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1

The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity  

Microsoft Academic Search

Background:Myostatin, also known as Growth and Differentiation Factor 8, is a secreted protein that inhibits muscle growth. Disruption of myostatin signaling increases muscle mass and decreases glucose, but it is unclear whether these changes are related. We treated mice on chow and high-fat diets with a soluble activin receptor type IIB (ActRIIB, RAP-031), which is a putative endogenous signaling receptor

I Akpan; M D Goncalves; R Dhir; X Yin; E E Pistilli; S Bogdanovich; T S Khurana; J Ucran; J Lachey; R S Ahima

2009-01-01

2

A soluble activin receptor Type IIA fusion protein (ACE011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys  

Microsoft Academic Search

Activin A belongs to the TGF-? superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to

Sutada Lotinun; R. Scott Pearsall; Monique V. Davies; Tod H. Marvell; Travis E. Monnell; Jeffrey Ucran; Roberto J. Fajardo; Ravindra Kumar; Kathryn W. Underwood; Jasbir Seehra; Mary L. Bouxsein; Roland Baron

2010-01-01

3

Gene expression profiling of skeletal muscles treated with a soluble activin type IIB receptor.  

PubMed

Inhibition of the myostatin signaling pathway is emerging as a promising therapeutic means to treat muscle wasting and degenerative disorders. Activin type IIB receptor (ActRIIB) is the putative myostatin receptor, and a soluble activin receptor (ActRIIB-Fc) has been demonstrated to potently inhibit a subset of transforming growth factor (TGF)-? family members including myostatin. To determine reliable and valid biomarkers for ActRIIB-Fc treatment, we assessed gene expression profiles for quadriceps muscles from mice treated with ActRIIB-Fc compared with mice genetically lacking myostatin and control mice. Expression of 134 genes was significantly altered in mice treated with ActRIIB-Fc over a 2-wk period relative to control mice (fold change > 1.5, P < 0.001), whereas the number of significantly altered genes in mice treated for 2 days was 38, demonstrating a time-dependent response to ActRIIB-Fc in overall muscle gene expression. The number of significantly altered genes in Mstn(-/-) mice relative to control mice was substantially higher (360), but for most of these genes the expression levels in the 2-wk treated mice were closer to the levels in the Mstn(-/-) mice than in control mice (P < 10?³?). Expression levels of 30 selected genes were further validated with quantitative real-time polymerase chain reaction (qPCR), and a correlation of ? 0.89 was observed between the fold changes from the microarray analysis and the qPCR analysis. These data suggest that treatment with ActRIIB-Fc results in overlapping but distinct gene expression signatures compared with myostatin genetic mutation. Differentially expressed genes identified in this study can be used as potential biomarkers for ActRIIB-Fc treatment, which is currently in clinical trials as a therapeutic agent for muscle wasting and degenerative disorders. PMID:21266502

Rahimov, Fedik; King, Oliver D; Warsing, Leigh C; Powell, Rachel E; Emerson, Charles P; Kunkel, Louis M; Wagner, Kathryn R

2011-04-27

4

The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity  

PubMed Central

Myostatin, also known as Growth and Differentiation Factor 8, is a secreted protein that inhibits muscle growth. Disruption of myostatin signaling increases muscle mass and decreases glucose, but it is unclear whether these changes are related. We treated mice on chow and high-fat diets with a soluble activin receptor type IIB (ActRIIB.Fc) which is a putative endogenous signaling receptor for myostatin and other ligands of the TGF-? superfamily. After 4 weeks, RAP-031 increased lean and muscle mass, grip strength, and contractile force. RAP-031 enhanced the ability of insulin to suppress glucose production under clamp conditions in high-fat fed mice, but did not significantly change insulin-mediated glucose disposal. The hepatic insulin sensitizing effect of RAP-031 treatment was associated with increased adiponectin levels. RAP-031 treatment for 10 weeks further increased muscle mass and drastically reduced fat content in mice on either chow or high-fat diet. RAP-031 suppressed hepatic glucose production and increased peripheral glucose uptake in chow fed mice. In contrast, RAP-031 suppressed glucose production with no apparent change in glucose disposal in high-fat diet mice. Our findings demonstrate that disruption of ActRIIB signaling is a viable pharmacological approach for treating obesity and diabetes.

Akpan, Imo; Goncalves, Marcus D.; Dhir, Ravindra; Yin, Xiaoyan; Pistilli, Emidio; Bogdanovich, Sasha; Khurana, Tejvir; Ucran, Jeffrey; Lachey, Jennifer; Ahima, Rexford S.

2009-01-01

5

Pretreatment with a soluble activin type IIB receptor/Fc fusion protein improves hypoxia-induced muscle dysfunction.  

PubMed

Hypoxia, or reduced oxygen, occurs in a variety of clinical and environmental situations. Hypoxic exposure is associated with decreased muscle mass and a concomitant reduction in exercise capacity, although the exact mechanisms are not completely understood. The activin type IIB receptor (ActRIIB) is a receptor for transforming growth factor-beta (TGFbeta) superfamily members that are involved in the negative regulation of lean tissue mass. Given that hypoxia has negative effects on muscle mass and function and that modulation of the ActRIIB has been shown to increase muscle mass, we tested the hypothesis that pharmacological targeting of the ActRIIB for 2 wk would attenuate the loss of muscle mass and function in mice after exposure to normobaric hypoxia. ActRIIB modulation was achieved using a soluble activin receptor/Fc fusion protein (sActRIIB) in mice housed in a hypoxic chamber for 1 or 2 wk. Hypoxia induced a reduction in body weight in PBS- and sActRIIB-treated mice, although sActRIIB-treated mice remained larger throughout the hypoxic exposure. The absolute forces generated by extensor digitorum longus muscles were also significantly greater in sActRIIB- than PBS-treated mice and were more resistant to eccentric contraction-induced force drop after eccentric lengthening contractions. In summary, sActRIIB pretreatment attenuated hypoxia-induced muscle dysfunction. These data suggest that targeting the ActRIIB is an effective strategy to counter hypoxia-induced muscle dysfunction and to preacclimatize to hypoxia in clinical or high-altitude settings. PMID:19864340

Pistilli, Emidio E; Bogdanovich, Sasha; Mosqueira, Matias; Lachey, Jennifer; Seehra, Jasbir; Khurana, Tejvir S

2010-01-01

6

Pretreatment with a soluble activin type IIB receptor/Fc fusion protein improves hypoxia-induced muscle dysfunction  

PubMed Central

Hypoxia, or reduced oxygen, occurs in a variety of clinical and environmental situations. Hypoxic exposure is associated with decreased muscle mass and a concomitant reduction in exercise capacity, although the exact mechanisms are not completely understood. The activin type IIB receptor (ActRIIB) is a receptor for transforming growth factor-? (TGF?) superfamily members that are involved in the negative regulation of lean tissue mass. Given that hypoxia has negative effects on muscle mass and function and that modulation of the ActRIIB has been shown to increase muscle mass, we tested the hypothesis that pharmacological targeting of the ActRIIB for 2 wk would attenuate the loss of muscle mass and function in mice after exposure to normobaric hypoxia. ActRIIB modulation was achieved using a soluble activin receptor/Fc fusion protein (sActRIIB) in mice housed in a hypoxic chamber for 1 or 2 wk. Hypoxia induced a reduction in body weight in PBS- and sActRIIB-treated mice, although sActRIIB-treated mice remained larger throughout the hypoxic exposure. The absolute forces generated by extensor digitorum longus muscles were also significantly greater in sActRIIB- than PBS-treated mice and were more resistant to eccentric contraction-induced force drop after eccentric lengthening contractions. In summary, sActRIIB pretreatment attenuated hypoxia-induced muscle dysfunction. These data suggest that targeting the ActRIIB is an effective strategy to counter hypoxia-induced muscle dysfunction and to preacclimatize to hypoxia in clinical or high-altitude settings.

Pistilli, Emidio E.; Bogdanovich, Sasha; Mosqueira, Matias; Lachey, Jennifer; Seehra, Jasbir

2010-01-01

7

Reconstitution and analysis of soluble inhibin and activin receptor complexes in a cell-free system.  

PubMed

Activins and inhibins compose a heterogeneous subfamily within the transforming growth factor-beta (TGF-beta) superfamily of growth and differentiation factors with critical biological activities in embryos and adults. They signal through a heteromeric complex of type II, type I, and for inhibin, type III receptors. To characterize the affinity, specificity, and activity of these receptors (alone and in combination) for the inhibin/activin subfamily, we developed a cell-free assay system using soluble receptor-Fc fusion proteins. The soluble activin type II receptor (sActRII)-Fc fusion protein had a 7-fold higher affinity for activin A compared with sActRIIB-Fc, whereas both receptors had a marked preference for activin A over activin B. Although inhibin A and B binding was 20-fold lower compared with activin binding to either type II receptor alone, the mixture of either type II receptor with soluble TGF-beta type III receptor (TbetaRIII; betaglycan)-Fc reconstituted a soluble high affinity inhibin receptor. In contrast, mixing either soluble activin type II receptor with soluble activin type I receptors did not substantially enhance activin binding. Our results support a cooperative model of binding for the inhibin receptor (ActRII.sTbetaRIII complex) but not for activin receptors (type II + type I) and demonstrate that a complex composed of activin type II receptors and TbetaRIII is both necessary and sufficient for high affinity inhibin binding. This study also illustrates the utility of this cell-free system for investigating hypotheses of receptor complex mechanisms resulting from crystal structure analyses. PMID:15475360

del Re, Elisabetta; Sidis, Yisrael; Fabrizio, David A; Lin, Herbert Y; Schneyer, Alan

2004-12-17

8

Combined effect of AAV-U7-induced dystrophin exon skipping and soluble activin Type IIB receptor in mdx mice.  

PubMed

Adeno-associated virus (AAV)-U7-mediated skipping of dystrophin-exon-23 restores dystrophin expression and muscle function in the mdx mouse model of Duchenne muscular dystrophy. Soluble activin receptor IIB (sActRIIB-Fc) inhibits signaling of myostatin and homologous molecules and increases muscle mass and function of wild-type and mdx mice. We hypothesized that combined treatment with AAV-U7 and sActRIIB-Fc may synergistically improve mdx muscle function. Bioactivity of sActRIIB-Fc on skeletal muscle was first demonstrated in wild-type mice. In mdx mice we show that AAV-U7-mediated dystrophin restoration improved specific muscle force and resistance to eccentric contractions when applied alone. Treatment of mdx mice with sActRIIB-Fc increased body weight, muscle mass and myofiber size, but had little effect on muscle function. Combined treatment stimulated muscle growth comparable to the effect of sActRIIB-Fc alone and dystrophin rescue was similar to AAV-U7 alone. Moreover, combined treatment improved maximal tetanic force and the resistance to eccentric contraction to similar extent as AAV-U7 alone. In conclusion, combination of dystrophin exon skipping with sActRIIB-Fc brings together benefits of each treatment; however, we failed to evidence a clear synergistic effect on mdx muscle function. PMID:22894762

Hoogaars, Willem M H; Mouisel, Etienne; Pasternack, Arja; Hulmi, Juha J; Relizani, Karima; Schuelke, Markus; Schirwis, Elja; Garcia, Luis; Ritvos, Olli; Ferry, Arnaud; 't Hoen, Peter A; Amthor, Helge

2012-12-01

9

A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys.  

PubMed

Activin A belongs to the TGF-beta superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to examine the skeletal effect of human ActRIIA-IgG1-Fc (ACE-011) in non-human primates. Young adult female Cynomolgus monkeys were given a biweekly subcutaneous injection of either 10mg/kg ACE-011 or vehicle (VEH) for 3months. Treatment effects were evaluated by histomorphometric analysis of the distal femur, femoral midshaft, femoral neck and 12th thoracic vertebrae, by muCT analysis of femoral neck and by biomarkers of bone turnover. Compared to VEH, at the distal femur ACE-011-treated monkeys had significantly increased cancellous bone volume (+93%), bone formation rate per bone surface (+166%) and osteoblast surface (+196%) indicating an anabolic action. Monkeys treated with ACE-011 also had decreased osteoclast surface and number. No differences were observed in parameters of cortical bone at the midshaft of the femur. Similar to distal femur, ACE-011-treated monkeys had significantly greater cancellous bone volume, bone formation rate and osteoblast surface at the femoral neck relative to VEH. A significant increase in bone formation rate and osteoblast surface with a decrease in osteoclast surface was observed in thoracic vertebrae. muCT analysis of femoral neck indicated more plate-like structure in ACE-011-treated monkeys. Monkeys treated with ACE-011 had no effect on serum bone-specific alkaline phosphatase and CTX at the end of the study. These observations demonstrate that ACE-011 is a dual anabolic-antiresorptive compound, improving cancellous bone volume by promoting bone formation and inhibiting bone resorption in non-human primates. Thus, soluble ActRIIA fusion protein may be useful in the prevention and/or treatment of osteoporosis and other diseases involving accelerated bone loss. PMID:20080223

Lotinun, Sutada; Pearsall, R Scott; Davies, Monique V; Marvell, Tod H; Monnell, Travis E; Ucran, Jeffrey; Fajardo, Roberto J; Kumar, Ravindra; Underwood, Kathryn W; Seehra, Jasbir; Bouxsein, Mary L; Baron, Roland

2010-04-01

10

Regulation of body mass growth through activin type IIB receptor in teleost fish.  

PubMed

Myostatin is a TGF-beta family member that plays a key role in regulating skeletal muscle growth. Previous studies in mammals have demonstrated that myostatin is capable of binding the two activin type II receptors. Additionally, activin type II receptors have been shown to be capable of binding a number of other TGF-beta family members besides myostatin. An injection of a soluble form of activin type IIB receptor obtained from CHO cells into wild-type mice generated up to a 60% increase in muscle mass in 2 weeks. The knowledge on the role of activin receptors in fish is limited. In the present study, we examined the growth effect of administering a recombinant, soluble form of goldfish activin type IIB receptor extracellular domain to juvenile and larval goldfish (Carassius auratus), African catfish (Clarias gariepinus) larvae and tilapia (Oreochromis aureus) larvae. We have expressed the goldfish activin type IIB receptor extracellular domain in the yeast Pichia pastoris and we have demonstrated for the first time that this recombinant molecule stimulates growth in teleost fish in a dose-dependent manner. We provide evidence that this body weight increase is achieved by an increase in muscle mass and protein content. Histological analysis of the goldfish muscle revealed that treated fish exhibited hyperplasia as compared to controls. These findings contribute to the understanding of the mechanisms that regulate growth in non-mammalian vertebrates and suggest a powerful biotechnology approach to improving fish growth in aquaculture. PMID:19056390

Carpio, Yamila; Acosta, Jannel; Morales, Reynold; Santisteban, Yaimín; Sanchéz, Aniel; Estrada, Mario Pablo

2009-01-15

11

Characterization of the ligand binding functionality of the extracellular domain of activin receptor type IIb.  

PubMed

The single transmembrane domain serine/threonine kinase activin receptor type IIB (ActRIIB) has been proposed to bind key regulators of skeletal muscle mass development, including the ligands GDF-8 (myostatin) and GDF-11 (BMP-11). Here we provide a detailed kinetic characterization of ActRIIB binding to several low and high affinity ligands using a soluble activin receptor type IIB-Fc chimera (ActRIIB.Fc). We show that both GDF-8 and GDF-11 bind the extracellular domain of ActRIIB with affinities comparable with those of activin A, a known high affinity ActRIIB ligand, whereas BMP-2 and BMP-7 affinities for ActRIIB are at least 100-fold lower. Using site-directed mutagenesis, we demonstrate that ActRIIB binds GDF-11 and activin A in different ways such as, for example, substitutions in ActRIIB Leu(79) effectively abolish ActRIIB binding to activin A yet not to GDF-11. Native ActRIIB has four isoforms that differ in the length of the C-terminal portion of their extracellular domains. We demonstrate that the C terminus of the ActRIIB extracellular domain is crucial for maintaining biological activity of the ActRIIB.Fc receptor chimera. In addition, we show that glycosylation of ActRIIB is not required for binding to activin A or GDF-11. Together, our findings reveal binding specificity and activity determinants of the ActRIIB receptor that combine to effect specificity in the activation of distinct signaling pathways. PMID:20385559

Sako, Dianne; Grinberg, Asya V; Liu, June; Davies, Monique V; Castonguay, Roselyne; Maniatis, Silas; Andreucci, Amy J; Pobre, Eileen G; Tomkinson, Kathleen N; Monnell, Travis E; Ucran, Jeffrey A; Martinez-Hackert, Erik; Pearsall, R Scott; Underwood, Kathryn W; Seehra, Jasbir; Kumar, Ravindra

2010-07-01

12

Osteogenic protein-1 binds to activin type II receptors and induces certain activin-like effects  

Microsoft Academic Search

Proteins in the TGF-(~ superfamily transduce their effects through binding to type I and type II serine\\/threonine kinase receptors. Osteogenic protein-1 (OP-1, also known as bone morphogenetic protein-7 or BMP-7), a member of the TGF-(3 superfamily which belongs to the BMP subfamily, was found to bind ac- tivin receptor type I (ActR-I), and BMP receptors type IA (BMPR-IA) and type

Hidetoshi Yamashita; Danny Huylebroeck; T. Kuber Sampath; Maria Andries; James C. Smith; Carl-Henrik Heldin; Kohei Miyazono

1995-01-01

13

Activin a is associated with impaired myocardial glucose metabolism and left ventricular remodeling in patients with uncomplicated type 2 diabetes  

PubMed Central

Background Activin A released from epicardial adipose tissue has been linked to contractile dysfunction and insulin resistance in cardiomyocytes. This study investigated the role of activin A in clinical diabetic cardiomyopathy by assessing whether circulating activin A levels associate with cardiometabolic parameters in men with uncomplicated type 2 diabetes (T2D), and the effects of treatment with pioglitazone versus metformin on these associations. Methods Seventy-eight men with uncomplicated T2D and fourteen healthy men with comparable age were included, in this randomized, double-blind, active comparator intervention study. All T2D men were on glimipiride monotherapy, and randomized to a 24-week intervention with either pioglitazone or metformin. Cardiac dimensions and -function were measured using magnetic resonance imaging, whilst myocardial glucose metabolism (MMRglu) was determined using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography during a hyperinsulinemic-euglycemic clamp. Results Circulating activin A levels were comparable in T2D men and controls. Activin A levels were independently inversely associated with MMRglu, and positively with left ventricular mass/volume (LVMV)-ratio in T2D men. Intervention with metformin decreased activin A levels, whereas pioglitazone did not alter activin A levels. The changes in plasma activin A levels were not correlated with the changes in MMRglu following either pioglitazone or metformin treatment. A borderline significant correlation (p?=?0.051) of changes in plasma activin A levels and changes in LVMV-ratio was observed after pioglitazone treatment. Conclusions Circulating activin A levels are associated with impaired myocardial glucose metabolism and high LVMV-ratio in patients with uncomplicated T2D, reflecting a potential detrimental role in early human diabetic cardiomyopathy. Trial registration number Current Controlled Trials SRCTN53177482

2013-01-01

14

An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy.  

PubMed

The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings. PMID:24298022

Lach-Trifilieff, Estelle; Minetti, Giulia C; Sheppard, KellyAnn; Ibebunjo, Chikwendu; Feige, Jerome N; Hartmann, Steffen; Brachat, Sophie; Rivet, Helene; Koelbing, Claudia; Morvan, Frederic; Hatakeyama, Shinji; Glass, David J

2014-02-01

15

Crystal structure of activin receptor type IIB kinase domain from human at 2.0 ? resolution  

PubMed Central

Activin receptor type IIB (ActRIIB), a type II TGF-? serine/threonine kinase receptor, is integral to the activin and myostatin signaling pathway. Ligands such as activin and myostatin bind to activin type II receptors (ActRIIA, ActRIIB), and the GS domains of type I receptors are phosphorylated by type II receptors. Myostatin, a negative regulator of skeletal muscle growth, is regarded as a potential therapeutic target and binds to ActRIIB effectively, and to a lesser extent, to ActRIIA. The high-resolution structure of human ActRIIB kinase domain in complex with adenine establishes the conserved bilobal architecture consistent with all other catalytic kinase domains. The crystal structure reveals that the adenine has a considerably different orientation from that of the adenine moiety of ATP observed in other kinase structures due to the lack of an interaction by ribose-phosphate moiety and the presence of tautomers with two different protonation states at the N9 nitrogen. Although the Lys217–Glu230 salt bridge is absent, the unphosphorylated activation loop of ActRIIB adopts a conformation similar to that of the fully active form. Unlike the type I TGF-? receptor, where a partially conserved Ser280 is a gatekeeper residue, the AcRIIB structure possesses Thr265 with a back pocket supported by Phe247. Taken together, these structural features provide a molecular basis for understanding the coupled activity and recognition specificity for human ActRIIB kinase domain and for the rational design of selective inhibitors.

Han, Seungil; Loulakis, Pat; Griffor, Matt; Xie, Zhi

2007-01-01

16

The structure of the follistatin:activin complex reveals antagonism of both type I and type II receptor binding  

SciTech Connect

TGF-{beta} ligands stimulate diverse cellular differentiation and growth responses by signaling through type I and II receptors. Ligand antagonists, such as follistatin, block signaling and are essential regulators of physiological responses. Here we report the structure of activin A, a TGF-{beta} ligand, bound to the high-affinity antagonist follistatin. Two follistatin molecules encircle activin, neutralizing the ligand by burying one-third of its residues and its receptor binding sites. Previous studies have suggested that type I receptor binding would not be blocked by follistatin, but the crystal structure reveals that the follistatin N-terminal domain has an unexpected fold that mimics a universal type I receptor motif and occupies this receptor binding site. The formation of follistatin:BMP:type I receptor complexes can be explained by the stoichiometric and geometric arrangement of the activin:follistatin complex. The mode of ligand binding by follistatin has important implications for its ability to neutralize homo- and heterodimeric ligands of this growth factor family.

Thompson, T.B.; Lerch, T.F.; Cook, R.W.; Woodruff, T.K.; Jardetzky, T.S. (NWU)

2010-03-08

17

Conditional Activin Receptor Type IB (Acvr1b) Knockout Mice Reveal Hair Loss Abnormality  

PubMed Central

The in vivo functions of the activin A receptor type 1b (Acvr1b) have been difficult to study because Acvr1b?/? mice die during embryogenesis. To investigate the roles of Acvr1b in the epithelial tissues, we created mice with a conditional disruption of Acvr1b (Acvr1bflox/flox) and crossed them with K14-Cre mice. Acvr1bflox/flox; K14-Cre mice displayed various degrees of hairlessness at postnatal day 5, and the phenotype is exacerbated by age. Histological analyses showed that those hair follicles that developed during morphogenesis were later disrupted by delays in hair cycle reentry. Failure in cycling of the hair follicles and regrowth of the hair shaft and the inner root sheath resulted in subsequent severe hair loss. Apart from previous reports of other members of the transforming growth factor-?/activin/bone morphogenic protein pathways, we demonstrate a specialized role for Acvr1b in hair cycling in addition to hair follicle development. Acvr1bflox/flox; K14-Cre mice also had a thicker epidermis than did wild-type mice, which resulted from persistent proliferation of skin epithelial cells; however, no tumor formation was observed by 18 months of age. Our analysis of this Acvr1b knockout mouse line provides direct genetic evidence that Acvr1b signaling is required for both hair follicle development and cycling.

Qiu, Wanglong; Li, Xiaojun; Tang, Hongyan; Huang, Alicia S.; Panteleyev, Andrey A.; Owens, David M.; Su, Gloria H.

2014-01-01

18

The Structure of FSTL3·Activin A Complex: Differential Binding of N-Terminal Domains Influences Follistatin-Type Antagonist Specificity  

SciTech Connect

Transforming growth factor beta family ligands are neutralized by a number of structurally divergent antagonists. Follistatin-type antagonists, which include splice variants of follistatin (FS288 and FS315) and follistatin-like 3 (FSTL3), have high affinity for activin A but differ in their affinity for other ligands, particularly bone morphogenetic proteins. To understand the structural basis for ligand specificity within FS-type antagonists, we determined the x-ray structure of activin A in complex with FSTL3 to a resolution of 2.5 A. Similar to the previously resolved FS.activin A structures, the ligand is encircled by two antagonist molecules blocking all ligand receptor-binding sites. Recently, the significance of the FS N-terminal domain interaction at the ligand type I receptor site has been questioned; however, our data show that for FSTL3, the N-terminal domain forms a more intimate contact with activin A, implying that this interaction is stronger than that for FS. Furthermore, binding studies revealed that replacing the FSTL3 N-terminal domain with the corresponding FS domain considerably lowers activin A affinity. Therefore, both structural and biochemical evidence support a significant interaction of the N-terminal domain of FSTL3 with activin A. In addition, structural comparisons with bone morphogenetic proteins suggest that the interface where the N-terminal domain binds may be the key site for determining FS-type antagonist specificity.

Stamler, Robin; Keutmann, Henry T.; Sidis, Yisrael; Kattamuri, Chandramohan; Schneyer, Alan; Thompson, Thomas B. (Pioneer Valley); (Mass. Gen. Hosp.); (UCIN-MED)

2009-03-06

19

Functional Redundancy of Type II BMP Receptor and Type IIB Activin Receptor in BMP2-Induced Osteoblast Differentiation  

PubMed Central

Signaling pathways for bone morphogenetic proteins (BMPs) are important in osteoblast differentiation. Although the precise function of type I BMP receptors in mediating BMP signaling for osteoblast differentiation and bone formation has been characterized previously, the role of type II BMP receptors in osteoblasts is to be well clarified. In this study, we investigated the role of type II BMP receptor (BMPR-II) and type IIB activin receptor (ActR-IIB) in BMP2-induced osteoblast differentiation. While osteoblastic 2T3 cells expressed BMPR-II and ActR-IIB, loss-of-function studies, using dominant negative receptors and siRNAs, showed that BMPR-II and ActR-IIB compensated each other functionally in mediating BMP2 signaling and BMP2-induced osteoblast differentiation. This was evidenced by two findings. First, unless there was loss of function of both type II receptors, isolated disruption of either BMPR-II or ActR-IIB did not remove BMP2 activity. Second, in cells with loss of function of both receptors, restoration of function of either BMPR-II or ActR-IIB by transfection of the wild-type forms, restored BMP2 activity. These findings suggest a functional redundancy between BMPR-II and ActR-IIB in osteoblast differentiation. Results from experiments to test the effects of transforming growth factor b (TGF-?), activin, and fibroblast growth factor (FGF) on osteoblast proliferation and differentiation suggest that inhibition of receptor signaling by double-blockage of BMPR-II and ActR-IIB is BMP-signaling specific. The observed functional redundancy of type II BMP receptors in osteoblasts is novel information about the BMP signaling pathway essential for initiating osteoblast differentiation.

LIU, HONGBIN; ZHANG, RONGRONG; CHEN, DI; OYAJOBI, BABATUNDE O.; ZHAO, MING

2013-01-01

20

Activin type IIA and IIB receptors mediate Gdf11 signaling in axial vertebral patterning.  

PubMed

Vertebral bodies are segmented along the anteroposterior (AP) body axis, and the segmental identity of the vertebrae is determined by the unique expression pattern of multiple Hox genes. Recent studies have demonstrated that a transforming growth factor beta (TGF-beta) family protein, Gdf11 (growth and differentiation factor 11), and the activin type II receptor, ActRIIB, are involved in controlling the spatiotemporal expression of multiple Hox genes along the AP axis, and that the disruption of each of these genes causes anterior transformation of the vertebrae. Skeletal defects are more severe in Gdf11-null mice than in ActRIIB-null mice, however, leaving it uncertain whether Gdf11 signals via ActRIIB. Here we demonstrate using genetic and biochemical studies that ActRIIB and its subfamily receptor, ActRIIA, cooperatively mediate the Gdf11 signal in patterning the axial vertebrae, and that Gdf11 binds to both ActRIIA and ActRIIB, and induces phosphorylation of Smad2. In addition, we also show that these two receptors can functionally compensate for one another to mediate signaling of another TGF-beta ligand, nodal, during left-right patterning and the development of anterior head structure. PMID:12414726

Oh, S Paul; Yeo, Chang-Yeol; Lee, Youngjae; Schrewe, Heindrich; Whitman, Malcolm; Li, En

2002-11-01

21

Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer ActRIB signaling induces Snail and S100A4 expressions in prostate cancer cells. Black-Right-Pointing-Pointer The prostate cancer cell lines expressing an active form of ActRIB were established. Black-Right-Pointing-Pointer ActRIB signaling promotes EMT and lymph node metastasis in xenograft model. -- Abstract: Activin, a member of the transforming growth factor-{beta} family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancer cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.

Nomura, Masatoshi, E-mail: nomura@med.kyushu-u.ac.jp [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan); Tanaka, Kimitaka; Wang, Lixiang; Goto, Yutaka; Mukasa, Chizu; Ashida, Kenji; Takayanagi, Ryoichi [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)] [Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582 (Japan)

2013-01-04

22

Homozygous deletion of the activin A receptor, type IB gene is associated with an aggressive cancer phenotype in pancreatic cancer  

PubMed Central

Background Transforming growth factor, beta (TGFB) signal is considered to be a tumor suppressive pathway based on the frequent genomic deletion of the SMAD4 gene in pancreatic cancer (PC); however; the role of the activin signal, which also belongs to the TGFB superfamily, remains largely unclear. Methods and results We found a homozygous deletion of the activin A receptor, type IB (ACVR1B) gene in 2 out of 8 PC cell lines using array-comparative genomic hybridization, and the absence of ACVR1B mRNA and protein expression was confirmed in these 2 cell lines. Activin A stimulation inhibited cellular growth and increased the phosphorylation level of SMAD2 and the expression level of p21CIP1/WAF1 in the Sui66 cell line (wild-type ACVR1B and SMAD4 genes) but not in the Sui68 cell line (homozygous deletion of ACVR1B gene). Stable ACVR1B-knockdown using short hairpin RNA cancelled the effects of activin A on the cellular growth of the PC cell lines. In addition, ACVR1B-knockdown significantly enhanced the cellular growth and colony formation abilities, compared with controls. In a xenograft study, ACVR1B-knockdown resulted in a significantly elevated level of tumorigenesis and a larger tumor volume, compared with the control. Furthermore, in clinical samples, 6 of the 29 PC samples (20.7%) carried a deletion of the ACVR1B gene, while 10 of the 29 samples (34.5%) carried a deletion of the SMAD4 gene. Of note, 5 of the 6 samples with a deletion of the ACVR1B gene also had a deletion of the SMAD4 gene. Conclusion We identified a homozygous deletion of the ACVR1B gene in PC cell lines and clinical samples and proposed that the deletion of the ACVR1B gene may mediate an aggressive cancer phenotype in PC. Our findings provide novel insight into the role of the activin signal in PC.

2014-01-01

23

Differential Antagonism of Activin, Myostatin and Growth and Differentiation Factor 11 by Wild-Type and Mutant Follistatin  

Microsoft Academic Search

Follistatin binds and neutralizes members of the TGF su- perfamily including activin, myostatin, and growth and dif- ferentiation factor 11 (GDF11). Crystal structure analysis of thefollistatin-activincomplexrevealedextensivecontactsbe- tween follistatin domain (FSD)-2 and activin that was critical for the high-affinity interaction. However, it remained un- knownwhetherfollistatinresiduesinvolvedwithmyostatin and GDF11 binding were distinct from those involved with activin binding. If so, this would allow

Alan L. Schneyer; Yisrael Sidis; Anisha Gulati; Jie L. Sun; Henry Keutmann; Philip A. Krasney

2008-01-01

24

A silent H-bond can be mutationally activated for high-affinity interaction of BMP2 and activin type IIB receptor  

Microsoft Academic Search

BACKGROUND: Bone morphogenetic proteins (BMPs) are key regulators in the embryonic development and postnatal tissue homeostasis in all animals. Loss of function or dysregulation of BMPs results in severe diseases or even lethality. Like transforming growth factors ? (TGF-?s), activins, growth and differentiation factors (GDFs) and other members of the TGF-? superfamily, BMPs signal by assembling two types of serine\\/threonine-kinase

Dionys Weber; Alexander Kotzsch; Joachim Nickel; Stefan Harth; Axel Seher; Uwe Mueller; Walter Sebald; Thomas D Mueller

2007-01-01

25

Endoglin-Mediated Suppression of Prostate Cancer Invasion Is Regulated by Activin and Bone Morphogenetic Protein Type II Receptors  

PubMed Central

Mortality from prostate cancer (PCa) is due to the formation of metastatic disease. Understanding how that process is regulated is therefore critical. We previously demonstrated that endoglin, a type III transforming growth factor ? (TGF?) superfamily receptor, suppresses human PCa cell invasion and metastasis. Endoglin-mediated suppression of invasion was also shown by us to be dependent upon the type I TGF? receptor, activin receptor-like kinase 2 (ALK2), and the downstream effector, Smad1. In this study we demonstrate for the first time that two type II TGF? receptors are required for endoglin-mediated suppression of invasion: activin A receptor type IIA (ActRIIA) and bone morphogenetic protein receptor type II (BMPRII). Downstream signaling through these receptors is predominantly mediated by Smad1. ActRIIA stimulates Smad1 activation in a kinase-dependent manner, and this is required for suppression of invasion. In contrast BMPRII regulates Smad1 in a biphasic manner, promoting Smad1 signaling through its kinase domain but suppressing it through its cytoplasmic tail. BMPRII’s Smad1-regulatory effects are dependent upon its expression level. Further, its ability to suppress invasion is independent of either kinase function or tail domain. We demonstrate that ActRIIA and BMPRII physically interact, and that each also interacts with endoglin. The current findings demonstrate that both BMPRII and ActRIIA are necessary for endoglin-mediated suppression of human PCa cell invasion, that they have differential effects on Smad1 signaling, that they make separate contributions to regulation of invasion, and that they functionally and physically interact.

Breen, Michael J.; Moran, Diarmuid M.; Liu, Wenzhe; Huang, Xiaoke; Vary, Calvin P. H.; Bergan, Raymond C.

2013-01-01

26

Differential antagonism of activin, myostatin and growth and differentiation factor 11 by wild-type and mutant follistatin.  

PubMed

Follistatin binds and neutralizes members of the TGFbeta superfamily including activin, myostatin, and growth and differentiation factor 11 (GDF11). Crystal structure analysis of the follistatin-activin complex revealed extensive contacts between follistatin domain (FSD)-2 and activin that was critical for the high-affinity interaction. However, it remained unknown whether follistatin residues involved with myostatin and GDF11 binding were distinct from those involved with activin binding. If so, this would allow development of myostatin antagonists that would not inhibit activin actions, a desirable feature for development of myostatin antagonists for treatment of muscle-wasting disorders. We tested this hypothesis with our panel of point and domain swapping follistatin mutants using competitive binding analyses and in vitro bioassays. Our results demonstrate that activin binding and neutralization are mediated primarily by FSD2, whereas myostatin binding is more dependent on FSD1, such that deletion of FSD2 or adding an extra FSD1 in place of FSD2 creates myostatin antagonists with vastly reduced activin antagonism. However, these mutants also bind GDF11, indicating that further analysis is required for creation of myostatin antagonists that will not affect GDF11 activity that could potentially elicit GDF11-induced side effects in vivo. PMID:18535106

Schneyer, Alan L; Sidis, Yisrael; Gulati, Anisha; Sun, Jie L; Keutmann, Henry; Krasney, Philip A

2008-09-01

27

Activin, neutrophils, and inflammation: just coincidence?  

PubMed

During the 26 years that have elapsed since its discovery, activin-A, a member of the transforming growth factor ? super-family originally discovered from its capacity to stimulate follicle-stimulating hormone production by cultured pituitary gonadotropes, has been established as a key regulator of various fundamental biological processes, such as development, homeostasis, inflammation, and tissue remodeling. Deregulated expression of activin-A has been observed in several human diseases characterized by an immuno-inflammatory and/or tissue remodeling component in their pathophysiology. Various cell types have been recognized as sources of activin-A, and plentiful, occasionally contradicting, functions have been described mainly by in vitro studies. Not surprisingly, both harmful and protective roles have been postulated for activin-A in the context of several disorders. Recent findings have further expanded the functional repertoire of this molecule demonstrating that its ectopic overexpression in mouse airways can cause pathology that simulates faithfully human acute respiratory distress syndrome, a disorder characterized by strong involvement of neutrophils. This finding when considered together with the recent discovery that neutrophils constitute an important source of activin-A in vivo and earlier observations of upregulated activin-A expression in diseases characterized by strong activation of neutrophils may collectively imply a more intimate link between activin-A expression and neutrophil reactivity. In this review, we provide an outline of the functional repertoire of activin-A and suggest that this growth factor functions as a guardian of homeostasis, a modulator of immunity and an orchestrator of tissue repair activities. In this context, a relationship between activin-A and neutrophils may be anything but coincidental. PMID:23385857

Sideras, Paschalis; Apostolou, Eirini; Stavropoulos, Athanasios; Sountoulidis, Alexandros; Gavriil, Arianna; Apostolidou, Anastasia; Andreakos, Evangelos

2013-07-01

28

Mutation Detection in Activin A Receptor, Type I (ACVR1) Gene in Fibrodysplasia Ossificans Progressiva in An Iranian Family.  

PubMed

Fibrodysplasia Ossificans Progressiva (FOP, MIM 135100) is a rare genetic disease that is often inherited sporadically in an autosomal dominant pattern. The disease manifests in early life with malformed great toes and, its episodic and progressive bone formation in skeletal muscle after trauma is led to extra-articular ankylosis. In this study, a 17 year-old affected girl born to a father with chemical injury due to exposure to Mustard gas during the Iran-Iraq war, and her first degree relatives were examined to find the genetic cause of the disease. The mutation c.617G>A in the Activin A receptor, type I (ACVR1) gene was found in all previously reported patients with FOP. Therefore, peripheral blood samples were taken from the patient and her first-degree relatives. DNA was extracted and PCR amplification for ACVR1 was performed. The sequencing of ACVR1 showed the existence of the heterozygous c.617G>A mutation in the patient and the lack of it in her relatives. Normal result of genetic evaluation in relatives of the patient, ruled out the possibility of the mutation being inherited from parents. Therefore, the mutation causing disease in the child, whether is a new mutation with no relation to the father's exposure to chemical gas, or in case of somatic mutation due to exposure to chemical gas, the mutant cells were created in father's germ cells and were not detectable in his blood sample. PMID:24518978

Morovvati, Ziba; Morovvati, Saeid; Alishiri, Gholamhossein; Moosavi, Seyed Hossein; Ranjbar, Reza; Bolouki Moghaddam, Yaser

2014-02-01

29

Mutation Detection in Activin A Receptor, Type I (ACVR1) Gene in Fibrodysplasia Ossificans Progressiva in An Iranian Family  

PubMed Central

Fibrodysplasia Ossificans Progressiva (FOP, MIM 135100) is a rare genetic disease that is often inherited sporadically in an autosomal dominant pattern. The disease manifests in early life with malformed great toes and, its episodic and progressive bone formation in skeletal muscle after trauma is led to extra-articular ankylosis. In this study, a 17 year-old affected girl born to a father with chemical injury due to exposure to Mustard gas during the Iran-Iraq war, and her first degree relatives were examined to find the genetic cause of the disease. The mutation c.617G>A in the Activin A receptor, type I (ACVR1) gene was found in all previously reported patients with FOP. Therefore, peripheral blood samples were taken from the patient and her first-degree relatives. DNA was extracted and PCR amplification for ACVR1 was performed. The sequencing of ACVR1 showed the existence of the heterozygous c.617G>A mutation in the patient and the lack of it in her relatives. Normal result of genetic evaluation in relatives of the patient, ruled out the possibility of the mutation being inherited from parents. Therefore, the mutation causing disease in the child, whether is a new mutation with no relation to the father’s exposure to chemical gas, or in case of somatic mutation due to exposure to chemical gas, the mutant cells were created in father’s germ cells and were not detectable in his blood sample.

Morovvati, Ziba; Morovvati, Saeid; Alishiri, Gholamhossein Alishiri; Moosavi, Seyed Hossein; Ranjbar, Reza; Bolouki Moghaddam, Yaser

2014-01-01

30

Elevated expression of activins promotes muscle wasting and cachexia.  

PubMed

In models of cancer cachexia, inhibiting type IIB activin receptors (ActRIIBs) reverse muscle wasting and prolongs survival, even with continued tumor growth. ActRIIB mediates signaling of numerous TGF-? proteins; of these, we demonstrate that activins are the most potent negative regulators of muscle mass. To determine whether activin signaling in the absence of tumor-derived factors induces cachexia, we used recombinant serotype 6 adeno-associated virus (rAAV6) vectors to increase circulating activin A levels in C57BL/6 mice. While mice injected with control vector gained ~10% of their starting body mass (3.8±0.4 g) over 10 wk, mice injected with increasing doses of rAAV6:activin A exhibited weight loss in a dose-dependent manner, to a maximum of -12.4% (-4.2±1.1 g). These reductions in body mass in rAAV6:activin-injected mice correlated inversely with elevated serum activin A levels (7- to 24-fold). Mechanistically, we show that activin A reduces muscle mass and function by stimulating the ActRIIB pathway, leading to deleterious consequences, including increased transcription of atrophy-related ubiquitin ligases, decreased Akt/mTOR-mediated protein synthesis, and a profibrotic response. Critically, we demonstrate that the muscle wasting and fibrosis that ensues in response to excessive activin levels is fully reversible. These findings highlight the therapeutic potential of targeting activins in cachexia. PMID:24378873

Chen, Justin L; Walton, Kelly L; Winbanks, Catherine E; Murphy, Kate T; Thomson, Rachel E; Makanji, Yogeshwar; Qian, Hongwei; Lynch, Gordon S; Harrison, Craig A; Gregorevic, Paul

2014-04-01

31

Differential Muscle Hypertrophy Is Associated with Satellite Cell Numbers and Akt Pathway Activation Following Activin Type IIB Receptor Inhibition in Mtm1 p.R69C Mice.  

PubMed

X-linked myotubular myopathy is a congenital myopathy caused by deficiency of myotubularin. Patients often present with severe perinatal weakness, requiring mechanical ventilation to prevent death from respiratory failure. We recently reported that an activin receptor type IIB inhibitor produced hypertrophy of type 2b myofibers and modest increases of strength and life span in the severely myopathic Mtm1?4 mouse model of X-linked myotubular myopathy. We have now performed a similar study in the less severely symptomatic Mtm1 p.R69C mouse in hopes of finding greater treatment efficacy. Activin receptor type IIB inhibitor treatment of Mtm1 p.R69C animals produced behavioral and histological evidence of hypertrophy in gastrocnemius muscles but not in quadriceps or triceps. The ability of the muscles to respond to activin receptor type IIB inhibitor treatment correlated with treatment-induced increases in satellite cell number and several muscle-specific abnormalities of hypertrophic signaling. Treatment-responsive Mtm1 p.R69C gastrocnemius muscles displayed lower levels of phosphorylated ribosomal protein S6 and higher levels of phosphorylated eukaryotic elongation factor 2 kinase than were observed in Mtm1 p.R69C quadriceps muscle or in muscles from wild-type littermates. Hypertrophy in the Mtm1 p.R69C gastrocnemius muscle was associated with increased levels of phosphorylated ribosomal protein S6. Our findings indicate that muscle-, fiber type-, and mutation-specific factors affect the response to hypertrophic therapies that will be important to assess in future therapeutic trials. PMID:24726641

Lawlor, Michael W; Viola, Marissa G; Meng, Hui; Edelstein, Rachel V; Liu, Fujun; Yan, Ke; Luna, Elizabeth J; Lerch-Gaggl, Alexandra; Hoffmann, Raymond G; Pierson, Christopher R; Buj-Bello, Anna; Lachey, Jennifer L; Pearsall, Scott; Yang, Lin; Hillard, Cecilia J; Beggs, Alan H

2014-06-01

32

Activin signaling as an emerging target for therapeutic interventions  

PubMed Central

After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-? (TGF-?) ligands such as myostatin, growth and differentiation factor-11 and nodal. Thus, although the activity of each ligand is distinct, they are also redundant, both physiologically and pathologically in vivo. Activin receptors activated by ligands phosphorylate the receptor-regulated Smads for TGF-?, Smad2 and 3. The Smad proteins then undergo multimerization with the co-mediator Smad4, and translocate into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. Signaling through receptors and Smads is controlled by multiple mechanisms including phosphorylation and other posttranslational modifications such as sumoylation, which affect potein localization, stability and transcriptional activity. Non-Smad signaling also plays an important role in activin signaling. Extracellularly, follistatin and related proteins bind to activins and related TGF-? ligands, and control the signaling and availability of ligands. The functions of activins through activin receptors are pleiotrophic, cell type-specific and contextual, and they are involved in the etiology and pathogenesis of a variety of diseases. Accordingly, activin signaling may be a target for therapeutic interventions. In this review, we summarize the current knowledge on activin signaling and discuss the potential roles of this pathway as a molecular target of therapy for metabolic diseases, musculoskeletal disorders, cancers and neural damages.

Tsuchida, Kunihiro; Nakatani, Masashi; Hitachi, Keisuke; Uezumi, Akiyoshi; Sunada, Yoshihide; Ageta, Hiroshi; Inokuchi, Kaoru

2009-01-01

33

A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor  

PubMed Central

Background Bone morphogenetic proteins (BMPs) are key regulators in the embryonic development and postnatal tissue homeostasis in all animals. Loss of function or dysregulation of BMPs results in severe diseases or even lethality. Like transforming growth factors ? (TGF-?s), activins, growth and differentiation factors (GDFs) and other members of the TGF-? superfamily, BMPs signal by assembling two types of serine/threonine-kinase receptor chains to form a hetero-oligomeric ligand-receptor complex. BMP ligand receptor interaction is highly promiscuous, i.e. BMPs bind more than one receptor of each subtype, and a receptor bind various ligands. The activin type II receptors are of particular interest, since they bind a large number of diverse ligands. In addition they act as high-affinity receptors for activins but are also low-affinity receptors for BMPs. ActR-II and ActR-IIB therefore represent an interesting example how affinity and specificity might be generated in a promiscuous background. Results Here we present the high-resolution structures of the ternary complexes of wildtype and a variant BMP-2 bound to its high-affinity type I receptor BMPR-IA and its low-affinity type II receptor ActR-IIB and compare them with the known structures of binary and ternary ligand-receptor complexes of BMP-2. In contrast to activin or TGF-?3 no changes in the dimer architecture of the BMP-2 ligand occur upon complex formation. Functional analysis of the ActR-IIB binding epitope shows that hydrophobic interactions dominate in low-affinity binding of BMPs; polar interactions contribute only little to binding affinity. However, a conserved H-bond in the center of the type II ligand-receptor interface, which does not contribute to binding in the BMP-2 – ActR-IIB interaction can be mutationally activated resulting in a BMP-2 variant with high-affinity for ActR-IIB. Further mutagenesis studies were performed to elucidate the binding mechanism allowing us to construct BMP-2 variants with defined type II receptor binding properties. Conclusion Binding specificity of BMP-2 for its three type II receptors BMPR-II, Act-RII and ActR-IIB is encoded on single amino acid level. Exchange of only one or two residues results in BMP-2 variants with a dramatically altered type II receptor specificity profile, possibly allowing construction of BMP-2 variants that address a single type II receptor. The structure-/function studies presented here revealed a new mechanism, in which the energy contribution of a conserved H-bond is modulated by surrounding intramolecular interactions to achieve a switch between low- and high-affinity binding.

Weber, Dionys; Kotzsch, Alexander; Nickel, Joachim; Harth, Stefan; Seher, Axel; Mueller, Uwe; Sebald, Walter; Mueller, Thomas D

2007-01-01

34

FOXL2-induced follistatin attenuates activin A-stimulated cell proliferation in human granulosa cell tumors.  

PubMed

Human granulosa cell tumors (GCTs) are rare, and their etiology remains largely unknown. Recently, the FOXL2 402C>G (C134W) mutation was found to be specifically expressed in human adult-type GCTs; however, its function in the development of human GCTs is not fully understood. Activins are members of the transforming growth factor-beta superfamily, which has been shown to stimulate normal granulosa cell proliferation; however, little is known regarding the function of activins in human GCTs. In this study, we examined the effect of activin A on cell proliferation in the human GCT-derived cell line KGN. We show that activin A treatment stimulates KGN cell proliferation. Treatment with the activin type I receptor inhibitor SB431542 blocks activin A-stimulated cell proliferation. In addition, our results show that cyclin D2 is induced by treatment with activin A and is involved in activin A-stimulated cell proliferation. Moreover, the activation of Smad signaling is required for activin A-induced cyclin D2 expression. Finally, we show that the overexpression of the wild-type FOXL2 but not the C134W mutant FOXL2 induced follistatin production. Treatment with exogenous follistatin blocks activin A-stimulated cell proliferation, and the overexpression of wild-type FOXL2 attenuates activin A-stimulated cell proliferation. These results suggest that FOXL2 may act as a tumor suppressor in human adult-type GCTs by inducing follistatin expression, which subsequently inhibits activin-stimulated cell proliferation. PMID:24332943

Cheng, Jung-Chien; Chang, Hsun-Ming; Qiu, Xin; Fang, Lanlan; Leung, Peter C K

2014-01-10

35

Targeting the Activin Type IIB Receptor to Improve Muscle Mass and Function in the mdx Mouse Model of Duchenne Muscular Dystrophy  

PubMed Central

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-? superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg?1 body weight. After 12 weeks of treatment, the 10.0 mg/kg?1 dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg?1), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies.

Pistilli, Emidio E.; Bogdanovich, Sasha; Goncalves, Marcus D.; Ahima, Rexford S.; Lachey, Jennifer; Seehra, Jasbir; Khurana, Tejvir

2011-01-01

36

Targeting the activin type IIB receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophy.  

PubMed

The activin receptor type IIB (ActRIIB) is a transmembrane receptor for transforming growth factor-? superfamily members, including myostatin, that are involved in the negative regulation of skeletal muscle mass. We tested the translational hypothesis that blocking ligand binding to ActRIIB for 12 weeks would stimulate skeletal muscle growth and improve muscle function in the mdx mouse. ActRIIB was targeted using a novel inhibitor comprised of the extracellular portion of the ActRIIB fused to the Fc portion of murine IgG (sActRIIB), at concentrations of 1.0 and 10.0 mg/kg(-1) body weight. After 12 weeks of treatment, the 10.0 mg/kg(-1) dose caused a 27% increase in body weight with a concomitant 33% increase in lean muscle mass. Absolute force production of the extensor digitorum longus muscle ex vivo was higher in mice after treatment with either dose of sActRIIB, and the specific force was significantly higher after the lower dose (1.0 mg/kg(-1)), indicating functional improvement in the muscle. Circulating creatine kinase levels were significantly lower in mice treated with sActRIIB, compared with control mice. These data show that targeting the ActRIIB improves skeletal muscle mass and functional strength in the mdx mouse model of DMD, providing a therapeutic rationale for use of this molecule in treating skeletal myopathies. PMID:21356379

Pistilli, Emidio E; Bogdanovich, Sasha; Goncalves, Marcus D; Ahima, Rexford S; Lachey, Jennifer; Seehra, Jasbir; Khurana, Tejvir

2011-03-01

37

Follistatin, an Activin Antagonist, Ameliorates Renal Interstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction  

PubMed Central

Activin, a member of the TGF-? superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO). The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial ?-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of ?-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.

Maeshima, Akito; Mishima, Keiichiro; Yamashita, Shin; Miya, Masaaki; Sakurai, Noriyuki; Sakairi, Toru; Hiromura, Keiju; Hasegawa, Yoshihisa; Kojima, Itaru; Nojima, Yoshihisa

2014-01-01

38

Activin C Antagonizes Activin A in Vitro and Overexpression Leads to Pathologies in Vivo  

PubMed Central

Activin A is a potent growth and differentiation factor whose synthesis and bioactivity are tightly regulated. Both follistatin binding and inhibin subunit heterodimerization block access to the activin receptor and/or receptor activation. We postulated that the activin-?C subunit provides another mechanism regulating activin bioactivity. To test our hypothesis, we examined the biological effects of activin C and produced mice that overexpress activin-?C. Activin C reduced activin A bioactivity in vitro; in LNCaP cells, activin C abrogated both activin A-induced Smad signaling and growth inhibition, and in L?T2 cells, activin C antagonized activin A-mediated activity of an follicle-stimulating hormone-? promoter. Transgenic mice that overexpress activin-?C exhibited disease in testis, liver, and prostate. Male infertility was caused by both reduced sperm production and impaired sperm motility. The livers of the transgenic mice were enlarged because of an imbalance between hepatocyte proliferation and apoptosis. Transgenic prostates showed evidence of hypertrophy and epithelial cell hyperplasia. Additionally, there was decreased evidence of nuclear Smad-2 localization in the testis, liver, and prostate, indicating that overexpression of activin-?C antagonized Smad signaling in vivo. Underlying the significance of these findings, human testis, liver, and prostate cancers expressed increased activin-?C immunoreactivity. This study provides evidence that activin-?C is an antagonist of activin A and supplies an impetus to examine its role in development and disease.

Gold, Elspeth; Jetly, Niti; O'Bryan, Moira K.; Meachem, Sarah; Srinivasan, Deepa; Behuria, Supreeti; Sanchez-Partida, L. Gabriel; Woodruff, Teresa; Hedwards, Shelley; Wang, Hong; McDougall, Helen; Casey, Victoria; Niranjan, Birunthi; Patella, Shane; Risbridger, Gail

2009-01-01

39

Interleukin-6 and activin A are independently associated with cardiovascular events and mortality in type 2 diabetes: the prospective Asker and Baerum Cardiovascular Diabetes (ABCD) cohort study  

PubMed Central

Background Novel and robust cardiovascular (CV) markers are needed to improve CV morbidity and mortality risk prediction in type 2 diabetes (T2D). We assessed the long term predictive value of 4 novel CV risk markers for major CV events and mortality. Methods We included patients with T2D who had cytokines (interleukin [IL]-6 and activin A [actA]), a maximum stress ECG test (evaluated by the normalization pattern in early recovery phase) and echocardiography (evaluated by a measure of the left ventricular filling pressure - E/Em) assessed at baseline. The primary endpoint was time to first of any of the following events: myocardial infarction, stroke, hospitalization for unstable angina pectoris and death. All outcomes were adjudicated by independent experts. We used Cox proportional hazard modeling, Harrell C-statistic and the net reclassification improvement (NRI) to assess the additional value beyond conventional markers (age, gender, prior CV disease, HDL, creatinine, diastolic BP, microalbuminuria). Results At baseline the study cohort (n?=?135, mean age/diabetes duration/HbA1c: 59 yrs/7 yrs/7.6% [59 mmol/mol], 26% females) had moderate elevated CV risk (42% microalbuminuria, mean Framingham 10 year CV-risk 9.6%). During 8.6 yrs/1153.7 person years, 26 patients experienced 36 events. All 4 novel risk markers were significantly associated with increased risk of the primary endpoint, however, only IL-6 and actA improved C-statistic and NRI (+0.119/43.2%, +0.065/20.3% respectively) compared with the conventional CV risk factors. Conclusions IL-6 and actA may provide prognostic information on CV events and mortality in T2D beyond conventional CV risk factors. Trial registration ClinicalTrials.gov: NCT00133718

2013-01-01

40

Activin A Plays a Critical Role in Proliferation and Differentiation of Human Adipose Progenitors  

PubMed Central

OBJECTIVE Growth of white adipose tissue takes place in normal development and in obesity. A pool of adipose progenitors is responsible for the formation of new adipocytes and for the potential of this tissue to expand in response to chronic energy overload. However, factors controlling self-renewal of human adipose progenitors are largely unknown. We investigated the expression profile and the role of activin A in this process. RESEARCH DESIGN AND METHODS Expression of INHBA/activin A was investigated in three types of human adipose progenitors. We then analyzed at the molecular level the function of activin A during human adipogenesis. We finally investigated the status of activin A in adipose tissues of lean and obese subjects and analyzed macrophage-induced regulation of its expression. RESULTS INHBA/activin A is expressed by adipose progenitors from various fat depots, and its expression dramatically decreases as progenitors differentiate into adipocytes. Activin A regulates the number of undifferentiated progenitors. Sustained activation or inhibition of the activin A pathway impairs or promotes, respectively, adipocyte differentiation via the C/EBP?-LAP and Smad2 pathway in an autocrine/paracrine manner. Activin A is expressed at higher levels in adipose tissue of obese patients compared with the expression levels in lean subjects. Indeed, activin A levels in adipose progenitors are dramatically increased by factors secreted by macrophages derived from obese adipose tissue. CONCLUSIONS Altogether, our data show that activin A plays a significant role in human adipogenesis. We propose a model in which macrophages that are located in adipose tissue regulate adipose progenitor self-renewal through activin A.

