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Chemical doping is an important approach to manipulating charge-carrier concentration and transport in organic semiconductors (OSCs)1-3 and ultimately enhances device performance4-7. However, conventional doping strategies often rely on the use of highly reactive (strong) dopants8-10, which are consumed during the doping process. Achieving efficient doping with weak and/or widely accessible dopants under mild conditions remains a considerable challenge. Here, we report a previously undescribed concept for the photocatalytic doping of OSCs that uses air as a weak oxidant (p-dopant) and operates at room temperature. This is a general approach that can be applied to various OSCs and photocatalysts, yielding electrical conductivities that exceed 3,000 S cm-1. We also demonstrate the successful photocatalytic reduction (n-doping) and simultaneous p-doping and n-doping of OSCs in which the organic salt used to maintain charge neutrality is the only chemical consumed. Our photocatalytic doping method offers great potential for advancing OSC doping and developing next-generation organic electronic devices.
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Upon replication fork stalling, the RPA-coated single-stranded DNA (ssDNA) formed behind the fork activates the ataxia telangiectasia-mutated and Rad3-related (ATR) kinase, concomitantly initiating Rad18-dependent monoubiquitination of PCNA. However, whether crosstalk exists between these two events and the underlying physiological implications of this interplay remain elusive. In this study, we demonstrate that during replication stress, ATR phosphorylates human Rad18 at Ser403, an adjacent residue to a previously unidentified PIP motif (PCNA-interacting peptide) within Rad18. This phosphorylation event disrupts the interaction between Rad18 and PCNA, thereby restricting the extent of Rad18-mediated PCNA monoubiquitination. Consequently, excessive accumulation of the tumor suppressor protein SLX4, now characterized as a novel reader of ubiquitinated PCNA, at stalled forks is prevented, contributing to the prevention of stalled fork collapse. We further establish that ATR preserves telomere stability in alternative lengthening of telomere (ALT) cells by restricting Rad18-mediated PCNA monoubiquitination and excessive SLX4 accumulation at telomeres. These findings shed light on the complex interplay between ATR activation, Rad18-dependent PCNA monoubiquitination, and SLX4-associated stalled fork processing, emphasizing the critical role of ATR in preserving replication fork stability and facilitating telomerase-independent telomere maintenance.
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Telomerase , Humanos , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Telomerase/genética , Ubiquitinação , Replicação do DNA , Telômero/genética , Telômero/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNARESUMO
The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.
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Proteínas de Ciclo Celular , Centrômero , Cromátides , Proteínas Cromossômicas não Histona , Cinetocoros , Cinetocoros/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Humanos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Cromátides/metabolismo , Cromátides/genética , Centrômero/metabolismo , Coesinas , Células HeLa , Ligação Proteica , Cristalografia por Raios XRESUMO
Studies using antigen-presenting systems at the single-cell and ensemble levels can provide complementary insights into T-cell signaling and activation. Although crucial for advancing basic immunology and immunotherapy, there is a notable absence of synthetic material toolkits that examine T cells at both levels, and especially those capable of single-molecule-level manipulation. Here we devise a biomimetic antigen-presenting system (bAPS) for single-cell stimulation and ensemble modulation of T-cell recognition. Our bAPS uses hexapod heterostructures composed of a submicrometer cubic hematite core (α-Fe2O3) and nanostructured silica branches with diverse surface modifications. At single-molecule resolution, we show T-cell activation by a single agonist peptide-loaded major histocompatibility complex; distinct T-cell receptor (TCR) responses to structurally similar peptides that differ by only one amino acid; and the superior antigen recognition sensitivity of TCRs compared with that of chimeric antigen receptors (CARs). We also demonstrate how the magnetic field-induced rotation of hexapods amplifies the immune responses in suspended T and CAR-T cells. In addition, we establish our bAPS as a precise and scalable method for identifying stimulatory antigen-specific TCRs at the single-cell level. Thus, our multimodal bAPS represents a unique biointerface tool for investigating T-cell recognition, signaling and function.
