Eigenvector Synchronization, Graph Rigidity and the Molecule Problem

The graph realization problem has received a great deal of attention in recent years, due to its importance in applications such as wireless sensor networks and structural biology. In this paper, we extend on previous work and propose the 3D-ASAP algorithm, for the graph realization problem in $\mathbb{R}^3$, given a sparse and noisy set of distance measurements. 3D-ASAP is a divide and conquer, non-incremental and non-iterative algorithm, which integrates local distance information into a global structure determination. Our approach starts with identifying, for every node, a subgraph of its 1-hop neighborhood graph, which can be accurately embedded in its own coordinate system. In the noise-free case, the computed coordinates of the sensors in each patch must agree with their global positioning up to some unknown rigid motion, that is, up to translation, rotation and possibly reflection. In other words, to every patch there corresponds an element of the Euclidean group Euc(3) of rigid transformations in $\mathbb{R}^3$, and the goal is to estimate the group elements that will properly align all the patches in a globally consistent way. Furthermore, 3D-ASAP successfully incorporates information specific to the molecule problem in structural biology, in particular information on known substructures and their orientation. In addition, we also propose 3D-SP-ASAP, a faster version of 3D-ASAP, which uses a spectral partitioning algorithm as a preprocessing step for dividing the initial graph into smaller subgraphs. Our extensive numerical simulations show that 3D-ASAP and 3D-SP-ASAP are very robust to high levels of noise in the measured distances and to sparse connectivity in the measurement graph, and compare favorably to similar state-of-the art localization algorithms.Comment: 49 pages, 8 figure

Much more than the sum of the parts: structures of the dual SH2 domains of ZAP-70 and Syp

AbstractProteins involved in signaling pathways frequently contain one or more SH2 domains. New structural information on proteins that carry two SH2 domains show, surprisingly, that the domains are closely interlinked, so the binding sites are rigidly oriented with respect to each other. Thus, only ligands with the right spacing of the phosphotyrosines will be tightly bound

Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant hypoxia-inducible factor (HIF)2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades. Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed, followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from idiopathic PAH patients were used to determine the impact of HIF2α-inhibition on endothelial function. Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH-associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline-exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyperproliferative phenotype and overactive arginase activity in blood outgrowth endothelial cells from idiopathic PAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population

The Alternatively Spliced Acid Box Region Plays a Key Role in FGF Receptor Autoinhibition

SummaryUncontrolled fibroblast growth factor (FGF) signaling can lead to human malignancies necessitating multiple layers of self-regulatory control mechanisms. Fibroblast growth factor receptor (FGFR) autoinhibition mediated by the alternatively spliced immunoglobulin (Ig) domain 1 (D1) and the acid box (AB)-containing linker between D1 and Ig domain 2 (D2) serves as the first line of defense to minimize inadvertent FGF signaling. In this report, nuclear magnetic resonance and surface plasmon resonance spectroscopy are used to demonstrate that the AB subregion of FGFR electrostatically engages the heparan sulfate (HS)-binding site on the D2 domain in cis to directly suppress HS-binding affinity of FGFR. Furthermore, the cis electrostatic interaction sterically autoinhibits ligand-binding affinity of FGFR because of the close proximity of HS-binding and primary ligand-binding sites on the D2 domain. These data, together with the strong amino acid sequence conservation of the AB subregion among FGFR orthologs, highlight the universal role of the AB subregion in FGFR autoinhibition

Does the availability of snack foods in supermarkets vary internationally?

