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991.
Yu Xin Chen Shen Mengwei Tang Zitao Guo Yi Shi Zhenghua Gu Jun Shao Liang Zhang 《The Journal of biological chemistry》2022,298(3)
N-demethylases have been reported to remove the methyl groups on primary or secondary amines, which could further affect the properties and functions of biomacromolecules or chemical compounds; however, the substrate scope and the robustness of N-demethylases have not been systematically investigated. Here we report the recreation of natural evolution in key microdomains of the Thermomicrobium roseum sarcosine oxidase (TrSOX), an N-demethylase with marked stability (melting temperature over 100 °C) and enantioselectivity, for enhanced substrate scope and catalytic efficiency on -C-N- bonds. We obtained the structure of TrSOX by crystallization and X-ray diffraction (XRD) for the initial framework. The natural evolution in the nonconserved residues of key microdomains—including the catalytic loop, coenzyme pocket, substrate pocket, and entrance site—was then identified using ancestral sequence reconstruction (ASR), and the substitutions that accrued during natural evolution were recreated by site-directed mutagenesis. The single and double substitution variants catalyzed the N-demethylation of N-methyl-L-amino acids up to 1800- and 6000-fold faster than the wild type, respectively. Additionally, these single substitution variants catalyzed the terminal N-demethylation of non-amino-acid compounds and the oxidation of the main chain -C-N- bond to a -C=N- bond in the nitrogen-containing heterocycle. Notably, these variants retained the enantioselectivity and stability of the initial framework. We conclude that the variants of TrSOX are of great potential use in N-methyl enantiomer resolution, main-chain Schiff base synthesis, and alkaloid modification or degradation. 相似文献
992.
Wentao Liu Bin Yan Haixin Yu Jiannan Ren Mou Peng Liang Zhu Yinhuai Wang Xin Jin Lu Yi 《International journal of biological sciences》2022,18(4):1401
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma and has the highest mortality rate. For metastatic RCC, systemic drug therapy is the most important method in addition to surgical tumor reduction. In recent years, tyrosine kinase inhibitors (TKIs) targeting the angiogenesis have been applied to treat ccRCC and achieved profound therapeutic effects. It has been reported that most patients receiving antiangiogenic therapy will develop resistance within 15 months. The mechanism of resistance to targeted therapy is extremely complex and has not been clarified. Ovarian tumor-associated protease domain-containing proteins (OTUDs) belonging to DUBs play a critical role in the tumorigenesis of solid tumors. However, the specific role of OTUDs in ccRCC is still elusive. Here, we investigated the clinicopathological role of OTUD family members in ccRCC. We demonstrated that OTUD1 was downregulated in renal cancer and involved in the poor prognosis of renal cancer. Then, we showed that OTUD1 inhibits cancer cell growth. Moreover, analysis of OTUD1 RNA-seq data indicated that OTUD1 inhibition triggers the AKT and NF-kappa B pathways in renal cancer cells. Furthermore, OTUD1 interacts with PTEN and regulates its stability. Subsequently, we revealed that downregulation of OTUD1 contributes to the sensitivity of renal cancer cells to TKIs, and this effect was blocked by TNF/NF-kappa B inhibitors and AKT inhibitors. Thus, we identified that the OTUD1-PTEN axis suppresses tumor growth and regulates the resistance of renal cancer to TKIs. 相似文献
993.
994.
The purpose of many microarray studies is to find the association between gene expression and sample characteristics such as treatment type or sample phenotype. There has been a surge of efforts developing different methods for delineating the association. Aside from the high dimensionality of microarray data, one well recognized challenge is the fact that genes could be complicatedly inter-related, thus making many statistical methods inappropriate to use directly on the expression data. Multivariate methods such as principal component analysis (PCA) and clustering are often used as a part of the effort to capture the gene correlation, and the derived components or clusters are used to describe the association between gene expression and sample phenotype. We propose a method for patient population dichotomization using maximally selected test statistics in combination with the PCA method, which shows favorable results. The proposed method is compared with a currently well-recognized method. 相似文献
995.
