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BACKGROUND: Cirrhosis represents the terminal stage of liver disease progression and timely intervention in a diseased liver can enhance the likelihood of recovery. Viscosity, a crucial parameter of the cellular microenvironment, is intricately linked to the advancement of cirrhosis. However, viscosity monitoring still faces significant challenges in achieving non-invasive and rapid early diagnosis of cirrhosis. Near-infrared (NIR) fluorescence imaging has the advantages of high sensitivity, non-destructive detection, and ignoring background fluorescence interference, plays an important role in diagnosing and treating various biological diseases. Hence, monitoring cellular viscosity changes with NIR fluorescence probe holds great significance in the early diagnosis of cirrhosis. RESULTS: In this study, the NIR fluorescence probe based on the intramolecular charge transfer (TICT) mechanism was developed for imaging applications in mouse model of liver cirrhosis. A molecular rotor-type viscosity-responsive probe was synthesized by linking dioxanthracene groups via carbon-carbon double bonds. The probe demonstrated remarkable sensitivity, high selectivity and photostability, with its responsiveness to viscosity largely unaffected by factors such as polarity, pH, and interfering ions. The probe could effectively detect various drug-induced changes in cellular viscosity, enabling the differentiation between normal cells and cancerous cells. Furthermore, the enhanced tissue penetration capabilities of probe facilitated its successful application in mouse model of liver cirrhosis, allowing for the assessment of liver disease severity based on fluorescence intensity and providing a powerful tool for early diagnosis of cirrhosis. SIGNIFICANCE: A NIR viscosity-sensitive fluorescent probe was specifically designed to effectively monitor alterations in cellular and organ viscosity, which could advance the understanding of the biological characteristics of cancer and provide theoretical support for the early diagnosis of cirrhosis. Overall, this probe held immense potential in monitoring viscosity-related conditions, expanding the range of biomedical tools available.
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Colorantes Fluorescentes , Cirrosis Hepática , Colorantes Fluorescentes/química , Colorantes Fluorescentes/síntesis química , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Animales , Humanos , Ratones , Imagen Óptica , Viscosidad , Rayos Infrarrojos , Estructura MolecularRESUMEN
Male animals often display higher levels of aggression than females. However, the neural circuitry mechanisms underlying this sexually dimorphic aggression remain elusive. Here, we identify a hypothalamic-amygdala circuit that mediates male-biased aggression in mice. Specifically, the ventrolateral part of the ventromedial hypothalamus (VMHvl), a sexually dimorphic region associated with eliciting male-biased aggression, projects densely to the posterior substantia innominata (pSI), an area that promotes similar levels of attack in both sexes of mice. Although the VMHvl innervates the pSI unidirectionally through both excitatory and inhibitory connections, it is the excitatory VMHvl-pSI projections that are strengthened in males to promote aggression, whereas the inhibitory connections that reduce aggressive behavior are strengthened in females. Consequently, the convergent hypothalamic input onto the pSI leads to heightened pSI activity in males, resulting in male-biased aggression. Our findings reveal a sexually distinct excitation-inhibition balance of a hypothalamic-amygdala circuit that underlies sexually dimorphic aggression.
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To coordinate cellular physiology, cells rely on the rapid exchange of molecules at specialized organelle-organelle contact sites. Lipid droplets (LDs) and nuclear membrane (NM) contact sites are particularly vital communication hubs, playing key roles in the exchange of signaling molecules, lipids, and metabolites. However, there is still a lack of understanding of the specific morphology of the contact sites. Here, we combine advanced three-dimensional (3D) imaging with a high-brightness fluorescent probe specifically targeting LDs to map the structural landscape of LD-NM contact sites. The probe exhibits exceptional photophysical properties, making it highly suitable for visualizing the changes occurring in LDs during the apoptosis process. In addition, we utilize the advantages of the probe to accurately monitor the overexpression of abnormal LDs in cirrhosis by 3D imaging for the first time. The outcomes of this investigation highlight that the probe has potential as a robust imaging tool to investigate intricate biological functions of LDs and their implications in related diseases.
