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1.
Cell ; 162(4): 836-48, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26276633

RESUMO

Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here, we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake.


Assuntos
Relógios Circadianos , Ritmo Circadiano , Drosophila/fisiologia , Animais , Relógios Biológicos , Membrana Celular/metabolismo , Drosophila/citologia , Proteínas de Drosophila/metabolismo , Técnicas de Silenciamento de Genes , Canais Iônicos/genética , Canais Iônicos/metabolismo , Proteínas de Membrana , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Técnicas de Patch-Clamp , Potássio/metabolismo , Sódio/metabolismo
2.
J Am Chem Soc ; 146(22): 15045-15052, 2024 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-38768128

RESUMO

Chiral Pb-free metal-halide semiconductors (MHSs) have attracted considerable attention in the field of spintronics due to various interesting spin-related properties and chiral-induced spin selectivity (CISS) effect. Despite their excellent chemical and structural tunability, the material scope and crystal structure of Pb-free chiral MHSs exhibiting the CISS effect are still limited; chiral MHSs that have metal-halide structures of octahedra and tetrahedra are only reported. Here, we report a new class of chiral MHSs, of which palladium (Pd)-halides are formed in 1D square-pyramidal structures or 0D square-planar structures, with a general formula of ((R/S-MBA)2PdBr4)1-x((R/S-MBA)2PdCl4)x (MBA = methylbenzylammonium; x = 0, 0.25, 0.5, 0.75, and 1) for the first time. The crystals adopt the 1D helical chain of Pd-halide square-pyramid (for x = 0, 0.25, 0.5, and 0.75) and 0D structure of Pd-halide square-plane (for x = 1). All the Pd-halides are distorted by the interaction between the halide and the chiral organic ammonium and arranged in a noncentrosymmetric position. Circular dichroism (CD) for ((R/S-MBA)2PdBr4)1-x((R/S-MBA)2PdCl4)x indicates that chirality was transferred from chiral organic ammonium to Pd-halide inorganics. ((R-MBA)2PdBr4)1-x((R-MBA)2PdCl4)x (x = 0, 0.25, 0.5, and 0.75) shows a distortion index of 0.127-0.128, which is the highest value among the previously reported chiral MHSs to the best of our knowledge. We also find that (R/S-MBA)2Pd(Br1-xClx)4 crystals grow along the out-of-plane direction during spin coating and have high c-axis orientation and crystallinity, and (R/S-MBA)2Pd(Br1-xClx)4 (x = 0 and 0.5) crystals exhibit a CISS effect in polycrystalline bulk films. These results demonstrate the possibility of a new metal-halide series with square-planar structures or square-pyramidal structures for future spintronic applications.

3.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-34799448

RESUMO

Circadian transcriptional timekeepers in pacemaker neurons drive profound daily rhythms in sleep and wake. Here we reveal a molecular pathway that links core transcriptional oscillators to neuronal and behavioral rhythms. Using two independent genetic screens, we identified mutants of Transport and Golgi organization 10 (Tango10) with poor behavioral rhythmicity. Tango10 expression in pacemaker neurons expressing the neuropeptide PIGMENT-DISPERSING FACTOR (PDF) is required for robust rhythms. Loss of Tango10 results in elevated PDF accumulation in nerve terminals even in mutants lacking a functional core clock. TANGO10 protein itself is rhythmically expressed in PDF terminals. Mass spectrometry of TANGO10 complexes reveals interactions with the E3 ubiquitin ligase CULLIN 3 (CUL3). CUL3 depletion phenocopies Tango10 mutant effects on PDF even in the absence of the core clock gene timeless Patch clamp electrophysiology in Tango10 mutant neurons demonstrates elevated spontaneous firing potentially due to reduced voltage-gated Shaker-like potassium currents. We propose that Tango10/Cul3 transduces molecular oscillations from the core clock to neuropeptide release important for behavioral rhythms.


