Impairment of photoreceptor ribbon synapses in a novel Pomt1 conditional knockout mouse model of dystroglycanopathy

15 p.Hypoglycosylation of α-dystroglycan (cx-DG) resulting from deficiency of protein O-mannosyltransferase 1 (POMT1) may cause severe neuromuscular dystrophies with brain and eye anomalies, named dystroglycanopathies. The retinal involvement of these disorders motivated us to generate a conditional knockout (cKO) mouse experiencing a Pomt1 intragenic deletion (exons 3–4) during the development of photoreceptors, mediated by the Cre recombinase expressed from the cone-rod homeobox (Crx) gene promoter. In this mouse, retinal α-DG was unglycosylated and incapable of binding laminin. Retinal POMT1 deficiency caused significant impairments in both electroretinographic recordings and optokinetic reflex in Pomt1 cKO mice, and immunohistochemical analyses revealed the absence of β-DG and of the α-DG-interacting protein, pikachurin, in the outer plexiform layer (OPL). At the ultrastructural level, noticeable alterations were observed in the ribbon synapses established between photoreceptors and bipolar cells. Therefore, O-mannosylation of α-DG in the retina carried out by POMT1 is crucial for the establishment of proper synapses at the OPL and transmission of visual information from cones and rods to their postsynaptic neurons

Spinal Manipulative Therapy Effects in Autonomic Regulation and Exercise Performance in Recreational Healthy Athletes : A Randomized Controlled Trial

7 p.Study design: A randomized, double blind, parallel groups, sham-controlled trial. Objective: The aim of this study was to analyze the acute effects of spinal manipulative therapy (SMT) on performance and autonomic modulation. Summary of background data: The use of SMT is progressively spreading from the clinical to the sporting context owing to its purported ergogenic effects. However, its effects remain unclear. Methods: Thirty-seven male recreational athletes (aged 37 ± 9 years) who had never received SMT were assigned to a sham (n = 19) or actual SMT group (n = 18). Study endpoints included autonomic modulation (heart rate variability), handgrip strength, jumping ability, and cycling performance [8-minute time trial (TT)]. Differences in custom effects between interventions were determined using magnitude-based inferences. Results: A significant and very likely lower value of a marker of sympathetic modulation, the stress score, was observed in response to actual compared with sham SMT [P = 0.007; effect size (ES) = -0.97]. A trend toward a significant and likely lower sympathetic:parasympathetic ratio (P = 0.055; ES = -0.96) and a likely higher natural logarithm of the root-mean-square differences of successive heartbeat intervals [(LnRMSSD), P = 0.12; ES = 0.36] was also found with actual SMT. Moreover, a significantly lower mean power output was observed during the TT with actual compared with sham SMT (P = 0.035; ES = -0.28). Nonsignificant (P > 0.05) and unclear or likely trivial differences (ES < 0.2) were found for the rest of endpoints, including handgrip strength, heart rate during the TT, and jump loss thereafter. Conclusion: A single pre-exercise SMT session induced an acute shift toward parasympathetic dominance and slightly impaired performance in recreational healthy athletes

Tools and Biomarkers for the Study of Retinal Ganglion Cell Degeneration

The retina is part of the central nervous system, its analysis may provide an idea of the health and functionality, not only of the retina, but also of the entire central nervous system, as has been shown in Alzheimer"s or Parkinson"s diseases. Within the retina, the ganglion cells (RGC) are the neurons in charge of processing and sending light information to higher brain centers. Diverse insults and pathological states cause degeneration of RGC, leading to irreversible blindness or impaired vision. RGCs are the measurable endpoints in current research into experimental therapies and diagnosis in multiple ocular pathologies, like glaucoma. RGC subtype classifications are based on morphological, functional, genetical, and immunohistochemical aspects. Although great efforts are being made, there is still no classification accepted by consensus. Moreover, it has been observed that each RGC subtype has a different susceptibility to injury. Characterizing these subtypes together with cell death pathway identification will help to understand the degenerative process in the different injury and pathological models, and therefore prevent it. Here we review the known RGC subtypes, as well as the diagnostic techniques, probes, and biomarkers for programmed and unprogrammed cell death in RGC

Role of ON and OFF Visual Pathways in Rod- and Cone-Driven Flicker Responses

Purpose: To evaluate the effects of various retinal neurotransmitters on temporal resolution, particularly, on the Critical Flicker Fusion Frequency (CFF), which has been previously applied in ophthalmic pathophysiologic research. Methods: A binocular physiologic electroretinogram was performed on adult mice. Animals in the control group were injected in the right eye with 1 & mu;L of phosphate-buffered saline (PBS). Animals in the experimental group were injected in the left eye with 1 & mu;L of PBS and in the right eye with 1 & mu;L of PBS to which different molecules were added: 2-amino-4-phosphonobutyric hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). Initially, rod response was recorded and later the cone response. Results: APB suppressed the rod-driven, but not the cone-driven flicker response. The other agents severely affected the lower flickering frequency response amplitude, in particular, at 3 Hz. The threshold of CFF was lowered from 50 Hz to 40 Hz after applying APB, Glycine, and HEPES. GABA remarkably enhanced rod-driven and cone-driven flicker response at 3 Hz, whereas Glutamate and GABA/Glutamate only did in rod-driven flicker response. Conclusions: Both ON and OFF visual pathways were implied in cone-driven response, but only the ON visual pathway appears to play a relevant role in rod-driven flicker response. Flicker response seems to be enhanced by horizontal cells both in roddriven and cone-driven response. In addition, due to the greater sensitivity of the flicker at low frequencies, it is suggested that pathophysiological studies should be carried out at said frequencies

