Magnetic topological states refer to a class of exotic phases in magnetic materials with the non‐trivial topological property determined by magnetic spin configurations. An example of such states is ...the quantum anomalous Hall (QAH) state, which is a zero magnetic field manifestation of the quantum Hall effect. Current research in this direction focuses on QAH insulators with a thickness of less than 10 nm. Here, molecular beam epitaxy (MBE) is employed to synthesize magnetic TI trilayers with a thickness of up to ≈106 nm. It is found that these samples exhibit well‐quantized Hall resistance and vanishing longitudinal resistance at zero magnetic field. By varying the magnetic dopants, gate voltages, temperature, and external magnetic fields, the properties of these thick QAH insulators are examined and the robustness of the 3D QAH effect is demonstrated. The realization of the well‐quantized 3D QAH effect indicates that the nonchiral side surface states of the thick magnetic TI trilayers are gapped and thus do not affect the QAH quantization. The 3D QAH insulators of hundred‐nanometer thickness provide a promising platform for the exploration of fundamental physics, including axion physics and image magnetic monopole, and the advancement of electronic and spintronic devices to circumvent Moore's law.
The first work in synthesizing 3D quantum anomalous Hall (QAH) insulators with a thickness of one hundred nanometers, exceeding ten times the thickest QAH sample record, is reported. The hundred‐nanometer‐thick QAH insulators provide a promising platform for the exploration of the topological magnetoelectric effect, image magnetic monopole, as well as high‐order topological insulator (TI) phase.
The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Phila?delphia chromosome(Ph) and is a hallmark of chronic myeloid leukemia(CML).In leukemia ...cells,Ph not only impairs the physiological signaling pathways but also disrupts genomic stability.This aberrant fusion gene encodes the breakpoint cluster region?proto?oncogene tyrosine?protein kinase(BCR?ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity.The kinase activity is responsible for maintaining proliferation,inhibiting differentia?tion,and conferring resistance to cell death.During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase,the expression patterns of different BCR?ABL1 transcripts vary.Each BCR?ABL1 transcript is present in a distinct leukemia phenotype,which predicts both response to therapy and clinical outcome.Besides CML,the Ph is found in acute lymphoblastic leukemia,acute myeloid leukemia,and mixed?phenotype acute leukemia.Here,we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph?positive leukemia and highlight key findings regarding leukemogenesis.
Current chemotherapy regimens on acute myeloid leukemia (AML) still have some drawbacks, such as intolerance and drug resistance, which calls need for the development of targeted therapy. Signal ...transducer and activator of transcription 5 (STAT5) is often overexpressed or abnormally activated in leukemia and involved in cell self‐renewal, proliferation, and stress adaptation. Overexpressed Aurora A (AURKA) is associated with poor prognosis in tumors, and inhibitors against AURKA are already in clinical trials. However, it has rarely been reported whether AURKA inhibitors restrain STAT5‐activated leukemia cells. In this study, we constructed STAT5 constitutively activated (cS5) cells and found that STAT5 promoted cell proliferation and colony formation. Moreover, cS5 cells showed elevated reactive oxygen species (ROS) and adenosine triphosphate (ATP) levels, which indicated higher mitochondrial metabolism in cS5 cells. A novel AURKA inhibitor AKI604 was synthesized and showed significant inhibitory effects to the proliferation and colony formation in both STAT5 constitutively activated and nonactivated AML cells. AKI604 induced mitochondrial impairment, leading to the disruption of mitochondrial membrane potential and the elevation of ROS as well as cellular calcium (Ca2+) levels. AKI604 could also decline basal oxygen consumption rate and ATP biosynthesis, indicating the damage of oxidative phosphorylation. Furthermore, AKI604 exhibited significant antitumor effect in the HL‐60 cS5 xenograft model of the BALB/c nude mice without an obvious influence on mice body weight and other healthy indicators. This study suggested that AKI604 was a potential strategy to overcome STAT5‐induced leukemic proliferation in AML treatment by inducing mitochondrial impairment.
AKI604 exhibited significant antitumor effect both in vitro and in vivo by inducing mitochondrial impairment.
The mammalian target of rapamycin (mTOR) pathway plays critical roles in intrinsic chemoresistance by regulating Fanconi anaemia complementation group D2 (FANCD2) expression. However, the mechanisms ...by which mTOR regulates FANCD2 expression and related inhibitors are not clearly elucidated. Extracts of Centipeda minima (C. minima) showed promising chemosensitizing effects by inhibiting FANCD2 activity. Here, we have aimed to identify the bioactive chemosensitizer in C. minima extracts and elucidate its underlying mechanism.
