Publications by authors named "Xin Bi"

51 Publications

Steroid-resistant nephrotic syndrome in infants caused by a novel compound heterozygous mutation of the NUP93: A CARE case report.

Medicine (Baltimore) 2021 Feb;100(6):e24627

Department of Nephrology and Rheumatology, Kunming Children's Hospital, Kunming.

Rationale: Steroid-resistant nephrotic syndrome (SRNS) is a special kidney disease. SRNS is characterized by steroid-resistant, clinical variability, and genetic heterogeneity. Patients with SRNS often may eventually need renal transplantation.

Patient Concerns: A 10-month-old Chinese male infant presented with oliguria, renal dysfunction, hypertension, and anemia.

Diagnoses: Combined with clinical manifestations, laboratory testing and sequencing results, the patient was diagnosed as SRNS.

Interventions: Combined intravenous methylprednisolone and cefoperazone sulbactam did not improve the patient's condition. Thus, SRNS associated with hereditary nephrotic syndrome was strongly suspected. Genetic testing for hereditary renal disease of the patient revealed 2 novel heterozygous mutations in the Nucleoporin 93 (NUP93) gene, which were predicted pathogenic and harmful by bioinformatic softwares of SIFT, PolyPhen_2 and REVEL.

Outcomes: As general physical health deterioration and renal dysfunction, the patient died of a severe infection.

Lessons: The novel NUP93 heterozygous mutations identified in the current study broadened the genetic spectrum of SRNS and further deepened our insight into pathogenic mutations of NUP93 to improve disease diagnosis.
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http://dx.doi.org/10.1097/MD.0000000000024627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886470PMC
February 2021

, a Human Plasma Lipid GWAS Locus, Regulates Lipoprotein Metabolism in Mice.

Circ Res 2020 Nov 11;127(11):1347-1361. Epub 2020 Sep 11.

Division of Translational Medicine and Human Genetics, Department of Medicine (X.B., T.K., P.C.L., J.S.M., D.J.R.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Rationale: Single-nucleotide polymorphisms near the (inflammation and lipid regulator with ubiquitin-associated-like and NBR1 [next to gene 1 protein]-like domains) gene are genome-wide significantly associated with plasma lipid traits and coronary artery disease (CAD), but the biological basis of this association is unknown.

Objective: To investigate the role of ILRUN in plasma lipid and lipoprotein metabolism.

Methods And Results: encodes a protein that contains a ubiquitin-associated-like domain, suggesting that it may interact with ubiquitinylated proteins. We generated mice globally deficient for and found they had significantly lower plasma cholesterol levels resulting from reduced liver lipoprotein production. Liver transcriptome analysis uncovered altered transcription of genes downstream of lipid-related transcription factors, particularly PPARα (peroxisome proliferator-activated receptor alpha), and livers from -deficient mice had increased PPARα protein. Human ILRUN was shown to bind to ubiquitinylated proteins including PPARα, and the ubiquitin-associated-like domain of ILRUN was found to be required for its interaction with PPARα.

Conclusions: These findings establish ILRUN as a novel regulator of lipid metabolism that promotes hepatic lipoprotein production. Our results also provide functional evidence that may be the casual gene underlying the observed genetic associations with plasma lipids at 6p21 in human.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644615PMC
November 2020

Vector magnetocardiography measurement with a compact elliptically polarized laser-pumped magnetometer.

Biomed Opt Express 2020 Feb 7;11(2):649-659. Epub 2020 Jan 7.

Collaborative Innovation Center for Bio-Med Physics Information Technology, College of Science, Zhejiang University of Technology, Hangzhou 310023, China.

We report on a practical approach to vector biomagnetism measurement with an optically pumped magnetometer for measuring total magnetic field intensity. Its application to vector magnetocardiography is experimentally demonstrated with a compact elliptically polarized laser-pumped atomic magnetometer (EPMx OPM). The approach is proved to be effective and able to provide more complete cardiac magnetic information. The cardiac magnetic vectors are displayed in three-dimensional space in the form of magnetic vector loops. The sensor configuration and the image processing method here are expected to form further values, especially for multi-channel vector biomagnetism measurement, clinical diagnosis, and field source reconstruction.
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http://dx.doi.org/10.1364/BOE.380314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041466PMC
February 2020

Impairment of spermatogenesis and sperm motility by the high-fat diet-induced dysbiosis of gut microbes.

Gut 2020 09 2;69(9):1608-1619. Epub 2020 Jan 2.

The School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong, China

Objective: High-fat diet (HFD)-induced metabolic disorders can lead to impaired sperm production. We aim to investigate if HFD-induced gut microbiota dysbiosis can functionally influence spermatogenesis and sperm motility.

Design: Faecal microbes derived from the HFD-fed or normal diet (ND)-fed male mice were transplanted to the mice maintained on ND. The gut microbes, sperm count and motility were analysed. Human faecal/semen/blood samples were collected to assess microbiota, sperm quality and endotoxin.

Results: Transplantation of the HFD gut microbes into the ND-maintained (HFD-FMT) mice resulted in a significant decrease in spermatogenesis and sperm motility, whereas similar transplantation with the microbes from the ND-fed mice failed to do so. Analysis of the microbiota showed a profound increase in genus and , both of which likely contributed to the metabolic endotoxaemia in the HFD-FMT mice. Interestingly, the gut microbes from clinical subjects revealed a strong negative correlation between the abundance of and sperm motility, and a positive correlation between blood endotoxin and abundance. Transplantation with HFD microbes also led to intestinal infiltration of T cells and macrophages as well as a significant increase of pro-inflammatory cytokines in the epididymis, suggesting that epididymal inflammation have likely contributed to the impairment of sperm motility. RNA-sequencing revealed significant reduction in the expression of those genes involved in gamete meiosis and testicular mitochondrial functions in the HFD-FMT mice.

