Does GDNF exert its neuroprotective effects on photoreceptors in the rd1 retina through the glial glutamate transporter GLAST?

PURPOSE: We previously demonstrated that exogenous glial cell line-derived neurotrophic factor (GDNF) induces histological and functional protection of photoreceptors in the retinal degeneration (rd1) mouse model. The mechanisms underlying such neuroprotection remain elusive. In parallel to this work, we provided evidence for the occurrence of glutamate-mediated excitotoxic phenomena contributing to rod photoreceptor death in the rd1 retina in the companion paper. In the present study, we investigated whether, as demonstrated in other models, GDNF could exert its neuroprotective effect on photoreceptors through Muller glial cells (MGC) by promoting the expression of the glial L-glutamate/L-aspartate transporter (GLAST), an endogenous neuroprotective mechanism against glutamate-mediated excitotoxicity. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to compare the mRNA expression levels of GDNF receptors between rd1 and wild-type mouse retinas as well as between MGC and mixed retinal cell cultures. Recombinant GDNF was applied to pure MGC cultures, to rd1 retinal organ cultures and injected subretinally into rd1 mouse eyes. GLAST expression following GDNF treatment was measured by RT-PCR, immunoblotting and immunohistochemistry. Free glutamate and glutamine levels were quantified in rd1 retinas after GDNF or control treatment using an amino acid analyzer. RESULTS: mRNA expression studies of GDNF receptors, GFRalpha-1 and Ret, demonstrated that GDNF receptors were not exclusively expressed by the degenerating photoreceptor cells but mainly by MGC. Exogenous GDNF application to MGC cultures, rd1 mouse retinal explants and in vivo rd1 mouse retinas increased the expression of GLAST by 48% in retinal explants (p<0.005) and by 25% in vivo (p<0.0005). GLAST protein expression in MGC was particularly increased around degenerative photoreceptors. Free glutamate and glutamine levels in the rd1 retina were not significantly modified by exogenous GDNF. CONCLUSIONS: Our data suggest that, in the rd1 mouse retina, GDNF neuroprotective effect on photoreceptors can be mediated indirectly through the activation of MGC. We demonstrate that injection of recombinant GDNF enhances the expression of GLAST and more particularly around the degenerating photoreceptors. Since we failed to demonstrate that GDNF decreases free glutamate levels, we could not ascertain whether GDNF promoted photoreceptor-survival via an increase of glutamate uptake and, therefore, a change in glutamate distributio

Evidence for glutamate-mediated excitotoxic mechanisms during photoreceptor degeneration in the rd1 mouse retina

PURPOSE: Kinetic studies of photoreceptor cell death in the retinal degeneration (rd1) mouse model suggest that photoreceptor degeneration could result from cumulative damage. Since alterations in glutamate metabolism have been described in different models of retinitis pigmentosa, we investigated in the present work whether changes in glutamate turnover occur in the degenerating rd1 retina and whether glutamate-mediated excitotoxic mechanisms may contribute to rod photoreceptor death in this model. METHODS: Free amino acid levels were quantified in rd1 and wild-type retinas using an amino acid analyzer selecting times corresponding to early, intermediate, and terminal phases of rod photoreceptor degeneration. Reverse transcription-polymerase chain reaction (RT-PCR) was used to compare the mRNA expression levels of the glial L-glutamate/L-aspartate transporter GLAST, glutamine synthetase (GS), and vimentin, a marker for retinal glia, between rd1 and wild-type mouse retinas. 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), an antagonist of both AMPA and kainate subtypes of ionotropic glutamate receptors, was then daily administered from postnatal day 3 (PN3) to PN21 to rd1 mice while control rd1 mice received only physiological saline solution (7 per treatment). At PN22, the respective numbers of surviving rods i

Synthèse d'un sulfatoferrate de potassium et son efficacité dans le traitement des eaux

