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Topology 1-3  and interactions are foundational concepts in the modern understanding of quantum matter. Their nexus yields three important research directions: (1) the competition between distinct interactions, as in several intertwined phases, (2) the interplay between interactions and topology that drives the phenomena in twisted layered materials and topological magnets, and (3) the coalescence of several topological orders to generate distinct novel phases. The first two examples have grown into major areas of research, although the last example remains mostly unexplored, mainly because of the lack of a material platform for experimental studies. Here, using tunnelling microscopy, photoemission spectroscopy and a theoretical analysis, we unveil a 'hybrid' topological phase of matter in the simple elemental-solid arsenic. Through a unique bulk-surface-edge correspondence, we uncover that arsenic features a conjoined strong and higher-order topology that stabilizes a hybrid topological phase. Although momentum-space spectroscopy measurements show signs of topological surface states, real-space microscopy measurements unravel a unique geometry of topologically induced step-edge conduction channels revealed on various natural nanostructures on the surface. Using theoretical models, we show that the existence of gapless step-edge states in arsenic relies on the simultaneous presence of both a non-trivial strong Z 2 invariant and a non-trivial higher-order topological invariant, which provide experimental evidence for hybrid topology. Our study highlights pathways for exploring the interplay of different band topologies and harnessing the associated topological conduction channels in engineered quantum or nano-devices., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Quantum phases can be classified by topological invariants, which take on discrete values capturing global information about the quantum state 1-13 . Over the past decades, these invariants have come to play a central role in describing matter, providing the foundation for understanding superfluids 5 , magnets 6,7 , the quantum Hall effect 3,8 , topological insulators 9,10 , Weyl semimetals 11-13 and other phenomena. Here we report an unusual linking-number (knot theory) invariant associated with loops of electronic band crossings in a mirror-symmetric ferromagnet 14-20 . Using state-of-the-art spectroscopic methods, we directly observe three intertwined degeneracy loops in the material's three-torus, T 3 , bulk Brillouin zone. We find that each loop links each other loop twice. Through systematic spectroscopic investigation of this linked-loop quantum state, we explicitly draw its link diagram and conclude, in analogy with knot theory, that it exhibits the linking number (2, 2, 2), providing a direct determination of the invariant structure from the experimental data. We further predict and observe, on the surface of our samples, Seifert boundary states protected by the bulk linked loops, suggestive of a remarkable Seifert bulk-boundary correspondence. Our observation of a quantum loop link motivates the application of knot theory to the exploration of magnetic and superconducting quantum matter., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The quantum-level interplay between geometry, topology and correlation is at the forefront of fundamental physics 1-15 . Kagome magnets are predicted to support intrinsic Chern quantum phases owing to their unusual lattice geometry and breaking of time-reversal symmetry 14,15 . However, quantum materials hosting ideal spin-orbit-coupled kagome lattices with strong out-of-plane magnetization are lacking 16-21 . Here, using scanning tunnelling microscopy, we identify a new topological kagome magnet, TbMn 6 Sn 6 , that is close to satisfying these criteria. We visualize its effectively defect-free, purely manganese-based ferromagnetic kagome lattice with atomic resolution. Remarkably, its electronic state shows distinct Landau quantization on application of a magnetic field, and the quantized Landau fan structure features spin-polarized Dirac dispersion with a large Chern gap. We further demonstrate the bulk-boundary correspondence between the Chern gap and the topological edge state, as well as the Berry curvature field correspondence of Chern gapped Dirac fermions. Our results point to the realization of a quantum-limit Chern phase in TbMn 6 Sn 6 , and may enable the observation of topological quantum phenomena in the RMn 6 Sn 6 (where R is a rare earth element) family with a variety of magnetic structures. Our visualization of the magnetic bulk-boundary-Berry correspondence covering real space and momentum space demonstrates a proof-of-principle method for revealing topological magnets.

