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The bone marrow microenvironment (BMM) can regulate leukemia stem cells (LSCs) via secreted factors. Increasing evidence suggests that dissecting the mechanisms by which the BMM maintains LSCs may lead to the development of effective therapies for the eradication of leukemia. Inhibitor of DNA binding 1 (ID1), a key transcriptional regulator in LSCs, previously identified by us, controls cytokine production in the BMM, but the role of ID1 in acute myeloid leukemia (AML) BMM remains obscure. Here, we report that ID1 is highly expressed in the BMM of patients with AML, especially in BM mesenchymal stem cells, and that the high expression of ID1 in the AML BMM is induced by BMP6, secreted from AML cells. Knocking out ID1 in mesenchymal cells significantly suppresses the proliferation of cocultured AML cells. Loss of Id1 in the BMM results in impaired AML progression in AML mouse models. Mechanistically, we found that Id1 deficiency significantly reduces SP1 protein levels in mesenchymal cells cocultured with AML cells. Using ID1-interactome analysis, we found that ID1 interacts with RNF4, an E3 ubiquitin ligase, and causes a decrease in SP1 ubiquitination. Disrupting the ID1-RNF4 interaction via truncation in mesenchymal cells significantly reduces SP1 protein levels and delays AML cell proliferation. We identify that the target of Sp1, Angptl7, is the primary differentially expression protein factor in Id1-deficient BM supernatant fluid to regulate AML progression in mice. Our study highlights the critical role of ID1 in the AML BMM and aids the development of therapeutic strategies for AML.
Assuntos
Proteína 7 Semelhante a Angiopoietina , Proteína 1 Inibidora de Diferenciação , Leucemia Mieloide Aguda , Animais , Camundongos , Proteína 7 Semelhante a Angiopoietina/genética , Proteína 7 Semelhante a Angiopoietina/metabolismo , Medula Óssea/metabolismo , Modelos Animais de Doenças , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Microambiente Tumoral , Humanos , Proteína 1 Inibidora de Diferenciação/metabolismoRESUMO
The blue-light hazard (BLH) has raised concerns with the increasing applications of white light-emitting diodes (LEDs). Many researchers believed that the shorter wavelength or more light components generally resulted in more severe retinal damage. In this study, based on the conventional phosphor-coated white LED, we added azure (484 nm), cyan (511 nm), and red (664 nm) light to fabricate the low-hazard light source. The low-hazard light sources and conventional white LED illuminated 68 Sprague-Dawley (SD) rats for 7 days. Before and after light exposure, we measured the retinal function, thickness of retinal layers, and fundus photographs. The expression levels of autophagy-related proteins and the activities of oxidation-related biochemical indicators were also measured to investigate the mechanisms of damaging or protecting the retina. With the same correlated color temperature (CCT), the low-hazard light source results in significantly less damage on the retinal function and photoreceptors, even if it has two times illuminance and blue-light hazard-weighted irradiance ([Formula: see text]) than conventional white LED. The results illustrated that [Formula: see text] proposed by IEC 62471 could not exactly evaluate the light damage on rats' retinas. We also figured out that more light components could result in less light damage, which provided evidence for the photobiomodulation (PBM) and spectral opponency on light damage.
Assuntos
Luz , Retina , Ratos , Animais , Ratos Sprague-DawleyRESUMO
Micro-LEDs can work under an extremely high injection level and are widely used in high-brightness micro-displays and visible light communication. With the increase of carrier concentration, many-body effects gradually become important factors affecting devices' characteristics. Considering the effects of carrier scattering, bandgap renormalization, and Coulomb enhancement (CE), changes in the electroluminescence spectra of micro-LEDs are analyzed as the current density increases from 49.2 to 358.2 kA/cm2, the latter representing an ultra-high injection level. Affected by plasma screening, CE decreases below about 150 kA/cm2. After that, polarization screening dominates and effectively alleviates the spatial separation of electrons and holes, which results in CE increases to the maximum injection level of 358.2 kA/cm2. It is established that CE promotes radiative recombination processes. Different from the traditional phenomenon of "efficiency droop", the enhanced attraction between carriers leads to an abnormal increase of external quantum efficiency at high current density.
RESUMO
In this study, we propose a low-cost, simple and feasible post-processing approach to improve the light extraction efficiency (LEE) of LED packages. Amorphous photonic structures (APSs) with only short-range order are fabricated from anodic aluminum oxide (AAO) and transferred to intermediate polymer stamp (IPS) by nanoimprint technology. The IPS with APSs is directly mounted onto the surface of an LED package, where the LEE is achieved as 94.6%. The scanning electron microscope (SEM) images of AAO templates and imprinted IPS are analyzed by radial distribution function and diameter histogram. The far-field patterns of APS-mounted LED packages are measured in electroluminescence (EL). The three-dimensional finite-difference time-domain (3D-FDTD) calculations of transmittance of APSs confirm that they improve the light extraction above the critical angle. Two-dimensional Fourier power spectra from SEM images of APSs are also calculated. The LEE enhancement is attributed to that the APSs have short-range order on a length scale comparable to emission wavelength of LED. We provide novel multistage simulations in a simplified FDTD model for the LED package. Finally, we discuss the influence of the morphology of APSs on the LEE of the APS mounted LEDs.
