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Potato is the third most important food crop worldwide. Potato production suffers from severe diseases caused by multiple detrimental plant pathogens, and broad-spectrum disease resistance genes are rarely identified in potato. Here we identified the potato non-specific lipid transfer protein StLTPa, which enhances species none-specific disease resistance against various pathogens, such as the oomycete pathogen Phytophthora infestans, the fungal pathogens Botrytis cinerea and Verticillium dahliae, and the bacterial pathogens Pectobacterium carotovorum and Ralstonia solanacearum. The StLTPa overexpression potato lines do not show growth penalty. Furthermore, we provide evidence that StLTPa binds to lipids present in the plasma membrane (PM) of the hyphal cells of P. infestans, leading to an increased permeability of the PM. Adding of PI(3,5)P2 and PI(3)P could compete the binding of StLTPa to pathogen PM and reduce the inhibition effect of StLTPa. The lipid-binding activity of StLTPa is essential for its role in pathogen inhibition and promotion of potato disease resistance. We propose that StLTPa enhances potato broad-spectrum disease resistance by binding to, and thereby promoting the permeability of the PM of the cells of various pathogens. Overall, our discovery illustrates that increasing the expression of a single gene in potato enhances potato disease resistance against different pathogens without growth penalty.
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Proteínas Portadoras , Membrana Celular , Resistencia a la Enfermedad , Phytophthora infestans , Enfermedades de las Plantas , Proteínas de Plantas , Solanum tuberosum , Solanum tuberosum/microbiología , Solanum tuberosum/genética , Solanum tuberosum/metabolismo , Solanum tuberosum/inmunología , Resistencia a la Enfermedad/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Membrana Celular/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Phytophthora infestans/patogenicidad , Proteínas Portadoras/metabolismo , Proteínas Portadoras/genética , Ralstonia solanacearum/patogenicidad , Ralstonia solanacearum/fisiología , Botrytis , Plantas Modificadas Genéticamente , Pectobacterium carotovorumRESUMEN
BACKGROUND: GEFT is a key regulator of tumorigenesis in rhabdomyosarcoma (RMS), and overexpression of GEFT is significantly correlated with distant metastasis, lymph node metastasis, and a poor prognosis, yet the underlying molecular mechanism is still poorly understood. This study aimed to investigate and validate the molecular mechanism of GEFT-activated lncRNAs in regulating mTOR expression to promote the progression of RMS. METHODS: GEFT-regulated lncRNAs were identified through microarray analysis. The effects of GEFT-regulated lncRNAs on the proliferation, apoptosis, invasion, and migration of RMS cells were confirmed through cell functional experiments. The target miRNAs of GEFT-activated lncRNAs in the regulation of mTOR expression were predicted by bioinformatics analysis combined with quantitative real-time polymerase chain reaction (qRT-PCR) analysis. The expression of lnc-PSMA8-1, miR-144-3p, and mTOR was measured by qRT-PCR in RMS tissue samples and cell lines. The regulatory mechanisms of the lnc-PSMA8-1-miR-144-3p-mTOR signaling axis were verified by RNA-binding protein immunoprecipitation (RIP), a luciferase reporter assay, qRT-PCR analysis, Western blot analysis, and cell functional experiments. RESULTS: The microarray-based analysis identified 31 differentially expressed lncRNAs (fold change > 2.0, P < 0.05). Silencing the 4 upregulated lncRNAs (lnc-CEACAM19-1, lnc-VWCE-2, lnc-GPX7-1, and lnc-PSMA8-1) and overexpressing the downregulated lnc-FAM59A-1 inhibited the proliferation, invasion, and migration and induced the apoptosis of RMS cells. Among the factors analyzed, the expression of lnc-PSMA8-1, miR-144-3p, and mTOR in RMS tissue samples and cells was consistent with the correlations among their expression indicated by the lncRNA-miRNA-mRNA regulatory network based on the ceRNA hypothesis. lnc-PSMA8-1 promoted RMS progression by competitively binding to miR-144-3p to regulate mTOR expression. CONCLUSION: Our research demonstrated that lnc-PSMA8-1 was activated by GEFT and that the former positively regulated mTOR expression by sponging miR-144-3p to promote the progression of RMS. Therefore, targeting this network may constitute a potential therapeutic approach for the management of RMS.
