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1.
Chem Commun (Camb) ; 60(48): 6142-6145, 2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38804211

ABSTRACT

A programmably engineered stochastic RNA nanowalker powered by duplex-specific nuclease (DSN) is developed. By utilizing poly-adenine-based spherical nucleic acids (polyA-SNA) to accurately regulate the densities of DNA tracks, the nanowalker showcases its capability to identify miRNA-21, miRNA-486, and miRNA-155 with quick kinetics and attomolar sensitivity, positioning it as a promising option for cancer clinical surveillance.


Subject(s)
MicroRNAs , MicroRNAs/analysis , Humans , Nanostructures/chemistry , Poly A/chemistry , DNA/chemistry , Stochastic Processes , Biosensing Techniques
2.
Microorganisms ; 11(12)2023 Dec 04.
Article in English | MEDLINE | ID: mdl-38138060

ABSTRACT

Tausonia pullulans 6A7 is a low-temperature yeast strain that can produce lipases. Yeast, which is made up of chassis cells, is an important part of synthetic biology, and the use of the lipase-producing properties of T. pullulans 6A7 for the production of fatty acids provides a new pathway for targeted synthesis in yeast cell factories. In this study, we performed RNA-seq on lipase-producing T. pullulans 6A7 at different temperatures (15 °C, 20 °C, 20 °C without corn oil, and 25 °C). Therefore, a total of 8455 differentially expressed genes were screened, and 16 of them were FAD candidate genes. A Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of group A (15 °C) vs. group D (25 °C) showed that the pathways of fatty acid biosynthesis (map00061) and the biosynthesis of unsaturated fatty acids (map01040) were significantly enriched. In the proposed temporal analysis of differentially expressed genes among the four temperature modulations, we found differentially expressed genes in nine clusters that had the same expression trends; these genes may be jointly involved in multiple biological processes in T. pullulans 6A7. In addition, we found 16 FAD candidate genes involved in fatty acid biosynthesis, and the expression of these genes had similar expression in the transcriptome trends with the different temperature treatments. These findings will help in future in-depth studies of the function and molecular mechanisms of these important FAD genes involved in fatty acid metabolism in yeast, and they could also be conducive to the establishment of a cellular factory for targeted fatty acid production by using yeast.

3.
J Fungi (Basel) ; 9(5)2023 May 15.
Article in English | MEDLINE | ID: mdl-37233284

ABSTRACT

3-Hydroxypropionic acid (3-HP) is an important intermediate compound in the chemical industry. Green and environmentally friendly microbial synthesis methods are becoming increasingly popular in a range of industries. Compared to other chassis cells, Yarrowia lipolytica possesses advantages, such as high tolerance to organic acid and a sufficient precursor required to synthesize 3-HP. In this study, gene manipulations, including the overexpression of genes MCR-NCa, MCR-CCa, GAPNSm, ACC1 and ACSSeL641P and knocking out bypass genes MLS1 and CIT2, leading to the glyoxylate cycle, were performed to construct a recombinant strain. Based on this, the degradation pathway of 3-HP in Y. lipolytica was discovered, and relevant genes MMSDH and HPDH were knocked out. To our knowledge, this study is the first to produce 3-HP in Y. lipolytica. The yield of 3-HP in recombinant strain Po1f-NC-14 in shake flask fermentation reached 1.128 g·L-1, and the yield in fed-batch fermentation reached 16.23 g·L-1. These results are highly competitive compared to other yeast chassis cells. This study creates the foundation for the production of 3-HP in Y. lipolytica and also provides a reference for further research in the future.

