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Extrachromosomal DNA (ecDNA) is prevalent in human cancers and mediates high expression of oncogenes through gene amplification and altered gene regulation1. Gene induction typically involves cis-regulatory elements that contact and activate genes on the same chromosome2,3. Here we show that ecDNA hubs-clusters of around 10-100 ecDNAs within the nucleus-enable intermolecular enhancer-gene interactions to promote oncogene overexpression. ecDNAs that encode multiple distinct oncogenes form hubs in diverse cancer cell types and primary tumours. Each ecDNA is more likely to transcribe the oncogene when spatially clustered with additional ecDNAs. ecDNA hubs are tethered by the bromodomain and extraterminal domain (BET) protein BRD4 in a MYC-amplified colorectal cancer cell line. The BET inhibitor JQ1 disperses ecDNA hubs and preferentially inhibits ecDNA-derived-oncogene transcription. The BRD4-bound PVT1 promoter is ectopically fused to MYC and duplicated in ecDNA, receiving promiscuous enhancer input to drive potent expression of MYC. Furthermore, the PVT1 promoter on an exogenous episome suffices to mediate gene activation in trans by ecDNA hubs in a JQ1-sensitive manner. Systematic silencing of ecDNA enhancers by CRISPR interference reveals intermolecular enhancer-gene activation among multiple oncogene loci that are amplified on distinct ecDNAs. Thus, protein-tethered ecDNA hubs enable intermolecular transcriptional regulation and may serve as units of oncogene function and cooperative evolution and as potential targets for cancer therapy.
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Neoplasias , Proteínas Nucleares , Azepinas/farmacología , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Amplificación de Genes , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias/genética , Proteínas Nucleares/genética , Oncogenes/genética , Factores de Transcripción/genéticaRESUMEN
Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resistance to blast fungus. Here, we identify PIBP1 (PigmR-INTERACTING and BLAST RESISTANCE PROTEIN 1), an RRM (RNA-recognition motif) protein that specifically interacts with PigmR and other similar NLRs to trigger blast resistance. PigmR-promoted nuclear accumulation of PIBP1 ensures full blast resistance. We find that PIBP1 and a homolog, Os06 g02240, bind DNA and function as unconventional transcription factors at the promoters of the defense genes OsWAK14 and OsPAL1, activating their expression. Knockout of PIBP1 and Os06 g02240 greatly attenuated blast resistance. Collectively, our study discovers previously unappreciated RRM transcription factors that directly interact with NLRs to activate plant defense, establishing a direct link between transcriptional activation of immune responses with NLR-mediated pathogen perception.
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Resistencia a la Enfermedad/genética , Proteínas NLR/genética , Oryza/genética , Enfermedades de las Plantas/genética , Proteínas de Plantas/genética , Factores de Transcripción/genética , Sitios de Unión , Hongos/patogenicidad , Regulación de la Expresión Génica de las Plantas , Oryza/microbiología , Enfermedades de las Plantas/microbiología , Inmunidad de la Planta/genética , Regiones Promotoras Genéticas , Unión Proteica/genética , Transducción de Señal/genéticaRESUMEN
The interaction between influenza A virus (IAV) and host proteins is an important process that greatly influences viral replication and pathogenicity. PB2 protein is a subunit of viral ribonucleoprotein (vRNP) complex playing distinct roles in viral transcription and replication. BAG6 (BCL2-associated athanogene 6) as a multifunctional host protein participates in physiological and pathological processes. Here, we identify BAG6 as a new restriction factor for IAV replication through targeting PB2. For both avian and human influenza viruses, overexpression of BAG6 reduced viral protein expression and virus titers, whereas deletion of BAG6 significantly enhanced virus replication. Moreover, BAG6-knockdown mice developed more severe clinical symptoms and higher viral loads upon IAV infection. Mechanistically, BAG6 restricted IAV transcription and replication by inhibiting the activity of viral RNA-dependent RNA polymerase (RdRp). The co-immunoprecipitation assays showed BAG6 specifically interacted with the N-terminus of PB2 and competed with PB1 for RdRp complex assembly. The ubiquitination assay indicated that BAG6 promoted PB2 ubiquitination at K189 residue and targeted PB2 for K48-linked ubiquitination degradation. The antiviral effect of BAG6 necessitated its N-terminal region containing a ubiquitin-like (UBL) domain (17-92aa) and a PB2-binding domain (124-186aa), which are synergistically responsible for viral polymerase subunit PB2 degradation and perturbing RdRp complex assembly. These findings unravel a novel antiviral mechanism via the interaction of viral PB2 and host protein BAG6 during avian or human influenza virus infection and highlight a potential application of BAG6 for antiviral drug development.
