RESUMO
NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.
Assuntos
Antígeno HLA-B7/imunologia , Epitopos Imunodominantes/imunologia , Proteínas do Nucleocapsídeo/imunologia , SARS-CoV-2/imunologia , Linfócitos T Citotóxicos/imunologia , Idoso , Sequência de Aminoácidos , Anticorpos Antivirais/imunologia , Afinidade de Anticorpos/imunologia , COVID-19/imunologia , COVID-19/patologia , Linhagem Celular Transformada , Feminino , Perfilação da Expressão Gênica , Humanos , Memória Imunológica/imunologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T/imunologia , Índice de Gravidade de Doença , Vaccinia virus/genética , Vaccinia virus/imunologia , Vaccinia virus/metabolismoRESUMO
The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4+ and/or CD8+ epitopes, including six immunodominant regions. Six optimized CD8+ epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8+ T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.
Assuntos
Antígenos Virais/imunologia , Betacoronavirus/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , COVID-19 , Vacinas contra COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/prevenção & controle , Epitopos de Linfócito T/imunologia , Humanos , Epitopos Imunodominantes/imunologia , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/imunologia , Reino Unido , Vacinas Virais/imunologiaRESUMO
HBXIP, also named LAMTOR5, has been well characterized as a transcriptional co-activator in various cancers. However, the role of Hbxip in normal development remains unexplored. Here, we demonstrated that homozygous knockout of Hbxip leads to embryonic lethality, with retarded growth around E7.5, and that depletion of Hbxip compromises the self-renewal of embryonic stem cells (ESCs), with reduced expression of pluripotency genes, reduced cell proliferation and decreased colony-forming capacity. In addition, both Hbxip-/- ESCs and E7.5 embryos displayed defects in ectodermal and mesodermal differentiation. Mechanistically, Hbxip interacts with other components of the Ragulator complex, which is required for mTORC1 activation by amino acids. Importantly, ESCs depleted of Ragulator subunits, Lamtor3 or Lamtor4, displayed differentiation defects similar to those of Hbxip-/- ESCs. Moreover, Hbxip-/-, p14-/- and p18-/- mice, lacking subunits of the Ragulator complex, also shared similar phenotypes, embryonic lethality and retarded growth around E7-E8. Thus, we conclude that Hbxip plays a pivotal role in the development and differentiation of the epiblast, as well as the self-renewal and differentiation of ESCs, through activating mTORC1 signaling.
Assuntos
Desenvolvimento Embrionário , Células-Tronco Embrionárias , Animais , Diferenciação Celular/genética , Desenvolvimento Embrionário/genética , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Transdução de SinaisRESUMO
Development of water-stable metal-organic frameworks (MOFs) for promising visible-light-driven photocatalytic water splitting is highly desirable but still challenging. Here we report a novel p-type nickel-based MOF single crystal (Ni-TBAPy-SC) and its exfoliated nanobelts (Ni-TBAPy-NB) that can bear a wide range of pH environment in aqueous solution. Both experimental and theoretical results indicate a feasible electron transfer from the H4TBAPy ligand (light-harvesting center) to the Ni-O cluster node (catalytic center), on which water splitting to produce hydrogen can be efficiently driven free of cocatalyst. Compared to the single crystal, the exfoliated two-dimensional (2D) nanobelts show more efficient charge separation due to its shortened charge transfer distance and remarkably enhanced active surface areas, resulting in 164 times of promoted water reduction activity. The optimal H2 evolution rate on the nanobelt reaches 98 µmol h-1 (ca. 5 mmol h-1 g-1) showing benchmarked apparent quantum efficiency (AQE) of 8.0% at 420 nm among water-stable MOFs photocatalysts.
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Using a specific antibody, we found that expression of the viral restriction factor IFITM3 differs across cell types within the immune compartment with higher expression in myeloid rather than lymphoid cells. IFITM3 expression was increased following IFN stimulation, mostly type I, in immune cells, with the exception of T cells.
