RESUMEN
CD4+ T cells with latent HIV-1 infection persist despite treatment with antiretroviral agents and represent the main barrier to a cure of HIV-1 infection. Pharmacological disruption of viral latency may expose HIV-1-infected cells to host immune activity, but the clinical efficacy of latency-reversing agents for reducing HIV-1 persistence remains to be proven. Here, we show in a randomized-controlled human clinical trial that the histone deacetylase inhibitor panobinostat, when administered in combination with pegylated interferon-α2a, induces a structural transformation of the HIV-1 reservoir cell pool, characterized by a disproportionate overrepresentation of HIV-1 proviruses integrated in ZNF genes and in chromatin regions with reduced H3K27ac marks, the molecular target sites for panobinostat. By contrast, proviruses near H3K27ac marks were actively selected against, likely due to increased susceptibility to panobinostat. These data suggest that latency-reversing treatment can increase the immunological vulnerability of HIV-1 reservoir cells and accelerate the selection of epigenetically privileged HIV-1 proviruses.
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Infecciones por VIH , VIH-1 , Inhibidores de Histona Desacetilasas , Interferón-alfa , Panobinostat , Provirus , Humanos , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Panobinostat/uso terapéutico , Provirus/efectos de los fármacos , Latencia del Virus , Inhibidores de Histona Desacetilasas/uso terapéutico , Interferón-alfa/uso terapéuticoRESUMEN
HIV-1-infected cells that persist despite antiretroviral therapy (ART) are frequently considered "transcriptionally silent," but active viral gene expression may occur in some cells, challenging the concept of viral latency. Applying an assay for profiling the transcriptional activity and the chromosomal locations of individual proviruses, we describe a global genomic and epigenetic map of transcriptionally active and silent proviral species and evaluate their longitudinal evolution in persons receiving suppressive ART. Using genome-wide epigenetic reference data, we show that proviral transcriptional activity is associated with activating epigenetic chromatin features in linear proximity of integration sites and in their inter- and intrachromosomal contact regions. Transcriptionally active proviruses were actively selected against during prolonged ART; however, this pattern was violated by large clones of virally infected cells that may outcompete negative selection forces through elevated intrinsic proliferative activity. Our results suggest that transcriptionally active proviruses are dynamically evolving under selection pressure by host factors.
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VIH-1/genética , Provirus/genética , Transcripción Genética , Anciano , Secuencia de Bases , Evolución Biológica , Cromatina/metabolismo , Células Clonales , ADN Viral/genética , Epigénesis Genética/efectos de los fármacos , Femenino , Humanos , Ionomicina/farmacología , Masculino , Persona de Mediana Edad , Filogenia , Provirus/efectos de los fármacos , ARN Viral/genética , Acetato de Tetradecanoilforbol/farmacología , Transcripción Genética/efectos de los fármacos , Integración Viral/genética , Latencia del Virus/efectos de los fármacos , Latencia del Virus/genéticaRESUMEN
Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.
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Infecciones por Coronavirus/inmunología , Centro Germinal/inmunología , Neumonía Viral/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , COVID-19 , Femenino , Centro Germinal/patología , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Bazo/inmunología , Bazo/patología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Multiple genome-wide studies have identified associations between outcome of human immunodeficiency virus (HIV) infection and polymorphisms in and around the gene encoding the HIV co-receptor CCR5, but the functional basis for the strongest of these associations, rs1015164A/G, is unknown. We found that rs1015164 marks variation in an activating transcription factor 1 binding site that controls expression of the antisense long noncoding RNA (lncRNA) CCR5AS. Knockdown or enhancement of CCR5AS expression resulted in a corresponding change in CCR5 expression on CD4+ T cells. CCR5AS interfered with interactions between the RNA-binding protein Raly and the CCR5 3' untranslated region, protecting CCR5 messenger RNA from Raly-mediated degradation. Reduction in CCR5 expression through inhibition of CCR5AS diminished infection of CD4+ T cells with CCR5-tropic HIV in vitro. These data represent a rare determination of the functional importance of a genome-wide disease association where expression of a lncRNA affects HIV infection and disease progression.
