A canine-specific anti-nerve growth factor antibody alleviates pain and improves mobility and function in dogs with degenerative joint disease-associated pain

BackgroundThere is a critical need for proven drugs other than non-steroidal anti-inflammatory drugs for treatment of degenerative joint disease (DJD) pain in dogs. Antibodies against nerve growth factor (NGF) are analgesic in rodent models and in humans with DJD. This pilot study aimed to evaluate the efficacy of a novel caninised anti-NGF antibody (NV-01) for the treatment of DJD pain in dogs. In a randomized, parallel group, stratified, double masked, placebo controlled, proof of principle clinical pilot study design, 26 dogs with DJD received NV-01 (200 mcg/kg IV) or placebo on day 0 (D0). In addition to objective accelerometry measures, owners completed clinical metrology instruments (Client-Specific Outcome Measures [CSOM], Canine Brief Pain Inventory [CBPI] and Liverpool Osteoarthritis in Dogs Index [LOAD]) on D0, D14 and D28. CBPI subscales (pain severity [PS] and pain interference [PI]), CSOM and LOAD scores were evaluated within and between groups for change over time. Recognized success/failure criteria were applied and success compared between groups.ResultsCBPI PS and PI scores significantly improved in the NV-01 group (PS: D0-14, P = 0.012 and D0-28, P = 0.019; PI: D0-14, P = 0.012 and D0-28, P = 0.032) but not in the placebo group. CSOM scores showed similar patterns with a significant difference between within-group changes at D14 and D28 (P = 0.038 and P = 0.009, respectively), and significantly more successes at D28 (P = 0.047). LOAD scores significantly improved in the NV-01 group (D0-14, P = 0.004 and D0-28, P = 0.002) but not in the placebo group. There were significant differences between the groups for change in LOAD score at D14 (P = 0.014) and D28 (P = 0.033). No side effects were noted. Activity in the NV-01 group increased over the study period compared to placebo (P = 0.063) and the difference between the groups for change in activity over the time period 9am-5pm (8 hours) was significant (P = 0.006).ConclusionsThese pilot data demonstrate a positive analgesic effect of anti-NGF antibody in dogs suffering from chronic pain. The magnitude of the effect appeared identical to that expected with an NSAID.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-015-0413-x) contains supplementary material, which is available to authorized users

Highly efficient separation of actinides from lanthanides by a phenanthroline-derived bis-triazine ligand

The synthesis, lanthanide complexation, and solvent ex- traction of actinide(III) and lanthanide(III) radiotracers from nitric acid solutions by a phenanthroline-derived quadridentate bis-triazine ligand are described. The ligand separates Am(III) and Cm(III) from the lanthanides with remarkably high efficiency, high selectivity, and fast extraction kinetics compared to its 2,2'-bipyridine counterpart. Structures of the 1:2 bis-complexes of the ligand with Eu(III) and Yb(III) were elucidated by X-ray crystallography and force field calculations, respec-tively. The Eu(III) bis-complex is the first 1:2 bis-complex of a quadridentate bis-triazine ligand to be characterized by crystallography. The faster rates of extraction were verified by kinetics measurements using the rotating membrane cell technique in several diluents. The improved kinetics of metal ion extraction are related to the higher surface activity of the ligand at the phase interface. The improvement in the ligand's properties on replacing the bipyridine unit with a phenanthroline unit far exceeds what was anticipated based on ligand design alone

The Tangential Nucleus Controls a Gravito-inertial Vestibulo-ocular Reflex

Whilst adult vertebrates sense changes in head position using two classes of accelerometer, at larval stages zebrafish lack functional semicircular canals and rely exclusively on their otolithic organs to transduce vestibular information. Despite this limitation, they perform an effective vestibulo-ocular reflex (VOR) that serves to stabilize gaze in response to pitch and roll tilts. Using single-cell electroporations and targeted laser-ablations, we identified a specific class of central vestibular neurons, located in the tangential nucleus, which are essential for the utricle-dependent VOR. Tangential nucleus neurons project contralaterally to extraocular motoneurons, and in addition, to multiple sites within the reticulospinal complex. We propose that tangential neurons function as a broadband inertial accelerometer, processing utricular acceleration signals to control the activity of extraocular and postural neurons, thus completing a fundamental three-neuron circuit responsible for gaze stabilization.Molecular and Cellular Biolog

