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1.
PLoS Pathog ; 20(7): e1012344, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38976714

RESUMO

AAV-mediated gene therapy typically requires a high dose of viral transduction, risking acute immune responses and patient safety, part of which is due to limited understanding of the host-viral interactions, especially post-transduction viral genome processing. Here, through a genome-wide CRISPR screen, we identified SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1), an epigenetic modifier, as a critical broad-spectrum restricting host factor for post-entry AAV transgene expression. SMCHD1 knock-down by RNAi and CRISPRi or knock-out by CRISPR all resulted in significantly enhanced transgene expression across multiple viral serotypes, as well as for both single-strand and self-complementary AAV genome types. Mechanistically, upon viral transduction, SMCHD1 effectively repressed AAV transcription by the formation of an LRIF1-HP1-containing protein complex and directly binding with the AAV genome to maintain a heterochromatin-like state. SMCHD1-KO or LRIF1-KD could disrupt such a complex and thus result in AAV transcriptional activation. Together, our results highlight the host factor-induced chromatin remodeling as a critical inhibitory mechanism for AAV transduction and may shed light on further improvement in AAV-based gene therapy.

2.
ACS Omega ; 9(23): 24654-24664, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38882114

RESUMO

The synthesis of metal macrocycle complexes holds paramount importance in coordination and supramolecular chemistry. Toward this end, we report a new, mild, and efficient protocol for the synthesis of cyclometalated macrocycle Ir(III) complexes: [Ir(L1)](PF6) (1), [Ir(L2)](PF6) (2), and [Ir(L3)](PF6) (3), where L1 presents 10,17-dioxa-3,6-diaza-2(2,8),7(8,2)-diquinolina-1,8(1,4)-dibenzenacyclooctadecaphane, L2 is 10,13,16,19,22,25-hexaoxa-3,6-diaza-2(2,8),7(8,2)-diquinolina-1,8(1,4)-dibenzenacyclohexacosaphane, and L3 is 4-methyl-10,13,16,19,22,25-hexaoxa-3,6-diaza-2(2,8),7(8,2)-diquinolina-1,8(1,4)-dibenzenacyclohexacosaphane. This synthesis involves the preassembly of two symmetric 2-phenylquinoline arms into C-shape complexes, followed by cyclization with diamine via in situ interligand C-N cross-coupling, employing a metal ion as a template. Moreover, the synthetic yield of these cyclometalated Ir(III) complexes, tethered by an 18-crown-6 ether-like chain, is significantly enhanced in the presence of K+ ion as a template. The resultant cyclometalated macrocycle Ir(III) complexes exhibit high stability, efficient singlet oxygen generation, and superior catalytic activity for the aerobic selective oxidation of sulfides into sulfoxides under visible light irradiation in aqueous media at room temperature. The photocatalyst 2 demonstrates recyclability and can be reused at least 10 times without a significant loss of catalytic activity. These results unveil a new and complementary approach to the design and in situ synthesis of cyclometalated macrocycle Ir(III) complexes via a mild interligand-coupling strategy.

