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Studying the mechanisms underlying clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer, may address an unmet need in ccRCC-targeted drug research. Growing evidences indicate that protein phosphatase 4 (PP4) plays an important role in cancer biology. Here, we characterized the upregulation of PP4 core component SMEK1 in ccRCC using tissue microarrays and revealed that its high expression is closely associated with reduced patient survival. We then conducted cell function experiments and animal experiments to prove the tumor-promoting effect of SMEK1. Next, RNA-seq was performed to explore its underlying mechanism, and the results revealed that SMEK1-regulated genes were extensively involved in cell motility, and the canonical tyrosine kinase receptor EGFR was one of its targets. Moreover, we verified the regulatory effect of SMEK1 on EGFR and its downstream MAPK and AKT pathway through molecular experiments, in which erlotinib, a tyrosine kinase inhibitor, can partially block this regulation, demonstrating that SMEK1 mediates its effects dependent on the tyrosine kinase activity of EGFR. Mechanistically, SMEK1 bond to PRMT5 and facilitated PRMT5-mediated histone methylation to promote the transcription of EGFR. Furthermore, we studied the upstream regulators of SMEK1 and demonstrated that the transcription factor E2F1 could directly bind to the SMEK1 promoter by chromatin immunoprecipitation. Functionally, E2F1 could also induce ccRCC progression by manipulating the expression of SMEK1. Collectively, our findings demonstrate the overexpression of SMEK1 in ccRCC, and reveal a novel E2F1/SMEK1/PRMT5/EGFR-tyrosine-kinase-dependent pathway for ccRCC progression.
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To achieve high power conversion efficiency in perovskite/silicon tandem solar cells, it is necessary to develop a promising wide-bandgap perovskite absorber and processing techniques in relevance. To date, the performance of devices based on wide-bandgap perovskite is still limited mainly by carrier recombination at their electron extraction interface. Here, we demonstrate assembling a binary two-dimensional perovskite by both alternating-cation-interlayer phase and Ruddlesden-Popper phase to passivate perovskite/C60 interface. The binary two-dimensional strategy takes effects not only at the interface but also in the bulk, which enables efficient charge transport in a wide-bandgap perovskite solar cell with a stabilized efficiency of 20.79% (1 cm2). Based on this absorber, a monolithic perovskite/silicon tandem solar cell is fabricated with a steady-state efficiency of 30.65% assessed by a third party. Moreover, the tandem devices retain 96% of their initial efficiency after 527 h of operation under full spectral continuous illumination, and 98% after 1000 h of damp-heat testing (85 °C with 85% relative humidity).
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X-linked hereditary Alport syndrome (XLAS) type 1 (OMIM: 301050) results from a pathogenic variant in the collagen type IV alpha 5 chain (COL4A5) gene.A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells of a 7-year-old male patient with XLAS using non-integrating episomal vector technique. The male donor had a heterozygous variant in the COL4A5 gene. The resulting iPSC line has a standard karyotype, can express pluripotent biomarkers, and is able to create germ layers in vivo. It can serve as a valuable cellular model for investigating the underlying mechanisms of XLAS.
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The practical application of aqueous zinc-ion batteries (AZIBs) is greatly challenged by rampant dendrites and pestilent side reactions resulting from an unstable Zn-electrolyte interphase. Herein, we report the construction of a reliable superstructured solid electrolyte interphase for stable Zn anodes by using mesoporous polydopamine (2D-mPDA) platelets as building blocks. The interphase shows a biomimetic nacre's "brick-and-mortar" structure and artificial transmembrane channels of hexagonally ordered mesopores in the plane, overcoming the mechanical robustness and ionic conductivity trade-off. Experimental results and simulations reveal that the -OH and -NH groups on the surface of artificial ion channels can promote rapid desolvation kinetics and serve as an ion sieve to homogenize the Zn2+ flux, thus inhibiting side reactions and ensuring uniform Zn deposition without dendrites. The 2D-mPDA@Zn electrode achieves an ultralow nucleation potential of 35 mV and maintains a Coulombic efficiency of 99.8% over 1500 cycles at 5 mA cm-2. Moreover, the symmetric battery exhibits a prolonged lifespan of over 580 h at a high current density of 20 mA cm-2. This biomimetic superstructured interphase also demonstrates the high feasibility in Zn//VO2 full cells and paves a new route for rechargeable aqueous metal-ion batteries.
