RESUMEN
In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4+ effector-GNLY (granulysin), CD8+ effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.
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Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Interferón Tipo I/metabolismo , Neumonía Viral/inmunología , Receptores Inmunológicos/metabolismo , Adolescente , Adulto , Anciano , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , COVID-19 , Estudios de Cohortes , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Femenino , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/inmunología , Proteínas Ligadas a GPI/metabolismo , Humanos , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Neumonía Viral/virología , RNA-Seq , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Análisis de la Célula IndividualRESUMEN
Clostridioides difficile infection (CDI) is a major cause of healthcare-associated gastrointestinal infections1,2. The exaggerated colonic inflammation caused by C. difficile toxins such as toxin B (TcdB) damages tissues and promotes C. difficile colonization3-6, but how TcdB causes inflammation is unclear. Here we report that TcdB induces neurogenic inflammation by targeting gut-innervating afferent neurons and pericytes through receptors, including the Frizzled receptors (FZD1, FZD2 and FZD7) in neurons and chondroitin sulfate proteoglycan 4 (CSPG4) in pericytes. TcdB stimulates the secretion of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) from neurons and pro-inflammatory cytokines from pericytes. Targeted delivery of the TcdB enzymatic domain, through fusion with a detoxified diphtheria toxin, into peptidergic sensory neurons that express exogeneous diphtheria toxin receptor (an approach we term toxogenetics) is sufficient to induce neurogenic inflammation and recapitulates major colonic histopathology associated with CDI. Conversely, mice lacking SP, CGRP or the SP receptor (neurokinin 1 receptor) show reduced pathology in both models of caecal TcdB injection and CDI. Blocking SP or CGRP signalling reduces tissue damage and C. difficile burden in mice infected with a standard C. difficile strain or with hypervirulent strains expressing the TcdB2 variant. Thus, targeting neurogenic inflammation provides a host-oriented therapeutic approach for treating CDI.
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Toxinas Bacterianas , Clostridioides difficile , Inflamación Neurogénica , Neuronas Aferentes , Pericitos , Animales , Ratones , Toxinas Bacterianas/administración & dosificación , Toxinas Bacterianas/farmacología , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Péptido Relacionado con Gen de Calcitonina/metabolismo , Clostridioides difficile/patogenicidad , Infecciones por Clostridium/microbiología , Inflamación Neurogénica/inducido químicamente , Inflamación Neurogénica/microbiología , Inflamación Neurogénica/patología , Pericitos/efectos de los fármacos , Pericitos/microbiología , Pericitos/patología , Receptores de Neuroquinina-1/metabolismo , Sustancia P/antagonistas & inhibidores , Sustancia P/metabolismo , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/microbiología , Neuronas Aferentes/patología , Mediadores de Inflamación/metabolismo , Ciego/efectos de los fármacos , Ciego/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.
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Nanopartículas , ARN Mensajero , Especies Reactivas de Oxígeno , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Animales , Nanopartículas/química , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Macrófagos/metabolismo , Macrófagos/efectos de los fármacos , Interleucina-4/metabolismo , Diabetes Mellitus Experimental , Humanos , Lípidos/química , Modelos Animales de Enfermedad , Masculino , LiposomasRESUMEN
The susceptibility single nucleotide polymorphisms (SNPs) obtained by genome-wide association studies leave some thorny questions, such as prioritization, false positives and unknown pathogenesis. Previous studies suggested that genetic variation may perturb the RNA secondary structure, influence protein recruitment and binding and ultimately affect splicing processes. Therefore, exploring the perturbation of SNPs to structure-function correlations may provide an effective bridge toward understanding the genetic contribution to diseases. Here, aiming to decipher the regulatory mechanism of myopia susceptibility variants, we systematically evaluated the roles of SNP-induced structural changes during splicing. In addition, 7.53% of myopia-related SNPs exhibited significant global structural changes, 19.53% presented noteworthy local structural disturbance and there were wide-ranging structural perturbations in the splice-related motifs. We established a comprehensive evaluation system for structural disturbance in the splicing-related motifs and gave the priority ranking for the SNPs at RNA structural level. These high-priority SNPs were revealed to widely disturb the molecular interaction properties between splicing-related proteins and pre-mRNAs by HDOCK. Moreover, mini-gene assays confirmed that structural perturbation could influence splicing efficiency through structural remodelling. This study deepens our understanding of the potential molecular regulatory mechanisms of susceptible SNPs in myopia and contributes to personalized diagnosis, personalized medicine, disease-risk prediction and functional verification study by guiding the prioritization of the susceptibility SNPs.