Aberrant methylated genes (DMGs) play an important role in the etiology and pathogenesis of esophageal squamous cell carcinoma (ESCC). In this study, we aimed to integrate three cohorts profile datasets to ascertain aberrant methylated-differentially expressed genes and pathways associated with ESCC by comprehensive bioinformatics analysis. We downloaded data of gene expression microarrays (GSE20347, GSE38129) and gene methylation microarrays (GSE52826) from the Gene Expression Omnibus (GEO) database. Aberrantly differentially expressed genes (DEGs) were obtained by GEO2R tool. The David database was then used to perform Gene ontology (GO) analysis and Kyoto Encyclopedia of Gene and Genome pathway enrichment analyses on selected genes. STRING and Cytoscape software were used to construct a protein-protein interaction (PPI) network, then the modules in the PPI networks were analyzed with MCODE and the hub genes chose from the PPI networks were verified by Oncomine and TCGA database. In total, 291 hypomethylation-high expression genes and 168 hypermethylation-low expression genes were identified at the screening step, and finally found six mostly changed hub genes including KIF14, CDK1, AURKA, LCN2, TGM1, and DSG1. Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process. After validation in multiple databases, most hub genes remained significant. Patients with high expression of AURKA were associated with shorter overall survival. To summarize, we have identified six feasible aberrant methylated-differentially expressed genes and pathways in ESCC by bioinformatics analysis, potentially providing valuable information for the molecular mechanisms of ESCC. Our data combined the analysis of gene expression profiling microarrays and gene methylation profiling microarrays, simultaneously, and in this way, it can shed a light for screening and diagnosis of ESCC in future.

Chemoresistance remains a major obstacle to successful treatment of breast cancer. Although soluble tumor necrosis factor-α (sTNF-α) has been implicated in mediating drug-resistance in human cancers, whether transmembrane tumor necrosis factor-α (tmTNF-α) plays a role in chemoresistance remains unclear. Here we found that over 50% of studied patients expressed tmTNF-α at high levels in breast cancer tissues and tmTNF-α expression positively correlated with resistance to anthracycline chemotherapy. Alteration of tmTNF-α expression changed the sensitivity of primary human breast cancer cells and breast cancer cell lines to doxorubicin (DOX). Overexpression of N-terminal fragment (NTF) of tmTNF-α, a mutant form with intact intracellular domain of tmTNF-α to transmit reverse signals, induced DOX-resistance. Mechanistically, the tmTNF-α/NTF-ERK-GST-π axis and tmTNF-α/NTF-NF-κB-mediated anti-apoptotic functions were required for tmTNF-α-induced DOX-resistance. In a xenograft mouse model, the combination of tmTNF-α suppression with chemotherapy significantly enhanced the efficacy of DOX. Our data indicate that tmTNF-α mediates DOX-resistance through reverse signaling and targeting tmTNF-α may be beneficial for the treatment of DOX-resistant breast cancer.

Tumor necrosis factor-alpha (TNF-α) exists in two forms: secretory TNF-α (sTNF-α) and transmembrane TNF-α (tmTNF-α). Although both forms of TNF-α induce tumor cell apoptosis, tmTNF-α is able to kill tumor cells that are resistant to sTNF-α-mediated cytotoxicity, indicating their differences in signal transduction. Here, we demonstrate that internalization of TNFR1 is crucial for sTNF-α- but not for tmTNF-α-induced apoptosis. sTNF-α induces binding of tumor necrosis factor receptor type 1-associated death domain protein (TRADD) to the death domain (DD) of TNFR1 and subsequent activation of nuclear factor kappa B (NF-κB), and the formation of death-inducing signaling complexes (DISCs) in the cytoplasm after internalization. In contrast, tmTNF-α induces DISC formation on the membrane in a DD-independent manner. It leads to the binding of signal transducer and activator of transcription 1 (STAT1) to a region spanning amino acids 319-337 of TNFR1 and induces phosphorylation of serine at 727 of STAT1. The phosphorylation of STAT1 promotes its binding to TRADD, and thus recruits Fas-associated protein with DD (FADD) and caspase 8 to form DISC complexes. This STAT1-dependent signaling results in apoptosis but not NF-κB activation. STAT1-deficiency in U3A cells counteracts tmTNF-α-induced DISC formation and apoptosis. Conversely, reconstitution of STAT1 expression restores tmTNF-α-induced apoptotic signaling in the cell line. Consistently, tmTNF-α suppresses the growth of STAT1-containing HT1080 tumors, but not of STAT1-deficient U3A tumors in vivo. Our data reveal an unappreciated molecular mechanism of tmTNF-α-induced apoptosis and may provide a new clue for cancer therapy.