Depuis le milieu du siècle dernier, nous savons que le fer existe à son degré d'oxydation supérieur VI dans l'ion tétraoxoferrate(VI) FeO42-, isostructural de SO42-, CrO42-, MnO42-. Cette espèce mise en solution aqueuse oxyde l'eau en O2, et ce quelque soit le pH de cette solution. La vitesse de cette réaction est très grande en milieu acide, plus lente en milieu alcalin où elle conduit à la précipitation de Fe(OH)3. On peut donc envisager son emploi comme réactif polyfonctionnel : oxydant et floculant, dans le traitement de certaines eaux. La première partie de ce travail décrit une voie originale de synthèse à l'état solide, à la température ambiante, du sel de formule K2(Fe,S)O4, appelé sulfatoferrate de potassium, qui contient l'entité FeO42-. En effet, jusqu'à ce jour seules des synthèses par voie aqueuse, à rendements très faibles, chimiques ou électrochimiques, ont été utilisées pour obtenir FeO42-.Dans une seconde partie, nous avons mesuré les propriétés oxydantes et floculantes du sulfatoferrate de potassium agissant sur deux types d'eaux usées urbaines, chargées (MEST=258 mg.L-1, DCO=549 mg.L-1) et peu chargées (MEST=9 mg.L-1, DCO=37 mg.L- 1). Cette étude effectuée en collaboration avec le Centre International de l'Eau de Nancy (NANC.I.E.) nous a permis de préciser les conditions optimales d'emploi de K2(Fe,S)O4 et de comparer ses performances à celles de FeCl3.6H2O et Al2(SO4)3.18H2O.Sur une eau chargée, l'abattement de la MEST est meilleur avec FeCl3.6H2O et Al2(SO4)3.18H2O, tandis que K2(Fe,S)O4 est plus efficace vis à vis de l'abattement de la DCO.Sur une eau peu chargée, c'est l'effet bactéricide de K2(Fe,S)O4 qui est le plus remarquable; une dose de 10 mg.L-1 en fer (VI) anéantit 99,70% des coliformes totaux et 99,90% des coliformes fécaux.Tetraoxoferrate(VI), FeO42-, possesses properties which make it potentially useful in certain areas of water purification: it is an excellent oxidizing agent, it has a powerful bactericidal action and it spontaneously decomposes over a short period of time. When reduced, the FeO42- ion generates base in solution and a Fe(OH)3 type gel which precipitates and carries down with it other ions (precipitation of hydroxide metal salts). These properties make ferrate(VI) useful in water disinfection and in wastewater treatment because it acts by an oxidation-coagulation-precipitation process. Iron, in its familiar form exists in the (II) and (III) oxidation states; ferrate(VI) ion has long been known, but, due to its instability and difficulty of preparation, it has not been studied extensively and has not been industrially produced. In this paper, we recommend a method of synthesis of alkali ferrate(VI) salts by a dry powder process, which occurs at room temperature and can be easily used for industrial production of Fe(VI). To minimize ferrate(VI) decomposition, we proceed in a strong alkaline medium (presence of a strong base like potash or caustic soda) where oxidation of an iron (bivalent or trivalent) containing salt becomes easier. By such a synthesis process, we produce stabilized ferrate(VI) which enters a solid solution with the formula:M2(Fe,X)O4where M designates Na or K, X is an element whose cation has the electronic structure of a rare gas, e.g. X=S. M2XO4 is an isomorph of K2FeO4 with closed unit cell parameters. The M2(Fe,X)O4 formula has been established by chemical means and by X-ray diffraction; [sup]57Fe Mössbauer spectrometry has been used to monitor the hexavalent iron oxidation state. This paper deals with sulfatoferrate K2(Fe,S)O4 properties for compounds having Fe/S ratios between 1 and 1.5. in aqueous solution, K2(Fe,S)O4 dissolves and gives rise to FeO42- and SO42- anions.In collaboration with NANC.I.E. (Centre International de l'Eau de Nancy), the effectiveness of K2(Fe,S)O4 in wastewater treatment has been studied. The product exhibits a real bactericidal effect on both coliforms and total bacteria. This bactericidal efficiency is reached in a short period of time with iron starting levels as low as 5-10 mg.L-¹. Comparative coagulation jar-tests were carried out on raw wastewater and on secondary effluent using FeCl3·6 H2O, Al2(SO4)3·18 H2O and K2(Fe[inf]0.54,S[inf]0.46)O4. Total suspended solids (TSS) removal on the raw wastewater was better with Al(III) and Fe(III) than with sulfatoferrate. On the secondary effluent, 40% removal was achieved with sulfatoferrate as well as with Fe(III). For removal of chemical oxygen demand (COD), better results were reached with Fe(VI) than with either Fe(III) or Al(III). The effectiveness of FeO42- after 30 minutes of contact with the bacterial medium (secondary effluent) has also been studied. At pH=8.5, a dose of 10 mg.L-¹ iron(VI) removes 99.70% of the total coliforms and 99.90% of the fecal coliforms

