EphA3 Expressed in the Chicken Tectum Stimulates Nasal Retinal Ganglion Cell Axon Growth and Is Required for Retinotectal Topographic Map Formation

BACKGROUND: Retinotopic projection onto the tectum/colliculus constitutes the most studied model of topographic mapping and Eph receptors and their ligands, the ephrins, are the best characterized molecular system involved in this process. Ephrin-As, expressed in an increasing rostro-caudal gradient in the tectum/colliculus, repel temporal retinal ganglion cell (RGC) axons from the caudal tectum and inhibit their branching posterior to their termination zones. However, there are conflicting data regarding the nature of the second force that guides nasal axons to invade and branch only in the caudal tectum/colliculus. The predominant model postulates that this second force is produced by a decreasing rostro-caudal gradient of EphA7 which repels nasal optic fibers and prevents their branching in the rostral tectum/colliculus. However, as optic fibers invade the tectum/colliculus growing throughout this gradient, this model cannot explain how the axons grow throughout this repellent molecule. METHODOLOGY/PRINCIPAL FINDINGS: By using chicken retinal cultures we showed that EphA3 ectodomain stimulates nasal RGC axon growth in a concentration dependent way. Moreover, we showed that nasal axons choose growing on EphA3-expressing cells and that EphA3 diminishes the density of interstitial filopodia in nasal RGC axons. Accordingly, in vivo EphA3 ectodomain misexpression directs nasal optic fibers toward the caudal tectum preventing their branching in the rostral tectum. CONCLUSIONS: We demonstrated in vitro and in vivo that EphA3 ectodomain (which is expressed in a decreasing rostro-caudal gradient in the tectum) is necessary for topographic mapping by stimulating the nasal axon growth toward the caudal tectum and inhibiting their branching in the rostral tectum. Furthermore, the ability of EphA3 of stimulating axon growth allows understanding how optic fibers invade the tectum growing throughout this molecular gradient. Therefore, opposing tectal gradients of repellent ephrin-As and of axon growth stimulating EphA3 complement each other to map optic fibers along the rostro-caudal tectal axis

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Stopping power accuracy and achievable spatial resolution of helium ion imaging using a prototype particle CT detector system

A precise relative stopping power map of the patient is crucial for accurate particle therapy. Charged particle imaging determines the stopping power either tomographically – particle computed tomography (pCT) – or by combining prior knowledge from particle radiography (pRad) and x-ray CT. Generally, multiple Coulomb scattering limits the spatial resolution. Compared to protons, heavier particles scatter less due to their lower charge/mass ratio. A theoretical framework to predict the most likely trajectory of particles in matter was developed for light ions up to carbon and was found to be the most accurate for helium comparing for fixed initial velocity. To further investigate the potential of helium in particle imaging, helium computed tomography (HeCT) and radiography (HeRad) were studied at the Heidel-berg Ion-Beam Therapy Centre (HIT) using a prototype pCT detector system registering individual particles, originally developed by the U.S. pCT collaboration. Several phantoms were investigated: modules of the Catphan QA phantom for analysis of spatial resolution and achievable stopping power accuracy, a paediatric head phantom (CIRS) and a custom-made phantom comprised of animal meat enclosed in a 2 % agarose mixture representing human tissue. The pCT images were reconstructed applying the CARP iterative reconstruction algorithm. The MTF10% was investigated using a sharp edge gradient technique. HeRad provides a spatial resolution above that of protons (MTF1010%=6.07 lp/cm for HeRad versus MTF10%=3.35 lp/cm for proton radiography). For HeCT, the spatial resolution was limited by the number of projections acquired (90 projections for a full scan). The RSP accuracy for all inserts of the Catphan CTP404 module was found to be 2.5% or better and is subject to further optimisation. In conclusion, helium imaging appears to offer higher spatial resolution compared to proton imaging. In future studies, the advantage of helium imaging compared to other imaging modalities in clinical applications will be further explored

Stopping power accuracy and achievable spatial resolution of helium ion imaging using a prototype particle CT detector system.

