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The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The trade-offs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild-type house mice (Mus musculus) to 1-h nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5 and 50 lx) and three correlated color temperatures (CCT; 1750, 1950 and 3000 K). Higher intensities of light (50 lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000 K, 53% for 1750 K). At the lowest intensity (0.01 lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750 K, 3% increase at 3000 K). Multiple linear regression confirmed the influence of both CCT and intensity on changes in activity, with the scaled effect size of intensity 3.6 times greater than that of CCT. Activity suppression was significantly lower for male than for female mice. Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50 lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior, and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.

In most organisms, dietary restriction (DR) increases lifespan. However, several studies have found that genotypes within the same species vary widely in how they respond to DR. To explore the mechanisms underlying this variation, we exposed 178 inbred Drosophila melanogaster lines to a DR or ad libitum (AL) diet, and measured a panel of 105 metabolites under both diets. Twenty four out of 105 metabolites were associated with the magnitude of the lifespan response. These included proteinogenic amino acids and metabolites involved in α-ketoglutarate (α-KG)/glutamine metabolism. We confirm the role of α-KG/glutamine synthesis pathways in the DR response through genetic manipulations. We used covariance network analysis to investigate diet-dependent interactions between metabolites, identifying the essential amino acids threonine and arginine as "hub" metabolites in the DR response. Finally, we employ a novel metabolic and genetic bipartite network analysis to reveal multiple genes that influence DR lifespan response, some of which have not previously been implicated in DR regulation. One of these is CCHa2R, a gene that encodes a neuropeptide receptor that influences satiety response and insulin signaling. Across the lines, variation in an intronic single nucleotide variant of CCHa2R correlated with variation in levels of five metabolites, all of which in turn were correlated with DR lifespan response. Inhibition of adult CCHa2R expression extended DR lifespan of flies, confirming the role of CCHa2R in lifespan response. These results provide support for the power of combined genomic and metabolomic analysis to identify key pathways underlying variation in this complex quantitative trait.

The progress made in aging research using laboratory organisms is undeniable. Yet, with few exceptions, these studies are conducted in a limited number of isogenic strains. The path from laboratory discoveries to treatment in human populations is complicated by the reality of genetic variation in nature. To model the effect of genetic variation on the action of the drug rapamycin, here we use the growth of Drosophila melanogaster larvae. We screened 140 lines from the Drosophila Genetic References Panel for the extent of developmental delay and found wide‐ranging variation in their response, from lines whose development time is nearly doubled by rapamycin, to those that appear to be completely resistant. Sensitivity did not associate with any single genetic marker, nor with any gene. However, variation at the level of genetic pathways was associated with rapamycin sensitivity and might provide insight into sensitivity. In contrast to the genetic analysis, metabolomic analysis showed a strong response of the metabolome to rapamycin, but only among the sensitive larvae. In particular, we found that rapamycin altered levels of amino acids in sensitive larvae, and in a direction strikingly similar to the metabolome response to nutrient deprivation. This work demonstrates the need to evaluate interventions across genetic backgrounds and highlights the potential of omic approaches to reveal biomarkers of drug efficacy and to shed light on mechanisms underlying sensitivity to interventions aimed at increasing lifespan. [ABSTRACT FROM AUTHOR]

The northwest European shelf (NWS) seas are environmentally and economically important, and an understanding of how their climate may change helps with their management. However, as the NWS seas are poorly represented in global climate models, a common approach is to dynamically downscale with an appropriate shelf sea model. We develop a set of physical marine climate projections for the NWS. We dynamically downscale 12 members of the HadGEM3-GC3.05 perturbed parameter ensemble (approximately 70 km horizontal resolution over Europe), developed for UKCP18, using the shelf sea model NEMO CO9 (7 km horizontal resolution). These are run under the RCP8.5 high-greenhouse-gas-emission scenario as continuous simulations over the period 1990–2098. We evaluate the simulations against observations in terms of tides, sea surface temperature (SST), surface and near-bed temperature and salinity, and sea surface height. These simulations represent the state of the art for NWS marine projections. We project an SST rise of 3.11 °C (± 2 σ = 0.98 °C) and a sea surface salinity (SSS) freshening of - 1.01 (± 2 σ = 0.93; on the (unitless) practical salinity scale) for 2079–2098 relative to 2000–2019, averaged over the NWS (approximately bounded by the 200 m isobar and excluding the Norwegian Trench, the Skagerrak and Kattegat), a substantial seasonal stratification increase (23 d over the NWS seas), and a general weakening of the NWS residual circulation. While the patterns of NWS changes are similar to our previous projections, there is a greater warming and freshening that could reflect the change from the A1B emissions scenario to the RCP8.5 concentrations pathway or the higher climate sensitivity exhibited by HadGEM3-GC3.05. Off the shelf, south of Iceland, there is limited warming, consistent with a reduction in the Atlantic Meridional Overturning Circulation and associated northward heat transport. These projections have been publicly released, along with a consistent 200-year present-day control simulation, to provide an evidence base for climate change assessments and to facilitate climate impact studies. For example, we illustrate how the two products can be used to estimate climate trends, unforced variability and the time of emergence (ToE) of the climate signals. We calculate the average NWS SST ToE to be 2034 (with an 8-year range) and 2046 (with a 33-year range) for SSS. We also discuss how these projections can be used to describe NWS conditions under 2 and 4 °C global mean warming (compared with 1850–1900), as a policy-relevant exemplar use case. [ABSTRACT FROM AUTHOR]

