Shirai et al. show that the glycolytic enzyme PKM2 serves as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation in macrophages from patients with atherosclerotic coronary artery disease.

The efficacy of the adaptive immune response declines dramatically with age, but the cell-intrinsic mechanisms driving immune aging in humans remain poorly understood. Immune aging is characterized by a loss of self-renewing naïve cells and the accumulation of differentiated but dysfunctional cells within the CD8 T cell compartment. Using ATAC-seq, we inferred the transcription factor binding activities correlated with naive and central and effector memory CD8 T cell states in young adults. Integrating our results with RNA-seq, we identified transcription networks associated with CD8 T cell differentiation, with prominent roles implicated for BATF, ETS1, Eomes, and Sp1. Extending our analysis to aged humans, we found that the differences between the memory and naive subsets were largely preserved across age, but that naive and central memory cells from older individuals exhibited a shift toward more differentiated patterns of chromatin openness. Additionally, aged naive cells displayed a loss in chromatin accessibility at gene promoters, largely associated with a decrease in NRF1 binding. This shift was implicated in a marked drop-off in the ability of the aged naive cells to transcribe respiratory chain genes, which may explain the reduced capacity of oxidative phosphorylation in older naïve cells. Our findings identify BATF- and NRF1-driven gene regulation as potential targets for delaying CD8 T cell aging and restoring function.

Synthetic methodologies integrating hydrophobic drug delivery and biomolecular targeting with mesoporous silica nanoparticles are described. Transferrin and cyclic-RGD peptides are covalently attached to the nanoparticles utilizing different techniques and provide selectivity between primary and metastatic cancer cells. The increase in cellular uptake of the targeted particles is examined using fluorescence microscopy and flow cytometry. Transferrin-modified silica nanoparticles display enhancement in particle uptake by Panc-1 cancer cells over that of normal HFF cells. The endocytotic pathway for these particles is further investigated through plasmid transfection of the transferrin receptor into the normal HFF cell line, which results in an increase in particle endocytosis as compared to unmodified HFF cells. By designing and attaching a synthetic cyclic-RGD, selectivity between primary cancer cells (BT-549) and metastatic cancer cells (MDA-MB 435) is achieved with enhanced particle uptake by the metastatic cancer cell line. Incorporation of the hydrophobic drug Camptothecin into these two types of biomolecular-targeted nanoparticles causes an increase in mortality of the targeted cancer cells compared to that caused by both the free drug and nontargeted particles. These results demonstrate successful biomolecular-targeted hydrophobic drug delivery carriers that selectively target specific cancer cells and result in enhanced drug delivery and cell mortality.

The exocytosis of phosphonate modified mesoporous silica nanoparticles (P‐MSNs) is demonstrated and lysosomal exocytosis is identified as the mechanism responsible for this event. Regulation of P‐MSN exocytosis can be achieved by inhibiting or accelerating lysosomal exocytosis. Slowing down P‐MSN exocytosis enhances the drug delivery effect of CPT‐loaded P‐MSNs by improving cell killing.