Zaragosi, Laure-Emmanuelle; Wdziekonski, Brigitte; Villageois, Phi; Keophiphath, Mayoura; Maumus, Marie; Tchkonia, Tamara; Bourlier, Virginie; Mohsen-Kanson, Tala; Ladoux, Annie; Elabd, Christian; Scheideler, Marcel; Trajanoski, Zlatko; Takashima, Yasuhiro; Amri, Ez-Zoubir; Lacasa, Daniele; Sengenes, Coralie; Ailhaud, Gerard; Clement, Karine; Bouloumie, Anne; Kirkland, James L.; Dani, Christian

2010-01-01

41

Activins and inhibins: Novel regulators of thymocyte development  

SciTech Connect

Activins and inhibins are members of the transforming growth factor-{beta} superfamily that act on different cell types and regulate a broad range of cellular processes including proliferation, differentiation, and apoptosis. Here, we provide the first evidence that activins and inhibins regulate specific checkpoints during thymocyte development. We demonstrate that both activin A and inhibin A promote the DN3-DN4 transition in vitro, although they differentially control the transition to the DP stage. Whereas activin A induces the accumulation of a CD8{sup +}CD24{sup hi}TCR{beta}{sup lo} intermediate subpopulation, inhibin A promotes the differentiation of DN4 to DP. In addition, both activin A and inhibin A appear to promote CD8{sup +}SP differentiation. Moreover, inhibin {alpha} null mice have delayed in vitro T cell development, showing both a decrease in the DN-DP transition and reduced thymocyte numbers, further supporting a role for inhibins in the control of developmental signals taking place during T cell differentiation in vivo.

Licona-Limon, Paula; Aleman-Muench, German [Departamento de Inmunologia, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Circuito Escolar s/n, Mexico, DF 04510 (Mexico); Chimal-Monroy, Jesus [Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, UNAM, Mexico, DF (Mexico); Macias-Silva, Marina [Departmento de Biologia Celular, Instituto de Fisiologia Celular, UNAM, Mexico, DF (Mexico); Garcia-Zepeda, Eduardo A. [Departamento de Inmunologia, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Circuito Escolar s/n, Mexico, DF 04510 (Mexico); Matzuk, Martin M. [Departments of Pathology, Molecular and Cellular Biology, and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX (United States); Fortoul, Teresa I. [Departamento de Biologia Celular y Tisular, Facultad de Medicina, UNAM, Mexico, DF (Mexico); Soldevila, Gloria [Departamento de Inmunologia, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de Mexico, Circuito Escolar s/n, Mexico, DF 04510 (Mexico)], E-mail: soldevi@servidor.unam.mx

2009-04-03

42

Activin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response  

PubMed Central

Activin is an important orchestrator of wound repair, but its potential role in skin carcinogenesis has not been addressed. Here we show using different types of genetically modified mice that enhanced levels of activin in the skin promote skin tumour formation and their malignant progression through induction of a pro-tumourigenic microenvironment. This includes accumulation of tumour-promoting Langerhans cells and regulatory T cells in the epidermis. Furthermore, activin inhibits proliferation of tumour-suppressive epidermal ?? T cells, resulting in their progressive loss during tumour promotion. An increase in activin expression was also found in human cutaneous basal and squamous cell carcinomas when compared with control tissue. These findings highlight the parallels between wound healing and cancer, and suggest inhibition of activin action as a promising strategy for the treatment of cancers overexpressing this factor.

Antsiferova, Maria; Huber, Marcel; Meyer, Michael; Piwko-Czuchra, Aleksandra; Ramadan, Tamara; MacLeod, Amanda S.; Havran, Wendy L.; Dummer, Reinhard; Hohl, Daniel; Werner, Sabine

2011-01-01

43

Impaired growth of pancreatic exocrine cells in transgenic mice expressing human activin {beta}E subunit  

SciTech Connect

Activins, TGF-{beta} superfamily members, have multiple functions in a variety of cells and tissues. Recently, additional activin {beta} subunit genes, {beta}C and {beta}E, have been identified. To explore the role of activin E, we created transgenic mice overexpressing human activin {beta}E subunit. There were pronounced differences in the pancreata of the transgenic animals as compared with their wild-type counterparts. Pancreatic weight, expressed relative to total body weight, was significantly reduced. Histologically, adipose replacement of acini in the exocrine pancreas was observed. There was a significant decrease in the number of PCNA-positive cells in the acinar cells, indicating reduced proliferation in the exocrine pancreas of the transgenic mice. However, quantitative pancreatic morphometry showed that the total number and mass of the islets of the transgenic mice were comparable with those of the nontransgenic control mice. Our findings suggest a role for activin E in regulating the proliferation of pancreatic exocrine cells.

Hashimoto, Osamu [Laboratory of Experimental Animal Science, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan)]. E-mail: ohashim@vmas.kitasato-u.ac.jp; Ushiro, Yuuki [Laboratory of Experimental Animal Science, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan); Sekiyama, Kazunari [Laboratory of Experimental Animal Science, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan); Yamaguchi, Osamu [Laboratory of Experimental Animal Science, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan); Yoshioka, Kazuki [Laboratory of Veterinary Anatomy, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan); Mutoh, Ken-Ichiro [Laboratory of Veterinary Anatomy, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan); Hasegawa, Yoshihisa [Laboratory of Experimental Animal Science, Faculty of Veterinary Medicine, Kitasato University, School of Veterinary Medicine and Animal Sciences, Towada, Aomori 034-8628 (Japan)

2006-03-10

44

Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators.  

PubMed

Myostatin is a secreted TGF-beta family member that controls skeletal muscle growth. Humans, cattle, and dogs carrying natural loss-of-function mutations in the myostatin gene and myostatin knockout mice exhibit significant increases in skeletal muscle mass. Treatment of adult mice with antimyostatin antibodies also resulted in significant muscle mass increases. However, myostatin-knockout mice that were treated with a soluble form of the activin type II receptor (ActRII) B increased their muscle mass by an additional 15-25%, indicating that there is at least one additional ligand, in addition to myostatin, that functions to limit muscle growth. Here, both soluble ActRII and -IIB fragment-crystallizable proteins were used to affinity purify their native ligands from human and mouse sera. Using mass spectrometry-based proteomics and in vitro binding assays we have identified and confirmed that a number of TGF-beta family members, including myostatin, activins-A, -B, and -AB, bone morphogenetic proteins (BMPs) -9, -10, and -11, bind to both ActRIIs. Many of these factors, such as BMPs-11, -9, and -10 were discovered in systemic circulation for the first time, indicating that these ligands may also act in an endocrine fashion. Using a promoter-specific gene reporter assay, we demonstrated that soluble ActRIIB fragment-crystallizable proteins can inhibit the canonical signaling induced by these ligands. In addition, like myostatin, these factors were able to block the differentiation of myoblast cells into myotubes. However, in addition to myostatin, only BMP-11, and activins-A, -B, and -AB could be blocked from inhibiting the myoblast-to-myotube differentiation with both soluble ActRIIs, thus implicating them as potential novel regulators of muscle growth. PMID:18927237

Souza, Tatyana A; Chen, Xuan; Guo, Yongjing; Sava, Parid; Zhang, Jimin; Hill, Jennifer J; Yaworsky, Paul J; Qiu, Yongchang

2008-12-01

45

Activation of the activin A-ALK-Smad pathway in systemic sclerosis.  

PubMed

Systemic sclerosis (SSc) is a chronic disease of unknown etiology that is characterized by multiple tissue fibrosis. Transforming Growth Factor-beta (TGF-?) is thought to be the most important mediator that induces fibrosis. However, the molecular mechanisms by which fibrosis is induced have not been fully elucidated. In this study, the role of activin, a member of the TGF-? superfamily, was investigated in the pathogenesis of fibrosis in SSc. Serum activin A levels in patients with SSc were measured by ELISA, and the expression of the activin receptor type IB (ACVRIB/ALK4) and the activity of the signaling pathway via ACVRIB/ALK4 were investigated using western blotting. To evaluate a potential therapeutic strategy for SSc, we also attenuated the ACVRIB/ALK4 pathway using an inhibitor. Serum activin A levels were significantly higher in SSc patients than in normal controls. Activin A and ACVRIB/ALK4 expression were also higher in cultured SSc fibroblasts. Activin A stimulation induced phosphorylation of Smad2/3 and CTGF expression in SSc fibroblasts. Procollagen production and Col1? mRNA also increased upon stimulation by activin A. The basal level of Smad2/3 phosphorylation was higher in cultured SSc fibroblasts than in control cells, and treatment with the ALK4/5 inhibitor SB431542 prevented phosphorylation of Smad2/3 and CTGF expression. Furthermore, production of collagen was also induced by activin A. Activin A-ACVRIB/ALK4-Smad-dependent collagen production was augmented in SSc fibroblasts, suggesting the involvement of this signaling mechanism in SSc. Inhibition of the activin A-ACVRIB/ALK4-Smad pathway would be a new approach for the treatment of SSc. PMID:21377836

Takagi, Kae; Kawaguchi, Yasushi; Kawamoto, Manabu; Ota, Yuko; Tochimoto, Akiko; Gono, Takahisa; Katsumata, Yasuhiro; Takagi, Masatoshi; Hara, Masako; Yamanaka, Hisashi

2011-05-01

46

Activin A Inhibits Antigen-Induced Allergy in Murine Epicutaneous Sensitization  

PubMed Central

Activin A, a member of the TGF? superfamily, is involved in physiological processes such as cell differentiation, tissue homeostasis, wound healing, reproduction, and in pathological conditions, such as fibrosis, cancer, and asthma. Activin enhances mast cell maturation, as well as regulatory T-cell and Langerhans cell differentiation. In this study we investigated the potential role of activin in epicutaneous sensitization with ovalbumin (OVA), notably with respect to its effect on known Th2-polarization. For this purpose, transgenic mice overexpressing activin in keratinocytes and their wild-type (WT) controls were sensitized epicutaneously with OVA. Skin biopsies were analyzed with regard to histopathological features and mRNA expression of pro-inflammatory and Th1/Th2 cytokines, and Ig levels were measured in the serum. Unexpectedly, activin overexpressing animals were protected from Th2-cytokine expression and induction of OVA-specific IgE levels compared to WT animals. On the other hand, transgenic mice were more susceptible to inflammation compared to WT littermates after tape-stripping and saline (vehicle) or OVA application, as shown by increased pro-inflammatory cytokine mRNA levels and neutrophil accumulation at the site of the treatment. We conclude that activin protects from antigen-induced cutaneous Th2-polarization through modulation of the immune response. These findings highlight the role of activin in cutaneous sensitization, allergy, and in skin homeostasis.

Kypriotou, Magdalini; Rivero, Dianelys; Haller, Sergio; Mariotto, Anita; Huber, Marcel; Acha-Orbea, Hans; Werner, Sabine; Hohl, Daniel

2013-01-01

47

Activin inhibits telomerase activity in cancer  

SciTech Connect

Activin is a pleiotropic cytokine with broad tissue distributions. Recent studies demonstrate that activin-A inhibits cancer cell proliferation with unknown mechanisms. In this report, we demonstrate that recombinant activin-A induces telomerase inhibition in cancer cells. In breast and cervical cancer cells, activin-A resulted in telomerase activity in a concentration-dependent manner. Significant inhibition was observed at 10 ng/ml of activin-A, with a near complete inhibition at 80 ng/ml. Consistently, activin-A induced repression of the telomerase reverse transcriptase (hTERT) gene, with the hTERT gene to be suppressed by 60-80% within 24 h. In addition, activin-A induced a concomitant increase in Smad3 signaling and decrease of the hTERT gene promoter activity in a concentration-dependent fashion. These data suggest that activin-A triggered telomerase inhibition by down-regulating hTERT gene expression is involved in activin-A-induced inhibition of cancer cell proliferation.

Katik, Indzi; Mackenzie-Kludas, Charley; Nicholls, Craig [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia); Jiang, Fang-Xu [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia)] [Centre for Diabetes Research, Western Australian Institute for Medical Research and The University of Western Australia, Perth (Australia); Zhou, Shufeng [School of Health Sciences, RMIT University, Melbourne (Australia)] [School of Health Sciences, RMIT University, Melbourne (Australia); Li, He [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia); Liu, Jun-Ping, E-mail: jun-ping.liu@med.monash.edu.au [Department of Immunology, Monash University, Melbourne (Australia)] [Department of Immunology, Monash University, Melbourne (Australia)

2009-11-27

48

R-Smad Competition Controls Activin Receptor Output in Drosophila  

PubMed Central

Animals use TGF-? superfamily signal transduction pathways during development and tissue maintenance. The superfamily has traditionally been divided into TGF-?/Activin and BMP branches based on relationships between ligands, receptors, and R-Smads. Several previous reports have shown that, in cell culture systems, “BMP-specific” Smads can be phosphorylated in response to TGF-?/Activin pathway activation. Using Drosophila cell culture as well as in vivo assays, we find that Baboon, the Drosophila TGF-?/Activin-specific Type I receptor, can phosphorylate Mad, the BMP-specific R-Smad, in addition to its normal substrate, dSmad2. The Baboon-Mad activation appears direct because it occurs in the absence of canonical BMP Type I receptors. Wing phenotypes generated by Baboon gain-of-function require Mad, and are partially suppressed by over-expression of dSmad2. In the larval wing disc, activated Baboon cell-autonomously causes C-terminal Mad phosphorylation, but only when endogenous dSmad2 protein is depleted. The Baboon-Mad relationship is thus controlled by dSmad2 levels. Elevated P-Mad is seen in several tissues of dSmad2 protein-null mutant larvae, and these levels are normalized in dSmad2; baboon double mutants, indicating that the cross-talk reaction and Smad competition occur with endogenous levels of signaling components in vivo. In addition, we find that high levels of Activin signaling cause substantial turnover in dSmad2 protein, providing a potential cross-pathway signal-switching mechanism. We propose that the dual activity of TGF-?/Activin receptors is an ancient feature, and we discuss several ways this activity can modulate TGF-? signaling output.

Shimell, MaryJane; Stefancsik, Ray; Wijayatonge, Ranjula; Herder, Rachel; Raftery, Laurel A.; O'Connor, Michael B.

2012-01-01

49

Soluble A? Promotes Wild-Type Tau Pathology in vivo  

PubMed Central

Growing evidence suggests that soluble A? species can drive Alzheimer disease (AD) pathogenesis by inducing a cascade of events including tau hyperphosphorylation, proteasome impairment and synaptic dysfunction. However, these studies have relied largely on in vitro approaches to examine the role of soluble A? in AD. In particular, it remains unknown whether soluble A? oligomers can facilitate the development of human wild-type tau pathology in vivo. To address this question, we developed a novel transgenic model that expresses low levels of APP with the Arctic familial AD mutation to enhance soluble A? oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of ?-site APP cleaving enzyme (BACE) in these “ArcTau” mice decreases soluble A? oligomers, rescues cognition, and more importantly also reduces tau accumulation and phosphorylation. Notably, BACE reduction decreases the postsynaptic mislocalization of tau in ArcTau mice, and reduces the association between NMDA receptors and PSD-95. These studies provide critical in vivo evidence for a strong mechanistic link between soluble A?, wild-type tau and synaptic pathology.

Chabrier, Meredith A.; Blurton-Jones, Mathew; Agazaryan, Andranik A.; Nerhus, Joy L.; Martinez-Coria, Hilda; LaFerla, Frank M.

2013-01-01

50

The Biology Of Activin: Recent Advances In Structure, Regulation And Function  

PubMed Central

Activin was discovered in the 1980’s as a gonadal protein that stimulated FSH release from pituitary gonadotropes and was thought of as a reproductive hormone. In the ensuing decades many additional activities of activin were described and it was found to be produced in a wide variety of cell types at nearly all stages of development. Its signaling and actions are regulated intracellularly as well as by extracellular antagonists. Over the past 5 years a number of important advances have been made that clarify our understanding of the structural basis for signaling and regulation, as well as the biological roles of activin in stem cells, embryonic development, and in adults. These include the crystallization of activin in complex with the activin type II receptor ActRIIB, or with the binding proteins follistatin and follistatin-like 3 (FSTL3), and identification of the activin roles in gonadal sex development, follicle development and luteolysis, in ?-cell proliferation and function in the islet, in stem cell self-renewal and differentiation into different cell types, and in immune cells. These advances are reviewed to provide perspective for future studies.

Xia, Yin; Schneyer, Alan L.

2009-01-01

51

Signal transduction pathway through activin receptors as a therapeutic target of musculoskeletal diseases and cancer.  

PubMed

Activin, myostatin and other members of the TGF-beta superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-beta, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers. PMID:17878607

Tsuchida, Kunihiro; Nakatani, Masashi; Uezumi, Akiyoshi; Murakami, Tatsuya; Cui, Xueling

2008-03-01

52

Activin Regulates Luteinizing Hormone ?-Subunit Gene Expression through Smad-Binding and Homeobox Elements  

PubMed Central

LH ?-subunit (LH?), which is essential for ovulation and reproductive fitness, is synthesized specifically in pituitary gonadotropes. In this study, we show that LH? gene expression is induced by activin in mouse primary pituitary cells if the cells are treated within 24 h after dispersion in culture. Furthermore, male mice deficient in Smad3, and therefore in activin signaling, have lower expression of both LH? and FSH? mRNAs compared with their wild-type littermates. Using the L?T2 immortalized mouse gonadotrope cell line that endogenously expresses LH, we identify specific elements in the regulatory region of the rat LH? gene necessary for its induction by activin. Activin responsiveness is conferred by a promoter-proximal region located ?121/?86 from the transcriptional start site. Maximal LH? induction by activin requires a homeobox element (HB) and a 5?-early growth response (Egr) site found in this region of the promoter. Juxtaposed to the HB are three Smad-binding elements (SBEs), which are essential for LH? induction. Interestingly, two of the SBEs are also critical for basal expression of the LH? gene. We demonstrate that Smad proteins are necessary and sufficient for activin induction of the LH? gene. Furthermore, Smad proteins can bind one of the identified SBEs. In addition to binding this SBE, Smad proteins interact with pituitary homeobox 1 (Ptx-1) and orthodenticle homeobox 1 (Otx-1), which can bind the HB located close to the Smad-binding site. Thus, activin induction of LH? gene expression requires a combination of several transcription factors, both basal and activin induced, as well as cooperation between multiple DNA elements.

Coss, Djurdjica; Thackray, Varykina G.; Deng, Chu-Xia; Mellon, Pamela L.

2010-01-01

53

Conversion of amylase-secreting rat pancreatic AR42J cells to neuronlike cells by activin A.  

PubMed Central

When AR42J cells, an amylase-secreting pancreatic exocrine cell line, were treated with activin A, cells extended neuritelike processes, and, concomitantly, amylase-containing vesicles disappeared. Immunofluorescence and immunoelectron microscopy revealed that these processes had neurite-specific cytoskeletal architectures: neurofilaments and microtubule bundles with cross-bridges of microtubule-associated protein 2. In addition to such morphological changes, activin-treated cells exhibited a marked increase in cytoplasmic free calcium concentration in response to depolarizing concentration of potassium. Moreover, activin-treated AR42J cells expressed mRNA for alpha 1 subunit of the neuroendocrine/beta cell-type voltage-dependent calcium channel. In naive AR42J cells, a sulfonylurea compound, tolbutamide, did not affect free calcium concentration, while it induced a marked elevation of free calcium in activin-treated cells. Single channel recording of the membrane patch revealed the existence of ATP-sensitive potassium channel in activin-treated cells. These results indicate that activin A converts amylase-secreting AR42J cells to neuronlike cells. Given that pancreatic endocrine cells possess neuronlike properties and express ATP-sensitive potassium channel as well as neuroendocrine/beta cell-type voltage-dependent calcium channel, activin treatment of AR42J cells may provide an in vitro model system to study the conversion of pancreatic exocrine cells to endocrine cells in islets. Images

Ohnishi, H; Ohgushi, N; Tanaka, S; Mogami, H; Nobusawa, R; Mashima, H; Furukawa, M; Mine, T; Shimada, O; Ishikawa, H

1995-01-01

54

Convergent animal and human evidence suggests the activin/inhibin pathway to be involved in antidepressant response  

PubMed Central

Despite the overt need for improved treatment modalities in depression, efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far. Here we present a translational approach combining results from hypothesis-free animal experiments with data from a genetic association study in depression. Comparing genes regulated by chronic paroxetine treatment in the mouse hippocampus with genes showing nominally significant association with antidepressant treatment response in two pharmacogenetic studies, the activin pathway was the only one to show this dual pattern of association and therefore selected as a candidate. We examined the regulation of activin A and activin receptor type IA mRNA following antidepressant treatment. We investigated the effects of stereotaxic infusion of activin into the hippocampus and the amygdala in a behavioural model of depression. To analyse whether variants in genes in the activin signalling pathway predict antidepressant treatment response, we performed a human genetic association study. Significant changes in the expression of genes in the activin signalling pathway were observed following 1 and 4 weeks of treatment. Injection of activin A into the hippocampus exerts acute antidepressant-like effects. Polymorphisms in the betaglycan gene, a co-receptor mediating functional antagonism of activin signalling, significantly predict treatment outcome in our system-wide pharmacogenetics study in depression. We provide convergent evidence from mouse and human data that genes in the activin signalling pathway are promising novel candidates involved in the neurobiogical mechanisms underlying antidepressant mechanisms of action. Further, our data suggest this pathway to be a target for more rapid-acting antidepressants in the future.

Ganea, K; Menke, A; Schmidt, M V; Lucae, S; Rammes, G; Liebl, C; Harbich, D; Sterlemann, V; Storch, C; Uhr, M; Holsboer, F; Binder, E B; Sillaber, I; Muller, M B

2012-01-01

55

Regulation of C-cadherin function during activin induced morphogenesis of Xenopus animal caps  

PubMed Central

Treatment of Xenopus animal pole tissue with activin results in the induction of mesodermal cell types and a dramatic elongation of the tissue. The morphogenetic movements involved in the elongation appear similar to those in normal gastrulation, which is driven by cell rearrangement and cell intercalations. We have used this system to explore the potential regulation of cell-cell adhesion and cadherin function during morphogenesis. Quantitative blastomere aggregation assays revealed that activin induction reduced the calcium-dependent adhesion between blastomeres. Activin-induced blastomeres formed smaller aggregates, and a greater proportion of the population remained as single cells compared to uninduced blastomeres. The aggregation was mediated by C-cadherin because C-cadherin was present in the blastomeres during the aggregation assay, and monoclonal antibodies against C-cadherin inhibited the calcium-dependent aggregation of blastomeres. E-cadherin was not detectable until after the completion of the assay and, therefore, does not explain the adhesive differences between induced and uninduced blastomeres. L cells stably expressing C- cadherin (LC cells) were used to demonstrate that C-cadherin activity was specifically altered after activin induction. Blastomeres induced with activin bound fewer LC cells than uninduced blastomers. L cells not expressing C-cadherin did not adhere to blastomeres. The changes in C-cadherin-mediated adhesion occurred without detectable changes in the steady-state levels of C-cadherin or the amount of C-cadherin present on the surface of the cell. Immunoprecipitation of C-cadherin and its associated catenins revealed that the ratio of C-cadherin and the catenins was not altered by activin induction. These results demonstrate that activin decreases the adhesive function of existing C- cadherin molecules on the surface of blastomeres and suggest that decreased cadherin mediated cell-cell adhesion is associated with increased morphogenetic movement.

1994-01-01

56

Rat activin-?E mRNA expression during development and in acute and chronic liver injury  

PubMed Central

Activin-?E mRNA expression was investigated in male and female rats using gel-based and quantitative RT-PCR, in fetal and post-natal liver during development and in a variety of tissues from 200 gm adult animals. Activin-?E expression was also assessed in rat liver after partial hepatectomy, and after repeated toxic insult. Male Sprague Dawley rats were subjected to partial hepatectomy or sham operations. Samples were collected from the caudate liver lobe during regeneration, from 12 to 240 hr after surgery. Three groups of 5 male rats were treated with CCl4 for 0 (control), 5 or 10 weeks, to induce liver fibrosis and cirrhosis. Activin-?E mRNA was predominantly expressed in liver, with much lower amounts of mRNA observed in pituitary, adrenal gland and spleen, in both males and females. Low activin-?E expression was observed in liver at fetal day 16, with higher levels seen between post-natal days 3 and 35 and a further increase noted by day 47, in both males and females. Liver activin-?E mRNA concentrations did not change from control values 12-72 hr after PHx, but significantly increased over six fold, 168 hr post-hepatectomy, when liver mass was restored. Activin-?E mRNA was up-regulated after 5 weeks of CCl4 treatment, but not after 10 weeks. The changes in activin-?E mRNA concentrations after liver insult did not always parallel those reported for the activin-?C subunit, suggesting activin-?E may have an independent role in liver under certain conditions.

Gold, Elspeth J; Monaghan, Marcel A; Fleming, Jean S

2006-01-01

57

Activin and Its Receptors during Gastrulation and the Later Phases of Mesoderm Development in the Chick Embryo  

Microsoft Academic Search

We have cloned chick homologues of the type-II activin receptor, which we have designated cActR-IIA and -IIB. Binding assays show that the two receptors are indistinguishable in their ability to bind activin-A, with comparablekds. Injection of mRNAs encoding these receptors intoXenopusembryos causes axial duplications. Expression of both receptors can first be detected in the primitive streak byin situhybridization. This suggests

Claudio D. Stern; Ruth T. Yu; Akira Kakizuka; Chris R. Kintner; Lawrence S. Mathews; Wylie W. Vale; Ronald M. Evans; Kazuhiko Umesono

1995-01-01

58

Solubility  

NSDL National Science Digital Library

Investigate what makes something soluble by exploring the effects of intermolecular attractions and what properties are necessary in a solution to overcome them. Interactive models simulate the process of dissolution, allowing you to experiment with how external factors, such as heat, can affect a substance's solubility.

Consortium, The C.

2011-12-11

59

Regulation of Cellular and System Function by Activin  

Microsoft Academic Search

Activin is an important molecule that regulates hormonogenesis, cellular homeostasis (divide or die pathways), and differentiation programs (developmentally and in adult cells). The cellular mechanisms that integrate an activin signal into a physiological response include a binary receptor complex and tandem serine threonine kinases, intracellular signal mediators, and nuclear transcription factors. Activin antagonists (inhibins) and bioneutralizing binding proteins (follistatins) act

Teresa K Woodruff

1998-01-01

60

Activins and inhibins in mammalian testis development: new models, new insights.  

PubMed

The discovery of activin and inhibins as modulators of the hypothalamic-pituitary-gonadal axis has set the foundation for understanding their central importance to many facets of development and disease. This review contains an overview of the processes and cell types that are central to testis development and spermatogenesis and then provides an update focussed on information gathered over the past five years to address new concepts about how these proteins function to control testis development in fetal and juvenile life. Current knowledge about the interactive nature of the transforming growth factor-? (TGF?) superfamily signalling network is applied to recent findings about activins and inhibins in the testis. Information about the regulated synthesis of signalling components and signalling regulators in the testis is integrated with new concepts that demonstrate their functional significance. The importance of activin bioactivity levels or dosage in controlling balanced growth of spermatogonial cells and their niche at different stages of testis development is highlighted. PMID:22406273

Barakat, B; Itman, C; Mendis, S H; Loveland, K L

2012-08-15

61

EW-7203, a novel small molecule inhibitor of transforming growth factor-? (TGF-?) type I receptor/activin receptor-like kinase-5, blocks TGF-?1-mediated epithelial-to-mesenchymal transition in mammary epithelial cells.  

PubMed

Recently, small molecule inhibitors of transforming growth factor? (TGF-?) type I receptor kinase ? activin receptor-like kinase-5 (ALK5) have been developed to target TGF-? signalling as a therapeutic strategy for combating cancer. In the present study, the authors examined a novel small molecule inhibitor of ALK5, 3-((5- ([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(6-methylpyridin-2-yl)thiazol-2-ylamino)methyl)benzonitrile (EW-7203) in breast cancer cells to determine if it has potential for cancer treatment. The inhibitory effects of EW-7203 on TGF-?-induced Smad signalling and epithelial- to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7203 on mammary cancer metastasis to the lung were examined using a Balb ? c xenograft model system. The novel ALK5 inhibitor, EW-7203, inhibited the TGF-?1-stimulated transcriptional activation of p3TP-Lux and pCA-GA??- Luc. In addition, EW-7203 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 was increased by TGF-?1. In addition, EW-7203 inhibited TGF-?1-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb ? c mice, EW-7203 inhibited metastasis to the lung from breast tumors. The novel ALK5 inhibitor, EW-7203, efficiently inhibited TGF-?1-induced Smad signalling, EMT and breast tumor metastasis to the lung in vivo, demonstrating that EW-7203 has therapeutic potential for breast cancer metastasis to the lung. PMID:21707864

Park, Chul-Yong; Kim, Dae-Kee; Sheen, Yhun Yhong

2011-10-01

62

Protein kinase C-induced activin A switches adrenocortical steroidogenesis to aldosterone by suppressing CYP17A1 expression.  

PubMed

Functional zonation of the adrenal cortex is a consequence of the zone-specific expression of P450c17 (CYP17A1) and its cofactors. Activin and inhibin peptides are differentially produced within the zones of the adrenal cortex and have been implicated in steroidogenic control. In this study, we investigated whether activin and inhibin can function as intermediates in functional zonation of the human adrenal cortex. Activin A suppressed CYP17A1 expression and P450c17 function in adrenocortical cell lines as well as in primary adrenal cell cultures. Inhibin ?A-subunit mRNA and activin A protein levels were found to be increased up to 1,900-fold and 49-fold, respectively, after protein kinase C (PKC) stimulation through PMA or angiotensin II in H295R adrenocortical carcinoma cells. This was confirmed in HAC15 cells and for PMA in primary adrenal cell cultures. Both PMA and Ang II decreased CYP17A1 expression in the adrenocortical cell lines, whereas PMA concurrently suppressed CYP17A1 levels in the primary cultures. Inhibition of activin signaling during PKC stimulation through silencing of the inhibin ?A-subunit or blocking of the activin type I receptor opposed the PMA-induced downregulation of CYP17A1 expression and P450c17 function. In contrast, PKA stimulation through adrenocorticotrophin or forskolin increased expression of the inhibin ?-subunit and betaglycan, both of which are antagonists of activin action. These data indicate that activin A acts as a PKC-induced paracrine factor involved in the suppression of CYP17A1 in the zona glomerulosa and can thereby contribute to functional adrenocortical zonation. PMID:23900415

Hofland, Johannes; Steenbergen, Jacobie; Hofland, Leo J; van Koetsveld, Peter M; Eijken, Marco; van Nederveen, Francien H; Kazemier, Geert; de Herder, Wouter W; Feelders, Richard A; de Jong, Frank H

2013-09-15

63

Activins and follistatins: Emerging roles in liver physiology and cancer  

PubMed Central

Activins are secreted proteins belonging to the TGF-? family of signaling molecules. Activin signals are crucial for differentiation and regulation of cell proliferation and apoptosis in multiple tissues. Signal transduction by activins relies mainly on the Smad pathway, although the importance of crosstalk with additional pathways is increasingly being recognized. Activin signals are kept in balance by antagonists at multiple levels of the signaling cascade. Among these, follistatin and FLRG, two members of the emerging family of follistatin-like proteins, can bind secreted activins with high affinity, thereby blocking their access to cell surface-anchored activin receptors. In the liver, activin A is a major negative regulator of hepatocyte proliferation and can induce apoptosis. The functions of other activins expressed by hepatocytes have yet to be more clearly defined. Deregulated expression of activins and follistatin has been implicated in hepatic diseases including inflammation, fibrosis, liver failure and primary cancer. In particular, increased follistatin levels have been found in the circulation and in the tumor tissue of patients suffering from hepatocellular carcinoma as well as in animal models of liver cancer. It has been argued that up-regulation of follistatin protects neoplastic hepatocytes from activin-mediated growth inhibition and apoptosis. The use of follistatin as biomarker for liver tumor development is impeded, however, due to the presence of elevated follistatin levels already during preceding stages of liver disease. The current article summarizes our evolving understanding of the multi-faceted activities of activins and follistatins in liver physiology and cancer.

Kreidl, Emanuel; Ozturk, Deniz; Metzner, Thomas; Berger, Walter; Grusch, Michael

2009-01-01

64

Autoinduction of activin genes in early Xenopus embryos.  

PubMed Central

Activin exhibits a potent mesoderm inducing activity towards the ectodermal tissue (animal cap) of Xenopus laevis blastulae. Thus in order to investigate the role of activin in morphogenesis of early Xenopus embryos, activation of genes for activin beta A and beta B was examined by the reverse transcription polymerase chain reaction. In vivo, activin beta B mRNA appears to be present in embryonic stage 1 whereas beta A mRNA is undetectable prior to gastrulation. beta B and beta A mRNAs were noted to accumulate after stages 9 and 15 respectively. Activin gene expression in Xenopus animal caps was examined after treatment with various concentrations of activin A. Under these treatment conditions, both activin beta A and beta B mRNAs accumulated in a dose-dependent fashion after 24 h. The same effect was noted for treatment with similar concentrations of activin B. Accumulation of mRNAs was inhibited by the addition of cycloheximide to the culture medium, consistent with the proposition that activin gene expression requires certain protein factors. In total, therefore, these data suggest that an autoinduction mechanism is involved in the regulation of activin mRNA levels in normal Xenopus embryos and that this mechanism may play a pivotal role during early embryonic development. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6

Suzuki, A; Nagai, T; Nishimatsu, S; Sugino, H; Eto, Y; Shibai, H; Murakami, K; Ueno, N

1994-01-01

65

Activin Potentiates Proliferation in Mature Avian Auditory Sensory Epithelium  

PubMed Central

Humans and other mammals are highly susceptible to permanent hearing and balance deficits due to an inability to regenerate sensory hair cells lost to inner ear trauma. In contrast, nonmammalian vertebrates, such as birds, robustly regenerate replacement hair cells and restore hearing and balance functions to near-normal levels. There is considerable interest in understanding the cellular mechanisms responsible for this difference in regenerative capacity. Here we report on involvement of the TGF? superfamily type II activin receptors, Acvr2a and Acvr2b, in regulating proliferation in mature avian auditory sensory epithelium. Cultured, posthatch avian auditory sensory epithelium treated with Acvr2a and Acvr2b inhibitors shows decreased proliferation of support cells, the cell type that gives rise to new hair cells. Conversely, addition of activin A, an Acvr2a/b ligand, potentiates support cell proliferation. Neither treatment (inhibitor or ligand) affected hair cell survival, suggesting a specific effect of Acvr2a/b signaling on support cell mitogenicity. Using immunocytochemistry, Acvr2a, Acvr2b, and downstream Smad effector proteins were differentially localized in avian and mammalian auditory sensory epithelia. Collectively, these data suggest that signaling through Acvr2a/b promotes support cell proliferation in mature avian auditory sensory epithelium and that this signaling pathway may be incomplete, or actively blocked, in the adult mammalian ear.

McCullar, Jennifer S.; Ty, Sidya; Campbell, Sean; Oesterle, Elizabeth C.

2010-01-01

66

Role of activin-a and myostatin and their signaling pathway in human myometrial and leiomyoma cell function.  

PubMed

Context: Uterine leiomyomas are highly prevalent benign tumors of premenopausal women and the most common indication for hysterectomy. However, the exact etiology of this tumor is not fully understood. Objective: The objective of the study was to evaluate the role of activin-A and myostatin and their signaling pathways in human myometrial and leiomyoma cells. Design: This was a laboratory study. Setting: Myometrial and leiomyoma cells (primary and cell lines) were cultured in vitro. Patients: The study included premenopausal women who were admitted to the hospital for myomectomy or hysterectomy. Interventions: Primary myometrial and leiomyoma cells and/or cell lines were treated with activin-A (4 nM) and myostatin (4 nM) for different days of interval (to measure proliferation rate) or 30 minutes (to measure signaling molecules) or 48 hours to measure proliferating markers, extracellular matrix mRNA, and/or protein expression by real-time PCR, Western blot, and/or immunocytochemistry. Results: We found that activin-A and myostatin significantly reduce cell proliferation in primary myometrial cells but not in leiomyoma cells as measured by a CyQUANT cell proliferation assay kit. Reduced expression of proliferating cell nuclear antigen and Ki-67 were also observed in myometrial cells in response to activin-A and myostatin treatment. Activin-A also significantly increased mRNA expression of fibronectin, collagen1A1, and versican in primary leiomyoma cells. Finally, we found that activin-A and myostatin activate Smad-2/3 signaling but do not affect ERK or p38 signaling in both myometrial and leiomyoma cells. Conclusions: This study results suggest that activin-A and myostatin can exert antiproliferative and/or fibrotic effects on these cell types via Smad-2/3 signaling. PMID:24606069

Islam, Md Soriful; Catherino, William H; Protic, Olga; Janjusevic, Milijana; Gray, Peter Clarke; Giannubilo, Stefano Raffaele; Ciavattini, Andrea; Lamanna, Pasquale; Tranquilli, Andrea Luigi; Petraglia, Felice; Castellucci, Mario; Ciarmela, Pasquapina

2014-05-01

67

Activin-A differentially regulates steroidogenesis by sheep granulosa cells.  

PubMed

Intra-ovarian factors, such as activin, are implicated in multiple aspects of follicular development in mammalian ovaries. This study was conducted to investigate a possible effect of activin-A on steroidogenesis in sheep granulosa cells in vitro. Sheep granulosa cells were obtained from medium antral follicles and cultured in a chemically defined RPMI -1640. Oestradiol and progesterone production, secreted by the cultured cells, was evaluated by enzyme-linked immunosorbent assay. In order to determine the dose effect of activin-A on steroidogenesis, granulosa cells were cultured in the presence of increasing concentrations of activin-A (0, 0.5, 5 and 50 ng ml(-1)) for 48 hours. The results revealed that activin-A exerts a differential effect on steroidogenesis in granulosa cells in such a way that it significantly (P < 0.05) suppressed progesterone production and enhanced oestradiol production. These results were confirmed by the time effect of activin-A on oestradiol and progesterone production in granulosa cells. In the absence of activin-A treatment, granulosa cells showed enhanced capacity to produce progesterone, but not oestradiol, as the time progressed from 12 to 48 hours. Treatment of sheep granulosa cells with 25 ng ml(-1)activin-A for 12, 24 and 48 hours significantly stimulated oestradiol production but inhibited progesterone production. These results suggest that activin-A is a local regulator of sheep folliculogenesis that might act to support differentiation in granulosa cells and suppress luteinisation. PMID:11666143

Shidaifat, F; Khamas, W; Hailat, N

2001-08-01

68

Assessment of the role of activin A and transforming growth factor beta in the regulation of AML12 cell growth.  

PubMed

The present study was conducted to determine the role of two autocrine factors, activin A and transforming growth factor beta (TGF-beta), in the growth regulation of AML12 hepatocytes. We overexpressed truncated type II activin and/or TGF-beta receptors in AML12 cells. In AML12 cells overexpressing truncated type II activin receptors (AML-tAR cells), the inhibitory effect of activin A on DNA synthesis was completely blocked. AML-tAR cells proliferated faster than parental cells, both in the presence and absence of epidermal growth factor (EGF). However, AML-tAR cells could not grow in soft agar. Follistatin augmented EGF-induced DNA synthesis in AML12 cells, whereas it was ineffective in AML-tAR cells. In AML12 cells overexpressing truncated type II TGF-beta receptor (AML-tTR cells), the inhibitory effect of TGF-beta on DNA synthesis was blocked. AML-tTR cells proliferated faster than parental cells, both in the presence and absence of EGF, but at a slower rate than that of AML-tAR cells. AML-tTR cells did not grow in soft agar. The growth rate of cells overexpressing both types of truncated receptors was identical to that of AML-tAR cells, and these cells did not grow in soft agar. These results indicate that both activin A and TGF-beta act as autocrine inhibitors of DNA synthesis in AML12 cells, and that the blocking of the actions of two factors does not lead to transformation. Activin A is a predominant autocrine factor in these cells. PMID:9185755

Zhang, Y Q; Mashima, H; Kanzaki, M; Shibata, H; Kojima, I

1997-06-01

69

Uterine Milk Protein, a Novel Activin-Binding Protein, Is Present in Ovine Allantoic Fluid  

Microsoft Academic Search

Activins are pluripotent growth factors that have recently been shown to be present in placental and fetal membrane preparations. Our previous studies have identified and purified activin A from ovine amniotic and allantoic fluids. In this study, ligand blots of side frac- tions from the isolation of activin A from allantoic fluid suggested the presence of activin-binding proteins other than

JAMES R. MCFARLANE; LYNDA M. FOULDS; DAVID J. PHILLIPS; GRAHAM JENKIN; MILTON T. W. HEARN; DAVID M. DE KRETSER

1999-01-01

70

Activin B promotes BM-MSC-mediated cutaneous wound healing by regulating cell migration via the JNK-ERK signaling pathway.  

PubMed

Bone marrow-derived mesenchymal stem cells (BM-MSCs) are able to differentiate intovarious types of skin cells and participate in skin regeneration and repair. Activin signalingcan regulate wound healing and reepithelialization. The present study assessed the impact ofactivin B on BM-MSC-mediated cutaneous wound healing in rats and explored the possiblemechanism involved. We found that CFSE-labeled BM-MSCs participated in wound healingin vivo, and compared to administration with PBS, activin B, or BM-MSCs, activin B plusBM-MSCs significantly promoted wound healing and hair follicle regeneration. Activin Binduced actin stress fiber formation and cell migration in BM-MSCs in vitro. Activation ofJNK and ERK, but not p38, was required for activin B-induced actin stress fiber formationand BM-MSC migration. These results show that activin B may promote BM-MSC-mediatedwound healing by inducing actin stress fiber formation and BM-MSC migration via the ERKand JNK signal pathways. Combined administration of BM-MSCs and cytokines may be apromising therapeutic strategy for the management of skin wounds. PMID:23582261

Zhang, Min; Sun, Li; Wang, Xueer; Chen, Shixuan; Jia, Qin; Liu, Nuyun; Chen, Yinghua; Kong, Yanan; Zhang, Lu; Zhang, And Lin

2013-04-12

71

Neuroendocrine control of female reproductive function by the activin receptor ALK7.  

PubMed

Activins are critical components of the signaling network that controls female reproduction. However, their roles in hypothalamus, and the specific functions of their different receptors, have not been elucidated. Here, we investigated the expression and function of the activin receptor ALK7 in the female reproductive axis using Alk7-knockout mice. ALK7 was found in subsets of SF1-expressing granulosa cells in the ovary, FSH gonadotrophs in the pituitary, and NPY-expressing neurons in the arcuate nucleus of the hypothalamus. Alk7-knockout females showed delayed onset of puberty and abnormal estrous cyclicity, had abnormal diestrous levels of FSH and LH in serum, and their ovaries showed premature depletion of follicles, oocyte degeneration, and impaired responses to exogenous gonadotropins. In the arcuate nucleus, mutant mice showed reduced expression of Npy mRNA and lower numbers of Npy-expressing neurons than wild-type controls. Alk7 knockouts showed a selective loss of arcuate NPY/AgRP innervation in the medial preoptic area, a key central regulator of reproduction. These results indicate that ALK7 is an important regulator of female reproductive function and reveal a new role for activin signaling in the control of hypothalamic gene expression and wiring. Alk7 gene variants may contribute to female reproductive disorders in humans, such as polycystic ovary syndrome. PMID:22954591

Sandoval-Guzmán, Tatiana; Göngrich, Christina; Moliner, Annalena; Guo, Tingqing; Wu, Haiya; Broberger, Christian; Ibáñez, Carlos F

2012-12-01

72

Activin A inhibits activation of human primordial follicles in vitro  

PubMed Central

Purpose To determine whether Activin A affects the activation and survival of human primordial follicles in vitro. Methods Ovarian cortical biopsies from eight women undergoing elective caesarean sections or benign gynaecological procedures were taken and cut into small pieces (1–3 mm3), cultured in serum-free medium for 7 days with/without human recombinant Activin A at a concentration of either 50 or 100 ng/ml. Ovarian tissue were analysed by histology for follicle viability, development and density. Result(s) Significant activation of primordial follicles within cultured cortical tissue was observed after 7 days in control medium. However, medium supplemented with Activin A at 50 ng/ml resulted in significant inhibition of follicular activation. Increasing the concentration of Activin A to 100 ng/ml reversed the inhibitory effect. The effect of Activin A appeared to be specific to activation of non-growing (primordial) follicles into the growing population since no significant differences in follicle viability was observed between treatment groups. Conclusion(s) Activin A at a concentration of 50 ng/ml can inhibit the spontaneous activation of human primordial follicles in vitro indicating that this may be a component of the signalling mechanisms that maintain follicular quiescence.

Ding, Chi Christina; Thong, K. Joo; Krishna, Archie

2010-01-01

73

Activin-?(c) reduces reproductive tumour progression and abolishes cancer-associated cachexia in inhibin-deficient mice.  

PubMed

Activins are involved in the regulation of a diverse range of physiological processes including development, reproduction, and fertility, and have been implicated in the progression of cancers. Bioactivity is regulated by the inhibin ?-subunit and by an activin-binding protein, follistatin. The activin-?(C) subunit was not considered functionally significant in this regard due to an absence of phenotype in knockout mice. However, activin-?(C) forms heterodimers with activin-?(A) and activin-C antagonizes activin-A in vitro. Thus, it is proposed that overexpression, rather than loss of activin-?(C) , regulates activin-A bioactivity. In order to prove biological efficacy, inhibin ?-subunit knockout mice (?-KO) were crossed with mice overexpressing activin-?(C) (ActC++). Deletion of inhibin leads to Sertoli and granulosa cell tumours, increased activin-A, and cancer-associated cachexia. Therefore, cachexia and reproductive tumour development should be modulated in ?-KO/ActC++ mice, where excessive activin-A is the underlying cause. Accordingly, a reduction in activin-A, no significant weight loss, and reduced incidence of reproductive tumours were evident in ?-KO/ActC++ mice. Overexpression of activin-?(C) antagonized the activin signalling cascade; thus, the tumourigenic effects of activin-A were abrogated. This study provides proof of the biological relevance of activin-?(C) . Being a regulator of activin-A, it is able to abolish cachexia and modulate reproductive tumour development in ?-KO mice. PMID:23180294

Gold, Elspeth; Marino, Francesco Elia; Harrison, Craig; Makanji, Yogeshwar; Risbridger, Gail

2013-03-01

74

Effect of B-activin on human T suppressor cells  

SciTech Connect

The authors studied the influence of B-activin on the effect of human concanavalin A (con A)-induced T suppressor cells and also on the process of induction of T suppressor cells by con A and stimulation of proliferative activity of lymphocytes by phytohemagglutinin (PHA). Con A-induced suppression and the effect of B-activin on it were studied in a system in which the test cell culture and the culture for induction of suppressors were prepared simultaneously. Peripheral blood was obtained from blood donors for the experiments and during the preparation of the experiments, /sup 3/H-thymidine was added. The results of investigation of the influence of B-activin on the effect of con A-induced suppressors and also on the process of their induction are given. It is concluded that B-activin blocks the effect of con A-induced human suppressor cells but does not affect their induction, and B-activin does not affect proliferative activity of lymphocytes induced by PHA.

Gambarov, S.S.; Khzardzhyan, A.M.; Adamyan, N.V.; Shakhsuvarov, A.V.; Suzdal'tseva, A.A.; Rakhmanova, G.A.

1986-10-01

75

Tumour necrosis factor-? stimulates human neutrophils to release preformed activin A.  

PubMed

Activin A, a member of the transforming growth factor-? superfamily, is a critical early mediator of acute inflammation. Activin A release coincides with the release of tumour necrosis factor-? (TNF-?) in models of lipopolysaccharide (LPS)-induced inflammation. The source of circulating activin A during acute inflammation has not been identified and the potential contribution of leukocyte subsets was examined in the following study. Human leukocytes from healthy volunteers were fractionated using Ficoll gradients and cultured under serum-free conditions. Freshly isolated human neutrophils contained 20-fold more activin A than blood mononuclear cells as measured by enzyme-linked immunosorbent assay (ELISA), and both dimeric and monomeric forms of activin A were detected in these cells by western blotting. Activin A was predominantly immunolocalized in the neutrophil cytoplasm. Purified neutrophils secreted activin A in culture when stimulated by TNF-?, but were unable to respond to LPS directly. Although TNF-? stimulated activin A release from neutrophils within 1 h, activin subunit mRNA expression did not increase until 12 h of culture, and the amount of activin A released following TNF-? stimulation did not change between 1 and 12 h. Specific inhibition of the p38 MAP kinase signalling pathway blocked TNF-?-induced activin release, and the secretion of activin A was not due to TNF-?-induced neutrophil apoptosis. These data provide the first evidence that neutrophils are a significant source of mature, stored activin A. Stimulation of the release of neutrophil activin A by TNF-? may contribute to the early peak in circulating activin A levels during acute inflammation. PMID:21445090

Chen, Yi; Wu, Hui; Winnall, Wendy R; Loveland, Kate L; Makanji, Yogeshwar; Phillips, David J; Smith, Julian A; Hedger, Mark P

2011-11-01

76

Activin stimulates CYP19A gene expression in human ovarian granulosa cell-like KGN cells via the Smad2 signaling pathway.  

PubMed

Activin, a transforming growth factor ? family member, has a wide range of physiological roles during embryonic development and organogenesis. In the ovary, activin, secreted from ovarian granulosa cells, not only acts on the pituitary gland to regulate the gonadotropin secretion from the pituitary gland in an endocrine manner but also acts on granulosa cells in a paracrine/autocrine manner to regulate folliculogenesis. Previously, we showed that activin signals through activin type IB receptor (ActRIB) and up-regulates follicle-stimulating hormone receptor expression and P450 aromatase activity in human ovarian granulose cell-like KGN cells. In the current study, we demonstrate the direct involvement of Smad2 as a downstream signal mediator of ActRIB in the transcriptional regulation of the P450 aromatase gene (CYP19A) in KGN cells. Upon activin stimulation, Smad2 activation and an increase in P450 aromatase messenger RNA (mRNA) were observed in KGN cells. Interestingly, Smad2 phosphorylation correlated well with the increase in P450 aromatase mRNA. Reciprocally, knockdown of Smad2 mRNA in KGN cells led to a decrease in the P450 aromatase mRNA expression, suggesting that Smad2 regulates CYP19A gene expression. Further analysis of CYP19A promoter activity revealed that the 5' upstream region between -2069 and -1271bp is required for the activation by Smad2. Finally, we provide compelling evidence that Smad2 shows follicular stage-specific expression, which is high in granulosa cells of preantral or early antral follicles in mice. Our results suggest that activin signaling through the ActRIB-Smad2 pathway plays a pivotal role in CYP19A expression and thus in follicular development. PMID:23747729

Nomura, Masatoshi; Sakamoto, Ryuichi; Morinaga, Hidetaka; Wang, Lixiang; Mukasa, Chizu; Takayanagi, Ryoichi

2013-07-01

77

X-ray structure of a soluble Rieske-type ferredoxin from Mus musculus  

PubMed Central

The 2.07?Å resolution X-ray crystal structure of a soluble Rieske-type ferredoxin from Mus musculus encoded by the gene Mm.266515 is reported. Although they are present as covalent domains in eukaryotic membrane oxidase complexes, soluble Rieske-type ferredoxins have not previously been observed in eukaryotes. The overall structure of the mouse Rieske-type ferredoxin is typical of this class of iron–sulfur proteins and consists of a larger partial ?-barrel domain and a smaller domain containing Cys57, His59, Cys80 and His83 that binds the [2Fe–2S] cluster. The S atoms of the cluster are hydrogen-bonded by six backbone amide N atoms in a pattern typical of membrane-bound high-potential eukaryotic respiratory Rieske ferredoxins. However, phylogenetic analysis suggested that the mouse Rieske-type ferredoxin was more closely related to bacterial Rieske-type ferredoxins. Correspondingly, the structure revealed an extended loop most similar to that seen in Rieske-type ferredoxin subunits of bacterial aromatic dioxygenases, including the positioning of an aromatic side chain (Tyr85) between this loop and the [2Fe–2S] cluster. The mouse Rieske-type ferredoxin was shown to be capable of accepting electrons from both eukaryotic and prokaryotic oxidoreductases, although it was unable to serve as an electron donor for a bacterial monooxygenase complex. The human homolog of mouse Rieske-type ferredoxin was also cloned and purified. It behaved identically to mouse Rieske-type ferredoxin in all biochemical characterizations but did not crystallize. Based on its high sequence identity, the structure of the human homolog is likely to be modeled well by the mouse Rieske-type ferredoxin structure.

Levin, Elena J.; Elsen, Nathaniel L.; Seder, Kory D.; McCoy, Jason G.; Fox, Brian G.; Phillips Jr, George N.

2008-01-01

78

Characterization of Soluble N-Ethylmaleimide-Sensitive Fusion Attachment Protein in Alveolar Type II Cells Implications in Lung Surfactant Secretion  

Microsoft Academic Search

N-ethylmaleimide-sensitive fusion protein (NSF) and soluble NSF attachment protein (-SNAP) are thought to be soluble factors that transiently bind and disassemble SNAP receptor complex during exocytosis in neuronal and endocrine cells. Lung surfactant is secreted via exocytosis of lamellar bodies from alveolar epithelial type II cells. However, the secretion of lung surfactant is a relatively slow process, and involvement of

Barack O. Abonyo; Pengcheng Wang; Telugu A. Narasaraju; William H. Rowan; David H. McMillan; Un-Jin Zimmerman; Lin Liu

79

Biphasic regulation of activin A secretion by gonadotropins in cultured human ovarian granulosa-luteal cells leads to decreasing activin:inhibin ratios during continuing gonadotropin stimulation  

Microsoft Academic Search

Pituitary gonadotropins mediate part of their effects on ovarian function via local hormones and growth factors produced by granulosa cells. Activins and inhibins are among these factors, and they have often opposite effects on various components of the reproductive system. The purpose of this study was to investigate the regulation of ovarian activin A secretion using cultured human ovarian granulosa-luteal

T Vanttinen; J Liu; C Hydén-Granskog; R Voutilainen

2002-01-01

80

Expression and dimerization of the rat activin subunits betaC and betaE: evidence for the ormation of novel activin dimers  

Microsoft Academic Search

Activins are cytokines of the transforming growth factor ? family, which plays a central role in the determination of cell fate and the regulation of tissue balance. Family members are composed of two subunits and this dimerization is critical for liganding their cognate receptors and execution of proper functions. In the current study we focused on the localization of activin

S Vejda; M Cranfield; B Peter; S L Mellor; N Groome; R Schulte-Hermann; W Rossmanith

2002-01-01

81

Immunohistochemical analysis of activin A expression in spinal cords of rats with clip compression injuries.  

PubMed

Activin A, a member of the TGF-? superfamily, plays roles in neuroprotection and immunomodulation. In the present study, activin A expression was investigated on days 1, 4 and 7 post-injury in female adult Sprague-Dawley rats with spinal cord injuries (SCIs). The spinal cord was compressed with a vascular clip for 1min following laminectomy at T9/T10. Western blot analysis showed that activin A levels peaked in SCI core lesions 4 days post-injury (p<0.01) and fell thereafter until day 7. Immunohistochemically, activin A was constitutively expressed in vascular endothelial cells, astrocytes and neurons of sham-operated controls, and in macrophages and reactive astrocytes of lesional cores and peripheries. As activin A plays an immunomodulatory role in the early stages of SCI and facilitates behavioral improvement, we postulate that transient upregulation of activin A in SCI tissue may contribute to modulation of inflammation development during SCI, thus leading to neuroprotection. PMID:24529943

Jeong, Jinwoo; Ahn, Meejung; Sim, Ki-Bum; Moon, Changjong; Shin, Taekyun

2014-06-01

82

Activin A induces growth arrest through a SMAD- dependent pathway in hepatic progenitor cells  

PubMed Central

Background Activin A, an important member of transforming growth factor-? superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation. Results Using the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model. Conclusion Activin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.

2014-01-01

83

Replica exchange molecular dynamics simulations of an ?/?-type small acid soluble protein (SASP).  

PubMed

Small acid soluble proteins (SASPs) of ?/?-type play a major role in the resistance of spore DNAs to external assaults. It has been found that ?/?-type SASP exhibits intrinsic disorder on isolation, but it acquires a defined native state upon binding to DNA. This disorder to order transition is not yet understood. Other questions related to the role of the thermodynamics and structure of the individual protein in the complex formation remain elusive. Characterization of the unbound state of ?/?-type SASP in experiments could be a challenging problem because of the heterogeneous nature of the ensemble. Here, computer simulations can help gain more insights into the unbound state of ?/?-type SASP. In the present work, by using replica exchange molecular dynamics (REMD), we simulated an ?/?-type SASP on isolation with an implicit solvent. We found that ?/?-type SASP undergoes a continuous phase transition with a small free energy barrier, a common feature of intrinsically disordered proteins (IDPs). Additionally, we detected the presence of residual ?-helical structures at local level and a high degree of plasticity in the chain which can contribute to the fast disorder to order transition by reducing the fly-casting mechanism. PMID:24029407

Ojeda-May, P; Pu, Jingzhi

2013-12-31

84

Water-soluble undenatured type II collagen ameliorates collagen-induced arthritis in mice.  

PubMed

Earlier studies have reported the efficacy of type II collagen (C II) in treating rheumatoid arthritis (RA). However, a few studies have investigated the ability of the antigenic collagen to induce oral tolerance, which is defined as active nonresponse to an orally administered antigen. We hypothesized that water-soluble undenatured C II had a similar effect as C II in RA. The present study was designed to examine the oral administration of a novel, water-soluble, undenatured C II (commercially known as NEXT-II) on collagen-induced arthritis (CIA) in mice. In addition, the underlying mechanism of NEXT-II was also identified. After a booster dose (collagen-Freund's complete adjuvant), mice were assigned to control CIA group, or NEXT-II treatment group, to which saline and NEXT-II were administered, respectively. The arthritis index in the NEXT-II group was significantly lower compared with the CIA group. Serum IL-6 levels in the NEXT-II group were significantly lower compared with the CIA group, while serum IL-2 level was higher. Furthermore, oral administration of NEXT-II enhanced the proportion of CD4+CD25+T (Treg) cells, and gene expressions of stimulated dendritic cells induced markers for regulatory T cells such as forkhead box p3 (Foxp3), transforming growth factor (TGF)-?1, and CD25. These results demonstrated that orally administered water-soluble undenatured C II (NEXT-II) is highly efficacious in the suppression of CIA by inducing CD4+CD25+ Treg cells. PMID:24175655

Yoshinari, Orie; Shiojima, Yoshiaki; Moriyama, Hiroyoshi; Shinozaki, Junichi; Nakane, Takahisa; Masuda, Kazuo; Bagchi, Manashi

2013-11-01

85

Mechanism of protection by soluble epoxide hydrolase inhibition in type 2 diabetic stroke.  

