Opiate-Induced Suppression of Rat Hypoglossal Motoneuron Activity and Its Reversal by Ampakine Therapy

Hypoglossal (XII) motoneurons innervate tongue muscles and are vital for maintaining upper-airway patency during inspiration. Depression of XII nerve activity by opioid analgesics is a significant clinical problem, but underlying mechanisms are poorly understood. Currently there are no suitable pharmacological approaches to counter opiate-induced suppression of XII nerve activity while maintaining analgesia. Ampakines accentuate alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor responses. The AMPA family of glutamate receptors mediate excitatory transmission to XII motoneurons. Therefore the objectives were to determine whether the depressant actions of mu-opioid receptor activation on inspiratory activity includes a direct inhibitory action at the inspiratory premotoneuron to XII motoneuron synapse, and to identify underlying mechanism(s). We then examined whether ampakines counteract opioid-induced depression of XII motoneuron activity.A medullary slice preparation from neonatal rat that produces inspiratory-related output in vitro was used. Measurements of inspiratory burst amplitude and frequency were made from XII nerve roots. Whole-cell patch recordings from XII motoneurons were used to measure membrane currents and synaptic events. Application of the mu-opioid receptor agonist, DAMGO, to the XII nucleus depressed the output of inspiratory XII motoneurons via presynaptic inhibition of excitatory glutamatergic transmission. Ampakines (CX614 and CX717) alleviated DAMGO-induced depression of XII MN activity through postsynaptic actions on XII motoneurons.The inspiratory-depressant actions of opioid analgesics include presynaptic inhibition of XII motoneuron output. Ampakines counteract mu-opioid receptor-mediated depression of XII motoneuron inspiratory activity. These results suggest that ampakines may be beneficial in countering opiate-induced suppression of XII motoneuron activity and resultant impairment of airway patency

Whole-exome Sequencing and an iPSC-Derived Cardiomyocyte Model Provides a Powerful Platform for Gene Discovery in Left Ventricular Hypertrophy

Rationale: Left ventricular hypertrophy (LVH) is a heritable predictor of cardiovascular disease, particularly in blacks. Objective: Determine the feasibility of combining evidence from two distinct but complementary experimental approaches to identify novel genetic predictors of increased LV mass. Methods: Whole-exome sequencing (WES) was conducted in seven African-American sibling trios ascertained on high average familial LV mass indexed to height (LVMHT) using Illumina HiSeq technology. Identified missense or nonsense (MS/NS) mutations were examined for association with LVMHT using linear mixed models adjusted for age, sex, body weight, and familial relationship. To functionally assess WES findings, human induced pluripotent stem cell-derived cardiomyocytes (induced pluripotent stem cell-CM) were stimulated to induce hypertrophy; mRNA sequencing (RNA-seq) was used to determine gene expression differences associated with hypertrophy onset. Statistically significant findings under both experimental approaches identified LVH candidate genes. Candidate genes were further prioritized by seven supportive criteria that included additional association tests (two criteria), regional linkage evidence in the larger HyperGEN cohort (one criterion), and publically available gene and variant based annotations (four criteria). Results: WES reads covered 91% of the target capture region (of size 37.2 MB) with an average coverage of 65×. WES identified 31,426 MS/NS mutations among the 21 individuals. A total of 295 MS/NS variants in 265 genes were associated with LVMHT with q-value <0.25. Of the 265 WES genes, 44 were differentially expressed (P < 0.05) in hypertrophied cells. Among the 44 candidate genes identified, 5, including HLA-B, HTT, MTSS1, SLC5A12, and THBS1, met 3 of 7 supporting criteria. THBS1 encodes an adhesive glycoprotein that promotes matrix preservation in pressure-overload LVH. THBS1 gene expression was 34% higher in hypertrophied cells (P = 0.0003) and a predicted conserved and damaging NS variant in exon 13 (A2099G) was significantly associated with LVHMT (P = 4 × 10−6). Conclusion: Combining evidence from cutting-edge genetic and cellular experiments can enable identification of novel LVH risk loci