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Virus de la Influenza A , Gripe Humana , Animales , Humanos , Ratones , Antivirales/metabolismo , Virus de la Influenza A/genética , Chaperonas Moleculares/metabolismo , ARN Polimerasa Dependiente del ARN/genética , ARN Polimerasa Dependiente del ARN/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismo , Replicación Viral/genéticaRESUMEN
Stimulator of IFN genes (STING) is a critical component of the innate immune system, playing an essential role in defending against DNA virus infections. However, the mechanisms governing basal STING regulation remain poorly understood. In this study, we demonstrate that the basal level of STING is critically maintained by hypoxia-inducible factor 1 (HIF-1)α through transcription. Under normal conditions, HIF-1α binds constitutively to the promoter region of STING, actively promoting its transcription. Knocking down HIF-1α results in a decrease in STING expression in multiple cell lines and zebrafish, which in turn reduces cellular responses to synthetic dsDNAs, including cell signaling and IFN production. Moreover, this decrease in STING levels leads to an increase in cellular susceptibility to DNA viruses HSV-1 and pseudorabies virus. These findings unveil a (to our knowledge) novel role of HIF-1α in maintaining basal STING levels and provide valuable insights into STING-mediated antiviral activities and associated diseases.
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Herpesvirus Humano 1 , Subunidad alfa del Factor 1 Inducible por Hipoxia , Inmunidad Innata , Proteínas de la Membrana , Pez Cebra , Animales , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/inmunología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Pez Cebra/inmunología , Herpesvirus Humano 1/inmunología , Herpesvirus Suido 1/inmunología , Inmunidad Celular , Regulación de la Expresión Génica/inmunología , Transducción de Señal/inmunología , Transcripción Genética/inmunología , Regiones Promotoras Genéticas , Células HEK293 , Línea Celular , Herpes Simple/inmunología , Seudorrabia/inmunologíaRESUMEN
Floral patterns are unique to rice and contribute significantly to its reproductive success. SL1 encodes a C2H2 transcription factor that plays a critical role in flower development in rice, but the molecular mechanism regulated by it remains poorly understood. Here, we describe interactions of the SL1 with floral homeotic genes, SPW1, and DL in specifying floral organ identities and floral meristem fate. First, the sl1 spw1 double mutant exhibited a stamen-to-pistil transition similar to that of sl1, spw1, suggesting that SL1 and SPW1 may located in the same pathway regulating stamen development. Expression analysis revealed that SL1 is located upstream of SPW1 to maintain its high level of expression and that SPW1, in turn, activates the B-class genes OsMADS2 and OsMADS4 to suppress DL expression indirectly. Secondly, sl1 dl displayed a severe loss of floral meristem determinacy and produced amorphous tissues in the third/fourth whorl. Expression analysis revealed that the meristem identity gene OSH1 was ectopically expressed in sl1 dl in the fourth whorl, suggesting that SL1 and DL synergistically terminate the floral meristem fate. Another meristem identity gene, FON1, was significantly decreased in expression in sl1 background mutants, suggesting that SL1 may directly activate its expression to regulate floral meristem fate. Finally, molecular evidence supported the direct genomic binding of SL1 to SPW1 and FON1 and the subsequent activation of their expression. In conclusion, we present a model to illustrate the roles of SL1, SPW1, and DL in floral organ specification and regulation of floral meristem fate in rice.
