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Polar bears are uniquely adapted to life in the High Arctic and have undergone drastic physiological changes in response to Arctic climates and a hyper-lipid diet of primarily marine mammal prey. We analyzed 89 complete genomes of polar bear and brown bear using population genomic modeling and show that the species diverged only 479-343 thousand years BP. We find that genes on the polar bear lineage have been under stronger positive selection than in brown bears; nine of the top 16 genes under strong positive selection are associated with cardiomyopathy and vascular disease, implying important reorganization of the cardiovascular system. One of the genes showing the strongest evidence of selection, APOB, encodes the primary lipoprotein component of low-density lipoprotein (LDL); functional mutations in APOB may explain how polar bears are able to cope with life-long elevated LDL levels that are associated with high risk of heart disease in humans.
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Evolução Biológica , Ursidae/classificação , Ursidae/genética , Adaptação Fisiológica , Tecido Adiposo/metabolismo , Animais , Apolipoproteínas B/química , Apolipoproteínas B/metabolismo , Regiões Árticas , Ácidos Graxos/metabolismo , Fluxo Gênico , Genética Populacional , Genoma , Ursidae/fisiologiaRESUMO
The respiratory tract is heavily populated with innate immune cells, but the mechanisms that control such cells are poorly defined. Here we found that the E3 ubiquitin ligase TRIM29 was a selective regulator of the activation of alveolar macrophages, the expression of type I interferons and the production of proinflammatory cytokines in the lungs. We found that deletion of TRIM29 enhanced macrophage production of type I interferons and protected mice from infection with influenza virus, while challenge of Trim29-/- mice with Haemophilus influenzae resulted in lethal lung inflammation due to massive production of proinflammatory cytokines by macrophages. Mechanistically, we demonstrated that TRIM29 inhibited interferon-regulatory factors and signaling via the transcription factor NF-κB by degrading the adaptor NEMO and that TRIM29 directly bound NEMO and subsequently induced its ubiquitination and proteolytic degradation. These data identify TRIM29 as a key negative regulator of alveolar macrophages and might have important clinical implications for local immunity and immunopathology.
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Infecções por Haemophilus/imunologia , Haemophilus influenzae/imunologia , Vírus da Influenza A/imunologia , Macrófagos/imunologia , Infecções por Orthomyxoviridae/imunologia , Sistema Respiratório/imunologia , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Imunidade Inata , Interferon Tipo I/genética , Interferon Tipo I/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Macrófagos/microbiologia , Macrófagos/virologia , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Proteólise , Transdução de Sinais , Fatores de Transcrição/genética , UbiquitinaçãoRESUMO
Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.
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Ansiedade , Microbioma Gastrointestinal , Microbiota , Animais , Ansiedade/metabolismo , Bactérias , Encéfalo/metabolismo , Microbioma Gastrointestinal/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microbiota/fisiologia , Bainha de Mielina , Fenóis/metabolismoRESUMO
Predicting therapeutic responses in cancer patients is a major challenge in the field of precision medicine due to high inter- and intra-tumor heterogeneity. Most drug response models need to be improved in terms of accuracy, and there is limited research to assess therapeutic responses of particular tumor types. Here, we developed a novel method DROEG (Drug Response based on Omics and Essential Genes) for prediction of drug response in tumor cell lines by integrating genomic, transcriptomic and methylomic data along with CRISPR essential genes, and revealed that the incorporation of tumor proliferation essential genes can improve drug sensitivity prediction. Concisely, DROEG integrates literature-based and statistics-based methods to select features and uses Support Vector Regression for model construction. We demonstrate that DROEG outperforms most state-of-the-art algorithms by both qualitative (prediction accuracy for drug-sensitive/resistant) and quantitative (Pearson correlation coefficient between the predicted and actual IC50) evaluation in Genomics of Drug Sensitivity in Cancer and Cancer Cell Line Encyclopedia datasets. In addition, DROEG is further applied to the pan-gastrointestinal tumor with high prevalence and mortality as a case study at both cell line and clinical levels to evaluate the model efficacy and discover potential prognostic biomarkers in Cisplatin and Epirubicin treatment. Interestingly, the CRISPR essential gene information is found to be the most important contributor to enhance the accuracy of the DROEG model. To our knowledge, this is the first study to integrate essential genes with multi-omics data to improve cancer drug response prediction and provide insights into personalized precision treatment.
