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Diagnosing, predicting disease outcome, and identifying effective treatment targets for virus-related cancers are lacking. Protein biomarkers have the potential to bridge the gap between prevention and treatment for these types of cancers. While it has been shown that certain antibodies against EBV proteins could be used to detect nasopharyngeal carcinoma (NPC), antibodies targeting are solely a tiny part of the about 80 proteins expressed by the EBV genome. Furthermore, it remains unclear what role other viruses play in NPC since many diseases are the result of multiple viral infections. For the first time, this study measured both IgA and IgG antibody responses against 646 viral proteins from 23 viruses in patients with NPC and control subjects using nucleic acid programmable protein arrays. Candidate seromarkers were then validated by ELISA using 1665 serum samples from three clinical cohorts. We demonstrated that the levels of five candidate seromarkers (EBV-BLLF3-IgA, EBV-BLRF2-IgA, EBV-BLRF2-IgG, EBV-BDLF1-IgA, EBV-BDLF1-IgG) in NPC patients were significantly elevated than controls. Additional examination revealed that NPC could be successfully diagnosed by combining the clinical biomarker EBNA1-IgA with the five anti-EBV antibodies. The sensitivity of the six-antibody signature at 95% specificity to diagnose NPC was comparable to the current clinically-approved biomarker combination, VCA-IgA, and EBNA1-IgA. However, the recombinant antigens of the five antibodies are easier to produce and standardize compared to the native viral VCA proteins. This suggests the potential replacement of the traditional VCA-IgA assay with the 5-antibodies combination to screen and diagnose NPC. Additionally, we investigated the prognostic significance of these seromarkers titers in NPC. We showed that NPC patients with elevated BLLF3-IgA and BDLF1-IgA titers in their serum exhibited significantly poorer disease-free survival, suggesting the potential of these two seromarkers as prognostic indicators of NPC. These findings will help develop serological tests to detect and treat NPC in the future.
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Neoplasias Nasofaríngeas , Proteoma , Humanos , Carcinoma Nasofaríngeo/diagnóstico , Neoplasias Nasofaríngeas/diagnóstico , Herpesvirus Humano 4/genética , Proteínas do Capsídeo , Antígenos Virais , Biomarcadores , Imunoglobulina G , Imunoglobulina ARESUMO
Drug-drug interaction (DDI) prediction is crucial for identifying interactions within drug combinations, especially adverse effects due to physicochemical incompatibility. While current methods have made strides in predicting adverse drug interactions, limitations persist. Most methods rely on handcrafted features, restricting their applicability. They predominantly extract information from individual drugs, neglecting the importance of interaction details between drug pairs. To address these issues, we propose MGDDI, a graph neural network-based model for predicting potential adverse drug interactions. Notably, we use a multiscale graph neural network (MGNN) to learn drug molecule representations, addressing substructure size variations and preventing gradient issues. For capturing interaction details between drug pairs, we integrate a substructure interaction learning module based on attention mechanisms. Our experimental results demonstrate MGDDI's superiority in predicting adverse drug interactions, offering a solution to current methodological limitations.
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Interações Medicamentosas , Redes Neurais de Computação , Humanos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , AlgoritmosRESUMO
Polymer waveguide devices have attracted increasing interest in several rapidly developing areas of broadband communications since they are easily adaptable to on-chip integration and promise low propagation losses. As a key member of the waveguide gain medium, lanthanide doped nanoparticles have been intensively studied to improve the downconversion luminescence. However, current research efforts are almost confined to erbium-doped nanoparticles and amplifiers operating at the C-band; boosting the downconversion luminescence of Tm3+ for S-band optical amplification still remains a challenge. Here we report a Tb3+-induced deactivation control to enhance Tm3+ downconversion luminescence in a stoichiometric Yb lattice without suffering from concentration quenching. We also demonstrate their potential application in an S-band waveguide amplifier and record a maximum optical gain of 18 dB at 1464 nm. Our findings provide valuable insights into the fundamental understanding of deactivation-controlled luminescence enhancement and open up a new avenue toward the development of an S-band polymer waveguide amplifier with high gain.