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Catalytic upcycling of polyolefins into high-value chemicals represents the direction in end-of-life plastics valorization, but poses great challenges. Here, we report the synthesis of a tandem porous catalyst via a micelle cascade assembly strategy for selectively catalytic cracking of polyethylene into olefins at a low temperature. A hierarchically porous silica layer from mesopore to macropore is constructed on the surface of microporous ZSM-5 nanosheets through cascade assembly of dynamic micelles. The outer macropore arrays can adsorb bulky polyolefins quickly by the capillary and hydrophobic effects, enhancing the diffusion and access to active sites. The middle mesopores present a nanoconfinement space, pre-cracking polyolefins into intermediates by weak acid sites, which then transport into zeolites micropores for further cracking by strong Brønsted acid sites. The hierarchically porous and acidic structures, mimicking biomimetic protease catalytic clefts, ideally match the tandem cracking steps of polyolefins, thus suppressing coke formation and facilitating product escape. As a result, light hydrocarbons (C1-C7) are produced with a yield of 443â mmol gZSM-5 -1, where 74.3 % of them are C3-C6 olefins, much superior to ZSM-5 and porous silica catalysts. This tandem porous catalyst exemplifies a superstructure design of catalytic cracking catalysts for industrial and economical upcycling of plastic wastes.
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Estimating and synthesizing the hand's manipulation of objects is central to understanding human behaviour. To accurately model the interaction between the hand and object (referred to as the "hand-object"), we must not only focus on the pose of the hand and object, but also consider the contact between them. This contact provides valuable information for generating semantically and physically plausible grasps. In this paper, we propose an explicit contact representation called Contact Potential Field (CPF). In CPF, we model the contact between a pair of hand-object vertices as a spring-mass system. This system encodes the distance of the pair, as well as a likelihood of that contact being stable. Therefore, the system of multiple extended and compressed springs forms an elastic potential field with minimal energy at the optimal grasp position. We apply CPF to two relevant tasks, namely, hand-object pose estimation and grasping pose generation. Extensive experiments on the two challenging tasks and three commonly used datasets have demonstrated that our method can achieve state-of-the-art in several reconstruction metrics, allowing us to produce more physically plausible hand-object poses even when the ground-truth exhibits severe interpenetration or disjointedness.
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The traditional methods for creating oxygen vacancies in materials present several challenges and limitations, such as high preparation temperatures, limited oxygen vacancy generation, and morphological destruction, which hinder the application of transition metal oxides in the field of zinc-air batteries (ZABs). In order to address these limitations, we have introduced a pioneering lithium reduction strategy for generating oxygen vacancies in δ-MnO2@MXene composite materials. This strategy stands out for its simplicity of implementation, applicability at room temperature, and preservation of the material's structural integrity. This research demonstrates that aqueous Ov-MnO2@MXene-5, with introduced oxygen vacancies, exhibits an outstanding oxygen reduction reaction (ORR) activity with an ORR half-wave potential reaching 0.787 V. DFT calculations have demonstrated that the enhanced activity could be attributed to adjustments in the electronic structure and alterations in adsorption bond lengths. These adjustments result from the introduction of oxygen vacancies, which in turn promote electron transport and catalytic activity. In the context of zinc-air batteries, cells with Ov-MnO2@MXene-5 as the air cathode exhibit outstanding performance, featuring a significantly improved maximum power density (198.3 mW cm-2) and long-term cycling stability. Through the innovative strategy of introducing oxygen vacancies, this study has successfully enhanced the electrochemical catalytic performance of MnO2, overcoming the limitations associated with traditional methods for creating oxygen vacancies. Consequently, this research opens up new avenues and directions for nonprecious metal catalyst application in ZABs.
