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Montanini B.,Protein Genomics | Chen P.-Y.,Academia Sinica, Taiwan | Chen P.-Y.,University of California | Morselli M.,Protein Genomics | And 6 more authors.
Genome Biology | Year: 2014

Background: We investigated how an extremely transposon element (TE)-rich organism such as the plant-symbiotic ascomycete truffle Tuber melanosporum exploits DNA methylation to cope with the more than 45,000 repeated elements that populate its genome. Results: Whole-genome bisulfite sequencing performed on different developmental stages reveals a high fraction of methylated cytosines with a strong preference for CpG sites. The methylation pattern is highly similar among samples and selectively targets TEs rather than genes. A marked trend toward hypomethylation is observed for TEs located within a 1 kb distance from expressed genes, rather than segregated in TE-rich regions of the genome. Approximately 300 hypomethylated or unmethylated TEs are transcriptionally active, with higher expression levels in free-living mycelium compared to fruitbody. Indeed, multiple TE-enriched, copy number variant regions bearing a significant fraction of hypomethylated and expressed TEs are found almost exclusively in free-living mycelium. A reduction of DNA methylation, restricted to non-CpG sites and accompanied by an increase in TE expression, is observed upon treatment of free-living mycelia with 5-azacytidine. Conclusions: Evidence derived from analysis of the T. melanosporum methylome indicates that a non-exhaustive, partly reversible, methylation process operates in truffles. This allows for the existence of hypomethylated, transcriptionally active TEs that are associated with copy number variant regions of the genome. Non-exhaustive TE methylation may reflect a role of active TEs in promoting genome plasticity and the ability to adapt to sudden environmental changes. © 2014 Montanini et al.; licensee BioMed Central Ltd.

Schaefer C.,Columbia University | Schaefer C.,Institute of Advanced Studies IAS | Schlessinger A.,University of California at San Francisco | Rost B.,Columbia University | And 2 more authors.
Bioinformatics | Year: 2010

Motivation: The mutation of amino acids often impacts protein function and structure. Mutations without negative effect sustain evolutionary pressure. We study a particular aspect of structural robustness with respect to mutations: regular protein secondary structure and natively unstructured (intrinsically disordered) regions. Is the formation of regular secondary structure an intrinsic feature of amino acid sequences, or is it a feature that is lost upon mutation and is maintained by evolution against the odds? Similarly, is disorder an intrinsic sequence feature or is it difficult to maintain? To tackle these questions, we in silico mutated native protein sequences into random sequence-like ensembles and monitored the change in predicted secondary structure and disorder. Results: We established that by our coarse-grained measures for change, predictions and observations were similar, suggesting that our results were not biased by prediction mistakes. Changes in secondary structure and disorder predictions were linearly proportional to the change in sequence. Surprisingly, neither the content nor the length distribution for the predicted secondary structure changed substantially. Regions with long disorder behaved differently in that significantly fewer such regions were predicted after a few mutation steps. Our findings suggest that the formation of regular secondary structure is an intrinsic feature of random amino acid sequences, while the formation of long-disordered regions is not an intrinsic feature of proteins with disordered regions. Put differently, helices and strands appear to be maintained easily by evolution, whereas maintaining disordered regions appears difficult. Neutral mutations with respect to disorder are therefore very unlikely. Contact: Supplementary Information: Supplementary data are available at Bioinformatics online. © The Author(s) 2010. Published by Oxford University Press.

