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1

A soluble activin Type IIA receptor induces bone formation and improves skeletal integrity  

Microsoft Academic Search

Diseases that affect the regulation of bone turnover can lead to skeletal fragility and increased fracture risk. Members of the TGF-beta superfamily have been shown to be involved in the regulation of bone mass. Activin A, a TGF-beta signaling ligand, is present at high levels in bone and may play a role in the regulation of bone metabolism. Here we

R. Scott Pearsall; Ernesto Canalis; Milton Cornwall-Brady; Kathryn W. Underwood; Brendan Haigis; Jeffrey Ucran; Ravindra Kumar; Eileen Pobre; Asya Grinberg; Eric D. Werner; Vaida Glatt; Lisa Stadmeyer; Deanna Smith; Jasbir Seehra; Mary L. Bouxsein

2008-01-01

2

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

3

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

2012-09-24

4

Activins bind and signal via bone morphogenetic protein receptor type II (BMPR2) in immortalized gonadotrope-like cells.  

PubMed

TGF? superfamily ligands greatly outnumber their receptors. Thus, receptors are shared between ligands and individual ligands can bind multiple receptors. Bone morphogenetic proteins (BMPs) bind and signal via both BMP type II (BMPR2) and activin type II (ACVR2) receptors. We hypothesized that, in addition to its canonical receptor ACVR2, activin A might similarly bind and signal via BMPR2. First, using surface plasmon resonance, we showed that activin A binds to the BMPR2 extracellular domain (ECD), though with lower affinity compared to the ACVR2-ECD. We confirmed these results in cells, where radiolabeled activin A bound to ACVR2 and BMPR2, but not to other type II receptors (AMHR2 or TGFBR2). Using homology modeling and site-directed mutagenesis, we identified key residues in BMPR2 that mediate its interaction with activin A. The soluble ECDs of ACVR2 or BMPR2 dose-dependently inhibited activin A-, but not TGF?-induced signaling in cells, suggesting that activin binding to BMPR2 could have functional consequences. To address this idea, we altered BMPR2 expression levels in immortalized murine gonadotrope-like cells, L?T2, in which activins potently stimulate follicle-stimulating hormone ? (Fshb) subunit transcription. BMPR2 expression potentiated activin A responses whereas depletion of endogenous BMPR2 with short interfering RNAs attenuated activin A-stimulated Fshb transcription. Additional data suggest, for the first time, that BMPR2 may form functional complexes with the canonical activin type I receptor, activin receptor-like kinase 4. Collectively, our data show that BMPR2, along with ACVR2, functions as a bona fide activin type II receptor in gonadotrope-like cells, thereby broadening our understanding of mechanisms of activin action. PMID:24018044

Rejon, Carlis A; Hancock, Mark A; Li, Yining N; Thompson, Thomas B; Hébert, Terence E; Bernard, Daniel J

2013-09-07

5

Activin-A up-regulates type I activin receptor mRNA levels in human immortalized extravillous trophoblast cells  

Microsoft Academic Search

Activin is known to play an important regulatory role in reproduction, including pregnancy. To further examine the role and signaling mechanism of activin in regulating placental function, the steady-state level of activin type I receptor (ActRI) mRNA in immortalized extravillous trophoblasts (IEVT) cells was measured using competitive PCR (cPCR). An internal standard of ActRI cDNA for cPCR was constructed for

Victor TS Chen; Chun Peng; Peter CK Leung

2003-01-01

6

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

2010-04-12

7

Characterization of the Ligand Binding Functionality of the Extracellular Domain of Activin Receptor Type IIB  

PubMed Central

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 Leu79 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.

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

2010-01-01

8

Gonadotropin regulation of activin betaA and activin type IIA receptor expression in the ovarian follicle cells of the zebrafish, Danio rerio.  

PubMed

We have previously demonstrated that both activin and its receptors are expressed in the zebrafish ovary, suggesting paracrine roles for activin in the ovarian functions. Activin significantly stimulated zebrafish oocyte maturation in vitro, and this effect could be blocked by follistatin, an activin-binding protein. Interestingly, follistatin also blocked the stimulatory effect of gonadotropin (hCG) on the oocyte maturation. Taken together, these results have led to a hypothesis that the ovarian activin system may play a role in mediating the actions of gonadotropin in the ovary. To test this hypothesis, the present study was undertaken to investigate if gonadotropin has any effect on the expression of activin betaA subunit and activin type IIA (ActRIIA) receptor in the zebrafish ovary. A primary culture of zebrafish ovarian follicle cells was established in the present study, and the cultured cells expressed both activin betaA and ActRIIA receptor when assayed with RT-PCR. The primary culture consisted of three major types of cells, presumably the fibroblasts, the thecal cells and the granulosa cells, according to the morphological features, histochemical staining for 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and RT-PCR for aromatase. Using a semi-quantitative RT-PCR with beta-actin as the internal control, we demonstrated that hCG significantly stimulated mRNA expression of both activin betaA and ActRIIA receptor in the cultured follicle cells in a time- and dose-dependent manner. Treatment of the cells with hCG quickly increased the steady-state mRNA levels of activin betaA and ActRIIA receptor, and the effect peaked at 2 h of treatment. The stimulatory effect of gonadotropin diminished with longer treatment and no effect was observed at 8 h of treatment. The effect of hCG also exhibited strong dose dependence when assayed at 2 h of treatment. The levels of activin betaA and ActRIIA receptor mRNA elevated with increasing dose of hCG; however, the effect significantly decreased at dosage higher than 15 IU/ml. Consistent with the stimulatory effect of gonadotropin on the expression of activin betaA and ActRIIA receptor, IBMX, forskolin and 8-Br-cAMP all significantly increased the mRNA levels of activin betaA and ActRIIA receptor. These results suggest that gonadotropin activates the activin system in the zebrafish ovary by increasing the expression of both activin and its receptors. PMID:11911957

Pang, Yefei; Ge, Wei

2002-02-25

9

Alantolactone inhibits cell proliferation by interrupting the interaction between Cripto-1 and activin receptor type II A in activin signaling pathway.  

PubMed

It has been suggested that deregulation of activin signaling contributes to tumor formation. Activin signaling is blocked in cancer cells due to the complex formed by Cripto-1, activin, and activin receptor type II (ActRII). In this study, the authors used a mammalian two-hybrid system to construct a drug screening model to obtain a small molecular inhibitor capable of interrupting the interaction between Cripto-1 and ActRII. They screened 300 natural components and identified alantolactone. Data suggested that alantolactone induced activin/SMAD3 signaling in human colon adenocarcinoma HCT-8 cells. The authors also found that alantolactone exhibited antiproliferative function specific to tumor cells, with almost no toxicity to normal cells at a concentration of 5 µg/mL. Furthermore, they proved that the antiproliferative function of alantolactone was activin/SMAD3 dependent. These results suggest that alantolactone performs its antitumor effect by interrupting the interaction between Cripto-1 and the activin receptor type IIA in the activin signaling pathway. Moreover, screening for inhibitors of Cripto-1/ActRII is a potentially beneficial approach to aid in discovering novel cancer treatment. PMID:21378277

Shi, Ying; Bao, Yong Li; Wu, Yin; Yu, Chun Lei; Huang, Yan Xin; Sun, Ying; Zheng, Li Hua; Li, Yu Xin

2011-03-04

10

Correlation between Blood Activin Levels and Clinical Parameters of Type 2 Diabetes  

PubMed Central

Aims. Activins A and B, and their binding protein, follistatin, regulate glucose metabolism and inflammation. Consequently, their role in type 2 diabetes (T2D) was examined. Methods. Blood was taken from fasted participants (34 males; 58 females; 50–75 years) with diabetes or during an oral glucose tolerance test (OGTT). Clinical parameters were assessed, and blood assayed for activins, follistatin, and C-reactive protein. Results. Serum levels of activin A (93.3 ± 27.0?pg/mL, mean ± SD), B (81.8 ± 30.8?pg/mL), or follistatin (6.52 ± 3.15?ng/mL) were not different (P > 0.05) between subjects with normal OGTT (n = 39), impaired glucose tolerance and/or fasting glucose (n = 17), or T2D (n = 36). However, activin A and/or activin B were positively correlated with parameters of insulin resistance and T2D, including fasting glucose (P < 0.001), fasting insulin (P = 0.02), glycated hemoglobin (P = 0.003), and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.001). Follistatin was positively correlated with HOMA-IR alone (P = 0.01). Conclusions. These data indicate that serum measurements of activin A, B, or follistatin cannot discriminate risk for T2D in individual patients, but the activins display a positive relationship with clinical parameters of the disease.

Wu, Hui; Wu, Michael; Chen, Yi; Allan, Carolyn A.; Phillips, David J.; Hedger, Mark P.

2012-01-01

11

Activin A, activin receptor type II, nodal, and cripto mRNA are expressed by eutopic and ectopic endometrium in women with ovarian endometriosis.  

PubMed

Activin A is a dimeric protein that regulates endometrial functions by signaling at its receptors, namely type I (ActRI) and type II (ActRII). Nodal is an activin competitor that requires the coreceptor cripto to assemble its signaling pathway through ActRI and ActRII. In the current study, we evaluated the expression of activin A, ActRII, nodal, and cripto in eutopic and ectopic endometrium collected from women with ovarian endometrioma (n = 15) and in eutopic endometrium of healthy participants (n = 15). Eutopic endometrial samples were evaluated according to the stage of menstrual cycle. Total RNA was extracted from tissue homogenates and analyzed by real-time polymerase chain reaction (PCR). Activin A messenger RNA (mRNA) expression in eutopic endometrium of patients with endometriosis was significantly higher than in controls (P < .001) with a 10.2-fold and 7.3-fold increase in the proliferative and secretory phases, respectively. ActRII and nodal mRNA expression were found to be similar in patients with and without endometriosis, while cripto mRNA was markedly lower in eutopic (fold change = 0.03 at proliferative phase, P < .001) and ectopic endometrium (fold change = 0.14, P < .001) of women with endometriosis compared with eutopic endometrium from healthy controls. In conclusion, the altered endometrial expression of activin A and cripto during the menstrual cycle and the differences observed in the endometriotic tissue support the involvement of the activin system in endometrial changes of women with endometriosis. PMID:19386982

Torres, Paulo B; Florio, Pasquale; Galleri, Letizia; Reis, Fernando M; Borges, Lavinia E; Petraglia, Felice

2009-04-22

12

Gonadotropin regulation of activin ?A and activin type IIA receptor expression in the ovarian follicle cells of the zebrafish, Danio rerio  

Microsoft Academic Search

We have previously demonstrated that both activin and its receptors are expressed in the zebrafish ovary, suggesting paracrine roles for activin in the ovarian functions. Activin significantly stimulated zebrafish oocyte maturation in vitro, and this effect could be blocked by follistatin, an activin-binding protein. Interestingly, follistatin also blocked the stimulatory effect of gonadotropin (hCG) on the oocyte maturation. Taken together,

Yefei Pang; Wei Ge

2002-01-01

13

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

14

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

15

Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5.  

PubMed

Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the TGF-beta superfamily that includes TGF-beta, activin, and bone morphogenetic proteins (BMPs). GDF-9 is indispensable for the development of ovarian follicles from the primary stage, and treatment with GDF-9 enhances the progression of early follicles into small preantral follicles. Similar to other TGF-beta family ligands, GDF-9 likely initiates signaling mediated by type I and type II receptors with serine/threonine kinase activity, followed by the phosphorylation of intracellular transcription factors named Smads. We have shown previously that GDF-9 interacts with the BMP type II receptor (BMPRII) in granulosa cells, but the type I receptor involved is unknown. Using P19 cells, we now report that GDF-9 treatment stimulated the CAGA-luciferase reporter known to be responsive to TGF-beta mediated by the type I receptor, activin receptor-like kinase (ALK)5. In contrast, GDF-9 did not stimulate BMP-responsive reporters. In addition, treatment with GDF-9 induced the phosphorylation of Smad2 and Smad3 in P19 cells, and the stimulatory effect of GDF-9 on the CAGA-luciferase reporter was blocked by the inhibitory Smad7, but not Smad6. We further reconstructed the GDF-9 signaling pathway using Cos7 cells that are not responsive to GDF-9. After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay. The roles of ALK5 and downstream pathway genes in mediating GDF-9 actions were further tested in ovarian cells. In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3. Furthermore, transfection with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 actions. In conclusion, although GDF-9 binds to the BMP-activated type II receptor, its downstream actions are mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins. Because ALK5 is a known receptor for TGF-beta, diverse members of the TGF-beta family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways. PMID:14684852

Mazerbourg, Sabine; Klein, Cynthia; Roh, Jaesook; Kaivo-Oja, Noora; Mottershead, David G; Korchynskyi, Olexander; Ritvos, Olli; Hsueh, Aaron J W

2003-12-18

16

Activins and activin antagonists in hepatocellular carcinoma  

PubMed Central

In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor ? (TGF?) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo- or heterodimers formed from four different ? subunits termed ?A, ?B, ?C, and ?E, respectively. Activin A, the dimer of two ?A subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

Deli, Alev; Kreidl, Emanuel; Santifaller, Stefan; Trotter, Barbara; Seir, Katja; Berger, Walter; Schulte-Hermann, Rolf; Rodgarkia-Dara, Chantal; Grusch, Michael

2008-01-01

17

Activins and activin antagonists in the prostate and prostate cancer.  

PubMed

Activins are members of the TGF-? super-family. There are 4 mammalian activin subunits (?(A), ?(B), ?(C) and ?(E)) that combine to form functional proteins. The role of activin A (?(A)?(A)) is well characterized and known to be a potent growth and differentiation factor. Two of the activin subunits (?(C) and ?(E)) were discovered more recently and little is known about their biological functions. In this review the evidence that activin-?(C) is a significant regulator of activin A bioactivity is presented and discussed. It is concluded that activin-?(C), like other antagonists of activin A, is an important growth regulator in prostate health and disease. PMID:21787836

Gold, Elspeth; Risbridger, Gail

2011-07-20

18

Activin A Promotes Neuronal Differentiation of Cerebrocortical Neural Progenitor Cells  

PubMed Central

Background Activin A is a protein that participates principally in reproductive functions. In the adult brain, Activin is neuroprotective, but its role in brain development is still elusive. Methodology/Principal Findings We studied if Activin A influences proliferation, differentiation or survival in rat cerebrocortical neural progenitor cells (NPC). After stimulation of NPC with Activin A, phosphorylation and nuclear translocation of Smad 2/3 were induced. In proliferating NPC, Activin produced a significant decrease in cell area and also a discrete increase in the number of neurons in the presence of the mitogen Fibroblast Growth Factor 2. The percentages of cells incorporating BrdU, or positive for the undifferentiated NPC markers Nestin and Sox2, were unchanged after incubation with Activin. In differentiating conditions, continuous treatment with Activin A significantly increased the number of neurons without affecting astroglial differentiation or causing apoptotic death. In cells cultured by extended periods, Activin treatment produced further increases in the proportion of neurons, excluding premature cell cycle exit. In clonal assays, Activin significantly increased neuronal numbers per colony, supporting an instructive role. Activin-induced neurogenesis was dependent on activation of its receptors, since incubation with the type I receptor inhibitor SB431542 or the ligand-trap Follistatin prevented neuronal differentiation. Interestingly, SB431542 or Follistatin by themselves abolished neurogenesis and increased astrogliogenesis, to a similar extent to that induced by Bone Morphogenetic Protein (BMP)4. Co-incubation of these Activin inhibitors with the BMP antagonist Dorsomorphin restored neuronal and astrocytic differentiation to control levels. Conclusions Our results show an instructive neuronal effect of Activin A in cortical NPC in vitro, pointing out to a relevant role of this cytokine in the specification of NPC towards a neuronal phenotype.

Rodriguez-Martinez, Griselda; Molina-Hernandez, Anayansi; Velasco, Ivan

2012-01-01

19

Effects of truncated activin and FGF receptors and of follistatin on the inducing activities of BVg1 and activin: does activin play a role in mesoderm induction?  

PubMed Central

Activin and Vg1, two members of the TGF-beta family, are believed to play roles in mesoderm induction and axis formation in the amphibian embryo. Both molecules are provided maternally, either as protein (activin) or as RNA and protein (Vg1), and experiments with a truncated form of a type IIB activin receptor have led to the conclusion that activin is required for induction of mesoderm in vivo. In this paper we first show that truncated versions of two different Xenopus activin receptors also have severe effects on the activity of the mature region of Vg1, suggesting that such receptors may block the function of several members of the TGF-beta family. We go on to demonstrate that follistatin, a secreted protein which binds activin and blocks its activity, does not interfere with Vg1 signalling. Furthermore, overexpression of follistatin mRNA in Xenopus embryos does not perturb mesoderm formation. Taken together, our data show that the effects of truncated activin receptors on Xenopus development can be explained by the inhibition of Vg1 activity, while the lack of effect of follistatin argues against a function for activin in mesoderm induction. Images

Schulte-Merker, S; Smith, J C; Dale, L

1994-01-01

20

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

21

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

22

Activation of Signalling by the Activin Receptor Complex  

Microsoft Academic Search

Activin exerts its effects by simultaneously binding to two types of protein serine\\/threonine kinase receptors, eachtypeexistinginvariousisoforms.UsingtheActR-IBandActR-IIBreceptorisoforms,wehaveinvestigated themechanismofactivinreceptoractivation.ActR-IBand-IIBarephosphoproteinswithdemonstrableaffinity for each other. However, activin addition strongly promotes an interaction between these two proteins. Activin binds directly to ActR-IIB, and this complex associates with ActR-IB, which does not bind ligand on its own. In the resulting complex, ActR-IB becomes hyperphosphorylated, and this requires

LILIANA ATTISANO; JEFFREY L. WRANA; ERMELINDA MONTALVO; ANDJOAN MASSAGUE ´

1996-01-01

23

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

24

Role of activin A in carbon tetrachloride-induced acute liver injury  

PubMed Central

AIM: To investigate the expression and role of activin A in a mouse model of acute chemical liver injury. METHODS: Acute liver injury in C57BL/6 male mice was induced by intraperitoneal injection with carbon tetrachloride (CCl4) (0.5 mL/kg, body weight) dissolved in olive oil (1:19 v/v). Mice were sacrificed 1, 3, 5 and 7 d after the treatment. The levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum were examined and pathological changes of liver observed by hematoxylin and eosin staining to evaluate the liver injury. Activin A protein levels in serum and hepatic tissue homogenate of mice were detected by enzyme-linked immunosorbent assay, and the expression pattern of activin A protein in livers of mice was examined by immunohistochemistry. Activin type IIA receptor (ActRIIA) and Smad3 expressions in the liver were analyzed by real-time quantitative reverse transcription-polymerase chain reaction. In order to further investigate the role of activin A, we also utilized activin A blocking experiment by anti-activin A antibody (500 ?g/kg, body weight) injection into mouse tail vein. RESULTS: In CCl4-treated mice, serum ALT and AST levels were significantly increased, compared with that in control mice (P < 0.01). Furthermore, the serious necrosis was observed around hepatic portal areas in CCl4-treated mice. Simultaneously, activin A levels in serum and hepatic tissue homogenate of mice treated with CCl4 for 1, 3 and 5 d increased significantly, compared with that in control mice (P < 0.01). Activin A protein expression in hepatocytes not within the necrotic area was also upregulated in mice following CCl4 treatment. Not only activin A, but also ActRIIA and activin signaling molecule Smad3 mRNA expressions in injury liver induced by CCl4 were significantly higher than that in control liver. In addition, levels of serum ALT and AST in CCl4-treated mice were significantly decreased by injection of anti-activin A antibody to block endogenous activin A action, compared with that in CCl4-treated mice by injection of immunoglobulin G instead of anti-activin A antibody (P < 0.01), and the severity of liver injury was also reduced remarkably. CONCLUSION: These data show that activin A is involved in CCl4-induced acute liver injury. Blocking activin A actions may be a therapeutic approach for acute liver injury.

Wang, Dong-Hui; Wang, Yi-Nan; Ge, Jing-Yan; Liu, Hai-Yan; Zhang, Hong-Jun; Qi, Yan; Liu, Zhong-Hui; Cui, Xue-Ling

2013-01-01

25

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

26

Activin-A attenuates several human natural killer cell functions.  

PubMed

Dendritic-cell (DC) and natural killer (NK)-cell interactions are critical in sculpting the adaptive immune response. However, the mechanisms by which DCs down-regulate NK-cell functions are not well understood. NK-cell function is inhibited by transforming growth factor beta (TGF-beta), but DCs do not appear to produce TGF-beta. We have previously shown that activated human DCs produce large amounts of activin-A, a TGF-beta superfamily member, which autoregulates DC function. The present report shows that NK-cells express type I and II activin receptors and that activin-A triggers NK-cell Smad 2/3 signaling. Furthermore, activin-A directly regulates NK cell functions by (1) down-regulating the T-box transcription factor T-bet and interferon gamma (IFN-gamma) but not perforin or granzyme mRNA; (2) suppressing NK-cell IFN-gamma production as potently as TGF-beta; and (3) suppressing NK-cell CD25 expression and proliferation and sculpting NK-cell cytokine and chemokine profiles. Interestingly, unlike TGF-beta, activin-A weakly down-regulates the NK-cell natural cytotoxicity receptors (NCRs) NKp30 and NKG2D but does not attenuate their cytotoxic function. These findings provide the first evidence for a novel immune regulatory role of activin-A during DC-mediated NK-cell regulation, highlighting the potential of antagonizing activin-A signaling in vivo to enhance NK cell-mediated immune functions and adaptive immunity. PMID:19141859

Robson, Neil C; Wei, Heng; McAlpine, Tristan; Kirkpatrick, Naomi; Cebon, Jonathan; Maraskovsky, Eugene

2009-01-13

27

[TGFbeta, activin and SMAD signalling in thyroid cancer].  

PubMed

TGFbeta and activin are members of the TGFbeta superfamily and play a wide role in development, proliferation and apoptosis. These growth factors exert their biological effects by binding to the type I and II membrane receptors to transduce their signalling through the nucleus by phosphorylation of R-SMADs (SMAD 2/3) and co-SMADs (Smad 4). The proper control of TGFbeta/activin pathway is negatively regulated by inhibitory SMAD (SMAD7) and by E3 ubiquitination enzymes (Smurfs). Physiologically, TGFbeta and activin act as potent growth inhibitors in thyroid follicular cell. Thus, alterations in the receptors and components of SMAD signalling pathway are associated with several types of tumors. Since TGFbeta and activin generate their intracellular signalling through the same components of the SMAD pathway, the unbalance of this pathway impairs both of anti-mitogenic signals in the cell. This review addresses aspects of the molecular mechanisms in the understanding of resistance to the growth inhibitory effects of TGFbeta and activin due to the disequilibrium in the SMAD inhibitory pathway in thyroid neoplasia. PMID:17891231

Kimura, Edna T; Matsuo, Sílvia E; Ricarte-Filho, Júlio Cézar

2007-07-01

28

FKBP12 functions as an adaptor of the Smad7Smurf1 complex on activin type I receptor  

Microsoft Academic Search

The cytoplasmic immunophilin FKBP12, a 12 kDa FK506-binding protein, has been shown to act as an inhibitor for transforming growth factor- (TGF-) signaling. FKBP12 binds to the glycine- and serine-rich motif (GS motif) of the TGF- type I receptor, and functions as a secure switch to prevent the leaky signal. Upon stimulation with ligand, FKBP12 is released from the receptor

T Yamaguchi; A Kurisaki; N Yamakawa; K Minakuchi; H Sugino

2006-01-01

29

Activin A promotes multiple myeloma-induced osteolysis and is a promising target for myeloma bone disease  

PubMed Central

Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-? family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox–5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.

Vallet, Sonia; Mukherjee, Siddhartha; Vaghela, Nileshwari; Hideshima, Teru; Fulciniti, Mariateresa; Pozzi, Samantha; Santo, Loredana; Cirstea, Diana; Patel, Kishan; Sohani, Aliyah R.; Guimaraes, Alex; Xie, Wanling; Chauhan, Dharminder; Schoonmaker, Jesse A.; Attar, Eyal; Churchill, Michael; Weller, Edie; Munshi, Nikhil; Seehra, Jasbir S.; Weissleder, Ralph; Anderson, Kenneth C.; Scadden, David T.; Raje, Noopur

2010-01-01

30

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

31

Soluble a? promotes wild-type tau pathology in vivo.  

PubMed

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, 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. PMID:23197725

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

2012-11-28

32

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

33

Activin disrupts somitogenesis in cultured chick embryos  

Microsoft Academic Search

The anatomical and cell biological aspects of somite formation in the chick embryo have been rather well studied. Molecular regulation of somitogenesis in vertebrates is just beginning to be understood. We have studied the effects of human recombinant activin on somitogenesis in gastrulating chick embryos cultured in vitro with a view to assessing the possible role of activin-related molecules in

Vidya Patwardhan; Surendra Ghaskadbi

2001-01-01

34

Toxoplasma gondii Activates Hypoxia-inducible Factor (HIF) by Stabilizing the HIF-1? Subunit via Type I Activin-like Receptor Kinase Receptor Signaling*  

PubMed Central

Toxoplasma gondii is an intracellular protozoan parasite that can cause devastating disease in fetuses and immune-compromised individuals. We previously reported that the ? subunit of the host cell transcription factor, hypoxia-inducible factor-1 (HIF-1), is up-regulated by infection and necessary for Toxoplasma growth. Under basal conditions, HIF-1? is constitutively expressed but rapidly targeted for proteasomal degradation after two proline residues are hydroxylated by a family of prolyl hydroxylases (PHDs). The PHDs are ?-ketoglutarate-dependent dioxygenases that have low Km values for oxygen, making them important cellular oxygen sensors. Thus, when oxygen levels decrease, HIF-1? is not hydroxylated, and HIF-1 is activated. How Toxoplasma activates HIF-1 under normoxic conditions remains unknown. Here, we report that Toxoplasma infection increases HIF-1? stability by preventing HIF-1? prolyl hydroxylation. Infection significantly decreases PHD2 abundance, which is the key prolyl hydroxylase for regulating HIF-1?. The effects of Toxoplasma on HIF-1? abundance and prolyl hydroxylase activity require activin-like receptor kinase signaling. Finally, parasite growth is severely diminished when signaling from this family of receptors is inhibited. Together, these data indicate that PHD2 is a key host cell factor for T. gondii growth and represent a novel mechanism by which a microbial pathogen subverts host cell signaling and transcription to establish its replicative niche.

Wiley, Mandi; Sweeney, Kristin R.; Chan, Denise A.; Brown, Kevin M.; McMurtrey, Curtis; Howard, Eric W.; Giaccia, Amato J.; Blader, Ira J.

2010-01-01

35

Involvement of p21WAF1\\/Cip1, CDK4 and Rb in activin A mediated signaling leading to hepatoma cell growth inhibition  

Microsoft Academic Search

Cytokines are growth inhibitory in a target cell specific manner. The signaling pathways that characterize each cell type play a crucial role in determining the responsiveness to cytokine triggering. Activin A has been shown to suppress the growth of primary hepatocytes. Similarly, the human HepG2 hepatoma cell line was growth arrested by activin A as judged by lack of cell

Ayelet Zauberman; Moshe Oren; Dov Zipori

1997-01-01

36

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

37

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

38

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

39

Effect of temperature on the solubility of carnallite type double salts  

Microsoft Academic Search

A method based on Pitzer's model has been used for calculation of the solubilities of carnallite type double salts crystallizing in the systems MeX-MgX2-H2O (Me=Li, NH4, K, Rb, Cs; X=Cl, Br). The solubility of congruently soluble double salts was also determined experimentally at 25–75°C. The results from studies of the solubility diagrams of ternary carnallite type water-salt systems over a

Chr Christov; Chr Balarew

1995-01-01

40

The activin signaling pathway promotes differentiation of dI3 interneurons in the spinal neural tube.  

PubMed

The generation of the appropriate types and numbers of mature neurons during the development of the spinal cord requires the careful coordination of patterning, proliferation, and differentiation. In the dorsal neural tube, this coordination is achieved by the combined action of multiple ligands of both the Wnt and TGF-beta families, and their effectors, such as the bHLH proteins. TGF-beta signaling acting through the BMP receptors is necessary for the generation of several dorsal interneuron types. Other TGF-beta ligands expressed in the dorsal neural tube interact with the Activin receptors, which signal via a different set of SMAD proteins than BMPs. The effects of Activin signaling on the developing neural tube have not been described. Here we have activated the Activin signal transduction pathway in a cell-autonomous manner in the developing chick neural tube. We find that a constitutively active Activin receptor promotes differentiation throughout the neural tube. Although most differentiated cell populations are unaffected by Activin signaling, the number of dorsal interneuron 3 (dI3) cells is specifically increased. Our data suggest that Activin signaling may promote the formation of the dI3 precursor cells within a region circumscribed by BMP signaling and that this function is not dependent upon BMP signaling. PMID:16039645

Timmer, John; Chesnutt, Catherine; Niswander, Lee

2005-09-01

41

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

2013-07-30

42

Activin Signaling: Effects on Body Composition and Mitochondrial Energy Metabolism  

PubMed Central

Activin-?A and activin-?B (encoded by Inhba and Inhbb genes, respectively) are closely related TGF-? superfamily members that participate in a variety of biological processes. We previously generated mice with an insertion allele at the Inhba locus, InhbaBK. In this allele, the sequence encoding the Inhba mature domain is replaced with that of Inhbb, rendering the gene product functionally hypomorphic. Homozygous (InhbaBK/BK) and hemizygous (InhbaBK/?) mice are smaller and leaner than their wild-type littermates, and many tissues are disproportionately small relative to total body weight. To determine the mechanisms that contribute to these phenomena, we investigated the metabolic consequences of the mutation. Although the growth of InhbaBK mice is improved by providing a calorie-rich diet, diet-induced obesity, fatty liver, and insulin resistance (hallmarks of chronic caloric excess) do not develop, despite greater caloric intake than wild-type controls. Physiological, molecular, and biochemical analyses all revealed characteristics that are commonly associated with increased mitochondrial energy metabolism, with a corresponding up-regulation of several genes that reflect enhanced mitochondrial biogenesis and function. Oxygen consumption, an indirect measure of the metabolic rate, was markedly increased in InhbaBK/BK mice, and polarographic analysis of liver mitochondria revealed an increase in ADP-independent oxygen consumption, consistent with constitutive uncoupling of the inner mitochondrial membrane. These findings establish a functional relationship between activin signaling and mitochondrial energy metabolism and further support the rationale to target this signaling pathway for the medical treatment of cachexia, obesity, and diabetes.