PubMed

Inhibition of soluble epoxide hydrolase (sEH) is a potential target of therapy for ischemic injury. sEH metabolizes neuroprotective epoxyeicosatrienoic acids (EETs). We recently demonstrated that sEH inhibition reduces infarct size after middle cerebral artery occlusion (MCAO) in type 1 diabetic mice. We hypothesized that inhibition of sEH would protect against ischemic injury in type 2 diabetic mice. Type 2 diabetes was produced by combined high-fat diet, nicotinamide and streptozotocin in male mice. Diabetic and control mice were treated with vehicle or the sEH inhibitor t-AUCB then subjected to 60-min MCAO. Compared to chow-fed mice, high fat diet-fed mice exhibited an upregulation of sEH mRNA and protein in brain, but no differences in brain EETs levels were observed between groups. Type 2 diabetic mice had increased blood glucose levels at baseline and throughout ischemia, decreased laser-Doppler perfusion of the MCA territory after reperfusion, and sustained larger cortical infarcts compared to control mice. t-AUCB decreased fasting glucose levels at baseline and throughout ischemia, improved cortical perfusion after MCAO and significantly reduced infarct size in diabetic mice. We conclude that sEH inhibition, as a preventative treatment, improves glycemic status, post-ischemic reperfusion in the ischemic territory, and stroke outcome in type 2 diabetic mice. PMID:24824753

Zuloaga, Kristen L; Krasnow, Stephanie M; Zhu, Xinxia; Zhang, Wenri; Jouihan, Sari A; Shangraw, Robert E; Alkayed, Nabil J; Marks, Daniel L

2014-01-01

86

Mechanism of Protection by Soluble Epoxide Hydrolase Inhibition in Type 2 Diabetic Stroke  

PubMed Central

Inhibition of soluble epoxide hydrolase (sEH) is a potential target of therapy for ischemic injury. sEH metabolizes neuroprotective epoxyeicosatrienoic acids (EETs). We recently demonstrated that sEH inhibition reduces infarct size after middle cerebral artery occlusion (MCAO) in type 1 diabetic mice. We hypothesized that inhibition of sEH would protect against ischemic injury in type 2 diabetic mice. Type 2 diabetes was produced by combined high-fat diet, nicotinamide and streptozotocin in male mice. Diabetic and control mice were treated with vehicle or the sEH inhibitor t-AUCB then subjected to 60-min MCAO. Compared to chow-fed mice, high fat diet-fed mice exhibited an upregulation of sEH mRNA and protein in brain, but no differences in brain EETs levels were observed between groups. Type 2 diabetic mice had increased blood glucose levels at baseline and throughout ischemia, decreased laser-Doppler perfusion of the MCA territory after reperfusion, and sustained larger cortical infarcts compared to control mice. t-AUCB decreased fasting glucose levels at baseline and throughout ischemia, improved cortical perfusion after MCAO and significantly reduced infarct size in diabetic mice. We conclude that sEH inhibition, as a preventative treatment, improves glycemic status, post-ischemic reperfusion in the ischemic territory, and stroke outcome in type 2 diabetic mice.

Zuloaga, Kristen L.; Krasnow, Stephanie M.; Zhu, Xinxia; Zhang, Wenri; Jouihan, Sari A.; Shangraw, Robert E.; Alkayed, Nabil J.; Marks, Daniel L.

2014-01-01

87

Antibodies to soluble liver antigen\\/liver pancreas and HLA risk factors for type 1 autoimmune hepatitis  

Microsoft Academic Search

OBJECTIVE:Antibodies to soluble liver antigen\\/liver-pancreas are highly specific markers of type 1 autoimmune hepatitis that have been associated with relapse. Our aim was to determine if these antibodies are reflective of a genetic predisposition for recrudescent disease.METHODS:One hundred forty-four white North American patients were evaluated by an enzyme immunoassay and by Western blot using recombinant soluble liver antigen\\/liver-pancreas; 122 were

Albert J. Czaja; Peter T. Donaldson; Ansgar W. Lohse

2002-01-01

88

Acute modulation of synaptic plasticity of pyramidal neurons by activin in adult hippocampus  

PubMed Central

Activin A is known as a neuroprotective factor produced upon acute excitotoxic injury of the hippocampus (in pathological states). We attempt to reveal the role of activin as a neuromodulator in the adult male hippocampus under physiological conditions (in healthy states), which remains largely unknown. We showed endogenous/basal expression of activin in the hippocampal neurons. Localization of activin receptors in dendritic spines (=postsynapses) was demonstrated by immunoelectron microscopy. The incubation of hippocampal acute slices with activin A (10 ng/mL, 0.4 nM) for 2 h altered the density and morphology of spines in CA1 pyramidal neurons. The total spine density increased by 1.2-fold upon activin treatments. Activin selectively increased the density of large-head spines, without affecting middle-head and small-head spines. Blocking Erk/MAPK, PKA, or PKC prevented the activin-induced spinogenesis by reducing the density of large-head spines, independent of Smad-induced gene transcription which usually takes more than several hours. Incubation of acute slices with activin for 2 h induced the moderate early long-term potentiation (moderate LTP) upon weak theta burst stimuli. This moderate LTP induction was blocked by follistatin, MAPK inhibitor (PD98059) and inhibitor of NR2B subunit of NMDA receptors (Ro25-6981). It should be noted that the weak theta burst stimuli alone cannot induce moderate LTP. These results suggest that MAPK-induced phosphorylation of NMDA receptors (including NR2B) may play an important role for activin-induced moderate LTP. Taken together, the current results reveal interesting physiological roles of endogenous activin as a rapid synaptic modulator in the adult hippocampus.

Hasegawa, Yoshitaka; Mukai, Hideo; Asashima, Makoto; Hojo, Yasushi; Ikeda, Muneki; Komatsuzaki, Yoshimasa; Ooishi, Yuuki; Kawato, Suguru

2014-01-01

89

Inhibines, activines et hormone anti-müllerienne : structure, signalisation, rôles et valeur prédictive en médecine de la reproduction  

Microsoft Academic Search

Anti-Müllerian hormone (AMH), inhibins and activins are members of the transforming growth factor (TGF?) superfamily and are known to have a variety of actions concerning reproduction, hormonogenesis, development processes and differentiation. Inhibins and activins are dimeric glycoproteins that are defined by their actions on the pituitary gonadotroph cells. AMH, inhibins and activins have a vast array of actions usually exerted

X Deffieux; J.-M Antoine

2003-01-01

90

Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins.  

PubMed

Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1-2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2B? protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances. PMID:23115080

Hulmi, Juha J; Oliveira, Bernardo M; Silvennoinen, Mika; Hoogaars, Willem M H; Ma, Hongqiang; Pierre, Philippe; Pasternack, Arja; Kainulainen, Heikki; Ritvos, Olli

2013-01-01

91

Exercise restores decreased physical activity levels and increases markers of autophagy and oxidative capacity in myostatin/activin-blocked mdx mice.  

PubMed

The importance of adequate levels of muscle size and function and physical activity is widely recognized. Myostatin/activin blocking increases skeletal muscle mass but may decrease muscle oxidative capacity and can thus be hypothesized to affect voluntary physical activity. Soluble activin receptor IIB (sActRIIB-Fc) was produced to block myostatin/activins. Modestly dystrophic mdx mice were injected with sActRIIB-Fc or PBS with or without voluntary wheel running exercise for 7 wk. Healthy mice served as controls. Running for 7 wk attenuated the sActRIIB-Fc-induced increase in body mass by decreasing fat mass. Running also enhanced/restored the markers of muscle oxidative capacity and autophagy in mdx mice to or above the levels of healthy mice. Voluntary running activity was decreased by sActRIIB-Fc during the first 3-4 wk correlating with increased body mass. Home cage physical activity of mice, quantified from the force plate signal, was decreased by sActRIIB-Fc the whole 7-wk treatment in sedentary mice. To understand what happens during the first weeks after sActRIIB-Fc administration, when mice are less active, healthy mice were injected with sActRIIB-Fc or PBS for 2 wk. During the sActRIIB-Fc-induced rapid 2-wk muscle growth period, oxidative capacity and autophagy were reduced, which may possibly explain the decreased running activity. These results show that increased muscle size and decreased markers of oxidative capacity and autophagy during the first weeks of myostatin/activin blocking are associated with decreased voluntary activity levels. Voluntary exercise in dystrophic mice enhances the markers of oxidative capacity and autophagy to or above the levels of healthy mice. PMID:23695214

Hulmi, Juha J; Oliveira, Bernardo M; Silvennoinen, Mika; Hoogaars, Willem M H; Pasternack, Arja; Kainulainen, Heikki; Ritvos, Olli

2013-07-15

92

Activin a plasma levels at birth: an index of fetal hypoxia in preterm newborn.  

PubMed

Activin-A is a growth factor involved in cell growth and differentiation, neuronal survival, early embryonic development and erythropoiesis. Hypoxemia is a specific trigger for increasing activin-A in fetal lamb circulation. We tested the hypothesis that fetal hypoxia induces activin-A secretion in preterm newborn infants. Fifty newborn infants with gestational ages ranging from 26 to 36 wk were enrolled in a prospective study performed at the Pediatrics, Obstetrics and Reproductive Medicine Department, University of Siena, Italy. Heparinized blood samples were obtained from the umbilical vein after cord clamping, immediately after delivery. Activin A, hypoxanthine (Hx), xanthine (Xa) plasma levels and absolute nucleated red blood cell (NRBC) count were measured. Activin-A levels (p < 0.0001) and NRBC (p < 0.0001) were significantly higher in hypoxic than in non hypoxic preterm newborns. Cord activin A levels were significantly related with Hx (taua=0.64, taub=0.64, p < 0.0001) and Xa (taua=0.56, taub=0.57, p < 0.0001) levels, NRBC ((taua=-0.45, taub=-0.46, p < 0.0001) count; pH (taua=-0.47, taub=-0.48, p < 0.0001) and base deficit (taua=-0.36, taub=0.-0.36, p = 0.0002). Preterm newborns with signs of perinatal hypoxia at birth have increased activin-A levels, suggesting that activin-A may reflect indirectly intrauterine hypoxia. PMID:12904593

Florio, Pasquale; Perrone, Serafina; Luisi, Stefano; Longini, Mariangela; Tanganelli, Donatella; Petraglia, Felice; Buonocore, Giuseppe

2003-11-01

93

The Role of Activin A and Akt/GSK Signaling in Ovarian Tumor Biology  

PubMed Central

Elevated activin A levels in serum, cyst fluid, and peritoneal fluid of ovarian cancer patients suggest a role for this peptide hormone in disease development. We hypothesize that activin A plays a role in ovarian tumor biology, and analyzed activin-mediated pro-oncogenic signaling in vitro and the expression of activin signaling pathway molecules in vivo. Activin A regulation of Akt and GSK, and the effects of repressing the activities of these molecules (with pharmacological inhibitors) on cellular proliferation were assessed in the cell line, OVCA429. Activin A activated Akt, which phosphorylated GSK, repressing GSK activity in vitro. Activin A stimulated cellular proliferation and repression of GSK augmented activin-regulated proliferation. To validate in vitro observations, immunostaining of the ?A-subunit of activin A and phospho-GSK?/? (Ser9/21) was performed, and the correlation between immunoreactivity levels of these markers and survival was evaluated in benign serous cystadenoma, borderline tumor, and cystadenocarcinoma microarrays. Analysis of tissue microarrays revealed that ?A expression in epithelia did not correlate with survival or malignancy, but expression was elevated in stromal cells from carcinomas when compared with benign tumors. Phospho-GSK?/? (Ser9/21) staining was more intense in mitotically active carcinoma cells and exhibited a polarized localization in benign neoplasms that was absent in carcinomas. Notably, lower phospho-GSK?/? (Ser9/21) immunoreactivity correlated with better survival for carcinoma patients (P = 0.046). Our data are consistent with a model in which activin A may mediate ovarian oncogenesis by activating Akt and repressing GSK to stimulate cellular proliferation.

Do, Thuy-Vy; Kubba, Lena A.; Antenos, Monica; Rademaker, Alfred W.; Sturgis, Charles D.; Woodruff, Teresa K.

2008-01-01

94

Proteomic identification of activin receptor-like kinase-1 as a differentially expressed protein during hyaloid vascular system regression.  

PubMed

The hyaloid vascular system (HVS) is a transient network of capillaries that nourishes the embryonic lens and the primary vitreous of the developing eye. We used proteomic analysis and immunohistochemical staining to identify activin receptor-like kinase-1 (ALK1), a type I receptor for transforming growth factor-beta1, during the HVS regression phase. In addition, we overexpressed ALK1 in corneas implanted with bFGF (basic fibroblast growth factor) pellets and observed that ALK1 overexpression resulted in inhibition of bFGF-induced corneal neovascularization in vivo. Our data suggest that ALK1 may play a role in HVS regression during ocular development. PMID:16223497

Albè, Elena; Escalona, Elizabeth; Rajagopal, Rama; Javier, Joel A; Chang, Jin-Hong; Azar, Dimitri T

2005-10-24

95

Identification of a new member of transforming growth factor-beta superfamily in Drosophila: the first invertebrate activin gene.  

PubMed

Activins, a subgroup of the transforming growth factor-beta (TGF-beta) superfamily, have been extensively studied in vertebrates for their roles in growth and development. However, activins are not thought to be expressed in invertebrates. The identification of the first invertebrate activin gene is reported here. A genomic clone representing 102 F region of the Drosophila chromosome 4 is found to encode a putative activin beta. The predicted protein sequence has a multibasic protease site that would generate a mature C-terminal peptide containing 113 amino acids showing > 60% similarity to the vertebrate activin beta B (inhibin beta B) sequences. A TGF-beta family signature as well as all 9 cysteine residues conserved in the vertebrate activins are also present in this mature peptide sequence. Northern blot and RT-PCR analyses indicated that the activin beta gene is expressed in embryo, larva and adult stages of Drosophila. PMID:9618266

Kutty, G; Kutty, R K; Samuel, W; Duncan, T; Jaworski, C; Wiggert, B

1998-05-29

96

Toxicity of copper salts is dependent on solubility profile and cell type tested.  

PubMed

Copper (Cu) is considered an essential metal for living organisms. However, disruption of Cu homeostasis is toxic and can lead to disorders such as Menkes and Wilson's diseases. The brain appears to be a vulnerable target organ. This study investigated the toxicity of Cu based on its solubility profile and cell type tested. Human A-172 (glioblastoma), SK-N-SH (neuroblastoma) and CCF-STTG1 (astrocytoma) cells were assessed after exposure to different concentrations (0.5-500?M) of copper sulfate (CuSO4) or copper (II) oxide (CuO). Since Cu is a redox active transition metal, we hypothesized that oxidative stress would be the main mechanism underlying cell toxicity. Therefore, cell viability was correlated with the extent of reactive oxygen species (ROS) formation. Cell viability decreased at the higher concentrations of the Cu salts and CuO was more toxic compared to CuSO4. The astrocytoma and glioblastoma cells were more vulnerable compared to the neuronal cells. Furthermore, it appears that oxidative stress only partially accounts for Cu-induced cell toxicity. Further studies are needed to better understand the unique susceptibility of glial cells and determine the physicochemical properties of insoluble Cu which accounts for its enhanced toxicity. PMID:23287045

Shaligram, Sonali; Campbell, Arezoo

2013-03-01

97

Soluble HLA-G serum levels depend on allergy type and IgE levels  

PubMed Central

Allergic rhinitis (AR) is characterized by Th2 polarized immune response. Soluble HLA (sHLA) molecules play an immunomodulatory activity. Two different studies evidenced that both patients with seasonal AR (SAR) and patients with perennial AR (PAR) had higher sHLA-G levels than normal controls. The aim of this study was to compare sHLA-G serum levels in SAR and PAR patients, also considering allergen-specific IgE. One hundred sixty-eight AR patients were enrolled, 94 with SAR and 74 with PAR. A group of 116 healthy subjects was considered as control. sHLA-G and allergen-specific IgE serum levels were determined by immunoenzymatic method. SAR patients had significantly higher levels of sHLA-G than PAR patients (p = 0.0194). sHLA-G was moderately related to allergen-specific IgE both in SAR (r = 0.497) and in PAR patients (r = 0.584). The present study provides evidence that sHLA-G serum levels depend on the type of allergy and are related to allergen-specific IgE serum levels. These findings may suggest that sHLA-G could be a biomarker of allergic reaction.

DeAmici, Mara

2014-01-01

98

Assessment of the function of the betaC-subunit of activin in cultured hepatocytes.  

PubMed

We assessed the function of the beta(C)-subunit of activin in hepatocytes. We studied the effect of conditioned medium of Chinese hamster ovary (CHO) cell line stably expressing the beta(C) gene (CHO-beta(C)) on growth of AML12 hepatocytes. We also examined the effect of recombinant activin C and transfection of the beta(C) gene by using adenovirus vector. CHO-beta(C) secreted activin C, a homodimer of the beta(C), as well as precursors of the beta(C). The conditioned medium of CHO-beta(C) increased both [(3)H]thymidine incorporation and the cell number in AML12 cells. It also supported survival of AML12 cells in a serum-free condition. Recombinant human activin C also increased both [(3)H]thymidine incorporation and the number of AML12 cells. Transfection of AML12 cells with the beta(C)-subunit led to the stimulation of [(3)H]thymidine incorporation. Analysis of the conditioned medium revealed that the beta(C)-subunit formed a heterodimer with the endogenous beta(A), the formation of which was dependent on the amount of beta(C) expressed. Recombinant activin C did not affect the binding of (125)I-activin A to its receptor or follistatin. These results indicate that activin C stimulates growth of AML12 cells. The beta(C)-subunit modifies the function of the beta(A)-subunit by multiple mechanisms. PMID:15039147

Wada, Wataru; Maeshima, Akito; Zhang, You-Qing; Hasegawa, Yoshihisa; Kuwano, Hiroyuki; Kojima, Itaru

2004-08-01

99

Activin A supplement in the hESCs culture enhances the endoderm differentiation efficiency.  

PubMed

Activin A is a critical regulator in human embryonic stem cells (hESCs) maintenance and differentiation. Different concentrations of Activin A affect hESC maintenance and differentiation in different ways. A high concentration favors anterior primitive streak and gives rise to DE if the stimulation persists. hESCs were cultured with and without 10?ng/mL Activin A supplement respectively. The two groups of cells were differentiated into endoderm cells with 100?ng/mL Activin A and other reagents. Microarray-based DNA methylation was analyzed with the Infinium Human Methylation450 BeadChip on these two groups. There was a significant difference in endoderm differentiation efficiency (average efficiency: 71 vs. 58.5%, P?Activin A supplement had an increased propensity to form definitive endoderm cells in response to Activin A and Wnt signal. Differentially Methylated Regions (DMRs) between these two groups were found. DMRs were related to the stem cell maintenance and gene regulation by peroxisome proliferators via PPAR?, indicating that hESCs maintained with Activin A supplement had stronger "stemness." PMID:24604611

Guo, Shuren; Mao, Xiaohuan; He, Fucheng; Liu, Hongchun; Ming, Liang

2014-07-01

100

Effect of glycemic control on soluble RAGE and oxidative stress in type 2 diabetic patients  

PubMed Central

Background The interaction of advanced glycation end products (AGEs) and its receptor (RAGE) has played an important role in the pathogenesis of diabetes and its complications. A soluble form of RAGE (sRAGE) has been reported as a decoy receptor for AGEs. Oxidative stress is demonstrated in pathological condition such as atherosclerosis and diabetes mellitus. It has been suggested to be involved in the pathogenesis of both macro- and microvascular complications. This study was designed to evaluate the effect of glycemic control on sRAGE and oxidative stress markers in type 2 diabetic patients. Methods Seventy patients with type 2 diabetes and 20 healthy subjects were recruited into the study. Blood glutathione (GSH) and plasma total nitric oxide (NOx) levels were measured using commercially available colorimetric kits, blood superoxide dismutase (SOD) activity was measured by the method of Marklund and Marklund, and plasma C-peptide, oxidized LDL (ox-LDL), sRAGE, and VCAM-1 levels were measured using competitive ELISA kits. Results Plasma sRAGE levels were significantly lower (p?

2013-01-01

101

Phosphodiesterase 5 restricts NOS3\\/Soluble guanylate cyclase signaling to L-type Ca 2+ current in cardiac myocytes  

Microsoft Academic Search

Endothelial nitric oxide synthase (NOS3) regulates the functional response to ?-adrenergic (?-AR) stimulation via modulation of the L-type Ca2+ current (ICa). However, the NOS3 signaling pathway modulating ICa is unknown. This study investigated the contribution of soluble guanylate cyclase (sGC) and phosphodiesterase type 5 (PDE5), a cGMP-specific PDE, in the NOS3-mediated regulation of ICa. Myocytes were isolated from NOS3 knockout

Honglan Wang; Mark J. Kohr; Christopher J. Traynham; Mark T. Ziolo

2009-01-01

102

Intermediates of adeno-associated virus type 2 assembly: identification of soluble complexes containing Rep and Cap proteins.  

PubMed Central

The proteins encoded by the adeno-associated virus type 2 (AAV-2) rep and cap genes obtained during a productive infection of HeLa cells with AAV-2 and adenovirus type 2 were fractionated according to solubility, cellular localization, and sedimentation properties. The majority of Rep and Cap proteins accumulated in the nucleus, where they distributed into a soluble and an insoluble fraction. Analysis of the soluble nuclear fraction of capsid proteins by sucrose density gradients showed that they formed at least three steady-state pools: a monomer pool sedimenting at about 6S, a pool of oligomeric intermediates sedimenting between 10 and 15S, and a broad pool of assembly products with a peak between 60 and 110S, the known sedimentation positions of empty and full capsids. While the soluble nuclear monomer and oligomer pool contained predominantly only two capsid proteins, the 30 to 180S assembly products contained VP1, VP2, and VP3 in a stoichiometry similar to that of purified virions. They probably represent different intermediates in capsid assembly, DNA encapsidation, and capsid maturation. In contrast, the cytoplasmic fraction of capsid proteins showed a pattern of oligomers continuously increasing in size without a defined peak, suggesting that assembly of 60S particles occurs in the nucleus. Soluble nuclear Rep proteins were distributed over the whole sedimentation range, probably as a result of association with AAV DNA. Subfractions of the Rep proteins with defined sedimentation values were obtained in the soluble nuclear and cytoplasmic fractions. We were able to coimmunoprecipitate capsid proteins sedimenting between 60 and 110S with antibodies against Rep proteins, suggesting that they exist in common complexes possibly involved in AAV DNA packaging. Antibodies against the capsid proteins, however, precipitated Rep78 and Rep68 predominantly with a peak around 30S representing a second complex containing Rep and Cap proteins.

Wistuba, A; Weger, S; Kern, A; Kleinschmidt, J A

1995-01-01

103

Inhibin removes the inhibitory effects of activin on steroid enzyme expression and androgen production by normal ovarian thecal cells  

PubMed Central

Activin and inhibin are important local modulators of theca cell steroidogenesis in the ovary. Using a serum-free primary theca cell culture system, this study investigated the effects of inhibin on theca cell androgen production and expression of steroidogenic enzymes. Androstenedione secretion from theca cells cultured in media containing activin, inhibin and follistatin was assessed by RIA over 144?h. Activin (1–100?ng/ml) suppressed androstenedione production. Inhibin (1–100?ng/ml) blocked the suppressive effects of added activin, but increased androstenedione production when added alone, suggesting it was blocking endogenous activin produced by theca cells. Addition of SB-431542 (activin receptor inhibitor) and follistatin (500?ng/ml) increased androstenedione production, supporting this concept. Infection of theca cells with adenoviruses expressing inhibitory Smad6 or 7 increased androstenedione secretion, confirming that the suppressive effects of activin required activation of the Smad2/3 pathway. Activin decreased the expression levels of steroidogenic acute regulatory protein (STAR), whereas STAR expression was increased by inhibin and SB-431542, alone and in combination. CYP11A was unaffected. The expression of CYP17 encoding 17?-hydroxylase was unaffected by activin but increased by inhibin and SB-431542, and when added in combination the effect was further enhanced. The expression of 3?-hydroxysteroid dehydrogenase (3?-HSD) was significantly decreased by activin, while inhibin alone and in combination with SB-431542 both potently increased the expression of 3?-HSD. In conclusion, activin suppressed theca cell androstenedione production by decreasing the expression of STAR and 3?-HSD. Inhibin and other blockers of activin action reversed this effect, supporting the concept that endogenous thecal activin modulates androgen production in theca cells.

Young, J M; McNeilly, A S

2012-01-01

104

An Activin Receptor IA/Activin-Like Kinase-2 (R206H) Mutation in Fibrodysplasia Ossificans Progressiva.  

PubMed

Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disease that is characterised by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomical areas. This disease is caused by a mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2). A Mexican family with one member affected by FOP was studied. The patient is a 19-year-old female who first presented with symptoms of FOP at 8 years old; she developed spontaneous and painful swelling of the right scapular area accompanied by functional limitation of movement. Mutation analysis was performed in which genomic DNA as PCR amplified using primers flanking exons 4 and 6, and PCR products were digested with Cac8I and HphI restriction enzymes. The most informative results were obtained with the exon 4 flanking primers and the Cac8I restriction enzyme, which generated a 253 bp product that carries the ACVR1 617G>A mutation, which causes an amino acid substitution of histidine for arginine at position 206 of the glycine-serine (GS) domain, and its mutation results in the dysregulation of bone morphogenetic protein (BMP) signalling that causes FOP. PMID:23653868

Herrera-Esparza, Rafael; Pacheco-Tovar, Deyanira; Bollain-Y-Goytia, Juan José; Torres Del Muro, Felipe; Ramírez-Sandoval, Roxana; Pacheco-Tovar, María Guadalupe; Castañeda-Ureña, María; Avalos-Díaz, Esperanza

2013-01-01

105

An Activin Receptor IA/Activin-Like Kinase-2 (R206H) Mutation in Fibrodysplasia Ossificans Progressiva  

PubMed Central

Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disease that is characterised by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomical areas. This disease is caused by a mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2). A Mexican family with one member affected by FOP was studied. The patient is a 19-year-old female who first presented with symptoms of FOP at 8 years old; she developed spontaneous and painful swelling of the right scapular area accompanied by functional limitation of movement. Mutation analysis was performed in which genomic DNA as PCR amplified using primers flanking exons 4 and 6, and PCR products were digested with Cac8I and HphI restriction enzymes. The most informative results were obtained with the exon 4 flanking primers and the Cac8I restriction enzyme, which generated a 253 bp product that carries the ACVR1 617G>A mutation, which causes an amino acid substitution of histidine for arginine at position 206 of the glycine-serine (GS) domain, and its mutation results in the dysregulation of bone morphogenetic protein (BMP) signalling that causes FOP.

Pacheco-Tovar, Deyanira; Bollain-y-Goytia, Juan Jose; Torres del Muro, Felipe; Ramirez-Sandoval, Roxana; Pacheco-Tovar, Maria Guadalupe; Castaneda-Urena, Maria; Avalos-Diaz, Esperanza

2013-01-01

106

Soluble IFN receptor potentiates in vivo type I IFN signaling and exacerbates TLR4-mediated septic shock.  

PubMed

Circulating levels of a soluble type I IFNR are elevated in diseases, such as chronic inflammation, infections, and cancer, but whether it functions as an antagonist, agonist, or transporter is unknown. In this study, we elucidate the in vivo importance of the soluble type I IFNAR, soluble (s)IFNAR2a, which is generated by alternative splicing of the Ifnar2 gene. A transgenic mouse model was established to mimic the 10-15-fold elevated expression of sIFNAR2a observed in some human diseases. We generated transgenic mouse lines, designated SolOX, in which the transgene mRNA and protein-expression patterns mirrored the expression patterns of the endogenous gene. SolOX were demonstrated to be more susceptible to LPS-mediated septic shock, a disease model in which type I IFN plays a crucial role. This effect was independent of "classical" proinflammatory cytokines, such as TNF-? and IL-6, whose levels were unchanged. Because the increased levels of sIFNAR2a did not affect the kinetics of the increased interferonemia, this soluble receptor does not potentiate its ligand signaling by improving IFN pharmacokinetics. Mechanistically, increased levels of sIFNAR2a are likely to facilitate IFN signaling, as demonstrated in spleen cells overexpressing sIFNAR2a, which displayed quicker, higher, and more sustained activation of STAT1 and STAT3. Thus, the soluble IFNR is an important agonist of endogenous IFN actions in pathophysiological processes and also is likely to modulate the therapeutic efficacy of clinically administered IFNs. PMID:24696235

Samarajiwa, Shamith A; Mangan, Niamh E; Hardy, Matthew P; Najdovska, Meri; Dubach, Daphne; Braniff, Susie-Jane; Owczarek, Catherine M; Hertzog, Paul J

2014-05-01

107

Recombinant soluble CD137 prevents type one diabetes in nonobese diabetic mice.  

PubMed

Nonobese diabetic (NOD) mice are genetically programmed to spontaneously develop type one diabetes (T1D). Multiple Insulin dependent diabetes (Idd) genetic loci have been identified but their functional effects are mostly poorly understood. TnfsfR9, expressing the protein product CD137, is a strong candidate gene in the Idd9.3 locus, and NOD.B10 Idd9.3 mice are significantly protected from type one diabetes (T1D). We previously showed that nonobese diabetic (NOD) mice have a deficiency in the numbers of CD137(pos) T regulatory cells, that CD137(pos) Tregs are the source of soluble CD137 (sCD137), and that NOD mice have low serum levels of sCD137. To test the hypothesis that correcting low levels of sCD137 could affect the disease, we constructed a lentiviral vector producing recombinant sCD137; this physiologic sCD137 is glycosylated and exists primarily as a dimer. NOD mice treated with the recombinant sCD137 are protected from developing T1D. Insulitis is significantly decreased, but not eliminated in the sCD137 treated mice, however insulin producing pancreatic beta cells are preserved despite residual insulitis. To begin to understand the protective immune mechanisms of sCD137, we tested sCD137 in vitro. It was previously suggested that sCD137 simply blocked the interaction between CD137 (on T cells) and CD137 ligand (on antigen presenting cells (APCs)). Here however, we use an APC independent assay and demonstrate that sCD137 can actively suppress highly purified CD4 T cells in a CD137L dependent fashion. These results support the hypothesis that sCD137 acts in a negative feedback loop to actively suppress over-zealous immune responses, and that it can be used clinically to suppress autoimmunity. sCD137 is an important Treg derived natural immunosuppressive molecule that regulates effector T cells to avert diabetes in vivo. PMID:24145149

Kachapati, Kritika; Bednar, Kyle J; Adams, David E; Wu, Yuehong; Mittler, Robert S; Jordan, Michael B; Hinerman, Jennifer M; Herr, Andrew B; Ridgway, William M

2013-12-01

108

EVects of soluble interleukin-1 type II receptor on rabbit antigen-induced arthritis: clinical, biochemical and histological assessment  

Microsoft Academic Search

Objectives. To investigate the eVects of soluble interleukin-1 (IL-1) type II receptor (sIL-1RII ) on a number of clinical, biochemical and histological parameters in rabbit antigen- induced arthritis. Methods. Arthritis was induced by intra-articular injection of methylated bovine serum albumin (mBSA) into rabbits pre-sensitized to the same antigen. An initial i.v. bolus of sIL-1RII was administered, followed by s.c. mini-pump

J. Dawson; P. Engelhardt; T. Kastelic; D. Cheneval; A. MacKenzie; P. Ramage

1999-01-01

109

Potential delivery of water-soluble protein hydrolysates to marine suspension feeders by three different microbound particle types  

Microsoft Academic Search

Spray-dried zein particles (SDZP), spray-water zein particles (SWZP) and gelatin-alginate beads (GAB) were prepared containing a defined dietary mixture and their performances were compared for delivering the soluble fraction of protein hydrolysates. Measures of performances of these three different microbound particle (MBP) types included inclusion, encapsulation, retention and delivery efficiencies in addition to T50 (time to 50% retention) values.SDZP had

Umur Önal; Chris Langdon

2009-01-01

110

Endogenous protection derived from activin A/Smads transduction loop stimulated via ischemic injury in PC12 cells.  

PubMed

Activin A (ActA), a member of transforming growth factor-beta (TGF-b) super- family, affects many cellular processes, including ischemic stroke. Though the neuroprotective effects of exogenous ActA on oxygen-glucose deprivation (OGD) injury have already been reported by us, the endogenous role of ActA remains poorly understood. To further define the role and mechanism of endogenous ActA and its signaling in response to acute ischemic damage, we used an OGD model in PC12 cells to simulate ischemic injury on neurons in vitro. Cells were pre-treated by monoclonal antibody against activin receptor type IIA (ActRII-Ab). We found that ActRII-Ab augments ischemic injury in PC12 cells. Further, the extracellular secretion of ActA as well as phosphorylation of smad3 in PC12 cells was also up-regulated by OGD, but suppressed by ActRII-Ab. Taken together, our results show that ActRII-Ab may augment ischemic injury via blocking of transmembrane signal transduction of ActA, which confirmed the existence of endogenous neuroprotective effects derived from the ActA/Smads pathway. ActRIIA plays an important role in transferring neuronal protective signals inside. It is highly possible that ActA transmembrance signaling is a part of the positive feed-back loop for extracellular ActA secretion. PMID:24141247

Mang, Jing; Mei, Chun-Li; Wang, Jiao-Qi; Li, Zong-Shu; Chu, Ting-Ting; He, Jin-Ting; Xu, Zhong-Xin

2013-01-01

111

Suppression of activin A in autoimmune lung disease associated with anti-GM-CSF.  

PubMed

Pulmonary alveolar proteinosis (PAP) is an autoimmune disorder characterized by neutralizing autoantibodies to granulocyte-macrophage colony stimulating factor (GM-CSF). Surfactant metabolism is severely dysregulated in PAP, resulting in a foam cell appearance of alveolar macrophages. Microarray analysis of RNA from PAP bronchoalveolar lavage (BAL) cells to explore autoimmune-related genes yielded evidence of a deficiency of activin A, a cytokine implicated in regulation of B-cell proliferation and reduction of foam cell formation. Subsequent studies confirmed a severe deficiency of activin A gene expression and protein secretion in PAP BAL cells and marked reduction of activin A protein in PAP BAL fluids compared to healthy controls. PAP cells, however, like those of healthy controls, were capable of elevated activin A production in response to GM-CSF. Treatment with activin A in vitro suppressed proliferation of PAP peripheral blood B-cells in a receptor-dependent manner and also reduced secretion of anti-GM-CSF autoantibody. These studies are the first to suggest that activin A may play a role in autoimmune disease. PMID:16337108

Bonfield, Tracey L; Barna, Barbara P; John, Nejimol; Malur, Anagha; Culver, Daniel A; Kavuru, Mani S; Thomassen, Mary Jane

2006-02-01

112

Activin A and follistatin as biomarkers for ectopic pregnancy and missed abortion.  

PubMed

Activin A as a predictor of pregnancy failure has been the focus of heated debate, but the value of a combined activin A and follistatin (FS) measurement in serum to predict pregnancy failure has not been reported yet. We assessed whether a single serum measurement of the two physiological antagonists at 6-8 weeks gestation could differentiate ectopic pregnancies (EP) or missed abortions (MA) from healthy intrauterine pregnancies (IUP). activin A concentrations were significantly lower in women with EP (n = 30, median value of 264 pg/mL) and women with MA (n = 30, median value of 350 pg/mL) compared to IUP (n = 33, median value of 788 pg/mL); P < 0.001. At a threshold value of 505 pg/mL, activin A had 87.9% sensitivity and 100% specificity and negative predictive value of 0.974 for discriminating an ectopic pregnancy from viable pregnancies. FS was able to discriminate IUP from EP (ROC curve P < 0.001) as was their ratio (ROC curve P = 0.008), but was unable to discriminate a MA from an EP. In EP, activin A did not correlate with beta HCG levels. The present findings support the thesis that activin A or FS could be considered promising biomarkers for the discrimination between an IUP and a failed pregnancy (MA or EP). PMID:24222717

Daponte, Alexandros; Deligeoroglou, Efthimios; Garas, Antonios; Pournaras, Spyros; Hadjichristodoulou, Christos; Messinis, Ioannis E

2013-01-01

113

Activin A decreases glucagon and arx gene expression in alpha-cell lines.  

PubMed

Activin A is a potent growth and differentiation factor involved in development, differentiation, and physiological functions of the endocrine pancreas; it increases insulin and pax4 gene expression in beta-cells and can induce transdifferentiation of the exocrine acinar cell line AR42J into insulin-producing cells. We show here that Activin A decreases glucagon gene expression in the alpha-cell lines InR1G9 and alphaTC1 in a dose- and time-dependent manner and that the effect is blocked by Follistatin. This effect is also observed in adult human islets. Glucagon gene expression is inhibited at the transcriptional level by the Smad signaling pathway through the G3 DNA control element. Furthermore, Activin A decreases cell proliferation of InR1G9 and alphaTC1 cells as well as cyclin D2 and arx gene expression, whose protein product Arx has been shown to be critical for alpha-cell differentiation. Overexpression of Arx in Activin A-treated InR1G9 cells does not prevent the decrease in glucagon gene expression but corrects the inhibition of cell proliferation, indicating that Arx mediates the Activin A effects on the cell cycle. We conclude that Activin A has opposite effects on alpha-cells compared with beta-cells, a finding that may have relevance during pancreatic endocrine lineage specification and physiological function of the adult islets. PMID:16988001

Mamin, Aline; Philippe, Jacques

2007-01-01

114

TGFbeta/Activin/Nodal pathway in inhibition of human embryonic stem cell differentiation by mechanical strain.  

PubMed

Cyclic biaxial mechanical strain has been reported to inhibit human embryonic stem cell differentiation without selecting against survival of differentiated or undifferentiated cells. We show that TGFbeta/Activin/Nodal signaling plays a crucial role in repression of human embryonic stem cell (hESC) differentiation under mechanical strain. Strain-induced transcription of TGFbeta1, Activin A, and Nodal, and upregulated Similar to Mothers Against Decapentaplegic homolog (Smad)2/3 phosphorylation in undifferentiated hESC. TGFbeta/Activin/Nodal receptor inhibitor SB431542 stimulated differentiation of hESCs cultured under biaxial strain. Exogenous addition of TGFbeta1, Activin A, or Nodal alone was insufficient to stimulate hESC self-renewal to replicate behavior of hESCs in presence of strain. However, exogenous TGFbeta1 and Activin A in combination partially replicated the self-renewing phenotype induced by strain but when combined with strain did not further stimulate self-renewal. In presence of mechanical strain, addition of a neutralizing antibody to TGFbeta1 promoted hESC differentiation whereas inhibition of Activin A by Follistatin promoted hESC differentiation to a lesser extent. Together, these findings show that TGFbeta superfamily activation of Smad2/3 is required for repression of spontaneous differentiation under strain and suggest that strain may induce autocrine or paracrine signaling through TGFbeta superfamily ligands. PMID:18234825

Saha, Somen; Ji, Lin; de Pablo, Juan J; Palecek, Sean P

2008-05-15

115

[Role of Activin A and Myostatin in cancer cachexia].  

PubMed

Recent works suggest that Activin A (ActA) and Myostatin (Mstn), two members of the TGF? superfamily, could contribute to skeletal muscle atrophy observed in some cancers. It is known that several human tumoral cell lines synthesize and secrete ActA and Mstn. In addition, systemic treatment with ActA and Mstn in mice induce muscle atrophy. Likewise, Inhibin-? knock-out mice, which are characterized by elevated circulating levels of ActA, exhibit muscle atrophy and die of cachexia. Finally, administration of ActA and Mstn antagonists prevents muscular atrophy and mortality induced by some animal tumors. Collectively, these findings suggest that ActA or Mstn production by several cancers could contribute to cachexia and thus to mortality associated with some cancers in human. This hypothesis is very interesting since new molecules that are able to inhibit ActA and Mstn, in particularly the sActRIIB, are under development. PMID:23566617

Thissen, Jean-Paul; Loumaye, Audrey

2013-05-01

116

Development of High Temperature Type Vacuum Insulation Panel using Soluble Polyimide and Characteristic Evaluation  

Microsoft Academic Search

The utilization is expected from the high-insulated characteristic as a tool for energy saving also in the high temperature insulation fields as in vacuum insulation panels (VIP) in the future. For high temperature, the material composition and process of VIP were reviewed, the SUS foil was adopted as packaging material, and soluble polyimide was developed as the thermo compression bonding

Kuninari Araki; Daigorou Kamoto; Shin-Ichi Matsuoka

2009-01-01

117

Development of High Temperature Type Vacuum Insulation Panel using Soluble Polyimide and Characteristic Evaluation  

NASA Astrophysics Data System (ADS)

The utilization is expected from the high-insulated characteristic as a tool for energy saving also in the high temperature insulation fields as in vacuum insulation panels (VIP) in the future. For high temperature, the material composition and process of VIP were reviewed, the SUS foil was adopted as packaging material, and soluble polyimide was developed as the thermo compression bonding material for high temperature VIP at 150°C. To lower the glass-transition temperature (Tg) under 200°C, we elaborated the new soluble polyimide using aliphatic diamine copolymer, and controlled Tg to about 176°C. By making from trial VIP and evaluations, it was possible to be maintain high performance concerning the coefficient of thermal conductivity [?<0.008 W/(m·K) at 150°C].

Araki, Kuninari; Kamoto, Daigorou; Matsuoka, Shin-Ichi

118

Spontaneously forming hydrogel from water-soluble random- and block-type phospholipid polymers  

Microsoft Academic Search

The mixed aqueous solutions of two water-soluble phospholipid polymers, such as poly[2-methacryloyloxyethyl phosphorylcholine(MPC)-co-methacrylic acid(MA)] (rPMA) and poly[MPC-co-n-butyl methacrylate(BMA)] (PMB), spontaneously form a hydrogel at room temperature without any chemical treatment due to hydrogen bonding formation between the carboxyl groups. With the objective of enhancing the hydrogen bonding efficiency, we have focused on the density of the carboxyl groups by controlling

Mizuna Kimura; Kikuko Fukumoto; Junji Watanabe; Madoka Takai; Kazuhiko Ishihara

2005-01-01

119

Serum activin A and B, and follistatin in critically ill patients with influenza A(H1N1) infection  

PubMed Central

Background Activin A and its binding protein follistatin (FS) are increased in inflammatory disorders and sepsis. Overexpression of activin A in the lung causes similar histopathological changes as acute respiratory distress syndrome (ARDS). ARDS and severe respiratory failure are complications of influenza A(H1N1) infection. Interleukin 6 (IL-6), which in experimental studies increases after activin A release, is known to be related to the severity of H1N1 infection. Our aim was to evaluate the levels of activin A, activin B, FS, IL-6 and IL-10 and their association with the severity of respiratory failure in critically ill H1N1 patients. Methods A substudy of a prospective, observational cohort of H1N1 patients in Finnish intensive care units (ICU). Clinical information was recorded during ICU treatment, and serum activin A, activin B, FS, IL-6 and IL-10 were measured at admission to ICU and on days 2 and 7. Results Blood samples from 29 patients were analysed. At the time of admission to intensive care unit, elevated serum levels above the normal range for respective age group and sex were observed in 44% for activin A, 57% for activin B, and 39% for FS. In 13 of the 29 patients, serial samples at all time points were available and in these the highest activin A, activin B and FS were above the normal range in 85%, 100% and 46% of the patients, respectively. No difference in baseline or highest activin A or activin B was found in patients with or without acute lung injury (ALI) or ARDS (P?>?0.05 for all). Peak levels of IL-6 were significantly elevated in ALI/ARDS patients. Peak activin A and activin A/FS were associated with ventilatory support free-days, severity of acute illness and length of ICU stay (P?

2014-01-01

120

Identification of gene networks modulated by activin in LbetaT2 cells using DNA microarray analysis.  

PubMed

Activins, members of the TGFbeta family of proteins, are widely expressed in a variety of tissues. First identified based on their ability to regulate biosynthesis and secretion of follicle-stimulating hormone (FSH), activins have also been shown to modulate development, cell growth, apoptosis, and inflammation. Despite their many known functions, the precise mechanisms and downstream signaling pathways by which activins mediate their diverse effects remain unknown. We have used a DNA microarray assay to identify genes that are regulated by activin, alone or in combination with gonadotropin-releasing hormone (GnRH), another major regulator of FSH, in a murine gonadotrope-derived cell line (LbetaT2). We used mRNA from these cells to screen Affymetrix Mu74av2 mouse Gene Chip oligonucleotide microarrays, representing approximately 12,400 mouse genes. Treatment of LbetaT2 cells with activin A, a gonadotropin-releasing hormone agonist (GnRHA) or activin A plus GnRHA resulted in alterations in levels of gene expression that ranged in magnitude from 15 to 67-fold. Data analysis identified 268 transcripts that were up- or down-regulated by two-fold or more. Distinct sets of genes were affected by treatment with activin, GnRHA and activin plus GnRHA, suggesting interactions between activin and GnRHA. Changes in expression of seven randomly selected representative genes identified by the microarray technique were confirmed by real-time quantitative PCR and semi-quantitative reverse transcription/PCR (RT/PCR). Modulation of expression of genes by activin suggests that activin may mediate its effects through a variety of signaling pathways. PMID:16329041

Mazhawidza, W; Winters, S J; Kaiser, U B; Kakar, S S

2006-02-01

121

Activin Modulates the Transcriptional Response of L?T2 Cells to Gonadotropin-Releasing Hormone and Alters Cellular Proliferation  

PubMed Central

Both GnRH and activin are crucial for the correct function of pituitary gonadotrope cells. GnRH regulates LH and FSH synthesis and secretion and gonadotrope proliferation, whereas activin is essential for expression of FSH. Little is known, however, about the interplay of signaling downstream of these two hormones. In this study, we undertook expression profiling to determine how activin pre-treatment alters the transcriptional response of L?T2 gonadotrope cells to GnRH stimulation. Activin treatment alone altered the transcriptional profile of 303 genes including inducing that of the 17?-hydroxysteroid dehydrogenase B1 gene that converts estrone to 17?-estradiol, altering the sensitivity of the cells to estrone. Furthermore, activin had a dramatic effect on the response of L?T2 cells to GnRH. Hierarchical clustering of 2453 GnRH-responsive genes identified groups of genes the response of which to GnRH was either enhanced or blunted after activin treatment. Mapping of these genes to gene ontology classifications or signaling pathways highlighted significant differences in the classes of altered genes. In the presence of activin, GnRH regulates genes in pathways controlling cell energetics, cytoskeletal rearrangements, organelle organization, and mitosis in the absence of activin, but genes controlling protein processing, cell differentiation, and secretion. Therefore, we demonstrated that activin enhanced GnRH induction of p38MAPK activity, caused GnRH-dependent phosphorylation of p53, and reduced the ability of GnRH to cause G1 arrest. Thus, although activin alone changes a modest number of transcripts, activin pretreatment dramatically alters the response to GnRH from an antiproliferative response to a more differentiated, synthetic response appropriate for a secretory cell.

Zhang, Hao; Bailey, Janice S.; Coss, Djurdjica; Lin, Bo; Tsutsumi, Rie; Lawson, Mark A.; Mellon, Pamela L.; Webster, Nicholas J. G.

2009-01-01

122

Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity  

PubMed Central

Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of ?-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or ?-cell function but does influence islet mass and proportion of ?-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets.

Bonomi, Lara; Brown, Melissa; Ungerleider, Nathan; Muse, Meghan; Matzuk, Martin M.

2012-01-01

123

Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through Smad3 and ERK1\\/ERK2 MAPK signaling pathways  

Microsoft Academic Search

Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons. However, the role of activin in regulating neuro- transmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood. In the present study, we report that activin A and basic fibroblast growth factor

Y L Bao; K Tsuchida; B Liu; A Kurisaki; T Matsuzaki; H Sugino

2005-01-01

124

Serum Activin A and Follistatin Levels in Gestational Diabetes and the Association of the Activin A-Follistatin System with Anthropometric Parameters in Offspring  

PubMed Central

Context The Activin A-Follistatin system has emerged as an important regulator of lipid and glucose metabolism with possible repercussions on fetal growth. Objective To analyze circulating activin A, follistatin and follistatin-like-3 (FSTL3) levels and their relationship with glucose metabolism in pregnant women and their influence on fetal growth and neonatal adiposity. Design and methods A prospective cohort was studied comprising 207 pregnant women, 129 with normal glucose tolerance (NGT) and 78 with gestational diabetes mellitus (GDM) and their offspring. Activin A, follistatin and FSTL3 levels were measured in maternal serum collected in the early third trimester of pregnancy. Serial fetal ultrasounds were performed during the third trimester to evaluate fetal growth. Neonatal anthropometry was measured to assess neonatal adiposity. Results Serum follistatin levels were significantly lower in GDM than in NGT pregnant women (8.21±2.32 ng/mL vs 9.22±3.41, P?=?0.012) whereas serum FSTL3 and activin A levels were comparable between the two groups. Serum follistatin concentrations were negatively correlated with HOMA-IR and positively with ultrasound growth parameters such as fractional thigh volume estimation in the middle of the third trimester and percent fat mass at birth. Also, in the stepwise multiple linear regression analysis serum follistatin levels were negatively associated with HOMA-IR (??=??0.199, P?=?0.008) and the diagnosis of gestational diabetes (??=??0.138, P?=?0.049). Likewise, fractional thigh volume estimation in the middle of third trimester and percent fat mass at birth were positively determined by serum follistatin levels (??=?0.214, P?=?0.005 and ??=?0.231, P?=?0.002, respectively). Conclusions Circulating follistatin levels are reduced in GDM compared with NGT pregnant women and they are positively associated with fetal growth and neonatal adiposity. These data suggest a role of the Activin-Follistatin system in maternal and fetal metabolism during pregnancy.

Naf, Silvia; Escote, Xavier; Ballesteros, Monica; Yanez, Rosa Elena; Simon-Muela, Inmaculada; Gil, Pilar; Albaiges, Gerard

2014-01-01

125

Expression of immunoreactive activin A protein in remodeling lesions associated with interstitial pulmonary fibrosis.  

PubMed Central

The expression of activin A, one of the transforming growth factor-beta supergene family, was studied in various pulmonary conditions associated with interstitial pulmonary fibrosis (3 cases with diffuse alveolar damage, 6 cases with idiopathic pulmonary fibrosis, and 1 case with pulmonary fibrosis associated with rheumatoid arthritis) using immunohistochemical techniques on paraffin-embedded sections. Controls consisted of 10 cases with normal pulmonary parenchyma, and 2 cases with primary pulmonary hypertension and 1 case with secondary pulmonary hypertension were also studied. The lung specimens from normal parenchyma weakly expressed immunoreactive activin A on the bronchiolar epithelium. In marked contrast, all of the specimens from cases with diffuse alveolar damage and interstitial pulmonary fibrosis demonstrated strong expression of activin A on metaplastic epithelium, hyperplastic smooth muscle cells, desquamated cells, and alveolar macrophages. Pulmonary arteries from patients with primary or secondary pulmonary hypertension showed abundant immunoreactive activin A on smooth muscle cells. These findings suggest a potential role for this growth factor, activin A, in the pathogenesis of pulmonary tissue remodeling associated with interstitial pulmonary fibrosis. Images Figure 1 Figure 2 Figure 3

Matsuse, T.; Ikegami, A.; Ohga, E.; Hosoi, T.; Oka, T.; Kida, K.; Fukayama, M.; Inoue, S.; Nagase, T.; Ouchi, Y.; Fukuchi, Y.

1996-01-01

126

Gonadotropic Control of Secretion of Dimeric Inhibins and Activin A by Human Granulosa–Luteal Cells In Vitro  

Microsoft Academic Search

Purpose: It is well established that human granulosa cells and luteal cells express inhibin\\/activin subunit protein and secrete immunoreactive inhibin. The gonadotropic control of secretion of different molecular forms of inhibin and activin A by granulose–luteal cells (G-LCs) was investigated using recently developed specific enzyme immunoassays (EIAs).

Shanthi Muttukrishna; Nigel Groome; William Ledger

1997-01-01

127

Muscle growth in teleost fish is regulated by factors utilizing the activin II B receptor.  

PubMed

The activin type IIB receptor (Acvr2b) is the cell surface receptor for multiple transforming growth factor ? (TGF-?) superfamily ligands, several of which regulate muscle growth in mammals. To investigate the role of the Acvr2b signaling pathway in the growth and development of skeletal muscle in teleost fish, transgenic rainbow trout (RBT; Oncorhynchus mykiss) expressing a truncated form of the acvr2b-2a (acvr2b(?)) in muscle tissue were produced. High levels of acvr2b(?) expression were detected in the majority of P1 transgenic fish. Transgenic P1 trout developed enhanced, localized musculature in both the epaxial and hypaxial regions (dubbed 'six pack'). The F1 transgenic offspring did not exhibit localized muscle growth, but rather developed a uniform body morphology with greater girth, condition factor and increased muscle fiber hypertrophy. There was a high degree of variation in the mass of both P1 and F1 transgenic fish, with several fish of each generation exhibiting enhanced growth compared with other transgenic and control siblings. The 'six pack' phenotype observed in P1 transgenic RBT overexpressing acvr2b(?) and the presence of F1 individuals with altered muscle morphology provides compelling evidence for the importance of TGF-? signaling molecules in regulating muscle growth in teleost fish. PMID:23788712

Phelps, Michael P; Jaffe, Ian M; Bradley, Terence M

2013-10-01

128

Follistatin antagonizes activin signaling and acts with notum to direct planarian head regeneration.  

PubMed

Animals establish their body plans in embryogenesis, but only a few animals can recapitulate this signaling milieu for regeneration after injury. In planarians, a pluripotent stem cell population and perpetual signaling of polarity axes collaborate to direct a steady replacement of cells during homeostasis and to power robust regeneration after even severe injuries. Several studies have documented the roles of conserved signaling pathways in maintaining and resetting axial polarity in planarians, but it is unclear how planarians reestablish polarity signaling centers after injury and whether these centers serve to influence identity decisions of stem cell progeny during their differentiation. Here we find that a planarian Follistatin homolog directs regeneration of anterior identity by opposing an Activin/ActR-1/Smad2/3 signaling pathway. Follistatin and Notum, a Wnt inhibitor, are mutually required to reestablish an anterior signaling center that expresses both cues. Furthermore, we show that the direction of cells down particular differentiation paths requires regeneration of this anterior signaling center. Just as its amphibian counterpart in the organizer signals body plan and cell fate during embryogenesis, planarian Follistatin promotes reestablishment of anterior polarity during regeneration and influences specification of cell types in the head and beyond. PMID:23297191

Roberts-Galbraith, Rachel H; Newmark, Phillip A

2013-01-22

129

Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine ?-thalassemia  

PubMed Central

In ?-thalassemia, unequal production of ?- and ?-globin chains in erythroid precursors causes apoptosis and inhibition of late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Here we used a murine model of ?-thalassemia intermedia (Hbbth1/th1 mice) to investigate effects of a modified activin receptor type IIB (ActRIIB) ligand trap (RAP-536) that inhibits Smad2/3 signaling. In Hbbth1/th1 mice, treatment with RAP-536 reduced overactivation of Smad2/3 in splenic erythroid precursors. In addition, treatment of Hbbth1/th1 mice with RAP-536 reduced ?-globin aggregates in peripheral red cells, decreased the elevated reactive oxygen species present in erythroid precursors and peripheral red cells, and alleviated anemia by promoting differentiation of late-stage erythroid precursors and reducing hemolysis. Notably, RAP-536 treatment mitigated disease complications of IE, including iron overload, splenomegaly, and bone pathology, while reducing erythropoietin levels, improving erythrocyte morphology, and extending erythrocyte life span. These results implicate signaling by the transforming growth factor-? superfamily in late-stage erythropoiesis and reveal potential of a modified ActRIIB ligand trap as a novel therapeutic agent for thalassemia syndrome and other red cell disorders characterized by IE.

Suragani, Rajasekhar N. V. S.; Cawley, Sharon M.; Li, Robert; Wallner, Samantha; Alexander, Mark J.; Mulivor, Aaron W.; Gardenghi, Sara; Rivella, Stefano; Grinberg, Asya V.; Pearsall, R. Scott

2014-01-01

130

Follistatin antagonizes Activin signaling and acts with Notum to direct planarian head regeneration  

PubMed Central

Animals establish their body plans in embryogenesis, but only a few animals can recapitulate this signaling milieu for regeneration after injury. In planarians, a pluripotent stem cell population and perpetual signaling of polarity axes collaborate to direct a steady replacement of cells during homeostasis and to power robust regeneration after even severe injuries. Several studies have documented the roles of conserved signaling pathways in maintaining and resetting axial polarity in planarians, but it is unclear how planarians reestablish polarity signaling centers after injury and whether these centers serve to influence identity decisions of stem cell progeny during their differentiation. Here we find that a planarian Follistatin homolog directs regeneration of anterior identity by opposing an Activin/ActR-1/Smad2/3 signaling pathway. Follistatin and Notum, a Wnt inhibitor, are mutually required to reestablish an anterior signaling center that expresses both cues. Furthermore, we show that the direction of cells down particular differentiation paths requires regeneration of this anterior signaling center. Just as its amphibian counterpart in the organizer signals body plan and cell fate during embryogenesis, planarian Follistatin promotes reestablishment of anterior polarity during regeneration and influences specification of cell types in the head and beyond.