Ruotolo R.,Protein Genomics | Calani L.,University of Parma | Fietta E.,Protein Genomics | Brighenti F.,University of Parma | And 5 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2013

Background and aims: Resveratrol, the most investigated dietary compound in studies aimed at linking wine consumption to human health, is an extremely minor component of this beverage and it is generally studied invitro as the unconjugated aglycone at concentrations largely exceeding those found in the human circulatory system after dietary intake. Moreover, following intestinal absorption, trans-resveratrol and its glucoside, which are naturally present in wine and other food sources, are converted to sulphate and glucuronide metabolites. An estrogenic activity has previously been documented for resveratrol, yet nothing is known about the activity of its blood-circulating metabolic derivatives. Methods and results: Using a yeast two-hybrid detection system relying on the interaction between the ligand-binding domain of the human oestrogen receptors α and β and the human coactivator Tif2, we have systematically examined the oestrogen agonist and antagonist activities of the two main resveratrol forms present in planta (trans-resveratrol and trans-resveratrol-3 O-glucoside) and of the three main metabolites found in human plasma (trans-resveratrol-3 O-sulphate, trans-resveratrol-3 O-glucuronide and trans-resveratrol-4' O-glucuronide). Only resveratrol-3 O-sulphate was found to display a fairly strong and oestrogen receptor α-preferential antagonistic activity, which was confirmed in a human breast adenocarcinoma cell line containing a luciferase reporter gene under the control of an oestrogen-responsive promoter. Conclusions: We show, for the first time, that resveratrol-3 O-sulphate, but neither of its metabolites, is endowed with anti-estrogenic activity and how human metabolism of phenolic substances plays a pivotal role in modulating their biological effect. © 2013 Elsevier B.V.

Kim N.H.,Protein Genomics | Jung H.J.,Protein Genomics | Shibasaki F.,Tokyo Metropolitan Institute of Medical Science | Kwon H.J.,Protein Genomics
Biochemical and Biophysical Research Communications | Year: 2010

Nuclear factor-κB (NF-κB) is a crucial transcription factor that contributes to cancer development by regulating a number of genes involved in angiogenesis and tumorigenesis. Here, we describe (Z)-N-(3-(7-nitro-3-oxobenzo[d][1,2]selenazol-2(3H)-yl)benzylidene)propa n-2-amine oxide (NBBA) as a new anti-angiogenic small molecule that targets NF-κB activity. NBBA showed stronger growth inhibition on human umbilical vein endothelial cells (HUVECs) than on the cancer cell lines we tested. Moreover, NBBA inhibited tumor necrosis factor-alpha (TNF-α)-induced tube formation and invasion of HUVECs. In addition, NBBA suppressed the neovascularization of chorioallantonic membrane from growing chick embryos in vivo. To address the mode of action of the compound, the effect of NBBA on TNF-α-induced NF-κB transcription activity was investigated. NBBA suppressed TNF-α-induced c-Jun N-terminal kinase phosphorylation, which resulted in suppression of transcription of NF-κB and its target genes, including interleukin-8, interleukin-1α, and epidermal growth factor. Collectively, these results demonstrated that NBBA is a new anti-angiogenic small molecule that targets the NF-κB signaling pathway. © 2009 Elsevier Inc. All rights reserved.

Kim J.H.,Protein Genomics | Kim J.H.,Max Planck Institute for Biophysical Chemistry | Alderson T.R.,University of Wisconsin - Madison | Frederick R.O.,Protein Genomics | And 2 more authors.
Journal of the American Chemical Society | Year: 2014

The structural mechanism by which Hsp70-type chaperones interact with Hsp40-type co-chaperones has been of great interest, yet still remains a matter of debate. Here, we used solution NMR spectroscopy to investigate the ATP-/ADP-dependent interactions between Escherichia coli HscA and HscB, the specialized Hsp70/Hsp40 molecular chaperones that mediate iron-sulfur cluster transfer. We observed that NMR signals assigned to amino acid residues in the J-domain and its HPD motif of HscB broadened severely upon the addition of ATP-bound HscA, but these signals were not similarly broadened by ADP-bound HscA or the isolated nucleotide binding domain of HscA complexed with either ATP or ADP. An HscB variant with an altered HPD motif, HscB(H32A,P33A,D34A), failed to manifest WT-like NMR signal perturbations and also abolished WT-like stimulation of ATP hydrolysis by HscA. In addition, residues 153-171 in the C-terminal region of HscB exhibited NMR signal perturbations upon interaction with HscA, alone or complexed with ADP or ATP. These results demonstrate that the HPD motif in the J-domain of HscB directly interacts with ATP-bound HscA and suggest that a second, less nucleotide-dependent binding site for HscA resides in the C-terminal region of HscB. © 2014 American Chemical Society.

