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The microtubule-associated protein tau oligomerizes, but the actions of oligomeric tau (oTau) are unknown. We have used Cry2-based optogenetics to induce tau oligomers (oTau-c). Optical induction of oTau-c elicits tau phosphorylation, aggregation, and a translational stress response that includes stress granules and reduced protein synthesis. Proteomic analysis identifies HNRNPA2B1 as a principle target of oTau-c. The association of HNRNPA2B1 with endogenous oTau was verified in neurons, animal models, and human Alzheimer brain tissues. Mechanistic studies demonstrate that HNRNPA2B1 functions as a linker, connecting oTau with N6-methyladenosine (m6A) modified RNA transcripts. Knockdown of HNRNPA2B1 prevents oTau or oTau-c from associating with m6A or from reducing protein synthesis and reduces oTau-induced neurodegeneration. Levels of m6A and the m6A-oTau-HNRNPA2B1 complex are increased up to 5-fold in the brains of Alzheimer subjects and P301S tau mice. These results reveal a complex containing oTau, HNRNPA2B1, and m6A that contributes to the integrated stress response of oTau.
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Adenosina/análogos & derivados , Doença de Alzheimer/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Processamento Pós-Transcricional do RNA , RNA/metabolismo , Proteínas tau/metabolismo , Adenosina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Progressão da Doença , Feminino , Células HEK293 , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Humanos , Masculino , Metilação , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Agregados Proteicos , Agregação Patológica de Proteínas , RNA/genética , Índice de Gravidade de Doença , Proteínas tau/genéticaRESUMO
Voltage oscillation at subzero in sodium-ion batteries (SIBs) has been a common but overlooked scenario, almost yet to be understood. For example, the phenomenon seriously deteriorates the performance of Na3V2(PO4)3 (NVP) cathode in PC (propylene carbonate)/EC (ethylene carbonate)-based electrolyte at -20 °C. Here, the correlation between voltage oscillation, structural evolution, and electrolytes has been revealed based on theoretical calculations, in-/ex-situ techniques, and cross-experiments. It is found that the local phase transition of the Na3V2(PO4)3 (NVP) cathode in PC/EC-based electrolyte at -20 °C should be responsible for the oscillatory phenomenon. Furthermore, the low exchange current density originating from the high desolvation energy barrier in NVP-PC/EC system also aggravates the local phase transformation, resulting in severe voltage oscillation. By introducing the diglyme solvent with lower Na-solvent binding energy, the voltage oscillation of the NVP can be eliminated effectively at subzero. As a result, the high capacity retentions of 98.3% at -20 °C and 75.3% at -40 °C are achieved. The finding provides insight into the abnormal SIBs degradation and brings the voltage oscillation behavior of rechargeable batteries into the limelight.
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High-performance sodium storage at low temperature is urgent with the increasingly stringent demand for energy storage systems. However, the aggravated capacity loss is induced by the sluggish interfacial kinetics, which originates from the interfacial Na+ desolvation. Herein, all-fluorinated anions with ultrahigh electron donicity, trifluoroacetate (TFA-), are introduced into the diglyme (G2)-based electrolyte for the anion-reinforced solvates in a wide temperature range. The unique solvation structure with TFA- anions and decreased G2 molecules occupying the inner sheath accelerates desolvation of Na+ to exhibit decreased desolvation energy from 4.16 to 3.49 kJ mol-1 and 24.74 to 16.55 kJ mol-1 beyond and below -20 °C, respectively, compared with that in 1.0 M NaPF6-G2. These enable the cell of Na||Na3V2(PO4)3 to deliver 60.2% of its room-temperature capacity and high capacity retention of 99.2% after 100 cycles at -40 °C. This work highlights regulation of solvation chemistry for highly stable sodium-ion batteries at low temperature.
