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During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.
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Infecções por Arenaviridae/imunologia , Linfócitos B/imunologia , Infecções por Vírus Epstein-Barr/imunologia , HIV/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular , Células Cultivadas , Regulação da Expressão Gênica , Centro Germinativo/patologia , Centro Germinativo/virologia , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
The maternal-to-zygotic transition (MZT) is a conserved and fundamental process during which the maternal environment is converted to an environment of embryonic-driven development through dramatic reprogramming. However, how maternally supplied transcripts are dynamically regulated during MZT remains largely unknown. Herein, through genome-wide profiling of RNA 5-methylcytosine (m5C) modification in zebrafish early embryos, we found that m5C-modified maternal mRNAs display higher stability than non-m5C-modified mRNAs during MZT. We discovered that Y-box binding protein 1 (Ybx1) preferentially recognizes m5C-modified mRNAs through π-π interactions with a key residue, Trp45, in Ybx1's cold shock domain (CSD), which plays essential roles in maternal mRNA stability and early embryogenesis of zebrafish. Together with the mRNA stabilizer Pabpc1a, Ybx1 promotes the stability of its target mRNAs in an m5C-dependent manner. Our study demonstrates an unexpected mechanism of RNA m5C-regulated maternal mRNA stabilization during zebrafish MZT, highlighting the critical role of m5C mRNA modification in early development.
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5-Metilcitosina/metabolismo , Embrião não Mamífero/embriologia , Desenvolvimento Embrionário/fisiologia , Estabilidade de RNA/fisiologia , RNA Mensageiro Estocado/metabolismo , Peixe-Zebra/embriologia , Animais , Células HeLa , Humanos , Camundongos , RNA Mensageiro Estocado/genética , Peixe-Zebra/genéticaRESUMO
Parental histone recycling is vital for maintaining chromatin-based epigenetic information during replication, yet its underlying mechanisms remain unclear. Here, we uncover an unexpected role of histone chaperone FACT and its N-terminus of the Spt16 subunit during parental histone recycling and transfer in budding yeast. Depletion of Spt16 and mutations at its middle domain that impair histone binding compromise parental histone recycling on both the leading and lagging strands of DNA replication forks. Intriguingly, deletion of the Spt16-N domain impairs parental histone recycling, with a more pronounced defect observed on the lagging strand. Mechanistically, the Spt16-N domain interacts with the replicative helicase MCM2-7 and facilitates the formation of a ternary complex involving FACT, histone H3/H4 and Mcm2 histone binding domain, critical for the recycling and transfer of parental histones to lagging strands. Lack of the Spt16-N domain weakens the FACT-MCM interaction and reduces parental histone recycling. We propose that the Spt16-N domain acts as a protein-protein interaction module, enabling FACT to function as a shuttle chaperone in collaboration with Mcm2 and potentially other replisome components for efficient local parental histone recycling and inheritance.
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Histonas , Proteínas de Saccharomyces cerevisiae , Fatores de Elongação da Transcrição , Cromatina/genética , DNA Helicases/genética , Chaperonas de Histonas/genética , Chaperonas de Histonas/metabolismo , Histonas/metabolismo , Chaperonas Moleculares/genética , Nucleossomos/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Elongação da Transcrição/metabolismo , Complexos Multiproteicos/metabolismoRESUMO
Uniparental embryos derived from only the mother (gynogenetic [GG]) or the father (androgenetic [AG]) are unique models for studying genomic imprinting and parental contributions to embryonic development. Human parthenogenetic embryos can be obtained following artificial activation of unfertilized oocytes, but the production of AG embryos by injection of two sperm into one denucleated oocyte leads to an extra centriole, resulting in multipolar spindles, abnormal cell division, and developmental defects. Here, we improved androgenote production by transferring the male pronucleus from one zygote into another haploid androgenote to prevent extra centrioles and successfully generated human diploid AG embryos capable of developing into blastocysts with an identifiable inner cell mass (ICM) and trophectoderm (TE). The GG embryos were also generated. The zygotic genome was successfully activated in both the AG and GG embryos. DNA methylome analysis showed that the GG blastocysts partially retain the oocyte transcription-dependent methylation pattern, whereas the AG blastocyst methylome showed more extensive demethylation. The methylation states of most known imprinted differentially methylated regions (DMRs) were recapitulated in the AG and GG blastocysts. Novel candidate imprinted DMRs were also identified. The production of uniparental human embryos followed by transcriptome and methylome analysis is valuable for identifying parental contributions and epigenome memory transitions during early human development.
