Intracellular Localization and Conformational State of Transglutaminase 2: Implications for Cell Death

Transglutaminase 2 (TG2) is a multifunctional enzyme that has guanine nucleotide binding and GTP hydrolyzing activity in addition to its transamidating function. Studies show that TG2 is a player in mediating cell death processes. However, there is far from a consensus about the role of this enzyme in cell death processes as it appears to be dependent upon the cell type, stimuli, subcellular localization and conformational state of the enzyme. The purpose of this study was to dissect the role of TG2 in the cell death processes. To this end, we created and characterized 4 distinct point mutants of TG2, each of which differs from the wild type by its conformation or by lacking an important function. We also prepared these mutants as nuclear targeted proteins. By overexpressing mutant or wild type forms of TG2 in HEK 293 cells, we investigated the modulatory role of the protein in the cell death process in response to three stressors: thapsigargin, hyperosmotic stress and oxygen/glucose deprivation (OGD). All of the TG2 constructs, except the R580A mutant (which cannot bind guanine nucleotides and is therefore more prone to exhibit transamidating activity), either did not significantly affect the cell death processes or were protective. However in the case of the R580A mutant, cell death in response to high thapsigargin concentrations, was significantly increased. Intriguingly, nuclear localization of R580A-TG2 was sufficient to counteract the pro-death role of cytoplasmic R580A-TG2. In addition, nuclear localization of TG2 significantly facilitated its protective role against OGD. Our data support the hypothesis that the transamidation activity of TG2, which is mostly quiescent except in extreme stress conditions, is necessary for its pro-death role. In addition, nuclear localization of TG2 generally plays a key role in its protective function against cell death processes, either counteracting the detrimental effect or strengthening the protective role of the protein

Tau Clearance Mechanisms and Their Possible Role in the Pathogenesis of Alzheimer Disease

One of the defining pathological features of Alzheimer disease (AD) is the intraneuronal accumulation of tau. The tau that forms these accumulations is altered both posttranslationally and conformationally, and there is now significant evidence that soluble forms of these modified tau species are the toxic entities rather than the insoluble neurofibrillary tangles. However there is still noteworthy debate concerning which specific pathological forms of tau are the contributors to neuronal dysfunction and death in AD. Given that increases in aberrant forms of tau play a role in the neurodegeneration process in AD, there is growing interest in understanding the degradative pathways that remove tau from the cell, and the selectivity of these different pathways for various forms of tau. Indeed, one can speculate that deficits in a pathway that selectively removes certain pathological forms of tau could play a pivotal role in AD. In this review we will discuss the different proteolytic and degradative machineries that may be involved in removing tau from the cell. How deficits in these different degradative pathways may contribute to abnormal accumulation of tau in AD will also be considered. In addition, the issue of the selective targeting of specific tau species to a given degradative pathway for clearance from the cell will be addressed

Predictive powers of chiral perturbation theory in Compton scattering off protons

We study low-energy nucleon Compton scattering in the framework of baryon chiral perturbation theory (B$\chi$PT) with pion, nucleon, and $\Delta$(1232) degrees of freedom, up to and including the next-to-next-to-leading order (NNLO). We include the effects of order $p^2$, $p^3$ and $p^4/\varDelta$, with $\varDelta\approx 300$ MeV the $\Delta$-resonance excitation energy. These are all "predictive" powers in the sense that no unknown low-energy constants enter until at least one order higher (i.e, $p^4$). Estimating the theoretical uncertainty on the basis of natural size for $p^4$ effects, we find that uncertainty of such a NNLO result is comparable to the uncertainty of the present experimental data for low-energy Compton scattering. We find an excellent agreement with the experimental cross section data up to at least the pion-production threshold. Nevertheless, for the proton's magnetic polarizability we obtain a value of $(4.0\pm 0.7)\times 10^{-4}$ fm$^3$, in significant disagreement with the current PDG value. Unlike the previous $\chi$PT studies of Compton scattering, we perform the calculations in a manifestly Lorentz-covariant fashion, refraining from the heavy-baryon (HB) expansion. The difference between the lowest order HB$\chi$PT and B$\chi$PT results for polarizabilities is found to be appreciable. We discuss the chiral behavior of proton polarizabilities in both HB$\chi$PT and B$\chi$PT with the hope to confront it with lattice QCD calculations in a near future. In studying some of the polarized observables, we identify the regime where their naive low-energy expansion begins to break down, thus addressing the forthcoming precision measurements at the HIGS facility.Comment: 24 pages, 9 figures, RevTeX4, revised version published in EPJ