Li, Liunan; Shen, Joseph J.; Bournat, Juan C.; Huang, Lihua; Chattopadhyay, Abanti; Li, Zhihong; Shaw, Chad; Graham, Brett H.; Brown, Chester W.

2009-01-01

43

Differential regulation of follicle stimulating hormone by activin A and TGFB1 in murine gonadotropes  

PubMed Central

Background Activins stimulate the synthesis of follicle stimulating hormone (FSH) in pituitary gonadotropes, at least in part, by inducing transcription of its beta subunit (Fshb). Evidence from several laboratories studying transformed murine LbetaT2 gonadotropes indicates that activins signal through Smad-dependent and/or Smad-independent pathways, similar to those used by transforming growth factor beta-1 (TGFB1) in other cell types. Therefore, given common intracellular signaling mechanisms of these two ligands, we examined whether TGFBs can also induce transcription of Fshb in LbetaT2 cells as well as in purified primary murine gonadotropes. Methods Murine Fshb promoter-reporter (-1990/+1 mFshb-luc) activity was measured in LbetaT2 cells treated with activin A or TGFB1, and in cells transfected with either activin or TGFB receptors. The ability of the ligands to stimulate phosphorylation of Smads 2 and 3 in LbetaT2 cells was measured by western blot analysis, and expression of TGFB type I and II receptors was assessed by reverse transcriptase polymerase chain reaction in both LbetaT2 cells and primary gonadotropes purified from male mice of different ages. Finally, regulation of endogenous murine Fshb mRNA levels by activin A and TGFB1 in purified gonadotropes and whole pituitary cultures was measured using quantitative RT-PCR. Results Activin A dose-dependently stimulated -1990/+1 mFshb-luc activity in LbetaT2 cells, but TGFB1 had no effect at doses up to 5 nM. Similarly, activin A, but not TGFB1, stimulated Smad 2 and 3 phosphorylation in these cells. Constitutively active forms of the activin (Acvr1b-T206D) and TGFB (TGFBR1-T204D) type I receptors strongly stimulated -1990/+1 mFshb-luc activity, showing that mechanisms down stream of Tgfbr1 seem to be intact in LbetaT2 cells. RT-PCR analysis of LbetaT2 cells and whole adult murine pituitaries indicated that both expressed Tgfbr1 mRNA, but that Tgfbr2 was not detected in LbetaT2 cells. When cells were transfected with a human TGFBR2 expression construct, TGFB1 acquired the ability to significantly stimulate -1990/+1 mFshb-luc activity. In contrast to LbetaT2 cells, primary murine gonadotropes from young mice (8–10 weeks) contained low, but detectable levels of Tgfbr2 mRNA and these levels increased in older mice (1 yr). A second surprise was the finding that treatment of purified primary gonadotropes with TGFB1 decreased murine Fshb mRNA expression by 95% whereas activin A stimulated expression by 31-fold. Conclusion These data indicate that TGFB1-insensitivity in LbetaT2 cells results from a deficiency in Tgfbr2 expression. In primary gonadotropes, however, expression of Tgfbr2 does occur, and its presence permits TGFB1 to inhibit Fshb transcription, whereas activin A stimulates it. These divergent actions of activin A and TGFB1 were unexpected and show that the two ligands may act through distinct pathways to cause opposing biological effects in primary murine gonadotropes.

Gore, A Jesse; Philips, Daniel P; Miller, William L; Bernard, Daniel J

2005-01-01

44

Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy.  

PubMed

Introduction: Formation of blood vessels from pre-existing ones, also termed angiogenesis, is of crucial importance for the outgrowth of tumours beyond 1 - 2 mm(3). Therefore, anti-angiogenic therapies, mainly focussing on inhibition of vascular endothelial growth factor (VEGF) are used in clinical therapy. However, although initially reducing tumour size, therapy resistance occurs frequently and new targets are needed. A possible target is activin receptor-like kinase (ALK)-1, a transforming growth factor (TGF)-? type-I receptor, which binds bone morphogenetic protein (BMP)-9 and -10 with high affinity and has an important role in regulating angiogenesis. Areas covered: Several approaches to interfere with ALK1 signalling have been developed, that is, ALK1 neutralising antibodies and a soluble ALK1 extracellular domain/Fc fusion protein (ALK1-Fc), acting as a ligand trap. In this review, we discuss the involvement of ALK1 in angiogenesis, in a variety of diseases and the current status of the development of ALK1 inhibitors for cancer therapy. Expert opinion: Based on current, mainly preclinical studies on inhibition of ALK1 signalling by ligand traps and neutralising antibodies, targeting ALK1 seems very promising. Both ALK1-Fc and neutralising antibodies strongly inhibit angiogenesis in vitro and in vivo. The results from the first Phase I clinical trials are to be reported soon and multiple Phase II studies are ongoing. PMID:24053899

Hawinkels, Lukas Jac; Garcia de Vinuesa, Amaya; Ten Dijke, Peter

2013-09-21

45

Activins and Leydig Cell Development Differentiation, and Disease  

Microsoft Academic Search

During development and differentiation of many tissues and organs, activins are potent stimulatory or inhibitory factors,\\u000a but generally during Leydig cell development they are inhibitory. Thus, the decline in activin bioactivity at puberty, corresponds\\u000a with the emergence of the adult Leydig cell population and differentiation from Leydig cell precursors. Once established,\\u000a activins inhibit steroidogenesis and oppose or balance luteinizing hormone

Gail P. Risbridger; Christopher Butler

46

Activin-A: a novel dendritic cell-derived cytokine that potently attenuates CD40 ligand-specific cytokine and chemokine production.  

PubMed

Activin-A is a transforming growth factor-beta (TGF-beta) superfamily member that plays a pivotal role in many developmental and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune-regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent autocrine effects on the capacity of human dendritic cells (DCs) to stimulate immune responses. Human monocyte-derived DCs (MoDCs) and the CD1c(+) and CD123(+) peripheral blood DC populations express both activin-A and the type I and II activin receptors. Furthermore, MoDCs and CD1c(+) myeloid DCs rapidly secrete high levels of activin-A after exposure to bacteria, specific toll-like receptor (TLR) ligands, or CD40 ligand (CD40L). Blocking autocrine activin-A signaling in DCs using its antagonist, follistatin, enhanced DC cytokine (IL-6, IL-10, IL-12p70, and tumor necrosis factor-alpha [TNF-alpha]) and chemokine (IL-8, IP-10, RANTES, and MCP-1) production during CD40L stimulation, but not TLR-4 ligation. Moreover, antagonizing DC-derived activin-A resulted in significantly enhanced expansion of viral antigen-specific effector CD8(+) T cells. These findings establish an immune-regulatory role for activin-A in DCs, highlighting the potential of antagonizing activin-A signaling in vivo to enhance vaccine immunogenicity. PMID:18156495

Robson, Neil C; Phillips, David J; McAlpine, Tristan; Shin, Amanda; Svobodova, Suzanne; Toy, Tracey; Pillay, Vinochani; Kirkpatrick, Naomi; Zanker, Damien; Wilson, Kathy; Helling, Imke; Wei, Heng; Chen, Weisan; Cebon, Jonathan; Maraskovsky, Eugene

2007-12-21

47

Activin A inhibits formation of skeletal muscle during chick development.  

PubMed

In this study we investigated the effect of recombinant activin A on the differentiation of limb muscle precursors of chick embryos. We show that treatment with activin resulted in a downregulation of Pax-3 and MyoD expression within 6 h after treatment, whereas expression of Myf-5 and Pax-7 was largely unaffected. The effect on gene expression was transient because 1 day after activin exposure the development of the premuscle masses had proceeded, and Pax-3 and MyoD expression was reexpressed at normal levels. Unlike other transforming growth factors-beta, activin did not induce programmed cell death in limb mesenchyme, thus myogenic cells were not permanently lost. In high-density cultures of embryonic chick limb mesenchyme (micromass cultures), activin repressed the generation of Pax-7-expressing muscle precursors. Furthermore, in the presence of activin, fewer muscle precursors differentiated, and the population of differentiating cells failed to fuse and form myotubes. Our data suggest that activin reversibly inhibited expression of two transcription factors, Pax-3 and MyoD, and thus transiently inhibited proliferation and differentiation of limb muscle precursors. However, myogenic cells were not lost as they continued to express Pax-7 and Myf-5, and this may have allowed precursors to commence development after the activin effect faded. We suggest that activin acts in conjunction with a closely related signalling molecule, myostatin, to prevent excessive growth of skeletal muscle. PMID:16007475

He, Liwen; Vichev, Konstantin; Macharia, Raymond; Huang, Ruijin; Christ, Bodo; Patel, Ketan; Amthor, Helge

2005-03-15

48

Serum activin A levels in different thyroid disorders.  

PubMed

Activin A belongs to the transforming growth factor-beta superfamily that exerts a wide range of biologic activities on cellular proliferation and differentiation. Although it was suggested that gonadal tissue is the primary site of activin production, several extragonadal sources have subsequently been identified, including human thyrocytes. The goal of the present study was to evaluate serum activin A levels in a series of patients with different thyroid disorders during the active state of the diseases and after recovery. Serum activin A levels were evaluated in 60 healthy subjects (controls), 8 with multinodular nontoxic goiter (MNG), 30 hyperthyroid (15 with Graves' disease (GD), 12 with autonomous hyperfunctioning adenoma (ATA), and 3 with thyrotropin (TSH)-secreting pituitary adenoma, 16 hypothyroid (11 with Hashimoto's thyroiditis and 5 after total thyroidectomy), and 9 patients with resistance to thyroid hormone (RTH) by commercial enzyme-linked immunosorbent assay (ELISA) kit. Patients with GD and ATA showed activin A levels higher than those found in controls and similar to those observed in MNG (GD, 0.74 +/- 0.3 ng/mL; ATA, 0.86 +/- 0.4; and MNG; 1.0 +/- 0.2 vs. controls: 0.39 +/- 0.5, p < 0.001), while in patients with Hashimoto's thyroiditis, total thyroidectomy or RTH activin A levels were similar to those of controls. In conclusion, this study demonstrates that thyroid hyperplasia and hyperfunction result in increased levels of activin A, although the normal levels observed in thyroidectomized patients clearly demonstrate that the thyroid gland is not the predominant source of activin A in normal conditions. Because activin A may exert negative action on thyrocyte proliferation, it is conceivable that activin A hypersecretion in thyroid disorders might represent a counteracting mechanism. PMID:12593725

Morpurgo, Paola S; Beck-Peccoz, Paolo; Reschini, Eugenio; Mannavola, Deborah; Borgato, Stefano; Vicentini, Leonardo; Spada, Anna

2002-12-01

49

A Role for Activin A and Betacellulin in Human Fetal Pancreatic Cell Differentiation and Growth  

Microsoft Academic Search

Activin A (Act.A), a member of the transforming growth factor b family of secreted proteins, has been implicated in the regulation of growth and differentiation of various cell types. Betacellulin (BTC), a member of the epidermal growth factor family, converts exocrine AR42J cells to insulin-expressing cells when combined with Act.A. We have used primary cultures of human fetal pancreatic tissue

CARLA DEMETERCO; GILLIAN M. BEATTIE; SERGIO ATALA DIB; ANA D. LOPEZ

2010-01-01

50

Inhibition of activin receptor-like kinase 5 attenuates Bleomycin-induced pulmonary fibrosis  

Microsoft Academic Search

Activin receptor-like kinase 5 (ALK5) is a type I receptor of transforming growth factor (TGF)-beta. ALK5 inhibition has been reported to attenuate the tissue fibrosis including pulmonary fibrosis, renal fibrosis and liver fibrosis. To elucidate the inhibitory mechanism of ALK5 inhibitor on pulmonary fibrosis in vivo, we performed the histopathological assessment, gene expression analysis of extracellular matrix (ECM) genes and

Hiroyuki Higashiyama; Daisuke Yoshimoto; Toshihiko Kaise; Shigeki Matsubara; Masatoshi Fujiwara; Hideo Kikkawa; Satoshi Asano; Mine Kinoshita

2007-01-01

51

Structures of an ActRIIB:activin A complex reveal a novel binding mode for TGF-beta ligand:receptor interactions  

SciTech Connect

The TGF-{beta} superfamily of ligands and receptors stimulate cellular events in diverse processes ranging from cell fate specification in development to immune suppression. Activins define a major subgroup of TGF-{beta} ligands that regulate cellular differentiation, proliferation, activation and apoptosis. Activins signal through complexes formed with type I and type II serine/threonine kinase receptors. We have solved the crystal structure of activin A bound to the extracellular domain of a type II receptor, ActRIIB, revealing the details of this interaction. ActRIIB binds to the outer edges of the activin finger regions, with the two receptors juxtaposed in close proximity, in a mode that differs from TGF-{beta}3 binding to type II receptors. The dimeric activin A structure differs from other known TGF-{beta} ligand structures, adopting a compact folded-back conformation. The crystal structure of the complex is consistent with recruitment of two type I receptors into a close packed arrangement at the cell surface and suggests that diversity in the conformational arrangements of TGF-{beta} ligand dimers could influence cellular signaling processes.

Thompson, T.B.; Woodruff, T.K.; Jardetzky, T.S.

2010-03-08

52

Preparation of a Foam Spray Dried Whole Milk Type Product with Good Sinkability, Dispersibility, and Solubility  

Microsoft Academic Search

Foam spray dried powder of whole milk type with good sinkability was pre- Fared by combining three influential fac- tors in the preparation procedure: (1) use of liquid milk fat, (2) high pressure homogenization, and (3) low foaming with carbon dioxide. A 26% liquid milk fat powder has somewhat adverse dis- persibility and solubility, but lowering the fat content to

A. Tamsma; A. Kontson

1974-01-01

53

Interleukin-1 ? enhances and interferon-? suppresses activin A actions by reciprocally regulating activin A and follistatin secretion from bone marrow stromal fibroblasts  

PubMed Central

Activin A is a multi-functional cytokine with a potent stimulation on erythroid cell differentiation in the bone marrow. The actions of activin A are determined by a balance of the levels of activin A and its inhibitor, follistatin (FS). However, the regulation of its actions in the bone marrow has been unclear. Here we show that bone marrow-derived stromal fibroblasts are the major source of activin A and FS in the bone marrow, and that the production of activin A is enhanced by interleukin-1? (IL-1?) and lipopolysaccharide (LPS), whereas interferon-? (IFN-?) inhibits the secretion of activin A by stromal fibroblasts. Concomitantly, IL-1? as well as LPS inhibits and IFN-? stimulates FS secretion from stromal fibroblasts. Thus, these cytokines potently regulate activin A actions by reciprocal modulation of activin A and FS secretion from stromal fibroblasts. Because activin A exhibits anti-inflammatory effects in various tissues, up-regulation of activin A actions by IL-1? and endotoxin in the bone marrow may play a protective role against inflammatory processes as well as anaemia. The present results also suggest that the inhibitory effect of IFN-? on erythropoiesis is mediated at least in part by a suppression of activin A actions in bone marrow.

Abe, M; Shintani, Y; Eto, Y; Harada, K; Fujinaka, Y; Kosaka, M; Matsumoto, T

2001-01-01

54

Vaccinia virus encodes a soluble type I interferon receptor of novel structure and broad species soecificity  

Microsoft Academic Search

Vaccinia virus (VV) and other orthopoxviruses express a soluble type I interferon (IFN) receptor that for VV strain Western Reserve is encoded by gene B1 OR. The 60–65 kDa glycoprotein is related to the interleukin-1 receptors and is a member of the immunoglobulin superfamily, unlike other type I IFN receptors, which belong to the class II cytokine receptor family. The

Julian A. Symons; Antonio Alcamí; Geoffrey L. Smith

1995-01-01

55

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

56

Regulation of Muscle Mass by Follistatin and Activins  

PubMed Central

Myostatin is a TGF-? family member that normally acts to limit skeletal muscle mass. Follistatin is a myostatin-binding protein that can inhibit myostatin activity in vitro and promote muscle growth in vivo. Mice homozygous for a mutation in the Fst gene have been shown to die immediately after birth but have a reduced amount of muscle tissue, consistent with a role for follistatin in regulating myogenesis. Here, we show that Fst mutant mice exhibit haploinsufficiency, with muscles of Fst heterozygotes having significantly reduced size, a shift toward more oxidative fiber types, an impairment of muscle remodeling in response to cardiotoxin-induced injury, and a reduction in tetanic force production yet a maintenance of specific force. We show that the effect of heterozygous loss of Fst is at least partially retained in a Mstn-null background, implying that follistatin normally acts to inhibit other TGF-? family members in addition to myostatin to regulate muscle size. Finally, we present genetic evidence suggesting that activin A may be one of the ligands that is regulated by follistatin and that functions with myostatin to limit muscle mass. These findings potentially have important implications with respect to the development of therapeutics targeting this signaling pathway to preserve muscle mass and prevent muscle atrophy in a variety of inherited and acquired forms of muscle degeneration.

Lee, Se-Jin; Lee, Yun-Sil; Zimmers, Teresa A.; Soleimani, Arshia; Matzuk, Martin M.; Tsuchida, Kunihiro; Cohn, Ronald D.; Barton, Elisabeth R.

2010-01-01

57

Pharmacokinetics of a water-soluble antioxidant of 3-hydroxypyridine type  

Microsoft Academic Search

An intensive search for physiologically active substances among derivatives of 3-hydroxypyridine (3-HP), which are water-soluble antioxidants of biogenic type and structural analogs of compounds of the vitamin B6 group, and the study of the mechanism of their action are currently in progress. It has been shown that 3-HP derivatives possess a broad spectrum of psychopharmacologic action which, in particular, embraces

V. P. Zherdev; A. K. Sariev; A. A. Dvoryaninov; T. A. Voronina; L. D. Smirnov

1986-01-01

58

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

SciTech Connect

The 2.07 {angstrom} 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 {beta}-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. (UW)

2009-03-11

59

Antiviral activities of the soluble extracellular domains of type I interferon receptors  

PubMed Central

Alternative splicing leads to the expression of multiple isoforms of the subunits (IFNAR1 and IFNAR2) of the type I IFN receptor. Here we describe two transcripts representing extracellular forms of ovine IFNAR1 and show that soluble extracellular forms of both IFNAR2 and IFNAR1, prepared in recombinant form in Escherichia coli, have antiviral (AV) activity in the absence of IFN. Exposure of Madin-Darby bovine kidney cells to the extracellular domain (R2E) of IFNAR2 at concentrations as low as 10 nM afforded complete protection against vesicular stomatitis virus and led to the rapid activation of the transcription factors ISGF3 and GAF. Although R2E can bind IFN (Kd ?70 nM), activity was observed irrespective of whether or not ligand was present. R2E was inactive on mouse L929 cells but active on L929 cells expressing a membraneanchored, ovine/human chimeric IFNAR2 with an ovine extracellular domain. The data suggest that AV activity is conferred by the ability of soluble R2E to associate with the transfected IFNAR2 subunit rather than resident murine IFNAR1. Soluble extracellular forms of IFNAR1 have lower AV activity than R2E on Madin-Darby bovine kidney cells but are less species-specific and protect wild-type L929 cells as efficiently as the transfected cell line, presumably by interacting with one of the murine receptor subunits.

Han, Chun-Sheng; Chen, Yizhen; Ezashi, Toshihiko; Roberts, R. Michael

2001-01-01

60

Follistatin and activin A serum concentrations in obese and non-obese patients with polycystic ovary syndrome  

Microsoft Academic Search

BACKGROUND: Activin promotes ovarian follicular development, inhibits androgen production and increases FSH and insulin secretion. Follistatin, an activin-binding protein, neutralizes activin bioactivity. Therefore, a decrease in the ratio of activin\\/follistatin might encourage characteristic features of polycystic ovary syndrome (PCOS). We investigated whether women with PCOS showed disordered follistatin and\\/or activin serum concentra- tions. METHODS: The study group included 24 obese

T. Eldar-Geva; I. M. Spitz; N. P. Groome; E. J. Margalioth; R. Homburg

2001-01-01

61

Soluble vs. insoluble fiber  

MedlinePLUS

Insoluble vs. soluble fiber; Fiber - soluble vs. insoluble ... There are two different types of fiber -- soluble and insoluble. Both are important for health, digestion, and preventing diseases. Soluble fiber attracts water and turns to gel during digestion. ...

62

Poly(pyridinium phenylene)s: water-soluble N-type polymers.  

PubMed

Poly(pyridinium phenylene) conjugated polymers are synthesized by a cross-coupling and cyclization sequence. These polyelectrolytes are freely soluble in water and display high degrees of electroactivity. When reduced (n-doped) these materials display in situ conductivities as high as 160 S/cm. The high conductivity is attributed to the planar structure that is enforced by the cyclic structures of the polymer. The electron affinities are compared to PCBM, a C(60) based n-type material. We find that these polymers undergo excited state electron transfer reactions with other donor conjugated polymers and hence may find utility in photovoltaic devices. PMID:19924995

Izuhara, Daisuke; Swager, Timothy M

2009-12-16

63

Direct Evidence for a Soluble Methane Monooxygenase from Type I Methanotrophic Bacteria: Purification and Properties of a Soluble Methane Monooxygenase from Methylomonassp. GYJ3  

Microsoft Academic Search

The hydroxylase and reductase components of a soluble methane monooxygenase from type I methanotrophs—Methylomonassp. GYJ3—were purified by a multiple-step LC procedure. The hydroxylase (approximately 240 kDa, determined by an HPLC–size exclusion chromatography method) has three subunits with molecular masses of 56, 43, and 27 kDa, suggesting that the enzyme has an (???)2subunit structure. The HPLC method was developed to purify

Run-nan Shen; Chi-li Yu; Qing-quan Ma; Shu-ben Li

1997-01-01

64

Presence of activin (erythroid differentiation factor) in unfertilized eggs and blastulae of Xenopus laevis.  

PubMed Central

Activin A, a member of the transforming growth factor beta superfamily, has recently been found to have potent mesoderm-inducing activity on isolated early Xenopus animal-cap cells. We measured the activin activity of the Xenopus egg extract by using an erythroid-differentiating test with Friend leukemia cells. The results showed that an activin homologue is, indeed, contained in unfertilized eggs and blastulae of Xenopus laevis in a considerable amount. This activity was eluted at the same retention time as human activin A when fractionated by reversed-phase HPLC. Furthermore, the fraction containing erythroid-differentiating factor activity had mesoderm-inducing activity on Xenopus animal-cap cells. The mesoderm-inducing activity of this fraction was suppressed when coincubated with follistatin, an activin-binding protein. These results suggest that an endogenous activin may be a natural mesoderm-inducing factor acting in Xenopus embryogenesis. Images

Asashima, M; Nakano, H; Uchiyama, H; Sugino, H; Nakamura, T; Eto, Y; Ejima, D; Nishimatsu, S; Ueno, N; Kinoshita, K

1991-01-01

65

Solubility survey of fragments of the neurofibromatosis type 1 protein neurofibromin.  

PubMed

The protein giant neurofibromin (320kDa) is the protein product of the NF1 tumor suppressor gene, alterations of which are responsible for the pathogenesis of neurofibromatosis type 1 (NF1). Neurofibromin is a Ras-specific GTPase activating protein (RasGAP) that, 15 years after the cloning of the gene, remains the only clearly defined function of the protein. In a structural proteomics approach, we aimed at defining functions beyond RasGAP activity based on the discovery of structural modules. Given the poor outcome of domain prediction tools, we have undertaken a fragment solubility survey covering the full protein sequence, with the aim of defining new domain boundaries or fragments that could be investigated by biochemical methods including structural analysis. More than 200 constructs have been expressed and tested for solubility in small scale assays. Boundaries were chosen based upon secondary structure predictions, sequence conservation among neurofibromin orthologues and chemical properties of amino acids. Using this strategy we recently discovered a novel bipartite module in neurofibromin. We have expanded our study to include ESPRIT, a library-based construct screen, to perform fragment testing at a finer level with respect to the choice of terminal residues. Our study confirms earlier notions about the challenges neurofibromin presents to the biochemist and points to strategies whereby the success rate may be enhanced in the future. PMID:19111619

Bonneau, Fabien; Lenherr, Esther D; Pena, Vladimir; Hart, Darren J; Scheffzek, Klaus

2008-12-10

66

Activin A Levels Are Associated With Abnormal Glucose Regulation in Patients With Myocardial Infarction  

PubMed Central

OBJECTIVE On the basis of the role of activin A in inflammation, atherogenesis, and glucose homeostasis, we investigated whether activin A could be related to glucometabolic abnormalities in patients with acute myocardial infarction (MI). RESEARCH DESIGN AND METHODS Activin A measurement and oral glucose tolerance tests (OGTTs) were performed in patients (n = 115) with acute MI, without previously known diabetes, and repeated after 3 months. Release of activin A and potential anti-inflammatory effects of activin A were measured in human endothelial cells. Activin A effects on insulin secretion and inflammation were tested in human pancreatic islet cells. RESULTS 1) In patients with acute MI, serum levels of activin A were significantly higher in those with abnormal glucose regulation (AGR) compared with those with normal glucose regulation. Activin A levels were associated with the presence of AGR 3 months later (adjusted odds ratio 5.1 [95% CI 1.73–15.17], P = 0.003). 2) In endothelial cells, glucose enhanced the release of activin A, whereas activin A attenuated the release of interleukin (IL)-8 and enhanced the mRNA levels of the antioxidant metallothionein. 3) In islet cells, activin A attenuated the suppressive effect of inflammatory cytokines on insulin release, counteracted the ability of these inflammatory cytokines to induce mRNA expression of IL-8, and induced the expression of transforming growth factor-?. CONCLUSIONS We found a significant association between activin A and newly detected AGR in patients with acute MI. Our in vitro findings suggest that this association represents a counteracting mechanism to protect against inflammation, hyperglycemia, and oxidative stress.

Andersen, Geir ?.; Ueland, Thor; Knudsen, Eva C.; Scholz, Hanne; Yndestad, Arne; Sahraoui, Afaf; Smith, Camilla; Lekva, Tove; Otterdal, Kari; Halvorsen, Bente; Seljeflot, Ingebj?rg; Aukrust, Pal

2011-01-01

67

Activin A inhibits vascular endothelial cell growth and suppresses tumour angiogenesis in gastric cancer  

PubMed Central

Background: Activin A is a multi-functional cytokine belonging to the transforming growth factor-? (TGF-?) superfamily; however, the effect of activin A on angiogenesis remains largely unclear. We found that inhibin ? A subunit (INHBA) mRNA is overexpressed in gastric cancer (GC) specimens and investigated the effect of activin A, a homodimer of INHBA, on angiogenesis in GC. Methods: Anti-angiogenic effects of activin A via p21 induction were evaluated using human umbilical vein endothelial cells (HUVECs) in vitro and a stable INHBA-introduced GC cell line in vivo. Results: Compared with TGF-?, activin A potently inhibited the cellular proliferation and tube formation of HUVECs with induction of p21. A promoter assay and a chromatin immunoprecipitation assay revealed that activin A directly regulates p21 transcriptional activity through Smads. Stable p21-knockdown significantly enhanced the cellular proliferation of HUVECs. Notably, stable p21-knockdown exhibited a resistance to activin-mediated growth inhibition in HUVECs, indicating that p21 induction has a key role on activin A-mediated growth inhibition in vascular endothelial cells. Finally, a stable INHBA-introduced GC cell line exhibited a decrease in tumour growth and angiogenesis in vivo. Conclusion: Our findings highlight the suppressive role of activin A, unlike TGF-?, on tumour growth and angiogenesis in GC.

Kaneda, H; Arao, T; Matsumoto, K; De Velasco, M A; Tamura, D; Aomatsu, K; Kudo, K; Sakai, K; Nagai, T; Fujita, Y; Tanaka, K; Yanagihara, K; Yamada, Y; Okamoto, I; Nakagawa, K; Nishio, K

2011-01-01

68

Characterization of soluble glycoprotein D-mediated herpes simplex virus type 1 infection  

SciTech Connect

Herpes simplex virus type 1 (HSV-1) entry into permissive cells involves attachment to cell-surface glycosaminoglycans (GAGs) and fusion of the virus envelope with the cell membrane triggered by the binding of glycoprotein D (gD) to cognate receptors. In this study, we characterized the observation that soluble forms of the gD ectodomain (sgD) can mediate entry of gD-deficient HSV-1. We examined the efficiency and receptor specificity of this activity and used sequential incubation protocols to determine the order and stability of the initial interactions required for entry. Surprisingly, virus binding to GAGs did not increase the efficiency of sgD-mediated entry and gD-deficient virus was capable of attaching to GAG-deficient cells in the absence of sgD. These observations suggested a novel binding interaction that may play a role in normal HSV infection.

Tsvitov, Marianna [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Frampton, Arthur R. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Shah, Waris A. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Wendell, Steven K. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Ozuer, Ali [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Kapacee, Zoher [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Goins, William F. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Cohen, Justus B. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States); Glorioso, Joseph C. [Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, E1246 Biomedical Science Tower, Pittsburgh, PA 15261 (United States)]. E-mail: glorioso@pitt.edu

2007-04-10

69

Neuroendocrine regulation of Drosophila metamorphosis requires TGF?/Activin signaling  

PubMed Central

In insects, initiation of metamorphosis requires a surge in the production of the steroid hormone 20-hydroxyecdysone from the prothoracic gland, the primary endocrine organ of juvenile larvae. Here, we show that blocking TGF?/Activin signaling, specifically in the Drosophila prothoracic gland, results in developmental arrest prior to metamorphosis. The terminal, giant third instar larval phenotype results from a failure to induce the large rise in ecdysteroid titer that triggers metamorphosis. We further demonstrate that activin signaling regulates competence of the prothoracic gland to receive PTTH and insulin signals, and that these two pathways act at the mRNA and post-transcriptional levels, respectively, to control ecdysone biosynthetic enzyme expression. This dual regulatory circuitry may provide a cross-check mechanism to ensure that both developmental and nutritional inputs are synchronized before initiating the final genetic program leading to reproductive adult development. As steroid hormone production in C. elegans and mammals is also influenced by TGF?/Activin signaling, this family of secreted factors may play a general role in regulating developmental transitions across phyla.