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Antineoplásicos , Neoplasias , Humanos , Genes Essenciais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Genômica/métodos , Medicina de Precisão/métodosRESUMO
The emergence of multidrug-resistant bacteria is a critical global crisis that poses a serious threat to public health, particularly with the rise of multidrug-resistant Staphylococcus aureus. Accurate assessment of drug resistance is essential for appropriate treatment and prevention of transmission of these deadly pathogens. Early detection of drug resistance in patients is critical for providing timely treatment and reducing the spread of multidrug-resistant bacteria. This study aims to develop a novel risk assessment framework for S. aureus that can accurately determine the resistance to multiple antibiotics. The comprehensive 7-year study involved Ë20 000 isolates with susceptibility testing profiles of six antibiotics. By incorporating mass spectrometry and machine learning, the study was able to predict the susceptibility to four different antibiotics with high accuracy. To validate the accuracy of our models, we externally tested on an independent cohort and achieved impressive results with an area under the receiver operating characteristic curve of 0. 94, 0.90, 0.86 and 0.91, and an area under the precision-recall curve of 0.93, 0.87, 0.87 and 0.81, respectively, for oxacillin, clindamycin, erythromycin and trimethoprim-sulfamethoxazole. In addition, the framework evaluated the level of multidrug resistance of the isolates by using the predicted drug resistance probabilities, interpreting them in the context of a multidrug resistance risk score and analyzing the performance contribution of different sample groups. The results of this study provide an efficient method for early antibiotic decision-making and a better understanding of the multidrug resistance risk of S. aureus.
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Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Humanos , Staphylococcus aureus , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Antibacterianos/farmacologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Aprendizado de Máquina , Medição de RiscoRESUMO
Melatonin (MLT), a conserved small indole compound, exhibits anti-inflammatory and antioxidant properties, contributing to its cardioprotective effects. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with atherosclerosis disease risk, and is known as an atherosclerosis risk biomarker. This study aimed to investigate the impact of MLT on Lp-PLA2 expression in the atherosclerotic process and explore the underlying mechanisms involved. In vivo, ApoE-/- mice were fed a high-fat diet, with or without MLT administration, after which the plaque area and collagen content were assessed. Macrophages were pretreated with MLT combined with ox-LDL, and the levels of ferroptosis-related proteins, NRF2 activation, mitochondrial function, and oxidative stress were measured. MLT administration significantly attenuated atherosclerotic plaque progression, as evidenced by decreased plaque area and increased collagen. Compared with those in the high-fat diet (HD) group, the levels of glutathione peroxidase 4 (GPX4) and SLC7A11 (xCT, a cystine/glutamate transporter) in atherosclerotic root macrophages were significantly increased in the MLT group. In vitro, MLT activated the nuclear factor-E2-related Factor 2 (NRF2)/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity while reducing lipid peroxidation and suppressing Lp-PLA2 expression in macrophages. Moreover, MLT reversed ox-LDL-induced ferroptosis, through the use of ferrostatin-1 (a ferroptosis inhibitor) and/or erastin (a ferroptosis activator). Furthermore, the protective effects of MLT on Lp-PLA2 expression, antioxidant capacity, lipid peroxidation, and ferroptosis were decreased in ML385 (a specific NRF2 inhibitor)-treated macrophages and in AAV-sh-NRF2 treated ApoE-/- mice. MLT suppresses Lp-PLA2 expression and atherosclerosis processes by inhibiting macrophage ferroptosis and partially activating the NRF2 pathway.