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Ativação Linfocitária , Linfócitos T , Linfócitos T/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Apresentação de Antígeno , Dióxido de Silício/química , Compostos Férricos/química , Peptídeos/química , Peptídeos/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Nanoestruturas/química , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismoRESUMO
Upon DNA damage, numerous proteins are targeted for ubiquitin-dependent proteasomal degradation, which is an integral part of the DNA repair program. Although details of the ubiquitination processes have been intensively studied, little is known about whether and how the 26S proteasome is regulated in the DNA damage response (DDR). Here, we show that human Rpn10/PSMD4, one of the three ubiquitin receptors of the 26S proteasome, is rapidly phosphorylated in response to different types of DNA damage. The phosphorylation occurs at Rpn10-Ser266 within a conserved SQ motif recognized by ATM/ATR/DNA-PK. Blockade of S266 phosphorylation attenuates homologous recombination-mediated DNA repair and sensitizes cells to genotoxic insults. In vitro and in cellulo experiments indicate that phosphorylation of S266, located in the flexible linker between the two ubiquitin-interacting motifs (UIMs) of Rpn10, alters the configuration of UIMs, and actually reduces ubiquitin chain (substrate) binding. As a result, essential DDR proteins such as BRCA1 are spared from premature degradation and allowed sufficient time to engage in DNA repair, a scenario supported by proximity labeling and quantitative proteomic studies. These findings reveal an inherent self-limiting mechanism of the proteasome that, by controlling substrate recognition through Rpn10 phosphorylation, fine-tunes protein degradation for optimal responses under stress.
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Dano ao DNA , Reparo do DNA , Complexo de Endopeptidases do Proteassoma , Complexo de Endopeptidases do Proteassoma/metabolismo , Humanos , Fosforilação , Ubiquitina/metabolismo , Proteína BRCA1/metabolismo , Especificidade por Substrato , Ubiquitinação , Proteínas de Ligação a RNARESUMO
The ring-shaped Cohesin complex, consisting of core subunits Smc1, Smc3, Scc1, and SA2 (or its paralog SA1), topologically entraps two duplicated sister DNA molecules to establish sister chromatid cohesion in S-phase. It remains largely elusive how the Cohesin release factor Wapl binds the Cohesin complex, thereby inducing Cohesin disassociation from mitotic chromosomes to allow proper resolution and separation of sister chromatids. Here, we show that Wapl uses two structural modules containing the FGF motif and the YNARHWN motif, respectively, to simultaneously bind distinct pockets in the extensive composite interface between Scc1 and SA2. Strikingly, only when both docking modules are mutated, Wapl completely loses the ability to bind the Scc1-SA2 interface and release Cohesin, leading to erroneous chromosome segregation in mitosis. Surprisingly, Sororin, which contains a conserved FGF motif and functions as a master antagonist of Wapl in S-phase and G2-phase, does not bind the Scc1-SA2 interface. Moreover, Sgo1, the major protector of Cohesin at mitotic centromeres, can only compete with the FGF motif but not the YNARHWN motif of Wapl for binding Scc1-SA2 interface. Our data uncover the molecular mechanism by which Wapl binds Cohesin to ensure precise chromosome segregation.
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Proteínas de Ciclo Celular , Proteínas Cromossômicas não Histona , Segregação de Cromossomos , Coesinas , Proteínas Cromossômicas não Histona/metabolismo , Proteínas Cromossômicas não Histona/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Humanos , Ligação Proteica , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Motivos de Aminoácidos , Mitose , Cromátides/metabolismo , Proteínas de Transporte , Proteínas Proto-OncogênicasRESUMO
Post-transcriptional regulation by small RNAs and post-translational modifications (PTM) such as lysine acetylation play fundamental roles in physiological circuits, offering rapid responses to environmental signals with low energy consumption. Yet, the interplay between these regulatory systems remains underexplored. Here, we unveil the cross-talk between sRNAs and lysine acetylation in Streptococcus mutans, a primary cariogenic pathogen known for its potent acidogenic virulence. Through systematic overexpression of sRNAs in S. mutans, we identified sRNA SmsR1 as a critical player in modulating acidogenicity, a key cariogenic virulence feature in S. mutans. Furthermore, combined with the analysis of predicted target mRNA and transcriptome results, potential target genes were identified and experimentally verified. A direct interaction between SmsR1 and 5'-UTR region of pdhC gene was determined by in vitro binding assays. Importantly, we found that overexpression of SmsR1 reduced the expression of pdhC mRNA and increased the intracellular concentration of acetyl-CoA, resulting in global changes in protein acetylation levels. This was verified by acetyl-proteomics in S. mutans, along with an increase in acetylation level and decreased activity of LDH. Our study unravels a novel regulatory paradigm where sRNA bridges post-transcriptional regulation with post-translational modification, underscoring bacterial adeptness in fine-tuning responses to environmental stress.
