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Highlight

posted Mar 10, 2013, 11:21 PM by Lanyi Chang


1.    PLoS One. 2013;8(3):e58169. doi: 10.1371/journal.pone.0058169. Epub 2013 Mar 5.

Concordant and Discordant Regulation of Target Genes by miR-31 and Its Isoforms.

Source

Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan ; Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Abstract

It has been shown that imprecise cleavage of a primary or precursor RNA by Drosha or Dicer, respectively, may yield a group of microRNA (miRNA) variants designated as "isomiR". Variations in the relative abundance of isoforms for a given miRNA among different species and different cell types beg the question whether these isomiRs might regulate target genes differentially. We compared the capacity of three miR-31 isoforms (miR-31-H, miR-31-P, and miR-31-M), which differ only slightly in their 5'- and/or 3'-end sequences, to regulate several known targets and a predicted target, Dicer. Notably, we found isomiR-31s displayed concordant and discordant regulation of 6 known target genes. Furthermore, we validated a predicted target gene, Dicer, to be a novel target of miR-31 but only miR-31-P could directly repress Dicer expression in both MCF-7 breast cancer cells and A549 lung cancer cells, resulting in their enhanced sensitivity to cisplatin, a known attribute of Dicer knockdown. This was further supported by reporter assay using full length 3'-untranslated region (UTR) of Dicer. Our findings not only revealed Dicer to be a direct target of miR-31, but also demonstrated that isomiRs displayed similar and disparate regulation of target genes in cell-based systems. Coupled with the variations in the distribution of isomiRs among different cells or conditions, our findings support the possibility of fine-tuning gene expression by miRNAs.

PMID:
 
23472152
 
[PubMed - in process] 
Free full text

2.
PLoS One. 2013;8(3):e57318. doi: 10.1371/journal.pone.0057318. Epub 2013 Mar 4.

A novel cell-penetrating Peptide derived from human eosinophil cationic protein.

Source

Institute of Molecular and Cellular Biology, National Tsing Hua University, Hsinchu, Taiwan, Republic of China.

Abstract

Cell-penetrating peptides (CPPs) are short peptides which can carry various types of molecules into cells; however, although most CPPs rapidly penetrate cells , their tissue-targeting specificities are low. Herein, we describe cell-binding, internalization, and targeting characteristics of a newly identified 10-residue CPP, denoted ECP, derived from the core heparin-binding motif of human eosinophil cationic protein (ECP). Besides traditional emphasis on positively charged residues, the presence of cysteine and tryptophan residues was demonstrated to be essential for internalization. ECP entered Beas-2B and wild-type CHO-K1 cells, but not CHO cells lacking of cell-surface glycosaminoglycans (GAGs), indicating that binding of ECP to cell-surface GAGs was required for internalization. When cells were cultured with GAGs or pre-treated with GAG-digesting enzymes, significant decreases in ECP internalization were observed, suggesting that cell-surface GAGs, especially heparan sulfate proteoglycans were necessary for ECP attachment and penetration. Furthermore, treatment with pharmacological agents identified two forms of energy-dependent endocytosis, lipid-raft endocytosis and macropinocytosis, as the major ECP internalization routes. ECP was demonstrated to transport various cargoes including fluorescent chemical, fluorescent protein, and peptidomimetic drug into cultured Beas-2B cells , and targeted broncho-epithelial and intestinal villi tissues . Hence this CPP has the potential to serve as a novel vehicle for intracellular delivery of biomolecules or medicines, especially for the treatment of pulmonary or gastrointestinal diseases.

PMID:
 
23469189
 
[PubMed - in process] 
Free full text

3.
Blood. 2013 Mar 5. [Epub ahead of print]

Aryl hydrocarbon receptor controls murine mast cell homeostasis.

Source

Johns Hopkins Asthma and Allergy Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States;

Abstract

Key points AhR ligands result in calcium- and ROS-dependent enhancement of mast cells activation.AhR is critical in controlling mast cell homeostasis.

PMID:
 
23462117
 
[PubMed - as supplied by publisher]

4.
J Immunol. 2013 Mar 1. [Epub ahead of print]

Galectin-3 Negatively Regulates Dendritic Cell Production of IL-23/IL-17-Axis Cytokines in Infection by Histoplasma capsulatum.

Source

Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei, 10051 Taiwan.

Abstract

Galectin-3 (gal3) is known for its immunoregulatory functions in infectious, autoimmune, and inflammatory diseases. However, little is known about its regulatory role in the host's IL-17A response to infection. Using a mouse model of histoplasmosis in which both Th1 and Th17 responses contribute to fungal clearance, we investigated how gal3 regulates IL-17A responses. Our study showed that Histoplasma infection induced gal3-/- dendritic cells to produce significantly higher levels of IL-23, TGF-β1, and IL-1β than did gal3+/+ cells. Infected by the same inoculum of Histoplasma, gal3-/- mice had lower fungal burden and produced higher levels of IL-23/IL-17-axis cytokines and lower levels of IL-12 and IFN-γ. Additionally, there was an increase in Th17 cells and a reduction in Th1 cells in infected gal3-/- mice. In vitro Th1/Th17-skewing experiments excluded the intrinsic effect of gal3 on Th cell differentiation. Although neutrophils from both gal3+/+ and gal3-/- mice produced IL-17A upon IL-23 stimulation, their contribution to IL-17A production was greater in gal3-/- mice than in gal3+/+ mice. Compared with gal3+/+ dendritic cells, adoptive transfer of gal3-/- dendritic cells resulted in production of significantly higher levels of IL-17-axis cytokines and reduced fungal burden. It appears that reduced fungal burden and preferential IL-17A response in gal3-/- mice by both Th17 cells and neutrophils were the result of preferential production of IL-23/IL-17-axis cytokines by dendritic cells. Our study showed that gal3 negatively regulates IL-17A responses through inhibition of IL-23/IL-17-axis cytokine production by dendritic cells.

PMID:
 
23455499
 
[PubMed - as supplied by publisher]

5.
Blood. 2013 Feb 28. [Epub ahead of print]

Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in patients with acute myeloid leukemia.

Source

Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan;

Abstract

Alterations of galectin-3 expression are often seen in cancers and may contribute to tumorigenesis, cancer progression and metastasis. The studies concerning clinical implications of galectin-3 expression in patients with acute myeloid leukemia (AML) are scarce. We investigated the expression of LGALS3, the gene encoding galectin-3, in the bone marrow (BM) mononuclear cells from an original cohort comprising 280 adults with primary non-M3 AML. Higher LGALS3 expression was closely associated with older age, French-American-British M4/M5 subtypes, CD14 expression on leukemic cells and PTPN11 mutation, but negatively correlated with CEBPA mutation and FLT3-ITD. Compared to patients with lower LGALS3 expression, those with higher expression had lower complete remission rates, higher primary refractory rates and shorter overall survival. This result was validated in an independent validation cohort. A scoring system incorporating higher LGALS3 expression and eight other risk factors, including age, white blood cell count, cytogenetics, and gene mutations, into survival analysis proved to be very useful to stratify AML patients into different prognostic groups (P<0.001). In conclusion, BM LGALS3 expression may serve as a new biomarker to predict clinical outcome in AML patients and galectin-3 may serve as a potential therapeutic target in those patients with higher expression of this protein.

PMID:
 
23449638
 
[PubMed - as supplied by publisher]

Highlights

posted Mar 3, 2013, 6:45 PM by Lanyi Chang

1.
Blood. 2013 Feb 28. [Epub ahead of print]

Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in patients with acute myeloid leukemia.

Source

Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan;

Abstract

Alterations of galectin-3 expression are often seen in cancers and may contribute to tumorigenesis, cancer progression and metastasis. The studies concerning clinical implications of galectin-3 expression in patients with acute myeloid leukemia (AML) are scarce. We investigated the expression of LGALS3, the gene encoding galectin-3, in the bone marrow (BM) mononuclear cells from an original cohort comprising 280 adults with primary non-M3 AML. Higher LGALS3 expression was closely associated with older age, French-American-British M4/M5 subtypes, CD14 expression on leukemic cells and PTPN11 mutation, but negatively correlated with CEBPA mutation and FLT3-ITD. Compared to patients with lower LGALS3 expression, those with higher expression had lower complete remission rates, higher primary refractory rates and shorter overall survival. This result was validated in an independent validation cohort. A scoring system incorporating higher LGALS3 expression and eight other risk factors, including age, white blood cell count, cytogenetics, and gene mutations, into survival analysis proved to be very useful to stratify AML patients into different prognostic groups (P<0.001). In conclusion, BM LGALS3 expression may serve as a new biomarker to predict clinical outcome in AML patients and galectin-3 may serve as a potential therapeutic target in those patients with higher expression of this protein.

