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Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The inflammatory cytokine storm causes systemic organ damage, especially acute lung injury in sepsis. In this study, we found that the expression of S-phase kinase-associated protein 2 (Skp2) was significantly decreased in sepsis-induced acute lung injury (ALI). Sepsis activated the MEK/ERK pathway and inhibited Skp2 expression in the pulmonary epithelium, resulting in a reduction of K48 ubiquitination of solute carrier family 3 member 2 (SLC3A2), thereby impairing its membrane localization and cystine/glutamate exchange function. Consequently, the dysregulated intracellular redox reactions induced ferroptosis in pulmonary epithelial cells, leading to lung injury. Finally, we demonstrated that intravenous administration of Skp2 mRNA-encapsulating lipid nanoparticles (LNPs) inhibited ferroptosis in the pulmonary epithelium and alleviated lung injury in septic mice. Taken together, these data provide an innovative understanding of the underlying mechanisms of sepsis-induced ALI and a promising therapeutic strategy for sepsis.
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Lesão Pulmonar Aguda , Ferroptose , Camundongos Endogâmicos C57BL , Proteínas Quinases Associadas a Fase S , Sepse , Ubiquitinação , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/etiologia , Sepse/metabolismo , Sepse/complicações , Sepse/patologia , Animais , Camundongos , Humanos , Masculino , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Pulmão/patologia , Pulmão/metabolismo , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genéticaRESUMO
PURPOSE: To identify factors and indicators that affect chronic pain and pain relief, and to develop predictive models using machine learning. METHODS: We analyzed the data of 67,028 outpatient cases and 11,310 valid samples with pain from a large retrospective cohort. We used decision tree, random forest, AdaBoost, neural network, and logistic regression to discover significant indicators and to predict pain and treatment relief. FINDINGS: The random forest model had the highest accuracy, F1 value, precision, and recall rates for predicting pain relief. The main factors affecting pain and treatment relief included body mass index, blood pressure, age, body temperature, heart rate, pulse, and neutrophil/lymphocyte × platelet ratio. The logistic regression model had high sensitivity and specificity for predicting pain occurrence. IMPLICATIONS: Machine learning models can be used to analyze the risk factors and predictors of chronic pain and pain relief, and to provide personalized and evidence-based pain management.
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Dor Crônica , Aprendizado de Máquina , Humanos , Estudos Retrospectivos , Dor Crônica/diagnóstico , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Resultado do Tratamento , Idoso , Manejo da Dor/métodos , Modelos Logísticos , Fatores de Risco , Árvores de DecisõesRESUMO
Quantum communication satellites have potential for applications in future quantum networks. Photonics integrated chips, due to their compact and lightweight nature, are well-suited for satellite deployment. However, the harsh radiation environment of space can cause permanent damage to these chips, resulting in degraded performance or complete loss of functionality. In this work, we conducted a series of radiation experiments to evaluate the effects of γ rays and high energy protons on quantum key distribution transmitter chips. The results suggest that the insertion loss of the chip is slightly reduced by about 1.5 dB after 100 krad (Si) γ ray irradiation, and further reduced by about 0.5 to 1 dB after 2.39 × 1011/cm2 proton radiation. The half-wave voltages, extinction ratios, and polarization angles are not changed significantly within the measurement error range. Our work proves the feasibility of deploying quantum constellations utilizing terminals based on photonics chips.