Conclusion: We revealed an intimate linkage between HFD-induced microbiota dysbiosis and defect in spermatogenesis with elevated endotoxin, dysregulation of testicular gene expression and localised epididymal inflammation as the potential causes.

Trial Registration Number: NCT03634644.
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http://dx.doi.org/10.1136/gutjnl-2019-319127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456731PMC
September 2020

Elliptically polarized laser-pumped magnetometer towards applications at room temperature.

Opt Express 2019 Nov;27(23):33027-33039

An atomic magnetometer operated with elliptically polarized light is investigated theoretically and experimentally. To explore the potential of this magnetometric configuration, the analytical form of the outgoing signal is derived. Parameters that significantly influence the performance are optimized, which lead to a sensitivity of 300 / at 45 C with a 2×2×2 cm uncoated Rb vapor cell. It is remarkable that a sensitivity of 690 / is achieved at room temperature of 24 C, which is improved by an order of magnitude compared with the conventional magnetometer under its own optimized condition. The elliptically polarized approach offers attractive features for developing compact, low-power magnetometers, which are available without heating the uncoated vapor cell.
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http://dx.doi.org/10.1364/OE.27.033027DOI Listing
November 2019

Total Syntheses of a Family of Cadinane Sesquiterpenes.

J Org Chem 2018 05 2;83(10):5825-5828. Epub 2018 May 2.

State Key Laboratory of Elemento-organic Chemistry, College of Chemistry , Nankai University , Tianjin 300071 , China.

Concise total syntheses of (-)-(1 R,6 S,7 S,10 R)-hydroxycadinan-3-en-5-one (1), (+)-(1 R,5 S,6 R,7 S,10 R)-cadinan-3-ene-1,5-diol (2), and (+)-(1 R,5 S,6 R,7 S,10 R)-cadinan-4(11)-ene-1,5-diol (3), three cadinane sesquiterpenes sharing identical trans-decalin carbon skeletons yet containing different oxidation states and substitution patterns, are reported. They were prepared from a common trans-decalin intermediate, which was readily prepared on gram scale through an aldol-Henry reaction cascade and oxidation sequence.
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http://dx.doi.org/10.1021/acs.joc.8b00505DOI Listing
May 2018

[Analysis of 10 patients with duplications of 15q11q13 region and autism features].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2018 Feb;35(1):23-28

Hubei Provincial Maternal and Child Health Care Hospital, Wuhan, Hubei 430070, China; Guangzhou KingMed Center for Clinical Laboratory Co., Ltd., Guangzhou, Guangdong 510005, China. Email:

OBJECTIVE To analyze the clinical and genetic features of 10 unrelated patients with duplications of 15q11q13 region and autism features.METHODS Karyotyping,chromosomal microarray analysis (CMA) and fluorescence in situ hybridization (FISH) were carried out for the patients and their parents.RESULTS Eight patients presented with a supernumerary marker chromosome (SMC) of unknown origin by G-banding analysis and triplication of the 15q11q13 region by high-resolution CMA analysis. Two remaining patients had normal karyotypes but duplications of the 15q11q13 region. All duplications have encompassed the Prader Willi/Angelman syndrome critical region (PWACR). Similar gains in copy number were not detected among the parents of the patients,suggesting a de novo origin for them. Analysis of SNP-array data of the family trios using Chromosome Analysis Suite Software found that the copy number gains have originated from the mothers.The diagnosis of 15q11q13 duplication syndrome was ascertained. For patients with SMC detected by karyotyping analysis,a FISH assay using probes specific for the 15q11q13 region showed that such SMC also derived from chromosome 15q11q13 region and contained two copy numbers, which was consistent with the result of CMA.CONCLUSION Ten patients with autism and 15q11q13 duplications were identified with combined karyotyping, CMA and FISH analysis. A phenotype - genotype correlation was established.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2018.01.005DOI Listing
February 2018

Identification of compound heterozygous variants in the noncoding RNU4ATAC gene in a Chinese family with two successive foetuses with severe microcephaly.

Hum Genomics 2018 01 25;12(1). Epub 2018 Jan 25.

UMR1078 "Génétique, Génomique Fonctionnelle et Biotechnologies", INSERM, EFS - Bretagne, Université de Brest, CHRU Brest, Brest, France.

Background: Whole-exome sequencing (WES) over the last few years has been increasingly employed for clinical diagnosis. However, one caveat with its use is that it inevitably fails to detect disease-causative variants that occur within noncoding RNA genes. Our experience in identifying pathogenic variants in the noncoding RNU4ATAC gene, in a Chinese family where two successive foetuses had been affected by severe microcephaly, is a case in point. These foetuses exhibited remarkably similar phenotypes in terms of their microcephaly and brain abnormalities; however, the paucity of other characteristic phenotypic features had made a precise diagnosis impossible. Given that no external causative factors had been reported/identified during the pregnancies, we sought a genetic cause for the phenotype in the proband, the second affected foetus.

Results: A search for chromosomal abnormalities and pathogenic copy number variants proved negative. WES was also negative. These initial failures prompted us to consider the potential role of RNU4ATAC, a noncoding gene implicated in microcephalic osteodysplastic primordial dwarfism type-1 (MOPD1), a severe autosomal recessive disease characterised by dwarfism, severe microcephaly and neurological abnormalities. Subsequent targeted sequencing of RNU4ATAC resulted in the identification of compound heterozygous variants, one being the most frequently reported MOPD1-causative mutation (51G>A), whereas the other was a novel 29T>A variant. Four distinct lines of evidence (allele frequency in normal populations, evolutionary conservation of the affected nucleotide, occurrence within a known mutational hotspot for MOPD1-causative variants and predicted effect on RNA secondary structure) allowed us to conclude that 29T>A is a new causative variant for MOPD1.