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Miopía , ARN , Humanos , ARN/genética , Polimorfismo de Nucleótido Simple/genética , Estudio de Asociación del Genoma Completo , Empalme del ARN/genética , Predisposición Genética a la EnfermedadRESUMEN
Thrombosis is a leading global cause of death, in part due to the low efficacy of thrombolytic therapy. Here, we describe a method for precise delivery and accurate dosing of tissue plasminogen activator (tPA) using an intelligent DNA nanodevice. We use DNA origami to integrate DNA nanosheets with predesigned tPA binding sites and thrombin-responsive DNA fasteners. The fastener is an interlocking DNA triplex structure that acts as a thrombin recognizer, threshold controller and opening switch. When loaded with tPA and intravenously administrated in vivo, these DNA nanodevices rapidly target the site of thrombosis, track the circulating microemboli and expose the active tPA only when the concentration of thrombin exceeds a threshold. We demonstrate their improved therapeutic efficacy in ischaemic stroke and pulmonary embolism models, supporting the potential of these nanodevices to provide accurate tPA dosing for the treatment of different thromboses.
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ADN , Terapia Trombolítica , Activador de Tejido Plasminógeno , Activador de Tejido Plasminógeno/química , Activador de Tejido Plasminógeno/administración & dosificación , Activador de Tejido Plasminógeno/uso terapéutico , ADN/química , Animales , Terapia Trombolítica/métodos , Nanoestructuras/química , Trombosis/tratamiento farmacológico , Ratones , Fibrinolíticos/administración & dosificación , Fibrinolíticos/química , Fibrinolíticos/uso terapéutico , HumanosRESUMEN
Post-translational modifications (PTMs) are critical molecular mechanisms that regulate protein functions temporally and spatially in various organisms. Since most PTMs are dynamically regulated, quantifying PTM events under different states is crucial for understanding biological processes and diseases. With the rapid development of high-throughput proteomics technologies, massive quantitative PTM proteome datasets have been generated. Thus, a comprehensive one-stop data resource for surfing big data will benefit the community. Here, we updated our previous phosphorylation dynamics database qPhos to the qPTM (http://qptm.omicsbio.info). In qPTM, 11 482 553 quantification events among six types of PTMs, including phosphorylation, acetylation, glycosylation, methylation, SUMOylation and ubiquitylation in four different organisms were collected and integrated, and the matched proteome datasets were included if available. The raw mass spectrometry based false discovery rate control and the recurrences of identifications among datasets were integrated into a scoring system to assess the reliability of the PTM sites. Browse and search functions were improved to facilitate users in swiftly and accurately acquiring specific information. The results page was revised with more abundant annotations, and time-course dynamics data were visualized in trend lines. We expected the qPTM database to be a much more powerful and comprehensive data repository for the PTM research community.
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Procesamiento Proteico-Postraduccional , Proteoma , Animales , Humanos , Ratones , Ratas , Fosforilación , Proteoma/metabolismo , Saccharomyces cerevisiae/metabolismo , Bases de Datos GenéticasRESUMEN
Histone deacetylases 1 and 2 (HDAC1/2) serve as the catalytic subunit of six distinct families of nuclear complexes. These complexes repress gene transcription through removing acetyl groups from lysine residues in histone tails. In addition to the deacetylase subunit, these complexes typically contain transcription factor and/or chromatin binding activities. The MIER:HDAC complex has hitherto been poorly characterized. Here, we show that MIER1 unexpectedly co-purifies with an H2A:H2B histone dimer. We show that MIER1 is also able to bind a complete histone octamer. Intriguingly, we found that a larger MIER1:HDAC1:BAHD1:C1QBP complex additionally co-purifies with an intact nucleosome on which H3K27 is either di- or tri-methylated. Together this suggests that the MIER1 complex acts downstream of PRC2 to expand regions of repressed chromatin and could potentially deposit histone octamer onto nucleosome-depleted regions of DNA.
