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Cell-to-cell mitochondrial transfer has recently been shown to play a role in maintaining physiological functions of cell. We previously illustrated that mitochondrial transfer within osteocyte dendritic network regulates bone tissue homeostasis. However, the mechanism of triggering this process has not been explored. Here, we showed that stressed osteocytes in mice release adenosine diphosphate (ADP), resulting in triggering mitochondrial transfer from healthy osteocytes to restore the oxygen consumption rate (OCR) and to alleviate reactive oxygen species accumulation. Furthermore, we identified that P2Y2 and P2Y6 transduced the ADP signal to regulate osteocyte mitochondrial transfer. We showed that mitochondrial metabolism is impaired in aged osteocytes, and there were more extracellular nucleotides release into the matrix in aged cortical bone due to compromised membrane integrity. Conditioned medium from aged osteocytes triggered mitochondrial transfer between osteocytes to enhance the energy metabolism. Together, using osteocyte as an example, this study showed new insights into how extracellular ADP triggers healthy cells to rescue energy metabolism crisis in stressed cells via mitochondrial transfer in tissue homeostasis.
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Adenosina Difosfato , Homeostasis , Mitocondrias , Osteocitos , Animales , Osteocitos/metabolismo , Mitocondrias/metabolismo , Ratones , Adenosina Difosfato/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Consumo de Oxígeno , Metabolismo Energético , Ratones Endogámicos C57BL , Estrés FisiológicoRESUMEN
Kidney transplantation (KT) serves as a highly effective treatment for end-stage renal disease (ESRD). Nonetheless, the administration of tacrolimus, a commonly used immunosuppressant in KT, faces challenges due to the lack of dependable biomarkers for its efficacy and the considerable variability in tacrolimus pharmacokinetics (TacIPV). In this study, 183 saliva samples from 48 KT recipients under tacrolimus therapy, alongside 9 healthy control samples, were subjected to 16S rRNA sequencing. The analysis revealed significant differences in the composition of salivary microbiota among KT recipients, patients with ESRD, and healthy controls. Moreover, trough blood concentrations (C0) of tacrolimus were associated with alterations in microbiota composition. Notably, Capnocytophage consistently exhibited a negative correlation in both group-level and individual trends. Furthermore, distinct taxa were identified that effectively distinguished recipients with varying TacIPV, as demonstrated by a cross-validation random forest model (mean AUC = 0.7560), with Anaerolinea emerging as a prominent contributor to the classifier. These findings suggest that salivary microbiota is closely linked to tacrolimus C0 levels and could aid clinicians in differentiating KT recipients based on TacIPV.
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With the widespread application of highly integrated electronic devices, the urgent development of multifunctional polymer-based composite materials with high electromagnetic interference shielding effectiveness (EMI SE) and thermal conductivity capabilities is critically essential. Herein, a graphene/carbon felt/polyimide (GCF/PI) composite is prepared through constructing 3D van der Waals heterostructure by heating carbon felt and graphene at high temperature. The GCF-3/PI composite exhibits the highest through-plane thermal conductivity with 1.31 W·m-1·K-1, when the content of carbon felt and graphene is 14.1 and 1.4 wt.%, respectively. The GCF-3/PI composite material achieves a thermal conductivity that surpasses pure PI by 4.9 times. Additionally, GCF-3/PI composite shows an outstanding EMI SE of 69.4 dB compared to 33.1 dB for CF/PI at 12 GHz. The 3D van der Waals heterostructure constructed by carbon felt and graphene sheets is conducive to the formation of continuous networks, providing fast channels for the transmission of phonons and carriers. This study provides a guidance on the impact of 3D van der Waals heterostructures on the thermal and EMI shielding properties of composites.
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Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.
