RESUMEN
Pathogens have co-evolved with mosquitoes to optimize transmission to hosts. Mosquito salivary-gland extract is known to modulate host immune responses and facilitate pathogen transmission, but the underlying molecular mechanisms of this have remained unknown. In this study, we identified and characterized a prominent 15-kilodalton protein, LTRIN, obtained from the salivary glands of the mosquito Aedes aegypti. LTRIN expression was upregulated in blood-fed mosquitoes, and LTRIN facilitated the transmission of Zika virus (ZIKV) and exacerbated its pathogenicity by interfering with signaling through the lymphotoxin-ß receptor (LTßR). Mechanically, LTRIN bound to LTßR and 'preferentially' inhibited signaling via the transcription factor NF-κB and the production of inflammatory cytokines by interfering with the dimerization of LTßR during infection with ZIKV. Furthermore, treatment with antibody to LTRIN inhibited mosquito-mediated infection with ZIKV, and abolishing LTßR potentiated the infectivity of ZIKV both in vitro and in vivo. This study provides deeper insight into the transmission of mosquito-borne diseases in nature and supports the therapeutic potential of inhibiting the action of LTRIN to disrupt ZIKV transmission.
Asunto(s)
Aedes/virología , Proteínas de Insectos/metabolismo , Saliva/metabolismo , Infección por el Virus Zika/transmisión , Virus Zika/patogenicidad , Animales , Humanos , Receptor beta de Linfotoxina/inmunología , Receptor beta de Linfotoxina/metabolismo , Ratones , Mosquitos Vectores/química , Mosquitos Vectores/inmunología , Mosquitos Vectores/metabolismo , Saliva/químicaRESUMEN
Fungal infections have emerged as a major concern among immunocompromised patients, causing approximately 2 million deaths each year worldwide. However, the regulatory mechanisms underlying antifungal immunity remain elusive and require further investigation. The E3 ligase Trim26 belongs to the tripartite motif (Trim) protein family, which is involved in various biological processes, including cell proliferation, antiviral innate immunity, and inflammatory responses. Herein, we report that Trim26 exerts protective antifungal immune functions after fungal infection. Trim26-deficient mice are more susceptible to fungemia than their wild-type counterparts. Mechanistically, Trim26 restricts inflammatory neutrophils infiltration and limits proinflammatory cytokine production, which can attenuate kidney fungal load and renal damage during Candida infection. Trim26-deficient neutrophils showed higher proinflammatory cytokine expression and impaired fungicidal activity. We further demonstrated that excessive neutrophils infiltration in the kidney was because of the increased production of chemokines CXCL1 and CXCL2, which are mainly synthesized in the macrophages or dendritic cells of Trim26-deficient mice after Candida albicans infections. Together, our study findings unraveled the vital role of Trim26 in regulating antifungal immunity through the regulation of inflammatory neutrophils infiltration and proinflammatory cytokine and chemokine expression during candidiasis.
Asunto(s)
Candidiasis , Neutrófilos , Animales , Ratones , Antifúngicos , Candida albicans , Candidiasis/metabolismo , Candidiasis/microbiología , Citocinas/metabolismo , Infiltración Neutrófila , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína LigasasRESUMEN
The enzyme cyclic GMP-AMP synthase (cGAS) is a key sensor for detecting misplaced double-stranded DNA (dsDNA) of genomic, mitochondrial, and microbial origin. It synthesizes 2'3'-cGAMP, which in turn activates the stimulator of interferon genes pathway, leading to the initiation of innate immune responses. Here, we identified Listerin as a negative regulator of cGAS-mediated innate immune response. We found that Listerin interacts with cGAS on endosomes and promotes its K63-linked ubiquitination through recruitment of the E3 ligase TRIM27. The polyubiquitinated cGAS is then recognized by the endosomal sorting complexes required for transport machinery and sorted into endosomes for degradation. Listerin deficiency enhances the innate antiviral response to herpes simplex virus 1 infection. Genetic deletion of Listerin also deteriorates the neuroinflammation and the ALS disease progress in an ALS mice model; overexpression of Listerin can robustly ameliorate disease progression in ALS mice. Thus, our work uncovers a mechanism for cGAS regulation and suggests that Listerin may be a promising therapeutic target for ALS disease.