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Accurately and rapidly acquiring the microscopic properties of a material is crucial for catalysis and electrochemistry. Characterization tools, such as spectroscopy, can be a valuable tool to infer these properties, and when combined with machine learning tools, they can theoretically achieve fast and accurate prediction results. However, on the path to practical applications, training a reliable machine learning model is faced with the challenge of uneven data distribution in a vast array of non-negligible solvent types. Herein, we employ a combination of the first-principles-based approach and data-driven model. Specifically, we utilize density functional theory (DFT) to calculate theoretical spectral data of CO-Ag adsorption in 23 different solvent systems as a data source. Subsequently, we propose a hierarchical knowledge extraction multiexpert neural network (HMNN) to bridge the knowledge gaps among different solvent systems. HMNN undergoes two training tiers: in tier I, it learns fundamental quantitative spectra-property relationships (QSPRs), and in tier II, it inherits the fundamental QSPR knowledge from previous steps through a dynamic integration of expert modules and subsequently captures the solvent differences. The results demonstrate HMNN's superiority in estimating a range of molecular adsorbate properties, with an error range of less than 0.008 eV for zero-shot predictions on unseen solvents. The findings underscore the usability, reliability, and convenience of HMNN and could pave the way for real-time access to microscopic properties by exploiting QSPR.
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BACKGROUND: Circular RNAs (circRNAs) play important roles in cancer progression and metastasis. However, the expression profiles and biological roles of circRNAs in non-small cell lung cancer (NSCLC) remain unclear. METHODS: In this study, we identified a novel circRNA, hsa_circ_0006834 (termed circ6834), in NSCLC by RNA-seq and investigated the biological role of circ6834 in NSCLC progression in vitro and in vivo. Finally, the molecular mechanism of circ6834 was revealed by tagged RNA affinity purification (TRAP), western blot, RNA immunoprecipitation, dual luciferase reporter gene assays and rescue experiments. RESULTS: Our results showed that circ6834 was downregulated in NSCLC tumor tissues and cell lines. Circ6834 overexpression inhibited NSCLC cell growth and metastasis both in vitro and in vivo, while circ6834 knockdown had the opposite effect. We found that TGF-ß treatment decreased circ6834 expression, which was associated with the QKI reduction in NSCLC cells and circ6834 antagonized TGF-ß-induced EMT and metastasis in NSCLC cells. Mechanistically, circ6834 bound to AHNAK protein, a key regulator of TGF-ß/Smad signaling, and inhibited its stability by enhancing TRIM25-mediated ubiquitination and degradation. In addition, circ6834 acted as a miRNA sponge for miR-873-5p and upregulated TXNIP gene expression, which together inactivated the TGF-ß/Smad signaling pathway in NSCLC cells. CONCLUSION: In conclusion, circ6834 is a tumor-suppressive circRNA that inhibits NSCLC progression by forming a negative regulatory feedback loop with the TGF-ß/Smad signaling pathway and represents a novel therapeutic target for NSCLC.
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Carcinoma Pulmonar de Células não Pequenas , Proteínas de Transporte , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , MicroRNAs , RNA Circular , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , RNA Circular/genética , MicroRNAs/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Animais , Camundongos , Linhagem Celular Tumoral , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Progressão da Doença , Movimento Celular/genética , Transdução de Sinais , Feminino , Fator de Crescimento Transformador beta/metabolismo , Masculino , Transição Epitelial-Mesenquimal/genéticaRESUMO
The ubiquitin-proteasome system (UPS) has a critical role in post-translational protein modification that is essential for the maintenance of all cellular functions, including immune responses. The proteasome complex is ubiquitously expressed and is responsible for degradation of short-lived structurally abnormal, misfolded and not-needed proteins that are targeted for degradation via ubiquitin conjugation. Over the last 14 years, an increasing number of human diseases have been linked to pathogenic variants in proteasome subunits and UPS regulators. Defects of the proteasome complex or its chaperons - which have a regulatory role in the assembly of the proteasome - disrupt protein clearance and cellular homeostasis, leading to immune dysregulation, severe inflammation, and neurodevelopmental disorders in humans. Proteasome-associated diseases have complex inheritance, including monogenic, digenic and oligogenic disorders and can be dominantly or recessively inherited. In this review, we summarize the current known genetic causes of proteasomal disease, and discuss the molecular pathogenesis of these conditions based on the function and cellular expression of mutated proteins in the proteasome complex.