Gibbens, Ying Y.; Warren, James T.; Gilbert, Lawrence I.; O'Connor, Michael B.

2011-01-01

70

A Two-Site Chemiluminescent Assay for Activin-Free Follistatin Reveals That Most Follistatin Circulating in Men and Normal Cycling Women Is in an Activin-Bound State  

Microsoft Academic Search

Follistatin (FS) is a monomeric protein that binds and regulates the bioavailability of activin. Previously, we found circulating levels of total FS to be similar in men and cycling women. Because relative amounts of activin-bound and free FS are important considerations in determining activin bioavailability, we asked here whether the relative proportions of these two changed during different physiologic states.

DANIEL S. MCCONNELL; QIFA WANG; PATRICK M. SLUSS; NICOLA BOLF; RITA H. KHOURY; ALAN L. SCHNEYER; A. REES MIDGLEY; NANCY E. REAME; WILLIAM F. CROWLEY; VASANTHA PADMANABHAN

71

A soluble transforming growth factor-beta (TGF-beta ) type I receptor mimics TGF-beta responses.  

PubMed

Transforming growth factor-beta (TGF-beta) signaling requires a ligand-dependent interaction of TGF-beta receptors Tau beta R-I and Tau beta R-II. It has been previously demonstrated that a soluble TGF-beta type II receptor could be used as a TGF-beta antagonist. Here we have generated and investigated the biochemical and signaling properties of a soluble TGF-beta type I receptor (Tau beta RIs-Fc). As reported for the wild-type receptor, the soluble Tau beta R-I does not bind TGF-beta 1 on its own. Surprisingly, in the absence of TGF-beta1, the Tau beta RIs-Fc mimicked TGF-beta 1-induced transcriptional and growth responses in mink lung epithelial cells (Mv1Lu). Signaling induced by the soluble TGF-beta type I receptor is mediated via the obligatory presence of both TGF-beta type I and type II receptors at the cell surface since no signal was observed in Mv1Lu-derivated mutants for TGF-beta receptors R-1B and DR-26. The comparison between the structures of TGF-betas and a three-dimensional model of the extracellular domain of Tau beta RI has shown that five residues of the supposed binding site of TGF-beta 1 (Lys(31), His(34), Glu(5), Tyr(91), and Lys(94)) were found with equivalent biochemical properties and similar spatial positions. PMID:11544249

Docagne, F; Colloc'h, N; Bougueret, V; Page, M; Paput, J; Tripier, M; Dutartre, P; MacKenzie, E T; Buisson, A; Komesli, S; Vivien, D

2001-12-01

72

An air-stable low-bandgap n-type organic polymer semiconductor exhibiting selective solubility in perfluorinated solvents.  

PubMed

A thin-film transistor: An n-type polymer semiconductor, poly(2,3-bis(perfluorohexyl)thieno[3,4-b]pyrazine), was synthesized through a Pd-catalyzed polycondensation employing a perfluorinated multiphase solvent system. This is the first example of an n-type polymer semiconductor with exclusive solubility in fluorinated solvents. The fabrication of organic field effect transistors containing this new n-type polymer semiconductor is shown. PMID:22887312

Takeda, Youhei; Andrew, Trisha L; Lobez, Jose M; Mork, A Jolene; Swager, Timothy M

2012-08-09

73

Activin and inhibin have opposite effects on steroid 5?-reductase activity in genital skin fibroblasts  

Microsoft Academic Search

The transforming growth factor ? (TGF-?) superfamily includes several closely related peptides including the activins and inhibins. Since we recently reported that TGF-?1 and ?2 are potent inducers of steroid 5?-reductase (5?R), we have now studied the effects of these other peptides using primary cultures of human scrotal skin fibroblasts. Recombinant human activin A or inhibin A were added to

I. Antonipillai; M. Wahe; J. Yamamoto; R. Horton

1995-01-01

74

Activin B Promotes Epithelial Wound Healing In Vivo through RhoA-JNK Signaling Pathway  

PubMed Central

Background Activin B has been reported to promote the proliferation and migration of keratinocytes in vitro via the RhoA-JNK signaling pathway, whereas its in vivo role and mechanism in wound healing process has not yet been elucidated. Principal Findings In this study, we explored the potential mechanism by which activin B induces epithelial wound healing in mice. Recombinant lentiviral plasmids, with RhoA (N19) and RhoA (L63) were used to infect wounded KM mice. The wound healing process was monitored after different treatments. Activin B-induced cell proliferation on the wounded skin was visualized by electron microscopy and analyzed by 5?-bromodeoxyuridine (BrdU) incorporation assay. Protein expression of p-JNK or p-cJun was determined by immunohistochemical staining and immunoblotting analysis. Activin B efficiently stimulated the proliferation of keratinocytes and hair follicle cells at the wound area and promoted wound closure. RhoA positively regulated activin B-induced wound healing by up-regulating the expression of p-JNK and p-cJun. Moreover, suppression of RhoA activation delayed activin B-induced wound healing, while JNK inhibition recapitulated phenotypes of RhoA inhibition on wound healing. Conclusion These results demonstrate that activin B promotes epithelial wound closure in vivo through the RhoA-Rock-JNK-cJun signaling pathway, providing novel insight into the essential role of activin B in the therapy of wound repair.

Wang, Xue-Er; Chen, Ying-Hua; Li, Qing-Lin; Lu, Kang-Rong; Sun, Li; Jia, Qin; Zhang, Lu; Zhang, Lin

2011-01-01

75

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

2013-05-21

76

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

2012-12-31

77

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

78

The novel water-soluble chiral PNNP-type ligand for the enantioselective reduction of ketones in aqueous media  

Microsoft Academic Search

The condensation of o-(diphenylphosphino)benzaldehyde and (R,R)-1,2-diaminocyclohexane in dichloromethane gives a diiminodiphosphine ligand, which is reduced with excess NaBH4 in refluxing ethanol to afford the corresponding diaminodiphosphine ligand [(R,R)-C6P2(NH)2]. The novel water-soluble PNNP-type tetradentate diaminodiphosphine ligand [(R,R)-C6P2(NH)2(SO3Na)4] has been prepared by the sulfonation of the chiral ligand [(R,R)-C6P2(NH)2] and also characterized by IR, NMR and CD. The water-soluble iridium catalyst is

Bao-Zhu Li; Jian-Shan Chen; Zhen-Rong Dong; Yan-Yun Li; Qing-Biao Li; Jing-Xing Gao

2006-01-01

79

Involvement of Cyclic Adenosine 3',5'Monophosphate in the Differential Regulation of Activin betaA and betaB Expression by Gonadotropin in the Zebrafish Ovarian Follicle Cells  

Microsoft Academic Search

Activin is a dimeric protein consisting of two similar but dis- tinct -subunits, A and B. In our previous studies, both activin A (AA) and activin B (BB) have been demon- strated to stimulate oocyte maturation and promote oocyte maturational competence in the zebrafish. Follistatin, a spe- cific activin-binding protein, can block both activin- and gonadotropin-induced final oocyte maturation in

YAJUN WANG; WEI GE

2003-01-01

80

Functional evaluation of ES cell-derived endodermal populations reveals differences between Nodal and Activin A-guided differentiation  

PubMed Central

Embryonic stem (ES) cells hold great promise with respect to their potential to be differentiated into desired cell types. Of interest are organs derived from the definitive endoderm, such as the pancreas and liver, and animal studies have revealed an essential role for Nodal in development of the definitive endoderm. Activin A is a related TGF? member that acts through many of the same downstream signaling effectors as Nodal and is thought to mimic Nodal activity. Detailed characterization of ES cell-derived endodermal cell types by gene expression analysis in vitro and functional analysis in vivo reveal that, despite their similarity in gene expression, Nodal and Activin-derived endodermal cells exhibit a distinct difference in functional competence following transplantation into the developing mouse embryo. Pdx1-expressing cells arising from the respective endoderm populations exhibit extended differences in their competence to mature into insulin/c-peptide-expressing cells in vivo. Our findings underscore the importance of functional cell-type evaluation during stepwise differentiation of stem cells.

Chen, Alice E.; Borowiak, Malgorzata; Sherwood, Richard I.; Kweudjeu, Anastasie; Melton, Douglas A.

2013-01-01

81

Inhibin, activin, follistatin, activin receptors and beta-glycan gene expression in the placental tissue of patients with pre-eclampsia.  

PubMed

The objective of this study was to quantify the relative expression of inhibin alpha, inhibin/activin beta(A), beta(B), beta(C), follistatin, activin receptors and beta-glycan genes in placental tissue of term pre-eclamptic patients and controls to investigate if these genes are up-regulated in the placenta in pre-eclampsia. Seven women with pre-eclampsia symptoms were matched with 10 normal pregnant controls for gestational age, maternal age, and parity. Total RNA was isolated from each sample. Complementary DNA samples produced by reverse transcription were used in the real time PCR to quantify the expression of inhibin alpha subunit, inhibin/activin beta(A), beta(B), beta(C) subunits, follistatin, ACTRIA, ACTRIB, ACTRIIA, ACTRIIB, beta-glycan and GAPDH genes. The ratio between the target and GAPDH expression was calculated to provide relative gene expression. Inhibin alpha:GAPDH and inhibin/activin beta(A): GAPDH ratios were significantly higher in placental tissue from women with pre-eclampsia (P = 0.04 and P = 0.01 respectively) compared with matched control placental gene expression. Placental samples from both groups expressed beta(B), beta(C), follistatin, activin receptors and beta-glycan genes. However, there was no significant difference in the relative expression of these genes between the groups. Increases in the placental expression of inhibin alpha and inhibin/activin beta(A) subunit genes could contribute to the rise in circulating levels of inhibin A and activin A in pre-eclampsia. The mechanism(s) involved in increased gene expression in pre-eclampsia is as yet unclear. PMID:12651901

Casagrandi, D; Bearfield, C; Geary, J; Redman, C W; Muttukrishna, S

2003-04-01

82

Effect of activin A on OVCAR-3 Ovarian epithelial cancer cells  

Microsoft Academic Search

Objective  To investigate the proliferation effect and its pathway of activin A on Ovarian epithelial cancer cells line OVCAR-3.\\u000a \\u000a \\u000a \\u000a Methods  OVCAR-3 cells were cultured in vitro and the membrane receptor ActR II was detected by immunohistochemical method. The OVCAR-3 cells were cultured with 10 ng\\/ml\\u000a activin A for 7 d to observe the effects. Activin A at 5, 10, 15 and 20

Xiu-qin Li; Bo Ren; Zhen-hua Du

2008-01-01

83

Extremely Variable Conservation of ?-Type Small, Acid-Soluble Proteins from Spores of Some Species in the Bacterial Order Bacillales ?  

PubMed Central

?-Type small, acid-soluble spore proteins (SASP) are the most abundant proteins in spores of at least some members of the bacterial order Bacillales, yet they remain an enigma from both functional and phylogenetic perspectives. Current work has shown that the ?-type SASP or their coding genes (sspE genes) are present in most spore-forming members of Bacillales, including at least some members of the Paenibacillus genus, although they are apparently absent from Clostridiales species. We have applied a new method of searching for sspE genes, which now appear to also be absent from a clade of Bacillales species that includes Alicyclobacillus acidocaldarius and Bacillus tusciae. In addition, no ?-type SASP were found in A. acidocaldarius spores, although several of the DNA-binding ?/?-type SASP were present. These findings have elucidated the phylogenetic origin of the sspE gene, and this may help in determining the precise function of ?-type SASP.

Vyas, Jay; Cox, Jesse; Setlow, Barbara; Coleman, William H.; Setlow, Peter

2011-01-01

84

Extremely variable conservation of ?-type small, acid-soluble proteins from spores of some species in the bacterial order Bacillales.  

PubMed

?-Type small, acid-soluble spore proteins (SASP) are the most abundant proteins in spores of at least some members of the bacterial order Bacillales, yet they remain an enigma from both functional and phylogenetic perspectives. Current work has shown that the ?-type SASP or their coding genes (sspE genes) are present in most spore-forming members of Bacillales, including at least some members of the Paenibacillus genus, although they are apparently absent from Clostridiales species. We have applied a new method of searching for sspE genes, which now appear to also be absent from a clade of Bacillales species that includes Alicyclobacillus acidocaldarius and Bacillus tusciae. In addition, no ?-type SASP were found in A. acidocaldarius spores, although several of the DNA-binding ?/?-type SASP were present. These findings have elucidated the phylogenetic origin of the sspE gene, and this may help in determining the precise function of ?-type SASP. PMID:21317325

Vyas, Jay; Cox, Jesse; Setlow, Barbara; Coleman, William H; Setlow, Peter

2011-02-11

85

Cytosolic proteins lose solubility as amyloid deposits in a transgenic mouse model of Alzheimer-type amyloidosis.  

PubMed

The extracellular accumulation of ?-amyloid peptide is a key trigger in the pathogenesis of Alzheimer's disease (AD). In humans, amyloid deposition precedes the appearance of intracellular inclusion pathology formed by cytosolic proteins such as Tau, ?-synuclein and TDP-43. These secondary pathologies have not been observed in mice that model Alzheimer-type amyloidosis by expressing mutant amyloid precursor protein, with or without mutant presenilin 1. The lack of secondary pathology in these models has made it difficult to establish how amyloid deposition initiates the cascade of events that leads to secondary intracellular pathology that characterizes human AD. In transgenic mice that model Alzheimer-type amyloidosis, we sought to determine whether there is evidence of altered cytosolic protein folding by assessing whether amyloid deposition causes normally soluble proteins to misfold. Using a method that involved detergent extraction and sedimentation coupled with proteomic approaches, we identified numerous cytosolic proteins that show specific losses in solubility as amyloid accumulates. The proteins identified included glycolytic enzymes and members of the 14-3-3 chaperone family. A substantial accumulation of lysine 48-linked polyubiquitin was also detected. Overall, the data demonstrate that the accumulation of amyloid by some manner causes the loss of solubility intracellular cytosolic proteins. PMID:23512986

Xu, Guilian; Stevens, Stanley M; Moore, Brenda D; McClung, Scott; Borchelt, David R

2013-03-19

86

Signaling through the TGF Beta-Activin Receptors ALK4/5/7 Regulates Testis Formation and Male Germ Cell Development  

PubMed Central

The developing testis provides an environment that nurtures germ cell development, ultimately ensuring spermatogenesis and fertility. Impacts on this environment are considered to underlie aberrant germ cell development and formation of germ cell tumour precursors. The signaling events involved in testis formation and male fetal germ cell development remain largely unknown. Analysis of knockout mice lacking single Tgf? family members has indicated that Tgf?'s are not required for sex determination. However, due to functional redundancy, it is possible that additional functions for these ligands in gonad development remain to be discovered. Using FACS purified gonadal cells, in this study we show that the genes encoding Activin's, TGF?'s, Nodal and their respective receptors, are expressed in sex and cell type specific patterns suggesting particular roles in testis and germ cell development. Inhibition of signaling through the receptors ALK4, ALK5 and ALK7, and ALK5 alone, demonstrated that TGF? signaling is required for testis cord formation during the critical testis-determining period. We also show that signaling through the Activin/NODAL receptors, ALK4 and ALK7 is required for promoting differentiation of male germ cells and their entry into mitotic arrest. Finally, our data demonstrate that Nodal is specifically expressed in male germ cells and expression of the key pluripotency gene, Nanog was significantly reduced when signaling through ALK4/5/7 was blocked. Our strategy of inhibiting multiple Activin/NODAL/TGF? receptors reduces the functional redundancy between these signaling pathways, thereby revealing new and essential roles for TGF? and Activin signaling during testis formation and male germ cell development.

Stringer, Jessica M.; van den Bergen, Jocelyn A.; Wilhelm, Dagmar; Sinclair, Andrew H.; Western, Patrick S.

2013-01-01

87

Activin A\\/Erythroid Differentiation Factor Is Induced during Human Monocyte Activation  

Microsoft Academic Search

Summary Activin A\\/erythroid differentiation factor (EDF), a dimeric polypeptide hormone composed of two OA subunits, regulates growth and erythroid differentiation of human hematopoietic progenitor and erythroleukemia cells. We have identified activated human peripheral blood monocytes as a natural source of activin A\\/EDF. In these cells, lipopolysaccharide (LPS) induced rapidly the expression of the OA subunit mRNAs through protein kinase C-dependent

Marja Eramaa; Mikko Hurme; Ulf-HAkan Stenman; Olli Ritvos

88

Induction of ?-A activin expression by synaptic activity and during neocortical development  

Microsoft Academic Search

?-A activin is a member of the transforming growth factor-? family and has been implicated in nerve cell survival and inhibition of differentiationin vitro [Hashimoto M.et al. (1990)Biochem. biophys. Res. Commun.173, 193–200; Schubert D.et al. (1990)Nature344, 868–870]. In our studies to identify genomic mechanisms involved in long-term neuronal responses to synaptic activity, we have determined that ?-A activin messenger RNA

K. Andreasson; P. F. Worley

1995-01-01

89

In Vitro Control of Organogenesis by ActivinA Treatment of Amphibian and Mouse Stem Cells  

Microsoft Academic Search

After identification of “organizer region” in amphibian embryos by Spemann-Mangold in 1930s, presence of limited number of\\u000a factors had been proposed for fundamental embryonic patterning with mesoderm formation. However, these factors had remained\\u000a unknown for a long time. In 1998, we have identified activin as the mesoderm-inducing factor. In this chapter, with various\\u000a conditions of activin A treatment, we demonstrated

Makoto Asashima; Akira Kurisaki; Tatsuo Michiue

90

Activin promotes differentiation of cultured mouse trophoblast stem cells towards a labyrinth cell fate.  

PubMed

Prolonged maintenance of trophoblast stem (TS) cells requires fibroblast growth factor (FGF) 4 and embryonic fibroblast feeder cells or feeder cell-conditioned medium. Previous studies have shown that TGF-beta and Activin are sufficient to replace embryonic fibroblast-conditioned medium. Nodal, a member of the TGF-beta superfamily, is also known to be important in vivo for the maintenance of TS cells in the developing placenta. Our current studies indicate that TS cells do not express the Nodal co-receptor, Cripto, and do not respond directly to active Nodal in culture. Conversely, Activin subunits and their receptors are expressed in the placenta and TS cell cultures, with Activin predominantly expressed by trophoblast giant cells (TGCs). Differentiation of TS cells in the presence of TGC-conditioned medium or exogenous Activin results in a reduction in the expression of TGC markers. In line with TGC-produced Activin representing the active component in TGC-conditioned medium, this differentiation-inhibiting effect can be reversed by the addition of follistatin. Additional experiments in which TS cells were differentiated in the presence or absence of exogenous Activin or TGF-beta show that Activin but not TGF-beta results in the maintenance of expression of TS cell markers, prolongs the expression of syncytiotrophoblast markers, and significantly delays the expression of spongiotrophoblast and TGC markers. These results suggest that Activin rather than TGF-beta (or Nodal) acts directly on TS cells influencing both TS cell maintenance and cell fate, depending on whether the cells are also exposed to FGF4. PMID:19716815

Natale, David R C; Hemberger, Myriam; Hughes, Martha; Cross, James C

2009-08-28

91

Regulation of activin A in cell proliferation and hormone secretion by human normal trophoblast cells  

Microsoft Academic Search

Regulation of activin A in cell proliferation as well as hCG and progesterone secretion was investigated using primary cultured\\u000a cytotrophoblast cells and normal placenta origin cytotrophoblast cell line-NPC cells in serum-free system. It was shown that\\u000a activin A promoted hCG and progesterone secretion in primary cultured cytotrophoblast cells as well as progesterone secretion\\u000a in NPC cells, while it had no

Yanling Wang; J. P. Mathe; T. Woodroff; Shuyi Luo; Linzhi Zhuang

1999-01-01

92

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

2013-10-17

93

Binding of soluble type I collagen to fibroblasts: specificities for native collagen types, triple helical structure, telopeptides, propeptides, and cyanogen bromide-derived peptides  

PubMed Central

Unlabeled collagenous proteins were quantified as inhibitors of binding of native, soluble, radioiodinated type I collagen to the fibroblast surface. Collagen types IV, V a minor cartilage isotype (1 alpha 2 alpha 3 alpha), and the collagenlike tail of acetylcholinesterase did not inhibit binding. Collagen types II and III behaved as competitive inhibitors of type I binding. Denaturation of native collagenous molecules exposed cryptic inhibitory determinants in the separated constituent alpha chains. Inhibition of binding by unlabeled type I collagen was not changed by enzymatic removal of the telopeptides. Inhibitory determinants were detected in cyanogen bromide-derived peptides from various regions of helical alpha 1 (I) and alpha 1(III) chains. The aminoterminal propeptide of chick pro alpha 1(I) was inhibitory for binding, whereas the carboxyterminal three-chain propeptide fragment of human type I procollagen was not. The data are discussed in terms of the proposal that binding to surface receptors initiates the assembly of periodic collagen fibrils in vivo.

1982-01-01

94

High levels of circulating soluble receptors for tumor necrosis factor in hairy cell leukemia and type B chronic lymphocytic leukemia.  

PubMed Central

The presence of soluble tumor necrosis factor (TNF) binding proteins (BP) was investigated in the sera of healthy volunteer blood donors and cancer patients. Two distinct types of TNFBP, types A and B, which are immunologically related to the cellular 75-kD TNF receptor (TNFR) and the cellular 55-kD TNFR, respectively, were assessed by immunoassays using nonblocking anti-receptor antibodies and 125I-recombinant human TNF alpha. As compared to the titers observed in 25 healthy controls, TNFBP types A and B titers were found to be elevated in almost all sera obtained from patients with underlying malignant disease. The highest amounts of TNFBP were seen in the sera of patients with B cell malignancies including hairy cell leukemia (HCL) and type B chronic lymphocytic leukemia. Treatment of HCL patients with recombinant human interferon-alpha was associated with decrease of circulating TNFBP.

Digel, W; Porzsolt, F; Schmid, M; Herrmann, F; Lesslauer, W; Brockhaus, M

1992-01-01

95

Identification of receptors and Smad proteins involved in activin signalling in a human epidermal keratinocyte cell line  

Microsoft Academic Search

Background: Activin A is a multifunctional protein, which is a member of the transforming growth factor-b (TGF-b) superfamily. Smad proteins have recently been shown to transduce signals for the TGF-b superfamily of proteins, and Smad2 was implicated in activin signalling in Xenopus embryos. Results: We identified the receptors and Smad proteins activated by activin A in a human epider- mal

Akira Shimizu; Mitsuyasu Kato; Atsuhito Nakao; Takeshi Imamura; Peter ten Dijke; Carl-Henrik Heldin; Masahiro Kawabata; Shinji Shimada; Kohei Miyazono

1998-01-01

96

Circulating angiopoietin-2 and soluble Tie2 in type 2 diabetes mellitus: a cross-sectional study  

Microsoft Academic Search

Background  Type 2 diabetes is associated with increased levels of Angiopoietin-2 (Ang-2) and soluble Tie-2 (sTie-2), but its impact on\\u000a vascular disease is still unknown. This study aimed to further explore the associations of Ang-2 and sTie-2 with metabolic\\u000a control and diabetic complications.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  In a cross-sectional designed study, levels of Ang-2 and sTie-2 as well as their relationships to cardiometabolic parameters

Sazan Rasul; Marie Helene Reiter; Aysegul Ilhan; Katharina Lampichler; Ludwig Wagner; Alexandra Kautzky-Willer

2011-01-01

97

Prevention of radiation-induced pneumonitis by recombinant adenovirus-mediated transferring of soluble TGF-? type II receptor gene  

Microsoft Academic Search

To investigate whether radiation-induced pneumonitis in the mouse-irradiated lung could be prevented by recombinant adenovirus-mediated soluble transforming growth factor-beta (TGF-?) type II receptor gene therapy. Radiation fibrosis-prone mice (C57BL\\/6J) were randomly divided into four groups consisting of a (1) control group (sham-irradiated); (2) radiation (RT)-alone group; (3) RT+AdCMVsT?R group and (4) RT+AdCMVluc group. The RT-alone and sham-irradiated mice were killed

Z Haiping; K Takayama; J Uchino; A Harada; Y Adachi; S Kura; Z Caicun; T Tsuzuki; Y Nakanishi

2006-01-01

98

Induced expression of the new cytokine, activin A, in human monocytes: inhibition by glucocorticoids and retinoic acid.  

PubMed Central

The capacity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), glucocorticoids or all-trans-retinoic acid to modulate production of activin A by human monocytes was studied. It was shown that GM-CSF stimulated monocytes to accumulate activin A RNA after as few as 4 hr of incubation, reaching a peak of stimulation at approximately 16 hr of incubation. The activin A transcripts accumulated in the monocytes after stimulation with only 5 U/ml of GM-CSF and reached a maximum plateau level of expression between 25 and 50 U/ml of GM-CSF. Biologically active activin A molecules were detected in the conditioned media by a bioassay, performed both in the absence and presence of a neutralizing antiserum for activin A. Accumulation of bioactive activin A in conditioned medium of monocyte cultures was detected after 24 hr of incubation with GM-CSF and high levels of activin A were maintained for 72 hr. The production of the dimeric beta A beta A in these monocytes was further confirmed by sandwich enzyme-linked immunosorbent assay (ELISA) specific for activin A. In contrast to the stimulatory effect of GM-CSF, hydrocortisone, dexamethasone or all-trans-retinoic acid at 1 x 10(-7) to 1 x 10(-5) M inhibited the constitutive expression of activin A and greatly suppressed the GM-CSF-stimulated production. Thus, the expression of activin A is modulated in monocytes by different agents. These observations may imply new roles for activin A at sites of inflammation where monocytes accumulate. Images Figure 1 Figure 2 Figure 3 Figure 4

Yu, J; Shao, L E; Frigon, N L; Lofgren, J; Schwall, R

1996-01-01

99

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

100

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

2013-06-20

101

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

2013-01-07

102

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

PubMed

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 family member 3 (Smad3) signaling, epithelial damage and fibrosis, suggesting a protective role for Alk3-mediated signaling in the kidney. A structure-function analysis of the BMP-Alk3-BMP receptor, type 2 (BMPR2) ligand-receptor complex, along with synthetic organic chemistry, led us to construct a library of small peptide agonists of BMP signaling that function through the Alk3 receptor. One such peptide agonist, THR-123, suppressed inflammation, apoptosis and the epithelial-to-mesenchymal transition program and reversed established fibrosis in five mouse models of acute and chronic renal injury. THR-123 acts specifically through Alk3 signaling, as mice with a targeted deletion for Alk3 in their tubular epithelium did not respond to therapy with THR-123. Combining THR-123 and the angiotensin-converting enzyme inhibitor captopril had an additive therapeutic benefit in controlling renal fibrosis. Our studies show that BMP signaling agonists constitute a new line of therapeutic agents with potential utility in the clinic to induce regeneration, repair and reverse established fibrosis. PMID:22306733

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

2012-02-05

103

Effects of age and pregnancy on the circulatory activin response of sheep to acute inflammatory challenge by lipopolysaccharide  

Microsoft Academic Search

The release of activin A in response to intravenous injection of the bacterial cell-wall component lipopolysac- charide (LPS) was investigated in an ovine model of acute inflammatory challenge in newborn and adult sheep, and in non-pregnant and pregnant ewes. Neonatal lambs (<20 days of age) showed a quantitatively similar response in terms of circulating concentrations of activin A, its binding

L McClure; A E O'Connor; S Hayward; G Jenkin; D W Walker; D J Phillips

2005-01-01

104

A second soluble Hox-type NiFe enzyme completes the hydrogenase set in Thiocapsa roseopersicina BBS.  

PubMed

Three functional NiFe hydrogenases were previously characterized in Thiocapsa roseopersicina BBS: two of them are attached to the periplasmic membrane (HynSL and HupSL), and one is localized in the cytoplasm (HoxEFUYH). The ongoing genome sequencing project revealed the presence of genes coding for another soluble Hox-type hydrogenase enzyme (hox2FUYH). Hox2 is a heterotetrameric enzyme; no indication for an additional subunit was found. Detailed comparative in vivo and in vitro activity and expression analyses of HoxEFUYH (Hox1) and the newly discovered Hox2 enzyme were performed. Functional differences between the two soluble NiFe hydrogenases were disclosed. Hox1 seems to be connected to both sulfur metabolism and dark/photofermentative processes. The bidirectional Hox2 hydrogenase was shown to be metabolically active under specific conditions: it can evolve hydrogen in the presence of glucose at low sodium thiosulfate concentration. However, under nitrogen-fixing conditions, it can oxidize H(2) but less than the other hydrogenases in the cell. PMID:20543059

Maróti, Judit; Farkas, Attila; Nagy, Ildikó K; Maróti, Gergely; Kondorosi, Eva; Rákhely, Gábor; Kovács, Kornél L

2010-06-11

105

Isolation and characterization of 5'-regulatory region of mouse activin beta A subunit gene.  