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Flores , Regulación de la Expresión Génica de las Plantas , Meristema , Oryza , Proteínas de Plantas , Oryza/genética , Oryza/crecimiento & desarrollo , Oryza/metabolismo , Meristema/genética , Meristema/crecimiento & desarrollo , Meristema/metabolismo , Flores/genética , Flores/crecimiento & desarrollo , Flores/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Plantas Modificadas Genéticamente , MutaciónRESUMEN
OBJECTIVE: The remodelling of gut mycobiome (ie, fungi) during pregnancy and its potential influence on host metabolism and pregnancy health remains largely unexplored. Here, we aim to examine the characteristics of gut fungi in pregnant women, and reveal the associations between gut mycobiome, host metabolome and pregnancy health. DESIGN: Based on a prospective birth cohort in central China (2017 to 2020): Tongji-Huaxi-Shuangliu Birth Cohort, we included 4800 participants who had available ITS2 sequencing data, dietary information and clinical records during their pregnancy. Additionally, we established a subcohort of 1059 participants, which included 514 women who gave birth to preterm, low birthweight or macrosomia infants, as well as 545 randomly selected controls. In this subcohort, a total of 750, 748 and 709 participants had ITS2 sequencing data, 16S sequencing data and serum metabolome data available, respectively, across all trimesters. RESULTS: The composition of gut fungi changes dramatically from early to late pregnancy, exhibiting a greater degree of variability and individuality compared with changes observed in gut bacteria. The multiomics data provide a landscape of the networks among gut mycobiome, biological functionality, serum metabolites and pregnancy health, pinpointing the link between Mucor and adverse pregnancy outcomes. The prepregnancy overweight status is a key factor influencing both gut mycobiome compositional alteration and the pattern of metabolic remodelling during pregnancy. CONCLUSION: This study provides a landscape of gut mycobiome dynamics during pregnancy and its relationship with host metabolism and pregnancy health, which lays the foundation of the future gut mycobiome investigation for healthy pregnancy.
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Microbioma Gastrointestinal , Micobioma , Humanos , Femenino , Embarazo , Microbioma Gastrointestinal/fisiología , Adulto , Estudios Prospectivos , China , Metaboloma , Hongos/aislamiento & purificación , Recién NacidoRESUMEN
Deep learning techniques have been applied to medical image segmentation and demonstrated expert-level performance. Due to the poor generalization abilities of the models in the deployment in different centres, common solutions, such as transfer learning and domain adaptation techniques, have been proposed to mitigate this issue. However, these solutions necessitate retraining the models with target domain data and annotations, which limits their deployment in clinical settings in unseen domains. We evaluated the performance of domain generalization methods on the task of MRI segmentation of nasopharyngeal carcinoma (NPC) by collecting a new dataset of 321 patients with manually annotated MRIs from two hospitals. We transformed the modalities of MRI, including T1WI, T2WI and CE-T1WI, from the spatial domain to the frequency domain using Fourier transform. To address the bottleneck of domain generalization in MRI segmentation of NPC, we propose a meta-learning approach based on frequency domain feature mixing. We evaluated the performance of MFNet against existing techniques for generalizing NPC segmentation in terms of Dice and MIoU. Our method evidently outperforms the baseline in handling the generalization of NPC segmentation. The MF-Net clearly demonstrates its effectiveness for generalizing NPC MRI segmentation to unseen domains (Dice = 67.59%, MIoU = 75.74% T1W1). MFNet enhances the model's generalization capabilities by incorporating mixed-feature meta-learning. Our approach offers a novel perspective to tackle the domain generalization problem in the field of medical imaging by effectively exploiting the unique characteristics of medical images.
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Imagen por Resonancia Magnética , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Imagen por Resonancia Magnética/métodos , Carcinoma Nasofaríngeo/diagnóstico por imagen , Neoplasias Nasofaríngeas/diagnóstico por imagen , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador/métodos , Femenino , Masculino , AlgoritmosRESUMEN
Pathogens commonly enter mucosal barrier tissues and tissue-resident memory T cells (TRM) are essential for preventing mucosal lesions. However, the immunological properties of TRM cells in nasal mucosa are poorly known. In comparison with control tissues, decreasing CD103+ TRM cells were observed in Chronic rhinosinusitis with nasal polyps (CRSwNPs) and sinonasal inverted papilloma (SNIP), which presented high capability to produce effector cytokines. In CRSwNPs, we found that CD103+ TRM cells with higher cytokine and Granzyme B coexpressed high PD-1, CD103- TRM cells expressed higher IL-10. Homogenates isolated from CRSwNPs induced CD103 expression on peripheral T cells which could be inhibited by blocking TGF-ß. The frequencies of CD103+ TRM cells in CRSwNPs were extremely negatively correlated with neutrophil infiltration. CD103+ TRM cells from Staphylococcus aureus positive CRSwNPs had a stronger response to SEB. Taken together, two phenotypically and functionally distinct subsets of TRM cells exist in nasal tissues and play critical roles in the progress of CRSwNPs and SNIPs.