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The plant cuticle, a structure primarily composed of wax and cutin, forms a continuous coating over most aerial plant surfaces. The cuticle plays important roles in plant tolerance to environmental stress, including stress imposed by drought. Some members of the 3-KETOACYL-COA SYNTHASE (KCS) family are known to act as metabolic enzymes involved in cuticular wax production. Here we report that Arabidopsis (Arabidopsis thaliana) KCS3, which was previously shown to lack canonical catalytic activity, instead functions as a negative regulator of wax metabolism by reducing the enzymatic activity of KCS6, a key KCS involved in wax production. We demonstrate that the role of KCS3 in regulating KCS6 activity involves physical interactions between specific subunits of the fatty acid elongation complex and is essential for maintaining wax homeostasis. We also show that the role of the KCS3-KCS6 module in regulating wax synthesis is highly conserved across diverse plant taxa from Arabidopsis to the moss Physcomitrium patens, pointing to a critical ancient and basal function of this module in finely regulating wax synthesis.
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Proteínas de Arabidopsis , Arabidopsis , Arabidopsis/metabolismo , Mutação , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismoRESUMO
DNA-RNA hybrids play various roles in many physiological progresses, but how this chromatin structure is dynamically regulated during spermatogenesis remains largely unknown. Here, we show that germ cell-specific knockout of Rnaseh1, a specialized enzyme that degrades the RNA within DNA-RNA hybrids, impairs spermatogenesis and causes male infertility. Notably, Rnaseh1 knockout results in incomplete DNA repair and meiotic prophase I arrest. These defects arise from the altered RAD51 and DMC1 recruitment in zygotene spermatocytes. Furthermore, single-molecule experiments show that RNase H1 promotes recombinase recruitment to DNA by degrading RNA within DNA-RNA hybrids and allows nucleoprotein filaments formation. Overall, we uncover a function of RNase H1 in meiotic recombination, during which it processes DNA-RNA hybrids and facilitates recombinase recruitment.
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Meiose , Ribonuclease H , Humanos , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , DNA/genética , DNA/metabolismo , Rad51 Recombinase/genética , Rad51 Recombinase/metabolismo , Recombinases/genética , Espermatócitos/metabolismo , Ribonuclease H/metabolismoRESUMO
Despite the need in various applications, accurate quantification of nucleic acids still remains a challenge. The widely-used qPCR has reduced accuracy at ultralow template concentration and is susceptible to nonspecific amplifications. The more recently developed dPCR is costly and cannot handle high-concentration samples. We combine the strengths of qPCR and dPCR by performing PCR in silicon-based microfluidic chips and demonstrate high quantification accuracy in a large concentration range. Importantly, at low template concentration, we observe on-site PCR (osPCR), where only certain sites of the channel show amplification. The sites have almost identical ct values, showing osPCR is a quasi-single molecule phenomenon. Using osPCR, we can measure both the ct values and the absolute concentration of templates in the same reaction. Additionally, osPCR enables identification of each template molecule, allowing removal of nonspecific amplification during quantification and greatly improving quantification accuracy. We develop sectioning algorithm that improves the signal amplitude and demonstrate improved detection of COVID in patient samples.
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Teste para COVID-19 , Reação em Cadeia da Polimerase , Humanos , COVID-19 , DNA/genética , MicrofluídicaRESUMO
Cervical cancer (CC) is one of the most common malignant tumors in gynecology. Immunotherapy and targeted therapy are two particularly effective treatments. In this study, weighted gene co-expression network analysis and CIBERSORT algorithm that quantifies the composition of immune cells were used to analyze CC expression data based on the GEO database and identify modules related to T cells. Five candidate hub genes were identified by tumor-infiltrating immune cells estimation and Kaplan-Meier survival analysis according to CC data from The Cancer Genome Atlas (TCGA). Chemotherapeutic response, methylation, and gene mutation analyses were implemented so that the five candidate hub genes identified may be the potential biomarkers and therapeutic targets which were related to T cell infiltration. Moreover, the results of RT-qPCR revealed that CD48 was a tumor suppressor gene, which was negatively correlated with CC stages, lymph node metastasis, and differentiation. Furthermore, the functional study verified that the interference of CD48 was able to boost the proliferation and migration ability in vitro and the growth of transplanted tumors in vivo. Overall, we identified molecular targets related to immune infiltration and prognosis, regarded CD48 as a key molecule involved in the progression of CC, thus providing new insights into the development of molecular therapy and immunotherapeutics against CC.