PubMed

We isolated genomic clones that contain the 5'-flanking region of the mouse activin beta A subunit gene. The nucleotide sequence determination of the 5'-flanking region of the gene and the comparison of that with the reported mouse cDNA structure identified the putative 5' regulatory region, a novel first exon and a part of the first intron of the gene within this region. The putative 5' regulatory region of the mouse activin beta A subunit gene directed the expression of CAT gene in transfected HT1080 cells. Successive deletions of this region demonstrated a 400-bp region that exerts a strong positive effect on promoter activity of the mouse activin beta A subunit gene. PMID:9530515

Yoshida, E; Tanimoto, K; Murakami, K; Fukamizu, A

1998-02-01

106

Induction of prostanoid, nitric oxide, and cytokine formation in rat bone marrow derived macrophages by activin A  

PubMed Central

In this study we describe that activin A, a transforming growth factor (TGF) ?-like polypeptide affects the expression of inflammatory response genes and their products. In rat bone marrow derived macrophages 15?nM activin A caused the stimulation of prostaglandin (PG) E2 and thromboxane (TX) A2 formation, production of nitrite as a marker for nitric oxide (NO) and the release of the cytokines tumour necrosis factor (TNF) ? and interleukin (IL) -1?. As shown by mRNA analysis induction of cyclo-oxygenase-2 and inducible nitric oxide synthase by activin A gave rise to the enhanced release of prostanoids and NO. Costimulation of bone marrow derived macrophages with 15?nM activin A and 100?nM 12-O-tetradecanoyl-phorbol 13-acetate (TPA) potentiated the synthesis of prostanoids in a synergistic manner. With respect to NO formation the effect of activin A and TPA was additive. In contrast to the nitrite production activin A induced PGE2 synthesis was susceptible to tyrosine kinase inhibition by genistein and tyrphostin 46 (IC50 was 10 and 20??M, respectively). This observed inhibition was caused by the selective suppression of activin A induced cyclo-oxygenase-2 mRNA expression. Further, the release of TNF? in the presence of activin A was potentiated by tyrosine kinase inhibition. In summary, we report that activin A exerts proinflammatory activity which results in the formation of prostanoids, NO and cytokines in rat bone marrow derived macrophages. Tyrosine kinase dependent and independent signalling pathways are involved leading to the increased synthesis of these metabolites. Based upon these results, we speculate that activin A may be considered as a possible component of inflammatory processes affecting at least the haematopoietic system.

Nusing, Rolf M; Barsig, Johannes

1999-01-01

107

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

2012-12-13

108

Regulation of the activin-inhibin-follistatin system by bone morphogenetic proteins in the zebrafish ovary.  

PubMed

In the zebrafish, the dynamic expression of the activin-inhibin-follistatin system during folliculogenesis and its exclusive localization (except follistatin) in follicle cells suggests that the system plays important roles in follicle development and that its expression is subject to tight controls, probably by external factors including those derived from the oocyte. We have previously identified zebrafish bone morphogenetic proteins (BMPs) as oocyte factors that may act on follicle cells; however, the targets of BMPs in the follicle cells remain unknown. Considering their spatiotemporal expression in the follicle, we hypothesized that members of the activin-inhibin-follistatin system in follicle cells could be potential target genes of BMPs. In the present study, we developed a novel coculture system to co-incubate zebrafish bone morphogenetic protein 2b or 4 (zfBMP2b/4)-producing Chinese hamster ovary (CHO) cells with zebrafish follicle cells. During incubation, the zfBMPs secreted from the CHO cells would act directly on the follicle cells in a paracrine manner. Our results showed that all activin beta subunits (inhbaa, inhbab, and inhbb) were down-regulated by both zfBMP2b and zfBMP4, while follistatin (fst, an activin-binding protein) and inhibin alpha (inha, an activin antagonist) were significantly up-regulated. The specificity of bone morphogenetic protein (BMP) actions was confirmed by short interfering RNA knockdown of zfBMP4 expression in the CHO cells. The robust response of inha to zfBMPs, together with our previous observation that inha expression surged at the full-grown stage prior to oocyte maturation, led us to hypothesize that the full-grown oocyte may signal upper levels of the hypothalamic-pituitary-gonadal axis its readiness to mature by releasing BMPs, which in turn stimulate inhibin production. As an ovarian hormone and activin antagonist, inhibin may suppress the action of activin in the pituitary to reduce follicle-stimulating hormone but increase luteinizing hormone (LH) biosynthesis. Meanwhile, by increasing the local follistatin level and reducing the activin production, BMPs could help prevent precocious maturation before preovulatory LH surge. PMID:23843234

Li, Cheuk Wun; Ge, Wei

2013-09-12

109

Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats.  

PubMed

This study investigated the effect of aqueous and ethanol soluble solid extracts of guava (Psidium guajava Linn.) leaves on hypoglycemia and glucose metabolism in type 2 diabetic rats. Low-dose streptozotocin (STZ) and nicotinamide were injected into Sprague-Dawley (SD) rats to induce type 2 diabetes. Acute and long-term feeding tests were carried out, and an oral glucose tolerance test (OGTT) to follow the changes in plasma glucose and insulin levels was performed to evaluate the antihyperglycemic effect of guava leaf extracts in diabetic rats.The results of acute and long-term feeding tests showed a significant reduction in the blood sugar level in diabetic rats fed with either the aqueous or ethanol extract of guava leaves (p < 0.05). Long-term administration of guava leaf extracts increased the plasma insulin level and glucose utilization in diabetic rats. The results also indicated that the activities of hepatic hexokinase, phosphofructokinase and glucose-6-phosphate dehydrogenase in diabetic rats fed with aqueous extracts were higher than in the normal diabetic group (p < 0.05). On the other hand, diabetic rats treated with the ethanol extract raised the activities of hepatic hexokinase and glucose-6-phosphate dehydrogenase (p < 0.05) only. The experiments provided evidence to support the antihyperglycemic effect of guava leaf extract and the health function of guava leaves against type 2 diabetes. PMID:18819164

Shen, Szu-Chuan; Cheng, Fang-Chi; Wu, Ning-Jung

2008-11-01

110

The activin receptor-like kinase 6 Booroola mutation enhances suppressive effects of bone morphogenetic protein 2 (BMP2), BMP4, BMP6 and growth and differentiation factor-9 on FSH release from ovine primary pituitary cell cultures  

Microsoft Academic Search

Bone morphogenetic proteins (BMPs) have been shown to influence the regulation of FSH synthesis and secretion at the level of the pituitary. Primary pituitary cells were harvested and cultured from Booroola ewes homozygous for a mutation in activin receptor-like kinase 6 (ALK6) also known as BMP receptor IB (BMPRIB), and from wild-type (WT) ewes to determine if the mutation caused

Julia M Young; Jennifer L Juengel; Kenneth G Dodds; Mhairi Laird; Peter K Dearden; Alan S McNeilly; Kenneth P McNatty; Theresa Wilson

2008-01-01

111

Lack of correlation between soluble CD4-induced shedding of the human immunodeficiency virus type 1 exterior envelope glycoprotein and subsequent membrane fusion events.  

PubMed Central

The noncovalent association of the gp120 and gp41 envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) is disrupted by soluble CD4 binding, resulting in shedding of the gp120 exterior envelope glycoprotein. This observation has led to the speculation that interaction of gp120 with the CD4 receptor triggers shedding of the exterior envelope glycoprotein, allowing exposure of gp41 domains necessary for membrane fusion steps involved in virus entry or syncytium formation. To test this hypothesis, a set of HIV-1 envelope glycoprotein mutants were used to examine the relationship of soluble CD4-induced shedding of the gp120 glycoprotein to envelope glycoprotein function in syncytium formation and virus entry. All mutants with a threefold or greater reduction in CD4-binding ability exhibited marked decreases in gp120 shedding in response to soluble CD4, even though several of these mutants exhibited significant levels of envelope glycoprotein function. Conversely, most fusion-defective mutants with wild-type gp120-CD4 binding affinity, including those with changes in the V3 loop, efficiently shed gp120 following soluble CD4 binding. Thus, soluble CD4-induced shedding of gp120 is not a generally useful marker for conformational changes in the HIV-1 envelope glycoproteins necessary for the virus entry or syncytium formation processes. Some gp120 mutants, despite being expressed on the cell surface and capable of efficiently binding soluble CD4, exhibited decreased gp120 shedding. These mutants were still sensitive to neutralization by soluble CD4, indicating that, for envelope glycoproteins exhibiting high affinity for soluble CD4, competitive inhibition may be more important than gp120 shedding for the antiviral effect. Images

Thali, M; Furman, C; Helseth, E; Repke, H; Sodroski, J

1992-01-01

112

Circulating soluble RAGE as a predictive biomarker of cardiovascular event risk in patients with type 2 diabetes.  

PubMed

It is still controversial whether circulating soluble form of receptor for AGE (sRAGE) is associated with atherosclerosis in diabetic patients. In this study, we enrolled 276 Japanese type 2 diabetic subjects without history of cardiovascular disease (CVD), assessed their baseline clinical and biochemical data including serum sRAGE levels, and prospectively evaluated the association between these parameters and CVD events. The median follow-up period was 5.6 years and there were 25 new CVD events. The tertile analysis showed that the risk for CVD events was higher as serum sRAGE levels were increased (p for trend = 0.046). A multivariate Cox proportional hazards regression analysis revealed that serum sRAGE levels were independently associated with CVD (HR per 1SD = 1.59, 95% CI 1.04-2.45, p = 0.034), even after adjusting for conventional coronary risk factors. In summary, elevated sRAGE levels were associated with the increased risk of CVD in Japanese type 2 diabetic subjects. PMID:23384720

Fujisawa, Keiko; Katakami, Naoto; Kaneto, Hideaki; Naka, Toyoko; Takahara, Mitsuyoshi; Sakamoto, Fumie; Irie, Yoko; Miyashita, Kazuyuki; Kubo, Fumiyo; Yasuda, Tetsuyuki; Matsuoka, Taka-Aki; Shimomura, Iichiro

2013-01-23

113

Binding of soluble type I collagen to fibroblasts: effects of thermal activation of ligand, ligand concentration, pinocytosis, and cytoskeletal modifiers  

PubMed Central

Efficient binding of native, soluble 125I-labeled type I rat collagen to mouse 3T3 fibroblast monolayers requires prior warming of the ligand to 35-37 degrees C for 10-30 min. Decreased binding at high ligand concentrations is ascribed to ligand-ligand interactions rather than to negative cooperativity. Addition of bacterial collagenase to monolayers labeled with the 125I-ligand releases a constant fraction (80%) of the bound ligand over a 2-h interval at 37 degrees C, indicating that little of the ligand becomes inaccessible by pinocytosis. Colchicine (10(-7) M) and vinblastine (5 X 10(-8) M) do not inhibit binding by morphologically intact monolayers. Cytochalasins and concanavalin A show dose-related inhibition of binding by intact monolayers that is due to a reduction in the number of available binding sites rather than to a change in binding site affinity. The collagen binding site on the fibroblast surface is proposed as an organizing center for the assembly of periodic type I collagen fibrils.

1982-01-01

114

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

2013-07-31

115

Expression and Function of Keratinocyte Growth Factor and Activin in Skin Morphogenesis and Cutaneous Wound Repair  

Microsoft Academic Search

Reepithelialization and granulation tissue formation during cutaneous wound repair are mediated by a wide variety of growth and differentiation factors. Recent studies from our laboratory provided evidence for an important role of keratinocyte growth factor (KGF) in the repair of the injured epithelium and for a novel function of the transforming growth factor-? superfamily member activin in granulation tissue formation.

Hans-Dietmar Beer; Marcus G. Gassmann; Barbara Munz; Heike Steiling; Felix Engelhardt; Kerstin Bleuel; Sabine Werner

2000-01-01

116

Tissue absence initiates regeneration through Follistatin-mediated inhibition of Activin signaling.  

PubMed

Regeneration is widespread, but mechanisms that activate regeneration remain mysterious. Planarians are capable of whole-body regeneration and mount distinct molecular responses to wounds that result in tissue absence and those that do not. A major question is how these distinct responses are activated. We describe a follistatin homolog (Smed-follistatin) required for planarian regeneration. Smed-follistatin inhibition blocks responses to tissue absence but does not prevent normal tissue turnover. Two activin homologs (Smed-activin-1 and Smed-activin-2) are required for the Smed-follistatin phenotype. Finally, Smed-follistatin is wound-induced and expressed at higher levels following injuries that cause tissue absence. These data suggest that Smed-follistatin inhibits Smed-Activin proteins to trigger regeneration specifically following injuries involving tissue absence and identify a mechanism critical for regeneration initiation, a process important across the animal kingdom. DOI:http://dx.doi.org/10.7554/eLife.00247.001. PMID:24040508

Gaviño, Michael A; Wenemoser, Danielle; Wang, Irving E; Reddien, Peter W

2013-09-10

117

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

118

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

2012-07-09

119

Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia  

PubMed Central

Pre-eclampsia is a common serious disorder of human pregnancy, which is associated with significant maternal and perinatal morbidity and mortality. The suspected aetiology of pre-eclampsia is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. Recently, we reported significant linkage to chromosome 2q22 in 34 Australian/New Zealand (Aust/NZ) pre-eclampsia/eclampsia families, and activin A receptor type IIA (ACVR2A) was identified as a strong positional candidate gene at this locus. In an attempt to identify the putative risk variants, we have now comprehensively re-sequenced the entire coding region of the ACVR2A gene and the conserved non-coding sequences in a subset of 16 individuals from these families. We identified 45 single nucleotide polymorphisms (SNPs), with 9 being novel. These SNPs were genotyped in our total family sample of 480 individuals from 74 Aust/NZ pre-eclampsia families (including the original 34 genome-scanned families). Our best associations between ACVR2A polymorphisms and pre-eclampsia were for rs10497025 (P = 0.025), rs13430086 (P = 0.010) and three novel SNPs: LF004, LF013 and LF020 (all with P = 0.018). After correction for multiple hypothesis testing, none of these associations reached significance (P > 0.05). Based on these data, it remains unclear what role, if any, ACVR2A polymorphisms play in pre-eclampsia risk, at least in these Australian families. However, it would be premature to rule out this gene as significant associations between ACVR2A SNPs and pre-eclampsia have recently been reported in a large Norwegian (HUNT) population sample.

Fitzpatrick, E.; Johnson, M.P.; Dyer, T.D.; Forrest, S.; Elliott, K.; Blangero, J.; Brennecke, S.P.; Moses, E.K.

2009-01-01

120

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

121

Hydrothermal synthesis of brookite-type titanium dioxide with snowflake-like nanostructures using a water-soluble citratoperoxotitanate complex  

NASA Astrophysics Data System (ADS)

Hydrothermal synthesis of brookite-type titanium dioxide was performed with excellent reproducibility using an aqueous NH3 solution of a water-soluble citratoperoxotitanate (CPT) complex. X-ray diffraction confirmed that the brookite phase was formed by hydrothermal treatment of the CPT complex in NH3 solution with a concentration of more than 6.5 wt%, whereas single phase anatase was obtained when distilled water without any additives was applied as the solvent. The aspect ratios of the obtained rod-like brookite particles increased from 5 up to 20 with an increase of the NH3 concentration. Transmission electron microscopy and selected area electron diffraction measurements provided evidence that the growth of the brookite particles is along the c-axis. Hydrothermal treatment of the CPT complex at high NH3 concentrations resulted in the formation of agglomerated brookite particles with unusual shapes, where many rod-like particles were branched around a somewhat longer central particle, and the side view of the agglomerated particles revealed two-dimensional crystal growth within a given restricted plane. The multi-needle agglomerate of particles was snowflake shaped. The reason for the formation of brookite with this unique morphology may be attributed to an intrinsic character of the CPT complex itself, although the mechanism is yet to be clarified.

Kobayashi, Makoto; Petrykin, Valery; Tomita, Koji; Kakihana, Masato

2011-12-01

122

Water-soluble LYNX1 residues important for interaction with muscle-type and/or neuronal nicotinic receptors.  

PubMed

Human LYNX1, belonging to the Ly6/neurotoxin family of three-finger proteins, is membrane-tethered with a glycosylphosphatidylinositol anchor and modulates the activity of nicotinic acetylcholine receptors (nAChR). Recent preparation of LYNX1 as an individual protein in the form of water-soluble domain lacking glycosylphosphatidylinositol anchor (ws-LYNX1; Lyukmanova, E. N., Shenkarev, Z. O., Shulepko, M. A., Mineev, K. S., D'Hoedt, D., Kasheverov, I. E., Filkin, S. Y., Krivolapova, A. P., Janickova, H., Dolezal, V., Dolgikh, D. A., Arseniev, A. S., Bertrand, D., Tsetlin, V. I., and Kirpichnikov, M. P. (2011) NMR structure and action on nicotinic acetylcholine receptors of water-soluble domain of human LYNX1. J. Biol. Chem. 286, 10618-10627) revealed the attachment at the agonist-binding site in the acetylcholine-binding protein (AChBP) and muscle nAChR but outside it, in the neuronal nAChRs. Here, we obtained a series of ws-LYNX1 mutants (T35A, P36A, T37A, R38A, K40A, Y54A, Y57A, K59A) and examined by radioligand analysis or patch clamp technique their interaction with the AChBP, Torpedo californica nAChR and chimeric receptor composed of the ?7 nAChR extracellular ligand-binding domain and the transmembrane domain of ?1 glycine receptor (?7-GlyR). Against AChBP, there was either no change in activity (T35A, T37A), slight decrease (K40A, K59A), and even enhancement for the rest mutants (most pronounced for P36A and R38A). With both receptors, many mutants lost inhibitory activity, but the increased inhibition was observed for P36A at ?7-GlyR. Thus, there are subtype-specific and common ws-LYNX1 residues recognizing distinct targets. Because ws-LYNX1 was inactive against glycine receptor, its "non-classical" binding sites on ?7 nAChR should be within the extracellular domain. Micromolar affinities and fast washout rates measured for ws-LYNX1 and its mutants are in contrast to nanomolar affinities and irreversibility of binding for ?-bungarotoxin and similar snake ?-neurotoxins also targeting ?7 nAChR. This distinction may underlie their different actions, i.e. nAChRs modulation versus irreversible inhibition, for these two types of three-finger proteins. PMID:23585571

Lyukmanova, Ekaterina N; Shulepko, Mikhail A; Buldakova, Svetlana L; Kasheverov, Igor E; Shenkarev, Zakhar O; Reshetnikov, Roman V; Filkin, Sergey Y; Kudryavtsev, Denis S; Ojomoko, Lucy O; Kryukova, Elena V; Dolgikh, Dmitry A; Kirpichnikov, Mikhail P; Bregestovski, Piotr D; Tsetlin, Victor I

2013-04-12

123

?1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-?/activin-mediated signaling.  

PubMed

It is well known that ?1,6-fucosyltransferase (Fut8) and its products, ?1,6-fucosylated N-glycans, are highly expressed in brain tissue. Recently, we reported that Fut8-knockout mice exhibited multiple behavioral abnormalities with a schizophrenia-like phenotype, suggesting that ?1,6-fucosylation plays important roles in the brain and neuron system. In the present study, we screened several neural cell lines and found that PC12 cells express the highest levels of ?1,6-fucosylation. The knockdown (KD) of Fut8 promoted a significant enhancement of neurite formation and induction of neurofilament expression. Surprisingly, the levels of phospho-Smad2 were greatly increased in the KD cells. Finally, we found that the activin-mediated signal pathway was essential for these changes in KD cells. Exogenous activin, not TGF-?1, induced neurite outgrowth and phospho-Smad2. In addition, the ?1,6-fucosylation level on the activin receptors was greatly decreased in KD cells, while the total expression level was unchanged, suggesting that ?1,6-fucosylation negatively regulated activin-mediated signaling. Furthermore, inhibition of activin receptor-mediated signaling or restoration of Fut8 expression rescued cell morphology and phospho-Smad2 levels, which were enhanced in KD cells. Considering the fact that ?1,6-fucosylation is important for TGF-?-mediated signaling, the results of this study strongly suggest that Fut8 plays a dual role in TGF-?/activin-mediated signaling.-Gu, W., Fukuda, T., Isaji, T., Hashimoto, H., Wang, Y., Gu, J. ?1,6-Fucosylation regulates neurite formation via the activin/phospho-Smad2 pathway in PC12 cells: the implicated dual effects of Fut8 for TGF-?/activin-mediated signaling. PMID:23796784

Gu, Wei; Fukuda, Tomohiko; Isaji, Tomoya; Hashimoto, Hirokazu; Wang, Yuqin; Gu, Jianguo

2013-06-24

124

Immunization of macaques with soluble HIV type 1 and influenza virus envelope glycoproteins results in a similarly rapid contraction of peripheral B-cell responses after boosting.  

PubMed

The envelope glycoproteins (Env) represent a critical component of a successful antibody-mediated human immunodeficiency virus type 1 (HIV-1) vaccine. However, immunization with soluble Env was reported to induce short-lived antibody responses, suggesting that Env has unusual immunogenic properties. Here, we directly compared the magnitude and durability of B-cell responses induced by HIV-1 Env and an unrelated soluble viral protein, influenza virus hemagglutinin (HA), in simultaneously inoculated macaques. We demonstrate robust peak responses followed by rapid contraction of circulating antibody and memory B cells for both antigens, suggesting that short-lived responses are not unique to HIV-1 Env but may be a common feature of soluble protein vaccines. PMID:23162135

Sundling, Christopher; Martinez, Paola; Soldemo, Martina; Spångberg, Mats; Bengtsson, Karin Lövgren; Stertman, Linda; Forsell, Mattias N E; Karlsson Hedestam, Gunilla B

2012-11-16

125

Regulatory expression of genes related to metastasis by TGF-? and activin A in B16 murine melanoma cells  

Microsoft Academic Search

TGF-? induces epithelial-mesenchymal transition, which occurs during tumor cell invasiveness in pathological state, in limited\\u000a cells. As a first step to understand the role of TGF-? and the structurally related activin during melanoma metastasis, expression\\u000a of metastasis-related genes was examined in murine melanoma cells. Treatment with TGF-?1 or activin A down-regulated E-cadherin\\u000a in B16 cells in a dose-dependent manner. In

Masaru Murakami; Makiko Suzuki; Yoshii Nishino; Masayuki Funaba

2010-01-01

126

Stimulating Effect of Both Human Recombinant Inhibin A and Activin A on Immature Porcine Leydig Cell Functions in Vitro  

Microsoft Academic Search

In addition to the regulation of FSH secretion, it has been clearly shown that inhibin and activin have paracrine\\/autocrine effects in the gonads. We have studied the effect of human recombinant inhibin A and human recombinant activin A on immature porcine Leydig cells in vitro. Leydig cells were prepared by collagenase digestion of testes from 3-week-old piglets, purified on Percoll

H. Lejeune; PASCALE SANCHEZ; PHILIPPE DURAND; JENNIE P. MATHER; JOSEM. SAEZ

1997-01-01

127

Lenalidomide in combination with an activin A-neutralizing antibody: preclinical rationale for a novel anti-myeloma strategy.  

PubMed

Given the prevalence of osteolytic bone disease in multiple myeloma (MM), novel therapies targeting bone microenvironment are essential. Previous studies have identified activin A to be of critical importance in MM-induced osteolysis. Lenalidomide is a known and approved treatment strategy for relapsed MM. Our findings demonstrate that lenalidomide acts directly on bone marrow stromal cells via an Akt-mediated increase in Jun N-terminal kinase-dependent signaling resulting in activin A secretion, with consequent inhibition of osteoblastogenesis. Here, we attempted to augment the antitumor benefits of lenalidomide while overcoming its effects on osteoblastogenesis by combining it with a neutralizing antibody to activin A. Increased activin A secretion induced by lenalidomide was abrogated by the addition of activin A-neutralizing antibody, which effectively restored osteoblast function and inhibited MM-induced osteolysis without negating the cytotoxic effects of lenalidomide on malignant cells. This provides the rationale for an ongoing clinical trial (NCT01562405) combining lenalidomide with an anti-activin A strategy. PMID:23417027

Scullen, T; Santo, L; Vallet, S; Fulciniti, M; Eda, H; Cirstea, D; Patel, K; Nemani, N; Yee, A; Mahindra, A; Raje, N

2013-02-18

128

Relationship of protein molecular structure to metabolisable proteins in different types of dried distillers grains with solubles: a novel approach.  

PubMed

To date, there has been no study of protein molecular structures affected by bioethanol processing in relation to protein nutritive values of the new co-products of bioethanol production. The objective of the present study was to investigate the relationship between protein molecular structures (in terms of protein ?-helix and ?-sheet spectral intensity and their ratio and amide I to amide II spectral intensity and their ratio) and protein rumen degradation kinetics (rate and extent), estimated protein intestinal digestibility and total truly absorbed protein in small intestine (metabolisable protein) in different types of dried distillers grains with solubles (DDGS), such as wheat DDGS, maize DDGS and blend DDGS (wheat:maize = 70:30). The protein molecular structures of the different types of DDGS affected by processing were identified using diffuse reflectance IR Fourier transform spectroscopy. The results showed that the protein structure ?-helix to ?-sheet ratio in the DDGS had a strongly negative correlation with estimated intestinal digestibility of ruminally undegraded protein (%dRUP, R - 0.95, P = 0.04), tended to have a significant correlation with the protein PC subfraction (which was undegradable and contained proteins associated with lignin and tannins and heat-damaged proteins) (R 0.91, P = 0.09) and had no correlation (P>0.10) with rumen degradation kinetics (rate and extent), total intestinally absorbed protein supply and degraded protein balance. However, the protein amide I to amide II ratio in the DDGS had a strongly positive correlation with soluble crude protein (CP) (R 0.99, P < 0.01), protein PA subfraction (which was instantaneously solubilised at time zero) (R 0.99, P < 0.01), protein PB2 subfraction (which was intermediately degradable) (R - 0.95, P = 0.04) and total digestible CP (R 0.95, P = 0.04). The amide I to amide II ratio also had strongly negative correlations with ruminally undegraded protein (%RUP: R - 0.96, P = 0.03) and the degraded protein balance (OEB: R - 0.97, P = 0.02), but had no correlation (P>0.10) with the total intestinally absorbed protein supply. Multiple regression results show that the protein structure ?-helix to ?-sheet ratio was a better predictor of %dRUP with R² 0.92. The amide I to II ratio was a better predictor of the degraded protein balance with R² 0.93 in the DDGS. In conclusion, the changes in the protein molecular structure ?-helix to ?-sheet ratio and the amide I to amide II ratio during bioethanol processing (either due to fermentation processing or due to heat drying) were highly associated with estimated protein intestinal digestibility and degraded protein balance, but were not associated with total intestinally absorbed protein supply from the DDGS to dairy cattle. The present study indicates that a potential novel method could be developed based on the protein molecular structure parameters to improve the estimation of protein value after a validation in a large-scale in vivo study is done. PMID:20594396

Yu, Peiqiang; Nuez-Ortín, Waldo G

2010-07-02

129

Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection  

PubMed Central

Objectives Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to ?3-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease. Design A single-centre prospective cohort study. Subjects and Methods Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA). Results The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r?=?0.475, p<0.001), maximum plasma creatinine concentration (r?=?0.378, p<0.001), change in weight during the hospitalization (r?=?0.406, p<0.001) and the length of hospitalization (r?=?0.325, p?=?0.001), and an inverse correlation with minimum platelet count (r?=??0.325, p?=?0.001) and minimum hematocrit (r?=??0.369, p<0.001). Conclusion Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates ?3-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.

Outinen, Tuula K.; Tervo, Laura; Makela, Satu; Huttunen, Reetta; Maenpaa, Niina; Huhtala, Heini; Vaheri, Antti; Mustonen, Jukka; Aittoniemi, Janne

2013-01-01

130

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

131

Activin A Induces Expression of Rat Sel-1l mRNA, a Negative Regulator of Notch Signaling, in Rat Salivary Gland-Derived Epithelial Cells  

Microsoft Academic Search

We previously established a rat submandibular gland (SMG)-derived epithelial cell line (RSMG-1) to study the mechanism of morphogenesis in salivary gland development and regeneration. We found that activin A regulated the branching morphogenesis of RSMG-1 cells, suggesting that it is involved in SMG morphogenesis. We used a subtraction cloning procedure with activin-A-treated and untreated RSMG-1 cells to identify activin-A-induced genes.

Miho Furue; Yan Zhang; Tetsuji Okamoto; Ryu-Ichiro Hata; Makoto Asashima

2001-01-01

132

Nodal signaling uses activin and transforming growth factor-beta receptor-regulated Smads.  

PubMed

Nodal, a member of the transforming growth factor beta (TGF-beta) superfamily, is implicated in many events critical to the early vertebrate embryo, including mesoderm formation, anterior patterning, and left-right axis specification. Here we define the intracellular signaling pathway induced by recombinant nodal protein treatment of P19 embryonal carcinoma cells. Nodal signaling activates pAR3-Lux, a luciferase reporter previously shown to respond specifically to activin and TGF-beta. However, nodal is unable to induce pTlx2-Lux, a reporter specifically responsive to bone morphogenetic proteins. We also demonstrate that nodal induces p(CAGA)(12), a reporter previously shown to be specifically activated by Smad3. Expression of a dominant negative Smad2 significantly reduces the level of luciferase reporter activity induced by nodal treatment. Finally, we show that nodal signaling rapidly leads to the phosphorylation of Smad2. These results provide the first direct biochemical evidence that nodal signaling is mediated by both activin-TGF-beta pathway Smads, Smad2 and Smad3. We also show here that the extracellular cripto protein is required for nodal signaling, making it distinct from activin or TGF-beta signaling. PMID:11024047

Kumar, A; Novoselov, V; Celeste, A J; Wolfman, N M; ten Dijke, P; Kuehn, M R

2001-01-01

133

A Soluble Transforming Growth Factor b Type III Receptor Suppresses Tumorigenicity and Metastasis of Human Breast Cancer MDA-MB-231 Cells1  

Microsoft Academic Search

Transforming growth factor b (TGF-b) can promote late stage tumor progression in a number of model systems. In the present study, we have examined whether expression of a truncated soluble extracellular domain of TGF-b type III receptor (sRIII) in human breast cancer MDA-MB-231 cells can antagonize the tumor-promoting activity of TGF-b by seques- tering active TGF-b isoforms that are produced

Abhik Bandyopadhyay; Yong Zhu; Michael L. Cibull; LiWei Bao; Changguo Chen; LuZhe Sun

134

Plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) and early mortality risk among patients enrolling for antiretroviral treatment in South Africa  

Microsoft Academic Search

BACKGROUND: Serum concentrations of soluble urokinase-type plasminogen activator receptor (suPAR) have a strong independent association with HIV-1-related mortality. The practical utility of plasma suPAR in assessing short-term all-cause mortality risk was evaluated in patients with advanced immunodeficiency enrolling in an antiretroviral treatment (ART) programme in South Africa. METHODS: An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma concentrations of

Stephen D Lawn; Landon Myer; Nonzwakazi Bangani; Monica Vogt; Robin Wood

2007-01-01

135

Changes in extracellular activin A:follistatin ratio during differentiation of a mesenchymal progenitor cell line, ROB-C26 into osteoblasts and adipocytes.  

