Highlights d Aging leads to the most profound changes in brain gene expression networks d Immune module led by Alzheimer's risk genes Trem2/Tyrobp is upregulated with aging d Alzheimer's risk allele APOE4 increases the expression of Serpina3 family genes d Alzheimer's protective allele APOE2 drives unique serum metabolome profiles

SUMMARY The contributions of the innate immune system to the development of pancreatic cancer are still ill-defined. Inflammatory macrophages can initiate metaplasia of pancreatic acinar cells to a duct-like phenotype (ADM), which then give rise to pancreatic intraepithelial neoplasia (PanIN) when oncogenic KRas is present. However, it remains unclear when and how this inflammatory macrophage population is replaced by tumor-promoting macrophages. We here demonstrate presence of interleukin-13 (IL-13), which can convert inflammatory into Ym1+ alternatively-activated macrophages, at ADM/PanIN lesions. We further show that Ym1+ macrophages release factors such as IL-1ra and CCL2 to drive pancreatic fibrogenesis and tumorigenesis. Treatment of mice expressing oncogenic KRas under an acinar cell-specific promoter with a neutralizing antibody for IL-13 significantly-decreased the accumulation of alternatively-activated macrophages at these lesions, resulting in decreased fibrosis and lesion growth.

Background: PKD inhibits actin-driven directed cell migration. Results: PKD regulates cofilin activity through LIMK and PAK4. Conclusion: PKD increases the net amount of inactive cofilin in cells. Significance: The regulation of cofilin activity at multiple levels explains the inhibitory effects of PKD on directed cell migration.

Background: Protein kinase D1 (PKD1) regulates actin reorganization processes at the leading edge. Results: PKD1 phosphorylates VASP at two serine residues, Ser-157 and Ser-322. Conclusion: VASP is a substrate for PKD1. Significance: We provide an additional mechanism of how VASP functions can be regulated.