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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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All sourcesNASA NTRSDOE OSTI
DOE OSTI2017

Rare Earth Adsorption and Desorption with PEGDA Beads

We synthesized PEGDA polymer hydrogel beads for cell embedding and compared REE biosorption with these beads via a gravity-driven flow through setup. One way to set up a flow through system is by cell encapsulation into polymer beads with a column setup similar to that used in the chromatography industry. To achieve this, we tested PEGDA for cell encapsulation, and tested REE biosorption under both batch mode and a follow through setup based on gravity . For making the cell embedded polymer beads, we used a fluidic device by which homogenous spherical particles of 0.5 to1 mm in diameter were synthesized. The beads are made relatively quickly, and the size of the beads can be controlled. PEGDA beads were polymerized by UV. Tb adsorption experiment was performed with beads with or without cells embedded.

15 GEOTHERMAL ENERGY↗
DOE OSTI2020

Electromagnetic coupling in tight-binding models for strongly correlated light and matter

In this work, we discuss the construction of low-energy tight-binding Hamiltonians for condensed-matter systems with a strong coupling to the quantum electromagnetic field. Such Hamiltonians can be obtained by projecting the continuum theory on a given set of Wannier orbitals. However, different representations of the continuum theory lead to different low-energy formulations because different representations may entangle light and matter, transforming orbitals into light-matter hybrid states before the projection. In particular, a multicenter Power-Zienau-Woolley transformation yields a dipolar Hamiltonian which incorporates the light-matter coupling via both Peierls phases and a polarization density. We compare this dipolar gauge Hamiltonian and the straightforward Coulomb gauge Hamiltonian for a one-dimensional solid to describe subcycle light-driven electronic motion in the semiclassical limit and a coupling of the solid to a quantized cavity mode which renormalizes the band-structure into electron-polariton bands. Both descriptions yield the same result when many bands are taken into account but the dipolar Hamiltonian is more accurate when the model is restricted to few electronic bands, while the Coulomb Hamiltonian requires fewer electromagnetic modes.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2020

Topological orders of monopoles and hedgehogs: From electronic and magnetic spin-orbit coupling to quarks

Topological states of matter are, generally, quantum liquids of conserved topological defects. We establish this by constructing and analyzing topological field theories which introduce gauge fields to describe the dynamics of singularities in the original field configurations. In this work, homotopy groups are utilized to identify topologically protected singularities, and the conservation of their protected number is captured by a topological action term that unambiguously obtains from the given set of symmetries. Stable phases of these theories include quantum liquids with emergent massless Abelian and non-Abelian gauge fields, as well as topological orders with long-range quantum entanglement, fractional excitations, boundary modes, and unconventional responses to external perturbations. This paper focuses on the derivation of topological field theories and basic phenomenological characterization of topological orders associated with homotopy groups π n (S n ), n ≥ 1 . These homotopies govern monopole and hedgehog topological defects in d = n + 1 dimensions, and enable the generalization of both weakly interacting and fractional quantum Hall liquids of vortices to d > 2 . Hedgehogs have not been in the spotlight so far, but they are particularly important defects of magnetic moments because they can be stimulated in realistic systems with spin-orbit coupling, such as chiral magnets and d = 3 topological materials. We predict topological orders in systems with U(1) × Spin(d) symmetry in which fractional electric charge attaches to hedgehogs. Monopoles, the analogous defects of charge or generic U(1) currents, may bind to hedgehogs via Zeeman effect, or effectively emerge in purely magnetic systems. The latter can lead to spin liquids with different topological orders than that of the resonant valence bond spin liquid. Charge fractionalization of quarks in atomic nuclei is also seen as possibly arising from the charge-hedgehog attachment.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2017

Structural, mutational and biophysical studies reveal a canonical mode of molecular recognition between immune receptor TIGIT and nectin-2