Asunto(s)
Esclerosis Amiotrófica Lateral , Ubiquitina-Proteína Ligasas , Animales , Ratones , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Esclerosis Amiotrófica Lateral/inmunología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Inmunidad Innata/genética , Nucleotidiltransferasas/metabolismo , Proteolisis , Transducción de Señal/fisiología , Modelos Animales de Enfermedad , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/inmunología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Lyme spirochetes have coevolved with ticks to optimize transmission to hosts using tick salivary molecules (TSMs) to counteract host defenses. TSMs modulate various molecular events at the tick-host interface. Lymphotoxin-beta receptor (LTßR) is a vital immune receptor and plays protective roles in host immunity against microbial infections. We found that Ltbr knockout mice were more susceptible to Lyme disease spirochetes, suggesting the involvement of LTßR signaling in tick-borne Borrelia infection. Further investigation showed that a 15-kDa TSM protein from Ixodes persulcatus (I. persulcatus salivary protein; IpSAP) functioned as an immunosuppressant to facilitate the transmission and infection of Lyme disease spirochetes. IpSAP directly interacts with LTßR to block its activation, thus inhibiting the downstream signaling and consequently suppressing immunity. IpSAP immunization provided mice with significant protection against I. persulcatus-mediated Borrelia garinii infection. Notably, the immunization showed considerable cross-protection against other Borrelia infections mediated by other ixodid ticks. One of the IpSAP homologs from other ixodid ticks showed similar effects on Lyme spirochete transmission. Together, our findings suggest that LTßR signaling plays an important role in blocking the transmission and pathogenesis of tick-borne Lyme disease spirochetes, and that IpSAP and its homologs are promising candidates for broad-spectrum vaccine development.
Asunto(s)
Grupo Borrelia Burgdorferi , Borrelia burgdorferi , Ixodes , Enfermedad de Lyme , Ratones , Animales , Borrelia burgdorferi/genética , Saliva , Ixodes/fisiología , Receptor beta de LinfotoxinaRESUMEN
Basophils and mast cells play a critical role in allergic inflammation and provide protective immunity against certain types of parasitic infections. Expansion of basophils and mast cells to the critical numbers is believed to be an essential step in enabling basophils and mast cells to carry out their protective functions. However, factors that drive basophil and mast cell expansion are still incompletely understood. We tested the roles of cytokines and growth factors IL-3, TSLP, GM-CSF, IL-5, SCF, IL-7, IL-25, and IL-33 in promoting the differentiation of pre-basophil and mast cell progenitors (pre-BMPs)in vitro.We found that while GM-CSF only expanded basophils, IL-3 promoted the differentiation of pre-BMPs into both basophils and mast cells. We found that IL-3 expanded the number of pre-BMPsin vivo. We showed that IL-3 upregulatedIl3ramRNA and protein expression on pre-BMPs, supporting that IL-3 expands pre-BMPs in part by upregulating the IL-3 receptor expression. Although Gata2 mRNA expression was upregulated by IL-3 treatment in pre-BMPs, it is dispensable for IL-3-mediated upregulation of IL-3 receptor expression. Our study reveals a novel mechanism through which IL-3 expands basophil and mast cells.
Asunto(s)
Basófilos , Receptores de Interleucina-3 , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-3 , MastocitosRESUMEN
It remains unclear whether basophils and mast cells are derived from a common progenitor. Furthermore, how basophil versus mast cell fate is specified has not been investigated. Here, we have identified a population of granulocyte-macrophage progenitors (GMPs) that were highly enriched in the capacity to differentiate into basophils and mast cells while retaining a limited capacity to differentiate into myeloid cells. We have designated these progenitor cells "pre-basophil and mast cell progenitors" (pre-BMPs). STAT5 signaling was required for the differentiation of pre-BMPs into both basophils and mast cells and was critical for inducing two downstream molecules: C/EBPα and MITF. We have identified C/EBPα as the critical basophil transcription factor for specifying basophil cell fate and MITF as the crucial transcription factor for specifying mast cell fate. C/EBPα and MITF silenced each other's transcription in a directly antagonistic fashion. Our study reveals how basophil and mast cell fate is specified.
