Fatty-Acid Preference Changes during Development in Drosophila melanogaster

Fatty-acids (FAs) are required in the diet of many animals throughout their life. However, the mechanisms involved in the perception of and preferences for dietary saturated and unsaturated FAs (SFAs and UFAs, respectively) remain poorly explored, especially in insects. Using the model species Drosophila melanogaster, we measured the responses of wild-type larvae and adults to pure SFAs (14, 16, and 18 carbons) and UFAs (C18 with 1, 2, or 3 double-bonds). Individual and group behavioral tests revealed different preferences in larvae and adults. Larvae preferred UFAs whereas SFAs tended to induce both a strong aversion and a persistent aggregation behavior. Adults generally preferred SFAs, and laid more eggs and had a longer life span when ingesting these substances as compared to UFAs. Our data suggest that insects can discriminate long-chain dietary FAs. The developmental change in preference shown by this species might reflect functional variation in use of FAs or stage-specific nutritional requirements, and may be fundamental for insect use of these major dietary components

Optimization of biguanide derivatives as selective antitumor agents blocking adaptive stress responses in the tumor microenvironment

Kosuke Narise, Kensuke Okuda, Yukihiro Enomoto, Tasuku Hirayama, Hideko Nagasawa Laboratory of Pharmaceutical and Medicinal Chemistry, Gifu Pharmaceutical University, Daigaku-nishi, Gifu, Japan Abstract: Adaptive cellular responses resulting from multiple microenvironmental stresses, such as hypoxia and nutrient deprivation, are potential novel drug targets for cancer treatment. Accordingly, we focused on developing anticancer agents targeting the tumor microenvironment (TME). In this study, to search for selective antitumor agents blocking adaptive responses in the TME, thirteen new compounds, designed and synthesized on the basis of the arylmethylbiguanide scaffold of phenformin, were used in structure activity relationship studies of inhibition of hypoxia inducible factor (HIF)-1 and unfolded protein response (UPR) activation and of selective cytotoxicity under glucose-deprived stress conditions, using HT29 cells. We conducted luciferase reporter assays using stable cell lines expressing either an HIF-1-responsive reporter gene or a glucose-regulated protein 78 promoter-reporter gene, which were induced by hypoxia and glucose deprivation stress, respectively, to screen for TME-targeting antitumor drugs. The guanidine analog (compound 2), obtained by bioisosteric replacement of the biguanide group, had activities comparable with those of phenformin (compound 1). Introduction of various substituents on the phenyl ring significantly affected the activities. In particular, the o-methylphenyl analog compound 7 and the o-chlorophenyl analog compound 12 showed considerably more potent inhibitory effects on HIF-1 and UPR activation than did phenformin, and excellent selective cytotoxicity under glucose deprivation. These compounds, therefore, represent an improvement over phenformin. They also suppressed HIF-1- and UPR-related protein expression and secretion of vascular endothelial growth factor-A. Moreover, these compounds exhibited significant antiangiogenic effects in the chick chorioallantoic membrane assay. Our structural development studies of biguanide derivatives provided promising candidates for a novel anticancer agent targeting the TME for selective cancer therapy, to be subjected to further in vivo study. Keywords: HIF-1, UPR, antiangiogenesis, hypoxia, glucose deprivatio

The NF-kB like factor DIF has weaker effects on Drosophila melanogaster immune defenses than previously thought.

International audienceThe Toll pathway of Drosophila melanogaster, when activated by the Beauveria bassiana fungus, directs the expression of the drosomycin and metchnikowin antimicrobial peptide genes by inducing the translocation into the nucleus of the DIF transcription factor. Accordingly, DIF mutants have been reported to have a lower resistance to fungi than control flies. However, as the longevity of non-infected DIF flies has not been measured in previous studies, it could be that survival times after infection are constrained by a low longevity. In the present study, DIF flies reared in conditions similar to those used in these previous studies had much lower survival time after infection than the control flies, but the longevity of non-infected DIF flies was also very low. Using rearing conditions controlling larval crowding, age of parents and mating status of experimental flies increased longevity of non-infected flies and survival time after infection in both strains. However, DIF flies had a similar survival time after infection as control ones or a slightly lower one, which shows that the effect of DIF is weaker than previously thought

Idiographic Prediction of Suicidal Thoughts: Building Personalized Machine Learning Models with Real-Time Monitoring Data

Suicide risk is highest immediately after psychiatric hospitalization, but the field lacks methods for identifying which patients are at greatest risk, and when. We built personalized models predicting suicidal thoughts after psychiatric hospital visits (N=89 patients), using ecological momentary assessment (EMA; average EMA responses per participant=311). We built several idiographic models, including baseline autoregressive and elastic net models (using single train/test split) and Gaussian Process (GP) models (using an iterative rolling-forward prediction method). Simple GP models provided the best prediction of suicidal urges (R2_average=0.17), outperforming baseline autoregressive (R2_average=0.10) and elastic net (R2_average=0.07) models. Similarly, simple GP models provided the best prediction of suicidal intent (R2_average=0.12) compared to autoregressive (R2_average=0.08) and elastic net (R2_average=0.06). Findings suggest idiographic prediction of suicidal thoughts is possible, though accuracy currently is modest. Building GP models that iteratively update and learn symptom dynamics over time could provide important information to inform development of just-in-time adaptive interventions