In addition to antigen-specific stimulation of T cell receptor (TCR) by a peptide-MHC complex, the functional outcome of TCR engagement is regulated by antigen-independent costimulatory signals. Costimulatory signals are provided by an array of interactions involving activating and inhibitory receptors expressed on T cells and their cognate ligands on antigen presenting cells. T cell immunoglobulin and ITIM domain (TIGIT), a recently identified immune receptor expressed on T and NK cells, upon interaction with either of its two ligands, nectin-2 or poliovirus receptor (PVR), inhibits activation of T and NK cells. Here we report the crystal structure of the human TIGIT ectodomain, which exhibits the classic two-layer β-sandwich topology observed in other immunoglobulin super family (IgSF) members. Biophysical studies indicate that TIGIT is monomeric in solution but can form a dimer at high concentrations, consistent with the observation of a canonical immunoglobulin-like dimer interface in the crystalline state. Based on existing structural data, we present a model of the TIGIT:nectin-2 complex and utilized complementary biochemical studies to map the nectin-binding interface on TIGIT. Our data provide important structural and biochemical determinants responsible for the recognition of nectin-2 by TIGIT. Defining the TIGIT:nectin-2 binding interface provides the basis for rational manipulation of this molecular interaction for the development of immunotherapeutic reagents in autoimmunity and cancer.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Behavior of Water Near Multimodal Chromatography Ligands and Its Consequences for Modulating Protein–Ligand Interactions

Multimodal chromatography is a powerful approach for purifying proteins that uses ligands containing multiple modes of interaction. Recent studies have shown that selectivity in multimodal chromatographic separations is a function of the ligand structure and geometry. Here, we performed molecular dynamics simulations to explore how the ligand structure and geometry affect ligand–water interactions and how these differences in solution affect the nature of protein–ligand interactions. Our investigation focused on three chromatography ligands: Capto MMC, Nuvia cPrime, and Prototype 4, a structural variant of Nuvia cPrime. First, the solvation characteristics of each ligand were quantified via three metrics: average water density, fluctuations, and residence time. We then explored how solvation was perturbed when the ligand was bound to the protein surface and found that the probability of the phenyl ring dewetting followed the order: Capto MMC > Prototype 4 > Nuvia cPrime. To explore how these differences in dewetting affect protein–ligand interactions, we calculated the probability of each ligand binding to different types of residues on the protein surface and found that the probability of binding to a hydrophobic residue followed the same order as the dewetting behavior. This study illustrates the role that wetting and dewetting play in modulating protein–ligand interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Time-Reversed Particle-Vibration Loops and Nuclear Gamow-Teller Response

The nuclear response theory for charge-exchange modes in the relativistic particle-vibration coupling approach is extended to include for the first time particle-vibration coupling effects in the ground state of the parent nucleus. In a framework based on the effective meson-nucleon Lagrangian, we investigate the role of such complex ground-state correlations in the description of Gamow-Teller transitions in 90 Zr in both (p, n) and (n, p) channels. In this work, the particle-vibration coupling effects are calculated without introducing new parameters. We find that this new correlation mechanism is fully responsible for the appearance of the strength in the n, p) branch. Comparison of our results to the available experimental data shows a very good agreement up to excitation energies beyond the giant resonance region when taking into account a phenomenological admixture of the isovector spin monopole transitions. The parent-daughter binding-energy differences are also greatly improved by the inclusion of the new correlations.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
NASA NTRS2011