BackgroundCross-country differences in dietary behaviours and obesity rates have been previously reported. Consumption of energy-dense snack foods and soft drinks are implicated as contributing to weight gain, however little is known about how the availability of these items within supermarkets varies internationally. This study assessed variations in the display of snack foods and soft drinks within a sample of supermarkets across eight countries.MethodsWithin-store audits were used to evaluate and compare the availability of potato chips (crisps), chocolate, confectionery and soft drinks. Displays measured included shelf length and the proportion of checkouts and end-of-aisle displays containing these products. Audits were conducted in a convenience sample of 170 supermarkets across eight developed nations (Australia, Canada, Denmark, Netherlands, New Zealand, Sweden, United Kingdom (UK), and United States of America (US)).ResultsThe mean total aisle length of snack foods (adjusted for store size) was greatest in supermarkets from the UK (56.4 m) and lowest in New Zealand (21.7 m). When assessed by individual item, the greatest aisle length devoted to chips, chocolate and confectionery was found in UK supermarkets while the greatest aisle length dedicated to soft drinks was in Australian supermarkets. Only stores from the Netherlands (41%) had less than 70% of checkouts featuring displays of snack foods or soft drinks.ConclusionWhilst between-country variations were observed, overall results indicate high levels of snack food and soft drinks displays within supermarkets across the eight countries. Exposure to snack foods is largely unavoidable within supermarkets, increasing the likelihood of purchases and particularly those made impulsively.<br /

Endothelial cell regulation of systemic haemodynamics and metabolism acts through the HIF transcription factors.

BackgroundThe vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role of the hypoxia-inducible factors, HIF-1α and HIF-2α in the pulmonary and systemic circulations as potential regulators of systemic vascular function in normoxic or hypoxic conditions and in response to inflammatory stress. We developed a series of transgenic mouse models, the HIF-1α Tie2Cre, deficient in HIF1-α in the systemic and pulmonary vascular endothelium and the L1Cre, a pulmonary endothelium specific knockout of HIF-1α or HIF-2α. In vivo, arterial blood pressure and metabolic activity were monitored continuously in normal atmospheric conditions and following an acute stimulus with hypoxia (10%) or lipopolysaccharide (LPS). Ex vivo, femoral artery reactivity was assessed using wire myography.ResultsUnder normoxia, the HIF-1α Tie2Cre mouse had increased systolic and diastolic arterial pressure compared to litter mate controls over the day-night cycle under normal environmental conditions. VO2 and VCO2 were also increased. Femoral arteries displayed impaired endothelial relaxation in response to acetylcholine mediated by a reduction in the nitric oxide dependent portion of the response. HIF-1α L1Cre mice displayed a similar pattern of increased systemic blood pressure, metabolic rate and impaired vascular relaxation without features of pulmonary hypertension, polycythaemia or renal dysfunction under normal conditions. In response to acute hypoxia, deficiency of HIF-1α was associated with faster resolution of hypoxia-induced haemodynamic and metabolic compromise. In addition, systemic haemodynamics were less compromised by LPS treatment.ConclusionsThese data show that deficiency of HIF-1α in the systemic or pulmonary endothelium is associated with increased systemic blood pressure and metabolic rate, a pattern that persists in both normoxic conditions and in response to acute stress with potential implications for our understanding of the pathophysiology of vascular dysfunction in acute and chronic disease

Magnetic scanning gate microscopy of CoFeB lateral spin valve

Devices comprised of CoFeB nanostructures with perpendicular magnetic anisotropy and non-magnetic Ta channel were operated in thermal lateral spin valve (LSV) mode and studied by magnetotransport measurements and magnetic scanning gate microscopy (SGM). Due to the short spin diffusion length of Ta, the spin diffusion signal was suppressed, allowing the study of the contribution from the anomalous Nernst (ANE) and anomalous Hall effects (AHE). The magnetotransport measurements identified the switching fields of the CoFeB nanostructures and demonstrated a combination of AHE and ANE when the devices were operated in thermally-driven spin-injection mode. Modified scanning probe microscopy probes were fabricated by placing a NdFeB magnetic bead (MB) on the apex of a commercial Si probe. The dipole magnetic field distribution around the MB was characterized by using differential phase contrast technique and direct measurement of the switching field induced by the bead in the CoFeB nanodevices. Using SGM we demonstrate the influence of localized magnetic field on the CoFeB nanostructures near the non-magnetic channel. This approach provides a promising route towards the study of thermal and spin diffusion effects using local magnetic fields