PMID:
 
23449638
 
[PubMed - as supplied by publisher]
2.
Mod Pathol. 2013 Mar 1. doi: 10.1038/modpathol.2013.29. [Epub ahead of print]

Expression of TNFRSF6B in kidneys is a novel predictor for progression of chronic kidney disease.

Source

Division of Nephrology, Department of Medicine, Taipei City Hospital Heping Fuyou Branch, Taipei, Taiwan.

Abstract

TNFRSF6B overexpression in tumors is a novel predictor for poor prognosis in various cancers; however, whether TNFRSF6B could be expressed in kidney tissues of patients with chronic kidney disease is unknown. Current established risk factors cannot fully predict the progression of chronic kidney disease, and, therefore, it is mandatory to develop a newer marker for predicting disease progression. We conducted a prospective cohort study comprised 167 patients with chronic kidney disease undergoing renal biopsy at a tertiary hospital with median follow-up of 30.5 months. Computer-assisted quantitative immunohistochemical staining analysis of TNFRSF6B in kidney tissues, the expression of α-smooth muscle actin and percentage of fibrosis in renal interstitium, estimated glomerular filtration rate, and urinary protein excretion rate were investigated. Study endpoint was a doubling of serum creatinine and/or end-stage renal failure requiring renal replacement therapy. We found that TNFRSF6B was predominantly expressed in the tubular epithelial cells of renal cortex. The higher the expression of TNFRSF6B, the more the expression of α-smooth muscle actin and fibrosis in interstitium (P<0.001). Forty patients reaching endpoint had lower baseline estimated glomerular filtration rate and higher expression of TNFRSF6B in renal tubular epithelial cells. Multivariate Cox regression analysis showed that high expression of TNFRSF6B independently predicted the risk toward the renal endpoint with a hazard ratio of 3.46 (95% confidence interval (CI) 1.76-6.80, P<0.001) by adjusting for clinical and pathologic variables. While added to a model of estimated glomerular filtration rate, proteinuria and other conventional risk factors, TNFRSF6B further significantly improved the model predictability for progression of chronic kidney disease (area under the curve, 0.82). In conclusion, TNFRSF6B is associated with renal fibrosis and high expression of TNFRSF6B is a novel biomarker for predicting the progression of chronic kidney disease.Modern Pathology advance online publication, 1 March 2013; doi:10.1038/modpathol.2013.29.

PMID:
 
23449012
 
[PubMed - as supplied by publisher]
3.
Org Biomol Chem. 2013 Feb 28. [Epub ahead of print]

Regioselective and stereoselective benzylidene installation and one-pot protection of d-mannose.

Source

Genomics Research Center, Academia Sinica, 128, Section 2, Academia Road, Taipei 115, Taiwan. schung@gate.sinica.edu.tw.

Abstract

Oligosaccharide syntheses are an important source of well-defined sugar constructs particularly needed for the evaluation of structure-activity relationships. The chemical assembly of oligosaccharides requires several building blocks, that is, glycosyl donors and acceptors, which are prepared in multistep processes and in a generally tedious and time-consuming manner. Having developed one-pot procedures meant to minimise the effort in sugar building block preparation, we tackled herein the one-pot preparation of fully protected and 2-, 3-, 4-, and 6-alcohol derivatives of d-mannose, a widely distributed monosaccharide. As a consequence of the hydroxyl group pattern of d-mannose, regioselective and stereoselective benzylidenations were developed and later seamlessly utilised as the first transformation in the one-pot procedure.

PMID:
 
23446759
 
[PubMed - as supplied by publisher]
4.
Pediatr Neonatol. 2013 Feb;54(1):5-11. doi: 10.1016/j.pedneo.2012.12.009. Epub 2013 Jan 22.

Influence and mechanisms of maternal and infant diets on the development of childhood asthma.

Source

Department of Pediatrics, Show Chwan Memorial Hospital, Changhua, Taiwan, ROC.

Abstract

Perinatal nutrition has been implicated in the programming of diseases in children and adults. The prevalence of asthma has dramatically increased in the past few decades, particularly in children. This suggests that the perinatal environment, including maternal and infant diets, may be involved in the increase in the prevalence of asthma. Recent studies have demonstrated that certain maternal and infant diets have a protective or augmentative effect on the development of asthma. Maternal diets with higher vitamin D, vitamin E, or/and probiotics are related to asthma prevention. Infants with breast feeding for at least 4 months and/or complementary diets between 4 and 6 months may have regulatory effects on the prevention of asthma. In summary, diets may have epigenetic or immune regulatory effects on the promotion or prevention of asthma. This article analyzes recent reports on the potential mechanism and mechanism-driven early prevention of childhood asthma by modification of maternal and infant diets.

Copyright © 2012. Published by Elsevier B.V.

PMID:
 
23445737
 
[PubMed - in process]
5.
Chem Commun (Camb). 2013 Feb 27. [Epub ahead of print]

Synthesis of l-hexoses and their related biomolecules.

Source

Genomics Research Center, Academia Sinica, 128, Section 2, Academia Road, Taipei 115, Taiwan. schung@gate.sinica.edu.tw.

Abstract

Carbohydrates either conjugated or as free entities are major players in numerous biological processes. The desire to comprehend the nature of their functions and further develop therapeutic and diagnostic applications has fuelled the recent upsurge in the glycoscience field. Mainly accessed through chemical synthesis, homogeneous and well-defined sugar constructs are on high demand for structure-activity evaluation. Although the d-sugars, particularly the d-hexoses, have dominated the carbohydrate landscape, l-hexoses also attracted attention because they are known components of important polysaccharides, antibiotics, and other natural products. Nonetheless, the l-hexose-based materials needed for making building blocks for sugar assemblies are rare and are usually expensive if commercially available. Thus, intense efforts were focused on the development of innovative and reliable methods for the acquisition of l-hexoses and their derivatives. This review outlines several efficient and cost-effective routes for the chemical syntheses of l-hexoses, particularly focusing on approaches that utilize commercially abundant sugars as starting materials. A sampling of the applications of the generated l-hexoses in preparing biologically relevant compounds is also provided.

PMID:
 
23443887
 
[PubMed - as supplied by publisher]

Highlights

posted Feb 3, 2013, 7:01 PM by Lanyi Chang


1.
J Proteome Res. 2013 Jan 31. [Epub ahead of print]

An iTRAQ Proteomic Study Reveals an Association between Diet-Induced Enhanced Fatty Acid Metabolism and the Development of Glucose Intolerance in Prediabetic Mice.

Source

Graduate Institute of Clinical Medicine, Taipei Medical University , Taipei, Taiwan.

Abstract

High-fat diet (HFD)-induced glucose intolerance and insulin resistance increases the chances of developing type-2 diabetes and cardiovascular disease. To study the mechanism(s) by which a HFD impairs glucose tolerance, we used a quantitative proteomic platform that integrated pI-based OFFGEL fractionation and iTRAQ labeling to profile the temporal changes in adipose membrane protein expression in mice fed a HFD for up to 8 months. Within 2 months of starting the diet, the mice adipose and liver tissues accumulated fat droplets, which contributed to subsequent insulin resistance and glucose intolerance within 6 months. The membrane proteomic delineation of such phenotypic expression resulted in quantification of 1713 proteins with 266, 343, and 125 differentially expressed proteins in 2-, 6-, and 8-month HFD-fed versus control mice, respectively. Pathway analysis of these differentially expressed proteins revealed the interplay between upregulation of fatty acid metabolism and downregulation of glucose metabolism. Substantial upregulation of adipose and liver carnitine palmitoyltransferase (Cpt) 1, the rate-limiting enzyme in the transport of long-chain fatty acids into mitochondria, occurred by 2 months. The increase in hepatic Cpt 1a expression was associated with a progressive decrease in glucose uptake as evidenced by downregulation of the liver glucose transporter protein (Glut) 2. Loss of glycogen storage was found in those hepatocytes full of fat droplets. Intriguingly, skeletal muscle Cpt 1b expression was unaltered by the HFD, whereas skeletal muscle Glut 4 and tyrosine phosphoryated insulin receptor substrate 1 (p-IRS1) were substantially upregulated at the same time as abnormal glucose metabolism developed in adipose and liver tissues. This study defines some of the molecular mechanisms as well as the relationship among adipose tissue, liver and skeletal muscle during development of HFD-induced glucose intolerance in vivo and identifies Cpt 1 as a potential drug target for the control or prevention of diabetes.

PMID:
 
23316967
 
[PubMed - as supplied by publisher]

2.

Glycobiology. 2013 Jan 30. [Epub ahead of print]

Advanced Mass Spectrometry and Chemical Analyses Reveal the Presence of Terminal Disialyl Motif on Mouse B Cell Glycoproteins.

Source

Institute of Biochemical Sciences, National Taiwan University.

