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Wheat is a vital global food crop, yet it faces challenges in saline-alkali soils where Fusarium crown rot significantly impacts growth. Variations in wheat growth across regions are often attributed to uneven terrain. To explore these disparities, we examined well-growing and poorly growing wheat samples and their rhizosphere soils. Measurements included wheat height, root length, fresh weight, and Fusarium crown rot severity. Well-growing wheat exhibited greater height, root length, and fresh weight, with a lower Fusarium crown rot disease index compared to poorly growing wheat. Analysis of rhizosphere soil revealed higher alkalinity; lower nutrient levels; and elevated Na, K, and Ca levels in poorly growing wheat compared to well-growing wheat. High-throughput sequencing identified a higher proportion of unique operational taxonomic units (OTUs) in poorly growing wheat, suggesting selection for distinct fungal species under stress. FUNGuild analysis indicated a higher prevalence of pathogenic microbial communities in poorly growing wheat rhizosphere soil. This study underscores how uneven terrains in saline-alkali soils affect pH, nutrient dynamics, mineral content, wheat health, and rhizosphere fungal community structure.
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Fusarium crown rot (FCR) is one of the most important soilborne diseases affecting wheat production. To investigate the diversity of the pathogens causing this disease, 199 diseased wheat samples were collected from 13 cities in Shandong province. In total, 468 isolates were obtained, and from these isolates, 11 Fusarium species were identified based on phylogenetic analyses with the translation elongation factor-1α (TEF-1α), RNA polymerase II largest subunit (RPB1), and RNA polymerase II second largest subunit (RPB2) gene sequences. Of these Fusarium isolates, 283 were identified as Fusarium pseudograminearum and the remaining isolates were identified as Fusarium graminearum (n = 113), Fusarium sinensis (n = 28), Fusarium acuminatum (n = 18), Fusarium incarnatum (n = 13), Fusarium ipomoeae (n = 5), Fusarium flocciferum (n = 3), Fusarium proliferatum (n = 2), Fusarium asiaticum (n = 1), Fusarium culmorum (n = 1), and Fusarium oxysporum (n = 1), suggesting that F. pseudograminearum is the dominant pathogen of FCR of wheat in Shandong province. Pathogenicity tests demonstrated that all 11 Fusarium species could cause typical symptoms of FCR on wheat seedlings. The results of the study indicate that a greater diversity of Fusarium species can cause FCR of wheat in Shandong province than that has been previously reported. This is the first report in the world of Fusarium incarnatum, Fusarium ipomoeae, and Fusarium flocciferum as pathogens causing FCR in wheat.
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The acetylation of histone lysine residues regulates multiple life processes, including growth, conidiation, and pathogenicity in filamentous pathogenic fungi. However, the specific function of each lysine residue at the N-terminus of histone H3 in phytopathogenic fungi remains unclear. In this study, we mutated the N-terminal lysine residues of histone H3 in Fusarium pseudograminearum, the main causal agent of Fusarium crown rot of wheat in China, which also produces deoxynivalenol (DON) toxins harmful to humans and animals. Our findings reveal that all the FpH3K9R, FpH3K14R, FpH3K18R, and FpH3K23R mutants are vital for vegetative growth and conidiation. Additionally, FpH3K14 regulates the pathogen's sensitivity to various stresses and fungicides. Despite the slowed growth of the FpH3K9R and FpH3K23R mutants, their pathogenicity towards wheat stems and heads remains unchanged. However, the FpH3K9R mutant produces more DON. Furthermore, the FpH3K14R and FpH3K18R mutants exhibit significantly reduced virulence, with the FpH3K18R mutant producing minimal DON. In the FpH3K9R, FpH3K14R, FpH3K18R, and FpH3K23R mutants, there are 1863, 1400, 1688, and 1806 downregulated genes, respectively, compared to the wild type. These downregulated genes include many that are crucial for growth, conidiation, pathogenicity, and DON production, as well as some essential genes. Gene ontology (GO) enrichment analysis indicates that genes downregulated in the FpH3K14R and FpH3K18R mutants are enriched for ribosome biogenesis, rRNA processing, and rRNA metabolic process. This suggests that the translation machinery is abnormal in the FpH3K14R and FpH3K18R mutants. Overall, our findings suggest that H3 N-terminal lysine residues are involved in regulating the expression of genes with important functions and are critical for fungal development and pathogenicity.