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MicroARNs , ARN Largo no Codificante , Rabdomiosarcoma , Serina-Treonina Quinasas TOR , Humanos , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , Rabdomiosarcoma/genética , Rabdomiosarcoma/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Regulación hacia ArribaRESUMEN
Pachymic acid (PA) is a lanostane-type triterpenoid with various pharmacological effects. However, little is known about the effect of PA on myocardial infarction (MI) induced by ischemia/reperfusion (I/R). In this study, we aimed to investigate the protective effect of PA and its underlying mechanism. A cellular MI model was established by oxygen-glucose deprivation and reperfusion (OGD/R) treatment in HL-1 cardiomyocytes, and we found that OGD/R treatment decreased cell viability and glutathione peroxide (GSH-Px) activity, increased Fe2+ concentration and lactate dehydrogenase (LDH) activity, promoted malondialdehyde (MDA) and reactive oxygen species (ROS) production, and inhibited the expression of ferroptosis marker proteins SLC7A11 and GPX4 in a time-dependent manner. OGD/R-induced HL-1 cells were pretreated with different concentrations of PA (0, 20, 40, 60 µg/mL) for 24 h, and toxicological experiments showed that 150 µg/mL PA decreased cell viability, while low concentrations of PA had no toxic effect on cells. 20 µg/mL PA reversed the inhibitory effect of OGD/R on cell viability, reduced MDA and ROS production, and Fe2+ accumulation, increased GSH-Px activity and the expression of SLC7A11 and GPX4, and decreased LDH activity, especially at 60 µg/mL PA. Meanwhile, PA promoted the phosphorylation of IRS-1, AKT, and AMPK proteins in a dose-dependent manner. AICAR, an AMPK activator, inhibited ferroptosis, while STO-609, an AMPK inhibitor, largely abolished the effect of PA on OGD/R-induced ferroptosis of HL-1 cells. In addition, PA inhibited ferroptosis and myocardial I/R injury in wild-type mice and AMPK knockout (AMPK-/- ) mice. Collectively, PA inhibited ferroptosis of cardiomyocytes through activating of the AMPK pathway, thereby alleviating myocardial I/R injury in mice.
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Ferroptosis , Infarto del Miocardio , Daño por Reperfusión Miocárdica , Daño por Reperfusión , Triterpenos , Ratones , Animales , Miocitos Cardíacos/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/metabolismo , Triterpenos/farmacología , Triterpenos/metabolismo , Triterpenos/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , ReperfusiónRESUMEN
BACKGROUND: Edaravone dexborneol has been reported as an effective neuroprotective agent in the treatment of acute ischemic stroke (AIS). This study aimed at investigating the impact of edaravone dexborneol on functional outcomes and systematic inflammatory response in AIS patient. METHODS: All participants were recruited from the AISRNA study (registered 21/11/2019, NCT04175691 [ClinicalTrials.gov]) between January 2022 and December 2022. The AIS patients were divided into two groups based on whether they received the treatment of edaravone dexborneol (37.5 mg/12 hours, IV) within 48 h after stroke onset. Inflammatory response was determined by detecting levels of cytokines (interleukin-2 [IL-2], IL-4, IL-5, IL-8, IL-6, IL-10, IL-12p70, IL-17, tumor necrosis factor-α [TNF-α], interferon-γ [IFN-γ], IFN-α, and IL-1ß) within 14 days after stroke onset. RESULTS: Eighty-five AIS patients were included from the AISRNA study. Patients treated with edaravone dexborneol showed a significantly higher proportion of modified Rankin Scale score < 2 compared to those who did not receive this treatment (70.7% versus 47.8%; P = 0.031). Furthermore, individuals receiving edaravone dexborneol injection exhibited lower expression levels of interleukin (IL)-1ß, IL-6, and IL-17, along with higher levels of IL-4 and IL-10 expression during the acute phase of ischemic stroke (P < 0.05). These trends were not observed for IL-2, IL-5, IL-8, IL-12p70, tumor necrosis factor-α, interferon-γ [IFN-γ], and IFN-α (P > 0.05). CONCLUSIONS: Treatment with edaravone dexborneol resulted in a favorable functional outcome at 90 days post-stroke onset when compared to patients without this intervention; it also suppressed proinflammatory factors expression while increasing anti-inflammatory factors levels. TRIAL REGISTRATION: ClinicalTrials.gov NCT04175691. Registered November 21, 2019, https://www. CLINICALTRIALS: gov/ct2/show/NCT04175691 .