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Regulación de la Expresión Génica , Variación Genética , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1 , ARN sin Sentido/genética , ARN Largo no Codificante/genética , Receptores CCR5/genética , Regiones no Traducidas 3' , Alelos , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Membrana Celular/metabolismo , Genes Reporteros , Genotipo , Infecciones por VIH/metabolismo , Humanos , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Grupos de Población/genética , Pronóstico , Estabilidad del ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CCR5/metabolismo , Carga ViralRESUMEN
Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ T cells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic T cell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ T cells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ T cells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ T cells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Viremia/inmunología , Viremia/virología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
A cardinal feature of COVID-19 is lung inflammation and respiratory failure. In a prospective multi-country cohort of COVID-19 patients, we found that increased Notch4 expression on circulating regulatory T (Treg) cells was associated with disease severity, predicted mortality, and declined upon recovery. Deletion of Notch4 in Treg cells or therapy with anti-Notch4 antibodies in conventional and humanized mice normalized the dysregulated innate immunity and rescued disease morbidity and mortality induced by a synthetic analog of viral RNA or by influenza H1N1 virus. Mechanistically, Notch4 suppressed the induction by interleukin-18 of amphiregulin, a cytokine necessary for tissue repair. Protection by Notch4 inhibition was recapitulated by therapy with Amphiregulin and, reciprocally, abrogated by its antagonism. Amphiregulin declined in COVID-19 subjects as a function of disease severity and Notch4 expression. Thus, Notch4 expression on Treg cells dynamically restrains amphiregulin-dependent tissue repair to promote severe lung inflammation, with therapeutic implications for COVID-19 and related infections.
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Interacciones Huésped-Patógeno , Inmunidad Celular , Neumonía Viral/etiología , Neumonía Viral/metabolismo , Receptor Notch4/metabolismo , Transducción de Señal , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Anfirregulina/farmacología , Animales , Biomarcadores , Citocinas/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno/inmunología , Humanos , Inmunohistoquímica , Inmunomodulación/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Virus de la Influenza A/fisiología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Ratones Transgénicos , Neumonía Viral/patología , Receptor Notch4/antagonistas & inhibidores , Receptor Notch4/genética , Índice de Severidad de la EnfermedadRESUMEN
Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.
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Linfocitos T CD4-Positivos , Infecciones por VIH , VIH-1 , Fenotipo , Latencia del Virus , Humanos , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/inmunología , VIH-1/aislamiento & purificación , Provirus/efectos de los fármacos , Provirus/genética , Provirus/aislamiento & purificación , Carga Viral , Latencia del Virus/efectos de los fármacos , Memoria Inmunológica , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Supervivencia Celular , Antígenos CD28 , Receptores de Interleucina-21RESUMEN
HIV-1 infection of CD4+ T cells leads to cytopathic effects and cell demise, which is counter to the observation that certain HIV-1-infected cells possess a remarkable long-term stability and can persist lifelong in infected individuals treated with suppressive antiretroviral therapy (ART). Using quantitative mass spectrometry-based proteomics, we showed that HIV-1 infection activated cellular survival programs that were governed by BIRC5, a molecular inhibitor of cell apoptosis that is frequently overexpressed in malignant cells. BIRC5 and its upstream regulator OX40 were upregulated in productively and latently infected CD4+ T cells and were functionally involved in maintaining their viability. Moreover, OX40-expressing CD4+ T cells from ART-treated patients were enriched for clonally expanded HIV-1 sequences, and pharmacological inhibition of BIRC5 resulted in a selective decrease of HIV-1-infected cells in vitro. Together, these findings suggest that BIRC5 supports long-term survival of HIV-1-infected cells and may lead to clinical strategies to reduce persisting viral reservoirs.
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Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Survivin/metabolismo , Latencia del Virus/fisiología , Adulto , Anciano , Apoptosis , Supervivencia Celular/fisiología , Femenino , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , VIH-1 , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed 'elite controllers'), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.
