A conserved PHD finger protein and endogenous RNAi modulate insulin signaling in Caenorhabditis elegans.

Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16-dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.

The evaluation of 3 diets for rearing Hyalella azteca and the influence of diet on acute ammonia toxicity.

Three Hyalella azteca cultures were reared on different diets since birth, reflecting the recommended diets of various investigators. The 3 diets consisted of fish flakes (FF), a mixture of fish flakes supplemented with the diatom Thalassiosira weissflogii (FF-D), and a mixture of fish flakes supplemented with yeast, cereal grass media, and trout chow (FF-YCT). The 3 diets were evaluated by comparing 20 wk of culturing data, along with the organism's response to standard 96-h toxicity testing with ammonium chloride over a range of pH and temperature. Hyalella azteca fed the FF-D diet had the highest overall survival rate (96.6%, standard deviation [SD] 4.3%) compared to those fed the FF diet (92.0%, SD 12.7%), or the FF-YCT diet (91.1%, SD 14.8%), although difference in survival was not statistically significant. Organisms fed the FF-D diet produced a higher number of young per week per adult (6.1, SD 2.8) than the FF diet (5.1, SD 2.2), or the FF-YCT diet (4.0, SD 1.2), although differences were not statistically significant. Of the diets evaluated, H. azteca reared on the FF-D diet were often significantly more resistant to total and un-ionized ammonia toxicity in acute 96-h testing than those reared on the other 2 diets across the 2 temperatures and 5 pHs tested, suggesting this may be the most optimal diet for this species. Environ Toxicol Chem 2016;35:2416-2424. © 2016 SETAC.

Cost-effectiveness of the AMOArray multifocal intraocular lens in cataract surgery.

PURPOSE: To compare the cost and outcomes of bilateral cataract surgery with the foldable AMOArray multifocal intraocular lens (MIOL) versus the foldable monofocal intraocular lens from the health care payer perspective. METHODS: A cost-effectiveness analysis was used to evaluate treatment with the MIOL compared to monofocal lens, using data from clinical trials, literature, expert opinion, and a review of the German health care funding and reimbursement system. RESULTS: The average total direct medical cost per patient (per procedure) with the MIOL was DM 1,774 compared to DM 1,716 with the monofocal lens (1DM = US$0.558 in April 1998). The MIOL was more cost-effective than the monofocal lens in terms of cost per patient (spectacle-free). Cost per patient without overall limitation in vision-related function and cost per patient without limited night vision were similar for both patient groups. The incremental cost of the MIOL for a one-point increase was DM 52 in the self-rated score "quality of vision," DM 82 in "satisfaction with day vision," and DM 115 in "satisfaction with night vision." CONCLUSION: The small additional cost of the MIOL was outweighed by the increased satisfaction with vision experienced by MIOL patients.

Neuronal migration is regulated by endogenous RNAi and chromatin-binding factor ZFP-1/AF10 in Caenorhabditis elegans.

Endogenous short RNAs and the conserved plant homeodomain (PHD) zinc-finger protein ZFP-1/AF10 regulate overlapping sets of genes in Caenorhabditis elegans, which suggests that they control common biological pathways. We have shown recently that the RNAi factor RDE-4 and ZFP-1 negatively modulate transcription of the insulin/PI3 signaling-dependent kinase PDK-1 to promote C. elegans fitness. Moreover, we have demonstrated that the insulin/IGF-1-PI3K-signaling pathway regulates the activity of the DAF-16/FOXO transcription factor in the hypodermis to nonautonomously promote the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. In this study, we implicate the PHD-containing isoform of ZFP-1 and endogenous RNAi in the regulation of HSN migration. ZFP-1 affects HSN migration in part through its negative effect on pdk-1 transcription and modulation of downstream DAF-16 activity. We also identify a novel role for ZFP-1 and RNAi pathway components, including RDE-4, in the regulation of HSN migration in parallel with DAF-16. Therefore, the coordinated activities of DAF-16, ZFP-1, and endogenous RNAi contribute to gene regulation during development to ensure proper neuronal positioning.

Nonautonomous regulation of neuronal migration by insulin signaling, DAF-16/FOXO, and PAK-1.

Neuronal migration is essential for nervous system development in all organisms and is regulated in the nematode, C. elegans, by signaling pathways that are conserved in humans. Here, we demonstrate that the insulin/IGF-1-PI3K signaling pathway modulates the activity of the DAF-16/FOXO transcription factor to regulate the anterior migrations of the hermaphrodite-specific neurons (HSNs) during embryogenesis of C. elegans. When signaling is reduced, DAF-16 is activated and promotes migration; conversely, when signaling is enhanced, DAF-16 is inactivated, and migration is inhibited. We show that DAF-16 acts nonautonomously in the hypodermis to promote HSN migration. Furthermore, we identify PAK-1, a p21-activated kinase, as a downstream mediator of insulin/IGF-1-DAF-16 signaling in the nonautonomous control of HSN migration. Because a FOXO-Pak1 pathway was recently shown to regulate mammalian neuronal polarity, our findings indicate that the roles of FOXO and Pak1 in neuronal migration are most likely conserved from C. elegans to higher organisms.

Subfunctionalization of PhyB1 and PhyB2 in the control of seedling and mature plant traits in maize.

Phytochromes are the primary red/far-red photoreceptors of higher plants, mediating numerous developmental processes throughout the life cycle, from germination to flowering. In seed plants, phytochromes are encoded by a small gene family with each member performing both distinct and redundant roles in mediating physiological responses to light cues. Studies in both eudicot and monocot species have defined a central role for phytochrome B in mediating responses to light in the control of several agronomically important traits, including plant height, transitions to flowering and axillary branch meristem development. Here we characterize Mutator-induced alleles of PhyB1 and a naturally occurring deletion allele of PhyB2 in Zea mays (maize). Using single and double mutants, we show that the highly similar PhyB1 and PhyB2 genes encode proteins with both overlapping and non-redundant functions that control seedling and mature plant traits. PHYB1 and PHYB2 regulate elongation of sheath and stem tissues of mature plants and contribute to the light-mediated regulation of PhyA and Cab gene transcripts. However, PHYB1 and not PHYB2 contributes significantly to the inhibition of mesocotyl elongation under red light, whereas PHYB2 and to a lesser extent PHYB1 mediate the photoperiod-dependent floral transition. This sub functionalization of PHYB activities in maize has probably occurred since the tetraploidization of maize, and may contribute to flowering time variation in modern-day varieties.