3.
Zhongguo Zhong Yao Za Zhi ; 49(10): 2575-2584, 2024 May.
Artigo em Chinês | MEDLINE | ID: mdl-38812158

RESUMO

Asari Radix et Rhizoma is a common drug for relieving exterior syndrome in clinics, but its toxicity limits its use. In this study, the mechanism of hepatic damage of Asari Radix et Rhizoma was studied by network pharmacology and metabolomics. The hepatic damage-related dataset, namely GSE54257 was downloaded from the GEO database. The Limma package was used to analyze the differentially expressed genes in the dataset GSE54257. Toxic components and target genes of Asari Radix et Rhizoma were screened by TCMSP, ECTM, and TOXNET. The hepatic damage target genes of Asari Radix et Rhizoma were obtained by mapping with the differentially expressed gene of GSE54257, and a PPI network was constructed. GO and KEGG enrichment analysis of target genes were performed, and a "miRNA-target gene-signal pathway" network was drawn with upstream miRNA information. Thirty rats were divided into a blank group, a high-dose Asari Radix et Rhizoma group, and a low-dose Asari Radix et Rhizoma group, which were administered once a day. After continuous administration for 28 days, liver function indexes and liver pathological changes were detected. Five liver tissue samples were randomly collected from the blank group and high-dose Asari Radix et Rhizoma group, and small molecule metabolites were analyzed by ultra-high performance liquid chromatography-mass spectrometry(UHPLC-MS). The orthogonal partial least squares-discriminant analysis(OPLS-DA) method was used to screen differential metabolites, and enrichment analysis, correlation analysis, and cluster analysis were conducted for differential metabolites. Finally, the MetaboAnalyst platform was used to conduct pathway enrichment analysis for differential metabolites. It was found that there were 14 toxic components in Asari Radix et Rhizoma, corresponding to 37 target genes, and 12 genes related to liver toxicity of Asari Radix et Rhizoma were obtained by mapping to differentially expressed genes of GSE54257. The animal test results showed that Asari Radix et Rhizoma could significantly increase the liver function index, reduce the activity of the free radical scavenging enzyme, change the liver oxidative stress level, and induce lipid peroxidation damage in rats. The results of untargeted metabolomics analysis showed that compared with the blank group, nine metabolites were up-regulated, and 16 metabolites were down-regulated in the liver tissue of the Asari Radix et Rhizoma group. These 25 metabolites had strong correlations and good clustering. Pathway enrichment analysis showed that these differential metabolites and the 12 hepatotoxic target genes of Asari Radix et Rhizoma were mainly involved in purine metabolism, as well as the biosynthesis and metabolism of valine, leucine, glycine, serine, and threonine. The study confirmed that the hepatica damage effect of Asari Radix et Rhizoma was the result of multi-component, multi-target, and multi-signaling pathways, and its mechanism may be related to inhibiting nucleotide synthesis and affecting protein metabolism.


Assuntos
Medicamentos de Ervas Chinesas , Fígado , Metabolômica , Animais , Ratos , Medicamentos de Ervas Chinesas/administração & dosagem , Fígado/metabolismo , Fígado/efeitos dos fármacos , Masculino , Farmacologia em Rede , Ratos Sprague-Dawley , Asarum/química , Asarum/genética , Asarum/metabolismo , Rizoma/química , Humanos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/genética
4.
Insect Sci ; 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38783625

RESUMO

Vitellogenin receptor (VgR) plays a crucial role in oogenesis by mediating endocytosis of vitellogenin and a portion of the yolk proteins in many insect species. However, the function of VgR in minute parasitoid wasps is largely unknown. Here, we applied Trichogramma dendrolimi, a minute egg parasitoid, as a study model to investigate the function of VgR in parasitoids. We developed RNA interference (RNAi) methods based on microinjection of prepupae in T. dendrolimi. RNAi employs nanomaterial branched amphipathic peptide capsules (BAPC) as a carrier for double-stranded RNA (dsRNA), significantly enhancing delivery efficiency. Also, artificial hosts without medium were used to culture the injected prepupae in vitro. Utilizing these methods, we found that ovarian growth was disrupted after knockdown of TdVgR, as manifested by the suppressed development of the ovariole and the inhibition of nurse cell internalization by oocytes. Also, the initial mature egg load in the ovary was significantly reduced. Notably, the parasitic capacity of the female adult with ovarian dysplasia was significantly decreased, possibly resulting from the low availability of mature eggs. Moreover, ovarian dysplasia in T. dendrolimi caused by VgR deficiency are conserved despite feeding on different hosts. The results confirmed a critical role of TdVgR in the reproductive ability of T. dendrolimi and provided a reference for gene functional studies in minute insects.

5.
Poult Sci ; 103(6): 103656, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38583308

RESUMO

Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.


Assuntos
Fator 4 Ativador da Transcrição , Apoptose , Proteínas Aviárias , Galinhas , Estresse do Retículo Endoplasmático , Células da Granulosa , Melatonina , Transdução de Sinais , Serina-Treonina Quinases TOR , Animais , Melatonina/farmacologia , Feminino , Galinhas/fisiologia , Células da Granulosa/efeitos dos fármacos , Células da Granulosa/fisiologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/genética , Fator 4 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/genética , Proteínas Aviárias/metabolismo , Proteínas Aviárias/genética , Tunicamicina/farmacologia
6.
ACS Omega ; 9(16): 18238-18248, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38680364

RESUMO

Preparation of nanocomposites based on fluorinated poly(3-octylthiophene-2,5-diyl) (POTF) and purified mesoporous carbon black (PMCB) as the solid-contact layer of a screen-printed carbon electrode (SPCE) is proposed. POTF is used as a dispersant for PMCB. The obtained nanocomposites possess unique characteristics including high conductivity, capacitance, and stability. The SPCE based on POTF and PMCB is characterized by electrochemical impedance spectroscopy and chronopotentiometry, demonstrating simultaneous detection of Na+, K+, Ca2+, and NO2- ions with detection limits of 10-6.5, 10-6.4, 10-6.7, and 10-6.3 M, respectively. Water layer and anti-interference tests revealed that the electrode has high hydrophobicity, and the static contact angle is >140°. The electrode shows excellent selectivity, repeatability, reproducibility, and stability and is not easily affected by light, O2, or CO2.