Conclusions: Our findings highlight the limitations of WES in failing to detect variants within noncoding RNA genes and provide support for a role for whole-genome sequencing as a first-tier genetic test in paediatric medicine. Additionally, the identification of a novel RNU4ATAC variant within the mutational hotspot for MOPD1-causative variants further strengthens the critical role of the 5' stem-loop structure of U4atac in health and disease. Finally, this analysis enabled us to provide prenatal diagnosis and genetic counselling for the mother's third pregnancy, the first report of its kind in the context of inherited RNU4ATAC variants.
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http://dx.doi.org/10.1186/s40246-018-0135-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784706PMC
January 2018

Lack of MTTP Activity in Pluripotent Stem Cell-Derived Hepatocytes and Cardiomyocytes Abolishes apoB Secretion and Increases Cell Stress.

Cell Rep 2017 05;19(7):1456-1466

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address:

Abetalipoproteinemia (ABL) is an inherited disorder of lipoprotein metabolism resulting from mutations in microsomal triglyceride transfer protein (MTTP). In addition to expression in the liver and intestine, MTTP is expressed in cardiomyocytes, and cardiomyopathy has been reported in several ABL cases. Using induced pluripotent stem cells (iPSCs) generated from an ABL patient homozygous for a missense mutation (MTTP), we show that human hepatocytes and cardiomyocytes exhibit defects associated with ABL disease, including loss of apolipoprotein B (apoB) secretion and intracellular accumulation of lipids. MTTP iPSC-derived cardiomyocytes failed to secrete apoB, accumulated intracellular lipids, and displayed increased cell death, suggesting intrinsic defects in lipid metabolism due to loss of MTTP function. Importantly, these phenotypes were reversed after the correction of the MTTP mutation by CRISPR/Cas9 gene editing. Together, these data reveal clear cellular defects in iPSC-derived hepatocytes and cardiomyocytes lacking MTTP activity, including a cardiomyocyte-specific regulated stress response to elevated lipids.
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http://dx.doi.org/10.1016/j.celrep.2017.04.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5555078PMC
May 2017

Adverse prognostic impact of T869C polymorphism in non-small-cell lung cancer.

Onco Targets Ther 2017 10;10:1513-1518. Epub 2017 Mar 10.

Department of Respiratory, The First Affiliated Hospital of Harbin Medical University.

Previously, several polymorphisms in have been identified in non-small-cell lung cancer (NSCLC), and the variants, C-509T, T869C, and G915C, have been demonstrated to associate with higher circulating levels of TGF-β1. However, little is known about the prognostic value of TGF-β1 polymorphisms in cancers. In this study, by genotyping the TGF-β1 T869C polymorphism in a total of 261 patients with NSCLC using DNA from blood lymphocytes, we first found that NSCLC patients, especially those with allele C carriers, had significantly higher serum TGF-β1 levels than healthy individuals. By using chi-square () test and Fisher's exact test, we noticed that TC/CC genotypes were positively correlated with smoking, clinical TNM stage, lymph node, and distant metastasis in NSCLC patients. Kaplan-Meier analysis showed that patients with TT genotype had a better overall survival than the allele C carriers (TC + CC). Finally, multivariate analysis confirmed histology, lymph node, and distant metastasis but not T869C polymorphism as independent prognostic factors for NSCLC. Taken together, our data, as a proof of principle, suggest that T869C polymorphism in may act as a genetic modifier in NSCLC progression and a promising prognostic marker of survival in NSCLC patients.
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http://dx.doi.org/10.2147/OTT.S123685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5354543PMC
March 2017

ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion.

EBioMedicine 2017 Apr 14;18:139-145. Epub 2017 Mar 14.

Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania and Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address:

Despite the recognized role of the ATP-binding Cassette Transporter A1 (ABCA1) in high-density lipoprotein (HDL) metabolism, our understanding of ABCA1 deficiency in human hepatocytes is limited. To define the functional effects of human hepatocyte ABCA1 deficiency, we generated induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (HLCs) from Tangier disease (TD) and matched control subjects. Control HLCs exhibited robust cholesterol efflux to apolipoprotein A-I (apoA-I) and formed nascent HDL particles. ABCA1-deficient HLCs failed to mediate lipid efflux or nascent HDL formation, but had elevated triglyceride (TG) secretion. Global transcriptome analysis revealed significantly increased ANGPTL3 expression in ABCA1-deficient HLCs. Angiopoietin-related protein 3 (ANGPTL3) was enriched in plasma of TD relative to control subjects. These results highlight the required role of ABCA1 in cholesterol efflux and nascent HDL formation by hepatocytes. Furthermore, our results suggest that hepatic ABCA1 deficiency results in increased hepatic TG and ANGPTL3 secretion, potentially underlying the elevated plasma TG levels in TD patients.
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http://dx.doi.org/10.1016/j.ebiom.2017.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5405159PMC
April 2017

Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport.

J Lipid Res 2017 04 30;58(4):731-741. Epub 2017 Jan 30.

Division of Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104.

Phospholipid transfer protein (PLTP) may affect macrophage reverse cholesterol transport (mRCT) through its role in the metabolism of HDL. Ex vivo cholesterol efflux capacity and in vivo mRCT were assessed in PLTP deletion and PLTP overexpression mice. PLTP deletion mice had reduced HDL mass and cholesterol efflux capacity, but unchanged in vivo mRCT. To directly compare the effects of PLTP overexpression and deletion on mRCT, human was overexpressed in the liver of wild-type animals using an adeno-associated viral (AAV) vector, and control and PLTP deletion animals were injected with AAV-null. PLTP overexpression and deletion reduced plasma HDL mass and cholesterol efflux capacity. Both substantially decreased ABCA1-independent cholesterol efflux, whereas ABCA1-dependent cholesterol efflux remained the same or increased, even though preβ HDL levels were lower. Neither PLTP overexpression nor deletion affected excretion of macrophage-derived radiocholesterol in the in vivo mRCT assay. The ex vivo and in vivo assays were modified to gauge the rate of cholesterol efflux from macrophages to plasma. PLTP activity did not affect this metric. Thus, deviations in PLTP activity from the wild-type level reduce HDL mass and ex vivo cholesterol efflux capacity, but not the rate of macrophage cholesterol efflux to plasma or in vivo mRCT.
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http://dx.doi.org/10.1194/jlr.M074625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5392748PMC
April 2017

Cell cycle-dependent positive and negative functions of Fun30 chromatin remodeler in DNA damage response.

