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BACKGROUND: Age-associated impairments in innate immunity are believed to be a causative factor responsible for severe pathogenesis of Staphylococcus aureus (S. aureus) infection in the bone tissue. However, the basis for age-associated decline in innate immune response upon S. aureus infection remains poorly understood. RESULTS: Our transcriptional data (GEO: GSE166522) from a mouse model of S. aureus osteomyelitis show up-regulated CXCL9 and CXCL10 (CXCL9/10), which is further confirmed in vitro and in vivo by the present study. Notably, monocytes are a main source for CXCL9/10 production in bone marrow upon S. aureus challenge, but this response declines in middle-aged mice. Interestingly, conditional medium of bone marrow monocytes from middle-aged mice has a strikingly decreased effect on bactericidal functions of neutrophils and macrophages compares with that from young mice. We further show that activation of CXCL9/10-CXCR3 axis between monocytes and macrophages/neutrophils promotes the bactericidal function of the cells, whereas blocking the axis impairs such function. Importantly, treatment with either exogenous CXCL9 or CXCL10 in a middle-aged mice model enhances, while pharmacological inhibition of CXCR3 in young mice model impairs, bacterial clearance and bone marrow structure. CONCLUSIONS: These findings demonstrate that bone marrow monocytes act as a critical promotor of innate immune response via the CXLCL9/10-CXCR3 axis upon S. aureus infection, and that the increased susceptibility to S. aureus infection in skeleton in an aged host may be largely attributable to the declined induction of CXCR9/10 in monocytes.
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Quimiocina CXCL10 , Quimiocina CXCL9 , Modelos Animais de Doenças , Imunidade Inata , Monócitos , Osteomielite , Infecções Estafilocócicas , Staphylococcus aureus , Animais , Osteomielite/microbiologia , Osteomielite/imunologia , Osteomielite/metabolismo , Osteomielite/patologia , Monócitos/imunologia , Monócitos/metabolismo , Quimiocina CXCL9/metabolismo , Quimiocina CXCL9/genética , Staphylococcus aureus/imunologia , Camundongos , Quimiocina CXCL10/metabolismo , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/patologia , Infecções Estafilocócicas/metabolismo , Camundongos Endogâmicos C57BL , Receptores CXCR3/metabolismo , Receptores CXCR3/genética , Envelhecimento/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismoRESUMO
Previous studies indicated that adipose tissue significantly influences cancer invasion and lymphatic metastasis. However, the impact of neck adipose tissue (NAT) on lymph node metastasis associated with head and neck cancer remains ambiguous. Here, we systematically assess the classification and measurement criteria of NAT and evaluate the association of adipose tissue and cancer-associated adipocytes with head and neck cancer. We delve into the potential mechanisms by which NAT facilitate cervical lymph node metastasis in head and neck cancer, particularly through the secretion of adipokines such as leptin, adiponectin, and Interleukin-6. Our aim is to elucidate the role of NAT in the progression and metastasis of head and neck cancer, offering new insights into prevention and treatment.
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Introduction: Primary ciliary dyskinesia (PCD) is a rare heterogeneous disease caused by abnormalities in motile cilia. In this case report, we first analyzed the clinical and genetic data of a proband who was suspected of having PCD on the basis of her clinical and radiological findings. Methods: Whole-exome sequencing was performed, and a variant in the RSPH4A gene was identified in the proband. Sanger sequencing was used for validation of RSPH4A variants in the proband, her sister, her daughter and her parents. Finally, the phenotypic features of the patient were analyzed, and the current literature was reviewed to better understand the gene variants in PCD related to hearing loss and the clinical manifestations of the RSPH4A variant in PCD. Results: The chief clinical symptoms of this proband included gradual mixed hearing loss, otitis media, anosmia, sinusitis, recurrent cough and infertility. Her DNA sequencing revealed a novel homozygous T to C transition at position 1321 within exon 3 of RSPH4A according to genetic testing results. This variant had never been reported before. The homozygous variant resulted in an amino acid substitution of tryptophan by arginine at position 441 (p.Trp441Arg). The same variant was also found in the proband's sister, and a heterozygous pathogenic variant was identified among immediate family members, including the proband's daughter and parents. Discussion: A literature review showed that 16 pathogenic variants in RSPH4A have been reported. Hearing loss had only been observed in patients with the RSPH4A (c.921+3_6delAAGT) splice site mutation, and the specific type of hearing loss was not described.
