The developmental arrest and intestinal phenotypes of CeTOR deficiency are due to an inhibition of global mRNA translation. Thus, TOR is a major upstream regulator of overall mRNA translation in C. elegans, as in yeast.
SummaryCaenorhabditis elegans is a leading model organism for studying the basic mechanisms of aging. Progress has been limited, however, by the lack of an automated system for quantitative analysis of longevity and mean lifespan. To address this barrier, we developed 'WormFarm', an integrated microfluidic device for culturing nematodes. Cohorts of 30-50 animals are maintained throughout their lifespan in each of eight separate chambers on a single WormFarm polydimethylsiloxane chip. Design features allow for automated removal of progeny and efficient control of environmental conditions. In addition, we have developed computational algorithms for automated analysis of video footage to quantitate survival and other phenotypes, such as body size and motility. As proof-of-principle, we show here that WormFarm successfully recapitulates survival data obtained from a standard plate-based assay for both RNAi-mediated and dietary-induced changes in lifespan. Further, using a fluorescent reporter in conjunction with WormFarm, we report an age-associated decrease in fluorescent intensity of GFP in transgenic worms expressing GFP tagged with a mitochondrial import signal under the control of the myo-3 promoter. This marker may therefore serve as a useful biomarker of biological age and aging rate.
FOXP3+ Regulatory T (Treg) cells play a key role in the maintenance of immune homeostasis and tolerance. Disruption of Foxp3 expression results in the generation of instable Treg cells and acquisition of effector T-cell-like function. Here we report that the E3 deubiquitinase USP21 prevents the depletion of FOXP3 at the protein level and restricts the generation of T-helper-1-like Treg cells. Mice depleted of Usp21 specifically in Treg cells display immune disorders characterized by spontaneous T-cell activation and excessive T-helper type 1 (Th1) skewing of Treg cells into Th1-like Treg cells. USP21 stabilizes FOXP3 protein by mediating its deubiquitination and maintains the expression of Treg signature genes. Our results demonstrate how USP21 prevents FOXP3 protein depletion and controls Treg lineage stability in vivo.
Ischemia-reperfusion injury is a common early complication after lung transplantation. It was reported that long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is involved in ischemia-reperfusion injury and regulates inflammation. This study aimed to explore the role of MALAT1 in inflammatory injury following lung transplant ischemia-reperfusion (LTIR). A LTIR rat model was successfully established, with the expression of MALAT1 and interleukin-8 (IL-8) in lung tissues detected. Then, in vitro loss- and gain-of-function investigations were conducted to evaluate the effect of MALAT1 on pulmonary epithelial cell apoptosis and IL-8 expression. The relationship among MALAT1, p300, and IL-8 was tested. Moreover, a sh-MALAT1-mediated model of LTIR was established in vivo to examine inflammatory injury and chemotaxis infiltration. Both IL-8 and MALAT1 were highly expressed in LTIR. MALAT1 interacted with p300 to regulate the IL-8 expression by recruiting p300. Importantly, silencing of MALAT1 inhibited the chemotaxis of neutrophils by downregulating IL-8 expression via binding to p300. Besides, MALAT1 silencing alleviated the inflammatory injury after LTIR by downregulating IL-8 and inhibiting infiltration and activation of neutrophils. Collectively, these results demonstrated that silencing of MALAT1 ameliorated the inflammatory injury after LTIR by inhibiting chemotaxis of neutrophils through p300-mediated downregulation of IL-8, providing clinical insight for LTIR injury.
Non–small cell lung cancer is one of the most common types of cancer, and the prognosis of non–small cell lung cancer is still poor. Recent evidence has proved that long noncoding RNA is involved in tumorigenesis. For non–small cell lung cancer, the expression profile of long noncoding RNA has been studied. Here, we identified a novel long noncoding RNA TRPM2-AS from published dataset and found TRPM2-AS is widely upregulated in non–small cell lung cancer tissues compared with adjacent non-tumor tissues. Higher expression level of TRPM2-AS was correlated with higher TNM stages and larger tumor size. Patients with high TRPM2-AS expression level had poor survival than those with low TRPM2-AS level. We silenced TRPM2-AS by small interfering RNA and found that cell proliferation was significantly inhibited after knockdown of TRPM2-AS. Annexin V/propidium iodide staining and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay confirmed that cell apoptosis increased after TRPM2-AS knockdown. Further experiments showed that silence of TRPM2-AS upregulated SHC1 and silence of SHC1 partially reversed cell apoptosis after TRPM2-AS knockdown. In summary, the novel long noncoding RNA TRPM2-AS upregulated in non–small cell lung cancer, and downregulation of TRPM2-AS promotes apoptosis in vitro.