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Transportador 1 de Casete de Unión a ATP , Colesterol , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Ratones Endogámicos C57BL , Podocitos , Animales , Podocitos/metabolismo , Podocitos/patología , Colesterol/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatías Diabéticas/metabolismo , Nefropatías Diabéticas/patología , Ratones , Masculino , Diabetes Mellitus Experimental/metabolismo , Ratones Noqueados , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismoRESUMEN
Delayed graft function (DGF) is a frequently observed complication following kidney transplantation (KT). Our prior research revealed dynamic shifts in salivary microbiota post-KT with immediate graft function (IGF), yet its behavior during DGF remains unexplored. Five recipients with DGF and 35 recipients with IGF were enrolled. Saliva samples were collected during the perioperative period, and 16S rRNA gene sequencing was performed. The salivary microbiota of IGFs changed significantly and gradually stabilized with the recovery of renal function. The salivary microbiota composition of DGFs was significantly different from that of IGFs, although the trend of variation appeared to be similar to that of IGFs. Salivary microbiota that differed significantly between patients with DGF and IGF at 1 day after transplantation were able to accurately distinguish the two groups in the randomForest algorithm (accuracy = 0.8333, sensitivity = 0.7778, specificity = 1, and area under curve = 0.85), with Selenomonas playing an important role. Bacteroidales (Spearman's r = - 0.4872 and p = 0.0293) and Veillonella (Spearmen's r = - 0.5474 and p = 0.0125) were significantly associated with the serum creatinine in DGF patients. Moreover, the significant differences in overall salivary microbiota structure between DGF and IGF patients disappeared upon long-term follow-up. This is the first study to investigate the dynamic changes in salivary microbiota in DGFs. Our findings suggested that salivary microbiota was able to predict DGF in the early stages after kidney transplantation, which might help the perioperative clinical management and early-stage intervention of kidney transplant recipients. KEY POINTS: ⢠Salivary microbiota on the first day after KT could predict DGF. ⢠Alterations in salivary taxa after KT are related to recovery of renal function.
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Funcionamiento Retardado del Injerto , Trasplante de Riñón , Microbiota , ARN Ribosómico 16S , Saliva , Humanos , Trasplante de Riñón/efectos adversos , Saliva/microbiología , Masculino , Femenino , Persona de Mediana Edad , ARN Ribosómico 16S/genética , Adulto , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genéticaRESUMEN
BACKGROUND: To evaluate the safety and effectiveness of a stepwise interventional strategy for the removal of adherent totally implanted central venous access port catheters, consisting of a guidewire support, antegrade coaxial separation, and retrograde coaxial separation with increasing technical complexity. METHODS: This study has a retrospective design. Thirty-two patients who had failed routine removal of the port catheter and were then transferred to interventional radiology between November 2017 and December 2023 were reviewed. The technical success and complication rates were recorded. RESULTS: All adherent catheters were successfully removed without catheter fragmentation, using guidewire support (n = 21), antegrade coaxial separation (n = 5), and retrograde coaxial separation (n = 6). The technical success rate was 100%, and no complications occurred. CONCLUSIONS: The proposed stepwise interventional strategy successfully removed adherent port catheters, with good safety and high effectiveness. It appeared to reduce the incidence of catheter fracture during the removal of adherent totally implantable central venous access port catheters.
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Cateterismo Venoso Central , Catéteres de Permanencia , Catéteres Venosos Centrales , Remoción de Dispositivos , Humanos , Estudios Retrospectivos , Cateterismo Venoso Central/efectos adversos , Cateterismo Venoso Central/instrumentación , Femenino , Masculino , Persona de Mediana Edad , Anciano , Resultado del Tratamiento , Adulto , Radiografía Intervencional , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Maternal exposure to multiple antibiotics exposure during pregnancy has attracted extensive attention, but biomonitoring studies linking prenatal antibiotic exposure to emotional and behavioural problems in children are limited. METHODS: A total of 2475 pregnant women from the Ma'anshan Birth Cohort were included, and the Strengths and Difficulties Questionnaire was completed when their children turned four years of age. The levels of 41 maternal urinary antibiotics and two metabolites were measured during the first, second and third trimesters. Generalized estimating equations and binary logistic regression models were applied to analyse the associations between maternal antibiotic exposure and emotional and behavioural problems in children and to determine the sensitive period, respectively. A quantile-based g-computation (QGC) approach was employed to examine the combined effects of multiple antibiotics on emotional and behavioural problems in children. RESULTS: Overall, florfenicol and preferred-as-veterinary antibiotic (PVA) exposure during pregnancy increased the risk of emotional problems in children, and ofloxacin exposure increased the risk of hyperactivity-inattention. Maternal exposure to trimethoprime, ciprofloxacin, florfenicol, other antibiotics and PVA exposure during the first trimester was positively associated with emotional problems in children. Second-trimester trimethoprime concentrations and third-trimester ciprofloxacin concentrations were positively associated with hyperactivity-inattention. Third-trimester veterinary antibiotic (VA) exposure was negatively associated with hyperactivity-inattention, and second-trimester VA and PVA exposure was negatively associated with peer problems. The QGC model revealed that mixed antibiotic exposure in the first trimester exacerbated the risk of childhood emotional problems (the contribution of ciprofloxacin is prominent), and mixed antibiotic exposure in the second trimester increased the risk of hyperactivity-inattention (the contribution of trimethoprime is prominent). CONCLUSION: Maternal mixed antibiotic exposure during the first and second trimesters increases the risk of emotional problems and hyperactivity-inattention in children at four years of age.