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Colorantes Fluorescentes , Imagenología Tridimensional , Gotas Lipídicas , Membrana Nuclear , Gotas Lipídicas/metabolismo , Gotas Lipídicas/química , Humanos , Colorantes Fluorescentes/química , Membrana Nuclear/metabolismo , Cirrosis Hepática/metabolismo , Cirrosis Hepática/diagnóstico por imagen , Cirrosis Hepática/patología , Animales , Células Hep G2RESUMEN
Purpose: This study investigated potential predictive models associated with natural killer (NK) cell mitochondrial membrane potential (MMP or ΔΨm) in predicting death among critically ill patients with COVID-19. Patients and Methods: We included 97 patients with COVID-19 of different severities attending Peking Union Medical College Hospital from December 2022 to January 2023. Patients were divided into three groups according to oxygen and mechanical ventilation use during specimen collection and were followed for survival and death at 3 months. The lymphocyte subpopulation MMP was detected via flow cytometry. We constructed a joint diagnostic model by integrating identified key indicators and generating receiver operating curves (ROCs) and evaluated its predictive performance for mortality risk in critically ill patients. Results: The NK-cell MMP median fluorescence intensity (MFI) was significantly lower in critically ill patients who died from COVID-19 (p<0.0001) and significantly and positively correlated with D-dimer content in critically ill patients (r=0.56, p=0.0023). The random forest model suggested that fibrinogen levels and NK-cell MMP MFI were the most important indicators. Integrating the above predictive models for the ROC yielded an area under the curve of 0.94. Conclusion: This study revealed the potential of combining NK-cell MMP with key clinical indicators (D-dimer and fibrinogen levels) to predict death among critically ill patients with COVID-19, which may help in early risk stratification of critically ill patients and improve patient care and clinical outcomes.
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The etiology of hemorrhagic fever with renal syndrome (HFRS) is significantly impacted by a variety of immune cells. Nevertheless, the existing techniques for sequencing peripheral blood T cell receptor (TCR) or B cell receptor (BCR) libraries in HFRS are constrained by both limitations and high costs. In this investigation, we utilized the computational tool TRUST4 to generate TCR and BCR libraries utilizing comprehensive RNA-seq data from peripheral blood specimens of HFRS patients. This facilitated the examination of clonality and diversity within immune libraries linked to the condition. Despite previous research on immune cell function, the underlying mechanisms remain intricate, and differential gene expression across immune cell types and cell-to-cell interactions within immune cell clusters have not been thoroughly explored. To address this gap, we performed clustering analysis on 11 cell subsets derived from raw single-cell RNA-seq data, elucidating characteristic changes in cell subset proportions under disease conditions. Additionally, we utilized CellChat, a tool for cell-cell communication analysis, to investigate the impact of MIF family, CD70 family, and GALECTIN family cytokines-known to be involved in cell communication-on immune cell subsets. Furthermore, hdWGCNA analysis identified core genes implicated in HFRS pathogenesis within T cells and B cells. Trajectory analysis revealed that most cell subsets were in a developmental stage, with high expression of transcription factors such as NFKB and JUN in Effector CD8+ T cells, as well as in Naive CD4+ T cells and Naive B cells. Our findings provide a comprehensive understanding of the dynamic changes in immune cells during HFRS pathogenesis, identifying specific V genes and J genes in TCR and BCR that contribute to advancing our knowledge of HFRS. These insights offer potential implications for the diagnosis and treatment of this autoimmune disease.
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Background: The pathogenesis of juvenile idiopathic arthritis (JIA) is strongly influenced by an impaired immune system. However, the molecular mechanisms underlying its development and progression have not been elucidated. In this study, the computational methods TRUST4 were used to construct a T-cell receptor (TCR) and B-cell receptor (BCR) repertoire from the peripheral blood of JIA patients via bulk RNA-seq data, after which the clonality and diversity of the immune repertoire were analyzed. Results: Our findings revealed significant differences in the frequency of clonotypes between the JIA and healthy control groups in terms of the TCR and BCR repertoires. This work identified specific V genes and J genes in TCRs and BCRs that could be used to expand our understanding of JIA. After single-cell RNA analysis, the relative percentages of CD14 monocytes were significantly greater in the JIA group. Cell-cell communication analysis revealed the significant role of the MIF signaling pathway in JIA. Conclusion: In conclusion, this work describes the immune features of both the TCR and BCR repertoires under JIA conditions and provides novel insight into immunotherapy for JIA.