7.
Sensors (Basel) ; 24(6)2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38544252

RESUMO

Lateral flow immunoassay (LFIA) is extensively utilized for point-of-care testing due to its ease of operation, cost-effectiveness, and swift results. This study investigates the flow dynamics and reaction mechanisms in LFIA by developing a three-dimensional model using the Richards equation and porous media transport, and employing numerical simulations through the finite element method. The study delves into the transport and diffusion behaviors of each reaction component in both sandwich LFIA and competitive LFIA under non-uniform flow conditions. Additionally, the impact of various parameters (such as reporter particle concentration, initial capture probe concentrations for the T-line and C-line, and reaction rate constants) on LFIA performance is analyzed. The findings reveal that, in sandwich LFIA, optimizing parameters like increasing reporter particle concentration and initial capture probe concentration for the T-line, as well as adjusting reaction rate constants, can effectively enhance detection sensitivity and broaden the working range. Conversely, in competitive LFIA, the effects are inverse. This model offers valuable insights for the design and enhancement of LFIA assays.


Assuntos
Nanopartículas Metálicas , Imunoensaio/métodos
8.
Biomaterials ; 307: 122533, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38493671

RESUMO

Myeloid-derived suppressor cells (MDSCs) play a crucial role in the immune escape mechanisms that limit the efficacy of immunotherapeutic strategies. In the tumor microenvironment, NLRP3 inflammasome-driven Interleukin-1ß (IL-1ß) production serves to dampen antitumor immune responses, promoting tumor growth, progression, and immunosuppression. In this study, we revealed that gold nanoparticles (Au NPs) with a size of 30 nm disrupted NLRP3 inflammasome, but not other inflammasomes, in bone marrow-derived macrophages through abrogating NLRP3-NEK7 interactions mediated by reactive oxygen species (ROS). Density functional theory (DFT) calculations provided insights into the mechanism underlying the exceptional ROS scavenging capabilities of Au NPs. Additionally, when coupled with H6, a small peptide targeting MDSCs, Au NPs demonstrated the capacity to effectively reduce IL-1ß levels and diminish the MDSCs population in tumor microenvironment, leading to enhanced T cell activation and increased immunotherapeutic efficacy in mouse tumor models that are sensitive and resistant to PD-1 inhibition. Our findings unraveled a novel approach wherein peptide-modified Au NPs relieved the suppressive impact of the tumor microenvironment by inhibiting MDSCs-mediated IL-1ß release, which is the first time reported the employing a nanostrategy at modulating MDSCs to reverse the immunosuppressive microenvironment and may hold promise as a potential therapeutic agent for cancer immunotherapy.


Assuntos
Nanopartículas Metálicas , Células Supressoras Mieloides , Neoplasias , Camundongos , Animais , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ouro , Receptor de Morte Celular Programada 1 , Espécies Reativas de Oxigênio , Imunoterapia , Microambiente Tumoral
9.
Int Immunopharmacol ; 131: 111899, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38513576

RESUMO

The prevalence rate of allergic diseases including asthma, atopic rhinitis (AR) and atopic dermatitis (AD) has been significantly increasing in recent decades due to environmental changes and social developments. With the study of innate lymphoid cells, the crucial role played by type 2 innate lymphoid cells (ILC2s) have been progressively unveiled in allergic diseases. ILC2s, which are a subset of innate lymphocytes initiate allergic responses. They respond swiftly during the onset of allergic reactions and produce type 2 cytokines, working in conjunction with T helper type 2 (Th2) cells to induce and sustain type 2 immune responses. The role of ILC2s represents an intriguing frontier in immunology; however, the intricate immune mechanisms of ILC2s in allergic responses remain relatively poorly understood. To gain a comphrehensive understanding of the research progress of ILC2, we summarize recent advances in ILC2s biology in pathologic allergic inflammation to inspire novel approaches for managing allergic diseases.


Assuntos
Imunidade Inata , Rinite Alérgica , Humanos , Linfócitos , Citocinas , Inflamação
10.
J Immunother Cancer ; 12(2)2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38388167

RESUMO

BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.


Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Indóis , Neoplasias Pulmonares , Pirróis , Humanos , Antígeno B7-H1/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Microambiente Tumoral
11.
ACS Appl Mater Interfaces ; 16(10): 12951-12964, 2024 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-38422377

RESUMO

Combining immune checkpoint blockade (ICB) therapy with chemotherapy can enhance the efficacy of ICB and expand its indications. However, the limited tumor specificity of chemotherapy drugs results in severe adverse reactions. Additionally, the low tissue penetration and immune-related adverse events associated with monoclonal antibodies restrict their widespread application. To address challenges faced by traditional combination therapies, we design a dual-responsive engineered nanoparticle based on ferritin (denoted as CMFn@OXA), achieving tumor-targeted delivery and controlled release of the anti-PD-L1 peptide CLP002 and oxaliplatin (OXA). Our results demonstrate that CMFn@OXA not only exhibits tumor-specific accumulation but also responds to matrix metalloproteinase-2/9 (MMP-2/9), facilitating the controlled release of CLP002 to block PD-1/PD-L1 interaction. Simultaneously, it ensures the precise delivery of the OXA to tumor cells and its subsequent release within the acidic environment of lysosomes, thereby fostering a synergistic therapeutic effect. Compared to traditional combination therapies, CMFn@OXA demonstrates superior performance in inhibiting tumor growth, extending the survival of tumor-bearing mice, and exhibiting excellent biocompatibility. Collectively, our results highlight CMFn@OXA as a novel and promising strategy in the field of cancer immunotherapy.


Assuntos
Nanopartículas , Neoplasias , Animais , Camundongos , Metaloproteinase 2 da Matriz , Preparações de Ação Retardada , Neoplasias/tratamento farmacológico , Oxaliplatina/farmacologia , Imunoterapia/métodos , Concentração de Íons de Hidrogênio , Microambiente Tumoral , Linhagem Celular Tumoral
12.
J Nat Prod ; 87(2): 396-403, 2024 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-38330072

RESUMO

Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.


Assuntos
Dysidea , Poríferos , Sesquiterpenos , Animais , Dysidea/química , Poríferos/química , Sesquiterpenos/farmacologia , Sesquiterpenos/química , Anti-Inflamatórios/farmacologia , NF-kappa B , Estrutura Molecular
14.
Front Immunol ; 15: 1348272, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38361946

RESUMO

The epithelial barrier serves as a critical defense mechanism separating the human body from the external environment, fulfilling both physical and immune functions. This barrier plays a pivotal role in shielding the body from environmental risk factors such as allergens, pathogens, and pollutants. However, since the 19th century, the escalating threats posed by environmental pollution, global warming, heightened usage of industrial chemical products, and alterations in biodiversity have contributed to a noteworthy surge in allergic disease incidences. Notably, allergic diseases frequently exhibit dysfunction in the epithelial barrier. The proposed epithelial barrier hypothesis introduces a novel avenue for the prevention and treatment of allergic diseases. Despite increased attention to the role of barrier dysfunction in allergic disease development, numerous questions persist regarding the mechanisms underlying the disruption of normal barrier function. Consequently, this review aims to provide a comprehensive overview of the epithelial barrier's role in allergic diseases, encompassing influencing factors, assessment techniques, and repair methodologies. By doing so, it seeks to present innovative strategies for the prevention and treatment of allergic diseases.


Assuntos
Hipersensibilidade , Humanos , Alérgenos
15.
Autophagy ; 20(5): 1205-1207, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38293807

RESUMO

Approximately half of the familial cases of amyotrophic lateral sclerosis (ALS) and frontal temporal dementia (FTD) are attributed to the abnormal GGGGCC repeat expansion within the first intron of C9orf72, potentializing C9orf72 and its product as the most promising target for ALS therapeutics. Nevertheless, the biological function of C9orf72 remains unclear. Previously, we reported that C9orf72 and its binding partner, SMCR8, form a GTPase-activating protein (GAP) complex, which is proposed to regulate membrane trafficking and autophagy. Hereby, we found that the C9orf72-SMCR8 complex negatively regulates primary ciliogenesis and hedgehog (HH) signaling. Furthermore, the biochemical analysis and cell biology experiments identified C9orf72 as the RAB8A binding subunit and SMCR8 as the GAP subunit within the complex. Further, we discussed the relationship among the C9orf72-SMCR8 complex, primary ciliogenesis, and autophagy.


