Accelerated age-related degradation of the tectorial membrane in the Ceacam16 βgal/βgal null mutant mouse, a model for late-onset human hereditary deafness DFNB113

CEACAM16 is a non-collagenous protein of the tectorial membrane, an extracellular structure of the cochlea essential for normal hearing. Dominant and recessive mutations in CEACAM16 have been reported to cause postlingual and progressive forms of deafness in humans. In a previous study of young Ceacam16 βgal/βgal null mutant mice on a C57Bl/6J background, the incidence of spontaneous otoacoustic emissions (SOAEs) was greatly increased relative to Ceacam16+/+ and Ceacam16+/βgal mice, but auditory brain-stem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs) were near normal, indicating auditory thresholds were not significantly affected. To determine if the loss of CEACAM16 leads to hearing loss at later ages in this mouse line, cochlear structure and auditory function were examined in Ceacam16+/+, Ceacam16+/βgal and Ceacam16βgal/βgal mice at 6 and 12 months of age and compared to that previously described at 1 month. Analysis of older Ceacam16βgal/βgal mice reveals a progressive loss of matrix from the core of the tectorial membrane that is more extensive in the apical, low-frequency regions of the cochlea. In Ceacam16βgal/βgal mice at 6-7 months, the DPOAE magnitude at 2f1-f2 and the incidence of SOAEs both decrease relative to young animals. By ~12 months, SOAEs and DPOAEs are not detected in Ceacam16βgal/βgal mice and ABR thresholds are increased by up to ~40 dB across frequency, despite a complement of hair cells similar to that present in Ceacam16+/+ mice. Although SOAE incidence decreases with age in Ceacam16βgal/βgal mice, it increases in ageing heterozygous Ceacam16+/βgal mice and is accompanied by a reduction in the accumulation of CEACAM16 in the tectorial membrane relative to controls. An apically-biased loss of matrix from the core of the tectorial membrane, similar to that observed in young Ceacam16βgal/βgal mice, is also seen in Ceacam16+/+ and Ceacam16+/βgal mice, and other strains of wild-type mice, but at much later ages. The loss of Ceacam16 therefore accelerates age-related degeneration of the tectorial membrane leading, as in humans with mutations in CEACAM16, to a late-onset progressive form of hearing loss

Wringing out DNA

The chiral nature of DNA plays a crucial role in cellular processes. Here we use magnetic tweezers to explore one of the signatures of this chirality, the coupling between stretch and twist deformations. We show that the extension of a stretched DNA molecule increases linearly by 0.42 nm per excess turn applied to the double helix. This result contradicts the intuition that DNA should lengthen as it is unwound and get shorter with overwinding. We then present numerical results of energy minimizations of torsionally restrained DNA that display a behaviour similar to the experimental data and shed light on the molecular details of this surprising effect.Comment: 4 pages revtex4, 4 figure

The giant outburst of 4U 0115+634 in 2011 with Suzaku and RXTE - Minimizing cyclotron line biases

We present an analysis of X-ray spectra of the high-mass X-ray binary 4U 0115+634 as observed with Suzaku and RXTE in 2011 July, during the fading phase of a giant X-ray outburst. We used a continuum model consisting of an absorbed cutoff power law and an ad hoc Gaussian emission feature centered around 8.5 keV, which we attribute to cyclotron emission. Our results are consistent with a fundamental cyclotron absorption line centered at ∼10.2 keV for all observed flux ranges. At the same time we rule out significant influence of the 8.5 kev Gaussian on the parameters of the cyclotron resonant scattering feature, which are not consistent with the cyclotron line energies or the depths of previously reported flux-dependent descriptions. We also show that some continuum models can lead to artificial line-like residuals in the analyzed spectra, which are then misinterpreted as unphysically strong cyclotron lines. Specifically, our results do not support the existence of a previously claimed additional cyclotron feature at ∼15 keV. Apart from these features, we find for the first time evidence for a He-like Fe XXV emission line at ∼6.7 keV and weak H-like Fe XXVI emission close to ∼7.0 keV.We acknowledge funding by the European Space Agency under contract number C4000115860/15/NL/IB, by the Bundesministerium für Wirtschaft und Technologie under Deutsches Zentrum für Luft- und Raumfahrt grants 50OR0808, 50OR0905, 50OR1113, and 50OR1207, and by the Deutscher Akademischer Austauschdienst. MTW is supported by the NASA Astrophysical Data Analysis Program and the Chief of Naval Research. VG is supported through the Margarethe von Wrangell fellowship by the ESF and the Ministry of Science, Research and the Arts Baden-Württemberg. SMN and JMT acknowledge Spanish Ministerio de Ciencia, Tecnología e Innovación (MICINN) through the grant ESP2016-76683-C3-1-R and ESP2017-85691-P, respectively

The Transient Accereting X-Ray Pulsar XTE J1946+274: Stability of the X-Ray Properties at Low Flux and Updated Orbital Solution

