Chaperoning steroid hormone signaling via reversible acetylation

Glucocorticoid receptor (GR) and related steroid hormone receptors are ligand-dependent transcription factors whose regulation is critical for both homeostasis and diseases. The structural maturation of the GR has been shown to require the Hsp90 molecular chaperone complex. Evidence indicates that Hsp90-dependent maturation is critical for GR ligand binding capacity and activity. While the role for Hsp90 in GR function is well established, the regulation of this process is not well understood. Here we discuss a recent finding that identifies reversible protein acetylation controlled by the deacetylase HDAC6 as a novel mechanism that regulates Hsp90-dependent GR maturation. We will also speculate on the implications of this finding in steroid hormone signaling, oncogenic transformation and its potential therapeutic utility

Distillation of GHZ states by selective information manipulation

Methods for distilling maximally entangled tripartite (GHZ) states from arbitrary entangled tripartite pure states are described. These techniques work for virtually any input state. Each technique has two stages which we call primary and secondary distillation. Primary distillation produces a GHZ state with some probability, so that when applied to an ensemble of systems, a certain percentage is discarded. Secondary distillation produces further GHZs from the discarded systems. These protocols are developed with the help of an approach to quantum information theory based on absolutely selective information, which has other potential applications.Comment: minor corrections, especially of some numerical values; conclusions unaffecte

UV Imaging Polarimetry of the peculiar Seyfert 2 galaxy Mrk 477

We present the results of UV imaging polarimetry of the Seyfert 2 galaxy Mrk 477 taken by the Faint Object Camera onboard the Hubble Space Telescope (HST). From a previous HST UV image (lambda ~ 2180A), Mrk 477 has been known to have a pointlike bright UV hotspot in the central region, peculiar among nearby Seyfert 2 galaxies. There are also claims of UV/optical variability, unusual for a Seyfert 2 galaxy. Our data show that there is an off-nuclear scattering region ~ 0."6 (~ 500 pc) NE from the hotspot. The data, after the subtraction of the instrumental effect due to this bright hotspot region, might indicate that the scattered light is also detected in the central 0."2 radius region and is extended to a very wide angle. The hotspot location is consistent with the symmetry center of the PA pattern, which represents the location of the hidden nucleus, but our data do not provide a strong upper limit to the distance between the symmetry center and the hotspot. We have obtained high spatial resolution color map of the continuum which shows that the nuclear spiral arm of 0."4 scale (~ 300pc) is significantly bluer than the off-nuclear mirror and the hotspot region. The nature of the hotspot is briefly discussed.Comment: To appear in Ap

Relation between repolarization and refractoriness in the human ventricle: Cycle length dependence and effect of procainamide

The cycle length dependence of the action potential duration and the effective refractory period of the right ventricular endocardium were investigated in 24 patients undergoing electrophysiologic studies for suspected ventricular tachycardia. The action potential duration at 90% repolarization and the effective refractory period at twice diastolic threshold strength were measured at the same catheter site at steady state cycle lengths of 350 to 600 ms. Both measurements decreased linearly with decreasing cycle length, maintaining a parallel relation. When the relation between action potential duration and effective refractory period was expressed as the effective refractory period-action potential duration difference, nearly constant values (range −12 to −15 ms) were obtained at all cycle lengths.To determine whether sodium channel blocking drugs influence the effective refractory period-action potential duration relation in humans, measurements of these two variables were obtained in 15 patients before and during the infusion of procainamide. Procainamide prolonged the action potential duration at each cycle length by a near constant amount over baseline values (p < 0.001). Procainamide also increased the effective refractory period at each cycle length but with a greater incremental increase at the shorter cycle lengths. The rate-dependent increase in the effective refractory period-action potential duration difference became significant at cycle lengths ≤400 ms; at these high rates, the effective refractory period-action potential duration difference became positive (1.6 ms, p < 0.01 compared with baseline).Thus, in the human ventricle, the action potential duration and the effective refractory period have a close relation that remains fixed over a wide range of cycle lengths. The cycle length-dependent increase in the effective refractory period relative to action potential duration induced by procainamide is consistent with use dependency of sodium channel blocking drugs observed in vitro and may be a useful marker for measuring antiarrhythmic drug activity in vivo

UV Imaging Polarimetry of the Seyfert 2 Galaxy Mrk 3

We present UV imaging polarimetry data of the Seyfert 2 galaxy Mrk 3 taken by the Hubble Space Telescope. The polarized flux is found to be extended to ~1 kpc from the nucleus, and the position angles of polarization are centrosymmetric, confirming that the polarization is caused by scattering. We determine the location of the hidden nucleus as the center of this centrosymmetric pattern. From the polarization images taken in two broad bands, we have obtained the color distribution of the polarized flux. Some regions have blue polarized flux, consistent with optically-thin dust scattering, but some bright knots have a color similar to that of Seyfert 1 nucleus. Also, the recent Chandra X-ray observation suggests that the ratio of scattered UV flux to scattered X-ray flux is rather similar to the intrinsic UV/X-ray ratio in a Seyfert 1 nucleus, if the observed extended X-ray continuum is scattered light. While the scattered X-ray would be essentially from electron scattering, the UV slope and UV/X-ray ratio both being similar to Seyfert 1's would lead to two possibilities as to the nature of the UV scatterers. One is that the UV may also be scattered by electrons, in which case the scattering gas is somehow dust-free. The other is that the UV is scattered by dust grains, but the wavelength-independent UV scattering with low efficiency indicated by the UV slope and UV/X-ray ratio would suggest that the grains reside in UV-opaque clouds, or the dust might be mainly composed of large grains and lacks small-grain population.Comment: 15 pages, 8 figures (plus 2 color versions of grayscale figures), To appear in ApJ; minor corrections for the proofs of the manuscrip