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Linfocitos T CD8-positivos , Neoplasias , Humanos , Células T de Memoria , Memoria Inmunológica , Citocinas/metabolismo , Mucosa Nasal/metabolismoRESUMEN
Ferroptosis is critical in the treatment of tumor therapies. Thus, monitoring reactive oxygen species (ROS) is of great significance for accurate assessment in ferroptosis without any interference. However, current probes for monitoring ROS during ferroptosis suffer from a drawback in that the probes consume ROS during detection, which inhibits the ferroptosis process and thus affects the accuracy and effectiveness of monitoring the process of ferroptosis. Herein, a new fluorescent donor probe, TFMU-SO2D, with the combination of the moiety of the SO2 donor is designed and synthesized by introducing the aryl boronate moieties that could give it the ability to effectively recognize ONOO-. The released SO2 could consume excess glutathione and regulate oxidative stress by elevating ROS levels, which would offset the ROS depletion by TFMU-SO2D and ensure accuracy in monitoring the ferroptosis process. The experimental results demonstrated that TFMU-SO2D possessed satisfactory performance for monitoring ONOO- as well as simultaneously releasing SO2 in oxidative stress stimulated by monensin and ferroptosis stimulated by erastin and RSL3. Additionally, the capability of SO2 synergized with ferroptosis to inhibit the viability of cancer cells was demonstrated by the CCK8 assay, which may be due to the fact that SO2 can potentiate ferroptosis cell death by increasing the ROS level. Overall, these combined results indicated that TFMU-SO2D possesses the excellent ability to precisely monitor ONOO- during ferroptosis without interference, which is significant for accurately accessing ferroptosis, cancer treatment, and drug development.
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Ferroptosis , Dióxido de Azufre , Especies Reactivas de Oxígeno/metabolismo , Muerte Celular , Estrés OxidativoRESUMEN
A new cocrystalline form of metronidazole (MET) with propyl gallate (PRO), referred to as MET-PRO, has been successfully synthesized and characterized. Structural characterization reveals that MET and PRO are present in a 1:1 ratio within the cocrystal lattice, with one water molecule equivalent incorporated into the structure. This arrangement facilitates the formation of MET-PRO heterodimers and multiple stable units, collectively constructing a three-dimensional supramolecular network. The solubility and permeability of the current cocrystal, along with the parent drug MET, are evaluated under physiological pH conditions. Experimental findings reveal that MET within the cocrystal exhibits a 1.54-2.37 folds increase in solubility and approximately a threefold improvement in permeability compared to its standalone form. Intriguingly, these concurrent enhancements in the physicochemical properties of MET lead to augmented antibacterial activity in vitro, evidenced by a reduction in minimum inhibitory concentration. Even more intriguingly, the enhanced physicochemical properties observed in vitro for the current cocrystal translate into tangible pharmacokinetic benefits in vivo, characterized by prolonged half-life and enhanced bioavailability. Consequently, this research not only introduces a fresh crystal structure for antibacterial medication but also presents approach for optimizing drug properties across in vitro and in vivo settings, while concurrently bolstering the antibacterial effectiveness of MET through pharmaceutical cocrystallization techniques.