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Complexo de Endopeptidases do Proteassoma , Ubiquitina , Humanos , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Síndrome , Ubiquitina/metabolismoRESUMO
Exosomes have been established as a valuable tool for clinical applications for the purpose of liquid biopsy and therapy. However, the clinical practice of exosomes as cancer biopsy markers is still to a very low extent. Active mode optical microcavity with microlaser emission has aroused as a versatile approach for chemical and biological sensing due to its benefits of larger photon population, increased effective Q-factor, decreased line width, and improved sensitivity. Herein, we report a label-free and precise quantification of exosome vesicles and surface protein profiling of breast cancer exosomes using functionalized active whispering gallery mode (WGM) microlaser probes. A detection limit of 40 exosomes per microresonator was achieved. The proposed system enabled a pilot assay of quantitative exosome analysis in cancer patients' blood with only a few microliters of sample consumption, holding good potential for large-scale cancer liquid biopsy. Multiplexed functionalization of the optical microresonator allowed us to profile cancer exosomal surface markers and distinct subclasses of breast cancer-associated exosomes and monitor drug treatment outcomes. Our findings speak volumes about the advantages of the WGM microlaser sensor, including very small sample consumption, low detection limit, high specificity, and ease of operation, offering a promising means for precious clinical sample analysis.
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Neoplasias da Mama , Exossomos , Humanos , Feminino , Exossomos/metabolismo , Biópsia Líquida , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , LasersRESUMO
Local density of states (LDOS) is emerging as powerful means of exploring classical-wave topological phases. However, the current LDOS detection method remains rare and merely works for static situations. Here, we introduce a generic dynamical method to detect both the static and Floquet LDOS, based on an elegant connection between dynamics of chiral density and local spectral densities. Moreover, we find that the Floquet LDOS allows to measure out Floquet quasienergy spectra and identify topological π modes. As an example, we demonstrate that both the static and Floquet higher-order topological phase can be universally identified via LDOS detection, regardless of whether the topological corner modes are in energy gaps, bands, or continuous energy spectra without band gaps. Our study opens a new avenue utilizing dynamics to detect topological spectral densities and provides a universal approach of identifying static and Floquet topological phases.
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Based on the typical similar repeat units (abcdefg)n of α-helical structure, the peptide H was designed to self-assemble into an organohydrogel in response to pH. Depending on the different pH, the proportions of secondary structure, microstructure, and mechanical properties of the gel were investigated. Circular dichroism (CD) and Fourier transform infrared (FT-IR) showed that the proportion of α-helical structure gradually increased to become dominant with the increase of pH. Combining transmission electron microscopy (TEM) and atomic force microscopy (AFM), it was found that the increase of the ordered α-helix structure promoted fiber formation. The further increase in pH changed the intermolecular forces, resulting in an increase in the α-helix content and the enhancement of helix-helix interaction, causing the gel fibers to converge into thicker and more dense ones. The temperature test showed the stable rheological properties of the organohydrogel between 20-60 °C. Drug release and cytotoxicity showed that the DOX-loaded organohydrogel could have a better release in an acidic environment, indicating its potential application as a drug local delivery carrier.
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Homogeneous wrinkles and localized patterns are ubiquitous in nature and are useful for a wide range of practical applications. Although various strain-driven surface instability modes have been extensively investigated in the past decades, understanding the coexistence, coevolution, and interaction of wrinkles and localized patterns is still a great challenge. Here, we report on the formation and evolution of coexisting wrinkle and ridge patterns in metal films deposited on poly(dimethylsiloxane) (PDMS) substrates by uniaxial compression. It is found that the evolving surface patterns show unique features of morphological transition from stages I to III: namely, transition from localized ridges to coexisting wrinkles and ridges, and finally to sinusoidal-like structures, as the compression increases. Based on the compressive strain-driven surface instability theory and finite element numerical simulation, the morphological features, transition behaviors, and underlying mechanisms of such complex patterns are investigated in detail, and the changes of amplitude and wavelength versus the strain are consistent with our experiments. This work could promote a better understanding of the effect of strain localization and the interaction of multiple surface patterns in hard film-soft substrate systems.