Epidermal growth factor receptor-targeted tyrosine kinase inhibitors (EGFR-TKIs) have become first-line drugs used for non-small cell lung cancer (NSCLC) treatment. However, drug resistance to EGFR-TKIs will be developed inevitably due to the repeated use of these drugs. In the present study, we isolated cancer stem cells (CSCs) from the PC9 NSCLC cell line. We then observed that the PC9 CSCs showed significant resistance to erlotinib compared with the PC9 non-CSCs. Erlotinib failed to suppress the phosphorylation of PI3K and AKT in PC9 CSCs, although the EGFR was inhibited sufficiently. Mechanically, we observed aberrant upregulation of microRNA-23a (miR-23a) and downregulation of PTEN in PC9 CSCs compared to PC9 non-CSCs. Luciferase reporter assays proved that PTEN was the target of miR-23a in PC9 CSCs. Furthermore, knockdown of miR-23a enhanced the antitumor effect of erlotinib by increasing the expression of PTEN. In addition, transfection with miR-23a inhibitors promoted the erlotinib-dependent inhibition of PI3K/AKT pathway, thus, suppressing the proliferation and inducing apoptosis in PC9 CSCs. These results propose that upregulation of miR-23a is a potential mechanism associated with resistance to EGFR-TKIs in lung cancer stem cells. Inhibition of miR-23a serves as a novel therapeutic strategy to eliminate the EGFR-TKIs resistance of lung cancer stem cells.
Background: Mediastinal teratoma is a rare disease, many cases were reported before, but few articles focus on large case analyses. The objective of this article is to summarize the clinical characteristics of benign mediastinal teratoma and the experience of surgical treatment, especially thoracoscopic surgery for benign mediastinal teratoma. Methods: The clinical data of 108 patients with benign mediastinal teratoma confirmed by operation and pathology from January 1992 to January 2018 were analyzed retrospectively. The clinical symptoms, imaging examination, surgical methods and prognosis of all patients were analyzed. We compared the difference of thoracoscopic surgery and thoracotomy surgery using 102 patients underwent only chest surgery. Normally distributed continuous variables were compared by independent sample t test. Categorical variables were analyzed by chi-square test. Results: Imaging examination showed that all 108 cases of mediastinal teratoma were located in the anterior region of mediastinum. All cases underwent surgical resection, postoperative pathology confirmed that all cases were benign. 1 case was taken simple neck collar incision, 5 case was taken median thoracotomy combined with neck incision, other 102 cases were taken thoracoscopic surgery (22) or thoracotomy surgery (80). 4 cases were treated with partial pericardial resection due to adhesions, 12 cases underwent partial pericardial resection, 5 cases underwent lobectomy, 9 cases underwent wedge resection of lobe, and 2 patients underwent anonymous vein angioplasty. 1 case underwent second operation because of postoperative bleeding, 1 case of chylothorax, 1 case of recurrent laryngeal nerve injury, 2 cases of wound infection, 1 case of secondary pulmonary infection. 106 cases were followed up, period from 12 months to 10 years, no recurrence of tumor was found. Comparing to take thoracotomy surgery, patients underwent thoracoscopic surgery has strong advantage on intraoperative blood loss and hospital stay days after surgery (P < 0.05). tumor maximum diameter is larger for thoracotomy surgery group, as well as more patients suffer estimated adhesions from preoperative imaging. so we compared above parameters in patients with tumor diameter less than 10 cm with or without estimated adhesions from preoperative imaging, a strong advantage still can be found in thoracoscopic surgery group, inpatients with estimated adhesions from preoperative imaging, intraoperative blood loss (38.75 ± 15.53 vs 169.17 ± 208.82., P = 0.04) and hospital stay days after surgery (5.50 ± 0.93 vs 9.43 ± 6.54., P = 0.04) were better. In patients without estimated adhesions from preoperative imaging, intraoperative blood loss (46.67 ± 10.00 vs 110.53 ± 123.13., P = 0.06) and hospital stay days after surgery (4.70 ± 1.16 vs 7.53 ± 2.32., P = 0.01) were better. Especially, in thoracoscopic surgery group, hospital stay days after surgery was significantly shorter. Conclusion: The clinical manifestations and imaging performance of benign mediastinal teratoma were ...
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