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The GLK gene family plays a crucial role in the regulation of chloroplast development and participates in chlorophyll synthesis. However, the precise mechanism by which GLK contributes to citrus's chlorophyll synthesis remains elusive. The GLK gene family causes variations in the photosynthetic capacity and chlorophyll synthesis of different citrus varieties. In this study, we identified tissue-specific members and the key CcGLKs involved in chlorophyll synthesis. A total of thirty CcGLK transcription factors (TFs) were discovered in the citrus genome, distributed across all nine chromosomes. The low occurrence of gene tandem duplication events and intronic variability suggests that intronic variation may be the primary mode of evolution for CcGLK TFs. Tissue-specific expression patterns were observed for various GLK family members; for instance, CcGLK12 and CcGLK15 were specifically expressed in the skin, while CcGLK30 was specific to the ovary, and CcGLK10, CcGLK6, CcGLK21, CcGLK2, CcGLK18, CcGLK9, CcGLK28, and CcGLK8 were specifically expressed in the leaves. CcGLK4, CcGLK5, CcGLK11, CcGLK23, CcGLKl7, CcGLK26, and CcGLK20 may participate in the regulation of the ALA, prochlorophylate, protoporphyrin IX, Mg-protoporphyrin IX, Chl b, T-Chl, MG-ProtoIX ME, and POR contents in citrus.
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Controlled synthesis of metal clusters through minor changes in surface ligands holds significant interest because the corresponding entities serve as ideal models for investigating the ligand environment's stereochemical and electronic contributions that impact the corresponding structures and properties of metal clusters. In this work, we obtained two Ag(0)-containing nanoclusters (Ag17 and Ag32) with near-infrared emissions by regulating phosphine auxiliary ligands. Ag17 and Ag32 bear similar shells wherein Ag17 features a trigonal bipyramid Ag5 kernel while Ag32 has a bi-icosahedral interpenetrating an Ag20 kernel. Ag17 and Ag32 showed a near-infrared emission (NIR) of around 830 nm. Benefiting from the rigid structure, Ag17 displayed a more intense near-infrared emission than Ag32. This work provides new insight into the construction of novel superatomic silver nanoclusters by regulating phosphine ligands.
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The emergence and re-emergence of abundant viruses from bats that impact human and animal health have resulted in a resurgence of interest in bat immunology. Characterizing the immune receptor repertoire is critical to understanding how bats coexist with viruses in the absence of disease and developing new therapeutics to target viruses in humans and susceptible livestock. In this study, IGH germline genes of Chiroptera including Rhinolophus ferrumequinum, Phyllostomus discolor, and Pipistrellus pipistrellus were annotated, and we profiled the characteristics of Rhinolophus affinis (RA) IGH CDR3 repertoire. The germline genes of Chiroptera are quite different from those of human, mouse, cow, and dog in evolution, but the three bat species have high homology. The CDR3 repertoire of RA is unique in many aspects including CDR3 subclass, V/J genes access and pairing, CDR3 clones, and somatic high-frequency mutation compared with that of human and mouse, which is an important point in understanding the asymptomatic nature of viral infection in bats. This study unveiled a detailed map of bat IGH germline genes on chromosome level and provided the first immune receptor repertoire of bat, which will stimulate new avenues of research that are directly relevant to human health and disease.IMPORTANCEThe intricate relationship between bats and viruses has been a subject of study since the mid-20th century, with more than 100 viruses identified, including those affecting humans. While preliminary investigations have outlined the innate immune responses of bats, the role of adaptive immunity remains unclear. This study presents a pioneering contribution to bat immunology by unveiling, for the first time, a detailed map of bat IGH germline genes at the chromosome level. This breakthrough not only provides a foundation for B cell receptor research in bats but also contributes to primer design and sequencing of the CDR3 repertoire. Additionally, we offer the first comprehensive immune receptor repertoire of bats, serving as a crucial library for future comparative analyses. In summary, this research significantly advances the understanding of bats' immune responses, providing essential resources for further investigations into viral tolerance and potential zoonotic threats.
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Quirópteros , Virosis , Virus , Animales , Humanos , Perros , Ratones , Virosis/veterinaria , Inmunidad Adaptativa , Células Germinativas , FilogeniaRESUMEN
Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive Mendelian genetic disorder characterized by neonatal jaundice and hemolytic anemia, affecting more than 400 million people worldwide. The purpose of this research was to investigate prevalence rates of G6PD deficiency and to evaluate and establish specific cut-off values in early prediction of G6PD deficiency by regions (HeFei, FuYang, AnQing) on different seasons, as well as to investigate the frequencies of G6PD gene mutations among three regions mentioned above. Methods: A total of 31,482 neonates (21,402, 7680, and 2340 for HeFei, FuYang, and AnQing cities, respectively) were recruited. Positive subjects were recalled to attend genetic tests for diagnosis. G6PD activity on the Genetic screening processor (GSP analyzer, 2021-0010) was measured following the manufacturerzs protocol. The cut-off value was first set to 35 U/dL. The receiver operating characteristics (ROC) curve was employed to assess and compare the efficiency in predicting G6PD deficiency among HeFei, FuYang, and AnQing cities in different seasons.