Roberts-Galbraith, Rachel H.; Newmark, Phillip A.

2013-01-01

131

Modified activin receptor IIB ligand trap mitigates ineffective erythropoiesis and disease complications in murine ?-thalassemia.  

PubMed

In ?-thalassemia, unequal production of ?- and ?-globin chains in erythroid precursors causes apoptosis and inhibition of late-stage erythroid differentiation, leading to anemia, ineffective erythropoiesis (IE), and dysregulated iron homeostasis. Here we used a murine model of ?-thalassemia intermedia (Hbb(th1/th1) mice) to investigate effects of a modified activin receptor type IIB (ActRIIB) ligand trap (RAP-536) that inhibits Smad2/3 signaling. In Hbb(th1/th1) mice, treatment with RAP-536 reduced overactivation of Smad2/3 in splenic erythroid precursors. In addition, treatment of Hbb(th1/th1) mice with RAP-536 reduced ?-globin aggregates in peripheral red cells, decreased the elevated reactive oxygen species present in erythroid precursors and peripheral red cells, and alleviated anemia by promoting differentiation of late-stage erythroid precursors and reducing hemolysis. Notably, RAP-536 treatment mitigated disease complications of IE, including iron overload, splenomegaly, and bone pathology, while reducing erythropoietin levels, improving erythrocyte morphology, and extending erythrocyte life span. These results implicate signaling by the transforming growth factor-? superfamily in late-stage erythropoiesis and reveal potential of a modified ActRIIB ligand trap as a novel therapeutic agent for thalassemia syndrome and other red cell disorders characterized by IE. PMID:24795345

Suragani, Rajasekhar N V S; Cawley, Sharon M; Li, Robert; Wallner, Samantha; Alexander, Mark J; Mulivor, Aaron W; Gardenghi, Sara; Rivella, Stefano; Grinberg, Asya V; Pearsall, R Scott; Kumar, Ravindra

2014-06-19

132

Influence of the presence of Co on the rare earth solubility in M-type hexaferrite powders  

NASA Astrophysics Data System (ADS)

Sr 1-xRE xFe 12O 19 and Sr 1-xRE xFe 12-xCo xO 19 ( x=0-0.4 and RE=Pr, Nd) M-type hexaferrite powders were produced according to a conventional ceramic process. The X-ray diffraction analysis of the calcinated material reveals the presence of secondary ?-Fe 2O 3, PrFeO 3 or NdFeO 3 and CoFe 2O 4 phases in substituted samples, with proportions that increase with x. However, for the same x value, the proportion of secondary phases is lower in Co-containing powders than in Co-free powders. This indicates that the presence of Co in the M-type phase increases the solubility of the rare earth. The results of the Mössbauer investigation indicate that the solubility of Pr is higher than that of Nd in Co-containing samples.

Lechevallier, L.; Le Breton, J. M.; Morel, A.; Tenaud, P.

2007-09-01

133

Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells  

PubMed Central

The activin A-myostatin-follistatin system is thought to play an important role in the regulation of muscle and bone mass throughout growth, development, and aging; however, the effects of these ligands on progenitor cell proliferation and differentiation in muscle and bone are not well understood. In addition, age-associated changes in the relative expression of these factors in musculoskeletal tissues have not been described. We therefore examined changes in protein levels of activin A, follistatin, and myostatin (GDF-8) in both muscle and bone with age in C57BL6 mice using ELISA. We then investigated the effects of activin A, myostatin and follistatin on the proliferation and differentiation of primary myoblasts and mouse bone marrow stromal cells (BMSCs) in vitro. Myostatin levels and the myostatin:follistatin ratio increased with age in the primarily slow-twitch mouse soleus muscle, whereas the pattern was reversed with age in the fast-twitch extensor digitorum longus muscle. Myostatin levels and the myostatin: follistatin ratio increased significantly (+75%) in mouse bone marrow with age, as did activin A levels (+17%). Follistatin increased the proliferation of primary myoblasts from both young and aged mice, whereas myostatin increased proliferation of younger myoblasts but decreased proliferation of older myoblasts. Myostatin reduced proliferation of both young and aged BMSCs in a dose-dependent fashion, and activin A increased mineralization in both young and aged BMSCs. Together these data suggest that aging in mice is accompanied by changes in the expression of activin A and myostatin, as well as changes in the response of bone and muscle progenitor cells to these factors. Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice.

Bowser, Matthew; Herberg, Samuel; Arounleut, Phonepasong; Shi, Xingming; Fulzele, Sadanand; Hill, William D.; Isales, Carlos M.; Hamrick, Mark W.

2013-01-01

134

MicroRNA-181a Suppresses Mouse Granulosa Cell Proliferation by Targeting Activin Receptor IIA  

PubMed Central

Activin, a member of the transforming growth factor-? superfamily, promotes the growth of preantral follicles and the proliferation of granulosa cells. However, little is known about the role of microRNAs in activin-mediated granulosa cell proliferation. Here, we reported a dose- and time-dependent suppression of microRNA-181a (miR-181a) expression by activin A in mouse granulosa cells (mGC). Overexpression of miR-181a in mGC suppressed activin receptor IIA (acvr2a) expression by binding to its 3?-untranslated region (3?-UTR), resulting in down-regulation of cyclin D2 and proliferating cell nuclear antigen expression, leading to inhibition of the cellular proliferation, while overexpression of acvr2a attenuated the suppressive effect of miR-181a on mGC proliferation. Consistent with the inhibition of acvr2a expression, miR-181a prevented the phosphorylation of the activin intracellular signal transducer, mothers against decapentaplegic homolog 2 (Smad2), leading to the inactivation of activin signaling pathway. Interestingly, we found that miR-181a expression decreased in ovaries of mice at age of 8, 12, and 21 days, as compared with that in ovaries of 3-day old mice, and its level was reduced in preantral and antral follicles of mice compared with that in primary ones. Moreover, the level of miR-181a in the blood of patients with premature ovarian failure was significantly increased compared with that in normal females. This study identifies an interplay between miR-181a and acvr2a, and reveals an important role of miR-181a in regulating granulosa cell proliferation and ovarian follicle development.

Jiang, Yue; Ding, Lijun; Wu, Shaogen; Fang, Ting; Yan, Guijun; Hu, Yali

2013-01-01

135

Bioinformatic Analysis of Pathogenic Missense Mutations of Activin Receptor Like Kinase 1 Ectodomain  

PubMed Central

Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1EC) has been elusive so far. We here describe the building of a homology model for ALK1EC, followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1EC potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1EC allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1EC and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms.

Scotti, Claudia; Olivieri, Carla; Boeri, Laura; Canzonieri, Cecilia; Ornati, Federica; Buscarini, Elisabetta; Pagella, Fabio; Danesino, Cesare

2011-01-01

136

Plasma levels of soluble CD14 and tumor necrosis factor-alpha type II receptor correlate with cognitive dysfunction during human immunodeficiency virus type 1 infection.  

PubMed

The relationship between monocyte immune responses and cognitive impairment during progressive human immunodeficiency virus type 1 (HIV-1) infection was investigated in 28 subjects receiving highly active antiretroviral therapy. The mean+/-SEM CD4(+) T lymphocyte count and virus load for all patients were 237+/-41 cells/mm(3) and 77,091+/-195,372 HIV-1 RNA copies/mL, respectively. Levels of soluble tumor necrosis factor-alpha type II receptor (sTNF-RII) and soluble CD14 (sCD14) were measured in plasma by ELISA and were correlated with results from neuropsychological, magnetic resonance imaging, and magnetic resonance spectroscopy tests. Plasma sCD14 and sTNF-RII levels were elevated in subjects with cognitive impairment and in those with brain atrophy. Furthermore, both factors were correlated with spectroscopic choline:creatine ratios. These findings support the idea that peripheral immune responses are linked to cognitive dysfunction during advanced HIV-1 disease. PMID:11517430

Ryan, L A; Zheng, J; Brester, M; Bohac, D; Hahn, F; Anderson, J; Ratanasuwan, W; Gendelman, H E; Swindells, S

2001-09-15

137

Key Role for Activin B in Cellular Transformation after Loss of the von Hippel-Lindau Tumor Suppressor ? †  

PubMed Central

The von Hippel-Lindau tumor suppressor gene (VHL) is mutated in clear cell renal cell carcinomas (RCC), leading to the activation of hypoxia-inducible factor (HIF)-mediated gene transcription. Several VHL/HIF targets, such as glycolysis, angiogenesis, cell growth, and chemotaxis of tumor cells, have been implicated in the transformed phenotype of RCC-regulating properties. Here, we show that VHL suppresses key features of cell transformation through downregulation of the HIF-dependent expression of activin B, a member of the transforming growth factor ? superfamily. Activin B expression is repressed by restoration of VHL in VHL-deficient RCC cells and upregulated by hypoxia. RCC tumor samples show increased expression of activin B compared to that in the normal kidney. VHL increases cell adhesion to the extracellular matrix, promotes cell flattening, and reduces invasiveness. These effects are completely phenocopied by RNA interference-mediated knockdown of activin B and reverted by treatment with recombinant activin B. Finally, knockdown of activin B reduces tumor growth of RCC cells in nude mice. Our data indicate that activin B is a key mediator of VHL/HIF-induced transformation in RCC.

Wacker, Ingrid; Sachs, Martin; Knaup, Karl; Wiesener, Michael; Weiske, Jorg; Huber, Otmar; Akcetin, Ziya; Behrens, Jurgen

2009-01-01

138

Activated leukocyte cell adhesion molecule soluble form: a potential biomarker of epithelial ovarian cancer is increased in type II tumors.  

PubMed

Activated leukocyte cell adhesion molecule (ALCAM) is involved in cell-cell interactions in cancer. Shedding of its ectodomain by the metalloprotease ADAM17/TACE generates a soluble form (sALCAM). Here, we show that serum sALCAM levels were significantly higher in epithelial ovarian cancer (EOC) (p < 0.005) than in controls. The performance of sALCAM as classifier, tested by receiver operating characteristic curve, resulted in an area under the curve (AUC) of 0.8067. Serum sALCAM levels showed direct correlation with Carbohydrate Antigen-125 (CA125/MUC16). Moreover, significantly higher levels were found in type II tumors, even in stage I/II, suggesting that elevated sALCAM is an early feature of aggressive EOC. In addition, sALCAM levels were higher in ascites than in sera, suggesting local processing of ALCAM in the peritoneal cavity. In immunodeficient mice, intraperitoneally implanted with a human EOC cell line, human sALCAM progressively increased in serum and was even higher in the ascites. The biochemical characterization of the sALCAM in EOC sera and ascites, showed two predominant forms of approximately 95 and 65 kDa but no EOC-specific isoform. In addition, full-length transmembrane ALCAM but no soluble form was detected in tumor-derived exosomes found in ascites. Finally, in vitro invasion assays showed that inhibition of ADAM17/TACE activity decreased EOC invasive properties, while opposite effects were mediated by a sALCAM-Fc chimera and by an antibody interfering with ALCAM/ALCAM interactions. Altogether these data suggest that sALCAM is a marker of EOC, which correlates with more aggressive type II tumors, and that ADAM17/TACE activity and sALCAM itself mediate enhanced invasiveness. PMID:23169448

Carbotti, Grazia; Orengo, Anna Maria; Mezzanzanica, Delia; Bagnoli, Marina; Brizzolara, Antonella; Emionite, Laura; Puppo, Andrea; Centurioni, Maria Grazia; Bruzzone, Milena; Marroni, Paola; Rossello, Armando; Canevari, Silvana; Ferrini, Silvano; Fabbi, Marina

2013-06-01

139

1?,25-dihydroxyvitamin D3 stimulates activin A production to fine-tune osteoblast-induced mineralization.  

PubMed

In healthy bones, mineralization has to be tightly controlled to avoid pathological phenotypes. In this study, we investigated interactions between 1?,25(OH)2 D3 (1,25D3) and activin A in the regulation of osteoblast induced mineralization. In human osteoblast cultures, we demonstrated that besides stimulation of mineralization, 1,25D3 also induced activin A, a strong inhibitor of mineralization. Simultaneously, follistatin (FST), the natural antagonist of activin A, was down-regulated by1,25D3. This resulted in an increase in activin A activity during 1,25D3 treatment. We also showed that in 1,25D3-treated osteoblasts, mineralization can be further increased when activin A activity was abrogated by adding exogenous FST. This observation implies that, besides stimulation of mineralization, 1,25D3 also controls activin A-mediated inhibition of mineralization. Besides activin A, 1,25D3 also induces osteocalcin (BGLAP), another inhibitor of mineralization. Warfarin, which has been shown to inactivate osteocalcin, increased 1,25D3-induced mineralization. Interaction between these two systems became evident from the synergistic increase in BGLAP expression upon blocking activin activity in 1,25D3-treated cultures. In conclusion, we demonstrate that 1,25D3 stimulation of mineralization by human osteoblasts is suppressed by concomitant induction of inhibitors of mineralization. Mineralization induction by 1,25D3 may actually be controlled via interplay with activin A and osteocalcin. Finally, this complex regulation of mineralization substantiates the significance of tight control of mineralization to prevent excessive mineralization and consequently reduction in bone quality and strength. PMID:23589129

Woeckel, V J; van der Eerden, B C J; Schreuders-Koedam, M; Eijken, M; Van Leeuwen, J P T M

2013-11-01

140

Activin and GDF11 collaborate in feedback control of neuroepithelial stem cell proliferation and fate.  

PubMed

Studies of the olfactory epithelium model system have demonstrated that production of neurons is regulated by negative feedback. Previously, we showed that a locally produced signal, the TGF? superfamily ligand GDF11, regulates the genesis of olfactory receptor neurons by inhibiting proliferation of the immediate neuronal precursors (INPs) that give rise to them. GDF11 is antagonized by follistatin (FST), which is also produced locally. Here, we show that Fst(-/-) mice exhibit dramatically decreased neurogenesis, a phenotype that can only be partially explained by increased GDF11 activity. Instead, a second FST-binding factor, activin ?B (ACT?B), inhibits neurogenesis by a distinct mechanism: whereas GDF11 inhibits expansion of INPs, ACT?B inhibits expansion of stem and early progenitor cells. We present data supporting the concept that these latter cells, previously considered two distinct types, constitute a dynamic stem/progenitor population in which individual cells alternate expression of Sox2 and/or Ascl1. In addition, we demonstrate that interplay between ACT?B and GDF11 determines whether stem/progenitor cells adopt a glial versus neuronal fate. Altogether, the data indicate that the transition between stem cells and committed progenitors is neither sharp nor irreversible and that GDF11, ACT?B and FST are crucial components of a circuit that controls both total cell number and the ratio of neuronal versus glial cells in this system. Thus, our findings demonstrate a close connection between the signals involved in the control of tissue size and those that regulate the proportions of different cell types. PMID:21852401

Gokoffski, Kimberly K; Wu, Hsiao-Huei; Beites, Crestina L; Kim, Joon; Kim, Euiseok J; Matzuk, Martin M; Johnson, Jane E; Lander, Arthur D; Calof, Anne L

2011-10-01

141

Presence of activin signal transduction in normal ovarian cells and epithelial ovarian carcinoma  

PubMed Central

In this study, we have investigated the expression of inhibin subunits and activin receptors (ActRs) in normal and malignant ovarian cells. Each product of the inhibin subunits (?, ?a, ?b) and activin receptors (ActRs) amplified by reverse transcription polymerase chain reaction were detected as a single band in human granulosa cells, surface epithelial cells (OSE), and the ovarian cancer cell lines OVCAR 3 and SKOV 3. Western blot analysis was performed using polyclonal antibodies against ActR IIa or IIb peptides based on 13 COOH-terminal amino acids; cultured human granulosa cells were used as a positive control. Using ActR IIa antibody, one major band corresponding to approximately 80 kDa and one minor band corresponding to 105 kDa were observed in the samples. One single band at approximately 60 kDa was detected in OVCAR 3 and a 50 kDa band was detected with ActR IIb antibody in cultured granulosa cell, OSE and SKOV 3. Although no detectable change was induced in Smad 4 mRNA in OVCAR 3, Smad 2 mRNA levels were increased during 48 h treatment with activin A (50 ng ml–1). These data provide a better understanding as the first step in the mechanism of action of the activin in the epithelial ovarian carcinoma. © 2000 Cancer Research Campaign

Ito, I; Minegishi, T; Fukuda, J; Shinozaki, H; Auersperg, N; Leung, P C K

2000-01-01

142

Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis  

Microsoft Academic Search

Molecules associated with the transforming growth factor ? (TGF-?) superfamily, such as bone morphogenic proteins (BMPs) and TGF-?, are key regulators of inflammation, apoptosis and cellular transitions. Here we show that the BMP receptor activin-like kinase 3 (Alk3) is elevated early in diseased kidneys after injury. We also found that its deletion in the tubular epithelium leads to enhanced TGF-?1–Smad

Hikaru Sugimoto; Valerie S LeBleu; Dattatreyamurty Bosukonda; Peter Keck; Gangadhar Taduri; Wibke Bechtel; Hirokazu Okada; William Carlson; Philippe Bey; Mary Rusckowski; Björn Tampe; Desiree Tampe; Keizo Kanasaki; Michael Zeisberg; Raghu Kalluri

2012-01-01

143

The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A.  

PubMed

Modulation of macrophage polarization underlies the onset and resolution of inflammatory processes, with polarization-specific molecules being actively sought as potential diagnostic and therapeutic tools. Based on their cytokine profile upon exposure to pathogenic stimuli, human monocyte-derived macrophages generated in the presence of GM-CSF or M-CSF are considered as proinflammatory (M1) or anti-inflammatory (M2) macrophages, respectively. We report in this study that the prolyl hydroxylase PHD3-encoding EGLN3 gene is specifically expressed by in vitro-generated proinflammatory M1(GM-CSF) human macrophages at the mRNA and protein level. Immunohistochemical analysis revealed the expression of PHD3 in CD163(+) lung macrophages under basal homeostatic conditions, whereas PHD3(+) macrophages were abundantly found in tissues undergoing inflammatory responses (e.g., Crohn's disease and ulcerative colitis) and in tumors. In the case of melanoma, PHD3 expression marked a subset of tumor-associated macrophages that exhibit a weak (e.g., CD163) or absent (e.g., FOLR2) expression of typical M2-polarization markers. EGLN3 gene expression in proinflammatory M1(GM-CSF) macrophages was found to be activin A dependent and could be prevented in the presence of an anti-activin A-blocking Ab or inhibitors of activin receptor-like kinase receptors. Moreover, EGLN3 gene expression was upregulated in response to hypoxia only in M2(M-CSF) macrophages, and the hypoxia-mediated upregulation of EGLN3 expression was significantly impaired by activin A neutralization. These results indicate that EGLN3 gene expression in macrophages is dependent on activin A both under basal and hypoxic conditions and that the expression of the EGLN3-encoded PHD3 prolyl hydroxylase identifies proinflammatory macrophages in vivo and in vitro. PMID:22778395

Escribese, María M; Sierra-Filardi, Elena; Nieto, Concha; Samaniego, Rafael; Sánchez-Torres, Carmen; Matsuyama, Takami; Calderon-Gómez, Elisabeth; Vega, Miguel A; Salas, Azucena; Sánchez-Mateos, Paloma; Corbí, Angel L

2012-08-15

144

Role of soluble epoxide hydrolase in exacerbation of stroke by streptozotocin-induced type 1 diabetes mellitus.  

PubMed

Hyperglycemia worsens stroke, yet rigorous glycemic control does not improve neurologic outcome. An alternative is to target downstream molecular mediator(s) triggered by hyperglycemia but independent of prevailing glycemia. Soluble epoxide hydrolase (sEH) is a potential mediator of injury via its metabolism of neuroprotective epoxyeicosatrienoic acids (EETs). We tested whether hyperglycemia exacerbates cerebral injury by upregulating sEH and decreasing brain EET levels. Type 1 diabetes mellitus was modeled by streptozotocin (STZ; 50 mg/kg per day intraperitoneally, 5 days) in male mice. At 4 weeks, STZ-treated and control mice underwent 45-minute middle cerebral artery occlusion (MCAO) with or without sEH blockade by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB; 1 mg/kg intraperitoneally daily for 6 days before MCAO). The STZ-treated mice had increased sEH mRNA expression in cerebral vessels and decreased EET concentrations in brain. There was no difference in cortical perfusion between groups. The STZ-treated mice sustained larger brain infarct than controls. Pretreatment with t-AUCB eliminated the difference in infarct size and EETs concentration between STZ-treated mice and controls, without altering glycemia. We conclude that type 1 diabetes mellitus upregulates sEH mRNA and decreases concentrations of neuroprotective EETs within the brain, leading to worse stroke outcome. The data indicate that sEH antagonism may be beneficial in the setting of hyperglycemic stroke. PMID:23899929

Jouihan, Sari A; Zuloaga, Kristen L; Zhang, Wenri; Shangraw, Robert E; Krasnow, Stephanie M; Marks, Daniel L; Alkayed, Nabil J

2013-10-01

145

Involvement of Smad proteins in the differentiation of pancreatic AR42J cells induced by activin A  

Microsoft Academic Search

Aims\\/hypothesis. Activin A induces differentiation of amylase-secreting pancreatic AR42J cells into endocrine cells. This study assesses\\u000a the role of Smad proteins in the actions of activin A in AR42J cells. Methods. The expression of Smad proteins was determined by northern blotting. Phosphorylation and translocation of Smad2 was measured\\u000a by transfecting flag-tagged Smad2. Involvement of Smad2 was examined by transfecting cDNA

Y.-Q. Zhang; M. Kanzaki; M. Furukawa; H. Shibata; M. Ozeki; I. Kojima

1999-01-01

146

Solubility of HFC-134a refrigerant in glycol-type compounds: Effects of glycol structure. [1,1,1,2-tetrafluoroethane  

SciTech Connect

Environmental concerns have dictated the replacement of CFC-12 refrigerant with HFC-134a in air-conditioning (A/C) systems. Since polyglycols are synthetic compounds compatible with HFC-134a and considered as lubricants for the A/C compressor, interactions of HFC-134a with glycol-type compounds and thermodynamic properties of the solutions are important in designing an A/C system. In this work, the solubility of HFC-134a in four glycol-type compounds was measured at [minus]5 to 80 C and 90 to 960 kPa. HFC-134a had the greatest solubility in tetraethylene glycol dimethyl ether. HFC-134a was less soluble in hexylene glycol and tetraethylene glycol and least soluble in triethylene glycol. Mixtures of HFC-134a with TRIG or TGDE showed phase separation. Solubility data were used to calculate the activity coefficient of HFC-134a in glycol solutions. An equation of the form, ln[gamma][sub r] = (1 [minus] x[sub r])[A + Bx[sub r

Tseregounis, S.I.; Riley, M.J. (General Motors Research and Development Center, Warren, MI (United States). Fuels and Lubricants Dept.)

1994-04-01

147

Different Small, Acid-Soluble Proteins of the Alpha/Beta Type Have Interchangeable Roles in the Heat and UV (Ultraviolet) Radiation Resistance of 'Bacillus subtilis' Spores,  

National Technical Information Service (NTIS)

Spores of Bacillus subtilis strains which carry deletion mutations in one gene (sspA) or two genes (sspA and sspB) which code for major alpha/beta-type small, acid-soluble spore proteins (SASP) are known to be much more sensitive to heat and UV radiation ...

J. M. Mason P. Setlow

1987-01-01

148

Type 10 Soluble Adenylyl Cyclase Is Overexpressed in Prostate Carcinoma and Controls Proliferation of Prostate Cancer Cells*  

PubMed Central

cAMP signaling plays an essential role in modulating the proliferation of different cell types, including cancer cells. Until now, the regulation of this pathway was restricted to the transmembrane class of adenylyl cyclases. In this study, significant overexpression of soluble adenylyl cyclase (sAC), an alternative source of cAMP, was found in human prostate carcinoma, and therefore, the contribution of this cyclase was investigated in the prostate carcinoma cell lines LNCaP and PC3. Suppression of sAC activity by treatment with the sAC-specific inhibitor KH7 or by sAC-specific knockdown mediated by siRNA or shRNA transfection prevented the proliferation of prostate carcinoma cells, led to lactate dehydrogenase release, and induced apoptosis. Cell cycle analysis revealed a significant rise in the G2 phase population 12 h after sAC inhibition, which was accompanied by the down-regulation of cyclin B1 and CDK1. sAC-dependent regulation of proliferation involves the EPAC/Rap1/B-Raf signaling pathway. In contrast, protein kinase A does not play a role. In conclusion, this study suggests a novel sAC-dependent signaling pathway that controls the proliferation of prostate carcinoma cells.

Flacke, Jan-Paul; Flacke, Hanna; Appukuttan, Avinash; Palisaar, Rein-Juri; Noldus, Joachim; Robinson, Brian D.; Reusch, H. Peter; Zippin, Jonathan H.; Ladilov, Yury

2013-01-01

149

Identification of a novel water-soluble activator of wild-type and F508del CFTR: GPact-11a.  

PubMed

One of the major therapeutic strategy in cystic fibrosis aims at developing modulators of cystic fibrosis transmembrane conductance regulator (CFTR) channels. We recently discovered methylglyoxal alpha-aminoazaheterocycle adducts, as a new family of CFTR inhibitors. In a structure-activity relationship study, we have now identified GPact-11a, a compound able not to inhibit but to activate CFTR. Here, we present the effect of GPact-11a on CFTR activity using in vitro (iodide efflux, fluorescence imaging and patch-clamp recordings), ex vivo (short-circuit current measurements) and in vivo (salivary secretion) experiments. We report that GPact-11a: 1) is an activator of CFTR in several airway epithelial cell lines; 2) activates rescued F508del-CFTR in nasal, tracheal, bronchial, pancreatic cell lines and in human CF ciliated epithelial cells, freshly dissociated from lung samples; 3) stimulates ex vivo the colonic chloride secretion and increases in vivo the salivary secretion in cftr(+/+) but not cftr(-/-) mice; and 4) is selective for CFTR because its effect is inhibited by CFTR(inh)-172, GlyH-101, glibenclamide and GPinh-5a. To conclude, this work identifies a selective activator of wild-type and rescued F508del-CFTR. This nontoxic and water-soluble agent represents a good candidate, alone or in combination with a F508del-CFTR corrector, for the development of a CFTR modulator in cystic fibrosis. PMID:20110398

Bertrand, J; Boucherle, B; Billet, A; Melin-Heschel, P; Dannhoffer, L; Vandebrouck, C; Jayle, C; Routaboul, C; Molina, M-C; Décout, J-L; Becq, F; Norez, C

2010-08-01

150

The impact of soluble dietary fibre on gastric emptying, postprandial blood glucose and insulin in patients with type 2 diabetes.  

PubMed

Dietary fibre plays an important role in controlling postprandial glycemic and insulin response in diabetic patients. The intake of dietary fibre has been shown to delay the gastric emptying in healthy subjects. The relationship between gastric emptying and postprandial blood glucose in diabetic patients with fibre-load liquids needs to be investigated. To investigate the impact of soluble dietary fibre (SDF) on gastric emptying, postprandial glycemic and insulin response in patients with type 2 diabetes. 30 patients with type 2 diabetes (DM) and 10 healthy subjects (HS) matched for gender and age were randomized to receive SDF-free liquid (500 mL, 500 Kcal) and isoenergetic SDF liquid (oat ?-glucan 7.5 g, 500 mL, 500 Kcal) on two separate days based on a cross-over with 6-day wash-out period. Gastric emptying was monitored by ultrasonography at intervals of 30 min for 2 hours. Fasting and postprandial blood was collected at intervals of 30-60 min for 180 min to determine plasma glucose and insulin. Proximal gastric emptying was delayed by SDF-treatment both in DM (p=0.001) and HS (p=0.037). SDF resulted in less output volume in the distal stomach in DM (p<0.05). SDF decreased postprandial glucose (p=0.001) and insulin (p=0.001) in DM subjects. Postprandial glucose (r=-0.547, p=0.047) and insulin (r=-0.566, p=0.004) were negatively correlated with distal emptying of SDF in DM subjects. Distal gastric emptying was delayed significantly in DM subjects with HbA1c levels ?6.5% (p=0.021) or with complications (p=0.011) by SDF, respectively. SDF improved postprandial glycaemia which was related to slowing of gastric emptying. PMID:24901089

Yu, Kang; Ke, Mei-Yun; Li, Wen-Hui; Zhang, Shu-Qin; Fang, Xiu-Cai

2014-06-01

151

Serum activin A and B levels predict outcome in patients with acute respiratory failure: a prospective cohort study  

PubMed Central

Introduction 30 day mortality in patients with Acute Respiratory Failure (ARF) is approximately 30%, defined as patients requiring ventilator support for more than 6 hours. Novel biomarkers are needed to predict patient outcomes and to guide potential future therapies. The activins A and B, members of the Transforming Growth Factor ? family of proteins, and their binding protein, follistatin, have recently been shown to be important regulators of inflammation and fibrosis but no substantial data are available concerning their roles in ARF. Our objectives were to evaluate whether the serum levels of activin A, B and follistatin are elevated in 518 patients with ARF from the FINNALI study compared the concentrations in 138 normal subjects that form a reference range. Methods Specific assays for activin A, B and follistatin were used and the results analyzed according to diagnostic groups as well as according to standard measures in intensive care. Multivariable logistic regression was used to create a model to predict death at 90 days and 12 months from the onset of the ARF. Results Serum activin A and B were significantly elevated in most patients and in most of the diagnostic groups. Patients who had activin A and/or B concentrations above the reference maximum were significantly more likely to die in the 12 months following admission [either activin A or B above reference maximum: Positive Likelihood Ratio [LR+] 1.65 [95% CI 1.28-2.12, P?=?0.00013]; both activin A and B above reference maximum: LR?+?2.78 [95% CI 1.96-3.95, P?activin A and B levels in these patients with ARF would have assisted in predicting those at greatest risk of death. Given the existing data from animal studies linking high activin A levels to significant inflammatory challenges, the results from this study suggest that approaches to modulate activin A and B bioactivity should be explored as potential therapeutic agents.

2013-01-01

152

Maternal Serum Activin A at 11–13 Weeks of Gestation in Hypertensive Disorders of Pregnancy  

Microsoft Academic Search

Objectives: To investigate whether the maternal serum concentration of activin A at 11–13 weeks of gestation in pregnancies that subsequently develop hypertensive disorders is different from those with a normal outcome and to examine whether any possible differences are related to uterine artery pulsatility index (PI), serum pregnancy-associated plasma protein A (PAPP-A) and serum tumor necrosis factor-? receptor-1 (TNF-R1). Material

Ranjit Akolekar; Adolfo Etchegaray; Yi Zhou; Nerea Maiz; Kypros H. Nicolaides

2009-01-01

153

Interplay between activin and Hox genes determines the formation of the kidney morphogenetic field.  

PubMed

The kidney develops in a specific position along the anterior-posterior axis. All vertebrate kidney tissues are derived from the intermediate mesoderm (IM), and early kidney genes such as Lim1 and Pax2 are expressed in amniotes posterior to the sixth somite axial level. IM cells anterior to this level do not express kidney genes owing to changes in their competence to respond to kidney-inductive signals present along the entire axis. We aimed to understand the molecular mechanisms governing the loss of competence of anterior IM cells and the formation of the anterior border of the kidney morphogenetic field. We identified the dorsal neural tube as the potential kidney-inductive tissue and showed that activin, a secreted morphogen, is necessary but insufficient for Lim1 induction and establishment of the kidney field. Activin or activin-like and BMP signaling cascades are activated along the entire axis, including in anterior non-kidney IM, suggesting that competence to respond to these signals involves downstream or other components. Detailed expression pattern analysis of Hox genes during early chick development revealed that paralogous group four genes share the same anterior border as the kidney genes. Ectopic expression of Hoxb4 in anterior non-kidney IM, either by retinoic acid (RA) administration or plasmid-mediated overexpression, resulted in ectopic kidney gene expression. The anterior expansion of Lim1 expression was restrained when Hoxb4 was co-expressed with a truncated form of activin receptor. We suggest a model in which the competence of IM cells to respond to TGFbeta signaling and express kidney genes is driven by RA and mediated by Hoxb4. PMID:19439491

Preger-Ben Noon, Ella; Barak, Hila; Guttmann-Raviv, Noga; Reshef, Ram

2009-06-01

154

The remedial effect of soluble interleukin-1 receptor type II on endometriosis in the nude mouse model?  

PubMed Central

Objective Recent studies have shown that the local expression of soluble interleukin (IL) -1 receptor type II (sIL-1 RII) in endometrial tissue of women with endometriosis is decreased, and the depression of IL-1 RII was more significant in infertile women than that in fertile women with endometriosis. In this research, we investigated the remedial effect of sIL-1-RII administration on endometriosis in the nude mouse model. Methods Nineteen nude model mice with endometriosis were randomly divided into three groups: group A was treated by intraperitoneal administration with only sIL-1 RII for two weeks, group B was similarly treated with only IL-1, and group C (control) was administered saline . After 2 weeks, the size of the ectopic endometrial lesions was calculated, and the expression of vascular endothelial growth factor (VEGF) and B-cell lymphoma leukemia-2 (Bcl-2) were detected by immunohistochemistry. The IL-8 and VEGF levels in the peritoneal fluid (PF) and serum were also measured by enzyme-linked immunosorbent assay (ELISA). Results The mean size of ectopic endometrial lesion did not differ between the three groups (P > 0.05). Compared with the control, the expression of VEGF and Bcl-2 was significantly lower in group A, and higher in group B. In the three groups, the levels of IL-8 in the PF and serum were highest in group A, and lowest in group B. Conclusion sIL-1 RII may suppresse hyperplasia of ectopic endometriosis, perhaps by reducing the expression of certain cytokines, such as VEGF, IL-8, and Bcl-2, which could provide a new clinical strategy for the treatment of endometriosis.

Gao, Liying; Sun, Liang; Cui, Yugui; Hou, Zhen; Gao, Li; Zhou, Jing; Mao, Yundong; Han, Suping; Liu, Jiayin

2010-01-01

155

Evaluation of soluble CD200 levels in type 2 diabetic foot and nephropathic patients: Association with disease activity  

PubMed Central

Background CD200 (OX-2) is a novel immune-effective molecule, existing in a cell membrane-bound form, as well as in a soluble form in serum (s OX-2), which acts to regulate inflammatory and acquired immune responses. Material/Methods We planned this study to evaluate the sOX-2 levels of type 2 diabetic foot (group B), and compare it with that of healthy controls (group A). The patient group had the following values: DM period: 27.9±10.3 year [mean ±SD], HbA1c: 9.52±2.44% [mean ±SD]. Results Blood samples for sCD200 measurement were always taken in the morning between 8 and 10 A.M.. The results were reported as means of duplicate measurements. Concentrations of sOX-2 in the serum samples were quantified using an ELISA kit. Serum hs-CRP levels were measured using an hs-CRP assay kit. The sOX-2 level in group B was 173.8±3.1 and in group A was 70.52±1.2 [p<0.0001). In subgroup analysis of T2DM-DFI patients, we noticed that sOX-2 levels were higher in WGS (Wagner grading system) I and II patients than in WGS III and IV patients. The HbA1c, BUN, creatinine, hs-CRP levels, and sedimentation rates were higher in the patient group (p<0.0001, p<0.001, p<0.001, p<0.005, and p<0.0001, respectively). Conclusions We suggest that there are vascular, immunologic, and neurologic components in DFI, whereas autoimmune diseases and inflammatory skin disorders have only an immunologic component. This is possibly evidence of a pro-inflammatory effect seen in DFI as a vascular complication.

Arik, Hasan Onur; Yalcin, Arzu Didem; Celik, Betul; Seyman, Derya; Tetik, Gulsum; Gursoy, Bensu; Kose, Sukran; Gumuslu, Saadet

2014-01-01

156

IL2RA Genetic Heterogeneity in Multiple Sclerosis and Type 1 Diabetes Susceptibility and Soluble Interleukin-2 Receptor Production  

PubMed Central

Multiple sclerosis (MS) and type 1 diabetes (T1D) are organ-specific autoimmune disorders with significant heritability, part of which is conferred by shared alleles. For decades, the Human Leukocyte Antigen (HLA) complex was the only known susceptibility locus for both T1D and MS, but loci outside the HLA complex harboring risk alleles have been discovered and fully replicated. A genome-wide association scan for MS risk genes and candidate gene association studies have previously described the IL2RA gene region as a shared autoimmune locus. In order to investigate whether autoimmunity risk at IL2RA was due to distinct or shared alleles, we performed a genetic association study of three IL2RA variants in a DNA collection of up to 9,407 healthy controls, 2,420 MS, and 6,425 T1D subjects as well as 1,303 MS parent/child trios. Here, we report “allelic heterogeneity” at the IL2RA region between MS and T1D. We observe an allele associated with susceptibility to one disease and risk to the other, an allele that confers susceptibility to both diseases, and an allele that may only confer susceptibility to T1D. In addition, we tested the levels of soluble interleukin-2 receptor (sIL-2RA) in the serum from up to 69 healthy control subjects, 285 MS, and 1,317 T1D subjects. We demonstrate that multiple variants independently correlate with sIL-2RA levels.

Cooper, Jason; Downes, Kate; Anderson, David E.; Severson, Christopher; Clark, Pamela M.; Healy, Brian; Walker, Neil; Aubin, Cristin; Oksenberg, Jorge R.; Hauser, Stephen L.; Compston, Alistair; Sawcer, Stephen; De Jager, Philip L.; Wicker, Linda S.

2009-01-01

157

Evaluation of soluble CD200 levels in type 2 diabetic foot and nephropathic patients: Association with disease activity.  

PubMed

Background CD200 (OX-2) is a novel immune-effective molecule, existing in a cell membrane-bound form, as well as in a soluble form in serum (s OX-2), which acts to regulate inflammatory and acquired immune responses. Material and Methods We planned this study to evaluate the sOX-2 levels of type 2 diabetic foot (group B), and compare it with that of healthy controls (group A). The patient group had the following values: DM period: 27.9±10.3 year [mean ±SD], HbA1c: 9.52±2.44% [mean ±SD]. Results Blood samples for sCD200 measurement were always taken in the morning between 8 and 10 A.M.. The results were reported as means of duplicate measurements. Concentrations of sOX-2 in the serum samples were quantified using an ELISA kit. Serum hs-CRP levels were measured using an hs-CRP assay kit. The sOX-2 level in group B was 173.8±3.1 and in group A was 70.52±1.2 [p<0.0001). In subgroup analysis of T2DM-DFI patients, we noticed that sOX-2 levels were higher in WGS (Wagner grading system) I and II patients than in WGS III and IV patients. The HbA1c, BUN, creatinine, hs-CRP levels, and sedimentation rates were higher in the patient group (p<0.0001, p<0.001, p<0.001, p<0.005, and p<0.0001, respectively). Conclusions We suggest that there are vascular, immunologic, and neurologic components in DFI, whereas autoimmune diseases and inflammatory skin disorders have only an immunologic component. This is possibly evidence of a pro-inflammatory effect seen in DFI as a vascular complication. PMID:24964809

Arik, Hasan Onur; Yalcin, Arzu Didem; Celik, Betul; Seyman, Derya; Tetik, Gulsum; Gursoy, Bensu; Kose, Sukran; Gumuslu, Saadet

2014-01-01

158

Water-soluble organic matter and soil solution acidity in the main soil types of the central forest state biosphere reserve  

NASA Astrophysics Data System (ADS)

The dynamics of the soluble organic carbon (CWSO) and pH in soil solutions of the main soil types of the Central Forest State Biosphere Reserve were described. Possible reasons for the pH variation were considered. It was found that different soils are characterized by specific levels of pH and CWSO. The structure of the soil solution acidity and its changes with depth were analyzed, and the relationship between the acidity and the content of water-soluble organics substances (WSOs) was determined. The predominantly hydrophilic nature and polydispersity of WSOs in soil solutions were revealed, as well as a decrease in the proportion of high-molecular soil fractions with depth. It was found that the mobility of metals in soils depends on the amphiphilic properties of WSOs to which they are bound, the metal features, and the soil type. The possibility of selective absorption of metals bound to the hydrophobic WSO fraction was shown.

Karavanova, E. I.; Belyanina, L. A.; Stepanov, A. A.

2007-05-01

159

Synthesis and photophysical properties of water-soluble sulfonato-Salen-type Schiff bases and their applications of fluorescence sensors for Cu2+ in water and living cells.  

PubMed

A series of water-soluble sulfonato-Salen-type ligands derived from different diamines including 1,2-ethylenediamine (Et-1-Et-4), 1,2-cyclohexanediamine (Cy-1 and Cy-2), 1,2-phenylenediamine (Ph-1-Ph-3 and PhMe-1-PhMe-4), and dicyano-1,2-ethenediamine (CN-1) has been designed and prepared. Sulfonate groups of ligands ensure good stability and solubility in water without affecting their excited state properties. These ligands exhibit strong UV/Vis-absorption and blue, green, or orange fluorescence. Time-dependent-density functional theory calculations have been undertaken to reveal the influence of ligand nature, especially sulfonate groups, on the frontier molecular orbitals. Since their fluorescence is selectively quenched by Cu(2+), the sulfonato-Salen-type ligands can be used as highly selective and sensitive turn-off fluorescence sensors for the detection of Cu(2+) in water and fluorescence imaging in living cells. PMID:22713922

Zhou, Li; Cai, Peiying; Feng, Yan; Cheng, Jinghui; Xiang, Haifeng; Liu, Jin; Wu, Di; Zhou, Xiangge

2012-07-20

160

Inhibin/activin expression in human and rodent liver: subunits ? and ?B as new players in human hepatocellular carcinoma?  

PubMed Central

Background: Activins and inhibins belong to the TGF?-superfamily, which controls cell proliferation and differentiation in many organs. Activin A, the dimer of inhibin ?A subunit, acts strongly anti-proliferative in hepatocytes. Little is known on the other activin/inhibin subunits in human liver and hepatocellular carcinoma (HCC). Methods: We studied the expression of the complete inhibin family ?, ?A, ?B, ?C, ?E in normal liver, tumour-adjacent and HCC tissue, 12 additional organs and rodent liver. A total of 16 HCC and 10 disease-free livers were analysed. Expression of inhibin subunits was determined by qRT–PCR, normalised to RNA input and by geNorm algorithm, and confirmed by immunohistochemistry. Results: Remarkably, ?A expression was not decreased in HCC. Similarly, ?C and ?E exhibited no major changes. In contrast, inhibin ?, barely detectable in normal liver, was strongly increased in tumour-adjacent liver and dramatically enhanced in HCC. ?B was strongly enhanced in some HCC. At variance with human liver, rodent liver showed higher inhibin ? and ?C expression, but ?A was somewhat, and ?B dramatically lower. Conclusions: Upregulation of inhibin ? – and possibly of ?B – may shield HCC cells from anti-proliferative effects of activin A. Dramatic variations between humans and rodents may reflect different functions of some inhibins/activins.

Frost, K; Seir, K; Lackner, A; Grusch, M; Grasl-Kraupp, B; Schulte-Hermann, R; Rodgarkia-Dara, C

2011-01-01

161

The prolonged culture of human immunodeficiency virus type 1 in primary lymphocytes increases its sensitivity to neutralization by soluble CD4  

Microsoft Academic Search

Primary strains of human immunodeficiency virus type 1 (HIV-1) are known to adapt to replication in cell lines in vitro by becoming sensitive to soluble CD4 (sCD4) and neutralizing antibodies (NAb). T-cell lines favor isolation of variants that use CXCR4 as a co-receptor, while primary isolates predominantly use CCR5. We have now studied how a primary R5 isolate, CC1\\/85, adapts

Pavel Pugach; Shawn E Kuhmann; Joann Taylor; Andre J Marozsan; Amy Snyder; Thomas Ketas; Steven M Wolinsky; Bette T Korber; John P Moore

2004-01-01

162

Controls on iron distributions in the deep water column of the North Pacific Ocean: Iron(III) hydroxide solubility and marine humic-type dissolved organic matter  

Microsoft Academic Search

Dissolved Fe in the western and central North Pacific Ocean was characterized by surface depletion, middepth maxima and, below that, a slight decrease with depth similar to the vertical distributions of nutrients, apparent oxygen utilization, Fe(III) hydroxide solubility, and humic-type fluorescence (H-flu) intensity. Dissolved Fe concentrations ([D-Fe], <0.22-?m fraction) in the deep water column were one-half lower in the central

Saori Kitayama; Kenshi Kuma; Eri Manabe; Koji Sugie; Hyoe Takata; Yutaka Isoda; Kenji Toya; Sei-ichi Saitoh; Shohgo Takagi; Yoshihiko Kamei; Keiichiro Sakaoka

2009-01-01

163

Enhanced P-selectin expression and increased soluble CD40 Ligand in patients with Type 1 diabetes mellitus and microangiopathy: evidence for platelet hyperactivity and chronic inflammation  

Microsoft Academic Search

Aims\\/hypothesis  Platelet activation, endothelial dysfunction and inflammation may be involved in early stages of diabetic microangiopathy. We therefore investigated patients with Type 1 diabetes mellitus, without (n=19) and with (n=20) microangiopathy, matched for glycaemic control and duration of disease, and matched with healthy control subjects (n=27).Methods  Platelet activation was measured as platelet P-selectin expression using whole blood flow cytometry and as soluble

M. Yngen; C.-G. Östenson; H. Hu; N. Li; P. Hjemdahl; N. H. Wallén

2004-01-01

164

Specificity and Structure of a High Affinity Activin Receptor-like Kinase 1 (ALK1) Signaling Complex  

PubMed Central

Activin receptor-like kinase 1 (ALK1), an endothelial cell-specific type I receptor of the TGF-? superfamily, is an important regulator of normal blood vessel development as well as pathological tumor angiogenesis. As such, ALK1 is an important therapeutic target. Thus, several ALK1-directed agents are currently in clinical trials as anti-angiogenic cancer therapeutics. Given the biological and clinical importance of the ALK1 signaling pathway, we sought to elucidate the biophysical and structural basis underlying ALK1 signaling. The TGF-? family ligands BMP9 and BMP10 as well as the three type II TGF-? family receptors ActRIIA, ActRIIB, and BMPRII have been implicated in ALK1 signaling. Here, we provide a kinetic and thermodynamic analysis of BMP9 and BMP10 interactions with ALK1 and type II receptors. Our data show that BMP9 displays a significant discrimination in type II receptor binding, whereas BMP10 does not. We also report the crystal structure of a fully assembled ternary complex of BMP9 with the extracellular domains of ALK1 and ActRIIB. The structure reveals that the high specificity of ALK1 for BMP9/10 is determined by a novel orientation of ALK1 with respect to BMP9, which leads to a unique set of receptor-ligand interactions. In addition, the structure explains how BMP9 discriminates between low and high affinity type II receptors. Taken together, our findings provide structural and mechanistic insights into ALK1 signaling that could serve as a basis for novel anti-angiogenic therapies.

Townson, Sharon A.; Martinez-Hackert, Erik; Greppi, Chloe; Lowden, Patricia; Sako, Dianne; Liu, June; Ucran, Jeffrey A.; Liharska, Katia; Underwood, Kathryn W.; Seehra, Jasbir; Kumar, Ravindra; Grinberg, Asya V.

2012-01-01

165

Antisense-Oligonucleotide Mediated Exon Skipping in Activin-Receptor-Like Kinase 2: Inhibiting the Receptor That Is Overactive in Fibrodysplasia Ossificans Progressiva  

PubMed Central

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G?A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients.

de Gorter, David J. J.; Sanchez-Duffhues, Gonzalo; Kemaladewi, Dwi U.; Hoogaars, Willem M. H.; Aartsma-Rus, Annemieke; 't Hoen, Peter A. C.; ten Dijke, Peter

2013-01-01

166

Different small, acid-soluble proteins of the alpha/beta type have interchangeable roles in the heat and uv (ultraviolet) radiation resistance of Bacillus subtilis spores  

SciTech Connect

Spores of Bacillus subtilis strains which carry deletion mutations in one gene (sspA) or two genes (sspA and sspB) which code for major alpha/beta-type small, acid-soluble spore proteins (SASP) are known to be much more sensitive to heat and UV radiation than wild-type spores. This heat- and UV-sensitive phenotype was cured completely or in part by introduction into these mutant strains of (i) one or more copies of the sspA or sspB genes themselves; (ii) multiple copies of the B. subtilis sspD gene, which codes for a minor alpha/beta-type SASP; or (iii) multiple copies of the SASP-C genes, which codes for a major alpha/beta-type SASP of Bacillus megaterium. These findings suggest that alpha-beta-type SASP play interchangeable roles in the heat and UV radiation resistance of bacterial spores.

Mason, J.M.; Setlow, P.

1987-08-01

167

Different small, acid-soluble proteins of the alpha/beta type have interchangeable roles in the heat and UV radiation resistance of Bacillus subtilis spores  

SciTech Connect

Spores of Bacillus subtilis strains which carry deletion mutations in one gene (sspA) or two genes (sspA and sspB) which code for major alpha/beta-type small, acid-soluble spore proteins (SASP) are known to be much more sensitive to heat and UV radiation than wild-type spores. This heat- and UV-sensitive phenotype was cured completely or in part by introduction into these mutant strains of one or more copies of the sspA or sspB genes themselves; multiple copies of the B. subtilis sspD gene, which codes for a minor alpha/beta-type SASP; or multiple copies of the SASP-C gene, which codes for a major alpha/beta-type SASP of Bacillus megaterium. These findings suggest that alpha/beta-type SASP play interchangeable roles in the heat and UV radiation resistance of bacterial spores.

Mason, J.M.; Setlow, P.

1987-08-01

168

[Characteristics of aerosol water-soluble inorganic ions in three types air-pollution incidents of Nanjing City].  

PubMed

In order to compare aerosol water-soluble inorganic species in different air-pollution periods, samples of PM10, PM2.1, PM1.1 and the main water-soluble ions (NH4+, Mg2+, Ca2+, Na+, K+, NO2(-), F(-), NO3(-), Cl(-), SO4(2-)) were measured, which were from 3 air-pollution incidents (continued pollution in October 16-30 of 2009, sandstorm pollution in April 27-30 of 2010, and crop burning pollution in June 14 of 2010. The results show that aerosol pollution of 3 periods is serious. The lowest PM2.1/PM10 is only 0.27, which is from sandstorm pollution period, while the largest is 0. 7 from crop burning pollution period. In continued pollution periods, NO3(-) and SO4(2-) are the dominant ions, and the total anions account for an average of 18.62%, 32.92% and 33.53% of PM10, PM2.1 and PM1.1. Total water-soluble ions only account for 13.36%, 23.72% and 28.54% of PM10, PM2.1 and PM1.1 due to the insoluble species is increased in sandstorm pollution period. The mass concentration of Ca2+ in sandstorm pollution period is higher than the other two pollution periods, and which is mainly in coarse particles with diameter larger than 1 microm. All the ten water-soluble ions are much higher in crop burning pollution especially K+ which is the tracer from crop burning. The peak mass concentrations of NO3(-), SO4(2-) and NH4+ are in 0.43-0.65 microm. PMID:22946180

Zhang, Qiu-Chen; Zhu, Bin; Su, Ji-Feng; Wang, Hong-Lei

2012-06-01

169

Human immunodeficiency virus type 2 infection and fusion of CD4-negative human cell lines: induction and enhancement by soluble CD4.  

PubMed Central

We describe human immunodeficiency type 2 (HIV-2) strains which induce cell-to-cell fusion and infect certain CD4- human cell lines. Soluble CD4 (sCD4) induces or enhances fusion by most HIV-2 strains tested. Soluble CD4-immunoglobulin G chimeras and conjugates of sCD4 and antibody to the third domain of CD4 block HIV-2 fusion of CD4- cells. We conclude that HIV-2 can enter CD4- cells via an alternative cell surface receptor to CD4. While some strains entered efficiently, others retained a dependency on an interaction with sCD4 to initiate changes in the virion envelope required for membrane fusion. Images

Clapham, P R; McKnight, A; Weiss, R A

1992-01-01

170

Solubility Database  

National Institute of Standards and Technology Data Gateway

SRD 106 IUPAC-NIST Solubility Database (Web, free access)   These solubilities are compiled from 18 volumes (Click here for List) of the International Union for Pure and Applied Chemistry(IUPAC)-NIST Solubility Data Series. The database includes liquid-liquid, solid-liquid, and gas-liquid systems. Typical solvents and solutes include water, seawater, heavy water, inorganic compounds, and a variety of organic compounds such as hydrocarbons, halogenated hydrocarbons, alcohols, acids, esters and nitrogen compounds. There are over 67,500 solubility measurements and over 1800 references.

171

Activin and TR3 orphan receptor: two 'atheroprotective' genes as evidenced in dedicated mouse models.  

PubMed

1. Atherosclerosis is a multifactorial, inflammatory disease of the arterial vessel wall that is promoted by various well-defined risk factors. Although numerous genes, expressed in different vascular and inflammatory cells, have been implicated in this disease, it is widely appreciated that most of the genes and gene products vital for initiation and progression of atherosclerosis are unknown. 2. We follow two strategies in an attempt to make up for the void of essential knowledge. First, we study candidate genes that have not been implied in human atherosclerosis before, notably the differentiation factor activin A. 3. Second, we performed a genome-wide search by differential display reverse transcription-polymerase chain reaction. This study indicated potential involvement of the TR3 orphan receptor transcription factor in smooth muscle cell (SMC) (patho)physiology. 4. To reveal functional involvement of these proteins in SMC during atherosclerosis, we performed experiments with mouse models, adjusted either to the characteristics of a secreted protein or to that of an intracellular transcription factor. 5. The secreted protein activin A was studied in mice infected systemically with recombinant adenoviral vehicles, resulting in predominant hepatic expression and subsequent high protein levels in the circulation. 6. To study the role of TR3 in atherosclerosis, we generated transgenic mice in which promoter sequences were applied that direct expression of the transgenes to SMC of the arterial tree. 7. Two approaches were taken to induce the formation of SMC-rich lesions: (i) activation of femoral artery SMC by placement of a loosely fitting cuff; and (ii) ligation of the carotid artery. 8. The aim of the present review is to illustrate the different approaches that can be taken to assess the potential relevance of genes in atherosclerosis in carefully selected mouse models. 9. Based on the results described, we propose that both activin A and TR3 prevent excessive SMC proliferation. PMID:14678255

Engelse, Marten A; Arkenbout, E Karin; Pannekoek, Hans; de Vries, Carlie J M

2003-11-01

172

Serum Activins and Follistatin during the Treatment of Chronic Hepatitis C Genotypes 1 and 4 and Their Correlations with Viral Load and Liver Enzymes: A Preliminary Report  

PubMed Central

Aims. To measure the effect of pegylated interferon-? therapy on serum activin-A, activin-B, and follistatin and their correlation with viral load and liver fibrosis in chronic hepatitis C (CHC). Methods. This study was cross-sectional and sera were collected from 165 participants classified into 7 groups: 40 healthy negative control, 33 treatment naïve patients as positive control, 19 patients at week 4, 22 at week 12, and 19 at week 24 of treatment initiation and 21 responders and 11 nonresponders at the end of 48-week treatment protocol. Serum candidate proteins were measured using ELISA and liver fibrosis was assessed by AST platelet ratio index (APRI). Results. CHC significantly increased activins and decreased follistatin compared to negative control (P < 0.05). Activin-A and follistatin levels returned to the levels of negative control group at weeks 4, 12, and 24 following treatment initiation and were significantly different from positive control (P < 0.05). Both proteins were significantly different between responders and nonresponders. Activin-A correlated positively and significantly with the viral load and APRI. Conclusion. CHC modulates serum activin-A and follistatin and they appear to be influenced by pegylated interferon-? therapy. Further studies are needed to explore the role of activins in CHC.