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BACKGROUND: HSK3486 (ciprofol), a new candidate drug similar to propofol, exerts sedative and hypnotic effects through gamma-aminobutyric acid type A receptors; however, its potential role in colorectal cancer is currently unknown. AIMS: This study aimed to evaluate the effects of HSK3486 on colorectal cancer cell proliferation. METHODS: Imaging was performed to detect reactive oxygen species and mitochondrial membrane potential. Western blotting was used to determine the expression of target signals. The HSK3486 molecular mechanism was investigated through ATPase inhibitory factor 1 knockdown and xenograft model experiments to assess mitochondrial function in colorectal cancer cells. RESULTS: Cell Counting Kit-8 and Annexin V/propidium iodide double staining assays showed that HSK3486 inhibited colorectal cancer cell proliferation in a concentration-dependent manner. In addition, HSK3486 treatment increased the expression of B-cell lymphoma-2-associated X, cleaved caspase 3, and cleaved poly (ADP-ribose) polymerase, whereas myeloid cell leukemia-1 and B-cell lymphoma 2 expression decreased. HSK3486 promoted mitochondrial dysfunction by inducing ATPase inhibitor factor 1 expression. Furthermore, HSK3486 promoted oxidative stress, as shown by the increase in reactive oxygen species and lactate dehydrogenase levels, along with a decrease in mitochondrial membrane potential and ATP levels. ATPase inhibitor factor 1 small interfering RNA pretreatment dramatically increased the mitochondrial membrane potential and tumor size in a xenograft model following exposure to HSK3486. CONCLUSION: Collectively, our findings revealed that HSK3486 induces oxidative stress, resulting in colorectal cancer cell apoptosis, making it a potential candidate therapeutic strategy for colorectal cancer.
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Apoptose , Neoplasias Colorretais , Humanos , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Adenosina Trifosfatases/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Potencial da Membrana Mitocondrial , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Proteína Inibidora de ATPase/efeitos dos fármacosRESUMO
Urban economic competitiveness is a fundamental indicator for assessing the level of urban development and serves as an effective approach for understanding regional disparities. Traditional economic competitiveness research that relies solely on traditional regression models and assumes feature relationship theory tends to fall short in fully exploring the intricate interrelationships and nonlinear associations among features. As a result, the study of urban economic disparities remains limited to a narrow range of urban features, which is insufficient for comprehending cities as complex systems. The ability of deep learning neural networks to automatically construct models of nonlinear relationships among complex features provides a new approach to research in this issue. In this study, a complex urban feature dataset comprising 1008 features was constructed based on statistical data from 283 prefecture-level cities in China. Employing a machine learning approach based on convolutional neural network (CNN), a novel analytical model is constructed to capture the interrelationships among urban features, which is applied to achieve accurate classification of urban economic competitiveness. In addition, considering the limited number of samples in the dataset owing to the fixed number of cities, this study developed a data augmentation approach based on deep convolutional generative adversarial network (DCGAN) to further enhance the accuracy and generalization ability of the model. The performance of the CNN classification model was effectively improved by adding the generated samples to the original sample dataset. This study provides a precise and stable analytical model for investigating disparities in regional development. In the meantime, it offers a feasible solution to the limited sample size issue in the application of deep learning in urban research.
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Aprendizado de Máquina , Redes Neurais de Computação , Cidades , ChinaRESUMO
Sepsis is a life-threatening systemic inflammatory response syndrome caused by the host imbalanced response to infection. Lung injury is the most common complication of sepsis and one of the leading causes of patient death. Pyroptosis is a specific programmed cell death characterized by the release of inflammatory cytokines. Appropriate pyroptosis can reduce tissue damage and exert a protective effect against infection during sepsis. However, overactivated pyroptosis results in massive cell death, leading to septic shock, multiple organ dysfunction syndrome, and even an increased risk of secondary infection. Recent studies suggest that pyroptosis can interact with and cross-regulate other types of cell death programs to establish a complex network of cell death, which participates in the occurrence and development of septic lung injury. This review will focus on the interactions between pyroptosis and other types of cell death, including apoptosis, necroptosis, PANoptosis, NETosis, autophagy, and ferroptosis, to summarize the role of pyroptosis in sepsis-induced lung injury, and will discuss the potential therapeutic strategies of targeting pyroptosis during sepsis treatment.