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Neoplasias do Colo do Útero , Feminino , Humanos , Algoritmos , Diferenciação Celular , Proliferação de Células/genética , Prognóstico , Microambiente Tumoral/genética , Neoplasias do Colo do Útero/genéticaRESUMO
Organic carbonyl electrode materials have shown great promise for high-performance lithium batteries due to their high capacity, renewability, and environmental friendliness. However, their practical application is hindered by the high solubility of these materials in traditional electrolytes, leading to poor cycling stability and serious shuttle effects. Here, we develop a series of hydrofluoroethers (HFEs) with weak electrostatic interaction toward organic carbonyl cathode materials, aiming to address the dissolution issue and achieve high cycling stability in lithium batteries. Theoretical calculations reveal that the electrostatic interactions between HFEs and pyrene-4,5,9,10-tetraone (PTO) are significantly weaker compared with common solvents such as 1,2-dimethoxyethane. Consequently, the dissolution of PTO in the HFE-based electrolyte is remarkably reduced, as observed by in situ ultraviolet-visible spectra. Notably, when using the electrolyte based on 1,1,1,3,3,3-hexafluoro-2-methoxypropane with a certain coordination ability, PTO exhibits excellent cycling stability with a high capacity retention of 78% after 1000 cycles. This work proposes the regulation of electrostatic interactions to inhibit the dissolution of organic carbonyl cathode materials and significantly enhance their cycle life.
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Cancer metastasis poses significant challenges in current clinical therapy. Osthole (OST) has demonstrated efficacy in treating cervical cancer and inhibiting metastasis. Despite these positive results, its limited solubility, poor oral absorption, low bioavailability, and photosensitivity hinder its clinical application. To address this limitation, a glutathione (GSH)-responded nano-herb delivery system (HA/MOS@OST&L-Arg nanoparticles, HMOA NPs) is devised for the targeted delivery of OST with cascade-activatable nitric oxide (NO) release. The HMOA NPs system is engineered utilizing enhanced permeability and retention (EPR) effects and active targeting mediated by hyaluronic acid (HA) binding to glycoprotein CD44. The cargoes, including OST and L-Arginine (L-Arg), are released rapidly due to the degradation of GSH-responsive mesoporous organic silica (MOS). Then abundant reactive oxygen species (ROS) are produced from OST in the presence of high concentrations of NAD(P)H quinone oxidoreductase 1 (NQO1), resulting in the generation of NO and subsequently highly toxic peroxynitrite (ONOO-) by catalyzing guanidine groups of L-Arg. These ROS, NO, and ONOO- molecules have a direct impact on mitochondrial function by reducing mitochondrial membrane potential and inhibiting adenosine triphosphate (ATP) production, thereby promoting increased apoptosis and inhibiting metastasis. Overall, the results indicated that HMOA NPs has great potential as a promising alternative for the clinical treatment of cervical cancer.
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ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for 2 weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum, left ventricle posterior wall diastole, and left ventricular posterior wall systole were significantly increased, and ejection fraction was decreased compared with control mice. Masson and Wheat Germ Agglutinin staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes, we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and neonatal rat cardiomyocytes. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase in dynamin-associated protein 1 (Drp1) phosphorylation at S616 and decrease in Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.
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Compostos Benzidrílicos , Cardiomegalia , Glucosídeos , Dinâmica Mitocondrial , Ratos , Camundongos , Masculino , Animais , Isoproterenol/farmacologia , Camundongos Endogâmicos C57BL , Cardiomegalia/metabolismo , Miócitos CardíacosRESUMO
To leverage complementary mechanisms for cancer cell removal, we developed a novel cell engineering and therapeutic strategy co-opting phagocytic clearance and antigen presentation activity into T cells. We engineered a chimeric engulfment receptor (CER)-1236, which combines the extracellular domain of TIM-4, a phagocytic receptor recognizing the "eat me" signal phosphatidylserine, with intracellular signaling domains (TLR2/TIR, CD28, and CD3ζ) to enhance both TIM-4-mediated phagocytosis and T cell cytotoxic function. CER-1236 T cells demonstrate target-dependent phagocytic function and induce transcriptional signatures of key regulators responsible for phagocytic recognition and uptake, along with cytotoxic mediators. Pre-clinical models of mantle cell lymphoma (MCL) and EGFR mutation-positive non-small cell lung cancer (NSCLC) demonstrate collaborative innate-adaptive anti-tumor immune responses both in vitro and in vivo. Treatment with BTK (MCL) and EGFR (NSCLC) inhibitors increased target ligand, conditionally driving CER-1236 function to augment anti-tumor responses. We also show that activated CER-1236 T cells exhibit superior cross-presentation ability compared with conventional T cells, triggering E7-specific TCR T responses in an HLA class I- and TLR-2-dependent manner, thereby overcoming the limited antigen presentation capacity of conventional T cells. Therefore, CER-1236 T cells have the potential to achieve tumor control by eliciting both direct cytotoxic effects and indirect-mediated cross-priming.
