RESUMO
Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.
Assuntos
Doenças Mitocondriais , NAD , Camundongos , Animais , NAD/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Mitocôndrias/metabolismo , Senescência Celular/fisiologia , Homeostase , Doenças Mitocondriais/metabolismo , Suplementos NutricionaisRESUMO
Despite the advent of genomic sequencing, molecular diagnosis remains unsolved in approximately half of patients with Mendelian disorders, largely due to unclarified functions of noncoding regions and the difficulty in identifying complex structural variations. In this study, we map a unique form of central iris hypoplasia in a large family to 6q15-q23.3 and 18p11.31-q12.1 using a genome-wide linkage scan. Long-read sequencing reveals a balanced translocation t(6;18)(q22.31;p11.22) with intergenic breakpoints. By performing Hi-C on induced pluripotent stem cells from a patient, we identify two chromatin topologically associating domains spanning across the breakpoints. These alterations lead the ectopic chromatin interactions between APCDD1 on chromosome 18 and enhancers on chromosome 6, resulting in upregulation of APCDD1. Notably, APCDD1 is specifically localized in the iris of human eyes. Our findings demonstrate that noncoding structural variations can lead to Mendelian diseases by disrupting the 3D genome structure and resulting in altered gene expression.
Assuntos
Cromatina , Iris , Linhagem , Translocação Genética , Humanos , Cromatina/metabolismo , Cromatina/genética , Iris/metabolismo , Masculino , Feminino , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 18/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Adulto , Doenças da Íris/genética , Doenças da Íris/metabolismo , Doenças da Íris/patologia , Ligação GenéticaRESUMO
Computational methods have been proposed to leverage spatially resolved transcriptomic data, pinpointing genes with spatial expression patterns and delineating tissue domains. However, existing approaches fall short in uniformly quantifying spatially variable genes (SVGs). Moreover, from a methodological viewpoint, while SVGs are naturally associated with depicting spatial domains, they are technically dissociated in most methods. Here, we present a framework (PROST) for the quantitative recognition of spatial transcriptomic patterns, consisting of (i) quantitatively characterizing spatial variations in gene expression patterns through the PROST Index; and (ii) unsupervised clustering of spatial domains via a self-attention mechanism. We demonstrate that PROST performs superior SVG identification and domain segmentation with various spatial resolutions, from multicellular to cellular levels. Importantly, PROST Index can be applied to prioritize spatial expression variations, facilitating the exploration of biological insights. Together, our study provides a flexible and robust framework for analyzing diverse spatial transcriptomic data.
Assuntos
Perfilação da Expressão Gênica , Transferência Intratubária do Zigoto , Transcriptoma/genética , Análise por Conglomerados , Reconhecimento PsicológicoRESUMO
In search of efficient phosphorus resource recovery and pollution remediation should be highly concerned due to the view of phosphorus nonrenewable and eutrophication. This work presented a new insight into conversion of sewage sludge into favorable carbonaceous adsorbent for accelerated removing and recovering phosphorus from aqueous solution, what addressed the issues of phosphorus recovery and pollution remediation as well as sludge disposal. Ca and water hyacinth were evolved to decorate sludge derived carbon. Effect of mass ratio of sludge, water hyacinth and calcium carbonate on the morphologies and adsorption kinetics was investigated. The adsorbents (SW-Ca-112) resulted from sludge in the presence of water hyacinth and CaCO3 in a mass ratio of 1:1:2 had the highest adsorption capacity of 49.50 mg/g P and adsorption rate. Decoration of Ca favored adsorption ability and the presence of water hyacinth accelerated the adsorption rate due to the enhanced porosity. Formation of acicular Ca5(PO4)3OH nanoparticles contributed to the favorable adsorption process. Thus, the contribution of decorated Ca and water hyacinth to the adsorption ability and rate to phosphorus was understand, providing important information on resource utilization of sewage sludge as efficient adsorbent for immobilizing phosphorus from aqueous solution.
RESUMO
The present study aimed to identify the association between microRNA (miR/miRNA)-449a, the cyclin-dependent kinase (CDK)6 protein and gastric carcinoma, and discuss the effect of miR-449a on the expression of the CDK6 protein. Quantitative (q)PCR and western blot analysis were used to analyze the expression of the miR-449a and the CDK6 protein in gastric carcinoma and tumor-adjacent normal tissues. The real-time cell analyzer and the DAPI staining test were used to monitor the different miR-449a levels regulating the proliferation and apoptosis of the MGC-803 cell line. Immunofluorescence and western blot analyses were used to detect the expression level of the CDK6 protein in the cells of the miR-449a upregulation and downregulation groups, and a control group. A scratch test was used to study the effects of miR-449a expression on migration and invasion. It was found that the expression of miR-449a was downregulated and the expression of CDK6 protein was upregulated in gastric carcinoma tissue. The level of MGC-803 cell proliferation was decreased and the apoptosis level was increased by the upregulation of miR-449a expression, and the opposite effect was shown by the downregulation of expression. The expression of the CDK6 protein in the MGC-803 cells was downregulated by upregulating the expression of miR-449a. The distance of the scratch was shortened markedly after 12 h by downregulating the expression of miR-449a in the MGC-803 cells. The present study identified that a lower expression level of miR-449 and a higher expression level of CDK6 may contribute to the occurrence and development of gastric cancer. Furthermore, it was shown that miR-449a is able to regulate the expression of the CDK6 protein.
RESUMO
Undifferentiated embryonal sarcoma of the liver (UESL) predominantly occurs in children under the age of 10 years, and ~90% of cases occur in children <15 years old. Patients may complain of abdominal pain, fever or other symptoms. No significant decrease has been identified in the hepatic function or elevation of α-fetoprotein, which differentiates UESL from primary carcinomas of the liver. In the present study, a rare and misdiagnosed case of an UESL arising in a male, which was mistaken for a hepatic abscess and retrospectively re-diagnosed, is reported. This case was misdiagnosed as a hepatic abscess initially, and it was diagnosed as UESL subsequent to performing tests, including a type-B ultrasonic scan and computed tomography (CT), and evaluating pathological findings. The rapid recurrence of the tumor in this patient was identified by CT, and this is associated with the malignancy of the disease. Currently, patients with UESL have a poor prognosis as there is not a successful treatment strategy. The present study analyzes the course of diagnosis and potential treatment for the disease.
RESUMO
Multidrug resistance (MDR) is a major challenge to the clinical treatment of esophageal cancer. The stress response gene activating transcription factor 4 (ATF4) is involved in homeostasis and cellular protection. However, relatively little is known about the expression and function of ATF4 in esophageal squamous cell carcinoma (ESCC) MDR. In this study, we investigate the potential role and mechanisms of ATF4 in ESCC MDR. We demonstrated that overexpression of ATF4 promotes the MDR phenotype in ESCC cells, while depletion of ATF4 in the MDR ESCC cell line induces drug re-sensitization. We also demonstrated that ATF4 transactivates STAT3 expression by directly binding to the signal transducers and activators of transcription 3 (STAT3) promoter, resulting in MDR in ESCC cells. Significantly, inhibition of STAT3 by small interfering RNA (siRNA) or a selective inhibitor (JSI-124) reintroduces therapeutic sensitivity. In addition, increased Bcl-2, survivin, and MRP1 expression levels were observed in ATF4-overexpressing cells. In conclusion, ATF4 may promote MDR in ESCC cells through the up-regulation of STAT3 expression, and thus is an attractive therapeutic target to combat therapeutic resistance in ESCC.