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Plasma kininogen and kininogen fragments are biomarkers of progressive renal decline in type-1 diabetes
The ability of microalbuminuria to predict early progressive renal function decline in type-1 diabetic patients has been questioned. To resolve this, we determined the plasma proteome differences between microalbuminuric patients with type-1 diabetes and stable renal function (controls) and patients at risk for early progressive renal function decline (cases) and asked whether these differences have value as surrogate biomarkers. Mass spectrometry was used to analyze small (less than 3 kDa) plasma peptides isolated from well-matched case and control plasma obtained at the beginning of an 8-12 year follow-up period. Spearman analysis of plasma peptide abundance and the rate of renal function decline during follow-up identified seven masses with a significant negative correlation with early progressive renal function decline. Tandem mass spectrometry identified three fragments of high molecular weight kininogen. Increased plasma high molecular weight kininogen in the cases was confirmed by immunoblot. One peptide, des-Arg9-BK(1-8), induced Erk1/2 phosphorylation when added apically to two proximal tubular cell lines grown on permeable inserts. Thus, we have identified plasma protein fragments, some of which have biological activity with moderate to strong correlation, with early progressive renal function decline in microalbuminuric patients with type-1 diabetes. Other peptides are candidates for validation as candidate biomarkers of diabetes-associated renal dysfunction
Proteomic Analysis of Protein Expression and Oxidative Modification in R6/2 Transgenic Mice A Model of Huntington Disease
Huntington disease (HD) is a hereditary neurodegenerative disorder characterized by motor, psychiatric, and cognitive symptoms. The genetic defect responsible for the onset of the disease, expansion of CAG repeats in exon 1 of the gene that codes for huntingtin on chromosome 4, has been unambiguously identified. On the other hand, the mechanisms by which the mutation causes the disease are not completely understood yet. However, defects in energy metabolism of affected cells may cause oxidative damage, which has been proposed as one of the underlying molecular mechanisms that participate in the etiology of the disease. In our effort to investigate the extent of oxidative damage occurring at the protein level, we used a parallel proteomic approach to identify proteins potentially involved in processes upstream or downstream of the disease-causing huntingtin in a well established HD mouse model (R6/2 transgenic mice). We have demonstrated that the expression levels of dihydrolipoamide S-succinyltransferase and aspartate aminotransferase increase consistently over the course of disease (10-week-old mice). In contrast, pyruvate dehydrogenase expression levels were found to be decreased in 10-week-old HD transgenic mice compared with young (4-week-old) mice. Our experimental approach also led to the identification of oxidatively modified proteins. Six proteins were found to be significantly oxidized in old R6/2 transgenic mice compared with either young transgenic mice or non-transgenic mice. These proteins are alpha-enolase, gamma-enolase (neuron-specific enolase), aconitase, the voltage-dependent anion channel 1, heat shock protein 90, and creatine kinase. Because oxidative damage has proved to play an important role in the pathogenesis and the progression of Huntington disease, our results for the first time identify specific oxidatively modified proteins that potentially contribute to the pathogenesis of Huntington disease
Comparative Proteomic Analyses of the Parietal Lobe from Rhesus Monkeys Fed a High-Fat/Sugar Diet With and Without Resveratrol Supplementation, Relative to a Healthy Diet: Insights Into the Roles of Unhealthy Diets and Resveratrol on Function
A diet consisting of a high intake of saturated fat and refined sugars is characteristic of a Western-diet and has been shown to have a substantial negative effect on human health. Expression proteomics were used to investigate changes to the parietal lobe proteome of rhesus monkeys consuming either a high fat and sugar (HFS) diet, a HFS diet supplemented with resveratrol (HFS+RSV), or a healthy control diet for 2 years. Here we discuss the modifications in the levels of 12 specific proteins involved in various cellular systems including metabolism, neurotransmission, structural integrity, and general cellular signaling following a nutritional intervention. Our results contribute to a better understanding of the mechanisms by which resveratrol functions through the up- or down-regulation of proteins in different cellular sub-systems to affect the overall health of the brain
Plasma and Serum Proteins Bound to Nanoceria: Insights into Pathways by which Nanoceria May Exert Its Beneficial and Deleterious Effects \u3cem\u3eIn Vivo\u3c/em\u3e