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Metal halide perovskite solar cells (PSCs) have garnered much attention in recent years. Despite the remarkable advancements in PSCs utilizing traditional metal electrodes, challenges such as stability concerns and elevated costs have necessitated the exploration of innovative electrode designs to facilitate industrial commercialization. Herein, a physically and chemically stable molybdenum (Mo) electrode is developed to fundamentally tackle the instability factors introduced by electrodes. The combined spatially resolved element analyses and theoretical study demonstrate the high diffusion barrier of Mo ions within the device. Structural and morphology characterization also reveals the negligible plastic deformation and halide-metal reaction during aging when Mo is in contact with perovskite (PVSK). The electrode/underlayer junction is further stabilized by a thin seed layer of titanium (Ti) to improve Mo film's uniformity and adhesion. Based on a corresponding p-i-n PSCs (ITO/PTAA/PVSK/C60/SnO2/ITO/Ti/Mo), the champion sample could deliver an efficiency of 22.25%, which is among the highest value for PSCs based on Mo electrodes. Meanwhile, the device shows negligible performance decay after 2000 h operation, and retains 91% of the initial value after 1300 h at 50-60 °C. In summary, the multilayer Mo electrode opens an effective avenue to all-round stable electrode design in high-performance PSCs.
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BACKGROUND: The association between myasthenia gravis (MG) and other autoimmune diseases is well established. In this study, we aimed to investigate the causal effects between MG and five other autoimmune diseases, including autoimmune thyroid disease (AITD), multiple sclerosis (MS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and type 1 diabetes (T1DM). METHODS: We conducted a bidirectional Mendelian randomization (MR) study by using seven published genome-wide association studies (GWAS), including MG (1873 patients versus 36,370 controls), AITD (autoimmune hypothyroidism) (22,997 patients versus 175,475 controls), AITD (autoimmune hyperthyroidism) (962 patients versus 172,976 controls), MS (47,429 patients versus 68,374 controls), RA (14,361 patients versus 43,923 controls), SLE (4222 patients versus 8431 controls), and T1DM (9266 patients versus 15,574 controls). We used the inverse-variance-weighted (IVW) method, weighted-median (WM) estimator, MR-Egger regression, and MR PRESSO in our analyses. We also carried out detailed sensitivity analyses for each direction using the aforementioned methods. RESULTS: When MG was treated as the exposure, MR evidence suggested a causal relationship between MG and T1DM, SLE, AITD (both hypothyroidism and hyperthyroidism), and MS (excluding RA). Using the IVW method, we found that MG was associated with increased risk of T1DM (OR = 1.94; 95% CI, 1.16-3.26; p = 0.012), SLE (OR = 1.47; 95% CI, 1.02-2.13; p = 0.04), AITD (hypothyroidism) (OR = 1.31; 95% CI, 1.02-1.68; p = 0.039), AITD (hyperthyroidism) (OR = 1.55; 95% CI, 1.15-2.09; p = 0.004), and MS (OR = 1.46; 95% CI, 1.01-2.09; p = 0.041). When MG was treated as the outcome, MR evidence suggested that RA, T1DM, and SLE were causal factors in MG. Using the IVW method, we found that the risk of MG increased with exposure to RA (OR = 1.21; 95% CI, 1.08-1.37; p = 0.002), T1DM (OR = 1.09; 95% CI, 1.02-1.16; p = 0.006), and SLE (OR = 1.12; 95% CI, 1.02-1.23; p = 0.018). CONCLUSIONS: This study demonstrated a causal relationship between MG and several other autoimmune diseases. Our results supported a bidirectional causal association between MG and SLE/T1DM. Our findings also provided reliable evidence that MG is associated with increased risk of AITD. Meanwhile, we also showed that RA is a possible causal driver of MG risk.