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Phosphors used in NIR spectroscopy require broadband emission, high external quantum yield, good ability, as well as a tunable spectral range to meet the detection criteria. Two-dimensional copper silicates MCuSi4O10 (M = Ca, Sr, Ba) play an important part in ancient art and technology as synthetic blue pigments. In the recent years, these compounds were reported to show a broad near-infrared emission when excited in the visible region. Inspired by the tunable structure of MCuSi4O10, a series of broadband phosphors Ca1-xSrxCuSi4O10 were designed for realizing continuously tunable NIR emission by a modulated Cu2+ crystal field environment. The emission maximum exhibits a red shift from 915 to 950 nm and the integral intensity enhances as the Sr2+ content varies in the range of 0-0.50, which is led by the lattice expansion and the following weakened crystal field splitting on tetrahedral-coordinated Cu2+. Compared to CaCuSi4O10, the optimized sample Ca0.5Sr0.5CuSi4O10 shows enhanced NIR emission by about 2.0-fold. It exhibits quite a high external quantum efficiency covering the NIR-I and -II regions (λmax = 950 nm, fwhm = 135 nm, EQE = 26.3%) with a strong absorption efficiency (74.7%) and a long excited-state lifetime (134 µs). These solid-solution phosphors (x = 0.0-0.5) show excellent thermal stability and maintain over 50% of the RT intensity at 200 °C. The optimized phosphor was encapsulated with red-light chips to fabricate NIR pc-LED and put into night-vision application. These good properties make these Cu2+-activated NIR phosphors appealing for multiple applications such as nondestructive testing, night version, lasers, and luminescent solar concentrators.
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Metal halide perovskites have emerged as versatile photocatalysts to convert solar energy for chemical processes. Perovskite photocatalyzed polymerization draws special attention due to its straightforward synthesis process and the ability to create advanced perovskite-polymer nanocomposites. Herein, this work employs Cs3Sb2Br9 perovskite nanoparticles (NPs) as a lead-free photocatalyst for light-controlled atom transfer radical polymerization (ATRP). Cs3Sb2Br9 NPs exhibit high reduction potential and interact with electronegative bromide initiator with Lewis acid Sb sites, enabling efficient photoinduced reduction of initiators and controlled polymerization under blue light irradiation. Methacrylate monomers with various functional groups are successfully polymerized, and the resulting polymer showcased a dispersity (D) as small as 1.27. The living nature of polymerization is confirmed by high chain end fidelity and kinetic studies. Moreover, Cs3Sb2Br9 NPs serve as heterogeneous photocatalysts, demonstrating recyclability and reusability for up to four cycles. This work presents a promising approach to overcome the limitations of lead-based perovskites in photoinduced controlled radical polymerization, offering a sustainable and efficient alternative for the synthesis of well-defined polymeric materials.
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Antimônio , Compostos de Cálcio , Nanopartículas , Óxidos , Polimerização , Titânio , Titânio/química , Óxidos/química , Catálise , Compostos de Cálcio/química , Nanopartículas/química , Antimônio/química , Processos Fotoquímicos , LuzRESUMO
Circular RNAs are a class of noncoding RNAs with covalently linked 5' and 3' ends that arise from backsplicing events. The absence of a 5' cap and a 3' poly(A) tail makes circular RNAs relatively more stable than their linear counterparts. They are evolutionary conserved and tissue-specific, and some show disease-specific expression patterns. Although their biological functions remain largely unknown, circular RNAs have been shown to play regulatory roles by acting as microRNA sponges, regulators of RNA-binding proteins, alternative splicing, and parental gene expression, and they could even encode proteins. Over the past few decades, circular RNAs have attracted wide attention in oncology owing to their implications in various tumors. Many circular RNAs have been characterized as key players in gastrointestinal cancers and influence cancer growth, progression, metastasis, and therapeutic resistance. Accumulating evidence reveals that their unique characteristics, coupled with their critical roles in tumorigenesis, make circular RNAs promising non-invasive clinical biomarkers for gastrointestinal cancers. In the present review, we summarized the biological roles of the emerging circular RNAs and their potential as biomarkers and therapeutic targets, which may help better understand their clinical significance in the management of gastrointestinal cancers.