A two-domain elevator mechanism for sodium/proton antiport

Sodium/proton (Na+/H+) antiporters, located at the plasma membrane in every cell, are vital for cell homeostasis1. In humans, their dysfunction has been linked to diseases, such as hypertension, heart failure and epilepsy, and they are well-established drug targets2. The best understood model system for Na+/H+ antiport is NhaA from Escherichia coli1, 3, for which both electron microscopy and crystal structures are available4, 5, 6. NhaA is made up of two distinct domains: a core domain and a dimerization domain. In the NhaA crystal structure a cavity is located between the two domains, providing access to the ion-binding site from the inward-facing surface of the protein1, 4. Like many Na+/H+ antiporters, the activity of NhaA is regulated by pH, only becoming active above pH 6.5, at which point a conformational change is thought to occur7. The only reported NhaA crystal structure so far is of the low pH inactivated form4. Here we describe the active-state structure of a Na+/H+ antiporter, NapA from Thermus thermophilus, at 3 Å resolution, solved from crystals grown at pH 7.8. In the NapA structure, the core and dimerization domains are in different positions to those seen in NhaA, and a negatively charged cavity has now opened to the outside. The extracellular cavity allows access to a strictly conserved aspartate residue thought to coordinate ion binding1, 8, 9 directly, a role supported here by molecular dynamics simulations. To alternate access to this ion-binding site, however, requires a surprisingly large rotation of the core domain, some 20° against the dimerization interface. We conclude that despite their fast transport rates of up to 1,500 ions per second3, Na+/H+ antiporters operate by a two-domain rocking bundle model, revealing themes relevant to secondary-active transporters in general

Integrating team science into interdisciplinary graduate education: an exploration of the SESYNC Graduate Pursuit

Complex socio-environmental challenges require interdisciplinary, team-based research capacity. Graduate students are fundamental to building such capacity, yet formal opportunities for graduate students to develop these capacities and skills are uncommon. This paper presents an assessment of the Graduate Pursuit (GP) program, a formal interdisciplinary team science graduate research and training program administered by the National Socio-Environmental Synthesis Center (SESYNC). Quantitative and qualitative assessment of the program’s first cohort revealed that participants became significantly more comfortable with interdisciplinary research and team science approaches, increased their capacity to work across disciplines, and were enabled to produce tangible research outcomes. Qualitative analysis of four themes—(1) discipline, specialization, and shared purpose, (2) interpersonal skills and personality, (3) communication and teamwork, and (4) perceived costs and benefits—encompass participants’ positive and negative experiences and support findings from past assessments. The findings also identify challenges and benefits related to individual personality traits and team personality orientation, the importance of perceiving a sense of autonomy and independence, and the benefit of graduate training programs independent of the university and graduate program environment

Prospectus, September 22, 1982

STUDENT VOTE SHOULD BE EXERCISED; News Digest; Election candidates present platforms; Children\u27s theater group performs new play; College remark causes reaction; Annex gets approval; C-U Happenings…; Club designed for business students; Bike is victim of \u27dastardly deed\u27; Microprecision department one of few in U.S.; Hough now teaches class; Community Calendar; Classified; Problem lyrics can\u27t overshadow great music; Hot Country Singles; TV season may bring surprises; TH\u27s delight CU at AH; Abbey\u27s job has variety; White leads for Parkland; ISU transfer looks like an asset; Fast Freddy Contesthttps://spark.parkland.edu/prospectus_1982/1010/thumbnail.jp

An ALMA survey of submillimetre galaxies in the COSMOS field: The extent of the radio-emitting region revealed by 3 GHz imaging with the Very Large Array

We determine the radio size distribution of a large sample of 152 SMGs in COSMOS that were detected with ALMA at 1.3 mm. For this purpose, we used the observations taken by the VLA-COSMOS 3 GHz Large Project. One hundred and fifteen of the 152 target SMGs were found to have a 3 GHz counterpart. The median value of the major axis FWHM at 3 GHz is derived to be $4.6\pm0.4$ kpc. The radio sizes show no evolutionary trend with redshift, or difference between different galaxy morphologies. We also derived the spectral indices between 1.4 and 3 GHz, and 3 GHz brightness temperatures for the sources, and the median values were found to be $\alpha=-0.67$ and $T_{\rm B}=12.6\pm2$ K. Three of the target SMGs, which are also detected with the VLBA, show clearly higher brightness temperatures than the typical values. Although the observed radio emission appears to be predominantly powered by star formation and supernova activity, our results provide a strong indication of the presence of an AGN in the VLBA and X-ray-detected SMG AzTEC/C61. The median radio-emitting size we have derived is 1.5-3 times larger than the typical FIR dust-emitting sizes of SMGs, but similar to that of the SMGs' molecular gas component traced through mid-$J$ line emission of CO. The physical conditions of SMGs probably render the diffusion of cosmic-ray electrons inefficient, and hence an unlikely process to lead to the observed extended radio sizes. Instead, our results point towards a scenario where SMGs are driven by galaxy interactions and mergers. Besides triggering vigorous starbursts, galaxy collisions can also pull out the magnetised fluids from the interacting disks, and give rise to a taffy-like synchrotron-emitting bridge. This provides an explanation for the spatially extended radio emission of SMGs, and can also cause a deviation from the well-known IR-radio correlation.Comment: 32 pages (incl. 5 appendices), 17 figures, 7 tables; accepted for publication in A&A; abstract abridged for arXi