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Antibacterianos , Monitoreo Biológico , Exposición Materna , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Embarazo , Antibacterianos/toxicidad , Preescolar , Estudios Prospectivos , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Exposición Materna/efectos adversos , Masculino , Adulto , China , Problema de ConductaRESUMEN
BACKGROUND: The associations between prenatal antibiotics exposure and attention-deficit/hyperactivity disorder (ADHD) in preschoolers, and the role of maternal vitamin D in these associations, remain to be explored. OBJECTIVES: To evaluate the relationships between multiple maternal urinary antibiotics levels and preschoolers' ADHD symptoms, and to identify the potential modifying effects of maternal vitamin D. METHODS: Based on a prospective birth cohort, the present study included 2033 motherchild pairs. Maternal urine and serum samples were collected during all three trimesters to measure the urinary concentrations of 43 antibiotics (including two metabolites) and the serum vitamin D levels. The ADHD symptoms of preschoolers were assessed using the Diagnostic and Statistical Manual-oriented ADHD problems scale in the Achenbach Child Behavior Checklist. Multiple informant models in the form of logistic regression were conducted to investigate the associations between prenatal antibiotics exposure and preschooler ADHD symptoms, and these associations were stratified by child sex and maternal vitamin D status. RESULTS: Compared with the lowest tertile concentrations, maternal exposure to the middle tertile concentrations of doxycycline and human antibiotics/preferred as human antibiotics (HAs/PHAs), and the highest tertile concentrations of doxycycline during the first trimester were associated with an increased risk of ADHD symptoms in children. An increased risk of ADHD symptoms was observed in girls exposed to the highest tertile levels of sulfamethazine during the second trimester. Furthermore, pregnant women with vitamin D deficiency have a greater risk of ADHD symptoms in their offspring after exposure to doxycycline in the first trimester. CONCLUSIONS: Maternal exposure to doxycycline and HAs/PHAs during the first trimester increases the risk of ADHD symptoms in preschoolers. Mid-pregnancy sulfamethazine exposure increases the risk of ADHD symptoms in girls. Maternal vitamin D deficiency during pregnancy may exacerbate the adverse effects of doxycycline exposure on ADHD symptoms.
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Antibacterianos , Trastorno por Déficit de Atención con Hiperactividad , Exposición Materna , Efectos Tardíos de la Exposición Prenatal , Vitamina D , Humanos , Trastorno por Déficit de Atención con Hiperactividad/inducido químicamente , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Femenino , Embarazo , Preescolar , Antibacterianos/efectos adversos , Masculino , Exposición Materna/efectos adversos , Exposición Materna/estadística & datos numéricos , Vitamina D/sangre , Vitamina D/análogos & derivados , Estudios Prospectivos , AdultoRESUMEN
Plesiomonas shigelloides, a Gram-negative bacillus, is the only member of the Enterobacteriaceae family able to produce polar and lateral flagella and cause gastrointestinal and extraintestinal illnesses in humans. The flagellar transcriptional hierarchy of P. shigelloides is currently unknown. In this study, we identified FlaK, FlaM, FliA, and FliAL as the four regulators responsible for polar and lateral flagellar regulation in P. shigelloides. To determine the flagellar transcription hierarchy of P. shigelloides, the transcriptomes of the WT and ΔflaK, ΔflaM, ΔfliA, and ΔfliAL were carried out for comparison in this study. Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) and luminescence screening assays were used to validate the RNA-seq results, and the Electrophoretic Mobility Shift Assay (EMSA) results revealed that FlaK can directly bind to the promoters of fliK, fliE, flhA, and cheY, while the FlaM protein can bind directly to the promoters of flgO, flgT, and flgA. Meanwhile, we also observed type VI secretion system (T6SS) and type II secretion system 2 (T2SS-2) genes downregulated in the transcriptome profiles, and the killing assay revealed lower killing abilities for ΔflaK, ΔflaM, ΔfliA, and ΔfliAL compared to the WT, indicating that there was a cross-talk between the flagellar hierarchy system and bacterial secretion system. Invasion assays also showed that ΔflaK, ΔflaM, ΔfliA, and ΔfliAL were less effective in infecting Caco-2 cells than the WT. Additionally, we also found that the loss of flagellar regulators causes the differential expression of some of the physiological metabolic genes of P. shigelloides. Overall, this study aims to reveal the transcriptional hierarchy that controls flagellar gene expression in P. shigelloides, as well as the cross-talk between motility, virulence, and physiological and metabolic activity, laying the groundwork for future research into P. shigelloides' coordinated survival in the natural environment and the mechanisms that infect the host.