Selective Reflection Spectroscopy on the UV Third Resonance Line of Cs : Simultaneous Probing of a van der Waals Atom-Surface Interaction Sensitive to Far IR Couplings and of Interatomic Collisions

We report on the analysis of FM selective reflection experiments on the 6S1/2->8P3/2 transition of Cs at 388 nm, and on the measurement of the surface van der Waals interaction exerted by a sapphire interface on Cs(8P3/2). Various improvements in the systematic fitting of the experiments have permitted to supersede the major difficulty of a severe overlap of the hyperfine components, originating on the one hand in a relatively small natural structure, and on the other hand on a large pressure broadening imposed by the high atomic density needed for the observation of selective reflection on a weak transition. The strength of the van der Waals surface interaction is evaluated to be 73$\pm$10 kHz.$\mu$m3. An evaluation of the pressure shift of the transition is also provided as a by-product of the measurement. We finally discuss the significance of an apparent disagreement between the experimental measurement of the surface interaction, and the theoretical value calculated for an electromagnetic vacuum at a null temperature. The possible influence of the thermal excitation of the surface is evoked, because, the dominant contributions to the vW interaction for Cs(8P3/2) lie in the far infrared range.Comment: submitted to Laser Physics - issue in the memory of Herbert Walther

Early and non-intrusive lameness detection in dairy cows using 3-dimensional video

ABSTRACTLameness is a major issue in dairy herds and its early and automated detection offers animal welfare benefits together with high potential commercial savings for farmers. Current advancements in automated detection have not achieved a sensitive measure for classifying early lameness. A novel proxy for lameness using 3-dimensional (3D) depth video data to analyse the animal’s gait asymmetry is introduced. This dynamic proxy is derived from the height variations in the hip joint during walking. The video capture setup is completely covert and it facilitates an automated process. The animals are recorded using an overhead 3D depth camera as they walk freely in single file after the milking session. A 3D depth image of the cow’s body is used to automatically track key regions such as the hooks and the spine. The height movements are calculated from these regions to form the locomotion signals of this study, which are analysed using a Hilbert transform. Our results using a 1-5 locomotion scoring (LS) system on 22 Holstein Friesian dairy cows, a threshold could be identified between LS 1 and 2 (and above). This boundary is important as it represents the earliest point in time at which a cow is considered lame, and its early detection could improve intervention outcome thereby minimising losses and reducing animal suffering. Using a linear Support Vector Machine (SVM) binary classification model, the threshold achieved an accuracy of 95.7% with a 100% sensitivity (detecting lame cows) and 75% specificity (detecting non-lame cows)

The Completed SDSS-IV extended Baryon Oscillation Spectroscopic Survey: Large-scale structure catalogues for cosmological analysis

We present large-scale structure catalogues from the completed extended Baryon Oscillation Spectroscopic Survey (eBOSS). Derived from Sloan Digital Sky Survey (SDSS) IV Data Release 16 (DR16), these catalogues provide the data samples, corrected for observational systematics, and random positions sampling the survey selection function. Combined, they allow large-scale clustering measurements suitable for testing cosmological models. We describe the methods used to create these catalogues for the eBOSS DR16 Luminous Red Galaxy (LRG) and Quasar samples. The quasar catalogue contains 343 708 redshifts with 0.8 1000 km s−1). For quasars, these rates are 95 and 2 per cent (with Δz > 3000 km s−1). We apply corrections for trends between the number densities of our samples and the properties of the imaging and spectroscopic data. For example, the quasar catalogue obtains a χ2/DoF = 776/10 for a null test against imaging depth before corrections and a χ2/DoF= 6/8 after. The catalogues, combined with careful consideration of the details of their construction found here-in, allow companion papers to present cosmological results with negligible impact from observational systematic uncertainties