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Biomarcadores Tumorais , Neoplasias Gastrointestinais , RNA Circular , RNA , Humanos , Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Neoplasias Gastrointestinais/patologia , RNA Circular/genética , RNA Circular/fisiologia , RNA Circular/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , RNA/genética , Terapia de Alvo Molecular , MicroRNAs/genética , MicroRNAs/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Processamento Alternativo/genética , Progressão da DoençaRESUMO
BACKGROUND: Pregnancy toxemia is a common disease, which occurs in older does that are pregnant with multiple lambs in the third trimester. Most of the sick goats die within a few days, which can seriously impact the economic benefits of goat breeding enterprises. The disease is believed to be caused by malnutrition, stress, and other factors, that lead to the disorder of lipid metabolism, resulting in increased ketone content, ketosis, ketonuria, and neurological symptoms. However, the changes in gut microbes and their metabolism in this disease are still unclear. The objective of this experiment was to evaluate the effect of toxemia of pregnancy on the fecal microbiome and metabolomics of does. RESULTS: Eight pregnant does suspected of having toxemia of pregnancy (PT group) and eight healthy does during the same pregnancy (NC group) were selected. Clinical symptoms and pathological changes at necropsy were observed, and liver tissue samples were collected for pathological sections. Jugular venous blood was collected before morning feeding to detect biochemical indexes. Autopsy revealed that the liver of the pregnancy toxemia goat was enlarged and earthy yellow, and the biochemical results showed that the serum levels of aspartate aminotransferase (AST) and ß-hydroxybutyric acid (B-HB) in the PT group were significantly increased, while calcium (Ca) levels were significantly reduced. Sections showed extensive vacuoles in liver tissue sections. The microbiome analysis found that the richness and diversity of the PT microbiota were significantly reduced. Metabolomic analysis showed that 125 differential metabolites were screened in positive ion mode and enriched in 12 metabolic pathways. In negative ion mode, 100 differential metabolites were screened and enriched in 7 metabolic pathways. CONCLUSIONS: Evidence has shown that the occurrence of pregnancy toxemia is related to gut microbiota, and further studies are needed to investigate its pathogenesis and provide research basis for future preventive measures of this disease.
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Doenças das Cabras , Microbiota , Pré-Eclâmpsia , Doenças dos Ovinos , Toxemia , Feminino , Gravidez , Ovinos , Animais , Pré-Eclâmpsia/veterinária , Cabras/metabolismo , Toxemia/veterinária , Metaboloma , Metabolômica , Carneiro Doméstico/metabolismo , RNA Ribossômico 16SRESUMO
Stimulated Raman Adiabatic Passage (STIRAP) and its variants, such as M-type chainwise-STIRAP, allow for efficiently transferring the populations in a multilevel system and have widely been used to prepare molecules in their rovibrational ground state. However, their transfer efficiencies are generally imperfect. The main obstacle is the presence of losses and the requirement to make the dynamics adiabatic. To this end, in the present paper, a new theoretical method is proposed for the efficient and robust creation and detection of deeply bound molecules in three-level Λ-type and five-level M-type systems via "Invariant-based shortcut-to-adiabaticity." In the regime of large detunings, we first reduce the dynamics of three- and five-level molecular systems to those of effective two- and three-level counterparts. By doing so, the major molecular losses from the excited states can be well suppressed. Consequently, the effective two-level counterpart can be directly compatible with two different "Invariant-based Inverse Engineering" protocols; the results show that both protocols give a comparable performance and have a good experimental feasibility. For the effective three-level counterpart, by considering a relation among the four incident pulses, we show that this model can be further generalized to an effective Λ-type one with the simplest resonant coupling. This generalized model permits us to borrow the "Invariant-based Inverse Engineering" protocol from a standard three-level Λ-type system to a five-level M-type system. Numerical calculations show that the weakly bound molecules can be efficiently transferred to their deeply bound states without strong laser pulses, and the stability against parameter variations is well preserved. Finally, the detection of ultracold deeply bound molecules is discussed.