Asunto(s)
Basófilos/inmunología , Proteína alfa Potenciadora de Unión a CCAAT/inmunología , Mastocitos/inmunología , Factor de Transcripción Asociado a Microftalmía/inmunología , Animales , Basófilos/citología , Basófilos/metabolismo , Western Blotting , Proteína alfa Potenciadora de Unión a CCAAT/genética , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Linaje de la Célula/inmunología , Células Cultivadas , Citometría de Flujo , Perfilación de la Expresión Génica , Células Progenitoras de Granulocitos y Macrófagos/citología , Células Progenitoras de Granulocitos y Macrófagos/inmunología , Células Progenitoras de Granulocitos y Macrófagos/metabolismo , Células HEK293 , Humanos , Mastocitos/citología , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factor de Transcripción Asociado a Microftalmía/genética , Factor de Transcripción Asociado a Microftalmía/metabolismo , Células Mieloides/inmunología , Células Mieloides/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/inmunología , Factor de Transcripción STAT5/metabolismo , Células Madre/inmunología , Células Madre/metabolismoRESUMEN
Silicon monoxide is a potentially viable anode material for high-performance lithium-ion batteries (LIBs). However, a low initial coulombic efficiency and large volume expansion limit its commercial application. Pre-lithiation is an efficient solution, but is expensive because of limited "pre-lithiation" sources. In this work, we theoretically investigated a novel multiple pre-doping SiO system (Li-NaMg-SiO). By comparing its lithiation behavior to that of the traditional Li-doping system (Li-SiO), we revealed the different doping effects during lithiation. Similar to the traditional Li-doping system, the insertion of Na and Mg disintegrates the Si-O host matrix to form Na-O and Mg-O bonds and active Si clusters. At the end of lithiation, the O-Li coordination number (CN) tends to saturate at CNO-Li ≈ 5 in Li-Na-SiO, Li-Mg-SiO, and Li-NaMg-SiO systems, while the value of CNO-Li in the Li-SiO system is more than 6, which suggests that there are reorganizations between Li, Na, and Mg in the silicate matrix. Doping sources of both Na and Mg can prevent the active Li ions from being trapped by O-Li bonds and increase the initial coulombic efficiency. From the density of states (DOS), we notice that all the different pre-doping systems have similar electronic structures, and they can be expected to undergo the same lithiation process. Furthermore, the higher ion-conductivity and smaller volume expansion during the lithiation process characterized by root mean square deviation (RMSD) and volume analysis prove the advantages of the binary doping system (Li-NaMg-SiO) for the improvement of cycle stability for Si-based materials. These advantages benefit from the loose and amorphous structures of doping systems during lithiation. Our work highlights the doping effects of multiple sources and the promotion of "inert compounds" on the entire lithiation process, which provide valuable insight for high-performance anode design.
RESUMEN
NLRs (nucleotide-binding domain and leucine-rich repeats) belong to a large family of cytoplasmic sensors that regulate an extraordinarily diverse range of biological functions. One of these functions is to contribute to immunity against infectious diseases, but dysregulation of their functional activity leads to the development of inflammatory and autoimmune diseases. Cytoplasmic innate immune sensors, including NLRs, are central regulators of intestinal homeostasis. NLRC3 (also known as CLR16.2 or NOD3) is a poorly characterized member of the NLR family and was identified in a genomic screen for genes encoding proteins bearing leucine-rich repeats (LRRs) and nucleotide-binding domains. Expression of NLRC3 is drastically reduced in the tumour tissue of patients with colorectal cancer compared to healthy tissues, highlighting an undefined potential function for this sensor in the development of cancer. Here we show that mice lacking NLRC3 are hyper-susceptible to colitis and colorectal tumorigenesis. The effect of NLRC3 is most dominant in enterocytes, in which it suppresses activation of the mTOR signalling pathways and inhibits cellular proliferation and stem-cell-derived organoid formation. NLRC3 associates with PI3Ks and blocks activation of the PI3K-dependent kinase AKT following binding of growth factor receptors or Toll-like receptor 4. These findings reveal a key role for NLRC3 as an inhibitor of the mTOR pathways, mediating protection against colorectal cancer.
