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In vitro fertilization (IVF) has revolutionized infertility treatment, benefiting millions of couples worldwide. However, current clinical practices for embryo selection rely heavily on visual inspection of morphology, which is highly variable and experience dependent. Here, we propose a comprehensive artificial intelligence (AI) system that can interpret embryo-developmental knowledge encoded in vast unlabeled multi-modal datasets and provide personalized embryo selection. This AI platform consists of a transformer-based network backbone named IVFormer and a self-supervised learning framework, VTCLR (visual-temporal contrastive learning of representations), for training multi-modal embryo representations pre-trained on large and unlabeled data. When evaluated on clinical scenarios covering the entire IVF cycle, our pre-trained AI model demonstrates accurate and reliable performance on euploidy ranking and live-birth occurrence prediction. For AI vs. physician for euploidy ranking, our model achieved superior performance across all score categories. The results demonstrate the potential of the AI system as a non-invasive, efficient, and cost-effective tool to improve embryo selection and IVF outcomes.
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Metastasis to the lungs is a leading cause of death for breast cancer patients. Therefore, effective therapies are urgently needed to prevent and treat breast cancer lung metastasis In this study, we uncovered a mechanism by which NAD(P)H:quinone oxidoreductase 1 (NQO1) orchestrates lung metastasis. NQO1 stabilized and upregulated peptidyl-prolyl cis-trans isomerase A (PPIA), a chaperone that regulates protein conformation and activity, by preventing its oxidation at a critical cysteine residue C161. PPIA subsequently activated CD147, a membrane protein that facilitates cell invasion. Moreover, NQO1-induced secretion of PPIA modulated the immune landscape of both primary and lung metastatic sites. Secreted PPIA engaged CD147 on neutrophils and triggered the release of neutrophil extracellular traps (NET) and neutrophil elastase, which enhanced tumor progression, invasiveness and lung colonization. Pharmacological targeting of PPIA effectively inhibited NQO1-mediated breast cancer lung metastasis. These findings reveal a previously unrecognized NQO1-PPIA-CD147-NET axis that drives breast cancer lung metastasis. Inhibiting this axis is a potential therapeutic strategy to limit lung metastasis in breast cancer patients.
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Flowering time is a crucial developmental stage in the life cycle of plants, as it determines the reproductive success and overall fitness of the organism. The precise regulation of flowering time is influenced by various internal and external factors, including genetic, environmental, and hormonal cues. This review provided a comprehensive overview of the molecular mechanisms and regulatory pathways of biological macromolecules (e.g. proteins and phytohormone) and environmental factors (e.g. light and temperature) involved in the control of flowering time in plants. We discussed the key proteins and signaling pathways that govern the transition from vegetative growth to reproductive development, highlighting the intricate interplay between genetic networks, environmental cues, and phytohormone signaling. Additionally, we explored the impact of flowering time regulation on plant adaptation, crop productivity, and agricultural practices. Moreover, we summarized the similarities and differences of flowering mechanisms between annual and perennial plants. Understanding the mechanisms underlying flowering time control is not only essential for fundamental plant biology research but also holds great potential for crop improvement and sustainable agriculture.
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Flores , Flores/crecimiento & desarrollo , Flores/fisiología , Reguladores del Crecimiento de las Plantas/metabolismo , Transducción de Señal/fisiología , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Regulación de la Expresión Génica de las Plantas , Plantas/metabolismo , Desarrollo de la Planta/fisiologíaRESUMEN
Oxygenated volatile organic compounds (OVOCs), emitted in large quantities by the chemical industry, are a major contributor to the formation of ozone and subsequent particulate matter. For the efficient catalytic oxidation of OVOCs, the challenges of molecular activation and intermediate inhibition remain. The construction of bifunctional active sites with specific structures offers a promising way to overcome these problems. Here, the Pd@Layered-CoOx/MFI bifunctional catalyst with core-shell active sites was rationally fabricated though a two-step ligand pyrolysis method, which exhibits a superb oxidation efficiency toward ethyl acetate (EA). Over this, 13.4% of EA (1000 ppm) can be oxidized at just 140 °C with a reaction rate of 13.85 mmol·gPd-1·s-1, around 176.7 times higher than that of the conventional Pd-CoOx/MFI catalyst. The electronic coupling of the Pd-Co pair promotes the electron back-donation from Pd nanoparticles to the layered CoOx shell and facilitates the formation of Pd2+ species, which greatly enhances the adsorption and activation of the electron-rich CâO bond of the EA molecules. In addition, the synergy of these core-shell Pd@Layered-CoOx sites accelerates the activation and transformation of *O species, which inhibit the formation of acetaldehyde and ethanol byproducts, ensuring the rapid total oxidation of EA molecules via the Mars-van Krevelen mechanism. This work established a solid foundation for exploring robust bifunctional catalysts for deep OVOC purification.