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Proteínas Bacterianas , Flagelos , Perfilación de la Expresión Génica , Regulación Bacteriana de la Expresión Génica , Plesiomonas , Flagelos/metabolismo , Flagelos/genética , Plesiomonas/genética , Plesiomonas/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Transcriptoma , Regiones Promotoras Genéticas , Sistemas de Secreción Bacterianos/genética , Sistemas de Secreción Bacterianos/metabolismo , Transcripción Genética , HumanosRESUMEN
BACKGROUND: Changes in healthy and inflamed pulp on periapical radiographs are traditionally so subtle that they may be imperceptible to human experts, limiting its potential use as an adjunct clinical diagnostic feature. AIM: This study aimed to investigate the feasibility of an image-analysis technique based on the convolutional neural network (CNN) to detect irreversible pulpitis in primary molars on periapical radiographs (PRs). DESIGN: This retrospective study was performed in two health centres. Patients who received indirect pulp therapy at Peking University Hospital for Stomatology were retrospectively identified and randomly divided into training and validation sets (8:2). Using PRs as input to an EfficientNet CNN, the model was trained to categorise cases into either the success or failure group and externally tested on patients who presented to our affiliate institution. Model performance was evaluated using sensitivity, specificity, accuracy and F1 score. RESULTS: A total of 348 PRs with deep caries were enrolled from the two centres. The deep learning model achieved the highest accuracy of 0.90 (95% confidence interval: 0.79-0.96) in the internal validation set, with an overall accuracy of 0.85 in the external test set. The mean greyscale value was higher in the failure group than in the success group (p = .013). CONCLUSION: The deep learning-based model could detect irreversible pulpitis in primary molars with deep caries on PRs. Moreover, this study provides a convenient and complementary method for assessing pulp status.
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With the development of brain-computer interface (BCI) technology and its translational application in clinical medicine, BCI medicine has emerged, ushering in profound changes to the practice of medicine, while also bringing forth a series of ethical issues related to BCI medicine. BCI medicine is progressively emerging as a new disciplinary focus, yet to date, there has been limited literature discussing it. Therefore, this paper focuses on BCI medicine, firstly providing an overview of the main potential medical applications of BCI technology. It then defines the discipline, outlines its objectives, methodologies, potential efficacy, and associated translational medical research. Additionally, it discusses the ethics associated with BCI medicine, and introduces the standardized operational procedures for BCI medical applications and the methods for evaluating the efficacy of BCI medical applications. Finally, it anticipates the challenges and future directions of BCI medicine. In the future, BCI medicine may become a new academic discipline or major in higher education. In summary, this article is hoped to provide thoughts and references for the development of the discipline of BCI medicine.
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Interfaces Cerebro-Computador , Interfaces Cerebro-Computador/tendencias , Humanos , Electroencefalografía , Encéfalo/fisiologíaRESUMEN
Implantable brain-computer interfaces (BCIs) have potentially important clinical applications due to the high spatial resolution and signal-to-noise ratio of electrodes that are closer to or implanted in the cerebral cortex. However, the surgery and electrodes of implantable BCIs carry safety risks of brain tissue damage, and their medical applications face ethical challenges, with little literature to date systematically considering ethical norms for the medical applications of implantable BCIs. In order to promote the clinical translation of this type of BCI, we considered the ethics of practice for the medical application of implantable BCIs, including: reducing the risk of brain tissue damage from implantable BCI surgery and electrodes, providing patients with customized and personalized implantable BCI treatments, ensuring multidisciplinary collaboration in the clinical application of implantable BCIs, and the responsible use of implantable BCIs, among others. It is expected that this article will provide thoughts and references for the research and development of ethics of the medical application of implantable BCI.