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Staphylococcus aureus (S. aureus) persistence in macrophages, potentially a reservoir for recurrence of chronic osteomyelitis, contributes to resistance and failure in treatment. As the mechanisms underlying survival of S. aureus in macrophages remain largely unknown, there has been no treatment approved. Here, in a mouse model of S. aureus osteomyelitis, we identified significantly up-regulated expression of SLC7A11 in both transcriptomes and translatomes of CD11b+F4/80+ macrophages, and validated a predominant distribution of SLC7A11 in F4/80+ cells around the S. aureus abscess. Importantly, pharmacological inhibition or genetic knockout of SLC7A11 promoted the bactericidal function of macrophages, reduced bacterial burden in the bone and improved bone structure in mice with S. aureus osteomyelitis. Mechanistically, aberrantly expressed SLC7A11 down-regulated the level of intracellular ROS and reduced lipid peroxidation, contributing to the impaired bactericidal function of macrophages. Interestingly, blocking SLC7A11 further activated expression of PD-L1 via the ROS-NF-κB axis, and a combination therapy of targeting both SLC7A11 and PD-L1 significantly enhanced the efficacy of clearing S. aureus in vitro and in vivo. Our findings suggest that targeting both SLC7A11 and PD-L1 is a promising therapeutic approach to reprogram the bactericidal function of macrophages and promote bacterial clearance in S. aureus osteomyelitis.
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Sistema y+ de Transporte de Aminoácidos , Macrófagos , Osteomielite , Infecções Estafilocócicas , Animais , Camundongos , Sistema y+ de Transporte de Aminoácidos/metabolismo , Sistema y+ de Transporte de Aminoácidos/genética , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Osteomielite/metabolismo , Osteomielite/microbiologia , Espécies Reativas de Oxigênio/metabolismo , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Staphylococcus aureusRESUMO
The pathogenesis of age-related hearing loss (ARHL) remains unclear. OPA1 is the sole fusion protein currently known to be situated in the inner mitochondrial membrane, which is pivotal for maintaining normal mitochondrial function. While it has already been demonstrated that mutations in OPA1 may lead to hereditary deafness, its involvement in the occurrence and development of ARHL has not been previously explored. In our study, we constructed D-gal-induced senescent HEI-OC1 cells and the cochlea of C57BL/6J mice with a mutated SUMOylation site of SIRT3 using CRISPR/Cas9 technology. We found enhanced L-OPA1 processing mediated by activated OMA1, and increased OPA1 acetylation resulting from reductions in SIRT3 levels in senescent HEI-OC1 cells. Consequently, the fusion function of OPA1 was inhibited, leading to mitochondrial fission and pyroptosis in hair cells, ultimately exacerbating the aging process of hair cells. Our results suggest that the dysregulation of mitochondrial dynamics in cochlear hair cells in aged mice can be ameliorated by activating the SIRT3/OPA1 signaling. This has the potential to alleviate the senescence of cochlear hair cells and reduce hearing loss in mice. Our study highlights the significant roles played by the quantities of long and short chains and the acetylation activity of OPA1 in the occurrence and development of ARHL. This finding offers new perspectives and potential targets for the prevention and treatment of ARHL.