Measurement and control of optical nonlinearities in dispersive dielectric multilayers

Dispersive dielectric multilayer mirrors, high-dispersion chirped mirrors in particular, are widely used in modern ultrafast optics to manipulate spectral chirps of ultrashort laser pulses. Dispersive mirrors are routinely designed for dispersion compensation in ultrafast lasers and are assumed to be linear optical components. In this work, we report the experimental characterization of an unexpectedly strong nonlinear response in these chirped mirrors. At modest peak intensities &lt;2 TW/cm2&mdash;well below the known laser-induced damage threshold of these dielectric structures&mdash;we observed a strong reflectivity decrease, local heating, transient spectral modifications, and time-dependent absorption of the incident pulse. Through computational analysis, we found that the incident laser field can be enhanced by an order of magnitude in the dielectric layers of the structure. The field enhancement leads to a wavelength-dependent nonlinear absorption, that shows no signs of cumulative damage before catastrophic failure. The nonlinear absorption is not a simply two-photon process but instead is likely mediated by defects that facilitate two-photon absorption. To mitigate this issue, we designed and fabricated a dispersive multilayer design that strategically suppresses the field enhancement in the high-index layers, shifting the high-field regions to the larger-bandgap, low-index layers. This strategy significantly increases the maximum peak intensity that the mirror can sustain. However, our finding of an onset of nonlinear absorption even at &lsquo;modest&rsquo; fluence and peak intensity has significant implications for numerous past published experimental works employing dispersive mirrors. Additionally, our results will guide future ultrafast experimental work and ultrafast laser design. &nbsp;</p

Antipsychotics and Torsadogenic Risk: Signals Emerging from the US FDA Adverse Event Reporting System Database

Background: Drug-induced torsades de pointes (TdP) and related clinical entities represent a current regulatory and clinical burden. Objective: As part of the FP7 ARITMO (Arrhythmogenic Potential of Drugs) project, we explored the publicly available US FDA Adverse Event Reporting System (FAERS) database to detect signals of torsadogenicity for antipsychotics (APs). Methods: Four groups of events in decreasing order of drug-attributable risk were identified: (1) TdP, (2) QT-interval abnormalities, (3) ventricular fibrillation/tachycardia, and (4) sudden cardiac death. The reporting odds ratio (ROR) with 95 % confidence interval (CI) was calculated through a cumulative analysis from group 1 to 4. For groups 1+2, ROR was adjusted for age, gender, and concomitant drugs (e.g., antiarrhythmics) and stratified for AZCERT drugs, lists I and II (http://www.azcert.org, as of June 2011). A potential signal of torsadogenicity was defined if a drug met all the following criteria: (a) four or more cases in group 1+2; (b) significant ROR in group 1+2 that persists through the cumulative approach; (c) significant adjusted ROR for group 1+2 in the stratum without AZCERT drugs; (d) not included in AZCERT lists (as of June 2011). Results: Over the 7-year period, 37 APs were reported in 4,794 cases of arrhythmia: 140 (group 1), 883 (group 2), 1,651 (group 3), and 2,120 (group 4). Based on our criteria, the following potential signals of torsadogenicity were found: amisulpride (25 cases; adjusted ROR in the stratum without AZCERT drugs = 43.94, 95 % CI 22.82-84.60), cyamemazine (11; 15.48, 6.87-34.91), and olanzapine (189; 7.74, 6.45-9.30). Conclusions: This pharmacovigilance analysis on the FAERS found 3 potential signals of torsadogenicity for drugs previously unknown for this risk

Fluorescence Nanoscopy in Whole Cells by Asynchronous Localization of Photoswitching Emitters

We demonstrate nanoscale resolution in far-field fluorescence microscopy using reversible photoswitching and localization of individual fluorophores at comparatively fast recording speeds and from the interior of intact cells. These advancements have become possible by asynchronously recording the photon bursts of individual molecular switching cycles. We present images from the microtubular network of an intact mammalian cell with a resolution of 40 nm