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Interfaces Cerebro-Computador , Humanos , Electroencefalografía , Prótesis e Implantes , ElectrodosRESUMEN
BACKGROUND: The phagocytosis and homeostasis of microglia play an important role in promoting blood clearance and improving prognosis after subarachnoid hemorrhage (SAH). LC3-assocaited phagocytosis (LAP) contributes to the microglial phagocytosis and homeostasis via autophagy-related components. With RNA-seq sequencing, we found potential signal pathways and genes which were important for the LAP of microglia. METHODS: We used an in vitro model of oxyhemoglobin exposure as SAH model in the study. RNA-seq sequencing was performed to seek critical signal pathways and genes in regulating LAP. Bioparticles were used to access the phagocytic ability of microglia. Western blot (WB), immunoprecipitation, quantitative polymerase chain reaction (qPCR) and immunofluorescence were performed to detect the expression change of LAP-related components and investigate the potential mechanisms. RESULTS: In vitro SAH model, there were increased inflammation and decreased phagocytosis in microglia. At the same time, we found that the LAP of microglia was inhibited in all stages. RNA-seq sequencing revealed the importance of P38 MAPK signal pathway and DAPK1 in regulating microglial LAP. P38 was found to regulate the expression of DAPK1, and P38-DAPK1 axis was identified to regulate the LAP and homeostasis of microglia after SAH. Finally, we found that P38-DAPK1 axis regulated expression of BECN1, which indicated the potential mechanism of P38-DAPK1 axis regulating microglial LAP. CONCLUSION: P38-DAPK1 axis regulated the LAP of microglia via BECN1, affecting the phagocytosis and homeostasis of microglia in vitro SAH model. Video Abstract.
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Microglía , Hemorragia Subaracnoidea , Humanos , Fagocitosis , Autofagia , Inflamación , Proteínas Quinasas Asociadas a Muerte CelularRESUMEN
Zwitterionic polyelectrolyte nanogels are prospective nanocarriers due to their soft loading pocket and regulated charges. We here report a facile strategy, namely, electrostatic-templated polymerization (ETP) for synthesizing zwitterionic nanogels with controlled size and properties. Specifically, with anionic-neutral diblock polymers as the template, zwitterionic monomers such as carboxybetaine methacrylate (CBMA) or carboxybetaine acrylamide (CBAA) are polymerized together with a cross-linker at pH 2 where the monomers exhibit only positive charge due to the protonation of the carboxyl group. The obtained polyelectrolyte complex micelles dissociate upon introducing a concentrated salt. The subsequent separation yields the released template and zwitterionic nanogels with regulated size and swelling ability, achieved by tuning the salt concentration and cross-linker fraction during polymerization. The obtained PCBMA nanogels exhibit charges depending on the pH, which enables not only the selective loading of different dye molecules, but also encapsulation and intracellular delivery of cytochrome c protein. Our study develops a facile and robust way for fabricating zwitterionic nanogels and validates their potential applications as promising nanocarriers for load and delivery of functional charged cargos.
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Gliomas account for about 80% of malignant brain tumors. The incidence of a new brain tumor is 6.4 per 100,000 persons per year with an overall 5-year survival rate of 33.4%. Regardless of the great advances that have been made in recent years, the causes and pathogenesis of glioma remain unclear. Here we study how phosphoglycerate mutase 4 (PGAM4) contributes to glioma. Using a variety of methods to examine glioma cell viability, proliferation, apoptosis, glycolysis, as well as ChIP coanalysis with modified histone H3, we showed that PGAM4 was significantly upregulated in patients with glioma and associated with poor survival. Silencing PGAM4 attenuated cell viability, proliferation, and glycolysis in T98G cells and suppressed tumor growth in vivo, while overexpressing PGAM4 promoted cell viability, proliferation, and glycolysis in U251 cells via regulating glycolysis pathway. Study also revealed that PGAM4 was regulated by EP300-mediated modifications of H3K27ac. PGAM4 silencing inhibited cell viability and proliferation, suppressed tumor growth, and decreased chemoresistance to temozolomide in glioma cells through suppressing glycolysis.