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Silenciador del Gen , Infecciones por VIH/genética , Infecciones por VIH/virología , VIH-1/genética , Heterocromatina/genética , Provirus/genética , Integración Viral/genética , Latencia del Virus/genética , Adulto , Anciano , Centrómero/genética , Cromosomas Humanos Par 19/genética , ADN Satélite/genética , Femenino , Genoma Viral/genética , Infecciones por VIH/sangre , VIH-1/aislamiento & purificación , Heterocromatina/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Provirus/aislamiento & purificación , Proteínas Represoras/genética , Sitio de Iniciación de la TranscripciónRESUMEN
HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4+ T cell% and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.
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Linfocitos T CD8-positivos , Infecciones por VIH , Humanos , Células Asesinas Naturales , Activación de Linfocitos , ARN , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , ViremiaRESUMEN
With more than 38 million people living with HIV-1 (PLWH) worldwide, developing a cure for HIV-1 remains a major global health priority. Lifelong persistence of HIV-1 is frequently attributed to a pool of stable, transcriptionally silent HIV-1 proviruses, which are unaffected by currently available antiretroviral therapy (ART) or host immune activity. In this opinion article, we propose a more dynamic interpretation of HIV-1 reservoir cell biology and argue that HIV-1 proviruses frequently display residual viral transcriptional activity, making them vulnerable to longitudinal immune-mediated selection processes. Such mechanisms may, over extended periods of ART, induce an attenuated viral reservoir profile characterized by intact proviruses preferentially integrated into heterochromatin locations. We suggest that intensifying and accelerating naturally occurring selection mechanisms might represent a promising strategy for finding a potential cure for HIV-1 infection.
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Infecciones por VIH , VIH-1 , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , Humanos , Provirus , Latencia del VirusRESUMEN
BACKGROUND & AIMS: Persons with chronic HBV infection coinfected with HIV experience accelerated progression of liver fibrosis compared to those with HBV monoinfection. We aimed to determine whether HIV and its proteins promote HBV-induced liver fibrosis in HIV/HBV-coinfected cell culture models through HIF-1α and TGF-ß1 signaling. METHODS: The HBV-positive supernatant, purified HBV viral particles, HIV-positive supernatant, or HIV viral particles were directly incubated with cell lines or primary hepatocytes, hepatic stellate cells, and macrophages in mono or 3D spheroid coculture models. Cells were incubated with recombinant cytokines and HIV proteins including gp120. HBV sub-genomic constructs were transfected into NTCP-HepG2 cells. We also evaluated the effects of inhibitor of HIF-1α and HIV gp120 in a HBV carrier mouse model that was generated via hydrodynamic injection of the pAAV/HBV1.2 plasmid into the tail vein of wild-type C57BL/6 mice. RESULTS: We found that HIV and HIV gp120, through engagement with CCR5 and CXCR4 coreceptors, activate AKT and ERK signaling and subsequently upregulate hypoxia-inducible factor-1α (HIF-1α) to increase HBV-induced transforming growth factor-ß1 (TGF-ß1) and profibrogenic gene expression in hepatocytes and hepatic stellate cells. HIV gp120 exacerbates HBV X protein-mediated HIF-1α expression and liver fibrogenesis, which can be alleviated by inhibiting HIF-1α. Conversely, TGF-ß1 upregulates HIF-1α expression and HBV-induced liver fibrogenesis through the SMAD signaling pathway. HIF-1α small-interfering RNA transfection or the HIF-1α inhibitor (acriflavine) blocked HIV-, HBV-, and TGF-ß1-induced fibrogenesis. CONCLUSIONS: Our findings suggest that HIV coinfection exacerbates HBV-induced liver fibrogenesis through enhancement of the positive feedback between HIF-1α and TGF-ß1 via CCR5/CXCR4. HIF-1α represents a novel target for antifibrotic therapeutic development in HBV/HIV coinfection. IMPACT AND IMPLICATIONS: HIV coinfection accelerates the progression of liver fibrosis compared to HBV monoinfection, even among patients with successful suppression of viral load, and there is no sufficient treatment for this disease process. In this study, we found that HIV viral particles and specifically HIV gp120 promote HBV-induced hepatic fibrogenesis via enhancement of the positive feedback between HIF-1α and TGF-ß1, which can be ameliorated by inhibition of HIF-1α. These findings suggest that targeting the HIF-1α pathway can reduce liver fibrogenesis in patients with HIV and HBV coinfection.
