The immune diet: meeting the metabolic demands of lymphocyte activation

During the adaptive immune response, lymphocytes undergo dramatic changes in metabolism that accompany the proliferative burst and differentiation into functional subsets. This brief overview focuses on recent advances in understanding the mechanisms of this metabolic reprogramming in T lymphocytes

Simultaneous measurement of displacement and temperature based on two cascaded balloon-like bent fibre structures

A low-cost optical fibre sensor based on two cascaded balloon-like bent fibre (BBF) structures for simultaneous displacement and temperature measurement is reported. The sensor is fabricated by cascading two balloon-like bent single-mode fibres (SMFs) which with different bending radii, generating two separate interference dips within a limited wavelength range. The wavelength of the two interference dips exhibits different responses to external displacement and temperature variations, hence simultaneous measurement of displacement and temperature is realized. Experimental results show that the proposed optical fibre sensor achieves a displacement sensitivity of −318.8 pm/μm and a temperature sensitivity of 47.4 pm/°C. Taking advantage of its low-cost, ease of fabrication, and experimentally determined high sensitivity, the sensor in this investigation can be potentially applied in both displacement and temperature measurement fields

Controllable Weyl nodes and Fermi arcs in a light-irradiated carbon allotrope

The precise control of Weyl physics in realistic materials oers a promising avenue to construct accessible topological quantum systems, and thus draw widespread attention in condensed-matter physics. Here, based on rst-principles calculations, maximally localized Wannier functions based tight-binding model, and Floquet theorem, we study the light-manipulated evolution of Weyl physics in a carbon allotrope C6 crystallizing a face-centered orthogonal structure (fco-C6), an ideal Weyl semimetal with two pairs of Weyl nodes, under the irradiation of a linearly polarized light (LPL). We show that the positions of Weyl nodes and Fermi arcs can be accurately controlled by changing light intensity. Moreover, we employ a low-energy eective k p model to understand light-controllable Weyl physics. The results indicate that the symmetry of light-irradiated fco-C6 can be selectively preserved, which guarantees that the light-manipulated Weyl nodes can only move in the highsymmetry plane in momentum space. Our work not only demonstrates the ecacy of employing periodic driving light elds as an ecient approach to manipulate Weyl physics, but also paves a reliable pathway for designing accessible topological states under light irradiation

Disrupting the CH1 Domain Structure in the Acetyltransferases CBP and p300 Results in Lean Mice with Increased Metabolic Control

SummaryOpposing activities of acetyltransferases and deacetylases help regulate energy balance. Mice heterozygous for the acetyltransferase CREB binding protein (CBP) are lean and insulin sensitized, but how CBP regulates energy homeostasis is unclear. In one model, the main CBP interaction with the glucagon-responsive factor CREB is not limiting for liver gluconeogenesis, whereas a second model posits that Ser436 in the CH1 (TAZ1) domain of CBP is required for insulin and the antidiabetic drug metformin to inhibit CREB-mediated liver gluconeogenesis. Here we show that conditional knockout of CBP in liver does not decrease fasting blood glucose or gluconeogenic gene expression, consistent with the first model. However, mice in which the CBP CH1 domain structure is disrupted by deleting residues 342–393 (ΔCH1) are lean and insulin sensitized, as are p300ΔCH1 mutants. CBPΔCH1/ΔCH1 mice remain metformin responsive. An intact CH1 domain is thus necessary for normal energy storage, but not for the blood glucose-lowering actions of insulin and metformin

Direct Femtosecond Laser Inscription of High-Order Bragg Gratings in Fluoroaluminate Glass Fiber

This letter reports the fabrication of fiber Bragg gratings (FBGs) within in-house fabricated fluoroaluminate (AlF3) glass fibers using femtosecond (fs) laser inscription at 800 nm. The grating strength of the FBGs was investigated for different pulse energies and different orders, and a 3rd-order FBG with Bragg wavelength at 1557 nm was found to have the highest reflectivity of 99.5%. In addition, the reflectivity of the mid-IR grating peaks for different orders was also studied, and a 2nd-order FBG with a reflectivity of 98.8% was obtained at 2864 nm. Finally, the temperature characteristics of a mid-IR FBG were studied between 30 °C and 150 °C, showing a linear wavelength dependence and an excellent stability for the refractive index modulation. Such highly reflectivity FBGs in AlF3 fiber have significant potential for applications in the development of compact all-fiber mid-IR fiber lasers

Selective Refueling of Car T Cells Using ADA1 and CD26 Boosts Antitumor Immunity

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor cell feeding. In mouse models of hepatocellular carcinoma and non-small cell lung cancer, metabolically refueled CAR T cells exhibit superior tumor reduction compared to unmodified CAR T cells. Overall, our study highlights the potential of selective inosine refueling to enhance CAR T therapy efficacy against solid tumors

Succinate dehydrogenase/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation

Effective T cell-mediated immune responses require the proper allocation of metabolic resources to sustain growth, proliferation, and cytokine production. Epigenetic control of the genome also governs T cell transcriptome and T cell lineage commitment and maintenance. Cellular metabolic programs interact with epigenetic regulation by providing substrates for covalent modifications of chromatin. By using complementary genetic, epigenetic, and metabolic approaches, we revealed that tricarboxylic acid (TCA) cycle flux fueled biosynthetic processes while controlling the ratio of succinate/α-ketoglutarate (α-KG) to modulate the activities of dioxygenases that are critical for driving T cell inflammation. In contrast to cancer cells, where succinate dehydrogenase (SDH)/complex II inactivation drives cell transformation and growth, SDH/complex II deficiency in T cells caused proliferation and survival defects when the TCA cycle was truncated, blocking carbon flux to support nucleoside biosynthesis. Replenishing the intracellular nucleoside pool partially relieved the dependence of T cells on SDH/complex II for proliferation and survival. SDH deficiency induced a proinflammatory gene signature in T cells and promoted T helper 1 and T helper 17 lineage differentiation. An increasing succinate/α-KG ratio in SDH-deficient T cells promoted inflammation by changing the pattern of the transcriptional and chromatin accessibility signatures and consequentially increasing the expression of the transcription factor, PR domain zinc finger protein 1. Collectively, our studies revealed a role of SDH/complex II in allocating carbon resources for anabolic processes and epigenetic regulation in T cell proliferation and inflammation.National Institute of Health (Cancer Moonshot program) 1UO1CA232488-01United States Department of Health & Human Services National Institutes of Health (NIH) - USA 2R01AI114581-06 RO1CA247941V-Foundation V2014-001American Cancer Society 128436-RSG-15-180-01-LIBSBP NCI Cancer Center Support Grant P30 CA030199Markey Cancer Center Support Grant P30CA17755

A Metabolism Toolbox for CAR T Therapy

The adoptive transfer of T cells expressing chimeric antigen receptors (CARs) through genetic engineering is one of the most promising new therapies for treating cancer patients. A robust CAR T cell-mediated anti-tumor response requires the coordination of nutrient and energy supplies with CAR T cell expansion and function. However, the high metabolic demands of tumor cells compromise the function of CAR T cells by competing for nutrients within the tumor microenvironment (TME). To substantially improve clinical outcomes of CAR T immunotherapy while treating solid tumors, it is essential to metabolically prepare CAR T cells to overcome the metabolic barriers imposed by the TME. In this review, we discuss a potential metabolism toolbox to improve the metabolic fitness of CAR T cells and maximize the efficacy of CAR T therapy

Revisiting the Multisite Phosphorylation That Produces the M-Phase Supershift of Key Mitotic Regulators

The term M-phase supershift denotes the phosphorylation-dependent substantial increase in the apparent molecular weight of numerous proteins of varied biological functions during M-phase induction. Although the M-phase supershift of multiple key mitotic regulators has been attributed to the multisite phosphorylation catalyzed by the Cdk1/cyclin B/Cks complex, this view is challenged by multiple lines of paradoxical observations. To solve this problem, we reconstituted the M-phase supershift of Xenopus Cdc25C, Myt1, Wee1A, APC3, and Greatwall in Xenopus egg extracts and characterized the supershift-producing phosphorylations. Our results demonstrate that their M-phase supershifts are each due to simultaneous phosphorylation of a considerable portion of S/T/Y residues in a long intrinsically disordered region that is enriched in both S/T residues and S/TP motifs. Although the major mitotic kinases in Xenopus egg extracts, Cdk1, MAPK, Plx1, and RSK2, are able to phosphorylate the five mitotic regulators, they are neither sufficient nor required to produce the M-phase supershift. Accordingly, inhibition of the four major mitotic kinase activities in Xenopus oocytes did not inhibit the M-phase supershift in okadaic acid-induced oocyte maturation. These findings indicate that the M-phase supershift is produced by a previously unrecognized category of mitotic phosphorylation that likely plays important roles in M-phase induction

c-Myc Is a Universal Amplifier of Expressed Genes in Lymphocytes and Embryonic Stem Cells

SummaryThe c-Myc HLH-bZIP protein has been implicated in physiological or pathological growth, proliferation, apoptosis, metabolism, and differentiation at the cellular, tissue, or organismal levels via regulation of numerous target genes. No principle yet unifies Myc action due partly to an incomplete inventory and functional accounting of Myc’s targets. To observe Myc target expression and function in a system where Myc is temporally and physiologically regulated, the transcriptomes and the genome-wide distributions of Myc, RNA polymerase II, and chromatin modifications were compared during lymphocyte activation and in ES cells as well. A remarkably simple rule emerged from this quantitative analysis: Myc is not an on-off specifier of gene activity, but is a nonlinear amplifier of expression, acting universally at active genes, except for immediate early genes that are strongly induced before Myc. This rule of Myc action explains the vast majority of Myc biology observed in literature