Primary sensory dorsal root ganglia (DRG) neurons are diverse, with distinct populations that respond to specific stimuli. Previously, we observed that functionally distinct populations of DRG neurons express mRNA transcript variants with different 3′ untranslated regions (3′UTRs). 3′UTRs harbor binding sites for interaction with RNA‐binding proteins (RBPs) for transporting mRNAs to subcellular domains, modulating transcript stability, and regulating the rate of translation. In the current study, analysis of publicly available single‐cell RNA‐sequencing data generated from adult mice revealed that 17 3′UTR‐binding RBPs were enriched in specific populations of DRG neurons. This included four members of the CUG triplet repeat (CUGBP) Elav‐like family (CELF): CELF2 and CELF4 were enriched in peptidergic, CELF6 in both peptidergic and nonpeptidergic, and CELF3 in tyrosine hydroxylase‐expressing neurons. Immunofluorescence studies confirmed that 60% of CELF4+ neurons are small‐diameter C fibers and 33% medium‐diameter myelinated (likely Aδ) fibers and showed that CELF4 is distributed to peripheral termini. Coexpression analyses using transcriptomic data and immunofluorescence revealed that CELF4 is enriched in nociceptive neurons that express GFRA3, CGRP, and the capsaicin receptor TRPV1. Reanalysis of published transcriptomic data from macaque DRG revealed a highly similar distribution of CELF members, and reanalysis of single‐nucleus RNA‐sequencing data derived from mouse and rat DRG after sciatic injury revealed differential expression of CELFs in specific populations of sensory neurons. We propose that CELF RBPs may regulate the fate of mRNAs in populations of nociceptors, and may play a role in pain and/or neuronal regeneration following nerve injury. [ABSTRACT FROM AUTHOR]

The North West European Shelf Seas (NWS) are environmentally and economically important, and an understanding of how their climate may change helps with their management. However, as the NWS are poorly represented in Global Climate Models, a common approach is to dynamically downscale with an appropriate shelf seas model. We develop a set of physical marine climate projections for the NWS. We dynamically downscale 12 members of the HadGEM3-GC3.05 Perturbed Parameter Ensemble (approximately 70 km horizontal resolution over Europe), developed for UKCP18, using the shelf-seas model NEMO CO9 (7 km horizontal resolution). These are run under the high greenhouse gas emissions RCP8.5 scenario as continuous simulations over the period 1990-2098. We evaluate the simulations against observations in terms of tides, sea surface temperature, surface and near-bed temperature and salinity, and sea surface-height. These simulations represent the state-of-the-art for marine UK projections. We project a Sea-Surface Temperature (SST) rise of 3.11 °C (±2σ = 0.98 °C), and a Sea-Surface Salinity (SSS) freshening of 1.01 psu (±2σ = 0.93 psu) for 2079-2098 relative to 2000- 2019, averaged over the NWS (approximately bounded by the 200m isobar and excluding the Norwegian Trench, Skagerrak, and Kattegat). While the patterns of NWS changes are similar to our previous projections, there is a greater warming and freshening, that could reflect the change from the A1B emissions scenario to the RCP8.5 concentrations pathway or the higher climate sensitivity exhibited by HadGEM3-GC3.05. Off the shelf, south of Iceland, there is limited warming, consistent with a reduction in the Atlantic Meridional Overturning Circulations and associated northward heat transport. These projections have been publicly released, along with a consistent 200-year present day control simulation, to provide an evidence-base for climate change assessments and to facilitate climate impact studies. For example, we illustrate how the two products can be used to estimate of climate trends, unforced variability, and the Time of Emergence (ToE) of the climate signals. We calculate the average NWS SST ToE to be 2034 (with an 8-year range) and 2046 (with a 33-year range) for SSS. We also discuss how these projections can be used to describe NWS conditions under 2°C and 4°C global mean warming (compared to 1850-1900), as a policy relevant exemplar use-case. [ABSTRACT FROM AUTHOR]