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Lesão Pulmonar , Sepse , Humanos , Piroptose , Lesão Pulmonar/complicações , Morte Celular , Apoptose , Sepse/complicações , Sepse/metabolismoRESUMO
Quantum key distribution (QKD) research has yielded highly fruitful results and is currently undergoing an industrialization transformation. In QKD systems, electro-optic modulators are typically employed to prepare the required quantum states. While various QKD systems operating at GHz repetition frequency have demonstrated exceptional performance, they predominantly rely on instruments or printed circuit boards to fulfill the driving circuit function of the electro-optic modulator. Consequently, these systems tend to be complex with low integration levels. To address this challenge, we have introduced a modulator driver integrated circuit in 0.18 µm SiGe BiCMOS technology. The circuit can generate multiple-level driving signals with a clock frequency of 1.25 GHz and a rising edge of â¼50 ps. Each voltage amplitude can be independently adjusted, ensuring the precise preparation of quantum states. The measured signal-to-noise ratio was more than 17 dB, resulting in a low quantum bit error rate of 0.24% in our polarization-encoding system. This work will contribute to the advancement of QKD system integration and promote the industrialization process in this field.
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BACKGROUND: As a newly discovered lncRNA, lncRNA High expression in hepatocellular carcinoma (HEIH) has been reported to correlate with poor clinical outcomes in several different cancers, In addition, studies have shown that HEIH is overexpressed in a variety of cancers and plays an oncogenic role. The present meta-analysis aims to elucidate the relationship between HEIH expression and prognosis and clinicopathological features among cancer patients. METHODS: PubMed, Web of Science, Cochrane Library, and EMBASE database were comprehensively and systematically searched. pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence interval (CI) were employed to assess the relationship between HEIH expression and clinical outcomes and clinicopathological features in cancer patients. CONCLUSION: The present study finally enrolled 11 studies which included 1227 cancer patients. The combined results indicated that HEIH overexpression was significantly associated with shorter overall survival (OS) (pooled HRâ =â 2.03, 95% CI 1.74-2.38, Pâ <â .00001).Meanwhile, regarding clinicopathology of cancer patients, upregulated HEIH expression was closely related to larger tumor size (ORâ =â 2.65, 95% CI: 1.52-4.65, Pâ =â .0006), advanced tumor T stage (ORâ =â 2.41, 95 % CI: 1.54-3.77, Pâ =â .0001), advanced TNM stage (ORâ =â 4.76, 95% CI: 2.73-8.29, Pâ <â .00001), distant metastasis (ORâ =â 2.94, 95% CI: 1.75-4.96, Pâ <â .0001) and lymph node metastasis (ORâ =â 2.07, 95% CI: 1.05-4.07, Pâ =â .04), respectively. CONCLUSIONS: High expression of HEIH in some cancers predicts shorter overall survival and higher clinical stage as well as larger tumor size. HEIH has great potential to become a prognostic marker for cancer patients.
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Neoplasias Hepáticas , Neoplasias , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias/patologia , Prognóstico , Metástase LinfáticaRESUMO
BACKGROUND: The aim of this study was to evaluate whether there is a superior clinical effect of unilateral biportal endoscopy compared with microscopic decompression in the treatment of lumbar spinal stenosis. METHODS: We searched CNKI, WANFANG, CQVIP, CBM, PubMed, and Web of Science up to January 2022, and selected studies that met our inclusion criteria. RESULTS: The results of this meta-analysis indicated that unilateral biportal endoscopy was demonstrated to be more beneficial for patients compared with microscopic decompression for the following outcomes: Operation time [standardized mean difference (SMD)â =â -0.943, 95% confidence interval (CI) (-1.856, -0.031), Pâ =â .043], hospital stays [SMDâ =â -2.652, 95% CI (-4.390, -0.914), Pâ =â .003], EuroQol 5-Dimension questionnaire [SMDâ =â 0.354, 95% CI (0.070, 0.638), Pâ =â .014], back pain visual analogue score [SMDâ =â -0.506, 95% CI (-0.861, -0.151), Pâ =â .005], leg pain visual analogue score [SMDâ =â -0.241, 95% CI (-0.371, -.0112), Pâ =â .000], the C-reactive protein level [SMDâ =â -1.492,95% CI (-2.432, -0.552), Pâ =â .002]. Other outcomes demonstrated no significant differences between the 2 groups. CONCLUSION: For patients with lumbar spinal stenosis, unilateral biportal endoscopy was found to be more superior than microscopic decompression in terms of operation time, hospital stays, EuroQol 5-Dimension questionnaire, back visual analogue score, leg visual analogue score and the C-reactive protein level. There was no significant difference between the 2 groups in other outcome indicators.
