Cross-presentation of glycolipid from tumor cells loaded with α-galactosylceramide leads to potent and long-lived T cell-mediated immunity via dendritic cells

We report a mechanism to induce combined and long-lived CD4+ and CD8+ T cell immunity to several mouse tumors. Surprisingly, the initial source of antigen is a single low dose of tumor cells loaded with α-galactosylceramide (α-GalCer) glycolipid (tumor/Gal) but lacking co-stimulatory molecules. After tumor/Gal injection intravenously (i.v.), innate NKT and NK cells reject the tumor cells, some of which are taken up by dendritic cells (DCs). The DCs in turn cross-present glycolipid on CD1d molecules to NKT cells and undergo maturation. For B16 melanoma cells loaded with α-GalCer (B16/Gal), interferon γ-producing CD8+ T cells develop toward several melanoma peptides, again after a single low i.v. dose of B16/Gal. In all four poorly immunogenic tumors tested, a single dose of tumor/Gal i.v. allows mice to become resistant to tumors given subcutaneously. Resistance requires CD4+ and CD8+ cells, as well as DCs, and persists for 6-12 mo. Therefore, several immunogenic features of DCs are engaged by the CD1d-mediated cross-presentation of glycolipid-loaded tumor cells, leading to particularly strong and long-lived adaptive immunity

Nanoscale imaging of equilibrium quantum Hall edge currents and of the magnetic monopole response in graphene

The recently predicted topological magnetoelectric effect and the response to an electric charge that mimics an induced mirror magnetic monopole are fundamental attributes of topological states of matter with broken time reversal symmetry. Using a SQUID-on-tip, acting simultaneously as a tunable scanning electric charge and as ultrasensitive nanoscale magnetometer, we induce and directly image the microscopic currents generating the magnetic monopole response in a graphene quantum Hall electron system. We find a rich and complex nonlinear behavior governed by coexistence of topological and nontopological equilibrium currents that is not captured by the monopole models. Furthermore, by utilizing a tuning fork that induces nanoscale vibrations of the SQUID-on-tip, we directly image the equilibrium currents of individual quantum Hall edge states for the first time. We reveal that the edge states that are commonly assumed to carry only a chiral downstream current, in fact carry a pair of counterpropagating currents, in which the topological downstream current in the incompressible region is always counterbalanced by heretofore unobserved nontopological upstream current flowing in the adjacent compressible region. The intricate patterns of the counterpropagating equilibrium-state orbital currents provide new insights into the microscopic origins of the topological and nontopological charge and energy flow in quantum Hall systems

Suppression of cell migration by phospholipase C-related catalytically inactive protein-dependent modulation of PI3K signalling

The metabolic processes of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] into PI(3,4,5)P3 and the subsequent PI(3,4,5)P3 signalling are involved in cell migration. Dysfunctions in the control of this pathway can cause human cancer cell migration and metastatic growth. Here we investigated whether phospholipase C-related catalytically inactive protein (PRIP), a PI(4,5)P2-binding protein, regulates cancer cell migration. PRIP overexpression in MCF-7 and BT-549 human breast cancer cells inhibited cell migration in vitro and metastasis development in vivo. Overexpression of the PRIP pleckstrin homology domain, a PI(4,5)P2 binding motif, in MCF-7 cells caused significant suppression of cell migration. Consistent with these results, in comparison with wild-type cells, Prip-deficient mouse embryonic fibroblasts exhibited increased cell migration, and this was significantly attenuated upon transfection with a siRNA targeting p110α, a catalytic subunit of class I phosphoinositide 3-kinases (PI3Ks). PI(3,4,5)P3 production was decreased in Prip-overexpressing MCF-7 and BT-549 cells. PI3K binding to PI(4,5)P2 was significantly inhibited by recombinant PRIP in vitro, and thus the activity of PI3K was downregulated. Collectively, PRIP regulates the production of PI(3,4,5)P3 from PI(4,5)P2 by PI3K, and the suppressor activity of PRIP in PI(4,5)P2 metabolism regulates the tumour migration, suggesting PRIP as a promising target for protection against metastatic progression.This work was supported by grants from JSPS KAKENHI Grant Numbers JP15K20372, JP17K11644, JP16K11503

Androgen’s effects in female

The metabolic effects of androgens and their underlying mechanisms in females have been revealed by recent studies. An excess of androgens can have adverse effects on feeding behavior and metabolic functions and induce metabolic disorders / diseases, such as obesity, insulin resistance, and diabetes, in women and experimental animals of reproductive age. Interestingly, these effects of androgens are not observed in ovariectomized animals, indicating that their effects might be dependent on the estrogen milieu. Central and peripheral mechanisms, such as alterations in the activity of hypothalamic factors, reductions in energy expenditure, skeletal muscle insulin resistance, and β-cell dysfunction, might be related to these androgens’ effects