Refaat, Bassem; El-Shemi, Adel Galal; Ashshi, Ahmed Mohamed; AlZanbagi, Adnan

2014-01-01

173

Dynamic Changes in the Intrafollicular Inhibin\\/Activin\\/ Follistatin Axis during Human Follicular Development: Relationship to Circulating Hormone Concentrations  

Microsoft Academic Search

Previous studies of normal human ovaries suggest that inhibins, activins, and follistatin (FS) are produced in a stage-specific pattern indicative of intraovarian, autocrine\\/paracrine roles in regulating follicle development. However, these studies relied largely on surgical specimens and thus include little information about the menstrual cycle stage or dominant follicle status at the time follicles or ovaries were obtained. The purpose

ALAN L. SCHNEYER; TOSHIHIRO FUJIWARA; JANIS FOX; CORRINE K. WELT; JUDITH ADAMS; GERALYN M. MESSERLIAN; ANN E. TAYLOR

174

Gonadotropins, Prolactin, Inhibin A, Inhibin B, and Activin A in Human Fetal Serum from Midpregnancy and Term Pregnancy  

Microsoft Academic Search

Using specific enzyme-linked immunosorbent assays we measured inhibin A, inhibin B, and activin A in relation to LH, FSH, and PRL in normal human fetal midpregnancy serum obtained by in utero cord venipuncture (n 5 25) and compared these results to those in fetal serum from term pregnancies (n 5 23). We also tested serum from fetuses with intrauterine growth

F. DEBIEVE; S. BEERLANDT; C. HUBINONT; K. THOMAS

2010-01-01

175

Activin Plays a Key Role in the Maintenance of Long-Term Memory and Late-LTP  

ERIC Educational Resources Information Center

A recent study has revealed that fear memory may be vulnerable following retrieval, and is then reconsolidated in a protein synthesis-dependent manner. However, little is known about the molecular mechanisms of these processes. Activin [beta]A, a member of the TGF-[beta] superfamily, is increased in activated neuronal circuits and regulates…

Ageta, Hiroshi; Ikegami, Shiro; Miura, Masami; Masuda, Masao; Migishima, Rika; Hino, Toshiaki; Takashima, Noriko; Murayama, Akiko; Sugino, Hiromu; Setou, Mitsutoshi; Kida, Satoshi; Yokoyama, Minesuke; Hasegawa, Yoshihisa; Tsuchida, Kunihiro; Aosaki, Toshihiko; Inokuchi, Kaoru

2010-01-01

176

Controls on iron distributions in the deep water column of the North Pacific Ocean: Iron(III) hydroxide solubility and marine humic-type dissolved organic matter  

NASA Astrophysics Data System (ADS)

Dissolved Fe in the western and central North Pacific Ocean was characterized by surface depletion, middepth maxima and, below that, a slight decrease with depth similar to the vertical distributions of nutrients, apparent oxygen utilization, Fe(III) hydroxide solubility, and humic-type fluorescence (H-flu) intensity. Dissolved Fe concentrations ([D-Fe], <0.22-?m fraction) in the deep water column were one-half lower in the central region (0.3-0.6 nM) than the western region (0.5-1.2 nM) although the Fe(III) solubility ([Fe(III)sol], <0.025-?m fraction) levels and distributions in deep waters were almost the same between both regions with middepth maxima (˜0.6 nM) at 500-1500-m depth range and then a gradual decrease to ˜0.3 nM at 5000-m depth. Higher [D-Fe] than [Fe(III)sol] in the deep water column of the western region results from the higher production of dissolved Fe from the decomposition of sinking particulate organic matter in the western region than the central region because of the high atmospheric and/or lateral Fe inputs in the western region. Similarity between [D-Fe] level and [Fe(III)sol] value at each deep water depth in the central region may be attributed to [D-Fe] being nearly in the solubility equilibrium with Fe(III) hydroxide in seawater. Strong linear correlation between [D-Fe] and H-flu intensity in the central region and relatively similar linear relationships between [Fe(III)sol] and H-flu intensity in the western and central regions are the first confirmation that humic-type fluorescent dissolved organic matter may be responsible for [D-Fe] in the deep water column as natural organic ligands complexing with Fe(III).

Kitayama, Saori; Kuma, Kenshi; Manabe, Eri; Sugie, Koji; Takata, Hyoe; Isoda, Yutaka; Toya, Kenji; Saitoh, Sei-Ichi; Takagi, Shohgo; Kamei, Yoshihiko; Sakaoka, Keiichiro

2009-08-01

177

The ontogeny of myostatin, follistatin and activin-B mRNA expression during chicken embryonic development.  

PubMed

The developmental pattern of myostatin, follistatin and activin-B genes in chick embryonic development was investigated. Total RNA was isolated from whole embryos on each of embryonic days (E) 0 to 6, from cranial halves of the embryo at E7 to 8, and from pectoralis muscle tissues at E9 to 20. Myostatin, follistatin and activin-B cDNAs were synthesized by reverse-transcription polymerase chain reaction (RT-PCR). Myostatin expression was first detected in embryos as early as the blastoderm stage (unincubated embryo, stage 1, E0). Myostatin mRNA concentration declined approximately 5 fold by E2 and remained lower through E6. Levels then increased 3 fold on E7 and plateaued through E16. Follistatin mRNA was first detected in the blastoderm stage of chick embryos. Overall follistatin mRNA increased 6 fold from E1 to E20 of development. Follistatin levels declined on E1 (approximately 2 fold) and remained low through E9. Follistatin mRNA reached the highest level prior to hatching. Activin-B mRNA from the whole embryo preparations (E0-E6) varied as the embryo matured. Overall activin-B gene expression from E11 to E20 appeared to decline (approximately 3.5 fold). This pattern is opposite of follistatin during the same period which is consistent with the opposing functions of these two proteins. We suggest that follistatin, activin-B and myostatin play an important role in embryogenesis and skeletal muscle development of the chick embryo. This study represents the first comprehensive report of myostatin mRNA patterns in chicken embryos. PMID:10892562

Kocamis, H; Kirkpatrick-Keller, D C; Richter, J; Killefer, J

1999-01-01

178

Inhibition of Type 1 Cytokine-mediated Inflammation by a Soluble CD30 Homologue Encoded by Ectromelia (Mousepox) Virus  

PubMed Central

CD30 is up-regulated in several human diseases and viral infections but its role in immune regulation is poorly understood. Here, we report the expression of a functional soluble CD30 homologue, viral CD30 (vCD30), encoded by ectromelia (mousepox) virus, a poxvirus that causes a severe disease related to human smallpox. We show that vCD30 is a 12-kD secreted protein that not only binds CD30L with high affinity and prevents its interaction with CD30, but it also induces reverse signaling in cells expressing CD30L. vCD30 blocked the generation of interferon ?–producing cells in vitro and was a potent inhibitor of T helper cell (Th)1- but not Th2-mediated inflammation in vivo. The finding of a CD30 homologue encoded by ectromelia virus suggests a role for CD30 in antiviral defense. Characterization of the immunological properties of vCD30 has uncovered a role of CD30–CD30L interactions in the generation of inflammatory responses.

Saraiva, Margarida; Smith, Philip; Fallon, Padraic G.; Alcami, Antonio

2002-01-01

179

Energy Deprivation Alters in a Leptin- and Cortisol-Independent Manner Circulating Levels of Activin A and Follistatin But Not Myostatin in Healthy Males  

PubMed Central

Context: Activin A, myostatin, and follistatin have recently emerged as important regulatory molecules of reproduction and the musculoskeletal system. Little is known, however, about their day/night patterns of secretion and their physiological regulation by energy availability. Objective: The objective of the study was to explore day/night patterns of secretion and assess whether energy deprivation alters circulating levels of activin A, myostatin, follistatin, and cortisol and to examine whether leptin may mediate this effect. Design, Setting and Patients, and Interventions: Seven healthy lean men (aged 23.2 ± 3.7 yr, body mass index 23.6 ± 1.7 kg/m2) were studied for 72 h under three different conditions: on their baseline/isocaloric diet and in a complete fasting state with administration of either placebo or metreleptin. The two fasting studies were randomized and double blinded. Blood samples were obtained every 15 min from 0800 h on d 3 until 0800 h on d 4 and pooled hourly. Main Outcome Measures: Serum concentrations of activin A, myostatin, follistatin, cortisol, and leptin were measured. Results: In contrast to cortisol, we demonstrated no day/night pattern of activin A, myostatin, and follistatin secretion. Activin A concentrations decreased significantly in response to energy deprivation (P < 0.01). Follistatin and cortisol concentrations increased significantly (P < 0.01 and P < 0.01, respectively). Myostatin remained unaffected (P = 0.40). Leptin administration reversed cortisol response (P < 0.01) but failed to alter activin A, follistatin, or myostatin concentrations. Conclusions: Unlike cortisol, there is no day/night variation in the concentrations of activin A, myostatin, and follistatin in healthy young males. Although energy deprivation-induced cortisol changes are leptin mediated, the changes in follistatin and activin A concentrations occur through a leptin-independent pathway.

Vamvini, Maria T.; Aronis, Konstantinos N.; Chamberland, John P.

2011-01-01

180

A high concentration of genistein down-regulates activin A, Smad3 and other TGF-? pathway genes in human uterine leiomyoma cells  

PubMed Central

Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis™, we identified genes (up- or down-regulated, ? 1.5 fold, P ? 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 µg/ml) in UtLM cells. Downregulation of TGF-? signaling pathway genes, activin A, activin B, Smad3, TGF-?2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real-time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that down-regulation of activin A and Smad3, both members of the TGF-? pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas.

Di, Xudong; Andrews, Danica M.K.; Tucker, Charles J.; Yu, Linda; Moore, Alicia B.; Zheng, Xiaolin; Castro, Lysandra; Hermon, Tonia; Xiao, Hang

2012-01-01

181

A high concentration of genistein down-regulates activin A, Smad3 and other TGF-? pathway genes in human uterine leiomyoma cells.  

PubMed

Previously, we found that high doses of genistein show an inhibitory effect on uterine leiomyoma (UtLM) cell proliferation. In this study, using microarray analysis and Ingenuity Pathways Analysis™, we identified genes (up- or down-regulated, ? 1.5 fold, P ? 0.001), functions and signaling pathways that were altered following treatment with an inhibitory concentration of genistein (50 ?g/ml) in UtLM cells. Downregulation of TGF-? signaling pathway genes, activin A, activin B, Smad3, TGF-?2 and genes related to cell cycle regulation, with the exception of the upregulation of the CDK inhibitor P15, were identified and validated by real- time RT-PCR studies. Western blot analysis further demonstrated decreased protein expression of activin A and Smad3 in genistein-treated UtLM cells. Moreover, we found that activin A stimulated the growth of UtLM cells, and the inhibitory effect of genistein was partially abrogated in the presence of activin A. Overexpression of activin A and Smad3 were found in tissue samples of leiomyoma compared to matched myometrium, supporting the contribution of activin A and Smad3 in promoting the growth of UtLM cells. Taken together, these results suggest that downregulation of activin A and Smad3, both members of the TGF-? pathway, may offer a mechanistic explanation for the inhibitory effect of a high-dose of genistein on UtLM cells, and might be potential therapeutic targets for treatment of clinical cases of uterine leiomyomas. PMID:22228119

Di, Xudong; Andrews, Danica M K; Tucker, Charles J; Yu, Linda; Moore, Alicia B; Zheng, Xiaolin; Castro, Lysandra; Hermon, Tonia; Xiao, Hang; Dixon, Darlene

2012-04-30

182

Multiple roles of Activin/Nodal, bone morphogenetic protein, fibroblast growth factor and Wnt/?-catenin signalling in the anterior neural patterning of adherent human embryonic stem cell cultures  

PubMed Central

Several studies have successfully produced a variety of neural cell types from human embryonic stem cells (hESCs), but there has been limited systematic analysis of how different regional identities are established using well-defined differentiation conditions. We have used adherent, chemically defined cultures to analyse the roles of Activin/Nodal, bone morphogenetic protein (BMP), fibroblast growth factor (FGF) and Wnt/?-catenin signalling in neural induction, anteroposterior patterning and eye field specification in hESCs. We show that either BMP inhibition or activation of FGF signalling is required for effective neural induction, but these two pathways have distinct outcomes on rostrocaudal patterning. While BMP inhibition leads to specification of forebrain/midbrain positional identities, FGF-dependent neural induction is associated with strong posteriorization towards hindbrain/spinal cord fates. We also demonstrate that Wnt/?-catenin signalling is activated during neural induction and promotes acquisition of neural fates posterior to forebrain. Therefore, inhibition of this pathway is needed for efficient forebrain specification. Finally, we provide evidence that the levels of Activin/Nodal and BMP signalling have a marked influence on further forebrain patterning and that constitutive inhibition of these pathways represses expression of eye field genes. These results show that the key mechanisms controlling neural patterning in model vertebrate species are preserved in adherent, chemically defined hESC cultures and reveal new insights into the signals regulating eye field specification.

Lupo, Giuseppe; Novorol, Claire; Smith, Joseph R.; Vallier, Ludovic; Miranda, Elena; Alexander, Morgan; Biagioni, Stefano; Pedersen, Roger A.; Harris, William A.

2013-01-01

183

Soluble Overexpression in Escherichia coli,and Purification and Characterization of Wild-Type Recombinant Tobacco Acetolactate Synthase  

Microsoft Academic Search

Acetolactate synthase (ALS) is the first common enzyme in the biosynthesis of L-leucine, L-isoleucine, and L-valine. The wild-type ALS gene fromNicotiana tabacumwas cloned into the bacterial expression vector pGEX-2T. The resulting recombinant plasmid pGEX-ALS2 was used to transformEscherichia colistrain XL1-Blue, and the wild-type tobacco ALS (wALS) was expressed in the bacteria as a protein fused with glutathioneS-transferase (GST). The fusion

Soo-Ik Chang; Moon-Kyeong Kang; Jung-Do Choi; Sung Keon Namgoong

1997-01-01

184

Parainfluenza Virus Type 3 Expressing the Native or Soluble Fusion (F) Protein of Respiratory Syncytial Virus (RSV) Confers Protection from RSV Infection in African Green Monkeys  

PubMed Central

Respiratory syncytial virus (RSV) causes respiratory disease in young children, the elderly, and immunocompromised individuals, often resulting in hospitalization and/or death. After more than 40 years of research, a Food and Drug Administration-approved vaccine for RSV is still not available. In this study, a chimeric bovine/human (b/h) parainfluenza virus type 3 (PIV3) expressing the human PIV3 (hPIV3) fusion (F) and hemagglutinin-neuraminidase (HN) proteins from an otherwise bovine PIV3 (bPIV3) genome was employed as a vector for RSV antigen expression with the aim of generating novel RSV vaccines. b/h PIV3 vaccine candidates expressing native or soluble RSV F proteins were evaluated for efficacy and immunogenicity in a nonhuman primate model. b/h PIV3 is suited for development of pediatric vaccines since bPIV3 had already been evaluated in clinical studies in 1- and 2-month-old infants and was found to be safe, immunogenic, and nontransmissible in a day care setting (Karron et al., Pediatr. Infect. Dis. J. 15:650-654, 1996; Lee et al., J. Infect. Dis. 184:909-913, 2001). African green monkeys immunized with b/h PIV3 expressing either the native or soluble RSV F protein were protected from challenge with wild-type RSV and produced RSV neutralizing and RSV F-protein specific immunoglobulin G serum antibodies. The PIV3-vectored RSV vaccines evaluated here further underscore the utility of this vector system for developing safe and immunogenic pediatric respiratory virus vaccines.

Tang, Roderick S.; MacPhail, Mia; Schickli, Jeanne H.; Kaur, Jasmine; Robinson, Christopher L.; Lawlor, Heather A.; Guzzetta, Jeanne M.; Spaete, Richard R.; Haller, Aurelia A.

2004-01-01

185

PEGylated recombinant human soluble tumour necrosis factor receptor type I (r-Hu-sTNF-RI): novel high affinity TNF receptor designed for chronic inflammatory diseases  

PubMed Central

The proinflammatory cytokine, tumour necrosis factor ? (TNF?) has been shown to play a pivotal part in mediating acute and chronic inflammation. The activities of TNF? are modulated by the proteolytic shedding of the soluble extracellular domains of the two TNF receptors, p55 sTNF-RI and p75 sTNF-RII. Amgen Inc has cloned and expressed a recombinant form of a natural inhibitor of TNF?, referred to as recombinant human soluble TNF receptor type I (r-Hu-sTNF-RI, sTNF-RI). sTNF-RI is an E coli recombinant, monomeric form of the soluble TNF-type I receptor. A high molecular weight polyethylene glycol (PEG) molecule is attached at the N-terminus position to form the molecule intended for clinical evaluations (PEG sTNF-RI). Preclinical studies to date demonstrate that PEG sTNF-RI is efficacious in rodent models of chronic inflammatory disease including rheumatoid arthritis and Crohn's disease at doses as low as 0.3 mg/kg given every other day. This dose results in plasma concentrations of 0.3 to 0.5 µg/ml. Higher doses with correspondingly higher plasma concentrations yield higher efficacy. It has also demonstrated efficacy in E coli lipopolysaccharide, and Staphylococcus enterotoxin B mediated models of acute inflammation in rodents and primates. Pharmacokinetic studies in mice, rats, cynomolgus monkeys, baboons, and chimpanzees have been conducted with PEG sTNF-RI. Absorption from a subcutaneous dose was slow, with the time to reach maximal plasma concentrations of 24-48 hours in rats, and in monkeys, and 3-29 hours in chimpanzees. The initial volume of distribution of PEG sTNF-RI was essentially equivalent to that of plasma (40 ml/kg). This suggests the protein does not appear to extensively distribute from the systemic circulation with a volume of distribution at steady state (Vss) less than 200 ml/kg in all species studied. These results are consistent with previous experience with PEGylated proteins in which PEGylation decreases both the rate of absorption and the plasma clearance of human recombinant proteins in animals and humans. The use of a PEG molecule will probably provide a more advantageous dosing schedule (that is, less frequent dosing) for the patient compared with a non-PEG sTNF-RI.??

Edwards, C.

1999-01-01

186

Solubility-limited extrinsic n-type doping of a high electron mobility polymer for thermoelectric applications.  

PubMed

The thermoelectric properties of a highperformance electron-conducting polymer, (P(NDIOD-T2), extrinsically doped with dihydro-1H-benzoimidazol-2-yl (NDBI) derivatives, are reported. The highest thermoelectric power factor that has been reported for a solution-processed n-type polymer is achieved; and it is concluded that engineering polymerdopant miscibility is essential for the development of organic thermoelectrics. PMID:24448874

Schlitz, Ruth A; Brunetti, Fulvio G; Glaudell, Anne M; Miller, P Levi; Brady, Michael A; Takacs, Christopher J; Hawker, Craig J; Chabinyc, Michael L

2014-05-01

187

High yield production of a soluble human interleukin-3 variant from E. coli with wild-type bioactivity and improved radiolabeling properties.  

PubMed

Human interleukin-3 (hIL-3) is a polypeptide growth factor that regulates the proliferation, differentiation, survival and function of hematopoietic progenitors and many mature blood cell lineages. Although recombinant hIL-3 is a widely used laboratory reagent in hematology, standard methods for its preparation, including those employed by commercial suppliers, remain arduous owing to a reliance on refolding insoluble protein expressed in E. coli. In addition, wild-type hIL-3 is a poor substrate for radio-iodination, which has been a long-standing hindrance to its use in receptor binding assays. To overcome these problems, we developed a method for expression of hIL-3 in E. coli as a soluble protein, with typical yields of >3mg of purified hIL-3 per litre of shaking microbial culture. Additionally, we introduced a non-native tyrosine residue into our hIL-3 analog, which allowed radio-iodination to high specific activities for receptor binding studies whilst not compromising bioactivity. The method presented herein provides a cost-effective and convenient route to milligram quantities of a hIL-3 analog with wild-type bioactivity that, unlike wild-type hIL?3, can be efficiently radio-iodinated for receptor binding studies. PMID:23991218

Hercus, Timothy R; Barry, Emma F; Dottore, Mara; McClure, Barbara J; Webb, Andrew I; Lopez, Angel F; Young, Ian G; Murphy, James M

2013-01-01

188

Ultraviolet irradiation of DNA complexed with. alpha. /. beta. -type small, acid-soluble proteins from spores of Bacillus or Clostridium species makes spore photoproduct but not thymine dimers  

SciTech Connect

UV irradiation of complexes of DNA and an {alpha}/{beta}-type small, acid-soluble protein (SASP) from Bacillus subtilis spores gave decreasing amounts of pyrimidine dimers and increasing amounts of spore photoproduct as the SASP/DNA ratio was increased. The yields of pyrimidine dimers and spore photoproduct were < 0.2% and 8% of total thymine, respectively, when DNA saturated with SASP was irradiated at 254 nm with 30 kJ/m{sup 2}; in the absence of SASP the yields were reversed - 4.5% and 0.3%, respectively. Complexes of DNA with {alpha}/{beta}-type SASP from Bacillus cereus, Bacillus megaterium, or Clostridium bifermentans spores also gave spore photoproduct upon UV irradiation. However, incubation of these SASPs with DNA under conditions preventing complex formation or use of mutant SASPs that do not form complexes did not affect the photoproducts formed in vitro. These results suggest that the UV photochemistry of bacterial spore DNA in vivo is due to the binding of {alpha}/{beta}-type SASP, a binding that is known to cause a change in DNA conformation in vitro from the B form to the A form. The yields of spore photoproduct in vitro were significantly lower than in vivo, perhaps because of the presence of substances other than SASP in spores. It is suggested that as these factors diffuse out in the first minutes of spore germination, spore photoproduct yields become similar to those observed for irradiation of SASP/DNA complexes in vitro.

Nicholson, W.L.; Setlow, B.; Setlow, P. (Univ. of Connecticut Health Center, Farmington (United States))

1991-10-01

189

Activin A signaling directly activates Xenopus winged helix factors XFD-4/4', the orthologues to mammalian MFH-1.  

PubMed

We investigated the Xenopus winged helix gene XFD-4, its cDNA, and a pseudoallelic cDNA, termed XFD-4', representing Xenopus orthologues to chicken CWH-2 and mammalian MFH-1. XFD-4/4' genes are activated after midblastula transition in dorsolateral mesoderm but not within the dorsal lip. Later, expression is found in two segmented lines of cells bordering the somites, in head mesenchyme, in ventral abdominal muscle, and in the tail tip. Smad2 RNA injection leads to ectopic expression of XFD-4'. Since activation is also observed in activin A treated animal cap explants in the presence of cycloheximide, XFD-4/4' genes represent direct targets of activin signaling. Note that the future nomenclature for XFD-4 will be FoxC2a and for XFD-4' will be FoxC2b (Fox Nomenclature Committee). PMID:11180837

Köster, M; Dillinger, K; Knöchel, W

2000-06-01

190

Structure, chromosomal localization, and expression analysis of the mouse inhibin/activin {beta}{sub c} (Inhbc) gene  

SciTech Connect

The mouse inhibin/activin {beta}{sub c} gene (Inhbc), a member of the transforming growth factor-{beta} (TGF-{beta}) superfamily, was cloned, mapped, and characterized. The gene spans approximately 14 kb, is composed of two exons, and maps to the distal region of mouse chromosome 10, which is syntenic to chromosome 12q13.1, where the human inhibin/activin {beta}{sub c} gene (INHBC) maps. The primary translation product is a preproprotein of 352 amino acids. The nature C-terminal domain of 116 amino acids shares 94% identity with its human homolog. Primer extension analysis shows that transcription starts approximately 130 bp upstream of the translation initiation site, and no TATA box was found in the promoter. Ribonuclease protection analyses reveal that mouse Inhbc is predominantly expressed in adult liver. Embryonic expression is detected beginning from Day 14.5 of gestation. 49 refs., 7 figs.

Schmitt, J.; Schrewe, H. [Max-Planck-Inst. of Immunobiology, Freiburg (Germany)] [Max-Planck-Inst. of Immunobiology, Freiburg (Germany); Hoetten, G.; Pohl, J. [Biopharm GmbH, Heidelberg (Germany)] [and others] [Biopharm GmbH, Heidelberg (Germany); and others

1996-03-05

191

The soluble ectodomain of RetC634Y inhibits both the wild-type and the constitutively active Ret.  

PubMed Central

Substitution of Cys-634 in the extracellular domain of the Ret tyrosine kinase receptor causes its dimerization and activation of its transforming potential. To gain further insight into the molecular basis leading to Ret activation we purified a mutant protein consisting of the entire ectodomain of the Ret carrying a Cys-634-->Tyr substitution (EC-Ret(C634Y)). The protein is glycosylated, like the native one, and is biologically active. By using an in vitro cell system we show that EC-Ret(C634Y) inhibits the membrane-bound receptor Ret(C634Y), interfering with its dimerization. Furthermore, we demonstrate that EC-Ret(C634Y) competes with the wild-type Ret receptor for ligand binding. The results presented support the notion of the possible involvment of glial cell line-derived neurotrophic factor (GDNF) with multiple endocrine neoplasia type 2A (MEN2A) tumours, and describe a useful tool for generating molecular mimetics directed towards specific mutations of the ret oncogene.

Cerchia, Laura; Libri, Domenico; Carlomagno, Maria Stella; de Franciscis, Vittorio

2003-01-01

192

Transgenic Non-Human Animals Expressing a Truncated Activin Type II Receptor.  

National Technical Information Service (NTIS)

The present invention provides a substantially purified growth differentiation factor (GDF) receptor, including a GDF-8 (myostatin) receptor, as well as functional peptide portions thereof. In addition, the invention provides a virtual representation of a...

A. C. McPherron, S. J. Lee

2005-01-01

193

Activin a efficiently specifies definitive endoderm from human embryonic stem cells only when phosphatidylinositol 3-kinase signaling is suppressed.  

PubMed

Human ESCs (hESCs) respond to signals that determine their pluripotency, proliferation, survival, and differentiation status. In this report, we demonstrate that phosphatidylinositol 3-kinase (PI3K) antagonizes the ability of hESCs to differentiate in response to transforming growth factor beta family members such as Activin A and Nodal. Inhibition of PI3K signaling efficiently promotes differentiation of hESCs into mesendoderm and then definitive endoderm (DE) by allowing them to be specified by Activin/Nodal signals present in hESC cultures. Under conditions where hESCs are grown in mouse embryo fibroblast-conditioned medium under feeder-free conditions, approximately 70%-80% are converted into DE following 5 days of treatment with inhibitors of the PI3K pathway, such as LY 294002 and AKT1-II. Microarray and quantitative polymerase chain reaction-based gene expression profiling demonstrates that definitive endoderm formation under these conditions closely parallels that following specification with elevated Activin A and low fetal calf serum (FCS)/knockout serum replacement (KSR). Reduced insulin/insulin-like growth factor (IGF) signaling was found to be critical for cell fate commitment into DE. Levels of insulin/IGF present in FCS/KSR, normally used to promote self-renewal of hESCs, antagonized differentiation. In summary, we show that generation of hESC-DE requires two conditions: signaling by Activin/Nodal family members and release from inhibitory signals generated by PI3K through insulin/IGF. These findings have important implications for our understanding of hESC self-renewal and early cell fate decisions. PMID:17204604

McLean, Amanda B; D'Amour, Kevin A; Jones, Karen L; Krishnamoorthy, Malini; Kulik, Michael J; Reynolds, David M; Sheppard, Alan M; Liu, Huiqing; Xu, Ying; Baetge, Emmanuel E; Dalton, Stephen

2007-01-01

194

GLI2-specific Transcriptional Activation of the Bone Morphogenetic Protein/Activin Antagonist Follistatin in Human Epidermal Cells*S?  

PubMed Central

Hedgehog (HH) signaling in the epidermis is primarily mediated by the zinc finger transcription factors GLI1 and GLI2. Exquisite regulation of HH/GLI signaling is crucial for proper specification of the epidermal lineage and development of its derivatives, whereas dysregulation of HH/GLI signaling disrupts tissue homeostasis and causes basal cell carcinoma (BCC). Similarly, bone morphogenetic proteins (BMPs) and activins have been described as key signaling factors in the complex regulation of epidermal fate decisions, although their precise interplay with HH/GLI is largely elusive. Here we show that, in human epidermal cells, expression of the activin/BMP antagonist follistatin (FST) is predominantly up-regulated by the HH effector GLI2. Consistently, we found strong FST expression in the outer root sheath of human hair follicles and BCC. Detailed promoter analysis showed that two sequences with homology to the GLI consensus binding site are required for GLI2-mediated activation. Interestingly, activation of the FST promoter is highly GLI2-specific, because neither GLI1 nor GLI3 can significantly increase FST transcription. GLI2 specificity requires the presence of a 518-bp fragment in the proximal FST promoter region. On the protein level, sequences C-terminal to the zinc finger are responsible for GLI2-specific activation of FST transcription, pointing to the existence of GLI-interacting cofactors that modulate GLI target specificity. Our results reveal a key role of GLI2 in activation of the activin/BMP antagonist FST in response to HH signaling and provide new evidence for a regulatory interaction between HH and activin/BMP signaling in hair follicle development and BCC.

Eichberger, Thomas; Kaser, Alexandra; Pixner, Claudia; Schmid, Carmen; Klingler, Stefan; Winklmayr, Martina; Hauser-Kronberger, Cornelia; Aberger, Fritz; Frischauf, Anna-Maria

2008-01-01

195

Reduced expression of activin receptor-like kinase 7 in breast cancer is associated with tumor progression.  

PubMed

To explore the clinical implication of activin receptor-like kinase 7 (ALK7) expression in breast cancer, we evaluated its protein level in six kinds of human breast tissue samples, including adjacent normal tissues, adenosis, breast fibroadenoma, ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), and lymph node metastases (LNM). Immunohistochemical analyses showed that ALK7 was more frequently and much more intensely expressed in adjacent normal tissues, adenosis, and fibroadenoma tissues than in malignant tissues (DCIS, IDC, and LNM). Furthermore, the ALK7 expression in primary tumors and the corresponding LNM was evaluated in parallel samples from 60 patients with IDC. Results showed that the ALK7 expression status in primary tumors and LNM was concordant in 53 patients (88%), suggesting that ALK7 expression was retained in LNM. Moreover, our results suggested that ALK7 expression inversely correlated with the tumor grade (P=0.009) and clinical stage (P=0.004) in IDC significantly. Finally, the effect of activin-ALK7 pathway on the breast cancer cell growth was elucidated, and results revealed that overexpression of ALK7 could restore the inhibitory effect of activin B on the growth of ALK7-negative breast cancer cell line, ZR-75-30. These findings provide the evidence that the reduction or lack of ALK7 expression may account for the loss of its ligand sensitivity of breast cancer cells, thereby leading to breast tumor progression. PMID:22086737

Zeng, Fancai; Xu, Guoxiong; Zhou, Tiejun; Yang, Chengwan; Wang, Xinyan; Peng, Chun; Zhou, Hong

2012-12-01

196

Arginine improves protein elution in hydrophobic interaction chromatography. The cases of human interleukin-6 and activin-A.  

PubMed

The effects of arginine on protein binding and elution in hydrophobic interaction chromatography (HIC) were examined using recombinant human interleukin-6 (IL-6) and activin-A. Binding of IL-6 in the presence of ammonium sulfate (AS) was tested using low- and high-substituted phenyl-sepharose. While inclusion of arginine during loading of IL-6 resulted in incomplete binding to the low-substituted phenyl-sepharose, binding was complete to the high-substituted phenyl-sepharose. Arginine facilitated elution of IL-6 from both columns. These results demonstrate that arginine weakens hydrophobic interactions between IL-6 and the phenyl-sepharose. More drastic results were obtained using activin-A, which showed undetectable recovery from phenyl-sepharose. Although no apparent elution of activin-A was observed from butyl-sepharose in aqueous buffer alone, the addition of arginine to the buffer resulted in partial elution recovery and, together with ethanol, resulted in greatly improved recovery of the protein. Two arginine derivatives, acetylarginine and agmatine, were also effective. These results show that arginine improves protein elution in HIC. PMID:17449045

Tsumoto, Kouhei; Ejima, Daisuke; Nagase, Kazuo; Arakawa, Tsutomu

2007-06-22

197

An activin receptor IIA ligand trap promotes erythropoiesis resulting in a rapid induction of red blood cells and haemoglobin.  

PubMed

Sotatercept (ACE-011), a recombinant human fusion protein containing the extracellular domain of the human Activin receptor IIA, binds to and inhibits activin and other members of the transforming growth factor -? (TGF-?) superfamily. Administration of sotatercept led to a rapid and sustained increase in red blood cell (RBC) count and haemoglobin (Hb) in healthy volunteers (phase I clinical trials), but the mechanism is not fully understood. Mice treated with RAP-011 (murine ortholog of ACE-011) respond with a rapid (within 24 h) increase in haematocrit, Hb, and RBC count. These effects are accompanied by an equally rapid stimulation of late-stage erythroid precursors in the bone marrow (BM). RAP-011 also induces a significant increase in erythroid burst-forming units and erythropoietin, which could contribute to additional, sustained effects on RBC production. Further in vitro co-culture studies demonstrate that BM accessory cells are required for RAP-011 effects. To better understand which TGF-? family ligand(s) mediate RAP-011 effects, we evaluated the impact of several of these ligands on erythroid differentiation. Our data suggest that RAP-011 may act to rescue growth differentiation factor 11/Activin A-induced inhibition of late-stage erythropoiesis. These data define the mechanism of action of a novel agent that regulates RBC differentiation and provide the rationale to develop sotatercept for the treatment of anaemia and ineffective erythropoiesis. PMID:24635723

Carrancio, Soraya; Markovics, Jennifer; Wong, Piu; Leisten, Jim; Castiglioni, Paola; Groza, Matthew C; Raymon, Heather K; Heise, Carla; Daniel, Tom; Chopra, Rajesh; Sung, Victoria

2014-06-01

198

Simultaneous enhancement of electron injection and air stability in N-type organic field-effect transistors by water-soluble polyfluorene interlayers.  

PubMed

Here, we report the simultaneous attainment of efficient electron injection and enhanced stability under ambient conditions for top-gate/bottom-contact (TG/BC), n-type, organic field-effect transistors (OFETs) using water-soluble polyfluorene derivatives (WPFs). When inserting the WPF interlayers between a semiconductor and the BC Au electrodes, initially the ambipolar (6,6)-phenyl-C61butyric acid methyl ester (PCBM) OFETs were fully converted to unipolar charge transport characteristics that were exclusively n-type with significantly increased electron mobilities as high as 0.12 cm(2)/(V s) and a decreased threshold voltage. These improvements were mostly attributed to the interfacial dipoles of WPF layers that aligned to form a favorable energy band structure for efficient electron injection and to effectively block counter charge carriers. These were confirmed when values for the reduced work function of metal electrodes with WPFs and their correlated contact resistance were measured via the ultraviolet photoemission spectroscopy and the transmission-line method, respectively. Moreover, the WPF interlayers played an important role in air stability of PCBM OFETs that exhibited higher and appreciably enhanced by increasing the ethylene-oxide side chain lengths of WPFs, which presumably was due to the water/oxygen/ion capturing effects in the hydrophilic interlayers. PMID:24840007

Kim, Jihong; Khim, Dongyoon; Kang, Rira; Lee, Seung-Hoon; Baeg, Kang-Jun; Kang, Minji; Noh, Yong-Young; Kim, Dong-Yu

2014-06-11

199

Granulosa cell tumor mutant FOXL2C134W suppresses GDF-9 and activin A-induced follistatin transcription in primary granulosa cells.  

PubMed

A single somatic FOXL2 mutation (FOXL2(C134W)) was identified in almost all granulosa cell tumor (GCT) patients. In the pituitary, FOXL2 and Smad3 coordinately regulate activin stimulation of follistatin transcription. We explored whether a similar regulation occurs in the ovary, and whether FOXL2(C134W) has altered activity. We show that in primary granulosa cells, GDF-9 and activin increase Smad3-mediated follistatin transcription. In contrast to findings in the pituitary, FOXL2 negatively regulates GDF-9 and activin-stimulated follistatin transcription in the ovary. Knockdown of endogenous FOXL2 confirmed this inhibitory role. FOXL2(C134W) displayed enhanced inhibitory activity, completely ablating GDF-9 and activin-induced follistatin transcription. GDF-9 and activin activity was lost when either the smad binding element or the forkhead binding element were mutated, indicating that both sites are required for Smad3 actions. This study highlights that FOXL2 negatively regulates follistatin expression within the ovary, and that the pathogenesis of FOXL2(C134W) may involve an altered interaction with Smad3. PMID:23567549

McTavish, Kirsten J; Nonis, David; Hoang, Yvonne D; Shimasaki, Shunichi

2013-06-15

200

Antisense-oligonucleotide mediated exon skipping in activin-receptor-like kinase 2: inhibiting the receptor that is overactive in fibrodysplasia ossificans progressiva.  

PubMed

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disease characterized by progressive heterotopic ossification of connective tissues, for which there is presently no definite treatment. A recurrent activating mutation (c.617G?A; R206H) of activin receptor-like kinase 2 (ACVR1/ALK2), a BMP type I receptor, has been shown as the main cause of FOP. This mutation constitutively activates the BMP signaling pathway and initiates the formation of heterotopic bone. In this study, we have designed antisense oligonucleotides (AONs) to knockdown mouse ALK2 expression by means of exon skipping. The ALK2 AON could induce exon skipping in cells, which was accompanied by decreased ALK2 mRNA levels and impaired BMP signaling. In addition, the ALK2 AON potentiated muscle differentiation and repressed BMP6-induced osteoblast differentiation. Our results therefore provide a potential therapeutic approach for the treatment of FOP disease by reducing the excessive ALK2 activity in FOP patients. PMID:23861958

Shi, Songting; Cai, Jie; de Gorter, David J J; Sanchez-Duffhues, Gonzalo; Kemaladewi, Dwi U; Hoogaars, Willem M H; Aartsma-Rus, Annemieke; 't Hoen, Peter A C; ten Dijke, Peter

2013-01-01

201

Soluble complement receptor type 1 (sCR1) in chronic liver diseases: serum levels at different stages of liver diseases  

PubMed Central

Complement receptor type 1 (CR1) is an integral membrane protein of many haematopoietic cells and plays an important role in the clearance of complement-associated immune complexes, favouring their transport to liver and spleen macrophages. A small amount of soluble CR1 (sCR1) is also found in plasma and might originate directly from release of leucocytes and other circulating cells. In previous studies, an increase in serum sCR1 level has been observed in liver cirrhosis and end-stage renal failure. High levels have also been found in patients with some haematologic malignancies. sCR1 serum levels were measured using a specific double sandwich ELISA assay. The present study demonstrates the correlation between mean serum sCR1 concentrations and disease severity in patients with chronic liver disease. In patients with liver cirrhosis, grouped according to the Child–Pugh classification, sCR1 rose as liver function decreased. The presence of neoplastic growth in the liver apparently does not play a role in the increase of sCR1. Serum sCR1 was not elevated in other solid malignancies. Since sCR1 accumulates in liver diseases, evaluation of its serum levels could be useful as a liver function test.

DI Bona, D; Montalto, G; Clemenza, L; Bascone, F; Accardo, P; Bellavia, D; CraxI, A; Brai, M

1998-01-01

202

Clinical Value of Plasma Soluble Urokinase-Type Plasminogen Activator Receptor Levels in Term Neonates with Infection or Sepsis: A Prospective Study  

PubMed Central

Background. suPAR, the soluble form of the urokinase-type plasminogen activator receptor, has been identified as a biomarker of infection in adults but its properties in neonatal infection are not known. Methods. Plasma suPAR levels were determined by ELISA in 47 term neonates with infection (19 bacterial and 28 viral) and in 18 healthy neonates as controls. Thirteen out of 47 infected neonates were septic. In all infected neonates, suPAR levels were repeated at 24 hours, 48 hours, 3–5 days, and 7–10 days following admission. Results. Plasma suPAR levels were significantly increased in infected neonates upon admission, whereas they were highest in septic neonates, in comparison with controls (P < 0.001) and correlated positively with serum CRP levels (P = 0.001). At infection subsidence, suPAR concentrations decreased significantly in comparison with baseline (P < 0.001) but remained higher than in controls (P = 0.01). Receiver operating characteristic analysis resulted in significant areas under the curve for detecting either infected or septic neonates, but not for discriminating between bacterial and viral cause of infection. Conclusions. suPAR is a diagnostic biomarker of infection or sepsis in term neonates; however, it cannot discriminate bacterial from viral infections and also its utility for monitoring the response to treatment is questioned.

Siahanidou, Tania; Margeli, Alexandra; Charoni, Stavroula; Giannaki, Maria; Vavourakis, Eustathios; Charisiadou, Athina; Papassotiriou, Ioannis

2014-01-01

203

Moisture solubility for differently conditioned transformer oils  

Microsoft Academic Search

It is important to monitor the moisture content of transformer oil in a transformer. One parameter of particular interest is the moisture solubility of transformer oil. It has been reported that transformer oils under different conditions have different solubility. Measurements of solubility for four different types of conditioned oil are presented in this paper: fresh Shell Diala AX oil, lab-aged

Y. DUI; A. V. Mamishev; B. C. Lesieutre; M. Zahn; S. H. Kang

2001-01-01

204

The Notch ligand Delta-like 1 integrates inputs from TGFbeta/Activin and Wnt pathways  

SciTech Connect

Unlike the well-characterized nuclear function of the Notch intracellular domain, it has been difficult to identify a nuclear role for the ligands of Notch. Here we provide evidence for the nuclear function of the Notch ligand Delta-like 1 in colon cancer (CC) cells exposed to butyrate. We demonstrate that the intracellular domain of Delta-like 1 (Dll1icd) augments the activity of Wnt signaling-dependent reporters and that of the promoter of the connective tissue growth factor (CTGF) gene. Data suggest that Dll1icd upregulates CTGF promoter activity through both direct and indirect mechanisms. The direct mechanism is supported by co-immunoprecipitation of endogenous Smad2/3 proteins and Dll1 and by chromatin immunoprecipitation analyses that revealed the occupancy of Dll1icd on CTGF promoter sequences containing a Smad binding element. The indirect upregulation of CTGF expression by Dll1 is likely due to the ability of Dll1icd to increase Wnt signaling, a pathway that targets CTGF. CTGF expression is induced in butyrate-treated CC cells and results from clonal growth assays support a role for CTGF in the cell growth-suppressive role of butyrate. In conclusion, integration of the Notch, Wnt, and TGFbeta/Activin signaling pathways is in part mediated by the interactions of Dll1 with Smad2/3 and Tcf4.

Bordonaro, Michael, E-mail: mbordonaro@tcmedc.org; Tewari, Shruti, E-mail: stewari@tcmedc.org; Atamna, Wafa, E-mail: watamna@tcmedc.org; Lazarova, Darina L., E-mail: dlazarova@tcmedc.org

2011-06-10

205

An activin receptor IIA ligand trap corrects ineffective erythropoiesis in ?-thalassemia.  

PubMed

The pathophysiology of ineffective erythropoiesis in ?-thalassemia is poorly understood. We report that RAP-011, an activin receptor IIA (ActRIIA) ligand trap, improved ineffective erythropoiesis, corrected anemia and limited iron overload in a mouse model of ?-thalassemia intermedia. Expression of growth differentiation factor 11 (GDF11), an ActRIIA ligand, was increased in splenic erythroblasts from thalassemic mice and in erythroblasts and sera from subjects with ?-thalassemia. Inactivation of GDF11 decreased oxidative stress and the amount of ?-globin membrane precipitates, resulting in increased terminal erythroid differentiation. Abnormal GDF11 expression was dependent on reactive oxygen species, suggesting the existence of an autocrine amplification loop in ?-thalassemia. GDF11 inactivation also corrected the abnormal ratio of immature/mature erythroblasts by inducing apoptosis of immature erythroblasts through the Fas-Fas ligand pathway. Taken together, these observations suggest that ActRIIA ligand traps may have therapeutic relevance in ?-thalassemia by suppressing the deleterious effects of GDF11, a cytokine which blocks terminal erythroid maturation through an autocrine amplification loop involving oxidative stress and ?-globin precipitation. PMID:24658077

Dussiot, Michael; Maciel, Thiago T; Fricot, Aurélie; Chartier, Céline; Negre, Olivier; Veiga, Joel; Grapton, Damien; Paubelle, Etienne; Payen, Emmanuel; Beuzard, Yves; Leboulch, Philippe; Ribeil, Jean-Antoine; Arlet, Jean-Benoit; Coté, Francine; Courtois, Geneviève; Ginzburg, Yelena Z; Daniel, Thomas O; Chopra, Rajesh; Sung, Victoria; Hermine, Olivier; Moura, Ivan C

2014-04-01

206

Activin A, exendin-4, and glucose stimulate differentiation of human pancreatic ductal cells.  

PubMed

Islet transplantation is one treatment option for diabetes mellitus. However, novel sources of pancreatic islets or insulin-producing cells are required because the amount of donor tissue available is severely limited. Pancreatic ductal cells are an alternative source of ?-cells because they have the potential to differentiate into insulin-producing cells. We investigated whether treatment of human pancreatic ductal cells with activin A (ActA) and exendin-4 (EX-4) stimulated transdifferentiation of the cells, both in vitro and in vivo. We treated human pancreatic ductal cells with ActA and EX-4 in high-glucose media to induce differentiation into insulin-producing cells and transplanted the cells into streptozotocin-induced diabetic nude mice. Co-treatment of mice with ActA and EX-4 promoted cell proliferation, induced expression of pancreatic ?-cell-specific markers, and caused glucose-induced insulin secretion compared with the ActA or EX-4 mono-treatment groups respectively. When pancreatic ductal cells treated with ActA and EX-4 in high-glucose media were transplanted into diabetic nude mice, their blood glucose levels normalized and insulin was detected in the graft. These findings suggest that pancreatic ductal cells have a potential to replace pancreatic islets for the treatment of diabetes mellitus when the ductal cells are co-treated with ActA, EX-4, and glucose to promote their differentiation into functional insulin-producing cells. PMID:23503774

Kim, Hyo-Sup; Hong, Seung-Hyun; Oh, Seung-Hoon; Kim, Jae-Hyeon; Lee, Myung-Shik; Lee, Moon-Kyu

2013-06-01

207

Triiodothyronine suppresses activin-induced differentiation of erythroleukemia K562 cells under hypoxic conditions.  

PubMed

Thyroid hormone stimulates erythropoietic differentiation. However, severe anemia is sometimes seen in patients with hyperthyroidism, and the mechanisms have not been fully elucidated. Bone marrow is comprised about 2-8% oxygen, and the characteristics of hematopoietic stem cells have been shown to be influenced under hypoxia. Hypoxia-inducible factor-1 is a critical mediator of cellular responses to hypoxia and an important mediator in signal transduction of thyroid hormone [triiodothyronine (T3)]. The aim of this study was to investigate the effect of T3 on erythropoiesis under hypoxia mimicking physiological conditions in the bone marrow. We maintained human erythroleukemia K562 cells under hypoxic atmosphere (2% O?) and examined their cellular characteristics. Compared to that under normal atmospheric conditions, cells under hypoxia showed a reduction in the proliferation rate and increase in the hemoglobin content or benzidine-positive rate, indicating promotion of erythroid differentiation. T3 had no effect on hypoxia-induced erythroid differentiation, but significantly inhibited activin A/erythroid differentiation factor-induced erythroid differentiation. Moreover, GATA2 mRNA expression was suppressed in association with erythroid differentiation, while T3 significantly diminished that suppression. These results suggest that T3 has a direct suppressive effect on erythroid differentiation under hypoxic conditions. PMID:24604674

Yamamoto, Yoritsuna; Shiraishi, Mieno; Fujita, Masanori; Kojima, Itaru; Tanaka, Yuji; Tachibana, Shoichi

2014-06-01

208

The structure of the homopolymeric O-specific chain from the phenol soluble LPS of the Rhizobium loti type strain NZP2213  

Microsoft Academic Search

The O-specific polysaccharide of the phenol soluble lipopolysaccharide (LPS) (LPS-P) of the Rhizobium loti NZP2213 strain consists of a homopolymeric chain of ?-1, 3-linked units of 2-O-acetyl-6-deoxy-l-talopyranose, very probably terminated by a single unit of 2-O-acetyl-6-deoxy-l-talopyranose. The hydrophobic character of the long O-chains explains the phenol solubility of LPS-P, in contrast to the water solubility of LPS-W, which is of

R. Russa; T. Urbanik-Sypniewska; A. S. Shashkov; H. Kochanowski; H. Mayer

1995-01-01

209

Hydrogen Solubility in Austenitic Stainless Steels  

SciTech Connect

Hydrogen solubility was directly measured in specimens of Types 304L, 21-6-9, and modified A-286 austenitic stainless steels saturated with hydrogen at 69 MPa pressure at 470 K. Nitrogen in Type 21-6-9 stainless steel and precipitate morphology in the modified Type A-286 stainless steel altered the hydrogen solubility. Cold work and surface treatment had only minor effects on hydrogen solubility in the three stainless steels. This reports discusses this study.

Caskey, G.R. Jr.

1981-05-21

210

Hydrogen Solubility in Austenitic Stainless Steels  

Microsoft Academic Search

Hydrogen solubility was directly measured in specimens of Types 304L, 21-6-9, and modified A-286 austenitic stainless steels saturated with hydrogen at 69 MPa pressure at 470 K. Nitrogen in Type 21-6-9 stainless steel and precipitate morphology in the modified Type A-286 stainless steel altered the hydrogen solubility. Cold work and surface treatment had only minor effects on hydrogen solubility in

Caskey; G. R. Jr

1981-01-01

211

Impact of injection sites for soluble insulin on glycaemic control in Type 1 (insulin-dependent) diabetic patients treated with a multiple insulin injection regimen  

Microsoft Academic Search

Summary  The absorption rate of rapid acting (soluble) insulin is slow from the subcutaneous tissue of the thigh compared to intramuscular injection into the thigh and s.c. injection into the abdominal wall. The aim of the study was to evaluate the impact of soluble insulin injected either intramuscularly into the thigh (IMT), s.c. into the abdominal wall (SCA) or s.c. into

J. E. Henriksen; M. S. Djurhuus; A. Vaag; P. Thye-Rønn; D. Knudsen; O. Hother-Nielsen; H. Beck-Nielsen

1993-01-01

212

Concentration and activity of the soluble form of the interleukin-7 receptor ? in type 1 diabetes identifies an interplay between hyperglycemia and immune function.  

PubMed

Soluble interleukin-7 (IL-7) receptor ? (sCD127) is implicated in the pathogenesis of autoimmune diseases. We show that serum sCD127 concentrations are increased at the onset of type 1 diabetes (T1D; n = 390) as compared with concentrations in age-matched islet autoantibody-negative first-degree relatives of patients (n = 392; P = 0.00001). sCD127 concentration in patients was influenced by islet autoantibody status (P = 0.003) and genotype of the rs6897932 single nucleotide polymorphism within the IL-7RA gene (P = 0.006). Release of sCD127 in vitro was strongly upregulated by activation of T lymphocytes and affected by exposure to cytokines. sCD127 bound IL-7 and was antagonistic to IL-7 signaling and IL-7-mediated T-cell proliferation, suggesting a regulatory feedback mechanism on T-cell expansion. Remarkably, high glucose led to a glycated form of sCD127 that was ineffective as an IL-7 antagonist. The finding of glycated sCD127 in the circulation of patients at onset of T1D suggested that physiological regulation of IL-7-mediated T-cell survival and expansion by sCD127 may be compromised in T1D. The findings indicate that genetic, immunologic, and metabolic factors contribute to a dysregulation of the IL-7/IL-7 receptor pathway in T1D and identify a novel hyperglycemia-mediated interference of immune regulatory networks. PMID:23454692

Monti, Paolo; Brigatti, Cristina; Krasmann, Miriam; Ziegler, Anette G; Bonifacio, Ezio

2013-07-01

213

A Soluble Factor(s) Secreted from CD8+ T Lymphocytes Inhibits Human Immunodeficiency Virus Type 1 Replication through STAT1 Activation  

PubMed Central

CD8+ T lymphocytes can suppress human immunodeficiency virus type 1 (HIV-1) replication by secreting a soluble factor(s) known as CD8+ T-lymphocyte antiviral factor (CAF). One site of CAF action is inhibition of HIV-1 RNA transcription, particularly at the step of long terminal repeat (LTR)-driven gene expression. However, the mechanism by which CAF inhibits LTR activation is not understood. Here, we show that conditioned media from several herpesvirus saimari-transformed CD8+ T lymphocytes inhibit, in a time- and dose-dependent manner, the replication of HIV-1 pseudotype viruses that express the envelope glycoproteins of vesicular stomatitis virus (HIV-1VSV). The same conditioned media also inhibit phorbol myristate acetate-induced activation of the HIV-1 LTR and activate the signal transducer and activator of transcription 1 (STAT1) protein. We have obtained direct evidence that STAT1 is necessary for CAF-mediated inhibition of LTR activation and HIV-1 replication. Thus, the inhibitory effect of CAF on HIV-1VSV replication was abolished in STAT1-deficient cells. Moreover, CAF inhibition of LTR activation was diminished both in STAT1-deficient cells and in cells expressing a STAT1 dominant negative mutant but was restored when STAT1 was reintroduced into the STAT1-deficient cells. We also observed that CAF induced the expression of interferon regulatory factor 1 (IRF-1), and that IRF-1 gene induction was STAT-1 dependent. Taken together, our results suggest that CAF activates STAT1, leading to IRF-1 induction and inhibition of gene expression regulated by the HIV-1 LTR. This study therefore helps clarify one molecular mechanism of host defense against HIV-1.

Chang, Theresa Li-Yun; Mosoian, Arevik; Pine, Richard; Klotman, Mary E.; Moore, John P.

2002-01-01

214

1H, 13C and 15N resonance assignments of a highly-soluble murine interleukin-3 analogue with wild-type bioactivity.  

PubMed

Interleukin-3 (IL-3) is a cytokine that acts as a critical mediator of inflammation and immune responses to infections. IL-3, like interleukin-5 (IL-5) and granulocyte-macrophage colony stimulating factor (GM-CSF), exerts its effects on target cells via receptors composed of cytokine-specific alpha-subunits and a common beta-subunit (betac-subunit, shared with IL-5 and GM-CSF). In contrast to humans, mice also possess an additional beta-receptor, beta(IL-3), that can specifically bind IL-3. Except for a study carried out on an analogue of human IL-3 that contains 14 mutations, structure-related studies of IL-3 have been very limited, largely because of its poor solution behaviour. Here we report (1)H, (13)C, and (15)N chemical shift assignments of murine IL-3 comprising residues 33-156 (SWISS-PROT accession number: P01586), in which the only mutation is an alanine substitution of Cys105. The mIL-3 construct used in the present study was engineered by eliminating residues 27-32 of the N-terminus (the first 26 residues of the primary sequence of mIL-3 are cleaved in vivo during secretion), the C-terminal 10 residues (157-166), and a disulfide bond between Cys105 and Cys166 that is poorly conserved in orthologue sequences. The new construct vastly improves the solubility of murine IL-3 while maintaining its wild-type biological activity. PMID:20174897

Yao, Shenggen; Murphy, James M; Low, Andrew; Norton, Raymond S

2010-04-01

215

Assessment of serum levels of soluble CD40L in Egyptian children and adolescents with type 1 diabetes mellitus: Relationship to microalbuminuria and glycemic control  

PubMed Central

Context: Soluble CD40 ligand (sCD40L) is known to be elevated in different clinical situations including hypercholesterolemia, acute coronary syndromes, and type 2 diabetes mellitus (T2DM), Data about the relationship between type 1 diabetes mellitus (T1DM) and sCD40L is limited. In addition, the potential role ofsCD40Lin the pathogenesis of vascular complications in children and adolescents with T1DM is to be clarified. Hence, the study aimed at assessment of sCD40L levels in children and adolescents with T1DM and correlation of these levels with glycemic control and microalbuminuria. Settings and Design: Cross-sectional controlled study. Materials and Methods: The study was performed in the Pediatric Endocrinology and Diabetes Unit, Assuit University Children Hospital, Assiut, Egypt. It included 70 children and adolescents with T1DM (mean age 14. 76 ± 2.21 years). Cases were further subdivided into 43 cases with normoalbuminuria and 27 cases with microalbuminuria according to presence or absence or microalbuminuria in fresh urine samples. Twentyfive healthy subjects, age- and sex-matched were included as control group (mean age = 13.62 ± 2.11 years). Studied cases were subjected to medical history, clinical examination, and laboratory assessment of fasting blood glucose (FBG), lipid profile, glycosylated hemoglobin (HbA1c), and sCD40L were performed. Results: Mean HbA1c and sCD40L were significantly higher in diabetic children (n = 70) compared to control (n = 25) (P < 0.001 for each). Mean HbA1c and sCD40L levels were significantly higher in microalbuminuric cases (n = 27) compared to normoalbuminuric cases (n = 43) (P < 0.05 and <0.01, respectively). We also observed a significant positive correlation between sCD40L levels and the age, diabetes duration, HbA1c, and urinary albumin creatinine ratio. Conclusions: The high serum sCD40L levels in children and adolescents with T1DM particularly in those with microalbminuria and its positive correlation with diabetes duration, urinary albumin excretion, and glycemic control may reflect the role of sCD40L in diabetic vasculopathy in the pediatric age group. Moreover, measurement of serum sCD40L levels in poorly controlled patients would help to identify those at high risk of developing nephropathy.

Metwalley, Kotb Abbass; Farghaly, Hekma Saad; El-Saied, Abdel-Rahman Abdel-Hamed

2013-01-01

216

Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development.  

PubMed Central

Xenopus in vitro studies have implicated both transforming growth factor beta (TGF-beta) and fibroblast growth factor (FGF) families in mesoderm induction. Although members of both families are present during mouse mesoderm formation, there is little evidence for their functional role in mesoderm induction. We show that mouse embryonic stem cells, which resemble primitive ectoderm, can differentiate to mesoderm in vitro in a chemically defined medium (CDM) in the absence of fetal bovine serum. In CDM, this differentiation is responsive to TGF-beta family members in a concentration-dependent manner, with activin A mediating the formation of dorsoanterior-like mesoderm and bone morphogenetic protein 4 mediating the formation of ventral mesoderm, including hematopoietic precursors. These effects are not observed in CDM alone or when TGF-beta 1, -beta 2, or -beta 3, acid FGF, or basic FGF is added individually to CDM. In vivo, at day 6.5 of mouse development, activin beta A RNA is detectable in the decidua and bone morphogenetic protein 4 RNA is detectable in the egg cylinder. Together, our data strongly implicate the TGF-beta family in mammalian mesoderm development and hematopoietic cell formation.