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Oxidación-Reducción , Catálisis , Paladio/química , Compuestos Orgánicos Volátiles/química , Acetatos/químicaRESUMEN
Melon (Cucumis melo L.) is a valuable horticultural crop of the Cucurbitaceae family. Downy mildew (DM), caused by Pseudoperonospora cubensis, is a significant inhibitor of the production and quality of melon. Brassinolide (BR) is a new type of phytohormone widely used in cultivation for its broad spectrum of resistance- and defense-mechanism-improving activity. In this study, we applied various exogenous treatments (0.5, 1.0, and 2.0 mg·L-1) of BR at four distinct time periods (6 h, 12 h, 24 h, and 48 h) and explored the impact of BR on physiological indices and the genetic regulation of melon seedling leaves infected by downy-mildew-induced stress. It was mainly observed that a 2.0 mg·L-1 BR concentration effectively promoted the enhanced photosynthetic activity of seedling leaves, and quantitative real-time polymerase chain reaction (qRT-PCR) analysis similarly exhibited an upregulated expression of the predicted regulatory genes of photosystem II (PSII) CmHCF136 (MELO3C023596.2) and CmPsbY (MELO3C010708.2), thus indicating the stability of the PSII reaction center. Furthermore, 2.0 mg·L-1 BR resulted in more photosynthetic pigments (nearly three times more than the chlorophyll contents (264.52%)) as compared to the control and other treatment groups and similarly upregulated the expression trend of the predicted key enzyme genes CmLHCP (MELO3C004214.2) and CmCHLP (MELO3C017176.2) involved in chlorophyll biosynthesis. Meanwhile, the maximum contents of soluble sugars and starch (186.95% and 164.28%) were also maintained, which were similarly triggered by the upregulated expression of the predicted genes CmGlgC (MELO3C006552.2), CmSPS (MELO3C020357.2), and CmPEPC (MELO3C018724.2), thereby maintaining osmotic adjustment and efficiency in eliminating reactive oxygen species. Overall, the exogenous 2.0 mg·L-1 BR exhibited maintained antioxidant activities, plastid membranal stability, and malondialdehyde (MDA) content. The chlorophyll fluorescence parameter values of F0 (42.23%) and Fv/Fm (36.67%) were also noticed to be higher; however, nearly three times higher levels of NPQ (375.86%) and Y (NPQ) (287.10%) were observed at 48 h of treatment as compared to all other group treatments. Increased Rubisco activity was also observed (62.89%), which suggested a significant role for elevated carbon fixation and assimilation and the upregulated expression of regulatory genes linked with Rubisco activity and the PSII reaction process. In short, we deduced that the 2.0 mg·L-1 BR application has an enhancing effect on the genetic modulation of physiological indices of melon plants against downy mildew disease stress.
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Designing efficient, inexpensive, and stable photocatalysts to degrade organic pollutants and antibiotics has become an effective way for environmental remediation. In this work, we successfully performed in situ growth of CdS QDs on the surface of elliptical BiVO4 to try to show the advantage of the binary heterojuncted photocatalyst (BVO@CdS) for the photocatalytic degradation of tetracycline (TC). The In situ growth of CdS QDs can provide a large number of reactive sites and also generate a larger contact area with BiVO4. In addition, compared with mechanical composite materials, in situ growth can significantly reduce the energy barrier at the interface between BiVO4 and CdS, providing more channels for the separation and migration of photogenerated charge carriers, and further improving reaction activity. As a result, BVO@CdS-0.05 shows the best degradation efficiency, with a degradation rate of 88% after 30 min under visible light. The TC photodegradation follows a pseudo-second-order reaction with a dynamic constant of 0.472 min-1, which is 6.47 times that of pure BiVO4, 7.24 times that of pure CdS QDs and 2 times that of the mechanical composite. The degradation rate of BVO@CdS-0.05 decreases to 77.8% with a retention rate of 88.5% after four cycles, demonstrating excellent stability. Through liquid chromatography-mass spectrometry (LC-MS) analysis, two possible pathways for TC degradation are proposed. Through free radical capture experiments, electron spin resonance measurements, and photoelectrochemical comprehensive analysis, it is confirmed that BVO@CdS composites have constructed an efficient Z-scheme heterojunction via in situ growth, thereby highly enhancing the separation and transport efficiency of charge carriers.