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Neoplasias Encefálicas , Glioma , Humanos , Temozolomida/farmacología , Fosfoglicerato Mutasa/metabolismo , Resistencia a Antineoplásicos , Glioma/metabolismo , Neoplasias Encefálicas/metabolismo , Apoptosis , Glucólisis , Línea Celular Tumoral , Proliferación CelularRESUMEN
BACKGROUND: Diabetic retinopathy (DR) is a common diabetic neurodegenerative disease that affects vision in severe cases. Current therapeutic drugs are ineffective for some patients with severe side effects, and ginsenoside-Rg1 (GRg1) has been shown to protect against DR and may serve as a new potential drug for DR. This study aimed to confirm the protective effect of GRg1 against DR and its molecular mechanism. METHODS: Human retinal microvascular endothelial cells (hRMECs) and rats were used to construct DR models in vitro and in vivo. Cell proliferation was detected by BrdU assays, the cell cycle was detected by flow cytometry, and TNF-α, IL-6 and IL-1ß levels were detected by ELISA. qRTâPCR, Western blotting and immunohistochemistry were used to detect the expression of related genes and proteins, and angiogenesis assays were used to assess angiogenesis. RIP and RNA pull down assays were used to determine the relationship between miR-216a-5p and TLR4; retinal structure and changes were observed by HE staining and retinal digestive spread assays. RESULTS: GRg1 effectively inhibited HG-induced hRMEC proliferation, cell cycle progression and angiogenesis and reduced the levels of intracellular inflammatory cytokines and growth factors. HG downregulated the expression of miR-216a-5p and upregulated the expression of TLR4/NF-kB signaling pathway-related proteins. Importantly, GRg1 inhibited TLR4/NF-kB signaling pathway activation by upregulating miR-216a-5p, thereby inhibiting HG-induced cell proliferation, cell cycle progression, angiogenesis, and the production of inflammatory cytokines and growth factors. In addition, animal experiments confirmed the results of the cell experiments. CONCLUSIONS: GRg1 inhibits TLR4/NF-kB signaling by upregulating miR-216a-5p to reduce growth factors and inflammatory cytokines in DR, providing a potential therapeutic strategy for DR.
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Retinopatía Diabética , Ginsenósidos , MicroARNs , Enfermedades Neurodegenerativas , Humanos , Ratas , Animales , FN-kappa B/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/genética , Retinopatía Diabética/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Células Endoteliales/metabolismo , Citocinas/genética , Citocinas/metabolismo , Ginsenósidos/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Ventilator-induced lung injury (VILI) is caused by overdistension of the alveoli by the repetitive recruitment and derecruitment of alveolar units. This study aims to investigate the potential role and mechanism of fibroblast growth factor 21 (FGF21), a metabolic regulator secreted by the liver, in VILI development. METHODS: Serum FGF21 concentrations were determined in patients undergoing mechanical ventilation during general anesthesia and in a mouse VILI model. Lung injury was compared between FGF21-knockout (KO) mice and wild-type (WT) mice. Recombinant FGF21 was administrated in vivo and in vitro to determine its therapeutic effect. RESULTS: Serum FGF21 levels in patients and mice with VILI were significantly higher than in those without VILI. Additionally, the increment of serum FGF21 in anesthesia patients was positively correlated with the duration of ventilation. VILI was aggravated in FGF21-KO mice compared with WT mice. Conversely, the administration of FGF21 alleviated VILI in both mouse and cell models. FGF21 reduced Caspase-1 activity, suppressed the mRNA levels of Nlrp3, Asc, Il-1ß, Il-18, Hmgb1 and Nf-κb, and decreased the protein levels of NLRP3, ASC, IL-1ß, IL-18, HMGB1 and the cleaved form of GSDMD. CONCLUSIONS: Our findings reveal that endogenous FGF21 signaling is triggered in response to VILI, which protects against VILI by inhibiting the NLRP3/Caspase-1/GSDMD pyroptosis pathway. These results suggest that boosting endogenous FGF21 or the administration of recombinant FGF21 could be promising therapeutic strategies for the treatment of VILI during anesthesia or critical care.
