Characterization of the Response of Primary Cells Relevant to Dialysis-Related Amyloidosis to β2-Microglobulin Monomer and Fibrils

The formation of insoluble amyloid fibrils is associated with an array of devastating human diseases. Dialysis-related amyloidosis (DRA) is a severe complication of hemodialysis that results in the progressive destruction of the bones and joints. Elevated concentrations of β2-microglobulin (β2m) in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in the osteoarticular tissues, but the cellular basis for the destruction of these tissues in DRA is poorly understood. In this study we performed a systematic analysis of the interaction of monomeric and fibrillar β2m with primary human cells of the types present in the synovial joints of subjects with DRA. Building upon observations that macrophages infiltrate β2m amyloid deposits in vivo we demonstrate that monocytes, the precursors of macrophages, cannot degrade β2m fibrils, and that both monomeric β2m and fibrillar β2m are cytotoxic to these cells. β2m fibrils also impair the formation of bone resorbing osteoclasts from monocytes and reduce the viability of osteoblasts, the cell type that produces bone. As a consequence, we predict that β2m amyloid will disrupt the remodelling of the bone, which is critical for the maintenance of this tissue. Moreover, we show that β2m fibrils reduce the viability of chondrocytes, rationalizing the loss of cartilage in DRA. Together, our observations demonstrate that β2m cytotoxicity has multiple cellular targets in the osteoarticular tissues and is likely to be a key factor in the bone and joint destruction characteristic of DRA

Serendipitous discovery of a dying Giant Radio Galaxy associated with NGC 1534, using the Murchison Widefield Array

Recent observations with the Murchison Widefield Array at 185 MHz have serendipitously unveiled a heretofore unknown giant and relatively nearby (z = 0.0178) radio galaxy associated with NGC 1534. The diffuse emission presented here is the first indication that NGC 1534 is one of a rare class of objects (along with NGC 5128 and NGC 612) in which a galaxy with a prominent dust lane hosts radio emission on scales of ∼700 kpc. We present details of the radio emission along with a detailed comparison with other radio galaxies with discs. NGC 1534 is the lowest surface brightness radio galaxy known with an estimated scaled 1.4-GHz surface brightness of just 0.2 mJy arcmin[superscript −2]. The radio lobes have one of the steepest spectral indices yet observed: α = −2.1 ± 0.1, and the core to lobe luminosity ratio is <0.1 per cent. We estimate the space density of this low brightness (dying) phase of radio galaxy evolution as 7 × 10[superscript −7] Mpc[superscript −3] and argue that normal AGN cannot spend more than 6 per cent of their lifetime in this phase if they all go through the same cycle

Data for "Mechanistic Study of the Conductance and Enhanced Single-Molecule Detection in a Polymer Electrolyte Nanopore"

The data set contains all relevant ionic current traces and voltammetric data recorded using pClamp system for the associated paper entitled: 'Mechanistic Study of the Conductance and Enhanced Single-Molecule Detection in a Polymer Electrolyte Nanopore'. The data is in the native pClamp format of abf files. Analysis routine can be performed with script that relies on abf files. The data set is aim to allow users to re-analysis the data and to reproduce the observations made in the associated publication

LOW-FREQUENCY OBSERVATIONS OF THE MOON WITH THE MURCHISON WIDEFIELD ARRAY

A new generation of low-frequency radio telescopes is seeking to observe the redshifted 21 cm signal from the epoch of reionization (EoR), requiring innovative methods of calibration and imaging to overcome the difficulties of wide-field low-frequency radio interferometry. Precise calibration will be required to separate the expected small EoR signal from the strong foreground emission at the frequencies of interest between 80 and 300 MHz. The Moon may be useful as a calibration source for detection of the EoR signature, as it should have a smooth and predictable thermal spectrum across the frequency band of interest. Initial observations of the Moon with the Murchison Widefield Array 32 tile prototype show that the Moon does exhibit a similar trend to that expected for a cool thermally emitting body in the observed frequency range, but that the spectrum is corrupted by reflected radio emission from Earth. In particular, there is an abrupt increase in the observed flux density of the Moon within the internationally recognized frequency modulated (FM) radio band. The observations have implications for future low-frequency surveys and EoR detection experiments that will need to take this reflected emission from the Moon into account. The results also allow us to estimate the equivalent isotropic power emitted by the Earth in the FM band and to determine how bright the Earth might appear at meter wavelengths to an observer beyond our own solar system.National Science Foundation (U.S.) (Grant AST-0457585)National Science Foundation (U.S.) (Grant AST-0908884)National Science Foundation (U.S.) (Grant PHY-0835713)United States. Air Force Office of Scientific Research (Grant FA9550-0510247)Smithsonian Astrophysical ObservatoryMIT School of Scienc

The Murchison Widefield Array: The Square Kilometre Array Precursor at Low Radio Frequencies

The Murchison Widefield Array (MWA) is one of three Square Kilometre Array Precursor telescopes and is located at the Murchison Radio-astronomy Observatory in the Murchison Shire of the mid-west of Western Australia, a location chosen for its extremely low levels of radio frequency interference. The MWA operates at low radio frequencies, 80–300 MHz, with a processed bandwidth of 30.72 MHz for both linear polarisations, and consists of 128 aperture arrays (known as tiles) distributed over a ~3-km diameter area. Novel hybrid hardware/software correlation and a real-time imaging and calibration systems comprise the MWA signal processing backend. In this paper, the as-built MWA is described both at a system and sub-system level, the expected performance of the array is presented, and the science goals of the instrument are summarised.National Science Foundation (U.S.) (Grant AST CAREER-0847753)National Science Foundation (U.S.) (Grant AST-0457585)National Science Foundation (U.S.) (Grant AST-0908884)National Science Foundation (U.S.) (Grant PHY-0835713)United States. Air Force Office of Scientific Research (Grant FA9550-0510247)Smithsonian Astrophysical ObservatoryMIT School of Scienc