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Ovarian cancer, one of the deadliest malignancies, lacks effective treatment, despite advancements in surgical techniques and chemotherapy. Thus, new therapeutic approaches are imperative to improving treatment outcomes. Immunotherapy, which has demonstrated considerable success in managing various cancers, has already found its place in clinical practice. This review aims to provide an overview of ovarian tumor immunotherapy, including its basics, key strategies, and clinical research data supporting its potential. In particular, this discussion highlights promising strategies such as checkpoint inhibitors, vaccines, and pericyte transfer, both individually and in combination. However, the advancement of new immunotherapies necessitates large controlled randomized trials, which will undoubtedly shape the future of ovarian cancer treatment.
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Vacunas contra el Cáncer , Neoplasias Ováricas , Humanos , Femenino , Inmunoterapia/métodos , Neoplasias Ováricas/tratamiento farmacológico , Resultado del Tratamiento , Vacunas contra el Cáncer/uso terapéuticoRESUMEN
BACKGROUND: Relapsing polychondritis (RP) is an inflammatory disease with significant individual heterogeneity that involves systemic cartilage tissues. This study aimed to perform a bibliometric analysis of RP-related publications to quantitatively assess the scholarly productivity in the field. METHODS: We extracted the RP-related original research articles and reviews published during 1960-2023 from the Web of Science database by using the keyword "relapsing polychondritis." By using R, CiteSpace, VOSviewer, and SCImago Graphica, the bibliometric analysis was performed on the retrieved publications. RESULTS: A total of 1096 articles, consisting of 909 original research articles and 187 reviews, were identified. A mean annual growth rate of 6.71% was found in the number of RP-related publications during 1960-2022. The United States accounted for the highest number of publications (21.9%), exhibited the highest mean citation number per publication (40.7), and engaged in the most frequent academic collaboration. Three clusters of RP-related journals were identified: 1) otology, rhinology, and laryngology; 2) respiratory and radiology medicine; and 3) rheumatology. Journals with a focus on rheumatology issued the most publications, and most of the RP-related publications were from The Journal of Rheumatology (n = 27). Most of these publications were co-authored by Dr. Jean-Charles Piette (n = 19), who also had the highest H-index (13) among all the authors. The co-citation network analysis revealed 11 highly connected clusters of RP research and indicated the "VEXAS Syndrome" as a hotspot. CONCLUSION: This overview of the RP research field comprehensively describes the progress in the field. The number of publications on RP has progressively increased but remains insufficient. The United States and European countries are at the forefront of RP-related research, and the journals related to rheumatology have covered the majority of publications. Additionally, several key topics for future investigations, such as "VEXAS Syndrome," have been identified. Key Points â¢We identified a mean annual growth rate of 6.71% in the number of the RP-related publications during 1960-2022. â¢The United States accounted for the majority of the publications, exhibited the highest mean citation number per publication, and engaged in the most frequent academic collaborations. â¢The journals of the publications were categorized into three clusters of research areas: 1) otology, rhinology, and laryngology; 2) respiratory and radiology medicine; and 3) rheumatology. Journals related to rheumatology issued the most publications, and most of the publications were from The Journal of Rheumatology â¢Most of the publications were co-authored by Dr. Jean-Charles Piette, who also had the highest scientific-research impact among the scholars in the field. â¢The co-citation network analysis revealed 11 highly connected clusters of RP research and indicated the "VEXAS Syndrome" as a key research area.