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Introduction: γ-Aminobutyric acid (GABA) type A receptors (GABAARs) are ligand-gated Cl-channels that mediate the bulk of inhibitory neurotransmission in the mature CNS and are targets of many drugs. During cortical development, GABAAR-mediated signals are significantly modulated by changing subunit composition and expression of Cl-transporters as part of developmental processes and early network activity. To date, this developmental evolution has remained understudied, particularly at the level of cortical layer-specific changes. In this study, we characterized the expression of nine major GABAAR subunits and K-Cl transporter 2 (KCC2) in mouse somatosensory cortex from embryonic development to postweaning maturity. Methods: We evaluated expression of α1-5, ß2-3, γ2, and δ GABAAR subunits using immunohistochemistry and Western blot techniques, and expression of KCC2 using immunohistochemistry in cortices from E13.5 to P25 mice. Results: We found that embryonic cortex expresses mainly α3, α5, ß3, and γ2, while expression of α1, α2, α4, ß2, δ, and KCC2 begins at later points in development; however, many patterns of nuanced expression can be found in specific lamina, cortical regions, and cells and structures. Discussion: While the general pattern of expression of each subunit and KCC2 is similar to previous studies, we found a number of unique temporal, regional, and laminar patterns that were previously unknown. These findings provide much needed knowledge of the intricate developmental evolution in GABAAR composition and KCC2 expression to accommodate developmental signals that transition to mature neurotransmission.
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The addition of Sudan dyes with carcinogenic effects to food threatens human health. Herein, a ratiometric fluorescence strip consisting of core-shell upconversion particles (NaYF4:Yb,Tm@NaYF4:Yb,Er), metal-organic frameworks and dual-template molecularly imprinted polymers was developed to selectively and sensitively detect four Sudan dyes based on inner filter effect (detection time only takes 8 min). The high adsorption capacity of metal-organic frameworks and the greater overlap between the emission of NaYF4:Yb,Tm@NaYF4:Yb,Er and the absorbance of four Sudan dyes enable the signal responses to be more sensitive. The limits of detection in chilli powder samples are as low as 29.87 ng/g, 37.55 ng/g, 47.89 ng/g and 51.02 ng/g, with satisfactory recovery (93.32-103.4%) and minor relative standard deviations (≤4.3%). This method broadens the idea for low-cost and portable detection of multiple illegal additives in complex substrates with high selectivity and sensitivity based on one kind of fluorescent strip.
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Estructuras Metalorgánicas , Impresión Molecular , Humanos , Colorantes , Fluorescencia , AlimentosRESUMEN
Thermal quenching is the core challenge that hinders the application of luminescent materials. Herein, a synergistic mechanism involving energy transfer and energy gap modulation is proposed based on the local crystal field regulation around sensitizers. The substitution of coordination cation V5+/P5+ weakens the crystal field strength of the sensitizer Bi3+, and the weakening of crystal field splitting causes an increase in the 3P1 energy level, thus increasing its energy gap. Compared with the YVO4:Bi3+,Eu3+ phosphor, the thermal stability of the YV0.25P0.75O4:Bi3+,Eu3+ phosphor is significantly improved, and the relative emission intensity of Eu3+ continuously increases with heating and reaches 1.24 times the original intensity at 523 K and does not show a decreasing trend in the studied temperature range. The anti-thermal quenching performance is mainly attributed to the increasing thermal quenching activation energy (ΔE) of the sensitizer by energy gap modulation, which enhances the energy transfer to compensate thermal quenching. Based on the thermal quenching characteristics of the materials, an optical thermometer is designed. The maximum relative sensitivity (Sr) and absolute sensitivity (Sa) are as high as 1.74% K-1 and 0.59 K-1, respectively, and the minimum temperature resolution reaches 0.288 K. The synergistic effect between energy gap modulation of the sensitizer and energy transfer enables the regulation of thermal quenching. Thus, this study provides a new strategy for exploiting high-performance luminescent materials.