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In this paper, an exact analytical solution is presented for achieving coherent population transfer and creating arbitrary coherent superposition states in a five-state chainwise system by a train of coincident pulses. We show that the solution of a five-state chainwise system can be reduced to an equivalent three-state Λ-type one with the simplest resonant coupling under the assumption of adiabatic elimination together with a requirement of the relation among the four coincident pulses. In this method, the four coincident pulses at each step all have the same time dependence, but with specific magnitudes. The results show that, by using a train of appropriately coincident pulses, this technique not only enables complete population transfer, but also creates any desired coherent superposition between the initial and final states, while the population in all intermediate states is effectively suppressed. Furthermore, this technique can also exhibit a one-way population transfer behavior. The results are of potential interest in applications where high-fidelity multi-state quantum control is essential, e.g., quantum information, atom optics, formation of ultracold molecules, cavity QED, nuclear coherent population transfer, and light transfer in waveguide arrays.
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KEY MESSAGE: Sl-lncRNA20718 acts as an eTM of Sl-miR6022 regulating its expression thereby affecting SlRLP6/10 expression. SlRLP6/10 regulate PRs expression, ROS accumulation, and JA/ET content thereby affecting tomato resistance to P. infestans. Tomato (Solanum lycopersicum) is an important horticultural and cash crop whose yield and quality can be severely affected by Phytophthora infestans (P. infestans). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are widely involved in plant defense responses against pathogens. The involvement of Sl-lncRNA20718 and Sl-miR6022 in tomato resistance to P. infestans as well as the targeting of Sl-miR6022 to receptor-like protein genes (RLPs) were predicted in our previous study. However, uncertainty exists regarding their potential interaction as well as the molecular processes regulating tomato resistance. Here, we found that Sl-lncRNA20718 and Sl-miR6022 are positive and negative regulators of tomato resistance to P. infestans by gain- and loss-of-function experiments, respectively. Overexpression of Sl-lncRNA20718 decreased the expression of Sl-miR6022, induced the expression of PRs, reduced the diameter of lesions (DOLs), thereby enhanced disease resistance. A six-point mutation in the binding region of Sl-lncRNA20718 to Sl-miR6022 disabled the interaction, indicating that Sl-lncRNA20718 acts as an endogenous target mimic (eTM) of Sl-miR6022. We demonstrated that Sl-miR6022 cleaves SlRLP6/10. Overexpression of Sl-miR6022 decreases the expression levels of SlRLP6/10, induces the accumulation of reactive oxygen species (ROS) and reduces the content of JA and ET, thus inhibiting tomato resistance to P. infestans. In conclusion, our study provides detailed information on the lncRNA20718-miR6022-RLPs module regulating tomato resistance to P. infestans by affecting the expression of disease resistance-related genes, the accumulation of ROS and the phytohormone levels, providing a new reference for tomato disease resistance breeding.
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Resistência à Doença , MicroRNAs , Phytophthora infestans , RNA Longo não Codificante , Solanum lycopersicum , Resistência à Doença/genética , Phytophthora infestans/patogenicidade , Melhoramento Vegetal , Espécies Reativas de Oxigênio , Solanum lycopersicum/genética , Solanum lycopersicum/microbiologia , MicroRNAs/genética , RNA Longo não Codificante/genética , Doenças das PlantasRESUMO
Diabetic kidney disease (DKD), a chronic kidney disease, is characterized by progressive fibrosis caused due to persistent hyperglycemia. The development of fibrosis in DKD determines the patient prognosis, but no particularly effective treatment. Here, small extracellular vesicles derived from mesenchymal stem cells (MSC-sEV) have been used to treat DKD fibrosis. Single-cell RNA sequencing was used to analyze 27,424 cells of the kidney, we have found that a novel fibrosis-associated TGF-ß1+Arg1+ macrophage subpopulation, which expanded and polarized in DKD and was noted to be profibrogenic. Additionally, Actin+Col4a5+ mesangial cells in DKD differentiated into myofibroblasts. Multilineage ligand-receptor and cell-communication analysis showed that fibrosis-associated macrophages activated the TGF-ß1/Smad2/3/YAP signal axis, which promotes mesangial fibrosis-like change and accelerates renal fibrosis niche. Subsequently, the transcriptome sequencing and LC-MS/MS analysis indicated that MSC-sEV intervention could restore the levels of the kinase ubiquitin system in DKD and attenuate renal interstitial fibrosis via delivering CK1δ/ß-TRCP to mediate YAP ubiquitination degradation in mesangial cells. Our findings demonstrate the unique cellular and molecular mechanisms of MSC-sEV in treating the DKD fibrosis niche at a single-cell level and provide a novel therapeutic strategy for renal fibrosis.