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Aterosclerose , Ferroptose , Melatonina , Fator 2 Relacionado a NF-E2 , Animais , Ferroptose/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Melatonina/farmacologia , Camundongos , Aterosclerose/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Aterosclerose/patologia , Masculino , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Dieta Hiperlipídica/efeitos adversos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Lipoproteínas LDL/metabolismo , Antioxidantes/farmacologiaRESUMO
Positive magnetoresistance (PMR) and negative magnetoresistance (NMR) describe two opposite responses of resistance induced by a magnetic field. Materials with giant PMR are usually distinct from those with giant NMR due to different physical natures. Here, we report the unusual photomagnetoresistance in the van der Waals heterojunctions of WSe2/quasi-two-dimensional electron gas, showing the coexistence of giant PMR and giant NMR. The PMR and NMR reach 1,007.5% at -9 T and -93.5% at 2.2 T in a single device, respectively. The magnetoresistance spans over two orders of magnitude on inversion of field direction, implying a giant unidirectional magnetoresistance (UMR). By adjusting the thickness of the WSe2 layer, we achieve the maxima of PMR and NMR, which are 4,900,000% and -99.8%, respectively. The unique magnetooptical transport shows the unity of giant UMR, PMR, and NMR, referred to as giant bipolar unidirectional photomagnetoresistance. These features originate from strong out-of-plane spin splitting, magnetic field-enhanced recombination of photocarriers, and the Zeeman effect through our experimental and theoretical investigations. This work offers directions for high-performance light-tunable spintronic devices.NMR).
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Lysosome plays important roles in cellular homeostasis, and its dysregulation contributes to tumor growth and survival. However, the understanding of regulation and the underlying mechanism of lysosome in cancer survival is incomplete. Here, we reveal a role for a histone acetylation-regulated long noncoding RNA termed lysosome cell death regulator (LCDR) in lung cancer cell survival, in which its knockdown promotes apoptosis. Mechanistically, LCDR binds to heterogenous nuclear ribonucleoprotein K (hnRNP K) to regulate the stability of the lysosomal-associated protein transmembrane 5 (LAPTM5) transcript that maintains the integrity of the lysosomal membrane. Knockdown of LCDR, hnRNP K, or LAPTM5 promotes lysosomal membrane permeabilization and lysosomal cell death, thus consequently resulting in apoptosis. LAPTM5 overexpression or cathepsin B inhibitor partially restores the effects of this axis on lysosomal cell death in vitro and in vivo. Similarly, targeting LCDR significantly decreased tumor growth of patient-derived xenografts of lung adenocarcinoma (LUAD) and had significant cell death using nanoparticles (NPs)-mediated systematic short interfering RNA delivery. Moreover, LCDR/hnRNP K/LAPTM5 are up-regulated in LUAD tissues, and coexpression of this axis shows the increased diagnostic value for LUAD. Collectively, we identified a long noncoding RNA that regulates lysosome function at the posttranscriptional level. These findings shed light on LCDR/hnRNP K/LAPTM5 as potential therapeutic targets, and targeting lysosome is a promising strategy in cancer treatment.
Assuntos
Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , Proteínas de Membrana/metabolismo , RNA Longo não Codificante/genética , Apoptose/genética , Morte Celular , Linhagem Celular Tumoral , Sobrevivência Celular , China , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Humanos , Membranas Intracelulares/metabolismo , Lisossomos/metabolismo , Neoplasias/genéticaRESUMO
Gastric cancer is one of the most common causes of cancer-related death worldwide. The N6 -methyladenosine (m6 A) reader IGF2BP1 (insulin-like growth factor-2 mRNA binding protein 1) has been reported to promote cancer progression by stabilizing oncogenic mRNAs through its m6 A-binding activity in some tumors. However, the role of IGF2BP1 in gastric carcinogenesis remains unclear. In this study, we found that IGF2BP1 is significantly downregulated in tumor tissues from patients with gastric cancer. Lower expression of IGF2BP1 is associated with poor prognosis. Gastric cancer cell proliferation is suppressed by IGF2BP1 in an m6 A-dependent manner. Additionally, IGF2BP1 is able to significantly attenuate tumor growth of gastric cancer cells. Further m6 A sequencing and m6 A-RNA immunoprecipitation assays show that MYC (c-myc proto-oncogene) mRNA is a target transcript of IGF2BP1 in gastric cancer cells. IGF2BP1 inhibits gastric cancer cell proliferation by reducing the mRNA and protein expression of MYC. Mechanistically, IGF2BP1 promotes the degradation of MYC mRNA and inhibits its translation efficiency. Taken together, these data suggest that IGF2BP1 plays a tumor-suppressive role in gastric carcinogenesis by downregulating MYC in an m6 A-dependent manner, thereby making the IGF2BP1-MYC axis a potential target for gastric cancer treatment.