Abstract

The occurrence of a terminal disialyl motif on mammalian O-glycans is increasingly being identified through recent mass spectrometry (MS)-based glycomic profiling. In most cases, it is carried on simple core 1 structure in which both the Gal and GalNAc can be disialylated. In contrast, a disialyl motif on N-glycans is less readily revealed by MS mapping since additional MS/MS analysis is required to determine the distribution of the various sialic acids on typically multi-sialylated complex type N-glycans. In our MS-based glycomic screening, we found that a mouse B lymphoma cell line, BCL1, ranks among those that has the highest amount of disialyl motif on its O-glycans, including those carried on CD45. More intriguingly, detailed chemical and MS/MS analyses unambiguously showed that the Neu5Gcα2-8Neu5Gc disialyl motif is also present on the N-glycans and that it can be carried on the termini of polylactosaminoglycan chains, which can be further sulfated on the proximal GlcNAc, occurring alongside other monosialylated sulfated LacNAc termini. Upon silencing the expression of mouse α2,8-sialyltransferase VI (ST8Sia VI), the overall disialyl content decreases significantly but more so for that on the N-glycans than the O-glycans. ST8Sia VI was further shown to be the most significantly up-regulated ST8Sia during plasma cell differentiation, which coincides with increasing content of the disialyl motif. Increasing terminal disialylation without leading to polysialylation may thus have important biological consequences awaiting further investigation. Likewise the expression of mono- and disialylated sulfated LacNAc may constitute novel recognition codes modulating B cell activation and differentiation.

PMID:
 
23363740
 
[PubMed - as supplied by publisher]
3.

Aging Male. 2013 Jan 28. [Epub ahead of print]

Androgen modulates cardiac fibrosis contributing to gender differences on heart failure.

Source

Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University , Taipei , Taiwan .

Abstract

Abstract Chronic heart failure (HF) is a major health problem throughout the world. Gender has significant effects on the pathophysiology of HF. Low levels of free testosterone are independently associated with increased chronic HF symptoms and mortality. Cardiac fibrosis plays a pivotal role in structural remodeling in HF. Transforming growth factor (TGF)-β, angiotensin II and oxidative stress contribute to the activity/extent of cardiac fibrosis. Androgen deficiency can up-regulate TGF-β expression under angiotensin II stimulation in vivo. In this review, we summarized the potential mechanisms accounting for the effects of androgen on cardiac fibrosis through regulating fibrocytes activity under TGF, which can explain wound healing and cardiac fibrosis in male with acute myocardial injury and chronic HF.

PMID:
 
23356882
 
[PubMed - as supplied by publisher]

4.

BMC Infect Dis. 2013 Jan 28;13(1):45. [Epub ahead of print]

Apoptosis-associated biomarkers in tuberculosis: promising for diagnosis and prognosis prediction.

Abstract

ABSTRACT:

BACKGROUND: Apoptosis-associated biomarkers are rarely studied, especially their role in predicting the development of tuberculosis (TB) from latent TB infection and in prognostication.

METHODS:

Patients with TB and interferon-gamma release assay (IGRA)-positive and IGRA-negative family contacts were evaluated to analyze changes in apoptosis-associated serum biomarkers, which included decoy receptor 3 (DcR3), prostaglandin 2 (PGE2), and lipoxin. The prognostic implications of these serum biomarkers were also analyzed.

RESULTS:

One hundred TB patients and 92 IGRA-negative and 91 IGRA-positive family contacts were recruited. The DcR3 and PGE2 levels decreased from the IGRA-negative group to the IGRA-positive group, and peaked in the TB group. Lipoxin decreased to trough in the TB group. The three apoptosis serum markers and age were independent factors discriminating active TB from latent TB infection. In active TB, older age, co-morbidity, and higher serum DcR3 and monocyte chemotactic protein (MCP)-1 were independently associated with poorer six-month survival.

CONCLUSION:

Apoptosis-associated serum biomarkers change along with the status of Mycobacterium tuberculosis infection. In close contacts with positive IGRA, high DcR3 and PGE2 and low lipoxin may increase the probability of active TB. Older age, co-morbidity, and high DcR3 and MCP-1 levels might be important prognostic factors that warrant further investigation.

PMID:
 
23356448
 
[PubMed - as supplied by publisher] 
Free full text
5.

Proc Natl Acad Sci U S A. 2013 Jan 28. [Epub ahead of print]

Cell-permeable probe for identification and imaging of sialidases.

Source

Genomics Research Center, Academia Sinica, Taipei 115, Taiwan.

Abstract

Alkyne-hinged 3-fluorosialyl fluoride (DFSA) containing an alkyne group was shown to be a mechanism-based target-specific irreversible inhibitor of sialidases. The ester-protected analog DFSA (PDFSA) is a membrane-permeable precursor of DFSA designed to be used in living cells, and it was shown to form covalent adducts with virus, bacteria, and human sialidases. The fluorosialyl-enzyme adduct can be ligated with an azide-annexed biotin via click reaction and detected by the streptavidin-specific reporting signals. Liquid chromatography-mass spectrometry/mass spectrometry analysis on the tryptic peptide fragments indicates that the 3-fluorosialyl moiety modifies tyrosine residues of the sialidases. DFSA was used to demonstrate influenza infection and the diagnosis of the viral susceptibility to the anti-influenza drug oseltamivir acid, whereas PDFSA was used for in situ imaging of the changes of sialidase activity in live cells.

PMID:
 
23359711
 
[PubMed - as supplied by publisher]

6.

Proc Natl Acad Sci U S A. 2013 Jan 25. [Epub ahead of print]

Carbohydrate-based vaccines with a glycolipid adjuvant for breast cancer.

Source

Genomics Research Center and Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program, Academia Sinica, Taipei 115, Taiwan.

Abstract

Globo H (GH) is a hexasaccharide specifically overexpressed on a variety of cancer cells and therefore, a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked GH to a carrier protein, including keyhole limpet hemocyanion, diphtheria toxoid cross-reactive material (CRM) 197 (DT), tetanus toxoid, and BSA, and combined with an adjuvant, and it was administered to mice for the study of immune response. Glycan microarray analysis of the antiserum obtained indicated that the combination of GH-DT adjuvanted with the α-galactosylceramide C34 has the highest enhancement of anti-GH IgG. Compared with the phase III clinical trial vaccine, GH-keyhole limpet hemocyanion/QS21, the GH-DT/C34 vaccine elicited more IgG antibodies, which are more selective for GH and the GH-related epitopes, stage-specific embryonic antigen 3 (SSEA3) and SSEA4, all of which were specifically overexpressed on breast cancer cells and breast cancer stem cells with SSEA4 at the highest level (>90%). We, therefore, further developed SSEA4-DT/C34 as a vaccine candidate, and after immunization, it was found that the elicited antibodies are also IgG-dominant and very specific for SSEA4.

PMID:
 
23355685
 
[PubMed - as supplied by publisher]

7.

Biochimie. 2013 Jan 23. pii: S0300-9084(13)00006-0. doi: 10.1016/j.biochi.2012.12.017. [Epub ahead of print]

Up-regulation of neutrophil activating protein in Helicobacter pylori under high-salt stress: Structural and phylogenetic comparison with bacterial iron-binding ferritins.

Source

Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.

Abstract

It is generally accepted that most gastrointestinal diseases are probably caused by the bacterial pathogen Helicobacter pylori (H. pylori). In this study we have focused on the comparison of protein expression profiles of H. pylori grown under normal and high-salt conditions by a proteomics approach. We have identified about 190 proteins whose expression levels changed after growth at high salt concentration. Among these proteins, neutrophil-activating protein (NapA) was found to be consistently up-regulated under osmotic stress brought by high salts. We have investigated the effect of high salt on secondary and tertiary structures of NapA by circular dichroism spectroscopy followed by analytical ultracentrifugation to monitor the change of quaternary structure of recombinant NapA with increasing salt concentration. The loss of iron-binding activity of NapA coupled with noticeable energetic variation in protein association of NapA as revealed by isothermal titration calorimetry was found under high salt condition. The phylogenetic tree analysis based on sequence comparison of 16 protein sequences encompassing NapA proteins and ferritin of H. pylori and other prokaryotic organisms pointed to the fact that all H. pylori NapA proteins of human origin are more homologous to NapA of Helicobacter genus than to other bacterial NapA. Based on computer modeling, NapA proteins from H. pylori of human isolates are found more similar to ferritin from H. pylori than to NapA from other species of bacteria. Taken together, these results suggested that divergent evolution of NapA and ferritin possessing dissimilar and diverse sequences follows a path distinct from that of convergent evolution of NapA and ferritin with similar dual functionality of iron-binding and ferroxidase activities.

Copyright © 2013 Elsevier Masson SAS. All rights reserved.

