Structure of the human K2P13.1 channel reveals a hydrophilic pore restriction and lipid cofactor site
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Nano-micro pore structure characteristics of carbon black and recycled carbon fiber reinforced alkali-activated materials
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Because proteins do not efficiently pass through the plasma membrane, protein therapeutics are limited to target ligands located at the cell surface or in serum. Lipid nanoparticles can facilitate delivery of polar molecules across a membrane. We hypothesized that because most proteins are amphoteric ionizable polycations, proteins would associate with anionic lipids, enabling microfluidic chip assembly of stable EP-LNPs (Encapsulated Proteins in Lipid NanoParticles). Here, by employing anionic lipids we were able to efficiently load proteins into EP-LNPs at protein:lipid w:w ratios of 1:20. Several proteins with diverse molecular weights and isoelectric points were encapsulated at efficiencies of 70 75%–90% and remained packaged for several months. Proteins packaged in EP-LNPs efficiently entered mammalian cells and fungal cells with cell walls. The proteins delivered intracellularly were functional. EP-LNPs technology should improve cellular delivery of medicinal antibodies, enzymes, peptide antimetabolites, and dominant negative proteins, opening new fields of protein therapeutics
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Autologous T-cell therapies show limited efficacy in chronic lymphocytic leukemia (CLL), where acquired immune dysfunction prevails. In CLL, disturbed mitochondrial metabolism has been linked to defective T-cell activation and proliferation. Recent research suggests that lipid metabolism regulates mitochondrial function and differentiation in T cells, yet its role in CLL remains unexplored. This comprehensive study compares T-cell lipid metabolism in CLL patients and healthy donors, revealing critical dependence on exogenous cholesterol for human T-cell expansion following TCR-mediated activation. Using multi-omics and functional assays, we found that T cells present in viably frozen samples of patients with CLL (CLL T cells) showed impaired adaptation to cholesterol deprivation and inadequate upregulation of key lipid metabolism transcription factors. CLL T cells exhibited altered lipid storage, with increased triacylglycerols and decreased cholesterol, and inefficient fatty acid oxidation (FAO). Functional consequences of reduced FAO in T cells were studied using samples from patients with inherent FAO disorders. Reduced FAO was associated with lower T-cell activation but did not affect proliferation. This implicates low cholesterol levels as a primary factor limiting T-cell proliferation in CLL. CLL T cells displayed fewer and less clustered lipid rafts, potentially explaining the impaired immune synapse formation observed in these patients. Our findings highlight significant disruptions in lipid metabolism as drivers of functional deficiencies in CLL T cells, underscoring the pivotal role of cholesterol in T-cell proliferation. This study suggests that modulating cholesterol metabolism could enhance T-cell function in CLL, presenting novel immunotherapeutic approaches to improve outcome in this challenging disease.
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