Abstract G-quadruplexes (G4s) can recruit transcription factors to activate gene expression, but detailed mechanisms remain enigmatic. Here, we demonstrate that G4s in the CCND1 promoter propel motility MAZ phase-separated condensates and subsequently transcription. Zinc finger (ZF) 2 of is a responsible for G4 binding, while ZF3-5, not highly disordered region, critical condensation. nuclear puncta overlaps with signals various coactivators including BRD4, MED1, CDK9 active RNA polymerase...

The directed evolution of enzymes promises to eliminate the long-standing limitations biocatalysis in organic chemistry and biotechnology—the often-observed limited substrate scope, insufficient activity, poor regioselectivity or stereoselectivity. Saturation mutagenesis at sites lining binding pocket with formation focused libraries has emerged as technique choice, but choosing optimal size randomization site reduced amino acid alphabet for minimizing labor-determining screening effort...

Directed evolution is an important research activity in synthetic biology and biotechnology. Numerous reports describe the application of tedious mutation/screening cycles for improvement proteins. Recently, knowledge-based approaches have facilitated prediction protein properties identification improved mutants. However, epistatic phenomena constitute obstacle which can impair predictions engineering. We present innovative sequence-activity relationship (innov'SAR) methodology based on...

Vascular maturity and functionality are closely associated with tumor progression chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit angiogenesis in metastatic breast cancer models. However, it remains unclear if or how remodels the abnormal vasculature of cancer, while inhibiting angiogenesis.Metastatic models were constructed compare microvessel density (MVD), vascular function, lung metastasis chemosensitivity metformin-treated untreated mice. Protein...

// Jichang Wang 2, 3, * , Guangyue Li 7, Yaochun 1 Shouching Tang 5, 6 Xin Sun 4 Xuefei Feng Yan 3 Gang Bao 2 Pingping Xiaona Mao Maode Peijun Liu Center for Translational Medicine, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China Department Neurosurgery, Vascular Surgery, Thoracic Surgery and Oncology, China 5 Breast Cancer Program Interdisciplinary Research Team, Georgia Regents University Center, Augusta, Georgia, 30912, United States...

Abstract As an oncogenic transcription factor, Yin Yang 1 (YY1) regulates enhancer and promoter connection. However, gaps still exist in understanding how YY1 coordinates coactivators chromatin elements to assemble enhancers super-enhancers. Here, we demonstrate that a histidine cluster YY1’s transactivation domain is essential for its formation of phase separation condensates, which can be extended additional proteins. The also required YY1-promoted cell proliferation, migration,...

Thymoquinone (TQ) is a natural compound extracted from the black seeds of Nigella sativa Linn. belonging to Ranunculaceae family. TQ exhibits anti-inflammatory and antineoplastic activities against various cancers. Many therapeutics in hepatocellular carcinoma (HCC) treatments, such as doxorubicin (DOX) cisplatin (DDP), exhibit considerable side effects on patients. We investigated cytotoxic TQ, alone or combination with DDP DOX HCC cells. exhibited selective killing HepG2 SMMC-7721 cells,...

Polydatin (PD) is a natural compound with anticancer activities, but the underlying mechanisms remain largely unclear. To understand how PD inhibited hepatocellular carcinoma (HCC), we studied treatments in HCC HepG2 and SK-HEP1 cells, normal liver HL-7702 cells. selectively blocked proliferation of cells showed low toxicity while effects doxorubicin (DOX) cisplatin (DDP) on were opposite. In cotreatment studies, synergistically improved inhibitory activities DOX DDP alleviated their...

Turn cool off and stay active: the thermostable alcohol dehydrogenase TbSADH originating from hot springs of Yellow Stone Park was successfully subjected to directed evolution for inducing high activity at ambient temperatures enabling short reaction times with minimal tradeoff in thermostability. Reversed enantioselectivity also evolved (99% ee).

Abstract Saturation mutagenesis at sites lining the binding pockets of enzymes constitutes a viable protein engineering technique for enhancing or inverting stereoselectivity. Statistical analysis shows that oversampling in screening step (the bottleneck) increases astronomically as number residues randomization site increases, which is reason why reduced amino acid alphabets have been employed, addition to splitting large into smaller ones. Limonene epoxide hydrolase (LEH) has previously...