Cytometer on a Chip

A cytometer now under development exploits spatial sorting of sampled cells on a microarray chip followed by use of grating-coupled surface-plasmon-resonance imaging (GCSPRI) to detect the sorted cells. This cytometer on a chip is a prototype of contemplated future miniature cytometers that would be suitable for rapidly identifying pathogens and other cells of interest in both field and laboratory applications and that would be attractive as alternatives to conventional flow cytometers. The basic principle of operation of a conventional flow cytometer requires fluorescent labeling of sampled cells, stringent optical alignment of a laser beam with a narrow orifice, and flow of the cells through the orifice, which is subject to clogging. In contrast, the principle of operation of the present cytometer on a chip does not require fluorescent labeling of cells, stringent optical alignment, or flow through a narrow orifice. The basic principle of operation of the cytometer on a chip also reduces the complexity, mass, and power of the associated laser and detection systems, relative to those needed in conventional flow cytometry. Instead of making cells flow in single file through a narrow flow orifice for sequential interrogation as in conventional flow cytometry, a liquid containing suspended sampled cells is made to flow over the front surface of a microarray chip on which there are many capture spots. Each capture spot is coated with a thin (.50-nm) layer of gold that is, in turn, coated with antibodies that bind to cell-surface molecules characteristic of the cell species of interest. The multiplicity of capture spots makes it possible to perform rapid, massively parallel analysis of a large cell population. The binding of cells to each capture spot gives rise to a minute change in the index of refraction at the surface of the chip. This change in the index of refraction is what is sensed in GCSPRI, as described briefly below. The identities of the various species in a sample of cells is spatially encoded in the chip by the pattern of capture spots. The number of cells of a particular species is determined from the magnitude of the GCSPRI signal from that spot. GCSPRI as used here can be summarized as follows: The cytometer chip is fabricated with a diffraction grating on its front surface. The chip is illuminated with a light emitting diode (LED) from the front. By proper choice of grating parameters and of the wavelength and the angle of incidence of a laser beam, laser light can be made to be coupled into an electromagnetic mode that resonates with surface plasmons and thus couples light into surface plasmons. Coupling of light into a surface plasmon at a given location reduces the amount of incident light reflected from that location. A change in the index of refraction at the surface of a capture spot gives rise to a change in the resonance condition. Depending on the specific design, the change in the index of refraction could manifest itself as a brightening or darkening, a change in the wavelength needed to excite the plasmon at a given angle of incidence, or a change in the angle of incidence needed to excite the plasmon at a given wavelength. Whereas a multiwavelength laser system with multichannel detection would be needed to detect multiple species in conventional flow cytometry, it suffices to use an LED and a single detector channel in the GCSPRI approach: this contributes significantly to reductions in cost, complexity, size, mass, and power. GCSPRI cytometer chips could be made of plastic and could be mass-produced cheaply by use of molding and other methods adopted from the manufacture of digital video disks. These methods are amenable to a high degree of miniaturization: such additional features as fluidic channels, reaction chambers, and fluid-coupling ports could readily be incorporated into the chips, without incurring substantial additional costs.

Fernandez, Salvador M.↗
NASA NTRS2011

Cytometer on a Chip

A cytometer now under development exploits spatial sorting of sampled cells on a microarray chip followed by use of grating-coupled surface-plasmon-resonance imaging (GCSPRI) to detect the sorted cells. This cytometer on a chip is a prototype of contemplated future miniature cytometers that would be suitable for rapidly identifying pathogens and other cells of interest in both field and laboratory applications and that would be attractive as alternatives to conventional flow cytometers. The basic principle of operation of a conventional flow cytometer requires fluorescent labeling of sampled cells, stringent optical alignment of a laser beam with a narrow orifice, and flow of the cells through the orifice, which is subject to clogging. In contrast, the principle of operation of the present cytometer on a chip does not require fluorescent labeling of cells, stringent optical alignment, or flow through a narrow orifice. The basic principle of operation of the cytometer on a chip also reduces the complexity, mass, and power of the associated laser and detection systems, relative to those needed in conventional flow cytometry. Instead of making cells flow in single file through a narrow flow orifice for sequential interrogation as in conventional flow cytometry, a liquid containing suspended sampled cells is made to flow over the front surface of a microarray chip on which there are many capture spots. Each capture spot is coated with a thin (approximately 50-nm) layer of gold that is, in turn, coated with antibodies that bind to cell-surface molecules characteristic of one the cell species of interest. The multiplicity of capture spots makes it possible to perform rapid, massively parallel analysis of a large cell population. The binding of cells to each capture spot gives rise to a minute change in the index of refraction at the surface of the chip. This change in the index of refraction is what is sensed in GCSPRI, as described briefly below. The identities of the various species in a sample of cells is spatially encoded in the chip by the pattern of capture spots. The number of cells of a particular species is determined from the magnitude of the GCSPRI signal from that spot. GCSPRI as used here can be summarized as follows: The cytometer chip is fabricated with a diffraction grating on its front surface. The chip is illuminated with a light emitting diode (LED) from the front. By proper choice of grating parameters and of the wavelength and the angle of incidence of a laser beam, laser light can be made to be coupled into an electromagnetic mode that resonates with surface plasmons and thus couples light into surface plasmons. Coupling of light into a surface plasmon at a given location reduces the amount of incident light reflected from that location. A change in the index of refraction at the surface of a capture spot gives rise to a change in the resonance condition. Depending on the specific design, the change in the index of refraction could manifest itself as a brightening or darkening, a change in the wavelength needed to excite the plasmon at a given angle of incidence, or a change in the angle of incidence needed to excite the plasmon at a given wavelength. Whereas a multiwavelength laser system with multichannel detection would be needed to detect multiple species in conventional flow cytometry, it suffices to use an LED and a single detector channel in the GCSPRI approach: this contributes significantly to reductions in cost, complexity, size, mass, and power. GCSPRI cytometer chips could be made of plastic and could be mass-produced cheaply by use of molding and other methods adopted from the manufacture of digital video disks. These methods are amenable to a high degree of miniaturization: such additional features as fluidic channels, reaction chambers, and fluid-coupling ports could readily be incorporated into the chips, without incurring substantial additional costs.

