Search

Additional file 3. eARRIVE Compliance Questionnaire.

Additional file 1: Additional Figure 1. Long-term treatment of adult rats maintained on a high fat diet with different dosages of FK506 induces weight loss and promotes maintenance of a healthier weight. Additional Figure 2. Tukey’s post-hoc test following ANOVA statistical test on timepoint reveals early but temporary anorexigenic effects of sibutramine, and significant changes due to fasting on Day 36. Additional Figure 3. Pancreatic Insulin levels at Day 42. Additional Figure 4. Combination treatment of bupropion and naltrexone impacts on the host gut microbiome. Additional Figure 5. Differentially abundant genes and species upon bupropion and naltrexone combination treatment. Additional Table 2. Current pharmacotherapies for obesity. Additional Table 2. Tukey’s post-hoc test significant comparisons following ANOVA on pancreatic insulin levels at Day 42. Additional Table 3. Percentage of unassigned reads per sample for representative genes fliC, flgE and motA.

Additional file 12: Figure S5. Spatial expression of jmjd-3.2 and utx-1. A-B: Animals overexpressing a full length jmjd-3.2::GFP construct in wildtype (A) and jmjd-3.2(tm3121) mutants (B) were visualised by epifluorescence microscopy and showed spatial expression in a specific subset of neurons (white arrows). C-D: Animals overexpressing full length utx-1::GFP in wildtype (C) and utx-1(tm3118) mutant background (D) both showed ubiquitous expression (white arrows). E-H: The expression of demethylase dead jmjd-3.2 (E-F) and utx-1 (G-H) constructs showed a very similar pattern to the non-mutated constructs. I-J: Whole worm images of animals overexpressing utx-1::GFP (I) and utx-1DD::GFP (J) show ubiquitous expression of utx-1. Scale Bar (A-H) = 10μM; Scale Bar (I-J) = 20μM.

Additional file 7: Table S4. Statistical analysis of lifespan data relating to Fig. 2. Full statistical analysis of lifespan data from Fig. 2 (****p

Additional file 4: Figure S2. Lifespan analysis of jmjd-3 mutants. The lifespan of jmjd-3.2 animals was comparable to that of the jmjd-3.1; jmjd-3.2; jmjd-3.3 triple mutants (p=0.19). jmjd-3.2 animals are longer-lived compared to WT animals (p=0.01 (*)). See Additional file 5: Table S3 for the full statistical analysis of the lifespan data, including repeats.

Additional file 5: Table S3. Statistical analysis of lifespan data relating to Figure S2. Full statistical analysis of lifespan data from Fig. S2 (****p

Additional file 9: Table S5. Statistical analysis of lifespan data relating to Fig. 3. Full statistical analysis of lifespan data from Fig. 3 (****p

Additional file 2: Table S1. Lifespan analysis of worms subjected to RNAi by feeding clones identified in and inspired by the primary lipofuscin screen. Lifespan was monitored following RNAi of the indicated gene. Average lifespan (in days) is shown, together with relevant p values compared with the control. In the case of cbp-1, where RNAi resulted in larval lethality of F1s, first generation P0 L4 worms were picked onto RNAi plates containing FUDR, and these were scored for lifespan extension. In the case of mes-3 and mes-6 RNAi, 2nd generation F2 worms were scored for lifespan extension. ****p

Additional file 3: Table S2. Statistical analysis of lifespan data relating to Fig. 1. Full statistical analysis of lifespan data from Fig. 1 (****p

Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor TFEB. Spermidine is depleted in the elderly, leading to reduced TFEB expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.

Background The interim analysis of the multicentre New EPOC trial demonstrated a significant reduction in progression free survival (PFS) for the group allocated to cetuximab (HR=1.48 95% CI 1.04-2.12, p=0.030). The focus of the present analysis was to determine the impact on overall survival (OS). Methods Patients with KRAS wild-type (codons 12, 13 and 61) resectable or suboptimally resectable colorectal liver metastases were randomised in a 1:1 ratio to receive chemotherapy with or without cetuximab before and after liver resection. The trial was open label and randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer (one or more of: ≥ 4 metastases, N2 disease or poor differentiation of primary cancer), and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m intravenously over 2 h and fluorouracil bolus 400 mg/m intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m repeated every 2 weeks (regimen one) or oxaliplatin 130 mg/m intravenously over 2 h and oral capecitabine 1000 mg/m twice daily on days 1–14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m every 2 weeks with regimen one and three or a loading dose of 400 mg/m followed by a weekly infusion of 250 mg/m with regimen two. The primary trial endpoint was progression free survival. The objective of this present study was to assess the secondary endpoint of overall survival. The trial completed recruitment on 1 Nov 2012 and these data are now presented at a median follow-up of 67 months. Secondary endpoints also included preoperative cancer response (response after the end of the preoperative treatment period using RECIST), pathological resection status (margin ≥1 cm