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Proteínas de Bactérias , Regulação Bacteriana da Expressão Gênica , Processamento de Proteína Pós-Traducional , Streptococcus mutans , Animais , Acetilação , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Cárie Dentária/microbiologia , Cárie Dentária/metabolismo , RNA Bacteriano/metabolismo , RNA Bacteriano/genética , Pequeno RNA não Traduzido/metabolismo , Pequeno RNA não Traduzido/genética , Streptococcus mutans/metabolismo , Streptococcus mutans/genética , Streptococcus mutans/patogenicidade , Virulência , Feminino , RatosRESUMO
The stabilization of stalled forks has emerged as a crucial mechanism driving resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient tumors. Here, we identify UFL1, a UFM1-specific E3 ligase, as a pivotal regulator of fork stability and the response to PARP inhibitors in BRCA1/2-deficient cells. On replication stress, UFL1 localizes to stalled forks and catalyzes the UFMylation of PTIP, a component of the MLL3/4 methyltransferase complex, specifically at lysine 148. This modification facilitates the assembly of the PTIP-MLL3/4 complex, resulting in the enrichment of H3K4me1 and H3K4me3 at stalled forks and subsequent recruitment of the MRE11 nuclease. Consequently, loss of UFL1, disruption of PTIP UFMylation or overexpression of the UFM1 protease UFSP2 protects nascent DNA strands from extensive degradation and confers resistance to PARP inhibitors in BRCA1/2-deficient cells. These findings provide mechanistic insights into the processes underlying fork instability in BRCA1/2-deficient cells and offer potential therapeutic avenues for the treatment of BRCA1/2-deficient tumors.
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Complex organisms generate differential gene expression through the same set of DNA sequences in distinct cells. The communication between chromatin and RNA regulates cellular behavior in tissues. However, little is known about how chromatin, especially histone modifications, regulates RNA polyadenylation. In this study, we found that FUS was recruited to chromatin by H3K36me3 at gene bodies. The H3K36me3 recognition of FUS was mediated by the proline residues in the ZNF domain. After these proline residues were mutated or H3K36me3 was abolished, FUS dissociated from chromatin and bound more to RNA, resulting in an increase in polyadenylation sites far from stop codons genome-wide. A proline mutation corresponding to a mutation in amyotrophic lateral sclerosis contributed to the hyperactivation of mitochondria and hyperdifferentiation in mouse embryonic stem cells. These findings reveal that FUS is an H3K36me3 reader protein that links chromatin-mediated alternative polyadenylation to human disease.
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Histonas , Poliadenilação , Proteína FUS de Ligação a RNA , Animais , Humanos , Camundongos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Diferenciação Celular/genética , Cromatina/metabolismo , Cromatina/genética , Células HEK293 , Histonas/metabolismo , Histonas/genética , Mitocôndrias/metabolismo , Mitocôndrias/genética , Células-Tronco Embrionárias Murinas , Mutação , Poliadenilação/genética , Proteína FUS de Ligação a RNA/genética , Proteína FUS de Ligação a RNA/metabolismo , Linhagem Celular , Domínios ProteicosRESUMO
Nuclear actin-based movements support DNA double-strand break (DSB) repair. However, molecular determinants that promote filamentous actin (F-actin) formation on the damaged chromatin remain undefined. Here we describe the DYRK1A kinase as a nuclear activity that promotes local F-actin assembly to support DSB mobility and repair, accomplished in part by its targeting of actin nucleator spire homolog 1 (Spir1). Indeed, perturbing DYRK1A-dependent phosphorylation of S482 mis-regulated Spir1 accumulation at damaged-modified chromatin, and led to compromised DSB-associated actin polymerization and attenuated DNA repair. Our findings uncover a role of the DYRK1A-Spir1 axis in nuclear actin dynamics during early DSB responses, and highlight the intricate details of nuclear cytoskeletal network in DSB repair and genome stability maintenance.