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Atherosclerotic plaque formation is considered the primary pathological mechanism underlying atherosclerotic cardiovascular diseases, leading to severe cardiovascular events such as stroke, acute coronary syndromes, and even sudden cardiac death. Early detection and timely intervention of plaques are challenging due to the lack of typical symptoms in the initial stages. Therefore, precise early detection and intervention play a crucial role in risk stratification of atherosclerotic plaques and achieving favorable post-interventional outcomes. The continuously advancing nanoplatforms have demonstrated numerous advantages including high signal-to-noise ratio, enhanced bioavailability, and specific targeting capabilities for imaging agents and therapeutic drugs, enabling effective visualization and management of atherosclerotic plaques. Motivated by these superior properties, various noninvasive imaging modalities for early recognition of plaques in the preliminary stage of atherosclerosis are comprehensively summarized. Additionally, several therapeutic strategies are proposed to enhance the efficacy of treating atherosclerotic plaques. Finally, existing challenges and promising prospects for accelerating clinical translation of nanoplatform-based molecular imaging and therapy for atherosclerotic plaques are discussed. In conclusion, this review provides an insightful perspective on the diagnosis and therapy of atherosclerotic plaques.
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Placa Aterosclerótica , Nanomedicina Teranóstica , Humanos , Placa Aterosclerótica/diagnóstico por imagen , Placa Aterosclerótica/terapia , Animales , Nanomedicina Teranóstica/métodos , Nanopartículas/química , Nanopartículas/uso terapéuticoRESUMEN
The widespread presence of formaldehyde (HCHO) pollutant has aroused significant environmental and health concerns. The catalytic oxidation of HCHO into CO2 and H2O at ambient temperature is regarded as one of the most efficacious and environmentally friendly approaches; to achieve this, however, accelerating the intermediate formate species formation and decomposition remains an ongoing obstacle. Herein, a unique tandem catalytic system with outstanding performance in low-temperature HCHO oxidation is proposed on well-structured Pd/Mn3O4-MnO catalysts possessing bifunctional catalytic centers. Notably, the optimized tandem catalyst achieves complete oxidation of 100 ppm of HCHO at just 18 °C, much better than the Pd/Mn3O4 (30%) and Pd/MnO (27%) counterparts as well as other physical tandem catalysts. The operando analyses and physical tandem investigations reveal that HCHO is primarily activated to gaseous HCOOH on the surface of Pd/Mn3O4 and subsequently converted to H2CO3 on the Pd/MnO component for deep decomposition. Theoretical studies disclose that Pd/Mn3O4 exhibits a favorable reaction energy barrier for the HCHO â HCOOH step compared to Pd/MnO; while conversely, the HCOOH â H2CO3 step is more facilely accomplished over Pd/MnO. Furthermore, the nanoscale intimacy between two components enhances the mobility of lattice oxygen, thereby facilitating interfacial reconstruction and promoting interaction between active sites of Pd/Mn3O4 and Pd/MnO in local vicinity, which further benefits sustained HCHO tandem catalytic oxidation. The tandem catalysis demonstrated in this work provides a generalizable platform for the future design of well-defined functional catalysts for oxidation reactions.