Assuntos
Relógios Circadianos/fisiologia , Proteínas de Drosophila/metabolismo , Neuropeptídeos/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Translocador Nuclear Receptor Aril Hidrocarboneto/genética , Translocador Nuclear Receptor Aril Hidrocarboneto/metabolismo , Proteínas Culina/genética , Proteínas Culina/metabolismo , Drosophila , Proteínas de Drosophila/genética , Neurônios/metabolismo , Neuropeptídeos/genética , Proteômica , Sono
4.
Small ; 19(44): e2301077, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37401792

RESUMO

A Joule heater made of emerging 2D nanosheets, i.e., MXene, has the advantage of low-voltage operation with stable heat generation owing to its highly conductive and uniformly layered structure. However, the self-heated MXene sheets easily get oxidized in warm and moist environments, which limits their intrinsic heating efficiencies. Herein, an ultrathin graphene skin is introduced as a surface-regulative coating on MXene to enhance its oxidative stability and Joule heating efficiency. The skin layer is deposited on MXene using a scalable solution-phased layer-by-layer assembly process without deteriorating the excellent electrical conductivity of the MXene. The graphene skin comprises narrow and hydrophobic channels, which results in ≈70 times higher water impermeability of the hybrid film of graphene and MXene (GMX) than that of the pristine MXene. A complementary electrochemical analysis confirms that the graphene skin facilitates longer-lasting protection than conventional polymer coatings owing to its tortuous pathways. In addition, the sp2 planar carbon surface with a low heat loss coefficient improves the heating efficiency of the GMX, indicating that this strategy is promising for developing adaptive heating materials with a tractable voltage range and high Joule heating efficiency.

5.
Nat Mater ; 21(12): 1396-1402, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36396958

RESUMO

Cations with suitable sizes to occupy an interstitial site of perovskite crystals have been widely used to inhibit ion migration and promote the performance and stability of perovskite optoelectronics. However, such interstitial doping inevitably leads to lattice microstrain that impairs the long-range ordering and stability of the crystals, causing a sacrificial trade-off. Here, we unravel the evident influence of the valence states of the interstitial cations on their efficacy to suppress the ion migration. Incorporation of a trivalent neodymium cation (Nd3+) effectively mitigates the ion migration in the perovskite lattice with a reduced dosage (0.08%) compared to a widely used monovalent cation dopant (Na+, 0.45%). The photovoltaic performances and operational stability of the prototypical perovskite solar cells are enhanced with a trace amount of Nd3+ doping while minimizing the sacrificial trade-off.

6.
Langmuir ; 39(6): 2358-2367, 2023 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-36734137

RESUMO

Surface modification to improve the oxidation stability and dispersibility of MXene in diverse organic media is a facile strategy for broadening its application. Among the various ligands that can be grafted on the MXene surface, oleylamine (OAm), with amine functionalities, is an advantageous candidate owing to its strong interactions and commercial viability. OAms are grafted onto MXene through covalent bonds induced by nucleophilic reactions and H bonds in liquid interface reactions at room temperature. In addition, this grafting behavior of the ligand was characterized by a reduction in the slope with an increase in the ligand concentration (Cl), confirming that the OAms were grafted via Langmuir-like behavior, and the monolayer of OAms was developed via two distinct steps (I: lying-down phase; II: ordered monolayer). MXene nanosheets modified by OAm (OAm-MX) are highly dispersible in a wide range of organic solvents owing to the alkyl chain of the OAms, which induces hydrophobic properties on the surface of MXene. The OAm-MX dispersion exhibits outstanding oxidation and dispersion stability and remarkable coating performance on a wide range of substrates owing to their excellent solution processability. Therefore, this study provides fundamental insights into the adsorption behavior and interaction between amine ligands and MXene nanosheets for the surface chemistry of MXene.