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Diabetes Mellitus Tipo 1 , Hipertireoidismo , Hipotireoidismo , Lúpus Eritematoso Sistêmico , Esclerose Múltipla , Miastenia Gravis , Humanos , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Análise da Randomização Mendeliana , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Miastenia Gravis/epidemiologia , Miastenia Gravis/genéticaRESUMO
The transition from vegetative to reproductive growth, known as flowering, is a critical developmental process in flowering plants to ensure reproductive success. This process is strictly controlled by various internal and external cues; however, the underlying molecular regulatory mechanisms need to be further characterized. Here, we report a plant-specific protein, FCS-LIKE ZINC FINGER PROTEIN 13 (FLZ13), which functions as a hitherto unknown negative modulator of flowering time in Arabidopsis thaliana. Biochemical analysis showed that FLZ13 directly interacts with FLOWERING LOCUS C (FLC), a major flowering repressor, and that FLZ13 largely depends on FLC to repress the transcription of two core flowering integrators: FLOWERING LOCUS T and SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1. In addition, FLZ13 works together with ABSCISIC ACID INSENSITIVE 5 to activate FLC expression to delay flowering. Taken together, our findings suggest that FLZ13 is an important component of the gene regulatory network for flowering time control in plants.
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Proteínas de Arabidopsis , Arabidopsis , Flores , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Flores/fisiologia , Regulação da Expressão Gênica de Plantas , Redes Reguladoras de Genes , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismoRESUMO
Cocculus orbiculatus (C. orbiculatus), the root of plants belonging to the Menispermaceae family, has been extensively used to treat various diseases, including malaria and rheumatism. The main chemicals in these plants are alkaloids; however, the spatial distribution of these compounds within the plant roots remains undefined. This study aimed to visualize the spatial distribution of C. orbiculatus using air flow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI). In total, the spatial distribution of four aporphine alkaloids, five benzyltetrahydroisoquinoline alkaloids, six bisbenzylisoquinoline alkaloids, and one morphinane alkaloid in the cork layer, xylem, and ray of the root of C. orbiculatus was observed; the distribution characteristics of the different compounds in C. orbiculatus were significantly different. This study provides a visualized spatial distribution analysis method for the characterization of metabolites in the root tissue of C. orbiculatus and also provides valuable information for the specificity of the root of C. orbiculatus, which is beneficial for understanding its chemical separation, biosynthesis, and pharmacological activities.
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Alcaloides , Benzilisoquinolinas , Cocculus , Espectrometria de Massas por Ionização por Electrospray/métodos , Cocculus/química , Estrutura Molecular , Alcaloides/química , Benzilisoquinolinas/química , Plantas , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
Achieving both high efficiency and long-term stability is the key to the commercialization of perovskite solar cells (PSCs)1,2. However, the diversity of perovskite (ABX3) compositions and phases makes it challenging to fabricate high-quality films3-5. Perovskite formation relies on the reaction between AX and BX2, whereas most conventional methods for film-growth regulation are based solely on the interaction with the BX2 component. Herein, we demonstrate an alternative approach to modulate reaction kinetics by anion-π interaction between AX and hexafluorobenzene (HFB). Notably, these two approaches are independent but work together to establish 'dual-site regulation', which achieves a delicate control over the reaction between AX and BX2 without unwanted intermediates. The resultant formamidinium lead halides (FAPbI3) films exhibit fewer defects, redshifted absorption and high phase purity without detectable nanoscale δ phase. Consequently, we achieved PSCs with power conversion efficiency (PCE) up to 26.07% for a 0.08-cm2 device (25.8% certified) and 24.63% for a 1-cm2 device. The device also kept 94% of its initial PCE after maximum power point (MPP) tracking for 1,258 h under full-spectrum AM 1.5 G sunlight at 50 ± 5 °C. This method expands the range of chemical interactions that occur in perovskite precursors by exploring anion-π interactions and highlights the importance of the AX component as a new and effective working site to improved photovoltaic devices with high quality and phase purity.