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Proteína HMGB1 , Lesión Pulmonar Inducida por Ventilación Mecánica , Animales , Ratones , Caspasa 1/metabolismo , Modelos Animales de Enfermedad , Inflamasomas , Interleucina-18 , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lesión Pulmonar Inducida por Ventilación Mecánica/tratamiento farmacológico , Lesión Pulmonar Inducida por Ventilación Mecánica/prevención & control , HumanosRESUMEN
This paper provides a critical review of the Bayesian perspective of causal inference based on the potential outcomes framework. We review the causal estimands, assignment mechanism, the general structure of Bayesian inference of causal effects and sensitivity analysis. We highlight issues that are unique to Bayesian causal inference, including the role of the propensity score, the definition of identifiability, the choice of priors in both low- and high-dimensional regimes. We point out the central role of covariate overlap and more generally the design stage in Bayesian causal inference. We extend the discussion to two complex assignment mechanisms: instrumental variable and time-varying treatments. We identify the strengths and weaknesses of the Bayesian approach to causal inference. Throughout, we illustrate the key concepts via examples. This article is part of the theme issue 'Bayesian inference: challenges, perspectives, and prospects'.
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PURPOSE: Zygomatic fractures involve complex anatomical structures of the mid-face and the diagnosis can be challenging and labor-consuming. This research aimed to evaluate the performance of an automatic algorithm for the detection of zygomatic fractures based on convolutional neural network (CNN) on spiral computed tomography (CT). MATERIALS AND METHODS: We designed a cross-sectional retrospective diagnostic trial study. Clinical records and CT scans of patients with zygomatic fractures were reviewed. The sample consisted of two types of patients with different zygomatic fractures statuses (positive or negative) in Peking University School of Stomatology from 2013 to 2019. All CT samples were randomly divided into three groups at a ratio of 6:2:2 as training set, validation set, and test set, respectively. All CT scans were viewed and annotated by three experienced maxillofacial surgeons, serving as the gold standard. The algorithm consisted of two modules as follows: (1) segmentation of the zygomatic region of CT based on U-Net, a type of CNN model; (2) detection of fractures based on Deep Residual Network 34(ResNet34). The region segmentation model was used first to detect and extract the zygomatic region, then the detection model was used to detect the fracture status. The Dice coefficient was used to evaluate the performance of the segmentation algorithm. The sensitivity and specificity were used to assess the performance of the detection model. The covariates included age, gender, duration of injury, and the etiology of fractures. RESULTS: A total of 379 patients with an average age of 35.43 ± 12.74 years were included in the study. There were 203 nonfracture patients and 176 fracture patients with 220 sites of zygomatic fractures (44 patients underwent bilateral fractures). The Dice coefficient of zygomatic region detection model and gold standard verified by manual labeling were 0.9337 (coronal plane) and 0.9269 (sagittal plane), respectively. The sensitivity and specificity of the fracture detection model were 100% (pï¼.05). CONCLUSION: The performance of the algorithm based on CNNs was not statistically different from the gold standard (manual diagnosis) for zygomatic fracture detection in order for the algorithm to be applied clinically.
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Fracturas Cigomáticas , Adulto , Humanos , Persona de Mediana Edad , Adulto Joven , Estudios Transversales , Redes Neurales de la Computación , Estudios Retrospectivos , Tomografía Computarizada por Rayos X/métodos , Fracturas Cigomáticas/diagnóstico por imagenRESUMEN
Recent studies have shown that the gut microbiota regulates intestinal function and maintains intestinal homeostasis, as well as interacting with the central nervous system to affect brain function and human behavior. Microglia are the most common immune cell type in the central nervous system during homeostasis. These cells play an important role in immune surveillance by responding to infections and other pathological conditions. Microglia also play a major role in maintaining brain homeostasis in both developing and adult mice by phagocytosing cell debris and regulating the formation of neural networks. The specific signaling pathways and cytokines that control the maturation and activation of microglia are currently not fully established. However, research on germ-free (GF) mice and specific pathogen-free (SPF) mice indicate that gut microbiota have important interactions with microglia. Here, we review the latest research findings on how gut microbiota can affect the morphology, maturation, phenotype and function of microglia. We also discuss recent advances in the gut microbiota-microglia-disease axis.