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase to mediate lysine 27 trimethylation in histone H3 (i.e., H3K27me3) and repress gene expression. In solid tumors, EZH2 promotes oncogenesis considered therapeutic target. As transcription factor, Yin Yang 1 (YY1) recruits through its oncoprotein binding (OPB) domain establish repression. this study, we mapped the YY1 protein (YPB) on region amino acids. Both YPB OPB synthetic peptides could disrupt YY1EZH2 interaction, markedly reduce...

// Ji-Chang Wang 1, 2, * , Guang-Yue Li 3, Ping-Ping 2 Xin Sun 4 Wei-Ming 1 Yan Shao-Ying Lu and Pei-Jun Liu Department of Vascular Surgery, First Affiliated Hospital Xi'an Jiaotong University, Xi'an, Shaanxi Province, 710061, P.R.China Center for Translational Medicine, 3 Science Technology, Thoracic Surgery Oncology, These two authors contributed equally to this work share co-first Correspondence to: Liu, email: liupeijun@mail.xjtu.edu.cn Lu, robertlu@mail.xjtu.edu.cn Keywords: metformin,...

The thermostable Baeyer–Villiger monooxygenase TmCHMO and evolved mutants are viable catalysts in stereoselective reactions of structurally different ketones.

Chiral 2-substituted-1,2,3,4-tetrahydroquinolines (2-substituted-THQs) can serve as invaluable building blocks for certain pharmaceutical agents. This study was conducted to expand the biocatalytic repertoire of a bacterial cyclohexylamine oxidase (CHAO) include rare access some key enantiomers. Principal results this work are generation six 2-substituted-THQs derivatives with high ee values (up 99%) and isolated yield in range 58%–92%. Synthesis these compounds made possible by derived...

Competitive endogenous RNAs (ceRNAs) absorb microRNAs and subsequently promote corresponding mRNA long noncoding RNA (lncRNA) expression, which may alter cancer cell malignancy. Thus, dissecting ceRNA networks reveal novel targets in therapies. In this study, we analyzed differentially expressed genes (DEGs) of mRNAs lncRNAs, (DE-miRNAs) circular (DE-circRNAs) extracted from high-throughput sequencing datasets hepatocellular carcinoma patients. Based on these data, identified 26 gene modules...

Directed evolution of stereo- or regioselective enzymes as catalysts in asymmetric transformations is particular interest organic synthesis. Upon evolving these biocatalysts, screening the bottleneck. To beat numbers problem most effectively, methods and strategies for building "small but smart" mutant libraries have been developed. Herein, we compared two different regarding application triple-code saturation mutagenesis (TCSM) at multiresidue sites Thermoanaerobacter brockii alcohol...

is a potent fungus that adversely affects rice yield. Combinatorial techniques of prevention, toxic chemicals, and fungicide are used to remedy blast infection. We reported the role Hrip1 in cell death elicitation expression systematic acquired resistance could potentially stifle

Abnormal tumor vasculature blocks the extravasation of T lymphocytes into tumor, thereby suppressing anti-tumor immunity. Recently, metformin has been shown to affect and enhance lymphocyte However, whether or how affects immunity via a vascular mechanism remains poorly understood. Herein, we show that large number CD8+ gathered in peri-tumoral region, while very few infiltrated tumor. Metformin administration increased expression immunity-associated genes tumor-infiltrating lymphocytes....

The development of chemoresistance which results in a poor prognosis often renders current treatments for colorectal cancer (CRC). In this study, we identified reduced microvessel density (MVD) and vascular immaturity resulting from endothelial apoptosis as therapeutic targets overcoming chemoresistance. We focused on the effect metformin MVD, maturity, CRCs with non-angiogenic phenotype, further investigated its situ transplanted models were established to compare function tumors metformin-...

G-quadruplexes (G4s) regulate DNA replication and gene transcription, are enriched in promoters without fully appreciated functional relevance. Here we show high selection pressure on putative G4 (pG4) forming sequences through investigating genetic genomic data. Analyses of 76,156 whole-genome reveal that G-tracts connecting loops promoter pG4s display lower or higher allele frequencies, respectively, than pG4-flanking regions, central guanines (Gs) other Gs. Additionally, pG4-promoters...

Y box protein 1 (YB-1) is a multifunctional cellular expressed in various cancers, and potential target cancer therapy. Although there evidence showing that YB-1 plays role human the clinical significance of expression glioma has not been established. In present study, we investigated level tumors analyzed relationship between grade malignant glioma, with aim providing new ideas for diagnosis treatment gliomas basic research settings. A total 108 patients, comprising 14, 31, 30, 33 Grades I,...