The chemosensitizing effects of arnicolide C (ArC), a bioactive compound in C. minima, on non-small cell lung cancer (NSCLC) were investigated using immunoblotting, immunofluorescence, flow cytometry, the comet assay, small interfering RNA (siRNA) transfection and animal models. The online SynergyFinder software was used to determine the synergistic effects of ArC and chemotherapeutic drugs on NSCLC cells.
ArC had synergistic cytotoxic effects with DNA cross-linking drugs such as cisplatin and mitomycin C in NSCLC cells. ArC treatment markedly decreased FANCD2 expression in NSCLC cells, thus attenuating cisplatin-induced FANCD2 nuclear foci formation, leading to DNA damage and apoptosis. ArC inhibited the mTOR pathway and attenuated mTOR-mediated expression of E2F1, a critical transcription factor of FANCD2. Co-administration of ArC and cisplatin exerted synergistic anticancer effects in the A549 xenograft mouse model by suppressing mTOR/FANCD2 signalling in tumour tissues.
ArC suppressed DNA cross-linking drug-induced DNA damage response by inhibiting the mTOR/E2F1/FANCD2 signalling axis, serving as a chemosensitizing agent. This provides insight into the anticancer mechanisms of ArC and offers a potential combinatorial anticancer therapeutic strategy.
This study aims to investigate the anticancer properties of Citrus grandis 'Tomentosa' (CGT) in non-small cell lung cancer (NSCLC).
The ethanol extract of CGT (CGTE) is prepared by using anhydrous ...ethanol and analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), revealing that the main chemical components in CGTE are flavonoids and coumarins, such as naringin, rhoifolin, apigenin, bergaptol, and osthole. CGTE at concentrations without inducing cell death significantly inhibits cell proliferation via inducing cell cycle G1 phase arrest by MTT, colony formation, and flow cytometry assays, implying that CGT has anticancer potential. CGTE markedly inhibits the activity of Skp2-SCF E3 ubiquitin ligase, decreases the protein level of Skp2, and promotes the accumulation of p27 by co-immunoprecipitation (co-IP) and in vivo ubiquitination assay; whereas Skp2 overexpression rescues the effects of CGTE in NSCLC cells. In subcutaneous LLC allograft and A549 xenograft mouse models, CGTE, without causing obvious side effects in mice, significantly inhibits lung tumor growth by targeting the Skp2/p27 signaling pathway.
These findings demonstrate that CGTE efficiently inhibits NSCLC proliferation both in vitro and in vivo by targeting the Skp2/p27 signaling pathway, suggesting that CGTE may serve as a therapeutic candidate for NSCLC treatment.
Abstract
An axion insulator is a three-dimensional (3D) topological insulator (TI), in which the bulk maintains the time-reversal symmetry or inversion symmetry but the surface states are gapped by ...surface magnetization. The axion insulator state has been observed in molecular beam epitaxy (MBE)-grown magnetically doped TI sandwiches and exfoliated intrinsic magnetic TI MnBi
2
Te
4
flakes with an even number layer. All these samples have a thickness of ~ 10 nm, near the 2D-to-3D boundary. The coupling between the top and bottom surface states in thin samples may hinder the observation of quantized topological magnetoelectric response. Here, we employ MBE to synthesize magnetic TI sandwich heterostructures and find that the axion insulator state persists in a 3D sample with a thickness of ~ 106 nm. Our transport results show that the axion insulator state starts to emerge when the thickness of the middle undoped TI layer is greater than ~ 3 nm. The 3D hundred-nanometer-thick axion insulator provides a promising platform for the exploration of the topological magnetoelectric effect and other emergent magnetic topological states, such as the high-order TI phase.
One-dimensional chiral interface channels can be created at the boundary of two quantum anomalous Hall (QAH) insulators with different Chern numbers. Such a QAH junction may function as a chiral edge ...current distributer at zero magnetic field, but its realization remains challenging. Here, by employing an in-situ mechanical mask, we use molecular beam epitaxy to synthesize QAH insulator junctions, in which two QAH insulators with different Chern numbers are connected along a one-dimensional junction. For the junction between Chern numbers of 1 and -1, we observe quantized transport and demonstrate the appearance of the two parallel propagating chiral interface channels along the magnetic domain wall at zero magnetic field. For the junction between Chern numbers of 1 and 2, our quantized transport shows that a single chiral interface channel appears at the interface. Our work lays the foundation for the development of QAH insulator-based electronic and spintronic devices and topological chiral networks.
Background
Declined skeletal muscle mass and function are inevitable consequences of long‐term diabetes and bring about many adverse events. Muscle fibre atrophy and interstitial fibrosis are major ...pathological manifestations of diabetic sarcopenia. Stimulator of interferon genes (STING) participates in various metabolic diseases. We aimed to explore whether and how STING regulates the above pathological manifestations of diabetic sarcopenia.
Methods
Wild‐type and STINGgt/gt C57BL/6J mice and C2C12 myotubes were used to study the role of STING in the regulation of diabetic sarcopenia and the underlying mechanisms.