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Formaldehído , Paladio , Temperatura , Dominio Catalítico , Oxidación-Reducción , Catálisis , Paladio/químicaRESUMEN
Air humidity significantly impacts plant physiology. However, the upstream elements that mediate humidity sensing and adaptive responses in plants remain largely unexplored. In this study, we define high humidity-induced cellular features of Arabidopsis plants and take a quantitative phosphoproteomics approach to obtain a high humidity-responsive landscape of membrane proteins, which we reason are likely the early checkpoints of humidity signaling. We found that a brief high humidity exposure (i.e., 0.5 h) is sufficient to trigger extensive changes in membrane protein abundance and phosphorylation. Enrichment analysis of differentially regulated proteins reveals high humidity-sensitive processes such as 'transmembrane transport', 'response to abscisic acid', and 'stomatal movement'. We further performed a targeted screen of mutants, in which high humidity-responsive pathways/proteins are disabled, to uncover genes mediating high humidity sensitivity. Interestingly, ethylene pathway mutants (i.e., ein2 and ein3eil1) display a range of altered responses, including hyponasty, reactive oxygen species level, and responsive gene expression, to high humidity. Furthermore, we observed a rapid induction of ethylene biosynthesis genes and ethylene evolution after high humidity treatment. Our study sheds light on the potential early signaling events in humidity perception, a fundamental but understudied question in plant biology, and reveals ethylene as a key modulator of high humidity responses in plants.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Humedad , Etilenos/metabolismo , Arabidopsis/metabolismo , Proteínas de la Membrana/metabolismo , Regulación de la Expresión Génica de las PlantasRESUMEN
Background: Prognosis is crucial for personalized treatment and surveillance suggestion of the resected non-small-cell lung cancer (NSCLC) patients in stage I-III. Although the tumor-node-metastasis (TNM) staging system is a powerful predictor, it is not perfect enough to accurately distinguish all the patients, especially within the same TNM stage. In this study, we developed an intelligent prognosis evaluation system (IPES) using pre-therapy CT images to assist the traditional TNM staging system for more accurate prognosis prediction of resected NSCLC patients. Methods: 20,333 CT images of 6371 patients from June 12, 2009 to March 24, 2022 in West China Hospital of Sichuan University, Mianzhu People's Hospital, Peking University People's Hospital, Chengdu Shangjin Nanfu Hospital and Guangan Peoples' Hospital were included in this retrospective study. We developed the IPES based on self-supervised pre-training and multi-task learning, which aimed to predict an overall survival (OS) risk for each patient. We further evaluated the prognostic accuracy of the IPES and its ability to stratify NSCLC patients with the same TNM stage and with the same EGFR genotype. Findings: The IPES was able to predict OS risk for stage I-III resected NSCLC patients in the training set (C-index 0.806; 95% CI: 0.744-0.846), internal validation set (0.783; 95% CI: 0.744-0.825) and external validation set (0.817; 95% CI: 0.786-0.849). In addition, IPES performed well in early-stage (stage I) and EGFR genotype prediction. Furthermore, by adopting IPES-based survival score (IPES-score), resected NSCLC patients in the same stage or with the same EGFR genotype could be divided into low- and high-risk subgroups with good and poor prognosis, respectively (p < 0.05 for all). Interpretation: The IPES provided a non-invasive way to obtain prognosis-related information from patients. The identification of IPES for resected NSCLC patients with low and high prognostic risk in the same TNM stage or with the same EGFR genotype suggests that IPES have potential to offer more personalized treatment and surveillance suggestion for NSCLC patients. Funding: This study was funded by the National Natural Science Foundation of China (grant 62272055, 92259303, 92059203), New Cornerstone Science Foundation through the XPLORER PRIZE, Young Elite Scientists Sponsorship Program by CAST (2021QNRC001), Clinical Medicine Plus X - Young Scholars Project, Peking University, the Fundamental Research Funds for the Central Universities (K.C.), Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer, Chinese Academy of Medical Sciences (2021RU002), BUPT Excellent Ph.D. Students Foundation (CX2022104).
