Hafnium and Zirconium Complexes Bearing SNN-Ligands Enhancing Catalytic Performances toward Ethylene/1-Octene Copolymerization

The development of efficient catalysts is an ongoing pursuit in the field of olefin polymerization in order to synthesize desired polyolefins and to advance the present polymerization processes. In this contribution, the synthesis and characterization of a class of Hf and Zr complexes bearing SNN-tridentate ligands were described. The Hf (Hf1 and Hf2) and Zr (Zr1 and Zr2) trimethyl complexes were synthesized by one-pot reactions of thio-imino-quinoline ligands with in situ formed MMe4 (M = Hf, Zr). Both NMR analysis and X-ray diffraction study suggest the formation of thio-amido-quinoline metal complexes via methyl migration from Hf (or Zr) to the carbon of imine. These Hf and Zr complexes exhibited high activity and excellent thermal stability toward ethylene/1-octene copolymerization and an activity as high as 2.57 × 106 g(PE)·mol–1(cat)·h–1 was obtained by Hf1 even at 150 °C. The resultant polymers had moderate to high molecular weights (6.1–41.3 × 104 g·mol–1) with very broad distributions (D̵ = 6.8–34.7). NMR study revealed that multiple active species were formed when Hf1 was activated by 1 equiv. of [Ph3C][B(C6F5)4]

Controlling Polyethylene Molecular Weights and Distributions Using Chromium Complexes Supported by SNN-Tridentate Ligands

The diverse properties and applications of polyethylenes depend on their molecular weights, molecular weight distributions, and chain topology. Considering the importance of chromium complexes in catalytic ethylene polymerization and oligomerization, we have synthesized a series of Cr complexes (Cr1–Cr6) bearing a SNN-tridentate ligand. In the presence of MAO as cocatalyst, complexes Cr1–Cr6 exhibited moderate to extremely high activity (up to 2.4 × 107 g­(PE) mol–1(Cr) h–1) toward ethylene polymerization. The influences of the ligand and of various reaction parameters, including the nature and amount of the cocatalyst and the reaction temperature and pressure, were systematically investigated with Cr1. It was found that lower reaction temperatures (50 °C) and ethylene pressure (5 atm) and larger MAO/Cr ratios (1500) favored bimodal distributions with the dominant high-Mw fraction. In contrast, higher reaction temperatures (≥80 °C) and ethylene pressure (40 atm) and lower MAO/Cr ratios (≤500) almost exclusively led to the production of low-Mw polyethylene waxes with monomodal and narrow distributions. Based on DFT calculations and UV–vis–NIR spectroscopy, two types of active species generated by Cr1 and MAO were proposed to be responsible for the production of bimodal polyethylene. By tuning the structures of the Cr complexes in the Cr1–Cr6/MAO systems and the reaction conditions, polyethylenes with molecular weights ranging from low-Mw waxes to UHMWPE and monomodal or bimodal distributions were readily synthesized

Controlling Polyethylene Molecular Weights and Distributions Using Chromium Complexes Supported by SNN-Tridentate Ligands

The diverse properties and applications of polyethylenes depend on their molecular weights, molecular weight distributions, and chain topology. Considering the importance of chromium complexes in catalytic ethylene polymerization and oligomerization, we have synthesized a series of Cr complexes (Cr1–Cr6) bearing a SNN-tridentate ligand. In the presence of MAO as cocatalyst, complexes Cr1–Cr6 exhibited moderate to extremely high activity (up to 2.4 × 107 g­(PE) mol–1(Cr) h–1) toward ethylene polymerization. The influences of the ligand and of various reaction parameters, including the nature and amount of the cocatalyst and the reaction temperature and pressure, were systematically investigated with Cr1. It was found that lower reaction temperatures (50 °C) and ethylene pressure (5 atm) and larger MAO/Cr ratios (1500) favored bimodal distributions with the dominant high-Mw fraction. In contrast, higher reaction temperatures (≥80 °C) and ethylene pressure (40 atm) and lower MAO/Cr ratios (≤500) almost exclusively led to the production of low-Mw polyethylene waxes with monomodal and narrow distributions. Based on DFT calculations and UV–vis–NIR spectroscopy, two types of active species generated by Cr1 and MAO were proposed to be responsible for the production of bimodal polyethylene. By tuning the structures of the Cr complexes in the Cr1–Cr6/MAO systems and the reaction conditions, polyethylenes with molecular weights ranging from low-Mw waxes to UHMWPE and monomodal or bimodal distributions were readily synthesized

Controlling Polyethylene Molecular Weights and Distributions Using Chromium Complexes Supported by SNN-Tridentate Ligands