7.
Int J Mol Sci ; 24(7)2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-37047042

RESUMO

Nitroreductase (NTR) has the ability to activate nitro group-containing prodrugs and decompose explosives; thus, the evaluation of NTR activity is specifically important in pharmaceutical and environmental areas. Numerous studies have verified effective fluorescent methods to detect and image NTR activity; however, near-infrared (NIR) fluorescence probes for biological applications are lacking. Thus, in this study, we synthesized novel NIR probes (NIR-HCy-NO2 1-3) by introducing a nitro group to the hemicyanine skeleton to obtain fluorescence images of NTR activity. Additionally, this study was also designed to propose a different water solubility and investigate the catalytic efficiency of NTR. NIR-HCy-NO2 inherently exhibited a low fluorescence background due to the interference of intramolecular charge transfer (ICT) by the nitro group. The conversion from the nitro to amine group by NTR induced a change in the absorbance spectra and lead to the intense enhancement of the fluorescence spectra. When assessing the catalytic efficiency and the limit of detection (LOD), including NTR activity imaging, it was demonstrated that NIR-HCy-NO2 1 was superior to the other two probes. Moreover, we found that NIR-HCy-NO2 1 reacted with type I mitochondrial NTR in live cell imaging. Conclusively, NIR-HCy-NO2 demonstrated a great potential for application in various NTR-related fields, including NTR activity for cell imaging in vivo.


Assuntos
Corantes Fluorescentes , Dióxido de Nitrogênio , Corantes Fluorescentes/farmacologia , Microscopia de Fluorescência/métodos , Imagem Óptica/métodos , Nitrorredutases/metabolismo
8.
Nature ; 537(7621): 567-571, 2016 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-27580033

RESUMO

Glutamate receptors are ligand-gated tetrameric ion channels that mediate synaptic transmission in the central nervous system. They are instrumental in vertebrate cognition and their dysfunction underlies diverse diseases. In both the resting and desensitized states of AMPA and kainate receptor subtypes, the ion channels are closed, whereas the ligand-binding domains, which are physically coupled to the channels, adopt markedly different conformations. Without an atomic model for the desensitized state, it is not possible to address a central problem in receptor gating: how the resting and desensitized receptor states both display closed ion channels, although they have major differences in the quaternary structure of the ligand-binding domain. Here, by determining the structure of the kainate receptor GluK2 subtype in its desensitized state by cryo-electron microscopy (cryo-EM) at 3.8 Å resolution, we show that desensitization is characterized by the establishment of a ring-like structure in the ligand-binding domain layer of the receptor. Formation of this 'desensitization ring' is mediated by staggered helix contacts between adjacent subunits, which leads to a pseudo-four-fold symmetric arrangement of the ligand-binding domains, illustrating subtle changes in symmetry that are important for the gating mechanism. Disruption of the desensitization ring is probably the key switch that enables restoration of the receptor to its resting state, thereby completing the gating cycle.


Assuntos
Microscopia Crioeletrônica , Receptores de Ácido Caínico/metabolismo , Receptores de Ácido Caínico/ultraestrutura , Animais , Sítios de Ligação , Regulação para Baixo , Ativação do Canal Iônico , Ligantes , Modelos Moleculares , Domínios Proteicos , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Ratos , Receptores de Ácido Caínico/química , Receptor de GluK2 Cainato
9.
Ecotoxicol Environ Saf ; 248: 114334, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36442398

RESUMO

Owing to their unique properties and biological activities, ionic liquids (ILs) have attracted research interest in pharmaceutics and medicine. Hypoxia-inducible factor (HIF)- 1α is an attractive cancer drug target involved in cancer malignancy in the hypoxic tumor microenvironment. Herein, we report the inhibitory activity of ILs on the HIF-1α pathway and their mechanism of action. Substitution of a dimethylamino group on pyridinium reduced hypoxia-induced HIF-1α activation. It selectively inhibited the viability of the human colon cancer cell line HCT116, compared to that of the normal fibroblast cell line WI-38. These activities were enhanced by increasing the alkyl chain length in the pyridinium. Under hypoxic conditions, dimethylaminopyridinium reduced the accumulation of HIF-1α and its target genes without affecting the HIF1A mRNA level in cancer cells. It suppressed the oxygen consumption rate and ATP production by directly inhibiting electron transfer chain complex I, which led to enhanced intracellular oxygen content and oxygen-dependent degradation of HIF-1α under hypoxia. These results indicate that dimethylaminopyridinium suppresses the mitochondria and HIF-1α-dependent glucose metabolic pathway in hypoxic cancer cells. This study provides insights into the anticancer activity of pyridinium-based ILs through the regulation of cancer metabolism, making them promising candidates for cancer treatment.