Assuntos
Neoplasias Gástricas , Humanos , Carcinogênese/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias Gástricas/genéticaRESUMO
Gout is of particularly high prevalence in the Maori and Pacific (Polynesian) populations of Aotearoa New Zealand (NZ). Here, we investigated the contribution of common population-specific copy number variation (CNV) to gout in the Aotearoa NZ Polynesian population. Microarray-generated genome-wide genotype data from Aotearoa NZ Polynesian individuals with (n = 1196) and without (n = 1249) gout were analyzed. Comparator population groups were 552 individuals of European ancestry and 1962 of Han Chinese ancestry. Levels of circulating major histocompatibility complex (MHC) class I polypeptide-related sequence A (MICA) were measured by enzyme-linked immunosorbent assay. Fifty-four CNV regions (CNVRs) appearing in at least 10 individuals were detected, of which seven common (>2%) CNVRs were specific to or amplified in Polynesian people. A burden test of these seven revealed associations of insertion/deletion with gout (odds ratio (OR) 95% confidence interval [CI] = 1.80 [1.01; 3.22], P = 0.046). Individually testing of the seven CNVRs for association with gout revealed nominal association of CNVR1 with gout in Western Polynesian (Chr6: 31.36-31.45 Mb, OR = 1.72 [1.03; 2.92], P = 0.04), CNVR6 in the meta-analyzed Polynesian sample sets (Chr1: 196.75-196.92 Mb, OR = 1.86 [1.16; 3.00], P = 0.01) and CNVR9 in Western Polynesian (Chr1: 189.35-189.54 Mb, OR = 2.75 [1.15; 7.13], P = 0.03). Analysis of European gout genetic association data demonstrated a signal of association at the CNVR1 locus that was an expression quantitative trait locus for MICA. The most common CNVR (CNVR1) includes deletion of the MICA gene, encoding an immunomodulatory protein. Expression of MICA was reduced in the serum of individuals with the deletion. In summary, we provide evidence for the association of CNVR1 containing MICA with gout in Polynesian people, implicating class I MHC-mediated antigen presentation in gout.
Assuntos
Variações do Número de Cópias de DNA , Gota , Antígenos de Histocompatibilidade Classe I , Havaiano Nativo ou Outro Ilhéu do Pacífico , Humanos , Genótipo , Gota/etnologia , Gota/genética , Antígenos de Histocompatibilidade Classe I/genética , Antígenos HLA , Havaiano Nativo ou Outro Ilhéu do Pacífico/genéticaRESUMO
Anoikis-Related Genes (ARGs) lead to the organism manifesting resistance to anoikis and are associated with unfavorable prognostic outcomes across various malignancies.Therefore, it is crucial to identify the pivotal target genes related to anoikis in HCC .We found that ARGs were significantly correlated with prognosis and immune responses in HCC. The core gene, SPP1, notably promoted anoikis resistance and metastasis in HCC through both in vivo and in vitro studies. The PI3K-Akt-mTOR pathway played a critical role in anoikis suppression within HCC contexts. Our research unveiled SPP1's role in enhancing PKCα phosphorylation, which in turn activated the PI3K-Akt-mTOR cascade. Additionally, SPP1 was identified as a key regulator of MDSCs and Tregs migration, directly affecting their immunosuppressive capabilities.These findings indicate that in HCC, SPP1 promoted anoikis resistance and facilitated immune evasion by modulating MDSCs and Tregs.