Bone regeneration required suitable scaffolding materials to support the proliferation and osteogenic differentiation of bone-related cells. In this study, a kind of hybridized nanofibrous scaffold material (CNF/BG) was prepared by incorporating bioactive glass (BG) nanoparticles into carbon nanofibers (CNF) via the combination of BG sol-gel and polyacrylonitrile (PAN) electrospinning, followed by carbonization. Three types (49 s, 68 s and 86 s) of BG nanoparticles were incorporated. To understand the mechanism of CNF/BG hybrids exerting osteogenic effects, bone marrow mesenchymal stromal cells (BMSCs) were cultured directly on these hybrids (contact culture) or cultured in transwell chambers in the presence of these materials (non-contact culture). The contributions of ion release and contact effect on cell proliferation and osteogenic differentiation were able to be correlated. It was found that the ionic dissolution products had limited effect on cell proliferation, while they were able to enhance osteogenic differentiation of BMSCs in comparison with pure CNF. Differently, the proliferation and osteogenic differentiation were both significantly promoted in the contact culture. In both cases, CNF/BG(68 s) showed the strongest ability in influencing cell behaviors due to its fastest release rate of soluble silicium-relating ions. The synergistic effect of CNF and BG would make CNF/BG hybrids promising substrates for bone repairing.

The roles of EZH2 in various subsets of CD4(+) T cells are controversial and its mechanisms of action are incompletely understood. FOXP3-positive Treg cells are a critical helper T cell subset, and dysregulation of Treg generation or function results in systemic autoimmunity. FOXP3 associates with EZH2 to mediate gene repression and suppressive function. Herein, we demonstrate that deletion of Ezh2 in CD4 T cells resulted in reduced numbers of Treg cells in vivo and differentiation in vitro and an increased proportion of memory CD4 T cells in part due to exaggerated production of effector cytokines. Furthermore, we found that both Ezh2-deficient Treg cells and T effector cells were functionally impaired in vivo: Tregs failed to constrain autoimmune colitis and T effector cells neither provided a protective response to T. gondii infection nor mediated autoimmune colitis. The dichotomous function of EZH2 in regulating differentiation and senescence in effector and regulatory T cells helps to explain the apparent existing contradictions in literature.

Analagous to a long-ranged rocket equipped with multi-stage engines, a luminescent compound with consistent emission signals across a large range of concentrations from two stages of sensitizers can be designed. In this approach, ACQ, aggregation-caused quenching effect of sensitizers, would stimulate lanthanide emission below 10(-4) M, and then at concentrations higher than 10(-3) M, the "aggregation-induced emission" (AIE) effect of luminophores would be activated with the next set of sensitizers for lanthanide emission. Simultaneously, the concentration of the molecules could be monitored digitally by the maximal excitation wavelengths, due to the good linear relationship between the maximal excitation wavelengths and the concentrations {lg(M)}. This model, wherein molecules are assembled with two stages (both AIE and ACQ effect) of sensitizers, may provide a practicable strategy for design and construction of smart lanthanide bioprobes, which are suitable in complicated bioassay systems in which concentration is variable.

Overexpression of the Yes-associated protein (YAP), and TP53 family members ΔNp63 and p73, have been independently detected in subsets of head and neck squamous cell carcinomas (HNSCCs). YAP may serve as a nuclear cofactor with ΔNp63 and p73, but the functional role of YAP and their potential relationship in HNSCCs are unknown. In this study, we show that in a subset of HNSCC lines and tumors, YAP expression is increased but localized in the cytoplasm in association with increased AKT and YAP phosphorylation, and with decreased expression of ΔNp63 and p73. In another subset, YAP expression is decreased but detectable in the nucleus in association with lower AKT and YAP phosphorylation, and with increased ΔNp63 and p73 expression. Inhibiting AKT decreased serine-127 phosphorylation and enhanced nuclear translocation of YAP. ΔNp63 bound to the YAP promoter and suppressed its expression. Transfection of a YAP-serine-127-alanine phosphoacceptor-site mutant or ΔNp63 knockdown significantly increased nuclear YAP and cell death. Conversely, YAP knockdown enhanced cell proliferation, survival, migration and cisplatin chemoresistance. Thus, YAP function as a tumor suppressor may alternatively be dysregulated by AKT phosphorylation at serine-127 and cytoplasmic sequestration, or by transcriptional repression by ΔNp63, in different subsets of HNSCC. AKT and/or ΔNp63 are potential targets for enhancing YAP-mediated apoptosis and chemosensitivity in HNSCCs.

