Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously

Biomechanical investigation of a novel ratcheting arthrodesis nail

<p>Abstract</p> <p>Background</p> <p>Knee or tibiotalocalcaneal arthrodesis is a salvage procedure, often with unacceptable rates of nonunion. Basic science of fracture healing suggests that compression across a fusion site may decrease nonunion. A novel ratcheting arthrodesis nail designed to improve dynamic compression is mechanically tested in comparison to existing nails.</p> <p>Methods</p> <p>A novel ratcheting nail was designed and mechanically tested in comparison to a solid nail and a threaded nail using sawbones models (Pacific Research Laboratories, Inc.). Intramedullary nails (IM) were implanted with a load cell (Futek LTH 500) between fusion surfaces. Constructs were then placed into a servo-hydraulic test frame (Model 858 Mini-bionix, MTS Systems) for application of 3 mm and 6 mm dynamic axial displacement (n = 3/group). Load to failure was also measured.</p> <p>Results</p> <p>Mean percent of initial load after 3-mm and 6-mm displacement was 190.4% and 186.0% for the solid nail, 80.7% and 63.0% for the threaded nail, and 286.4% and 829.0% for the ratcheting nail, respectively. Stress-shielding (as percentage of maximum load per test) after 3-mm and 6-mm displacement averaged 34.8% and 28.7% (solid nail), 40.3% and 40.9% (threaded nail), and 18.5% and 11.5% (ratcheting nail), respectively. In the 6-mm trials, statistically significant increase in initial load and decrease in stress-shielding for the ratcheting vs. solid nail (<it>p </it>= 0.029, <it>p </it>= 0.001) and vs. threaded nail (<it>p </it>= 0.012, <it>p </it>= 0.002) was observed. Load to failure for the ratcheting nail; 599.0 lbs, threaded nail; 508.8 lbs, and solid nail; 688.1 lbs.</p> <p>Conclusion</p> <p>With significantly increase of compressive load while decreasing stress-shielding at 6-mm of dynamic displacement, the ratcheting mechanism in IM nails may clinically improve rates of fusion.</p

(Correcting) misdiagnoses of asthma: A cost effectiveness analysis

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The prevalence of physician-diagnosed-asthma has risen over the past three decades and misdiagnosis of asthma is potentially common. Objective: to determine whether a secondary-screening-program to establish a correct diagnosis of asthma in those who report a physician diagnosis of asthma is cost effective.Method: Randomly selected physician-diagnosed-asthmatic subjects from 8 Canadian cities were studied with an extensive diagnostic algorithm to rule-in, or rule-out, a correct diagnosis of asthma. Subjects in whom the diagnosis of asthma was excluded were followed up for 6-months and data on asthma medications and heath care utilization was obtained. Economic analysis was performed to estimate the incremental lifetime costs associated with secondary screening of previously diagnosed asthmatic subjects. Analysis was from the perspective of the Canadian healthcare system and is reported in Canadian dollars.Results: Of 540 randomly selected patients with physician diagnosed asthma 150 (28%; 95%CI 19-37%) did not have asthma when objectively studied. 71% of these misdiagnosed patients were on some asthma medications. Incorporating the incremental cost of secondary-screening for the diagnosis of asthma, we found that the average cost savings per 100 individuals screened was $35,141 (95$4,588-$69,278).Conclusion: Cost savings primarily resulted from lifetime costs of medication use averted in those who had been misdiagnosed.This work was funded by the Canadian Institute of Health Research, Canada and the University Of Ottawa Division Of Respiratory Medicine

Science Requirements and Conceptual Design for a Polarized Medium Energy Electron-Ion Collider at Jefferson Lab

This report presents a brief summary of the science opportunities and program of a polarized medium energy electron-ion collider at Jefferson Lab and a comprehensive description of the conceptual design of such a collider based on the CEBAF electron accelerator facility.Comment: 160 pages, ~93 figures This work was supported by the U.S. Department of Energy, Office of Nuclear Physics, under Contract No. DE-AC05-06OR23177, DE-AC02-06CH11357, DE-AC05-060R23177, and DESC0005823. The U.S. Government retains a non-exclusive, paid-up, irrevocable, world-wide license to publish or reproduce this manuscript for U.S. Government purpose

Visual Orbits of Spectroscopic Binaries with the CHARA Array. III. HD 8374 and HD 24546