Assuntos
Neoplasias do Colo , Líquidos Iônicos , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Líquidos Iônicos/toxicidade , Hipóxia , Oxigênio , Microambiente Tumoral
10.
Can J Anaesth ; 68(11): 1651-1658, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34405354

RESUMO

PURPOSE: Breaking of disposable blades during emergency endotracheal intubation has been reported. Breakage can cause serious injury and foreign body ingestion. We aimed to measure and analyze the strength characteristics of different disposable videolaryngoscope blades with the application of an upward-lifting force. METHODS: We measured the strength of four disposable videolaryngoscope blades (C-Mac® S Video laryngoscope MAC #3, Glidescope GVL® 3 stat, Pentax AWS® PBlade TL type, and King Vision® aBlade #3) using the fracture test. The strength of 12 samples of each type of disposable videolaryngoscope blade was measured using an Instron 5,966 tensile tester by applying an upward-lifting force. RESULTS: After the fracture test using C-Mac, Glidescope GVL, Pentax AWS, and King Vision, the number of deformed blades were 0, 12, 3, and 7, respectively, and the number of broken blades were 12, 0, 9, and 5, respectively. The mean (standard deviation) maximum force strengths of Pentax AWS, C-Mac, King Vision, and Glidescope GVL blades were 408.4 (27.4) N, 325.8 (26.5) N, 291.8 (39.3) N, and 262.7 (3.8) N, respectively (P < 0.001). CONCLUSION: Clinicians should be aware of the varied strength characteristics of the four types of disposable videolaryngoscope blades when they are used in endotracheal intubation.


RéSUMé: OBJECTIF: Des bris des lames jetables pendant l'intubation endotrachéale d'urgence ont été rapportés. Un bris peut causer des blessures graves et l'ingestion de corps étrangers. Nous avons cherché à mesurer et à analyser les caractéristiques de résistance de différentes lames de vidéolaryngoscope jetables en appliquant une force de traction vers le haut. MéTHODE: Nous avons mesuré la résistance de quatre lames de vidéolaryngoscope jetables (C-Mac® S Video laryngoscope MAC #3, Glidescope GVL® 3 stat, Pentax AWS® type PBlade TL, et King Vision® aBlade #3) en utilisant un test de rupture. La résistance de 12 échantillons de chaque type de lame de vidéolaryngoscope jetable a été mesurée à l'aide d'un dynamomètre Instron 5,966 en appliquant une force de traction vers le haut. RéSULTATS: Après le test de rupture sur les lames C-Mac, Glidescope GVL, Pentax AWS et King Vision, le nombre de lames déformées était de 0, 12, 3 et 7, respectivement, et le nombre de lames brisées était de 12, 0, 9 et 5, respectivement. Les forces de résistance maximales moyennes (écart type) des lames Pentax AWS, C-Mac, King Vision et Glidescope GVL étaient de 408,4 (27,4) N, 325,8 (26,5) N, 291,8 (39,3) N et 262,7 (3,8) N, respectivement (P < 0,001). CONCLUSION: Les cliniciens devraient être conscients des variations dans les caractéristiques de résistance de ces quatre types de lames de vidéolaryngoscope jetables lors de leur utilisation pour l'intubation endotrachéale.