We present a timing and spectral analysis of the X-ray pulsar XTE J1946+274 observed with Suzaku during an outburst decline in 2010 October and compare with previous results. XTE J1946+274 is a transient X-ray binary consisting of a Be-type star and a neutron star with a 15.75 s pulse period in a 172 days orbit with 2–3 outbursts per orbit during phases of activity. We improve the orbital solution using data from multiple instruments. The X-ray spectrum can be described by an absorbed Fermi–Dirac cut-off power-law model along with a narrow Fe Kα line at 6.4 keV and a weak Cyclotron Resonance Scattering Feature (CRSF) at ~35 keV. The Suzaku data are consistent with the previously observed continuum flux versus iron line flux correlation expected from fluorescence emission along the line of sight. However, the observed iron line flux is slightly higher, indicating the possibility of a higher iron abundance or the presence of non-uniform material. We argue that the source most likely has only been observed in the subcritical (non-radiation dominated) state since its pulse profile is stable over all observed luminosities and the energy of the CRSF is approximately the same at the highest (~5 × 10^(37) erg s^(−1)) and lowest (~5 × 10^(36) erg s^(−1)) observed 3–60 keV luminosities

Communications Research

Contains reports on seven research projects

Hypoplastic Left Heart Syndrome Current Considerations and Expectations

In the recent era, no congenital heart defect has undergone a more dramatic change in diagnostic approach, management, and outcomes than hypoplastic left heart syndrome (HLHS). During this time, survival to the age of 5 years (including Fontan) has ranged from 50% to 69%, but current expectations are that 70% of newborns born today with HLHS may reach adulthood. Although the 3-stage treatment approach to HLHS is now well founded, there is significant variation among centers. In this white paper, we present the current state of the art in our understanding and treatment of HLHS during the stages of care: 1) pre-Stage I: fetal and neonatal assessment and management; 2) Stage I: perioperative care, interstage monitoring, and management strategies; 3) Stage II: surgeries; 4) Stage III: Fontan surgery; and 5) long-term follow-up. Issues surrounding the genetics of HLHS, developmental outcomes, and quality of life are addressed in addition to the many other considerations for caring for this group of complex patients

RNA Structural Dynamics As Captured by Molecular Simulations: A Comprehensive Overview

With both catalytic and genetic functions, ribonucleic acid (RNA) is perhaps the most pluripotent chemical species in molecular biology, and its functions are intimately linked to its structure and dynamics. Computer simulations, and in particular atomistic molecular dynamics (MD), allow structural dynamics of biomolecular systems to be investigated with unprecedented temporal and spatial resolution. We here provide a comprehensive overview of the fast-developing field of MD simulations of RNA molecules. We begin with an in-depth, evaluatory coverage of the most fundamental methodological challenges that set the basis for the future development of the field, in particular, the current developments and inherent physical limitations of the atomistic force fields and the recent advances in a broad spectrum of enhanced sampling methods. We also survey the closely related field of coarse-grained modeling of RNA systems. After dealing with the methodological aspects, we provide an exhaustive overview of the available RNA simulation literature, ranging from studies of the smallest RNA oligonucleotides to investigations of the entire ribosome. Our review encompasses tetranucleotides, tetraloops, a number of small RNA motifs, A-helix RNA, kissing-loop complexes, the TAR RNA element, the decoding center and other important regions of the ribosome, as well as assorted others systems. Extended sections are devoted to RNA-ion interactions, ribozymes, riboswitches, and protein/RNA complexes. Our overview is written for as broad of an audience as possible, aiming to provide a much-needed interdisciplinary bridge between computation and experiment, together with a perspective on the future of the field

Power efficiency of outer hair cell somatic electromotility

© 2009 Rabbitt et al. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS Computational Biology 5 (2009): e1000444, doi:10.1371/journal.pcbi.1000444.Cochlear outer hair cells (OHCs) are fast biological motors that serve to enhance the vibration of the organ of Corti and increase the sensitivity of the inner ear to sound. Exactly how OHCs produce useful mechanical power at auditory frequencies, given their intrinsic biophysical properties, has been a subject of considerable debate. To address this we formulated a mathematical model of the OHC based on first principles and analyzed the power conversion efficiency in the frequency domain. The model includes a mixture-composite constitutive model of the active lateral wall and spatially distributed electro-mechanical fields. The analysis predicts that: 1) the peak power efficiency is likely to be tuned to a specific frequency, dependent upon OHC length, and this tuning may contribute to the place principle and frequency selectivity in the cochlea; 2) the OHC power output can be detuned and attenuated by increasing the basal conductance of the cell, a parameter likely controlled by the brain via the efferent system; and 3) power output efficiency is limited by mechanical properties of the load, thus suggesting that impedance of the organ of Corti may be matched regionally to the OHC. The high power efficiency, tuning, and efferent control of outer hair cells are the direct result of biophysical properties of the cells, thus providing the physical basis for the remarkable sensitivity and selectivity of hearing.This work was supported by NIDCD R01 DC04928 (Rabbitt), NIDCD R01 DC00384 (Brownell) and NASA Ames GSRA56000135 (Breneman)

Measurement of the W-boson mass in pp collisions at √s=7 TeV with the ATLAS detector

A measurement of the mass of the W boson is presented based on proton–proton collision data recorded in 2011 at a centre-of-mass energy of 7 TeV with the ATLAS detector at the LHC, and corresponding to 4.6 fb−1 of integrated luminosity. The selected data sample consists of 7.8×106 candidates in the W→μν channel and 5.9×106 candidates in the W→eν channel. The W-boson mass is obtained from template fits to the reconstructed distributions of the charged lepton transverse momentum and of the W boson transverse mass in the electron and muon decay channels, yielding mW=80370±7 (stat.)±11(exp. syst.) ±14(mod. syst.) MeV =80370±19MeV, where the first uncertainty is statistical, the second corresponds to the experimental systematic uncertainty, and the third to the physics-modelling systematic uncertainty. A measurement of the mass difference between the W+ and W−bosons yields mW+−mW−=−29±28 MeV