RESUMEN
The epidemic of novel coronavirus disease was first reported in China in late December 2019 and was brought under control after some 2 months in China. However, it has become a global pandemic, and the number of cases and deaths continues to increase outside of China. We describe the emergence of the pandemic, detail the first 100 days of China's response as a phase 1 containment strategy followed by phase 2 containment, and briefly highlight areas of focus for the future. Specific, simple, and pragmatic strategies used in China for risk assessment, prioritization, and deployment of resources are described. Details of implementation, at different risk levels, of the traditional public health interventions are shared. Involvement of society in mounting a whole country response and challenges experienced with logistics and supply chains are described. Finally, the methods China is employing to cautiously restart social life and economic activity are outlined.
Asunto(s)
COVID-19 , China/epidemiología , Humanos , Pandemias , Salud Pública , SARS-CoV-2RESUMEN
COVID-19 was declared a pandemic by WHO on March 11, 2020, the first non-influenza pandemic, affecting more than 200 countries and areas, with more than 5·9 million cases by May 31, 2020. Countries have developed strategies to deal with the COVID-19 pandemic that fit their epidemiological situations, capacities, and values. We describe China's strategies for prevention and control of COVID-19 (containment and suppression) and their application, from the perspective of the COVID-19 experience to date in China. Although China has contained severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and nearly stopped indigenous transmission, a strong suppression effort must continue to prevent re-establishment of community transmission from importation-related cases. We believe that case finding and management, with identification and quarantine of close contacts, are vitally important containment measures and are essential in China's pathway forward. We describe the next steps planned in China that follow the containment effort. We believe that sharing countries' experiences will help the global community manage the COVID-19 pandemic by identifying what works in the struggle against SARS-CoV-2.
Asunto(s)
Manejo de Caso/organización & administración , Trazado de Contacto , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/prevención & control , Pandemias/prevención & control , Neumonía Viral/epidemiología , Neumonía Viral/prevención & control , Betacoronavirus , COVID-19 , China/epidemiología , Infecciones por Coronavirus/transmisión , Transmisión de Enfermedad Infecciosa/prevención & control , Humanos , Neumonía Viral/transmisión , Cuarentena , SARS-CoV-2RESUMEN
Exposure to diesel exhaust particles (DEPs) is associated with acute inflammatory responses in the lung and exacerbation of respiratory diseases. However, the mechanism by which DEPs trigger the inflammatory responses remains unclear. Here, we demonstrated that the IFN response factors IRF3 and IRF7 played pivotal roles in DEP-induced pulmonary inflammation. DEPs could not directly induce inflammatory cytokine expression in mouse cells, whereas DEPs triggered autophagy both in vitro and in vivo. The DEP-induced autophagy was augmented in the absence of IRF3 and IRF7, but not in the absence of IFNAR. The expression of Raptor was induced by IRF3 and IRF7 in response to DEPs treatment. Furthermore, administration of the mechanistic target of rapamycin (mTOR) inhibitor alleviated the inflammatory responses in the lung during DEP exposure. Our findings define an IFNAR-independent role of increased autophagy in the absence of IRF3 and IRF7 during pulmonary DEP exposure, and provide the basis to develop new therapeutic approaches to counteract the adverse effects of DEPs and possibly other ambient particulate matters.