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Blastocisto , Epigenoma , Blastocisto/metabolismo , Metilação de DNA , Feminino , Impressão Genômica , Humanos , Masculino , Oócitos/metabolismo , Pais , GravidezRESUMO
Joint models for recurrent event and terminating event data are increasingly used for the analysis of clinical trials. However, few methods have been proposed for designing clinical trials using these models. In this article, we develop a Bayesian clinical trial design methodology focused on evaluating the effect of an investigational product (IP) on both recurrent event and terminating event processes considered as multiple primary endpoints, using a multifrailty joint model. Dependence between the recurrent and terminating event processes is accounted for using a shared frailty. Inferences for the multiple primary outcomes are based on posterior model probabilities corresponding to mutually exclusive hypotheses regarding the benefit of IP with respect to the recurrent and terminating event processes. We propose an approach for sample size determination to ensure the trial design has a high power and a well-controlled type I error rate, with both operating characteristics defined from a Bayesian perspective. We also consider a generalization of the proposed parametric model that uses a nonparametric mixture of Dirichlet processes to model the frailty distributions and compare its performance to the proposed approach. We demonstrate the methodology by designing a colorectal cancer clinical trial with a goal of demonstrating that the IP causes a favorable effect on at least one of the two outcomes but no harm on either.
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Fragilidade , Neoplasias Primárias Múltiplas , Humanos , Teorema de Bayes , Tamanho da Amostra , Modelos Estatísticos , Simulação por ComputadorRESUMO
Autism spectrum disorder (ASD) is a highly variable neurodevelopmental disorder that typically manifests childhood, characterized by a triad of symptoms: impaired social interaction, communication difficulties, and restricted interests with repetitive behaviors. De novo variants in related genes can cause ASD. We present the case of a 6-year-old Chinese boy with autistic behavior, including language communication impairments, intellectual disabilities, stunted development, and irritability in social interactions. Using Sanger sequencing, we confirmed a pathogenic in the RERE gene (NM_012102.4) (c.3732delC, p.Tyr1245Thrfs*12; EX21; Het). Subsequently, we generated an RERE point mutation cell line (ReMut) using CRISPR/Cas9 Targeted Genome Editing. Immunofluorescence was conducted to determine the location of the mutant RERE. RNA-sequencing and mass spectrometry analyses were performed to elucidate the ASD-related genes and signaling pathways disrupted by this variant in RERE. We identified 3790 differentially expressed genes and 684 differentially expressed proteins. The SHH signaling pathway was found to be downregulated, and the Hippo pathway was upregulated in ReMut. Genes implicated in autism, such as CNTNAP2, STX1A, FARP2, and GPC1, were significantly downregulated. Simultaneously, we noted alterations in HDAC1 and HDAC2, which are members of the WHHERE complex, suggesting their role in the pathogenesis of this patient. In conclusion, we report a de novo variant in RERE associated with autistic behavior. The finding that ASD is associated with RERE variants underscore the role of genetic factors in ASD and provides insights regarding the mechanisms underlying RERE variants in disease onset.