Godfrey D.I.,University of Melbourne | Pellicci D.G.,University of Melbourne | Patel O.,Protein Genomics | Kjer-Nielsen L.,University of Melbourne | And 2 more authors.
Seminars in Immunology | Year: 2010

αβ T cell receptors (TCRs) have traditionally been viewed as receptors for peptide antigens presented by either Major Histocompatibility Complex (MHC) class I (for CD8 T cells) or MHC class II (for CD4 T cells) antigen-presenting molecules. However, it is now clear that some T cell lineages express TCRs that are specialized for recognition of lipid-based antigens presented by the MHC class I-like CD1 family. Recently, the molecular basis for the TCR recognition of glycolipid antigens presented by CD1d has revealed an evolutionarily conserved-docking mode that is distinct from that of peptide-based recognition. T cells carrying these receptors follow a unique developmental pathway that results not only in unconventional antigen specificity, but also seemingly exaggerated functional capabilities, which makes these cells and their antigens highly attractive targets for immunotherapeutic manipulation. © 2009 Elsevier Ltd. All rights reserved.

Choi I.-K.,Protein Genomics | Cho Y.S.,Protein Genomics | Jung H.J.,Protein Genomics | Kwon H.J.,Protein Genomics
Biochemical and Biophysical Research Communications | Year: 2010

Autophagy is an apoptosis-independent mechanism of cell death that protects the cell from environmental imbalances and infection by pathogens. We identified a novel small molecule, 2-(3-Benzyl-4-oxo-3,4,5,6,7,8-hexahydro-benzo[4,5]thieno[2,3-d]pyrimidin -2-ylsulfanylmethyl)-oxazole-4-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide (referred as autophagonizer), using high-content cell-based screening and the autophagosome marker EGFP-LC3. Autophagonizer inhibited growth and induced cell death in the human tumor cell lines MCF7, HeLa, HCT116, A549, AGS, and HT1080 via a caspase-independent pathway. Conversion of cytosolic LC3-I to autophagosome-associated LC3-II was greatly enhanced by autophagonizer treatment. Transmission electron microscopy and acridine orange staining revealed increased autophagy in the cytoplasm of autophagonizer-treated cells. In conclusion, autophagonizer is a novel autophagy inducer with unique structure, which induces autophagic cell death in the human tumor cell lines. © 2010 Elsevier Inc. All rights reserved.

Agency: National Science Foundation | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 199.21K | Year: 2010

This Small Business Innovation Research (SBIR) Phase I project proposes to make new blood vessels by using a synthesized human protein as a guide for growing human cells into tissues. The guide will be molded into a tubular shape. The protein, a water soluble form of human elastin can be produced by fermentation and will be purified, mixed with a catalyst and cast into tubular shaped molds made of glass or plastic. After the protein has set up in the tubular mold, it will be removed, tested for its strength and ability to stretch, and mixed with human epithelial cells in tissue culture media. The cells will be allowed to grow on and within the solidified protein to form a combination of a strong, elastic vessel surrounded by layers of human cells. The broader impacts of this research are the availability of new and better performing blood vessel material for dialysis patients. Dialysis patients experience problems with damage to their blood vessels during the dialysis procedure. These complications currently cost a total of $1.5 billion extra. Reducing the costs, pain and complications by using a new vascular material represents a large benefit to patients and physicians.

Protein Genomics | Date: 2012-09-28

The present invention relates to biocompatible polymeric scaffold materials, methods for making the materials and methods of using the materials. More particularly, the present invention relates to implants and grafts comprising polymeric scaffold materials of cross-linked human tropoelastin polypeptides and methods of making and using the same. In addition, the present invention provides alternatively spliced tropoelastin polynucleotides and polypeptides.

Protein Genomics | Date: 2010-06-01

Cosmetic preparations for skin renewal.

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