A precise relative stopping power map of the patient is crucial for accurate particle therapy. Charged particle imaging determines the stopping power either tomographically - particle computed tomography (pCT) - or by combining prior knowledge from particle radiography (pRad) and x-ray CT. Generally, multiple Coulomb scattering limits the spatial resolution. Compared to protons, heavier particles scatter less due to their lower charge/mass ratio. A theoretical framework to predict the most likely trajectory of particles in matter was developed for light ions up to carbon and was found to be the most accurate for helium comparing for fixed initial velocity. To further investigate the potential of helium in particle imaging, helium computed tomography (HeCT) and radiography (HeRad) were studied at the Heidelberg Ion-Beam Therapy Centre (HIT) using a prototype pCT detector system registering individual particles, originally developed by the U.S. pCT collaboration. Several phantoms were investigated: modules of the Catphan QA phantom for analysis of spatial resolution and achievable stopping power accuracy, a paediatric head phantom (CIRS) and a custommade phantom comprised of animal meat enclosed in a 2 % agarose mixture representing human tissue. The pCT images were reconstructed applying the CARP iterative reconstruction algorithm. The MTF10% was investigated using a sharp edge gradient technique. HeRad provides a spatial resolution above that of protons (MTF1010%=6.07 lp/cm for HeRad versus MTF10%=3.35 lp/cm for proton radiography). For HeCT, the spatial resolution was limited by the number of projections acquired (90 projections for a full scan). The RSP accuracy for all inserts of the Catphan CTP404 module was found to be 2.5% or better and is subject to further optimisation. In conclusion, helium imaging appears to offer higher spatial resolution compared to proton imaging. In future studies, the advantage of helium imaging compared to other imaging modalities in clinical applications will be further explored

The impact of secondary fragments on the image quality of helium ion imaging.

Single-event ion imaging enables the direct reconstruction of the relative stopping power (RSP) information required for ion-beam therapy. Helium ions were recently hypothesized to be the optimal species for such technique. The purpose of this work is to investigate the effect of secondary fragments on the image quality of helium CT (HeCT) and to assess the performance of a prototype proton CT (pCT) scanner when operated with helium beams in Monte Carlo simulations and experiment. Experiments were conducted installing the U.S. pCT consortium prototype scanner at the Heidelberg Ion-Beam Therapy Center (HIT). Simulations were performed with the scanner using the TOPAS toolkit. HeCT images were reconstructed for a cylindrical water phantom, the CTP404 (sensitometry), and the CTP528 (line-pair) [Formula: see text] ® modules. To identify and remove individual events caused by fragmentation, the multistage energy detector of the scanner was adapted to function as a [Formula: see text] telescope. The use of the developed filter eliminated the otherwise arising ring artifacts in the HeCT reconstructed images. For the HeCT reconstructed images of a water phantom, the maximum RSP error was improved by almost a factor 8 with respect to unfiltered images in the simulation and a factor 10 in the experiment. Similarly, for the CTP404 module, the mean RSP accuracy improved by a factor 6 in both the simulation and the experiment when the filter was applied (mean relative error 0.40% in simulation, 0.45% in experiment). In the evaluation of the spatial resolution through the CTP528 module, the main effect of the filter was noise reduction. For both simulated and experimental images the spatial resolution was  ∼4 lp cm-1. In conclusion, the novel filter developed for secondary fragments proved to be effective in improving the visual quality and RSP accuracy of the reconstructed images. With the filter, the pCT scanner is capable of accurate HeCT imaging

Anodic Deposition of Enantiopure Hexahelicene Layers

International audienceHelicenes are polyaromatic compounds with chiral properties useful for many applications in optoelectronics, separation processes, chiral recognition and catalysis. Here we focused on the electrochemistry of carbo[n]helicenes (n=5,6,7). The cyclic voltammograms of racemic mixtures of target compounds in acetonitrile/0.1M tetrabutylammonium perchlorate at a glassy carbon electrode reveal the diffusion-controlled reactions in both anodic and cathodic potential regions. Electrochemical behaviors are different for individual helicenes, [7]helicene undergoes redox transformation easily in comparison to the other investigated compounds, which is in agreement with DFT (density functional theory) calculations. Generally, the multi-component anodic process of helicenes is observable at potentials from +1.5 to +2.5V, leading to the formation of deposited structures (layers) on the electrode surface. The helicenes were electrodeposited onto transparent indium tin oxide (ITO) electrodes and characterized by atomic force microscopy, UV/Vis, Raman spectroscopy and ellipsometry. Finally, the anodic deposition of P and M enantiomers of [6]helicene was performed using ITO substrates, resulting in the formation of enantiopure layers of nanometer thicknesses, as confirmed by circular dichroism spectroscopy. The discovered electrosynthetic procedure opens up a new possibility for the immobilization of chiral helicene layers onto solid supports