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Policondritis Recurrente , Humanos , Bibliometría , Bases de Datos Factuales , Europa (Continente)RESUMEN
Xanthomonas oryzae pv. oryzicola (Xoo) is a type of bacteria that causes bacterial leaf blight disease in rice plants. This disease is substantially harmful, and the current prevention and control measures are facing challenges. This study has investigated the effectiveness of the control activity that the endophytic fungus NS7 fermented from Dendrobium candidum possessed against Xoo. Twenty-eight novel mesoionic compounds were designed and synthesized based on the natural compound D. These compounds displayed moderate to excellent anti-Xoo activity in vitro. Notably, compound 24 exhibited prominent anti-Xoo activity in vitro with an EC50 value of 40.3 mg/L, which was better than that of the positive control thiodiazole copper (TC)(71.2 mg/L) and the lead compound D (108.1 mg/L). In vivo pot experiments on Xoo showed that compound 24 exhibited protective and curative activities of 39.4 and 30.4%, respectively, which were better than those of TC (35.7 and 28.8%, respectively). Further, a preliminary mechanism study indicated that compound 24 could enhance the activity of defense enzymes to improve the ability for anti-Xoo. Meanwhile, compound 24 could also regulate the carbon fixation in photosynthetic organisms, which might be related to the enhanced immune function of rice. This study offers a new strategy for discovering antibacterial agents based on natural products.
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Oryza , Xanthomonas , Oxadiazoles , Pruebas de Sensibilidad Microbiana , Enfermedades de las Plantas/prevención & control , Enfermedades de las Plantas/microbiología , Antibacterianos/farmacología , Oryza/microbiologíaRESUMEN
Bean aphid (Aphis craccivora) resistance to commonly used insecticides has made controlling these pests increasingly difficult. In this study, we introduced isoxazole and isoxazoline, which possess insecticidal activity, into pyrido[1,2-a]pyrimidinone through a scaffold hopping strategy. We designed and synthesized a series of novel mesoionic compounds that exhibited a range of insecticidal activities against A. craccivora. The LC50 values of compounds E1 and E2 were 0.73 and 0.88 µg/mL, respectively, better than triflumezopyrim (LC50 = 2.43 µg/mL). Proteomics and molecular docking analyses showed that E1 might influence the A. craccivora nervous system by interacting with neuronal nicotinic acetylcholine receptors (nAChRs). This research offers a new approach to the advancement of novel mesoionic insecticides.
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Insecticidas , Pirimidinonas , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/farmacología , Insecticidas/síntesis química , Insecticidas/química , Insecticidas/farmacología , Isoxazoles/química , Estructura Molecular , Proteómica , Áfidos , Animales , Relación Estructura-ActividadRESUMEN
Cuphea hookeriana Walp. is an ornamental plant belonging to the Lythraceae. In this study, we reported the complete chloroplast (cp) genome sequence here and analyzed the phylogenetic relationship among Lythraceae plants. The length of the cp genome was 158,999 bp, including a large single-copy (LSC, 89,311 bp) region and a small single-copy (SSC, 18,436 bp) region separated by a pair of inverted repeats (IRs, 25,626 bp). There were 72 unique protein-coding genes (PCGs), 30 transfer RNA (tRNA) genes, and four ribosomal RNA (rRNA) genes in the cp genome of C. hookeriana. A total of 223 simple sequence repeats (SSRs) and 34 long repeat sequences were identified. Phylogenetic analyses using maximum-likelihood (ML) revealed that C. hookeriana was close to C. hyssopifolia. In addition, the two Cuphea species were the sister group of Woodfordia fruticosa.
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Introduction: Bats are recognized as natural reservoirs for many viruses, and their unique immune system enables them to coexist with these viruses without frequently exhibiting disease symptoms. However, the current understanding of the bat adaptive immune system is limited due to the lack of a database or tool capable of processing T-cell receptor (TCR) sequences for bats. Methods: We performed germline gene annotation in three bat species using homologous genes and RSSs (Recombinational Signal Sequences) scanning method. Then we used the conserved C gene to construct the TCRß chain receptor library of the Intermediate Horseshoe Bat. Bats' TCRß data will be analyzed using MiXCR and constructed reference library. Results: Regarding the annotation results, we found that the Pale Spear-nosed Bat has 37 members in the TRBV12 family, which is more than the total number of TRBV genes in the Greater Horseshoe Bat. The average number of unique TCRß chain receptor sequences in each Intermediate Horseshoe Bat sample reached 24,904. Discussion: The distinct variations in the distribution of TRBV genes among the three types of bats could have a direct impact on the diversity of the TCR repertoire, as evidenced by the presence of conserved amino acids that indicate the T-cell recognition of antigens in bats is MHC-restricted. The bats' TCRß repertoire is formed through the rearrangement of the V-D-J-C genes, with D-J/V-D deletions and insertions resulting in high diversity.