PubMed

We investigated the effects of BMP-2 and dexamethasone (Dex) on follistatin (FS) and activin A expressions in a mesenchymal progenitor cell line, ROB-C26 (C26). C26 cells stimulated to differentiate into osteoblastic cells by blocking myogenic differentiation after BMP-2 treatment and into adipocytes with Dex treatment. Alkaline phosphatase (ALP) mRNA expression and its activity in the confluent C26 cells were dose- and time-dependently stimulated by BMP-2, but inhibited by Dex. The stimulatory effect on FS and activin A mRNA expressions by BMP-2 and Dex were dose-dependent. Cycloheximide pre-treatment indicated that FS and activin A expressions appear to be the direct target of BMP-2 and Dex signaling. BMP-2 time-dependently increased FS and activin A levels. Dex also increased FS level, but induced a time-dependent biphasic effect on activin A level, a decrease (2-6 h) followed by an increase (12-72 h). The data of the ratio of activin A concentration in the culture media to that of FS (activin A:FS ratio) measured by ELISA showed that BMP-2-induced osteoblastic differentiation involved an activin-dominant microenvironment, whereas Dex-induced adipocyte differentiation involved a FS-dominant microenvironment. Excess FS suppressed the stimulatory ALP activity of BMP-2, whereas activin A prevented not only Dex-induced inhibitory ALP activity, but also adipogenesis via suppression of the adipocyte transcriptional factor cascade. These results indicate that BMP-2-induced activin-dominant microenvironment may be critical for osteoblastic differentiation by restricting the antagonistic effects of FS on BMP activity, while Dex-induced FS-dominant microenvironment may be critical for adipocyte differentiation by restricting the inhibitory action of activin A on adipocyte differentiation. PMID:17512555

Kawabata, Niki; Kamiya, Naoko; Suzuki, Naoto; Matsumoto, Mitsuhiko; Takagi, Minoru

2007-04-21

136

Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes  

Microsoft Academic Search

Aims\\/hypothesis  Activation of the receptor for AGE (RAGE) is implicated in the development and progression of vascular complications of diabetes.\\u000a In this study, we explore factors and mortality outcomes associated with soluble RAGE (sRAGE) in a multicentre nationwide\\u000a cohort of Finnish adults with type 1 diabetes.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Baseline sRAGE concentrations were estimated in 3,100 adults with type 1 diabetes. Clinical and biological

M. C. Thomas; J. Söderlund; M. Lehto; V.-P. Mäkinen; J. L. Moran; M. E. Cooper; C. Forsblom; P.-H. Groop

137

A truncated, activin-induced Smad3 isoform acts as a transcriptional repressor of FSH? expression in mouse pituitary  

PubMed Central

The receptor-regulated protein Smad3 is key player in the signaling cascade stimulated by the binding of activin to its cell surface receptor. Upon phosphorylation, Smad3 forms a heterocomplex with Smad2 and Smad4, translocates to the nucleus and acts as a transcriptional co-activator. We have identified a unique isoform of Smad3 that is expressed in mature pituitary gonadotropes. 5' RACE revealed that this truncated Smad3 isoform is transcribed from an ATG site within exon 4 and consists of 7 exons encoding half of the linker region and the MH2 region. In pituitary cells, the truncated Smad3 isoform was phosphorylated upon activin treatment, in a manner that was temporally distinct from the phosphorylation of full-length Smad3. Activin-induced phosphorylation of Smad3 and the truncated Smad3 isoform was blocked by both follistatin and siRNA-mediated knockdown of Smad3. The truncated Smad3 isoform antagonized Smad3-mediated, activin-responsive promoter activity. We propose that the pituitary gonadotrope contains an ultra-short, activin-responsive feedback loop utilizing two different isoforms of Smad3, one which acts as an agonist (Smad3) and another that acts as an intracrine antagonist (truncated Smad3 isoform) to regulate FSH? production.

Kim, So-Youn; Zhu, Jie; Woodruff, Teresa K.

2011-01-01

138

Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells  

Microsoft Academic Search

Soluble forms of HLA-G (sHLA-G) have been implicated in immune regulation. Fetal trophoblast cells are a prime source of HLA-G. Hence, an interaction between sHLA-G and uterine lymphocytes in the decidual tissues can easily be envisaged. These lymphocytes, when properly activated, are implicated in successful trophoblast invasion, placental maturation and maintenance of pregnancy. However, so far, no data are available

A. van der Meer; H. G. M. Lukassen; B. van Cranenbroek; E. H. Weiss; D. D. M. Braat; M. J. C. van Lierop; I. Joosten

2007-01-01

139

Stimulation of Activin A/Nodal signaling is insufficient to induce definitive endoderm formation of cord blood-derived unrestricted somatic stem cells  

PubMed Central

Introduction Unrestricted somatic stem cells (USSC) derived from umbilical cord blood are an attractive alternative to human embryonic stem cells (hESC) for cellular therapy. USSC are capable of forming cells representative of all three germ line layers. The aim of this study was to determine the potential of USSC to form definitive endoderm following induction with Activin A, a protein known to specify definitive endoderm formation of hESC. Methods USSC were cultured for (1) three days with or without 100 ng/ml Activin A in either serum-free, low-serum or serum-containing media, (2) three days with or without 100 ng/ml Activin A in combination with 10 ng/ml FGF4 in pre-induction medium, or (3) four days with or without small molecules Induce Definitive Endoderm (IDE1, 100 nM; IDE2, 200 nM) in serum-free media. Formation of definitive endoderm was assessed using RT-PCR for gene markers of endoderm (Sox17, FOXA2 and TTF1) and lung epithelium (surfactant protein C; SPC) and cystic fibrosis transmembrane conductance regulator; CFTR). The differentiation capacity of Activin A treated USSC was also assessed. Results Activin A or IDE1/2 induced formation of Sox17+ definitive endoderm from hESC but not from USSC. Activin A treated USSC retained their capacity to form cells of the ectoderm (nerve), mesoderm (bone) and endoderm (lung). Activin A in combination with FGF4 did not induce formation of Sox17+ definitive endoderm from USSC. USSC express both Activin A receptor subunits at the mRNA and protein level, indicating that these cells are capable of binding Activin A. Conclusions Stimulation of the Nodal signaling pathway with Activin A or IDE1/2 is insufficient to induce definitive endoderm formation from USSC, indicating that USSC differ in their stem cell potential from hESC.

2011-01-01

140

R7 photoreceptor axon growth is temporally controlled by the transcription factor Ttk69, which inhibits growth in part by promoting transforming growth factor-?/activin signaling.  

PubMed

Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-?/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-?/Activin-independent mechanism. PMID:23345225

Kniss, Jonathan S; Holbrook, Scott; Herman, Tory G

2013-01-23

141

R7 Photoreceptor Axon Growth Is Temporally Controlled by the Transcription Factor Ttk69, Which Inhibits Growth in Part by Promoting Transforming Growth Factor-?/Activin Signaling  

PubMed Central

Work on axon growth has classically focused on understanding how extrinsic cues control growth cone dynamics independent of the cell body. However, more recently, neuron-intrinsic transcription factors have been shown to influence both normal and regenerative axon growth, suggesting that understanding their mechanism of action is of clinical importance. We are studying axon targeting in the Drosophila visual system and here show that the BTB/POZ zinc-finger transcription factor Tramtrack69 (Ttk69) plays an instructive role in inhibiting the growth of R7 photoreceptor axon terminals. Although ttk69 mutant R7 axons project to the correct medullar target layer, M6, their terminals fail to remain retinotopically restricted and instead grow laterally within M6. This overgrowth is not caused by an inability to be repelled by neighboring R7 axons or by an inability to recognize and initiate synapse formation with postsynaptic targets. The overgrowth is progressive and occurs even if contact between ttk69 mutant R7 axons and their normal target layer is disrupted. Ttk69 is first expressed in wild-type R7s after their axons have reached the medulla; ttk69 mutant R7 axon terminal overgrowth begins shortly after this time point. We find that expressing Ttk69 prematurely in R7s collapses their growth cones and disrupts axon extension, indicating that Ttk69 plays an instructive role in this process. A TGF-?/Activin pathway was shown previously to inhibit R7 axon terminal growth. We find that Ttk69 is required for normal activation of this pathway but that Ttk69 likely also inhibits R7 axon growth by a TGF-?/Activin-independent mechanism.

Kniss, Jonathan S.; Holbrook, Scott

2013-01-01

142

Soluble NCAM  

Microsoft Academic Search

\\u000a The neural cell adhesion molecule (NCAM) is a membrane-bound glycoprotein involved in homophilic interactions that facilitate\\u000a cell-cell adhesion. In addition to a number of membrane-bound isoforms, NCAM also exists in several soluble isoforms that\\u000a have been identified in cerebrospinal fluid, blood serum, brain tissue, and cell culture media. Soluble NCAM can be produced\\u000a in a number of ways, such as

Thomas Secher

143

Graded Nodal/Activin signaling titrates conversion of quantitative phospho-Smad2 levels into qualitative embryonic stem cell fate decisions.  

PubMed

Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression. PMID:21731500

Lee, Kian Leong; Lim, Sandy Keat; Orlov, Yuriy Lvovich; Yit, Le Yau; Yang, Henry; Ang, Lay Teng; Poellinger, Lorenz; Lim, Bing

2011-06-23

144

Graded Nodal/Activin Signaling Titrates Conversion of Quantitative Phospho-Smad2 Levels into Qualitative Embryonic Stem Cell Fate Decisions  

PubMed Central

Nodal and Activin are morphogens of the TGFbeta superfamily of signaling molecules that direct differential cell fate decisions in a dose- and distance-dependent manner. During early embryonic development the Nodal/Activin pathway is responsible for the specification of mesoderm, endoderm, node, and mesendoderm. In contradiction to this drive towards cellular differentiation, the pathway also plays important roles in the maintenance of self-renewal and pluripotency in embryonic and epiblast stem cells. The molecular basis behind stem cell interpretation of Nodal/Activin signaling gradients and the undertaking of disparate cell fate decisions remains poorly understood. Here, we show that any perturbation of endogenous signaling levels in mouse embryonic stem cells leads to their exit from self-renewal towards divergent differentiation programs. Increasing Nodal signals above basal levels by direct stimulation with Activin promotes differentiation towards the mesendodermal lineages while repression of signaling with the specific Nodal/Activin receptor inhibitor SB431542 induces trophectodermal differentiation. To address how quantitative Nodal/Activin signals are translated qualitatively into distinct cell fates decisions, we performed chromatin immunoprecipitation of phospho-Smad2, the primary downstream transcriptional factor of the Nodal/Activin pathway, followed by massively parallel sequencing, and show that phospho-Smad2 binds to and regulates distinct subsets of target genes in a dose-dependent manner. Crucially, Nodal/Activin signaling directly controls the Oct4 master regulator of pluripotency by graded phospho-Smad2 binding in the promoter region. Hence stem cells interpret and carry out differential Nodal/Activin signaling instructions via a corresponding gradient of Smad2 phosphorylation that selectively titrates self-renewal against alternative differentiation programs by direct regulation of distinct target gene subsets and Oct4 expression.

Orlov, Yuriy Lvovich; Yit, Le Yau; Yang, Henry; Ang, Lay Teng; Poellinger, Lorenz; Lim, Bing

2011-01-01

145

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

146

Lipid accumulation impairs adiponectin-mediated induction of activin A by increasing TGFbeta in primary human hepatocytes  

Microsoft Academic Search

Fatty liver is commonly detected in obesity and has been identified as a risk factor for the progression of hepatic fibrosis in a wide range of liver diseases. Transforming growth factor beta (TGF?) and activin A, both members of the TGF? superfamiliy, are central regulators in liver fibrosis and regeneration, and the effect of hepatocyte lipid accumulation on the release

Josef Wanninger; Markus Neumeier; Claus Hellerbrand; Doris Schacherer; Sabrina Bauer; Thomas S. Weiss; Hanna Huber; Andreas Schäffler; Charalampos Aslanidis; Jürgen Schölmerich; Christa Buechler

2011-01-01

147

Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK.  

PubMed

Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ET(B)) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-?B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-?B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ET(B) receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ET(B) receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ET(B) receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ET(B) receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ET(B) receptors. Thus, the MAPK-mediated upregulation of contractile ET(B) receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke. PMID:20716444

Sandhu, Hardip; Xu, Cang Bao; Edvinsson, Lars

2010-08-15

148

The soluble amino-terminal region of HVEM mediates efficient herpes simplex virus type 1 infection of gD receptor-negative cells  

PubMed Central

Background Previous studies from our own and other labs reported the surprising finding that the soluble V domain of the herpes simplex virus type 1 (HSV-1) entry receptor nectin-1 can both block HSV infection of receptor-bearing cells and mediate infection of receptor-deficient cells. Here we show that this property is not unique to nectin-1. We generated a pair of truncated, soluble forms of the other major HSV-1 entry receptor, herpes virus entry mediator (HVEM or HveA), and examined its effects on HSV-1 infection of receptor-deficient cells. Results In cultures of CHO-K1 cells, sHveA102 comprising the two amino-terminal cysteine-rich pseudorepeats (CRPs) of HVEM enabled infection of greater than 80% of the cells at an MOI of 3, while sHveA162 comprising the complete ectodomain failed to mediate infection. Both sHveA102 and sHveA162 blocked infection of CHO-K1 cells stably expressing HVEM in a dose-dependent manner, indicating that both were capable of binding to viral gD. We found that sHveA102-mediated infection involves pH-independent endocytosis whereas HSV infection of HVEM-expressing CHO-K1 cells is known to be pH-dependent. Conclusions Our results suggest that the C-terminal portion of the soluble HVEM ectodomain inhibits gD activation and that this effect is neutralized in the full-length form of HVEM in normal infection.

2012-01-01

149

Use of plasma C-reactive protein, procalcitonin, neutrophils, macrophage migration inhibitory factor, soluble urokinase-type plasminogen activator receptor, and soluble triggering receptor expressed on myeloid cells-1 in combination to diagnose infections: a prospective study  

PubMed Central

Introduction Accurate and timely diagnosis of community-acquired bacterial infections in patients with systemic inflammation remains challenging both for clinician and laboratory. Combinations of markers, as opposed to single ones, may improve diagnosis and thereby survival. We therefore compared the diagnostic characteristics of novel and routinely used biomarkers of sepsis alone and in combination. Methods This prospective cohort study included patients with systemic inflammatory response syndrome who were suspected of having community-acquired infections. It was conducted in a medical emergency department and department of infectious diseases at a university hospital. A multiplex immunoassay measuring soluble urokinase-type plasminogen activator (suPAR) and soluble triggering receptor expressed on myeloid cells (sTREM)-1 and macrophage migration inhibitory factor (MIF) was used in parallel with standard measurements of C-reactive protein (CRP), procalcitonin (PCT), and neutrophils. Two composite markers were constructed – one including a linear combination of the three best performing markers and another including all six – and the area under the receiver operating characteristic curve (AUC) was used to compare their performance and those of the individual markers. Results A total of 151 patients were eligible for analysis. Of these, 96 had bacterial infections. The AUCs for detection of a bacterial cause of inflammation were 0.50 (95% confidence interval [CI] 0.40 to 0.60) for suPAR, 0.61 (95% CI 0.52 to 0.71) for sTREM-1, 0.63 (95% CI 0.53 to 0.72) for MIF, 0.72 (95% CI 0.63 to 0.79) for PCT, 0.74 (95% CI 0.66 to 0.81) for neutrophil count, 0.81 (95% CI 0.73 to 0.86) for CRP, 0.84 (95% CI 0.71 to 0.91) for the composite three-marker test, and 0.88 (95% CI 0.81 to 0.92) for the composite six-marker test. The AUC of the six-marker test was significantly greater than that of the single markers. Conclusion Combining information from several markers improves diagnostic accuracy in detecting bacterial versus nonbacterial causes of inflammation. Measurements of suPAR, sTREM-1 and MIF had limited value as single markers, whereas PCT and CRP exhibited acceptable diagnostic characteristics. Trial registration NCT 00389337

Kofoed, Kristian; Andersen, Ove; Kronborg, Gitte; Tvede, Michael; Petersen, Janne; Eugen-Olsen, Jesper; Larsen, Klaus

2007-01-01

150

Lectin-Dependent Enhancement of Ebola Virus Infection via Soluble and Transmembrane C-type Lectin Receptors  

PubMed Central

Mannose-binding lectin (MBL) is a key soluble effector of the innate immune system that recognizes pathogen-specific surface glycans. Surprisingly, low-producing MBL genetic variants that may predispose children and immunocompromised individuals to infectious diseases are more common than would be expected in human populations. Since certain immune defense molecules, such as immunoglobulins, can be exploited by invasive pathogens, we hypothesized that MBL might also enhance infections in some circumstances. Consequently, the low and intermediate MBL levels commonly found in human populations might be the result of balancing selection. Using model infection systems with pseudotyped and authentic glycosylated viruses, we demonstrated that MBL indeed enhances infection of Ebola, Hendra, Nipah and West Nile viruses in low complement conditions. Mechanistic studies with Ebola virus (EBOV) glycoprotein pseudotyped lentiviruses confirmed that MBL binds to N-linked glycan epitopes on viral surfaces in a specific manner via the MBL carbohydrate recognition domain, which is necessary for enhanced infection. MBL mediates lipid-raft-dependent macropinocytosis of EBOV via a pathway that appears to require less actin or early endosomal processing compared with the filovirus canonical endocytic pathway. Using a validated RNA interference screen, we identified C1QBP (gC1qR) as a candidate surface receptor that mediates MBL-dependent enhancement of EBOV infection. We also identified dectin-2 (CLEC6A) as a potentially novel candidate attachment factor for EBOV. Our findings support the concept of an innate immune haplotype that represents critical interactions between MBL and complement component C4 genes and that may modify susceptibility or resistance to certain glycosylated pathogens. Therefore, higher levels of native or exogenous MBL could be deleterious in the setting of relative hypocomplementemia which can occur genetically or because of immunodepletion during active infections. Our findings confirm our hypothesis that the pressure of infectious diseases may have contributed in part to evolutionary selection of MBL mutant haplotypes.

Lear, Calli; Chen, Li; Yantosca, L. Michael; Scully, Corinne; Sarraju, Ashish; Sokolovska, Anna; Zariffard, M. Reza; Eisen, Damon P.; Mungall, Bruce A.; Kotton, Darrell N.; Omari, Amel; Huang, I-Chueh; Farzan, Michael; Takahashi, Kazue; Stuart, Lynda; Stahl, Gregory L.; Ezekowitz, Alan B.; Spear, Gregory T.; Olinger, Gene G.; Schmidt, Emmett V.; Michelow, Ian C.

2013-01-01

151

Parasite-Specific IL-17-Type Cytokine Responses and Soluble IL-17 Receptor Levels in Alveolar Echinococcosis Patients  

PubMed Central

Alveolar Echinococcosis (AE) caused by the cestode Echinococcus multilocularis, is a severe helminth infection of man, where unrestricted parasite growth will ultimately result in organ failure and fatality. The tissue-infiltrative growth of the larval metacestode and the limited efficacy of available drugs complicate successful intervention in AE; patients often need life-long medication, and if possible, surgical resection of affected tissues and organs. Resistance to AE has been reported, but the determinants which confer protection are not known. ln this study, we analyzed in patients at distinct stages of Alveolar Echirococcosis, that is cured, stable and progressive AE, as well as in infection-free controls, the cellular production and plasma levels of pro-inflammatory cytokines lL-17A, lL-17B, lL-17F and their soluble receptors lL-17RA (slL-17RA) and IL-17RB (sIL-17RB). Significantly elevated levels of IL-17B and slL-17RB were observed, whilst lL-17F and slL-17RA were reduced in patients with AE. Similarly, the cellular production of lL-17F and slL-L7RA in response to E. multilocularis antigens was low in AE patients, while levels of slL-17RB were highly enhanced. These observations suggest immune-modulating properties of E. multitocularis on lL-17 cytokine-mediated pro-inflammatory immune responses; this may facilitate the tissue infiltrative growth of the parasite and its persistence in the human host.

Lechner, Christian J.; Gruner, Beate; Huang, Xiangsheng; Hoffmann, Wolfgang H.; Kern, Peter; Soboslay, Peter T.

2012-01-01

152

A Vacuolar-Type H+-ATPase in a Nonvacuolar Organelle Is Required for the Sorting of Soluble Vacuolar Protein Precursors in Tobacco Cells.  

PubMed Central

In plant cells, vacuolar matrix proteins are separated from the secretory proteins at the Golgi complex for transport to the vacuoles. To investigate the involvement of vacuolar-type ATPase (V-ATPase) in the vacuolar targeting of soluble proteins, we analyzed the effects of bafilomycin A1 and concanamycin A on the transport of vacuolar protein precursors in tobacco cells. Low concentrations of these inhibitors caused the missorting of several vacuolar protein precursors; sorting was more sensitive to concanamycin A than to bafilomycin A1. Secretion of soluble proteins from tobacco cells was also inhibited by bafilomycin A1 and concanamycin A. We next analyzed the subcellular localization of V-ATPase. V-ATPase was found in a wide variety of endomembrane organelles. Both ATPase activity and ATP-dependent proton-pumping activity in the Golgi-enriched fraction were more sensitive to concanamycin A than to bafilomycin A1, whereas these activities in the tonoplast fraction were almost equally sensitive to both reagents. Our observations indicate that the V-ATPase in the organelle that was recovered in the Golgi-enriched fraction is required for the transport of vacuolar protein precursors and that this V-ATPase is distinguishable from the tonoplast-associated V-ATPase.

Matsuoka, K; Higuchi, T; Maeshima, M; Nakamura, K

1997-01-01

153

Soluble HLA-G promotes Th1-type cytokine production by cytokine-activated uterine and peripheral natural killer cells.  

PubMed

Soluble forms of HLA-G (sHLA-G) have been implicated in immune regulation. Fetal trophoblast cells are a prime source of HLA-G. Hence, an interaction between sHLA-G and uterine lymphocytes in the decidual tissues can easily be envisaged. These lymphocytes, when properly activated, are implicated in successful trophoblast invasion, placental maturation and maintenance of pregnancy. However, so far, no data are available on the effect of sHLA-G on the function and phenotype of these cells. Herein, we used a recombinant sHLA-G construct to determine the effect of sHLA-G on uterine lymphocyte cells present in endometrium at the time that it is optimally receptive to trophoblast invasion. In addition, we ascertained the effect of sHLA-G on peripheral lymphocytes. We found that upon co-culture with sHLA-G, proliferation of unfractionated IL-15-stimulated uterine mononuclear cells (UMCs) was inhibited. However, sHLA-G increased both interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha production by these cells. Vascular endothelial growth factor (VEGF) production was reduced. Notably, in contrast to membrane-bound HLA-G, sHLA-G did not affect the natural cytolytic activity of UMCs. Similarly, sHLA-G inhibited proliferation but stimulated pro-inflammatory cytokine production by cytokine-activated, unfractionated peripheral blood mononuclear cells (PBMCs). In addition, we showed that the overall inhibitory effect of sHLA-G on proliferation of the whole cell population could be ascribed to selective inhibition of CD4(+) T cells. In contrast, sHLA-G induced proliferation and IFN-gamma production by both uterine and peripheral natural killer (NK) cells. In conclusion, our data show that the sHLA-G modulates both UMC and PBMC function. sHLA-G, by promoting IFN-gamma production by uterine NK cells, may contribute to vascular remodelling of spiral arteries to allow for successful embryo implantation. PMID:17121749

van der Meer, A; Lukassen, H G M; van Cranenbroek, B; Weiss, E H; Braat, D D M; van Lierop, M J; Joosten, I

2006-11-22

154

Activin-A: a novel dendritic cell-derived cytokine that potently attenuates CD40 ligand-specific cytokine and chemokine production  

Microsoft Academic Search

Activin-A is a transforming growth factor-(TGF-) superfamily member that plays a pivotal role in many developmen- tal and reproductive processes. It is also involved in neuroprotection, apoptosis of tumor and some immune cells, wound healing, and cancer. Its role as an immune- regulating protein has not previously been described. Here we demonstrate for the first time that activin-A has potent

Neil C. Robson; David J. Phillips; Tristan McAlpine; Amanda Shin; Suzanne Svobodova; Tracey Toy; Vinochani Pillay; Naomi Kirkpatrick; Damien Zanker; Kathy Wilson; Imke Helling; Heng Wei; Weisan Chen; Jonathan Cebon; Eugene Maraskovsky

2008-01-01

155

GnRH agonist stimulation of the pituitary - gonadal axis in children: age and sex differences in circulating inhibin-B and activin-A  

Microsoft Academic Search

BACKGROUND: Inhibin-B decreases and activin increases FSH secretion in adults. We investigated whether an FSH- inhibin\\/activin feedback loop exists before or during puberty. METHODS: FSH secretion was stimulated with 10mg\\/kg leuprolide acetate (GnRH agonist) in 18 girls, ages 1.0-13.2 years, and 11 boys, ages 8.9-15.2 years, with variations in pubertal development, and in five normal 9- to 10-year-old girls. Blood,

Daniel D. Elsholz; Vasantha Padmanabhan; Robert L. Rosenfield; Pamela R. Olton; David J. Phillips; Carol M. Foster

2004-01-01

156

Retinoic acid promotes Sertoli cell differentiation and antagonises activin-induced proliferation.  

PubMed

From puberty and throughout adult spermatogenesis, retinoid signalling is essential for germ cell differentiation and male fertility. The initiation of spermatogonial differentiation and germ cell meiosis occurs under the direction of local retinoid signalling in the testis, and corresponds with the final phase of somatic Sertoli cell differentiation at puberty. Here, we consider the cellular and molecular basis of retinoid actions upon Sertoli cell differentiation. Primary rat Sertoli cells were isolated during the pubertal proliferative and quiescent phases at postnatal days 10- and 20- respectively, and cultured with all-trans-retinoic acid. We show that retinoid signalling can potently suppress activin-induced proliferation by antagonising G1 phase progression and entry into the cell cycle. Retinoid signalling was also found to initiate tight junction formation in primary Sertoli cells, consistent with a pro-differentiative role. This study implicates retinoid signalling in the differentiation of both somatic and germ cells in the testis at puberty. PMID:23831638

Nicholls, Peter K; Harrison, Craig A; Rainczuk, Katarzyna E; Wayne Vogl, A; Stanton, Peter G

2013-07-02

157

Effect of neuraminidase treatment of cells and effect of soluble glycoproteins on type 3 reovirus attachment to murine L cells.  

PubMed Central

The effect of pretreatment of murine L cells with bacterial neuraminidases on type 3 reovirus attachment was examined. We observed that such treatments resulted in a 60 to 80% decrease of subsequent attachment of 35S-labeled type 3 reovirus in a time- and dose-dependent manner. This result was specific for removal of cell surface sialic acid residues since the specific neuraminidase inhibitor 2-deoxy-2,3-dehydro-n-acetyl neuraminic acid completely prevented the observed effect. Although the total amount of radiolabeled virus bound to neuraminidase-treated cells was greatly reduced, unlabeled reovirus competed only slightly less efficiently for the attachment of 35S-labeled reovirus to neuraminidase-treated versus mock-treated L cells, suggesting that the specificity of the virus interaction with cellular receptor sites was only slightly diminished. Saturation experiments with mock-treated cells or with cells treated with Vibrio cholerae or with V. cholerae plus Arthrobacter ureafaciens neuraminidases indicated that the number of specific cellular receptor sites for type 3 reovirus were reduced by about 47%. We determined that under the neuraminidase digestion conditions used in this experiment we were able to remove a maximum 75% of the total N-acetylneuraminic acid of L cells. Our results also demonstrated that glycoproteins bearing a large amount of sialic acid containing oligosaccharides as well as purified N-acetylneuraminic acid, N-glycolylneuraminic acid, and N-acetylneuraminyl lactose were inhibitors of attachment, while proteins containing no sialic acid or negligible amounts of sialic acid did not inhibit attachment. High concentrations of various monosaccharides and lactose had no effect on reovirus attachment, in agreement with the recent results of Armstrong and his collaborators (Armstrong et al., Virology, 138:37-48, 1984). These data are also supported by the observation that gangliosides are inhibitors of viral attachment (Armstrong et al., Virology, 138:37-48, 1984). Taken together, our results suggest that cell surface sialic acid-containing glycoconjugates are involved in type 3 reovirus binding to murine L cells.

Gentsch, J R; Pacitti, A F

1985-01-01

158

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

159

Cellular mechanisms and modulation of activin A- and transforming growth factor beta-mediated differentiation in cultured hen granulosa cells.  