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Edaravona , Accidente Cerebrovascular Isquémico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Citocinas/metabolismo , Edaravona/uso terapéutico , Edaravona/administración & dosificación , Edaravona/farmacología , Inflamación/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Fármacos Neuroprotectores/administración & dosificación , Resultado del TratamientoRESUMEN
Resistance to proteasome inhibitors like Bortezomib is a major challenge in the treatment of multiple myeloma (MM). Proteolysis targeting chimeras (PROTACs), an emerging therapeutic approach that induces selective degradation of target proteins, offer a promising solution to overcome drug resistance. In this study, we designed and synthesized novel small-molecule PROTACs that induce 20S proteasome subunit ß5 degradation as a strategy to overcome Bortezomib resistance. These 20S proteasome subunit ß5 PROTACs demonstrated considerable binding affinity to 20S proteasome subunit ß5 and cereblon (CRBN), effectively induced 20S proteasome subunit ß5 degradation, and exhibited potent antiproliferative activity against a panel of cancer cell lines. Notably, PROTACs 12f and 14 displayed robust antitumor effects against both the pharyngeal carcinoma cell line FaDu and the Bortezomib-resistant MM cell line KM3/BTZ in vitro and in vivo with excellent safety profiles. Taken together, our findings highlight the potential of PROTACs 12f and 14 as novel 20S proteasome subunit ß5-degrading agents for the treatment of pharyngeal carcinoma and overcoming Bortezomib resistance in MM.
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OBJECTIVE: To investigate the influence of hyperglycemia on motor symptoms, especially axial signs, and potential mechanisms related to insulin resistance (IR) in patients with Parkinson's disease (PWP). METHODS: According to glycated hemoglobin (HbA1c) level, PWP were divided into the low-HbA1c and the high-HbA1c groups. Demographic information, glucose metabolism-related variables, Hoehn-Yahr stage, and motor function were compared between the two groups. Correlations between levels of HbA1c and the homeostatic model assessment (HOMA)-IR and motor function in PWP were further analyzed. RESULTS: HbA1c level was significantly and positively correlated with the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part III score, axial signs subscore, the Timed Get Up and Go test time, the center of pressure displacement of standing with eyes open and closed, and significantly and negatively correlated with the 10-m walk test comfortable gait speed. HOMA-IR level was significantly and negatively correlated with 10-m walk test comfortable gait speed, but not with others. CONCLUSIONS: PWP with high HbA1c showed worse axial symptoms, including dysfunction of automatic walking, dynamic balance, and postural control than those with low HbA1c. In PWP, the effects of hyperglycemia on automatic walking speed may be associated with the IR-related mechanisms, and the effects on dynamic balance and postural control may be related to mechanisms other than IR.
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Hiperglucemia , Resistencia a la Insulina , Enfermedad de Parkinson , Humanos , Hemoglobina Glucada , Enfermedad de Parkinson/complicaciones , Caminata , Hiperglucemia/complicaciones , Equilibrio Postural/fisiologíaRESUMEN
BACKGROUND: Epidemiological studies have shown that sarcopenia was associated with depression among older adults. However, most of these investigations used a cross-sectional design, limiting the ability to establish a causal relation, the present study examined whether sarcopenia was associated with incident depressive symptoms. METHODS: This is a prospective cohort study with participants from the Western China Health and Aging Trends (WCHAT) study. Participants could complete anthropometric measurements and questionnaires were included. The exposure was sarcopenia, defined according to the Asian Working Group for Sarcopenia in 2019, the outcome was depressive symptoms, evaluated by GDS-15. We excluded depression and depressive symptoms at baseline and calculated the risk of incident depressive symptoms during the follow-up year. RESULTS: A total of 2612 participants (mean age of 62.14 ± 8.08 years) were included, of which 493 with sarcopenia. 78 (15.82%) participants with sarcopenia had onset depressive symptoms within the next year. After multivariable adjustment, sarcopenia increased the risk of depressive symptoms (RR = 1.651, 95%CI = 1.087-2.507, P = 0.0187) in overall participants. Such relationship still exists in gender and sarcopenia severity subgroups. Low muscle mass increased the risk of depressive symptoms (RR = 1.600, 95%CI = 1.150-2.228, P = 0.0053), but low muscle strength had no effect (RR = 1.250, 95%CI = 0.946-1.653, P = 0.117). CONCLUSIONS: Sarcopenia is an independent risk factor for depressive symptoms, Precautions to early detect and targeted intervene for sarcopenia should continue to be employed in adult with sarcopenia to achieve early prevention for depression and reduce the incidence of adverse clinical outcomes.