DNA Repair (Amst) 2017 02 5;50:61-70. Epub 2017 Jan 5.

Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address:

The evolutionally conserved Fun30 chromatin remodeler in Saccharomyces cerevisiae has been shown to contribute to cellular resistance to genotoxic stress inflicted by camptothecin (CPT), methyl methanesulfonate (MMS) and hydroxyurea (HU). Fun30 aids in extensive DNA resection of DNA double stranded break (DSB) ends, which is thought to underlie its role in CPT-resistance. How Fun30 promotes MMS- or HU-resistance has not been resolved. Interestingly, we have recently found Fun30 to also play a negative role in cellular tolerance to MMS and HU in the absence of the Rad5-dependent DNA damage tolerance pathway. In this report, we show that Fun30 acts to down regulate Rad9-dependent DNA damage checkpoint triggered by CPT or MMS, but does not affect Rad9-independent intra-S phase replication checkpoint induced by MMS or HU. These results support the notion that Fun30 contributes to cellular response to DSBs by preventing excessive DNA damage checkpoint activation in addition to its role in facilitating DNA end resection. On the other hand, we present evidence suggesting that Fun30's negative function in MMS- and HU-tolerance in the absence of Rad5 is not related to its regulation of checkpoint activity. Moreover, we find Fun30 to be cell cycle regulated with its abundance peaking in G2/M phase of the cell cycle. Importantly, we demonstrate that artificially restricting Fun30 expression to G2/M does not affect its positive or negative function in genotoxin-resistance, but confining Fun30 to S phase abolishes its functions. These results indicate that both positive and negative functions of Fun30 in DNA damage response occur mainly in G2/M phase.
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http://dx.doi.org/10.1016/j.dnarep.2016.12.009DOI Listing
February 2017

Proliferating cell nuclear antigen (PCNA) contributes to the high-order structure and stability of heterochromatin in Saccharomyces cerevisiae.

Chromosome Res 2017 06 16;25(2):89-100. Epub 2016 Dec 16.

Department of Biology, University of Rochester, Rochester, NY, 14627, USA.

Heterochromatin plays important roles in the structure, maintenance, and function of the eukaryotic genome. It is associated with special histone modifications and specialized non-histone proteins and assumes a more compact structure than euchromatin. Genes embedded in heterochromatin are generally transcriptionally silent. It was found previously that several mutations of proliferating cell nuclear antigen (PCNA), a DNA replication processivity factor, reduce transcriptional silencing at heterochromatin loci in Saccharomyces cerevisiae. However, the notion that PCNA plays a role in transcriptional silencing was recently questioned because of a potential problem concerning the silencing assays used in prior studies. To determine if PCNA is a bona fide contributor to heterochromatin-mediated transcriptional silencing, we examined the effects of PCNA mutations on heterochromatin structure. We found evidence implicating PCNA in the maintenance of the high-order structure and stability of heterochromatin, which indicates a role of DNA replication in heterochromatin maintenance.
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http://dx.doi.org/10.1007/s10577-016-9540-xDOI Listing
June 2017

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice.

J Lipid Res 2017 01 3;58(1):236-246. Epub 2016 Nov 3.

Departments of Internal Medicine/Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157

G protein-coupled receptor (GPR)120/FFA receptor (FFAR)4 (GPR120/FFAR4) activation by n-3 PUFAs attenuates inflammation, but its impact on atherosclerosis is unknown. We determined whether in vivo activation of leukocyte GPR120/FFAR4 by n-3 versus n-6 PUFAs is atheroprotective. Leukocyte GPR120/FFAR4 WT or KO mice in the LDL receptor KO background were generated by bone marrow transplantation. Mice were fed one of the four atherogenic diets containing 0.2% cholesterol and 10% calories as palm oil (PO) + 10% calories as: 1) PO, 2) fish oil (FO; 20:5 n-3 and 22:6 n-3 enriched), 3) echium oil (EO; 18:4 n-3 enriched), or 4) borage oil (BO; 18:3 n-6 enriched) for 16 weeks. Compared with PO, mice fed BO, EO, and FO had significantly reduced plasma cholesterol, TG, VLDL cholesterol, hepatic neutral lipid, and atherosclerosis that were equivalent for WT and KO mice. In BO-, EO-, and FO-fed mice, but not PO-fed mice, lack of leukocyte GPR120/FFAR4 resulted in neutrophilia, pro-inflammatory Ly6C monocytosis, increased aortic root monocyte recruitment, and increased hepatic inflammatory gene expression. In conclusion, leukocyte GPR120 expression has minimal effects on dietary PUFA-induced plasma lipid/lipoprotein reduction and atheroprotection, and there is no distinction between n-3 versus n-6 PUFAs in activating anti-inflammatory effects of leukocyte GPR120/FFAR4 in vivo.
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http://dx.doi.org/10.1194/jlr.M072769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234726PMC
January 2017

Up-regulation of long non-coding HOTTIP functions as an oncogene by regulating HOXA13 in non-small cell lung cancer.

Am J Transl Res 2016 15;8(5):2022-32. Epub 2016 May 15.