PMID:
 
23352965
 
[PubMed - as supplied by publisher]

Highlights

posted Jan 20, 2013, 5:58 PM by Lanyi Chang

Source

Department of Chemistry, National Sun Yat-sen University, No. 70, Lienhai Rd, Kaohsiung, Taiwan. pclin@mail.nsysu.edu.tw.

Abstract

A nanomaterial-assisted method that combines thin layer chromatography (TLC) with matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) was developed to directly monitor chemical transformations. A substrate-dependent extraction strategy was studied and successfully used to identify target molecules from the depths of a developed TLC plate. By using this strategy, a hydrophobic sample of interest was enriched on the surface of the TLC plate in the presence of acetonitrile, in contrast to using water and methanol to identify hydrophilic samples. The successful enrichment of samples by specific solvents provided stable desorption/ionization efficiencies of compounds of interest and led to very good sensitivity near the attomole scale. The method was then used to monitor 4-dimethylaminopyridine (DMAP)-catalyzed acylation in preparation of bifunctional sulfonamides. The labile DMAP-acyl intermediate and final sulfonamide product were clearly identified on TLC plates without external purification or sample preparation. Furthermore, in combination with collision-induced dissociation (CID) to provide structural information, the technique was successfully used in the natural product discovery of anti-inflammatory flavonoids from Helminthostachys zeylanica, a traditional Chinese herb. The newly proposed method provides a very low background from silica supports or organic matrices in the low molecular weight range (100-1000 Da). The technique may greatly accelerate studies of metabolomics, drug discovery, and organic synthesis.

PMID:
 
23330148
 
[PubMed - as supplied by publisher]
2.
J Proteome Res. 2013 Jan 15. [Epub ahead of print]

An iTRAQ Proteomic Study Reveals an Association between Diet-induced Enhanced Fatty-acid Metabolism and the Development of Glucose Intolerance in Prediabetic Mice.

Abstract

High-fat diet (HFD)-induced glucose intolerance and insulin resistance increases the chances of developing type-2 diabetes and cardiovascular disease. To study the mechanism(s) by which a HFD impairs glucose tolerance, we used a quantitative proteomic platform that integrated pI-based OFFGEL fractionation and iTRAQ labeling to profile the temporal changes in adipose membrane protein expression in mice fed a HFD for up to 8 months. Within 2 months of starting the diet, the mice adipose and liver tissues accumulated fat droplets, which contributed to subsequent insulin resistance and glucose intolerance within 6 months. The membrane proteomics delineation of such phenotypic expression resulted in quantification of 1713 proteins with 266, 343 and 125 differentially expressed proteins in 2-, 6-, and 8-month HFD-fed versus control mice, respectively. Pathway analysis of these differentially expressed proteins revealed the interplay between up-regulation of fatty acid metabolism and down-regulation of glucose metabolism. Substantial upregulation of adipose and liver carnitine palmitoyltransferase (Cpt) 1, the rate-limiting enzyme in the transport of long-chain fatty acids into mitochondria, occurred by 2 months. The increase in hepatic Cpt 1a expression was associated with a progressive decrease in glucose uptake as evidenced by downregulation of the liver glucose transporter protein (Glut) 2. Loss of glycogen storage was found in those hepatocytes full of fat droplets. Intriguingly, skeletal muscle Cpt 1b expression was unaltered by the HFD, whereas skeletal muscle Glut 4 and tyrosine phosphoryated insulin receptor substrate 1 (p-IRS1) were substantially upregulated at the same time as abnormal glucose metabolism developed in adipose and liver tissues. This study defines some of the molecular mechanisms as well as the relationship among adipose tissue, liver and skeletal muscle during development of HFD-induced glucose intolerance in vivo and identifies Cpt 1 as a potential drug target for the control or prevention of diabetes.

PMID:
 
23316967
 
[PubMed - as supplied by publisher]
3.
Anal Chem. 2013 Jan 8. [Epub ahead of print]

A critical examination of gas-phase protein conformation/multimer ion formation by Electrospray Ion Mobility-Mass Spectrometry.

Abstract

The generally accepted view of protein structure in the gas-phase is that protein ions produced by electrospray ionization (ESI) exist in a number of different states and the resulting charge state distribution (CSD) and ion mobility spectrum is interpreted as evidence for protein ions retaining some memory of solution-phase conformation. Even with the inclusion of ion mobility information reports of protein ion structure in the gas-phase are oftentimes in disagreement not only within the discipline but also as interpreted by other gas-phase techniques. The focus of this work will be to correctly distinguish truly different ion conformations formed by ESI versus homomultimeric complexes with the same m/z. The concentration of cytochrome c in solution was varied over a wide range and the multiply charged multimers (MCMs) present in the ion mobility/mass spectrum were unambiguously assigned by m/z selection and dissociation prior to ion mobility/mass spectrometry analysis. The results revealed false negatives for protein oligomer formation and false positives for protein conformational states, and no evidence that gas-phase cytochrome c ions retain memory of solution-phase conformation, characteristics of great importance for structural biology. The results also suggest that the total IM-MS distribution for a protein is the complex result of individual MCMs either surviving until detection (undissociated) or dissociating into lower order multimers or a number of product ions for each m/z.

PMID:
 
23298466
 
[PubMed - as supplied by publisher]
4.
J Proteome Res. 2013 Jan 4;12(1):33-44. doi: 10.1021/pr300829r. Epub 2012 Dec 20.

Decoding the disease-associated proteins encoded in the human chromosome 4.

Source

Institute of Information Science, Academia Sinica , Taipei, Taiwan.

Abstract

Chromosome 4 is the fourth largest chromosome, containing approximately 191 megabases (∼6.4% of the human genome) with 757 protein-coding genes. A number of marker genes for many diseases have been found in this chromosome, including genetic diseases (e.g., hepatocellular carcinoma) and biomedical research (cardiac system, aging, metabolic disorders, immune system, cancer and stem cell) related genes (e.g., oncogenes, growth factors). As a pilot study for the chromosome 4-centric human proteome project (Chr 4-HPP), we present here a systematic analysis of the disease association, protein isoforms, coding single nucleotide polymorphisms of these 757 protein-coding genes and their experimental evidence at the protein level. We also describe how the findings from the chromosome 4 project might be used to drive the biomarker discovery and validation study in disease-oriented projects, using the examples of secretomic and membrane proteomic approaches in cancer research. By integrating with cancer cell secretomes and several other existing databases in the public domain, we identified 141 chromosome 4-encoded proteins as cancer cell-secretable/shedable proteins. Additionally, we also identified 54 chromosome 4-encoded proteins that have been classified as cancer-associated proteins with successful selected or multiple reaction monitoring (SRM/MRM) assays developed. From literature annotation and topology analysis, 271 proteins were recognized as membrane proteins while 27.9% of the 757 proteins do not have any experimental evidence at the protein-level. In summary, the analysis revealed that the chromosome 4 is a rich resource for cancer-associated proteins for biomarker verification projects and for drug target discovery projects.

PMID:
 
23256888
 
[PubMed - in process]
5.
Biomacromolecules. 2013 Jan 14;14(1):160-8. doi: 10.1021/bm301567w. Epub 2012 Dec 14.

A chemically functionalized magnetic nanoplatform for rapid and specific biomolecular recognition and separation.

Source

Department of Chemistry, National Sun Yat-sen University , 70, Lienhai Road, Kaohsiung 80424, Taiwan.

Abstract

We have developed a target-molecule-functionalized magnetic nanoparticle (MNP)-based method to facilitate the study of biomolecular recognition and separation. The superparamagnetic property of MNPs allows the corresponding biomolecules to be rapidly separated from crude biofluids with a significant improvement in recovery yield and specificity. Various MNPs functionalized with tag molecules (chitin, heparin, and amylose) were synthesized for recombinant protein purification, and several probe-functionalized MNPs, such as nitrilotriacetic acid (NTA)@MNP and P(k)@MNP, exhibited excellent extraction efficiency for proteins. In a cell recognition study, mannose-functionalized MNPs allowed specific purification of Escherichia coli with FimH adhesin on the surface. In an immunoprecipitation assay, the antibody-conjugated MNPs reduced the incubation time from 12 to 1 h while maintaining a comparable efficiency. The functionalized MNPs were also used in a membrane proteomic study that utilized the interaction between streptavidin-functionalized MNPs and biotinylated cell membrane proteins. Overall, the functionalized MNPs were demonstrated to be promising probes for the specific separation of targets from proteins to cells and proteomics.

PMID:
 
23198853
 
[PubMed - in process]
6.

Nucleic Acids Res. 2013 Jan 1;41(D1):D295-305. doi: 10.1093/nar/gks1229. Epub 2012 Nov 27.

dbPTM 3.0: an informative resource for investigating substrate site specificity and functional association of protein post-translational modifications.