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Sarcopenia , Humanos , Anciano , Sarcopenia/diagnóstico , Sarcopenia/epidemiología , Sarcopenia/complicaciones , Depresión/diagnóstico , Depresión/epidemiología , Depresión/etiología , Estudios Transversales , Estudios Prospectivos , Fuerza Muscular/fisiología , Fuerza de la ManoRESUMEN
Background: Extracorporeal life support echniques as an Adjunct to Advanced Cardiac Life Support is usually suitable for complex heart surgery such as cardiopulmonary bypass (CPB). Cerebral perfusion is a clinically feasible neuroprotective strategy; however, the lack of a reliable small animal model.Methods: Based on the rat model of ECLS we evaluate the effects of ECLS-CP using HE staining, Nissl staining, TUNEL staining and ELISA.Result: We found that ECLS combined with the cerebral perfusion model did not cause brain injury and immune inflammation. There was no difference between the two by a left carotid artery or right carotid artery CP.Conclusion: These experimental results can provide the experimental basis for selecting blood vessels for ECLS patients and clinical CP to offers a trustworthy animal model for future exploration of applying brain perfusion strategies during ECLS-CP.
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Male gametophyte development in plants relies on the functions of numerous genes, whose expression is regulated by transcription factors (TFs), non-coding RNAs, hormones, and diverse environmental stresses. Several excellent reviews are available that address the genes and enzymes associated with male gametophyte development, especially pollen wall formation. Growing evidence from genetic studies, transcriptome analysis, and gene-by-gene studies suggests that TFs coordinate with epigenetic machinery to regulate the expression of these genes and enzymes for the sequential male gametophyte development. However, very little summarization has been performed to comprehensively review their intricate regulatory roles and discuss their downstream targets and upstream regulators in this unique process. In the present review, we highlight the research progress on the regulatory roles of TF families in the male gametophyte development of flowering plants. The transcriptional regulation, epigenetic control, and other regulators of TFs involved in male gametophyte development are also addressed.
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Magnoliopsida , Factores de Transcripción , Humanos , Factores de Transcripción/genética , Epigenómica , Perfilación de la Expresión Génica , Polen/genéticaRESUMEN
In this research, SCAPS-1D simulation software (Version: 3.3.10) was employed to enhance the efficiency of CsSnX3 (X = Cl, Br, I) all-inorganic perovskite solar cells. By fine-tuning essential parameters like the work function of the conductive glass, the back contact point, defect density, and the thickness of the light absorption layer, we effectively simulated the optimal performance of CsSnX3 (X = Cl, Br, I) all-inorganic perovskite solar cells under identical conditions. The effects of different X-site elements on the overall performance of the device were also explored. The theoretical photoelectric conversion efficiency of the device gradually increases with the successive substitution of halogen elements (Cl, Br, I), reaching 6.09%, 17.02%, and 26.74%, respectively. This trend is primarily attributed to the increasing size of the halogen atoms, which leads to better light absorption and charge transport properties, with iodine (I) yielding the highest theoretical conversion efficiency. These findings suggest that optimizing the halogen element in CsSnX3 can significantly enhance device performance, providing valuable theoretical guidance for the development of high-efficiency all-inorganic perovskite solar cells.
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Perovskite solar cells (PSCs) are gaining prominence in the photovoltaic industry due to their exceptional photoelectric performance and low manufacturing costs, achieving a significant power conversion efficiency of 26.4%, which closely rivals that of silicon solar cells. Despite substantial advancements, the effective area of high-efficiency PSCs is typically limited to about 0.1 cm2 in laboratory settings, with efficiency decreasing as the area increases. The limitation poses a major obstacle to commercialization, as large-area, high-quality perovskite films are crucial for commercial applications. This paper reviews current techniques for producing large-area perovskites, focusing on slot-die coating, a method that has attracted attention for its revolutionary potential in PSC manufacturing. Slot-die coating allows for precise control over film thickness and is compatible with roll-to-roll systems, making it suitable for large-scale applications. The paper systematically outlines the characteristics of slot-die coating, along with its advantages and disadvantages in commercial applications, suggests corresponding optimization strategies, and discusses future development directions to enhance the scalability and efficiency of PSCs, paving the way for broader commercial deployment.