CD4(+) T-helper cells that selectively produce interleukin (IL)-17 (T(H)17), are critical for host defence and autoimmunity. Although crucial for T(H)17 cells in vivo, IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been proposed to be the factors responsible for initiating specification. Here we show that T(H)17 differentiation can occur in the absence of TGF-β signalling. Neither IL-6 nor IL-23 alone efficiently generated T(H)17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naive precursors, independently of TGF-β. Epigenetic modification of the Il17a, Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed RORγt (encoded by Rorc) and T-bet. T-bet(+)RORγt(+) T(H)17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred T(H)17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data indicate an alternative mode for T(H)17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore may have therapeutic implications.

Small DNA lesions such as oxidized or alkylated bases are repaired by the base excision repair (BER) pathway. BER includes removal of the damaged base by a lesion-specific DNA glycosylase, strand scission by apurinic/apyrimidinic endonuclease, DNA resynthesis and ligation. BER may be further subdivided into DNA beta-polymerase (beta-pol)-dependent single-nucleotide repair and beta-pol-dependent or -independent long patch repair subpathways. Two important enzymatic steps in mammalian single-nucleotide BER are contributed by beta-pol: DNA resynthesis of the repair patch and lyase removal of 5'-deoxyribose phosphate (dRP). Fibroblasts from beta-pol null mice are hypersensitive to mono-functional DNA-methylating agents, resulting in increases in chromosomal damage, apoptosis and necrotic cell death. Here we show that only the dRP lyase activity of beta-pol is required to reverse methylating agent hypersensitivity in beta-pol null cells. These results indicate that removal of the dRP group is a pivotal step in BER in vivo. Persistence of the dRP moiety in DNA results in the hypersensitivity phenotype of beta-pol null cells and may signal downstream events such as apoptosis and necrotic cell death.

To examine potential intracellular signalling abnormalities of endothelin-1 (ET-1) and vasopressin (AVP) which may contribute to blood pressure elevation, contractility and inositol phosphate levels in intact arteries and calcium transients in vascular smooth muscle cells were investigated after stimulation with these peptides in pre-hypertensive 5 week-old spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. Contractility of aorta in response to ET-1, AVP and norepinephrine (NE) was blunted in SHR relative to WKY. Contraction of mesenteric resistance arteries induced by ET-1 was similar in both groups, whereas sensitivity in response to NE and AVP was greater in SHR. Basal inositol phosphate in aorta and mesenteric arteries was elevated in SHR, but ET-1 and AVP-stimulated inositol phosphate responses were similar in both groups. Calcium transients induced by ET-1 and AVP in vascular smooth muscle cells were similar in young SHR and WKY. In contrast, in adult rats inositol phosphate responses to ET-1 were blunted in aorta of SHR, but were normal in mesenteric arteries. Inositol phosphate responses to AVP were similar in both rat strains of rats both in aorta and mesenteric arteries except for accumulation of inositol trisphosphate, which was enhanced in mesenteric arteries of SHR. Calcium mobilization in vascular smooth muscle cells from adult SHR also exhibited enhanced responses to AVP. In conclusion, in young SHR, blunted ET-1 and AVP-induced contraction in aorta and enhanced AVP-induced mesenteric artery contraction are associated with normal inositol phosphate production and calcium mobilization. Signal transduction in response to ET-1 and AVP is depressed in aorta of pre-hypertensive SHR after the step of inositol phosphate generation and calcium mobilization. Resistance vessel reactivity to AVP is enhanced in young SHR at steps following inositol phosphate generation and calcium mobilization. These results argue against a role of ET-1, but suggest the possible involvement of AVP in the development of this model of genetic hypertension.