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ConspectusElectrocatalytic reactions, such as oxygen reduction/evolution reactions and CO2 reduction reaction that are pivotal for the energy transition, are multistep processes that occur in a nanoscale electric double layer (EDL) at a solid-liquid interface. Conventional analyses based on the Sabatier principle, using binding energies or effective electronic structure properties such as the d-band center as descriptors, are able to grasp overall trends in catalytic activity in specific groups of catalysts. However, thermodynamic approaches often fail to account for electrolyte effects that arise in the EDL, including pH, cation, and anion effects. These effects exert strong impacts on electrocatalytic reactions. There is growing consensus that the local reaction environment (LRE) prevailing in the EDL is the key to deciphering these complex and hitherto perplexing electrolyte effects. Increasing attention is thus paid to designing electrolyte properties, positioning the LRE at center stage. To this end, unraveling the LRE is becoming essential for designing electrocatalysts with specifically tailored properties, which could enable much needed breakthroughs in electrochemical energy science.Theory and modeling are getting more and more important and powerful in addressing this multifaceted problem that involves physical phenomena at different scales and interacting in a multidimensional parametric space. Theoretical models developed for this purpose should treat intrinsic multistep kinetics of electrocatalytic reactions, EDL effects from subnm scale to the scale of 10 nm, and mass transport phenomena bridging scales from <0.1 to 100 µm. Given the diverse physical phenomena and scales involved, it is evident that the challenge at hand surpasses the capabilities of any single theoretical or computational approach.In this Account, we present a hierarchical theoretical framework to address the above challenge. It seamlessly integrates several modules: (i) microkinetic modeling that accounts for various reaction pathways; (ii) an LRE model that describes the interfacial region extending from the nanometric EDL continuously to the solution bulk; (iii) first-principles calculations that provide parameters, e.g., adsorption energies, activation barriers and EDL parameters. The microkinetic model considers all elementary steps without designating an a priori rate-determining step. The kinetics of these elementary steps are expressed in terms of local concentrations, potential and electric field that are codetermined by EDL charging and mass transport in the LRE model. Vital insights on electrode kinetic phenomena, i.e., potential-dependent Tafel slopes, cation effects, and pH effects, obtained from this hierarchical framework are then reviewed. Finally, an outlook on further improvement of the model framework is presented, in view of recent developments in first-principles based simulation of electrocatalysis, observations of dynamic reconstruction of catalysts, and machine-learning assisted computational simulations.
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Cellulose nanofiber (CNF) possesses excellent intrinsic properties, and many CNF-based high-performance structural and functional materials have been developed recently. However, the coordination of the mechanical properties and functionality is still a considerable challenge. Here, a CNF-based structural material is developed by a bioinspired gradient structure design using hollow magnetite nanoparticles and the phosphorylation-modified CNF as building blocks, which simultaneously achieves a superior mechanical performance and electromagnetic wave absorption (EMA) ability. Benefiting from the gradient design, the flexural strength of the structural material reached â¼205 MPa. Meanwhile, gradient design improves impedance matching, contributing to the high EMA ability (-59.5 dB) and wide effective absorption width (5.20 GHz). Besides, a low coefficient of thermal expansion and stable storage modulus was demonstrated as the temperature changes. The excellent mechanical, thermal, and EMA performance exhibited great potential for application in stealth equipment and electromagnetic interference protecting electronic packaging materials.
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Toll-like receptors (TLRs) play an important role in inducing innate and acquired immune responses against infection. However, the effect of Toll-like receptor 7 (TLR7) on follicular helper T (Tfh) cells in mice infected with Plasmodium is still not clear. The results showed that the splenic CD4+ CXCR5+ PD-1+ Tfh cells were accumulated after Plasmodium yoelii NSM infection, the content of splenic Tfh cells was correlated to parasitemia and/or the red blood cells (RBCs) counts in the blood. Moreover, the expression of TLR7 was found higher than TLR2, TLR3 and TLR4 in splenic Tfh cells of the WT mice. TLR7 agonist R848 and the lysate of red blood cells of infected mice (iRBCs) could induce the activation and differentiation of splenic Tfh cells. Knockout of TLR7 leads to a decrease in the proportion of Tfh cells, down-regulated expression of functional molecules CD40L, IFN-γ, IL-21 and IL-10 in Tfh cells; decreased the proportion of plasma cells and antibody production and reduces the expression of STAT3 and Ikzf2 in Tfh cells. Administration of R848 could inhibit parasitemia, enhance splenic Tfh cell activation and increase STAT3 and Ikzf2 expression in Tfh cells. In summary, this study shows that TLR7 could regulate the function of Tfh cells, affecting the immune response in the spleen of Plasmodium yoelii NSM-infected mice.