目的 血清抗磷脂酶A2受体抗体IgG (PLA2R-IgG)水平是诊断和治疗特发性膜性肾病(IMN)的重要依据,而目前国内外常规检测手段主要是酶免法。为提升检测的便捷性,同时满足灵敏、宽量程分析需求,本研究构建了一种新的PLA2R-IgG检测技术。方法 采用包裹铕元素的微球示踪,对反应步骤进行选择,对微球制备液的p H、微球-抗体反应比例和反应时间优化,本文基于间接法构建了PLA2R-IgG的荧光定量免疫层析检测方法,并进行了初步临床评价。结果 本方法的灵敏度达0.7 RU/ml,标准曲线方程为y=0.771x-1.437,相关系数0.995,线性测量范围为0.7~1 500 RU/ml,回收率为86.27%~98.98%,平均批内变异系数为8.13%,交叉反应率均小于0.1%,试剂37℃储存10 d稳定。本方法与市售酶免试剂盒相关性为0.953,阴阳性判断一致,对IMN的检出率为76.9%。结论 采用两步法反应的PLA2R-IgG间接荧光定量免疫层析分析,快速、灵敏、准确,具有临床实用性。 相似文献
996.
Ruilong Zhang Zhiping Zhou Yi Wang Xiaohui Dai Li Chen Jiangdong Dai 《仿生工程学报(英文版)》2021,18(3):559-573
Mimicry of nature drives the development of bionic materials.Bionic superhydrophobic materials are a kind of high-efficiency materials to handle oil spills and ... 相似文献
997.
Hae Yon Jeon Jinwook Choi Lianne Kraaier Young Hoon Kim David Eisenbarth Kijong Yi JuGyeong Kang Jin Woo Kim Hyo Sup Shim JooHyeon Lee DaeSik Lim 《The EMBO journal》2022,41(8)
Tissue homeostasis requires lineage fidelity of stem cells. Dysregulation of cell fate specification and differentiation leads to various diseases, yet the cellular and molecular mechanisms governing these processes remain elusive. We demonstrate that YAP/TAZ activation reprograms airway secretory cells, which subsequently lose their cellular identity and acquire squamous alveolar type 1 (AT1) fate in the lung. This cell fate conversion is mediated via distinctive transitional cell states of damage‐associated transient progenitors (DATPs), recently shown to emerge during injury repair in mouse and human lungs. We further describe a YAP/TAZ signaling cascade to be integral for the fate conversion of secretory cells into AT1 fate, by modulating mTORC1/ATF4‐mediated amino acid metabolism in vivo. Importantly, we observed aberrant activation of the YAP/TAZ‐mTORC1‐ATF4 axis in the altered airway epithelium of bronchiolitis obliterans syndrome, including substantial emergence of DATPs and AT1 cells with severe pulmonary fibrosis. Genetic and pharmacologic inhibition of mTORC1 activity suppresses lineage alteration and subepithelial fibrosis driven by YAP/TAZ activation, proposing a potential therapeutic target for human fibrotic lung diseases. 相似文献
998.
999.
Bolong Yi Hao Li Heng Cai Xin Lou Mingjun Yu Zhen Li 《Journal of cellular and molecular medicine》2022,26(2):475
At present, growing evidence indicates that long non‐coding RNAs (lncRNAs) participate in the progression of glioma. The function of LOXL1‐AS1 in vasculogenic mimicry (VM) in glioma remains unclear. First, the expressions of TIAR, the lncRNA LOXL1‐AS1, miR‐374b‐5p and MMP14 were examined by qRT‐PCR and Western blot in both, glioma tissues and glioma cell lines. Proliferation, migration, invasion and tube formation assays were conducted to evaluate the roles of TIAR, LOXL1‐AS1, miR‐374b‐5p and MMP14 in malignant cellular behaviours in glioma cells. A nude mouse xenograft model and dual staining for CD34 and PAS were used to assess whether VM was affected by TIAR, LOXL1‐AS1 or miR‐374b‐5p in vivo. In this study, low levels of TIAR and high levels of LOXL1‐AS1 were found in glioma cells and tissues. TIAR downregulated the expression of LOXL1‐AS1 by destabilizing it. LOXL1‐AS1 acted like a miRNA sponge towards miR‐374b‐5p so that downregulation of the former greatly inhibited cell proliferation, migration, invasion and VM. Additionally, miR‐374b‐5p overexpression repressed malignant biological behaviours and VM in glioma by modifying MMP14. In summary, we demonstrated that TIAR combined with LOXL1‐AS1 modulates VM in glioma via the miR‐374b‐5p/MMP14 axis, revealing novel targets for glioma therapy. 相似文献
1000.