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Coinfección , Infecciones por VIH , Virus de la Hepatitis B , Subunidad alfa del Factor 1 Inducible por Hipoxia , Cirrosis Hepática , Transducción de Señal , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratones , Cirrosis Hepática/metabolismo , Cirrosis Hepática/virología , Cirrosis Hepática/patología , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/metabolismo , Infecciones por VIH/patología , Virus de la Hepatitis B/genética , Coinfección/virología , Ratones Endogámicos C57BL , Hepatitis B Crónica/complicaciones , Hepatitis B Crónica/metabolismo , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Proteína gp120 de Envoltorio del VIH/metabolismo , Hepatocitos/metabolismo , Hepatocitos/virología , Hepatocitos/patología , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/virología , Modelos Animales de Enfermedad , Células Hep G2 , MasculinoRESUMEN
The human leukocyte antigens HLA-B27 and HLA-B57 are associated with protection against progression of disease that results from infection with human immunodeficiency virus type 1 (HIV-1), yet most people with alleles encoding HLA-B27 and HLA-B57 are unable to control HIV-1. Here we found that HLA-B27-restricted CD8(+) T cells in people able to control infection with HIV-1 (controllers) and those who progress to disease after infection with HIV-1 (progressors) differed in their ability to inhibit viral replication through targeting of the immunodominant epitope of group-associated antigen (Gag) of HIV-1. This was associated with distinct T cell antigen receptor (TCR) clonotypes, characterized by superior control of HIV-1 replication in vitro, greater cross-reactivity to epitope variants and enhanced loading and delivery of perforin. We also observed clonotype-specific differences in antiviral efficacy for an immunodominant HLA-B57-restricted response in controllers and progressors. Thus, the efficacy of such so-called 'protective alleles' is modulated by specific TCR clonotypes selected during natural infection, which provides a functional explanation for divergent HIV-1 outcomes.
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Infecciones por VIH/inmunología , VIH-1/inmunología , Antígenos HLA-B/inmunología , Antígeno HLA-B27/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , Células Cultivadas , Epítopos de Linfocito T/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/virología , Sobrevivientes de VIH a Largo Plazo , Humanos , Perforina/inmunología , Replicación Viral/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunologíaRESUMEN
Doping Co atoms into Ru lattices can tune the electronic structure of active sites, and the conductive MXene can adjust the electrical conductivity of catalysts, which are both favorable for improving the electrocatalytic activity of the catalyst for water splitting. Here, ruthenium-cobalt bimetallic nanoalloys coupled with exfoliated Ti3 C2 Tx MXene (RuCo-Ti3 C2 Tx ) have been constructed by ice-templated and thermal activation. Due to the strong interaction between the RuCo nanoalloys and conductive MXene, RuCo-Ti3 C2 Tx not only exhibits an excellent hydrogen evolution reaction (HER) performance with a low overpotential and Tafel slope (60â mV, 34.8â mV dec-1 in 0.5â M H2 SO4 and 52â mV, 38.7â mV dec-1 in 1â M KOH), but also good oxygen evolution reaction (OER) performance in an alkaline electrolyte (266â mV, 111.1â mV dec-1 in 1â M KOH). The assembled RuCo-Ti3 C2 Tx ||RuCo-Ti3 C2 Tx electrolyzer requires a lower potential (1.56â V) than does the Pt/C||RuO2 electrolyzer at 10â mA cm-2 . A boosted catalytic HER activity from immobilizing the RuCo nanoalloys on MXene was unveiled by density functional theory calculations. This study provides a feasible and efficient strategy for developing MXene-based catalysts for overall water splitting.
