Advancing age is the dominant risk factor for most of the major killer diseases in developed countries. Hence, ameliorating the effects of ageing may prevent multiple diseases simultaneously. Drugs licensed for human use against specific diseases have proved to be effective in extending lifespan and healthspan in animal models, suggesting that there is scope for drug repurposing in humans. New bioinformatic methods to identify and prioritise potential anti-ageing compounds for humans are therefore of interest. In this study, we first used drug-protein interaction information, to rank 1,147 drugs by their likelihood of targeting ageing-related gene products in humans. Among 19 statistically significant drugs, 6 have already been shown to have pro-longevity properties in animal models (p < 0.001). Using the targets of each drug, we established their association with ageing at multiple levels of biological action including pathways, functions and protein interactions. Finally, combining all the data, we calculated a ranked list of drugs that identified tanespimycin, an inhibitor of HSP-90, as the top-ranked novel anti-ageing candidate. We experimentally validated the pro-longevity effect of tanespimycin through its HSP-90 target in Caenorhabditis elegans.
A -Relative expression of HSF-1 target genes following heat shock (33°C, 30 min) compared to control treated animals (20°C) on day 3 of adulthood. Values plotted are the mean of 4 biological replicates.B -Relative expression of HSF-1 target genes on day 3 of adulthood in wild type animals exposed to control conditions (20°C), 25°C for 1 hour or 28°C for 1 hour. Expression was calculated relative to the HK genes cdc-42, rpb-2 and pmp-3. Values plotted are the mean of 4 biological replicates.
C -Representative images and fluorescence quantification of hsp-6p::gfp and hsp-16.2p::mcherry reporters on day 3 of adulthood following treatment with DMSO, antimycin A, rotenone or paraquat. Values plotted are the mean fluorescence of at least 15 worms per treatment group. D & E -Representative images and fluorescence quantification of day 3 adult wild type and (D) clk-1(qm30) or (E) glp-1(e2144ts) worms expressing hsp-16.2p::mcherry following exposure to empty vector (EV) control (L4440) or cox-6c(RNAi). Experiments involving glp-1 and clk-1 mutants were performed at 25°C and 20°C respectively. Values plotted are the mean fluorescence of at least 15 worms per treatment group. F-H -Representative images of (F) daf-16p::daf-16::GFP, (G) hsp-6p::gfp and (H) cyp14Ap::gfp worms following growth on empty vector (EV) control, cox-6c(RNAi) or EV/cox-6c(RNAi) combined with (F), daf-16(RNAi), (G) atfs-1(RNAi) or (H) nhr-45(RNAi). I -Fluorescence quantification of day 3 adult daf-16p::daf-16::GFP, hsp-6p::gfp and cyp14Ap::gfp worms. Values plotted are the mean fluorescence of at least 15 worms per treatment group. All scale bars = 250 µM. Statistical significance was calculated by: (B and C) one-way ANOVA with Tukey postanalysis comparison of groups and (D and E) two-way ANOVA with post analysis pairwise comparison of groups. All error bars represent SEM. * p < 0.05, ** p < 0.01, *** p < 0.001.
Many students find environmental justice to be emotionally overwhelming and/or politically alienating, and there is currently little work that provides instructors with effective techniques for addressing these types of challenges. In this paper, upon situating the environmental studies classroom and the broader undergraduate experience in sociohistorical context, we identify four sequential strategies for engaging and empowering students on environmental justice issues. First, instructors can
facilitate an open and honest dialogue
by strategically framing course content for the unique composition of the audience, sharing their own racialized experiences (or working with a guest speaker who would be willing to do so), and using interactive assignments to encourage student participation. Second,
can be presented to students as complimentary (rather than competing) ideas which can be used for creative, real-world problem solving. Third, instructors and students can
cultivate empathy by acknowledging different standpoints
, particularly those that have been historically marginalized. Lastly, by
working in partnerships
with community-based organizations, instructors and students can think and work beyond hero/savior and perpetrator/victim narratives. These strategies are not intended as a set of silver bullets, but rather as a series of potential starting points that are informed by recent scholarship on these topics.
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