Asunto(s)
Autofagia/fisiología , Factor 3 Regulador del Interferón/fisiología , Factor 7 Regulador del Interferón/fisiología , Diana Mecanicista del Complejo 1 de la Rapamicina/fisiología , Neumonía/etiología , Emisiones de Vehículos/toxicidad , Animales , Citocinas/biosíntesis , Ratones , Ratones Endogámicos C57BL , Receptor de Interferón alfa y beta/fisiología , Sirolimus/farmacologíaRESUMEN
The Zika virus (ZIKV) has two lineages, Asian and African, and their impact on developing brains has not been compared. Dengue virus (DENV) is a close family member of ZIKV and co-circulates with ZIKV. Here, we performed intracerebral inoculation of embryonic mouse brains with dengue virus 2 (DENV2), and found that DENV2 is sufficient to cause smaller brain size due to increased cell death in neural progenitor cells (NPCs) and neurons. Compared with the currently circulating Asian lineage of ZIKV (MEX1-44), DENV2 grows slower, causes less neuronal death and fails to cause postnatal animal death. Surprisingly, our side-by-side comparison uncovered that the African ZIKV isolate (MR-766) is more potent at causing brain damage and postnatal lethality than MEX1-44. In comparison with MEX1-44, MR-766 grows faster in NPCs and in the developing brain, and causes more pronounced cell death in NPCs and neurons, resulting in more severe neuronal loss. Together, these results reveal that DENV2 is sufficient to cause smaller brain sizes, and suggest that the ZIKV African lineage is more toxic and causes more potent brain damage than the Asian lineage.
Asunto(s)
Encéfalo/patología , Encéfalo/virología , Virus del Dengue/patogenicidad , Filogenia , Virus Zika/patogenicidad , África , Animales , Animales Recién Nacidos , Asia , Encéfalo/embriología , Muerte Celular , Corteza Cerebral/patología , Virus del Dengue/crecimiento & desarrollo , Gliosis/patología , Gliosis/virología , Ratones Endogámicos C57BL , Microcefalia/patología , Microglía/patología , Microglía/virología , Células-Madre Neurales/patología , Neuronas/patología , Virulencia , Virus Zika/crecimiento & desarrolloRESUMEN
Animal models of Zika virus (ZIKV) infection have recently been established in mice, guinea pigs, and nonhuman primates. Tree shrews (Tupaia belangeri) are an emerging experimental animal in biomedical applications, but their susceptibility to ZIKV infection has not been explored. In the present study, we show that subcutaneous inoculation of ZIKV led to rapid viremia and viral secretion in saliva, as well as to typical dermatological manifestations characterized by massive diffuse skin rash on the trunk. Global transcriptomic sequencing of peripheral blood mononuclear cells isolated from ZIKV-infected animals revealed systematic gene expression changes related to the inflammatory response and dermatological manifestations. Importantly, ZIKV infection readily triggered the production of high-titer neutralizing antibodies, thus preventing secondary homologous infection in tree shrews. However, neonatal tree shrews succumbed to ZIKV challenge upon intracerebral infection. The tree shrew model described here recapitulates the most common dermatological manifestations observed in ZIKV-infected patients and may greatly facilitate the elucidation of ZIKV pathogenesis and the development of novel vaccines and therapeutics.IMPORTANCE The reemergence of Zika virus (ZIKV) has caused a global public health crisis since 2016, and there are currently no vaccines or antiviral drugs to prevent or treat ZIKV infection. However, considerable advances have been made in understanding the biology and pathogenesis of ZIKV infection. In particular, various animal models have been successfully established to mimic ZIKV infection and its associated neurological diseases and to evaluate potential countermeasures. However, the clinical symptoms in these mouse and nonhuman primate models are different from the common clinical manifestations seen in human ZIKV patients; in particular, dermatological manifestations are rarely recapitulated in these animal models. Here, we developed a new animal model of ZIKV infection in tree shrews, a rat-sized, primate-related mammal. In vitro and in vivo characterization of ZIKV infection in tree shrews established a direct link between ZIKV infection and the immune responses and dermatological manifestations. The tree shrew model described here, as well as other available animal models, provides a valuable platform to study ZIKV pathogenesis and to evaluate vaccines and therapeutics.