Completed SDSS-IV extended Baryon Oscillation Spectroscopic Survey: Cosmological implications from two decades of spectroscopic surveys at the Apache Point Observatory

We present the cosmological implications from final measurements of clustering using galaxies, quasars, and Ly α forests from the completed Sloan Digital Sky Survey (SDSS) lineage of experiments in large-scale structure. These experiments, composed of data from SDSS, SDSS-II, BOSS, and eBOSS, offer independent measurements of baryon acoustic oscillation (BAO) measurements of angular-diameter distances and Hubble distances relative to the sound horizon, r_{d}, from eight different samples and six measurements of the growth rate parameter, fσ_{8}, from redshift-space distortions (RSD). This composite sample is the most constraining of its kind and allows us to perform a comprehensive assessment of the cosmological model after two decades of dedicated spectroscopic observation. We show that the BAO data alone are able to rule out dark-energy-free models at more than eight standard deviations in an extension to the flat, Λ CDM model that allows for curvature. When combined with Planck Cosmic Microwave Background (CMB) measurements of temperature and polarization, under the same model, the BAO data provide nearly an order of magnitude improvement on curvature constraints relative to primary CMB constraints alone. Independent of distance measurements, the SDSS RSD data complement weak lensing measurements from the Dark Energy Survey (DES) in demonstrating a preference for a flat Λ CDM cosmological model when combined with Planck measurements. The combined BAO and RSD measurements indicate σ_{8} = 0.85 ± 0.03, implying a growth rate that is consistent with predictions from Planck temperature and polarization data and with General Relativity. When combining the results of SDSS BAO and RSD, Planck, Pantheon Type Ia supernovae (SNe Ia), and DES weak lensing and clustering measurements, all multiple-parameter extensions remain consistent with a Λ CDM model. Regardless of cosmological model, the precision on each of the three parameters, Ω_{Λ}, H_{0}, and σ_{8}, remains at roughly 1%, showing changes of less than 0.6% in the central values between models. In a model that allows for free curvature and a time-evolving equation of state for dark energy, the combined samples produce a constraint Ω_{k} = −0.0022 ± 0.0022. The dark energy constraints lead to w_{0} = −0.909 ± 0.081 and w_{a} = −0.49^{+0.35}_{-0.30}, corresponding to an equation of state of w_{p} = 1.018 ± 0.032 at a pivot redshift z_{p} = 0.29 and a Dark Energy Task Force Figure of Merit of 94. The inverse distance ladder measurement under this model yields H_{0} = 68.18 ± 0.79 km s^{-1} Mpc^{-1}, remaining in tension with several direct determination methods; the BAO data allow Hubble constant estimates that are robust against the assumption of the cosmological model. In addition, the BAO data allow estimates of H_{0} that are independent of the CMB data, with similar central values and precision under a Λ CDM model. Our most constraining combination of data gives the upper limit on the sum of neutrino masses at ∑m_{v} < 0.115 eV (95% confidence). Finally, we consider the improvements in cosmology constraints over the last decade by comparing our results to a sample representative of the period 2000–2010. We compute the relative gain across the five dimensions spanned by w, Ω_{k}, ∑m_{v}, H_{0}, H_{0}, and σ_{8} and find that the SDSS BAO and RSD data reduce the total posterior volume by a factor of 40 relative to the previous generation. Adding again the Planck, DES, and Pantheon SN Ia samples leads to an overall contraction in the five-dimensional posterior volume of 3 orders of magnitude

Exome-wide association study to identify rare variants influencing COVID-19 outcomes : Results from the Host Genetics Initiative

Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.Peer reviewe