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Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adulto , Linfócitos T , Apresentação Cruzada , Fosfatidilserinas , Antígenos de Neoplasias , Receptores ErbB , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
The investigation of atmospheric aerosols holds paramount importance within the environmental realm. This significance arises from the intricate nature of aerosol distribution and size in real-life hazy weather conditions. In this work, we have employed the equivalent radius of the aerosols in haze weather obtained from the volume spectrum, and then the scattering characteristics of these aerosols are obtained using the equivalent radius. Pearson correlation coefficients have been used for revealing a strong correlation by comparing Aeronet website data and simulation results with a minimum value of 0.657.
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Forsythia suspensa tea is a popular traditional Chinese medicine decoction for its healthy and therapeutic benefits. However, its effects in bone metabolism were not clear. In recent study, we uncovered anti-osteoclastogenesis property of Phillygenin (Phi), a compound abundant in Forsythia suspensa leaves, and aimed to investigate the effect and mechanism of Phi on bone metabolism in vivo and in vitro. Lipopolysaccharides-induced murine calvaria osteolysis and ovariectomy-induced bone loss animal models were used to identify the bone-protective effect of Phi in vivo and micro-CT, pQCT, and TRAP staining were applied. We used CCK8, TUNEL, BrdU, and TRAP staining to evaluate the efficacy of Phi on the proliferation and formation of OCs in primary mBMMs. RNA sequence, activity-based protein profiling, molecular docking, G-LISA, and WB were used to inspect the target and underlying mechanism of Phi's actions in mBMMs. We found Phi significantly inhibited bone resorption in vivo and inhibited mBMMs osteoclastogenesis in vitro. Ras homolog gene family member A (RhoA) was identified as the direct target of Phi. It counteracted the effects of RhoA activator and acted as a RhoA inhibitor. By targeting RhoA, Phi modulated Rho-associated coiled-coil containing protein kinase 1 (ROCK1) activity and regulated its downstream NF-κB/NFATc1/c-fos pathway. Furthermore, Phi depressed the disassembling of F-actin ring through cofilin and myosin1a. Our findings provided Phi as a potential option for treating bone loss diseases by targeting RhoA and highlighted the importance of F. suspensa as a preventive approach in bone disorders.
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Doenças Ósseas Metabólicas , Reabsorção Óssea , Lignanas , Osteólise , Animais , Feminino , Camundongos , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/prevenção & controle , Diferenciação Celular , Lignanas/farmacologia , Simulação de Acoplamento Molecular , NF-kappa B/metabolismo , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/farmacologia , Osteoclastos , Osteogênese , Osteólise/induzido quimicamenteRESUMO
Albinism is characterized by a variable degree of hypopigmentation affecting the skin and the hair, and causing ophthalmologic abnormalities. Its oculocutaneous, ocular and syndromic forms follow an autosomal or X-linked recessive mode of inheritance, and 22 disease-causing genes are implicated in their development. Our aim was to clarify the genetic background of a Hungarian albinism cohort. Using a 22-gene albinism panel, the genetic background of 11 of the 17 Hungarian patients was elucidated. In patients with unidentified genetic backgrounds (n = 6), whole exome sequencing was performed. Our investigations revealed a novel, previously unreported rare variant (N687S) of the two-pore channel two gene (TPCN2). The N687S variant of the encoded TPC2 protein is carried by a 15-year-old Hungarian male albinism patient and his clinically unaffected mother. Our segregational analysis and in vitro functional experiments suggest that the detected novel rare TPCN2 variant alone is not a disease-causing variant in albinism. Deep genetic analyses of the family revealed that the patient also carries a phenotype-modifying R305W variant of the OCA2 protein, and he is the only family member harboring this genotype. Our results raise the possibility that this digenic combination might contribute to the observed differences between the patient and the mother, and found the genetic background of the disease in his case.