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Malária , Plasmodium yoelii , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Parasitemia/metabolismo , Plasmodium yoelii/metabolismo , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Auxiliares-Indutores , Receptor 7 Toll-Like/metabolismoRESUMO
The total syntheses of penicibilaenes A and B are described. The key step is the tBuOK/DMSO-mediated tandem 5-exo-dig Conia-ene type reaction and 6-exo-dig Conia-ene type reaction to install the tricyclic [6.3.1.01,5] dodecane core of penicibilaenes from dibutynyl cyclohexanone in a single step, together with a sequence of copper-mediated conjugate addition and Crabtree's hydrogenation to forge the stereogenic centers at C5 and C2, respectively.
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In pursuit of a sustainable future powered by renewable energy, hydrogen production through water splitting should achieve high energy efficiency with economical materials. Here, we present a nanofluidic electrolyzer that leverages overlapping cathode and anode electric double layers (EDLs) to drive the splitting of pure water. Convective flow is introduced between the nanogap electrodes to suppress the crossover of generated gases. The strong electric field within the overlapping EDLs enhances ion migration and facilitates the dissociation of water molecules. Acidic and basic environments, which are created in situ at the cathode and anode, respectively, enable the use of nonprecious metal catalysts. All these merits allow the reactor to exhibit a current density of 2.8 A·cm-2 at 1.7 V with a nickel anode. This paves the way toward a new type of water electrolyzer that needs no membrane, no supporting electrolyte, and no precious metal catalysts.
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Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) is a benchmark hole-transporting (p-type) polymer that finds applications in diverse electronic devices. Most of its success is due to its facile synthesis in water, exceptional processability from aqueous solutions, and outstanding electrical performance in ambient. Applications in fields like (opto-)electronics, bioelectronics, and energy harvesting/storage devices often necessitate the complementary use of both p-type and n-type (electron-transporting) materials. However, the availability of n-type materials amenable to water-based polymerization and processing remains limited. Herein, we present a novel synthesis method enabling direct polymerization in water, yielding a highly conductive, water-processable n-type conjugated polymer, namely, poly[(2,2'-(2,5-dihydroxy-1,4-phenylene)diacetic acid)-stat-3,7-dihydrobenzo[1,2-b:4,5-b']difuran-2,6-dione] (PDADF), with remarkable electrical conductivity as high as 66 S cm-1, ranking among the highest for n-type polymers processed using green solvents. The new n-type polymer PDADF also exhibits outstanding stability, maintaining 90% of its initial conductivity after 146 days of storage in air. Our synthetic approach, along with the novel polymer it yields, promises significant advancements for the sustainable development of organic electronic materials and devices.
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Unraveling the mechanism of chirality transfer across length scales is crucial to the rational development of functional materials with hierarchical chirality. The key obstacle is the lack of structural information, especially at the mesoscopic level. We report herein the structural identification of helical covalent organic frameworks (heliCOFs) with hierarchical chirality, which integrate molecular chirality, channel chirality, and morphology chirality into one crystalline entity. Specifically, benefiting from the highly ordered structure of heliCOFs, the existence of chiral channels at the mesoscopic level has been confirmed by electron crystallography, and the handedness of these chiral channels has been directly determined through the stereopair imaging technique. Accordingly, the chirality transfer in heliCOFs from microscopic to macroscopic levels could be rationalized with a layer-rotating model that has been supported by both crystal structure analysis and theoretical calculations. Observation of chiral channels in heliCOFs not only provides unprecedented data for the understanding of the chirality transfer process but also sheds new light on the rational construction of highly ordered polymeric materials with hierarchical chirality.
