Architecture and Selectivity in Aquaporins: 2.5 Å X-Ray Structure of Aquaporin Z

Aquaporins are a family of water and small molecule channels found in organisms ranging from bacteria to animals. One of these channels, the E. coli protein aquaporin Z (AqpZ), has been shown to selectively conduct only water at high rates. We have expressed, purified, crystallized, and solved the X-ray structure of AqpZ. The 2.5 Å resolution structure of AqpZ suggests aquaporin selectivity results both from a steric mechanism due to pore size and from specific amino acid substitutions that regulate the preference for a hydrophobic or hydrophilic substrate. This structure provides direct evidence on the molecular mechanisms of specificity between water and glycerol in this family of channels from a single species. It is to our knowledge the first atomic resolution structure of a recombinant aquaporin and so provides a platform for combined genetic, mutational, functional, and structural determinations of the mechanisms of aquaporins and, more generally, the assembly of multimeric membrane proteins

Spectral decomposition of internal gravity wave sea surface height in global models

Two global ocean models ranging in horizontal resolution from 1/12° to 1/48° are used to study the space and time scales of sea surface height (SSH) signals associated with internal gravity waves (IGWs). Frequency‐horizontal wavenumber SSH spectral densities are computed over seven regions of the world ocean from two simulations of the HYbrid Coordinate Ocean Model (HYCOM) and three simulations of the Massachusetts Institute of Technology general circulation model (MITgcm). High wavenumber, high‐frequency SSH variance follows the predicted IGW linear dispersion curves. The realism of high‐frequency motions (>0.87  cpd) in the models is tested through comparison of the frequency spectral density of dynamic height variance computed from the highest‐resolution runs of each model (1/25° HYCOM and 1/48° MITgcm) with dynamic height variance frequency spectral density computed from nine in situ profiling instruments. These high‐frequency motions are of particular interest because of their contributions to the small‐scale SSH variability that will be observed on a global scale in the upcoming Surface Water and Ocean Topography (SWOT) satellite altimetry mission. The variance at supertidal frequencies can be comparable to the tidal and low‐frequency variance for high wavenumbers (length scales smaller than ∼50 km), especially in the higher‐resolution simulations. In the highest‐resolution simulations, the high‐frequency variance can be greater than the low‐frequency variance at these scales.Key PointsTwo high‐resolution ocean models compare well against data in frequency spectral density of dynamic heightSea surface height frequency‐horizontal wavenumber spectral densities show high variance along internal gravity wave dispersion curvesTwo high‐resolution ocean models give different estimates of variance in high‐frequency, high wavenumber phenomenaPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/1/jgrc22465-sup-0002-2017JC013009-fs01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/2/jgrc22465-sup-0003-2017JC013009-fs02.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/3/jgrc22465_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/4/jgrc22465.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/5/jgrc22465-sup-0007-2017JC013009-fs06.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/6/jgrc22465-sup-0009-2017JC013009-fs08.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/7/jgrc22465-sup-0004-2017JC013009-fs03.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/8/jgrc22465-sup-0005-2017JC013009-fs04.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/9/jgrc22465-sup-0006-2017JC013009-fs05.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/10/jgrc22465-sup-0001-2017JC013009-s01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139946/11/jgrc22465-sup-0008-2017JC013009-fs07.pd

Coincident, 100 kpc-scale damped Lyman alpha absorption towards a binary QSO: how large are galaxies at z ~ 3?

We report coincident damped Lyman alpha (DLA) and sub-DLA absorption at z = 2.66 and z = 2.94 towards the z ~ 3 13.8 arcsecond separation binary quasar SDSS 1116+4118 AB. At the redshifts of the absorbers, this angular separation corresponds to a proper transverse separation of ~ 110 kpc. A third absorber, a sub-DLA at z = 2.47, is detected towards SDSS 1116+4118 B, but no corresponding high column density absorber is present towards SDSS 1116+4118 A. We use high resolution galaxy simulations and a clustering analysis to interpret the coincident absorption and its implications for galaxy structure at z ~ 3. We conclude that the common absorption in the two lines of sight is unlikely to arise from a single galaxy, or a galaxy plus satellite system, and is more feasibly explained by a group of two or more galaxies with separations ~ 100 kpc. The impact of these findings on single line of sight observations is also discussed; we show that abundances of DLAs may be affected by up to a few tenths of a dex by line of sight DLA blending. From a Keck ESI spectrum of the two quasars, we measure metal column densities for all five absorbers and determine abundances for the three absorbers with log N(HI) > 20. For the two highest N(HI) absorbers, we determine high levels of metal enrichment, corresponding to 1/3 and 1/5 solar. These metallicities are amongst the highest measured for DLAs at any redshift and are consistent with values measured in Lyman break galaxies at 2 < z < 3. For the DLA at z = 2.94 we also infer an approximately solar ratio of alpha-to-Fe peak elements from [S/Zn] = +0.05, and measure an upper limit for the molecular fraction in this particular line of sight of log f(H_2)< -5.5.Comment: Accepted for publication in MNRAS. Full resolution simulation images available in pdf copy of the manuscript at http://www.astro.uvic.ca/~sara/1116.pd