Discovery of a Dynamical Cold Point in the Heart of the Sagittarius dSph Galaxy with Observations from the APOGEE Project

The dynamics of the core of the Sagittarius (Sgr) dwarf spheroidal (dSph) galaxy are explored using high-resolution (R~22,500), H-band, near-infrared spectra of over 1,000 giant stars in the central 3 deg^2 of the system, of which 328 are identified as Sgr members. These data, among some of the earliest observations from the SDSS-III/Apache Point Observatory Galactic Evolution Experiment (APOGEE) and the largest published sample of high resolution Sgr dSph spectra to date, reveal a distinct gradient in the velocity dispersion of Sgr from 11-14 km/s for radii >0.8 degrees from center to a dynamical cold point of 8 km/s in the Sgr center --- a trend differing from that found in previous kinematical analyses of Sgr over larger scales that suggest a more or less flat dispersion profile at these radii. Well-fitting mass models with either cored and cusped dark matter distributions can be found to match the kinematical results, although the cored profile succeeds with significantly more isotropic stellar orbits than required for a cusped profile. It is unlikely that the cold point reflects an unusual mass distribution. The dispersion gradient may arise from variations in the mixture of populations with distinct kinematics within the dSph; this explanation is suggested (e.g., by detection of a metallicity gradient across similar radii), but not confirmed, by the present data. Despite these remaining uncertainties about their interpretation, these early test data (including some from instrument commissioning) demonstrate APOGEE's usefulness for precision dynamical studies, even for fields observed at extreme airmasses.Comment: 15 pages, 3 figure

Very Metal-poor Stars in the Outer Galactic Bulge Found by the Apogee Survey

Despite its importance for understanding the nature of early stellar generations and for constraining Galactic bulge formation models, at present little is known about the metal-poor stellar content of the central Milky Way. This is a consequence of the great distances involved and intervening dust obscuration, which challenge optical studies. However, the Apache Point Observatory Galactic Evolution Experiment (APOGEE), a wide-area, multifiber, high-resolution spectroscopic survey within Sloan Digital Sky Survey III (SDSS-III), is exploring the chemistry of all Galactic stellar populations at infrared wavelengths, with particular emphasis on the disk and the bulge. An automated spectral analysis of data on 2,403 giant stars in twelve fields in the bulge obtained during APOGEE commissioning yielded five stars with low metallicity([Fe/H]$\le-1.7$), including two that are very metal-poor [Fe/H]$\sim-2.1$ by bulge standards. Luminosity-based distance estimates place the five stars within the outer bulge, where other 1,246 of the analyzed stars may reside. A manual reanalysis of the spectra verifies the low metallicities, and finds these stars to be enhanced in the $\alpha$-elements O, Mg, and Si without significant $\alpha$-pattern differences with other local halo or metal-weak thick-disk stars of similar metallicity, or even with other more metal-rich bulge stars. While neither the kinematics nor chemistry of these stars can yet definitively determine which, if any, are truly bulge members, rather than denizens of other populations co-located with the bulge, the newly-identified stars reveal that the chemistry of metal-poor stars in the central Galaxy resembles that of metal-weak thick-disk stars at similar metallicity.Comment: 6 pages, 3 figures, 2 table

The Erotic and the Vulgar: Visual Culture and Organized Labor's Critique of U.S. Hegemony in Occupied Japan

This essay engages the colonial legacy of postwar Japan by arguing that the political cartoons produced as part of the postwar Japanese labor movement’s critique of U.S. cultural hegemony illustrate how gendered discourses underpinned, and sometimes undermined, the ideologies formally represented by visual artists and the organizations that funded them. A significant component of organized labor’s propaganda rested on a corpus of visual media that depicted women as icons of Japanese national culture. Japan’s most militant labor unions were propagating anti-imperialist discourses that invoked an engendered/endangered nation that accentuated the importance of union roles for men by subordinating, then eliminating, union roles for women