Johansson, B M; Wiles, M V

1995-01-01

217

Differential Expression and Regulation by Activin of the Neurotrophins BDNF and NT4 During Human and Mouse Ovarian Development  

PubMed Central

The tropomyosin-related kinase (Trk) B neurotrophin receptor is essential for ovarian germ cell survival and primordial follicle formation, but the contributions of its ligands, brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4), are unknown. We have investigated their expression and regulation in developing human and mouse ovaries. BDNF expression increased with increasing gestation, expression of human NTF4 and of both Ntf5 and Bdnf in the mouse was unchanged. Bdnf expression was dramatically lower than Ntf5 in the mouse, but levels were comparable in the human. Human fetal ovarian somatic cells expressed BDNF. Activin A selectively regulated BDNF and Ntf5 expression in human and mouse, respectively, identifying an oocyte/somatic signaling pathway which might mediate the pro-survival effects of activin. These data reveal that expression and regulation of the TrkB ligands are differentially controlled in the developing ovaries of humans and mice, and identify BDNF as a potential regulator of germ cell fate in the human fetal ovary. Developmental Dynamics 239:1211–1219, 2010. © 2010 Wiley-Liss, Inc.

Childs, Andrew J; Bayne, Rosemary AL; Murray, Alison A; Martins Da Silva, Sarah J; Collins, Craig S; Spears, Norah; Anderson, Richard A

2010-01-01

218

Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila melanogaster.  

PubMed

The ability to maintain cellular and physiological metabolic homeostasis is key for the survival of multicellular organisms in changing environmental conditions. However, our understanding of extracellular signaling pathways that modulate metabolic processes remains limited. In this study we show that the Activin-like ligand Dawdle (Daw) is a major regulator of systemic metabolic homeostasis and cellular metabolism in Drosophila. We find that loss of canonical Smad signaling downstream of Daw leads to defects in sugar and systemic pH homeostasis. Although Daw regulates sugar homeostasis by positively influencing insulin release, we find that the effect of Daw on pH balance is independent of its role in insulin signaling and is caused by accumulation of organic acids that are primarily tricarboxylic acid (TCA) cycle intermediates. RNA sequencing reveals that a number of TCA cycle enzymes and nuclear-encoded mitochondrial genes including genes involved in oxidative phosphorylation and ?-oxidation are up-regulated in the daw mutants, indicating either a direct or indirect role of Daw in regulating these genes. These findings establish Activin signaling as a major metabolic regulator and uncover a functional link between TGF-? signaling, insulin signaling, and metabolism in Drosophila. PMID:24706779

Ghosh, Arpan C; O'Connor, Michael B

2014-04-15

219

PCSK6 regulated by LH inhibits the apoptosis of human granulosa cells via activin A and TGF?2.  

PubMed

Mammalian proprotein convertases (PCs) play an important role in folliculogenesis, as they proteolytically activate a variety of substrates such as the transforming growth factor beta (TGF?) superfamily. PC subtilism/kexin 6 (PCSK6) is a member of the PC family and is ubiquitously expressed and implicated in many physiological and pathological processes. However, in human granulosa cells, the expression of the PC family members, their hormonal regulation, and the function of PCs are not clear. In this study, we found that PCSK6 is the most highly expressed PC family member in granulosa cells. LH increased PCSK6 mRNA level and PCSK6 played an anti-apoptosis function in KGN cells. Knockdown of PCSK6 not only increased the secretion of activin A and TGF?2 but also decreased the secretion of follistatin, estrogen, and the mRNA levels of FSH receptor (FSHR) and P450AROM (CYP19A1). We also found that, in the KGN human granulosa cell line, TGF?2 and activin A could promote the apoptosis of KGN cells and LH could regulate the follistatin level. These data indicate that PCSK6, which is regulated by LH, is highly expressed in human primary granulosa cells of pre-ovulatory follicles and plays important roles in regulating a series of downstream molecules and apoptosis of KGN cells. PMID:24860148

Wang, Ying; Wang, Xiao-Hui; Fan, Deng-Xuan; Zhang, Yuan; Li, Ming-Qing; Wu, Hai-Xia; Jin, Li-Ping

2014-07-01

220

Novel ball-type four dithioerythritol bridged metallophthalocyanines and their water-soluble derivatives: Synthesis and characterization, and electrochemical, electrocatalytic, electrical and gas sensing properties.  

PubMed

The phthalodinitrile derivative 3 was prepared by the reaction of 1,4-dithioerythritol 1 and 4-nitrophthalonitrile 2 in dry DMF as the solvent in the presence of K(2)CO(3) as the base by the method of nucleophilic substitution of an activated nitro group in an aromatic ring. The template reaction of compound 3 with the corresponding metal salts gave the novel binuclear MPcs of ball-type (M = Zn 4, Co 5, Cu 6) and their water soluble phthalocyanines 7-9 were obtained from refluxing a suspension of the compounds bearing eight OH side groups, in aqueous NaOH (%30) solution. Newly synthesized compounds were characterized by elemental analysis, UV/VIS, IR, MALDI TOF mass and (1)H-NMR spectroscopy techniques. The electronic spectra exhibit an intense ???* transition of characteristic Q and B bands of the phthalocyanine core. The electrochemical measurements showed the formation of various mixed-valence oxidation and reduction species of 4 and 6 due to weak intramolecular interactions between the two MPc units. Complex 5 displayed a much higher catalytic activity than those of 4 and 6. It was found that oxygen reduction on the 5-based catalyst occurs through a direct 4-electron transfer pathway with a high water selectivity. However, the overpotential for oxygen reduction is high, probably due to a long distance between the two CoPc units in 5. A.c. and d.c. conductivity measurements were performed as a function of temperature (300-543 K) and frequency (40-10(5) Hz). It was found from d.c. measurements that the values of the pre-exponential factor ?(0) for the investigated samples are in the interval from 1.36 × 10(-3) to 6.20 × 10(2)?(-1) cm(-1), inferring that the conduction occurs most probably by hopping between the localized states in band tails. Based on the existing theory of a.c. conduction, it has been concluded that for the low frequency region the dominant conduction mechanism is multihopping at high temperatures (>390 K) whereas for the high frequency region the correlated barrier hopping model is the dominant mechanism. The sensing properties of the films for CO(2) gas were also investigated. PMID:20848044

Ceyhan, Tanju; Alt?ndal, Ahmet; Ozkaya, Ali R?za; Salih, Bekir; Bekaro?lu, Ozer

2010-11-01

221

Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes: a randomised trial  

PubMed Central

Objective Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of insulin degludec (70%) and insulin aspart (IAsp: 30%). Here, we compare the efficacy and safety of IDegAsp, an alternative IDegAsp formulation (AF: containing 45% IAsp), and biphasic IAsp 30 (BIAsp 30). Design Sixteen-week, open-label, randomised, treat-to-target trial. Methods Insulin-naive subjects with type 2 diabetes (18–75 years) and a HbA1c of 7–11% were randomised to twice-daily IDegAsp (n=61), AF (n=59) or BIAsp 30 (n=62), all in combination with metformin. Insulin was administered pre-breakfast and dinner (main evening meal) and titrated to pre-breakfast and pre-dinner plasma glucose (PG) targets of 4.0–6.0?mmol/l. Results Mean HbA1c after 16 weeks was comparable for IDegAsp, AF and BIAsp 30 (6.7, 6.6 and 6.7% respectively). With IDegAsp, 67% of subjects achieved HbA1c <7.0% without confirmed hypoglycaemia in the last 4 weeks of treatment compared with 53% (AF) and 40% (BIAsp 30). Mean fasting PG was significantly lower for IDegAsp vs BIAsp 30 (treatment difference (TD): ?0.99?mmol/l (95% confidence interval: ?1.68; 0.29)) and AF vs BIAsp 30 (TD: ?0.88?mmol/l (?1.58; ?0.18)). A significant, 58% lower rate of confirmed hypoglycaemia was found for IDegAsp vs BIAsp 30 (rate ratio (RR): 0.42 (0.23; 0.75)); rates were similar for AF vs BIAsp 30 (RR: 0.92 (0.54; 1.57)). IDegAsp and AF had numerically lower rates of nocturnal confirmed hypoglycaemia vs BIAsp 30 (RR: 0.33 (0.09; 1.14) and 0.66 (0.22; 1.93) respectively). Conclusions IDegAsp provided comparable overall glycaemic control to BIAsp 30 with a significantly lower rate of hypoglycaemia.

Niskanen, Leo; Leiter, Lawrence A; Franek, Edward; Weng, Jianping; Damci, Taner; Munoz-Torres, Manuel; Donnet, Jean-Paul; Endahl, Lars; Skj?th, Trine Vang; Vaag, Allan

2012-01-01

222

Reduced soluble receptor for advanced glycation end-products (sRAGE) scavenger capacity precedes pre-eclampsia in Type 1 diabetes  

PubMed Central

Objective Increased advanced glycation end-products (AGEs) and their soluble receptors (sRAGE) have been implicated in the pathogenesis of pre-eclampsia (PE). However, this association has not been elucidated in pregnancies complicated by diabetes. We aimed to investigate the serum levels of these factors in pregnant women with Type 1 diabetes mellitus (T1DM), a condition associated with a four-fold increase in PE. Design Prospective study in women with T1DM at 12.2 ± 1.9, 21.6 ± 1.5 and 31.5 ± 1.7 weeks of gestation [mean ± standard deviation (SD); no overlap] before PE onset. Setting Antenatal clinics. Population Pregnant women with T1DM (n = 118; 26 developed PE) and healthy nondiabetic pregnant controls (n = 21). Methods Maternal serum levels of sRAGE (total circulating pool), N?-(carboxymethyl)lysine (CML), hydroimidazolone (methylglyoxal-modified proteins) and total AGEs were measured by immunoassays. Main outcome measures Serum sRAGE and AGEs in pregnant women with T1DM who subsequently developed PE (DM PE+) versus those who remained normotensive (DM PE–). Results In DM PE+ versus DM PE–, sRAGE was significantly lower in the first and second trimesters, prior to the clinical manifestation of PE (P < 0.05). Further, reflecting the net sRAGE scavenger capacity, sRAGE : hydroimidazolone was significantly lower in the second trimester (P < 0.05) and sRAGE : AGE and sRAGE : CML tended to be lower in the first trimester (P < 0.1) in women with T1DM who subsequently developed PE versus those who did not. These conclusions persisted after adjusting for prandial status, glycated haemoglobin (HbA1c), duration of diabetes, parity and mean arterial pressure as covariates. Conclusions In the early stages of pregnancy, lower circulating sRAGE levels, and the ratio of sRAGE to AGEs, may be associated with the subsequent development of PE in women with T1DM.

Yu, Y; Hanssen, KF; Kalyanaraman, V; Chirindel, A; Jenkins, AJ; Nankervis, AJ; Torjesen, PA; Scholz, H; Henriksen, T; Lorentzen, B; Garg, SK; Menard, MK; Hammad, SM; Scardo, JA; Stanley, JR; Wu, M; Basu, A; Aston, CE; Lyons, TJ

2014-01-01

223

Altered Sex Hormone Concentrations and Gonadal mRNA Expression Levels of Activin Signaling Factors in Hatchling Alligators From a Contaminated Florida Lake  

PubMed Central

Activins and estrogens participate in regulating the breakdown of ovarian germ cell nests and follicle assembly in mammals. In 1994, our group reported elevated frequencies of abnormal, multioocytic ovarian follicles in 6 month old, environmental contaminant-exposed female alligators after gonadotropin challenge. Here, we investigated if maternal contribution of endocrine disrupting contaminants to the egg subsequently alters estrogen/inhibin/activin signaling in hatchling female offspring, putatively predisposing an increased frequency of multioocytic follicle formation. We quantified basal and exogenous gonadotropin-stimulated concentrations of circulating plasma steroid hormones and ovarian activin signaling factor mRNA abundance in hatchling alligators from the same contaminated (Lake Apopka) and reference (Lake Woodruff) Florida lakes, as examined in 1994. Basal circulating plasma estradiol and testosterone concentrations were greater in alligators from the contaminated environment, whereas activin/inhibin ?A subunit and follistatin mRNA abundances were lower than values measured in ovaries from reference lake animals. Challenged, contaminant-exposed animals showed a more robust increase in plasma estradiol concentration following an acute follicle stimulating hormone (FSH) challenge compared with reference site alligators. Aromatase and follistatin mRNA levels increased in response to an extended FSH challenge in the reference site animals, but not in the contaminant-exposed animals. In hatchling alligators, ovarian follicles have not yet formed; therefore, these endocrine differences are likely to affect subsequent ovarian development, including ovarian follicle assembly.

MOORE, BRANDON C.; KOHNO, SATOMI; COOK, ROBERT W.; ALVERS, ASHLEY L.; HAMLIN, HEATHER J.; WOODRUFF, TERESA K.; GUILLETTE, LOUIS J.

2014-01-01

224

FGF signaling via MAPK is required early and improves Activin A-induced definitive endoderm formation from human embryonic stem cells  

SciTech Connect

Highlights: Black-Right-Pointing-Pointer Deep study the FGF signaling role during DE specification in the context of hESCs. Black-Right-Pointing-Pointer DE differentiation from hESCs has an early dependence on FGF signaling. Black-Right-Pointing-Pointer A serum-free DE protocol is developed based on the findings. Black-Right-Pointing-Pointer The DE cells showed potential to differentiate into pancreatic progenitor cells. -- Abstract: Considering their unlimited proliferation and pluripotency properties, human embryonic stem cells (hESCs) constitute a promising resource applicable for cell replacement therapy. To facilitate this clinical translation, it is critical to study and understand the early stage of hESCs differentiation wherein germ layers are defined. In this study, we examined the role of FGF signaling in Activin A-induced definitive endoderm (DE) differentiation in the absence of supplemented animal serum. We found that activated FGF/MAPK signaling is required at the early time point of Activin A-induced DE formation. In addition, FGF activation increased the number of DE cells compared to Activin A alone. These DE cells could further differentiate into PDX1 and NKX6.1 positive pancreatic progenitors in vitro. We conclude that Activin A combined with FGF/MAPK signaling efficiently induce DE cells in the absence of serum. These findings improve our understanding of human endoderm formation, and constitute a step forward in the generation of clinical grade hESCs progenies for cell therapy.

Sui, Lina, E-mail: linasui@vub.ac.be [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)] [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Mfopou, Josue K. [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)] [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Geens, Mieke; Sermon, Karen [Department of Embryology and Genetics, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)] [Department of Embryology and Genetics, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium); Bouwens, Luc [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)] [Cell Differentiation Unit, Diabetes Research Center, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels (Belgium)

2012-09-28

225

Bone Morphogenetic Protein 2 Stimulates Noncanonical SMAD2/3 Signaling via the BMP Type 1A Receptor in Gonadotrope-Like Cells: Implications for FSH Synthesis.  

PubMed

FSH is an essential regulator of mammalian reproduction. Its synthesis by pituitary gonadotrope cells is regulated by multiple endocrine and paracrine factors, including TGF? superfamily ligands, such as the activins and inhibins. Activins stimulate FSH synthesis via transcriptional regulation of its ?-subunit gene (Fshb). More recently, bone morphogenetic proteins (BMPs) were shown to stimulate murine Fshb transcription alone and in synergy with activins. BMP2 signals via its canonical type I receptor, BMPR1A (or activin receptor-like kinase 3 [ALK3]), and SMAD1 and SMAD5 to stimulate transcription of inhibitor of DNA binding proteins. Inhibitor of DNA binding proteins then potentiate the actions of activin-stimulated SMAD3 to regulate the Fshb gene in the gonadotrope-like L?T2 cell line. Here, we report the unexpected observation that BMP2 also stimulates the SMAD2/3 pathway in these cells and that it does so directly via ALK3. Indeed, this novel, noncanonical ALK3 activity is completely independent of ALK4, ALK5, and ALK7, the type I receptors most often associated with SMAD2/3 pathway activation. Induction of the SMAD2/3 pathway by ALK3 is dependent upon its own previous activation by associated type II receptors, which phosphorylate conserved serine and threonine residues in the ALK3 juxtamembrane glycine-serine-rich domain. ALK3 signaling via SMAD3 is necessary for the receptor to stimulate Fshb transcription, whereas its activation of the SMAD1/5/8 pathway alone is insufficient. These data challenge current dogma that ALK3 and other BMP type I receptors signal via SMAD1, SMAD5, and SMAD8 and not SMAD2 or SMAD3. Moreover, they suggest that BMPs and activins may use similar intracellular signaling mechanisms to activate the murine Fshb promoter in immortalized gonadotrope-like cells. PMID:24601881

Wang, Ying; Ho, Catherine C; Bang, Eunjin; Rejon, Carlis A; Libasci, Vanessa; Pertchenko, Pavel; Hébert, Terence E; Bernard, Daniel J

2014-05-01

226

3,4-seco-24-homo-28-nor-Cycloartane and drimane-type sesquiterpenes and their lactams from the EtOAc-soluble fraction of a leaf extract of Cinnamosma fragrans and their biological activity.  

PubMed

From the EtOAc-soluble fraction of a MeOH extract of leaves of Cinnamosma fragrans, seven new compounds, including 3,4-seco-24-homo-28-nor-cycloartane, drimane-type sesquiterpenes and their lactams, and two known compounds were isolated. Their structures were elucidated by extensive analyses of spectroscopic data. The cytotoxicity, anti-multidrug resistance activity, and anti-Leishmania activity of a cycloartane derivative and drimane-type sesquiterpene derivatives were assayed. The cycloartane derivative showed strong cytotoxicity, and some drimanes and drimane lactam showed moderate anti-multidrug resistance and anti-Leishmania activity. PMID:24633883

Nomoto, Yuya; Harinantenaina, Liva; Sugimoto, Sachiko; Matsunami, Katsuyoshi; Otsuka, Hideaki

2014-07-01

227

Schistosoma mansoni soluble egg antigens are internalized by human dendritic cells through multiple C-type lectins and suppress TLR-induced dendritic cell activation  

Microsoft Academic Search

In schistosomiasis, a parasitic disease caused by helminths, the parasite eggs induce a T helper 2 cell (TH2) response in the host. Here, the specific role of human monocyte-derived dendritic cells (DCs) in initiation and polarization of the egg-specific T cell responses was examined. We demonstrate that immature DCs (iDCs) pulsed with schistosome soluble egg antigens (SEA) do not show

Ellis van Liempt; Sandra J. van Vliet; Anneke Engering; Juan Jesus García Vallejo; Christine M. C. Bank; Marta Sanchez-Hernandez; Yvette van Kooyk; Irma van Die

2007-01-01

228

A decatungstate-type polyoxoniobate with centered manganese: [H2Mn(IV)Nb10O32]8- as a soluble tetramethylammonium salt.  

PubMed

A highly symmetric Mn(IV)-centered polyoxoniobate [H2Mn(IV)Nb10O32](8-) was synthesized via hydrothermal methods as a soluble tetramethylammonium salt. The structure is similar to decatungstate structure [W10O32](4-), except for the central heteroatom. The cluster is stable between 4 < pH < 10, as was characterized with ESI-MS and UV-Vis spectroscopy. PMID:23942463

Son, Jung-Ho; Casey, William H

2013-10-01

229

Bioactivity of nacre water-soluble organic matrix from the bivalve mollusk Pinctada maxima in three mammalian cell types: fibroblasts, bone marrow stromal cells and osteoblasts  

Microsoft Academic Search

In vivo and in vitro studies provide strong evidence of the osteogenic activity of nacre obtained from Pinctada maxima. The in vitro studies indicate that diffusible factors from nacre are involved in cell stimulation. The water-soluble matrix (WSM) was extracted from nacre by a non-decalcifying process, and four fractions (SE1–SE4) were separated by SE-HPLC. Those fractions were tested in vitro

Lucilia Pereira Mouriès; Maria-José Almeida; Christian Milet; Sophie Berland; Evelyne Lopez

2002-01-01

230

Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets  

Microsoft Academic Search

The emergence and subsequent swift and global spread of the swine-origin influenza virus A(H1N1) in 2009 once again emphasizes the strong need for effective vaccines that can be developed rapidly and applied safely. With this aim, we produced soluble, multimeric forms of the 2009 A(H1N1) HA (sHA3) and NA (sNA4) surface glycoproteins using a virus-free mammalian expression system and evaluated

B. J. Bosch; R. Bodewes; R. P. de Vries; J. H. C. M. Kreijtz; W. Bartelink; G. van Amerongen; G. F. Rimmelzwaan; C. A. M. de Haan; A. D. M. E. Osterhaus; P. J. M. Rottier

2010-01-01

231

Water Soluble Products of Camptothecin.  

National Technical Information Service (NTIS)

The object of the invention is to improve upon results of past use of camptothecin by converting the drug to a water-soluble form. Further, an attempt is made to provide an improved method of treating certain types of cancer using camptothecin and its ana...

R. Vishnvvajjala A. Garzon-Aburbey

1987-01-01

232

Starch crystal solubility and starch granule gelatinisation  

Microsoft Academic Search

The solubility and dissolution behaviour of A- and B-type crystals of short chain amylose were measured both directly and using differential scanning calorimetry in the temperature range 30–110°C. Dissolution in the calorimeter was affected by superheating to the extent of 24–28°C. Following trends previously found by calorimetry the B-type crystal polymorph was more soluble than the A-type. Analysis of the

Perrine Crochet; Thierry Beauxis-Lagrave; Timothy R. Noel; Roger Parker; Stephen G. Ring

2005-01-01

233

Theory of Solubility  

Microsoft Academic Search

Theory of solubility.-(1) Statement. The theory of solubility advocated by the writer in a series of papers is restated. Raoult's law will be obeyed by any liquid mixture in which the internal forces of attraction and repulsion do not change with changing composition of the mixture. When this condition holds, the solubility of a gas may be calculated approximately from

Joel H. Hildebrand

1923-01-01

234

Small-molecule inhibitors of bone morphogenic protein and activin/nodal signals promote highly efficient neural induction from human pluripotent stem cells.  

PubMed

The balance of bone morphogenic protein (BMP), transforming growth factor-? (TGF?)/activin/nodal, and Wnt signals regulates the early lineage segregation of human embryonic stem cells (ESCs). Here we demonstrate that a combination of small-molecule inhibitors of BMP (Dorsomorphin) and TGF?/activin/nodal (SB431542) signals promotes highly efficient neural induction from both human ESCs and induced pluripotent stem cells (iPSCs). The combination of small molecules had effects on both cell survival and purity of neural differentiation, under conditions of stromal (PA6) cell coculture and feeder-free floating aggregation culture, for all seven pluripotent stem cell lines that we studied, including three ESC and four iPSC lines. Small molecule compounds are stable and cost effective, so our findings provide a promising strategy for controlled production of neurons in regenerative medicine. PMID:21162120

Morizane, Asuka; Doi, Daisuke; Kikuchi, Tetsuhiro; Nishimura, Kaneyasu; Takahashi, Jun

2011-02-01

235

Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure  

Microsoft Academic Search

OBJECTIVESTo evaluate the effects of an angiotensin (Ang II) type 1 receptor antagonist on immune markers in patients with congestive heart failure (CHF).BACKGROUNDAng II stimulates production of immune factors via the Ang II type 1 receptor in vitro, and the long-term effects of Ang II type 1 receptor antagonists on plasma markers of immune activation are unknown in patients with

Takayoshi Tsutamoto; Atsuyuki Wada; Keiko Maeda; Naoko Mabuchi; Masaru Hayashi; Takashi Tsutsui; Masato Ohnishi; Masahide Sawaki; Masanori Fujii; Takehiro Matsumoto; Masahiko Kinoshita

2000-01-01

236

Positive and Negative Regulation of the Transforming Growth Factor  \\/Activin Target Gene goosecoid by the TFII-I Family of Transcription Factors  

Microsoft Academic Search

Goosecoid (Gsc) is a homeodomain-containing transcription factor present in a wide variety of vertebrate species and known to regulate formation and patterning of embryos. Here we show that in embryonic carcinoma P19 cells, the transcription factor TFII-I forms a complex with Smad2 upon transforming growth factor (TGF)\\/activin stimulation, is recruited to the distal element (DE) of the Gsc promoter, and

Manching Ku; Sergei Y. Sokol; Jack Wu; Maria Isabel Tussie-Luna; Ananda L. Roy; Akiko Hata

2005-01-01

237

p38 Mitogen-Activated Protein Kinase Is Critical for Synergistic Induction of the FSH? Gene by Gonadotropin-Releasing Hormone and Activin through Augmentation of c-Fos Induction and Smad Phosphorylation  

PubMed Central

GnRH and activin independently and synergistically activate transcription of the FSH ?-subunit gene, the subunit that provides specificity and is the limiting factor in the synthesis of the mature hormone. This synergistic interaction, as determined by two-way ANOVA, is specific for FSH? and may, therefore, contribute to differential expression of the two gonadotropin hormones, which is critical for the reproductive cycle. We find that the cross-talk between the GnRH and activin signaling pathways occurs at the level of p38 MAPK, because the synergy is dependent on p38 MAPK activity, which is activated by GnRH, and activin cotreatment augments p38 activation by GnRH. Both the Smad and activator protein-1 binding sites on the FSH? promoter are necessary and sufficient for synergy. After cotreatment, Smad 3 proteins are more highly phosphorylated on the activin-receptor signaling-dependent residues on the C terminus than with activin treatment alone, and c-Fos is more highly expressed than with GnRH treatment alone. Inhibition of p38 by either of two different inhibitors or a dominant-negative p38 kinase abrogates synergy on FSH? expression, reduces c-Fos induction by GnRH, and prevents the further increase in c-Fos levels that occurs with cotreatment. Additionally, p38 is necessary for maximal Smad 3 C-terminal phosphorylation by activin treatment alone and for the further increase caused by cotreatment. Thus, p38 is the pivotal signaling molecule that integrates GnRH and activin interaction on the FSH? promoter through higher induction of c-Fos and elevated Smad phosphorylation.

Coss, Djurdjica; Hand, Cameron M.; Yaphockun, Karen K. J.; Ely, Heather A.; Mellon, Pamela L.

2010-01-01

238

A sandwich type acridinium-linked immunosorbent assay (ALISA) detects soluble ErbB1 (sErbB1) in normal human sera.  

PubMed

The epidermal growth factor receptor (ErbB1) is overexpressed in various human tumor-derived cell lines and neoplasms, where it is believed that receptor dysregulation plays a role in oncogenic transformation and tumor progression. In addition to the ErbB1 holoreceptor, numerous studies demonstrate that cells synthesize soluble or secreted forms of ErbB1, i.e., sErbB1. Overexpression of ErbB1 in a variety of tumors has led us to hypothesize that sErbB levels also may be altered during oncogenesis, tumor progression, and/or metastasis; and that these molecules may be useful tumor biomarkers. To address this hypothesis we have developed an acridinium-linked immunosorbent assay (ALISA) specific for the extracellular domain of ErbB1 that can be used to quantify the levels of sErbB1 molecules in body fluids and conditioned culture media. This assay can also detect full-length ErbB1 in cell and tissue extracts. Our ALISA is characterized by high sensitivity (intra-assay LLD < 1 fmol/ml), a broad linear range (approximately 1 to 4000 fmol/ml), and good reproducibility (CVs < 10%). Specificity experiments show that this ALISA detects p170 ErbB1 and soluble forms of ErbB1 that embody extracellular subdomains I through IV, but not forms of sErbB1 lacking subdomain IV. Our ALISA does not detect full-length ErbB2, ErbB3, or ErbB4; or p105 soluble ErbB2. We report that serum sErbB1 levels of healthy women (median = 3716 fmol/ml), ranging in age from 43 to 76 years, differ significantly from those of healthy men (median = 24,512 fmol/ml), ranging in age from 25 to 79 years. Additional analyses do not indicate that serum sErbB1 levels change with age in either healthy men or women. Immunoprecipitation experiments show that monoclonal antibodies specific for extracellular epitopes of ErbB1 completely neutralize the detection of sErbB1 in normal human sera by ALISA. Finally, we show by immunoprecipitation and Western immunoblot analyses with monoclonal antibodies specific for the extracellular domain of ErbB1 that normal human female and male sera contain a approximately 110-kDa protein. We conclude that our ALISA is measuring the relative levels of this p110 sErbB1 analog in normal human sera. Our ALISA, therefore, should be useful for measuring the levels of ErbB1 and sErbB1 molecules in tumor biopsy specimens and body fluids, respectively, and for determining whether sErbB1, like ErbB1, is a useful tumor biomarker. PMID:9831386

Baron, A T; Lafky, J M; Connolly, D C; Peoples, J; O'Kane, D J; Suman, V J; Boardman, C H; Podratz, K C; Maihle, N J

1998-10-01

239

The structure-activity relationship study on 2-, 5-, and 6-position of the water soluble 1,4-dihydropyridine derivatives blocking N-type calcium channels.  

PubMed

In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure-activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708. PMID:18684623

Yamamoto, Takashi; Niwa, Seiji; Ohno, Seiji; Tokumasu, Munetaka; Masuzawa, Yoko; Nakanishi, Chika; Nakajo, Akira; Onishi, Tomoyuki; Koganei, Hajime; Fujita, Shin-Ichi; Takeda, Tomoko; Kito, Morikazu; Ono, Yukitsugu; Saitou, Yuki; Takahara, Akira; Iwata, Seinosuke; Shoji, Masataka

2008-09-01

240

Hydrogen solubility in austenitic stainless steels  

Microsoft Academic Search

The effects of thermomechanical treatment and surface condition on hydrogen solubility in Types 304L, 21-6-9, and modified A-286 austenitic stainless steels were determined. Three thermomechanical treatments were studied: annealed, 100% cold-worked, and high-energy rate forged (HERFed). Solubility in the modified Type A-286 was less in the HERFed specimens than in solution-annealed specimens. 8 refs.

G. R. Jr. Caskey; R. D. Jr. Sisson

1981-01-01

241

Hydrogen solubility in austenitic stainless steels  

SciTech Connect

The effects of thermomechanical treatment and surface condition on hydrogen solubility in Types 304L, 21-6-9, and modified A-286 austenitic stainless steels were determined. Three thermomechanical treatments were studied: annealed, 100% cold-worked, and high-energy rate forged (HERFed). Solubility in the modified Type A-286 was less in the HERFed specimens than in solution-annealed specimens. 8 refs.

Caskey, G.R. Jr.; Sisson, R.D. Jr.

1981-11-01

242

Soluble CD40 Ligand, Plasminogen Activator Inhibitor1 and Thrombin-Activatable Fibrinolysis Inhibitor1Antigen in Normotensive Type 2 Diabetic Subjects without Diabetic Complications  

Microsoft Academic Search

Objective: To evaluate subclinical inflammation and fibrinolysis in low-risk type 2 diabetic subjects and to assess the efficacy of metformin and rosiglitazone in this group. Subjects and Methods: Sixty-one normotensive, normoalbuminuric type 2 diabetic subjects without diabetes-related complications were included in a 4-week standardization period with glimepiride. After the standardization period, 21 subjects were excluded and the remaining 40 were

Serkan Yener; Abdurrahman Comlekci; Baris Akinci; Tevfik Demir; Faize Yuksel; Mehmet Ali Ozcan; Firat Bayraktar; Sena Yesil

2009-01-01

243

Assessment of biomarkers of cardiovascular risk among HIV type 1-infected adolescents: role of soluble vascular cell adhesion molecule as an early indicator of endothelial inflammation.  

PubMed

Cardiovascular disease (CVD) biomarkers were examined in a cohort of HIV-infected and HIV-uninfected adolescents who participated in Adolescent Trials Network study 083 utilizing samples from the Reaching for Excellence in Adolescent Care cohort, a longitudinal study of youth infected through adult risk behavior. Nonfasting blood samples from 97 HIV-infected and 81 HIV-uninfected adolescents infected by adult risk behaviors were analyzed for total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), very low-density lipoprotein (VLDL), triglycerides, apolipoprotein A-I, high-sensitivity C-reactive protein (hsCRP), soluble vascular adhesion molecule-1 (sVCAM-1), myeloperoxidase, and neopterin at baseline and 18 months later. Results were analyzed using ANOVA, Wilcoxon signed-rank, and paired t tests. Among infected subjects 67 received antiretroviral therapy and 30 were treatment naive. The HIV-infected and HIV-uninfected subjects were similar in gender, ethnicity, and cardiovascular risk factors such as smoking and obesity. In all groups lipid parameters were within accepted guidelines for cardiovascular risk. Among HIV-infected youth on antiretroviral therapy (ART), HDL and apoprotein A-I were significantly lower when compared to uninfected youth. hsCRP was not elevated and thus not predictive for risk in any group. sVCAM-1 levels were significantly elevated in both HIV-infected groups: 1,435 ng/ml and 1,492 ng/ml in untreated and treated subjects, respectively, and 1,064 ng/ml in the uninfected group (p<0.0001). Across all groups neopterin correlated with sVCAM at 18 months (Spearman correlation coefficient 0.58, p<0.0001). Only 9% of ART-treated subjects fully suppressed virus. Lipid profiles and hsCRP, traditional markers of cardiovascular disease, are not abnormal among HIV-infected youth but elevated sVCAM may be an early marker of atherosclerosis. PMID:23062187

Syed, Salma S; Balluz, Rula S; Kabagambe, Edmond K; Meyer, William A; Lukas, Susan; Wilson, Craig M; Kapogiannis, Bill G; Nachman, Sharon A; Sleasman, John W

2013-03-01

244

Tumor necrosis factor alpha, interleukin 2, and soluble interleukin 2 receptor levels in human immunodeficiency virus type 1-infected individuals receiving intermittent cycles of interleukin 2.  

PubMed

HIV-infected individuals with 200-500 CD4(+) T cell/microl were enrolled in a controlled study of three interleukin 2 (IL-2) plus antiretroviral therapy (ART) regimens: (1) continuous intravenous administration of 12 million international units (MIU) of IL-2 followed by subcutaneous high-dose IL-2 (7.5 MIU, twice daily) for 5 days every 8 weeks; (2) high-dose subcutaneous IL-2 for 5 days every 8 weeks; (3) low-dose (3 MIU, twice daily) subcutaneous IL-2 for 5 days every 4 weeks; and (4) ART alone. Serum concentrations of IL-2, soluble IL-2 receptor (sIL-2R), tumor necrosis factor alpha (TNF-alpha), and IL-6 were determined. A progressive decrease over time of the circulating levels of IL-2 was observed in individuals receiving the highest doses of IL-2, but not in those belonging to the low-dose arm. Conversely, increased levels of sIL-2R were observed in all cytokine-treated individuals. The levels of TNF-alpha increased in the high-dose IL-2 regimens, but decreased in individuals receiving low-dose IL-2. IL-2-related toxicity was significantly correlated to the peak IL-2 serum levels, and was substantially lower in those individuals receiving low-dose IL-2. In conclusion, intermittent IL-2 administration causes the elevation of peripheral CD4(+) T cells, but also a profound cytokine response and systemic toxicity. The latter was correlated to the peak serum level of IL-2, but not to those of TNF-alpha and IL-6. PMID:12015902

Fortis, Claudio; Soldini, Laura; Ghezzi, Silvia; Colombo, Stefania; Tambussi, Giuseppe; Vicenzi, Elisa; Gianotti, Nicola; Nozza, Silvia; Veglia, Fabrizio; Murone, Michelangelo; Lazzarin, Adriano; Poli, Guido

2002-05-01

245

Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets.  

PubMed

The emergence and subsequent swift and global spread of the swine-origin influenza virus A(H1N1) in 2009 once again emphasizes the strong need for effective vaccines that can be developed rapidly and applied safely. With this aim, we produced soluble, multimeric forms of the 2009 A(H1N1) HA (sHA(3)) and NA (sNA(4)) surface glycoproteins using a virus-free mammalian expression system and evaluated their efficacy as vaccines in ferrets. Immunization twice with 3.75-microg doses of these antigens elicited strong antibody responses, which were adjuvant dependent. Interestingly, coadministration of both antigens strongly enhanced the HA-specific but not the NA-specific responses. Distinct patterns of protection were observed upon challenge inoculation with the homologous H1N1 virus. Whereas vaccination with sHA(3) dramatically reduced virus replication (e.g., by lowering pulmonary titers by about 5 log(10) units), immunization with sNA(4) markedly decreased the clinical effects of infection, such as body weight loss and lung pathology. Clearly, optimal protection was achieved by the combination of the two antigens. Our observations demonstrate the great vaccine potential of multimeric HA and NA ectodomains, as these can be easily, rapidly, flexibly, and safely produced in high quantities. In particular, our study underscores the underrated importance of NA in influenza vaccination, which we found to profoundly and specifically contribute to protection by HA. Its inclusion in a vaccine is likely to reduce the HA dose required and to broaden the protective immunity. PMID:20686020

Bosch, Berend Jan; Bodewes, Rogier; de Vries, Robert P; Kreijtz, Joost H C M; Bartelink, Willem; van Amerongen, Geert; Rimmelzwaan, Guus F; de Haan, Cornelis A M; Osterhaus, Albert D M E; Rottier, Peter J M

2010-10-01

246

Immunization of rabbits with highly purified, soluble, trimeric human immunodeficiency virus type 1 envelope glycoprotein induces a vigorous B cell response and broadly cross-reactive neutralization.  

PubMed

Previously we described induction of cross-reactive HIV-1 neutralizing antibody responses in rabbits using a soluble HIV-1 gp140 envelope glycoprotein (Env) in an adjuvant containing monophosphoryl lipid A (MPL) and QS21 (AS02A). Here, we compared different forms of the same HIV-1 strain R2 Env for antigenic and biophysical characteristics, and in rabbits characterized the extent of B cell induction for specific antibody expression and secretion and neutralizing responses. The forms of this Env that were produced in and purified from stably transformed 293T cells included a primarily dimeric gp140, a trimeric gp140 appended to a GCN4 trimerization domain (gp140-GCN4), gp140-GCN4 with a 15 amino acid flexible linker between the gp120 and gp41 ectodomain (gp140-GCN4-L), also trimeric, and a gp140 with the flexible linker purified from cell culture supernatants as either dimer (gp140-L(D)) or monomer (gp140-L(M)). Multimeric states of the Env proteins were assessed by native gel electrophoresis and analytical ultracentrifugation. The different forms of gp140 bound broadly cross-reactive neutralizing (BCN) human monoclonal antibodies (mAbs) similarly in ELISA and immunoprecipitation assays. All Envs bound CD4i mAbs in the presence and absence of sCD4, as reported for the R2 Env. Weak neutralization of some strains of HIV-1 was seen after two additional doses in AS02A. Rabbits that were given a seventh dose of gp140-GCN4-L developed BCN responses that were weak to moderate, similar to our previous report. The specificity of these responses did not appear similar to that of any of the known BCN human mAbs. Induction of spleen B cell and plasma cells producing immunoglobulins that bound trimeric gp140-GCN4-L was vigorous, based on ELISpot and flow cytometry analyses. The results demonstrate that highly purified gp140-GCN4-L trimer in adjuvant elicits BCN responses in rabbits accompanied by vigorous B cell induction. PMID:24846288

Quinnan, Gerald V; Onabajo, Olusegun; Zhang, Pengfei; Yan, Lianying; Mattapallil, Joseph J; Zhang, Zhiqiang; Dong, Ming; Lu, Min; Montefiori, David; LaBranche, Celia; Broder, Christopher C

2014-01-01

247

Immunization of Rabbits with Highly Purified, Soluble, Trimeric Human Immunodeficiency Virus Type 1 Envelope Glycoprotein Induces a Vigorous B Cell Response and Broadly Cross-Reactive Neutralization  

PubMed Central

Previously we described induction of cross-reactive HIV-1 neutralizing antibody responses in rabbits using a soluble HIV-1 gp140 envelope glycoprotein (Env) in an adjuvant containing monophosphoryl lipid A (MPL) and QS21 (AS02A). Here, we compared different forms of the same HIV-1 strain R2 Env for antigenic and biophysical characteristics, and in rabbits characterized the extent of B cell induction for specific antibody expression and secretion and neutralizing responses. The forms of this Env that were produced in and purified from stably transformed 293T cells included a primarily dimeric gp140, a trimeric gp140 appended to a GCN4 trimerization domain (gp140-GCN4), gp140-GCN4 with a 15 amino acid flexible linker between the gp120 and gp41 ectodomain (gp140-GCN4-L), also trimeric, and a gp140 with the flexible linker purified from cell culture supernatants as either dimer (gp140-L(D)) or monomer (gp140-L(M)). Multimeric states of the Env proteins were assessed by native gel electrophoresis and analytical ultracentrifugation. The different forms of gp140 bound broadly cross-reactive neutralizing (BCN) human monoclonal antibodies (mAbs) similarly in ELISA and immunoprecipitation assays. All Envs bound CD4i mAbs in the presence and absence of sCD4, as reported for the R2 Env. Weak neutralization of some strains of HIV-1 was seen after two additional doses in AS02A. Rabbits that were given a seventh dose of gp140-GCN4-L developed BCN responses that were weak to moderate, similar to our previous report. The specificity of these responses did not appear similar to that of any of the known BCN human mAbs. Induction of spleen B cell and plasma cells producing immunoglobulins that bound trimeric gp140-GCN4-L was vigorous, based on ELISpot and flow cytometry analyses. The results demonstrate that highly purified gp140-GCN4-L trimer in adjuvant elicits BCN responses in rabbits accompanied by vigorous B cell induction.

Quinnan, Gerald V.; Onabajo, Olusegun; Zhang, Pengfei; Yan, Lianying; Mattapallil, Joseph J.; Zhang, Zhiqiang; Dong, Ming; Lu, Min; Montefiori, David; LaBranche, Celia; Broder, Christopher C.

2014-01-01

248

Bone morphogenetic protein-9 inhibits lymphatic vessel formation via activin receptor-like kinase 1 during development and cancer progression  

PubMed Central

Lymphatic vessels (LVs) play critical roles in the maintenance of fluid homeostasis and in pathological conditions, including cancer metastasis. Although mutations in ALK1, a member of the transforming growth factor (TGF)-?/bone morphogenetic protein (BMP) receptor family, have been linked to hereditary hemorrhagic telangiectasia, a human vascular disease, the roles of activin receptor-like kinase 1 (ALK-1) signals in LV formation largely remain to be elucidated. We show that ALK-1 signals inhibit LV formation, and LVs were enlarged in multiple organs in Alk1-depleted mice. These inhibitory effects of ALK-1 signaling were mediated by BMP-9, which decreased the number of cultured lymphatic endothelial cells. Bmp9-deficient mouse embryos consistently exhibited enlarged dermal LVs. BMP-9 also inhibited LV formation during inflammation and tumorigenesis. BMP-9 downregulated the expression of the transcription factor prospero-related homeobox 1, which is necessary to maintain lymphatic endothelial cell identity. Furthermore, silencing prospero-related homeobox 1 expression inhibited lymphatic endothelial cell proliferation. Our findings reveal a unique molecular basis for the physiological and pathological roles of BMP-9/ALK-1 signals in LV formation.

Yoshimatsu, Yasuhiro; Lee, Yulia G.; Akatsu, Yuichi; Taguchi, Luna; Suzuki, Hiroshi I.; Cunha, Sara I.; Maruyama, Kazuichi; Suzuki, Yuka; Yamazaki, Tomoko; Katsura, Akihiro; Oh, S. Paul; Zimmers, Teresa A.; Lee, Se-Jin; Pietras, Kristian; Koh, Gou Young; Miyazono, Kohei; Watabe, Tetsuro

2013-01-01

249

Blockade of the Activin Receptor IIB Activates Functional Brown Adipogenesis and Thermogenesis by Inducing Mitochondrial Oxidative Metabolism  

PubMed Central

Brown adipose tissue (BAT) is a key tissue for energy expenditure via fat and glucose oxidation for thermogenesis. In this study, we demonstrate that the myostatin/activin receptor IIB (ActRIIB) pathway, which serves as an important negative regulator of muscle growth, is also a negative regulator of brown adipocyte differentiation. In parallel to the anticipated hypertrophy of skeletal muscle, the pharmacological inhibition of ActRIIB in mice, using a neutralizing antibody, increases the amount of BAT without directly affecting white adipose tissue. Mechanistically, inhibition of ActRIIB inhibits Smad3 signaling and activates the expression of myoglobin and PGC-1 coregulators in brown adipocytes. Consequently, ActRIIB blockade in brown adipose tissue enhances mitochondrial function and uncoupled respiration, translating into beneficial functional consequences, including enhanced cold tolerance and increased energy expenditure. Importantly, ActRIIB inhibition enhanced energy expenditure only at ambient temperature or in the cold and not at thermoneutrality, where nonshivering thermogenesis is minimal, strongly suggesting that brown fat activation plays a prominent role in the metabolic actions of ActRIIB inhibition.

Fournier, Brigitte; Murray, Ben; Gutzwiller, Sabine; Marcaletti, Stefan; Marcellin, David; Bergling, Sebastian; Brachat, Sophie; Persohn, Elke; Pierrel, Eliane; Bombard, Florian; Hatakeyama, Shinji; Trendelenburg, Anne-Ulrike; Morvan, Frederic; Richardson, Brian; Lach-Trifilieff, Estelle

2012-01-01

250

Comparison of the function of the beta(C) and beta(E) subunits of activin in AML12 hepatocytes.  

PubMed

To investigate the function of the beta(C) and beta(E) subunits of activin, we overexpressed these subunits in AML12 cells, a normal hepatocyte cell line, using adenovirus vector. Overexpression of the beta(C) subunit increased [3H]thymidine incorporation and the cell number. In contrast, both [3H]thymidine incorporation and the cell number were reduced in the beta(E) overexpressing cells. When AML cells overexpressing the beta(E) subunit were cultured in medium containing 1% serum for 48 h, many of the cells died by apoptosis, whereas cells overexpressing the beta(C) subunit or beta-galactosidase survived in the same condition. To examine dimer formation, the beta(C) and beta(E) subunits were expressed in AML12 cells. In these cells, the beta(C) homodimer, the beta(E) homodimer and the beta(C)-beta(E) heterodimer were detected. When the expression level of the beta(E) subunit was increased, formation of the beta(E) homodimer was increased, while formation of the beta(C)-beta(E) heterodimer was slightly reduced. Overexpression of the beta(E) subunit did not significantly affect the formation of the beta(C) homodimer. These results indicate that the beta(C) and beta(E) subunits form homo- and heterodimers, and that the functions of the two subunits are quite different. PMID:15863943

Wada, Wataru; Medina, Johan J; Kuwano, Hiroyuki; Kojima, Itaru

2005-04-01

251

Development of a small-molecule screening method for inhibitors of cellular response to myostatin and activin A.  

PubMed

Myostatin, a member of the transforming growth factor (TGF)-? family of secreted ligands, is a strong negative regulator of muscle growth. As such, therapeutic inhibitors of myostatin are actively being investigated for their potential in the treatment of muscle-wasting diseases such as muscular dystrophy and sarcopenia. Here, we sought to develop a high-throughput screening (HTS) method for small-molecule inhibitors that target myostatin. We created a HEK293 stable cell line that expresses the (CAGA)12-luciferase reporter construct and robustly responds to signaling of certain classes of TGF-? family ligands. After optimization and miniaturization of the assay to a 384-well format, we successfully screened a library of compounds for inhibition of myostatin and the closely related activin A. Selection of some of the tested compounds was directed by in silico screening against myostatin, which led to an enrichment of target hits as compared with random selection. Altogether, we present an HTS method that will be useful for screening potential inhibitors of not only myostatin but also many other ligands of the TGF-? family. PMID:23543431

Cash, Jennifer N; Angerman, Elizabeth B; Kirby, R Jason; Merck, Lisa; Seibel, William L; Wortman, Matthew D; Papoian, Ruben; Nelson, Sandra; Thompson, Thomas B

2013-08-01

252

EFFECTS OF SOLUBLE FRACTIONS OF USED LIGHT-WEIGHT LIGNOSULFONATE TYPE MUD AND HEXAVALENT CHROMIUM ON THE COMPLETE LARVAL DEVELOPMENT OF THE CRABS, 'RHITHROPANOPEUS HARRISII' AND 'CALLINECTES SAPIDUS'  

EPA Science Inventory

The mud aqueous fractions (MAF) and suspended particulate phase (SPP) of lignosulfonate type mud were nontoxic to the complete larval development of Rhithropanopeus harrisii. Five percent MAF and SPP were not toxic to Callinectes sapidus. Differential survival of C. sapidus larva...

253

What Variables Affect Solubility?  

ERIC Educational Resources Information Center

Helps middle school students understand the concept of solubility through hands-on experience with a variety of liquids and solids. As they explore factors that affect solubility and saturation, students gain content mastery and an understanding of the inquiry process. Also enables teachers to authentically assess student performance on several…

Baker, William P.; Leyva, Kathryn

2003-01-01

254

Applications of Solubility Data  

ERIC Educational Resources Information Center

This article describes several applications of the use of solubility data. It is not meant to be exhaustive but rather to show that knowledge of solubility data is required in a variety of technical applications that assist in the design of chemical processes. (Contains 3 figures and 1 table.)

Tomkins, Reginald P. T.

2008-01-01

255

Solubility of C60  

Microsoft Academic Search

All the published data on the solubility of C60 in 140 organic and inorganic solvents are summarized and the critical features of the experimental techniques are treated. Data on die temperature dependence of solubility are also listed and analyzed. Experimental evidences on the molecular state of dissolved C60 as well as the interactions between the solute and solvents are discussed.

Mihály T. Beck; Géza Mándi

1997-01-01

256

Blocking of antibody passive hemagglutination reaction (Bl-AbHAp) as a test for in vitro recognition of type-specific soluble antigens of Clostridium botulinum.  

PubMed

The blocking of hemagglutination reaction (Bl-AbHAp) was used as a new indicating version of the HAp-test applied for rapid, type-specific in vitro identification of the Cl. botulinum A, B, E and F toxic culture supernatants. The laboratory diagnostic system based on the described method and a special computation table is proposed for simple indicating set with 30 minutes results reading of the test. PMID:3539066

Ligieza, J; Reiss, J

1986-01-01

257

Soluble Mimetics of Human Immunodeficiency Virus Type 1 Viral Spikes Produced by Replacement of the Native Trimerization Domain with a Heterologous Trimerization Motif: Characterization and Ligand Binding Analysis  

Microsoft Academic Search

The human immunodeficiency virus type 1 (HIV-1) exterior envelope glycoprotein, gp120, mediates binding to the viral receptors and, along with the transmembrane glycoprotein gp41, is a major target for neutralizing antibodies. We asked whether replacing the gp41 fusion\\/trimerization domain with a stable trimerization motif might lead to a more stable gp120 trimer that would be amenable to structural and immunologic

Marie Pancera; Jacob Lebowitz; Arne Schon; Ping Zhu; Ernesto Freire; Peter D. Kwong; Kenneth H. Roux; Joseph Sodroski; Richard Wyatt

2005-01-01

258

Notch initiates the endothelial-to-mesenchymal transition in the atrioventricular canal through autocrine activation of soluble guanylyl cyclase.  

PubMed

The heart is the most common site of congenital defects, and valvuloseptal defects are the most common of the cardiac anomalies seen in the newborn. The process of endothelial-to-mesenchymal transition (EndMT) in the cardiac cushions is a required step during early valve development, and Notch signaling is required for this process. Here we show that Notch activation induces the transcription of both subunits of the soluble guanylyl cyclase (sGC) heterodimer, GUCY1A3 and GUCY1B3, which form the nitric oxide receptor. In parallel, Notch also promotes nitric oxide (NO) production by inducing Activin A, thereby activating a PI3-kinase/Akt pathway to phosphorylate eNOS. We thus show that the activation of sGC by NO through a Notch-dependent autocrine loop is necessary to drive early EndMT in the developing atrioventricular canal (AVC). PMID:21839921

Chang, Alex C Y; Fu, YangXin; Garside, Victoria C; Niessen, Kyle; Chang, Linda; Fuller, Megan; Setiadi, Audi; Smrz, Justin; Kyle, Alastair; Minchinton, Andrew; Marra, Marco; Hoodless, Pamela A; Karsan, Aly

2011-08-16

259

What Should We Teach Beginners about Solubility and Solubility Products?  

ERIC Educational Resources Information Center

Argues that consideration should be given to whether teaching solubility product calculations is at all useful. Claims that experienced teachers seriously misunderstand and misuse solubility product calculations. (DDR)

Hawkes, Stephen J.

1998-01-01

260

Gonadotropin-induced changes in oviducal mRNA expression levels of sex steroid hormone receptors and activin-related signaling factors in the alligator  

PubMed Central

Oviducts respond to hormonal cues from ovaries with tissue proliferation and differentiation in preparation of transporting and fostering gametes. These responses produce oviducal microenvironments conducive to reproductive success. Here we investigated changes in circulating plasma sex steroid hormones concentrations and ovarian and oviducal mRNA expression to an in vivo gonadotropin (FSH) challenge in sexually immature, five-month-old alligators. Further, we investigated differences in these observed responses between alligators hatched from eggs collected at a heavily-polluted (Lake Apopka, FL) and minimally-polluted (Lake Woodruff, FL) site. In oviducts, we measured mRNA expression of estrogen, progesterone, and androgen receptors and also beta A and B subunits which homo- or heterodimerize to produce the transforming growth factor activin. In comparison, minimal inhibin alpha subunit mRNA expression suggests that these oviducts produce a primarily activin-dominated signaling milieu. Ovaries responded to a five-day FSH challenge with increased expression of steroidogenic enzyme mRNA which was concomitant with increased circulating sex steroid hormone concentrations. Oviducts in the FSH-challenged Lake Woodruff alligators increased mRNA expression of progesterone and androgen receptors, proliferating cell nuclear antigen, and the activin signaling antagonist follistatin. In contrast, Lake Apopka alligators displayed a diminished increase in ovarian CYP19A1 aromatase expression and no increase in oviducal AR expression, as compared to those observed in Lake Woodruff alligators. These results demonstrate that five-month-old female alligators display an endocrine-responsive ovarian-oviducal axis and environmental pollution exposure may alter these physiological responses.

Moore, Brandon C.; Forouhar, Sara; Kohno, Satomi; Botteri, Nicole L.; Hamlin, Heather J.; Guillette, Louis J.

2011-01-01

261

Immunohistochemical localization of inhibin/activin alpha, betaA and betaB subunits and follistatin in bovine oocytes during in vitro maturation and fertilization.  

PubMed

The aim of this study was to evaluate the distribution of inhibin/activin alpha, beta(A) and beta(B) subunits and follistatin in immature oocytes and in matured oocytes before and after IVF. Denuded oocytes were submitted to a whole-mount immunofluorescence procedure. Specimens were imaged and fluorescent intensities quantified by scanning laser confocal microscopy. Immunoreactivity for inhibin alpha subunit (both alpha(C) and pro-alpha regions), abundant in the ooplasm of immature oocytes, decreased after maturation (a 68% and 88% decrease, respectively; P < 0.001), but increased after IVF by 2- and 5.7-fold, respectively (P < 0.01). Intense staining for beta(A) was detected in immature oocytes (predominantly in the outer ooplasm and zona pellucida) but after maturation and fertilization it was localized mainly in the zona pellucida, perivitelline space and oolemma. Immunoreactivity for beta(A) in the ooplasm decreased by 58% after maturation (P < 0.001) but increased again by 75% after fertilization (P < 0.01). Immunoreactivity for beta(B) was localized mainly in the zona pellucida and did not change after maturation. However, immunoreactivity for beta(B) was not detected in the zona pellucida after fertilization, but remained unchanged in unfertilized oocytes. Immunoreactivity for follistatin was detected in the ooplasm and zona pellucida of immature oocytes but decreased progressively in the ooplasm after maturation (a 63% decrease; P < 0.001) and did not change after IVF. Examination of partially denuded cumulus-oocyte complexes confirmed abundant expression of alpha(C), pro-alpha, beta(A) and follistatin immunoreactivity in cumulus cells, whereas beta(B) subunit staining was weak or absent in cumulus cells, but intense in the zona pellucida. In conclusion, the present study shows that qualitative and quantitative changes in the distribution of inhibin/activin subunits and follistatin accompany oocyte maturation and fertilization. The possibility, indicated by these observations, that activin A and activin B may play distinct roles in bovine oocyte maturation and fertilization warrants further study. PMID:12622694

Silva, C C; Groome, N P; Knight, P G

2003-01-01

262

Solubility of Organic Compounds  

ERIC Educational Resources Information Center

Outlines factors to be considered in choosing suitable solvents for non-electrolytes and salts of weak acids and bases. Describes how, in some simple situation, the degree of solubility can be estimated. (Author/DF)

James, K. C.

1972-01-01

263

Protein solubility modeling  

NASA Technical Reports Server (NTRS)

A thermodynamic framework (UNIQUAC model with temperature dependent parameters) is applied to model the salt-induced protein crystallization equilibrium, i.e., protein solubility. The framework introduces a term for the solubility product describing protein transfer between the liquid and solid phase and a term for the solution behavior describing deviation from ideal solution. Protein solubility is modeled as a function of salt concentration and temperature for a four-component system consisting of a protein, pseudo solvent (water and buffer), cation, and anion (salt). Two different systems, lysozyme with sodium chloride and concanavalin A with ammonium sulfate, are investigated. Comparison of the modeled and experimental protein solubility data results in an average root mean square deviation of 5.8%, demonstrating that the model closely follows the experimental behavior. Model calculations and model parameters are reviewed to examine the model and protein crystallization process. Copyright 1999 John Wiley & Sons, Inc.

Agena, S. M.; Pusey, M. L.; Bogle, I. D.