4.
Front Immunol ; 13: 947712, 2022.
Article in English | MEDLINE | ID: mdl-35935970

ABSTRACT

Objective: It has been controversial whether tumor mutation burden (TMB) affects the prognosis and the efficacy of immunotherapy in different tumor types. We provided a comprehensive analysis of mutation status and immune landscape of squamous cell carcinomas (SCCs) from four sites in order to investigate the relationship of TMB with prognosis and immune cell infiltration in different SCCs. Methods: The transcriptome profiles and somatic mutation data of SCCs downloaded from the Cancer Genome Atlas (the Cancer Genome Atlas) database were analyzed and visualized. Then, TMB was calculated to analyze its correlations with prognosis and clinical features. Differentially expressed genes (DEGs) between the high and low TMB groups were screened for functional enrichment analysis. CIBERSORT algorithm was used to compare differences of immune cell infiltration between two groups in different SCCs. In addition, immune DEGs associated with prognosis were identified and risk prediction model was constructed via Cox regression analysis. Results: Missense mutation was the most dominant mutation type in SCCs. The difference was that the top10 mutated genes varied widely among different SCCs. High TMB group had better prognosis in lung squamous cell carcinoma (LUSC) and cervical squamous cell carcinoma (CESC), while the result was reverse in head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). In addition, patients with older age, smoking history, earlier pathological stage and no lymphatic invasion had higher TMB. The identified DEGs were mainly enriched in the regulation of immune system, muscular system and the activity of epidermal cells. The proportions of CD8+T cells, CD4+ memory T cells, follicular helper T cells, macrophages were distinct between two groups. The prognosis-related hub genes (CHGB, INHBA, LCN1 and VEGFC) screened were associated with poor prognosis. Conclusion: This study reveals the mutation status and immune cell infiltration of SCCs at different anatomical sites. TMB is closely related to the prognosis of SCCs, and its effects on prognosis are diverse in different SCCs, which might result from the situation of immune cell infiltration. These findings contribute to the exploration of biomarkers for predicting the efficacy of immunotherapy in SCCs and providing innovative insights for accurate application of immunotherapy.


Subject(s)
Carcinoma, Squamous Cell , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Lung Neoplasms , Biomarkers, Tumor/genetics , Humans , Lung Neoplasms/pathology , Mutation
5.
Proc Natl Acad Sci U S A ; 119(29): e2117054119, 2022 07 19.
Article in English | MEDLINE | ID: mdl-35858343

ABSTRACT

The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for ß-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-ß-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Cell Cycle Proteins , Lung Neoplasms , Receptors, G-Protein-Coupled , Transcription Factors , Bile Acids and Salts/metabolism , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Cycle Proteins/metabolism , Cholic Acids/pharmacology , Cryoelectron Microscopy , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Receptors, G-Protein-Coupled/agonists , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Transcription Factors/metabolism , beta-Arrestin 1/metabolism
6.
Curr Oncol ; 29(5): 2920-2927, 2022 04 20.
Article in English | MEDLINE | ID: mdl-35621628

ABSTRACT

In this study, we aimed to evaluate the efficacy of PD-1 inhibitors in combination with concurrent CRT/CT for patients with inoperable ESCC in the real world and to find predictors for the efficacy of PD-1 inhibitors. Patients with unresectable ESCC were evaluated at baseline. The clinical data of patients with ESCC who received CRT/CT with or without PD-1 inhibitor were collected and retrospectively reviewed. The objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) were analyzed statistically. A total of 96 patients with ESCC were included. As compared with a control group (n = 48), the PFS (6.0 months vs. 5.0 months, p = 0.025) and 6-month OS (70.8% vs. 47.9%, p < 0.001) were significantly longer in the ICIs group (n = 48). There were no significant differences in ORR and 12-month OS between the two groups. In addition, we found that body mass index (BMI) was associated with PFS (HR 0.85, 95% CI 0.76−0.95, and p = 0.004) and OS (HR 0.82, 95% CI 0.69−0.98, and p = 0.033) in the ICIs group. PD-1 inhibitors combined with CRT/CT is safe with acceptable complications and improved survival for patients with inoperable ESCC. CRT plus PD-1 inhibitor has superior antitumor efficacy. BMI was positively correlated with the efficacy of PD-1 inhibitors.


Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Chemoradiotherapy , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Humans , Immune Checkpoint Inhibitors , Retrospective Studies , Treatment Outcome
7.
New Phytol ; 232(6): 2400-2417, 2021 12.
Article in English | MEDLINE | ID: mdl-34618923