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Transtorno do Espectro Autista , Transtorno Autístico , Masculino , Humanos , Criança , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transdução de Sinais/genética , Mutação Puntual , Expressão Gênica , Proteínas de Transporte/genética , Fatores de Troca do Nucleotídeo Guanina/genéticaRESUMO
BACKGROUND: Airway epithelium is an important component of airway structure and the initiator of airway remodeling in asthma. The changes of extracellular matrix (ECM), such as collagen deposition and structural disturbance, are typical pathological features of airway remodeling. Thus, identifying key mediators that derived from airway epithelium and capable of modulating ECM may provide valuable insights for targeted therapy of asthma. METHODS: The datasets from Gene Expression Omnibus database were analyzed to screen differentially expressed genes in airway epithelium of asthma. We collected bronchoscopic biopsies and serum samples from asthmatic and healthy subjects to assess lysyl oxidase like 2 (LOXL2) expression. RNA sequencing and various experiments were performed to determine the influences of LOXL2 knockdown in ovalbumin (OVA)-induced mouse models. The roles and mechanisms of LOXL2 in bronchial epithelial cells were explored using LOXL2 small interfering RNA, overexpression plasmid and AKT inhibitor. RESULTS: Both bioinformatics analysis and further experiments revealed that LOXL2 is highly expressed in airway epithelium of asthmatics. In vivo, LOXL2 knockdown significantly inhibited OVA-induced ECM deposition and epithelial-mesenchymal transition (EMT) in mice. In vitro, the transfection experiments on 16HBE cells demonstrated that LOXL2 overexpression increases the expression of N-cadherin and fibronectin and reduces the expression of E-cadherin. Conversely, after silencing LOXL2, the expression of E-cadherin is up-regulated. In addition, the remodeling and EMT process that induced by transforming growth factor-ß1 could be enhanced and weakened after LOXL2 overexpression and silencing in 16HBE cells. Combining the RNA sequencing of mouse lung tissues and experiments in vitro, LOXL2 was involved in the regulation of AKT signaling pathway. Moreover, the treatment with AKT inhibitor in vitro partially alleviated the consequences associated with LOXL2 overexpression. CONCLUSIONS: Taken together, the results demonstrated that epithelial LOXL2 plays a role in asthmatic airway remodeling partly via the AKT signaling pathway and highlighted the potential of LOXL2 as a therapeutic target for airway remodeling in asthma.
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Remodelação das Vias Aéreas , Aminoácido Oxirredutases , Asma , Ovalbumina , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Aminoácido Oxirredutases/metabolismo , Aminoácido Oxirredutases/genética , Aminoácido Oxirredutases/biossíntese , Ovalbumina/toxicidade , Remodelação das Vias Aéreas/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos , Humanos , Asma/patologia , Asma/metabolismo , Asma/enzimologia , Asma/genética , Transdução de Sinais/fisiologia , Feminino , Camundongos Endogâmicos BALB C , Masculino , Transição Epitelial-Mesenquimal/fisiologiaRESUMO
BACKGROUND: Airway epithelial cell (AEC) necroptosis contributes to airway allergic inflammation and asthma exacerbation. Targeting the tumor necrosis factor-like ligand 1 A (TL1A)/death receptor 3 (DR3) axis has a therapeutic effect on asthmatic airway inflammation. The role of TL1A in mediating necroptosis of AECs challenged with ovalbumin (OVA) and its contribution to airway inflammation remains unclear. METHODS: We evaluated the expression of the receptor-interacting serine/threonine-protein kinase 3(RIPK3) and the mixed lineage kinase domain-like protein (MLKL) in human serum and lung, and histologically verified the level of MLKL phosphorylation in lung tissue from asthmatics and OVA-induced mice. Next, using MLKL knockout mice and the RIPK3 inhibitor GSK872, we investigated the effects of TL1A on airway inflammation and airway barrier function through the activation of necroptosis in experimental asthma. RESULTS: High expression of necroptosis marker proteins was observed in the serum of asthmatics, and necroptosis was activated in the airway epithelium of both asthmatics and OVA-induced mice. Blocking necroptosis through MLKL knockout or RIPK3 inhibition effectively attenuated parabronchial inflammation, mucus hypersecretion, and airway collagen fiber accumulation, while also suppressing type 2 inflammatory factors secretion. In addition, TL1A/ DR3 was shown to act as a death trigger for necroptosis in the absence of caspases by silencing or overexpressing TL1A in HBE cells. Furthermore, the recombinant TL1A protein was found to induce necroptosis in vivo, and knockout of MLKL partially reversed the pathological changes induced by TL1A. The necroptosis induced by TL1A disrupted the airway barrier function by decreasing the expression of tight junction proteins zonula occludens-1 (ZO-1) and occludin, possibly through the activation of the NF-κB signaling pathway. CONCLUSIONS: TL1A-induced airway epithelial necroptosis plays a significant role in promoting airway inflammation and barrier dysfunction in asthma. Inhibition of the TL1A-induced necroptosis pathway could be a promising therapeutic strategy.
