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Elife ; 82019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31318331


Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS, thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.

Drosophila melanogaster/fisiologia , Retroalimentação Fisiológica , Ácido Glutâmico/toxicidade , Neurônios Motores/fisiologia , Neurotoxinas/toxicidade , Espécies Reativas de Oxigênio/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neurônios Motores/efeitos dos fármacos , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/metabolismo , Estresse Oxidativo/efeitos dos fármacos
J Immunother Cancer ; 6(1): 144, 2018 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-30526672


Immunotherapy has ushered in a new era of cancer therapy, and this is also applicable to therapy of hepatocellular carcinoma (HCC). In this context, effective development of therapeutic strategies requires an HCC mouse model with known tumor-associated antigens (TAAs) and an HCC growth reporter. We created such a model using hydrodynamic injection and a transposon system to introduce AKT and NRAS and open reading frames (ORFs) encoding surrogate tumor antigens and luciferase into chromosomes of hepatocytes to induce nodular and diffuse tumors in the liver. TAA-specific CD8+ T cells were detected during HCC progression; however, these showed exhausted-like phenotypes and were unable to control tumor growth. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAM) from the tumor microenvironment were found to contribute to the suppression of the CD8+ T-cell response. The transposon-based Akt/N-Ras-induced HCC mouse model we developed enables researchers to monitor tumor growth non-invasively and to quantify and characterize endogenous or adoptively transferred TAA-specific CD8+ T-cell responses. These features make it a suitable preclinical model for exploration and evaluation of immune checkpoint inhibitors and cell-based immunotherapies for HCC treatment.

Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Linfócitos T/imunologia , Microambiente Tumoral/imunologia , Transferência Adotiva , Animais , Biomarcadores Tumorais , Carcinoma Hepatocelular/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Genes Reporter , Genes ras , Humanos , Hospedeiro Imunocomprometido , Imuno-Histoquímica , Neoplasias Hepáticas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Oncogenes , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/metabolismo
PLoS Biol ; 15(4): e2000931, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28414717


Clathrin-mediated endocytosis (CME) and activity-dependent bulk endocytosis (ADBE) are two predominant forms of synaptic vesicle (SV) endocytosis, elicited by moderate and strong stimuli, respectively. They are tightly coupled with exocytosis for sustained neurotransmission. However, the underlying mechanisms are ill defined. We previously reported that the Flower (Fwe) Ca2+ channel present in SVs is incorporated into the periactive zone upon SV fusion, where it triggers CME, thus coupling exocytosis to CME. Here, we show that Fwe also promotes ADBE. Intriguingly, the effects of Fwe on CME and ADBE depend on the strength of the stimulus. Upon mild stimulation, Fwe controls CME independently of Ca2+ channeling. However, upon strong stimulation, Fwe triggers a Ca2+ influx that initiates ADBE. Moreover, knockout of rodent fwe in cultured rat hippocampal neurons impairs but does not completely abolish CME, similar to the loss of Drosophila fwe at the neuromuscular junction, suggesting that Fwe plays a regulatory role in regulating CME across species. In addition, the function of Fwe in ADBE is conserved at mammalian central synapses. Hence, Fwe exerts different effects in response to different stimulus strengths to control two major modes of endocytosis.

Canais de Cálcio/metabolismo , Proteínas de Drosophila/metabolismo , Endocitose/fisiologia , Sinapses/metabolismo , Animais , Animais Geneticamente Modificados , Cálcio/metabolismo , Cálcio/farmacologia , Canais de Cálcio/genética , Linhagem Celular , Clatrina/metabolismo , Proteínas de Drosophila/genética , Endocitose/efeitos dos fármacos , Exocitose/fisiologia , Técnicas de Silenciamento de Genes , Lantânio/farmacologia , Camundongos , Mutação , Neurônios/metabolismo , Isoformas de Proteínas , Ratos , Vesículas Sinápticas/metabolismo
Proc Natl Acad Sci U S A ; 113(51): 14656-14661, 2016 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-27930314


Silicene, analogous to graphene, is a one-atom-thick 2D crystal of silicon, which is expected to share many of the remarkable properties of graphene. The buckled honeycomb structure of silicene, along with enhanced spin-orbit coupling, endows silicene with considerable advantages over graphene in that the spin-split states in silicene are tunable with external fields. Although the low-energy Dirac cone states lie at the heart of all novel quantum phenomena in a pristine sheet of silicene, a hotly debated question is whether these key states can survive when silicene is grown or supported on a substrate. Here we report our direct observation of Dirac cones in monolayer silicene grown on a Ag(111) substrate. By performing angle-resolved photoemission measurements on silicene(3 × 3)/Ag(111), we reveal the presence of six pairs of Dirac cones located on the edges of the first Brillouin zone of Ag(111), which is in sharp contrast to the expected six Dirac cones centered at the K points of the primary silicene(1 × 1) Brillouin zone. Our analysis shows clearly that the unusual Dirac cone structure we have observed is not tied to pristine silicene alone but originates from the combined effects of silicene(3 × 3) and the Ag(111) substrate. Our study thus identifies the case of a unique type of Dirac cone generated through the interaction of two different constituents. The observation of Dirac cones in silicene/Ag(111) opens a unique materials platform for investigating unusual quantum phenomena and for applications based on 2D silicon systems.

Sci Rep ; 6: 18993, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-26764118


We predict planar Sb/Bi honeycomb to harbor a two-dimensional (2D) topological crystalline insulator (TCI) phase based on first-principles computations. Although buckled Sb and Bi honeycombs support 2D topological insulator (TI) phases, their structure becomes planar under tensile strain. The planar Sb/Bi honeycomb structure restores the mirror symmetry, and is shown to exhibit non-zero mirror Chern numbers, indicating that the system can host topologically protected edge states. Our computations show that the electronic spectrum of a planar Sb/Bi nanoribbon with armchair or zigzag edges contains two Dirac cones within the band gap and an even number of edge bands crossing the Fermi level. Lattice constant of the planar Sb honeycomb is found to nearly match that of hexagonal-BN. The Sb nanoribbon on hexagonal-BN exhibits gapped edge states, which we show to be tunable by an out-of-the-plane electric field, providing controllable gating of edge state important for device applications.

Nano Lett ; 14(5): 2505-8, 2014 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-24734779


We use first-principles electronic structure calculations to predict a new class of two-dimensional (2D) topological insulators (TIs) in binary compositions of group III elements (B, Al, Ga, In, and Tl) and bismuth (Bi) in a buckled honeycomb structure. We identify band inversions in pristine GaBi, InBi, and TlBi bilayers, with gaps as large as 560 meV, making these materials suitable for room-temperature applications. Furthermore, we demonstrate the possibility of strain engineering in that the topological phase transition in BBi and AlBi could be driven at ∼6.6% strain. The buckled structure allows the formation of two different topological edge states in the zigzag and armchair edges. More importantly, isolated Dirac-cone edge states are predicted for armchair edges with the Dirac point lying in the middle of the 2D bulk gap. A room-temperature bulk band gap and an isolated Dirac cone allow these states to reach the long-sought topological spin-transport regime. Our findings suggest that the buckled honeycomb structure is a versatile platform for hosting nontrivial topological states and spin-polarized Dirac fermions with the flexibility of chemical and mechanical tunability.