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Albinismo , Proteínas de Membrana Transportadoras , Humanos , Masculino , Adolescente , Hungria , Mutação , Proteínas de Membrana Transportadoras/metabolismo , Albinismo/genética , Patrimônio GenéticoRESUMO
Sodium dual-ion batteries (Na-DIBs) have attracted increasing attention due to their high operative voltages and low-cost raw materials. However, the practical applications of Na-DIBs are still hindered by the issues, such as low capacity and poor Coulombic efficiency, which is highly correlated with the compatibility between electrode and electrolyte but rarely investigated. Herein, fluoroethylene carbonate (FEC) is introduced into the electrolyte to regulate cation/anion solvation structure and the stability of cathode/anode-electrolyte interphase of Na-DIBs. The FEC modulates the environment of PF6 - solvation sheath and facilitates the interaction of PF6 - on graphite. In addition, the NaF-rich interphase caused by the preferential decomposition of FEC effectively inhibits side reactions and pulverization of anodes with the electrolyte. Consequently, Sb||graphite full cells in FEC-containing electrolyte achieve an improved capacity, cycling stability and Coulombic efficiency. This work elucidates the underlying mechanism of bifunctional FEC and provides an alternative strategy of building high-performance dual ion batteries.
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Suppressor of cytokine signalling (SOCS) 1/2/3/4 are involved in the occurrence and progression of multiple malignancies; however, their prognostic and developmental value in patients with glioblastoma (GBM) remains unclear. The present study used TCGA, ONCOMINE, SangerBox3.0, UALCAN, TIMER2.0, GENEMANIA, TISDB, The Human Protein Atlas (HPA) and other databases to analyse the expression profile, clinical value and prognosis of SOCS1/2/3/4 in GBM, and to explore the potential development mechanism of action of SOCS1/2/3/4 in GBM. The majority of analyses showed that SOCS1/2/3/4 transcription and translation levels in GBM tissues were significantly higher than those in normal tissues. qRT-PCR, western blotting (WB) and immunohistochemical staining were used to verify that SOCS3 was expressed at higher mRNA and protein levels in GBM than in normal tissues or cells. High SOCS1/2/3/4 mRNA expression was associated with poor prognosis in patients with GBM, especially SOCS3. SOCS1/2/3/4 were highly contraindicated, which had few mutations, and were not associated with clinical prognosis. Furthermore, SOCS1/2/3/4 were associated with the infiltration of specific immune cell types. In addition, SOCS3 may affect the prognosis of patients with GBM through JAK/STAT signalling pathway. Analysis of the GBM-specific protein interaction (PPI) network showed that SOCS1/2/3/4 were involved in multiple potential carcinogenic mechanisms of GBM. In addition, colony formation, Transwell, wound healing and western blotting assays revealed that inhibition of SOCS3 decreased the proliferation, migration and invasion of GBM cells. In conclusion, the present study elucidated the expression profile and prognostic value of SOCS1/2/3/4 in GBM, which may provide potential prognostic biomarkers and therapeutic targets for GBM, especially SOCS3.
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Glioblastoma , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas , Prognóstico , Proteínas Supressoras da Sinalização de Citocina/genética , Proteínas Supressoras da Sinalização de Citocina/metabolismo , RNA Mensageiro/metabolismo , BiomarcadoresRESUMO
This study aimed to build a comprehensive model for predicting the overall survival (OS) of cervical cancer patients who received standard treatments and to build a series of new stages based on the International Federation of Gynecologists and Obstetricians (FIGO) stages for better such predictions. We collected the cervical cancer patients diagnosed since the year 2000 from the Surveillance, Epidemiology, and End Results (SEER) database. Cervical cancer patients who received radiotherapy or surgery were included. Log-rank tests and Cox regression were used to identify potential factors of OS. Bayesian networks (BNs) were built to predict 3- and 5-year survival. We also grouped the patients into new stages by clustering their 5-year survival probabilities based on FIGO stage, age, and tumor differentiation. Cox regression suggested black ethnicity, adenocarcinoma, and single status as risks for poorer prognosis, in addition to age and stage. A total of 43,749 and 39,333 cases were finally eligible for the 3- and 5-year BNs, respectively, with 11 variables included. Cluster analysis and Kaplan-Meier curves indicated that it was best to divide the patients into nine modified stages. The BNs had excellent performance, with area under the curve and maximum accuracy of 0.855 and 0.804 for 3-year survival, and 0.851 and 0.787 for 5-year survival, respectively. Thus, BNs are excellent candidates for predicting cervical cancer survival. It is necessary to consider age and tumor differentiation when estimating the prognosis of cervical cancer using FIGO stages.