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Estenose Espinal , Humanos , Estenose Espinal/cirurgia , Descompressão Cirúrgica/métodos , Proteína C-Reativa , Vértebras Lombares/cirurgia , Endoscopia/métodos , Endoscopia Gastrointestinal , Resultado do Tratamento , Estudos RetrospectivosRESUMO
Biofilms are multicellular communities with a spatial structure. Different from single-cell scale diffusion in planktonic systems, the diffusion distance becomes the dimension of multicellular clusters in a biofilm. Such differences in diffusion behavior affect the tolerance and response to exogenous stress. Here, we found that at the same doses of exogenous hydrogen peroxide (H2O2), planktonic Escherichia coli were completely killed within two hours, whereas the biofilm resumed growth in six hours by building a catalase barrier to block H2O2 penetration, despite the growth burden. Unexpectedly, when we changed the carbon source from glucose to glycerol, H2O2 instantly counterintuitively boosted biofilm growth due to supplemental oxygen, which was the growth-limiting factor. We further demonstrated that the energy metabolism modes determined the growth-limiting factor, which then determined the two patterns of biofilms resistances to H2O2.
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Biofilmes , Peróxido de Hidrogênio , Peróxido de Hidrogênio/farmacologia , Estresse Oxidativo , Difusão , Escherichia coli/fisiologia , PlânctonRESUMO
Osteosarcoma (OS) is the most malignant bone tumor which mainly occurs in childhood or adolescence. The previous studies indicated that OS is difficult to treat. KIAA1429 is one of the components of m6A complex that regulating the process of m6A modification, which plays a crucial role in tumorigenesis. But the mechanism of KIAA1429 regulating OS cell identity was not entirely clear, which needs further investigate. RT-qPCR and western blotting were applied to determine KIAA1429 expression station in OS cells and tissues. To further detect the KIAA1429 function in OS cells, the ability of proliferation, migration and invasion were analyzed by Edu, wound-healing and transwell experiments respectively. Besides, RNA sequencing was also used to further find the downstream of KIAA1429 regulation and small molecule inhibitor was added to explore the specific role of signaling pathway. Our data found that KIAA1429 is up-regulated in human OS cell lines compared to the human osteoblast cells. Meanwhile, the deletion of KIAA1429 significantly decreased cell proliferation, migration, and invasion. Interestingly, the JAK2/STAT3 signal pathway was involved in KIAA1429 regulation on OS cell characters. The KIAA1429 eliminated OS cells exhibited a decreased activity of JAK2/STAT3 signal. And the addition of JAK2/STAT3 stimulator (colivelin) could distinctly rescue the decreased OS cells' proliferation, migration, and invasion upon KIAA1429 knockdown. In summary, these data demonstrated that KIAA1429/JAK2/STAT3 axis may a new target for OS therapy.
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BACKGROUND: Bone grafting is necessary in spinal tuberculosis surgery. Structural bone grafting is considered the gold standard treatment for spinal tuberculosis bone defects; however, nonstructural bone grafting via the posterior approach has recently gained attention. In this meta-analysis, we evaluated the clinical efficacy of structural versus nonstructural bone grafting via the posterior approach in the treatment of thoracic and lumbar tuberculosis. METHODS: Studies comparing the clinical efficacy of structural and nonstructural bone grafting via the posterior approach in spinal tuberculosis surgery were identified from 8 databases from inception to August 2022. Study selection, data extraction, and evaluation of the risk of bias were performed, and meta-analysis was conducted. RESULTS: Ten studies including 528 patients with spinal tuberculosis were enrolled. Meta-analysis revealed no between-group differences in fusion rate (P = 0.29), complications (P = 0.21), postoperative Cobb angle (P = 0.7), visual analog scale score (P = 0.66), erythrocyte sedimentation rate (P = 0.74), or C-reactive protein level (P = 0.14) at the final follow-up. Nonstructural bone grafting was associated with less intraoperative blood loss (P < 0.00001), shorter operation time (P < 0.0001), shorter fusion time (P < 0.01), and shorter hospital stay (P < 0.00001), while structural bone grafting was associated with lower Cobb angle loss (P = 0.002). CONCLUSIONS: Both techniques can achieve a satisfactory bony fusion rate for spinal tuberculosis. Nonstructural bone grafting has the advantages of less operative trauma, shorter fusion time, and shorter hospital stay, making it an attractive option for short-segment spinal tuberculosis. Nevertheless, structural bone grafting is superior for maintaining corrected kyphotic deformities.