Neuroprotective Effect of Tauroursodeoxycholic Acid on N-Methyl-D-Aspartate-Induced Retinal Ganglion Cell Degeneration

Retinal ganglion cell degeneration underlies the pathophysiology of diseases affecting the retina and optic nerve. Several studies have previously evidenced the anti-apoptotic properties of the bile constituent, tauroursodeoxycholic acid, in diverse models of photoreceptor degeneration. The aim of this study was to investigate the effects of systemic administration of tauroursodeoxycholic acid on N-methyl-D-aspartate (NMDA)-induced damage in the rat retina using a functional and morphological approach. Tauroursodeoxycholic acid was administered intraperitoneally before and after intravitreal injection of NMDA. Three days after insult, full-field electroretinograms showed reductions in the amplitudes of the positive and negative-scotopic threshold responses, scotopic a- and b-waves and oscillatory potentials. Quantitative morphological evaluation of whole-mount retinas demonstrated a reduction in the density of retinal ganglion cells. Systemic administration of tauroursodeoxycholic acid attenuated the functional impairment induced by NMDA, which correlated with a higher retinal ganglion cell density. Our findings sustain the efficacy of tauroursodeoxycholic acid administration in vivo, suggesting it would be a good candidate for the pharmacological treatment of degenerative diseases coursing with retinal ganglion cell loss.This work was supported by project grants from Spanish Ministerio de Economía y Competitividad-FEDER (http://www.mineco.gob.es) #BFU2012‐36845, Instituto de Salud Carlos III RETICS (http://www.oftared.com) #RD12/0034/0010 and Organización Nacional de Ciegos Españoles (http://www.once.es) to NC; Ministerio de Ciencia e Innovación #JCI‐2009‐05224 to VGV; Universidad de Alicante (http://www.ua.es) #2010-48536273 to GE; Instituto de Salud Carlos III (http://www.isciii.es) #PI13/02098 and RETICS #RD12/0034/0006 to PdV; and FUNDALUCE

Deleterious Effect of NMDA Plus Kainate on the Inner Retinal Cells and Ganglion Cell Projection of the Mouse

Combined administration of N-Methyl-D-Aspartate (NMDA) and kainic acid (KA) on the inner retina was studied as a model of excitotoxicity. The right eye of C57BL6J mice was injected with 1 µL of PBS containing NMDA 30 mM and KA 10 mM. Only PBS was injected in the left eye. One week after intraocular injection, electroretinogram recordings and immunohistochemistry were performed on both eyes. Retinal ganglion cell (RGC) projections were studied by fluorescent-cholerotoxin anterograde labeling. A clear decrease of the retinal “b” wave amplitude, both in scotopic and photopic conditions, was observed in the eyes injected with NMDA/KA. No significant effect on the “a” wave amplitude was observed, indicating the preservation of photoreceptors. Immunocytochemical labeling showed no effects on the outer nuclear layer, but a significant thinning on the inner retinal layers, thus indicating that NMDA and KA induce a deleterious effect on bipolar, amacrine and ganglion cells. Anterograde tracing of the visual pathway after NMDA and KA injection showed the absence of RGC projections to the contralateral superior colliculus and lateral geniculate nucleus. We conclude that glutamate receptor agonists, NMDA and KA, induce a deleterious effect of the inner retina when injected together into the vitreous chamber.This research was funded by the Instituto de Salud Carlos III and co‐funded by the European Regional Development Fund (ERDF) within the “Plan Estatal de Investigación Científica y Técnica y de Innovación 2017–2020” (grant numbers #RD16/0008/0016; #RD16/0008/0020; #FIS/PI 18‐00754)

Mannose-modified hyaluronic acid nanocapsules for the targeting of tumor-associated macrophages