The coronal line regions of planetary nebulae NGC6302 and NGC6537: 3-13um grating and echelle spectroscopy

We report on advances in the study of the cores of NGC6302 and NGC6537 using infrared grating and echelle spectroscopy. In NGC6302, emission lines from species spanning a large range of ionization potential, and in particular [SiIX]3.934um, are interpreted using photoionization models (including CLOUDY), which allow us to reestimate the central star's temperature to be about 250000K. All of the detected lines are consistent with this value, except for [AlV] and [AlVI]. Aluminium is found to be depleted to one hundredth of the solar abundance, which provides further evidence for some dust being mixed with the highly ionized gas (with photons harder than 154eV). A similar depletion pattern is observed in NGC6537. Echelle spectroscopy of IR coronal ions in NGC6302 reveals a stratified structure in ionization potential, which confirms photoionization to be the dominant ionization mechanism. The lines are narrow (< 22km/s FWHM), with no evidence of the broad wings found in optical lines from species with similar ionization potentials, such as [NeV]3426A. We note the absence of a hot bubble, or a wind blown bipolar cavity filled with a hot plasma, at least on 1'' and 10km/s scales. We also provide accurate new wavelengths for several of the infrared coronal lines observed with the echelle.Comment: Accepted for publication in MNRA

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam

Cytosolic Guanine Nucledotide Binding Deficient Form of Transglutaminase 2 (R580a) Potentiates Cell Death in Oxygen Glucose Deprivation

Transglutaminase 2 (TG2) is a hypoxia-responsive protein that is a calcium-activated transamidating enzyme, a GTPase and a scaffolding/linker protein. Upon activation TG2 undergoes a large conformational change, which likely affects not only its enzymatic activities but its non-catalytic functions as well. The focus of this study was on the role of transamidating activity, conformation and localization of TG2 in ischemic cell death. Cells expressing a GTP binding deficient form of TG2 (TG2-R580A) with high basal transamidation activity and a more extended conformation showed significantly increased cell death in response to oxygen-glucose deprivation; however, targeting TG2-R580A to the nucleus abrogated its detrimental role in oxygen-glucose deprivation. Treatment of cells expressing wild type TG2, TG2-C277S (a transamidating inactive mutant) and TG2-R580A with Cp4d, a reversible TG2 inhibitor, did not affect cell death in response to oxygen-glucose deprivation. These findings indicate that the pro-cell death effects of TG2 are dependent on its localization to the cytosol and independent of its transamidation activity. Further, the conformational state of TG2 is likely an important determinant in cell survival and the prominent function of TG2 in ischemic cell death is as a scaffold to modulate cellular processes

Adding the s-Process Element Cerium to the APOGEE Survey: Identification and Characterization of Ce II Lines in the H-band Spectral Window

Nine Ce ii lines have been identified and characterized within the spectral window observed by the Apache Point Observatory Galactic Evolution Experiment (APOGEE) survey (between λ1.51 and 1.69 μm). At solar metallicities, cerium is an element that is produced predominantly as a result of the slow capture of neutrons (the s-process) during asymptotic giant branch stellar evolution. The Ce ii lines were identified using a combination of a high-resolution ($R=\lambda /\delta \lambda ={\rm{100,000}}$) Fourier Transform Spectrometer (FTS) spectrum of α Boo and an APOGEE spectrum (R = 22,400) of a metal-poor, but s-process enriched, red giant (2M16011638-1201525). Laboratory oscillator strengths are not available for these lines. Astrophysical gf-values were derived using α Boo as a standard star, with the absolute cerium abundance in α Boo set by using optical Ce ii lines that have precise published laboratory gf-values. The near-infrared Ce ii lines identified here are also analyzed, as consistency checks, in a small number of bright red giants using archival FTS spectra, as well as a small sample of APOGEE red giants, including two members of the open cluster NGC 6819, two field stars, and seven metal-poor N- and Al-rich stars. The conclusion is that this set of Ce ii lines can be detected and analyzed in a large fraction of the APOGEE red giant sample and will be useful for probing chemical evolution of the s-process products in various populations of the Milky Way