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Presbiacusia , Sirtuína 3 , Animais , Camundongos , Acetilação , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/genética , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
OBJECTIVE: Systemic chemotherapy is the first-line therapeutic option for head and neck squamous cell carcinoma (HNSCC), but it often fails. This study aimed to develop an effective prognostic model for evaluating the therapeutic effects of systemic chemotherapy. METHODS: This study utilized CRISPR/cas9 whole gene loss-of-function library screening and data from The Cancer Genome Atlas (TCGA) HNSCC patients who have undergone systemic therapy to examine differentially expressed genes (DEGs). A lipid metabolism-related clustered polygenic model called the lipid metabolism related score (LMRS) model was established based on the identified functionally enriched DEGs. The prediction efficiency of the model for survival outcome, chemotherapy, and immunotherapy response was evaluated using HNSCC datasets, the GEO database and clinical samples. RESULTS: Screening results from the study demonstrated that genes those were differentially expressed were highly associated with lipid metabolism-related pathways, and patients receiving systemic therapy had significantly different prognoses based on lipid metabolism gene characteristics. The LMRS model, consisting of eight lipid metabolism-related genes, outperformed each lipid metabolism gene-based model in predicting outcome and drug response. Further validation of the LMRS model in HNSCCs confirmed its prognostic value. CONCLUSION: In conclusion, the LMRS polygenic prognostic model is helpful to assess outcome and drug response for HNSCCs and could assist in the timely selection of the appropriate treatment for HNSCC patients. This study provides important insights for improving systemic chemotherapy and enhancing patient outcomes.
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Cholesterol is the most abundant sterol molecule in mammalian cells, which not only constitutes the cell membrane but also plays essential roles in the synthesis of important hormones, synapse formation, and cell signal transduction. The effect of hypercholesterolemia on hearing has been studied extensively, and multiple studies have demonstrated that hypercholesterolemia is a risk factor for hearing loss. However, the impact of cholesterol homeostasis within auditory cells on peripheral auditory development and maintenance has not been evaluated in detail. Mutations in certain cholesterol metabolism-related genes, such as NPC1, SERAC1, DHCR7, and OSBPL2, as well as derivatives of cholesterol metabolism-related ototoxic drugs, such as ß-cyclodextrin, can lead to disruptions of cholesterol homeostasis within auditory cells, resulting in hearing loss. This article aims to review the impact of cholesterol homeostasis within auditory cells on the peripheral auditory function from the following two perspectives: (1) changes in cholesterol homeostasis regulatory genes in various hearing loss models; (2) mechanisms underlying the effects of some drugs that have a therapeutic effect on hearing loss via regulating cholesterol homeostasis. This article aims to summarize and analyze the impact of disruption of cellular cholesterol homeostasis within auditory cells on hearing, in order to provide evidence regarding the underlying mechanisms.
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Recent studies showed that lipid metabolism reprogramming contributes to tumorigenicity and malignancy by interfering energy production, membrane formation, and signal transduction in cancers. HNSCCs are highly reliant on aerobic glycolysis and glutamine metabolism. However, the mechanisms underlying lipid metabolism reprogramming in HNSCCs remains obscure. The present review summarizes and discusses the "vital" cellular signaling roles of the lipid metabolism reprogramming in HNSCCs. We also address the differences between HNSCCs regions caused by anatomical heterogeneity. We enumerate these recent findings into our current understanding of lipid metabolism reprogramming in HNSCCs and introduce the new and exciting therapeutic implications of targeting the lipid metabolism.
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A great number of patients with Coronavirus Disease 2019 (COVID-19) experience olfactory dysfunction, typically of a short duration and with a high incidence rate, during the early stages of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This kind of olfactory dysfunction appears more likely in young people and women. This study presents a review of the clinical features and pathogenic mechanism of the olfactory dysfunction related to SARS-CoV-2 infection, aiming to provide a clinical reference for the diagnosis, differential diagnosis, treatment, and prevention of olfactory dysfunction in COVID-19 patients.
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COVID-19 , Transtornos do Olfato , Adolescente , Feminino , Humanos , Transtornos do Olfato/etiologia , SARS-CoV-2 , OlfatoRESUMO
OBJECTIVE: We aim to review the roles of plasmacytoid dendritic cells (pDCs) in head and neck squamous cell carcinoma (HNSCC) and explore the effects of hypoxia on the tolerogenic transformation of pDCs. BACKGROUND: pDCs, best known as professional type I interferon-secreting cells, play key roles in immune surveillance and antitumor immunity. Recently, pDCs have been shown to be tolerogenic and correlate with poor prognosis in a variety of cancers, including HNSCC. However, it remains unclear what drives the tolerogenic transformation of pDCs in the HNSCC microenvironment. Hypoxia, a prominent hallmark of the tumor microenvironment (TME) of HNSCC, can interfere with multiple immune cells and establish an immunosuppressive TME. METHODS: In this review, we summarize the antitumor and protumor functions of pDCs, explore the effects of hypoxia on the migration and maturation of pDCs, and discuss related mechanisms in HNSCC. CONCLUSIONS: pDCs mainly display protumor functions in HNSCC. The hypoxic TME in HNSCC can enhance the migration of pDCs and inhibit the differentiation and maturation of pDCs, promoting the tolerogenic phenotype of pDCs.