Assuntos
Laringoscópios , Serviço Hospitalar de Emergência , Humanos , Intubação Intratraqueal , Laringoscopia , Gravação em Vídeo
11.
12.
Sensors (Basel) ; 21(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802767

RESUMO

This paper introduces a method for improving the sensitivity to NO2 gas of a p-type metal oxide semiconductor gas sensor. The gas sensor was fabricated using CuO nanowires (NWs) grown through thermal oxidation and decorated with ZnO nanoparticles (NPs) using a sol-gel method. The CuO gas sensor with a ZnO heterojunction exhibited better sensitivity to NO2 gas than the pristine CuO gas sensor. The heterojunction in CuO/ZnO gas sensors caused a decrease in the width of the hole accumulation layer (HAL) and an increase in the initial resistance. The possibility to influence the width of the HAL helped improve the NO2 sensing characteristics of the gas sensor. The growth morphology, atomic composition, and crystal structure of the gas sensors were analyzed using field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray spectroscopy, and X-ray diffraction, respectively.

13.
Nano Lett ; 20(6): 4673-4680, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32437162

RESUMO

The present study systematically investigates the morphology and crystallization process of inorganic CsPbBr3 perovskite layer films fabricated by thermal coevaporation in conjunction with continuous low-temperature thermal annealing to promote in situ dynamic thermal crystallization. The results confirm for the first time that both the crystal grain size and the compactness of the CsPbBr3 films can be tuned during the thermal coevaporation fabrication process via in situ dynamic thermal crystallization. The performance of the PeLEDs employing the CsPbBr3 films as the emitter layer is investigated in detail with respect to the substrate temperature and deposition rate employed during deposition of the CsPbBr3 film. This study provides guidelines for developing suitable film production processes and highlights future challenges that must be addressed to facilitate the commercial development of large-area, uniform, and flexible perovskite-based optoelectronic devices.

14.
J Am Chem Soc ; 142(47): 20071-20079, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33196182

RESUMO

Defect passivation constitutes one of the most commonly used strategies to fabricate highly efficient perovskite solar cells (PSCs). However, the durability of the passivation effects under harsh operational conditions has not been extensively studied regardless of the weak and vulnerable secondary bonding between the molecular passivation agents and perovskite crystals. Here, we incorporated strategically designed passivating agents to investigate the effect of their interaction energies on the perovskite crystals and correlated these with the performance and longevity of the passivation effects. We unraveled that the passivation agents with a stronger interaction energy are advantageous not only for effective defect passivation but also to suppress defect migration. The prototypical PSCs treated with the optimal passivation agent exhibited superior performance and operational stability, retaining 81.9 and 85.3% of their initial performance under continuous illumination or nitrogen at 85 °C after 1008 h, respectively, while the reference device completely degraded during that time. This work provides important insights into designing operationally durable defect passivation agents for perovskite optoelectronic devices.

15.
Nano Lett ; 19(4): 2223-2230, 2019 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-30517789

RESUMO

Single-walled carbon nanotubes (CNTs) has been considered as a promising material for a top electrode of perovskite solar cells owing to its hydrophobic nature, earth-abundance, and mechanical robustness. However, its poor conductivity, a shallow work function, and nonreflective nature have limited further enhancement in power conversion efficiency (PCE) of top CNT electrode-based perovskite solar cells. Here, we introduced a simple and scalable method to address these issues by utilizing an ex-situ vapor-assisted doping method. Trifluoromethanesulfonic acid (TFMS) vapor doping of the free-standing CNT sheet enabled tuning of conductivity and work function of the CNT electrode without damaging underneath layers. The sheet resistance of the CNT sheet was decreased by 21.3% with an increase in work function from 4.75 to 4.96 eV upon doping of TFMS. In addition, recently developed 2D perovskite-protected Cs-containing formamidium lead iodide (FACsPbI3) technology was employed to maximize the absorption. Because of the lowered resistance, better energy alignment, and improved absorption, the CNT electrode-based PSCs produced a PCE of 17.6% with a JSC of 24.21 mA/cm2, VOC of 1.005 V, and FF of 0.72. Furthermore, the resulting TFMS-doped CNT-PSCs demonstrated higher thermal and operational stability than bare CNT and metal electrode-based devices.