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Histona Desacetilasas , Nucleosomas , Cromatina/genética , Histona Desacetilasas/metabolismo , Histonas/metabolismo , Complejos Multiproteicos/metabolismo , Nucleosomas/genética , Factores de Transcripción/metabolismo , HumanosRESUMEN
Ubiquitin A-52 residue ribosomal protein fusion product 1 (UBA52) has a role in the occurrence and development of tumours. However, the mechanism by which UBA52 regulates hepatocellular carcinoma (HCC) tumorigenesis and progression remains poorly understood. By using the Cell Counting Kit (CCK-8), colony formation, wound healing and Transwell assays, we assessed the effects of UBA52 knockdown and overexpression on the proliferation and migration of HCC cells in vitro. By establishing subcutaneous and metastatic tumour models in nude mice, we evaluated the effects of UBA52 on HCC cell proliferation and migration in vivo. Through bioinformatic analysis of data from the Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) databases, we discovered that UBA52 is associated with autophagy. In addition, we discovered that HCC tissues with high UBA52 expression had a poor prognosis in patients. Moreover, knockdown of UBA52 reduced HCC cell growth and metastasis both in vitro and in vivo. Mechanistically, knockdown of UBA52 induced autophagy through EMC6 in HCC cells. These findings suggest that UBA52 promoted the proliferation and migration of HCC cells through autophagy regulation via EMC6 and imply that UBA52 may be a viable novel treatment target for HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Animales , Humanos , Ratones , Autofagia/genética , Carcinogénesis/genética , Carcinoma Hepatocelular/genética , Transformación Celular Neoplásica , Neoplasias Hepáticas/genética , Proteínas de la Membrana , Ratones DesnudosRESUMEN
MafA and c-Maf are close members of the Maf transcription factor family and indicators of poor prognosis of multiple myeloma (MM). Our previous study finds that the ubiquitin ligase HERC4 induces c-Maf degradation but stabilizes MafA, and the mechanism is elusive. In the present study, we find that HERC4 interacts with MafA and mediates its K63-linked polyubiquitination at K33. Moreover, HERC4 inhibits MafA phosphorylation and its transcriptional activity triggered by glycogen synthase kinase 3ß (GSK3ß). The K33R MafA variant prevents HERC4 from inhibiting MafA phosphorylation and increases MafA transcriptional activity. Further analyses reveal that MafA can also activate the STAT3 signaling, but it is suppressed by HERC4. Lastly, we demonstrate that lithium chloride, a GSK3ß inhibitor, can upregulate HERC4 and synergizes dexamethasone, a typical anti-MM drug, in inhibiting MM cell proliferation and xenograft growth in nude mice. These findings thus highlight a novel regulation of MafA oncogenic activity in MM and provide the rationale by targeting HERC4/GSK3ß/MafA for the treatment of MM.
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Glucógeno Sintasa Quinasa 3 beta , Factores de Transcripción Maf de Gran Tamaño , Mieloma Múltiple , Poliubiquitina , Ubiquitina-Proteína Ligasas , Ubiquitinación , Animales , Humanos , Ratones , Proliferación Celular , Dexametasona/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Cloruro de Litio/farmacología , Factores de Transcripción Maf de Gran Tamaño/antagonistas & inhibidores , Factores de Transcripción Maf de Gran Tamaño/metabolismo , Ratones Desnudos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/genética , Mieloma Múltiple/metabolismo , Fosforilación , Poliubiquitina/metabolismo , Factor de Transcripción STAT3/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Spermatogenesis is a highly regulated and complex process in which DNA methylation plays a crucial role. This study aimed to explore the differential methylation profiles in sperm DNA between patients with asthenospermia (AS) and healthy controls (HCs), those with oligoasthenospermia (OAS) and HCs, and patients with AS and those with OAS. RESULTS: Semen samples and clinical data were collected from five patients with AS, five patients with OAS, and six age-matched HCs. Reduced representation bisulfite sequencing (RRBS) was performed to identify differentially methylated regions (DMRs) in sperm cells among the different types of patients and HCs. A total of 6520, 28,019, and 16,432 DMRs were detected between AS and HC, OAS and HC, and AS and OAS groups, respectively. These DMRs were predominantly located within gene bodies and mapped to 2868, 9296, and 9090 genes in the respective groups. Of note, 12, 9, and 8 DMRs in each group were closely associated with spermatogenesis and male infertility. Furthermore, BDNF, SMARCB1, PIK3CA, and DDX27; RBMX and SPATA17; ASZ1, CDH1, and CHDH were identified as strong differentially methylated candidate genes in each group, respectively. Meanwhile, the GO analysis of DMR-associated genes in the AS vs. HC groups revealed that protein binding, cytoplasm, and transcription (DNA-templated) were the most enriched terms in the biological process (BP), cellular component (CC), and molecular function (MF), respectively. Likewise, in both the OAS vs. HC and AS vs. OAS groups, GO analysis revealed protein binding, nucleus, and transcription (DNA-templated) as the most enriched terms in BP, CC, and MF, respectively. Finally, the KEGG analysis of DMR-annotated genes and these genes at promoters suggested that metabolic pathways were the most significantly associated across all three groups. CONCLUSIONS: The current study results revealed distinctive sperm DNA methylation patterns in the AS vs. HC and OAS vs. HC groups, particularly between patients with AS and those with OAS. The identification of key genes associated with spermatogenesis and male infertility in addition to the differentially enriched metabolic pathways may contribute to uncovering the potential pathogenesis in different types of abnormal sperm parameters.
