Crystallization and preliminary x-ray diffraction analysis of the unliganded human growth hormone receptor

The crystal structure of the extracellular domain of growth hormone receptor complexed to its ligand, growth hormone, has been known since 1992. However, no information exists for the unliganded form of the receptor. The human growth hormone receptor's extracellular ligand-binding domain, encompassing amino-acid residues 1 - 238, has been expressed in Escherichia coli, purified by anion ion-exchange chromatography and crystallized in its unliganded state by the hanging-drop vapour-diffusion method in 100 mM HEPES pH 7.0 containing 27.5%(w/v) PEG 5000 monomethyl ether and 200 mM ammonium sulfate as the co-precipitants. The crystals belong to the othorhombic space group C222(1), have unit-cell parameters a = 99.7, b = 112.2, c = 93.2 Angstrom and diffract to 2.5 Angstrom resolution using synchrotron radiation. The crystal structure will shed light on the nature of any conformation changes that occur upon ligand binding and will provide information to develop potential low-molecular-weight agonists/antagonists to treat clinical diseases in which the growth hormone receptor is implicated

The Southampton-York Natural Scenes (SYNS) dataset: statistics of surface attitude

Recovering 3D scenes from 2D images is an under-constrained task; optimal estimation depends upon knowledge of the underlying scene statistics. Here we introduce the Southampton-York Natural Scenes dataset (SYNS: https://syns.soton.ac.uk), which provides comprehensive scene statistics useful for understanding biological vision and for improving machine vision systems. In order to capture the diversity of environments that humans encounter, scenes were surveyed at random locations within 25 indoor and outdoor categories. Each survey includes (i) spherical LiDAR range data (ii) high-dynamic range spherical imagery and (iii) a panorama of stereo image pairs. We envisage many uses for the dataset and present one example: an analysis of surface attitude statistics, conditioned on scene category and viewing elevation. Surface normals were estimated using a novel adaptive scale selection algorithm. Across categories, surface attitude below the horizon is dominated by the ground plane (0° tilt). Near the horizon, probability density is elevated at 90°/270° tilt due to vertical surfaces (trees, walls). Above the horizon, probability density is elevated near 0° slant due to overhead structure such as ceilings and leaf canopies. These structural regularities represent potentially useful prior assumptions for human and machine observers, and may predict human biases in perceived surface attitude

High-Field Superconductivity at an Electronic Topological Transition in URhGe

The emergence of superconductivity at high magnetic fields in URhGe is regarded as a paradigm for new state formation approaching a quantum critical point. Until now, a divergence of the quasiparticle mass at the metamagnetic transition was considered essential for superconductivity to survive at magnetic fields above 30 tesla. Here we report the observation of quantum oscillations in URhGe revealing a tiny pocket of heavy quasiparticles that shrinks continuously with increasing magnetic field, and finally disappears at a topological Fermi surface transition close to or at the metamagnetic field. The quasiparticle mass decreases and remains finite, implying that the Fermi velocity vanishes due to the collapse of the Fermi wavevector. This offers a novel explanation for the re-emergence of superconductivity at extreme magnetic fields and makes URhGe the first proven example of a material where magnetic field-tuning of the Fermi surface, rather than quantum criticality alone, governs quantum phase formation.Comment: A revised version has been accepted for publication in Nature Physic

A central bioactive region of LTBP-2 stimulates the expression of TGF-β1 in fibroblasts via akt and p38 signalling pathways

Latent transforming growth factor-β-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-β1 (TGF-β1) but appears to be implicated in the regulation of TGF-β1 bioactivity, although the mechanisms are largely unknown. In experiments originally designed to study the displacement of latent TGF-β1 complexes from matrix storage, we found that the addition of exogenous LTBP-2 to cultured human MSU-1.1 fibroblasts caused an increase in TGF-β1 levels in the medium. However, the TGF-β1 increase was due to an upregulation of TGF-β1 expression and secretion rather than a displacement of matrix-stored TGF-β1. The secreted TGF-β1 was mainly in an inactive form, and its concentration peaked around 15 h after addition of LTBP-2. Using a series of recombinant LTBP-2 fragments, the bioactivity was identified to a small region of LTBP-2 consisting of an 8-Cys motif flanked by four epidermal growth factor (EGF)-like repeats. The LTBP-2 stimulation of TGF-β expression involved the phosphorylation of both Akt and p38 mitogen-activated protein kinase (MAPK) signalling proteins, and specific inactivation of each protein individually blocked TGF-β1 increase. The search for the cell surface receptor mediating this LTBP-2 activity proved inconclusive. Inhibitory antibodies to integrins β1 and αVβ5 showed no reduction of LTBP-2 stimulation of TGF-β1. However, TGF-β1 upregulation was partially inhibited by anti-αVβ3 integrin antibodies, suggestive of a direct or indirect role for this integrin. Overall, the study indicates that LTBP-2 can directly upregulate cellular TGF-β1 expression and secretion by interaction with cells via a short central bioactive region. This may be significant in connective tissue disorders involving aberrant TGF-β1 signallin