Interactions Between Ground Water and Wetlands, Southern Shore of Lake Michigan, USA

Wetlands between, and within, dune-beach complexes along the south shore of Lake Michigan are strongly affected by ground water. The hydrogeology of the glacial drift aquifer system in a 26 km2 area was investigated to determine the effects of ground water on the hydrology and hydrochemistry of Cowles Bog and its adjacent wetlands. The investigation showed that ground water from intermediate- and regional-scale flow systems discharges to Cowles Bog from confined aquifers that underlie the wetland. These flow systems are recharged in moraines south of the dune- beach complexes. Water from the confined aquifers discharges into the surficial aquifer mainly by upward leakage through a buried till sheet that serves as the confining layer. However, the till sheet is breached below a raised peat mound in Cowles Bog, allowing direct upward discharge from the confined aquifer into the surficial sand, marl, and peat. The shallow ground and wetland water in the area influenced by this leakage is a calcium magnesium bicarbonate type, with low tritium concentrations consistent with mixing of older ground water and more recent precipitation. Ground water and wetland water from surrounding areas are less mineralized and have higher tritium concentrations characteristic of precipitation in the late 1970s. The results of this study suggest that wetlands in complex hydrogeologic settings may be influenced by multiple ground-water flow systems that are affected by geomorphic features, stratigraphic discontinuities, and changes in sediment types. Discharge and recharge zones may both occur in the same wetland. Multidisciplinary studies incorporating hydrological, hydrochemical, geophysical, and sedimentological data are necessary to identify such complexities in wetland hydrology

Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein

The economic implications of HLA matching in cadaveric renal transplantation.

Abstract Background: The potential economic effects of the allocation of cadaveric kidneys on the basis of tissue-matching criteria are controversial. We analyzed the economic costs associated with the transplantation of cadaveric kidneys with various numbers of HLA mismatches and examined the potential economic benefits of a local, as compared with a national, system designed to minimize HLA mismatches between donor and recipient in first cadaveric renal transplantations. Methods: All data were supplied by the U.S. Renal Data System. Data on all payments made by Medicare from 1991 through 1997 for the care of recipients of a first cadaveric renal transplant were analyzed according to the number of HLA-A, B, and DR mismatches between donor and recipient and the duration of cold ischemia before transplantation. Results: Average Medicare payments for renal-transplant recipients in the three years after transplantation increased from $60,436 per patient for fully HLA-matched kidneys (those with no HLA-A, B, or DR mismatches) to$80,807 for kidneys with six HLA mismatches between donor and recipient, a difference of 34 percent (P\u3c0.001). By three years after transplantation, the average Medicare payments were $64,119 for transplantations of kidneys with less than 12 hours of cold-ischemia time and$74,997 for those with more than 36 hours (P\u3c0.001). In simulations, the assignment of cadaveric kidneys to recipients by a method that minimized HLA mismatching within a local geographic area (i.e., within one of the approximately 50 organ-procurement organizations, which cover widely varying geographic areas) produced the largest cost savings ($4,290 per patient over a period of three years) and the largest improvements in the graft-survival rate (2.3 percent) when the potential costs of longer cold-ischemia time were considered. Conclusions: Transplantation of better-matched cadaveric kidneys could have substantial economic advantages. In our simulations, HLA-based allocation of kidneys at the local level produced the largest estimated cost savings, when the duration of cold ischemia was taken into account. No additional savings were estimated to result from a national allocation program, because the additional costs of longer cold-ischemia time were greater than the advantages of optimizing HLA matching

Intrinsic Tau Acetylation Is Coupled to Auto-Proteolytic Tau Fragmentation

Tau proteins are abnormally aggregated in a range of neurodegenerative tauopathies including Alzheimer’s disease (AD). Recently, tau has emerged as an extensively post-translationally modified protein, among which lysine acetylation is critical for normal tau function and its pathological aggregation. Here, we demonstrate that tau isoforms have different propensities to undergo lysine acetylation, with auto-acetylation occurring more prominently within the lysine-rich microtubule-binding repeats. Unexpectedly, we identified a unique intrinsic property of tau in which auto-acetylation induces proteolytic tau cleavage, thereby generating distinct N- and C-terminal tau fragments. Supporting a catalytic reaction-based mechanism, mapping and mutagenesis studies showed that tau cysteines, which are required for acetyl group transfer, are also essential for auto-proteolytic tau processing. Further mass spectrometry analysis identified the C-terminal 2nd and 4th microtubule binding repeats as potential sites of auto-cleavage. The identification of acetylation-mediated auto-proteolysis provides a new biochemical mechanism for tau self-regulation and warrants further investigation into whether auto-catalytic functions of tau are implicated in AD and other tauopathies