We present the visual orbits of two long period spectroscopic binary stars, HD 8374 and HD 24546, using interferometric observations acquired with the CHARA Array and the Palomar Testbed Interferometer. We also obtained new radial velocities from echelle spectra using the APO 3.5 m and Fairborn 2.0 m telescopes. By combining the visual and spectroscopic observations, we solve for the full, three-dimensional orbits and determine the stellar masses and distances to within 3% uncertainty. We then estimate the effective temperature and radius of each component star through Doppler tomography and spectral energy distribution analyses, in order to compare the observed stellar parameters to the predictions of stellar evolution models. For HD 8374, we find masses of M1 = 1.636 +/- 0.050 Msun and M2 = 1.587 +/- 0.049 Msun, radii of R1 = 1.84 +/- 0.05 Rsun and R2 = 1.66 +/- 0.12 Rsun, temperatures of Teff1 = 7280 +/- 110 K and Teff2 = 7280 +/- 120 K, and an estimated age of 1.0 Gyr. For HD 24546, we find masses of M1 = 1.434 +/- 0.014 Msun and M2 = 1.409 +/- 0.014 Msun, radii of R1 = 1.67 +/- 0.06 Rsun and R2 = 1.60 +/- 0.10 Rsun, temperatures of Teff1 = 6790 +/- 120 K and Teff2 = 6770 +/- 90 K, and an estimated age of 1.4 Gyr. HD 24546 is therefore too old to be a member of the Hyades cluster, despite its physical proximity to the group.Comment: 18 pages, 10 figures. Accepted for publication in A

Spectroscopy, MOST Photometry, and Interferometry of MWC 314: Is it an LBV or an interacting binary?

MWC 314 is a bright candidate luminous blue variable that resides in a fairly close binary system, with an orbital period of 60.753$\pm$0.003 d. We observed MWC 314 with a combination of optical spectroscopy, broad-band ground- and space-based photometry, as well as with long baseline, near-infrared interferometry. We have revised the single-lined spectroscopic orbit and explored the photometric variability. The orbital light curve displays two minima each orbit that can be partially explained in terms of the tidal distortion of the primary that occurs around the time of periastron. The emission lines in the system are often double-peaked and stationary in their kinematics, indicative of a circumbinary disc. We find that the stellar wind or circumbinary disc is partially resolved in the K\prime-band with the longest baselines of the CHARA Array. From this analysis, we provide a simple, qualitative model in an attempt to explain the observations. From the assumption of Roche Lobe overflow and tidal synchronisation at periastron, we estimate the component masses to be M1 $\approx 5$ M$_\odot$ and M2$\approx 15$ M$_\odot$, which indicates a mass of the LBV that is extremely low. In addition to the orbital modulation, we discovered two pulsational modes with the MOST satellite. These modes are easily supported by a low-mass hydrogen-poor star, but cannot be easily supported by a star with the parameters of an LBV. The combination of these results provides evidence that the primary star was likely never a normal LBV, but rather is the product of binary interactions. As such, this system presents opportunities for studying mass-transfer and binary evolution with many observational techniques.Comment: 26 pages, 7 figures, 5 tables, 2 appendices with 7 additional tables and 2 additional figures. Accepted for publication in MNRA

Masses, radii, and orbits of small Kepler planets : The transition from gaseous to rocky planets

We report on the masses, sizes, and orbits of the planets orbiting 22 Kepler stars. There are 49 planet candidates around these stars, including 42 detected through transits and 7 revealed by precise Doppler measurements of the host stars. Based on an analysis of the Kepler brightness measurements, along with high-resolution imaging and spectroscopy, Doppler spectroscopy, and (for 11 stars) asteroseismology, we establish low false-positive probabilities (FPPs) for all of the transiting planets (41 of 42 have an FPP under 1%), and we constrain their sizes and masses. Most of the transiting planets are smaller than three times the size of Earth. For 16 planets, the Doppler signal was securely detected, providing a direct measurement of the planet's mass. For the other 26 planets we provide either marginal mass measurements or upper limits to their masses and densities; in many cases we can rule out a rocky composition. We identify six planets with densities above 5 g cm-3, suggesting a mostly rocky interior for them. Indeed, the only planets that are compatible with a purely rocky composition are smaller than 2 R ⊕. Larger planets evidently contain a larger fraction of low-density material (H, He, and H2O).Peer reviewedFinal Accepted Versio

A direct physical interaction between Nanog and Sox2 regulates embryonic stem cell self-renewal

Embryonic stem (ES) cell self-renewal efficiency is determined by the Nanog protein level. However, the protein partners of Nanog that function to direct self-renewal are unclear. Here, we identify a Nanog interactome of over 130 proteins including transcription factors, chromatin modifying complexes, phosphorylation and ubiquitination enzymes, basal transcriptional machinery members, and RNA processing factors. Sox2 was identified as a robust interacting partner of Nanog. The purified Nanog–Sox2 complex identified a DNA recognition sequence present in multiple overlapping Nanog/Sox2 ChIP-Seq data sets. The Nanog tryptophan repeat region is necessary and sufficient for interaction with Sox2, with tryptophan residues required. In Sox2, tyrosine to alanine mutations within a triple-repeat motif (S X T/S Y) abrogates the Nanog–Sox2 interaction, alters expression of genes associated with the Nanog-Sox2 cognate sequence, and reduces the ability of Sox2 to rescue ES cell differentiation induced by endogenous Sox2 deletion. Substitution of the tyrosines with phenylalanine rescues both the Sox2–Nanog interaction and efficient self-renewal. These results suggest that aromatic stacking of Nanog tryptophans and Sox2 tyrosines mediates an interaction central to ES cell self-renewal

A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation

SummaryCalcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA−/− mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis