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Yang Z.,University of Rochester | Yang Z.,Joint Center for Biosciences | Hayes J.J.,University of Rochester
Biochemistry | Year: 2011

We previously reported that reconstituted nucleosomes undergo sequence-dependent translational repositioning upon removal of the core histone tail domains under physiological conditions, indicating that the tails influence the choice of position. We report here that removal of the core histone tail domains increases the exposure of the DNA backbone in nucleosomes to hydroxyl radicals, a nonbiased chemical cleavage reagent, indicative of an increase in the motility of the DNA on the histone surface. Moreover, we demonstrate that the divalent cations Mg 2+ and Ca 2+ can replace the role of the tail domains with regard to stabilization of histone-DNA interactions within the nucleosome core and restrict repositioning of nucleosomes upon tail removal. However, when nucleosomes were incubated with Mg 2+ after tail removal, the original distribution of translational positions was not re-established, indicating that divalent cations increase the energy barrier between translational positions rather than altering the free energy differences between positions. Interestingly, other divalent cations such as Zn 2+, Fe 2+, Co 2+, and Mn 2+ had little or no effect on the stability of histone-DNA interactions within tailless nucleosomes. These results support the idea that specific binding sites for Mg 2+ and Ca 2+ ions exist within the nucleosome and play a critical role in nucleosome stability that is partially redundant with the core histone tail domains. © 2011 American Chemical Society.


Shon S.-M.,Dongguk University | Choi Y.,National Cancer Center | Kim J.-Y.,Dongguk University | Lee D.K.,Joint Center for Biosciences | And 3 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2013

Objective-To investigate whether an intravenously injected cathepsin-B activatable theranostic agent (L-SR15) would be cleaved in and release a fluorescent agent (chlorin-e6) in mouse atheromata, allowing both the diagnostic visualization and therapeutic application of these fluorophores as photosensitizers during photodynamic therapy to attenuate plaquedestabilizing cathepsin-B activity by selectively eliminating macrophages. Approach and Results-Thirty-week-old apolipoprotein E knock-out mice (n=15) received intravenous injection of L-SR15 theranostic agent, control agent D-SR16, or saline 3× (D0, D7, D14). Twenty-four hours after each injection, the bilateral carotid arteries were exposed, and Cy5.5 near-infrared fluorescent imaging was performed. Fluorescent signal progressively accumulated in the atheromata of the L-SR15 group animals only, indicating that photosensitizers had been released from the theranostic agent and were accumulating in the plaque. After each imaging session, photodynamic therapy was applied with a continuous-wave diode-laser. Additional near-infrared fluorescent imaging at a longer wavelength (Cy7) with a cathepsin-B-sensing activatable molecular imaging agent showed attenuation of cathepsin- B-related signal in the L-SR15 group. Histological studies demonstrated that L-SR15-based photodynamic therapy decreased macrophage infiltration by inducing apoptosis without significantly affecting plaque size or smooth muscle cell numbers. Toxicity studies (n=24) showed that marked erythematous skin lesion was generated in C57/BL6 mice at 24 hours after intravenous injection of free chlorin-e6 and ultraviolet light irradiation; however, L-SR15 or saline did not cause cutaneous phototoxicity beyond that expected of ultraviolet irradiation alone, neither did we observe systemic toxicity or neurobehavioral changes. Conclusions-This is the first study showing that macrophage-secreted cathepsin-B activity in atheromata could be attenuated by photodynamic therapy using a protease-mediated theranostic agent. © 2013 American Heart Association, Inc.


Valera E.,La Jolla Salk Institute | Valera E.,Joint Center for Biosciences | Isaacs M.J.,Joint Center for Biosciences | Kawakami Y.,La Jolla Salk Institute | And 4 more authors.
PLoS ONE | Year: 2010

Background Bone Morphogenetic Protein (BMP) signaling pathways are involved in differentiation of stem cells into diverse cell types, and thus BMPs can be used as main guidance molecules for in vitro differentiation of human stem cells. Methodology/Principal Findings We have analyzed the ability for inducing differentiation of the heterodimer BMP-2/BMP-6 (BMP-2/6) compared to the homodimers BMP-2 or BMP-6, using human embryonic stem (hES) cells H9 as model system. When incubated in a medium with high concentration of basic fibroblastic growth factor (FGF2), 100 ng/ml of human recombinant BMPs induced morphological changes and differentiation of hES cells in 24 to 48 hours. After 5 days, expression of differentiation markers was induced and quantified by quantitative PCR (qPCR) and flow cytometry. BMP-2/6 exhibited stronger activity for the induction of the expression of trophectodermal (CDX2) and endodermal (SOX17, GATA4, AFP) markers than BMP-2 or BMP-6 homodimers. BMP-2/6 also induced the expression of BMPR2 gene more effectively than BMP-2 or BMP-6 when used at the same concentration and time. Moreover, the percentage of cells expressing the surface endodermal marker CXCR4 was also increased for the heterodimer when compared to both homodimers. BMP-2/6 was a more potent activator of Smad-dependent (SMAD1/5) and Smad-independent signaling (mitogen-activated protein kinases ERK and p38) than BMP-2 and BMP-6, and the activation of these pathways might play a role in its increased potency for inducing hES cell differentiation. Conclusions/Significance Therefore, we conclude that BMP-2/6 is more potent than BMP-2 or BMP-6 for inducing differentiation of hES cells, and it can be used as a more powerful substitute of these BMPs in in vitro differentiation guidance. © 2010 Valera et al.