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BACKGROUND: While circulating metabolites have been increasingly linked to cancer risk, the causality underlying these associations remains largely uninterrogated. METHODS: We conducted a comprehensive 2-sample Mendelian randomization (MR) study to evaluate the potential causal relationship between 913 plasma metabolites and the risk of seven cancers among European-ancestry individuals. Data on variant-metabolite associations were obtained from a genome-wide association study (GWAS) of plasma metabolites among 14,296 subjects. Data on variant-cancer associations were gathered from large-scale GWAS consortia for breast (N = 266,081), colorectal (N = 185,616), lung (N = 85,716), ovarian (N = 63,347), prostate (N = 140,306), renal cell (N = 31,190), and testicular germ cell (N = 28,135) cancers. MR analyses were performed with the inverse variance-weighted (IVW) method as the primary strategy to identify significant associations at Bonferroni-corrected P < 0.05 for each cancer type separately. Significant associations were subjected to additional scrutiny via weighted median MR, Egger regression, MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO), and reverse MR analyses. Replication analyses were performed using an independent dataset from a plasma metabolite GWAS including 8,129 participants of European ancestry. RESULTS: We identified 94 significant associations, suggesting putative causal associations between 66 distinct plasma metabolites and the risk of seven cancers. Remarkably, 68.2% (45) of these metabolites were each associated with the risk of a specific cancer. Among the 66 metabolites, O-methylcatechol sulfate and 4-vinylphenol sulfate demonstrated the most pronounced positive and negative associations with cancer risk, respectively. Genetically proxied plasma levels of these two metabolites were significantly associated with the risk of lung cancer and renal cell cancer, with an odds ratio and 95% confidence interval of 2.81 (2.33-3.37) and 0.49 (0.40-0.61), respectively. None of these 94 associations was biased by weak instruments, horizontal pleiotropy, or reverse causation. Further, 64 of these 94 were eligible for replication analyses, and 54 (84.4%) showed P < 0.05 with association patterns consistent with those shown in primary analyses. CONCLUSIONS: Our study unveils plausible causal relationships between 66 plasma metabolites and cancer risk, expanding our understanding of the role of circulating metabolites in cancer genetics and etiology. These findings hold promise for enhancing cancer risk assessment and prevention strategies, meriting further exploration.
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Carcinoma de Células Renales , Neoplasias Renales , Neoplasias Pulmonares , Masculino , Humanos , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/genéticaRESUMEN
High power conversion efficiencies (PCEs) in perovskite solar cells (PSCs) have always been awe-inspiring, but perovskite films scalability is an exacting precondition for PSCs commercial deployment, generally unachievable through the antisolvent technique. On the contrary, in the two-step sequential method, the perovskite's uncontrolled crystallization and unnecessary PbI2 residue impede the device's performance. These two issues motivated to empower the PbI2 substrate with orthorhombic RbPbI3 crystal seeds, which act as grown nuclei and develop orientated perovskites lattice stacks, improving the perovskite films morphologically and reducing the PbI2 content in eventual perovskite films. Thence, achieving a PCE of 24.17% with suppressed voltage losses and an impressive life span of 1140 h in the open air.
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The N6-methyladenosine (m6A) mRNA modification is crucial for plant development and stress responses. In rice, the male sterility resulting from the deficiency of OsFIP37, a core component of m6A methyltransferase complex, emphasizes the significant role of m6A in male fertility. m6A is reversible and can be removed by m6A demethylases. However, whether mRNA m6A demethylase regulates male fertility in rice has remained unknown. Here, we identify the mRNA m6A demethylase OsALKBH9 and demonstrate its involvement in male fertility regulation. Knockout of OsALKBH9 causes male sterility, dependent on its m6A demethylation activity. Cytological analysis reveals defective tapetal programmed cell death (PCD) and excessive accumulation of microspores exine in Osalkbh9-1. Transcriptome analysis of anthers shows up-regulation of genes involved in tapetum development, sporopollenin synthesis, and transport pathways in Osalkbh9-1. Additionally, we demonstrate that OsALKBH9 demethylates the m6A modification in TDR and GAMYB transcripts, which affects the stability of these mRNAs and ultimately leads to excessive accumulation of pollen exine. Our findings highlight the precise control of mRNA m6A modification and reveal the pivotal roles played by OsALKBH9-mediated m6A demethylation in tapetal PCD and pollen exine accumulation in rice.