ABSTRACT

Mitogen-activated protein kinase (MPK) is a critical regulator of the antioxidant defence system in response to various stimuli. However, how MPK directly and exactly regulates antioxidant enzyme activities is still unclear. Here, we demonstrated that a NAC transcription factor ZmNAC49 mediated the regulation of antioxidant enzyme activities by ZmMPK5. ZmNAC49 expression is induced by oxidative stress. ZmNAC49 enhances oxidative stress tolerance in maize, and it also reduces superoxide anion generation and increases superoxide dismutase (SOD) activity. A detailed study showed that ZmMPK5 directly interacts with and phosphorylates ZmNAC49 in vitro and in vivo. ZmMPK5 directly phosphorylates Thr-26 in NAC subdomain A of ZmNAC49. Mutation at Thr-26 of ZmNAC49 does not affect the interaction with ZmMPK5 and its subcellular localisation. Further analysis found that ZmNAC49 activates the ZmSOD3 expression by directly binding to its promoter. ZmMPK5-mediated ZmNAC49 phosphorylation improves its ability to bind to the ZmSOD3 promoter. Thr-26 of ZmNAC49 is essential for its transcriptional activity. In addition, ZmSOD3 enhances oxidative stress tolerance in maize. Our results show that phosphorylation of Thr-26 in ZmNAC49 by ZmMPK5 increased its DNA-binding activity to the ZmSOD3 promoter, enhanced SOD activity and thereby improved oxidative stress tolerance in maize.


Subject(s)
Gene Expression Regulation, Plant , Zea mays , Mitogen-Activated Protein Kinases/metabolism , Oxidative Stress , Plant Proteins , Zea mays/genetics , Zea mays/metabolism
8.
Int J Radiat Biol ; 97(10): 1333-1340, 2021.
Article in English | MEDLINE | ID: mdl-34264176

ABSTRACT

PURPOSE: Radiation-induced heart disease (RIHD) is one of the most serious complications of radiotherapy. The purpose of this paper is to review recent researches about cardiac toxicity of radiotherapy in clinical characteristics, mechanisms, diagnosis, and prevention. CONCLUSIONS: Powered by the rapid development of medicine, the overall survival (OS) of cancer has been improved significantly. Surgery, chemotherapy, and radiotherapy (RT) are three critical ways in the comprehensive treatments of cancer. There is a consensus that early diagnosis and interventions for the prevention of RIHD are crucial. This review concludes recent clinical and experimental studies on RIHD. RIHD, a heterogeneous and serious disease, is a spectrum of heart disease including myocardial disease, pericarditis, coronary artery disease, valvular heart disease, and conduction system dysfunction. Mean heart dose, biomarkers, and detecting techniques are important components in detecting heart injury. Improvements in radiotherapy regimens remain the primary goal of prevention. Further investigation is needed beyond the observation period of most of these studies.


Subject(s)
Heart Diseases , Radiation Injuries , Cardiotoxicity/diagnosis , Cardiotoxicity/etiology , Cardiotoxicity/prevention & control , Heart , Heart Diseases/diagnosis , Heart Diseases/etiology , Heart Diseases/prevention & control , Humans , Neoplasms , Radiation Injuries/diagnosis , Radiation Injuries/etiology , Radiation Injuries/prevention & control , Radiotherapy/adverse effects
9.
J Exp Bot ; 72(4): 1399-1410, 2021 02 24.
Article in English | MEDLINE | ID: mdl-33130877

ABSTRACT

Drought stress severely limits the growth, development, and productivity of crops, and therefore understanding the mechanisms by which plants respond to drought is crucial. In this study, we cloned a maize NAC transcription factor, ZmNAC49, and identified its function in response to drought stress. We found that ZmNAC49 is localized in the nucleus and has transcriptional activation activity. ZmNAC49 expression is rapidly and strongly induced by drought stress, and overexpression enhances stress tolerance in maize. Overexpression also significant decreases the transpiration rate, stomatal conductance, and stomatal density in maize. Detailed study showed that ZmNAC49 overexpression affects the expression of genes related to stomatal development, namely ZmTMM, ZmSDD1, ZmMUTE, and ZmFAMA. In addition, we found that ZmNAC49 can directly bind to the promoter of ZmMUTE and suppress its expression. Taken together, our results show that the transcription factor ZmNAC49 represses ZmMUTE expression, reduces stomatal density, and thereby enhances drought tolerance in maize.


Subject(s)
Droughts , Plant Proteins , Stress, Physiological , Transcription Factors , Zea mays , Gene Expression Regulation, Plant , Plant Proteins/genetics , Plant Proteins/metabolism , Plants, Genetically Modified/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Zea mays/genetics , Zea mays/metabolism
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