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Light alkanes make up a class of widespread volatile organic compounds (VOCs), bringing great environmental hazards and health concerns. However, the low-temperature catalytic destruction of light alkanes is still a great challenge to settle due to their high reaction inertness and weak polarity. Herein, a Co3O4 sub-nanometer porous sheet (Co3O4-SPS) was fabricated and comprehensively compared with its bulk counterparts in the catalytic oxidation of C3H8. Results demonstrated that abundant low-coordinated Co atoms on the Co3O4-SPS surface boost the activation of adsorbed oxygen and enhance the catalytic activity. Moreover, Co3O4-SPS has better surface metal properties, which is beneficial to electron transfer between the catalyst surface and the reactant molecules, promoting the interaction between C3H8 molecules and dissociated O atoms and facilitating the activation of C-H bonds. Due to these, Co3O4-SPS harvests a prominent performance for C3H8 destruction, 100% of which decomposed at 165 °C (apparent activation energy of 49.4 kJ mol-1), much better than the bulk Co3O4 (450 °C and 126.9 kJ mol-1) and typical noble metal catalysts. Moreover, Co3O4-SPS also has excellent thermal stability and water resistance. This study deepens the atomic-level insights into the catalytic capacity of Co3O4-SPS in light alkane purification and provides references for designing efficacious catalysts for thermocatalytic oxidation reactions.
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Colorectal cancer (CRC) is a common and deadly disease of the digestive system, but its targeted therapy is hampered by the lack of reliable and specific biomarkers. Hence, discovering new therapeutic targets and agents for CRC is an urgent and challenging task. Here we report that carnitine palmitoyltransferase 1A (CPT1A), a mitochondrial enzyme that catalyzes fatty acid oxidation (FAO), is a potential target for CRC treatment. We show that CPT1A is overexpressed in CRC cells and that its inhibition by a secolignan-type compound, 2,6-dihydroxypeperomin B (DHP-B), isolated from the plant Peperomia dindygulensis, suppresses tumor cell growth and induces apoptosis. We demonstrate that DHP-B covalently binds to Cys96 of CPT1A, blocks FAO, and disrupts the mitochondrial CPT1A-VDAC1 interaction, leading to increased mitochondrial permeability and reduced oxygen consumption and energy metabolism in CRC cells. We also reveal that CPT1A expression correlates with the survival of tumor-bearing animals and that DHP-B exhibits anti-CRC activity in vitro and in vivo. Our study uncovers the molecular mechanism of DHP-B as a novel CPT1A inhibitor and provides a rationale for its preclinical development as well as a new strategy for CRC targeted therapy.
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Carnitina O-Palmitoiltransferasa , Neoplasias Colorrectales , Animales , Apoptosis , Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Ácidos Grasos/metabolismo , Metabolismo de los Lípidos , Oxidación-Reducción , Canales Aniónicos Dependientes del Voltaje/metabolismoRESUMEN
Multi-drug resistant (MDR) bacterial infections are gradually increasing in the global scope, causing a serious burden to patients and society. The formation of bacterial biofilms, which is one of the key reasons for antibiotic resistance, blocks antibiotic penetration by forming a physical barrier. Nano/micro motors (MNMs) are micro-/nanoscale devices capable of performing complex tasks in the bacterial microenvironment by transforming various energy sources (including chemical fuels or external physical fields) into mechanical motion or actuation. This autonomous movement provides significant advantages in breaking through biological barriers and accelerating drug diffusion. In recent years, MNMs with high penetrating power have been used as carriers of antibiotics to overcome bacterial biofilms, enabling efficient drug delivery and improving the therapeutic effectiveness of MDR bacterial infections. Additionally, non-antibiotic antibacterial strategies based on nanomaterials, such as photothermal therapy and photodynamic therapy, are continuously being developed due to their non-invasive nature, high effectiveness, and non-induction of resistance. Therefore, multifunctional MNMs have broad prospects in the treatment of MDR bacterial infections. This review discusses the performance of MNMs in the breakthrough and elimination of bacterial biofilms, as well as their application in the field of anti-infection. Finally, the challenges and future development directions of antibacterial MNMs are introduced.