Source

Department of Computer Science and Engineering, Yuan Ze University, Gradulate Program in Biomedical Informatics, Yuan Ze University, Chung-Li 320, Institute of Tropical Plant Sciences, National Cheng Kung University, Tainan 701, Institute of Chemistry, Academia Sinica, Taipei 115, Institute of Bioinformatics and Systems Biology and Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu 300, Taiwan.

Abstract

Protein modification is an extremely important post-translational regulation that adjusts the physical and chemical properties, conformation, stability and activity of a protein; thus altering protein function. Due to the high throughput of mass spectrometry (MS)-based methods in identifying site-specific post-translational modifications (PTMs), dbPTM (http://dbPTM.mbc.nctu.edu.tw/) is updated to integrate experimental PTMs obtained from public resources as well as manually curated MS/MS peptides associated with PTMs from research articles. Version 3.0 of dbPTM aims to be an informative resource for investigating the substrate specificity of PTM sites and functional association of PTMs between substrates and their interacting proteins. In order to investigate the substrate specificity for modification sites, a newly developed statistical method has been applied to identify the significant substrate motifs for each type of PTMs containing sufficient experimental data. According to the data statistics in dbPTM, >60% of PTM sites are located in the functional domains of proteins. It is known that most PTMs can create binding sites for specific protein-interaction domains that work together for cellular function. Thus, this update integrates protein-protein interaction and domain-domain interaction to determine the functional association of PTM sites located in protein-interacting domains. Additionally, the information of structural topologies on transmembrane (TM) proteins is integrated in dbPTM in order to delineate the structural correlation between the reported PTM sites and TM topologies. To facilitate the investigation of PTMs on TM proteins, the PTM substrate sites and the structural topology are graphically represented. Also, literature information related to PTMs, orthologous conservations and substrate motifs of PTMs are also provided in the resource. Finally, this version features an improved web interface to facilitate convenient access to the resource.

PMID:
 
23193290
 
[PubMed - in process] 

Highlights

posted Jan 6, 2013, 6:34 PM by Lanyi Chang   [ updated Jan 13, 2013, 6:55 PM ]

1.

J Allergy Clin Immunol. 2012 Dec 28. pii: S0091-6749(12)01865-9. doi: 10.1016/j.jaci.2012.11.027. [Epub ahead of print]

Clara cell 10-kDa protein inhibits T(H)17 responses through modulating dendritic cells in the setting of allergic rhinitis.

Source

Department of Otolaryngology-Head and Neck Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

BACKGROUND:

T(H)17 responses have recently been implicated to play a role in allergic airway diseases, but their local expression in the setting of allergic rhinitis (AR) and their regulation in allergic airway diseases remain unclear.

OBJECTIVE:

We sought to investigate the regulatory role of Clara cell 10-kDa protein (CC10), an endogenous regulator of airway inflammation, on T(H)17 responses in the setting of AR.

METHODS:

Wild-type and homozygous CC10-null mice were used to establish an ovalbumin (OVA)-induced AR model. Human recombinant CC10 was given during sensitization or challenge. T(H)17 responses in human subjects and mice were examined by using flow cytometry, quantitative RT-PCR assay, immunohistochemistry, and ELISA. The direct effect of CC10 on T(H)17 cells and CD11c(+) dendritic cells (DCs) was studied by means of cell culture. Adoptive transfer was used to examine the influence of CC10-conditioned DCs on airway inflammation. The regulatory effect of CC10 on the expression of the CCL20 gene was tested by using the BEAS-2B cell line.

RESULTS:

Compared with those of control subjects, T(H)17 responses were enhanced in the nasal mucosa of patients with AR. CC10-null mice with AR showed enhanced T(H)17 responses, and CC10 treatment significantly decreased T(H)17 responses. CC10 had no direct effect on in vitro T(H)17 cell differentiation. CC10 could significantly decrease the expression of OX40 ligand, IL-23, and IL-6 but enhance CD86 and TGF-β expression in DCs. Importantly, CC10 was able to inhibit T(H)17 cell polarization in the presence of OVA-pulsed DCs. CC10 pretreatment inhibited T(H)17 responses elicited by adoptive transfer of OVA-pulsed DCs. Furthermore, CC10 decreased the expression of CCL20 in BEAS-2B cells induced by inflammatory cytokines.

CONCLUSION:

T(H)17 responses are enhanced in patients with AR, and CC10 inhibits T(H)17 responses through modulation of the function of DCs.

Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

PMID:
 
23273949
 
[PubMed - as supplied by publisher]
2.
Int J Biol Markers. 2012 Dec 13:0. doi: 10.5301/JBM.2012.10361. [Epub ahead of print]

Surface markers in stem cells and cancer from the perspective of glycomic analysis.

Source

Institute of Cellular and Organismic Biology, Academia Sinica, Taipei - Taiwan.

Abstract

Most cancers are detected when patients present with symptoms, and at that point the disease is usually quite advanced and often not curable. Therefore, new biomarkers are needed for detection and therapy. The recent success of using monoclonal antibodies against nonprotein gangliosides for the treatment of high-risk neuroblastoma provides an incentive to search for new glycan-targeted immunotherapies for cancer using markers found through glycomic analysis as targets. Since more than 85% of cell surface components are glycosylated, glycomic analysis is useful to probe systematically the cancer cell surface, in search for novel glycoproteins and glycolipids. Furthermore, cancer cells tend to dedifferentiate and express many oncofetoproteins, since human embryonic stem cells (ESCs) are derived from epiblast of embryo, representing the early stage of normal embryonic development before gastrulation. Unique ESC surface markers are likely to be found in cancer cells, but not in normal mature tissues. Moreover, stem cells and cancer cells share several common features in related regulatory mechanisms and signaling pathways. Thus, identification of the cancer stem cells in cancer and definition of the glycoproteomic changes that accompany their transformation are important for the development of strategies for early detection and treatment of cancer.

PMID:
 
23250773
 
[PubMed - as supplied by publisher]
3.
Blood. 2013 Jan 3;121(1):95-106. doi: 10.1182/blood-2012-05-430090. Epub 2012 Nov 14.

CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages.

Source

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan;

Abstract

Persistent high fever is one of the most typical clinical symptoms in dengue virus (DV)-infected patients. However, the source of endogenous pyrogen (eg, IL-1β) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1β and IL-18 secretion, during dengue infection have not been elucidated yet. Macrophages can be polarized into distinct phenotypes under the influence of GM-CSF or M-CSF, denoted as GM-Mϕ and M-Mϕ, respectively. We found that DV induced high levels of IL-1β and IL-18 from GM-Mϕ (inflammatory macrophage) and caused cell death (pyroptosis), whereas M-Mϕ (resting macrophage) did not produce IL-1β and IL-18 on DV infection even with lipopolysaccharide priming. This observation demonstrates the distinct responses of GM-Mϕ and M-Mϕ to DV infection. Moreover, up-regulation of pro-IL-1β, pro-IL-18, and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-Mϕ, whereas blockade of CLEC5A/MDL-1, a C-type lectin critical for dengue hemorrhagic fever and Japanese encephalitis virus infection, inhibits NLRP3 inflammasome activation and pyrotopsis in GM-Mϕ. Thus, DV can activate NLRP3 inflammasome via CLEC5A, and GM-Mϕ plays a more important role than M-Mϕ in the pathogenesis of DV infection.

PMID:
 
23152543
 
[PubMed - in process]
4.
Inflamm Res. 2013 Jan;62(1):89-96. doi: 10.1007/s00011-012-0555-2. Epub 2012 Sep 18.

Lipopolysaccharide/adenosine triphosphate-mediated signal transduction in the regulation of NLRP3 protein expression and caspase-1-mediated interleukin-1β secretion.

Source

Department of Biotechnology and Animal Science, National Ilan University, 1, Sec. 1, Shen-Lung Road, Ilan, 260, Taiwan.

Abstract

OBJECTIVE:

Reactive oxygen species (ROS) plays a critical role in the regulation of NLRP3 inflammasome activation. However, the ROS-mediated signaling pathways controlling NLRP3 inflammasome activation are not well defined.

METHODS:

Using lipopolysaccharide (LPS) and adenosine triphosphate (ATP) activated murine macrophages as the testing model, cytokine release and protein expression were quantified by enzyme-linked immunosorbent assay and Western blot, respectively. ROS was scavenged by N-acetyl cysteine; NADPH oxidase, the major source of ROS, was inhibited by diphenyliodonium, apocynin or gp91-phox siRNA transfection; and protein kinase was inhibited by its specific inhibitor.

RESULTS:

LPS-induced NLRP3 protein expression was regulated through the NADPH oxidase/ROS/NF-κB-dependent, JAK2/PI3-kinase/AKT/NF-κB-dependent, and MAPK-dependent pathways, while ATP-induced caspase-1 activation was regulated through the NADPH oxidase/ROS-dependent pathway.

CONCLUSIONS:

These results demonstrate that ROS regulates not only the priming stage, but also the activation stage, of NLRP3 inflammasome activation in LPS + ATP-activated macrophages.

PMID:
 
22986467
 
[PubMed - in process]
5.
Nat Prod Commun. 2012 Nov;7(11):1435-40.

Freshwater clam extract inhibits inflammatory responses in LPS-activated macrophages by reducing the activation of mitogen-activated protein kinases and NF-kappaB.

Source

Department of Biotechnology and Animal Science, National Ilan University, 1 Shen-Lung Rd., Ilan, Taiwan 260.

Abstract

Recent studies demonstrated that freshwater clam (Corbicula fluminea) has lipid-lowering and hepatoprotective activities, but its effect on immune responses has not yet been addressed. Here we showed that ethanol extracts of C. fluminea (ECF) reduced nitrite oxide, interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in lipopolysaccharide-activated macrophages. Further, ECF was fractionated into n-hexane, ethyl acetate, ethanol, and water soluble fractions. Of these, the ethyl acetate soluble fraction (EACF) had the highest capacity to inhibit pro-inflammatory mediators expression. The underlying mechanisms for the anti-inflammatory activity of EACF were demonstrated as down-regulation of ERK1/2, JNK1/2, and p38 phosphorylation and NF-kappaB activity. Using gas chromatography-mass spectrometric analysis EACF was found to be composed mainly of fatty acids and steroids. Our results provide evidence that freshwater clam has anti-inflammatory activity, and support the possibility for the development of freshwater clam as a health supplement or adjuvant therapeutic agent for either preventing or treating inflammation related diseases.

PMID:
 
23285802
 
[PubMed - in process]

Highlights

posted Jan 1, 2013, 6:12 PM by Lanyi Chang   [ updated Jan 6, 2013, 6:38 PM ]

1.
Glycobiology. 2013 Feb;23(2):144-6. doi: 10.1093/glycob/cws167.

The Third ACGG-DB Meeting Report: Towards an international collaborative infrastructure for glycobioinformatics.

Source

Department of Bioinformatics, Faculty of Engineering, Soka University, Japan.

PMID:
 
23271684
 
[PubMed - in process]
2.
Proc Natl Acad Sci U S A. 2012 Dec 24. [Epub ahead of print]

Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer.

Source

Institute of Biochemical Sciences, National Taiwan University, Taipei 106, Taiwan.

Abstract

The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial-mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.

PMID:
 
23267084
 
[PubMed - as supplied by publisher]
3.
J Clin Endocrinol Metab. 2012 Dec 21. [Epub ahead of print]

Prognostic Implications of miR-146b Expression and Its Functional Role in Papillary Thyroid Carcinoma.

Source

Division of Metabolism (C.-K.C., Y.-W.L., Y.-F.L., R.-T.L.), Department of Internal Medicine; Departments of Surgery (F.-F.C.) and Pathology (C.-C.H.), Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung Hsien, Taiwan; and Graduate Institute of Clinical Medical Sciences (C.-K.C., H.-Y.K.), Chang Gung University, Taiwan; and Department of Medical Research (K.D.Y.), Show Chwan Memorial Hospital in Chang Bing, Changhua, Taiwan.

Abstract

Context:Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model.Methodology:Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined.Results:Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis.Conclusions:Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC.

PMID:
 
23264400
 
[PubMed - as supplied by publisher]

Highlights

posted Dec 23, 2012, 6:32 PM by Lanyi Chang   [ updated Jan 6, 2013, 6:38 PM ]

1.
J Proteome Res. 2012 Dec 20. [Epub ahead of print]

Decoding the Disease-Associated Proteins Encoded in the Human Chromosome 4.

Source

Institute of Information Science, Academia Sinica , Taipei, Taiwan.

Abstract

Chromosome 4 is the fourth largest chromosome, containing approximately 191 megabases (∼6.4% of the human genome) with 757 protein-coding genes. A number of marker genes for many diseases have been found in this chromosome, including genetic diseases (e.g., hepatocellular carcinoma) and biomedical research (cardiac system, aging, metabolic disorders, immune system, cancer and stem cell) related genes (e.g., oncogenes, growth factors). As a pilot study for the chromosome 4-centric human proteome project (Chr 4-HPP), we present here a systematic analysis of the disease association, protein isoforms, coding single nucleotide polymorphisms of these 757 protein-coding genes and their experimental evidence at the protein level. We also describe how the findings from the chromosome 4 project might be used to drive the biomarker discovery and validation study in disease-oriented projects, using the examples of secretomic and membrane proteomic approaches in cancer research. By integrating with cancer cell secretomes and several other existing databases in the public domain, we identified 141 chromosome 4-encoded proteins as cancer cell-secretable/shedable proteins. Additionally, we also identified 54 chromosome 4-encoded proteins that have been classified as cancer-associated proteins with successful selected or multiple reaction monitoring (SRM/MRM) assays developed. From literature annotation and topology analysis, 271 proteins were recognized as membrane proteins while 27.9% of the 757 proteins do not have any experimental evidence at the protein-level. In summary, the analysis revealed that the chromosome 4 is a rich resource for cancer-associated proteins for biomarker verification projects and for drug target discovery projects.

PMID:
 
23256888
 
[PubMed - as supplied by publisher]
2.
J Infect Dis. 2012 Dec 18. [Epub ahead of print]

Galectin-3 regulates the innate immune response of human monocytes.

Source

Dirks/Dougherty Laboratory for Cancer Research, Department of Translational Immunology, John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA 90404.

Abstract

Galectin-3 is a β-galactoside binding lectin widely expressed on epithelial and hematopoietic cells and its expression is frequently associated with a poor prognosis in cancer. Since it has not been well-studied in human infectious disease, we examined galectin-3 expression in mycobacterial infection by studying leprosy, an intracellular infection caused by Mycobacterium leprae. Galectin-3 was highly expressed on macrophages in lesions of patients with the clinically progressive lepromatous form of leprosy; in contrast, galectin-3 was almost undetectable in self-limited tuberculoid lesions. We investigated the potential function of galectin-3 in cell-mediated immunity using peripheral blood monocytes. Galectin-3 enhanced monocyte IL-10 production to a TLR2/1 ligand, while IL-12p40 secretion was unaffected. Furthermore, galectin-3 diminished monocyte to DC differentiation and T cell antigen presentation. These data demonstrate an association of galectin-3 with unfavorable host response in leprosy and a potential mechanism for impaired host defense in humans.

PMID:
 
23255567
 
[PubMed - as supplied by publisher]

3.
Glycobiology. 2012 Dec 18. [Epub ahead of print]

KSGal6ST Generates Galactose-6-O-Sulfate in High Endothelial Venules but Does Not Contribute to L-Selectin Dependent Lymphocyte Homing.

Source

Department of Anatomy and Program in Biomedical Sciences, University of California, San Francisco, California 94143-0452, USA.

Abstract

The addition of sulfate to glycan structures can regulate their ability to serve as ligands for glycan-binding proteins. While sulfate groups present on the monosaccharides glucosamine, uronate, N-acetylglucosamine, and N-acetylgalactosamine are recognized by defined receptors that mediate important functions, the functional significance of galactose-6-O-sulfate (Gal6S) is not known. However, in vitro studies using synthetic glycans and sulfotransferase overexpression implicate Gal6S as a binding determinant for the lymphocyte homing receptor, L-selectin. Only two sulfotransferases have been shown to generate Gal6S, namely keratan sulfate galactose 6-O-sulfotransferase (KSGal6ST) and chondroitin 6-O-sulfotransferase-1 (C6ST-1). In the present study, we use mice deficient in KSGal6ST and C6ST-1 to test whether Gal6S contributes to ligand recognition by L-selectin in vivo. First, we establish that KSGal6ST is selectively expressed in high endothelial venules (HEVs) in lymph nodes and Peyer's patches. We also determine by mass spectrometry, that KSGal6ST generates Gal6S on several classes of O-glycans in peripheral lymph nodes. Furthermore, KSGal6ST but not C6ST-1 is required for the generation of the Gal6S-containing glycan, 6,6'-disulfo-3'sLN (Siaα2→3[6S]Galβ1→4[6S]GlcNAc) or a closely related structure in lymph node HEVs. Nevertheless, L-selectin-dependent short-term homing of lymphocytes is normal in KSGal6ST-deficient mice, indicating that the Gal6S-containing structures we detected do not contribute to L-selectin ligand recognition in this setting. These results refine our understanding of the biological ligands for L-selectin and introduce a mouse model for investigating the functions of Gal6S in other contexts.