Imaging de Haas-van Alphen quantum oscillations and milli-Tesla pseudomagnetic fields

A unique attribute of atomically thin quantum materials is the in-situ tunability of their electronic band structure by externally controllable parameters like electrostatic doping, electric field, strain, electron interactions, and displacement or twisting of atomic layers. This unparalleled control of the electronic bands has led to the discovery of a plethora of exotic emergent phenomena. But despite its key role, there is currently no versatile method for mapping the local band structure in advanced 2D materials devices in which the active layer is commonly embedded in various insulating layers and metallic gates. Utilizing a scanning superconducting quantum interference device, we image the de Haas-van Alphen quantum oscillations in a model system, the Bernal-stacked trilayer graphene with dual gates, which displays multiple highly-tunable bands. By resolving thermodynamic quantum oscillations spanning over 100 Landau levels in low magnetic fields, we reconstruct the band structure and its controllable evolution with the displacement field with unprecedented precision and spatial resolution of 150 nm. Moreover, by developing Landau level interferometry, we reveal shear-strain-induced pseudomagnetic fields and map their spatial dependence. In contrast to artificially-induced large strain, which leads to pseudomagnetic fields of hundreds of Tesla, we detect naturally occurring pseudomagnetic fields as low as 1 mT corresponding to graphene twisting by just 1 millidegree over one {\mu}m distance, two orders of magnitude lower than the typical angle disorder in high-quality twisted bilayer graphene devices. This ability to resolve the local band structure and strain on the nanoscale opens the door to the characterization and utilization of tunable band engineering in practical van der Waals devices.Comment: Nature (2023

The Kiloparsec-scale Neutral Atomic Carbon Outflow in the Nearby Type-2 Seyfert Galaxy NGC 1068: Evidence for Negative AGN Feedback

Active galactic nucleus (AGN) feedback is postulated as a key mechanism for regulating star formation within galaxies. Studying the physical properties of the outflowing gas from AGN is thus crucial for understanding the co-evolution of galaxies and supermassive black holes. Here we report 55 pc resolution ALMA neutral atomic carbon [CI] $^3P_1\text{-}^3P_0$ observations toward the central 1 kpc of the nearby type-2 Seyfert galaxy NGC 1068, supplemented by 55 pc resolution CO($J=1\text{-}0$) observations. We find that [CI] emission within the central kpc is strongly enhanced by a factor of $>$5 compared to the typical [CI]/CO intensity ratio of $\sim$0.2 for nearby starburst galaxies (in units of brightness temperature). The most [CI]-enhanced gas (ratio $>$ 1) exhibits a kpc-scale elongated structure centered at the AGN that matches the known biconical ionized gas outflow entraining molecular gas in the disk. A truncated, decelerating bicone model explains well the kinematics of the elongated structure, indicating that the [CI] enhancement is predominantly driven by the interaction between the ISM in the disk and the highly inclined ionized gas outflow (which is likely driven by the radio jet). Our results strongly favor the "CO dissociation scenario" rather than the "in-situ C formation" one which prefers a perfect bicone geometry. We suggest that the high [CI]/CO intensity ratio gas in NGC 1068 directly traces ISM in the disk that is currently dissociated and entrained by the jet and the outflow, i.e., the "negative" effect of the AGN feedback.Comment: 12 pages, 5 figures, accepted for publication in The Astrophysical Journal Letter

de Haas-van Alphen spectroscopy and fractional quantization of magnetic-breakdown orbits in moir\'e graphene

Quantum oscillations originating from the quantization of the electron cyclotron orbits provide ultrasensitive diagnostics of electron bands and interactions in novel materials. We report on the first direct-space nanoscale imaging of the thermodynamic magnetization oscillations due to the de Haas-van Alphen effect in moir\'e graphene. Scanning by SQUID-on-tip in Bernal bilayer graphene crystal-axis-aligned to hBN reveals abnormally large magnetization oscillations with amplitudes reaching 500 {\mu}_B/electron in weak magnetic fields, unexpectedly low frequencies, and high sensitivity to the superlattice filling fraction. The oscillations allow us to reconstruct the complex band structure in exquisite detail, revealing narrow moir\'e bands with multiple overlapping Fermi surfaces separated by unusually small momentum gaps. We identify distinct sets of oscillations that violate the textbook Onsager Fermi surface sum rule, signaling formation of exotic broad-band particle-hole superposition states induced by coherent magnetic breakdown.Comment: 30 pages, 5 main text figures, 6 supplementary figure