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Células Dendríticas , Neoplasias de Cabeça e Pescoço , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hipóxia/metabolismo , Fenótipo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Microambiente TumoralRESUMO
Sigma factor, as a unit of RNA polymerase holoenzyme, is a critical factor in the process of gene transcriptional regulation. It recognizes the specific DNA sites and brings the core enzyme of RNA polymerase to the upstream regions of target genes. Therefore, the prediction of the promoters for a particular sigma factor is essential for interpreting functional genomic data and observation. This paper develops a new method to predict sigma-54 promoters in bacterial genomes. The new method organically integrates motif finding and machine learning strategies to capture the intrinsic features of sigma-54 promoters. The experiments on E. coli benchmark test set show that our method has good capability to distinguish sigma-54 promoters from surrounding or randomly selected DNA sequences. The applications of the other three bacterial genomes indicate the potential robustness and applicative power of our method on a large number of bacterial genomes. The source code of our method can be freely downloaded at https://github.com/maqin2001/PromotePredictor.
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Biologia Computacional/métodos , Proteínas de Escherichia coli/genética , Escherichia coli/genética , Genoma Bacteriano , Aprendizado de Máquina , Regiões Promotoras Genéticas , RNA Polimerase Sigma 54/genética , Motivos de Aminoácidos , Sequência de Bases , RNA Polimerases Dirigidas por DNA , Reações Falso-Positivas , Modelos Estatísticos , Reprodutibilidade dos Testes , Software , Transcrição GênicaRESUMO
An N-heterocyclic carbene-catalyzed oxidative LUMO activation of the ß-cabons of saturated carboxylic esters is disclosed. This approach allows for efficient asymmetric access to lactams and lactones by directly installing functional groups to the typically inert ß-sp3 carbons of saturated esters. The use of HOBt as an additive was found to significantly improve both yields and enantioselectivities of the reactions.
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A carbene-catalyzed LUMO activation of α,ß-unsaturated alkyne esters is reported. This catalytic process allows for effective reactions of alkyne esters with enamides to synthesize functional pyridines via simple protocols. A previously unexplored unsaturated alkyne acyl azolium intermediate is involved in the key step of the reaction.
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The present study aimed to investigate the mechanism by which Aurora kinase A (AURKA) promotes cell migration and invasion in head and neck squamous cell carcinoma (HNSCC). Transwell assays were performed to investigate the cell migration and invasion abilities of AURKA, whilst western blotting was used to analyze the protein expression in FaDu and Hep2 cells, each treated with pharmacological inhibitors. Following the inhibition of AURKA, Akt and focal adhesion kinase (FAK), the migration and invasion of the FaDu and Hep2 cells decreased. The expression of phosphorylated (p)-AURKA and p-FAK (Y397) was observed to decrease following FaDu and Hep2 cell treatment with VX-680, a small molecular inhibitor of AURKA. The expression of p-Akt and p-FAK (Y397) ceased following treatment with the Akt inhibitor triciribine. The expression of p-FAK (Y397) decreased, however, p-Akt expression did not change following treatment with the FAK inhibitor TAE226. In conclusion, AURKA activates FAK through the AURKA/Akt/FAK signaling pathway, promoting the migration and invasion of HNSCC cells, which may subsequently provide a novel approach for the treatment of HNSCC.
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For the first time, we study the sorting of permutations by length-weighted transpositions under a wide class of cost functions, namely f(l)=l(alpha), where l is the length of the transposition. For different alpha, we give corresponding upper and lower bounds of the cost of sorting any binary sequences or any permutations. Furthermore, an O(log n)-approximation algorithm and an exact algorithm are given to determine the optimal transposition series of sorting a permutation of length n when 1< alpha < 2 and alpha > or =2 respectively. Our work poses some interesting questions to both biologists and computer scientists and suggests some new bioinformatic insights that are currently being studied.