Assuntos
Antivirais/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Ligação a RNA/metabolismo , Células A549 , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Linfócitos/metabolismoRESUMO
OBJECTIVE: To systematically describe the short stature of patients with Diamond-Blackfan anemia and to explore factors affecting the height development of patients with Diamond-Blackfan anemia. STUDY DESIGN: This cross-sectional study was conducted at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, and the height, weight, and clinical data of 129 patients with Diamond-Blackfan anemia were collected from June 2020 to September 2020. RESULTS: The median height-age-z score (HAZ) of children affected by Diamond-Blackfan anemia was -1.54 (-6.36-1.96). Short stature was found in 37.98% of the patients. Specific Diamond-Blackfan anemia growth curves were developed for weight, height, and body mass index, separately for male and female patients. Multivariable logistic regression models showed that female sex (aOR 4.92; 95% CI 1.29-18.71; P = .0195), underweight (aOR 10.41, 95% CI 1.41-76.98, P = .0217), cardiovascular malformations (aOR 216.65; 95% CI 3.29-14279.79; P = .0118), and RPL11(aOR 29.14; 95% CI 1.18-719.10; P = .0392) or RPS26 (aOR 53.49; 95% CI 1.40-2044.30; P = .0323) mutations were independent risk factors for short stature. In the subgroup of patients who were steroid-dependent, patients with a duration of steroid therapy over 2 years (OR 2.95; 95% CI 1.00-8.66; P = .0494) or maintenance dose of prednisone >0.1 mg/kg per day (OR 3.30; 95% CI 1.02-10.72; P = .0470) had a higher incidence of short stature. CONCLUSIONS: Patients with Diamond-Blackfan anemia had a high prevalence of short stature. The risk of short stature increased with age and was associated with sex, underweight, congenital malformations, and RPL11 or RPS26 mutations. The duration of steroid therapy and maintenance dose of steroid was significantly associated with the incidence of short stature in steroid-dependent patients with Diamond-Blackfan anemia.
Assuntos
Anemia de Diamond-Blackfan/epidemiologia , Nanismo/epidemiologia , Anormalidades Múltiplas/epidemiologia , Adolescente , Fatores Etários , Anemia de Diamond-Blackfan/tratamento farmacológico , Anemia de Diamond-Blackfan/genética , Criança , Pré-Escolar , China , Estudos Transversais , Nanismo/etiologia , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Lactente , Masculino , Mutação , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Proteínas Ribossômicas , Fatores SexuaisRESUMO
OBJECTIVES: To study the association between paroxysmal nocturnal hemoglobinuria (PNH) clone and immunosuppressive therapy (IST) in children with severe aplastic anemia (SAA). METHODS: A retrospective analysis was performed on the medical data of 151 children with SAA who were admitted and received IST from January 2012 to May 2020. According to the status of PNH clone, these children were divided into a negative PNH clone group (n=135) and a positive PNH clone group (n=16). Propensity score matching was used to balance the confounding factors, and the impact of PNH clone on the therapeutic effect of IST was analyzed. RESULTS: The children with positive PNH clone accounted for 10.6% (16/151), and the median granulocyte clone size was 1.8%. The children with positive PNH clone had an older age and a higher reticulocyte count at diagnosis (P<0.05). After propensity score matching, there were no significant differences in baseline features between the negative PNH clone and positive PNH clone groups (P>0.05). The positive PNH clone group had a significantly lower overall response rate than the negative PNH clone group at 6, 12, and 24 months after IST (P<0.05). The evolution of PNH clone was heterogeneous after IST, and the children with PNH clone showed an increase in the 3-year cumulative incidence rate of aplastic anemia-PNH syndrome (P<0.05). CONCLUSIONS: SAA children with positive PNH clone at diagnosis tend to have poor response to IST and are more likely to develop aplastic anemia-PNH syndrome.