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Nanomaterial-based cancer therapy faces significant limitations due to the complex nature of the tumor microenvironment (TME). Starvation therapy is an emerging therapeutic approach that targets tumor cell metabolism using glucose oxidase (GOx). Importantly, it can provide a material or environmental foundation for other diverse therapeutic methods by manipulating the properties of the TME, such as acidity, hydrogen peroxide (H2O2) levels, and hypoxia degree. In recent years, this cascade strategy has been extensively applied in nanoplatforms for ongoing synergetic therapy and still holds undeniable potential. However, only a few review articles comprehensively elucidate the rational designs of nanoplatforms for synergetic therapeutic regimens revolving around the conception of the cascade strategy. Therefore, this review focuses on innovative cascade strategies for GOx-based synergetic therapy from representative paradigms to state-of-the-art reports to provide an instructive, comprehensive, and insightful reference for readers. Thereafter, we discuss the remaining challenges and offer a critical perspective on the further advancement of GOx-facilitated cancer treatment toward clinical translation.
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Nanopartículas , Nanoestructuras , Neoplasias , Humanos , Glucosa Oxidasa/uso terapéutico , Glucosa Oxidasa/metabolismo , Peróxido de Hidrógeno/uso terapéutico , Neoplasias/terapia , Nanoestructuras/uso terapéutico , Microambiente TumoralRESUMEN
Background: Recurrence of atrial fibrillation (AF) after catheter ablation (CA) remains a challenge today. Although it is believed that evaluating the structural and functional remodeling of the left atrium (LA) may be helpful in predicting AF recurrence, there is a lack of consensus on prediction accuracy. Ultrasound-based radiomics is currently receiving increasing attention because it might aid in the diagnosis and prognosis prediction of AF recurrence. However, research on LA ultrasound radiomics is limited. Objective: We aim to investigate the incremental predictive utility of LA radiomics and construct a radiomics nomogram to preoperatively predict AF recurrence following CA. Methods: A training cohort of 232 AF patients was designed for nomogram construction, while a validation cohort (n = 100) served as the model performance test. AF recurrence during a follow-up period of 3-12 months was defined as the endpoint. The radiomics features related to AF recurrence were extracted and selected to create the radiomics score (rad score). These rad scores, along with other morphological and functional indicators for AF recurrence, were included in the multivariate Cox analysis to establish a nomogram for the prediction of the likelihood of AF recurrence within 1 year following CA. Results: In the training and validation cohorts, AF recurrence rates accounted for 32.3% (75/232) and 25.0% (25/100), respectively. We extracted seven types of radiomics features associated with AF recurrence from apical four-chamber view echocardiography images and established a rad score for each patient. The radiomics nomogram was built with the rad score, AF type, left atrial appendage emptying flow velocity, and peak atrial longitudinal strain. It outperformed the nomogram building without the rad score in terms of the predictive efficacy of CA outcome and showed favorable performance in both cohorts. Conclusion: We revealed the incremental utility of a radiomics signature in the prediction of AF recurrence and preliminarily developed and validated a radiomics nomogram for identifying patients who were at high risk of post-CA recurrence, which contributed to an appropriate management strategy for AF.
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Curcumin shows an anti-cancer role in many kinds of tumors. However, the mechanism of its anti-tumor function in esophageal squamous cell carcinoma (ESCC) remains largely unknown. Herein, we explored the therapeutic potential of curcumin for esophageal cancer. Curcumin could time- and dose-dependently inhibit ESCC cells activity. Additionally, ESCC cells exposed to 20 µM of curcumin exhibited significantly decreased proliferative and invasive capacities, as well as enhanced cell apoptosis. ESCC tissues and cells exhibited significantly increased circNRIP1 expression when compared to their counterparts. circNRIP1 knockdown markedly impaired cell proliferation, clone formation, cell migration and invasion but promoted apoptosis. Exposure to 10-20 µM of curcumin inhibited circNRIP1 expression, however, overexpression of circNRIP1 could significantly restored the biological characteristics that were inhibited by curcumin exposure in vivo and in vitro. circNRIP1 promoted the malignancy of ESCC by combining miR-532-3p, and downstream AKT3. Curcumin inhibited AKT phosphorylation by up-regulating miR-532-3p expression, thereby inhibiting the activation of the AKT pathway. In summary, curcumin is a potent inhibitor of ESCC growth, which can be achieved through the regulation of the circNRIP1/miR-532-3p/AKT pathway. This research may provide new mechanisms for curcumin to inhibit the malignant development of ESCC.