Results
STING was abnormally activated in diabetic muscles and in PA‐treated myotubes (P < 0.01 for all parameters). The diabetic mice demonstrated decreased forelimb grip strength, lean mass, muscle weight and hanging impulse, which were improved by STING deficiency due to alleviated muscle fibre atrophy and interstitial fibrosis (P < 0.05 for all parameters). STING deficiency alleviated muscle fibre atrophy through the following mechanisms. Firstly, STING deficiency or inhibition increased the contents of pDRP1Ser616, PINK1, Parkin and LC3‐II, decreased p62 content, and increased the amount of mito‐Keima fluorescent dots at 578 nm in diabetic state (P < 0.05 for all parameters), suggesting improved mitofission and mitophagy. Secondly, STING deficiency or inhibition increased the expression of pAKTSer473 and GLUT4 post‐insulin change in diabetic state (P < 0.05 for all), indicating alleviated insulin resistance (IR). Mechanically, STING deficiency or inhibition increased peroxisome proliferator activated receptors γ (PPARγ) protein content by reducing the degradation of ubiquitinated PPARγ through the proteasome pathway and thus increased the expression of fatty acid oxidation (FAO)‐related proteins in diabetic state (P < 0.05 for all parameters). Decreased expression of FAO‐related proteins caused by PPARγ inhibition abolished the improvements in mitofission, mitophagy and IR achieved by STING inhibition in PA‐treated myotubes and thus promoted muscle fibre atrophy (P < 0.05 for all parameters). STING deficiency alleviated interstitial fibrosis by decreasing TGFβ1 expression in diabetic state and TGFβ1 promoted the fibrogenic differentiation of fibro‐adipogenic progenitors (P < 0.05 for all parameters). PPARγ inhibition abolished the effect of STING inhibition on reducing TGFβ1 content in PA‐treated myotubes (P < 0.01).
Conclusions
STING deficiency exerted protective effects in diabetic sarcopenia by inhibiting the degradation of ubiquitinated PPARγ through the proteasome pathway and enhancing PPARγ‐mediated FAO, which alleviated muscle fibre atrophy by promoting mitophagy and ameliorating IR, and alleviated interstitial fibrosis by reducing TGFβ1 production and suppressing the fibrogenic differentiation of fibro‐adipogenic progenitors.
The interface between two different materials can show unexpected quantum phenomena. In this study, we used molecular beam epitaxy to synthesize heterostructures formed by stacking together two ...magnetic materials, a ferromagnetic topological insulator (TI) and an antiferromagnetic iron chalcogenide (FeTe). We observed emergent interface-induced superconductivity in these heterostructures and demonstrated the co-occurrence of superconductivity, ferromagnetism, and topological band structure in the magnetic TI layer-the three essential ingredients of chiral topological superconductivity (TSC). The unusual coexistence of ferromagnetism and superconductivity is accompanied by a high upper critical magnetic field that exceeds the Pauli paramagnetic limit for conventional superconductors at low temperatures. These magnetic TI/FeTe heterostructures with robust superconductivity and atomically sharp interfaces provide an ideal wafer-scale platform for the exploration of chiral TSC and Majorana physics.
•The erosion of grouting material by chloride ion was studied.•Nano-clay additive and high water-cement ratio were studied.•The nano-clay has greatly improved the resistance of chloride ion ...erosion.•The real engineering condition is simulated, the specimens are not cured.•The effect of nano-clay on the hydration and microstructure changed obviously.
The main objective of this study was to investigate the influence of nano-clay (NC) on the mechanical and microcosmic properties of sulfoaluminate cement grouting material in 5% sodium chloride (NaCl) solution. All specimens were prepared with a water/cement ratio (W/C) of 1.0. The setting time, bleeding ratio, flow time, mass change rate, and uniaxial compressive strength were obtained by various tests. Further, the resistance toward chloride ion penetration and the permeability of pastes were also evaluated. Hydration products and micro-morphology were investigated through X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscope, and energy dispersive spectroscopy. The test results revealed that with the addition of NC, both the setting time and flow time were significantly shortened and bleeding capacity and mass loss rate decreased; nonetheless, the uniaxial compressive strength increased significantly. Moreover, addition of NC reduced the chloride ion penetration and permeability. Furthermore, the theoretical model based on permeability and immersion time was established, and its correctness was successfully verified by experimental data. As a result, the grouting material with added 2% NC exhibited the best experimental performance, whereas 3% and more content of NC resulted in inferior performance; however, it was still better than that of the control group (NC = 0%). Moreover, microcosmic test results showed that ettringite is the main product of the dominant hydration reaction. It was thus proved that NC could promote the hydration process, and thus it weakens the chloride ion erosion due to the porosity reduction effect.
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