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Asma , Camundongos Knockout , Necroptose , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Animais , Asma/metabolismo , Asma/patologia , Necroptose/fisiologia , Humanos , Camundongos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo , Masculino , Feminino , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Camundongos Endogâmicos C57BL , Proteínas Quinases/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Ovalbumina/toxicidadeRESUMO
Cross-dehydrogenative couplings (CDC) present an efficient strategy for the assembly of biorelevant heterocycles, but are thus far largely limited to toxic transition metals and rather harsh reaction conditions. In sharp contrast, we, herein report on a mild photoelectrocatalyzed CDC-[4+2] annulation enabling the synthesis of functionalized isothiochromenes enabled by a proton-coupled electron transfer (PCET) strategy. The transformative photoelectrocatalysis obviated toxic transition-metal, high reaction temperatures, and stoichiometric chemical redox reagents. This approach was characterized by exceedingly mild conditions, ample substrate scope, and a commercially available catalyst. Gram-scale reactions and a telescoped synthesis route reflected the unique potential in the green synthesis of important S-heterocycles.
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An electrochemical and selective decarboxylation and dehydration using α-keto acids with amines is accomplished, which leads to the easy accessibility of amides and α-ketoamides, which are not only ubiquitous and valuable structure motifs found in pharmaceuticals, but also versatile building blocks in synthetic chemistry. Notably, for this efficient and green protocol, neither metal catalysts nor external oxidants are required. The process exhibits a broad scope and functional group tolerance to deliver various amides and α-ketoamides. Moreover, these two reactions have also been applied to late-stage derivatization and can be safely conducted on gram scale.
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RATIONALE: Phenylethylamines are one of the most common types of new psychoactive substances, following synthetic cannabinoids and synthetic cathinones. They are regulated in many countries because of their strong hallucinogenic effects, which can cause serious nerve damage. There is a wide variety of phenylethylamines, exhibiting rapid renewal and extremely similar structures, therefore accurate qualitative analysis of isomers is a difficult problem in current drug analysis. METHODS: The dissociation pathways of the position isomers 2-(2-methylaminoprolyl)benzofuran (2-MAPB) and 5-(2-methylaminopropyl)benzofuran (5-MAPB) were investigated by gas chromatography-mass spectrometry and liquid chromatography coupled to high-resolution quadrupole Orbitrap MS. The dissociation patterns of the phenethylamine-based designer drugs 2-MAPB and 5-MAPB were explored and extended in this work based on MS combined with density functional theory studies. RESULTS: For electron ionization mass spectrometry (EI-MS) analysis, the dissociation patterns of 2-MAPB were similar to those of 5-MAPB. For electrospray ionization mass spectrometry (ESI-MSn ) analysis, the hydrogen atom on amino group was facile to form a intramolecular hydrogen bond with the oxygen atom on the parent nucleus of benzofuran in the structure of 2-MAPB, leading to higher abundance of the product ion at m/z 58. However, there was a conjugated system between the positive charge formed by the cleavage of the 5-MAPB side chain and the benzofuran ring, enabling the 5-MAPB to generate a product ion at m/z 131. Computational study showed that energy barrier and spin density difference distribution jointly control the selective dissociation in EI-MS, while different types of orbital interaction induced by intramolecular hydrogen bond led to different dissociation results in ESI-MSn . CONCLUSIONS: These different dissociation patterns could be used to distinguish 2-MAPB from 5-MAPB. This could assist forensic laboratories in the differentiation and characterization of potential isomers in these kinds of compounds, especially in mixtures.