Department of Respiratory, The First Affiliated Hospital of Harbin Medical University Harbin 150086, China.

Non-small cell lung cancer (NSCLC) is the major cause of cancer death worldwide. Increasing evidences show that long non coding RNAs (lncRNAs) are widely involved in the development and progression of NSCLC. The lncRNA HOTTIP has been identified as an oncogene in several human cancers, but its role in NSCLC remains unknown. The present study was to determine the expression and function of HOTTIP in NSCLC. Quantitative real-time PCR was used to detect the expressions of HOTTIP in 53 paired NSCLC tissues and cell lines. Furthermore, RNA interference (RNAi) and over-expression approaches were used to investigate the biological function of HOTTIP in lung cancer cell line. The impacts of HOTTIP on cell migration, proliferation and apoptosis were analyzed using wound scratch assay, MTT and flow cytometry, respectively. The results revealed that the HOTTIP expression was significantly up-regulated in NSCLC tissues and cells when compared with corresponding adjacent normal tissues and normal bronchial epithelial cells (p<0.05). Furthermore, knock-down of HOTTIP significantly inhibited cell proliferation, migration and induced cell apoptosis in vitro, while over-expression of HOTTIP led to the opposite effects. In addition, we identified HOTTIP as a transcriptional regulator of HOXA13 in lung cancer cell. Ectopic expression of HOTTIP suppressed the endogenous level of HOXA13, while knock-down of HOTTIP increased HOXA13 expression. Knock-down of HOXA13 by RNA interference (siHOXA13) revealed that HOTTIP promoted lung cell proliferation, migration, and inhibited apoptosis, at least partly by regulating HOXA13. The present study is the first to identify that HOTTIP functions as an oncogene by regulating HOXA13 in NSCLC, which may represent a new biomarker and a potential therapeutic target for NSCLC intervention.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891416PMC
June 2016

Mechanism of DNA damage tolerance.

Authors:
Xin Bi

World J Biol Chem 2015 Aug;6(3):48-56

Xin Bi, Department of Biology, University of Rochester, Rochester, NY 14627, United States.

DNA damage may compromise genome integrity and lead to cell death. Cells have evolved a variety of processes to respond to DNA damage including damage repair and tolerance mechanisms, as well as damage checkpoints. The DNA damage tolerance (DDT) pathway promotes the bypass of single-stranded DNA lesions encountered by DNA polymerases during DNA replication. This prevents the stalling of DNA replication. Two mechanistically distinct DDT branches have been characterized. One is translesion synthesis (TLS) in which a replicative DNA polymerase is temporarily replaced by a specialized TLS polymerase that has the ability to replicate across DNA lesions. TLS is mechanistically simple and straightforward, but it is intrinsically error-prone. The other is the error-free template switching (TS) mechanism in which the stalled nascent strand switches from the damaged template to the undamaged newly synthesized sister strand for extension past the lesion. Error-free TS is a complex but preferable process for bypassing DNA lesions. However, our current understanding of this pathway is sketchy. An increasing number of factors are being found to participate or regulate this important mechanism, which is the focus of this editorial.
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http://dx.doi.org/10.4331/wjbc.v6.i3.48DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549768PMC
August 2015

Multiple ligand detection and affinity measurement by ultrafiltration and mass spectrometry analysis applied to fragment mixture screening.

Anal Chim Acta 2015 Jul 9;886:98-106. Epub 2015 Jul 9.

Key Laboratory of Systems Microbial Biotechnology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China. Electronic address:

Binding affinity of a small molecule drug candidate to a therapeutically relevant biomolecular target is regarded the first determinant of the candidate's efficacy. Although the ultrafiltration-LC/MS (UF-LC/MS) assay enables efficient ligand discovery for a specific target from a mixed pool of compounds, most previous analysis allowed for relative affinity ranking of different ligands. Moreover, the reliability of affinity measurement for multiple ligands with UF-LC/MS has hardly been strictly evaluated. In this study, we examined the accuracy of K(d) determination through UF-LC/MS by comparison with classical ITC measurement. A single-point K(d) calculation method was found to be suitable for affinity measurement of multiple ligands bound to the same target when binding competition is minimized. A second workflow based on analysis of the unbound fraction of compounds was then developed, which simplified sample preparation as well as warranted reliable ligand discovery. The new workflow implemented in a fragment mixture screen afforded rapid and sensitive detection of low-affinity ligands selectively bound to the RNA polymerase NS5B of hepatitis C virus. More importantly, ligand identification and affinity measurement for mixture-based fragment screens by UF-LC/MS were in good accordance with single ligand evaluation by conventional SPR analysis. This new approach is expected to become a valuable addition to the arsenal of high-throughput screening techniques for fragment-based drug discovery.
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http://dx.doi.org/10.1016/j.aca.2015.06.017DOI Listing
July 2015

ABCA1 and Inflammation: From Animal Models to Humans.

Arterioscler Thromb Vasc Biol 2015 Jul;35(7):1551-3

From the Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1161/ATVBAHA.115.305547DOI Listing
July 2015

Functions of Fun30 chromatin remodeler in regulating cellular resistance to genotoxic stress.

PLoS One 2015 25;10(3):e0121341. Epub 2015 Mar 25.

Department of Biology, University of Rochester, Rochester, New York, United States of America.