Fernandez, Salvador M.↗
DOE OSTI2025

Repetitive proteins that undergo large conformational changes evade structural prediction algorithms

Protein structure prediction algorithms, such as AlphaFold, have accelerated protein design and advanced the understanding of the relationship between amino acid sequence and protein structure. However, these algorithms are limited in their ability to predict the structures of conformationally dynamic, intrinsically disordered, and stimuli-responsive proteins. To evaluate sequence-to-structure predictions of such challenging proteins, we explored a class of conformationally dynamic, repeats-in-toxin (RTX) proteins. RTX proteins adopt intrinsically disordered conformations in the absence of calcium and undergo reversible folding into β-roll structures upon binding to calcium. RTX proteins are characterized by tandem repeats of the sequence GGXGXDXUX, in which X can be any amino acid and U is an aliphatic amino acid. We designed RTX sequence variants with global substitutions of nonconserved amino acids, tandem repeats of consensus sequences GGAGXDTLY, and tandem repeats of scrambled sequences GGAGXDTYL. AlphaFold2 and AlphaFold3 predicted that all of these RTX variants adopt β-roll structures, characteristic of wild-type RTX bound to calcium. However, modeling the predicted structures with molecular dynamics simulations and characterizing the protein variants with circular dichroism spectroscopy, small-angle x-ray scattering, and x-ray crystallography revealed that variants adopt diverse, sequence-dependent structures in the absence and presence of calcium. To better design proteins for applications in biotechnology and sustainability, it is critical to build predictive tools that consider intrinsically disordered protein states and validate these tools with multi-mode, multi-scale experimental data.

Chang, Marina P. [Stanford Univ., CA (United State↗
DOE OSTI2018

The type II Weyl semimetals at low temperatures: Chiral anomaly, elastic deformations, zero sound

We consider the properties of the type II Weyl semimetals at low temperatures basing on the particular tight-binding model. In the presence of electric field directed along the line connecting the Weyl points of opposite chirality the occupied states flow along this axis giving rise to the creation of electron–hole pairs. The electrons belong to a vicinity of one of the two type II Weyl points while the holes belong to the vicinity of the other. This process may be considered as the manifestation of the chiral anomaly that exists without any external magnetic field. It may be observed experimentally through the measurement of conductivity. Next, we consider the modification of the theory in the presence of elastic deformations. In the domain of the considered model, where it describes the type I Weyl semimetals the elastic deformations lead to the appearance of emergent gravity. In the domain of the type II Weyl semimetals the form of the Fermi surface is changed due to the elastic deformations, and its fluctuations represent the special modes of the zero sound. We find that there is one to one correspondence between them and the sound waves of the elasticity theory. Next, we discuss the influence of the elastic deformations on the conductivity. The particularly interesting case is when our model describes the intermediate state between the type I and the type II Weyl semimetal. Then without the elastic deformations there are the Fermi lines instead of the Fermi points/Fermi surface, while the DC conductivity vanishes. However, even small elastic deformations may lead to the appearance of large conductivity.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2026