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Astenozoospermia , Metilación de ADN , Oligospermia , Humanos , Masculino , Astenozoospermia/genética , Adulto , Oligospermia/genética , Espermatozoides/metabolismo , Espermatogénesis/genética , Estudios de Casos y Controles , Epigénesis GenéticaRESUMEN
Gastric cancer (GC) is one of the most common clinical malignant tumors worldwide, with high morbidity and mortality. Presently, the overall response rate to immunotherapy is low, and current methods for predicting the prognosis of GC are not optimal. Therefore, novel biomarkers with accuracy, efficiency, stability, performance ratio, and wide clinical application are needed. Based on public data sets, the chemotherapy cohort and immunotherapy cohort from Sun Yat-sen University Cancer Center, a series of bioinformatics analyses, such as differential expression analysis, survival analysis, drug sensitivity prediction, enrichment analysis, tumor immune dysfunction and exclusion analysis, single-sample gene set enrichment analysis, stemness index calculation, and immune cell infiltration analysis, were performed for screening and preliminary exploration. Immunohistochemical staining and in vitro experiments were performed for further verification. Overexpression of COX7A1 promoted the resistance of GC cells to Oxaliplatin. COX7A1 may induce immune escape by regulating the number of fibroblasts and their cellular communication with immune cells. In summary, measuring the expression levels of COX7A1 in the clinic may be useful in predicting the prognosis of GC patients, the degree of chemotherapy resistance, and the efficacy of immunotherapy.
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Antineoplásicos , Resistencia a Antineoplásicos , Inmunoterapia , Oxaliplatino , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/terapia , Oxaliplatino/uso terapéutico , Oxaliplatino/farmacología , Resistencia a Antineoplásicos/genética , Inmunoterapia/métodos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Línea Celular Tumoral , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Masculino , Femenino , Pronóstico , Persona de Mediana EdadRESUMEN
Ferroptosis, as a new form of regulated cell death, is implicated in various physiological and pathological processes. Developing a single probe for an independent analysis of multiple analytes related to ferroptosis can provide more accurate information and simplify the detection procedures, but it faces great challenges. In this work, we develop a fluorescent probe for the simultaneous detection of GSH through ratiometric fluorescence response and microviscosity via a fluorescence lifetime model. Based on the reversible Michael addition reaction between GSH and unsaturated CâC bond, the probe responds reversibly to GSH with a ratiometric fluorescence variation and a fast response time (t1/2 = 4.7 s). At the same time, the probe is sensitive to environmental viscosity by changing its fluorescence lifetimes. The probe was applied to monitor the drug-induced ferroptosis process through both the classical Xc-/GSH/GPX4- and DHODH-mediated defense mechanisms. We hope that the probe will provide a useful molecular tool for the real-time live-cell imaging of GSH dynamics, which is benefit to unveiling related physiological and pathological processes.