The Saccharomyces cerevisiae Fun30 chromatin remodeler has recently been shown to facilitate long-range resection of DNA double strand break (DSB) ends, which proceeds homologous recombination (HR). This is believed to underlie the role of Fun30 in promoting cellular resistance to DSB inducing agent camptothecin. We show here that Fun30 also contributes to cellular resistance to genotoxins methyl methanesulfonate (MMS) and hydroxyurea (HU) that can stall the progression of DNA replication. We present evidence implicating DNA end resection in Fun30-dependent MMS-resistance. On the other hand, we show that Fun30 deletion suppresses the MMS- and HU-sensitivity of cells lacking the Rad5/Mms2/Ubc13-dependent error-free DNA damage tolerance mechanism. This suppression is not the result of a reduction in DNA end resection, and is dependent on the key HR component Rad51. We further show that Fun30 negatively regulates the recovery of rad5Δ mutant from MMS induced G2/M arrest. Therefore, Fun30 has two functions in DNA damage repair: one is the promotion of cellular resistance to genotoxic stress by aiding in DNA end resection, and the other is the negative regulation of a Rad51-dependent, DNA end resection-independent mechanism for countering replicative stress. The latter becomes manifest when Rad5 dependent DNA damage tolerance is impaired. In addition, we find that the putative ubiquitin-binding CUE domain of Fun30 serves to restrict the ability of Fun30 to hinder MMS- and HU-tolerance in the absence of Rad5.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121341PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4373758PMC
February 2016

Type II anti-CD20 mAb-induced lysosome mediated cell death is mediated through a ceramide-dependent pathway.

Biochem Biophys Res Commun 2015 Feb 17;457(4):572-7. Epub 2015 Jan 17.

Department of Thoracic Surgery, General Hospital of Armed Police Forces, 69 Yongding Road, Beijing 100039, PR China.

In the past decade, monoclonal antibodies (mAbs) have revolutionized the treatment of non-Hodgkin lymphomas (NHLs). Although Fc-dependent mechanisms of mAb-mediated tumor clearance have been extensively studied, the ability of mAbs to directly evoke programmed cell death (PCD) and the underlying mechanisms involved remain unclear. It is well established that type II anti-CD20 mAb (Tositumomab) potently evoked PCD through a caspases-independent, lysosome-mediated process, which is related to homotypic adhesion (HA) in NHL cell lines. Herein, we reveal that the induction of ceramide generation by anti-CD20 mAbs directly correlates with their ability to induce PCD. The inhibition of ceramide abrogated Tositumomab-induced PCD indicating that ceramide is required for the execution of cell death. Further experimental results revealed that ceramide was generated downstream of mAb-induced HA and upstream of lysosome leakage. These findings provide further insights into a previously unrecognized role for ceramide generation in mediating PCD evoked by type II anti-CD20 mAbs in Burkitt's lymphoma cells. This newly characterized cell death pathway may potentially be exploited to eliminate malignant cells.
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http://dx.doi.org/10.1016/j.bbrc.2015.01.026DOI Listing
February 2015

Heterochromatin structure: lessons from the budding yeast.

Authors:
Xin Bi

IUBMB Life 2014 Oct 30;66(10):657-66. Epub 2014 Oct 30.

Department of Biology, University of Rochester, Rochester, NY, USA.

The eukaryotic genome can be roughly divided into euchromatin and heterochromatin domains that are structurally and functionally distinct. Heterochromatin is characterized by its high compactness and its inhibitory effect on DNA transactions such as gene expression. Formation of heterochromatin involves special histone modifications and the recruitment and spread of silencing complexes and causes changes in the primary and higher order structures of chromatin. The past two decades have seen dramatic advances in dissecting the molecular aspects of heterochromatin because of the identification of the histone code for heterochromatin as well as its writers and erasers (histone-modifying enzymes) and readers (silencing factors recognizing histone modifications). How heterochromatic histone modifications and silencing factors contribute to the special primary and higher order structures of heterochromatin has begun to be understood. The budding yeast Saccharomyces cerevisiae has long been used as a model organism for heterochromatin studies. Results from these studies have contributed significantly to the elucidation of the general principles governing the formation, maintenance, and function of heterochromatin. This review is focused on investigations into the structural aspects of heterochromatin in S. cerevisiae. Current understanding of other aspects of heterochromatin including how it promotes gene silencing and its epigenetic inheritance is briefly summarized.
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http://dx.doi.org/10.1002/iub.1322DOI Listing
October 2014

Myeloid cell-specific ATP-binding cassette transporter A1 deletion has minimal impact on atherogenesis in atherogenic diet-fed low-density lipoprotein receptor knockout mice.

Arterioscler Thromb Vasc Biol 2014 Sep 15;34(9):1888-99. Epub 2014 May 15.

From the Department of Pathology/Section on Lipid Sciences (X.B., X.Z., C.G., S.S., Q.C., M.L., E.B., A.K.G., M.D.W., A.L.B., J.S.P.) and Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC (J.S.P.).

Objective: Transplantation studies suggest that bone marrow cell ATP-binding cassette transporter A1 protects against atherosclerosis development. However, the in vivo effect of macrophage ATP-binding cassette transporter A1 expression on atherogenesis is not fully understood because bone marrow contains other leukocytes and hematopoietic stem and progenitor cells. Myeloid-specific ATP-binding cassette transporter A1 knockout mice in the low-density lipoprotein (LDL) receptor knockout C57BL/6 background were developed to address this question.

Approach And Results: Chow-fed myeloid-specific ATP-binding cassette transporter A1 knockout/LDL receptor knockout (double knockout [DKO]) versus LDL receptor knockout (single knockout [SKO]) mice had similar plasma lipid concentrations, but atherogenic diet (AD)-fed DKO mice had reduced plasma very-LDL (VLDL)/LDL concentrations resulting from decreased hepatic VLDL triglyceride secretion. Resident peritoneal macrophages from AD-fed DKO versus SKO mice had significantly higher cholesterol content but similar proinflammatory gene expression. Atherosclerosis extent was similar between genotypes after 10 to 16 weeks of AD but increased modestly in DKO mice by 24 weeks of AD. Lesional macrophage content was similar, likely because of the higher monocyte flux through aortic root lesions in DKO versus SKO mice. After transplantation of DKO or SKO bone marrow into SKO mice and 16 weeks of AD feeding, atherosclerosis extent was similar and plasma apolipoprotein B lipoproteins were reduced in mice receiving DKO bone marrow. When differences in plasma VLDL/LDL concentrations were minimized by maintaining mice on chow for 24 weeks, DKO mice had modest, but significantly more, atherosclerosis compared with SKO mice.