Dipole Strength Distribution of 8 He and Decay Characteristics

The weak binding and spatially extended neutron densities characteristic of drip-line nuclei give rise to a distinctive low-energy dipole response. The drip-line nucleus 8 He is the most neutron-rich bound nucleus with a mass-to-charge ratio of 𝐴/𝑍 = 4. We measure the dipole response of 8 He, including for the first time the four-neutron decay channel. A total dipole strength of ∑𝐵⁡(𝐸⁢1)(𝐸*< 15 MeV) = 0.95⁢(16)⁢𝑒 2 fm 2 and a dipole polarizability of 𝛼 𝐷 = 0.61⁢(1) fm 3 are extracted from the differential Coulomb-excitation cross section and compared to state-of-the-art theoretical calculations employing coupled cluster and three-body approaches. We find that the dipole continuum is dominated, even at high excitation energies well above the 4⁢𝑛 decay threshold, by two-neutron emission, pointing to a 6 He + 2⁢𝑛 structure of the excited dipole mode. No indication was found for a 4⁢𝑛 final-state correlation, while pronounced 𝑛⁢𝑛 and 6 He−𝑛 final-state correlations are apparent.

Lehr, C. [Technical University of Darmstadt (Germa↗
DOE OSTI2016

High-resolution photoelectron imaging spectroscopy of cryogenically cooled Fe{sub 4}O{sup −} and Fe{sub 5}O{sup −}

We report high-resolution photodetachment spectra of the cryogenically cooled iron monoxide clusters Fe{sub 4}O{sup −} and Fe{sub 5}O{sup −} obtained with slow photoelectron velocity-map imaging (cryo-SEVI). Well-resolved vibrational progressions are observed in both sets of spectra, and transitions to low-lying excited states of both species are seen. In order to identify the structural isomers, electronic states, and vibrational modes that contribute to the cryo-SEVI spectra of these clusters, experimental results are compared with density functional theory calculations and Franck-Condon simulations. The main bands observed in the SEVI spectra are assigned to the {sup 15}A{sub 2}←{sup 16}B{sub 2} photodetachment transition of Fe{sub 4}O{sup −} and the {sup 17}A′←{sup 18}A″ photodetachment transition of Fe{sub 5}O{sup −}. We report electron affinities of 1.6980(3) eV for Fe{sub 4}O and 1.8616(3) eV for Fe{sub 5}O, although there is some uncertainty as to whether the {sup 15}A{sub 2} state is the true ground state of Fe{sub 4}O. The iron atoms have a distorted tetrahedral geometry in Fe{sub 4}O{sup 0/−} and a distorted trigonal-bipyramidal arrangement in Fe{sub 5}O{sup 0/−}. For both neutral and anionic species, the oxygen atom preferably binds in a μ{sub 2}-oxo configuration along the cluster edge. This finding is in contrast to prior predictions that Fe{sub 5}O{sup 0/−} exhibits a μ{sub 3} face-bound structure.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2026

Cascading economic losses from port disruptions under capacity constrained multimodal freight networks

This study quantifies how throughput disruptions at major seaports cascade through capacity-constrained multimodal freight networks and interregional production systems. We couple an agent-based model (ABM) multimodal freight simulation that resolves rerouting, terminal queueing, and inventory drawdown under binding modal and facility capacities with a multiregional output loss input-output (MRIIM) model that propagates realized delivery shortfalls across regions and sectors. The framework is demonstrated for the Port of Los Angeles using Freight Analysis Framework flows and Bureau of Economic Analysis input-output accounts and is evaluated over a 52-week horizon under deterministic sector targeted shocks and stochastic disruption realizations with uncertain severity and duration. Results indicate nonlinear amplification: realized national losses concentrate in manufacturing and transportation/warehousing even when exogenous port shocks are dispersed, suggesting that congestion spillback and limited short-run substitution can dominate the initial shock allocation. We further evaluate a tabular reinforcement-learning (Q-learning) intervention layer that selects among a small set of implementable system level levers (truck-to-rail and truck-to-barge shift settings) without overriding shipper routing, finding that such interventions reduce total losses for moderate disruptions but yield diminishing returns once substitute modes approach capacity. By linking operational freight behavior to system wide impacts under uncertainty, the proposed ABM-MRIIM pipeline provides a reusable workflow for port disruption stress testing, identification of structurally critical sectors/corridors, and evaluation of resilience interventions under realistic capacity limits.