Park S.,University of Minnesota | Park S.,Joint Center for Biosciences | Ozga J.A.,University of Alberta | Cohen J.D.,University of Minnesota | Reinecke D.M.,University of Alberta
Journal of Plant Growth Regulation | Year: 2010

The auxins 4-chloroindole-3-acetic acid (4-Cl-IAA) and indole-3-acetic acid (IAA) occur naturally in pea vegetative and fruit tissues (Pisum sativum L.). Previous work has shown that 4-Cl-IAA can substitute for the seeds in the stimulation of pea pericarp growth, whereas IAA is ineffective. Both auxins are found as free acids and as low-molecular-weight conjugates from organic solvent-soluble extracts from pea fruit. Here we present evidence for an additional conjugated auxin species that was not soluble in organic solvent and yielded 4-Cl-IAA and IAA after strong alkaline hydrolysis, suggestive of auxin attachment to pea seed and pericarp proteins. The solvent-insoluble conjugated 4-Cl-IAA in young pericarp was on average 15-fold greater than solvent-soluble 4-Cl-IAA. The solvent-insoluble conjugated IAA was approximately half the levels reported for the solvent-soluble IAA fraction. To identify putative 4-Cl-IAA-bound proteins, polyclonal antibodies were raised to 4-Cl-IAA linked to bovine serum albumin protein (BSA). Immunoblots probed with anti-4-Cl-IAA-BSA antiserum detected three to four unique bands (32-40 kDa) in primarily maternal tissues, and a different set of protein bands were detected in mainly embryonic tissues (ca. 65-74 kDa in mature seed). 4-Cl-IAA and IAA were also identified from protein fractions separated by polyacrylamide gel electrophoresis using GC-MS. These data show that the majority of 4-Cl-IAA, the growth-active auxin in young pea pericarp, and significant levels of IAA are linked to protein fractions. Auxin-proteins may function in regulation of free bioactive 4-Cl-IAA and IAA levels, and/or 4-Cl-IAA or IAA may be targeted to specific proteins post-translationally to modify protein function or stability. © Springer Science+Business Media, LLC 2009.


Kim S.,Joint Center for Biosciences | Choe S.,Joint Center for Biosciences | Choe S.,Drug Discovery Collaboratory | Lee D.K.,Joint Center for Biosciences
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016

Although BMP-9 has been reported to induce browning of white adipose tissues (WATs) and suppress high fat diet-induced obesity, detailed molecular mechanism needs to be further elucidated. We report here that administration of MB109, a recombinant derivative of human BMP-9, into obese mice enhanced gene expression of fibroblast growth factor 21 (FGF21), a metabolic regulator, and alleviates a spectrum of pathological symptoms due to high fat diet-induced obesity. In addition, periodical injection of MB109 (500 μg/kg/week) reduced an amount of lipid droplets in the liver, serum levels of alanine aminotransferase (ALT), and total cholesterol. These results indicate that MB109 is also effective to treat obesity-mediated non-alcoholic fatty liver disease (NAFLD). © 2016.


Kuo M.M.C.,Joint Center for Biosciences | Kim S.,Joint Center for Biosciences | Tseng C.-Y.,Joint Center for Biosciences | Jeon Y.-H.,Joint Center for Biosciences | And 2 more authors.
Biomaterials | Year: 2014

BMP-9, whose expression is highest in liver cells, has been demonstrated to regulate expression of enzymes involved in glucose homeostasis. However, the underlying mechanism of this effect has yet to be elucidated. We observed that MB109, a recombinant BMP-9 derivative, enhanced brown adipogenesis of human adipose tissue derived stem cells. With this observation of the cell culture system, we hypothesized that MB109 may be able to improve glucose metabolism by regulating expression of brown adipogenic genes. Systemic intraperitoneal injection of MB109 (200 μg/kg/wk) suppressed weight gaining of high fat diet-induced obese mice by reducing sizes of white adipocytes and decreased 16 h fasting blood glucose levels without changing food consumption or apparent behavioral performances. MB109 induced expression of brown adipogenic genes in the subcutaneous but not in the visceral fat tissues from the mice fed with high fat diet. In addition, systematic injection of MB109 enhanced fatty acid synthase expression in the liver of obese mice, which may help attenuate an obesity-associated increase of blood glucose levels. Our results demonstrate a role of BMP-9 in brown adipogenesis and suppressing pathophysiology of high fat diet-induced obesity, presumably through the activin receptor like kinase 1 signaling pathway. © 2013 Elsevier Ltd.


Patent
Joint Center For Biosciences | Date: 2014-10-16

The disclosure provides for the expression and purification of bioactive recombinant bone morphogenetic protein (BMP)-9 from bacteria (MB109) and the use of the MB109 to treat various diseases and disorders, including cancer and obesity associated disorders.


Patent
Joint Center For Biosciences and Salk Institute for Biological Studies | Date: 2012-09-05

Provided herein are methods and compositions for efficient accumulation of structural information (e.g., three dimensional structural information) for amino acid sequences.


Patent
Salk Institute for Biological Studies and Joint Center For Biosciences | Date: 2014-12-30

The present disclosure relates to chimeric polypeptide having TGF-beta activity, nucleic acids encoding the polypeptides, and host cells for producing the polypeptides.


Patent
Salk Institute for Biological Studies and Joint Center For Biosciences | Date: 2010-02-24

The present disclosure relates to chimeric polypeptide having TGF-beta activity, nucleic acids encoding the polypeptides, and host cells for producing the polypeptides.

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