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BACKGROUND: Mineralocorticoid receptor blockade could be a potential approach for the inhibition of chronic kidney disease (CKD) progression. The benefits and harms of different mineralocorticoid receptor antagonists (MRAs) in CKD are inconsistent. OBJECTIVES: The aim of the study was to summarize the benefits and harms of MRAs for CKD patients. METHODS: We searched MEDLINE, EMBASE, and the Cochrane databases for trials assessing the effects of MRAs on non-dialysis-dependent CKD populations. Treatment and adverse effects were summarized using meta-analysis. RESULTS: Fifty-three trials with 6 different MRAs involving 22,792 participants were included. Compared with the control group, MRAs reduced urinary albumin-to-creatinine ratio (weighted mean difference [WMD], -90.90 mg/g, 95% CI, -140.17 to -41.64 mg/g), 24-h urinary protein excretion (WMD, -0.20 g, 95% CI, -0.28 to -0.12 g), estimated glomerular filtration rate (eGFR) (WMD, -1.99 mL/min/1.73 m2, 95% CI, -3.28 to -0.70 mL/min/1.73 m2), chronic renal failure events (RR, 0.86, 95% CI, 0.79-0.93), and cardiovascular events (RR, 0.84, 95% CI, 0.77-0.92). MRAs increased the incidence of hyperkalemia (RR, 2.04, 95% CI, 1.73-2.40) and hypotension (RR, 1.80, 95% CI, 1.41-2.31). MRAs reduced the incidence of peripheral edema (RR, 0.65, 95% CI, 0.56-0.75) but not the risk of acute kidney injury (RR, 0.94, 95% CI, 0.79-1.13). Nonsteroidal MRAs (RR, 0.66, 95% CI, 0.57-0.75) but not steroidal MRAs (RR, 0.20, 95% CI, 0.02-1.68) significantly reduced the risk of peripheral edema. Steroidal MRAs (RR, 5.68, 95% CI, 1.26-25.67) but not nonsteroidal MRAs (RR, 0.52, 95% CI, 0.22-1.22) increased the risk of breast disorders. CONCLUSIONS: In the CKD patients, MRAs, particularly in combination with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, reduced albuminuria/proteinuria, eGFR, and the incidence of chronic renal failure, cardiovascular and peripheral edema events, whereas increasing the incidence of hyperkalemia and hypotension, without the augment of acute kidney injury events. Nonsteroidal MRAs were superior in the reduction of more albuminuria with fewer peripheral edema events and without the augment of breast disorder events.
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Lesión Renal Aguda , Hiperpotasemia , Hipotensión , Fallo Renal Crónico , Insuficiencia Renal Crónica , Humanos , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Hiperpotasemia/inducido químicamente , Hiperpotasemia/epidemiología , Albuminuria/inducido químicamente , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/inducido químicamente , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , EdemaRESUMEN
Interface engineering has proven to be a highly efficient strategy for modulating the physicochemical properties of electrocatalysts and further enhancing their electrochemical performance in related energy applications. In this context, the newly proposed crystalline-amorphous (c-a) heterostructures with unusual atomic arrangements at interfaces show strong competitiveness. Nonetheless, few efforts have been made to reveal and summarize the structure-activity relationship at the two-phase interface and the corresponding electrocatalytic mechanism. This concept is devoted to comprehensively discussing the fundamental characteristics of crystalline-amorphous electrocatalysts and their application in the field of energy conversion with typical examples. In addition, the development prospects and opportunities of crystalline-amorphous heterostructure are summarized to provide potential development directions for other types of clean energy development.