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The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia-telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1-Bcl-2 autophagy-regulatory complex formation in a ROS-dependent fashion. We further demonstrate that CHK2-mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2-/- mice display aggravated infarct phenotypes and reduced Beclin 1 p-Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2-induced autophagy in cell survival. Taken together, these results indicate that the ROS-ATM-CHK2-Beclin 1-autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress-induced tissue damage.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Proteína Beclina-1/metabolismo , Quinase do Ponto de Checagem 2/metabolismo , AVC Isquêmico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Autofagia , Linhagem Celular , Modelos Animais de Doenças , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Camundongos , Estresse Oxidativo , FosforilaçãoRESUMO
This study delivers a comprehensive evaluation of the efficacy and pharmacokinetics of high-dose methotrexate (HDMTX) in a large cohort of Chinese paediatric acute lymphoblastic leukaemia patients. A total of 533 patients were included in the prognostic analysis. An association was observed between lower steady-state MTX concentrations (<56 µmol/L) and poorer outcomes in intermediate-/high-risk (IR/HR) patients. Subgroup analysis further revealed that this relationship between concentrations and prognosis was even more pronounced in patients with MLL rearrangements. In contrast, such an association did not emerge within the low-risk patient group. Additionally, utilizing population pharmacokinetic modelling (6051 concentrations from 815 patients), we identified the significant impact of physiological maturation, estimated glomerular filtration rate, sex and concurrent dasatinib administration on MTX pharmacokinetics. Simulation-based recommendations include a reduced dosage regimen for those with renal insufficiency and a specific 200 mg/kg dosage for infants under 1 year. The findings underscore the critical role of HDMTX in treating IR/HR populations and call for a reassessment of its application in lower-risk groups. An individualized pharmacokinetic dosage regimen could achieve the most optimal results, ensuring the largest proportion of steady-state concentrations within the optimal range.
Assuntos
Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Lactente , Humanos , Antimetabólitos Antineoplásicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/induzido quimicamente , Prognóstico , Fatores de RiscoRESUMO
Small extracellular vesicles (sEVs) are heterogeneous biological nanoparticles (NPs) with wide biomedicine applications. Tracking individual nanoscale sEVs can reveal information that conventional microscopic methods may lack, especially in cellular microenvironments. This usually requires biolabeling to identify single sEVs. Here, we developed a light scattering imaging method based on dark-field technology for label-free nanoparticle diffusion analysis (NDA). Compared with nanoparticle tracking analysis (NTA), our method was shown to determine the diffusion probabilities of a single NP. It was demonstrated that accurate size determination of NPs of 41 and 120 nm in diameter is achieved by purified Brownian motion (pBM), without or within the cell microenvironments. Our pBM method was also shown to obtain a consistent size estimation of the normal and cancerous plasma-derived sEVs without and within cell microenvironments, while cancerous plasma-derived sEVs are statistically smaller than normal ones. Moreover, we showed that the velocity and diffusion coefficient are key parameters for determining the diffusion types of the NPs and sEVs in a cancerous cell microenvironment. Our light scattering-based NDA and pBM methods can be used for size determination of NPs, even in cell microenvironments, and also provide a tool that may be used to analyze sEVs for many biomedical applications.
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Vesículas Extracelulares , Vesículas Extracelulares/química , Humanos , Luz , Nanopartículas/química , Espalhamento de Radiação , Microambiente Celular , Tamanho da Partícula , Difusão , Microambiente Tumoral , Linhagem Celular Tumoral , Movimento (Física)RESUMO
Aptamer-based detection targeting glycoconjugates has attracted significant attention for its remarkable potential in identifying structural changes in saccharides in different stages of various diseases. However, the challenges in screening aptamers for small carbohydrates or glycoconjugates, which contain highly flexible and diverse glycosidic bonds, have hindered their application and commercialization. In this study, we investigated the binding conformations between three glycosidic bond-containing small molecules (GlySMs; glucose, N-acetylneuraminic acid, and neomycin) and their corresponding aptamers in silico, and analyzed factors contributing to their binding affinities. Based on the findings, a novel binding mechanism was proposed, highlighting the central role of the stem structure of the aptamer in binding and recognizing GlySMs and the auxiliary role of the mismatched bases in the adjacent loop. Guided by this binding mechanism, an aptamer with a higher 6'-sialyllactose binding affinity was designed, achieving a KD value of 4.54 ± 0.64 µM in vitro through a single shear and one mutation. The binding mechanism offers crucial guidance for designing high-affinity aptamers, enhancing the virtual screening efficiency for GlySMs. This streamlined workflow filters out ineffective binding sites, accelerating aptamer development and providing novel insights into glycan-nucleic acid interactions.
