The proteins that coordinate complex adipogenic transcriptional networks are poorly understood. 14-3-3ζ is a molecular adaptor protein that regulates insulin signalling and transcription factor networks. Here we report that 14-3-3ζ-knockout mice are strikingly lean from birth with specific reductions in visceral fat depots. Conversely, transgenic 14-3-3ζ overexpression potentiates obesity, without exacerbating metabolic complications. Only the 14-3-3ζ isoform is essential for adipogenesis based on isoform-specific RNAi. Mechanistic studies show that 14-3-3ζ depletion promotes autophagy-dependent degradation of C/EBP-δ, preventing induction of the master adipogenic factors, Pparγ and C/EBP-α. Transcriptomic data indicate that 14-3-3ζ acts upstream of hedgehog signalling-dependent upregulation of Cdkn1b/p27Kip1. Indeed, concomitant knockdown of p27Kip1 or Gli3 rescues the early block in adipogenesis induced by 14-3-3ζ knockdown in vitro. Adipocyte precursors in 14-3-3ζKO embryos also appear to have greater Gli3 and p27Kip1 abundance. Together, our in vivo and in vitro findings demonstrate that 14-3-3ζ is a critical upstream driver of adipogenesis.

These findings indicate that ductal cells are primed to form that become invasive PDAC in the presence of oncogenic Kras and deletion, while acinar cells with the same mutations appear to require a prolonged period of transition or reprogramming to initiate PDAC. Our findings illustrate that PDAC can develop in multiple ways and the cellular context in which mutations are acquired has significant impact on precursor lesion initiation, disease progression and tumour phenotype.

2-1). The collection and processing of the specimens via PancoBank was supported by Heidelberger 48 Stiftung Chirurgie. I.R. is a recipient of an Odysseus I fellowship of the Fund for Scientific Research 49 Flanders (FWO). E.E. was a recipient of an EMBO long-term fellowship (ALTF 344-2013).

Body size is a fundamental ecological trait and is correlated with population dynamics, community structure and function, and ecosystem fluxes. Laboratory data from broad taxonomic groups suggest that a widespread response to a warming world may be an overall decrease in organism body size. However, given the myriad of biotic and abiotic factors that can also influence organism body size in the wild, it is unclear whether results from these laboratory assays hold in nature. Here we use datasets spanning 30 to 100 years to examine whether the body size of wild-caught beetles has changed over time, whether body size changes are correlated with increased temperatures, and we frame these results using predictions derived from a quantitative review of laboratory responses of 22 beetle species to temperature. We found that 95% of laboratory-reared beetles decreased in size with increased rearing temperature, with larger-bodied species shrinking disproportionately more than smaller-bodied beetles. In addition, the museum datasets revealed that larger-bodied beetle species have decreased in size over time, that mean beetle body size explains much of the interspecific variation in beetle responses to temperature, and that long-term beetle size changes are explained by increases in autumn temperature and decreases in spring temperature in this region. Our data demonstrate that the relationship between body size and temperature of wild-caught beetles matches relatively well with results from laboratory studies, and that variation in this relationship is largely explained by interspecific variation in mean beetle body size. This long-term beetle dataset is one of the most comprehensive arthropod body size datasets compiled to date, it improves predictions regarding the shrinking of organisms with global climate change, and together with the meta-analysis data, call for new hypotheses to explain why larger-bodied organisms may be more sensitive to temperature.

<p>Supplementary Methods Figure 1</p>

<div>Abstract<p>Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive desmoplasia, which challenges the molecular analyses of bulk tumor samples. Here we FACS-purified epithelial cells from human PDAC and normal pancreas and derived their genome-wide transcriptome and DNA methylome landscapes. Clustering based on DNA methylation revealed two distinct PDAC groups displaying different methylation patterns at regions encoding repeat elements. Methylation^low tumors are characterized by higher expression of endogenous retroviral transcripts and double-stranded RNA sensors, which lead to a cell-intrinsic activation of an interferon signature (IFNsign). This results in a protumorigenic microenvironment and poor patient outcome. Methylation^low/IFNsign^high and Methylation^high/IFNsign^low PDAC cells preserve lineage traits, respective of normal ductal or acinar pancreatic cells. Moreover, ductal-derived <i>Kras</i>^G12D/<i>Trp53</i>^−/− mouse PDACs show higher expression of IFNsign compared with acinar-derived counterparts. Collectively, our data point to two different origins and etiologies of human PDACs, with the aggressive Methylation^low/IFNsign^high subtype potentially targetable by agents blocking intrinsic IFN signaling.</p>Significance:<p>The mutational landscapes of PDAC alone cannot explain the observed interpatient heterogeneity. We identified two PDAC subtypes characterized by differential DNA methylation, preserving traits from normal ductal/acinar cells associated with IFN signaling. Our work suggests that epigenetic traits and the cell of origin contribute to PDAC heterogeneity.</p><p><i>This article is highlighted in the In This Issue feature, p. 521</i></p></div>

<p>PDACvsNP enrichment results</p>

<p>Genesets used in the study</p>