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SCOPE: This study aims to investigate the effect and mechanism of Urolithin A (UA) on neuronal stress damage on cognitive impairment in type 2 diabetes mellitus (T2DM) mouse model induced by high-fat diet (HFD) and streptozotocin (STZ). METHODS AND RESULTS: T2DM mice fed with UA display an attenuated cognitive impairment along with suppressed endoplasmic reticulum (ER) stress and Tau hyperphosphorylation in brain. Similar restraint effect of UA on Tau hyperphosphorylation and ER stress is also observed in high glucose-treated primary hippocampal neurons. Moreover, UA ameliorates oxidative stress, ER stress, aberrant energy metabolism, and apoptosis in 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) induced HT22 cells. Atp2a3 is identified as a potential target gene of UA which is closely related to intracellular calcium homeostasis, ER stress, and apoptosis, so that UA significantly down-regulated Atp2a3 expression in DMNQ-induced cells. Furthermore, the protection effect of UA against ER stress and apoptosis is abolished by Atp2a3 over-expression in HT22 cells. Taken together, these data suggest that UA performs anti-stress effect by suppressing the expression of Atp2a3 in damaged neuronal cells and thus attenuates diabetes-associated cognitive impairment in T2DM mice. CONCLUSION: The study implies UA as a potential novel pharmaceutic target for neurodegeneration and stress damage through regulating the expression of Atp2a3.
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Diabetes Mellitus Tipo 2 , Camundongos , Animais , Apoptose , Neurônios , Estresse do Retículo EndoplasmáticoRESUMO
Wide-bandgap perovskites are promising absorbers for state-of-the-art tandem solar cells to feasibly surpass Shockley-Queisser limit with low cost. However, the commonly used mixed halide perovskites suffer from poor stability; particularly, photoinduced phase segregation. Electrospray deposition is developed to bridge the gap of growth rate between iodide and bromide components during film growth by spatially confining the anion diffusion and eliminating the kinetic difference, which universally improves the initial homogeneity of perovskite films regardless of device architectures. It thus promotes the efficiency and stability of corresponding solar cells based on wide-bandgap (1.68 eV) absorbers. Remarkable power conversion efficiencies (PCEs) of 21.44% and 20.77% are achieved in 0.08 cm2 and 1.0 cm2 devices, respectively. In addition, these devices maintain 90% of their initial PCE after 1550 h of stabilized power output (SPO) tracking upon one sun irradiation (LED) at room temperature.
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The misdiagnosis of tumors due to insufficient penetration depth or signal interference and damage to normal tissues due to indiscriminate treatment are the biggest challenges in using photothermal agents for clinical translation. To overcome these limitations, a strategy of switching from the near-infrared (NIR)-I region to the NIR-II region was developed based on tumor microenvironment (TME)-mediated gold (Au) self-assembly. Using zeolitic imidazolate framework-8 (ZIF-8) metal-organic framework-coated gold nanorods (AuNRs@ZIF-8) as a model photothermal agent, we demonstrated that only a NIR-I photoacoustic imaging signal was observed in normal tissue because ZIF-8 could prevent the aggregation of AuNRs. However, when ZIF-8 dissociated in the TME, the AuNRs aggregated to activate NIR-II photoacoustic imaging and attenuate the NIR-I signal, thereby allowing an accurate diagnosis of tumors based on signal transformation. Notably, TME-activated NIR-II photothermal therapy could also inhibit tumor growth. Therefore, this TME-activated NIR-I-to-NIR-II switching strategy could improve the accuracy of deep-tumor diagnoses and avoid the injury caused by undifferentiated treatment. STATEMENT OF SIGNIFICANCE: Photothermal agents used for photoacoustic imaging and photothermal therapy have garnered great attention for tumor theranostics. However, always "turned on" near-infrared (NIR)-I laser (700-1000 nm)-responsive photothermal agents face issues of penetration depth and damage to normal tissues. In contrast, tumor microenvironment-activated NIR-II "smart" photothermal agents exhibit deeper penetration depth and tumor selectivity. Therefore, a NIR-I-to-NIR-II switching strategy was developed based on tumor microenvironment-mediated Au self-assembly. This work provides a new strategy for developing tumor microenvironment-activated NIR-II smart photothermal agents.