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BACKGROUND: The provincial-level sero-survey was launched to learn the updated seroprevalence of hepatitis B virus (HBV) infection in the general population aged 1-69 years in Chongqing and to assess the risk factors for HBV infection to effectively screen persons with chronic hepatitis B (CHB). METHODS: A total of 1828 individuals aged 1-69 years were investigated, and hepatitis B surface antigen (HBsAg), antibody to HBsAg (HBsAb), and antibody to B core antigen (HBcAb) were detected. Logistic regression and three machine learning (ML) algorithms, including random forest (RF), support vector machine (SVM), and stochastic gradient boosting (SGB), were developed for analysis. RESULTS: The HBsAg prevalence of the total population was 3.83%, and among persons aged 1-14 years and 15-69 years, it was 0.24% and 4.89%, respectively. A large figure of 95.18% (770/809) of adults was unaware of their occult HBV infection. Age, region, and immunization history were found to be statistically associated with HBcAb prevalence with a logistic regression model. The prediction accuracies were 0.717, 0.727, and 0.725 for the proposed RF, SVM, and SGB models, respectively. CONCLUSIONS: The logistic regression integrated with ML models could helpfully screen the risk factors for HBV infection and identify high-risk populations with CHB.
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Hepatite B Crônica , Hepatite B , Adulto , Humanos , Vírus da Hepatite B , Antígenos de Superfície da Hepatite B , Estudos Soroepidemiológicos , Fatores de Risco , Hepatite B/epidemiologia , Anticorpos Anti-Hepatite B , Hepatite B Crônica/epidemiologia , Aprendizado de MáquinaRESUMO
BACKGROUND: To assess the immunogenicity of the current primary polio vaccination schedule in China and compare it with alternative schedules using Sabin or Salk-strain IPV (sIPV, wIPV). METHODS: A cross-sectional investigation was conducted at four sites in Chongqing, China, healthy infants aged 60-89 days were conveniently recruited and divided into four groups according to their received primary polio vaccination schedules (2sIPV + bOPV, 2wIPV + bOPV, 3sIPV, and 3wIPV). The sero-protection and neutralizing antibody titers against poliovirus serotypes (type 1, 2, and 3) were compared after the last dose. RESULTS: There were 408 infants completed the protocol. The observed seropositivity was more than 96% against poliovirus types 1, 2, and 3 in all groups. IPV-only groups induced higher antibody titers(GMT) against poliovirus type 2 (Median:192, QR: 96-384, P<0.05) than the "2IPV + bOPV" group. While the "2IPV + bOPV" group induced significantly higher antibody titers against poliovirus type 1 (Median:2048, QR: 768-2048, P<0.05)and type 3 (Median:2048, QR: 512-2048, P<0.05) than the IPV-only group. CONCLUSIONS: Our findings have proved that the two doses of IPV with one dose of bOPV is currently the best polio routine immunization schedule in China.
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Anticorpos Neutralizantes , Anticorpos Antivirais , Esquemas de Imunização , Poliomielite , Vacina Antipólio de Vírus Inativado , Vacina Antipólio Oral , Poliovirus , Humanos , Vacina Antipólio de Vírus Inativado/imunologia , Vacina Antipólio de Vírus Inativado/administração & dosagem , Poliomielite/prevenção & controle , Poliomielite/imunologia , Lactente , Vacina Antipólio Oral/imunologia , Vacina Antipólio Oral/administração & dosagem , Masculino , Feminino , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Estudos Transversais , China , Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Poliovirus/imunologia , Imunogenicidade da Vacina , VacinaçãoRESUMO
Upon fertilization, drastic chromatin reorganization occurs during preimplantation development 1 . However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) 2 . We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing3-5. Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization.