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Quirópteros , Animales , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Regiones Determinantes de Complementariedad/genética , Linfocitos T , Receptores de Antígenos de Linfocitos TRESUMEN
Apple polyphenols exert neuroprotective effects by improving the mitochondrial tricarboxylic acid (TCA) cycle function, but the details of their mechanisms are still not fully understood. TCA cycle metabolites regulate the level of 5-hydroxymethylcytosine (5hmC) by affecting the ten-eleven translocation (TET) enzyme activity. Therefore, we hypothesized that thinned young apple polyphenols (TYAPs) inhibit neuronal apoptosis by up-regulating the level of 5hmC in the cerebral cortex of high-fat diet-induced diabetic mice. C57BL/6J mice were randomly divided into 5 groups (n = 10 each group): the control (CON) group, the high-fat diet (HFD, negative control) group, the lovastatin (LOV, positive drug control) group, the resveratrol (RES, positive polyphenol control) group and the TYAP group during an eight-week intervention. The presented results verified that in the HFD group, the level of 5hmC and the expression of TET2 in the cerebral cortex were significantly lower, and the ratio of (succinic acid + fumaric acid)/α-ketoglutarate and the neuronal apoptosis rate were significantly higher than those in the CON group. However, TYAP intervention effectively restored the level of 5hmC through up-regulating the expression and activity of TET2, so as to improve diabetes symptoms and prevent diabetes-induced neuronal apoptosis.
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Diabetes Mellitus Experimental , Polifenoles , Ratones , Animales , Polifenoles/farmacología , Dieta Alta en Grasa/efectos adversos , Diabetes Mellitus Experimental/tratamiento farmacológico , Ratones Endogámicos C57BL , Corteza CerebralRESUMEN
OBJECTIVE: This study aimed to investigate the significance of miRNA expression levels in peripheral blood lymphocytes of patients clinically diagnosed with pulmonary tuberculosis. METHOD: Pulmonary tuberculosis-related datasets in the Gene Expression Omnibus (GEO) database were analyzed, and DE-miRNAs were screened for Gene Ontology (GO) analysis and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment to construct a DE-miRNA-DE-mRNA network. The peripheral blood lymphocytes of 10 patients with pulmonary tuberculosis, 10 patients with rifampicin-resistant tuberculosis and 10 healthy volunteers were selected for validation of RNA expression levels. qRT-PCR was done to verify the expression of DE-miRNA, and western blotting was done to check the expression levels of genes of associated pathways. RESULTS: Differential expression of miR-660 was found in pulmonary tuberculosis through data analysis and literature mining. The differential expression was also confirmed by qRT-PCR in samples from patients and healthy controls. The expression of miR-660 was significantly upregulated (p < 0.01) in patients with pulmonary tuberculosis and rifampicin-resistant pulmonary tuberculosis compared with the healthy controls. According to western blotting results, the expression levels of P-NF-κB and AKT in patients with pulmonary tuberculosis and NF-κB, P-NF-κB, AKT and p-AKT in patients with rifampicin-resistant tuberculosis were significantly upregulated (p < 0.01). CONCLUSION: The high expression levels of miR-660 may activate the AKT/NF-κB signalling pathway and has the potential to serve as a potential biomarker for the diagnosis of pulmonary tuberculosis.
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MicroARNs , Tuberculosis Pulmonar , Humanos , FN-kappa B , Proteínas Proto-Oncogénicas c-akt/genética , Rifampin/farmacología , Perfilación de la Expresión Génica , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/genética , Linfocitos/metabolismoRESUMEN
Human RNA binding protein Musashi-1 (MSI1) plays a critical role in neural progenitor cells (NPCs) by binding to various host RNA transcripts. The canonical MSI1 binding site (MBS), A/GU(1-3)AG single-strand motif, is present in many RNA virus genomes, but only Zika virus (ZIKV) genome has been demonstrated to bind MSI1. Herein, we identified the AUAG motif and the AGAA tetraloop in the Xrn1-resistant RNA 2 (xrRNA2) as the canonical and non-canonical MBS, respectively, and both are crucial for ZIKV neurotropism. More importantly, the unique AGNN-type tetraloop is evolutionally conserved, and distinguishes ZIKV from other known viruses with putative MBSs. Integrated structural analysis showed that MSI1 binds to the AUAG motif and AGAA tetraloop of ZIKV in a bipartite fashion. Thus, our results not only identified an unusual viral RNA structure responsible for MSI recognition, but also revealed a role for the highly structured xrRNA in controlling viral neurotropism.