1999-01-01

264

Soluble human IL-1 receptor type 2 inhibits ectopic endometrial tissue implantation and growth: identification of a novel potential target for endometriosis treatment.  

PubMed

Endometriosis is often associated with a chronic pelvic immuno-inflammatory process, which is closely related to disease pathogenesis and major symptoms. Our studies led to the detection of a marked imbalance between IL-1 and its natural inhibitor IL-1 receptor type 2 (IL1R2) in women with endometriosis. This points to a deficiency in the local control of IL-1 that, in view of the cytokine's elevated levels and potent proinflammatory, angiogenic, and growth-promoting effects, may contribute to endometriosis development. Using an in vivo model in which human endometrial tissue was inoculated into nude mice and left to establish before any further treatment, our data showed that sIL1R2 interferes with the capability of endometrial tissue to invade, grow, disseminate, and stimulate angiogenesis into the host tissue. sIL1R2 significantly down-regulated the expression of major cell adhesion receptors (?v and ?3 integrins), matrix metalloproteinases (MMP-2 and -9), and vascular endothelial cell growth factor. Interestingly, treatment with sILR2 (5 ?g/kg) led to a concomitant upregulation of matrix metalloproteinases natural inhibitors (TIMP1 and TIMP2) and down-regulation of BclII, a potent anti-apoptotic protein. This creates an imbalance between pro- and anti-proteolytic and apoptotic factors and may further contribute to IL1R2 growth-inhibitory effects. This study provides evidence that sIL1R2 alters ectopic endometrial tissue growth, remodeling, and survival in vivo and may represent an interesting potential therapeutic tool. PMID:22841820

Khoufache, Khaled; Bondza, Patrick Kibangou; Harir, Noria; Daris, Marleen; Leboeuf, Mathieu; Mailloux, Jacques; Lemyre, Madeleine; Foster, Warren; Akoum, Ali

2012-10-01

265

Lack of Evidence from Studies of Soluble Protein Fragments that Knops Blood Group Polymorphisms in Complement Receptor-Type 1 Are Driven by Malaria  

PubMed Central

Complement receptor-type 1 (CR1, CD35) is the immune-adherence receptor, a complement regulator, and an erythroid receptor for Plasmodium falciparum during merozoite invasion and subsequent rosette formation involving parasitized and non-infected erythrocytes. The non-uniform geographical distribution of Knops blood group CR1 alleles Sl1/2 and McCa/b may result from selective pressures exerted by differential exposure to infectious hazards. Here, four variant short recombinant versions of CR1 were produced and analyzed, focusing on complement control protein modules (CCPs) 15–25 of its ectodomain. These eleven modules encompass a region (CCPs 15–17) key to rosetting, opsonin recognition and complement regulation, as well as the Knops blood group polymorphisms in CCPs 24–25. All four CR1 15–25 variants were monomeric and had similar axial ratios. Modules 21 and 22, despite their double-length inter-modular linker, did not lie side-by-side so as to stabilize a bent-back architecture that would facilitate cooperation between key functional modules and Knops blood group antigens. Indeed, the four CR1 15–25 variants had virtually indistinguishable affinities for immobilized complement fragments C3b (KD?=?0.8–1.1 µM) and C4b (KD?=?5.0–5.3 µM). They were all equally good co-factors for factor I-catalysed cleavage of C3b and C4b, and they bound equally within a narrow affinity range, to immobilized C1q. No differences between the variants were observed in assays for inhibition of erythrocyte invasion by P. falciparum or for rosette disruption. Neither differences in complement-regulatory functionality, nor interactions with P. falciparum proteins tested here, appear to have driven the non-uniform geographic distribution of these alleles.

Tetteh-Quarcoo, Patience B.; Schmidt, Christoph Q.; Tham, Wai-Hong; Hauhart, Richard; Mertens, Haydyn D. T.; Rowe, Arthur; Atkinson, John P.; Cowman, Alan F.; Rowe, J. Alexandra; Barlow, Paul N.

2012-01-01

266

Activins, Inhibins, and Bone Morphogenetic Proteins as Modulators and Biomarkers of Prostate Cancer Progression  

Microsoft Academic Search

The transforming growth factor-? (TGF-?) superfamily consists of over 35 structurally related proteins, which regulate a myriad\\u000a of cellular processes. Signaling by these growth regulatory molecules is initiated by ligand-induced hetero-oligomerization\\u000a of distinct type II and type I serine\\/threonine kinase receptors that activate receptor-activated Smad proteins as well as\\u000a Smad-independent pathways. TGF-?-related ligands and receptors are expressed in the prostate

Tetsu Hayashida; Vandana Gupta; Sam Thiagalingam; Shyamala Maheswaran

267

Formulation of soluble oils with synthetic and petroleum sulfonates  

Microsoft Academic Search

Metalworking fluids for metal removal are formulated to provide cooling, lubrication, and rust protection when cutting and machining metals. There are basically four types of cutting fluids: straight oils, synthetics, semisynthetic fluids and soluble oils. The last type is the most widely used for metal removal operations such as cutting, drilling and grinding. Soluble oils used for metalworking operations are

A. Eckard; I. Riff; J. Weaver

1997-01-01

268

cDNA cloning, expression studies and chromosome mapping of human type I serine/threonine kinase receptor ALK7 (ACVR1C)  

Microsoft Academic Search

Transforming growth factor-? (TGF-?) superfamily related growth factors signal by binding to transmembrane type I and type II receptor serine\\/threonine kinases (RSTK), which phosphorylate intracellular Smad transcription factors in response to ligand binding. Here we describe the cloning of the human type I RSTK activin receptor-like kinase 7 (ALK7), an orthologue of the previously identified rat ALK7. Nodal, a TGF-?

J. Bondestam; M.-A. Huotari; A. Morén; J. Ustinov; N. Kaivo-oja; J. Kallio; N. Horelli-Kuitunen; J. Aaltonen; M. Fujii; A. Moustakas; P. ten Dijke; T. Otonkoski; O. Ritvos

2001-01-01

269

Angiomodulin is required for cardiogenesis of embryonic stem cells and is maintained by a feedback loop network of p63 and Activin-A.  

PubMed

The transcription factor p63, member of the p53 gene family, encodes for two main isoforms, TAp63 and ?Np63 with distinct functions on epithelial homeostasis and cancer. Recently, we discovered that TAp63 is essential for in vitro cardiogenesis and heart development in vivo. TAp63 is expressed by embryonic endoderm and acts on cardiac progenitors by a cell-non-autonomous manner. In the present study, we search for cardiogenic secreted factors that could be regulated by TAp63 and, by ChIP-seq analysis, identified Angiomodulin (AGM), also named IGFBP7 or IGFBP-rP1. We demonstrate that AGM is necessary for cardiac commitment of embryonic stem cells (ESCs) and its regulation depends on TAp63 isoform. TAp63 directly activates both AGM and Activin-A during ESC cardiogenesis while these secreted factors modulate TAp63 gene expression by a feedback loop mechanism. The molecular circuitry controlled by TAp63 on AGM/Activin-A signaling pathway and thus on cardiogenesis emphasizes the importance of p63 during early cardiac development. PMID:24145187

Wolchinsky, Zohar; Shivtiel, Shoham; Kouwenhoven, Evelyn Nathalie; Putin, Daria; Sprecher, Eli; Zhou, Huiqing; Rouleau, Matthieu; Aberdam, Daniel

2014-01-01

270

Exogenous GDF9 but not Activin A, BMP15 or TGF? alters tight junction protein transcript abundance in zebrafish ovarian follicles.  

PubMed

The tight junction (TJ) complex plays an important role in regulating paracellular permeability and provides mechanical stability in vertebrate epithelia and endothelia. In zebrafish ovarian follicles, TJ complexes in the follicular envelope degenerate as the follicles develop towards maturation. In the current study, transcript abundance of claudins (cldn d, g, h, 1, and 12) and occludins (ocln, and ocln b) were assessed in mid-vitellogenic follicles in response to treatment with exogenous growth factors that are reported to be involved in zebrafish follicle development (i.e. Activin A, BMP15, GDF9 and TGF?). Exogenous GDF9 reduced the transcript abundance of cldn g, ocln and ocln b in mid-vitellogenic follicles, whereas Activin A, BMP15, and TGF? had no effect. Subsequent studies with GDF9 revealed that this factor did not alter TJ protein transcript abundance in pre-vitellogenic follicles but did increase the abundance of ocln b in fully grown (maturing) follicles. GDF9 was also seen to increase the abundance of StAR mRNA in all but primary stage follicles. These data suggest a role for GDF9 in the regulation of TJ integrity in zebrafish ovarian follicles, perhaps in the facilitation of ovulation, and support a previously postulated role for GDF9 in zebrafish ovarian follicle development. In addition, data also support the idea that endocrine factors play an important role in the regulation of TJ proteins during ovarian follicle development. PMID:21291886

Clelland, Eric S; Kelly, Scott P

2011-04-01

271

Elimination of soluble sup 123 I-labeled aggregates of IgG in patients with systemic lupus erythematosus. Effect of serum IgG and numbers of erythrocyte complement receptor type 1  

SciTech Connect

Using soluble {sup 123}I-labeled aggregates of human IgG ({sup 123}I-AHIgG) as a probe, we examined the function of the mononuclear phagocyte system in 22 patients with systemic lupus erythematosus (SLE) and 12 healthy controls. In SLE patients, a decreased number of erythrocyte complement receptor type 1 was associated with less binding of {sup 123}I-AHIgG to erythrocytes and a faster initial rate of elimination of {sup 123}I-AHIgG (mean +/- SEM half-maximal clearance time 5.23 +/- 0.2 minutes, versus 6.58 +/- 0.2 minutes in the controls), with possible spillover of the material outside the mononuclear phagocyte system of the liver and spleen. However, multiple regression analysis showed that serum concentrations of IgG were the most important factor predicting the rate of {sup 123}I-AHIgG elimination. IgG concentration may thus reflect immune complex clearance, which in turn, would influence the inflammatory reaction, in SLE.

Halma, C.; Breedveld, F.C.; Daha, M.R.; Blok, D.; Evers-Schouten, J.H.; Hermans, J.; Pauwels, E.K.; van Es, L.A. (Univ. Hospital Leiden (Netherlands))

1991-04-01

272

Efficient organic photovoltaics from soluble discotic liquid crystalline materials  

Microsoft Academic Search

Two different types of soluble discotic liquid crystalline materials and a crystalline perylene dye have been used to create, directly from solution, photovoltaic devices which are compared in this work. Self-organisation of the soluble electron-accepting perylene derivative and the soluble liquid crystalline (LC) discotic material which is stable in a LC phase at room temperature (HBC-PhC12) leads to segregated structures

L. Schmidt-Mende; A. Fechtenkötter; K. Müllen; R. H Friend; J. D MacKenzie

2002-01-01

273

The relationship between early atherosclerosis and endothelial dysfunction in type 1 diabetic patients as evidenced by measurement of carotid intima-media thickness and soluble CD146 levels: a cross sectional study  

PubMed Central

Background Detection of early vascular changes prior to clinical manifestations of atherosclerosis, such as increased arterial carotid intima-media thickness (CIMT) and impaired endothelial function is of paramount importance for early identification of subjects at increased risk of accelerated atherosclerosis. The present study was designed to evaluate the relationship between early atherosclerosis and endothelial dysfunction in type 1 diabetic patients based on measurements of CIMT and soluble CD146 (sCD146) levels. Methods Thirty-seven patients with type 1 diabetes, 14 males (37.8%) and 23 females (62.2%), of mean (SD) age 26.2 (4.1) years admitted to the outpatient diabetes clinic at Okmeydani Training and Research Hospital, Istanbul, between January 2008 and December 2012, and 37 healthy controls, 16 males (43.2%) and 21 females (56.8%), of mean (SD) age 25.8 (3.1) years, selected from relatives of patients, were included. Anthropometric measures; fasting plasma glucose; and serum HbA1c, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride and creatinine concentrations were compared, as were CIMT and serum sCD146. Results Mean (SD) sCD146 levels were significantly higher in patients than in controls (314.6 (141.9) ng/ml vs. 207.8 (34.5) ng/ml, p?=?0.001), but mean (SD) CIMT did not differ (0.5 (0.1) mm vs. 0.4 (0.1) mm). ROC curves for sCD146 significantly differed in differentiating type 1 diabetics from healthy controls (p?=?0.0047) with a significantly higher percentage of patients than controls having sCD146 levels >260 ng/ml (21/37 (56.8%) vs. 2/37 (5.4%), p?=?0.00011). Conclusion Our findings emphasize that sCD146 levels may be a more sensitive marker than CIMT for earlier identification of type 1 diabetic patients at high risk for atherosclerosis.

2013-01-01

274

Ozone Solubility in Liquids  

Microsoft Academic Search

A comprehensive and critical survey of the available data on ozone solubility in different liquids—in water and aqueous solutions, as well as in organic solvents has been made. Apart of comparing the data published by the various authors after 1981 for water and aqueous solutions, special attention has been paid to the effects of pH and the composition of the

Andrzej K. Bi?

2006-01-01

275

Influence of dispersants on the solubility of calcined kaolin  

Microsoft Academic Search

The solubility of calcined kaolin relative to different aqueous solution chemistries is important to its industrial application. When used in paper-making, a calcined kaolin product is required to have good flow characteristics and viscosity stability, both of which are largely controlled by the type and level of soluble salts in the kaolin suspension. In this study, five common dispersing agents

Jun Yuan; William L Garforth; Robert J Pruett

1998-01-01

276

Water soluble oxidized starches by peroxide reactive extrusion  

Microsoft Academic Search

Oxidation of starches of different amylose content was investigated to increase carboxyl and carbonyl content and to increase water solubility. Three types of cornstarches containing up to 70% amylose were oxidized by a reactive extrusion-drum drying process, using hydrogen peroxide and a ferrous–cupric sulfate catalyst. Increasing the peroxide level increased oxidation and solubility. Starches with higher amylose content gave reduced

R. E Wing; J. L Willett

1997-01-01

277

Influence of various denaturing agents on the solubility of gossypulin  

Microsoft Academic Search

In the present communication we give results showing the changes in the solubility of gossypulin under the action of various types of denaturing agents. To study solubility we used the method of turbidimetric titration of dilute solutions, C 0.03% [3]. Table 1 gives the pH values of the precipitation maxima of the denatured proteins under various conditions. Thermal treatment of

G. A. Piyakina; T. S. Yunusov

1986-01-01

278

SOLUBILITY CORRELATION OF [60]FULLERENE IN DIFFERENT SOLVENTS  

Microsoft Academic Search

The solubility of [60]fullerene in various solvents has been correlated to the molar volume ratio of [60]fullerene and the respective solvent. The solubility varies linearly with the molar volume for the alcohol series and the heteroatom containing solvents, though specific interactions of the charge transfer type seem to dominate in the case of aromatic hydrocarbons and the halogenated solvents. The

C. N. Murthy; K. E. Geckeler

2001-01-01

279

The Soluble Form of LR11 Protein Is a Regulator of Hypoxia-induced, Urokinase-type Plasminogen Activator Receptor (uPAR)-mediated Adhesion of Immature Hematological Cells*  

PubMed Central

A key property of hematopoietic stem and progenitor cells (HSPCs) regarding differentiation from the self-renewing quiescent to the proliferating stage is their adhesion to the bone marrow (BM) niche. An important molecule involved in proliferation and pool size of HSPCs in the BM is the hypoxia-induced urokinase-type plasminogen activator receptor (uPAR). Here, we show that the soluble form (sLR11) of LR11 (also called SorLA or SORL1) modulates the uPAR-mediated attachment of HSPCs under hypoxic conditions. Immunohistochemical and mRNA expression analyses revealed that hypoxia increased LR11 expression in hematological c-Kit+ Lin? cells. In U937 cells, hypoxia induced a transient rise in LR11 transcription, production of cellular protein, and release of sLR11. Attachment to stromal cells of c-Kit+ Lin? cells of lr11?/? mice was reduced by hypoxia much more than of lr11+/+ animals. sLR11 induced the adhesion of U937 and c-Kit+ Lin? cells to stromal cells. Cell attachment was increased by sLR11 and reduced in the presence of anti-uPAR antibodies. Furthermore, the fraction of uPAR co-immunoprecipitated with LR11 in membrane extracts of U937 cells was increased by hypoxia. CoCl2, a chemical inducer of HIF-1?, enhanced the levels of LR11 and sLR11 in U937 cells. The decrease in hypoxia-induced attachment of HIF-1?-knockdown cells was largely prevented by exogenously added sLR11. Finally, hypoxia induced HIF-1? binding to a consensus binding site in the LR11 promoter. Thus, we conclude that sLR11 regulates the hypoxia-enhanced adhesion of HSPCs via an uPAR-mediated pathway that stabilizes the hematological pool size by controlling cell attachment to the BM niche.

Nishii, Keigo; Nakaseko, Chiaki; Jiang, Meizi; Shimizu, Naomi; Takeuchi, Masahiro; Schneider, Wolfgang J.; Bujo, Hideaki

2013-01-01

280

A Perspective on Solubility Rules.  

ERIC Educational Resources Information Center

Presents four generalizations about solubilities. These generalizations (rules), are useful in introducing the dynamic topics of solubility and in helping high school and introductory college chemistry students make some order out of the tremendous number of facts available. (JN)

Monroe, Manus; Abrams, Karl

1984-01-01

281

The Ksp-Solubility Conundrum  

Microsoft Academic Search

The calculation of solubility from Ksp values, and its converse have long been a part of general college chemistry textbooks. The agreement between actual solubility and simple calculations of solubility from Ksp values has been questioned many times. Incomplete dissociation, hydrolysis reactions, complex ion formation, ion pair formation and activity coefficients conspire to make such calculations crude at best. The

Roy W. Clark; Judith M. Bonicamp

1998-01-01

282

Solubility and Solubility Product Determination of a Sparingly Soluble Salt: A First-Level Laboratory Experiment  

ERIC Educational Resources Information Center

A simple experiment was devised to let students determine the solubility and solubility product, "K"[subscript sp], of calcium sulfate dihydrate in a first-level laboratory. The students experimentally work on an intriguing equilibrium law: the constancy of the product of the ion concentrations of a sparingly soluble salt. The determination of…

Bonomo, Raffaele P.; Tabbi, Giovanni; Vagliasindi, Laura I.

2012-01-01

283

Microbial Release of Soluble Phosphate in an Activated Sludge Environment.  

National Technical Information Service (NTIS)

Batch type laboratory units were used to study the mechanisms and factors that determine the amount of soluble phosphate that will be released from activated sludge during typical plant operation. In addition to studying the effect of typical operational ...

C. W. Randall

1970-01-01

284

Pitx2, a Bicoid-Type Homeobox Gene, Is Involved in a Lefty-Signaling Pathway in Determination of Left-Right Asymmetry  

Microsoft Academic Search

Signaling molecules such as Activin, Sonic hedgehog, Nodal, Lefty, and Vg1 have been found to be involved in determination of left-right (L-R) asymmetry in the chick, mouse, or frog. However, a common signaling pathway has not yet been identified in vertebrates. We report that Pitx2, a bicoid-type homeobox gene expressed asymmetrically in the left lateral plate mesoderm, may be involved

Hidefumi Yoshioka; Chikara Meno; Kazuko Koshiba; Minoru Sugihara; Hiroyuki Itoh; Yoshiyasu Ishimaru; Takashi Inoue; Hideyo Ohuchi; Elena V Semina; Jeffrey C Murray; Hiroshi Hamada; Sumihare Noji

1998-01-01

285

[Molecular cloning of the DNA sequence of activin beta A subunit gene mature peptides from panda and related species and its application in the research of phylogeny and taxonomy].  

PubMed

Activin, which is included in the transforming growth factor-beta (TGF beta) superfamily of proteins and receptors, is known to have broad-ranging effects in the creatures. The mature peptide of beta A subunit of this gene, one of the most highly conserved sequence, can elevate the basal secretion of follicle-stimulating hormone (FSH) in the pituitary and FSH is pivotal to organism's reproduction. Reproduction block is one of the main reasons which cause giant panda to extinct. The sequence of Activin beta A subunit gene mature peptides has been successfully amplified from giant panda, red panda and malayan sun bear's genomic DNA by using polymerase chain reaction (PCR) with a pair of degenerate primers. The PCR products were cloned into the vector pBlueScript+ of Esherichia coli. Sequence analysis of Activin beta A subunit gene mature peptides shows that the length of this gene segment is the same (359 bp) and there is no intron in all three species. The sequence encodes a peptide of 119 amino acid residues. The homology comparison demonstrates 93.9% DNA homology and 99% homology in amino acid among these three species. Both GenBank blast search result and restriction enzyme map reveal that the sequences of Activin beta A subunit gene mature peptides of different species are highly conserved during the evolution process. Phylogeny analysis is performed with PHYLIP software package. A consistent phylogeny tree has been drawn with three different methods. The software analysis outcome accords with the academic view that giant panda has a closer relationship to the malayan sun bear than the red panda. Giant panda should be grouped into the bear family (Uersidae) with the malayan sun bear. As to the red panda, it would be better that this animal be grouped into the unique family (red panda family) because of great difference between the red panda and the bears (Uersidae). PMID:12561224

Wang, Xiao-Jing; Wang, Xiao-Xing; Wang, Ya-Jun; Wang, Xi-Zhong; He, Guang-Xin; Chen, Hong-Wei; Fei, Li-Song

2002-09-01

286

Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.  

PubMed

Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity. PMID:12702875

Kayed, Rakez; Head, Elizabeth; Thompson, Jennifer L; McIntire, Theresa M; Milton, Saskia C; Cotman, Carl W; Glabe, Charles G

2003-04-18

287

Analytic evaluation of the solubility of structural metals in melts of low-melting metals  

Microsoft Academic Search

This paper deals with different methods of analytic evaluation of the solubility of structural metals in melts of low-melting metals. The possibility of estimating solubility by using the approach of ideal and infinitely dilute solutions is examined for different types of binary phase diagrams. A correlation between solubility and the physical properties of the components of solution is established.

H. B. Vasyliv; M. I. Kitsak

1994-01-01

288

Water soluble laser dyes  

DOEpatents

Novel water soluble dyes of the formula I are provided ##STR1## wherein R.sup.1 and R.sup.4 are alkyl of 1 to 4 carbon atoms or hydrogen; or R.sup.1 -R.sup.2 or R.sup.2 -R.sup.4 form part of aliphatic heterocyclic rings; R.sup.2 is hydrogen or joined with R.sup.1 or R.sup.4 as described above; R.sup.3 is --(CH.sub.2).sub.m --SO.sub.3.sup.-, where m is 1 to 6; X is N, CH or ##STR2## where Y is 2 --SO.sub.3.sup.- ; Z is 3, 4, 5 or 6 --SO.sub.3.sup.-. The novel dyes are particularly useful as the active media in water solution dye lasers.

Hammond, Peter R. (Livermore, CA); Feeman, James F. (Wyomissing, PA); Field, George F. (Santa Ana, CA)

1998-01-01

289

Pure Phase Solubility Limits: LANL  

SciTech Connect

The natural and engineered system at Yucca Mountain (YM) defines the site-specific conditions under which one must determine to what extent the engineered and the natural geochemical barriers will prevent the release of radioactive material from the repository. Most important mechanisms for retention or enhancement of radionuclide transport include precipitation or co-precipitation of radionuclide-bearing solid phases (solubility limits), complexation in solution, sorption onto surfaces, colloid formation, and diffusion. There may be many scenarios that could affect the near-field environment, creating chemical conditions more aggressive than the conditions presented by the unperturbed system (such as pH changes beyond the range of 6 to 9 or significant changes in the ionic strength of infiltrated waters). For an extended period of time, the near-field water composition may be quite different and more extreme in pH, ionic strength, and CO{sub 2} partial pressure (or carbonate concentration) than waters at some distance from the repository. Reducing conditions, high pH (up to 11), and low carbonate concentration may be present in the near-field after reaction of infiltrating groundwater with engineered barrier systems, such as cementitious materials. In the far-field, conditions are controlled by the rock-mass buffer providing a near-neutral, oxidizing, low-ionic-strength environment that controls radionuclide solubility limits and sorption capacities. There is the need for characterization of variable chemical conditions that affect solubility, speciation, and sorption reactions. Modeling of the groundwater chemistry is required and leads to an understanding of solubility and speciation of the important radionuclides. Because experimental studies cannot be performed under the numerous potential chemical conditions, solubility limitations must rely on geochemical modeling of the radionuclide's chemistry. Fundamental thermodynamic properties, such as solubility products, complex stability constants, and redox potentials for radionuclides in different oxidation states, form the underlying database to be used for those calculations. The potentially low solubilities of many radionuclides in natural waters constitute the first barrier for their migration from the repository into the environment. Evaluation of this effect requires a knowledge of the site-specific water chemistry and the expected spatial and temporal ranges of its variability. Quantitative determinations of radionuclide solubility in waters within the range of chemistry must be made. Speciation and molecular complexation must be ascertained to interpret and apply solubility results. The solubilities thus determined can be used to assess the effectiveness of solubility in limiting radionuclide migration. These solubilities can also be used to evaluate the effectiveness of other retardation processes expected to occur once dissolution of the source material and migration begin. Understanding the solubility behavior of radionuclides will assist in designing valuable sorption experiments that must be conducted below the solubility limit since only soluble species participate in surface reactions and sorption processes. The present strategy for radionuclide solubility tasks has been to provide a solubility model from bulk-experiments that attempt to bracket the estimate made for this Analysis and Modeling Report (AMR) of water conditions on site. The long-term goal must be to develop a thermodynamic database for solution speciation and solid-state determination as a prerequisite for transport calculations and interpretation of empirical solubility data. The model has to be self-consistent and tested against known solubility studies in order to predict radionuclide solubilities over the continuous distribution ranges of potential water compositions for performance assessment of the site. Solubility studies upper limits for radionuclide concentrations in natural waters. The concentration in the aqueous phase is controlled by the radionuclide-bearing solid phase and by

C. Stockman

2001-01-26

290

Computer Simulations of Salt Solubility  

NSDL National Science Digital Library

Computer Simulations of Salt Solubility provides an animated, visual interpretation of the different solubilities of related salts based on simple entropy changes associated with dissolution: configurational disorder and thermal disorder. This animation can also help improve students conceptual understanding of chemical equilibrium before any quantitative interpretation of equilibrium constants is attempted.

291

The Ksp-Solubility Conundrum.  

ERIC Educational Resources Information Center

Argues that there are only a few cases in which solubility and Ksp are related in a simple way. States that illustrations of the solubility product principle for one-to-one salts are adequate for students. Contains 23 references. (DDR)

Clark, Roy W.; Bonicamp, Judith M.

1998-01-01

292

Comparative Calculations of Solubility Equilibria  

SciTech Connect

The uncertainties in calculated solubilities in the Na-F-PO{sub 4}-HPO{sub 4}-OH system. at 25 C for NaOH concentrations up to 5 mol/kg were assessed. These uncertainties were based on an evaluation of the range of values for the Gibbs energies of the solids. Comparative calculations using the Environmental Simulation Program (ESP) and SOLGASMIX indicated that the variation in activity coefficients with NaOH concentration is much greater in the ESP code than in SOLGASMIX. This resulted in ESP calculating a higher solubility in water and a lower solubility in NaOH concentrations above 1 mol/kg: There was a marked discrepancy in the solubilities of the pure components sodium fluoride and trisodium phosphate predicted by ESP and SOLGASMIX. In addition, different solubilities for these components were obtained using different options in ESP. Because of these observations, a Best Practices Guide for ESP will be assembled.

Beahm, E.C.

2000-07-25

293

Estimating drug solubility in the gastrointestinal tract  

Microsoft Academic Search

Solubilities measured in water are not always indicative of solubilities in the gastrointestinal tract. The use of aqueous solubility to predict oral drug absorption can therefore lead to very pronounced underestimates of the oral bioavailability, particularly for drugs which are poorly soluble and lipophilic. Mechanisms responsible for enhancing the luminal solubility of such drugs are discussed. Various methods for estimating

J. B. Dressman; M. Vertzoni; K. Goumas; C. Reppas

2007-01-01

294

Activin receptor-like kinase5 inhibition suppresses mouse melanoma by ubiquitin degradation of Smad4, thereby derepressing eomesodermin in cytotoxic T lymphocytes  

PubMed Central

Varieties of transforming growth factor-? (TGF-?) antagonists have been developed to intervene with excessive TGF-? signalling activity in cancer. Activin receptor-like kinase5 (ALK5) inhibitors antagonize TGF-? signalling by blocking TGF-? receptor-activated Smad (R-Smad) phosphorylation. Here we report the novel mechanisms how ALK5 inhibitors exert a therapeutic effect on a mouse B16 melanoma model. Oral treatment with a novel ALK5 inhibitor, EW-7197 (2.5 mg/kg daily) or a representative ALK5 inhibitor, LY-2157299 (75 mg/kg bid) suppressed the progression of melanoma with enhanced cytotoxic T-lymphocyte (CTL) responses. Notably, ALK5 inhibitors not only blocked R-Smad phosphorylation, but also induced ubiquitin-mediated degradation of the common Smad, Smad4 mainly in CD8+ T cells in melanoma-bearing mice. Accordingly, T-cell-specific deletion of Smad4 was sufficient to suppress the progression of melanoma. We further identified eomesodermin (Eomes), the T-box transcription factor regulating CTL functions, as a specific target repressed by TGF-? via Smad4 and Smad3 in CD8+ T cells. Thus, ALK5 inhibition enhances anti-melanoma CTL responses through ubiquitin-mediated degradation of Smad4 in addition to the direct inhibitory effect on R-Smad phosphorylation.

Yoon, Jeong-Hwan; Jung, Su Myung; Park, Seok Hee; Kato, Mitsuyasu; Yamashita, Tadashi; Lee, In-Kyu; Sudo, Katsuko; Nakae, Susumu; Han, Jin Soo; Kim, Ok-Hee; Oh, Byung-Chul; Sumida, Takayuki; Kuroda, Masahiko; Ju, Ji-Hyeon; Jung, Kyeong Cheon; Park, Seong Hoe; Kim, Dae-Kee; Mamura, Mizuko

2013-01-01

295

Method for enhancing the solubility of boron and indium in silicon  

DOEpatents

A method for enhancing the equilibrium solubility of boron and indium in silicon. The method involves first-principles quantum mechanical calculations to determine the temperature dependence of the equilibrium solubility of two important p-type dopants in silicon, namely boron and indium, under various strain conditions. The equilibrium thermodynamic solubility of size-mismatched impurities, such as boron and indium in silicon, can be raised significantly if the silicon substrate is strained appropriately. For example, for boron, a 1% compressive strain raises the equilibrium solubility by 100% at 1100.degree. C.; and for indium, a 1% tensile strain at 1100.degree. C., corresponds to an enhancement of the solubility by 200%.

Sadigh, Babak (Oakland, CA); Lenosky, Thomas J. (Pleasanton, CA); Diaz de la Rubia, Tomas (Danville, CA); Giles, Martin (Hillsborough, OR); Caturla, Maria-Jose (Livermore, CA); Ozolins, Vidvuds (Pleasanton, CA); Asta, Mark (Evanston, IL); Theiss, Silva (St. Paul, MN); Foad, Majeed (Santa Clara, CA); Quong, Andrew (Livermore, CA)

2002-01-01

296

A Semiconductor Material And Method For Enhancing Solubility Of A Dopant Therein  

DOEpatents

A method for enhancing the equilibrium solubility of boron ad indium in silicon. The method involves first-principles quantum mechanical calculations to determine the temperature dependence of the equilibrium solubility of two important p-type dopants in silicon, namely boron and indium, under various strain conditions. The equilibrium thermodynamic solubility of size-mismatched impurities, such as boron and indium in silicon, can be raised significantly if the silicon substrate is strained appropriately. For example, for boron, a 1% compressive strain raises the equilibrium solubility by 100% at 1100.degree. C.; and for indium, a 1% tensile strain at 1100.degree. C., corresponds to an enhancement of the solubility by 200%.

Sadigh, Babak (Oakland, CA); Lenosky, Thomas J. (Pleasanton, CA); Diaz de la Rubia, Tomas (Danville, CA); Giles, Martin (Hillsborough, OR); Caturla, Maria-Jose (Livermore, CA); Ozolins, Vidvuds (Pleasanton, CA); Asta, Mark (Evanston, IL); Theiss, Silva (St. Paul, MN); Foad, Majeed (Santa Clara, CA); Quong, Andrew (Livermore, CA)

2005-03-29

297

Mineral oil soluble borate compositions  

SciTech Connect

Alkali metal borates are reacted with fatty acids or oils in the presence of a low hlb value surfactant to give a stable mineral oil-soluble product. Mineral oil containing the borate can be used as a cutting fluid.

Dulat, J.

1981-09-15

298

water-soluble fluorocarbon coating  

NASA Technical Reports Server (NTRS)

Water-soluble fluorocarbon proves durable nonpolluting coating for variety of substrates. Coatings can be used on metals, masonry, textiles, paper, and glass, and have superior hardness and flexibility, strong resistance to chemicals fire, and weather.

Nanelli, P.

1979-01-01

299

Thermodynamics of chromium in UO2 fuel: A solubility model  

NASA Astrophysics Data System (ADS)

The solubility and speciation of chromium in doped uranium oxide are measured in carefully controlled temperature and oxygen potential conditions using electron probe microanalysis (EPMA) and scanning electron spectroscopy (SEM). The examination of the samples by X-ray Absorption Spectroscopy (XAS) provides evidence that (i) chromium is soluble in the UO2 matrix under the +3 oxidation state only regardless of the sintering conditions which is in accordance with a soluble species of type CrO3/2 and (ii) soluble chromium exhibits octahedral symmetry with 6 atoms of oxygen forming CrO6 patterns in the UO2 structure. In consistency with all available experimental information including previously published data, the solubility of chromium in UO2 corresponding to each two-phase field with either Cr, CrO and Cr2O3 may be described in the ranges 1500 °C < T < 2000 °C and ?460 < ?O2 < ?360 kJ/mol using the standard thermodynamic equations governing solubility equilibria. The characteristic parameters of the solubility laws in UO2 for the three chromium phases are derived.

Riglet-Martial, Ch.; Martin, Ph.; Testemale, D.; Sabathier-Devals, C.; Carlot, G.; Matheron, P.; Iltis, X.; Pasquet, U.; Valot, C.; Delafoy, C.; Largenton, R.

2014-04-01

300

Solubility of Nd in brine.  

National Technical Information Service (NTIS)

The solubility of Nd(III) has been measured in a synthetic brine at pcH 6.4, 8.4, 10.4 and 12.4. The brine consisted predominantly of (Na+K)Cl and MgCl(sub 2), with an ionic strength of 7.8M (9.4m). The experimental solubility is much less than that estim...

F. Khalili V. Symeopoulos J. F. Chen G. R. Choppin

1993-01-01

301

Tough, Soluble, Aromatic, Thermoplastic Copolyimides  

NASA Technical Reports Server (NTRS)

Tough, soluble, aromatic, thermoplastic copolyimides were prepared by reacting 4,4'-oxydiphthalic anhydride, 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydianiline. These copolyimides were found to be soluble in common amide solvents such as N,N'-dimethyl acetamide, N-methylpyrrolidinone, and dimethylformamide allowing them to be applied as the fully imidized copolymer and to be used to prepare a wide range of articles.

Bryant, Robert G. (Inventor)

1998-01-01

302

DETERMINATION OF ANTIBODY TITERS AGAINST SOLUBLE ANTIGEN BY INDIRECT FLUORESCENT ANTIBODY (IFA) ASSAY USING LATEX PARTICLES COUPLED WITH SOLUBLE ANTIGEN: A PRELIMINARY STUDY  

Microsoft Academic Search

A method for indirect fluorescent antibody (IFA) assay for soluble antigen has been developed using latex particles (latex) as a carrier for soluble antigen. Two types of latex having grain sizes of 1.0 and 6.0 µm were used for IFA assay and were evaluated in this study. Bovine IgG and rabbit anti-bovine IgG antibody were used as soluble antigen and as

Takashi Kuribayashi; Tetsurou Seita; Toshio Honjyo; Katsuhito Kawato; Kayoko Takada; Shizuo Yamamoto

2012-01-01

303

Experimental Studies on Rutile Solubility  

NASA Astrophysics Data System (ADS)

Rutile (TiO2) is an important high field strength element (HFSE) sequestering mineral, and has been implicated in the observed depletion of HFSE in arc magmas. It is thought that rutile is insoluble in slab-derived fluids, and remains residual in the subducted slab. Indeed, experimental data indicates a very low solubility of rutile in pure H2O (Tropper and Manning, 2005), and this low solubility may result in HFSE depleted fluids imparting a depleted signature to arc magmas. However, there is scant experimental data available on rutile solubility in fluids of more complex compositions (Ayers and Watson, 1993). We are carrying out a systematic experimental study into the effect of specific chemical components on rutile solubility in fluids and also silicate melts. This should further our understanding of HFSE mobility in metamorphic rocks within subduction zones. References: J. C. Ayers and E. B. Watson (1993) Rutile solubility in supercritical aqueous fluids and the high P-T mobility of elements it concentrates. Contrib. Mineral. Petrol. 114, 321-330. P. Tropper and C. E. Manning (2005) Very low solubility of rutile in H2O at high pressure and temperature, and its implications for Ti mobility in subduction zones. American Mineralogist 90(2-3), 502-505.

Rapp, J. F.; Klemme, S.; Butler, I. B.; Harley, S. L.

2007-12-01

304

Hydrogen adsorption on and solubility in graphites  

SciTech Connect

The experimental data on sorption and solubility of hydrogen isotopes in graphite in a wide ranges of temperature and pressure are reviewed. The Langmuir type adsorption is proposed for the hydrogen -- graphites interaction with taking into account dangling sp{sup 2}{minus}bonds relaxation. Three kinds of traps are proposed: Carbon interstitial loops with the adsorption enthalpy of {minus}4.4 eV/H{sub 2} (Traps l); carbon network edge atoms with the adsorption enthalpy of {minus}2.3 eV/H{sub 2} (Traps 2): Basal planes adsorption sites with enthalpy of +2.43 eV/H{sub 2} (Traps 3). The sorption capacity of every kind of graphite could be described with its own unique set of traps. The number of potential sites for the ``true solubility`` (Traps 3) we assume as 1E+6 appm, or HC=l, but endothermic character of this solubility leads to negligible amount of inventory in comparison with Traps 1 and Traps 2. The irradiation with neutrons or carbon atoms increases the number of Traps 1 and Traps 2. At damage level of {approximately}1 dpa under room temperature irradiation the number of these traps was increased up to 1500 and 5000 appm respectively. Traps 1 and Traps 2 are stable under high temperature annealing.

Kanashenko, S.L.; Gorodetsky, A.E.; Chernikov, V.N.; Markin, A.V.; Zakharov, A.P.

1995-12-01

305

The Solubility Parameters of Ionic Liquids  

PubMed Central

The Hildebrand’s solubility parameters have been calculated for 18 ionic liquids from the inverse gas chromatography measurements of the activity coefficients at infinite dilution. Retention data were used for the calculation. The solubility parameters are helpful for the prediction of the solubility in the binary solvent mixtures. From the solubility parameters, the standard enthalpies of vaporization of ionic liquids were estimated.

Marciniak, Andrzej

2010-01-01

306

Regulation of immunoreactive inhibin A and B secretion in cultured human granulosa-luteal cells by gonadotropins, activin A and insulin-like growth factor type-1 receptor  

Microsoft Academic Search

Inhibins are gonadal glycoproteins with endocrine effects on pituitary FSH secretion and para\\/autocrine effects on ovarian and testicular function. The purpose of this study was to investigate the endocrine and para\\/autocrine regulation of inhibin A and inhibin B secretion in human ovarian granulosa-luteal cells. The cells were obtained from women undergoing in vitro fertilization, and the primary cultures were treated

T Vanttinen; J Liu; C Hydén-Granskog; M Parviainen; I Penttilä; R Voutilainen

2000-01-01

307

Thorium oxalate solubility and morphology  

SciTech Connect

Thorium was used as a stand-in for studying the solubility and precipitation of neptunium and plutonium oxalates. Thorium oxalate solubility was determined over a range of 0.001 to 10.0 in the concentration parameter (H/sub 2/C/sub 2/O/sub 4/)/(HNO/sub 3/)/sup 2/. Morphology of thorium oxide made from the oxalate precipitates was characterized by scanning electron microscopy. The different morphologies found for oxalate-lean and oxalate-rich precipitations were in agreement with predictions based on precipitation theory.

Monson, P.R. Jr.; Hall, R.

1981-10-01

308

Development of microemulsion for solubility enhancement of clopidogrel.  

PubMed

Clopidogrel, an inhibitor of platelet aggregation, selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Oral bioavailability of clopidogrel is very low (less than 50%), due to its poor water solubility. The aim of this investigation was to design and develop a microemulsion formulation of clopidogrel for enhancing its solubility, and hence its oral bioavailability. For this purpose, initially, solubility of clopidogrel was determined in various vehicles. Next, pseudo-ternary phase diagrams were constructed to identify the microemulsion existing zone. Solubility study was also performed for optimization of formulation. The optimized microemulsion formulation was characterized for its transparency, droplet size, zeta potential, viscosity, conductivity, % assay, and phase separation study. Particle size and zeta potential of the optimized microemulsion formulation were found to be 12.3 nm, and -6.34 mV, respectively. The viscosity and conductivity data indicated that the microemulsion was of the o/w type. Solubility of clopidogrel was successfully enhanced by 80.66 times, via capmul microemulsion, compared with distilled water (pH = 7.4). 75.53% and 71.2 % of the drug content were found to be released within 9 h in the in-vitro and ex-vivo studies, respectively. Hence, by formulating into microemulsion, the solubility of clopidogrel was found to be significantly enhanced. PMID:24381597

Patel, Vandana; Kukadiya, Hirenkumar; Mashru, Rajshree; Surti, Naazneen; Mandal, Surjyanarayan

2010-01-01

309

Solubility of Mg-containing ?-tricalcium phosphate at 25 ?C  

PubMed Central

The equilibrium solubility of Mg-containing ?-tricalcium phosphate (?MgTCP) with various magnesium contents was determined by immersing ?MgTCP powder for 27 months in a CH3COOH–CH3COONa buffer solution at 25 °C under a nitrogen gas atmosphere. The negative logarithm of the solubility product (pKsp) of ?MgTCP was expressed as pKsp = 28.87432 + 1.40348C ? 0.3163C2 + 0.04218C3 ? 0.00275C4 + 0.0000681659C5, where C is the magnesium content in ?MgTCP (mol.%). The solubility of ?MgTCP decreased with increasing magnesium content owing to the increased structural stability and possible formation of a whitlockite-type phase on the surface. As a result, ?MgTCP with 10.1 mol.% magnesium had a lower solubility than that of hydroxyapatite below pH 6.0. ?MgTCP was found to be more soluble than zinc-containing ?-tricalcium phosphate given the same molar content of zinc or magnesium. The solubility of ?MgTCP and release rate of magnesium from ?MgTCP can be controlled by adjusting the Mg content by selecting the appropriate pKsp.

Li, Xia; Ito, Atsuo; Sogo, Yu; Wang, Xiupeng; LeGeros, R.Z.

2008-01-01

310

[Preliminary study on correlation between diversity of soluble proteins and producing area of Cordyceps sinensis].  

PubMed

To analyze the content and type of soluble proteins in Cordyceps sinensis from different producing areas and processed with different methods with bradford method and 2-DE technology, in order to discover significant differences in soluble proteins in C. sinensis processed with different methods and from different producing areas. The preliminary study indicated that the content and diversity of soluble proteins were related to producing areas and processing methods to some extent. PMID:23944072

Ren, Yan; Qiu, Yi; Wan, De-Guang; Lu, Xian-Ming; Guo, Jin-Lin

2013-05-01

311

Aqueous Solubility of CL-20.  

National Technical Information Service (NTIS)

The Energetics and Warheads Division of the U.S. Army Armament Research, Development and Engineering Center has been involved in the development of CL-20. An aqueous solubility study was performed to better understand the fate and transport of CL-20 throu...

P. Karakaya M. Sidhoum C. Christodoulatos W. Balas S. Nicolich

2005-01-01

312

Oat Soluble Dietary Fiber Compositions.  

National Technical Information Service (NTIS)

Water-soluble dietary fiber compositions can be prepared by treatment of oat-milled products with alpha-amylases. The dietary fiber compositions are colorless and devoid of inherent undesirable flavors and are, therefore, uniquely suitable for use in a va...

G. E. Inglett

1989-01-01

313

Comparative Calculations of Solubility Equilibria.  

National Technical Information Service (NTIS)

The uncertainties in calculated solubilities in the Na-F-PO,-HPO,-OH system. at 25 deg C for NaOH concentrations up to 5 mol/kg were assessed. These uncertainties were based on an evaluation of the range of values for the Gibbs energies of the solids. Com...

E. C. Beahm R. K. Toghiani C. F. Weber

2000-01-01

314

21 CFR 101.77 - Health claims: fruits, vegetables, and grain products that contain fiber, particularly soluble...  

Code of Federal Regulations, 2011 CFR

...whether a particular type of soluble fiber...limited to, some types of soluble fiber...disease. (1) Coronary...blood pressure, diabetes, cigarette smoking...some types of dietary fiber,” “some...information. (1) The claim...cigarette smoking, diabetes, and...

2011-04-01

315

Acylation of Membrane Proteins to Enhance Their Water Solubility  

Microsoft Academic Search

Membrane proteins are an integral part of the structure of membranes providing the functional aspect of the membrane with respect to the transport of water soluble molecules, signal recognition and reaction cataylsis. Primary, secondary and tertiary structure of these types of proteins warrant investigation in order to better understand their individual function. Both DNA sequencing and standard protein sequencing can

Robert Christopher Morton

1991-01-01

316

Acylation of membrane proteins to enhance their water solubility  

Microsoft Academic Search

Membrane proteins are an integral part of the structure of membranes providing the functional aspect of the membrane with respect to the transport of water soluble molecules, signal recognition and reaction catalysis. Primary, secondary and tertiary structure of these types of proteins warrant investigation in order to better understand their individual function. Both DNA sequencing and standard protein sequencing can

Robert Christopher Morton

1991-01-01

317

A comparative immunogenicity study in rabbits of disulfide-stabilized, proteolytically cleaved, soluble trimeric human immunodeficiency virus type 1 gp140, trimeric cleavage-defective gp140 and monomeric gp120  

Microsoft Academic Search

The human immunodeficiency virus type 1 (HIV-1) surface envelope glycoprotein (Env) complex, a homotrimer containing gp120 surface glycoprotein and gp41 transmembrane glycoprotein subunits, mediates the binding and fusion of the virus with susceptible target cells. The Env complex is the target for neutralizing antibodies (NAbs) and is the basis for vaccines intended to induce NAbs. Early generation vaccines based on

Simon Beddows; Michael Franti; Antu K. Dey; Marc Kirschner; Sai Prasad N. Iyer; Danielle C. Fisch; Thomas Ketas; Eloisa Yuste; Ronald C. Desrosiers; Per Johan Klasse; Paul J. Maddon; William C. Olson; John P.. Moore

2007-01-01

318

Carbon solubility in mantle minerals  

NASA Astrophysics Data System (ADS)

The solubility of carbon in olivine, enstatite, diopside, pyrope, MgAl 2O 4 spinel, wadsleyite, ringwoodite, MgSiO 3-ilmenite and MgSiO 3-perovskite has been quantified. Carbon-saturated crystals were grown from carbonatite melts at 900-1400 °C and 1.5 to ˜ 26 GPa in piston cylinder or multi-anvil presses using carbon enriched to > 99% in the 13C isotope. In upper mantle silicates, carbon solubility increases as a function of pressure to a maximum of ˜ 12 ppm by weight in olivine at 11 GPa. No clear dependence of carbon solubility on temperature, oxygen fugacity or iron content was observed. The observation that carbon solubility in olivine is insensitive to oxygen fugacity implies that the oxidation state of carbon in the carbonatite melt and in olivine is the same, i.e., carbon dissolves as C 4+ in olivine. Carbon solubility in spinel MgAl 2O 4, transition zone minerals (wadsleyite and ringwoodite), MgSiO 3-ilmenite and MgSiO 3-perovskite are below the limit of detection of our SIMS-based analytical technique (i.e., below 30-200 ppb by weight). The differences in carbon solubilities between the various minerals studied appear to correlate with the polyhedral volume of the Si 4+ site, consistent with a direct substitution of C 4+ for Si 4+. These results show that other, minor carbon-rich phases, rather than major, nominally volatile-free minerals, dominate the carbon budget within the bulk Earth's mantle. A significant fraction of total carbon could only be stored in silicates in a thin zone in the lowermost upper mantle, just above the transition zone, and only if the bulk carbon content is at the lower limit of published estimates. The carbon budget of the remaining mantle is dominated by carbonates and possibly diamond. The low melting point of carbonates and the high mobility of carbonate melts suggest that carbon distribution in the mantle may be highly heterogeneous, including the possibility of massive carbon enrichments on a local scale, particularly in the shallow subcontinental mantle.

Shcheka, Svyatoslav S.; Wiedenbeck, Michael; Frost, Daniel J.; Keppler, Hans

2006-05-01

319

Purification, Characterization, and Immunogenicity of a Soluble Trimeric Envelope Protein Containing a Partial Deletion of the V2 Loop Derived from SF162, an R5Tropic Human Immunodeficiency Virus Type 1 Isolate  

Microsoft Academic Search

The envelope (Env) glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the major target of neutralizing antibody responses and is likely to be a critical component of an effective vaccine against AIDS. Although monomeric HIV envelope subunit vaccines (gp120) have induced high-titer antibody responses and neutralizing antibodies against laboratory-adapted HIV-1 strains, they have failed to induce neutralizing antibodies against

Indresh K. Srivastava; Leonidas Stamatatos; Elaine Kan; Michael Vajdy; Ying Lian; Susan Hilt; Loic Martin; Claudio Vita; Ping Zhu; Kenneth H. Roux; Lucia Vojtech; David C. Montefiori; John Donnelly; Jeffrey B. Ulmer; Susan W. Barnett

2003-01-01

320

Interactions between dietary fat type and xylanase supplementation when rye?based diets are fed to broiler chickens 2. Performance, nutrient digestibility and the fat?soluble vitamin status of livers  

Microsoft Academic Search

1. The interactions between dietary fat type and xylanase supplementation of rye?based diets were investigated using a 2×2 factorial design in which a rye?based diet (610 g rye\\/kg) was combined with 100 g\\/kg of soya oil or beef tallow, with or without xylanase supplementation at 3000 IU\\/kg, and fed to 1?d?old male broilers for 35 d. Growth, nutrient digestibility and

S. Dänicke; O. Simon; H. Jeroch; M. Bedford

1997-01-01

321

Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction  

Microsoft Academic Search

Recent evidence has suggested a role for soluble oligomeric A? species in the pathology of Alzheimer's disease (AD). Fibrillar plaque deposits are present in non-demented individuals and levels of soluble A? correlate better with cognitive dysfunction in AD and transgenic mouse models. We have previously reported that there are at least two conformationally distinct types of A? oligomers: prefibrillar oligomers

Jennifer L. Tomic; Anna Pensalfini; Elizabeth Head; Charles G. Glabe

2009-01-01

322

Development of models for prediction of solubility for HFC working fluids in pentaerythritol ester compressor oils  

Microsoft Academic Search

This study aims to further develop a model of the group contribution type that can predict the solubility of mixtures of HFC working fluids and pentaerythritol ester compressor oils. The investigation is based on solubility data for 20 systems of five different HFCs in four different pentaerythritol esters. First, five different activity factor-based thermodynamic models were investigated to determine to

Åsa Wahlström; Lennart Vamling

2000-01-01

323

Solubilities of tetracosane in hydrocarbon solvents  

SciTech Connect

The solubilities of tetracosane (n-C[sub 24]H[sub 50]) in heptane (n-C[sub 7]H[sub 16]), dodecane (n-C[sub 12]H[sub 26]), a mixture of isomers of decahydronaphthalene (C[sub 10]H[sub 18]), and m and p-xylene (C[sub 8]H[sub 10]) have been determined over the temperature range 279.3--305.8 K. These solvents were chosen as being representative of the types of molecules present in fuel oils. The results are well described by the equation ln x[sub 2] = [minus]([Delta]H[sup d]/RT) + ([Delta]S[sup d]/R) for which the parameters [Delta]H[sup d] and [Delta]S[sup d] are given. The liquid-phase activity coefficients for the solid at 293.2 K have been derived from the measured solubilities and compared with values calculated from the Scatchard-Hildebrand equation and the UNIFAC group contribution method. Relatively good agreement is obtained using the Scatchard-Hildebrand equation, especially in the case of normal hydrocarbon solvents.

Brecevic, L.; Garside, J. (Univ. of Manchester Inst. of Science and Technology, Manchester (United Kingdom). Dept. of Chemical Engineering)

1993-10-01

324

Re-Examination of Muscle Protein Solubility.  

National Technical Information Service (NTIS)

Muscle proteins are conveniently characterized by their solubility properties. Sarcoplasmic proteins are defined as those soluble when muscle is extracted with water or solutions of low ionic strength, i.e., physiological or less. Myofibrillar proteins ar...

H. O. Hultin Y. Feng D. W. Stanley

1995-01-01

325

Tough soluble aromatic thermoplastic copolyimides  

NASA Technical Reports Server (NTRS)

Tough, soluble, aromatic, thermoplastic copolyimides were prepared by reacting 4,4'-oxydiphthalic anhydride, 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydianiline. Alternatively, these copolyimides may be prepared by reacting 4,4'-oxydiphthalic anhydride with 3,4,3',4'-biphenyltetracarboxylic dianhydride and 3,4'-oxydiisocyanate. Also, the copolyimide may be prepared by reacting the corresponding tetra acid and ester precursors of 4,4'-oxydiphthalic anhydride and 3,4,3',4'-biphenyltetracarboxylic dianhydride with 3,4'-oxydianiline. These copolyimides were found to be soluble in common amide solvents such as N,N'-dimethyl acetamide, N-methylpyrrolidinone, and dimethylformamide allowing them to be applied as the fully imidized copolymer and to be used to prepare a wide range of articles.

Bryant, Robert G. (Inventor)

2000-01-01

326

Constructing soluble quantum spin models  

NASA Astrophysics Data System (ADS)

By applying the bond operator method, we construct several soluble quantum spin models in two and three dimensions. We first generalize the spin-1/2 bond operators developed by Sachdev and Bhatt [Phys. Rev. B 41 (1990) 9323] to spin S?1. Then we study two and three-dimensional antiferromagnetic spin- S Heisenberg models and establish conditions on the couplings such that the completely dimerized state is an eigenstate of the model Hamiltonians.

Shik, H. Y.; Li, Y. Q.; Lin, H. Q.

2003-09-01

327

Water soluble adenosine kinase inhibitors  

US Patent & Trademark Office Database

This invention relates to adenosine kinase inhibitors and to nucleoside analogs, specifically to water soluble, aryl substituted 4-amino pyrrolo[2,3-d] pyrimidine and pyrazolo[3,4-d] pyrimidine nucleoside analogs having activity as adenosine kinase inhibitors The invention also relates to the preparation and use of these adenosine kinase inhibitors in the treatment of cardiovascular, and cerebrovascular diseases, inflammation and other diseases which can be regulated by increasing the local concentration of adenosine.

1998-08-18

328

Comparative Calculations of Solubility Equilibria  

Microsoft Academic Search

The uncertainties in calculated solubilities in the Na-F-POâ-HPOâ-OH system. at 25 C for NaOH concentrations up to 5 mol\\/kg were assessed. These uncertainties were based on an evaluation of the range of values for the Gibbs energies of the solids. Comparative calculations using the Environmental Simulation Program (ESP) and SOLGASMIX indicated that the variation in activity coefficients with NaOH concentration

E. C. Beahm; R. K. Toghiani; C. F. Weber

2000-01-01

329

Determination of soluble tumor necrosis factor receptor 2 produced by alternative splicing.  

PubMed

Soluble cytokine receptors have proven to be very useful biomarkers in a large variety of diseases, including cancer, infections, and chronic inflammatory diseases. These soluble receptors are produced by proteolytic cleavage or alternative splicing. Several cytokine receptors including tumor necrosis factor receptor 2 (TNFR2) can be generated by both mechanisms. However, the conventional ELISA systems do not differentiate between these two types of soluble receptors. We describe a sandwich ELISA to specifically quantify soluble TNFR2 protein generated by alternative splicing. This method requires the use of a capturing monoclonal antibody (mAb) specific of an epitope present in the soluble TNFR2 generated by alternatively splicing but absent in the proteolytically generated isoform. Here we present a detailed protocol for the production and validation of such a mAb. This method has the potential to be applied for measuring other soluble cell surface molecules generated by alternative splicing. PMID:24788183

Romero, Xavier; Cañete, Juan D; Engel, Pablo

2014-01-01

330

Resonance properties of soluble gas bubbles  

Microsoft Academic Search

Soluble gas bubbles in a liquid experiencing radial oscillations created by an acoustic field are considered. It is shown that the resonance frequency of large soluble gas bubbles practically coincides with the natural frequency of gas bubbles as determined by the Minnaert formula. In the case of small gas bubbles, the presence of capillary effects and solubility of the gas

Nail S. Khabeev

2006-01-01

331

Protein solubility: sequence based prediction and experimental  

Microsoft Academic Search

Motivation: Obtaining soluble proteins in sufficient concentrations is a recurring limiting factor in various experimental studies. Solubility is an individual trait of proteins which, under a given set of experi- mental conditions, is determined by their amino acid sequence. Accurate theoretical prediction of solubility from sequence is instru- mental for setting priorities on targets in large-scale proteomics pro- jects. Results:

Pawel Smialowski; Antonio J. Martin-Galiano; Aleksandra Mikolajka; Tobias Girschick; Tad A. Holak; Dmitrij Frishman

332

Irrigated precipitator for sampling soluble aerosols.  