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Infecciones Bacterianas , Nanoestructuras , Humanos , Nanotecnología , Antibacterianos/farmacología , Bacterias , BiopelículasRESUMEN
BACKGROUND: Light-harvesting chlorophyll a/b b evelopment of higher plants and in response to abiotic stress. Previous works has demonstrated that that Lhcb genes were involved in the phytochrome regulation and responded to the different light and temperature conditions in Poaceae (such as maize). However, the evolution and functions of Lhcb genes remains poorly characterized in important Rosaceae species. RESULTS: In this investigation, we conducted a genome-wide analysis and identified a total of 212 Lhcb genes across nine Rosaceae species. Specifically, we found 23 Lhcb genes in Fragaria vesca, 20 in Prunus armeniaca, 33 in Malus domestica 'Gala', 21 in Prunus persica, 33 in Rosa chinensis, 29 in Pyrus bretschneideri, 18 in Rubus occidentalis, 20 in Prunus mume, and 15 in Prunus salicina. Phylogenetic analysis revealed that the Lhcb gene family could be classified into seven major subfamilies, with members of each subfamily sharing similar conserved motifs. And, the functions of each subfamily was predicted based on the previous reports from other species. The Lhcb proteins were highly conserved within their respective subfamilies, suggesting similar functions. Interestingly, we observed similar peaks in Ks values (0.1-0.2) for Lhcb genes in apple and pear, indicating a recent whole genome duplication event (about 30 to 45 million years ago). Additionally, a few Lhcb genes underwent tandem duplication and were located across all chromosomes of nine species of Rosaceae. Furthermore, the analysis of the cis-acting elements in the 2000 bp promoter region upstream of the pear Lhcb gene revealed four main categories: light response correlation, stress response correlation, hormone response correlation, and plant growth. Quantitative expression analysis demonstrated that Lhcb genes exhibited tissue-specific expression patterns and responded differently to low-temperature stress in Rosaceae species. CONCLUSIONS: These findings shed light on the evolution and phylogeny of Lhcb genes in Rosaceae and highlight the critical role of Lhcb in pear's response to low temperatures. The results obtained provide valuable insights for further investigations into the functions of Lhcb genes in Rosaceae, and these functional genes will be used for further fruit tree breeding and improvement to cope with the current climate changes.
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Malus , Pyrus , Rosaceae , Rosaceae/genética , Rosaceae/metabolismo , Frutas/genética , Frutas/metabolismo , Filogenia , Clorofila A/metabolismo , Genoma de Planta/genética , Fitomejoramiento , Malus/genética , Malus/metabolismo , Pyrus/genética , Genómica , Evolución Molecular , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
The occurrence of plant disease is determined by interactions among host, pathogen, and environment. Air humidity shapes various aspects of plant physiology and high humidity has long been known to promote numerous phyllosphere diseases. However, the molecular basis of how high humidity interferes with plant immunity to favor disease has remained elusive. Here we show that high humidity is associated with an "immuno-compromised" status in Arabidopsis plants. Furthermore, accumulation and signaling of salicylic acid (SA), an important defense hormone, are significantly inhibited under high humidity. NPR1, an SA receptor and central transcriptional co-activator of SA-responsive genes, is less ubiquitinated and displays a lower promoter binding affinity under high humidity. The cellular ubiquitination machinery, particularly the Cullin 3-based E3 ubiquitin ligase mediating NPR1 protein ubiquitination, is downregulated under high humidity. Importantly, under low humidity the Cullin 3a/b mutant plants phenocopy the low SA gene expression and disease susceptibility that is normally observed under high humidity. Our study uncovers a mechanism by which high humidity dampens a major plant defense pathway and provides new insights into the long-observed air humidity influence on diseases.
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Proteínas de Arabidopsis , Arabidopsis , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Ácido Salicílico/metabolismo , Humedad , Proteínas Cullin/genética , Proteínas Cullin/metabolismo , Arabidopsis/metabolismo , Plantas/metabolismo , Factores de Transcripción/metabolismo , Enfermedades de las Plantas/genética , Regulación de la Expresión Génica de las PlantasRESUMEN
Sonodynamic therapy (SDT) has gained significant attention in the treatment of deep tumors and multidrug-resistant (MDR) bacterial infections due to its high tissue penetration depth, high spatiotemporal selectivity, and noninvasive therapeutic method. SDT combines low-intensity ultrasound (US) and sonosensitizers to produce lethal reactive oxygen species (ROS) and external damage, which is the main mechanism behind this therapy. However, traditional organic small-molecule sonosensitizers display poor water solubility, strong phototoxicity, and insufficient targeting ability. Inorganic sonosensitizers, on the other hand, have low ROS yield and poor biocompatibility. These drawbacks have hindered SDT's clinical transformation and application. Hence, designing stimuli-responsive nano-sonosensitizers that make use of the lesion's local microenvironment characteristics and US stimulation is an excellent alternative for achieving efficient, specific, and safe treatment. In this review, we provide a comprehensive overview of the currently accepted mechanisms in SDT and discuss the application of responsive nano-sonosensitizers in the treatment of tumor and bacterial infections. Additionally, we emphasize the significance of the principle and process of response, based on the classification of response patterns. Finally, this review emphasizes the potential limitations and future perspectives of SDT that need to be addressed to promote its clinical transformation.
