications in fields ranging from solid-state physics, chemistry, and materials science to Earth and planetary science. The present Special Issue represents a good example of such a broad interest and shows some of the latest advancements in the investigation of transition metals under extreme conditions of pressure and temperature

Ocean colour signature of climate change

Monitoring changes in marine phytoplankton is important as they form the foundation of the marine food web and are crucial in the carbon cycle. Often Chlorophyll-a (Chl-a) is used to track changes in phytoplankton, since there are global, regular satellite-derived estimates. However, satellite sensors do not measure Chl-a directly. Instead, Chl-a is estimated from remote sensing reflectance (RRS): the ratio of upwelling radiance to the downwelling irradiance at the ocean’s surface. Using a model, we show that RRS in the blue-green spectrum is likely to have a stronger and earlier climate-change-driven signal than Chl-a. This is because RRS has lower natural variability and integrates not only changes to in-water Chl-a, but also alterations in other optically important constituents. Phytoplankton community structure, which strongly affects ocean optics, is likely to show one of the clearest and most rapid signatures of changes to the base of the marine ecosystem

The Electrothermal Instability on Pulsed Power Ablations of Thin Foils.

The electrothermal instability (ETI) is an exponentially growing temperature perturbation that arises due to nonuniformities in Ohmic heating of a current-carrying material with a temperature-dependent resistivity. When resistivity increases with temperature, as in most solid and liquid metals, ETI forms striations of hot and cold material perpendicular to the flow of current. On a pulsed-power driven ablation of an initially solid metal, these striations can cause local vaporization before the bulk material vaporizes, leading to a mass perturbation that can seed plasma instabilities, such as the magneto Rayleigh-Taylor (MRT) instability. These instabilities have been identified as the primary impediment to producing energy gain in a pulsed power-driven nuclear fusion concept called magnetized liner implosion fusion (MagLIF). Understanding of ETI may provide better means to mitigate plasma instabilities and achieve fusion gain on MagLIF experiments. A diagnostic has been developed to measure spatially resolved temperature using an ultrafast framing camera from self-emission of planar foil ablations conducted in atmospheric conditions. These temperature measurements provide the first time-resolved experimental observations of ETI as a growing temperature perturbation on ablations of initially solid metal targets. Growth rates of experimentally observed perturbations show good agreement with theoretical predictions of ETI and demonstrate expected quadratic dependence on current density. Additional experiments were conducted on the MAIZE linear transformer driver (LTD), a 1-MA pulsed power facility at the University of Michigan, to study the coupling of ETI to later-time plasma instabilities. Liners of aluminum, titanium, and tantalum were ablated to compare material-dependent effects, and ablations of aluminum with and without dielectric coatings (which had previously been shown to reduce the impact of ETI) were performed to compare instability growth on the same material with varying ETI seeding. It was observed that tantalum liners, which have lower predicted ETI growth, exhibit dramatically less plasma instability growth than aluminum or titanium. Additionally, ablations of aluminum liners with external dielectric coatings exhibited less azimuthal symmetry than bare aluminum liners, which was anticipated because ETI tends to azimuthally self-correlate. These results support the theory that ETI provides the surface perturbation that is responsible for seeding plasma instabilities on liner ablations.PHDNuclear Engineering & Radiological SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/135827/1/amsteine_1.pd

Code comparison of methane hydrate reservoir simulators using CMG STARS

Natural gas is an important energy source contributing to 23% of the total energy consumption in United States. Domestic conventional natural gas production does not keep pace with increase in natural gas demand. Development of new alternatives like natural gas from methane hydrate can play a major role in ensuring adequate future energy supplies in the United States.;Methane hydrates are crystalline solids, very similar to ice, in which non-polar molecules are trapped inside the cages of water molecules. Methane hydrates could be potentially a vast source of energy. It is estimated that the total amount of natural gas trapped inside the hydrate is approximately two times the total unconventional oil-gas reserves in the world. The production of natural gas from hydrates economically poses a big challenge to today\u27s scientific world. Over the years, different reservoir simulators were developed and different approaches have been used to model the gas hydrate dissociation behavior. The National Energy Technology Laboratory (NETL) and the U.S Geological Survey (USGS) gas hydrate code comparison project is the first of its kind and it aims at a worldwide understanding of the hypotheses involved in the gas hydrate modeling and problem solving. This code comparison study is conducted to compare various hydrate reservoir simulators like CMG STARS, TOUGH-Fx/Hydrate, MH21, STOMP, HydrateResSim and a code form University of Houston.;The objective of this Project is to generate results for different problems set by the code comparison participants using CMG STARS and to validate its results with other reservoir simulators. Results obtained are in good agreement with other simulators in the study. However minor differences were observed for a problem with ice in the system. Long term simulations were conducted for Mt Elbert, Prudhoe Bay L-PAD like deposits. The Production rates obtained using CMG STARS were in good agreement with other packages.;In addition to the code comparison problems, simulations to analyze the sensitivity to various parameters were performed. Studies were carried out with heterogeneity introduced in the reservoir properties using the Mt. Elbert stratigraphic test well data and results showed that higher production was observed with the incorporation of heterogeneity. Sensitivity analysis of seven reservoir parameters was done using Plackett-Burman design to gain a better understanding on production performance. The reservoir parameters were ranked based on effects of the reservoir parameters on production rates