Conclusions: Myeloid cell ATP-binding cassette transporter A1 increases hepatic VLDL triglyceride secretion and plasma VLDL/LDL concentrations in AD-fed LDL receptor knockout mice, offsetting its atheroprotective role in decreasing macrophage cholesterol content, resulting in a minimal increase in atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.114.303791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140956PMC
September 2014

A case of ultraviolet B-induced linear IgA bullous dermatosis.

Indian J Dermatol Venereol Leprol 2014 Jan-Feb;80(1):67-8

Department of Dermatology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.

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http://dx.doi.org/10.4103/0378-6323.125537DOI Listing
April 2016

Hepatic apolipoprotein M (apoM) overexpression stimulates formation of larger apoM/sphingosine 1-phosphate-enriched plasma high density lipoprotein.

J Biol Chem 2014 Jan 6;289(5):2801-14. Epub 2013 Dec 6.

From the Departments of Pathology-Lipid Sciences and.

Apolipoprotein M (apoM), a lipocalin family member, preferentially associates with plasma HDL and binds plasma sphingosine 1-phosphate (S1P), a signaling molecule active in immune homeostasis and endothelial barrier function. ApoM overexpression in ABCA1-expressing HEK293 cells stimulated larger nascent HDL formation, compared with cells that did not express apoM; however, the in vivo role of apoM in HDL metabolism remains poorly understood. To test whether hepatic apoM overexpression increases plasma HDL size, we generated hepatocyte-specific apoM transgenic (APOM Tg) mice, which had an ∼3-5-fold increase in plasma apoM levels compared with wild-type mice. Although HDL cholesterol concentrations were similar to wild-type mice, APOM Tg mice had larger plasma HDLs enriched in apoM, cholesteryl ester, lecithin:cholesterol acyltransferase, and S1P. Despite the presence of larger plasma HDLs in APOM Tg mice, in vivo macrophage reverse cholesterol transport capacity was similar to that in wild-type mice. APOM Tg mice had an ∼5-fold increase in plasma S1P, which was predominantly associated with larger plasma HDLs. Primary hepatocytes from APOM Tg mice generated larger nascent HDLs and displayed increased sphingolipid synthesis and S1P secretion. Inhibition of ceramide synthases in hepatocytes increased cellular S1P levels but not S1P secretion, suggesting that apoM is rate-limiting in the export of hepatocyte S1P. Our data indicate that hepatocyte-specific apoM overexpression generates larger nascent HDLs and larger plasma HDLs, which preferentially bind apoM and S1P, and stimulates S1P biosynthesis for secretion. The unique apoM/S1P-enriched plasma HDL may serve to deliver S1P to extrahepatic tissues for atheroprotection and may have other as yet unidentified functions.
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http://dx.doi.org/10.1074/jbc.M113.499913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908412PMC
January 2014

Investigation of Pokemon-regulated proteins in hepatocellular carcinoma using mass spectrometry-based multiplex quantitative proteomics.

Eur J Mass Spectrom (Chichester) 2013 ;19(2):111-21

Department of Chemistry, Tsinghua University, Beijing 100084, China.

Pokemon is a transcription regulator involved in embryonic development, cellular differentiation and oncogenesis. It is aberrantly overexpressed in multiple human cancers including Hepatocellular carcinoma (HCC) and is considered as a promising biomarker for HCC. In this work, the isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomics strategy was used to investigate the proteomic profile associated with Pokemon in human HCC cell line QGY7703 and human hepatocyte line HL7702. Samples were labeled with four-plex iTRAQ reagents followed by two-dimensional liquid chromatography coupled with tandem mass spectrometry analysis. A total of 24 differentially expressed proteins were selected as significant. Nine proteins were potentially up-regulated by Pokemon while 15 proteins were potentially down-regulated and many proteins were previously identified as potential biomarkers for HCC. Gene ontology (GO) term enrichment revealed that the listed proteins were mainly involved in DNA metabolism and biosynthesis process. The changes of glucose-6-phosphate 1-dehydrogenase (G6PD, up-regulated) and ribonucleoside-diphosphate reductase large sub-unit (RIM1, down-regulated) were validated by Western blotting analysis and denoted as Pokemon's function of oncogenesis. We also found that Pokemon potentially repressed the expression of highly clustered proteins (MCM3, MCM5, MCM6, MCM7) which played key roles in promoting DNA replication. Altogether, our results may help better understand the role of Pokemon in HCC and promote the clinical applications.
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http://dx.doi.org/10.1255/ejms.1221DOI Listing
December 2013

Myeloid cell-specific ABCA1 deletion does not worsen insulin resistance in HF diet-induced or genetically obese mouse models.

J Lipid Res 2013 Oct 27;54(10):2708-17. Epub 2013 Jul 27.

Department of Pathology/Lipid Sciences and Wake Forest School of Medicine, Winston-Salem, NC; and.