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Neoplasias , Terapia por Ultrasonido , Humanos , Especies Reactivas de Oxígeno , Neoplasias/terapia , Neoplasias/patología , Nanomedicina Teranóstica , Línea Celular Tumoral , Microambiente TumoralRESUMEN
Prophylactic tumor vaccines hold great promise against tumor occurrence. However, their clinical efficacy remains low due to inadequate activation of strong-sustainable immunity. Herein, a biomembrane hydrogel was designed as a powerful single-shot prophylactic tumor vaccine. Mannose-decorated hybrid biomembrane (MHCM) modified with oxidized sodium alginate (OSA) was designed as a gelator (O-MHCM), where the hybrid biomembrane (HCM) is a hybridization of bacterial outer membrane vesicles (OMV) and tumor cell membranes (TCM). The O-MHCM enables quick gelation subcutaneously where the cysteine protease inhibitor E64 is encapsulated in hydrogel micropores. After a single vaccination of E64@O-MHCM hydrogel, MHCM and E64 are released sustainably due to OSA moiety degradation. The MHCM enables active targeting to dendritic cells (DC) and effective DC maturation. Meanwhile, the E64 enables sufficient antigen availability for subsequent cross presentation. Ultimately, strong and sustainable T lymphocyte-mediated immunity was elicited, demonstrating a strong prophylactic effect against breast tumors. This study provides a long-lasting platform to prevent tumor occurrence, opening an innovative avenue for the design of a single-shot prophylactic tumor vaccine. STATEMENT OF SIGNIFICANCE: Developing a single-shot prophylactic tumor vaccine to elicit strong-sustainable immunity is of great interest clinically. Here, a prophylactic tumor vaccine was designed using an injectable biomembrane hydrogel for achieving strong-sustainable immunity. The mannose-tailored hybrid biomembrane was modified with oxidized sodium alginate to result in a gelator, which enabled the formation of the hydrogel after subcutaneous injection. Cysteine protease inhibitor E64 was incorporated into the micropores of the hydrogel. The hydrogel induced strong-sustainable immunity through the continuous release of active components. This was facilitated by the mannose moiety, which enabled active targeting, as well as the antigen and adjuvant function of biomembrane, and the E64-enabled suppression of antigen degradation. The biomembrane hydrogel demonstrated powerful prevention of 4T1 breast tumors. This study offers an attractive strategy for designing a single-shot prophylactic tumor vaccine.
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Neoplasias de la Mama , Vacunas contra el Cáncer , Humanos , Femenino , Hidrogeles/farmacología , Manosa , Linfocitos T , Antígenos , Neoplasias de la Mama/tratamiento farmacológico , Células DendríticasRESUMEN
Host-pathogen interactions and pathogen evolution are underpinned by protein-protein interactions between viral and host proteins. An understanding of how viral variants affect protein-protein binding is important for predicting viral-host interactions, such as the emergence of new pathogenic SARS-CoV-2 variants. Here we propose an artificial intelligence-based framework called UniBind, in which proteins are represented as a graph at the residue and atom levels. UniBind integrates protein three-dimensional structure and binding affinity and is capable of multi-task learning for heterogeneous biological data integration. In systematic tests on benchmark datasets and further experimental validation, UniBind effectively and scalably predicted the effects of SARS-CoV-2 spike protein variants on their binding affinities to the human ACE2 receptor, as well as to SARS-CoV-2 neutralizing monoclonal antibodies. Furthermore, in a cross-species analysis, UniBind could be applied to predict host susceptibility to SARS-CoV-2 variants and to predict future viral variant evolutionary trends. This in silico approach has the potential to serve as an early warning system for problematic emerging SARS-CoV-2 variants, as well as to facilitate research on protein-protein interactions in general.