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Efficient, low-cost photocatalysts with mild synthesis conditions and stable photocatalytic behavior have always been the focus in the field of photocatalysis. This study proves that non-quantum-dot Cs2PbI2Cl2-based materials, created by a simple method, can be successfully employed as new high-efficient photocatalysts. The results demonstrate that two-dimensional Cs2PbI2Cl2 perovskite can achieve over three times higher photocatalytic performance compared to three-dimensional CsPbBr3 perovskite. Moreover, the photocatalytic performance of Cs2PbI2Cl2 can be further improved by constructing a heterojunction structure, such as Cs2PbI2Cl2/CsPbBr3. Cs2PbI2Cl2 can connect well with CsPbBr3 through a simple method, resulting in tight bonding at the interface and efficient carrier transfer. Cs2PbI2Cl2/CsPbBr3 exhibits notable 5-fold and 10-fold improvements in photocatalytic performance and rate compared to CsPbBr3. Additionally, Cs2PbI2Cl2/CsPbBr3 demonstrates superb stable catalytic performance, with nearly no decrease in photocatalytic performance after 7 months (RH = 20% ± 10, T = 25 °C ± 5). This study also reveals that the photocatalytic process based on Cs2PbI2Cl2/CsPbBr3 can directly oxidize organic matter using holes, without relying on the generation of intermediate reactive oxygen species from water or oxygen (such as ·OH or ·O2-), showcasing further potential for achieving high photocatalytic efficiency and selectivity in anhydrous/anaerobic catalytic reactions and treating recalcitrant pollutants.
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The new 3-monosubstituted acetylacetone ligands, 3-(phenyl(1H-pyrazol-1-yl)methyl)pentane-2,4-dione (HLacPz) and 3-((3,5-dimethyl-1H-pyrazol-1-yl)(phenyl)methyl)pentane-2,4-dione (HLacPzMe), were synthesized and used as supporting ligands for new copper(II) and copper(I) phosphane complexes of the general formulae [Cu(HLacX)2(LacX)2] and [Cu(PPh3)2(HLacX)]PF6 (X = Pz (pyrazole) or PzMe (3,5-dimethylpyrazole)), respectively. In the syntheses of the Cu(I) complexes, the triphenylphosphine coligand (PPh3) was used to stabilize copper in the +1 oxidation state, avoiding oxidation to Cu(II). All compounds were characterized by CHN analysis, 1H-NMR, 13C-NMR, FT-IR spectroscopy, and electrospray ionization mass spectrometry (ESI-MS). The ligands HLacPz (1) and HLacPzMe (2) and the copper complex [Cu(PPh3)2(HLacPz)]PF6 (3) were also characterized by X-ray crystallography. The reactivity of these new compounds was investigated and the new compounds 4-phenyl-4-(1H-pyrazol-1-yl)butan-2-one (7) and 4-(3,5-dimethyl-1H-pyrazol-1-yl)-4-phenylbutan-2-one (8) were obtained in basic conditions via the retro-Claisen reaction of related 3-monosubstituted acetylacetone, providing efficient access to synthetically useful ketone compounds. Compound 8 was also characterized by X-ray crystallography.
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To find novel anti-inflammatory drugs, we screened anti-inflammatory compounds from 18 different types of Artemisia argyi seed extracts. The in vitro and in vivo anti-inflammatory activities of the screened compounds and their mechanisms were characterized. We first detected the cytotoxic effect of the compounds on RAW264.7 cells and the inhibitory effect on LPS-induced NO release. It was found that sesquiterpenoids CA-2 and CA-4 had low cytotoxic and strong NO inhibitory activity with an IC50 of 4.22 ± 0.61 µM and 2.98 ± 0.23 µM for NO inhibition, respectively. Therefore, compound CA-4 was studied in depth. We found that compound CA-4 inhibited LPS-induced pro-inflammatory factor production and M1 macrophage differentiation in RAW264.7 cells. Additionally, CA-4 inhibited the expression of p-ERK1/2, p-JNK, iNOS, and COX-2 by blocking the MAPK signaling pathway. CA-4 also promoted the expression of autophagy-related proteins such as LC3 II and Beclin-1 by inhibiting activation of the PI3K/AKT/mTOR signaling pathway, and promoted the generation of autophagosomes. Finally, CA-4 significantly inhibited the degree of inflammation in mice with acute peritonitis, showing good anti-inflammatory activity in vivo. Consequently, compound CA-4 may be a promising drug for the treatment of acute inflammatory diseases and provide new ideas for the synthesis of novel anti-inflammatory compounds.