PubMed

Undifferentiated granulosa cells from prehierarchal (6- to 8-mm-diameter) hen follicles express very low to undetectable levels of LH receptor (LH-R) mRNA, P450 cholesterol side chain cleavage (P450scc) enzyme activity, and steroidogenic acute regulatory (StAR) protein, and produce negligible progesterone, in vitro, following an acute (3-h) challenge with either FSH or LH. It has previously been established that culturing such cells with FSH for 18-20 h induces LH-R, P450scc, and StAR expression, which enables the initiation of progesterone production. The present studies were conducted to characterize the ability of activin and transforming growth factor (TGF) beta, both alone and in combination with FSH, to promote hen granulosa cell differentiation, in vitro. A 20-h culture of prehierarchal follicle granulosa cells with activin A or transforming growth factor beta (TGFbeta)1 increased LH-R mRNA levels compared with control cultured cells. Activin A and TGFbeta1 also promoted FSH-receptor (FSH-R) mRNA expression when combined with FSH treatment. Neither activin A nor TGFbeta1 alone stimulated progesterone production after 20 h culture. However, preculture with either factor for 20 h (to induce gonadotropin receptor mRNA expression) followed by a 3-h challenge with FSH or LH potentiated StAR expression and progesterone production compared with cells challenged with gonadotropin in the absence of activin A or TGFbeta1 preculture. Significantly, activation of the mitogen-activated protein (MAP) kinase pathway with transforming growth factor alpha (TGFalpha) (monitored by Erk phosphorylation) blocked TGFbeta1-induced LH-R expression, and this effect was associated with the inhibition of Smad2 phosphorylation. We conclude that a primary differentiation-inducing action of activin A and TGFbeta1 on hen granulosa cells from prehierarchal follicles is directed toward LH-R expression. Enhanced LH-R levels subsequently sensitize granulosa cells to LH, which in turn promotes StAR plus P450scc expression and subsequently an increase in P4 production. Significantly, the finding that TGFbeta signaling is negatively regulated by MAP kinase signaling is proposed to represent a mechanism that prevents premature differentiation of granulosa cells. PMID:15269104

Johnson, A L; Bridgham, J T; Woods, D C

2004-07-21

160

Differential reduction in soluble and membrane-bound c-type cytochrome contents in a Paracoccus denitrificans mutant partially deficient in 5-aminolevulinate synthase activity.  

PubMed Central

A mutant of Paracoccus denitrificans, DP104, unable to grow anaerobically with nitrate as the terminal electron acceptor or aerobically with methanol as the electron donor and staining negatively in the dimethylphenylene diamine oxidation (Nadi) test, was isolated by transposon Tn5::phoA mutagenesis. P. denitrificans DP104 grown aerobically with succinate or choline had very low levels (2 to 3% of the wild-type levels) of spectroscopically detectable soluble c-type cytochromes. In contrast, membrane cytochromes of the a, b, and c types were present at 50% of the levels found in the wild type. The apo form of cytochrome c550, at an approximately 1:1 molar ratio with the holo form, was found in the periplasm of DP104. The TnphoA element was shown to be inserted immediately upstream of the translational start of hemA, the gene coding for 5-aminolevulinate synthase, which was sequenced. Low-level expression of this gene, driven off an incidental promoter provided by TnphoA-cointegrated suicide vector DNA, is the basis of the phenotype which could be complemented by the addition of 5-aminolevulinate to growth media. Disruption of the hemA gene generated a P. denitrificans strain auxotrophic for 5-aminolevulinate, establishing that there is no hemA-independent pathway of heme synthesis in this organism. The differential deficiency in periplasmic c-type cytochromes relative to membrane cytochromes in DP104 is suggested to arise from unequal competition for the restricted supply of heme which results from the effects of the transposon insertion. Images

Page, M D; Ferguson, S J

1994-01-01

161

Upregulation of contractile endothelin type B receptors by lipid-soluble cigarette smoking particles in rat cerebral arteries via activation of MAPK  

SciTech Connect

Cigarette smoke exposure increases the risk of stroke. However, the underlying molecular mechanisms are poorly understood. Endothelin system plays key roles in the pathogenesis of stroke. The present study was designed to examine if lipid-soluble (dimethyl sulfoxide-soluble) cigarette smoke particles (DSP) induces upregulation of contractile endothelin type B (ET{sub B}) receptors in rat cerebral arteries and if activation of mitogen activated protein kinase (MAPK) and nuclear factor-kappaB (NF-{kappa}B) mediate the upregulation of contractile endothelin receptors in the cerebral arteries. Rat middle cerebral arteries were isolated and organ cultured in serum free medium for 24 h in the presence of DSP with or without specific inhibitors: MEK specific (U0126), p38 specific (SB202190), JNK specific (SP600125), NF-{kappa}B specific (BMS-345541) or (IMD-0354), transcription inhibitor (actinomycin D), or translation blocker (cycloheximide). Contractile responses to the ET{sub B} receptor agonist sarafotoxin 6c were investigated by a sensitive myograph. The expression of the ET{sub B} receptors were studied at mRNA and protein levels using quantitative real time PCR and immunohistochemistry, respectively. Results show that organ culture per se induced transcriptional upregulation of contractile ET{sub B} receptors in the cerebral vascular smooth muscle cells. This upregulation was further increased at the translational level by addition of DSP to the organ culture, but this increase was not seen by addition of nicotine or water-soluble cigarette smoke particles to the organ culture. The increased upregulation of contractile ET{sub B} receptors by DSP was abrogated by U0126, SP600125, actinomycin D, and cycloheximide, suggesting that the underlying molecular mechanisms involved in this process include activation of MEK and JNK MAPK-mediated transcription and translation of new contractile ET{sub B} receptors. Thus, the MAPK-mediated upregulation of contractile ET{sub B} receptors in cerebral arteries might be a pharmacological target for the treatment of smoke-associated cerebral vascular disease like stroke.

Sandhu, Hardip, E-mail: sandhu.hardip@gmail.co [Department of Clinical Experimental Research, Glostrup Research Institute, Ndr. Ringvej 69, 2600 Glostrup (Denmark); Xu, Cang Bao [Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, University Hospital of Lund, Lund (Sweden); Edvinsson, Lars [Department of Clinical Experimental Research, Glostrup Research Institute, Ndr. Ringvej 69, 2600 Glostrup (Denmark); Division of Experimental Vascular Research, Institute of Clinical Sciences in Lund, University Hospital of Lund, Lund (Sweden)

2010-11-15

162

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

163

Haplotype Association Mapping of Acute Lung Injury in Mice Implicates Activin A Receptor, Type 1  

PubMed Central

Rationale: Because acute lung injury is a sporadic disease produced by heterogeneous precipitating factors, previous genetic analyses are mainly limited to candidate gene case-control studies. Objectives: To develop a genome-wide strategy in which single nucleotide polymorphism associations are assessed for functional consequences to survival during acute lung injury in mice. Methods: To identify genes associated with acute lung injury, 40 inbred strains were exposed to acrolein and haplotype association mapping, microarray, and DNA-protein binding were assessed. Measurements and Main Results: The mean survival time varied among mouse strains with polar strains differing approximately 2.5-fold. Associations were identified on chromosomes 1, 2, 4, 11, and 12. Seven genes (Acvr1, Cacnb4, Ccdc148, Galnt13, Rfwd2, Rpap2, and Tgfbr3) had single nucleotide polymorphism (SNP) associations within the gene. Because SNP associations may encompass “blocks” of associated variants, functional assessment was performed in 91 genes within ± 1 Mbp of each SNP association. Using 10% or greater allelic frequency and 10% or greater phenotype explained as threshold criteria, 16 genes were assessed by microarray and reverse real-time polymerase chain reaction. Microarray revealed several enriched pathways including transforming growth factor-? signaling. Transcripts for Acvr1, Arhgap15, Cacybp, Rfwd2, and Tgfbr3 differed between the strains with exposure and contained SNPs that could eliminate putative transcriptional factor recognition sites. Ccdc148, Fancl, and Tnn had sequence differences that could produce an amino acid substitution. Mycn and Mgat4a had a promoter SNP or 3?untranslated region SNPs, respectively. Several genes were related and encoded receptors (ACVR1, TGFBR3), transcription factors (MYCN, possibly CCDC148), and ubiquitin-proteasome (RFWD2, FANCL, CACYBP) proteins that can modulate cell signaling. An Acvr1 SNP eliminated a putative ELK1 binding site and diminished DNA–protein binding. Conclusions: Assessment of genetic associations can be strengthened using a genetic/genomic approach. This approach identified several candidate genes, including Acvr1, associated with increased susceptibility to acute lung injury in mice.

Leikauf, George D.; Concel, Vincent J.; Liu, Pengyuan; Bein, Kiflai; Berndt, Annerose; Ganguly, Koustav; Jang, An Soo; Brant, Kelly A.; Dietsch, Maggie; Pope-Varsalona, Hannah; Dopico, Richard A.; Di, Y. P. Peter; Li, Qian; Vuga, Louis J.; Medvedovic, Mario; Kaminski, Naftali; You, Ming; Prows, Daniel R.

2011-01-01

164

Soluble Receptor for Advanced Glycation End-Product (sRAGE)/Pentosidine Ratio: A Potential Risk Factor Determinant for Type 2 Diabetic Retinopathy.  

PubMed

This study aims to investigate potential diabetic retinopathy (DR) risk factors by evaluating the circulating levels of pentosidine, soluble receptor for advanced glycation end-product (sRAGE), advanced oxidation protein product (AOPP) as well as glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities in DR patients. A total of 235 healthy controls, 171 type 2 diabetic without retinopathy (DNR) and 200 diabetic retinopathy (DR) patients were recruited. Plasma was extracted for the estimation of pentosidine, sRAGE, AOPP levels and GPx activity whereas peripheral blood mononuclear cells were disrupted for SOD activity measurement. DNR and DR patients showed significantly higher levels of plasma pentosidine, sRAGE and AOPP but lower GPx and SOD activities when compared to healthy controls. The sRAGE/pentosidine ratio in DR patients was significantly lower than the ratio detected in DNR patients. Proliferative DR patients had significantly higher levels of plasma pentosidine, sRAGE, AOPP and sRAGE/pentosidine ratio than non-proliferative DR patients. High HbA1c level, long duration of diabetes and low sRAGE/pentosidine ratio were determined as the risk factors for DR. This study suggests that sRAGE/pentosidine ratio could serve as a risk factor determinant for type 2 DR as it has a positive correlation with the severity of DR. PMID:23552832

Ng, Zhi Xiang; Chua, Kek Heng; Iqbal, Tajunisah; Kuppusamy, Umah Rani

2013-04-03

165

Salts & Solubility  

NSDL National Science Digital Library

In this online interactive simulation, learners will add different salts to water and then watch the salts dissolve and achieve a dynamic equilibrium with solid precipitate. Learners will also compare the number of ions in NaCl to other slightly soluble salts, and they will relate the charges on ions to the number of ions in the formula of a salt. Learners will also learn how to calculate Ksp values. This activity includes an online simulation, sample learning goals, a teacher's guide, and translations in over 20 languages.

Adams, Wendy; Koch, Linda; Lemaster, Ron; Loeblein, Trish; Perkins, Kathy; Harlow, Danielle

2011-01-01

166

Stimulation of circus movement by activin, bFGF and TGF-?2 in isolated animal cap cells of Xenopus laevis  

Microsoft Academic Search

Lobopodium is a hyaline cytoplasmic protrusion which rotates circumferencially around a cell. This movement is called circus movement, which is seen in dissociated cells of amphibian embryos. Relative abundance of the lobopodia-forming cells changes temporally and spatially within Xenopus embryos, reflecting stage-dependent difference of morphogenetic movements. The lobopodia-forming activity of dissociated animal cap cells was stimulated strongly by activin and

Itsushi Minoura; Hisashi Nakamura; Kosuke Tashiro; Koichiro Shiokawa

1995-01-01

167

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

168

Activin A Efficiently Specifies Definitive Endoderm from Human Embryonic Stem Cells Only When Phosphatidylinositol 3Kinase Signaling Is Suppressed  

Microsoft Academic Search

Human ESCs (hESCs) respond to signals that determine their pluripotency, proliferation, survival, and differentiation status. In this report, we demonstrate that phosphatidylinositol 3-ki- nase (PI3K) antagonizes the ability of hESCs to differentiate in response to transforming growth factor family members such as Activin A and Nodal. Inhibition of PI3K signaling efficiently promotes differentiation of hESCs into mes- endoderm and then

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

2007-01-01

169

Tissue Stretch Decreases Soluble TGF-?1 and Type-1 Procollagen in Mouse Subcutaneous Connective Tissue: Evidence From Ex Vivo and In Vivo Models  

PubMed Central

Transforming growth factor beta 1 (TGF-?1) plays a key role in connective tissue remodeling, scarring, and fibrosis. The effects of mechanical forces on TGF-?1 and collagen deposition are not well understood. We tested the hypothesis that brief (10 min) static tissue stretch attenuates TGF-?1-mediated new collagen deposition in response to injury. We used two different models: (1) an ex vivo model in which excised mouse subcutaneous tissue (N = 44 animals) was kept in organ culture for 4 days and either stretched (20% strain for 10 min 1 day after excision) or not stretched; culture media was assayed by ELISA for TGF-?1; (2) an in vivo model in which mice (N = 22 animals) underwent unilateral subcutaneous microsurgical injury on the back, then were randomized to stretch (20–30% strain for 10 min twice a day for 7 days) or no stretch; subcutaneous tissues of the back were immunohistochemically stained for Type-1 procollagen. In the ex vivo model, TGF-?1 protein was lower in stretched versus non-stretched tissue (repeated measures ANOVA, P < 0.01). In the in vivo model, microinjury resulted in a significant increase in Type-1 procollagen in the absence of stretch (P < 0.001), but not in the presence of stretch (P = 0.21). Thus, brief tissue stretch attenuated the increase in both soluble TGF-?1 (ex vivo) and Type-1 procollagen (in vivo) following tissue injury. These results have potential relevance to the mechanisms of treatments applying brief mechanical stretch to tissues (e.g., physical therapy, respiratory therapy, mechanical ventilation, massage, yoga, acupuncture).

Bouffard, Nicole A.; Cutroneo, Kenneth R.; Badger, Gary J.; White, Sheryl L.; Buttolph, Thomas R.; Ehrlich, H. Paul; Stevens-Tuttle, Debbie; Langevin, Helene M.

2011-01-01

170

Alterations in the immunogenic properties of soluble trimeric human immunodeficiency virus type 1 envelope proteins induced by deletion or heterologous substitutions of the V1 loop.  

PubMed

HIV-1 gp140 envelope immunogens express conserved epitopes that are targeted by broadly cross-reactive neutralizing antibodies, but they fail to elicit similar antibodies upon immunization. The poor immunogenicity of conserved epitopes on gp140 could be linked to the high immunogenicity of variable Env regions on such constructs. Previous studies have shown that the first hypervariable region (V1 loop) is immunogenic on soluble gp140s but elicits type-specific antibodies. To address issues related to the high immunogenicity of the V1 loop, two conceptually opposite approaches were tested. In the first approach, we eliminated the V1 loop from our gp140 construct and examined how V1 deletion altered the immunogenic properties of other Env regions. In the second approach, we took advantage of the high immunogenicity of the V1 loop and engrafted four diverse V1 loops onto a common gp140 Env "scaffold." These four scaffolds were used as a cocktail of immunogens to elicit diverse anti-V1 antibodies, under the hypothesis that eliciting diverse anti-V1 antibodies would expand the neutralizing breadth of immune sera. Our study indicates that three of four heterologous V1 loops were immunogenic on the common Env backbone "scaffold," but heterologous anti-V1 neutralizing responses were observed in only one case. Both types of V1 modification dampened the immunogenicity of the V3 loop, differentially altered the immunogenicity of the transmembrane gp41 subunit, and altered the relative immunogenicities of unknown Env regions, including potentially the CD4-binding site (CD4-bs) and trimer-specific targets, which elicited cross-reactive neutralizing antibodies but of limited breadth. PMID:20660181

Ching, Lance; Stamatatos, Leonidas

2010-07-21

171

Activation of FGFR(IIIc) isoforms promotes activin-induced mesendoderm development in mouse embryonic stem cells and reduces Sox17 coexpression in EpCAM+ cells.  

PubMed

Activin induces the formation of definitive endoderm from mouse ES cells dependent on active fibroblast growth factor (Fgf) signaling. Here we report that Fgf4 is dispensable for activin A-induced differentiation of mouse ES cells into endoderm. We find that Fgf4(-/-) cells readily differentiate into definitive endoderm without exogenous administration of Fgf4. Additionally, we investigate the spatio-temporal dynamics of Fgf receptor (FGFR) isoform distribution in activin A-treated ES cell cultures and find that FGFR(III)c isoforms are expressed in DE as well as non-DE populations, whereas FGFR2(III)b and FGFR4 are found specifically enriched in the DE fraction. Ligands that preferentially activate the FGFR(III)c isoforms induce mesendoderm markers T and Gsc, but reduce expression of the DE marker Sox17 in activin-induced EpCAM(+) cells. In contrast, ligands specifically activating FGFR(III)b isoforms have no effect on either population. Activation of FGFR(III)c isoforms results in a strong mitogenic effect on activin A-induced ES cell progeny early in the differentiation period whereas activation of FGFR(III)b isoforms has only a moderate mitogenic effect confined to the late differentiation period. We conclude that FGFR(III)c-isoform activation selectively drives the differentiation of mES cells toward mesendoderm and that Fgf4 is dispensable for the differentiation into definitive endoderm. PMID:21513905

Peterslund, Janny M L; Serup, Palle

2011-02-27

172

Roles of activin receptor-like kinase 7 signaling and its target, peroxisome proliferator-activated receptor ?, in lean and obese adipocytes  

PubMed Central

We recently discovered a novel signaling pathway involving activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-? receptors. ALK7 and activated Smads 2, 3, and 4 inhibit the master regulators of adipogenesis, CCAAT/enhancer-binding protein ? (C/EBP?) and peroxisome proliferator-activated receptor ? (PPAR?) specifically in differentiated adipocytes, but surprisingly increase both the adipocyte size and lipid content by suppressing lipolysis. Here, we show that, although both transcription factors are suppressed by ALK7 in either the obese or lean state, PPAR?, but not C/EBP?, is further suppressed under obesity through an ALK7-independent pathway. As a result, PPAR? and adipose lipolytic activities are severely downregulated in obesity. Reactivation of PPAR? by ALK7 inactivation leads to downregulation of inflammatory adipocytokines and upregulation of adiponectin. We propose that PPAR? promotes lipid turnover and remodeling by stimulating both triglyceride synthesis and breakdown in differentiated adipocytes. Finally, we discuss the physiological and evolutionary roles of the ALK7-signaling pathway and consider it as a potential target of therapy for obesity.

Yogosawa, Satomi; Izumi, Tetsuro

2013-01-01

173

Expression of activin receptor-like kinase 7 in adipose tissues.  

PubMed

The tissue distribution of activin receptor-like kinase 7 (Alk7) expression, the signaling ability of Alk7 variants, and Alk7 expression in response to ?3-adrenergic receptor activation were examined. Expression levels of Alk7 varied greatly among tissues but were highest in white adipose tissue and brown adipose tissue. In addition to full-length Alk7 (Alk7-v1), Alk7-v3, an Alk7 variant, was expressed in adipose tissues, brain, and ovary. Nodal transmits signals via Alk7 in cooperation with its coreceptor, Cripto. Evaluation of the ability of Alk7 variants to confer Nodal signaling using luciferase-based reporter assays showed that Alk7-v3 does not transmit Nodal-Cripto-mediated signals. Expression of Alk7 was down-regulated in brown but not in white adipose tissue treated with CL316,243, a ?3-adrenergic receptor agonist. These results suggest involvement of Alk7 in modulation of metabolism in the adipose tissues in response to ?3-adrenergic receptor activation. PMID:23264230

Murakami, Masaru; Shirai, Mitsuyuki; Ooishi, Ryo; Tsuburaya, Asako; Asai, Kumiko; Hashimoto, Osamu; Ogawa, Kenji; Nishino, Yoshii; Funaba, Masayuki

2012-12-21

174

Improvement of the metabolic syndrome profile by soluble fibre - guar gum - in patients with type 2 diabetes: a randomised clinical trial.  

PubMed

A diet rich in fibre seems to protect against the metabolic syndrome (MetS), but there is scarce information about the role of fibre intake in patients with the MetS and diabetes. The aim of the present study was to evaluate the effects of soluble fibre from partially hydrolysed guar gum (PHGG) on the MetS and cardiovascular risk factors in patients with type 2 diabetes. In the present randomised controlled clinical trial, forty-four patients with type 2 diabetes (males 38·6 %, age 62 (sd 9) years, diabetes duration 14·2 (sd 9·6) years) and the MetS underwent clinical, laboratory and dietary evaluations at baseline, 4 and 6 weeks. All patients followed their usual diet and the intervention group (n 23) received an additional 10 g/d of PHGG. In the intervention group, waist circumference (WC), glycated Hb (HbA1c), 24 h urinary albumin excretion (UAE) and serum trans-fatty acids (FA) were reduced in comparison with baseline after 4 and 6 weeks: WC 103·5 (sd 9·5) to 102·1 (sd 10) to 102·3 (sd 9·7) cm; HbA1c 6·88 (sd 0·99) to 6·64 (sd 0·94) to 6·57 (sd 0·84) %; 24 h UAE 6·8 (interquartile range 3·0-17·5) to 4·5 (interquartile range 3·0-10·5) to 6·2 (interquartile range 3·0-9·5) mg; trans-FA 71 (interquartile range 46-137) to 67 (interquartile range 48-98) to 57 (interquartile range 30-110) mg/l (P< 0·05 for all). The only change in the control group was weight reduction: 77·0 (sd 13·5) to 76·2 (sd 13·3) to 76·1 (sd 13·4) kg (P= 0·005). Other MetS components (blood pressure, TAG, HDL-cholesterol, fasting plasma glucose), total and LDL-cholesterol, C-reactive protein and endothelin-1 did not change in either group. In patients with type 2 diabetes and the MetS, the addition of PHGG to the usual diet improved cardiovascular and metabolic profiles by reducing WC, HbA1c, UAE and trans-FA. PMID:23551992

Dall'alba, Valesca; Silva, Flávia Moraes; Antonio, Juliana Peçanha; Steemburgo, Thais; Royer, Caroline Persh; Almeida, Jussara Carnevale; Gross, Jorge Luiz; Azevedo, Mirela Jobim

2013-04-01

175

Adenoviral gene transfer allows Smad-responsive gene promoter analyses and delineation of type I receptor usage of transforming growth factor-beta family ligands in cultured human granulosa luteal cells.  

PubMed

In the human ovary, cell growth and differentiation are regulated by members of the TGF-beta superfamily, including growth differentiation factor-9 (GDF9), TGF-beta, and activin. TGF-beta and activin are known to signal via Smad3 activation, and we have recently shown the involvement of Smad3 in cellular responses to GDF9. Recent studies with Smad3-deficient mice have also indicated a key role for this signaling mediator in ovarian folliculogenesis. We now demonstrate the use of a Smad3 reporter (CAGA-luciferase) adenovirus in primary cultures of human granulosa-luteal (hGL) cells to detect GDF9, TGF-beta, and activin responses. In rodent granulosa cells, TGF-beta and GDF9 signal through the TGF-beta type I receptor or activin receptor-like kinase 5 (Alk5), whereas the effect of activin is mediated though the activin type IB receptor, also known as Alk4. We now show that the GDF9 response in hGL cells is markedly potentiated upon overexpression of Alk5 by adenoviral gene transduction, as measured by the CAGA-luciferase reporter activity. A similar response to Alk5 overexpression was observed for TGF-beta, but not for activin. Adenoviral overexpression of the activin type IB receptor Alk4 in hGL cells specifically potentiated activin signaling, but not GDF9 or TGF-beta signaling. Alk5 overexpression in hGL cells also potentiated the GDF9 response when inhibin B production was used as the read-out. These results indicate that the CAGA-luciferase adenovirus can be used to study Smad3 signaling in primary cultures of human cells, and that adenoviral overexpression of wild-type receptors of the TGF-beta superfamily can be used to amplify the cellular response to ligands such as GDF9, TGF-beta, and activin. Furthermore, these studies indicate the involvement of Alk5 in GDF9 signaling in human cells and therefore, along with other recent studies, highlight how a limited number of type I and II receptors cooperate to generate specificity of action within the TGF-beta superfamily. PMID:15483083

Kaivo-Oja, Noora; Mottershead, David G; Mazerbourg, Sabine; Myllymaa, Samu; Duprat, Sébastien; Gilchrist, Robert B; Groome, Nigel P; Hsueh, Aaron J; Ritvos, Olli

2004-10-13

176

Involvement of cyclic adenosine 3',5'-monophosphate in the differential regulation of activin betaA and betaB expression by gonadotropin in the zebrafish ovarian follicle cells.  

PubMed

Activin is a dimeric protein consisting of two similar but distinct beta-subunits, betaA and betaB. In our previous studies, both activin A (betaAbetaA) and activin B (betaBbetaB) have been demonstrated to stimulate oocyte maturation and promote oocyte maturational competence in the zebrafish. Follistatin, a specific activin-binding protein, can block both activin- and gonadotropin-induced final oocyte maturation in vitro, suggesting that activin is likely a downstream mediator of gonadotropin actions in the zebrafish ovary. In the present study, a full-length cDNA encoding zebrafish ovarian activin betaA was cloned and sequenced. The precursor of zebrafish activin betaA consists of 395 amino acids and its mature region exhibits about 78% homology with that of mammals. Using an in vitro primary culture of the ovarian follicle cells and semiquantitative RT-PCR assays, we examined the regulation of activin betaA and betaB expression by human chorionic gonadotropin (hCG) and its intracellular signal transduction mechanisms. hCG (15 IU/ml) increased the mRNA level of activin betaA-subunit; however, it significantly down-regulated the steady-state expression level of activin betaB in a time- and dose-dependent manner. The differential regulation of the two beta-subunits by hCG could be mimicked by 3-isobutyl-1-methylxanthine, forskolin, and dibutyryl-cAMP, suggesting involvement of the intracellular cAMP pathway. Interestingly, H89 (a specific inhibitor of protein kinase A, PKA) could effectively block hCG- and forskolin-stimulated activin betaA expression at 10 micro M, but it was unable to reverse the inhibitory effects of hCG and forskolin on betaB expression. This suggests that the hCG-stimulated activin betaA expression is dependent on the activation of the cAMP-PKA pathway, whereas the inhibitory effect of hCG on activin betaB expression is likely mediated by PKA-independent pathway(s). PMID:12538609

Wang, Yajun; Ge, Wei

2003-02-01

177

Suppression of in vivo tumorigenicity of rat hepatoma cell line KDH-8 cells by soluble TGF-beta receptor type II.  

PubMed

We have previously reported that transforming growth factor beta (TGF-beta) produced by rat hepatoma cell line KDH-8 cells suppressed the interleukin-2 (IL-2) production of T cells and the tumoricidal activity of macrophages in KDH-8 tumor-bearing rats and that the inhibition of TGF-beta production by low-dose bleomycin restored these activities significantly. In this study, we established three transfectant clones with stable expression of soluble TGF-beta receptor type II (sTRII), namely KT1, KT2 and KT3, and one with an empty vector used as control vector (KV), and then investigated the effects of sTRII on the tumorigenicity of KDH-8 cells and immune responses in syngeneic Wistar King Aptekman/Hok (WKAH) rats. We found that sTRII expressed in sTRII transfectants could abolish growth inhibition of Mv1Lu cells by TGF-beta1 produced by the cells themselves, and that tumor growth of KT2 and KT3 clones in vivo was suppressed significantly compared with that of parent, KV and KT1 clones. Furthermore, we demonstrated that IL-2 production of splenocytes and IL12p40 mRNA expression in tumor tissues were restored in rats inoculated with KT2 and KT3 clones, whereas such restoration was not observed in rats inoculated with parent, KV and KT1 clones. Combined with a low expression of sTRII in KT1 tumor tissues, these results suggest that sTRII may to some extent be able to abolish the tumor-promoting activity of TGF-beta, and imply that sTRII might have a therapeutic effect on TGF-beta-producing tumors. PMID:12192538

Zhao, Wenli; Kobayashi, Masonobu; Ding, Wei; Yuan, Lan; Seth, Prem; Cornain, Santoso; Wang, Jingxin; Okada, Futoshi; Hosokawa, Masuo

2002-06-25

178

Increases in soluble CD8 antigen in plasma, and CD8+ and CD8+CD38+ cells in human immunodeficiency virus type-1 infection.  

PubMed

Increases in plasma levels of soluble CD8 (SCD8) antigen and expansion of the CD8+ CD38+ lymphocyte compartment were early immunologic alterations frequently observed prior to detection of antibodies against human immunodeficiency virus type 1 (HIV-1) and diminution of CD4+ cells in subjects at risk to develop AIDS. These increases identified in the 49 seronegative homosexual men were manifest in all 164 homosexual subjects and 45 intravenous drug users (IVDU) positive for HIV-1 antibodies (HIV-1+), 19 patients with ARC, and 29 AIDS patients. Augmentation of plasma sCD8 antigen correlated with increases in both CD8+ and CD8+ CD38+ cells in HIV-1(-) homosexual men (r = 0.35, P less than 0.013; r = 0.48, P less than 0.0005; respectively) and the 258 HIV-1+ subjects (r = 0.25, P less than 0.0003; r = 0.33, P less than 0.0001, respectively). In vitro examination of unstimulated peripheral blood lymphocytes from HIV-1+ homosexuals and IVDU confirmed the fivefold higher constitutive levels of cellular release of sCD8 antigen in these subjects compared to heterosexual controls. Inclusion of radiolabeled amino acids during the 3-day culture period in the presence or absence of phytohemagglutinin resulted in negligible levels of radioactivity associated with the sCD8 antigen indicative of a lack of de novo synthesis. Throughout clinical progression to AIDS, sCD8 antigen levels continued to escalate relative to the numbers of CD8+ cells bearing CD38+ antigen. The data confirm the interrelationship between sCD8+ antigen and CD8+ and CD8+ CD38+ cells. PMID:1611715

Yagi, M J; Chu, F N; Jiang, J D; Wallace, J; Mason, P; Liu, Y; Carafa, J; Bekesi, J G

1992-05-01

179

Deletion of soluble epoxide hydrolase gene improves renal endothelial function and reduces renal inflammation and injury in streptozotocin-induced type 1 diabetes  

PubMed Central

Studies suggest that soluble epoxide hydrolase (sEH) inhibition reduces end-organ damage in cardiovascular diseases. We hypothesize that sEH gene (Ephx2) knockout (KO) improves endothelial function and reduces renal injury in streptozotocin-induced diabetes. After 6 wk of diabetes, afferent arteriolar relaxation to acetylcholine was impaired in diabetic wild-type (WT) mice, as the maximum relaxation was 72% of baseline diameter in the WT but only 31% in the diabetic mice. Ephx2 KO improved afferent arteriolar relaxation to acetylcholine in diabetes as maximum relaxation was 58%. Urinary monocyte chemoattractant protein-1 (MCP-1) excretion significantly increased in diabetic WT mice compared with control (868 ± 195 vs. 31.5 ± 7 pg/day), and this increase was attenuated in diabetic Ephx2 KO mice (420 ± 98 pg/day). The renal phospho-IKK-to-IKK ratio and nuclear factor-?B were significantly decreased, and hemeoxygenase-1 (HO-1) expression increased in diabetic Ephx2 KO compared with diabetic WT mice. Renal NADPH oxidase and urinary thiobarbituric acid reactive substances excretion were reduced in diabetic Ephx2 KO compared with diabetic WT mice. Albuminuria was also elevated in diabetic WT mice compared with control (170 ± 43 vs. 37 ± 13 ?g/day), and Ephx2 KO reduced this elevation (50 ± 15 ?g/day). Inhibition of sEH using trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (tAUCB) also reduced renal inflammation and injury in diabetic WT mice. Furthermore, inhibition of HO with stannous mesoporphyrin negated the reno-protective effects of tAUCB or Ephx2 KO during diabetes. These data demonstrate that Ephx2 KO improves endothelial function and reduces renal injury during diabetes. Additionally, our data also suggest that activation of HO-1 contributes to improved renal injury in diabetic Ephx2 KO mice.