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Curcumina , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , MicroARNs , Humanos , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Neoplasias Esofágicas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Curcumina/farmacología , MicroARNs/metabolismo , Línea Celular Tumoral , Proliferación Celular , Movimiento Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
Biological seed dressing is a cost-effective means to protect plant roots from pathogens. Trichoderma is generally considered as one of the most common biological seed dressings. However, there is still a dearth of information on the effects of Trichoderma on microbial community of rhizosphere soil. High-throughput sequencing was used to analyze the effects of Trichoderma viride and a chemical fungicide on microbial community of soybean rhizosphere soil. The results showed that both T. viride and chemical fungicide could significantly reduce the disease index of soybean (15.11% for Trichoderma and 17.33% for Chemical), while no significant difference was observed between them. Both T. viride and chemical fungicide could affect the structure of rhizosphere microbial community, they increased the ß-diversity of microbial community and significantly reduce the relative abundance of Saprotroph-Symbiotroph. Chemical fungicide could reduce the complexity and stability of co-occurrence network. However, T. viride is beneficial for maintaining network stability and increasing network complexity. There were 31 bacterial genera and 21 fungal genera significantly correlated with the disease index. Furthermore, several potential plant pathogenic microorganisms were also positively correlated with disease index, such as Fusarium, Aspergillus, Conocybe, Naganishia, and Monocillium. From this work, T. viride may be used as a substitute for chemical fungicide to control soybean root rot and be more friendly to soil microecology.
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An up-conversion molecularly imprinted ratiometric fluorescent probe with a monodisperse nuclear-satellite structure and its test strip are designed which can avoid fluorescent background interference to detect Sudan I in chili powder highly selective and sensitive. The detection mechanism is based on the selective recognition of Sudan I by imprinted cavities on the surface of ratiometric fluorescent probe and the inner filter effect between Sudan I molecules and the emission of up-conversion materials (NaYF4:Yb,Tm). Under optimized experimental conditions, the response of fluorescent ratio signals (F475/F645) of this test strip show a good linear relationship in the range 0.02-50 µM Sudan I. The limits of detection and quantitation are as low as 6 nM and 20 nM, respectively. Sudan I is selectively detected in the presence of fivefold higher concentrations of interfering substances (imprinting factor up to 4.4). Detection of Sudan I in chili powder samples show ultra-low LOD (44.7 ng/g), satisfactory recoveries (94.99-105.5%) and low relative standard deviation (≤ 2.0%). This research offers a reliable strategy and promising scheme for highly selective and sensitive detection of illegal additives in complex food matrix via an up-conversion molecularly imprinted ratiometric fluorescent test strip.
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Impresión Molecular , Colorantes Fluorescentes , Polvos , Límite de DetecciónRESUMEN
INTRODUCTION: Acute postoperative pain is a major concern among surgical patients. Thus, this study established a new acute pain management model and compared the effects of the acute pain service (APS) model in 2020 and the virtual pain unit (VPU) model in 2021 on postoperative analgesia quality. METHODS: This retrospective, single-center clinical study involved 21,281 patients from 2020 to 2021. First, the patients were grouped on the basis of their pain management model (APS and VPU). The incidence of moderate to severe postoperative pain (MSPP) [numeric rating scale (NRS) score ≥ 5], postoperative nausea and vomiting (PONV), and postoperative dizziness were recorded. RESULTS: The VPU group recorded significantly lower MSPP incidence (1-12 months), PONV, and postoperative dizziness (1-10 months and 12 months) compared with the APS group. In addition, the annual average incidence of MSPP, PONV, and postoperative dizziness in the VPU group was significantly lower than in the APS group. CONCLUSIONS: The VPU model reduces the incidence of moderate to severe postoperative pain, nausea, vomiting, and dizziness; hence, it is a promising acute pain management model.