PubMed

The design and performance of a simple parallel plate, irrigated, precipitator for use in the sampling of soluble aerosols is described. Unifrom surface coverage of 0.044 +/- 0.003 mL/cm2 by the gravity fed collection fluid is provided with a fiberglass mat (Gelman type A/E filter), while a surface washout of approximately 45% occurs in fluid residence time tf = V/q for a collector surface inclination of 40 degrees relative to horizontal. Efficiency tests using laboratory generated DOP aerosols and field tests of sulfate-bearing particles indicate good correlation with the Deutsch equation. Values of V/Q, proportional to the instrument sampling time, representing the ration of collection fluid volume to air flow rate for the present design compare favorably with other available instrumentation. PMID:696624

Forney, L J; Lee, S S; Szurgot, A M

1978-08-01

333

Protective immune responses induced by secretion of a chimeric soluble protein from a recombinant Mycobacterium bovis bacillus Calmette-Gu?rin vector candidate vaccine for human immunodeficiency virus type 1 in small animals.  

PubMed Central

A recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vector-based vaccine that secretes the V3 principal neutralizing epitope of human immunodeficiency virus (HIV) could induce immune response to the epitope and prevent the viral infection. By using the Japanese consensus sequence of HIV-1, we successfully constructed chimeric protein secretion vectors by selecting an appropriate insertion site of a carrier protein and established the principal neutralizing determinant (PND)-peptide secretion system in BCG. The recombinant BCG (rBCG)-inoculated guinea pigs were initially screened by delayed-type hypersensitivity (DTH) skin reactions to the PND peptide, followed by passive transfer of the DTH by the systemic route. Further, immunization of mice with the rBCG resulted in induction of cytotoxic T lymphocytes. The guinea pig immune antisera showed elevated titers to the PND peptide and neutralized HIVMN, and administration of serum IgG from the vaccinated guinea pigs was effective in completely blocking the HIV infection in thymus/liver transplanted severe combined immunodeficiency (SCID)/hu or SCID/PBL mice. In addition, the immune serum IgG was shown to neutralize primary field isolates of HIV that match the neutralizing sequence motif by a peripheral blood mononuclear cell-based virus neutralization assay. The data support the idea that the antigen-secreting rBCG system can be used as a tool for development of HIV vaccines. Images Fig. 1

Honda, M; Matsuo, K; Nakasone, T; Okamoto, Y; Yoshizaki, H; Kitamura, K; Sugiura, W; Watanabe, K; Fukushima, Y; Haga, S

1995-01-01

334

Solubility evaluation of murine hybridoma antibodies  

PubMed Central

The successful development of antibody therapeutics depends on the molecules having properties that are suitable for manufacturing, as well as use by patients. Because high solubility is a desirable property for antibodies, screening for solubility has become an essential step during the early candidate selection process. In considering the screening process, we formed a hypothesis that hybridoma antibodies are filtered by nature to possess high solubility and tested this hypothesis using a large number of murine hybridoma-derived antibodies. Using the cross-interaction chromatography (CIC) method, we screened the solubility of 92 murine hybridoma-derived monoclonal antibodies and found that all of these molecules exhibited CIC profiles that are indicative of high solubility (>100mg/mL). Further investigations revealed that variable region N-linked glycosylation or isoelectric parameters are unlikely to contribute to the high solubility of these antibodies. These results support the general hypothesis that hybridoma monoclonal antibodies are highly soluble.

Spencer, Stacey; Bethea, Deidra; Raju, T. Shantha; Giles-Komar, Jill; Feng, Yiqing

2012-01-01

335

40 CFR 799.6786 - TSCA water solubility: Generator column method.  

Code of Federal Regulations, 2012 CFR

...grade, are recommended to minimize the effects of dissolved salts and other impurities on water solubility. ASTM Type II water...appropriate concentration for determining RFs of standard solutions of basic chromate for determining the sample-loop volume. The...

2012-07-01

336

40 CFR 799.6786 - TSCA water solubility: Generator column method.  

Code of Federal Regulations, 2011 CFR

...grade, are recommended to minimize the effects of dissolved salts and other impurities on water solubility. ASTM Type II water...appropriate concentration for determining RFs of standard solutions of basic chromate for determining the sample-loop volume. The...

2011-07-01

337

Marangoni Flow of Soluble Amphiphiles  

NASA Astrophysics Data System (ADS)

Surfactant distribution heterogeneities at a fluid-fluid interface trigger the Marangoni effect, i.e., a bulk flow due to a surface tension gradient. The influence of surfactant solubility in the bulk on these flows remains incompletely characterized. Here we study Marangoni flows sustained by injection of hydrosoluble surfactants at the air-water interface. We show that these flows have a finite size that increases with a decrease of the critical micelle concentration of the surfactants. We document the universality of the surface velocity field of these finite flows and predict scaling laws based on hydrodynamics and surfactant physical chemistry that capture the flow features.

Roché, Matthieu; Li, Zhenzhen; Griffiths, Ian M.; Le Roux, Sébastien; Cantat, Isabelle; Saint-Jalmes, Arnaud; Stone, Howard A.

2014-05-01

338

Construction of a Soluble Adenylyl Cyclase Activated by G_salpha and Forskolin  

Microsoft Academic Search

A soluble adenylyl cyclase was constructed by linkage of portions of the cytosolic domains of the mammalian type I and type II enzymes. The soluble enzyme was stimulated by both forskolin and the alpha subunit of the heterotrimeric guanine nucleotide-binding protein (G protein) G_s (G_salpha). Expression of the construct complemented the catabolic defect in a strain of Escherichia coli that

Wei-Jen Tang; Alfred G. Gilman

1995-01-01

339

Ovarian follicle development in the laying hen is accompanied by divergent changes in inhibin A, inhibin B, activin A and follistatin production in granulosa and theca layers.  

PubMed

To study the potential involvement of inhibin A (inhA), inhibin B (inhB), activin A (actA) and follistatin (FS) in the recruitment of follicles into the preovulatory hierarchy, growing follicles (ranging from 1 mm to the largest designated F1) and the three most recent postovulatory follicles (POFs) were recovered from laying hens (n=11). With the exception of <4 mm follicles and POFs, follicle walls were dissected into separate granulosa (G) and theca (T) layers before extraction. Contents of inhA, inhB, actA and FS in tissue extracts were assayed using specific two-site ELISAs and results are expressed per mg DNA. InhB content of both G and T followed a similar developmental pattern, although the content was >4-fold higher in G than in T at all stages. InhB content was very low in follicles <4 mm but increased ~50-fold (P<0.0001) to peak in 7-9 mm follicles, before falling steadily as follicles entered and moved up the follicular hierarchy (40-fold; 8 mm vs F2). In stark contrast, inhA remained very low in prehierarchical follicles (< or =9 mm) but then increased progressively as follicles moved up the preovulatory hierarchy to peak in F1 (approximately 100-fold increase; P<0.0001); In F1 >97% of inhA was confined to the G layer whereas in 5-9 mm follicles inhA was only detected in the T layer. Both inhA and inhB contents of POFs were significantly reduced compared with F1. Follicular actA was mainly confined to the T layer although detectable levels were present in G from 9 mm; actA was low between 1 and 9 mm but increased sharply as follicles entered the preovulatory hierarchy (approximately 6-fold higher in F4; P<0.0001); levels then fell approximately 2-fold as the follicle progressed to F1. Like actA, FS predominated in the T although significant amounts were also present in the G of prehierarchical follicles (4-9 mm), in contrast to actA, which was absent from the G. The FS content of T rose approximately 3-fold from 6 mm to a plateau which was sustained until F1. In contrast, the FS content of G was greatest in prehierarchical follicles and fell approximately 4-fold in F4-F1 follicles. ActA and FS contents of POFs were reduced compared with F1. In vitro studies on follicle wall explants confirmed the striking divergence in the secretion of inhA and inhB during follicle development. These findings of marked stage-dependent differences in the expression of inhA, inhB, actA and FS proteins imply a significant functional role for these peptides in the recruitment and ordered progression of follicles within the avian ovary. PMID:12697036

Lovell, T M; Gladwell, R T; Groome, N P; Knight, P G

2003-04-01

340

Extraction of soluble fiber from distillers' grains.  

PubMed

The feasibility of using coproducts from dry grind corn ethanol production as a substrate for the production of soluble fiber was examined. Acid- and base-catalyzed hydrolysis experiments were performed using sulfuric acid and sodium hydroxide to partially hydrolyze hemicellulose content of whole stillage, a precursor to distillers' grains, to soluble fiber. The influences of temperature, reaction time, and hydrolyzing agent concentration on the formation of soluble fiber were studied. Soluble fiber was recovered by precipitation in a 95% ethanol solution. Results indicate that appreciable quantities of soluble fiber may be extracted using either acid- or base-catalyzed reactions. The highest yield of soluble fibers was 13.2 g per 100 g-db of treated whole stillage using one weight percent sodium hydroxide at 80ºC for 1 h. HPLC analysis was used to quantify the amount of monomeric sugars which were formed during the hydrolysis procedures. PMID:22203395

Flodman, Hunter R; Boyer, Elizabeth J; Muthukumarappan, Arthy; Noureddini, Hossein

2012-02-01

341

Thorium(IV) hydrous oxide solubility  

SciTech Connect

The results of a study of the solubility of amorphous, hydrous ThO/sub 2/ over the pH range 3.5 - 14.2 are reported. The solubility is high at pH 3.5 and decreases rapidly at pH 4.5. The chemical modes of solubility over various pH ranges are discussed. No conclusive evidence for any amphoteric behavior of Th(IV) is reported. 22 references, 1 figure.

Ryan, J.L.; Rai, D.

1987-12-02

342

Solubility of solid phases in eutectic systems  

SciTech Connect

A problem which takes into account the temperature dependence of interfacial energy is solved in order to describe quasi-equilibrium lines of solid-phase solubility in eutectic systems. The chosen reference point is the point of the eutectic horizontal corresponding to the limiting solubility of the second component in the solid solution. An expression is obtained which makes it possible to equate empirical values of solubility and to almost exactly represent its temperature path for the eutectic systems examined.

Psarev, V.I.

1987-04-01

343

A soluble and multichromic conducting polythiophene derivative  

Microsoft Academic Search

A new soluble polythiophene derivative was synthesized by both chemical and electrochemical oxidative polymerization of 1-4-nitrophenyl-2,5-di(2-thienyl)-1H-pyrrole (SNSNO2). Chemical method produces a polymer which is completely soluble in organic solvents. The structures of both the monomer and the soluble polymer were elucidated by 1H and 13C-NMR and FTIR. The average molecular weight has been determined by GPC to be Mn=6.3×103 for

Serhat Varis; Metin Ak; Cihangir Tanyeli; Idris Mecidoglu Akhmedov; Levent Toppare

2006-01-01

344

Solubility of hydrogen sulfide in organic solvents  

Microsoft Academic Search

The solubilities of hydrogen sulfide expressed in mole fractions may be related, through multiparameter equations, to parameters\\u000a that account for the specific and nonspecific solvation ability of the solvent and for the cohesion energy. The key factors\\u000a are the self-association of the solvent, which reduces the solubility, and the complexing ability with hydrogen sulfide, which\\u000a increases the solubility.

S. D. Bryk; R. G. Makitra; E. Ya. Pal’chikova

2006-01-01

345

Soluble interleukin 2 receptor in dialyzed patients.  

PubMed

Azotemic patients are usually characterized by a state of so-called preactivation resulting in excessive expression of interleukin 2 receptors (IL-2R) on T lymphocytes. The etiological mechanism of this preactivation is, however, still speculative. We studied the serum level of the soluble form of IL-2R (sIL-2R) in azotemic patients on either hemodialysis (HD) (n = 49) or continuous ambulatory peritoneal dialysis (CAPD) (n = 45). Both patient groups had significantly higher sIL-2R levels (1,750+/-664 U/ml in the HD group and 1,769+/-647 U/ml in the CAPD group, respectively) p < 0.00001 as compared to the normal control group (511+/-436 U/ml). However, there was no significant difference between the levels of the HD and CAPD group patients. When clinical parameters were studied for their influence on sIL-2R levels, none of the following caused any significant changes: blood transfusion, type of dialyzer used, type of dialysis fluid used, treatment with erythropoietin, hepatitis B infection, or liver function profile. We conclude that chronic renal failure per se is the major cause of the preactivation of T lymphocytes. The modes of treatment and various clinical variables in these patients have no significant influence on sIL-2R levels. PMID:9491905

Shu, K H; Lu, Y S; Cheng, C H; Lian, J D

1998-02-01

346

Hydrocarbon-soluble low-melting corrosion inhibitor TAL3  

Microsoft Academic Search

The inhibitor TAL-3 is intended for the corrosion protection of metals that come into contact with two-phase systems of the hydrocarbon-water type. It is applicable to the service conditions of equipment and pipelines of the petroleum and petroleum refining industries. The purpose of this paper was to electrochemically assess its solubility in such systems and its inhibitory properties on samples

S. A. Nesterenko; V. I. Sorokin; O. V. Naumenko

1987-01-01

347

Water Soluble Polymersfor Immunoisolation I: Complex Coacervation and Cytotoxicity  

Microsoft Academic Search

Seventy five synthetic, semi-synthetic, natural and biological water soluble polymers have been evaluated as potential biomaterials\\u000a for cell and islet immunoisolation. Measurements have included the cytotoxicity of polyanion and polycation solutions towards\\u000a insulinoma cells as well as the type of complex coacervate interaction produced. These results have been coupled with metrics\\u000a delineating the quality of the capsular membrane produced and

A. Prokop; D. Hunkeler; S. DiMari; M. A. Haralson; T. G. Wang

348

Use of whey protein soluble aggregates for thermal stability-a hypothesis paper.  

PubMed

Forming whey proteins into soluble aggregates is a modification shown to improve or expand the applications in foaming, emulsification, gelation, film-formation, and encapsulation. Whey protein soluble aggregates are defined as aggregates that are intermediates between monomer proteins and an insoluble gel network or precipitate. The conditions under which whey proteins denature and aggregate have been extensively studied and can be used as guiding principles of producing soluble aggregates. These conditions are reviewed for pH, ion type and concentration, cosolutes, and protein concentration, along with heating temperature and duration. Combinations of these conditions can be used to design soluble aggregates with desired physicochemical properties including surface charge, surface hydrophobicity, size, and shape. These properties in turn can be used to obtain target macroscopic properties, such as viscosity, clarity, and stability, of the final product. A proposed approach to designing soluble aggregates with improved thermal stability for beverage applications is presented. PMID:23957418

Ryan, Kelsey N; Zhong, Qixin; Foegeding, Edward A

2013-08-01

349

Novel Ex Vivo Culture Method for the Study of Dupuytren's Disease: Effects of TGF? Type 1 Receptor Modulation by Antisense Oligonucleotides.  

PubMed

Dupuytren's disease (DD) is a benign fibroproliferative disease of the hand. It is characterized by the excessive production of extracellular matrix (ECM) proteins, which form a strong fibrous tissue between the handpalm and fingers, permanently disrupting the fine movement ability. The major contractile element in DD is the myofibroblast (MFB). This cell has both fibroblast and smooth muscle cell-type characteristics and causes pathological collagen deposition. MFBs generate contractile forces that are transmitted to the surrounding collagen matrix. ?ajor profibrotic factors are members of the transforming growth factor-? (TGF?) pathway which directly regulate the expression levels of several fibrous proteins such as collagen type 1, type 3, and ?-smooth muscle actin. Molecular modulation of this signaling pathway could serve as a therapeutic approach. We, therefore, have developed an ex vivo "clinical trial" system to study the properties of intact, patient-derived resection specimens. In these culture conditions, Dupuytren's tissue retains its three-dimensional (3D) structure and viability. As a novel antifibrotic therapeutic approach, we targeted TGF? type 1 receptor (also termed activin receptor-like kinase 5) expression in cultured Dupuytren's specimens by antisense oligonucleotide-mediated exon skipping. Antisense oligonucleotides targeting activin receptor-like kinase 5 showed specific reduction of ECM and potential for clinical application.Molecular Therapy-Nucleic Acids (2014) 3, e142; doi:10.1038/mtna.2013.69; published online 21 January 2014. PMID:24448195

Karkampouna, Sofia; Kruithof, Boudewijn Pt; Kloen, Peter; Obdeijn, Miryam C; van der Laan, Annelies Ma; Tanke, Hans J; Kemaladewi, Dwi U; Hoogaars, Willem Mh; 't Hoen, Peter Ac; Aartsma-Rus, Annemieke; Clark, Ian M; Ten Dijke, Peter; Goumans, Marie-José; Kruithof-de Julio, Marianna

2014-01-01

350

Novel Ex Vivo Culture Method for the Study of Dupuytren's Disease: Effects of TGF? Type 1 Receptor Modulation by Antisense Oligonucleotides  

PubMed Central

Dupuytren's disease (DD) is a benign fibroproliferative disease of the hand. It is characterized by the excessive production of extracellular matrix (ECM) proteins, which form a strong fibrous tissue between the handpalm and fingers, permanently disrupting the fine movement ability. The major contractile element in DD is the myofibroblast (MFB). This cell has both fibroblast and smooth muscle cell-type characteristics and causes pathological collagen deposition. MFBs generate contractile forces that are transmitted to the surrounding collagen matrix. ?ajor profibrotic factors are members of the transforming growth factor-? (TGF?) pathway which directly regulate the expression levels of several fibrous proteins such as collagen type 1, type 3, and ?-smooth muscle actin. Molecular modulation of this signaling pathway could serve as a therapeutic approach. We, therefore, have developed an ex vivo “clinical trial” system to study the properties of intact, patient-derived resection specimens. In these culture conditions, Dupuytren's tissue retains its three-dimensional (3D) structure and viability. As a novel antifibrotic therapeutic approach, we targeted TGF? type 1 receptor (also termed activin receptor-like kinase 5) expression in cultured Dupuytren's specimens by antisense oligonucleotide-mediated exon skipping. Antisense oligonucleotides targeting activin receptor-like kinase 5 showed specific reduction of ECM and potential for clinical application.

Karkampouna, Sofia; Kruithof, Boudewijn PT; Kloen, Peter; Obdeijn, Miryam C; van der Laan, Annelies MA; Tanke, Hans J; Kemaladewi, Dwi U; Hoogaars, Willem MH; 't Hoen, Peter AC; Aartsma-Rus, Annemieke; Clark, Ian M; ten Dijke, Peter; Goumans, Marie-Jose; Kruithof-de Julio, Marianna

2014-01-01

351

Rigorous nonlinear regression analysis of phase solubility diagrams to obtain complex stoichiometry and true thermodynamic drug-cyclodextrin complexation parameters  

Microsoft Academic Search

This work reports rigorous nonlinear regression procedures aimed at analyzing various types of phase solubility diagrams (PSDs)\\u000a corresponding to the different soluble and insoluble complex stoichiometries, which are generally encountered in drug-cyclodextrin\\u000a (CD) complexation studies. These are depicted in final equations that can be modeled to fit experimental data of measured\\u000a drug solubility against CD concentration utilizing simple spreadsheet software

M. B. Zughul

2007-01-01

352

Evaluation of anti-wear performance of PFPE-soluble additives under sliding contact in high vacuum  

Microsoft Academic Search

The anti-wear performances of perfluoropolyether (PEPE)-soluble additives were evaluated under vacuum using a vacuum four-ball tribometer with 440C stainless steel balls as test specimens. PEPE derivatives having the hydroxyl, carboxyl and phosphate groups at the end of the Type D-PEPE molecules were studied. The addition of either PEPE-soluble carboxylic acid or PEPE-soluble phosphates to the PEPE base oil remarkably reduced

Masabumi Masuko; Nobuhiko Takeshita; Heihachiro Okabe

1995-01-01

353

Solubility and speciation of atmospheric iron in buffer systems simulating cloud conditions  

NASA Astrophysics Data System (ADS)

The solubility of iron (Fe) in atmospheric particulate matter (PM) is important to understand its chemistry and potential bioavailability to ocean phytoplankton. However, current studies on Fe solubility and its speciation are highly uncertain partly due to inconsistencies in analytical protocols. In this study, cloud-processing of atmospheric PM was simulated in acetate, formate, and oxalate buffers (pH = 4.30 ± 0.05) at 0.5, 1, 5, and 20 mM. Colorimetric analysis of Fe(II)-ferrozine complex showed that Fe solubility increased by an order of magnitude when acetate and formate concentrations increased from 0.5 mM to 5 mM, with a higher fraction of soluble Fe in acetate than in formate at lower buffer concentration (0.5 mM). Measured pH of sample extracts revealed that weak buffers are unable to maintain pH, presumably due to acidic or alkaline components of PM, requiring an optimum concentration (5 mM in this study) of acetate and formate for Fe solubility measurements. Similar extraction procedures revealed that oxalate buffer inhibits the formation of Fe(II)-ferrozine complex, especially with Fe(III)-containing solutions, rendering it unsuitable for Fe solubility measurements by Ferrozine method. Application of the optimized analytical method to PM samples from different environments showed quite variable Fe solubility, with the lowest (<1%) in dust-impacted samples and the highest (5%) in urban samples. The highest solubility (6.8%) was observed in ambient PM2.5 samples influenced by anthropogenic sources (car emissions) with more than 90% of soluble Fe in the form of Fe(II). Results from this study highlight the importance of the type and strength of buffer at a given pH for Fe solubility and provide further evidence of a higher Fe solubility in urban PM samples compared to desert dust.

Upadhyay, Nabin; Majestic, Brian J.; Herckes, Pierre

2011-04-01

354

Calculation of Drug Solubilities by Pharmacy Students.  

ERIC Educational Resources Information Center

A method of estimating the solubilities of drugs in water is reported that is based on a principle applied in quantitative structure-activity relationships. This procedure involves correlation of partition coefficient values using the octanol/water system and aqueous solubility. (Author/MLW)

Cates, Lindley A.

1981-01-01

355

SOLUBILITY OF THORIUM DIHYDRIDE IN THORIUM METAL  

Microsoft Academic Search

The saturation solubility of thorium dihydride in thorium was studied by ; saturation of samples and subsequent analysis. The solubility increased from ; about 1 at. % at 300 deg C to above 20 at. % at 8O0\\/\\/4\\/DEC. Over this ; temperature range the 1% of the solubilty was a linear function of the ; reciprocal, absolute temperature for thorium

D. T. Peterson; D. G. Westlake

1959-01-01

356

Pharmaceutical cocrystals and poorly soluble drugs.  

PubMed

In recent years cocrystal formation has emerged as a viable strategy towards improving the solubility and bioavailability of poorly soluble drugs. In this review the success of numerous pharmaceutical cocrystals for the improvement of the solubility and dissolution rates of poorly soluble drugs is demonstrated using various examples taken from the literature. The role of crystal engineering principles in the selection of appropriate coformers and the nature of the supramolecular synthons present within the crystals are described. Evidence for improved animal pharmacokinetic data is given for several systems. A summary is provided of our current understanding of the relationship between cocrystal structure and solution phase interactions on solubility as well as those factors that influence overall cocrystal thermodynamic stability. PMID:23207015

Thakuria, Ranjit; Delori, Amit; Jones, William; Lipert, Maya P; Roy, Lilly; Rodríguez-Hornedo, Naír

2013-08-30

357

In silico prediction of aqueous solubility.  

PubMed

The fundamentals of aqueous solubility, and the factors that affect it, are briefly outlined, followed by a short introduction to quantitative structure-property relationships. Early (pre-1990) work on aqueous solubility prediction is summarised, and a more detailed presentation and critical discussion are given of the results of most, if not all, of those published in silico prediction studies from 1990 onwards that have used diverse training sets. A table is presented of a number of studies that have used a 21-compound test set of drugs and pesticides to validate their aqueous solubility models. Finally, the results are given of a test of 15 commercially available software programs for aqueous solubility prediction, using a test set of 122 drugs with accurately measured aqueous solubilities. PMID:23506031

Dearden, John C

2006-06-01

358

Soluble minerals in chemical evolution  

NASA Astrophysics Data System (ADS)

The adsorption of 5'-AMP onto solid CaSO4 · 2H2O was studied in a saturated suspension as a function of pH and electrolyte concentration. The adsorption is pH-dependent and is directly correlated with the charge on the 5'-AMP molecule which is determined by the state of protonation of the N-1 nitrogen of the purine ring and the phosphate oxygens. It is proposed that the binding that occurs between the nucleotide and the salt is electrostatic in nature. The adsorption decreases with increasing ionic strength of the solution which means that in a fluctuating environment of wetting and drying cycles, a biomolecule similar to 5'-AMP could be expected to desorb during the drying phase. The results indicate that CaSO4 · 2H2O can serve as a concentrating surface for biomolecules. The significance of this is discussed with regard to the possible role of soluble minerals and their surfaces in a geochemical model consistent with the evolution of the Earth and the origin of life.

Orenberg, James B.; Chan, Stephen; Calderon, John; Lahav, Noam

1985-06-01

359

Water-soluble conductive polymers  

DOEpatents

Polymers which are soluble in water and are electrically conductive. The monomer repeat unit is a thiophene or pyrrole molecule having an alkyl group substituted for the hydrogen atom located in the beta position of the thiophene or pyrrole ring and having a surfactant molecule at the end of the alkyl chain. Polymers of this class having 8 or more carbon atoms in the alkyl chain exhibit liquid crystalline behavior, resulting in high electrical anisotropy. The monomer-to-monomer bonds are located between the carbon atoms which are adjacent to the sulfur or nitrogen atoms. The number of carbon atoms in the alkyl group may vary from 1 to 20 carbon atoms. The surfactant molecule consists of a sulfonate group, or a sulfate group, or a carboxylate group, and hydrogen or an alkali metal. Negative ions from a supporting electrolyte which may be used in the electrochemical synthesis of a polymer may be incorporated into the polymer during the synthesis and serve as a dopant to increase the conductivity.

Aldissi, Mahmoud (Sante Fe, NM)

1990-01-01

360

Soluble Thrombomodulin Protects Ischemic Kidneys  

PubMed Central

Altered coagulation and inflammation contribute to the pathogenesis of ischemic renal injury. Thrombomodulin is a necessary factor in the anticoagulant protein C pathway and has inherent anti-inflammatory properties. We studied the effect of soluble thrombomodulin (sTM) in a hypoperfusion model of ischemic kidney injury. To markedly reduce infrarenal aortic blood flow and femoral arterial pressures, we clamped the suprarenal aorta of rats, occluding them 90%, for 60 min. Reversible acute kidney injury (AKI) occurred at 24 h in rats subjected to hypoperfusion. Histologic analysis at 24 h revealed acute tubular necrosis (ATN), and intravital two-photon microscopy showed flow abnormalities in the microvasculature and defects of endothelial permeability. Pretreatment with rat sTM markedly reduced both I-R-induced renal dysfunction and tubular histologic injury scores. sTM also significantly improved microvascular erythrocyte flow rates, reduced microvascular endothelial leukocyte rolling and attachment, and minimized endothelial permeability to infused fluorescence dextrans, assessed by intravital quantitative multiphoton microscopy. Furthermore, sTM administered 2 h after reperfusion protected against ischemia-induced renal dysfunction at 24 h and improved survival. By using an sTM variant, we also determined that the protective effects of sTM were independent of its ability to generate activated protein C. These data suggest that sTM may have therapeutic potential for ischemic AKI.

Sharfuddin, Asif A.; Sandoval, Ruben M.; Berg, David T.; McDougal, Grant E.; Campos, Silvia B.; Phillips, Carrie L.; Jones, Bryan E.; Gupta, Akanksha; Grinnell, Brian W.; Molitoris, Bruce A.

2009-01-01

361

Synthesis, stability, and antimalarial activity of new hydrolytically stable and water-soluble (+)-deoxoartelinic acid.  

PubMed

(+)-Deoxoartelinic acid (13), a new hydrolytically stable, water-soluble, and potent non-acetal-type antimalarial drug candidate, was successfully prepared from artemisinic acid by using sulfur ylide and photooxygenative cyclization in seven steps. This compound showed superior in vitro antimalarial activity against the chloroquine-resistant K1 strain of Plasmodium falciparum and higher suppression (98.7%) than arteether in vivo against Plasmodium chabaudi infected mice. (+)-Deoxoartelinic acid also showed remarkable stability with a half-life of 258.66 h, 23 times more stable than clinically useful arteether in simulated stomach acid, and improved solubility, 4 times more soluble than artemisinin in water. PMID:12383020

Jung, Mankil; Lee, Kyunghoon; Kendrick, Howard; Robinson, Brian L; Croft, Simon L

2002-10-24

362

Controls of solubility parameter and crosslinking density in polyurethane acrylate based holographic polymer dispersed liquid crystal  

NASA Astrophysics Data System (ADS)

The effect of solubility parameter mismatch between liquid crystal (LC) and resin, and crosslinking density of resin phase on morphology and diffraction efficiency of holographic polymer dispersed liquid crystal (HPDLC) have seen systematically studied by varing the chemical structure of polyurethane acrylate resin with regard to the prepolymer molecular weight, type of diisocyanate, and functionality of reactive diluent. It has been found that with dissimilar chemical structure leading to large difference in solubility parameter between LC and resin, and with high crosslinking density under similar solubility parameter difference, fast formation of grating, large droplet size and high diffraction efficiency were generally obtained.

Jung, Ju Ai; Kim, Byung Kyu

2005-03-01

363

Optimization of diarylazines as anti-HIV agents with dramatically enhanced solubility.  

PubMed

Non-nucleoside inhibitors of HIV-1 reverse transcriptase are reported that have ca. 100-fold greater solubility than the structurally related drugs etravirine and rilpivirine, while retaining high anti-viral activity. The solubility enhancements come from strategic placement of a morpholinylalkoxy substituent in the entrance channel of the NNRTI binding site. Compound 4d shows low-nanomolar activity similar to etravirine towards wild-type HIV-1 and key viral variants. PMID:23937980

Bollini, Mariela; Cisneros, José A; Spasov, Krasimir A; Anderson, Karen S; Jorgensen, William L

2013-09-15

364

Influence of 2-phenyl alkane and tetralin content on solubility and viscosity of linear alkylbenzene sulfonate  

Microsoft Academic Search

Cloud and clear points and viscosities of linear alkylbenzene sulfonates (LAS) have been determined as a function of 2-phenyl\\u000a alkane and\\/or tetralin content over a wide interval. While the 2-phenyl content significantly affects the solubility, tetralins\\u000a have a marked depressive effect on viscosity. The investigation has established that LAS solubility can be explained by assuming\\u000a eutectic types of isomer and

L. Cohen; R. Vergara; A. Moreno; J. L. Berna

1995-01-01

365

Temperature Effects on Reactivity in Light Water Moderated U02 Cores with Soluble Poisons  

Microsoft Academic Search

Experimental and computational studies have been performed on the temperature coefficients of reactivity in light-water moderated and reflected UO2 cores with soluble poisons such as boron and gadolinium. Experiments were carried out using the Tank-type Critical Assembly (TCA) in Japan Atomic Energy Research Institute (JAERI). Temperature coefficients of the cores with soluble poisons were measured by changing the temperature of

Yoshinori MIYOSHI; Toshihiro YAMAMOTO; Takenori SUZAKI; Iwao KOBAYASHI

1992-01-01

366

Antiviral activities of various water and methanol soluble substances isolated from Ganoderma lucidum  

Microsoft Academic Search

In order to find antiviral substances from basidiomycetes, two water soluble substances, GLhw and GLlw, and eight methanol soluble substances, GLMe-1–8, were prepared from carpophores of Ganoderma lucidum. These substances were examined for their activities against five strains of pathogenic viruses such as herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), influenza A virus (Flu A) and vesicular stomatitis

Seong-Kug Eo; Young-So Kim; Chong-Kil Lee; Seong-Sun Han

1999-01-01

367

Synthesis and characterization of water-soluble two-photon excited blue fluorescent chromophores for bioimaging.  

PubMed

We report here the synthesis and characterization of a new type of non-ionic blue fluorescent water-soluble chromophores specifically designed for two-photon absorption microscopy. The water solubility is induced by introduction of short oligo(ethylene glycol) monomethyl ether moieties. This work has led to low molecular weight dyes with efficient two-photon absorption cross sections and high fluorescence quantum yield in organic solvents as well as in aqueous solutions. PMID:16395434

Hayek, Ali; Bolze, Frédéric; Nicoud, Jean-François; Baldeck, Patrice L; Mély, Yves

2006-01-01

368

Dynamic viscoelastic properties, water absorption, and solubility of home reliners.  

PubMed

Scant rheological information is available regarding home reliners (liner type denture adhesives). We evaluated 6 different home reliners in regard to their viscoelastic properties, water absorption and solubility. Dynamic viscoelastic properties and changes over time were determined using a dynamic viscoelastometer, while weight changes, absorption, and solubility during immersion in water were also investigated. We found that the dynamic viscoelasticity of the tested home reliners was sensitive to changes in frequency, while the materials used had nearly no elasticity and exhibited viscous behaviors. They showed a dramatic change in viscoelastic properties and increase in weight after approximately 1 day of water immersion. A considerably high percentage of water absorption was also observed. From the viewpoint of dynamic viscoelastic properties and durability, our results indicate that the tested home reliners would not be suitable for improvement of ill-fitting dentures. PMID:20733263

Murata, Hiroshi; Hong, Guang; Yamakado, Chiaki; Kurogi, Tadafumi; Kano, Hiroshi; Hamada, Taizo

2010-10-01

369

High shear treatment of concentrates and drying conditions influence the solubility of milk protein concentrate powders.  

PubMed

The solubility of milk protein concentrate (MPC) powders was influenced by the method used for preparing the concentrate, drying conditions, and the type of dryer used. Increasing total solids of the ultrafiltered concentrates (23% total solids, TS) by diafiltration to 25% TS or evaporation to 31% TS decreased the solubility of MPC powders (80-83% protein, w/w dry basis), with ultrafiltration followed by evaporation to higher total solids having the greater detrimental effect on solubility. High shear treatment (homogenisation at 350/100 bar, microfluidisation at 800 bar or ultrasonication at 24 kHz, 600 watts) of ultrafiltered and diafiltered milk protein concentrates prior to spray drying increased the nitrogen solubility of MPC powders (82% protein, w/w dry basis). Of the treatments applied, microfluidisation was the most effective for increasing nitrogen solubility of MPC powders after manufacture and during storage. Manufacture of MPC powders (91% protein, w/w dry basis) prepared on two different pilot-scale dryers (single stage or two stage) from milk protein concentrates (20% TS) resulted in powders with different nitrogen solubility and an altered response to the effects of microfluidisation. Microfluidisation (400, 800 and 1200 bar) of the concentrate prior to drying resulted in increased long term solubility of MPC powders that were prepared on a single stage dryer but not those produced on a two stage spray dryer. This work demonstrates that microfluidisation can be used as a physical intervention for improving MPC powder solubility. Interactions between the method of preparation and treatment of concentrate prior to drying, the drying conditions and dryer type all influence MPC solubility characteristics. PMID:22998771

Augustin, Mary Ann; Sanguansri, Peerasak; Williams, Roderick; Andrews, Helen

2012-11-01

370

21 CFR 520.1044c - Gentamicin sulfate soluble powder.  

Code of Federal Regulations, 2010 CFR

...2010-04-01 2010-04-01 false Gentamicin sulfate soluble powder. 520...NEW ANIMAL DRUGS § 520.1044c Gentamicin sulfate soluble powder. (a) Specifications. Each gram of gentamicin sulfate soluble powder...

2010-04-01

371

21 CFR 520.1044c - Gentamicin sulfate soluble powder.  

Code of Federal Regulations, 2010 CFR

...2009-04-01 2009-04-01 false Gentamicin sulfate soluble powder. 520...NEW ANIMAL DRUGS § 520.1044c Gentamicin sulfate soluble powder. (a) Specifications. Each gram of gentamicin sulfate soluble powder...

2009-04-01

372

21 CFR 520.110 - Apramycin sulfate soluble powder.  

Code of Federal Regulations, 2013 CFR

...2013-04-01 false Apramycin sulfate soluble powder. 520.110 Section 520.110 Food... § 520.110 Apramycin sulfate soluble powder. (a) Specifications. A water soluble powder used to make a medicated drinking...

2013-04-01

373

Water Soluble Derivatives of Frederimacycin A.  

National Technical Information Service (NTIS)

The present invention is related generally to fredericamycin A. More particularly, the present invention is related to new, water soluble, biologically active derivatives of fredericamycin A and a process for making the same.

R. Misra

1986-01-01

374

Soluble high molecular weight polyimide resins  

NASA Technical Reports Server (NTRS)

High molecular weight polyimide resins have greater than 20 percent /by weight/ solubility in polar organic solvents. They permit fabrication into films, fibers, coatings, reinforced composite, and adhesive product forms. Characterization properties for one typical polyimide resin are given.

Jones, R. J.; Lubowitz, H. R.

1970-01-01

375

An Introduction to the Understanding of Solubility.  

ERIC Educational Resources Information Center

Explores different solubility processes and related issues, including the second law of thermodynamics and ideal mixtures, real liquids, intermolecular forces, and solids in liquids or gases in liquids. (Contains 22 references.) (ASK)

Letcher, Trevor M.; Battino, Rubin

2001-01-01

376

Water Solubility Behavior of Binary Hydrocarbon Mixtures.  

National Technical Information Service (NTIS)

The aqueous solubility equilibrium behavior of seven medium molecular weight, liquid, binary hydrocarbon mixtures has been determined at 20 C. Binary hydrocarbon mixtures containing structurally similar compounds exhibited ideal solution behavior, but dev...

D. R. Burris W. G. MacIntyre

1985-01-01

377

THE SOLUBILITY OF LEAD IN LIQUID IRON  

Microsoft Academic Search

Measurements of the solubility of lead in liquid iron were made at 1550, ; 1600, 1650, and 1700 deg C using two different methods: liquid iron-liquid lead ; equilibration and liquid iron-lead vapor equilibration. (auth);

A. E. Lord; N. A. Parlee

1960-01-01

378

Water-Soluble Polyphosphazenes and Their Hydrogels.  

National Technical Information Service (NTIS)

Water-soluble polymers and hydrogels are important in areas as varied as biomedicine adhesion, membranes, and viscosity enhancement. They are possible replacements in technology and medicine for many naturally-occurring polymers. Unfortunately, relatively...

H. R. Allcock

1994-01-01

379

Enamel Solubility Reduction by Stannous Hexafluorozirconate.  

National Technical Information Service (NTIS)

Solutions of stannous fluoride, solutions of stannous hexafluorozirconate, and solutions of stannous fluoride plus zirconium fluoride were compared as to their ability to reduce enamel solubility. All solutions were so prepared as to contain tin in amount...

I. L. Shannon V. A. Segreto

1969-01-01

380

Solubility of Injectable Valium in Intravenous Solutions.  

National Technical Information Service (NTIS)

A study of the solubility of Valium in commonly used intravenous solutions showed Valium to be equally insoluble in 5% dextrose in saline, normal saline, and Ringer's lactate. However, the precipitate which was formed became completely resuspended when mi...

M. F. Grower E. A. Russell L. Getter

1978-01-01

381

Studies on Plasma Soluble Fluorescent Melanins.  

National Technical Information Service (NTIS)

Plasma soluble fluroescent compounds termed rheomelanins have been isolated using paper chromatography. The fluorescent characteristic of these compounds ally them with tissue lipofuscins. Chemical composition studies using modified tissue lipofuscin hist...

S. H. Kuttab

1979-01-01

382

The Solubility of Phenylborate Compounds in Benzene  

SciTech Connect

The original goal of this scoping study was to determine if the solubility of sodium and potassium tetraphenylborates in benzene was sufficiently large to justify designing and performing kinetic studies on a benzene-phase catalytic reaction.

Eibling, R.E. [Westinghouse Savannah River Company, AIKEN, SC (United States)

1998-04-01

383

Correlation of Helium Solubility in Liquid Nitrogen  

NASA Technical Reports Server (NTRS)

A correlation has been developed for the equilibrium mole fraction of soluble gaseous helium in liquid nitrogen as a function of temperature and pressure. Experimental solubility data was compiled and provided by National Institute of Standards and Technology (NIST). Data from six sources was used to develop a correlation within the range of 0.5 to 9.9 MPa and 72.0 to 119.6 K. The relative standard deviation of the correlation is 6.9 percent.

VanDresar, Neil T.; Zimmerli, Gregory A.

2012-01-01

384

Hydrogen solubility in garnet at high pressures  

NASA Astrophysics Data System (ADS)

Garnet is the most important secondary mineral whose fraction ranges from ~ 20% in the shallow upper mantle for the pyrolite model to ~ 80% in the transition zone for the piclogite model. Therefore understanding the solubility and dissolution mechanisms of hydrogen in garnet is important for water budget as well as for understanding plastic properties of the mantle. However, there is little consensus on the solubility and dissolution mechanisms of hydrogen in garnet. For example, under deep upper mantle conditions (P>7 GPa), Withers et al. (1998) concluded virtually no hydrogen solubility in pyrope whereas Lu and Keppler (1997) showed small hydrogen solubility (~ 200 ppm wt of H2O). In order to address possible causes of such discrepancy, we have initiated a systematic study on hydrogen solubility under a broad range of pressure and controlled chemical environment. In contrast with the previous study, preliminary results indicate that natural garnet crystal surrounded by powder of olivine, orthopyroxene and clinopyroxene, could host around 1000 ppm wt of H2O at 9 GPa and 1100 °C conditions. Possible interpretation is that the enrichment of hydrogen is due to the increased Mg/Si ratio (activity of MgO) due to the coexistence of garnet with olivine. If hydrogarnet substitution (O4H4) is the dominant mechanism of hydrogen dissolution, then the increase in the activity of MgO will increase the hydrogen solubility. Further experiments are performed (i) to investigate the hydrogen solubility under deep upper mantle conditions (P=6-9 GPa T=1373-1573 K) where the previous results have a major discrepancy, and (ii) to investigate the kinetics and the influence of oxide buffer on hydrogen solubility.

Mookherjee, M.; Karato, S.-

2007-12-01

385

Solubilities of phenols in supercritical carbon dioxide  

SciTech Connect

Equilibrium solubilities of pure anthracene at 50 C, 1-naphthol at 35, 45, and 55 C, and hydroquinone at 35 and 45 C in supercritical carbon dioxide over a pressure range of about 85--300 bar have been measured using a supercritical fluid extractor coupled with an external high-pressure liquid chromatographer. The solubility results, along with those for other phenols reported in the literature, are correlated with the translated-modified Peng Robinson equation of state.

Coutsikos, P.; Magoulas, K.; Tassios, D. [National Technical Univ. of Athens (Greece)

1995-07-01

386

Serum soluble fas levels in ovarian cancer  

Microsoft Academic Search

Objective: To determine the value of serum soluble Fas levels as a prognostic marker for survival of women with ovarian cancer and as a discriminator between benign and malignant adnexal masses.Methods: Serum soluble Fas levels were measured with an enzyme-linked immunosorbent assay in 52 women with ovarian cancer, 30 women with benign ovarian cysts, and 35 healthy women.Results: Median serum

Lukas Hefler; Klaus Mayerhofer; Alessandra Nardi; Alexander Reinthaller; Christian Kainz; Clemens Tempfer

2000-01-01

387

Solubility of red phosphorus in molten lead  

Microsoft Academic Search

The solubility in molten lead of P4(g) generated by red phosphorus was measured by means of a two-zone isopiestic technique. The solubility of phosphorus vapor increases with temperatureT,especially atT> 800 K. Linear regression analysis of the results was used to determine the infinite-dilution activity coefficient and first-order interaction coefficient for hypothetical liquid phosphorus dissolved in liquid lead.

Sean E. Walker; Mark E. Schlesinger

1995-01-01

388

Metastable Equilibrium Solubility Behavior of Bone Mineral  

Microsoft Academic Search

.   Previous studies have shown that carbonated apatites with a range of carbonate contents and crystallinities exhibit the phenomenon\\u000a of metastable equilibrium solubility (MES) distributions. The purpose of the present study was to investigate the solubility\\u000a behavior of bone mineral using the concepts of MES and MES distributions and, together with crystallinity and chemical composition\\u000a data, examine the similarity of

A. A. Baig; J. L. Fox; Z. Wang; W. I. Higuchi; S. C. Miller; A. M. Barry; M. Otsuka

1999-01-01

389

Solubility of nitrous oxide in amine solutions  

Microsoft Academic Search

The solubility of nitrous oxide (NâO) in 13 amine solvents and solutions was correlated to amine mole fractions and temperature using feedforward neural networks. This general correlation, using a massive database, predicted NâO solubility at temperatures between 283 and 398 K in pure solvents [HâO, monoethanolamine (MEA), diethanolamine (DEA), methyldiethanolamine (MDEA), and 2-amino-2-methyl-1-propanolamine (AMP)], in binary aqueous amine solutions [HâO\\/MEA,

Z. Bensetiti; I. Iliuta; F. Larachi; B. P. A. Grandjean

1999-01-01

390

Evaluation of anti-wear performance of PFPE-soluble additives under sliding contact in high vacuum  

SciTech Connect

The anti-wear performances of perfluoropolyether (PEPE)-soluble additives were evaluated under vacuum using a vacuum four-ball tribometer with 440C stainless steel balls as test specimens. PEPE derivatives having the hydroxyl, carboxyl and phosphate groups at the end of the Type D-PEPE molecules were studied. The addition of either PEPE-soluble carboxylic acid or PEPE-soluble phosphates to the PEPE base oil remarkably reduced steady wear rates in a vacuum environment, whereas the addition of PEPE-soluble alcohol did not. Contrary to the performance in vacuum, an appreciable increase in wear rate was observed in the air atmosphere with all the types of additives used. The effect of moisture is studied in explaining the high wear rates obtained with the additives in the air environment. The mechanism of boundary lubrication with PEPE-soluble additives is discussed.

Masuko, M.; Takeshita, N.; Okabe, H. [Tokyo Institute of Technology, Tokyo (Japan)

1995-07-01

391

Soluble microbial products (SMP) and soluble extracellular polymeric substances (EPS) from wastewater sludge.  

PubMed

Laspidou and Rittmann (Water Research 36:2711-2720, 2002) proposed that the soluble extracellular polymeric substances (EPS) are identical to soluble microbial products (SMP) in sludge liquor. In this paper, we compared the physicochemical characteristics of the SMP and soluble EPS from original and aerobically or anaerobically digested wastewater sludge. The surface charges, particle sizes, residual turbidities of polyaluminum chloride (PACl) coagulated supernatant, and chemical compositions of the SMP and soluble EPS containing suspensions were used as comparison index. Experimental results revealed that the particles in SMP and soluble EPS fractions extracted from original wastewater sludge, before and after digestion, were not identical in all physicochemical characteristics herein measured. The current test cannot support the proposal by Laspidou and Rittmann (Water Research 36:2711-2720, 2002) that SMP is identical to the soluble EPS from a wastewater sludge. PMID:16791591

Ramesh, A; Lee, Duu-Jong; Hong, S G

2006-11-01

392

Gadolinium Solubility in Peraluminous Borosilicate Glasses  

SciTech Connect

This paper discussed the results of a study, using 18 peraluminous (Na/Al <1) borosilicate glasses, to understand the effect of glass composition on gadolinium solubility. Above Gd solubility, liquid-liquid phase separation occurs in some of the glasses; in others, sodium gadolinium silicate crystallizes. For the samples in which liquid-liquid phase separation occurs, Gd solubility is determined by the concentration of excess Al (i.e., [AlO1.5]-[NaO0.5]-0.2*[BO1.5]). Increasing excess Al increases Gd solubility. For the samples in which sodium gadolinium silicate crystallizes, Gd solubility is determined by the concentration of Na. Increasing Na decreases Gd solubility. When the Al concentration in the baseline glass is high, a minimum amount of Gd is needed to form a clear glass. Otherwise, mullite crystallizes. The minimum concentration of Gd is determined by the [AlO1.5]-[NaO0.5]-[BO1.5] value in the melt. The higher this value is, the more Gd is needed to form a clear glass. In general, the solution behavior of Gd in peraluminous borosilicate melt is similar to that in peralkaline borosilicate melt, and is mostly determined by the ratio of excess Al to equivalent B in the melt.

Li, Liyu; Li, Hong; Qian, Maoxu; Strachan, Denis M.

2001-03-05

393

Solubility of uranium in alkaline salt solutions  

SciTech Connect

The solubility of uranium in alkaline salt solutions was investigated to screen for significant factors and interactions among the major salt components and temperature. The components included in the study were the sodium salts of hydroxide, nitrate, nitrite, aluminate, sulfate, and carbonate. General findings from the study included: (1) uranium solubilities are very low (1-20 mg/L) for all solution compositions at hydroxide concentrations from 0.1 to 17 molar (2) carbonate, sulfate, and aluminate are not effective complexants for uranium at high hydroxide concentration, (3) uranium solubility decreases with increasing temperature for most alkaline salt solutions, and (4) uranium solubility increases with changes in solution chemistry that reflect aging of high level waste (increase in nitrite and carbonate concentrations, decrease in nitrate and hydroxide concentrations). A predictive model for the concentration of uranium as a function of component concentrations and temperature was fitted to the data. All of the solution components and temperature were found to be significant. There is a significant lack of fit for the model, which suggests that the dependence on the uranium solubility over the wide range of solution compositions is non-linear and/or that there are other uncontrolled parameters which are important to the uranium solubility.

Hobbs, D.T.; Edwards, T.B.

1994-03-29

394

Sibutramine characterization and solubility, a theoretical study  

NASA Astrophysics Data System (ADS)

Solubility data from sibutramine (SBA) in a family of alcohols were obtained at different temperatures. Sibutramine was characterized by using thermal analysis and X-ray diffraction technique. Solubility data were obtained by the saturation method. The van't Hoff equation was used to obtain the theoretical solubility values and the ideal solvent activity coefficient. No polymorphic phenomena were found from the X-ray diffraction analysis, even though this compound is a racemic mixture of (+) and (-) enantiomers. Theoretical calculations showed that the polarisable continuum model was able to reproduce the solubility and stability of sibutramine molecule in gas phase, water and a family of alcohols at B3LYP/6-311++G (d,p) level of theory. Dielectric constant, dipolar moment and solubility in water values as physical parameters were used in those theoretical calculations for explaining that behavior. Experimental and theoretical results were compared and good agreement was obtained. Sibutramine solubility increased from methanol to 1-octanol in theoretical and experimental results.

Aceves-Hernández, Juan M.; Nicolás Vázquez, Inés; Hinojosa-Torres, Jaime; Penieres Carrillo, Guillermo; Arroyo Razo, Gabriel; Miranda Ruvalcaba, René

2013-04-01

395

Structural characterization of cleaved, soluble HIV-1 envelope glycoprotein trimers.  

PubMed

Human immunodeficiency virus type 1 (HIV-1) infection is a significant global public health problem for which development of an effective prophylactic vaccine remains a high scientific priority. Many concepts for a vaccine are focused on induction of appropriate titers of broadly neutralizing antibodies (bNAbs) against the viral envelope (Env) glycoproteins gp120 and gp41, but no immunogen has yet accomplished this goal in animals or humans. One approach to induction of bNAbs is to design soluble, trimeric mimics of the native viral Env trimer. Here, we describe structural studies by negative-stain electron microscopy of several variants of soluble Env trimers based on the KNH1144 subtype A sequence. These Env trimers are fully cleaved between the gp120 and gp41 components and stabilized by specific amino acid substitutions. We also illustrate the structural consequences of deletion of the V1/V2 and V3 variable loops from gp120 and the membrane-proximal external region (MPER) from gp41. All of these variants adopt a trimeric configuration that appropriately mimics native Env spikes, including the CD4 receptor-binding site and the epitope for the VRC PG04 bNAb. These cleaved, soluble trimer designs can be adapted for use with multiple different env genes for both vaccine and structural studies. PMID:23824817

Khayat, Reza; Lee, Jeong Hyun; Julien, Jean-Philippe; Cupo, Albert; Klasse, Per Johan; Sanders, Rogier W; Moore, John P; Wilson, Ian A; Ward, Andrew B

2013-09-01

396

Structural Characterization of Cleaved, Soluble HIV-1 Envelope Glycoprotein Trimers  

PubMed Central

Human immunodeficiency virus type 1 (HIV-1) infection is a significant global public health problem for which development of an effective prophylactic vaccine remains a high scientific priority. Many concepts for a vaccine are focused on induction of appropriate titers of broadly neutralizing antibodies (bNAbs) against the viral envelope (Env) glycoproteins gp120 and gp41, but no immunogen has yet accomplished this goal in animals or humans. One approach to induction of bNAbs is to design soluble, trimeric mimics of the native viral Env trimer. Here, we describe structural studies by negative-stain electron microscopy of several variants of soluble Env trimers based on the KNH1144 subtype A sequence. These Env trimers are fully cleaved between the gp120 and gp41 components and stabilized by specific amino acid substitutions. We also illustrate the structural consequences of deletion of the V1/V2 and V3 variable loops from gp120 and the membrane-proximal external region (MPER) from gp41. All of these variants adopt a trimeric configuration that appropriately mimics native Env spikes, including the CD4 receptor-binding site and the epitope for the VRC PG04 bNAb. These cleaved, soluble trimer designs can be adapted for use with multiple different env genes for both vaccine and structural studies.

Khayat, Reza; Lee, Jeong Hyun; Julien, Jean-Philippe; Cupo, Albert; Klasse, Per Johan; Sanders, Rogier W.; Moore, John P.; Wilson, Ian A.

2013-01-01

397

Solubility effects in waste-glass/demineralized-water systems  

SciTech Connect

Aqueous systems involving demineralized water and four glass compositions (including standins for actinides and fission products) at temperatures of up to 150/sup 0/C were studied. Two methods were used to measure the solubility of glass components in demineralized water. One method involved approaching equilibrium from subsaturation, while the second method involved approaching equilibrium from supersaturation. The aqueous solutions were analyzed by induction-coupled plasma spectrometry (ICP). Uranium was determined using a Scintrex U-A3 uranium analyzer and zinc and cesium were determined by atomic absorption. The system that results when a waste glass is contacted with demineralized water is a complex one. The two methods used to determine the solubility limits gave very different results, with the supersaturation method yielding much higher solution concentrations than the subsaturation method for most of the elements present in the waste glasses. The results show that it is impossible to assign solubility limits to the various glass components without thoroughly describing the glass-water systems. This includes not only defining the glass type and solution temperature, but also the glass surface area-to-water volume ratio (S/V) of the system and the complete thermal history of the system. 21 figures, 22 tables. (DLC)

Fullam, H.T.

1981-06-01

398

Solubility Prediction of Satranidazole in Aqueous N,N-dimethylformamide Mixtures Using Extended Hildebrand Solubility Approach  

PubMed Central

The solubility of satranidazole in several water–N,N-dimethylformamide mixtures was analysed in terms of solute–solvent interactions and data were treated on the basis of extended Hildebrand solubility approach. The solubility profile of satranidazole in water–N,N-dimethylformamide mixtures shows a curve with a solubility maxima well above the ideal solubility of drug. This is attributed to solvation of the drug with the water–N,N-dimethylformamide mixture, and indicates that the solute–solvent interaction energy (W) is larger than the geometric mean (?1?2) of regular solution theory. The new approach provides an accurate prediction of solubility once the interaction energy (W) is obtained. In this case, the energy term is regressed against a polynomial in ?1 of the binary solvent mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the mole fraction solubility of satranidazole in the studied mixtures. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design.

Rathi, P. B.; Mourya, V. K.

2012-01-01

399

Hydroxypropyl-beta-cyclodextrin increases aqueous solubility and stability of anandamide.  

PubMed

Anandamide (arachidonylethanolamide; AEA) is an endogenous ligand for the cannabinoid receptor and its pharmacological effects are under intensive study. However, AEA has a low aqueous solubility and stability which may restrict its use and may eventually endanger the reliability of the obtained results. In the present study, it was found that AEA forms inclusion complexes with cyclodextrins (CDs), resulting in greater aqueous solubility and stability of AEA as AEA/CD complex. Aqueous solubility increased 1 000 to 30 000-fold, depending on the type of CD (10% solution) used. The half-life of AEA in aqueous hydroxypropyl-beta-cyclodextrin solution (10%) at 50 degree C was 2.9 years. These results suggest that CD-technology will be a very useful method to overcome the solubility and stability problems of AEA. PMID:8602110

Jarho, P; Urtti, A; Järvinen, K; Pate, D W; Järvinen, T

1996-01-01

400

Dissolution rate and apparent solubility of poorly soluble drugs in biorelevant dissolution media.  

PubMed

A series of poorly soluble BCS class II compounds with "grease ball" characteristics were assessed for solubility and dissolution rate in biorelevant dissolution media (BDM) with the purpose of investigating which molecular structures gain most in solubility when dissolved under physiologically relevant conditions. The compounds were studied in four media (simulated intestinal fluid in fasted (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0), and their corresponding blank buffers (FaSSIF(blk) and FeSSIF(blk))) at a temperature of 37 °C. The experimental results were used to analyze which molecular characteristics are of importance for the solubility in BDM and for in silico modeling using multivariate data analysis. It was revealed that a majority of the compounds exhibited a higher dissolution rate and higher solubility in the FaS