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Ferroptosis , Viscosidad , Colorantes Fluorescentes/química , Microscopía Fluorescente/métodos , Imagen Óptica , Glutatión/análisisRESUMEN
Hepatic stellate cells (HSCs) perform a significant function in liver regeneration (LR) by becoming active. We propose to investigate if activated HSCs enhance glycolysis via PFKFB3, an essential glycolytic regulator, and whether targeting this pathway could be beneficial for LR. The liver and isolated HSCs of mice subjected to 2/3 partial hepatectomy (PHx) exhibited a significant rise in PFKFB3 expression, as indicated by quantitative RT-PCR analyses and Western blotting. Also, the primary HSCs of mice subjected to PHx have a significant elevation of the glycolysis level. Knocking down PFKFB3 significantly diminished the enhancement of glycolysis by PDGF in human LX2 cells. The hepatocyte proliferation in mice treated with PHx was almost completely prevented when the PFKFB3 inhibitor 3PO was administered, emerging that PFKFB3 is essential in LR. Furthermore, there was a decline in mRNA expression of immediate early genes and proinflammatory cytokines. In terms of mechanism, both the p38 MAP kinase and ERK1/2 phosphorylation in LO2 cells and LO2 proliferation were significantly reduced by the conditioned medium (CM) obtained from LX2 cells with either PFKFB3 knockdown or inhibition. Compared to the control group, isolated hepatocytes from 3PO-treated mice showed decreased p38 MAP kinase and ERK1/2 phosphorylation and proliferation. Thus, LR after PHx involves the activation of PFKFB3 in HSCs, which enhances glycolysis and promotes lactate production, thereby facilitating hepatocyte proliferation via the p38/ERK MAPK signaling pathway.
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Proliferación Celular , Glucólisis , Células Estrelladas Hepáticas , Regeneración Hepática , Ratones Endogámicos C57BL , Fosfofructoquinasa-2 , Fosfofructoquinasa-2/metabolismo , Fosfofructoquinasa-2/genética , Animales , Células Estrelladas Hepáticas/metabolismo , Células Estrelladas Hepáticas/citología , Humanos , Ratones , Masculino , Línea Celular , Hepatectomía , Células Cultivadas , Hígado/metabolismoRESUMEN
A major issue with Fenton-like reaction is the excessive consumption of H2O2 caused by the sluggish regeneration rate of low-valent metal, and how to improve the activation efficiency of H2O2 has become a key in current research. Herein, a nano-heterostructure catalyst (1.0-MnCu/C) based on nano-interface engineering is constructed by supporting Cu and MnO on carbon skeleton, and its kinetic rate for the degradation of tetracycline hydrochloride is 0.0436 min-1, which is 2.9 times higher than that of Cu/C system (0.0151 min-1). The enhancement of removal rate results from the introduced Mn species can aggregate and transfer electrons to Cu sites through the electron bridge Mn-N/O-Cu, thus preventing Cu2+ from oxidizing H2O2 to form O2 â¢-, and facilitating the reduction of Cu2+ and generating more reactive oxygen species (1O2 and ·OH) with stronger oxidation ability, resulting in H2O2 utilization efficiency is 1.9 times as much as that of Cu/C. Additionally, the good and stable practical application capacity in different bodies demonstrates that it has great potential for practical environmental remediation.
RESUMEN
The magnitude of terrestrial carbon (C)-climate feedback largely depends on the temperature sensitivity of soil organic matter (SOM) decomposition (Q10). However, our understanding of determinants of Q10 for SOM fractions such as particulate and mineral-associated organic matter (POM and MAOM, respectively) is still inadequate. Particularly, it remains unclear whether microbial effects on Q10 are fraction-dependent, which induces large uncertainties in projecting soil C dynamics. Here, we conducted large-scale topsoil sampling on the Tibetan Plateau, in combination with SOM fractionation and 300-day laboratory incubation to assess SOM fraction-dependent linkages between Q10 and microbial properties. We found that compared with MAOM, POM had larger Q10 and greater microbial diversity, and also structured distinct microbial communities as well as their co-occurrence patterns. Furthermore, associations of Q10 with microbial properties differed between the two SOM fractions. Bacterial community composition and relative abundance of bacterial keystone taxa affected Q10 for POM and MAOM respectively, while bacterial alpha diversity showed opposite relationships with Q10 for POM and MAOM. These findings highlight the necessity of incorporating SOM fraction-dependent microbial properties and their linkages with Q10 into Earth system models to accurately predict terrestrial C-climate feedback.