42 ENGINEERING↗
DOE OSTI2016

Negative Cooperativity in the Nitrogenase Fe Protein Electron Delivery Cycle

Nitrogenase catalyzes the ATP-dependent reduction of dinitrogen (N2) to two ammonia (NH3) molecules. Catalysis involves the participation of two protein components designated the MoFe and Fe proteins. Electron transfer (ET) from the Fe protein to the catalytic MoFe protein involves a series of synchronized events requiring the transient association of one Fe protein with each aß half of the MoFe protein. This process is referred to as the Fe protein cycle and includes: binding of two ATP to an Fe protein, association of an Fe protein with the MoFe protein, ET from the Fe protein to the MoFe protein, hydrolysis of two ATP to two ADP and two Pi for each ET, Pi release, and dissociation of oxidized Fe protein-(ADP)2 from the MoFe protein. Because the MoFe protein tetramer has two separate aß active units, it has the capacity to participate in two independent Fe protein cycles. The present work examines whether the two catalytic halves of an individual MoFe protein function independently or, instead, communicate with each other during catalysis. Kinetic analyses of ET, ATP hydrolysis, and Pi release during the pre-steady state phase indicate that the two halves of the complex in fact cooperate. A global fit of the data is consistent with a two-branch negative-cooperativity kinetic model. A possible mechanism for communication between the two halves of nitrogenase is suggested by normal-mode calculations suggesting correlated and anti-correlated motions between the two nitrogenase halves.

Danyal, Karamatullah↗
DOE OSTI2025

Cross-reactive sarbecovirus antibodies induced by mosaic RBD nanoparticles

Broad immune responses are needed to mitigate viral evolution and escape. To induce antibodies against conserved receptor-binding domain (RBD) regions of SARS-like betacoronavirus (sarbecovirus) spike proteins that recognize SARS-CoV-2 variants of concern and zoonotic sarbecoviruses, we developed mosaic-8b RBD nanoparticles presenting eight sarbecovirus RBDs arranged randomly on a 60-mer nanoparticle. Mosaic-8b immunizations protected animals from challenges from viruses whose RBDs were matched or mismatched to those on nanoparticles. Here, we describe neutralizing mAbs isolated from mosaic-8b-immunized rabbits, some on par with Pemgarda, the only currently FDA-approved therapeutic mAb. Deep mutational scanning, in vitro selection of spike resistance mutations, and single-particle cryo-electron microscopy structures of spike–antibody complexes demonstrated targeting of conserved RBD epitopes. Rabbit mAbs included critical D-gene segment RBD-recognizing features in common with human anti-RBD mAbs, despite rabbit genomes lacking an equivalent human D-gene segment, thus demonstrating that the immune systems of humans and other mammals can utilize different antibody gene segments to arrive at similar modes of antigen recognition. These results suggest that animal models can be used to elicit anti-RBD mAbs with similar properties to those raised in humans, which can then be humanized for therapeutic use, and that mosaic RBD nanoparticle immunization coupled with multiplexed screening represents an efficient way to generate and select broadly cross-reactive therapeutic pan-sarbecovirus and pan-SARS-CoV-2 variant mAbs.

Science & Technology - Other Topics↗
DOE OSTI2021

Plasmons in two-dimensional topological insulators

Here, we analyze collective excitations in models of two-dimensional topological insulators using the random phase approximation. In a two-dimensional extension of the Su-Schrieffer-Heeger model, edge plasmonic excitations with induced charge-density distributions localized at the boundaries of the system are found in the topologically nontrivial phase, dispersing similarly as one-dimensional bulk plasmons in the conventional Su-Schrieffer-Heeger chain. For two-dimensional bulk collective modes, we reveal regimes of enhanced interband wave function correlations, leading to characteristic hardening and softening of inter- and intraband bulk plasmonic branches, respectively. In the two-dimensional Haldane Chern insulator model, chiral, unidirectional edge plasmons in nano-ribbon architectures are observed, which can be characterized by an effective Coulomb interaction cross section. Bulk collective excitations in the two-dimensional Haldane model are shown to be originated by single-particle band structure details in different topological phases.