Nanoceria (CeO2, cerium oxide nanoparticles) is proposed as a therapeutic for multiple disorders. In blood, nanoceria becomes protein-coated, changing its surface properties to yield a different presentation to cells. There is little information on the interaction of nanoceria with blood proteins. The current study is the first to report the proteomics identification of plasma and serum proteins adsorbed to nanoceria. The results identify a number of plasma and serum proteins interacting with nanoceria, proteins whose normal activities regulate numerous cell functions: antioxidant/detoxification, energy regulation, lipoproteins, signaling, complement, immune function, coagulation, iron homeostasis, proteolysis, inflammation, protein folding, protease inhibition, adhesion, protein/RNA degradation, and hormonal. The principal implications of this study are: 1) The protein corona may positively or negatively affect nanoceria cellular uptake, subsequent organ bioprocessing, and effects; and 2) Nanoceria adsorption may alter protein structure and function, including pro- and inflammatory effects. Consequently, prior to their use as therapeutic agents, better understanding of the effects of nanoceria protein coating is warranted
The role of charge in the toxicity of polymer-coated cerium oxide nanomaterials to Caenorhabditis elegans
This study examined the impact of surface functionalization and charge on ceria nanomaterial toxicity to Caenorhabditis elegans. The examined endpoints included mortality, reproduction, protein expression, and protein oxidation profiles. Caenorhabditis elegans were exposed to identical 2–5 nm ceria nanomaterial cores which were coated with cationic (diethylaminoethyl dextran; DEAE), anionic (carboxymethyl dextran; CM), and non-ionic (dextran; DEX) polymers. Mortality and reproductive toxicity of DEAE-CeO2 was approximately two orders of magnitude higher than for CM-CeO2 or DEX-CeO2. Two-dimensional gel electrophoresis with orbitrap mass spectrometry identification revealed changes in the expression profiles of several mitochondrial-related proteins and proteins that are expressed in the C. elegans intestine. However, each type of CeO2 material exhibited a distinct protein expression profile. Increases in protein carbonyls and protein-bound 3-nitrotyrosine were also observed for some proteins, indicating oxidative and nitrosative damage. Taken together the results indicate that the magnitude of toxicity and toxicity pathways vary greatly due to surface functionalization of CeO2 nanomaterials
Early Use of Adjunctive Therapies for Pediatric Acute Respiratory Distress Syndrome:A PARDIE Study
Rationale: Few data exist to guide early adjunctive therapy use in pediatric acute respiratory distress syndrome (PARDS). Objectives: To describe contemporary use of adjunctive therapies for early PARDS as a framework for future investigations. Methods: This was a preplanned substudy of a prospective, international, cross-sectional observational study of children with PARDS from 100 centers over 10 study weeks. Measurements and Main Results: We investigated six adjunctive therapies for PARDS: continuous neuromuscular blockade, corticosteroids, inhaled nitric oxide (iNO), prone positioning, high-frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation. Almost half (45%) of children with PARDS received at least one therapy. Variability was noted in the median starting oxygenation index of each therapy; corticosteroids started at the lowest oxygenation index (13.0; interquartile range, 7.6–22.0) and HFOV at the highest (25.7; interquartile range, 16.7–37.3). Continuous neuromuscular blockade was the most common, used in 31%, followed by iNO (13%), corticosteroids (10%), prone positioning (10%), HFOV (9%), and extracorporeal membrane oxygenation (3%). Steroids, iNO, and HFOV were associated with comorbidities. Prone positioning and HFOV were more common in middle-income countries and less frequently used in North America. The use of multiple ancillary therapies increased over the first 3 days of PARDS, but there was not an easily identifiable pattern of combination or order of use. Conclusions: The contemporary description of prevalence, combinations of therapies, and oxygenation threshold for which the therapies are applied is important for design of future studies. Region of the world, income, and comorbidities influence adjunctive therapy use and are important variables to include in PARDS investigations
The Atacama Cosmology Telescope: Data Characterization and Map Making
We present a description of the data reduction and mapmaking pipeline used
for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The
data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from
2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours
of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours
of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2
hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were
devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial
equator. We discuss sources of statistical and systematic noise, calibration,
telescope pointing, and data selection. Out of 1260 survey hours and 1024
detectors per array, 816 hours and 593 effective detectors remain after data
selection for this frequency band, yielding a 38% survey efficiency. The total
sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in
the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units.