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Nanopartículas , Neoplasias , Humanos , Medicina de Precisão , Microambiente Tumoral , Neoplasias/patologia , Luz , Ouro/farmacologia , Ouro/uso terapêutico , Linhagem Celular Tumoral , Nanopartículas/uso terapêutico , Fototerapia/métodos , Nanomedicina Teranóstica/métodosRESUMO
SnRK1, an evolutionarily conserved heterotrimeric kinase complex that acts as a key metabolic sensor in maintaining energy homeostasis in plants, is an important upstream activator of autophagy that serves as a cellular degradation mechanism for the healthy growth of plants. However, whether and how the autophagy pathway is involved in regulating SnRK1 activity remains unknown. In this study, we identified a clade of plant-specific and mitochondria-localized FCS-like zinc finger (FLZ) proteins as currently unknown ATG8-interacting partners that actively inhibit SnRK1 signaling by repressing the T-loop phosphorylation of the catalytic α subunits of SnRK1, thereby negatively modulating autophagy and plant tolerance to energy deprivation caused by long-term carbon starvation. Interestingly, these AtFLZs are transcriptionally repressed by low-energy stress, and AtFLZ proteins undergo a selective autophagy-dependent pathway to be delivered to the vacuole for degradation, thereby constituting a positive feedback regulation to relieve their repression of SnRK1 signaling. Bioinformatic analyses show that the ATG8-FLZ-SnRK1 regulatory axis first appears in gymnosperms and seems to be highly conserved during the evolution of seed plants. Consistent with this, depletion of ATG8-interacting ZmFLZ14 confers enhanced tolerance, whereas overexpression of ZmFLZ14 leads to reduced tolerance to energy deprivation in maize. Collectively, our study reveals a previously unknown mechanism by which autophagy contributes to the positive feedback regulation of SnRK1 signaling, thereby enabling plants to better adapt to stressful environments.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Retroalimentação , Autofagia/genética , Regulação da Expressão Gênica de PlantasRESUMO
Enterovirus D68 (EV-D68) is a member of the species Enterovirus D in the genus Enterovirus of the family Picornaviridae. As an emerging non-polio enterovirus, EV-D68 is widely spread all over the world and causes severe neurological and respiratory illnesses. Although the intrinsic restriction factors in the cell provide a frontline defense, the molecular nature of virus-host interactions remains elusive. Here, we provide evidence that the major histocompatibility complex class II chaperone, CD74, inhibits EV-D68 replication in infected cells by interacting with the second hydrophobic region of 2B protein, while EV-D68 attenuates the antiviral role of CD74 through 3Cpro cleavage. 3Cpro cleaves CD74 at Gln-125. The equilibrium between CD74 and EV-D68 3Cpro determines the outcome of viral infection. IMPORTANCE As an emerging non-polio enterovirus, EV-D68 is widely spread all over the world and causes severe neurological and respiratory illnesses. Here, we report that CD74 inhibits viral replication in infected cells by targeting 2B protein of EV-D68, while EV-D68 attenuates the antiviral role of CD74 through 3Cpro cleavage. The equilibrium between CD74 and EV-D68 3Cpro determines the outcome of viral infection.
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Enterovirus Humano D , Infecções por Enterovirus , Enterovirus , Humanos , Antígenos Virais , Antivirais/farmacologia , Replicação ViralRESUMO
Infectious bursal disease (IBD) is an acute, highly contagious, immunosuppressive, and fatal infectious disease of young chickens caused by infectious bursal disease virus (IBDV). Since 2017, a new trend has been discovered in the IBDV epidemic, with very virulent IBDV (vvIBDV) and novel variant IBDV (nVarIBDV) becoming the two current dominant strains in East Asia including China. In this study, we compared the biological characteristics of the vvIBDV (HLJ0504 strain), nVarIBDV (SHG19 strain), and attenuated IBDV (attIBDV, Gt strain) using specific-pathogen-free (SPF) chicken infection model. The results showed that vvIBDV distributed in multiple tissues, replicated the fastest in lymphoid organs such as bursa of Fabricius, induced significant viremia and virus excretion, and is the most pathogenic virus with a mortality of more than 80%. The nVarIBDV had a weaker replication capability and did not kill the chickens but caused severe damage to the central immune organ bursa of Fabricius and B lymphocytes and induced significant viremia and virus excretion. The attIBDV strain was found not to be pathogenic. Further studies preliminarily suggested that the expression level of inflammatory factors triggered by HLJ0504 was the highest, followed by the SHG19 group. This study is the first to systematically compare the pathogenic characteristics of three IBDVs closely related to poultry industry from the perspectives of clinical signs, micro-pathology, virus replication, and distribution. It is of great importance to obtain an extensive knowledge of epidemiology, pathogenicity, and comprehensive prevention, and control of various IBDV strains.