PMID:
 
23254996
 
[PubMed - as supplied by publisher]
4.
Int J Biol Markers. 2012 Dec 13:0. doi: 10.5301/JBM.2012.10361. [Epub ahead of print]

Surface markers in stem cells and cancer from the perspective of glycomic analysis.

Source

Institute of Cellular and Organismic Biology, Academia Sinica, Taipei - Taiwan.

Abstract

Most cancers are detected when patients present with symptoms, and at that point the disease is usually quite advanced and often not curable. Therefore, new biomarkers are needed for detection and therapy. The recent success of using monoclonal antibodies against nonprotein gangliosides for the treatment of high-risk neuroblastoma provides an incentive to search for new glycan-targeted immunotherapies for cancer using markers found through glycomic analysis as targets. Since more than 85% of cell surface components are glycosylated, glycomic analysis is useful to probe systematically the cancer cell surface, in search for novel glycoproteins and glycolipids. Furthermore, cancer cells tend to dedifferentiate and express many oncofetoproteins, since human embryonic stem cells (ESCs) are derived from epiblast of embryo, representing the early stage of normal embryonic development before gastrulation. Unique ESC surface markers are likely to be found in cancer cells, but not in normal mature tissues. Moreover, stem cells and cancer cells share several common features in related regulatory mechanisms and signaling pathways. Thus, identification of the cancer stem cells in cancer and definition of the glycoproteomic changes that accompany their transformation are important for the development of strategies for early detection and treatment of cancer.

PMID:
 
23250773
 
[PubMed - as supplied by publisher]
5.

J Am Chem Soc. 2012 Dec 14. [Epub ahead of print]

Divergent Synthesis of 48 Heparan Sulfate-Based Disaccharides and Probing the Specific Sugar-Fibroblast Growth Factor-1 Interaction.

Source

Genomics Research Center and §Institute of Chemistry, Academia Sinica , 128, Section 2, Academia Road, Taipei 115, Taiwan.

Abstract

Several biological processes involve glycans, yet understanding their ligand specificities is impeded by their inherent diversity and difficult acquisition. Generating broad synthetic sugar libraries for bioevaluations is a powerful tool in unraveling glycan structural information. In the case of the widely distributed heparan sulfate (HS), however, the 48 theoretical possibilities for its repeating disaccharide call for synthetic approaches that should minimize the effort in an undoubtedly huge undertaking. Here we employed a divergent strategy to afford all 48 HS-based disaccharides from just two orthogonally protected disaccharide precursors. Different combinations and sequence of transformation steps were applied with many downstream intermediates leading up to multiple target products. With the full disaccharide library in hand, affinity screening with fibroblast growth factor-1 (FGF-1) revealed that four of the synthetic sugars bind to FGF-1. The molecular details of the interaction were further clarified through X-ray analysis of the sugar-protein cocrystals. The capability of comprehensive sugar libraries in providing key insights in glycan-ligand interaction is, thus, highlighted.

PMID:
 
23240683
 
[PubMed - as supplied by publisher]

Highlights

posted Dec 16, 2012, 5:47 PM by Lanyi Chang


1.

Chemistry. 2012 Dec 11. doi: 10.1002/chem.201203418. [Epub ahead of print]

Highly Stereoselective Glycosyl-Chloride-Mediated Synthesis of 2-Deoxyglucosides.

Source

Institute of Chemistry, Academia Sinica, Nankang, Taipei 115 (Taiwan), Fax: (+886) 2-27831237; Genomics Research Center, Academia Sinica, Nankang, Taipei 115 (Taiwan).

Abstract

Cl intermediates: The glycosylation of per-O-benzylated 2-deoxy- and 2,6-dideoxythioglycosides, promoted by the combination of para-toluenesulfenyl chloride (p-TolSCl) and silver triflate (AgOTf), furnished the products in high yields and high stereoselectivity. The glycosyl chloride was the intermediate..

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
 
23233443
 
[PubMed - as supplied by publisher]
2.

Chemistry. 2012 Dec 11. doi: 10.1002/chem.201203251. [Epub ahead of print]

Rapid Preparation of Mycobacterium N-Glycolyl Lipid I and Lipid II Derivatives: A Biocatalytic Approach.

Source

Genomics Research Center, Academia Sinica, 128 Academia Road, Section 2, Nankang,Taipei, 115 (Taiwan); Department of Pharmacy, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 10051 (Taiwan).

Abstract

Breaking down barriers: A rapid, inexpensive preparation of the structurally complex mycobacterial N-glycolyl Lipid I, Lipid II, and their analogues from a range of different synthetic N-glycolyl and N-glycinyl Park's nucleotides is described. The biotransformations were catalyzed by a readily available biocatalyst obtained from a bacterial cell-free membrane fraction. The unnatural N-glycinyl Lipid II was found to be a substrate of Mycobacterium tuberculosis (Mtb) transglycosylase, PonA, and N-glycolyl Lipid I was a weak inhibitor against PonA.

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
 
23229320
 
[PubMed - as supplied by publisher]

Highlights

posted Dec 9, 2012, 6:19 PM by Lanyi Chang   [ updated Jan 6, 2013, 6:37 PM ]

1.


Biomacromolecules. 2012 Dec 3. [Epub ahead of print]

A Chemically Functionalized Magnetic Nanoplatform for Rapid and Specific Biomolecular Recognition and Separation.

Abstract

We have developed a target-molecule-functionalized magnetic nanoparticle (MNP)-based method to facilitate the study of bio-molecular recognition and separation. The superparamagnetic property of MNPs allows the corresponding biomolecules to be rapidly separated from crude biofluids with a significant improvement in recovery yield and specificity. Various MNPs functionalized with tag molecules (chitin, heparin, and amylose) were synthesized for recombinant protein purification, and several probe-functionalized MNPs, such as nitrilotriacetic acid (NTA)@MNP and Pk@MNP, exhibited excellent extraction efficiency for proteins. In a cell recognition study, mannose-functionalized MNPs allowed specific purification of Escherichia coli with FimH adhesion on the surface. In an immunoprecipitation assay, the antibody-conjugated MNPs reduced the incubation time from 12 hours to 1 hour while maintaining a comparable efficiency. The functionalized MNPs were also used in a membrane proteomic study that utilized the interaction between streptavidin-functionalized MNPs and biotinylated cell membrane proteins. Overall, the functionalized MNPs were demonstrated to be promising probes for the specific separation of targets from proteins to cells and proteomics.

PMID:
 
23198853
 
[PubMed - as supplied by publisher]
2.

PLoS One. 2012;7(11):e50337. doi: 10.1371/journal.pone.0050337. Epub 2012 Nov 28.

The impact of influenza vaccinations on the adverse effects and hospitalization rate in the elderly: a national based study in an asian country.

Source

Department of Otolaryngology, Buddhist Dalin Tzu Chi General Hospital, Chiayi, Taiwan.

Abstract

OBJECTIVES:

To examine the risk of adverse effects of special interest in persons vaccinated against seasonal influenza compared with unvaccinated persons aged 65 and above.

METHODS:

We retrospectively observed 41,986 vaccinated elderly persons and 50,973 unvaccinated elderly persons in Taiwan from October 1, 2008, through September 30, 2009, using the National Health Insurance database. Neurological and autoimmune disorders and one-year hospitalization rates and in-hospital mortality rates were analyzed according to the vaccination status. Propensity score analysis was used to assess the relationship between adverse outcomes, hospitalization rates, and vaccination status.

RESULTS:

45% of the elderly received influenza vaccination. Multiple logistic regression showed that the probability of being vaccinated was related to more patients visiting for URI symptoms (odds ratio (OR), 1.03; 95% CI, 1.02-1.03), men (OR, 1.15; 95% CI, 1.12-1.17), increased age (OR, 1.02; 95% CI, 1.02-1.03), and more comorbidities (OR, 1.2; 95% CI, 1.17-1.23). There were no statistical differences in neurological and autoimmune diseases between the vaccinated and unvaccinated individuals using propensity score analysis, but vaccinated persons had a reduced hospitalization rate of 19% (odds ratio [OR], 0.81; 95% CI, 0.77-0.84) for the first six-months and 13% for one-year of follow-up (OR, 0.87; 95% CI, 0.85-0.9).

CONCLUSIONS:

Based on data from the one-year follow-ups among 93,049 elderly persons in Taiwan, reassuring results for selected neurological and autoimmune diseases were found among the vaccinated individuals after adjusting other factors. Influenza vaccination decreased the risk for hospitalization. Public health strategies must continue to improve the influenza vaccination rate among the elderly with information based upon tangible evidence.

PMID:
 
23209714
 
[PubMed - in process] 
Free PMC Article
3.

Beilstein J Org Chem. 2012;8:1601-9. doi: 10.3762/bjoc.8.183. Epub 2012 Sep 21.