Asunto(s)
Enfermedades Cutáneas Virales , Tupaia , Infección por el Virus Zika , Virus Zika/metabolismo , Animales , Línea Celular , Cricetinae , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/metabolismo , Inflamación/patología , Inflamación/veterinaria , Inflamación/virología , Masculino , Saliva/metabolismo , Saliva/virología , Enfermedades Cutáneas Virales/metabolismo , Enfermedades Cutáneas Virales/patología , Enfermedades Cutáneas Virales/veterinaria , Enfermedades Cutáneas Virales/virología , Tupaia/metabolismo , Tupaia/virología , Viremia/metabolismo , Viremia/patología , Viremia/virología , Infección por el Virus Zika/metabolismo , Infección por el Virus Zika/patología , Infección por el Virus Zika/veterinariaRESUMEN
Natural selection in domestic dogs is of great interest in evolutionary biology since dogs have migrated to every inhabited continent of the world alongside humans, and adapted to diverse environments. Here, we explored their demographic history and genetic basis of adaptation to the tropical African environment using whole genome analyses of 19 African indigenous dogs from Nigeria. Demographic analysis suggests that the ancestors of these dogs migrated into Africa from Eurasia 14,000 years ago and underwent a severe founder effect before population expansion. Admixture analysis further reveals that African dog genomes contain about 1.88-3.50% introgression from African golden wolves (Canis anthus). Population genetic analysis identifies 50 positively selected genes linked with immunity, angiogenesis, ultraviolet protection, as well as insulin secretion and sensitivity that may contribute to adaptation to tropical conditions. One of the positively selected genes, adhesion G protein-coupled receptor E1 (ADGRE1), has also been found to be association with severe malaria resistance in African human populations. Functional assessments showed that ADGRE1 provides protective host defense against Plasmodium infections. This result, together with the fact that the inflammatory response to canine babesiosis is similar to complicated falciparum malaria in humans, support the dogs as a model for the study of malaria control and treatment.
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Adaptación Biológica , Evolución Biológica , Perros/genética , Flujo Génico , Lobos/genética , África , Animales , Perros/inmunología , Perros/parasitología , Variación Genética , Plasmodium/inmunología , Selección Genética , Clima Tropical , Secuenciación Completa del GenomaRESUMEN
The commercial transfection reagent Lipofectamine has been widely used for cytoplasmic delivery of nucleic acids and for cytosolic engagement with intracellular innate immune sensors to trigger type I interferon (IFN) production. However, the effect of Lipofectamine alone on type I IFN response has not been studied in detail. Here, we show that Lipofectamine induced type I IFN signaling in both RAW 264.7 macrophage-like cells and primary bone marrow-derived macrophages. Type I IFN induction was dependent on interferon regulatory factor (IRF)3 and IRF7 and partially required the toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-ß. In contrast, the transfection reagent Xfect did not activate type I IFN signaling. Our study highlights the potential confounding experimental interpretation when using Lipofectamine-based transfection for delivering intracellular ligands and provides important insights into lipid signaling in innate immune responses.
Asunto(s)
Interferón Tipo I/biosíntesis , Lípidos/farmacología , Macrófagos/efectos de los fármacos , Transfección , Animales , Factor 3 Regulador del Interferón/genética , Factor 3 Regulador del Interferón/inmunología , Factor 7 Regulador del Interferón/genética , Factor 7 Regulador del Interferón/inmunología , Interferón Tipo I/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunologíaRESUMEN
Inflammasome activation is essential for host immune responses during pathogenic infection and sterile signals insult, whereas excessive activation is injurious. Thus, inflammasome activation is tightly regulated at multiple layers. Ubiquitination is an important post-translational modification for orchestrating inflammatory immune responses during pathogenic infection, and a major target hijacked by pathogenic bacteria for promoting their survival and proliferation. This review summarizes recent insights into distinct mechanisms of the inflammasome activation and ubiquitination process triggered by bacterial infection. We discuss the complex regulatory of inflammasome activation mediated by ubiquitination machinery during bacterial infection, and provide therapeutic approaches for specifically targeting aberrant inflammasome activation.