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Infecções por Birnaviridae , Vírus da Doença Infecciosa da Bursa , Doenças das Aves Domésticas , Animais , Aves Domésticas , Galinhas , Virulência , Viremia/veterinária , Infecções por Birnaviridae/epidemiologia , Infecções por Birnaviridae/veterináriaRESUMO
BACKGROUND: The aryl hydrocarbon receptor (AhR) is a critical regulator of the pathogenesis of autoimmune disorders. We aimed to investigate the therapeutic effect of the AhR agonist tapinarof during the development of systemic lupus erythematosus (SLE). METHODS: MRL/lpr mice were intraperitoneally injected with 1 or 5 mg/kg tapinarof for 6 weeks. Kidney histopathology was evaluated using hematoxylin and eosin (H&E) and Periodic-Acid-Schiff (PAS) staining. Immunofluorescence microscopy was performed to detect immune complex renal depositions. Flow cytometry (FCM) analysis was carried out to determine the proportions of T and B cell subsets. Realtime qPCR was used to quantify the expression of Tfh cell-associated genes. We conducted an in vitro polarization experiment to observe the effect of tapinarof on Tfh differentiation. Western blotting was used to detect the expression of target proteins. RESULTS: We found that tapinarof treatment ameliorated lupus phenotypes, including splenomegaly, lymph node enlargement, kidney damages, immune complex deposition, and excessive secretion of antibodies. Additionally, we showed that Treg subpopulation frequencies significantly increased in MRL/lpr mice treated with tapinarof, while the proportion of Th1/Th2 cells was reduced after tapinarof administration. Moreover, tapinarof suppressed Tfh cell differentiation and germinal center (GC) reaction in vivo. The inhibitory effect of tapinarof on Tfh cells was further verified in the in vitro Tfh cell polarization experiment. Realtime qPCR revealed that tapinarof repressed the expression of Tfh signature genes. Mechanistically, tapinarof significantly inhibited the phosphorylation levels of JAK2 and STAT3. The capacity for Tfh differentiation was partially rescued by the STAT3 activator Colivelin TFA. Furthermore, our in vitro Tfh polarization experiments indicated that tapinarof suppressed Tfh cell development in SLE. CONCLUSIONS: Our data demonstrated that tapinarof modulated the JAK2-STAT3 pathway to suppress Tfh cell differentiation for the treatment of lupus symptoms in MRL/lpr mice.
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Lúpus Eritematoso Sistêmico , Células T Auxiliares Foliculares , Animais , Camundongos , Complexo Antígeno-Anticorpo , Autoimunidade , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Camundongos Endogâmicos MRL lpr , Receptores de Hidrocarboneto Arílico/agonistasRESUMO
The bZIP transcription factor ABSCISIC ACID INSENSITIVE5 (ABI5) is a master regulator of seed germination and post-germinative growth in response to abscisic acid (ABA), but the detailed molecular mechanism by which it represses plant growth remains unclear. In this study, we used proximity labeling to map the neighboring proteome of ABI5 and identified FCS-LIKE ZINC FINGER PROTEIN 13 (FLZ13) as a novel ABI5 interaction partner. Phenotypic analysis of flz13 mutants and FLZ13-overexpressing lines demonstrated that FLZ13 acts as a positive regulator of ABA signaling. Transcriptomic analysis revealed that both FLZ13 and ABI5 downregulate the expression of ABA-repressed and growth-related genes involved in chlorophyll biosynthesis, photosynthesis, and cell wall organization, thereby repressing seed germination and seedling establishment in response to ABA. Further genetic analysis showed that FLZ13 and ABI5 function together to regulate seed germination. Collectively, our findings reveal a previously uncharacterized transcriptional regulatory mechanism by which ABA mediates inhibition of seed germination and seedling establishment.