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The Lassa virus (LASV) is endemic in West Africa and causes severe hemorrhagic Lassa fever in humans. The glycoprotein complex (GPC) of LASV is highly glycosylation-modified, with 11 âN-glycosylation sites. All 11 N-linked glycan chains play critical roles in GPC cleavage, folding, receptor binding, membrane fusion, and immune evasion. In this study, we focused on the first glycosylation site because its deletion mutant (N79Q) results in an unexpected enhanced membrane fusion, whereas it exerts little effect on GPC expression, cleavage, and receptor binding. Meanwhile, the pseudotype virus bearing GPCN79Q was more sensitive to the neutralizing antibody 37.7H and was attenuated in virulence. Exploring the biological functions of the key glycosylation site on LASV GPC will help elucidate the mechanism of LASV infection and provide strategies for the development of attenuated vaccines against LASV infection.
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Fiebre de Lassa , Virus Lassa , Humanos , Virus Lassa/genética , Glicosilación , Fusión de Membrana , Glicoproteínas/genética , Fiebre de Lassa/prevención & controlRESUMEN
Chemotherapy was the main treatment method for esophageal cancer (EC) patients. However, chemotherapy resistance due to multiple factors is a major barrier to EC treatment. For investigating how small nucleolar RNA host gene 6 (SNHG6) affected the 5-fluorouracil (5-FU) resistance in EC as well as its possible molecular mechanism. This work conducted cell viability assay, clone formation, scratch assays together with cell apoptosis for evaluating the roles of SNHG6 and enhancer of zeste homolog 2 (EZH2, the histone-lysine N-methyltransferase). Relevant molecular mechanism was identified by RT-qPCR analysis together with Western-blot (WB) assays. Our data showed that SNHG6 expression increased in EC cells. SNHG6 promotes colony formation and migration, whereas suppresses EC cell apoptosis. SNHG6 silencing markedly promoted 5-FU-mediated suppression on KYSE150 and KYSE450 cells. Additional mechanism studies showed that SNHG6 modulating STAT3 and H3K27me3 via promoting EZH2 level. Similar to the function of SNHG6, abnormal expression of EZH2 promotes the malignancy of EC and intensifies its resistance to 5-FU. In addition, overexpression of EZH2 abolished the role of SNHG6 silencing in 5-FU sensitivity in EC cells. SNHG6 overexpression promoted malignancy of EC and increased EC cell resistance to 5-FU. Besides, further molecular mechanism studies provided a novel regulatory pathways that SNHG6 knockdown promoted EC cell sensitivity to 5-FU by modulating STAT3 and H3K27me3 via promoting EZH2 expression.
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Neoplasias Esofágicas , MicroARNs , ARN Largo no Codificante , Humanos , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Línea Celular Tumoral , Histonas/metabolismo , Proliferación Celular/genética , Fluorouracilo/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/metabolismo , Regulación Neoplásica de la Expresión Génica , MicroARNs/genéticaRESUMEN
Developing full-spectrum photocatalysts with simultaneous broadband light absorption, excellent charge separation, and high redox capabilities is becoming increasingly significant. Herein, inspired by the similarities in crystalline structures and compositions, a unique 2D-2D Bi4 O5 I2 /BiOBr:Yb3+ ,Er3+ (BI-BYE) Z-scheme heterojunction with upconversion (UC) functionality is successfully designed and fabricated. The co-doped Yb3+ and Er3+ harvest near-infrared (NIR) light and then convert it into visible light via the UC function, expanding the optical response range of the photocatalytic system. The intimate 2D-2D interface contact provides more charge migration channels and enhances the Förster resonant energy transfer of BI-BYE, leading to significantly improved NIR light utilization efficiency. Density functional theory (DFT) calculations and experimental results confirm that the Z-scheme heterojunction is formed and that this heterojunction endows the BI-BYE heterostructure with high charge separation and strong redox capability. Benefit from these synergies, the optimized 75BI-25BYE heterostructure exhibits the highest photocatalytic performance for Bisphenol A (BPA) degradation under full-spectrum and NIR light irradiation, outperforming BYE by 6.0 and 5.3 times, respectively. This work paves an effective approach for designing highly efficient full-spectrum responsive Z-scheme heterojunction photocatalysts with UC function.