The giant lobes of Centaurus A observed at 118 MHz with the Murchison Widefield Array

We present new wide-field observations of Centaurus A (Cen A) and the surrounding region at 118 MHz with the Murchison Widefield Array (MWA) 32-tile prototype, with which we investigate the spectral-index distribution of Cen A's giant radio lobes. We compare our images to 1.4 GHz maps of Cen A and compute spectral indices using temperature–temperature plots and spectral tomography. We find that the morphologies at 118 MHz and 1.4 GHz match very closely apart from an extra peak in the southern lobe at 118 MHz, which provides tentative evidence for the existence of a southern counterpart to the northern middle lobe of Cen A. Our spatially averaged spectral indices for both the northern and southern lobes are consistent with previous analyses, however we find significant spatial variation of the spectra across the extent of each lobe. Both the spectral-index distribution and the morphology at low radio frequencies support a scenario of multiple outbursts of activity from the central engine. Our results are consistent with inverse-Compton modelling of radio and gamma-ray data that support a value for the lobe age of between 10 and 80 Myr.National Science Foundation (U.S.) (Grant AST-0457585)National Science Foundation (U.S.) (Grant PHY-0835713)National Science Foundation (U.S.) (Grant CAREER-0847753)National Science Foundation (U.S.) (Grant AST-0908884)United States. Air Force Office of Scientific Research (Grant FA9550-0510247)Smithsonian Astrophysical ObservatoryMIT School of Scienc

Structural mapping of oligomeric intermediates in an amyloid assembly pathway

Transient oligomers are commonly formed in the early stages of amyloid assembly. Determining the structure(s) of these species and defining their role(s) in assembly is key to devising new routes to control disease. Here, using a combination of chemical kinetics, NMR spectroscopy and other biophysical methods, we identify and structurally characterize the oligomers required for amyloid assembly of the protein ΔN6, a truncation variant of human β2-microglobulin (β2m) found in amyloid deposits in the joints of patients with dialysis-related amyloidosis. The results reveal an assembly pathway which is initiated by the formation of head-to-head non-toxic dimers and hexamers en route to amyloid fibrils. Comparison with inhibitory dimers shows that precise subunit organization determines amyloid assembly, while dynamics in the C-terminal strand hint to the initiation of cross-β structure formation. The results provide a detailed structural view of early amyloid assembly involving structured species that are not cytotoxic

?2-Microglobulin Amyloid Fibril-Induced Membrane Disruption Is Enhanced by Endosomal Lipids and Acidic pH

Although the molecular mechanisms underlying the pathology of amyloidoses are not well understood, the interaction between amyloid proteins and cell membranes is thought to play a role in several amyloid diseases. Amyloid fibrils of ?2-microglobulin (?2m), associated with dialysis-related amyloidosis (DRA), have been shown to cause disruption of anionic lipid bilayers in vitro. However, the effect of lipid composition and the chemical environment in which ?2m-lipid interactions occur have not been investigated previously. Here we examine membrane damage resulting from the interaction of ?2m monomers and fibrils with lipid bilayers. Using dye release, tryptophan fluorescence quenching and fluorescence confocal microscopy assays we investigate the effect of anionic lipid composition and pH on the susceptibility of liposomes to fibril-induced membrane damage. We show that ?2m fibril-induced membrane disruption is modulated by anionic lipid composition and is enhanced by acidic pH. Most strikingly, the greatest degree of membrane disruption is observed for liposomes containing bis(monoacylglycero)phosphate (BMP) at acidic pH, conditions likely to reflect those encountered in the endocytic pathway. The results suggest that the interaction between ?2m fibrils and membranes of endosomal origin may play a role in the molecular mechanism of ?2m amyloid-associated osteoarticular tissue destruction in DRA

Simple Sequence Repeats in the National Longitudinal Study of Adolescent Health: An Ethnically Diverse Resource for Genetic Analysis of Health and Behavior

Simple sequence repeats (SSRs) are one of the earliest available forms of genetic variation available for analysis and have been utilized in studies of neurological, behavioral, and health phenotypes. Although findings from these studies have been suggestive, their interpretation has been complicated by a variety of factors including, among others, limited power due to small sample sizes. The current report details the availability, diversity, and allele and genotype frequencies of six commonly examined SSRs in the ethnically diverse, population-based National Longitudinal Study of Adolescent Health (Add Health). A total of 106,743 genotypes were generated across 15,140 participants that included four microsatellites and two di-nucleotide repeats in three dopamine genes (DAT1, DRD4, DRD5), the serotonin transporter (5HTT), and monoamine oxidase A (MAOA). Allele and genotype frequencies showed a complex pattern and differed significantly between populations. For both di-nucleotide repeats we observed a greater allelic diversity than previously reported. The availability of these six SSRs in a large, ethnically diverse sample with extensive environmental measures assessed longitudinally offers a unique resource for researchers interested in health and behavior