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BACKGROUND: Despite the functions of TLRs in the parasitic infections have been extensively reported, few studies have addressed the role of TLR3 in the immune response to Schistosoma japonicum infections. The aim of this study was to investigate the properties of TLR3 in the liver of C57BL/6 mice infected by S. japonicum. METHODS: The production of TLR3+ cells in CD4+T cells (CD4+CD3+), CD8+T cells (CD8+CD3+), γδT cells (γδTCR+CD3+), NKT cells (NK1.1+CD3+), B cells (CD19+CD3-), NK (NK1.1-CD3+) cells, MDSC (CD11b+Gr1+), macrophages (CD11b+F4/80+), DCs (CD11c+CD11b+) and neutrophils (CD11b+ Ly6g+) were assessed by flow cytometry. Sections of the liver were examined by haematoxylin and eosin staining in order to measure the area of granulomas. Hematological parameters including white blood cell (WBC), red blood cell (RBC), platelet (PLT) and hemoglobin (HGB) were analyzed. The levels of ALT and AST in the serum were measured using biochemical kits. The relative titers of anti-SEA IgG and anti-SEA IgM in the serum were measured by enzyme-linked immunosorbent assay (ELISA). CD25, CD69, CD314 and CD94 molecules were detected by flow cytometry. RESULTS: Flow cytometry results showed that the expression of TLR3 increased significantly after S. japonicum infection (P < 0.05). Hepatic myeloid and lymphoid cells could express TLR3, and the percentages of TLR3-expressing MDSC, macrophages and neutrophils were increased after infection. Knocking out TLR3 ameliorated the damage and decreased infiltration of inflammatory cells in infected C57BL/6 mouse livers.,The number of WBC was significantly reduced in TLR3 KO-infected mice compared to WT-infected mice (P < 0.01), but the levels of RBC, platelet and HGB were significantly increased in KO infected mice. Moreover, the relative titers of anti-SEA IgG and anti-SEA IgM in the serum of infected KO mice were statistically decreased compared with the infected WT mice. We also compared the activation-associated molecules expression between S.japonicum-infected WT and TLR3 KO mice. CONCLUSIONS: Taken together, our data indicated that TLR3 played potential roles in the context of S. japonicum infection and it may accelerate the progression of S. japonicum-associated liver pathology.
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Schistosoma japonicum , Animais , Camundongos , Schistosoma japonicum/metabolismo , Receptor 3 Toll-Like/metabolismo , Camundongos Endogâmicos C57BL , Imunoglobulina G , Imunoglobulina MRESUMO
Patients with caspase-associated recruitment domain-9 (CARD9) deficiency are more likely to develop invasive fungal disease that affect CNS. However, the understanding of how Candida invades and persists in CNS is still limited. We here reported a 24-year-old woman who were previously immunocompetent and diagnosed with CNS candidiasis. A novel autosomal recessive homozygous CARD9 mutation (c.184 + 5G > T) from this patient was identified using whole genomic sequencing. Furthermore, we extensively characterized the impact of this CARD9 mutation on the host immune response in monocytes, neutrophils and CD4 + T cells, using single cell sequencing and in vitro experiments. Decreased pro-inflammatory cytokine productions of CD14 + monocyte, impaired Th17 cell differentiation, and defective neutrophil accumulation in CNS were found in this patient. In conclusion, this study proposed a novel mechanism of CNS candidiasis development. Patients with CNS candidiasis in absence of known immunodeficiencies should be analyzed for CARD9 gene mutation as the cause of invasive fungal infection predisposition.
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Proteínas Adaptadoras de Sinalização CARD , Humanos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/deficiência , Feminino , Adulto Jovem , Mutação , Neutrófilos/imunologia , Células Th17/imunologia , Candidíase Mucocutânea Crônica/genética , Candidíase Mucocutânea Crônica/imunologia , Monócitos/imunologia , CitocinasRESUMO
Acute myeloid leukaemia (AML) is a highly heterogeneous disease, exhibiting diverse subtypes according to the characteristics of tumour cells. The immunophenotype is one of the aspects acquired routinely through flow cytometry in the diagnosis of AML. Here, we characterized the antigen expression in paediatric AML cases across both morphological and molecular genetic subgroups. We discovered a subgroup of patients with unfavourable prognosis that can be immunologically characterized, irrespective of morphological FAB results or genetic aberrations. Cox regression analysis unveiled key antigens influencing the prognosis of AML patients. In terms of underlying genotypes, we observed that the antigenic profiles and outcomes of one specific group, primarily composed of CBFA2T3::GLIS2 and FUS::ERG, were analogous to the reported RAM phenotype. Overall, our data highlight the significance of immunophenotype to tailor treatment for paediatric AML.