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Combination therapy is an effective way to alleviate the shortcoming of monotherapy and enhances therapeutic efficacy. Herein, a distinctive hollow mesoporous silica nanoparticle (HMSNs) encapsulated with folic acid-modified bovine serum albumin (BSA-FA), denoted as HBF, was engineered for tumor targeting and dual-responsive release of loaded-therapeutic agents MD (methylene blue (MB) and doxorubicin (DOX)). The BSA molecule as a ''gatekeeper'' prevents premature drug leakage and actively unloads the cargos through BSA detachment in response to intracellular glutathione (GSH). Folic acid (FA) promotes the specific intracellular delivery of the drug to folate receptor (FR)-expressing cancer cells to improve the efficacy of chemo-photodynamic therapy (PDT). In vitro drug release profiles showed that the drug carrier could achieve pH/redox-responsive drug release from MD@HBF owing to the cleavage of the imine bonds between HMSNs-CHO and BSA-FA and BSA intramolecular disulfide bond. Additionally, a series of biological evaluations, such as cell uptake experiments, toxicity experiments, and in vivo therapeutic assays indicated that MD@HBF possesses the features of accurately targeting FR-expressing 4T1 cells to induce cells apoptosis in vitro, exhibits outstanding tumor cell synergistic killing efficiency of chemo-photodynamic therapy (combination index CI = 0.325), and inhibits tumors growth. These results demonstrated that the strategy of combining HMSNs with stimuli-responsive biodegradable protein molecules could provide a new potential direction toward the ''on-demand'' drug release for precision chemo-photodynamic therapy in cancer treatment.
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Neoplasias de la Mama , Nanopartículas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Dióxido de Silicio/química , Albúmina Sérica Bovina/química , Doxorrubicina/química , Nanopartículas/química , Ácido Fólico , Sistemas de Liberación de Medicamentos/métodos , Porosidad , Liberación de FármacosRESUMEN
Colorectal cancer (CRC) is the fourth most deadly cancer worldwide, drug resistance impedes treatment of CRC. It is still urgent to find new molecular targets to improve the sensitivity of chemotherapeutic drugs. In this study, circ-ERBB2 was upregulated in CRC cells. Upregulation of circ-ERBB2 promoted CRC cells proliferation and clone formation, but inhibited apoptosis. We identified miR-181a-5p as circ-ERBB2's target. The effect of miR-181a-5p on CRC cells was contrary to circ-ERBB2, miR-181a-5p downregulation abolished the function of circ-ERBB2 silencing in CRC cells. In addition, phosphatase and tensin homolog (PTEN) was verified as miR-181a-5p's downstream target, circ-ERBB2 activates the Akt pathway and inhibits cell apoptosis through modulating miR-181a-5p/PTEN. Circ-ERBB2 silencing significantly reduced CRC cell resistance to 5-FU. miR-181a-5p downregulation abolished the role of circ-ERBB2 knockdown in CRC cell resistance to 5-FU. In conclusion, upregulation of circ-ERBB2 promoted the malignancy of CRC and reduced CRC cell resistance to 5-FU. Besides, additional mechanism study provided a novel regulatory pathways that circ-ERBB2 knockdown promoted CRC cell sensitivity to 5-FU by regulating miR-181a-5p/PTEN/Akt pathway. This research indicated that circ-ERBB2 may be a valuable biomarker for the diagnosis and treatment of CRC.