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Aptâmeros de Nucleotídeos , Glicosídeos , Aptâmeros de Nucleotídeos/química , DNA de Cadeia Simples , Sítios de Ligação , Glicoconjugados , Técnica de Seleção de AptâmerosRESUMO
Accurate measurement of cancer markers in urine is a convenient method for tumor monitoring. However, the concentration of cancer markers in urine is so low that it is difficult to achieve their measurement. Photoelectrochemical (PEC) sensors are a promising technology to realize the detection of trace cancer markers due to their high sensitivity. Currently, the interference of nonspecific biomolecules in urine is the main reason affecting the high sensitivity and selectivity of PEC sensors in detecting cancer markers. In this work, a strategy of oxygen vacancy (OV) modulation is proposed to construct a fouling-resistant PEC aptamer sensing platform for the detection of α-fetoprotein (AFP), a liver cancer marker. The introduction of OVs induces the formation of intermediate localized states in the photoelectric material, which not only facilitates the separation of photogenerated carriers but also leads to the redshift of the light absorption edge. More importantly, OVs with positive electrical properties can be employed to modify the antifouling layer (C-PEG) with negatively charged groups through an electrostatic interaction. The synergistic effect of OVs, antifouling layer, and aptamer resulted in a TiO2/OVs/C-PEG-based PEC sensor achieves a wide linear range from 1 pg/mL to 100 ng/mL and a low detection limit of 0.3 pg/mL for AFP. In addition, the sensor successfully realized the determination of AFP in urine samples and accurately differentiated between normal people and liver cancer patients in the early and advanced stages. This project is of great significance in advancing the application of photoelectrochemical bioanalytical technology to achieve the detection of cancer markers in urine by investigating the construction of an OVs-regulated fouling-resistant sensing interface.
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Incrustação Biológica , Técnicas Biossensoriais , Neoplasias Hepáticas , Humanos , alfa-Fetoproteínas , Oxigênio , Técnicas Eletroquímicas/métodos , Técnicas Biossensoriais/métodos , Limite de DetecçãoRESUMO
Microorganism are ubiquitous and intimately connected with human health and disease management. The accurate and fast identification of pathogenic microorganisms is especially important for diagnosing infections. Herein, three tetraphenylethylene derivatives (S-TDs: TBN, TPN, and TPI) featuring different cationic groups, charge numbers, emission wavelengths, and hydrophobicities were successfully synthesized. Benefiting from distinct cell wall binding properties, S-TDs were collectively utilized to create a sensor array capable of imaging various microorganisms through their characteristic fluorescent signatures. Furthermore, the interaction mechanism between S-TDs and different microorganisms was explored by calculating the binding energy between S-TDs and cell membrane/wall constituents, including phospholipid bilayer and peptidoglycan. Using a combination of the fluorescence sensor array and a deep learning model of residual network (ResNet), readily differentiation of Gram-negative bacteria (G-), Gram-positive bacteria (G+), fungi, and their mixtures was achieved. Specifically, by extensive training of two ResNet models with large quantities of images data from 14 kinds of microorganism stained with S-TDs, identification of microorganism was achieved at high-level accuracy: over 92.8% for both Gram species and antibiotic-resistant species, with 90.35% accuracy for the detection of mixed microorganism in infected wound. This novel method provides a rapid and accurate method for microbial classification, potentially aiding in the diagnosis and treatment of infectious diseases.