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Cromatina/genética , Cromatina/metabolismo , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/genética , Epigênese Genética , Genoma/genética , Zigoto/metabolismo , Animais , Sítios de Ligação , Ilhas de CpG/genética , Metilação de DNA , Embrião de Mamíferos/citologia , Embrião de Mamíferos/embriologia , Células-Tronco Embrionárias/citologia , Feminino , Inativação Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Camundongos , Oócitos/citologia , Oócitos/metabolismo , Células-Tronco Pluripotentes/citologia , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Transposases/metabolismoRESUMO
In this Letter, the 'Open chromatin' label in Fig. 4a should have been centred above the first three columns, and the black horizontal line underneath the label should have been removed. In addition, there should have been a vertical black line between the last two sets of panels for consistency. Minor changes have also been made to Fig. 1 and to the legend of Fig. 3. These errrors have been corrected online, and see Supplementary Information to the accompanying Amendment for the original Fig. 4.
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The Influenza A virus (IAV) is a zoonotic pathogen that infects humans and various animal species. Infection with IAV can cause fever, anorexia, and dyspnea and is often accompanied by pneumonia characterized by an excessive release of cytokines (i.e., cytokine storm). Nanodrug delivery systems and nanoparticles are a novel approach to address IAV infections. Herein, UiO-66 nanoparticles (NPs) are synthesized using a high-temperature melting reaction. The in vitro and in vivo optimal concentrations of UiO-66 NPs for antiviral activity are 200 µg mL-1 and 60 mg kg-1, respectively. Transcriptome analysis revealed that UiO-66 NPs can activate the RIG-I-like receptor signaling pathway, thereby enhancing the downstream type I interferon antiviral effect. These NPs suppress inflammation-related pathways, including the FOXO, HIF, and AMPK signaling pathways. The inhibitory effect of UiO-66 NPs on the adsorption and entry of IAV into A549 cells is significant. This study presents novel findings that demonstrate the effective inhibition of IAV adsorption and entry into cells via UiO-66 NPs and highlights their ability to activate the cellular RIG-I-like receptor signaling pathway, thereby exerting an anti-IAV effect in vitro or in mice. These results provide valuable insights into the mechanism of action of UiO-66 NPs against IAV and substantial data for advancing innovative antiviral nanomedicine.
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Vírus da Influenza A , Influenza Humana , Estruturas Metalorgânicas , Infecções por Orthomyxoviridae , Ácidos Ftálicos , Camundongos , Humanos , Animais , Infecções por Orthomyxoviridae/tratamento farmacológico , Transdução de Sinais , Antivirais/farmacologia , Antivirais/uso terapêuticoRESUMO
BACKGROUND: Nowadays, diabetic wound healing remains a crucial challenge due to their protracted and uncertain healing process. Traditional Chinese medicine (TCM) has demonstrated the therapeutic value of Sanguis draconis (SD)-Salvia miltiorrhiza (SMR) Herb Pair in diabetic wound healing. However, new administration modes are urgently needed for their convenient and wide-ranging applications. OBJECTIVE: We propose a soluble polyvinylpyrrolidone-based microneedle patch containing the herbal extracts of SD and SMR (MN-SD@SMR) for diabetic wound healing. METHODS: The herbal extracts of SD and SMR are purification and concentration via traditional lyophilization. SD endowed MN-SD@SMR with functions to improve high glycemic blood environment and migration of keratinocyte and fibroblast cells. RESULTS: SMR in MN-SD@SMR could improve blood flow velocity and microcirculation in the wound area. The effectiveness of transdermal release and mechanical strengths of MN-SD@SMR were verified. CONCLUSION: Integrating the advantages of these purified herbal compositions, we demonstrated that MN-SD@SMR had a positive healing effect on the wounds in vitro and vivo. These results indicate that soluble polyvinylpyrrolidone-based microneedle patch containing the herbal extracts of SD and SMR has a promising application value due to their superior capability to promote diabetic wound healing.