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Neoplasias Colorrectales , MicroARNs , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Fluorouracilo/farmacología , Proliferación Celular , Fosfohidrolasa PTEN/genética , Receptor ErbB-2/genéticaRESUMEN
Lassa virus (LASV) is a highly pathogenic virus that is categorized as a biosafety level-4 pathogen. Currently, there are no approved drugs or vaccines specific to LASV. In this study, high-throughput screening of a fragment-based drug discovery library was performed against LASV entry using a pseudotype virus bearing the LASV envelope glycoprotein complex (GPC). Two compounds, F1920 and F1965, were identified as LASV entry inhibitors that block GPC-mediated membrane fusion. Analysis of adaptive mutants demonstrated that the transient mutants L442F and I445S, as well as the constant mutant F446L, were located on the same side on the transmembrane domain of the subunit GP2 of GPC, and all the mutants conferred resistance to both F1920 and F1965. Furthermore, F1920 antiviral activity extended to other highly pathogenic mammarenaviruses, whereas F1965 was LASV-specific. Our study showed that both F1920 and F1965 provide a potential backbone for the development of lead drugs for preventing LASV infection.
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Arenaviridae , Inhibidores de Fusión de VIH , Fiebre de Lassa , Humanos , Virus Lassa , Antivirales/farmacología , Antivirales/uso terapéutico , Descubrimiento de Drogas , Inhibidores de Fusión de VIH/uso terapéuticoRESUMEN
Immune-related adverse events, particularly severe toxicities such as myocarditis, are major challenges to the utility of immune checkpoint inhibitors (ICIs) in anticancer therapy1. The pathogenesis of ICI-associated myocarditis (ICI-MC) is poorly understood. Pdcd1-/-Ctla4+/- mice recapitulate clinicopathological features of ICI-MC, including myocardial T cell infiltration2. Here, using single-cell RNA and T cell receptor (TCR) sequencing of cardiac immune infiltrates from Pdcd1-/-Ctla4+/- mice, we identify clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8-depleting, but not anti-CD4-depleting, antibodies improved the survival of Pdcd1-/-Ctla4+/- mice. Adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients, which required CD8+ T cells. The cardiac-specific protein α-myosin, which is absent from the thymus3,4, was identified as the cognate antigen source for three major histocompatibility complex class I-restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-MC were expanded by α-myosin peptides. Moreover, these α-myosin-expanded T cells shared TCR clonotypes with diseased heart and skeletal muscle, which indicates that α-myosin may be a clinically important autoantigen in ICI-MC. These studies underscore the crucial role for cytotoxic CD8+ T cells, identify a candidate autoantigen in ICI-MC and yield new insights into the pathogenesis of ICI toxicity.
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Linfocitos T CD8-positivos , Inmunoterapia , Miocarditis , Miosinas Ventriculares , Animales , Ratones , Autoantígenos/inmunología , Linfocitos T CD8-positivos/inmunología , Antígeno CTLA-4/deficiencia , Antígeno CTLA-4/genética , Inmunoterapia/efectos adversos , Miocarditis/inducido químicamente , Miocarditis/etiología , Miocarditis/mortalidad , Miocarditis/patología , Miosinas Ventriculares/inmunologíaRESUMEN
Spontaneous polarization induced by the unique crystal structure of ferroelectric semiconductor photocatalyst facilitates charge separation and injects new vitality into the improvement of the photocatalytic activity. However, due to the complexity of multi-electric field coupling, the actual efficiency of charge separation driven by the depolarization field is restricted by the shielding field, which is lower than theoretical expectations. Here, we take Bi4NbO8Cl as a model system and selectively construct a BiOI dielectric layer on its positive polarized surface through the adsorption-self-assembly method, aiming to reduce the attenuation of the shielding field to the depolarization field. The enhanced residual depolarization field (RDF) is quantitatively characterized by ferroelectric performance test. Moreover, the charge transfer path and final position are elaborated by photo-deposition experiments, while high-quality interface and calculated difference of the potential between Bi4NbO8Cl and BiOI is responsible for the formation of charge transfer channel. The enhanced RDF promotes the separation of charges, which causes that Bi4NbO8Cl/BiOI photo-degradation of bisphenol A (BPA) gives 7.35-fold greater efficiency than Bi4NbO8Cl. This scheme of weakening the shielding field by surface reconstruction engineering is promising to be extended to more ferroelectric photocatalyst systems.