Assuntos
Autofagia , Proteína C9orf72 , Cílios , Proteínas rab de Ligação ao GTP , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Cílios/metabolismo , Humanos , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Autofagia/genética , Animais , Transdução de Sinais , Proteínas Hedgehog/metabolismo , Células HEK293 , Proteínas Ativadoras de GTPase/metabolismo , Proteínas Ativadoras de GTPase/genética , Ligação Proteica , Camundongos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Proteínas de Transporte
16.
J Chem Phys ; 160(4)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38265088

RESUMO

The aging phenomenon is commonly observed in quantum-dot light emitting diodes (QLEDs), involving complex chemical or physical processes. Resolving the underlying mechanism of these aging issues is crucial to deliver reliable electroluminescent devices in future display applications. Here, we report a reversible positive aging phenomenon that the device brightness and efficiency significantly improve after device operation, but recover to initial states after long-time storage or mild heat treatment, which can be termed as warming-up effects. Steady and transient equivalent circuit analysis suggest that the radiative recombination current dramatically increases but electron leakage from the quantum dots (QDs) to hole transport layer becomes more accessible during the warming-up process. Further analysis discloses that the notable enhancement of device efficiency can be ascribed to the filling of shell traps in gradient alloyed QDs. This work reveals a distinct positive aging phenomenon featured with reversibility, and further guidelines would be provided to achieve stable QLED devices in real display applications.

17.
Molecules ; 29(2)2024 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-38276602

RESUMO

A series of reported Pt(II) carbene complexes possibly have the ability to serve as the new generation of blue emitters in luminescent devices because of their narrow emission spectra, high photoluminescence quantum yields (PLQYs), and rigid molecular skeleton. However, the combination of all carbene ligands with different multidentate structures will affect the overall planarity and horizontal dipole ratio to varying degrees, but the specific extent of this effect has not previously been analyzed in detail. In this work, density functional computation is used to study a class of platinum tetracarbene bidentate complexes with similar absorption and emission band characteristics, which is the main reason for the remarkable difference in quantum efficiency due to subtle differences in electronic states caused by different ligands. From the calculation results, the major reason, which results in significantly decrease in quantum efficiency for [Pt(cyim)2]2+, is that [Pt(cyim)2]2+ can reach the non-radiative deactivation metal-centered d-d excited state through an easier pathway compared with [Pt(meim)2]2+. The result, based on changes in the dihedral angle between ligands, can achieve the goal of improving and designing materials by adjusting the degree of the dihedral angle. (meim: bis(1,1'-dimethyl-3,3'-methylene-diimidazoline-2,2'-diylidene); cyim: bis(1,1'-dicyclohexyl-3,3'-methylene-diimidazoline-2,2'-diylidene).

18.
JCI Insight ; 8(23)2023 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-38063198

RESUMO

Gout commonly manifests as a painful, self-limiting inflammatory arthritis. Nevertheless, the understanding of the inflammatory and immune responses underlying gout flares and remission remains ambiguous. Here, based on single-cell RNA-Seq and an independent validation cohort, we identified the potential mechanism of gout flare, which likely involves the upregulation of HLA-DQA1+ nonclassical monocytes and is related to antigen processing and presentation. Furthermore, Tregs also play an essential role in the suppressive capacity during gout remission. Cell communication analysis suggested the existence of altered crosstalk between monocytes and other T cell types, such as Tregs. Moreover, we observed the systemic upregulation of inflammatory and cytokine genes, primarily in classical monocytes, during gout flares. All monocyte subtypes showed increased arachidonic acid metabolic activity along with upregulation of prostaglandin-endoperoxide synthase 2 (PTGS2). We also detected a decrease in blood arachidonic acid and an increase in leukotriene B4 levels during gout flares. In summary, our study illustrates the distinctive immune cell responses and systemic inflammation patterns that characterize the transition from gout flares to remission, and it suggests that blood monocyte subtypes and Tregs are potential intervention targets for preventing recurrent gout attacks and progression.


Assuntos
Gota , Humanos , Gota/genética , Gota/metabolismo , Monócitos/metabolismo , Ácido Araquidônico , Exacerbação dos Sintomas , Perfilação da Expressão Gênica
20.
Proc Natl Acad Sci U S A ; 120(50): e2220496120, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38064514

RESUMO

Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.


Assuntos
Esclerose Lateral Amiotrófica , Proteína C9orf72 , Cílios , Demência Frontotemporal , Animais , Camundongos , Esclerose Lateral Amiotrófica/metabolismo , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Cílios/metabolismo , Expansão das Repetições de DNA , Demência Frontotemporal/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Células HEK293
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