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Nefropatias Diabéticas , Vesículas Extracelulares , Fibrose , Células-Tronco Mesenquimais , Análise de Célula Única , Transcriptoma , Vesículas Extracelulares/metabolismo , Células-Tronco Mesenquimais/metabolismo , Animais , Camundongos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/terapia , Masculino , Camundongos Endogâmicos C57BL , Humanos , Macrófagos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Células Mesangiais/metabolismo , Rim/patologia , Rim/metabolismoRESUMO
Myocardial infarction (MI) is one of the leading causes of death. This is attributed to the dramatic changes in the myocardial microenvironment post-MI. Therefore, effective intervention in the early stages of MI is significant for inhibiting its progression and improving cardiac function. Herein, an injectable composite hydrogel scaffold (Gel-pBP@Mg) was developed by integrating magnesium (Mg)-modified black phosphorus nanosheets (pBP@Mg) into a reactive oxygen species-responsive hydrogel (Gel). This loose and porous Gel provides a natural platform for carrying pBP@Mg. In situ, sustained release of pBP@Mg is achieved via responsive ROS degradation in the infarct site. The high ROS reactivity of Black phosphorus nanosheets (BPNSs) can effectively inhibit the progression of oxidative stress in the infarct area and reduce inflammatory response by down-regulating the NF-κB pathway. Additionally, the sustained release of Mg loaded on the surface of BPNSs can effectively promote angiogenesis in MI, which is significant for the long-term prognosis after infarction. Our developed Gel-pBP@Mg effectively blocked infarction progression and improved myocardial function by sustainably inhibiting the "oxidative stress-inflammation" reaction chain and pro-angiogenesis. This study reveals Gel-pBP@Mg composite therapeutic potential in treating MI through In vitro and In vivo studies, providing a promising modality for MI treatment.
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Antioxidantes , Infarto do Miocárdio , Estresse Oxidativo , Fósforo , Espécies Reativas de Oxigênio , Animais , Masculino , Camundongos , Angiogênese , Antioxidantes/farmacologia , Antioxidantes/química , Hidrogéis/química , Magnésio/química , Magnésio/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Nanoestruturas/química , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fósforo/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
BACKGROUND: Population aging is accelerating, particularly in Asian countries. Falls are the leading cause of unintentional injuries in the elderly over 60 years old in China. Hence, it is crucial to anticipate the risk factors associated with fall risk. We aimed to explore whether oral frailty and fall risk were reciprocally related and whether nutrition mediated their association. METHODS: From October 2022 to March 2023, a total of 409 elderly individuals from the Yangzhou community were selected using the convenience sampling method. Cross-sectional data on older adults' oral frailty, nutrition, and fall risk were collected using questionnaires. Data analysis was performed using SPSS 27.0 and PROCESS macro. RESULTS: The fall risk score was 1.0 (ranging from 0 to 4.0), with 107 cases (26.2%) identified as being at risk of falling. Spearman correlation analysis revealed a positive correlation between oral frailty and the risk of falls (rs = 0.430, P < 0.01). Nutrition was found to have a negative correlation with both oral frailty and fall risk (rs=-0.519ã-0.457, P < 0.01). When controlling for covariates, it was observed that nutrition mediated the relationship between oral frailty and falls. The mediating effect value accounted for 48.8% of the total effect (P < 0.01). CONCLUSIONS: Oral frailty was significantly associated with fall risk, and nutrition might be a mediating factor for adverse effects of oral frailty and fall risk. Enhancing the nutrition of older individuals is a vital approach to mitigating fall risk among those with oral frailty.