Maternal opioids age-dependently impair neonatal respiratory control networks

19 pagesInfants exposed to opioids in utero are an increasing clinical population and these infants are often diagnosed with Neonatal Abstinence Syndrome (NAS). Infants with NAS have diverse negative health consequences, including respiratory distress. However, many factors contribute to NAS, confounding the ability to understand how maternal opioids directly impact the neonatal respiratory system. Breathing is controlled centrally by respiratory networks in the brainstem and spinal cord, but the impact of maternal opioids on developing perinatal respiratory networks has not been studied. Using progressively more isolated respiratory network circuitry, we tested the hypothesis that maternal opioids directly impair neonatal central respiratory control networks. Fictive respiratory-related motor activity from isolated central respiratory networks was age-dependently impaired in neonates after maternal opioids within more complete respiratory networks (brainstem and spinal cords), but unaffected in more isolated networks (medullary slices containing the preBötzinger Complex). These deficits were due, in part, to lingering opioids within neonatal respiratory control networks immediately after birth and involved lasting impairments to respiratory pattern. Since opioids are routinely given to infants with NAS to curb withdrawal symptoms and our previous work demonstrated acute blunting of opioid-induced respiratory depression in neonatal breathing, we further tested the responses of isolated networks to exogenous opioids. Isolated respiratory control networks also demonstrated age-dependent blunted responses to exogenous opioids that correlated with changes in opioid receptor expression within a primary respiratory rhythm generating region, the preBötzinger Complex. Thus, maternal opioids agedependently impair neonatal central respiratory control and responses to exogenous opioids, suggesting central respiratory impairments contribute to neonatal breathing destabilization after maternal opioids and likely contribute to respiratory distress in infants with NAS. These studies represent a significant advancement of our understanding of the complex effects of maternal opioids, even late in gestation, contributing to neonatal breathing deficits, necessary first steps in developing novel therapeutics to support breathing in infants with NAS

Tales of diversity: Genomic and morphological characteristics of forty-six <i>Arthrobacter</i> phages

<div><p>The vast bacteriophage population harbors an immense reservoir of genetic information. Almost 2000 phage genomes have been sequenced from phages infecting hosts in the phylum Actinobacteria, and analysis of these genomes reveals substantial diversity, pervasive mosaicism, and novel mechanisms for phage replication and lysogeny. Here, we describe the isolation and genomic characterization of 46 phages from environmental samples at various geographic locations in the U.S. infecting a single <i>Arthrobacter</i> sp. strain. These phages include representatives of all three virion morphologies, and Jasmine is the first sequenced podovirus of an actinobacterial host. The phages also span considerable sequence diversity, and can be grouped into 10 clusters according to their nucleotide diversity, and two singletons each with no close relatives. However, the clusters/singletons appear to be genomically well separated from each other, and relatively few genes are shared between clusters. Genome size varies from among the smallest of siphoviral phages (15,319 bp) to over 70 kbp, and G+C contents range from 45–68%, compared to 63.4% for the host genome. Although temperate phages are common among other actinobacterial hosts, these <i>Arthrobacter</i> phages are primarily lytic, and only the singleton Galaxy is likely temperate.</p></div

Genome organization of <i>Arthrobacter</i> phage Laroye, Cluster AL.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Gordon, Cluster AU.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Maggie, Cluster AN.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Amigo, Cluster AQ.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Jawnski, Cluster AO.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Korra, Cluster AK.

<p>The genome of <i>Arthrobacter</i> phage Korra is shown with predicted genes depicted as boxes either above (rightwards-expressed) or below (leftwards-expressed) the genome. Genes are colored according to the phamily designations using Phamerator and database Actinobacteriophage_692, with the phamily number shown above each gene with the number of phamily members in parentheses.</p