MEF2C regulates NK cell effector functions through control of lipid metabolism.

Natural killer (NK) cells are a critical first line of defense against viral infection. Rare mutations in a small subset of transcription factors can result in decreased NK cell numbers and function in humans, with an associated increased susceptibility to viral infection. However, our understanding of the specific transcription factors governing mature human NK cell function is limited. Here we use a non-viral CRISPR-Cas9 knockout screen targeting genes encoding 31 transcription factors differentially expressed during human NK cell development. We identify myocyte enhancer factor 2C (MEF2C) as a master regulator of human NK cell functionality ex vivo. MEF2C-haploinsufficient patients and mice displayed defects in NK cell development and effector function, with an increased susceptibility to viral infection. Mechanistically, MEF2C was required for an interleukin (IL)-2- and IL-15-mediated increase in lipid content through regulation of sterol regulatory element-binding protein (SREBP) pathways. Supplementation with oleic acid restored MEF2C-deficient and MEF2C-haploinsufficient patient NK cell cytotoxic function. Therefore, MEF2C is a critical orchestrator of NK cell antiviral immunity by regulating SREBP-mediated lipid metabolism.

Complexation of High-Valency Mid-Actinides by a Lipophilic Schiff Base Ligand: Synthesis, Structural Characterization, and Progress toward Selective Extraction.

Separation of U, Np, and Pu from used nuclear fuel (UNF) would result in lower long-term radiotoxicity, alleviating constraints on the storage and handling of the material. The complexity of UNF requires several industrial-scale processes with multiple waste streams. A one-step solution to the group removal of the elements, U-Pu, is desirable. Here we present a possible solution to group actinide separation utilizing the unique dioxy conformation of An(V/VI) cations and demonstrate the ability of a tetradentate lipophilic Schiff base ligand (L) to yield isostructural complexes of the general formula [(AnVIO2)(L)(CH3CN)] (where An = U, Np, or Pu). Extraction of An(VI) with the ligand follows the order U > Pu > Np, likely reflecting the decreased stability of the hexavalent actinide across the series. While the results indicate a promising path toward a one-step process, further improvement in the ligand stability and control of the redox chemistry is required.

Water-soluble Schiff base-actinyl complexes and their effect on the solvent extraction of f-elements.

Conventional solvent extraction of selected f-element cations by bis(2-ethylhexyl)phosphoric acid (HDEHP) yields increased extraction from aqueous to organic solution along the series Np(v) < Cm(iii) < Eu(iii) < U(vi), with distribution ratios all within two orders of magnitude. However, in the presence of the water-soluble tetradentate Schiff base (N,N'-bis(5-sulfonatosalicylidene)-ethylenediamine or H2salenSO3), selective complexation of the two actinyl cations (Np(v) and U(vi)) resulted in an extraction order of Np(v) < U(vi) ≪ Eu(iii) < Cm(iii). The extraction of neither Cm(iii) or Eu(iii) by HDEHP are significantly impacted by the presence of the aqueous phase Schiff base. Despite observed hydrolytic decomposition of H2salenSO3 in aqueous solutions, the calculated high conditional stability constant (ß11 = 26) for the complex [UO2(salenSO3)]2- demonstrates its capacity for aqueous hold-back of U(vi). UV-visible-NIR spectroscopy of solutions prepared with a Np(vi) stock and H2salenSO3 suggest that reduction of Np(vi) to Np(v) by the ligand was rapid, resulting in a pentavalent Np complex that was substantially retained in the aqueous phase. Results from 1H NMR of aqueous solutions of H2salenSO3 with U(vi) and La(iii), Eu(iii), and Lu(iii) provides additional evidence that the ligand readily chelates U(vi), but has only weak interactions with trivalent lanthanide ions.