Tumor-associated macrophages (TAMs), a class of immune cells that play a key role in tumor immunosuppression, are recognized as important targets to improve cancer prognosis and treatment. Consequently, the engineering of drug delivery nanocarriers that can reach TAMs has acquired special relevance. This work describes the development and biological evaluation of a panel of hyaluronic acid (HA) nanocapsules (NCs), with different compositions and prepared by different techniques, designed to target macrophages. The results showed that plain HA NCs did not significantly influence the polarization of M0 and M2-like macrophages towards an M1-like pro-inflammatory phenotype; however, the chemical functionalization of HA with mannose (HA-Man) led to a significant increase of NCs uptake by M2 macrophages in vitro and to an improved biodistribution in a MN/MNCA1 fibrosarcoma mouse model with high infiltration of TAMs. These functionalized HA-Man NCs showed a higher accumulation in the tumor compared to non-modified HA NCs. Finally, the pre-administration of the liposomal liver occupying agent Nanoprimer™ further increased the accumulation of the HA-Man NCs in the tumor. This work highlights the promise shown by the HA-Man NCs to target TAMs and thus provides new options for the development of nanomedicine and immunotherapy-based cancer treatmentsOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by the 2^2-INTRATARGET project (A20/00028) funded by the ISCIII under the umbrella of the ERA NET EuroNanoMed GA N 723770 of the EU Horizon 2020 Research and Innovation Programme. This work was also supported by the Xunta de Galicia (ED431C 2018/30, and “Centro singular de investigación de Galicia” accreditation 2019 − 2022, ED431G2019/03), and the European Union (European Regional Development Fund-ERDF)S

Inclusive J/ψ production at forward and backward rapidity in p-Pb collisions at √sNN=8.16 TeV

Inclusive J/psi production is studied in p-Pb interactions at a centre-of-mass energy per nucleon-nucleon collision sqrt(s_NN) = 8.16TeV, using the ALICE detector at the CERN LHC. The J/psi meson is reconstructed, via its decay to a muon pair, in the centre-of-mass rapidity intervals 2.03 < ycms < 3.53 and -4.46 < ycms < -2.96, where positive and negative ycms refer to the p-going and Pb-going direction, respectively. The transverse momentum coverage is pT < 20 GeV/c. In this paper, ycms- and pT-differential cross sections for inclusive J/psi production are presented, and the corresponding nuclear modification factors RpPb are shown. Forward results show a suppression of the J/psi yield with respect to pp collisions, concentrated in the region pT < 5 GeV/c. At backward rapidity no significant suppression is observed. The results are compared to previous measurements by ALICE in p-Pb collisions at sqrt(s_NN) = 5.02TeV and to theoretical calculations. Finally, the ratios RFB between forward- and backward-ycms RpPb values are shown and discussed

Energy dependence and fluctuations of anisotropic flow in Pb-Pb collisions at √sNN=5.02 and 2.76 TeV

Measurements of anisotropic flow coefficients with two- and multi-particle cumulants for inclusive charged particles in Pb-Pb collisions at sqrt(s_NN) = 5.02 and 2.76TeV are reported in the pseudorapidity range |eta|< 0.8 and transverse momentum 0.2 < pT < 50 GeV/c. The full data sample collected by the ALICE detector in 2015 (2010), corresponding to an integrated luminosity of 12.7 (2.0) ub^-1 in the centrality range 0-80%, is analysed. Flow coefficients up to the sixth flow harmonic (v6) are reported and a detailed comparison among results at the two energies is carried out. The pT dependence of anisotropic flow coefficients and its evolution with respect to centrality and harmonic number n are investigated. An approximate power-law scaling of the form vn(pT) ~ pT^(n/3) is observed for all flow harmonics at low pT (0.2 < pT < 3 GeV/c). At the same time, the ratios vn/vm^(n/m) are observed to be essentially independent of pT for most centralities up to about pT = 10 GeV/c. Analysing the differences among higher-order cumulants of elliptic flow (v2), which have different sensitivities to flow fluctuations, a measurement of the standardised skewness of the event-by-event v2 distribution P(v2) is reported and constraints on its higher moments are provided. The Elliptic Power distribution is used to parametrise P(v2), extracting its parameters from fits to cumulants. The measurements are compared to different model predictions in order to discriminate among initial-state models and to constrain the temperature dependence of the shear viscosity to entropy-density ratio

First measurement of Ξc0 production in pp collisions at s=7 TeV

The production of the charm-strange baryon Csi0c is measured for the first time at the LHC via its semileptonic decay into e+Csi-νe in pp collisions at sqrt(s) = 7 TeV with the ALICE detector. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 1 &lt; pT &lt; 8 GeV/c at mid-rapidity, |y| &lt; 0.5. The transverse momentum dependence of the Csi0c baryon production relative to the D0 meson production is compared to predictions of event generators with various tunes of the hadronisation mechanism, which are found to underestimate the measured cross- section ratio.The production of the charm-strange baryon Csi0c is measured for the first time at the LHC via its semileptonic decay into e+Csi-νe in pp collisions at sqrt(s) = 7 TeV with the ALICE detector. The transverse momentum (pT) differential cross section multiplied by the branching ratio is presented in the interval 1 &lt; pT &lt; 8 GeV/c at mid-rapidity, |y| &lt; 0.5. The transverse momentum dependence of the Csi0c baryon production relative to the D0 meson production is compared to predictions of event generators with various tunes of the hadronisation mechanism, which are found to underestimate the measured cross- section ratio