Characterisation of two snake toxin-targeting human monoclonal immunoglobulin G antibodies expressed in tobacco plants

Current snakebite antivenoms are based on polyclonal animal-derived antibodies, which can neutralize snake venom toxins in envenomed victims, but which are also associated with adverse reactions. Therefore, several efforts within antivenom research aim to explore the utility of recombinant monoclonal antibodies, such as human immunoglobulin G (IgG) antibodies, which are routinely used in the clinic for other indications. In this study, the feasibility of using tobacco plants as bioreactors for expressing full-length human monoclonal IgG antibodies against snake toxins was investigated. We show that the plant-produced antibodies perform similarly to their mammalian cell-expressed equivalents in terms of in vitro binding. Complete neutralization was achieved by both the plant and mammalian cell-produced anti-α-cobratoxin antibody. The feasibility of using plant-based expression systems may potentially make it easier for laboratories in resource-poor settings to work with human monoclonal IgG antibodies

Adenoma development in familial adenomatous polyposis andMUTYH-associated polyposis: somatic landscape and driver genes

Familial adenomatous polyposis (FAP) and MUTYH‐associated polyposis (MAP) are inherited disorders associated with multiple colorectal adenomas that lead to a very high risk of colorectal cancer. The somatic mutations that drive adenoma development in these conditions have not been investigated comprehensively. In this study we performed analysis of paired colorectal adenoma and normal tissue DNA from individuals with FAP or MAP, sequencing 14 adenoma whole exomes (eight MAP, six FAP), 55 adenoma targeted exomes (33 MAP, 22 FAP) and germline DNA from each patient, and a further 63 adenomas by capillary sequencing (41 FAP, 22 MAP). With these data we examined the profile of mutated genes, the mutational signatures and the somatic mutation rates, observing significant diversity in the constellations of mutated driver genes in different adenomas, and loss‐of‐function mutations in WTX (9%; p < 9.99e‐06), a gene implicated in regulation of the WNT pathway and p53 acetylation. These data extend our understanding of the early events in colorectal tumourigenesis in the polyposis syndromes. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland

Reconfigurable binary optical routing switches with fan-out based on the integration of GaAs/AlGaAs surface-emitting lasers and heterojunction phototransistors

Includes bibliographical references.The design, fabrication, and experimental demonstration of dynamically reconfigurable binary optical switches based on the integration of GaAs/AlGaAs vertical-cavity surface-emitting lasers and heterojunction phototransistors are reported. These new monolithic optical switches can perform spatial routing and optical amplification functions on input optical data with a fan-out of two, and can be programmed using simple voltage control. The 1 × 2 and 2 × 2 devices provide the basis for a high performance, two-dimensional optical switching fabric with electrical interfaces for optical switching and interconnection networks.The work at UNM was supported by Rome Laboratories (Griffiss AFB), the Advanced Research Projects Agency-MTO, and the Air Force Office of Scientific Research (Bolling AFB). The work performed at Sandia was supported by DOE Contract No. DE-AC04-76DP00789

Binary optical switch and programmable optical logic gate based on the integration of GaAs/AlGaAs surface-emitting lasers and heterojunction phototransistors

Includes bibliographical references.Optical switches based on GaAs/AlGaAs vertical-cavity surface-emitting lasers and heterojunction phototransistors are combined monolithically into new switching configurations that perform optical logic and spatial routing in a dynamically programmable manner. Using simple voltage control, many different logic and routing configurations, including AND and OR gates with variable fan-out, can be implemented using the same hardware.The work at UNM was supported by AFOSR (Bolling AFB), ARPA, and Rome Labs (Griffiss AFB). The Sandia effort was supported by DOE Contract No. DE-AC04-94AL85000