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Desmetilación , Regulación de la Expresión Génica de las Plantas , Oryza , Proteínas de Plantas , Polen , Oryza/genética , Oryza/metabolismo , Polen/genética , Polen/metabolismo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Adenosina/análogos & derivados , Adenosina/metabolismo , Apoptosis/genética , Infertilidad Vegetal/genéticaRESUMEN
Type I interferon (IFN-I) response plays a prominent role in innate immunity, which is frequently modulated during viral infection. Here, we report DNA methylation regulator UHRF1 as a potent negative regulator of IFN-I induction during alphaherpesvirus infection, whereas the viruses in turn regulates the transcriptional expression of UHRF1. Knockdown of UHRF1 in cells significantly increases interferon-ß (IFN-ß)-mediated gene transcription and viral inhibition against herpes simplex virus 1 (HSV1) and pseudorabies virus (PRV). Mechanistically, UHRF1 deficiency promotes IFN-I production by triggering dsRNA-sensing receptor RIG-I and activating IRF3 phosphorylation. Knockdown of UHRF1 in cells upregulates the accumulation of double-stranded RNA (dsRNA), including host endogenous retroviral sequence (ERV) transcripts, while the treatment of RNase III, known to specifically digest dsRNA, prevents IFN-ß induction by siUHRF1. Furthermore, the double-knockdown assay of UHRF1 and DNA methyltransferase DNMT1 suggests that siUHRF1-mediated DNA demethylation may play an important role in dsRNA accumulation and subsequently IFN induction. These findings establish the essential role of UHRF1 in IFN-I-induced antiviral immunity and reveal UHRF1 as a potential antivrial target. IMPORTANCE Alphaherpesviruses can establish lifelong infections and cause many diseases in humans and animals, which rely partly on their interaction with IFN-mediated innate immune response. Using alphaherpesviruses PRV and HSV-1 as models, we identified an essential role of DNA methylation regulator UHRF1 in IFN-mediated immunity against virus replication, which unravels a novel mechanism employed by epigenetic factor to control IFN-mediated antiviral immune response and highlight UHRF1, which might be a potential target for antiviral drug development.
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Herpesvirus Humano 1 , Herpesvirus Suido 1 , Interferón Tipo I , Animales , Humanos , Antivirales , Proteínas Potenciadoras de Unión a CCAAT/genética , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Expresión Génica , Herpesvirus Humano 1/genética , Herpesvirus Suido 1/genética , Inmunidad Innata , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/metabolismo , Interferón Tipo I/metabolismo , Interferón beta/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Alphaherpesvirinae , Receptores Inmunológicos/inmunologíaRESUMEN
Activation of the NF-κB signaling pathway by Protein Kinase C (PKC) agonists is a potent mechanism for human immunodeficiency virus (HIV) latency disruption in vitro. However, significant toxicity risks and the lack of evidence supporting their activity in vivo have limited further evaluation of PKC agonists as HIV latency-reversing agents (LRA) in cure strategies. Here we evaluated whether GSK445A, a stabilized ingenol-B derivative, can induce HIV/simian immunodeficiency virus (SIV) transcription and virus production in vitro and demonstrate pharmacological activity in nonhuman primates (NHP). CD4+ T cells from people living with HIV and from SIV+ rhesus macaques (RM) on antiretroviral therapy (ART) exposed in vitro to 25 nM of GSK445A produced cell-associated viral transcripts as well as viral particles at levels similar to those induced by PMA/Ionomycin, indicating that GSK445A can potently reverse HIV/SIV latency. Importantly, these concentrations of GSK445A did not impair the proliferation or survival of HIV-specific CD8+ T cells, but instead, increased their numbers and enhanced IFN-γ production in response to HIV peptides. In vivo, GSK445A tolerability was established in SIV-naïve RM at 15 µg/kg although tolerability was reduced in SIV-infected RM on ART. Increases in plasma viremia following GSK445A administration were suggestive of increased SIV transcription in vivo. Collectively, these results indicate that GSK445A is a potent HIV/SIV LRA in vitro and has a tolerable safety profile amenable for further evaluation in vivo in NHP models of HIV cure/remission.
