Spill your thoughts to me! * Clear inputs Help me write a research paper abstract with the following text:[A major limitation of chimeric antigen receptor (CAR) T cell therapies is ...]
Try: A major limitation of chimeric antigen receptor (CAR) T cell therapies is the poor persistence of these cells in vivo1. The expression of memory-associated genes in CAR T cells is linked to their long-term persistence in patients and clinical efficacy2,3,4,5,6, suggesting that memory programs may underpin durable CAR T cell function. Here we show that the transcription factor FOXO1 is responsible for promoting memory and restraining exhaustion in human CAR T cells. Pharmacological inhibition or gene editing of endogenous FOXO1 diminished the expression of memory-associated genes, promoted an exhaustion-like phenotype and impaired the antitumour activity of CAR T cells. Overexpression of FOXO1 induced a gene-expression program consistent with T cell memory and increased chromatin accessibility at FOXO1-binding motifs. CAR T cells that overexpressed FOXO1 retained their function, memory potential and metabolic fitness in settings of chronic stimulation, and exhibited enhanced persistence and tumour control in vivo. By contrast, overexpression of TCF1 (encoded by TCF7) did not enforce canonical memory programs or enhance the potency of CAR T cells. Notably, FOXO1 activity correlated with positive clinical outcomes of patients treated with CAR T cells or tumour-infiltrating lymphocytes, underscoring the clinical relevance of FOXO1 in cancer immunotherapy. Our results show that overexpressing FOXO1 can increase the antitumour activity of human CAR T cells, and highlight memory reprogramming as a broadly applicable approach for optimizing therapeutic T cell states. Dielectric electrostatic capacitors1, due to their ultrafast charge-discharge capability, are attractive for high power energy storage applications. Along with ultrafast operation, on-chip integration can enable miniaturized energy storage devices for emerging autonomous microelectronics and microsystems2-5. Additionally, state-of-the-art miniaturized electrochemical energy storage systems – microsupercapacitors and microbatteries – currently face safety, packaging, materials, and microfabrication challenges preventing on-chip technological readiness2,3,6, leaving an opportunity for electrostatic microcapacitors. Here we report record-high electrostatic energy storage density (ESD) and power density (PD) in HfO2- ZrO2-based thin film microcapacitors integrated on silicon, through a three-pronged approach. First, to increase intrinsic energy storage, atomic-layer-deposited antiferroelectric HfO2-ZrO2 films are engineered near a field-driven ferroelectric phase transition to exhibit amplified charge storage via the negative capacitance effect7-12, which enhances volumetric-ESD beyond the best-known back-end-of-the-line (BEOL) compatible dielectrics (115 J-cm-3)13. Second, to increase total energy storage, antiferroelectric superlattice engineering14 scales the energy storage performance beyond the conventional thickness limitations of HfO2-ZrO2-based (anti)ferroelectricity15 (100-nm regime). Third, to increase storage-per-footprint, the superlattices are conformally integrated into three-dimensional capacitors, which boosts areal-ESD (areal-PD) 9-times (170-times) the best-known electrostatic capacitors: 80 mJ-cm-2 (300 kW-cm-2). This simultaneous demonstration of ultrahigh energy- and power-density overcomes the traditional capacity-speed trade-off across the electrostatic-electrochemical energy storage hierarchy1,16. Furthermore, integration of ultrahigh-density and ultrafast-charging thin films within a BEOL-compatible process enables monolithic integration of on-chip microcapacitors5, which can unlock substantial energy storage and power delivery performance for electronic microsystems
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