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Microbiota , Microbiología del Suelo , Suelo , Temperatura , Suelo/química , Tibet , Bacterias/clasificación , Bacterias/metabolismo , Bacterias/aislamiento & purificación , Carbono/análisis , Carbono/metabolismoRESUMEN
BACKGROUND: Polycystic ovary syndrome (PCOS) is the main cause of anovulatory infertility in women of reproductive age, and low-grade chronic inflammation plays a key role in the occurrence and development of PCOS. However, obesity, as a likely confounding factor, can affect the inflammatory state of PCOS patients. OBJECTIVE: The aim of this study was to comprehensively investigate intra-ovarian inflammatory states and their impact on embryo quality in PCOS patients with a normal BMI undergoing IVF treatment. METHODS: DIA-mass spectrometry-based proteomics and bioinformatic analysis were combined to comprehensively profile the protein expression of granulosa cells (GCs) from 5 normal-BMI PCOS patients and 5 controls. Thirty-four cytokines were further systematically detected in follicular fluid (FF) from 32 age- and BMI-matched normal-BMI patients using Luminex liquid chip suspension technology. Next, the differentially expressed cytokines were evaluated by enzyme-linked immunosorbent assay (ELISA) in 24 newly recruited subjects, and the relationship between these cytokines and embryo quality in PCOS patients was analysed. Finally, these cytokine levels were compared and evaluated in PCOS patients with different androgen levels. RESULTS: Proteomic analysis showed that the suppression of substance metabolism and steroid biosynthesis, more interestingly, resulted in an enhanced immune and inflammatory response in the GCs of normal-BMI PCOS patients and prompted the involvement of cytokines in this process. Luminex analysis further showed that FF macrophage inflammatory protein-1 beta (MIP-1ß) and stromal cell-derived factor-1 alpha (SDF-1α) levels were significantly increased in normal-BMI PCOS patients compared to controls (P = 0.005; P = 0.035, respectively), and the ELISA results were consistent with these findings. Besides, FF MIP-1ß showed an inverse correlation with the number of D3 good-quality embryos and the good-quality blastocyst rate in patients with PCOS (P = 0.006; P = 0.003, respectively), which remained significant after correction for multiple comparisons. Moreover, SDF-1α levels had no relationship with embryo development in PCOS patients. Additionally, SDF-1α levels were significantly lower in PCOS patients with high androgen levels than in controls (P = 0.031). CONCLUSIONS: Local ovarian inflammation was present in normal-BMI PCOS patients, affecting follicular development, and FF MIP-1ß may be a potential biomarker associated with embryo quality in normal-BMI PCOS patients.
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Síndrome del Ovario Poliquístico , Humanos , Femenino , Síndrome del Ovario Poliquístico/metabolismo , Quimiocina CCL4/metabolismo , Quimiocina CXCL12/metabolismo , Proteómica , Andrógenos/metabolismo , Índice de Masa Corporal , Líquido Folicular/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Fertilización In VitroRESUMEN
Two novel indole acetic acid-producing strains, 5MLIRT and D4N7, were isolated from Indosasa shibataeoides in Yongzhou, Hunan province, and Phyllostachys edulis in Hangzhou, Zhejiang province, respectively. Based on their 16S rRNA sequences, strains 5MLIRT and D4N7 were closely related to Comamonas antarcticus 16-35-5T (98.4â% sequence similarity), and the results of 92-core gene phylogenetic trees showed that strains 5MLIRT and D4N7 formed a phylogenetic lineage within the clade comprising Comamonas species. The complete genome size of strain 5MLIRT was 4.49 Mb including two plasmids, and the DNA G+C content was 66.5âmol%. The draft genome of strain D4N7 was 4.26 Mb with 66.7âmol% G+C content. The average nucleotide identity and digital DNA-DNA hybridization values among strain 5MLIRT and species in the genus Comamonas were all below the species delineation threshold. The colonies of strain 5MLIRT and D4N7 were circular with regular margins, convex, pale yellow and 1.0-2.0 mm in diameter when incubated at 30â°C for 3 days. Strains 5MLIRT and D4N7 grew optimally at 30â°C, pH 7.0 and 1.0â% NaCl. The respiratory isoprenoid quinone was ubiquinone-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Polyphasic analyses indicated that strains 5MLIRT and D4N7 could be distinguished from related validly named Comamonas species and represent a novel species of the genus Comamonas, for which the name Comamonas endophytica sp. nov. is proposed. The type strain is 5MLIRT (=ACCC 62069T=GDMCC 1.2958T=JCM 35331T).