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A significant variation in chromatin accessibility is an epigenetic feature of leukemia. The cause of this variation in leukemia, however, remains elusive. Here, we identify SMARCA5, a core ATPase of the imitation switch (ISWI) chromatin remodeling complex, as being responsible for aberrant chromatin accessibility in leukemia cells. We find that SMARCA5 is required to maintain aberrant chromatin accessibility for leukemogenesis and then promotes transcriptional activation of AKR1B1, an aldo/keto reductase, by recruiting transcription co-activator DDX5 and transcription factor SP1. Higher levels of AKR1B1 are associated with a poor prognosis in leukemia patients and promote leukemogenesis by reprogramming fructose metabolism. Moreover, pharmacological inhibition of AKR1B1 has been shown to have significant therapeutic effects in leukemia mice and leukemia patient cells. Thus, our findings link the aberrant chromatin state mediated by SMARCA5 to AKR1B1-mediated endogenous fructose metabolism reprogramming and shed light on the essential role of AKR1B1 in leukemogenesis, which may provide therapeutic strategies for leukemia.
Assuntos
Frutose , Humanos , Animais , Camundongos , Frutose/metabolismo , Cromatina/metabolismo , Aldeído Redutase/metabolismo , Aldeído Redutase/genética , Leucemia/metabolismo , Leucemia/patologia , Leucemia/genética , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Montagem e Desmontagem da Cromatina , Carcinogênese/metabolismo , Carcinogênese/patologia , Carcinogênese/genética , Linhagem Celular Tumoral , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Adenosina TrifosfatasesRESUMO
Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 (ROBO1) mutations in patients with MDS, while the exact role of ROBO1 in hematopoiesis remains poorly delineated. Here, we report that ROBO1 deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, Robo1 deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that Cdc42, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for Robo1 in HSPCs. Overexpression of Cdc42 partially restores the self-renewal and erythropoiesis of HSPCs in Robo1-deficient mice. Collectively, our result implicates the essential role of ROBO1 in maintaining HSPC homeostasis and erythropoiesis via CDC42.
Assuntos
Eritropoese , Síndromes Mielodisplásicas , Animais , Humanos , Camundongos , Eritropoese/genética , Síndromes Mielodisplásicas/genética , Proteínas do Tecido Nervoso/genética , Prognóstico , Receptores Imunológicos/genética , Proteínas RoundaboutRESUMO
Nanorod array and planar green-emission InGaN/GaN multi-quantum well (MQW) LEDs were fabricated by lithography, nano-imprinting, and top-down etching technology. The defect-pinning effect of the nanostructure was found for the first time. The ratio of the bright regions to the global area in the panchromatic CL images of green MQW samples increased from 30% to about 90% after nano-fabrication. The overall luminous performance significantly improved. Throughout temperature-dependent photoluminescence (TDPL) and time-resolved PL (TRPL) measurements, the migration and recombination of carriers in the MQWs of green LEDs were analyzed. It was proved that nanostructures can effectively prevent carriers from being captured by surrounding nonradiative recombination centers. The overall PL integral intensity can be enhanced to above 18 times. A much lower carrier lifetime (decreasing from 91.4 to 40.2 ns) and a higher internal quantum efficiency (IQE) (increasing from 16.9% to 40.7%) were achieved. Some disputes on the defect influence were also discussed and clarified.
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Aberrant self-renewal of leukemia initiation cells (LICs) drives aggressive acute myeloid leukemia (AML). Here, we report that UHRF1, an epigenetic regulator that recruits DNMT1 to methylate DNA, is highly expressed in AML and predicts poor prognosis. UHRF1 is required for myeloid leukemogenesis by maintaining self-renewal of LICs. Mechanistically, UHRF1 directly interacts with Sin3A-associated protein 30 (SAP30) through two critical amino acids, G572 and F573 in its SRA domain, to repress gene expression. Depletion of UHRF1 or SAP30 derepresses an important target gene, MXD4, which encodes a MYC antagonist, and leads to suppression of leukemogenesis. Further knockdown of MXD4 can rescue the leukemogenesis by activating the MYC pathway. Lastly, we identified a UHRF1 inhibitor, UF146, and demonstrated its significant therapeutic efficacy in the myeloid leukemia PDX model. Taken together, our study reveals the mechanisms for altered epigenetic programs in AML and provides a promising targeted therapeutic strategy against AML.
Assuntos
Leucemia Mieloide Aguda , Humanos , Carcinogênese , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Histona Desacetilases , Leucemia Mieloide Aguda/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismoRESUMO
Localized surface plasmon (LSP) coupling with many radiators are investigated. The LSP is generated by excitation of laser or electron beam on the random Ag nano particles (NPs) and arrayed ones embedded in the p-GaN of green LEDs. They couple with the excitons or radiative recombination in the quantum well (QW) and electron beam, which enhance or suppress the luminescence of the radiators. The photoluminescence (PL) intensity of periodic Ag NPs can get as much as 4.5 times higher than that of bare LED. In addition to the periodic structure, the morphology of Ag NPs also affects the localized SP (LSP) resonance intensity and light scattering efficiency. In the finite difference time domain (FDTD) simulation, five x-polarized dipoles are approximated to five quantum wells. Considering the interaction between the five dipoles and their feedback effect on LSP, the enhancement effect of SP dipole coupling with Ag NPs is amplified and the energy dissipation is reduced. The enhancement of cathodoluminescence (CL) was also found in green LEDs with Ag NPs. The three-body model composed of two orthogonal dipoles and an Ag NP is used for 3D FDTD simulation. The LSP-QWs coupling effect is separated from the electron beam (e-beam)-LSP-QW system by linear approximation. Under the excitation of electron beam, the introduction of z-dipole greatly reduces the energy dissipation. In the cross-sectional sample, z-polarized dipoles in QWs show more coupling strength to the dipole and quadrupole modes of LSP. The perturbation theory is used to separate the LSP coupling effects to x-dipole and z-dipole. At last, the resonator and the antenna effects are discussed for LSP coupling at different positions to the Ag NP.