Effectiveness of emamectin benzoate for treatment of Lepeophtheirus salmonis on farmed Atlantic salmon Salmo salar in the Bay of Fundy, Canada

Emamectin benzoate (an avermectin chemotherapeutant administered to fish as an in-feed treatment) has been used to treat infestations of sea lice Lepeophtheirus salmonis on farmed Atlantic salmon Salmo salar in the Bay of Fundy, New Brunswick, Canada, since 1999. This retrospective study examined the effectiveness of 114 emamectin benzoate treatment episodes from 2004 to 2008 across 54 farms. Study objectives were to establish whether changes in the effectiveness of emamectin benzoate were present for this period, examine factors associated with treatment outcome, and determine variables that influenced differences in L. salmonis abundance after treatment. The analysis was carried out in 2 parts: first, trends in treatment effectiveness and L. salmonis abundance were explored, and second, statistical modelling (linear and logistic regression) was used to examine the effects of multiple variables on post-treatment abundance and treatment outcome. Post-treatment sea lice abundance increased in the later years examined. Mean abundance differed between locations in the Bay of Fundy, and higher numbers were found at farms closer to the mainland and lower levels were found in the areas around Grand Manan Island. Treatment effectiveness varied by geographical region and decreased over time. There was an increased risk for unsuccessful treatments in 2008, and treatments applied during autumn months were more likely to be ineffective than those applied during summer months

RNF17 blocks promiscuous activity of PIWI proteins in mouse testes

PIWI proteins and their associated piRNAs protect germ cells from the activity of mobile genetic elements. Two classes of piRNAs-primary and secondary-are defined by their mechanisms of biogenesis. Primary piRNAs are processed directly from transcripts of piRNA cluster loci, whereas secondary piRNAs are generated in an adaptive amplification loop, termed the ping-pong cycle. In mammals, piRNA populations are dynamic, shifting as male germ cells develop. Embryonic piRNAs consist of both primary and secondary species and are mainly directed toward transposons. In meiotic cells, the piRNA population is transposon-poor and largely restricted to primary piRNAs derived from pachytene piRNA clusters. The transition from the embryonic to the adult piRNA pathway is not well understood. Here we show that RNF17 shapes adult meiotic piRNA content by suppressing the production of secondary piRNAs. In the absence of RNF17, ping-pong occurs inappropriately in meiotic cells. Ping-pong initiates piRNA responses against not only transposons but also protein-coding genes and long noncoding RNAs, including genes essential for germ cell development. Thus, the sterility of Rnf17 mutants may be a manifestation of a small RNA-based autoimmune reaction

Effect of timing of count events on estimates of sea lice abundance and interpretation of effectiveness following bath treatments

Effectiveness of sea lice bath treatment is often assessed by comparing pre- and post-treatment counts. However, in practice, the post-treatment counting window varies from the day of treatment to several days after treatment. In this study, we assess the effect of post-treatment lag time on sea lice abundance estimates after chemical bath treatment using data from the sea lice data management program (Fish-iTrends) between 2010 and 2014. Data on two life stages, (i) adult female (AF) and (ii) pre-adult and adult male (PAAM), were aggregated at the cage level and log-transformed. Average sea lice counts by post-treatment lag time were computed for AF and PAAM and compared relative to treatment day, using linear mixed models. There were 720 observations (treatment events) that uniquely matched pre- and post-treatment counts from 53 farms. Lag time had a significant effect on the estimated sea lice abundance, which was influenced by season and pre-treatment sea lice levels. During summer, sea lice were at a minimum when counted 1 day post-treatment irrespective of pre-treatment sea lice levels, whereas in the spring and autumn, low levels were observed for PAAM over a longer interval of time, provided the pre-treatment sea lice levels were >5-10

Variation in pre-treatment count lead time and its effect on baseline estimates of cage-level sea lice abundance

Treatment efficacy studies typically use pre-treatment sea lice abundance as the baseline. However, the pre-treatment counting window often varies from the day of treatment to several days before treatment. We assessed the effect of lead time on baseline estimates, using historical data (2010-14) from a sea lice data management programme (Fish-iTrends). Data were aggregated at the cage level for three life stages: (i) chalimus, (ii) pre-adult and adult male and (iii) adult female. Sea lice counts were log-transformed, and mean counts by lead time relative to treatment day were computed and compared separately for each life stage, using linear mixed models. There were 1,658 observations (treatment events) from 56 sites in 5 Bay Management Areas. Our study showed that lead time had a significant effect on the estimated sea lice abundance, which was moderated by season. During the late summer and autumn periods, counting on the day of treatment gave significantly higher values than other days and would be a more appropriate baseline estimate, while during spring and early summer abundance estimates were comparable among counts within 5 days of treatment. A season-based lead time window may be most appropriate when estimating baseline sea lice levels

Evaluating bath treatment effectiveness in the control of sea lice burdens on Atlantic salmon in New Brunswick, Canada