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Artemisia , Peritonitis , Sesquiterpenos , Ratones , Animales , Lipopolisacáridos/farmacología , Fosfatidilinositol 3-Quinasas , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Peritonitis/tratamiento farmacológico , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Autofagia , Sesquiterpenos/farmacologíaRESUMEN
A balanced inflammatory response is crucial for the organism to defend against external infections, however, an exaggerated response may lead to detrimental effects, including tissue damage and even the onset of disease. Therefore, anti-inflammatory drugs are essential for the rational control of inflammation. In this study, we found that a previously screened peptide TaY (KEKKEVVEYGPSSYGYG) was able to inhibit the LPS-induced RAW264.7 inflammatory response by decreasing a series of proinflammatory cytokines, such as TNF-α, IL-6, and nitric oxide (NO). To elucidate the underlying mechanism, we conducted further investigations. Western blot analysis showed that TaY reduced the phosphorylation of key proteins (IKK-α/ß, IκB-α,NF-κB (P65)) in the TLR4-NF-κB signaling pathway and inhibited the inflammatory response. Furthermore, molecular docking and molecular dynamic simulations suggested that TaY binds to the hydrophobic pocket of MD2 through hydrogen bonding and hydrophobic interactions, potentially competing with LPS for MD2 binding. Collectively, TaY is a promising candidate for the development of novel therapeutic strategies against inflammatory disorders.
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Inflamación , Lipopolisacáridos , Antígeno 96 de los Linfocitos , Simulación del Acoplamiento Molecular , FN-kappa B , Transducción de Señal , Ratones , Animales , Transducción de Señal/efectos de los fármacos , FN-kappa B/metabolismo , Células RAW 264.7 , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Antígeno 96 de los Linfocitos/metabolismo , Antígeno 96 de los Linfocitos/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Péptidos/química , Péptidos/farmacología , Simulación de Dinámica Molecular , Citocinas/metabolismo , Receptor Toll-Like 4/metabolismo , Unión Proteica , Óxido Nítrico/metabolismoRESUMEN
Small-cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non-small-cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole-exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker-directed drug development and targeted therapies in clinical trials. Our study would provide an in-depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype-specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/patología , Medicina de Precisión , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/terapia , Carcinoma Pulmonar de Células Pequeñas/patología , Mutación , GenómicaRESUMEN
The O-carbamoyltransferase VtdB catalyzes the carbamoylation of venturicidin B, which is essential for the biosynthesis of the antibiotic venturicidin A. Here, the crystal structures of VtdB and VtdB in complex with the intermediate carbamoyladenylate (VtdBCAO) were determined at resolutions of 2.99 Å and 2.90 Å, respectively. The structures resemble the conserved YrdC-like and specific Kae1-like domains. A magnesium ion and the intermediate carbamoyladenylate were also observed in the Kae1-like domain of VtdB. The structure of VtdBCAO in complex with the substrate venturicidin B was modeled by a molecular docking method to better understand the substrate binding mode, revealing a novel venturicidin B binding pocket.