Lengua, comunicación e información

This book, which emerges from the presentations made in the Faculty of Information and Communication in 2017 during two academic meetings: the Colloquium Communication, language and information: reading and writing in academic key and the thematic table Multiple looks for multiple literacies, made in the II Research Days. The written versions of these works are available, which have allowed to start a dialogue about academic reading and writing from three perspectives: communication, information and language sciences. It is hoped that this text will contribute to the dialogue between disciplines not only with the aim of improving the understanding of the same object - writing practices and the processing and communication of information in academic fields - but also contribute to improving teaching, a primary goal of the University of the Republic

Lengua, comunicación e información

This book, which emerges from the presentations made in the Faculty of Information and Communication in 2017 during two academic meetings: the Colloquium Communication, language and information: reading and writing in academic key and the thematic table Multiple looks for multiple literacies, made in the II Research Days. The written versions of these works are available, which have allowed to start a dialogue about academic reading and writing from three perspectives: communication, information and language sciences. It is hoped that this text will contribute to the dialogue between disciplines not only with the aim of improving the understanding of the same object - writing practices and the processing and communication of information in academic fields - but also contribute to improving teaching, a primary goal of the University of the Republic

Lengua, comunicación e información

This book, which emerges from the presentations made in the Faculty of Information and Communication in 2017 during two academic meetings: the Colloquium Communication, language and information: reading and writing in academic key and the thematic table Multiple looks for multiple literacies, made in the II Research Days. The written versions of these works are available, which have allowed to start a dialogue about academic reading and writing from three perspectives: communication, information and language sciences. It is hoped that this text will contribute to the dialogue between disciplines not only with the aim of improving the understanding of the same object - writing practices and the processing and communication of information in academic fields - but also contribute to improving teaching, a primary goal of the University of the Republic

Bath application of CX614 or CX717 counters DAMGO-induced inspiratory depression.

<p>∫XII nerve activity recorded from a medullary slice preparation and group data illustrating that the depression of respiratory activity evoked by bath-applied DAMGO (500 nM) was significantly attenuated by bath application of (A) CX614 (5–20 µM, n = 5) or (B) CX717 (50–100 µM, n = 6). Expanded time scale excerpts from control, DAMGO and AMPAKINE conditions are shown on the right hand side of the continuous time trace in (A) and (B). *  =  significantly different from control, #  =  significantly different from DAMGO (p<0.05).</p

Differential expression of voltage-activated calcium channels in III and XII motoneurones during development in the rat

To further our understanding of the role that voltage-activated Ca2+ channels play in the development, physiology and pathophysiology of motoneurones (MNs), we used whole-cell patch-clamp recording to compare voltage-activated Ca2+ currents in oculomotor (III) and hypoglossal (XII) MNs of neonatal [postnatal day (P)1-5] and juvenile (P14-19) rats. In contrast to III MNs that innervate extraocular muscles, XII MNs that innervate tongue muscles mature more rapidly, fire bursts of low frequency action potentials and are vulnerable to degeneration in amyotrophic lateral sclerosis. In neonates, low voltage-activated (LVA) Ca2+ current densities are similar in XII and III MNs but high voltage-activated (HVA) Ca2+ current densities are twofold higher in XII MNs. The HVA Ca2+ channel antagonists (nimodipine and nifedipine for L-type, omega-agatoxin-TK for P/Q-type and omega-conotoxin-GVIA for N-type) revealed that, while N- and P/Q-type HVA Ca2+ channels are present in both MN pools, a 3.5-fold greater P/Q-type Ca2+ current in XII MNs accounts for their greater HVA Ca2+ currents. Developmentally, LVA and HVA Ca2+ current densities decrease in III MNs but remain unchanged in XII MNs. Thus, the differences between these MN pools increase developmentally so that, in juveniles, the LVA Ca2+ current density is twofold greater and the HVA Ca2+ current density is threefold greater in XII compared with III MNs. We propose that this differential expression of LVA and HVA Ca2+ channels in XII and III MNs during development contributes to their distinct physiology and may also be a factor contributing to the greater susceptibility of XII MNs to degeneration as seen in amyotrophic lateral sclerosis.</p