Assuntos
Anemia Aplástica , Hemoglobinúria Paroxística , Anemia Aplástica/tratamento farmacológico , Criança , Células Clonais , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/tratamento farmacológico , Hemoglobinúria Paroxística/etiologia , Humanos , Terapia de Imunossupressão , Estudos RetrospectivosRESUMO
OBJECTIVES: To investigate the distribution of body mass index (BMI) and risk factors for obesity in children with Diamond-Blackfan Anemia (DBA). METHODS: The children with DBA who attended National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, from January 2003 to December 2020 were enrolled as subjects. The related clinical data and treatment regimens were recorded. The height and weight data measured within 1 week before or after follow-up time points were collected to calculate BMI. The risk factors for obesity were determined by multivariate regression analysis in children with DBA. RESULTS: A total of 129 children with DBA were enrolled, among whom there were 80 boys (62.0%) and 49 girls (38.0%), with a median age of 49 months (range 3-189 months). The prevalence rate of obesity was 14.7% (19/129). The multivariate logistic regression analysis showed that the absence of ribosomal protein gene mutation was closely associated with obesity in children with DBA (adjusted OR=3.63, 95%CI: 1.16-11.38, adjusted P=0.027). In children with glucocorticoid-dependent DBA, obesity was not associated with age of initiation of glucocorticoid therapy, duration of glucocorticoid therapy, and maintenance dose of glucocorticoids (P>0.05). CONCLUSIONS: There is a high prevalence rate of obesity in children with DBA, and the absence of ribosomal protein gene mutation is closely associated with obesity in children with DBA.
Assuntos
Anemia de Diamond-Blackfan , Obesidade Infantil , Criança , Masculino , Feminino , Humanos , Anemia de Diamond-Blackfan/epidemiologia , Anemia de Diamond-Blackfan/genética , Obesidade Infantil/complicações , Glucocorticoides/uso terapêutico , Prevalência , Fatores de Risco , Proteínas Ribossômicas/genética , MutaçãoRESUMO
Layered two-dimensional (2D) lead halide perovskites are a class of quantum well (QW) materials, holding dramatic potentials for optical and optoelectronic applications. However, the thermally activated exciton dissociation into free carriers in 2D perovskites, a key property that determines their optoelectronic performance, was predicted to be weak due to large exciton binding energy (Eb, about 100-400 meV). Herein, in contrast to the theoretical prediction, we discover an ultrafast (<1.4 ps) and highly efficient (>80%) internal exciton dissociation in (PEA)2(MA)n-1PbnI3n+1 (PEA = C6H5C2H4NH3+, MA = CH3NH3+, n = 2-4) 2D perovskites despite the large Eb. We demonstrate that the exciton dissociation activity in 2D perovskites is significantly promoted because of the formation of exciton-polarons with considerably reduced exciton binding energy (down to a few tens of millielectronvolts) by the polaronic screening effect. This ultrafast and high-yield exciton dissociation limits the photoluminescence of 2D perovskites but on the other hand well explains their exceptional performance in photovoltaic devices. The finding should represent a common exciton property in the 2D hybrid perovskite family and provide a guideline for their rational applications in light emitting and photovoltaics.
RESUMO
Two-dimensional (2D) layered perovskites are naturally formed multiple quantum-well (QW) materials, holding great promise for applications in many optoelectronic devices. However, the further use of 2D layered perovskites in some devices is limited by the lack of QW-to-QW carrier transport/transfer due to the energy barrier formed by the insulating ligands between QWs. Herein, we report an Auger-assisted electron transfer between adjacent QWs in (CmH2m+1NH3)2PbI4 2D perovskites particularly with m = 12 and 18, where the electron energy barrier (Eb) is similar to the QW band gap energy (Eg). This Auger-assisted QW-to-QW electron transfer mechanism is established by the observation of a long-lived and derivative-like transient absorption feature, which is a signature of the quantum confined Stark effect induced by the electron-hole separation (thus an internal electric field) between different QW layers. Our finding provides a new guideline to design 2D perovskites with an optically tunable QW-to-QW charge transport property, advancing their applications in optoelectronics and optical modulations.
RESUMO
Layered two-dimensional (2D) hybrid perovskites are naturally formed multiple quantum well (QW) materials with promising applications in quantum and optoelectronic devices. In principle, the transport of excitons in 2D perovskites is limited by their short lifetime and small mobility to a distance within a few hundred nanometers. Herein, we report an observation of long-distance carrier transport over 2 to 5 µm in 2D perovskites with various well thicknesses. Such a long transport distance is enabled by trap-induced exciton dissociation into long-lived and nonluminescent electron-hole separated state, followed by a trap-mediated charge transport process. This unique property makes 2D perovskites comparable with 3D perovskites and other traditional semiconductor QWs in terms of a carrier transport property and highlights their potential application as an efficient energy/charge-delivery material.