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Streptomyces , Simulación del Acoplamiento Molecular , Sitios de Unión , Cristalografía por Rayos X , Especificidad por SustratoRESUMEN
Interfacial solar steam generators (ISSGs) can capture solar energy and concentrate the heat at the gas-liquid interface, resulting in efficient water evaporation. However, traditional ISSGs have limitations in long-term seawater desalination processes, such as limited light absorption area, slow water transport speed, severe surface salt accumulation, and weak mechanical performance. Inspired by lotus seedpods, a novel ISSG (rGO-SA-PSF) is developed by treating a 3D warp-knitted spacer fabric with plasma (PSF) and combining it with sodium alginate (SA) and reduces graphene oxide (rGO). The rGO-SA-PSF utilizes a core-suction effect to achieve rapid water pumping and employs aerogel to encapsulate the plasma-treated spacer yarns to create the lotus seedpod-inspired hydrophilic stems, innovatively constructing multiple directional water transport channels. Simultaneously, the large holes of rGO-SA-PSF on the upper layer form lotus seedpod-inspired head concave holes, enabling efficient light capture. Under 1 kW m-2 illumination, rGO-SA-PSF exhibits a rapid evaporation rate of 1.85 kg m-2 h-1 , with an efficiency of 96.4%. Additionally, it shows superior salt tolerance (with no salt accumulation during continuous evaporation for 10 h in 10% brine) and self-desalination performance during long-term seawater desalination processes. This biomimetic ISSG offers a promising solution for efficient and stable seawater desalination and wastewater purification.
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Bacillus thuringiensis (Bt)-secreted crystal (Cry) toxins form oligomeric pores in host cell membranes and are a common element in generating insect-resistant transgenic crops. Although Cry toxin function has been well documented, cellular defences against pore-formation have not been as well developed. Elucidation of the processes underlying this defence, however, could contribute to the development of enhanced Bt crops. Here, we demonstrate that Cry1Ca-mediated downregulation of microRNA-7322-5p (miR-7322-5p), which binds to the 3' untranslated region of p38, negatively regulates the susceptibility of Chilo suppressalis to Cry1Ca. Moreover, Cry1Ca exposure enhanced phosphorylation of Hsp19, and hsp19 downregulation increased susceptibility to Cry1Ca. Further, Hsp19 phosphorylation occurs downstream of p38, and pull-down assays confirmed the interactions between Hsp19 and Cry1Ca, suggesting that activation of Hsp19 by the miR-7322-5p/p38/Hsp19 pathway promotes Cry1Ca sequestration. To assess the efficacy of targeting this pathway in planta, double-stranded RNA (dsRNA) targeting C. suppressalis p38 (dsp38) was introduced into a previously generated cry1Ca-expressing rice line (1CH1-2) to yield a single-copy cry1Ca/dsp38 rice line (p38-rice). Feeding on this rice line triggered a significant reduction in C. suppressalis p38 expression and the line was more resistant to C. suppressalis than 1CH1-2 in both short term (7-day) and continuous feeding bioassays as well as field trials. These findings provide new insights into invertebrate epithelium cellular defences and demonstrate a potential new pyramiding strategy for Bt crops.
Asunto(s)
Bacillus thuringiensis , MicroARNs , Mariposas Nocturnas , Oryza , Animales , Oryza/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Larva/genética , Control Biológico de Vectores , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Plantas Modificadas Genéticamente/metabolismo , Mariposas Nocturnas/fisiología , Endotoxinas/genética , Endotoxinas/metabolismo , Proteínas Hemolisinas/genética , Proteínas Hemolisinas/metabolismo , Bacillus thuringiensis/genética , Bacillus thuringiensis/metabolismoRESUMEN
This study investigates the propagation and evolution of self-focusing circular Pearcey-Airy Gaussian vortex beams (CPAGVB) through high numerical aperture objective lenses. CPAGVB demonstrates a unique light field distribution compared to the circular Pearcey vortex beam and circular Airy Gaussian vortex beam. By adjusting optical distribution factors, main radii, and off-axis vortex pair positions, a variety of light field structures can be generated, including asymmetric micro-optical bottles, quasi-flat-top beam micro-optical bottles, and dual optical bottles. The particle trapping performance of CPAGVB is examined, revealing a gradient force eight orders of magnitude larger than its scattering force, up to twice the peak gradient force, and 2.5 times the scattering force of CAGVB. Further analysis of lateral power flow density, spin density vector, and total angular momentum distribution at the focal plane unveils the dynamics of particle motion toward the center. The Gouy phase difference under varying main radii reveals two types of normalized spin density vectors, characterized by helical and oscillating distributions. Additionally, the study examines the two-dimensional polarization ellipse distribution at the focal plane, elucidating the formation of central polarization singularities with axial vortices and the impact of peripheral polarization rearrangement on phase singularities. This research advances the comprehension of CPAGVB's distinctive properties and potential applications in micro-optical systems and particle manipulation.