16.
J Virol ; 92(15)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29743376

RESUMO

Interferon-stimulated gene 15 (ISG15) encodes a ubiquitin-like protein that can be conjugated to proteins via an enzymatic cascade involving the E1, E2, and E3 enzymes. ISG15 expression and protein ISGylation modulate viral infection; however, the viral mechanisms regulating the function of ISG15 and ISGylation are not well understood. We recently showed that ISGylation suppresses the growth of human cytomegalovirus (HCMV) at multiple steps of the virus life cycle and that the virus-encoded pUL26 protein inhibits protein ISGylation. In this study, we demonstrate that the HCMV UL50-encoded transmembrane protein, a component of the nuclear egress complex, also inhibits ISGylation. pUL50 interacted with UBE1L, an E1-activating enzyme for ISGylation, and (to a lesser extent) with ISG15, as did pUL26. However, unlike pUL26, pUL50 caused proteasomal degradation of UBE1L. The UBE1L level induced in human fibroblast cells by interferon beta treatment or virus infection was reduced by pUL50 expression. This activity of pUL50 involved the transmembrane (TM) domain within its C-terminal region, although pUL50 could interact with UBE1L in a manner independent of the TM domain. Consistently, colocalization of pUL50 with UBE1L was observed in cells treated with a proteasome inhibitor. Furthermore, we found that RNF170, an endoplasmic reticulum (ER)-associated ubiquitin E3 ligase, interacted with pUL50 and promoted pUL50-mediated UBE1L degradation via ubiquitination. Our results demonstrate a novel role for the pUL50 transmembrane protein of HCMV in the regulation of protein ISGylation.IMPORTANCE Proteins can be conjugated covalently by ubiquitin or ubiquitin-like proteins, such as SUMO and ISG15. ISG15 is highly induced in viral infection, and ISG15 conjugation, termed ISGylation, plays important regulatory roles in viral growth. Although ISGylation has been shown to negatively affect many viruses, including human cytomegalovirus (HCMV), viral countermeasures that might modulate ISGylation are not well understood. In the present study, we show that the transmembrane protein encoded by HCMV UL50 inhibits ISGylation by causing proteasomal degradation of UBE1L, an E1-activating enzyme for ISGylation. This pUL50 activity requires membrane targeting. In support of this finding, RNF170, an ER-associated ubiquitin E3 ligase, interacts with pUL50 and promotes UL50-mediated UBE1L ubiquitination and degradation. Our results provide the first evidence, to our knowledge, that viruses can regulate ISGylation by directly targeting the ISGylation E1 enzyme.


Assuntos
Citomegalovirus/metabolismo , Regulação para Baixo , Fibroblastos/metabolismo , Proteólise , Enzimas Ativadoras de Ubiquitina/metabolismo , Ubiquitinação , Proteínas Virais/metabolismo , Citomegalovirus/genética , Fibroblastos/virologia , Glicosilação , Células HEK293 , Humanos , Domínios Proteicos , Enzimas Ativadoras de Ubiquitina/genética , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Virais/genética
17.
PLoS Pathog ; 13(6): e1006423, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28570668