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Adenocarcinoma , Neoplasias do Colo do Útero , Feminino , Humanos , Neoplasias do Colo do Útero/patologia , Estadiamento de Neoplasias , Teorema de Bayes , Prognóstico , Adenocarcinoma/patologiaRESUMO
Structure elucidation of unknown compounds based on nuclear magnetic resonance (NMR) remains a challenging problem in both synthetic organic and natural product chemistry. Library matching has been an efficient method to assist structure elucidation. However, it is limited by the coverage of libraries. In addition, prior knowledge such as molecular fragments is neglected. To solve the problem, we propose a conditional molecular generation net (CMGNet) to allow input of multiple sources of information. CMGNet not only uses 13C NMR spectrum data as input but molecular formulas and fragments of molecules are also employed as input conditions. Our model applies large-scale pretraining for molecular understanding and fine-tuning on two NMR spectral data sets of different granularity levels to accommodate structure elucidation tasks. CMGNet generates structures based on 13C NMR data, molecular formula, and fragment information, with a recovery rate of 94.17% in the top 10 recommendations. In addition, the generative model performed well in the generation of various classes of compounds and in the structural revision task. CMGNet has a deep understanding of molecular connectivities from 13C NMR, molecular formula, and fragments, paving the way for a new paradigm of deep learning-assisted inverse problem-solving.
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Corannulene (Cor), a special carbon material, evidenced strong protein binding capacity which regulating lysozyme crystallization and controlling reactive oxygen species (ROS) generation. Ion channel protein play role in regulating ion channel functions to affect physiological functions. However, the interaction between Cor and ion channel protein have not been studied. In this study, PEG/Cor nanoparticles (PEG/Cor Nps) were prepared by mPEG-DSPE. The PEG/Cor Nps localized in cytoplasm and produced cytotoxicity at high concentration. Whole cell patch clamp examined ion channel functions after incubate PEG/Cor Nps with PC-12 cell. we found that PEG/Cor Nps inhibited voltage-gated Na+ ion channels in a dose- and time-dependent manner but not act on voltage-gated K+ ion channels. The potential mechanisms were revealed by all-atom molecular dynamic (MD) simulations. The results showed that PEG/Cor Nps block the pore of sodium ion channel protein due to dose- and time-dependent accumulation. Besides, the orientation angle (θ) configuration of PEG/Cor Nps will be inverted with the accumulation to generate two blocking mechanisms. Different from other carbon nanomaterials, the blockage mechanism of PEG/Cor Nps provides novel insights into the mechanisms of interaction between carbon nanomaterials and protein.
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Hidrocarbonetos Policíclicos Aromáticos , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Sódio Disparados por Voltagem , Ligação ProteicaRESUMO
Understanding the direct interaction of nanostructures per se with biological systems is important for biomedical applications. However, whether nanostructures regulate biological systems by targeting specific cellular proteins remains largely unknown. In the present work, self-assembling nanomicelles are constructed using small-molecule oleanolic acid (OA) as a molecular template. Unexpectedly, without modifications by functional ligands, OA nanomicelles significantly activate cellular proteasome function by directly binding to 20S proteasome subunit alpha 6 (PSMA6). Mechanism study reveals that OA nanomicelles interact with PSMA6 to dynamically modulate its N-terminal domain conformation change, thereby controlling the entry of proteins into 20S proteasome. Subsequently, OA nanomicelles accelerate the degradation of several crucial proteins, thus potently driving cancer cell pyroptosis. For translational medicine, OA nanomicelles exhibit a significant anticancer potential in tumor-bearing mouse models and stimulate immune cell infiltration. Collectively, this proof-of-concept study advances the mechanical understanding of nanostructure-guided biological effects via their inherent capacity to activate proteasome.