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Fusão Vertebral , Tuberculose da Coluna Vertebral , Humanos , Tuberculose da Coluna Vertebral/diagnóstico por imagem , Tuberculose da Coluna Vertebral/cirurgia , Estudos Retrospectivos , Transplante Ósseo/métodos , Fusão Vertebral/métodos , Vértebras Torácicas/cirurgia , Resultado do Tratamento , Desbridamento , Vértebras Lombares/cirurgiaRESUMO
BACKGROUND: Cryptococcus neoformans, an opportunistic fungal pathogen, seldom causes infection in immunocompetent people. Cryptococcal osteomyelitis is an uncommon condition in which Cryptococcus invades the bone. It usually occurs as part of a disseminated infection and rarely in isolation. The spine has been reported as the most common site of cryptococcal osteomyelitis; however, isolated case of sacrum involvement in immunocompetent patients has never been reported. CASE PRESENTATION: We report the case of a 37-year-old man without underlying disease who presented with progressive low back and sacrococcygeal pain. The patient was initially diagnosed with sacral tumour by a local doctor, and subsequently, after admission, was diagnosed with sacral tuberculosis. He was empirically treated with antitubercular drugs. The patient failed to respond to antitubercular drugs and complained of worsening low back pain. Additionally, he developed persistent radiating pain and numbness in his legs. For further diagnosis, we performed a computed tomography-guided puncture biopsy of the sacrum, which revealed granulomatous inflammation with massive macrophage infiltration and special staining revealed a fungal infection. We performed sacral debridement and drainage and obtained purulent specimens for pathological examination and microbial culture. Microbial identification and drug susceptibility tests revealed a Cryptococcus neoformans infection sensitive to fluconazole. Postoperatively, the persistent radiating pain and numbness in the legs resolved. After 12 consecutive weeks of antifungal therapy, all his symptoms resolved. The patient remained without any signs of recurrence at the 8-month follow-up. CONCLUSION: We reported a rare case of isolated sacrum cryptococcal osteomyelitis in an immunocompetent patient. Furthermore, we identified and reviewed 18 published cases of spine cryptococcal osteomyelitis. Immunocompetent individuals are also at risk for cryptococcal osteomyelitis. Clinical manifestation and imaging are insufficient to diagnose cryptococcal osteomyelitis of the spine, and invasive examinations, such as puncture biopsy and fungal examinations, are needed. Antifungal therapy yields satisfactory results for the treatment of cryptococcal osteomyelitis of the spine, however, if the infective lesion is large, especially when it compresses the spinal cord and nerves, a regimen combining aggressive surgery with antifungal therapy is indispensable.
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Criptococose , Cryptococcus neoformans , Osteomielite , Masculino , Humanos , Adulto , Antifúngicos/uso terapêutico , Sacro/patologia , Hipestesia/tratamento farmacológico , Criptococose/diagnóstico , Osteomielite/microbiologia , Antituberculosos/uso terapêuticoRESUMO
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction caused by sepsis that manifests as a range of brain dysfunctions from delirium to coma. It is a relatively common complication of sepsis associated with poor patient prognosis and mortality. The pathogenesis of SAE involves neuroinflammatory responses, neurotransmitter dysfunction, blood-brain barrier (BBB) disruption, abnormal blood flow regulation, etc. Neuroinflammation caused by hyperactivation of microglia is considered to be a key factor in disease development, which can cause a series of chain reactions, including BBB disruption and oxidative stress. Metabolic reprogramming has been found to play a central role in microglial activation and executive functions. In this review, we describe the pivotal role of energy metabolism in microglial activation and functional execution and demonstrate that the regulation of microglial metabolic reprogramming might be crucial in the development of clinical therapeutics for neuroinflammatory diseases like SAE.