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Diterpenos/farmacología , VIH , Proteína Quinasa C/efectos de los fármacos , Virus de la Inmunodeficiencia de los Simios , Activación Viral/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Humanos , Macaca mulatta , Proteína Quinasa C/metabolismo , ARN Viral/efectos de los fármacos , Transcripción GenéticaRESUMEN
Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a heterogeneous disease characterized by local inflammation of the upper airway and sinus mucosa. T cell-mediated immune responses play irreplaceable roles in the pathogenesis of nasal polyps. CD161+ T cells have been implicated in the pathology of several diseases through cytokine production and cytotoxic activity. However, the immunological characteristics of CD161+ T cells in nasal mucosa are still not well understood, particularly in CRSwNPs. Our research revealed a notable enrichment of CD161+ T cells in nasal tissues compared to peripheral blood, with a significantly more infiltration of CD161+ T cells in CRSwNPs compared to control nasal samples. Phenotypical analysis found that CD161+ T cells predominantly co-expressed tissue-resident memory surface markers CD103, CD69, and CD45RO. CD161+CD103+ T cells demonstrated complicated effector functions, marked by elevated levels of PD-1, CTLA-4, IL-17, and IFN-γ and diminished expression of FoxP3 and CD25. Interestingly, despite CD161+ T cells was more abundant in polyp tissues compared to normal control tissues, and then further categorizing polyp samples into distinct groups based on clinical characteristics, only the recurrent CRSwNP group showed a significant reduction in CD161+CD8+ T cells compared to the primary CRSwNP group. This finding suggested the necessity for further research to comprehensively understand the underlying mechanisms and the broader significance of CD161+ T cells in the advancement and relapse of CRSwNPs.
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Antígenos CD , Cadenas alfa de Integrinas , Subfamilia B de Receptores Similares a Lectina de Células NK , Pólipos Nasales , Rinosinusitis , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antígenos CD/metabolismo , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/metabolismo , Antígenos de Diferenciación de Linfocitos T/inmunología , Enfermedad Crónica , Antígeno CTLA-4/metabolismo , Antígeno CTLA-4/inmunología , Cadenas alfa de Integrinas/metabolismo , Cadenas alfa de Integrinas/inmunología , Interferón gamma/metabolismo , Interferón gamma/inmunología , Interleucina-17/metabolismo , Interleucina-17/inmunología , Lectinas Tipo C , Mucosa Nasal/inmunología , Pólipos Nasales/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/metabolismo , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Rinosinusitis/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
BACKGROUND: The mycotoxin zearalenone (ZEA) produced by toxigenic fungi is widely present in cereals and its downstream products. The danger of ZEA linked to various human health issues has attracted increasing attention. Thus, powerful ZEA-degrading or detoxifying strategies are urgently needed. Biology-based detoxification methods are specific, efficient, and environmentally friendly and do not lead to negative effects during cereal decontamination. Among these, ZEA detoxification using degrading enzymes was documented to be a promising strategy in broad research. Here, two efficient ZEA-degrading lactonases from the genus Gliocladium, ZHDR52 and ZHDP83, were identified for the first time. This work studied the degradation capacity and properties of ZEA using purified recombinant ZHDR52 and ZHDP83. RESULTS: According to the ZEA degradation study, transformed Escherichia coli BL21(DE3) PLySs cells harboring the zhdr52 or zhdp83 gene could transform 20 µg/mL ZEA within 2 h and degrade > 90% of ZEA toxic derivatives, α/ß-zearalanol and α/ß-zearalenol, within 6 h. Biochemical analysis demonstrated that the optimal pH was 9.0 for ZHDR52 and ZHDP83, and the optimum temperature was 45 °C. The purified recombinant ZHDR52 and ZHDP83 retained > 90% activity over a wide range of pH values and temperatures (pH 7.0-10.0 and 35-50 °C). In addition, the specific activities of purified ZHDR52 and ZHDP83 against ZEA were 196.11 and 229.64 U/mg, respectively. The results of these two novel lactonases suggested that, compared with ZHD101, these two novel lactonases transformed ZEA into different products. The slight position variations in E126 and H242 in ZDHR52/ZEA and ZHDP83/ZEA obtained via structural modelling may explain the difference in degradation products. Moreover, the MCF-7 cell proliferation assay indicated that the products of ZEA degradation using ZHDR52 and ZHDP83 did not exhibit estrogenic activity. CONCLUSIONS: ZHDR52 and ZHDP83 are alkali ZEA-degrading enzymes that can efficiently and irreversibly degrade ZEA into non-estrogenic products, indicating that they are potential candidates for commercial application. This study identified two excellent lactonases for industrial ZEA detoxification.