Faulkner, Jessica; Al-Shabrawey, Mohammed; Wang, Mong-Heng; Maddipati, Krishna Rao; Imig, John D.

2011-01-01

180

Transforming Growth Factor ? Receptor Type 1 Is Essential for Female Reproductive Tract Integrity and Function  

Microsoft Academic Search

The transforming growth factor ? (TGF?) superfamily proteins are principle regulators of numerous biological functions. Although recent studies have gained tremendous insights into this growth factor family in female reproduction, the functions of the receptors in vivo remain poorly defined. TGF? type 1 receptor (TGFBR1), also known as activin receptor-like kinase 5, is the major type 1 receptor for TGF?

Qinglei Li; Julio E. Agno; Mark A. Edson; Ankur K. Nagaraja; Takashi Nagashima; Martin M. Matzuk

2011-01-01

181

Growth of HPV-18 immortalized human prostatic intraepithelial neoplasia cell lines. Influence of IL-10, follistatin, activin-A, and DHT.  

PubMed

Cultures from high grade prostatic intraepithelial neoplasia (HGPIN) have been established and immortalized by HPV-18 infection. The cultures were identified as PIN by Western blotting with anti-cytokeratin (34betaE12) and prostate specific antigen (PSA) antibodies. We examined the growth capabilities of the cultures in the presence of TGF-beta1, activin-A, follistatin (FS), androgens (DHEA, DHT) and several cytokines (IL-10, IL-2, IL-4). IL-10, FS, and DHT stimulated cell proliferation and colony forming ability, while the other cytokines and growth factors had no discernable effect. In addition, DHT and to a lesser extent IL-10 both stimulated PSA production. Activin-A blocked IL-10, FS, and DHT stimulated growth and PSA production. We interpret the data to mean that IL-10 induction of FS secretion (and FS binding of activin A) restores the normal growth capabilities of HGPIN cultures. PMID:10339677

Wang, M; Liu, A; Garcia, F U; Rhim, J S; Stearns, M E

1999-06-01

182

Human retroviral gag- and gag-pol-like proteins interact with the transforming growth factor-beta receptor activin receptor-like kinase 1.  

PubMed

Mutations in activin receptor-like kinase 1 (ALK1), a transforming growth factor (TGF)-beta type I receptor, lead to the vascular disorder hereditary hemorrhagic telangiectasia caused by abnormal vascular remodeling. The underlying molecular cause of this disease is not well understood. Identifying binding partners for ALK1 will help to understand its cellular function. Using the two-hybrid system, we identified an ALK1-binding protein encoded by an ancient retroviral/retrotransposon element integrated as a single copy gene known as PEG10 on human chromosome 7q21. PEG10 contains two overlapping reading frames from which two proteins, PEG10-RF1 and PEG10-RF1/2, are translated by a typical retroviral -1 ribosomal frameshift mechanism. Reverse transcription-PCR and Northern blot analysis showed a broad range of PEG10 expression in different tissues and cell types, i.e. human placenta, brain, kidney, endothelial cells, lymphoblasts, and HepG2 and HEK293 cells. However, endogenous PEG10-RF1 and PEG10-RF1/2 proteins were only detected in HepG2 and HEK293 cells. PEG10-RF1, which is the major PEG10 protein product, represents a gag-like protein, and PEG10-RF1/2 represents a gag-pol-like protein. PEG10-RF1 also interacts with different members of TGF-beta superfamily type I and II receptors. PEG10-RF1 binding to ALK1 is mediated by a 200-amino acid domain with no recognized motif. PEG10-RF1 inhibits ALK1 as well as ALK5 signaling. Co-expression of ALK1 and PEG10-RF1 in different cell types induced morphological changes reminiscent of neuronal cells or sprouting cells. This is the first report of a human retroviral-like protein interacting with members of the TGF-beta receptor family. PMID:15611116

Lux, Andreas; Beil, Christian; Majety, Meher; Barron, Suzanne; Gallione, Carol J; Kuhn, Hella-Monika; Berg, Jonathan N; Kioschis, Petra; Marchuk, Douglas A; Hafner, Mathias

2004-12-16

183

Nodal/Activin Signaling Predicts Human Pluripotent Stem Cell Lines Prone to Differentiate Toward the Hematopoietic Lineage  

PubMed Central

Lineage-specific differentiation potential varies among different human pluripotent stem cell (hPSC) lines, becoming therefore highly desirable to prospectively know which hPSC lines exhibit the highest differentiation potential for a certain lineage. We have compared the hematopoietic potential of 14 human embryonic stem cell (hESC)/induced pluripotent stem cell (iPSC) lines. The emergence of hemogenic progenitors, primitive and mature blood cells, and colony-forming unit (CFU) potential was analyzed at different time points. Significant differences in the propensity to differentiate toward blood were observed among hPSCs: some hPSCs exhibited good blood differentiation potential, whereas others barely displayed blood-differentiation capacity. Correlation studies revealed that the CFU potential robustly correlates with hemogenic progenitors and primitive but not mature blood cells. Developmental progression of mesoendodermal and hematopoietic transcription factors expression revealed no correlation with either hematopoietic initiation or maturation efficiency. Microarray studies showed distinct gene expression profile between hPSCs with good versus poor hematopoietic potential. Although neuroectoderm-associated genes were downregulated in hPSCs prone to hematopoietic differentiation many members of the Nodal/Activin signaling were upregulated, suggesting that this signaling predicts those hPSC lines with good blood-differentiation potential. The association between Nodal/Activin signaling and the hematopoietic differentiation potential was confirmed using loss- and gain-of-function functional assays. Our data reinforce the value of prospective comparative studies aimed at determining the lineage-specific differentiation potential among different hPSCs and indicate that Nodal/Activin signaling seems to predict those hPSC lines prone to hematopoietic specification.

Ramos-Mejia, Veronica; Melen, Gustavo J; Sanchez, Laura; Gutierrez-Aranda, Ivan; Ligero, Gertrudis; Cortes, Jose L; Real, Pedro J; Bueno, Clara; Menendez, Pablo

2010-01-01

184

Coherent solubility limits of {gamma}{prime}-type phases in Ni-Al, Ni-Ga and Ni-Ti alloys  

SciTech Connect

One of the predictions of Cahn`s theory of spinodal decomposition in cubic crystals is that the solubility limits of coherent phases in thermodynamic equilibrium can differ from their counterparts in incoherent, unstressed equilibrium. Williams later realized that the equilibrium solubilities limits of coherent phases in a binary alloy should depend on the volume fraction, f, of the two phases, or equivalently, on the overall concentration of solute in the alloy, C{sup o}. The primary objective of this work was therefore to conduct aging experiments on several alloys to measure the coherent solubility limits as a function of the initial alloy content, and to determine whether the shift with C{sup o} could be correlated directly with the magnitude of {delta}.

Li, F.; Ardell, A.J. [Univ. of California, Los Angeles, CA (United States). Dept. of Materials Science and Engineering

1997-10-15

185

Activin, BMP and FGF pathways cooperate to promote endoderm and pancreatic lineage cell differentiation from human embryonic stem cells.  

PubMed

The study of how human embryonic stem cells (hESCs) differentiate into insulin-producing beta cells has twofold significance: first, it provides an in vitro model system for the study of human pancreatic development, and second, it serves as a platform for the ultimate production of beta cells for transplantation into patients with diabetes. The delineation of growth factor interactions regulating pancreas specification from hESCs in vitro is critical to achieving these goals. In this study, we describe the roles of growth factors bFGF, BMP4 and Activin A in early hESC fate determination. The entire differentiation process is carried out in serum-free chemically-defined media (CDM) and results in reliable and robust induction of pancreatic endoderm cells, marked by PDX1, and cell clusters co-expressing markers characteristic of beta cells, including PDX1 and insulin/C-peptide. Varying the combinations of growth factors, we found that treatment of hESCs with bFGF, Activin A and BMP4 (FAB) together for 3-4days resulted in strong induction of primitive-streak and definitive endoderm-associated genes, including MIXL1, GSC, SOX17 and FOXA2. Early proliferative foregut endoderm and pancreatic lineage cells marked by PDX1, FOXA2 and SOX9 expression are specified in EBs made from FAB-treated hESCs, but not from Activin A alone treated cells. Our results suggest that important tissue interactions occur in EB-based suspension culture that contribute to the complete induction of definitive endoderm and pancreas progenitors. Further differentiation occurs after EBs are embedded in Matrigel and cultured in serum-free media containing insulin, transferrin, selenium, FGF7, nicotinamide, islet neogenesis associated peptide (INGAP) and exendin-4, a long acting GLP-1 agonist. 21-28days after embedding, PDX1 gene expression levels are comparable to those of human islets used for transplantation, and many PDX1(+) clusters are formed. Almost all cells in PDX1(+) clusters co-express FOXA2, HNF1ß, HNF6 and SOX9 proteins, and many cells also express CPA1, NKX6.1 and PTF1a. If cells are then switched to medium containing B27 and nicotinamide for 7-14days, then the number of insulin(+) cells increases markedly. Our study identifies a new chemically defined culture protocol for inducing endoderm- and pancreas-committed cells from hESCs and reveals an interplay between FGF, Activin A and BMP signaling in early hESC fate determination. PMID:21855631

Xu, Xiaofang; Browning, Victoria L; Odorico, Jon S

2011-08-10

186

Inhibin\\/activin-betaE subunit is expressed in normal and pathological human placental tissue including chorionic carcinoma cell lines  

Microsoft Academic Search

Background  Inhibins and activins are important regulators of the female reproductive system. Recently, a novel inhibin subunit, named\\u000a betaE, has been identified and shown to be expressed in several human tissues. However, only limited data on the expression\\u000a of this novel inhibin-betaE subunit in normal and pathological human placenta as well as and human chorionic carcinoma cell\\u000a lines exist.\\u000a \\u000a \\u000a \\u000a \\u000a Materials and

Andrea Gingelmaier; Ansgar Brüning; Tanja Kimmich; Josef Makovitzky; Florian Bergauer; Barbara Schiessl; Klaus Friese; Ioannis Mylonas

2011-01-01

187

Cloning of a Type I TGF-beta Receptor and Its Effect on TGFbeta Binding to the Type II Receptor  

Microsoft Academic Search

Transforming growth factor-beta (TGF-beta) affects cellular proliferation, differentiation, and interaction with the extracellular matrix primarily through interaction with the type I and type II TGF-beta receptors. The type II receptors for TGF-beta and activin contain putative serine-threonine kinase domains. A murine serine-threonine kinase receptor, Tsk 7L, was cloned that shared a conserved extracellular domain with the type II TGF-beta receptor.

Reinhard Ebner; Ruey-Hwa Chen; Lillian Shum; Sean Lawler; Thomas F. Zioncheck; Angela Lee; Alfredo R. Lopez; Rik Derynck

1993-01-01

188

Activin receptor-like kinase-7 induces apoptosis through activation of MAPKs in a Smad3-dependent mechanism in hepatoma cells.  

PubMed

Activin receptor-like kinase (ALK)7 is a type I serine/threonine kinase receptor of the transforming growth factor (TGF)-beta family of proteins that has similar properties to other type I receptors when activated. To see whether ALK7 can induce apoptosis as can some of the other ALK proteins, we infected the FaO rat hepatoma cell line with adenovirus expressing a constitutively active form of the ALK7. Cells infected with active ALK7 adenovirus showed an apoptotic-positive phenotype, as opposed to those that were infected with a control protein. DNA fragmentation assays and fluorescence-activated cell sorter analysis also indicated that ALK7 infection induced apoptosis in FaO cells. We also confirmed this finding in Hep3B human hepatoma cells by transiently transfecting the constitutively active form of ALK7, ALK7(T194D). Investigation into the downstream targets and mechanisms involved in ALK7-induced apoptosis revealed that the TGF-beta signaling intermediates, Smad2 and -3, were activated, as well as the MAPKs JNK and p38. In addition, caspase-3 and -9 were also activated, and cytochrome c release from the mitochondria was observed. Short interfering RNA-mediated inhibition of Smad3 markedly suppressed ALK7-induced caspase-3 activation. Treatment with protein synthesis inhibitors or the expression of the dominant-negative form of the stress-activated protein/extracellular signal-regulated kinase 1 abolished not only JNK activation but apoptosis as well. Taken together, these results suggest that ALK7 induces apoptosis through activation of the traditional TGF-beta pathway components, thus resulting in new gene transcription and JNK and p38 activation that initiates cross-talk with the cellular stress death pathway and ultimately leads to apoptosis. PMID:15107418

Kim, Byung-Chul; van Gelder, Howard; Kim, Tae Aug; Lee, Ho-Jae; Baik, Kim G; Chun, Hyun Hye; Lee, David A; Choi, Kyeong Sook; Kim, Seong-Jin

2004-04-23

189

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

190

Fibroblast growth factor, but not activin, is a potent activator of mitogen-activated protein kinase in Xenopus explants.  

PubMed Central

Isolated explants from the animal hemisphere of Xenopus embryos were incubated with Xenopus basic fibroblast growth factor (XbFGF) or human activin A. XbFGF incubation resulted in the rapid activation of mitogen-activated protein kinase (MAPK) and ribosomal S6 protein kinase (pp90rsk) in a dose-dependent manner with the highest levels of activation occurring at 50 ng/ml. Maximal activation occurred within 6-10 min after the addition of growth factor, and the activity of both kinases declined to unstimulated levels after 30 min. Activin was unable to activate either MAPK or pp90rsk in the Xenopus explants to a substantial level, although it induced dorsal mesoderm better than XbFGF under the same experimental conditions. The regulatory protein Xwnt-8 did not activate MAPK, nor did it enhance the activation of MAPK by XbFGF. XbFGF was able to activate MAPK through at least the midgastrula stage, suggesting that this family of growth factors may have a role in gastrula-stage events. Images

Graves, L M; Northrop, J L; Potts, B C; Krebs, E G; Kimelman, D

1994-01-01

191

Systemic and Intraluteal Infusion of Inhibin A or Activin A in Rhesus Monkeys during the Luteal Phase of the Menstrual Cycle1  

Microsoft Academic Search

The endocrine or local actions of inhibin-related peptides synthesized by the primate corpus luteum (CL) remain undefi ned. This in vivo study was designed to determine whether exogenous inhibin or activin modulates pituitary gonadotropin secretion and the functional life span of the CL during the luteal phase of the menstrual cycle. Beginning at midluteal phase of the cycle, either vehicle

RICHARD L. STOUFFER; KRISTINE D. DAHL; DAVID L. HESS; TERESA K. WOODRUFF; JENNIE P. MATHER; THEODORE A. MOLSKNESS

192

C-Glycosyl flavonoids and coloratane-type sesquiterpene glucosides from the water-soluble fraction of a leaf extract of a Malagasy endemic plant, Cinnamosma fragrans (Canellaceae).  

PubMed

Leaves of Cinnamosma fragrans were extracted with MeOH, and the concentrated MeOH extract was partitioned with EtOAc and H2O. From the H2O-soluble fraction, three new flavonol C-glycosides and two coloratane glucosides were isolated, along with nine known compounds. On extensive spectroscopic analysis, C-glycosylation was found to have occurred on the B-ring. PMID:23274915

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

2012-12-29

193

Identification of Smad Response Elements in the Promoter of Goldfish FSH? Gene and Evidence for Their Mediation of Activin and GnRH Stimulation of FSH? Expression  

PubMed Central

As an essential hormone regulating gonads in vertebrates, the biosynthesis and secretion of follicle-stimulating hormone (FSH) is controlled by a variety of endocrine and paracrine factors in both mammalian and non-mammalian vertebrates. Activin was initially discovered in the ovary for its specific stimulation of FSH secretion by the pituitary cells. Our earlier studies in fish have shown that activin stimulates FSH? but suppresses LH? expression in both the goldfish and zebrafish. Further experiments showed that the regulation of FSH? in fish occurred at the promoter level involving Smads, in particular Smad3. To further understand the mechanisms by which activin/Smad regulates FSH? transcription, the present study was undertaken to analyze the promoter of goldfish FSH? gene (fshb) with the aim to identify potential cis-regulatory elements responsible for activin/Smad stimulation. Both serial deletion and site-directed mutagenesis were used, and the promoter activity was tested in the L?T-2 cells, a murine gonadotroph cell line. The reporter constructs of goldfish FSH? promoter-SEAP (secreted alkaline phosphatase) were co-transfected with an expression plasmid for Smads (2 or 3) followed by measurement of SEAP activity in the medium. Two putative Smad responsive elements were identified in the promoter at distal and proximal regions, respectively. The distal site contained a consensus Smad binding element (AGAC, ?1675/?1672) whereas the proximal site (GACCTTGA, ?212/?205) was identical to an SF-1 binding site reported in humans, which was preceded by a sequence (AACACTGA) highly conserved between fish and mammals. The proximal site also seemed to be involved in mediating stimulation of FSH? expression by gonadotropin-releasing hormone and its potential interaction with activin. In conclusion, we have identified two potential cis-regulatory elements in the promoter of goldfish FSH? that are responsible for activin-induced expression of the gene. Since activin stimulation of FSH? expression is functionally conserved in fish and mammals, our findings contribute to the understanding of the fundamental mechanisms of this regulation across vertebrates.

Lau, Man-Tat; Lin, Sze-Wah; Ge, Wei

2012-01-01

194

Comparative c-type cytochrome expression analysis in Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C grown with soluble and insoluble oxidised metal electron acceptors  

SciTech Connect

The genomes of Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C encode 40 and 69 putative c-type cytochrome genes, respectively. Deletion mutant and biochemical studies have assigned specific functions to a few c-type cytochromes involved in electron transfer to oxidised metals in Shewanella oneidensis strain MR-1. Although promising, the genetic approach is limited to gene deletions that produce a distinct phenotype, and organism for which a genetic system is available. To more comprehensively investigate and compare c-type cytochrome expression in Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C, proteomic measurements were used to characterise lysates of cells grown with soluble Fe(III) (as ferric citrate) and insoluble Mn(IV) (as MnO2) as electron acceptors. Strain MR-1 expressed 19 and 20, and strain 2CP-C expressed 27 and 25 c-type cytochromes when grown with Fe(III) and Mn(IV), respectively. The majority of c-type cytochromes (77% for strain MR-1 and 63% for strain 2CP-C) were expressed under both growth conditions; however, the analysis also revealed unique c-type cytochromes that were specifically expressed in cells grown with soluble Fe(III) or insoluble Mn(IV). Proteomic characterisation proved to be a promising approach for determining the c-type cytochrome complement expressed under different growth conditions, and will help elucidating the specific functions of more c-type cytochromes that are the basis for Shewanella and Anaeromyxobacter respiratory versatility.

Nissen, Silke [ORNL; Liu, Xiaoxin [ORNL; Chourey, Karuna [ORNL; Hettich, Robert {Bob} L [ORNL; Wagner, Darlene D [Georgia Institute of Technology; Pffifner, Susan [University of Tennessee, Knoxville (UTK); Loeffler, Frank E [ORNL

2012-01-01

195

Comparative c-type cytochrome expression analysis in Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C grown with soluble and insoluble oxidized metal electron acceptors.  

PubMed

The genomes of Shewanella oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C encode 40 and 69 putative c-type cytochrome genes respectively. Deletion mutant and biochemical studies have assigned specific functions to a few c-type cytochromes involved in electron transfer to oxidized metals in S. oneidensis strain MR-1. Although promising, the genetic approach is limited to gene deletions that produce a distinct phenotype and to an organism for which a genetic system is available. To investigate and compare c-type cytochrome expression in S. oneidensis strain MR-1 and Anaeromyxobacter dehalogenans strain 2CP-C more comprehensively, proteomic measurements were used to characterize lysates of cells grown with soluble Fe(III) (as ferric citrate) and insoluble Mn(IV) (as MnO2) as electron acceptors. Strain MR-1 expressed 19 and 20, and strain 2CP-C expressed 27 and 25, c-type cytochromes when grown with Fe(III) and Mn(IV) respectively. The majority of c-type cytochromes (77% for strain MR-1 and 63% for strain 2CP-C) were expressed under both growth conditions; however, the analysis also revealed unique c-type cytochromes that were specifically expressed in cells grown with soluble Fe(III) or insoluble Mn(IV). Proteomic characterization proved to be a promising approach for determining the c-type cytochrome complement expressed under different growth conditions, and will help to elucidate the specific functions of more c-type cytochromes that are the basis for Shewanella and Anaeromyxobacter respiratory versatility. PMID:23176455

Nissen, Silke; Liu, Xiaoxin; Chourey, Karuna; Hettich, Robert L; Wagner, Darlene D; Pfiffner, Susan M; Löffler, Frank E

2012-12-01

196

TAK-1/p38/nNF?B signaling inhibits myoblast differentiation by increasing levels of Activin A  

PubMed Central

Background Skeletal-muscle differentiation is required for the regeneration of myofibers after injury. The differentiation capacity of satellite cells is impaired in settings of old age, which is at least one factor in the onset of sarcopenia, the age-related loss of skeletal-muscle mass and major cause of frailty. One important cause of impaired regeneration is increased levels of transforming growth factor (TGF)-? accompanied by reduced Notch signaling. Pro-inflammatory cytokines are also upregulated in aging, which led us hypothesize that they might potentially contribute to impaired regeneration in sarcopenia. Thus, in this study, we further analyzed the muscle differentiation-inhibition pathway mediated by pro-inflammatory cytokines in human skeletal muscle cells (HuSKMCs). Methods We studied the modulation of HuSKMC differentiation by the pro-inflammatory cytokines interleukin (IL)-1? and tumor necrosis factor (TNF)-? The grade of differentiation was determined by either imaging (fusion index) or creatine kinase (CK) activity, a marker of muscle differentiation. Secretion of TGF-? proteins during differentiation was assessed by using a TGF-?-responsive reporter-gene assay and further identified by means of pharmacological and genetic inhibitors. In addition, signaling events were monitored by western blotting and reverse transcription PCR, both in HuSKMC cultures and in samples from a rat sarcopenia study. Results The pro-inflammatory cytokines IL-1? and TNF-? block differentiation of human myoblasts into myotubes. This anti-differentiation effect requires activation of TGF-?-activated kinase (TAK)-1. Using pharmacological and genetic inhibitors, the TAK-1 pathway could be traced to p38 and NF?B. Surprisingly, the anti-differentiation effect of the cytokines required the transcriptional upregulation of Activin A, which in turn acted through its established signaling pathway: ActRII/ALK/SMAD. Inhibition of Activin A signaling was able to rescue human myoblasts treated with IL-1? or TNF-?, resulting in normal differentiation into myotubes. Studies in aged rats as a model of sarcopenia confirmed that this pro-inflammatory cytokine pathway identified is activated during aging. Conclusions In this study, we found an unexpected connection between cytokine and Activin signaling, revealing a new mechanism by which cytokines affect skeletal muscle, and establishing the physiologic relevance of this pathway in the impaired regeneration seen in sarcopenia.

2012-01-01

197

Soluble oil additive concentrate  

SciTech Connect

An additive concentrate was proposed which consisted of 1 to 12 parts alkyl aryl sulfonates (mixture of oil-soluble and water-soluble sulfonates) per part of secondary butyl alcohol. This concentrate was to be combined with the appropriate proportions of liquid hydrocarbon and water to form anhydrous and water-containing soluble oils.

Holm, L.W.

1973-10-30

198

The Fibroblast Integrin ?11?1 Is Induced in a Mechanosensitive Manner Involving Activin A and Regulates Myofibroblast Differentiation*  

PubMed Central

Fibrotic tissue is characterized by an overabundance of myofibroblasts. Thus, understanding the factors that induce myofibroblast differentiation is paramount to preventing fibrotic healing. Previous studies have shown that mechanical stress derived from the integrin-mediated interaction between extracellular matrix and the cytoskeleton promotes myofibroblast differentiation. Integrin ?11?1 is a collagen receptor on fibroblasts. To determine whether ?11?1 can act as a mechanosensor to promote the myofibroblast phenotype, mouse embryonic fibroblasts and human corneal fibroblasts were utilized. We found that ?11 mRNA and protein levels were up-regulated in mouse embryonic fibroblasts grown in attached three-dimensional collagen gels and conversely down-regulated in cells grown in floating gels. ?11 up-regulation could be prevented by manually detaching the collagen gels or by cytochalasin D treatment. Furthermore, SB-431542, an inhibitor of signaling via ALK4, ALK5, and ALK7, prevented the up-regulation of ?11 and the concomitant phosphorylation of Smad3 under attached conditions. In attached gels, TGF-?1 was secreted in its inactive form but surprisingly not further activated, thus not influencing ?11 regulation. However, inhibition of activin A attenuated the up-regulation of ?11. To determine the role of ?11 in myofibroblast differentiation, human corneal fibroblasts were transfected with small interfering RNA to ?11, which decreased ?-smooth muscle actin expression and myofibroblast differentiation. Our data suggest that ?11?1 is regulated by cell/matrix stress involving activin A and Smad3 and that ?11?1 regulates myofibroblast differentiation.

Carracedo, Sergio; Lu, Ning; Popova, Svetlana N.; Jonsson, Roland; Eckes, Beate; Gullberg, Donald

2010-01-01

199

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

2008-07-27

200

New type of microfabricated carbon electrodes for high-performance liquid chromatography—Amperometric detection of fat-soluble vitamins and antioxidants  

Microsoft Academic Search

This study evaluates performance of thin-film carbon electrodes prepared by physical vapor deposition of the electrode material on a polyetheretherketone substrate and compares their performance with that of a standard type of glassy carbon electrodes for chromatographic detection cell of thin-layer type. Kaempferol, retinol, retinyl acetate, cholecalciferol, ?-tocopherol and ?-tocopherol were selected for the study and their respective detection limits

Jun Cheng; Petr Jandik

2008-01-01

201

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

202

Recombinant Soluble, Multimeric HA and NA Exhibit Distinctive Types of Protection against Pandemic Swine-Origin 2009 A(H1N1) Influenza Virus Infection in Ferrets?  

PubMed Central

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 their efficacy as vaccines in ferrets. Immunization twice with 3.75-?g 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 sHA3 dramatically reduced virus replication (e.g., by lowering pulmonary titers by about 5 log10 units), immunization with sNA4 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.

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.

2010-01-01

203

Production, characterization, and reconstitution of recombinant quinoprotein glucose dehydrogenase (soluble type; EC 1.1.99.17) apoenzyme of Acinetobacter calcoaceticus.  

PubMed

Soluble, periplasmic quinoprotein glucose dehydrogenase of Acinetobacter calcoaceticus (sGDH; EC 1.1.99.17) was produced in good yield in the apoenzyme form (without the cofactor pyrroloquinoline quinone, PQQ) by an Escherichia coli recombinant strain provided with a plasmid containing the gene under control of a lac promoter. Structural analysis of the purified apoenzyme revealed that the E. coli strain used produces the correct mature protein. Titration of the apoenzyme with PQQ in the presence of Ca2+ showed that a linear relation exists between the amount of added PQQ and activity observed, and that the subunit and PQQ associate in a molar ratio of 1:1. Based on spectral and enzymatic criteria, it is concluded that the present holoenzyme preparation has a better quality than the previously described preparations of authentic holoenzyme. As isolated here, the recombinant apoenzyme was in the dimeric form. Partial monomerization occurred upon gel filtration in a buffer with chelator and the process could be reversed with Ca2+. PQQ binds to the dimer in the presence of chelator, not to the monomer. However, the PQQ-containing dimer was not active and showed an unusual absorption spectrum which was slowly converted into a PQQH2-like spectrum when glucose was added. Full restoration of activity was achieved upon addition of Ca2+ and the spectra were immediately converted into those of normal holoenzyme in the oxidized and reduced form, respectively. Addition of chelator to holoenzyme did not lead to inactivation or monomerization. It is concluded, therefore, that Ca2+ has a dual role in this enzyme, being required for dimerization of the subunits as well as for functionalization of the bound PQQ, and that it is more firmly attached to the holoenzyme than to the apoenzyme. PMID:8951033

Olsthoorn, A J; Duine, J A

1996-12-01

204

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

2012-12-03

205

BMP Type II Receptor Is Required for Gastrulation and Early Development of Mouse Embryos  

Microsoft Academic Search

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-? superfamily, play a variety of roles during mouse development. BMP type II receptor (BMPR-II) is a type II serine\\/threonine kinase receptor, which transduces signals for BMPs through heteromeric complexes with type I receptors, including activin receptor-like kinase 2 (ALK2), ALK3\\/BMPR-IA, and ALK6\\/BMPR-IB. To elucidate the function of BMPR-II in mammalian

Hideyuki Beppu; Masahiro Kawabata; Toshiaki Hamamoto; Anna Chytil; Osamu Minowa; Tetsuo Noda; Kohei Miyazono

2000-01-01

206

APPLICATIONS OF SOLUBLE DIETARY FIBERS IN BEVERAGES APLICACIONES DE LA FIBRA DIETETICA SOLUBLE EN BEBIDAS  

Microsoft Academic Search

In this work the importance of soluble dietary fibers in the human diet is discussed. Traditional and new sources of soluble dietary fiber are mentioned, and a description of how to apply them in different types of beverages such as energy drinks, sport drinks, carbonated beverages and protein-based beverages in order to achieve enhanced functional properties is given.