Asunto(s)
Comamonas , Endófitos , Composición de Base , Endófitos/genética , Filogenia , ARN Ribosómico 16S/genética , Análisis de Secuencia de ADN , ADN Bacteriano/genética , Técnicas de Tipificación Bacteriana , Ácidos Grasos/química , China , PoaceaeRESUMEN
BACKGROUND: Tumor immunotherapy brings new light and vitality to breast cancer patients, but low response rate and limitations of therapeutic targets become major obstacles to its clinical application. Recent studies have shown that CD24 is involved in an important process of tumor immune regulation in breast cancer and is a promising target for immunotherapy. METHODS: In this study, singleR was used to annotate each cell subpopulation after t-distributed stochastic neighbor embedding (t-SNE) methods. Pseudo-time trace analysis and cell communication were analyzed by Monocle2 package and CellChat, respectively. A prognostic model based on CD24-related genes was constructed using several machine learning methods. Multiple quantitative immunofluorescence (MQIF) was used to evaluate the spatial relationship between CD24+PANCK+cells and exhausted CD8+T cells. RESULTS: Based on the scRNA-seq analysis, 1488 CD24-related differential genes were identified, and a risk model consisting of 15 prognostic characteristic genes was constructed by combining the bulk RNA-seq data. Patients were divided into high- and low-risk groups based on the median risk score. Immune landscape analysis showed that the low-risk group showed higher infiltration of immune-promoting cells and stronger immune reactivity. The results of cell communication demonstrated a strong interaction between CD24+epithelial cells and CD8+T cells. Subsequent MQIF demonstrated a strong interaction between CD24+PANCK+ and exhausted CD8+T cells with FOXP3+ in breast cancer. Additionally, CD24+PANCK+ and CD8+FOXP3+T cells were positively associated with lower survival rates. CONCLUSION: This study highlights the importance of CD24+breast cancer cells in clinical prognosis and immunosuppressive microenvironment, which may provide a new direction for improving patient outcomes.
Asunto(s)
Neoplasias de la Mama , Antígeno CD24 , Microambiente Tumoral , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/genética , Antígeno CD24/genética , Antígeno CD24/inmunología , Microambiente Tumoral/inmunología , Femenino , Pronóstico , Linfocitos T CD8-positivos/inmunología , Aprendizaje Automático , MultiómicaRESUMEN
Incorporating a sulfonyl group into parent molecules has been shown to effectively improve their synthetic applications and bioactivities. In this study, we present a straightforward and practical approach for the ring-opening reaction of alkenyl-aryl sulfonium salts with sodium sulfinates to produce a range of sulfur-containing alkyl sulfones. This method offers the benefits of mild reaction conditions, easily accessible raw materials, wide substrate applicability, good functional group compatibility, and operational simplicity. Importantly, the resulting products can be readily converted into sulfoxides, sulfones, sulfoximines, and some heterocyclic compounds.
RESUMEN
BACKGROUND AND OBJECTIVES: Intraoperative bile duct injury is a significant complication in laparoscopic cholecystectomy (LC). Near-infrared fluorescence cholangiography (NIFC) can reduce this complication. Therefore, determining the optimal indocyanine green (ICG) dosage for effective NIFC is crucial. This study aimed to determine the optimal ICG dosage for NIFC. METHODS: This was a prospective, randomized, double-blind clinical trial at a single tertiary referral center, including 195 patients randomly assigned to three groups: lower dose (0.01 mg/BMI) ICG (n = 63), medium dose (0.02 mg/BMI) ICG (n = 68), and higher dose (0.04 mg/BMI) ICG (n = 64). Surgeon satisfaction and detection rates for seven biliary structures were compared among the three dose groups. RESULTS: Demographic parameters did not significantly differ among the groups. The medium dose (72.1%) and higher dose ICG groups (70.3%) exhibited superior visualization of the common hepatic duct compared to the lower dose group (41.3%) (p < 0.001). No differences existed between the medium and higher dose groups. Similar trends were observed for the common bile duct and cystic common bile duct junction. CONCLUSIONS: In patients undergoing fluorescent laparoscopic cholecystectomy, the 0.02 mg/BMI dose of indocyanine green demonstrated better biliary structure detection rates than the 0.01 mg/BMI dose and was non-inferior to the 0.04 mg/BMI dose.