The use of medicinal bath treatment for sea lice is becoming more common, due to increasing resistance to in-feed treatments with emamectin benzoate. Common treatment modalities in New Brunswick, Canada, include Salmosan administered by tarpaulin or wellboat, and Paramove administered by wellboat. In this study, we assessed the effectiveness of these treatment modalities in the field between 2010 and 2015 using a web-based sea lice data management system (Fish-iTrends© ). Effectiveness was evaluated for adult female (AF) and for pre-adult and adult male (PAAM) life stages separately. We also investigated the impact of variability in pretreatment lead and post-treatment lag time on effectiveness measures. There were 1185 treatment events at 57 farms that uniquely matched our pre- and post-treatment count criteria. The effectiveness of treatment modality was significantly influenced by season, pretreatment level of sea lice and by lead and lag times. In summer, Salmosan administered by tarpaulin had the greatest effectiveness on both AF and PAAM, when pretreatment levels were above 10 sea lice; whereas in autumn, the performance of treatment modalities varied significantly, depending on the pretreatment levels for the life stages. Ignoring the lead or lag time effect generally resulted in an underestimation of treatment effectiveness

Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD

Discovery of Outlying, High-Velocity Oxygen-Rich Ejecta in Cassiopeia A

Hubble Space Telescope images of the young Galactic supernova remnant Cassiopeia A reveal a far larger population of outlying, high-velocity knots of ejecta with a broader range of chemical properties than previously suspected. We identify three main classes of outer ejecta: 1) Knots dominated by [N II] 6548,6583 emission; 2) Knots dominated by oxygen emission lines especially [O II] 7319,7330; and 3) Knots with emission line strengths similar to the [S II] strong FMK ejecta commonly seen in the main emission shell. The discovery of a significant population of O-rich ejecta situated in between the suspected N-rich outer photospheric layer and S-rich FMK-like ejecta suggests that the Cas A progenitor's chemical layers were not completely disrupted by the supernova explosion outside of the remnant's NE and SW high velocity `jet' regions. In addition, we find the majority of O-rich outer ejecta at projected locations out beyond (v = 6500 - 9000 km/s) the remnant's fastest moving Fe-rich X-ray emission material (6000 km/s) seen in Chandra and XMM data along the eastern limb. This suggests that penetration of Fe-rich material up through the S and Si-rich mantle did not extend past the progenitor's N or O-rich outer layers for at least this section of the remnant.Comment: 17 pages including 3 tables and 7 figures. To appear in Ap

DAF-12 Regulates a Connected Network of Genes to Ensure Robust Developmental Decisions

The nuclear receptor DAF-12 has roles in normal development, the decision to pursue dauer development in unfavorable conditions, and the modulation of adult aging. Despite the biologic importance of DAF-12, target genes for this receptor are largely unknown. To identify DAF-12 targets, we performed chromatin immunoprecipitation followed by hybridization to whole-genome tiling arrays. We identified 1,175 genomic regions to be bound in vivo by DAF-12, and these regions are enriched in known DAF-12 binding motifs and act as DAF-12 response elements in transfected cells and in transgenic worms. The DAF-12 target genes near these binding sites include an extensive network of interconnected heterochronic and microRNA genes. We also identify the genes encoding components of the miRISC, which is required for the control of target genes by microRNA, as a target of DAF-12 regulation. During reproductive development, many of these target genes are misregulated in daf-12(0) mutants, but this only infrequently results in developmental phenotypes. In contrast, we and others have found that null daf-12 mutations enhance the phenotypes of many miRISC and heterochronic target genes. We also find that environmental fluctuations significantly strengthen the weak heterochronic phenotypes of null daf-12 alleles. During diapause, DAF-12 represses the expression of many heterochronic and miRISC target genes, and prior work has demonstrated that dauer formation can suppress the heterochronic phenotypes of many of these target genes in post-dauer development. Together these data are consistent with daf-12 acting to ensure developmental robustness by committing the animal to adult or dauer developmental programs despite variable internal or external conditions

SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes

Expression of the p53-inducible antiproliferative gene BTG2 is suppressed in many cancers in the absence of inactivating gene mutations, suggesting alternative mechanisms of silencing. Using a shRNA screen targeting 43 histone lysine methyltransferases (KMTs), we show that SETD1A suppresses BTG2 expression through its induction of several BTG2-targeting miRNAs. This indirect but highly specific mechanism, by which a chromatin regulator that mediates transcriptional activating marks can lead to the downregulation of a critical effector gene, is shared with multiple genes in the p53 pathway. Through such miRNA-dependent effects, SETD1A regulates cell cycle progression in vitro and modulates tumorigenesis in mouse xenograft models. Together, these observations help explain the remarkably specific genetic consequences associated with alterations in generic chromatin modulators in cancer

Computational Prediction of Intronic microRNA Targets using Host Gene Expression Reveals Novel Regulatory Mechanisms

Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene's mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it allows a large number of expression profiling studies to be used but needs refinement because mRNAs can be targeted by multiple miRNAs and not all intronic miRNAs are co-expressed with their host genes