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Encefalopatias , Encefalopatia Associada a Sepse , Sepse , Humanos , Encefalopatia Associada a Sepse/complicações , Encefalopatia Associada a Sepse/metabolismo , Encefalopatia Associada a Sepse/patologia , Microglia/metabolismo , Doenças Neuroinflamatórias , Sepse/complicações , Barreira Hematoencefálica/metabolismo , Encefalopatias/etiologia , Encefalopatias/patologiaRESUMO
BACKGROUND: In recent years, unilateral biportal endoscopic spinal surgery has been used for the treatment of lumbar spinal stenosis with good results. Some investigators counted the total incidence of complications in unilateral biportal endoscopic surgery for lumbar spinal stenosis, but none have analyzed the incidence of specific complications. The present study further counted the incidence of specific complications and gave the possible causes of the complications. METHODS: English databases including PubMed were searched to collect relevant literature on unilateral biportal endoscopic spinal surgery for lumbar spinal stenosis. The inquiry period is from January 1, 2015, to July 1, 2022. The literature was screened, information extracted, and risk of bias evaluated by the researchers, followed by Meta analysis using R4.2.1 and RStudio statistical software. RESULTS: In total, we included 14 studies involving 707 patients. The included studies were retrospective case series, The results of the single-arm rate meta-analysis showed that the total complication rate of unilateral biportal endoscopic surgery treatment of lumbar spinal stenosis was 8.1% (95% confidence interval [CI] [0.060; 0.103]); of which, the highest incidence of dural tear was 4.5% (95% CI [0.030; 0.064]), the incidence of symptomatic postoperative spinal epidural hematoma was approximately 1.1% (95% CI [0.001; 0.027]), the incidence of incomplete decompression was 2.0% (95% CI [0.007; 0.038]), the incidence of transient palsy was 2.6% (95% CI [0.005; 0.057]). CONCLUSIONS: The incidence of total complications of unilateral biportal endoscopic surgery for lumbar spinal stenosis was 8.1%, dural tear remained a major complication with an incidence of 4.5%, incomplete decompression was 2.0%, transient palsy was 2.6%, and, unexpectedly, symptomatic postoperative spinal epidural hematoma was only 1.1%.
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Hematoma Epidural Espinal , Estenose Espinal , Humanos , Descompressão Cirúrgica/efeitos adversos , Descompressão Cirúrgica/métodos , Endoscopia/efeitos adversos , Endoscopia/métodos , Hematoma Epidural Espinal/cirurgia , Vértebras Lombares/cirurgia , Estudos Retrospectivos , Estenose Espinal/cirurgia , Estenose Espinal/complicações , Resultado do TratamentoRESUMO
Emerging evidence suggests that pyroptosis is involved in sepsis. However, the role of neutrophil pyroptosis in sepsis and the mechanisms remains elusive. We find that N-acetyltransferase 10 (NAT10), an acetyltransferase responsible for the N4-acetylation of Cytidine (ac4C) in mRNA, is significantly downregulated in neutrophils from septic mice. Neutrophil-specific over-expression of NAT10 improves the survival and ameliorates lung injury in septic mice by inhibiting neutrophil pyroptosis. Notably, UNC-52-like kinase 1 (ULK1) is identified as the target of NAT10 in neutrophils. The decreased expression of NAT10 resultes in the decay of ULK1 transcripts and therefore the reduced expression of ULK1. As a regulator of STING phosphorylation, the loss of ULK1 enhances the activation of STING-IRF3 signaling and subsequently the elevated pyroptosis-inducing NLRP3 inflammasome in neutrophils. While over-expression of NAT10 restrains pyroptosis in neutrophils as well as septic lethality in mice by reversing the ULK1-STING-NLRP3 axis. The decreased expression of NAT10 are also observed in sepsis patients and its correlation with clinical severity is found. Collectively, our findings disclose that NAT10 is a negative regulator of neutrophil pyroptosis and its downregulation contributes to the progress of sepsis by exacerbating pyroptosis via the ULK1-STING-NLRP3 axis, therefore revealing a potential therapeutic target for sepsis.