Obesity-associated low-grade chronic inflammation plays an important role in the development of insulin resistance. The membrane lipid transporter ATP-binding cassette transporter A1 (ABCA1) promotes formation of nascent HDL particles. ABCA1 also dampens macrophage inflammation by reducing cellular membrane cholesterol and lipid raft content. We tested the hypothesis that myeloid-specific ABCA1 deletion may exacerbate insulin resistance by increasing the obesity-associated chronic low-grade inflammation. Myeloid cell-specific ABCA1 knockout (MSKO) and wild-type (WT) mice developed obesity, insulin resistance, mild hypercholesterolemia, and hepatic steatosis to a similar extent with a 45% high-fat (HF) diet feeding or after crossing into the ob/ob background. Resident peritoneal macrophages and stromal vascular cells from obese MSKO mice accumulated significantly more cholesterol. Relative to chow, HF diet markedly induced macrophage infiltration and inflammatory cytokine expression to a similar extent in adipose tissue of WT and MSKO mice. Among pro-inflammatory cytokines examined, only IL-6 was highly upregulated in MSKO-ob/ob versus ob/ob mouse peritoneal macrophages, indicating a nonsignificant effect of myeloid ABCA1 deficiency on obesity-associated chronic inflammation. In conclusion, myeloid-specific ABCA1 deficiency does not exacerbate obesity-associated low-grade chronic inflammation and has minimal impact on the pathogenesis of insulin resistance in both HF diet-induced and genetically obese mouse models.
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http://dx.doi.org/10.1194/jlr.M038943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3770084PMC
October 2013

Detection of an altered heterochromatin structure in the absence of the nucleotide excision repair protein Rad4 in Saccharomyces cerevisiae.

Cell Cycle 2013 Aug 3;12(15):2435-42. Epub 2013 Jul 3.

Department of Biochemistry and Molecular Biology; University of Miami Miller School of Medicine; Miami, FL USA.

Rad4p is a DNA damage recognition protein essential for global genomic nucleotide excision repair in Saccharomyces cerevisiae. Here, we show that Rad4p binds to the heterochromatic HML locus. In a yeast mutant lacking Rad4p, an increased level of SIR complex binding at the HML locus is accompanied by an altered, more compact heterochromatin structure, as revealed by a topological analysis of chromatin circles released from the locus. In addition, gene silencing at the HML locus is enhanced in the rad4Δ mutant. Importantly, re-expression of Rad4p in the rad4Δ mutant restores the altered heterochromatin structure to a conformation similar to that detected in wild-type cells. These findings reveal a novel role of Rad4p in the regulation of heterochromatin structure and gene silencing.
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http://dx.doi.org/10.4161/cc.25457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841322PMC
August 2013

Liver ABCA1 deletion in LDLrKO mice does not impair macrophage reverse cholesterol transport or exacerbate atherogenesis.

Arterioscler Thromb Vasc Biol 2013 Oct 27;33(10):2288-96. Epub 2013 Jun 27.

From the Section on Lipid Sciences, Department of Pathology (X.B., X.Z., M.D., E.Y.B., M.D.W., A.K.G., J.S.P.), and Department of Biochemistry (J.S.P.), Wake Forest School of Medicine, Winston-Salem, NC.

Objective: Hepatic ATP binding cassette transporter A1 (ABCA1) expression is critical for maintaining plasma high-density lipoprotein (HDL) concentrations, but its role in macrophage reverse cholesterol transport and atherosclerosis is not fully understood. We investigated atherosclerosis development and reverse cholesterol transport in hepatocyte-specific ABCA1 knockout (HSKO) mice in the low-density lipoprotein (LDL) receptor KO (LDLrKO) C57BL/6 background.

Approach And Results: Male and female LDLrKO and HSKO/LDLrKO mice were switched from chow at 8 weeks of age to an atherogenic diet (10% palm oil, 0.2% cholesterol) for 16 weeks. Chow-fed HSKO/LDLrKO mice had HDL concentrations 10% to 20% of LDLrKO mice, but similar very low-density lipoprotein and LDL concentrations. Surprisingly, HSKO/LDLrKO mice fed the atherogenic diet had significantly lower (40% to 60%) very low-density lipoprotein, LDL, and HDL concentrations (50%) compared with LDLrKO mice. Aortic surface lesion area and cholesterol content were similar for both genotypes of mice, but aortic root intimal area was significantly lower (20% to 40%) in HSKO/LDLrKO mice. Although macrophage (3)H-cholesterol efflux to apoB lipoprotein-depleted plasma was 24% lower for atherogenic diet-fed HSKO/LDLrKO versus LDLrKO mice, variation in percentage efflux among individual mice was <2-fold compared with a 10-fold variation in plasma HDL concentrations, suggesting that HDL levels, per se, were not the primary determinant of plasma efflux capacity. In vivo reverse cholesterol transport, resident peritoneal macrophage sterol content, biliary lipid composition, and fecal cholesterol mass were similar between both genotypes of mice.

Conclusions: The markedly reduced plasma HDL pool in HSKO/LDLrKO mice is sufficient to maintain macrophage reverse cholesterol transport, which, along with reduced plasma very low-density lipoprotein and LDL concentrations, prevented the expected increase in atherosclerosis.
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http://dx.doi.org/10.1161/ATVBAHA.112.301110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793209PMC
October 2013

N-phosphorylation labeling for analysis of twenty natural amino acids and small peptides by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Analyst 2013 May;138(9):2632-9

Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Hong Kong, SAR, China.

N-phosphorylation labeling was utilized to analyze the low molecular weight compounds by using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). A wide range of natural amino acids and short peptides was successfully analyzed by MALDI-TOF MS without matrix background interferences. The N-phosphorylation labeling reaction was carried out easily within 30 min in a one-pot reaction under mild reaction conditions. The phosphoryl derivatization reaction is a global labeling approach with high selectivity and high specificity with targeting only on the N-terminal and ε-amino group of Lys. The incorporation of a neutral phosphoryl group with high gas-phase affinity of protons not only improves the ionization efficiency of target molecules and simultaneously decreases the ion suppression effects in MALDI-TOF MS analysis, but also greatly reduces or eliminates the matrix background interferences by suppressing the matrix signals and increasing the molecular weight of the targeted compounds. By applying the N-phosphorylation labeling approach, many amino acids could be detected in serum samples by using MALDI-TOF MS.
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http://dx.doi.org/10.1039/c3an00036bDOI Listing
May 2013