The diverse properties and applications of polyethylenes depend on their molecular weights, molecular weight distributions, and chain topology. Considering the importance of chromium complexes in catalytic ethylene polymerization and oligomerization, we have synthesized a series of Cr complexes (Cr1–Cr6) bearing a SNN-tridentate ligand. In the presence of MAO as cocatalyst, complexes Cr1–Cr6 exhibited moderate to extremely high activity (up to 2.4 × 107 g­(PE) mol–1(Cr) h–1) toward ethylene polymerization. The influences of the ligand and of various reaction parameters, including the nature and amount of the cocatalyst and the reaction temperature and pressure, were systematically investigated with Cr1. It was found that lower reaction temperatures (50 °C) and ethylene pressure (5 atm) and larger MAO/Cr ratios (1500) favored bimodal distributions with the dominant high-Mw fraction. In contrast, higher reaction temperatures (≥80 °C) and ethylene pressure (40 atm) and lower MAO/Cr ratios (≤500) almost exclusively led to the production of low-Mw polyethylene waxes with monomodal and narrow distributions. Based on DFT calculations and UV–vis–NIR spectroscopy, two types of active species generated by Cr1 and MAO were proposed to be responsible for the production of bimodal polyethylene. By tuning the structures of the Cr complexes in the Cr1–Cr6/MAO systems and the reaction conditions, polyethylenes with molecular weights ranging from low-Mw waxes to UHMWPE and monomodal or bimodal distributions were readily synthesized

DataSheet_1_Potential methylation-regulated genes and pathways in hepatocellular neoplasm, not otherwise specified.zip

Background and AimsThe molecular basis of hepatocellular neoplasm, not otherwise specified (HCN-NOS) is unknown. We aimed to identify gene expression patterns, potential methylation-regulated genes and pathways that characterize the tumor, and its possible relationship to hepatoblastoma and hepatocellular carcinoma (HCC).Approach & ResultsParallel genome-wide profiling of gene expression (RNAseq) and DNA methylation (EPIC850) was performed on 4 pairs of pre-treatment HCN-NOS tumors and adjacent non-tumor controls. 2530 significantly differentially expressed genes (DEGs) were identified between tumors and controls. Many of these DEGs were associated with hepatoblastoma and/or HCC. Analysis Match in Ingenuity Pathway Analysis determined that the gene expression profile of HCN-NOS was unique but significantly similar to that of both hepatoblastoma and HCC. A total of 27,195 CpG sites (CpGs) were significantly differentially methylated (DM) between tumors and controls, with a global hypomethylation pattern and predominant CpG island hypermethylation in promotor regions. Aberrant DNA methylation predominated in Developmental Process and Molecular Function Regulator pathways. Embryonic stem cell pathways were significantly enriched. In total, 1055 aberrantly methylated (at CpGs) and differentially expressed genes were identified, including 25 upstream regulators and sixty-one potential CpG island methylation-regulated genes. Eight methylation-regulated genes (TCF3, MYBL2, SRC, HMGA2, PPARGC1A, SLC22A1, COL2A1 and MYCN) had highly consistent gene expression patterns and prognostic value in patients with HCC, based on comparison to publicly available datasets.ConclusionsHCN-NOS has a unique, stem-cell like gene expression and DNA methylation profile related to both hepatoblastoma and HCC but distinct therefrom. Further, 8 methylation-regulated genes associated with prognosis in HCC were identified.</p

Image_2_Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients.tif

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.</p

Table_2_Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients.doc

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.</p

Table_4_Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients.doc

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.</p

Table_3_Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients.doc

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.</p

Data_Sheet_1_Two Novel Pathogenic Variants of TJP2 Gene and the Underlying Molecular Mechanisms in Progressive Familial Intrahepatic Cholestasis Type 4 Patients.doc

Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that accounts for 10%–15% childhood cholestasis and could lead to infant disability or death. There are three well-established types of PFIC (1–3), caused by mutations in the ATP8B1, ABCB11, and ABCB4 genes. Biallelic pathogenic variants in the tight junction protein 2 gene (TJP2) were newly reported as a cause for PFIC type 4; however, only a limited number of patients and undisputable variants have been reported for TJP2, and the underlying mechanism for PFIC 4 remains poorly understood. To explore the diagnostic yield of TJP2 analysis in suspected PFIC patients negative for the PFIC1–3 mutation, we designed a multiplex polymerase chain reaction-based next-generation sequencing method to analyze TJP2 gene variants in 267 PFIC patients and identified biallelic rare variants in three patients, including three known pathogenic variants and two novel variants in three patients. By using CRISPR-cas9 technology, we demonstrated that TJP2 c.1202A > G was pathogenic at least partially by increasing the expression and nuclear localization of TJP2 protein. With the minigene assay, we showed that TJP2 c.2668-11A > G was a new pathogenic variant by inducing abnormal splicing of TJP2 gene and translation of prematurely truncated TJP2 protein. Furthermore, knockdown of TJP2 protein by siRNA technology led to inhibition of cell proliferation, induction of apoptosis, dispersed F-actin, and disordered microfilaments in LO2 and HepG2celles. Global gene expression profiling of TJP2 knockdown LO2 cells and HepG2 cells identified the dysregulated genes involved in the regulation of actin cytoskeleton. Microtubule cytoskeleton genes were significantly downregulated in TJP2 knockdown cells. The results of this study demonstrate that TJP2 c.1202A > G and TJP2 c.2668-11A > G are two novel pathogenic variants and the cytoskeleton-related functions and pathways might be potential molecular pathogenesis for PFIC.</p