RESUMO
The Hippo pathway modulates the transcriptional activity of Yap to regulate the differentiation of the inner cell mass (ICM) and the trophectoderm (TE) in blastocysts. Yet how Hippo signaling is differentially regulated in ICM and TE cells is poorly understood. Through an inhibitor/activator screen, we have identified Rho as a negative regulator of Hippo in TE cells, and PKA as a positive regulator of Hippo in ICM cells. We further elucidated a novel mechanism by which Rho suppresses Hippo, distinct from the prevailing view that Rho inhibits Hippo signaling through modulating cytoskeleton remodeling and/or cell polarity. Active Rho prevents the phosphorylation of Amot Ser176, thus stabilizing the interaction between Amot and F-actin, and restricting the binding between Amot and Nf2. Moreover, Rho attenuates the interaction between Amot and Nf2 by binding to the coiled-coil domain of Amot. By blocking the association of Nf2 and Amot, Rho suppresses Hippo in TE cells.
Assuntos
Blastocisto/citologia , Blastocisto/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas dos Microfilamentos/metabolismo , Neurofibromina 2/metabolismo , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Actinas/metabolismo , Angiomotinas , Animais , Linhagem Celular , Membrana Celular/metabolismo , Polaridade Celular , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Citoesqueleto/metabolismo , Ectoderma/citologia , Ectoderma/metabolismo , Feminino , Peptídeos e Proteínas de Sinalização Intercelular/química , Camundongos Endogâmicos ICR , Proteínas dos Microfilamentos/química , Modelos Biológicos , Fosforilação , Ligação Proteica , Domínios Proteicos , Quinases Associadas a rho/metabolismoRESUMO
Based on their excellent stability, high carrier mobility, and wide photoresponse range, composites formed by embedding perovskite quantum dots (PQDs) into metal-organic frameworks (PQDs@MOF) show great development potential in the field of photocatalysis, including the toxic hexavalent chromium (Cr6+) degradation, CO2 reduction, H2 production, etc. However, the rapid recombination of photogenerated carriers is still a major obstacle to the improvement of photocatalytic performance, and the internal mechanism of photocatalysis is still unclear. In this work, we construct a novel double heterojunction photocatalyst by encapsulating CsPbBr3 PQDs in Zr-based metal-organic frameworks (UiO-67) and loading additional hole-acceptor pentylenetetrazol (PTZ). Spontaneous photoinduced charge-transfer and separation between interfaces are confirmed by time-resolved photoluminescence and transient absorption spectroscopy. Furthermore, compared with pure UiO-67, the photoactivity of CsPbBr3 PQDs@UiO-67@PTZ increased 3-fold due to the long-lived charge-separated state. Our findings provide a new guideline for the design of PQDs@MOF-based photocatalysts with long-lived photogenerated carriers and outstanding photocatalytic activity.
RESUMO
Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two SARS-CoV-2 nucleoprotein CD8+ epitopes, we investigated the contribution of these flanking mutations to proteasomal processing and T cell activation. We found decreased NP9-17-B*27:05 CD8+ T cell responses to the NP-Q7K mutation, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103 N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-B*07:02 epitopes, respectively, increased CD8+ T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on proteasomal processing, either contributing to T cell escape or enhancement that may be exploited for future vaccine design.