RESUMO

Several viruses have been found to encode a deubiquitinating protease (DUB). These viral DUBs are proposed to play a role in regulating innate immune or inflammatory signaling. In human cytomegalovirus (HCMV), the largest tegument protein encoded by UL48 contains DUB activity, but its cellular targets are not known. Here, we show that UL48 and UL45, an HCMV-encoded inactive homolog of cellular ribonucleotide reductase (RNR) large subunit (R1), target receptor-interacting protein kinase 1 (RIP1) to inhibit NF-κB signaling. Transfection assays showed that UL48 and UL45, which binds to UL48, interact with RIP1 and that UL48 DUB activity and UL45 cooperatively suppress RIP1-mediated NF-κB activation. The growth of UL45-null mutant virus was slightly impaired with showing reduced accumulation of viral late proteins. Analysis of a recombinant virus expressing HA-UL45 showed that UL45 interacts with both UL48 and RIP1 during virus infection. Infection with the mutant viruses also revealed that UL48 DUB activity and UL45 inhibit TNFα-induced NF-κB activation at late times of infection. UL48 cleaved both K48- and K63-linked polyubiquitin chains of RIP1. Although UL45 alone did not affect RIP1 ubiquitination, it could enhance the UL48 activity to cleave RIP1 polyubiquitin chains. Consistently, UL45-null virus infection showed higher ubiquitination level of endogenous RIP1 than HA-UL45 virus infection at late times. Moreover, UL45 promoted the UL48-RIP1 interaction and re-localization of RIP1 to the UL48-containing virion assembly complex. The mouse cytomegalovirus (MCMV)-encoded DUB, M48, interacted with mouse RIP1 and M45, an MCMV homolog of UL45. Collectively, our data demonstrate that cytomegalovirus-encoded DUB and inactive R1 homolog target RIP1 and cooperatively inhibit RIP1-mediated NF-κB signaling at the late stages of HCMV infection.


Assuntos
Infecções por Citomegalovirus/virologia , Citomegalovirus/enzimologia , Enzimas Desubiquitinantes/metabolismo , NF-kappa B/metabolismo , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonucleotídeo Redutases/metabolismo , Proteínas Virais/metabolismo , Citomegalovirus/genética , Enzimas Desubiquitinantes/genética , Humanos , NF-kappa B/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Proteínas de Ligação a RNA/genética , Ribonucleotídeo Redutases/genética , Transdução de Sinais , Proteínas Virais/genética
18.
Neuropediatrics ; 50(4): 228-234, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30939601

RESUMO

Recent reports have suggested an association between rotavirus infection and a distinctive pattern of white matter injury (WMI) in neonates with seizures; however, the connection between the two is not fully understood. To evaluate the underlying mechanism, we profiled and compared eight cytokines (IL [interleukin]-1ß, IL-6, IL-8, IL-10, IFN-γ [interferon-γ ], MCP-1 [monocyte chemoattractant protein-1], MIP-1ß [macrophage inflammatory protein-1ß], and TNF-α [tumor necrosis factor-α]) in the cerebrospinal fluid (CSF) of 33 neonates with seizures who had no other well-known causes of seizures and 13 control patients (rotavirus-induced gastroenteritis but without seizures). Among the 33 neonates with seizures, 9 showed WMI and all were infected with rotavirus (R + W + ). Among the 24 patients without WMI, 11 were infected with rotavirus (R + W - ) and 13 were not (R - W - ).Only MCP-1 and MIP-1ß were different between the groups. MCP-1 was increased in R+ W+ compared with R + W- (p < 0.01), R - W- (p < 0.01), and control (p = 0.03) patients. MIP-1ß was decreased in R + W+ compared with R - W- (p < 0.01) and control (p < 0.01), but not R + W- (p = 0.23) patients. MCP-1 and MIP-1ß are C-C chemokines that recruit immune cells to the site of inflammation. Our pilot study suggests MCP-1-mediated monocyte recruitment may be linked with this complication caused by rotavirus.


Assuntos
Encéfalo/diagnóstico por imagem , Quimiocina CCL2/líquido cefalorraquidiano , Leucoencefalopatias/líquido cefalorraquidiano , Infecções por Rotavirus/complicações , Substância Branca/diagnóstico por imagem , Encéfalo/virologia , Citocinas/líquido cefalorraquidiano , Imagem de Difusão por Ressonância Magnética , Feminino , Humanos , Recém-Nascido , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/virologia , Masculino , Rotavirus , Infecções por Rotavirus/diagnóstico por imagem , Substância Branca/virologia
19.
Environ Res ; 172: 367-374, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30825687