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Aprendizado Profundo , Humanos , Estilbenos/química , Bactérias Gram-Positivas/isolamento & purificação , Corantes Fluorescentes/química , Bactérias Gram-Negativas/isolamento & purificação , Infecção dos Ferimentos/microbiologia , Infecção dos Ferimentos/diagnóstico , Fungos/isolamento & purificaçãoRESUMO
Core@shell catalyst composited of dual aluminosilicate zeolite can effectively regulate the distribution of acid sites to control hydrocarbon conversion process for the stable formation of target product. However, the diffusion restriction reduces the accessibility of inner active sites and affects synergy between core and shell. Herein, hollow ZSM-5 zeolite nanoreactor with inverse aluminum distribution and double shells are prepared and employed for methanol aromatization. It is demonstrated that the intershell cavity alleviated the steric hindrance from zeolites channel and provided more paths and pore entrance for guest molecule. Correspondingly, olefin intermediates generated from methanol over the external shell are easier to adsorb at internal acid sites for further reactions. Importantly, the diffusion of generated aromatic macromolecules to the external surface is also promoted, which slows down the formation of internal coke, and ensures the use of internal acid sites for aromatization. The aromatics selectivity of the nanoreactor remained at 8% after 154 h, while that of solid core@shell catalyst decreased to 2% after 75 h. This finding promises broader insight to improve internal active site utilization of core@shell catalyst at the diffusion level and can be great aid in the flexible design of multifunctional nanoreactors to enhance the relay efficiency.
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The free radical generation efficiency of nanozymes in cancer therapy is crucial, but current methods fall short. Alloy nanoparticles (ANs) hold promise for improving catalytic performance due to their inherent electronic effect, but there are limited ways to modulate this effect. Here, a self-driven electric field (E) system utilizing triboelectric nanogenerator (TENG) and AuPd ANs with glucose oxidase (GOx)-like, catalase (CAT)-like, and peroxidase (POD)-like activities is presented to enhance the treatment of 4T1 breast cancer in mice. The E stimulation from TENG enhances the orbital electrons of AuPd ANs, resulting in increased CAT-like, GOx-like, and POD-like activities. Meanwhile, the catalytic cascade reaction of AuPd ANs is further amplified after catalyzing the production of H2 O2 from the GOx-like activities. This leads to 89.5% tumor inhibition after treatment. The self-driven E strategy offers a new way to enhance electronic effects and improve cascade catalytic therapeutic performance of AuPd ANs in cancer therapy.
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Nanopartículas , Neoplasias , Neoplasias Orbitárias , Animais , Camundongos , Elétrons , Neoplasias Orbitárias/tratamento farmacológico , Neoplasias/tratamento farmacológico , Glucose Oxidase , Peróxido de HidrogênioRESUMO
Chirality is a prevalent characteristic in nature, where biological systems exhibit a significant preference for specific enantiomers of biomolecules. However, there is a limited exploration into utilizing nanomaterials' chirality to modulate their interactions with intracellular substances. In this study, self-assembled copper-cysteine chiral nanoparticles and explore the influence of their charity on cancer chemodynamic therapy (CDT) are fabricated. Experimental and molecular dynamics (MD) simulation results demonstrate that the copper-l-cysteine chiral nanoparticles (Cu-l-Cys NPs) exhibit a stronger affinity toward l-glutathione (l-GSH) that is overproduced in cancer cells, compared to the copper-d-cysteine enantiomer (Cu-d-Cys NPs). The interaction between Cu-l-Cys NPs and l-GSH triggers a redox reaction that depletes l-GSH and converts Cu2+ into Cu+. Subsequently, Cu+ catalyzes a Fenton-like reaction, decomposing H2O2 into highly cytotoxic hydroxyl radicals (â¢OH) for cancer CDT. In vivo, results confirm that Cu-l-Cys NPs with good biocompatibility elicit a pronounced cancer cell death and effectively inhibit tumor growth. This work proposes a new perspective on chirality-enhanced cancer therapy.