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Diabetes Mellitus , Medicamentos de Ervas Chinesas , Salvia miltiorrhiza , Humanos , Povidona , Diabetes Mellitus/tratamento farmacológico , CicatrizaçãoRESUMO
Zygotic genome activation (ZGA) is a critical event in early embryonic development, and thousands of genes are involved in this delicate and sophisticated biological process. To date, however, only a handful of these genes have revealed their core functions in this special process, and therefore the roles of other genes still remain unclear. In the present study, we used previously published transcriptome profiling to identify potential key genes (candidate genes) in minor ZGA and major ZGA in both human and mouse specimens, and further identified the conserved genes across species. Our results showed that 887 and 760 genes, respectively, were thought to be specific to human and mouse in major ZGA, and the other 135 genes were considered to be orthologous genes. Moreover, the conserved genes were most enriched in rRNA processing in the nucleus and cytosol, ribonucleoprotein complex biogenesis, ribonucleoprotein complex assembly and ribosome large subunit biogenesis. The findings of this first comprehensive identification and characterization of candidate genes in minor and major ZGA provide relevant insights for future studies on ZGA.
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Genoma , Zigoto , Animais , Zigoto/metabolismo , Camundongos , Humanos , Genoma/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Transcriptoma/genética , Feminino , Desenvolvimento Embrionário/genética , Mamíferos/genéticaRESUMO
In this work, a two-parameter inversion problem is analyzed, related to surface crack widths for measuring depths of normal surface notches, based on a laser-based ultrasonic measurement method in the time domain. In determining the depth measurement formulas, the main technique is the time delay between reflected and scattered waves. Scattered waves are generated by two reflections along the bottom and three mode transformations at the surface of the crack tips. Moreover, the scattering angle of the mode-conversion waves is 30°. These two key factors lead to corrected item "2wß" in the depth measurement formula. A laser-based ultrasonic experimental platform is built to generate and receive surface waves in a non-contact manner on aluminum and steel specimens with surface cracks. The depth measurement method proposed in this paper has been validated through theoretical, simulation, and experimental methods. Finally, in this paper, an effective approach for quantitatively measuring crack depths, based on laser ultrasound, using the time-domain properties of surface wave propagation is provided.
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In the development and progression of cervical cancer, oxidative stress plays an important role within the cells. Among them, Solute Carrier Family 7 Member 11 (SLC7A11/xCT) is crucial for maintaining the synthesis of glutathione and the antioxidant system in cervical cancer cells. In various tumor cells, studies have shown that SLC7A11 inhibits ferroptosis, a form of cell death, by mediating cystine uptake and maintaining glutathione synthesis. Additionally, SLC7A11 is also involved in promoting tumor metastasis and immune evasion. Therefore, inhibiting the SLC7A11/xCT axis has become a potential therapeutic strategy for cervical cancer. In this study, through structure-based high-throughput virtual screening, a compound targeting the SLC7A11/xCT axis named compound 1 (PubChem CID: 3492258) was discovered. In vitro experiments using HeLa cervical cancer cells as the experimental cell model showed that compound 1 could reduce intracellular glutathione levels, increase glutamate and reactive oxygen species (ROS) levels, disrupt the oxidative balance within HeLa cells, and induce cell death. Furthermore, molecular dynamics simulation results showed that compound 1 has a stronger binding affinity with SLC7A11 compared to the positive control erastin. Overall, all the results mentioned above indicate the potential of compound 1 in targeting the SLC7A11/xCT axis and treating cervical cancer both in vitro and in silico.