Atmospheric brightness fluctuations constitute the main contaminant in the data
and dominate the detector noise covariance at low frequencies in the TOD. The
maps were made by solving the least-squares problem using the Preconditioned
Conjugate Gradient method, incorporating the details of the detector and noise
correlations. Cross-correlation with WMAP sky maps, as well as analysis from
simulations, reveal that our maps are unbiased at multipoles ell > 300. This
paper accompanies the public release of the 148 GHz southern stripe maps from
2008. The techniques described here will be applied to future maps and data
releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape
The Atacama Cosmology Telescope: Extragalactic Sources at 148 GHz in the 2008 Survey
We report on extragalactic sources detected in a 455 square-degree map of the
southern sky made with data at a frequency of 148 GHz from the Atacama
Cosmology Telescope 2008 observing season. We provide a catalog of 157 sources
with flux densities spanning two orders of magnitude: from 15 to 1500 mJy.
Comparison to other catalogs shows that 98% of the ACT detections correspond to
sources detected at lower radio frequencies. Three of the sources appear to be
associated with the brightest cluster galaxies of low redshift X-ray selected
galaxy clusters. Estimates of the radio to mm-wave spectral indices and
differential counts of the sources further bolster the hypothesis that they are
nearly all radio sources, and that their emission is not dominated by
re-emission from warm dust. In a bright (>50 mJy) 148 GHz-selected sample with
complete cross-identifications from the Australia Telescope 20 GHz survey, we
observe an average steepening of the spectra between 5, 20, and 148 GHz with
median spectral indices of , , and . When the
measured spectral indices are taken into account, the 148 GHz differential
source counts are consistent with previous measurements at 30 GHz in the
context of a source count model dominated by radio sources. Extrapolating with
an appropriately rescaled model for the radio source counts, the Poisson
contribution to the spatial power spectrum from synchrotron-dominated sources
with flux density less than 20 mJy is C^{\rm Sync} = (2.8 \pm 0.3) \times
10^{-6} \micro\kelvin^2.Comment: Accepted to Ap
The Atacama Cosmology Telescope: A Measurement of the Cosmic Microwave Background Power Spectrum at 148 and 218 GHz from the 2008 Southern Survey
We present measurements of the cosmic microwave background (CMB) power
spectrum made by the Atacama Cosmology Telescope at 148 GHz and 218 GHz, as
well as the cross-frequency spectrum between the two channels. Our results
clearly show the second through the seventh acoustic peaks in the CMB power
spectrum. The measurements of these higher-order peaks provide an additional
test of the {\Lambda}CDM cosmological model. At l > 3000, we detect power in
excess of the primary anisotropy spectrum of the CMB. At lower multipoles 500 <
l < 3000, we find evidence for gravitational lensing of the CMB in the power
spectrum at the 2.8{\sigma} level. We also detect a low level of Galactic dust
in our maps, which demonstrates that we can recover known faint, diffuse
signals.Comment: 19 pages, 13 figures. Submitted to ApJ. This paper is a companion to
Hajian et al. (2010) and Dunkley et al. (2010
The Atacama Cosmology Telescope: Sunyaev Zel'dovich Selected Galaxy Clusters at 148 GHz in the 2008 Survey
We report on twenty-three clusters detected blindly as Sunyaev-Zel'dovich
(SZ) decrements in a 148 GHz, 455 square-degree map of the southern sky made
with data from the Atacama Cosmology Telescope 2008 observing season. All SZ
detections announced in this work have confirmed optical counterparts. Ten of
the clusters are new discoveries. One newly discovered cluster, ACT-CL
J0102-4915, with a redshift of 0.75 (photometric), has an SZ decrement
comparable to the most massive systems at lower redshifts. Simulations of the
cluster recovery method reproduce the sample purity measured by optical
follow-up. In particular, for clusters detected with a signal-to-noise ratio
greater than six, simulations are consistent with optical follow-up that
demonstrated this subsample is 100% pure. The simulations further imply that
the total sample is 80% complete for clusters with mass in excess of 6x10^14
solar masses referenced to the cluster volume characterized by five hundred
times the critical density. The Compton y -- X-ray luminosity mass comparison
for the eleven best detected clusters visually agrees with both self-similar
and non-adiabatic, simulation-derived scaling laws.Comment: 13 pages, 7 figures, Accepted for publication in Ap
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