Automated synthesis of sialylated oligosaccharides.

Source

Max-Planck-Institute of Colloids and Interfaces, Department of Biomolecular Systems, Am Mühlenberg 1, 14476 Potsdam, Germany ; Freie Universität Berlin, Institute of Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin, Germany.

Abstract

Sialic acid-containing glycans play a major role in cell-surface interactions with external partners such as cells and viruses. Straightforward access to sialosides is required in order to study their biological functions on a molecular level. Here, automated oligosaccharide synthesis was used to facilitate the preparation of this class of biomolecules. Our strategy relies on novel sialyl α-(2→3) and α-(2→6) galactosyl imidates, which, used in combination with the automated platform, provided rapid access to a small library of conjugation-ready sialosides of biological relevance.

PMID:
 
23209492
 
[PubMed - in process] 
Free PMC Article

Highlights

posted Nov 28, 2012, 2:32 AM by Lanyi Chang   [ updated Nov 28, 2012, 2:39 AM ]


1.
Proteome Sci. 2012 Nov 21;10(1):69. [Epub ahead of print]

Label-free quantitative proteomics of CD133-positive liver cancer stem cells.

Abstract

ABSTRACT:

BACKGROUND: CD133-positive liver cancer stem cells, which are characterized by their resistance to conventional chemotherapy and their tumor initiation ability at limited dilutions, have been recognized as a critical target in liver cancer therapeutics. In the current work, we developed a label-free quantitative method to investigate the proteome of CD133-positive liver cancer stem cells for the purpose of identifying unique biomarkers that can be utilized for targeting liver cancer stem cells. Label-free quantitation was performed in combination with ID-based Elution time Alignment by Linear regression Quantitation (IDEAL-Q) and MaxQuant.

RESULTS:

Initially, IDEAL-Q analysis revealed that 151 proteins were differentially expressed in the CD133-positive hepatoma cells when compared with CD133-negative cells. We then analyzed these 151 differentially expressed proteins by MaxQuant software and identified 10 significantly up-regulated proteins. The results were further validated by RT-PCR, western blot, flow cytometry or immunofluorescent staining which revealed that prominin-1, annexin A1, annexin A3, transgelin, creatine kinase B, vimentin, and EpCAM were indeed highly expressed in the CD133-positive hepatoma cells.

CONCLUSIONS:

These findings confirmed that mass spectrometry-based label-free quantitative proteomics can be used to gain insights into liver cancer stem cells.

PMID:
 
23170877
 
[PubMed - as supplied by publisher] 
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2.
Blood. 2012 Nov 14. [Epub ahead of print]

CLEC5A is critical for dengue virus-induced inflammasome activation in human macrophages.

Source

Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan;

Abstract

Persistent high fever is one of the most typical clinical symptoms in dengue virus (DV)-infected patients. However, the source of endogenous pyrogen (such as IL-1β) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1β and IL-18 secretion, during dengue infection have not been elucidated yet. Macrophages can be polarized into distinct phenotypes under the influence of GM-CSF or M-CSF, denoted as GM-Mϕ and M-Mϕ, respectively. We found that DV induced high levels of IL-1β and IL-18 from GM-Mϕ (inflammatory macrophage) and caused cell death (pyroptosis), while M-Mϕ (resting macrophage) did not produce IL-1β and IL-18 upon DV infection even with LPS priming. This observation demonstrates the distinct responses of GM-Mϕ and M-Mϕ to DV infection. Moreover, upregulation of pro-IL-1β, pro-IL-18 and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-Mϕ, while blockade of CLEC5A/MDL-1, a C-type lectin critical for dengue hemorrhagic fever (DHF) and Japanese encephalitis virus (JEV) infection, inhibits NLRP3 inflammasome activation and pyrotopsis in GM-Mϕ. Thus DV can activate NLRP3 inflammasome via CLEC5A, and GM-Mϕ play more important role than M-Mϕ in the pathogenesis of DV infection.

PMID:
 
23152543
 
[PubMed - as supplied by publisher]
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3.
Angew Chem Int Ed Engl. 2012 Nov 13. doi: 10.1002/anie.201204062. [Epub ahead of print]

Chemical Probes for Drug-Resistance Assessment by Binding Competition (RABC): Oseltamivir Susceptibility Evaluation.

Source

The Genomics Research Center, Academia Sinica, Taipei, 11529 (Taiwan).

Abstract

The wizard of OS (resistance): The binding difference of neuraminidase inhibitors (zanamivir versus oseltamivir (OS)) was used to establish an assay to identify the influenza subtypes that are resistant to OS but still sensitive to zanamivir. This assay used a zanamivir-biotin conjugate to determine the OS susceptibility of a wide range of influenza viruses and over 200 clinical isolates.

Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PMID:
 
23150231
 
[PubMed - as supplied by publisher]
Icon for John Wiley & Sons, Inc.
4.
Chem Commun (Camb). 2012 Nov 5. [Epub ahead of print]

Rapid synthesis of oligomannosides with orthogonally protected monosaccharides.

Source

Institute of Biochemical Sciences, National Taiwan University, Taipei 10617, Taiwan.

Abstract

We developed a facile synthesis to yield orthogonally protected mannose building blocks with high overall yields. The protection/glycosylation steps can be carried out in a successive manner without purification of intermediate products. This developed synthesis led to formation of linear/branched tri-, penta- and heptasaccharides.

PMID:
 
23124079
 
[PubMed - as supplied by publisher]
Icon for Royal Society of Chemistry
5.
J Dermatol Sci. 2012 Dec;68(3):187-93. doi: 10.1016/j.jdermsci.2012.09.015. Epub 2012 Oct 8.

Sialic acid cyclization of human Th homing receptor glycan associated with recurrent exacerbations of atopic dermatitis.

Source

Division of Molecular Pathology, Aichi Cancer Center, Nagoya, Aichi 464-8681, Japan.

Abstract

BACKGROUND:

The molecular pathogenesis underlying recurrent exacerbations of atopic dermatitis (AD) is unclear. Some peripheral CCR4(+) and CCR7(+) helper memory T cells express the specific homing receptor, sialyl 6-sulfo Lewis X (G152 glycan). This glycan loses receptor activity via cyclization of its sialic acid moiety, thus becoming cyclic sialyl 6-sulfo Lewis X (G159 glycan). These findings suggest that the disordered expression of G152 and G159 glycans may be associated with recurrent exacerbations of AD.

OBJECTIVE:

To assess the possible association of G152 and G159 glycans, which are expressed on peripheral helper T (Th) cells, with frequency of exacerbations.

METHODS:

The percentage of glycan-expressing cells among peripheral blood CD4(+)CD45RO(+) lymphocytes was determined by flow cytometry. The association of glycans with the frequency of exacerbations determined by recurrence scores as well as with current disease activity was statistically tested.

RESULTS:

Current disease activity was significantly associated with CCR4(+)CCR7(-) memory Th cells expressing CSLEX-1 glycan, the conventional skin-trafficking receptor without sialic-acid-cyclization activity. In contrast, the frequency of exacerbations was positively and negatively associated with CCR4(+)CCR7(+) memory Th cells expressing G152 and G159 glycans, respectively. Receiver operating characteristics analyses indicated that the ratio of the G152(+)/G159(+) cell percentages discriminated patients with highly recurrent AD with the best accuracy.

CONCLUSION:

Flow cytometric determination of G159 and G152 glycans on peripheral helper memory T cells may be clinically useful for identifying patients with highly recurrent AD. Disordered sialic acid cyclization of G152 glycan may underlie highly recurrent AD, which may provide a novel therapeutic approach.

Copyright © 2012 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

PMID:
 
23088960
 
[PubMed - in process]
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6.
J Am Chem Soc. 2012 Sep 26;134(38):16074-9. Epub 2012 Sep 18.

Stereoselective synthesis of S-linked α(2→8) and α(2→8)/α(2→9) hexasialic acids.

Source

Department of Chemistry, National Tsing Hua University, 101 Section 2, Kuang Fu Road, Hsinchu 30013, Taiwan.

Abstract

A new approach for the synthesis of S-linked α(2→8) and alternating α(2→8)/α(2→9) oligosialic acids by S-alkylation has been developed, using chemo- and stereoselective alkylation of a C2-thiolated sialoside donor (nucleophile) with either a C8- or C9-iodide-activated sialoside acceptor (electrophile). An efficient intramolecular acetyl group migration from the C7 to C9-position of the sialoside under mild basic conditions was used to generate the C8-iodide, the key sialyl acceptor (electrophile). Using this strategy, the syntheses of S-linked α(2→8) and α(2→8)/α(2→9) hexasialic acids were achieved.

PMID:
 
22957651
 
[PubMed - in process]
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