RESUMO

The effective removal technique is necessary for the real world treatment of a hazardous pollutant (e.g., gaseous benzene). In an effort to develop such technique, the adsorption efficiency of benzene in a nitrogen stream (5 Pa (50 ppm) at 50 mL atm min-1 flow rate and 298 K) was assessed against 10 different metal oxide/GO composite materials (i.e., 1: graphene oxide Co (GO-Co (OH)2), 2: graphene oxide Cu (GO-Cu(OH)2), 3: graphene oxide Mn (GO-MnO), 4: graphene oxide Ni (GO-Ni(OH)2), 5: graphene oxide Sn (GO-SnO2), 6: reduced graphene oxide Co (rGO-Co(OH)2), 7: reduced graphene oxide Cu (rGO-Cu(OH)2), 8: reduced graphene oxide Mn (rGO-MnO), 9: reduced graphene oxide Ni (rGO-Ni(OH)2), and 10: reduced graphene oxide Sn (rGO-SnO2)) in reference to their pristine forms of graphene oxide (GO) and reduced graphene oxide (rGO). The highest adsorption capacities (at 100% breakthrough) were observed as ~23 mg g-1 for both GO-Ni(OH)2 and rGO-SnO2, followed by GO (~19.1 mg g-1) and GO-Co(OH)2 (~18.8 mg g-1). Therefore, the GO-Ni(OH)2 and rGO-SnO2 composites exhibited considerably high capacities to treat streams containing >5 Pa of benzene. However, the lowest adsorption capacity was found for GO-MnO (0.05 mg g-1). Alternately, if expressed in terms of the 10% breakthrough volume (BTV), the five aforementioned materials showed values of 0.50, 0.46, 0.40, 0.44, and 0.39 L g-1, respectively. The experimental data of target sorbents were fitted to linearized Langmuir, Freundlich, Elovich, and Dubinin-Radushkevich isotherm models. Accordingly, the non-linear Langmuir isotherm model revealed the presence of two or more distinct sorption profiles for several of the tested sorbents. Most of the sorbents showed type-III isotherm profiles where the sorption capacity proportional to the loaded volume.


Assuntos
Benzeno , Gases , Grafite , Metais , Óxidos , Adsorção , Benzeno/química , Gases/química , Grafite/química , Metais/análise , Óxidos/análise
20.
PLoS Genet ; 12(1): e1005810, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26815659

RESUMO

At the Drosophila NMJ, BMP signaling is critical for synapse growth and homeostasis. Signaling by the BMP7 homolog, Gbb, in motor neurons triggers a canonical pathway-which modulates transcription of BMP target genes, and a noncanonical pathway-which connects local BMP/BMP receptor complexes with the cytoskeleton. Here we describe a novel noncanonical BMP pathway characterized by the accumulation of the pathway effector, the phosphorylated Smad (pMad), at synaptic sites. Using genetic epistasis, histology, super resolution microscopy, and electrophysiology approaches we demonstrate that this novel pathway is genetically distinguishable from all other known BMP signaling cascades. This novel pathway does not require Gbb, but depends on presynaptic BMP receptors and specific postsynaptic glutamate receptor subtypes, the type-A receptors. Synaptic pMad is coordinated to BMP's role in the transcriptional control of target genes by shared pathway components, but it has no role in the regulation of NMJ growth. Instead, selective disruption of presynaptic pMad accumulation reduces the postsynaptic levels of type-A receptors, revealing a positive feedback loop which appears to function to stabilize active type-A receptors at synaptic sites. Thus, BMP pathway may monitor synapse activity then function to adjust synapse growth and maturation during development.


Assuntos
Junção Neuromuscular/genética , Organogênese , Sinapses/genética , Transmissão Sináptica/genética , Animais , Animais Geneticamente Modificados , Proteínas Morfogenéticas Ósseas/genética , Proteínas Morfogenéticas Ósseas/metabolismo , Proteínas de Ligação a DNA/genética , Drosophila melanogaster/genética , Drosophila melanogaster/crescimento & desenvolvimento , Regulação da Expressão Gênica no Desenvolvimento , Neurônios Motores/metabolismo , Junção Neuromuscular/crescimento & desenvolvimento , Transdução de Sinais/genética , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
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