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AIMS: This study aims to establish a population pharmacokinetic (PK) model of teicoplanin in Chinese adult patients to evaluate the dosing regimen in the label sheet and optimize it. METHODS: Nonlinear mixed-effects modelling was used to estimate PK parameters. Monte Carlo simulations were used to evaluate the attainment of various dosing regimens in achieving the target trough concentrations in patients with normal or decreased renal function. RESULTS: A total of 115 patients were enrolled in this retrospective study. Creatinine clearance (CrCL) and albumin (ALB) were identified as covariates on the clearance of teicoplanin. For the treatment of non-complicated methicillin-resistant Staphylococcus aureus (MRSA) infections in patients with normal renal function and serum ALB concentration, the recommended dosing regimen was 600 mg q12h with five administrations as the loading dose followed by 600 mg qd as the maintenance dose; for the treatment of serious and/or complicated MRSA infections, the recommended dosing regimen was 800 mg q12h with five administrations as the loading dose followed by 800 mg qd as the maintenance dose. It is worth noting that both the loading and maintenance doses ought to be modified based on the patient's renal function and serum ALB concentration. In addition, trough concentrations of teicoplanin were significantly increased every other week. CONCLUSIONS: Both loading dosing and maintenance dosing regimens were recommended to be adjusted according to patient's renal function and serum ALB concentration. In addition, it is necessary to perform follow-up therapeutic drug monitoring of teicoplanin at least once every week.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Adulto , Humanos , Teicoplanina/uso terapéutico , Antibacterianos , Estudios Retrospectivos , Monitoreo de Drogas , Albúmina Sérica , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
The hallmark of severe COVID-19 is an uncontrolled inflammatory response, resulting from poorly understood immunological dysfunction. We hypothesized that perturbations in FoxP3+ T regulatory cells (Treg), key enforcers of immune homeostasis, contribute to COVID-19 pathology. Cytometric and transcriptomic profiling revealed a distinct Treg phenotype in severe COVID-19 patients, with an increase in Treg proportions and intracellular levels of the lineage-defining transcription factor FoxP3, correlating with poor outcomes. These Tregs showed a distinct transcriptional signature, with overexpression of several suppressive effectors, but also proinflammatory molecules like interleukin (IL)-32, and a striking similarity to tumor-infiltrating Tregs that suppress antitumor responses. Most marked during acute severe disease, these traits persisted somewhat in convalescent patients. A screen for candidate agents revealed that IL-6 and IL-18 may individually contribute different facets of these COVID-19-linked perturbations. These results suggest that Tregs may play nefarious roles in COVID-19, by suppressing antiviral T cell responses during the severe phase of the disease, and by a direct proinflammatory role.
Asunto(s)
COVID-19/etiología , Linfocitos T Reguladores/fisiología , Adulto , Anciano , Linfocitos T CD4-Positivos/virología , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inflamación/metabolismo , Inflamación/virología , Interleucina-18/genética , Interleucina-18/metabolismo , Subunidad alfa del Receptor de Interleucina-2/genética , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Linfocitos Infiltrantes de Tumor/fisiología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/virología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
It is imperative to develop an efficient catalyst to reduce the energy barrier of electrochemical water decomposition. In this study, a well-designed electrocatalyst featuring a core-shell structure was synthesized with cobalt sulfides as the core and molybdenum disulfide nanosheets as the shell. The core-shell structure can prevent the agglomeration of MoS2, expose more active sites, and facilitate electrolyte ion diffusion. A CoS2/MoS2 heterostructure is formed between CoS2 and MoS2 through the chemical interaction, and the surface chemistry is adjusted. Due to the morphological merits and the formation of the CoS2/MoS2 heterostructure, CoS2@MoS2 exhibits excellent electrocatalytic performance during the oxygen evolution reaction (OER) process in an alkaline electrolyte. To reach the current density of 10 mA cm-2, only 254 mV of overpotential is required for CoS2@MoS2, which is smaller than that of pristine CoS2 and MoS2. Meanwhile, the small Tafel slope (86.9 mV dec-1) and low charge transfer resistance (47 Ω) imply the fast dynamic mechanism of CoS2@MoS2. As further confirmed by cyclic voltammetry curves for 1000 cycles and the CA test for 10 h, CoS2@MoS2 shows exceptional catalytic stability. This work gives a guideline for constructing the core-shell heterostructure as an efficient catalyst for oxygen evolution reaction.