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Infecciones Bacterianas/metabolismo , Inflamasomas/metabolismo , Animales , Bacterias/inmunología , Bacterias/metabolismo , Infecciones Bacterianas/inmunología , Infecciones Bacterianas/microbiología , Biomarcadores , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunidad , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Procesamiento Proteico-Postraduccional , Transducción de Señal , UbiquitinaciónRESUMEN
Fluorescent supramolecular polymers are an important kind of smart material. In this work, a new fluorescent supramolecular hyperbranched polymer (FSHP) is constructed by orthogonal self-assembly: pillararene-based host-guest interaction and metal ion complexation interaction. The FSHP exhibits concentration-controllable fluorescence emissions. The photoluminescence spectra and light-emitting colors of FSHP can be effectively tuned by changing metal ion types or using mixed metal ions. The fluorescence quenching of FSHP solutions or FSHP-based films would occur when removing the metal ions from the backbone of FSHP. This study supplies a convenient approach toward the construction of structure-tunable fluorescent supramolecular materials with different colors.
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Polímeros/química , Colorantes/química , Complejos de Coordinación/química , Metales/química , Estructura MolecularRESUMEN
Transcription factor GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte-monocyte progenitor differentiation, and basophil and mast cell differentiation. However, precise roles of GATA2 in basophil and mast cell differentiation and maintenance have not been delineated. We have identified GATA2 as an essential transcription factor in differentiation of newly identified common basophil and mast cell progenitors into basophils and mast cells. We observed Gata2 haploinsufficiency for mast cell differentiation, but not for basophil differentiation. We examined the precise role of GATA2 in maintaining the expression of a wide range of genes that are important for performing basophil or mast cell functions. The effects of GATA2 on gene expression were broadly based. We demonstrated that GATA2 was required for maintaining Fcer1a mRNA and FcεRIα protein expression on both basophils and mast cells, as well as for maintaining Kit mRNA and c-Kit protein expression on mast cells. GATA2 was required for histamine synthesis and was also critical for Il4 mRNA expression in basophils and Il13 mRNA expression in mast cells. We demonstrate a STAT5-GATA2 connection, showing that the STAT5 transcription factor directly bound to the promoter and an intronic region of the Gata2 gene. Overexpression of the Gata2 gene was sufficient to direct basophil and mast cell differentiation in the absence of the Stat5 gene. Our study reveals that the STAT5-GATA2 pathway is critical for basophil and mast cell differentiation and maintenance.
Asunto(s)
Basófilos/citología , Basófilos/metabolismo , Diferenciación Celular , Factor de Transcripción GATA2/metabolismo , Mastocitos/citología , Mastocitos/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Animales , Animales Modificados Genéticamente , Células de la Médula Ósea/citología , Células de la Médula Ósea/metabolismo , Factor de Transcripción GATA2/genética , Regulación de la Expresión Génica , Haploinsuficiencia , Histamina/biosíntesis , Ratones , Proteínas Proto-Oncogénicas c-kit/genética , Receptores de IgE/genética , Factor de Transcripción STAT5/genética , Células Madre/citología , Células Madre/metabolismoRESUMEN
Novel 1D nanostructures offer new opportunities for improving the performance of electrochemical sensors. In this study, highly ordered 1D nanostructure array electrodes composed of SnO2 nanoparticle-coated ZnO (SnO2 @ZnO) nanotubes are designed and fabricated. The composite nanotube array architecture not only endows the electrochemical electrodes with large surface areas, but also allows electrons to be quickly transferred along the nanotubes. Modifying the SnO2 @ZnO nanotube arrays with negatively charged polymer film and employing them as a working electrode, sensitive and selective electrochemical detection of an important neurotransmitter, i.e., dopamine, is realized via the cycle voltammetry (CV) and differential pulse voltammetry (DPV) techniques. Interference from ascorbic acid can be successfully eliminated. The oxidative peak currents recorded from CV linearly depend on the dopamine concentrations from 0.1 to 100 µM with a sensitivity of 2.16 × 10(-7) A µM(-1) cm(-2) and detection limit of 45.2 nM. Using the DPV technique, an improved sensitivity and detection limit of 1.94 × 10(-6) A µM(-1) cm(-2) and 17.7 nM are respectively achieved. Moreover, the SnO2 @ZnO nanotube array electrodes can be reused through simple ultrasonical cleaning and no obvious deterioration is observed in the performance.