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Most existing studies characterizing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell responses are peptide based. This does not allow evaluation of whether tested peptides are processed and presented canonically. In this study, we use recombinant vaccinia virus (rVACV)-mediated expression of SARS-CoV-2 spike protein and SARS-CoV-2 infection of angiotensin-converting enzyme (ACE)-2-transduced B cell lines to evaluate overall T cell responses in a small cohort of recovered COVID-19 patients and uninfected donors vaccinated with ChAdOx1 nCoV-19. We show that rVACV expression of SARS-CoV-2 antigen can be used as an alternative to SARS-CoV-2 infection to evaluate T cell responses to naturally processed spike antigens. In addition, the rVACV system can be used to evaluate the cross-reactivity of memory T cells to variants of concern (VOCs) and to identify epitope escape mutants. Finally, our data show that both natural infection and vaccination could induce multi-functional T cell responses with overall T cell responses remaining despite the identification of escape mutations.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , ChAdOx1 nCoV-19 , Vacinação , Anticorpos AntiviraisRESUMO
Accurate characterization of the longitudinal (along the thickness direction) carrier transport property is of significant importance for evaluating the quality and performance of perovskite thin films. Herein, we report the development of a modified transient reflection (TR) spectroscopy method to realize the direct observation and determination of the longitudinal carrier transport process in MAPbI3 polycrystalline thin films. Unlike the traditional TR spectroscopy, the carrier transport dynamics along the film thickness is resolved by making the pump (excitation) and probe beams spatially separated on each side of the film, so that the carrier transport from the excitation side to the probe side is directly captured. Utilizing this method, the longitudinal carrier diffusion coefficients (D) in various perovskite films with different thicknesses and grain sizes (extracted from SEM images) are determined, showing D values of â¼1.5 to 1.8 cm2 s-1 (â¼0.5 to 0.8 cm2 s-1) for films with grain size larger (smaller) than the thickness. This empirical correlation between the longitudinal D and film thickness/grain size provides a reference for quick quality screening and evaluation of perovskite polycrystalline thin films.
RESUMO
Immunodominance is a complex and highly debated topic of T cell biology. The current SARS-CoV-2 pandemic has provided the opportunity to profile adaptive immune responses and determine molecular factors contributing to emerging responses towards immunodominant viral epitopes. Here, we discuss parameters that alter the dynamics of CD8 viral epitope processing, generation and T-cell responses, and how immunodominance counteracts viral immune escape mechanisms that develop in the context of emerging SARS-CoV-2 variants.
Assuntos
Epitopos Imunodominantes/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Apresentação de Antígeno , Citosol/metabolismo , Humanos , Complexo de Endopeptidases do Proteassoma/fisiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T Citotóxicos/imunologiaRESUMO
The temperature-induced phase transition in two-dimensional (2D) layered perovskites was recently found to be incomplete even if the temperature dropped to tens of kelvin. However, its intrinsic cause still remains unclear, and the information on the phase transition in individual single crystals (SCs) is also limited. Herein, we study the phase transition process in individual (n-C4H9NH3)2PbI4 SCs using a home-built photoluminescence (PL)-scanned image microscope. At 83 K, the phase transition is indeed incomplete, leading to the coexistence and inhomogeneous distributions of room-temperature and low-temperature phases. We map the distribution of phase transition degree on individual SCs at 83 K, which exhibits a strong positive (negative) correlation with the distribution of local defects (PL lifetimes) at 293 K, indicating that the phase transition is enhanced by initial defects. Our findings might provide new insight into the phase transition of (n-C4H9NH3)2PbI4 crystals, which is of potential value for applications based on 2D layered perovskites.
RESUMO
The encapsulation of perovskite quantum dots (PQDs) in metal organic frameworks (MOFs) is a promising strategy for fabricating stable and functional perovskite solid composites (denoted as PQDs@MOF), which have exhibited great potential for optoelectronics, catalysis, and luminesce applications. However, the exciton diffusion distance, one of the key factors determining the performance of PQDs@MOF in these applications, remains unknown. Herein, by using time-resolved and photoluminescence-scanned imaging microscopy, we report the observation of long-distance exciton transport (278 ± 12.6 nm) and high diffusion coefficient (0.0428 ± 0.0039 cm2/s) in MAPbBr3 PQDs@MOF microcrystals. We show that the long exciton diffusion length, which is seven times longer than that in colloid MAPbBr3 PQD solid films, can be attributed to the strong dipole-dipole coupling between adjacent PQDs embedded in the MOF matrix and their long carrier lifetimes. These findings demonstrate the great potential of PQDs@MOF crystals for optoelectronic applications.