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Gliocladium , Zearalenona , Zeranol/análogos & derivados , Humanos , Zearalenona/química , Gliocladium/metabolismo , BiotransformaciónRESUMEN
OBJECTIVE: In recent years, a series of clinical guidelines on neonatal hypoglycemia have been developed in different countries and regions. This systematic review was aimed at providing evidence for clinical decision-making and providing ideas for future research by comparatively analyzing the contents of various guidelines. METHODS: A multilateral approach was used, including comprehensive literature searches and online research. The retrieved studies were screened by two independent reviewers according to our inclusion criteria. The two reviewers independently extracted the descriptive data. Four appraisers assessed the guidelines using the AGREE-II instrument. RESULTS: Ten clinical guidelines on neonatal hypoglycemia were included, with a mean score of 45.28%-83.45% in six domains. The guidelines are relatively consistent in their recommendations on clinical symptoms of neonatal hypoglycemia, but different in risk factors, preventive measures, thresholds for clinical management of hypoglycemia, target glucose ranges for its control, and pharmacotherapy. CONCLUSION: By summarising the recommendations in the guidelines on neonatal hypoglycemia, we found that blood glucose values were not the only observational indicator, and other indicators (e.g., ketone bodies, lactate) related to glucose metabolism should also be considered for a comprehensive assessment. There is still a lack of consensus on thresholds for the clinical management of hypoglycemia and target glucose ranges for its control, and the recommendations on its pharmacotherapy are rather simple and sketchy. In the future, more high-quality studies are required to further improve the early identification of neonatal hypoglycemia and intervention strategies against it.
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Hipoglucemia , Enfermedades del Recién Nacido , Recién Nacido , Humanos , Hipoglucemia/diagnóstico , Hipoglucemia/prevención & control , Medición de Riesgo , Toma de Decisiones Clínicas , GlucosaRESUMEN
In this paper, a simple sensing method based on a silicon oxide microcavity optomechanical oscillator (OMO) is proposed and demonstrated for the detection of acoustic signals. Firstly, the resonance damping was reduced by improving the optical quality factor (Qo) and increasing the sphere-to-neck ratio. After optimizing the process, a microsphere OMO was fabricated, which has an ultra-high mechanical quality factor (6.8 × 106) and greater sphere-to-neck ratio (â¼11:1), based on which ultra-narrow linewidth phonon laser (â¼1â Hz) is constructed. Secondly, by changing the refractive index of the coupling interval, the low-frequency acoustic pressure signal is efficiently coupled into the microcavity OMO to construct a high-resolution acoustic sensor. This sensing mechanism can not only measure the acoustic pressure, but also use the sideband signal in the modulation mechanism to measure the frequency of acoustic signals (15â Hzâ¼16 kHz), the sensitivity is 10.3 kHz/Pa, the minimum detectable pressure is 1.1â mPa, and noise-limited minimum detectable pressure is 28.8 µPa/Hz1/2. It is the highest detection resolution compared with the same type of low-frequency acoustic signal detection currently reported. This OMO-based acoustic sensing detection method opens up a new path for future miniaturized, ultra-high-precision, and cost-effective acoustic sensing.
RESUMEN
Wide-range high-precision velocity detection with nitrogen-vacancy (NV) color center has been realized. By treating the NV color center as a mixer, the high-precision microwave measurement is realized. Through optimization of acquisition time, the microwave frequency resolution is improved to the mHz level. Combined with the frequency-velocity conversion model, velocity detection is realized in the range of 0-100â cm/s, and the velocity resolution is up to 0.012â cm/s. The maximum deviation in repeated measurements does not exceed 1/1000. Finally, combined with the multiplexed microwave reference technique, the range of velocity can be extended to 7.4 × 105 m/s. All of the results provide reference for high-precision velocity detection and play a significant role in various domains of quantum precision measurement. This study provides a crucial technical foundation for the development of high-dynamic-range velocity detectors and novel quantum precision velocity measurement technologies.