2-dimensional systems↗
NASA NTRS1999

Molecular Mechanisms Regulating Muscle Fiber Composition Under Microgravity

The overall goal of this project is to reveal the molecular mechanisms underlying the selective and debilitating atrophy of specific skeletal muscle fiber types that accompanies sustained conditions of microgravity. Since little is currently known about the regulation of fiber-specific gene expression programs in mammalian muscle, elucidation of the basic mechanisms of fiber diversification is a necessary prerequisite to the generation of therapeutic strategies for attenuation of muscle atrophy on earth or in space. Vertebrate skeletal muscle development involves the fusion of undifferentiated mononucleated myoblasts to form multinucleated myofibers, with a concomitant activation of muscle-specific genes encoding proteins that form the force-generating contractile apparatus. The regulatory circuitry controlling skeletal muscle gene expression has been well studied in a number of vertebrate animal systems. The goal of this project has been to achieve a similar level of understanding of the mechanisms underlying the further specification of muscles into different fiber types, and the role played by innervation and physical activity in the maintenance and adaptation of different fiber phenotypes into adulthood. Our recent research on the genetic basis of fiber specificity has focused on the emergence of mature fiber types and have implicated a group of transcriptional regulatory proteins, known as E proteins, in the control of fiber specificity. The restriction of E proteins to selected muscle fiber types is an attractive hypothetical mechanism for the generation of muscle fiber-specific patterns of gene expression. To date our results support a model wherein different E proteins are selectively expressed in muscle cells to determine fiber-restricted gene expression. These studies are a first step to define the molecular mechanisms responsible for the shifts in fiber type under conditions of microgravity, and to determine the potential importance of E proteins as upstream targets for the effects of weightlessness. In the past year we have determined that the expression of E Proteins is restricted to specific fiber types by post-transcriptional mechanisms. By far, the most prevalent mechanism of cellular control for achieving post-transcriptional regulation of gene expression is selective proteolysis -through the ubiquitin -proteasome pathway. Steady-state levels of HEB message are similar in all fast and slow skeletal muscle fiber types, yet the protein is restricted to Type IIX fibers. HEB appears to be a nodal point for regulating fiber-specific transcription, as expression of the transcription factor is regulated at the post-transcriptional level. It is not clear at present whether the regulation is at the level of protein synthesis or degradation. We are now poised to evaluate the biological role of ubiquitination in fiber specific-gene expression by controlling the post-transcriptional expression of E Proteins. The use of metabolic labelling and pharmacological inhibitors of the ubiquitin pathway will be used to identify the mode of regulation of the Type IIX expression pattern. The potential role of specific kinases in effecting the restriction of HEB expression will be examined by using both inhibitors and activators. The results of these studies will provide the necessary information to evaluate the biological role of E proteins in controlling fiber type transitions, and in potentially attenuating the atrophic effects of microgravity conditions. We have also recently shown that ectopic expression of the HEB protein transactivates the Type IIX-specific skeletal a-actin reporter. The 218 bp skeletal a-actin promoter drives transgene expression solely in mature Type IIX fibers. A mouse also carrying the transgene MLCI/HEB (which ectopically expresses the E Protein HEB in Type IIB fibers) forces expression of the skeletal a-actin reporter gene in Type IIB fibers. We can now dissect the composition of this fiber-specific cis-element. The skeletal a-actin promoter is quite compact and has been extensively characterized in vitro for activity and binding factors. The single E box may act as a binding target of myogenic factor/HEB heterodimer to allow for IIX expression. The HEB transcription factor may recognize either the precise flanking sequences of the E Box, or perhaps interacting with other proteins bound nearby, and activating expression in Type IIX fibers. This E box will be both ablated, and alternatively, as ablation may well destroy any muscle-specific transcriptional activity, flanking sequences substituted with those surrounding the E box (El) of the myogenin promoter. Modification of fiber-specific transgene expression will be tested in transgenic mice. The results of these studies will provide basic information on the regulatory circuitry underlying fiber specificity, and will form the basis for building appropriate transgenic regulatory cassettes to effect fiber transitions in subsequent experimental manipulations on unweighted muscles.

Rosenthal, Nadia A.↗