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Piroptose , Sepse , Acetiltransferases , Animais , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neutrófilos/metabolismo , RNA , Sepse/genética , Sepse/metabolismoRESUMO
Neutrophil extracellular traps (NETs) assist pathogen clearance, while excessive NETs formation is associated with exacerbated inflammatory responses and tissue injury in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Autophagy is generally considered to be a protective process, but autophagy dysfunction is harmful. Whether and how NETs affect autophagic flux during sepsis-induced ALI are currently unknown. Here, we confirmed that the level of NETs was increased in ARDS patients and mice models, which led to impairment of autophagic flux and deterioration of the disease. Mechanistically, NETs activated METTL3 mediated m6A methylation of Sirt1 mRNA in alveolar epithelial cells, resulting in abnormal autophagy. These findings provide new insights into how NETs contribute to the development of sepsis-associated ALI/ARDS.
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As a clinical subtype of SWI/SNF-related intellectual disability syndromes, Nicolaides-Baraitser syndrome (NCBRS, OMIM601358) has a unique genotype-phenotype. Due to the scarcity of the number of cases reported and the limitations of diagnosis methods, so far only more than 80 cases have been reported worldwide. In this article, a new patient with a de novo mutation was followed up for 10 years; it includes the epilepsy treatment process, the characteristics of NBCRS with seizures, typical faces, sparse hair, prominent interphalangeal joints, and intellectual disability, and we also summarized the genotype-phenotype of the 80 reported cases for comparison. Due to insufficient studies and lack of attention paid to the syndrome, it is believed that the actual number of cases should be far more than the reported number. The syndrome is phased and progressive. The genotype-phenotype correlation of the disease is related to the location of the gene locus, especially closely related to the SNF2 ATPase domain. CONCLUSIONS: The understanding of NCBRS is lagging, we need to strengthen the screening process of the phenotypic disease with intellectual disability, and perfecting multiple types of diagnostic techniques will help the discovery of the disease; its clinical features are staged and are slowly progressive, and long-term prognosis must be taken precautious with long-term follow-up required.
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Anormalidades Múltiplas , Deficiência Intelectual , Fatores de Transcrição , Anormalidades Múltiplas/genética , Adenosina Trifosfatases/genética , Face , Fácies , Seguimentos , Deformidades Congênitas do Pé , Humanos , Hipotricose , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Mutação , Fatores de Transcrição/genéticaRESUMO
Sepsis is an acute life-threatening disorder associated with multiorgan dysfunction that remains the leading cause of death in intensive care units. As sepsis progresses, it causes prolonged immunosuppression, which results in sustained mortality, morbidity, and susceptibility to secondary infections. Using a mouse model of sepsis, we found that the long noncoding RNA HOTAIRM1 (HOXA transcript antisense RNA myeloid-specific 1) was highly expressed in mice during the late phase of sepsis. The upregulation of HOTAIRM1 was induced by Notch/Hes1 activation and, moreover, was critical for the formation of an immunosuppressive microenvironment. HOTAIRM1 induced T cell exhaustion by increasing the percentage of PD-1+ T cells and regulatory T cells, accompanied by elevated PD-L1. Blockade of either Notch/Hes1 signaling or HOTAIRM1 inhibited T cell exhaustion in late sepsis, having alleviated lung injury and improved survival of mice. Further mechanistic studies identified HOXA1 as a key transcription factor targeted by HOTAIRM1 to regulate PD-L1 expression in lung alveolar epithelial cells. These results implicated that the Notch/Hes1/HOTAIRM1/HOXA1/PD-L1 axis was critical for sepsis-induced immunosuppression and could be a potential target for sepsis therapies.