Observation of Binding and Rotation of Methane and Hydrogen within a Functional Metal-Organic Framework

The key requirement for a portable store of natural gas is to maximize the amount of gas within the smallest possible space. The packing of methane (CH₄) in a given storage medium at the highest possible density is, therefore, a highly desirable but challenging target. We report a microporous hydroxyl-decorated material, MFM-300­(In) (MFM = Manchester Framework Material, replacing the NOTT designation), which displays a high volumetric uptake of 202 v/v at 298 K and 35 bar for CH₄ and 488 v/v at 77 K and 20 bar for H₂. Direct observation and quantification of the location, binding, and rotational modes of adsorbed CH₄ and H₂ molecules within this host have been achieved, using neutron diffraction and inelastic neutron scattering experiments, coupled with density functional theory (DFT) modeling. These complementary techniques reveal a very efficient packing of H₂ and CH₄ molecules within MFM-300­(In), reminiscent of the condensed gas in pure component crystalline solids. We also report here, for the first time, the experimental observation of a direct binding interaction between adsorbed CH₄ molecules and the hydroxyl groups within the pore of a material. This is different from the arrangement found in CH₄/water clathrates, the CH₄ store of nature

Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial

We aimed to determine the persistence of glycaemic control 1 year after a limited period of intensive glycaemic management of type 2 diabetes

A useful savagery: The invention of violence in nineteenth-century England

‘A Useful Savagery: The Invention of Violence in Nineteenth-Century England’ considers a particular configuration of attitudes toward violence that emerged in the early decades of the nineteenth century. As part of a longer-term process of emerging ‘sensibilities,’ violence was, seemingly paradoxically, ‘invented’ as a social issue while concurrently relocated in the ‘civilised’ imagination as an anti-social feature mainly of ‘savage’ working-class life. The dominant way this discourse evolved was through the creation of a narrative that defined ‘civilisation’ in opposition to the presumed ‘savagery’ of the working classes. Although the refined classes were often distanced from the physical experience of violence, concern with violence and brutality became significant parts of social commentary aimed at a middle-class readership. While stridently redefining themselves in opposition to ‘brutality,’ one of the purposes of this literature was to create a new middle class and justify the expansion of state power. By the closing decades of the nineteenth century, as the working classes adopted tenets of Victorian respectability, a proliferating number of social and psychological ‘others’ were identified against which ‘civilised’ thought could define itself

Genome-wide Association Study Identifies Two Susceptibility Loci for Osteosarcoma

Osteosarcoma is the most common primary bone malignancy of adolescents and young adults. In order to better understand the genetic etiology of osteosarcoma, we performed a multi-stage genome-wide association study (GWAS) consisting of 941 cases and 3,291 cancer-free adult controls of European ancestry. Two loci achieved genome-wide significance: rs1906953 at 6p21.3, in the glutamate receptor metabotropic 4 [GRM4] gene (P = 8.1 ×10-9), and rs7591996 and rs10208273 in a gene desert on 2p25.2 (P = 1.0 ×10-8 and 2.9 ×10-7). These two susceptibility loci warrant further exploration to uncover the biological mechanisms underlying susceptibility to osteosarcoma

Expression of NF-κB p50 in Tumor Stroma Limits the Control of Tumors by Radiation Therapy

Radiation therapy aims to kill cancer cells with a minimum of normal tissue toxicity. Dying cancer cells have been proposed to be a source of tumor antigens and may release endogenous immune adjuvants into the tumor environment. For these reasons, radiation therapy may be an effective modality to initiate new anti-tumor adaptive immune responses that can target residual disease and distant metastases. However, tumors engender an environment dominated by M2 differentiated tumor macrophages that support tumor invasion, metastases and escape from immune control. In this study, we demonstrate that following radiation therapy of tumors in mice, there is an influx of tumor macrophages that ultimately polarize towards immune suppression. We demonstrate using in vitro models that this polarization is mediated by transcriptional regulation by NFκB p50, and that in mice lacking NFκB p50, radiation therapy is more effective. We propose that despite the opportunity for increased antigen-specific adaptive immune responses, the intrinsic processes of repair following radiation therapy may limit the ability to control residual disease