C. I. Beristain; F. Cruz-Sosa; C. Lobato-Calleros; R. Pedroza-Islas; M. E. Rodríguez; J. R. Verde-Calvo

207

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...

208

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

209

Effect of the interaction of heat-processing style and fat type on the micellarization of lipid-soluble pigments from green and red pungent peppers (Capsicum annuum).  

PubMed

The high diversity of carotenoids and chlorophylls in foods contrasts with the reduced number of pigments that typically are investigated in micellarization studies. In this study, pepper samples (raw and heat-treated) contained 68 individual pigments, but only 38 of them were micellarized after in vitro digestion. The micellarization of pigments was majorly determined by the interaction effect of processing style (food matrix effect) and fat type (saturated and unsaturated). The highest micellarization was observed with raw peppers. Unsaturated fat increased the micellarization of carotenoid esters, while the impact of fat on the micellarization of free carotenoids seemed to be dependent on pigment structure. The micellarization efficiency was diminished as the esterification level of carotenoids increased. The type of fatty acid moiety and the polarity of the carotenoids modulated their micellarization. Chlorophylls were transformed into pheophytins by heat-processing and digestion, with the pheophytins being stable under gastrointestinal conditions. Micellarization of pheophytins was improved by fat. PMID:23517119

Victoria-Campos, Claudia I; Ornelas-Paz, José de Jesús; Yahia, Elhadi M; Failla, Mark L

2013-04-05

210

Cell-type specific regulation of myostatin signaling.  

PubMed

The transforming growth factor (TGF)-? family member myostatin is an important regulator of myoblast, adipocyte, and fibroblast growth and differentiation, but the signaling mechanisms remain to be established. We therefore determined the contribution of myostatin type I receptors activin receptor-like kinase-4 (ALK4) and -5 (ALK5) and different coreceptors in C2C12 myoblasts, C3H10T1/2 mesenchymal stem cells, and 3T3-L1 fibroblasts, as well as in primary myoblast and fibroblasts. We performed siRNA-mediated knockdown of each receptor and measured signaling activity using Smad3-dependent luciferase and Smad2 phosphorylation assays with nontargeting siRNA as control. We find that myostatin utilizes ALK4 in myoblasts, whereas it has a preference for ALK5 in nonmyogenic cells. Notably, our results show that coreceptor Cripto is expressed in myoblasts but not in the nonmyogenic cells and that it regulates myostatin activity. More specifically, myostatin requires Cripto in myoblasts, whereas Cripto represses activin activity and TGF-? signaling is Cripto independent. Cripto-mediated myostatin signaling is dependent on both epidermal growth factor (EGF)-like and Cripto-FRL1-cryptic (CFC) domains, whereas activin signaling is solely conferred by the CFC domain. Furthermore, Cripto down-regulation enhances myoblast differentiation, showing its importance in myostatin signaling. Together, our results identify a molecular mechanism that explains the cell-type specific aspects of signaling by myostatin and other TGF-? family members. PMID:22202673

Kemaladewi, Dwi U; de Gorter, David J J; Aartsma-Rus, Annemieke; van Ommen, Gert-Jan; ten Dijke, Peter; 't Hoen, Peter A C; Hoogaars, Willem M

2011-12-27

211

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  

SciTech Connect

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 monomeric gp120 subunits did not confer protection from infection; one alternative approach is therefore to make and evaluate soluble forms of the trimeric Env complex. We have directly compared the immunogenicity in rabbits of two forms of soluble trimeric Env and monomeric gp120 based on the sequence of HIV-1{sub JR-FL}. Both protein-only and DNA-prime, protein-boost immunization formats were evaluated, DNA-priming having little or no influence on the outcome. One form of trimeric Env was made by disrupting the gp120-gp41 cleavage site by mutagenesis (gp140{sub UNC}), the other contains an intramolecular disulfide bond to stabilize the cleaved gp120 and gp41 moieties (SOSIP.R6 gp140). Among the three immunogens, SOSIP.R6 gp140 most frequently elicited neutralizing antibodies against the homologous, neutralization-resistant strain, HIV-1{sub JR-FL}. All three proteins induced NAbs against more sensitive strains, but the breadth of activity against heterologous primary isolates was limited. When antibodies able to neutralize HIV-1{sub JR-FL} were detected, antigen depletion studies showed they were not directed at the V3 region but were targeted at other, undefined gp120 and also non-gp120 epitopes.

Beddows, Simon [Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021 (United States); Franti, Michael [Progenics Pharmaceuticals, Inc. Tarrytown, New York, NY 10591 (United States); Dey, Antu K. [Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021 (United States); Kirschner, Marc [Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021 (United States); Iyer, Sai Prasad N. [Progenics Pharmaceuticals, Inc. Tarrytown, New York, NY 10591 (United States); Fisch, Danielle C. [Progenics Pharmaceuticals, Inc. Tarrytown, New York, NY 10591 (United States); Ketas, Thomas [Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021 (United States); Progenics Pharmaceuticals, Inc. Tarrytown, New York, NY 10591 (United States); Yuste, Eloisa [New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, MA 01772 (United States); Desrosiers, Ronald C. [New England Primate Research Center, Department of Microbiology and Molecular Genetics, Harvard Medical School, Southborough, MA 01772 (United States); Klasse, Per Johan [Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021 (United States); Maddon, Paul J. [Progenics Pharmaceuticals, Inc. Tarrytown, New York, NY 10591 (United States); Olson, William C. [Progenics Pharmaceuticals, Inc. Tarrytown, New York, NY 10591 (United States); Moore, John P. [Department of Microbiology and Immunology, Weill Medical College of Cornell University, 1300 York Avenue, Room W-805, New York, NY 10021 (United States)]. E-mail: jpm2003@med.cornell.edu

2007-04-10

212

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

2012-07-27

213

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

214

Multiplex Bead Array Assay for Detection of 25 Soluble Cytokines in Blister Fluid of Patients with Complex Regional Pain Syndrome Type 1  

PubMed Central

Inflammatory processes are known to be involved at least in the early phase of complex regional pain syndrome type 1 (CRPS1). Blister fluid obtained from the involved extremities displayed increased amounts of proinflammatory cytokines IL-6 and TNF? compared with the noninvolved extremities. The aim of this paper is to investigate the involvement of mediators by measurement of several other cytokines using new detection techniques that enable multiple cytokine measurement in small samples. The use of a multiplex-25 bead array cytokine assay and Luminex technology enabled simultaneous measurement of representative (1) proinflammatory cytokines such as GM-CSF, IL-1?, IL-1RA, IL-6, IL-8, and TNF-?; (2) Th1/Th2 distinguishing cytokines IFN-?, IL-2, IL-2R, IL-4, IL-5, and IL-10; (3) nonspecific acting cytokines IFN-?, IL-7, IL-12p40/p70, IL-13, IL-15, and IL-17; and (4) chemokines eotaxin, IP-10, MCP-1, MIP-1?, MIP-1?, MIG, and RANTES. Although minimal detection levels are significantly higher in the bead array system than those in common ELISA assays, in blister fluid, IL-1RA, IL-6, IL-8, TNF-?, IL-12p40/p70, MCP-1, and MIP-1? were detectable and increased in CRPS1 affected extremities. Levels of IL-6 and TNF-? simultaneously measured by ELISA (Sanquin Compact kit) and by multiplex-25 bead array assay (Biosource) were highly correlated (r = 0.85, P < .001 for IL-6 and r = 0.88, P < .001 for TNF-?). Furthermore, IP-10 and eotaxin were detectable but diminished in CRPS1, whereas detectable amounts of IL-10 were similar in involved and noninvolved extremities. Multiplex bead array assays are useful systems to establish the involvement of cytokines in inflammatory processes by measurements in blister fluids of CRPS1. Ten representative cytokines were detectable. However, detection levels and amounts measured are at least 3 times higher in the multiplex-25 array assay than in the ELISA assays used simultaneously for the measurement of cytokines.

Heijmans-Antonissen, Claudia; Wesseldijk, Feikje; Munnikes, Renate JM; Huygen, Frank JPM; van der Meijden, Patrick; Hop, Wim C. J.; Hooijkaas, Herbert; Zijlstra, Freek J.

2006-01-01

215

DEVELOPMENT OF SOLUBILITY PRODUCT VISUALIZATION TOOLS  

SciTech Connect

Western Research Institute (WRI) has developed software for the visualization of data acquired from solubility tests. The work was performed in conjunction with AB Nynas Petroleum, Nynashamn, Sweden who participated as the corporate cosponsor for this Jointly Sponsored Research (JSR) task. Efforts in this project were split between software development and solubility test development. The Microsoft Windows-compatible software developed inputs up to three solubility data sets, calculates the parameters for six solid body types to fit the data, and interactively displays the results in three dimensions. Several infrared spectroscopy techniques have been examined for potential use in determining bitumen solubility in various solvents. Reflectance, time-averaged absorbance, and transmittance techniques were applied to bitumen samples in single and binary solvent systems. None of the techniques were found to have wide applicability.

T.F. Turner; A.T. Pauli; J.F. Schabron

2004-05-01

216

An evaluation of serum soluble CD30 levels and serum CD26 (DPPIV) enzyme activity as markers of type 2 and type 1 cytokines in HIV patients receiving highly active antiretroviral therapy.  

PubMed

This study evaluates serum CD26 (dipeptidyl peptidase IV, DPPIV) enzyme activity and serum levels of soluble CD30 as markers of T1 and T2 cytokine environments in HIV patients who achieved immune reconstitution after highly active antiretroviral therapy (HAART). Patients who had experienced inflammatory disease associated with pre-existent opportunistic infections after HAART (immune restoration diseases, IRD) were considered separately. Serum sCD30 levels and CD26 (DPPIV) enzyme activity were compared with IFN-gamma production by PBMC cultured with cytomegalovirus (CMV) antigen in controls and patient groups. High sCD30 levels were associated with low IFN-gamma production after antigenic stimulation in control subjects and, to a lesser extent, in immune reconstituted HIV patients. There was no association between serum CD26 (DPPIV) enzyme activity and IFN-gamma production or sCD30 levels. Serum sCD30 levels and CD26 (DPPIV) enzyme activity were significantly increased in immune reconstituted patients with high HIV viral loads. Patients who had experienced CMV retinitis as an IRD had significantly higher sCD30 levels than all other patient groups. Hence, high sCD30 levels may be a marker of a T2 cytokine environment in HIV patients with immune reconstitution and are associated with higher HIV viral loads and a history of CMV associated IRD. PMID:11678906

Keane, N M; Price, P; Lee, S; Stone, S F; French, M A

2001-10-01

217

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

218

Inhibition by 1?,25-Dihydroxyvitamin D 3of Activin A-Induced Differentiation of Murine Erythroleukemic F5-5 Cells  

Microsoft Academic Search

1?,25-Dihydroxyvitamin D3(1?,25-(OH)2D3) and other vitamin D3(VD3) analogs enhanced the inhibitory effect of Activin A on murine erythroleukemia (MEL) cell proliferation and differentiation in a dose-dependent manner. 1?,25-(OH)2D3inhibited differentiation more potently than proliferation by one order of magnitude. The VD3analog study demonstrated either effect of VD3on MEL cells via vitamin D receptor (VDR), as evidenced from the close relationship with the

Toshiki Nagasaki; Masayuki Hino; Masaaki Inaba; Yoshiki Nishizawa; Hirotoshi Morii; Shuzo Otani

1997-01-01

219

Identification and expression of Smads associated with TGF-?/activin/nodal signaling pathways in the rainbow trout (Oncorhynchus mykiss).  

PubMed

The Smad proteins are essential components of the TGF-?/activin/nodal family signaling pathway. We report the identification and expression of transcripts representing three receptor Smads (Smad2a, Smad2b, and Smad3), two common Smads (Smad4a and Smad4b), and one inhibitory Smad (Smad7). Phylogenetic analysis suggests this gene family evolved through the combination of ancient and more recent salmonid genome duplication events. Tissue distribution, embryonic expression, and expression in growth hormone (GH) treated fish were assessed by reverse transcription PCR or qPCR. All six Smad transcripts were ubiquitously expressed in adult tissues. We observed the highest expression of the receptor Smads in unfertilized eggs, generally decreasing during early embryonic development and slightly increasing around 11 days post-fertilization (dpf). Smad7 expression was low for most of embryonic development, with a dramatic increase at the onset of muscle development (6 dpf), and at hatch (24 dpf). Smad4 expression was low during early embryonic development and increased after 14 dpf. The increased expression of Smad4 and Smad7 during late embryonic development may indicate modulation of gene expression by GH axis, which initiates activity during late embryonic development. These data were supported by the modulation of these Smads in the gill filament, stomach, and muscle following a GH treatment. Additionally, these changes are concurrent with the modulation of expression of TGF-? family members. Most significantly, the increased expression of Smad7 in the muscle is simultaneous with increased expression of MSTN1A and not MSTN1B during both embryonic development and following GH treatment. These data indicate a promyogenic role for Smad7 as previously identified in other non-fish species. PMID:22290475

Gahr, Scott A; Weber, Gregory M; Rexroad, Caird E

2012-10-01

220

Water solubility in aluminosilicate melts  

Microsoft Academic Search

We have compiled water solubility data for a wide range of natural and synthetic aluminosilicate melts in a search for correlations between melt composition and solubility. The published data reveal some interesting systematics. For example, molar water solubility increases with decreasing silica content in binary and pseudobinary silicates, and much higher solubilities are associated with alkali systems compared to alkaline

Paul F. McMillan; John R. Holloway

1987-01-01

221

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

222

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

2011-02-01

223

mNanog Possesses Dorsal Mesoderm-Inducing Ability by Modulating Both BMP and Activin/Nodal Signaling in Xenopus Ectodermal Cells  

PubMed Central

Background In Xenopus early embryogenesis, various genes are involved with mesoderm formation. In particular, dorsal mesoderm contains the organizer region and induces neural tissues through the inhibition of bone morphogenetic protein (BMP) signaling. In our initial study to identify novel genes necessary for maintaining the undifferentiated state, we unexpectedly revealed mesoderm-inducing activity for mNanog in Xenopus. Methodology/Principal Findings The present series of experiments investigated the effect of mNanog gene expression on Xenopus embryo. Ectopic expression of mNanog induced dorsal mesoderm gene activity, secondary axis formation, and weakly upregulated Activin/nodal signaling. The injection of mNanog also effectively inhibited the target genes of BMP signaling, while Xvent2 injection downregulated the dorsal mesoderm gene expression induced by mNanog injection. Conclusions/Significance These results suggested that mNanog expression induces dorsal mesoderm by regulating both Activin/nodal signaling and BMP signaling in Xenopus. This finding highlights the possibly novel function for mNanog in stimulating the endogenous gene network in Xenopus mesoderm formation.

Yamashita, Satoshi; Nejigane, Susumu; Matsukawa, Shinya; Ito, Yuzuru; Onuma, Yasuko; Asashima, Makoto; Michiue, Tatsuo

2012-01-01

224

[Soluble adhesion molecules in muscular dystrophy].  

PubMed

To determine whether soluble adhesion molecules are affected in muscular dystrophy, we measured serum levels of creatine kinase (CK), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), soluble (s) E-selectin, and fibrin and fibrinogen degradation products (FDP) in 25 patients with Duchenne muscular dystrophy (DMD), 7 with Becker muscular dystrophy, 7 with Fukuyama type congenital muscular dystrophy, 6 with myotonic dystrophy (MyD), and 5 with spinal muscular atrophy (SMA) type 2, and also serum sVCAM-1, sICAM-1, and sE-selectin in 9 healthy controls. The levels of sVCAM-1 in the patients with DMD were 367.0-852.0 ng/ml (552.8 +/- 23.1) and significantly elevated than those in the patients with MyD, SMA type 2, and controls. The levels of sICAM-1 and sE-selectin in the patients with muscular dystrophy were 0.2-376.0 ng/ml and 17.9-119.0 ng/ml, respectively. They were also elevated than those in the patients with SMA type 2 and controls, but not significantly. The levels of sVCAM-1 and sE-selectin in the patients with DMD significantly correlated with age. There was no correlation between the levels of soluble adhesion molecules and those of CK or FDP in any groups. These changes of soluble adhesion molecules may reflect the process of muscle destruction and endothelial cell activation in muscular dystrophy. PMID:12134684

Saito, Toshio; Yamamoto, Yuko; Shinno, Susumu

2002-07-01

225

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

226

Water soluble conductive polymers  

Microsoft Academic Search

This patent describes 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

Aldissi

1989-01-01

227

High resolution structures of the bone morphogenetic protein type II receptor in two crystal forms: Implications for ligand binding  

SciTech Connect

BMPRII is a type II TGF-{beta} serine threonine kinase receptor which is integral to the bone morphogenetic protein (BMP) signalling pathway. It is known to bind BMP and growth differentiation factor (GDF) ligands, and has overlapping ligand specificity with the activin type II receptor, ActRII. In contrast to activin and TGF-{beta} type ligands, BMPs bind to type II receptors with lower affinity than type I receptors. Crystals of the BMPRII ectodomain were grown in two different forms, both of which diffracted to high resolution. The tetragonal form exhibited some disorder, whereas the entire polypeptide was seen in the orthorhombic form. The two structures retain the basic three-finger toxin fold of other TGF-{beta} receptor ectodomains, and share the main hydrophobic patch used by ActRII to bind various ligands. However, they present different conformations of the A-loop at the periphery of the proposed ligand-binding interface, in conjunction with rearrangement of a disulfide bridge within the loop. This particular disulfide (Cys94-Cys117) is only present in BMPRII and activin receptors, suggesting that it is important for their likely shared mode of binding. Evidence is presented that the two crystal forms represent ligand-bound and free conformations of BMPRII. Comparison with the solved structure of ActRII bound to BMP2 suggests that His87, unique amongst TGF-{beta} receptors, may play a key role in ligand recognition.

Mace, Peter D. [Department of Biochemistry, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin 9001 (New Zealand); Cutfield, John F. [Department of Biochemistry, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin 9001 (New Zealand); Cutfield, Sue M. [Department of Biochemistry, Otago School of Medical Sciences, University of Otago, P.O. Box 56, Dunedin 9001 (New Zealand)]. E-mail: sue.cutfield@otago.ac.nz

2006-12-29

228

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

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. PMID:23486467

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

2013-03-13

229

Soluble VEGF receptors  

Microsoft Academic Search

The three human VEGF receptors 1–3 mediate biological signals important for new blood vessel formation and lymphangiogenesis.\\u000a Soluble VEGF receptors contain all the information necessary for high affinity ligand binding and have been used as experimental\\u000a tools and regulators in several angiogenic in vitro and in vivo models. Recombinant receptor molecules can be used for specific\\u000a inhibition of VEGF mediated

Carsten Hornig; Herbert A. Weich

1999-01-01

230

The solubility of uranium hexafluoride in perfluoroethers  

SciTech Connect

The polyperfluoroethers are compatible with uranium hexafluoride (UF/sub 6/) and are suitable for use in diffusion pumps and in mechanical vacuum pumps which rely on oil as both the lubricant and the seal. The UF/sub 6/ is soluble in all fluids with which it is compatible. Because a number of vacuum pumps in the BOP facilities of the GCEP plant employ these perfluoroether oils as the working fluid and have oil chambers which are large, questions have been raised as to the relationships governing the solubility of UF/sub 6/ in these materials and the maximum quantities of UF/sub 6/ which could be dissolved in these oils under credible accident conditions. This report summarizes these solubility relations and the interaction of the UF/sub 6/ solubility and the pumping capability of this type of vacuum pump. It will be shown that, whereas the solubility of UF/sub 6/ in Fomblin Y25 fluoroether fluid under a UF/sub 6/ pressure of 760 torr and at the pump operating temperature of 160/sup 0/F is about 500 g of UF/sub 6/ per liter of oil, the system controls are such as to isolate the system from the pumps before the quantity of UF/sub 6/ dissolved in the perfluoroether exceeds about 10 g of UF/sub 6/ per liter of oil. 13 refs., 7 figs.

Barber, E.J.

1984-07-15

231

THE SOLUBLE SPECIFIC SUBSTANCE OF PNEUMOCOCCUS  

PubMed Central

1. Refinements in the methods for the isolation of the soluble specific substances of Types II and III pneumococcus are described. These improvements have resulted in the isolation of the end-products in a form free from nitrogen and of enhanced activity with immune serum. 2. The soluble specific substance of Type I pneumococcus is described and shown to differ sharply from the corresponding substances of the other two types, each of which, in turn, differs from the other. 3. Progress is reported on the identification of the sugar units from which the polysaccharides are built up. 4. The evidence so far accumulated is believed to favor strongly the view that the polysaccharides isolated are the actual specific substances of Pneumococcus.

Heidelberger, Michael; Goebel, Walther F.; Avery, Oswald T.

1925-01-01

232

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

233

Thermoresponsive diblock copolymer with tunable soluble-insoluble and soluble-insoluble-soluble transitions.  

PubMed

The thermoresponsive transition behavior of a diblock copolymer consisting of poly(ethylene glycol) methyl ether (mPEG) and poly(N,N-dimethylaminoethyl methacrylate) (PDMAEMA) in aqueous solutions has been investigated. With a specific composition, the copolymer showed a unique tunable phase transition from no response in acidic media to a soluble-insoluble (S-I) transition in neutral media and an S-I-S transition in basic media either in the presence of salt or for salt-free solutions. The S-I-S transition can be tuned over a wide temperature range even to an S-I type transition just by adding salts. In addition, phase transitions can occur in both pure water and saline solution under practical conditions (30-80 °C), which makes them suitable for a broad range of applications. PMID:23440768

Han, Xia; Zhang, Xuxia; Yin, Quanyi; Hu, Jun; Liu, Honglai; Hu, Ying

2013-02-26

234

Water soluble lubricant  

SciTech Connect

This patent describes a water soluble metal working lubricant concentrate consisting essentially of: (a) From about 10 to about 60 percent by weight of a polyalkylene glycol polymer; (b) from about 1 to about 25 percent by weight of an ethoxylated carboxylic acid or alcohol, (c) from about 1 to about 25 percent by weight of a complex organic phosphate ester, (d) from about 1 to about 20 percent by weight of an alkanolamine, such as mono-, di- or triethanolamine; and (e) from about 0 to about 65 percent by weight water.

Kipp, E.M.; Kirk, T.E.; Riddle, B.L.

1987-01-13

235

Water-soluble conducting polymers  

Microsoft Academic Search

It has only been within the last few months that organic-solvent-soluble conducting polymers have been developed. Previously, solubility in a mixture of arsenic trifluoride\\/pentafluoride was the singular path available to processability of conducting polymers. In this paper they report their success in the preparation of two polymers which are soluble in water in the doped and undoped statesexclamation Sodium poly(3-thiophene-..beta..-ethanesulfonate)

A. O. Patil; Y. Ikenoue; Fred Wudl; A. J. Heeger

1987-01-01

236

Ruthenium solubility in hematite  

SciTech Connect

Solid binary oxides of the platinum-group elements (PGE) decompose on heating in air to metal, oxygen, and often, a mixture of volatile PGE oxides. Compared to most other transition metal oxides, these decomposition temperatures are low, generally below 1100 C. The modest exception is RuO{sub 2}, which remains stable in air until 1400 C. Because of its comparatively high oxide stability, Ru, among all the PGE, is the one with the greatest potential for a significant oxidic, i.e., lithophile, geochemistry. A series of 1 atm phase equilibrium experiments were made to establish the limits of solid solution of Ru in hematite (Fe{sub 2}O{sub 3}) and help evaluate the significance of the oxidic geochemistry of Ru. The solid-solution limit for Ru in hematite may be represented by the following oxidation-reduction reaction: 2RuO{sub 2} + Fe{sub 2}O{sub 3} = 2FeRuO{sub 3} + 1/20{sub 2}. Experiments equilibrated between 1012 and 1490 C were buffered with respect to oxygen fugacity by the coexistence of Ru metal and solid RuO{sub 2}, both as essentially pure phases. Solution of Ru in hematite is enhanced at lower oxygen fugacity, but reaches a maximum fixed by the presence of Ru metal. An endothermic enthalpy for the reaction (188.1 {+-} 0.7 kJ/mol) was retrieved from the redox-controlled solubilities was as a regular solution interaction parameter (18.5 {+-} 0.5 kJ/mol) that indicated small positive deviations from ideality in the solid-solution region investigated. Estimates based on the new data for solubilities of Ru in a rhombohedral oxide at geologic conditions suggest that natural concentrations might be accommodated at high temperatures without saturation in Ru metal, but that exsolution of Ru metal from oxides would be favored at low temperature.

Capobianco, C.J. [Univ. of Arizona, Tucson, AZ (United States). Lunar and Planetary Lab.

1998-11-01

237

[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

238

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

239

Soluble ?-synuclein is a novel modulator of Alzheimer's disease pathophysiology  

PubMed Central

Recent evidence has emphasized soluble species of amyloid-? (A?) and tau as pathogenic effectors in AD. Despite the fact that A?, tau and ?-synuclein (?Syn) can promote each other’s aggregation, the potential contribution of soluble ?Syn to Alzheimer’s disease (AD) pathogenesis is unknown. Here, we found a ~2-fold increase over controls in soluble ?Syn levels in AD brains in the absence of LB cytopathology. Importantly, soluble ?Syn levels were a quantitatively stronger correlate of cognitive impairment than soluble A? and tau levels. To examine a putative role for ?Syn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type ?Syn. The results revealed that a ~3-fold elevation of ?Syn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble ?Syn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between A?/APP and human tau appears to be responsible for the abnormal elevation of soluble ?Syn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal ?Syn in AD pathophysiology.

Larson, Megan E.; Sherman, Mathew A.; Greimel, Susan; Kuskowski, Michael; Schneider, Julie A.; Bennett, David A.; Lesne, Sylvain E.

2012-01-01

240

Fluoride Incorporation and Apatite Solubility  

Microsoft Academic Search

The classical theory on the solubility of ionic compounds has been extended to solid solutions and deviations from stoichiometry by combination of thermodynamical and solid state chemical principles. Theory predicts that the incorporation of foreign ions in enamel apatite can change its solubility product over several orders of magnitude in several ways. Experimental data on the composition of enamel indicate

F. C. M. Driessens

1973-01-01

241

Thorium Oxalate Solubility and Morphology.  

National Technical Information Service (NTIS)

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 ...

P. R. Monson R. Hall

1981-01-01

242

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.

243

Scoring function to predict solubility mutagenesis  

PubMed Central

Background Mutagenesis is commonly used to engineer proteins with desirable properties not present in the wild type (WT) protein, such as increased or decreased stability, reactivity, or solubility. Experimentalists often have to choose a small subset of mutations from a large number of candidates to obtain the desired change, and computational techniques are invaluable to make the choices. While several such methods have been proposed to predict stability and reactivity mutagenesis, solubility has not received much attention. Results We use concepts from computational geometry to define a three body scoring function that predicts the change in protein solubility due to mutations. The scoring function captures both sequence and structure information. By exploring the literature, we have assembled a substantial database of 137 single- and multiple-point solubility mutations. Our database is the largest such collection with structural information known so far. We optimize the scoring function using linear programming (LP) methods to derive its weights based on training. Starting with default values of 1, we find weights in the range [0,2] so that predictions of increase or decrease in solubility are optimized. We compare the LP method to the standard machine learning techniques of support vector machines (SVM) and the Lasso. Using statistics for leave-one-out (LOO), 10-fold, and 3-fold cross validations (CV) for training and prediction, we demonstrate that the LP method performs the best overall. For the LOOCV, the LP method has an overall accuracy of 81%. Availability Executables of programs, tables of weights, and datasets of mutants are available from the following web page: http://www.wsu.edu/~kbala/OptSolMut.html.

2010-01-01

244

Understanding Solubility through Excel Spreadsheets  

NASA Astrophysics Data System (ADS)

This article describes assignments related to the solubility of inorganic salts that can be given in an introductory general chemistry course. Le Châtelier's principle, solubility, unit conversion, and thermodynamics are tied together to calculate heats of solution by two methods: heats of formation and an application of the van't Hoff equation. These assignments address the need for math, graphing, and computer skills in the chemical technology program by developing skill in the use of Microsoft Excel to prepare spreadsheets and graphs and to perform linear and nonlinear curve-fitting. Background information on the value of understanding and predicting solubility is provided.

Brown, Pamela

2001-02-01

245

In silico prediction of aqueous solubility: the solubility challenge.  

PubMed

The dissolution of a chemical into water is a process fundamental to both chemistry and biology. The persistence of a chemical within the environment and the effects of a chemical within the body are dependent primarily upon aqueous solubility. With the well-documented limitations hindering the accurate experimental determination of aqueous solubility, the utilization of predictive methods have been widely investigated and employed. The setting of a solubility challenge by this journal proved an excellent opportunity to explore several different modeling methods, utilizing a supplied dataset of high-quality aqueous solubility measurements. Four contrasting approaches (simple linear regression, artificial neural networks, category formation, and available in silico models) were utilized within our laboratory and the quality of these predictions was assessed. These were chosen to span the multitude of modeling methods now in use, while also allowing for the evaluation of existing commercial solubility models. The conclusions of this study were surprising, in that a simple linear regression approach proved to be superior over more complex modeling methods. Possible explanations for this observation are discussed and also recommendations are made for future solubility prediction. PMID:19877720

Hewitt, M; Cronin, M T D; Enoch, S J; Madden, J C; Roberts, D W; Dearden, J C

2009-11-01

246

THE SOLUBLE SPECIFIC SUBSTANCE OF PNEUMOCOCCUS  

PubMed Central

1. The method for the concentration and purification of the soluble specific substance of Pneumococcus has been improved. 2. Highly purified specific substance of Type II pneumococcus of polysaccharide nature is shown to be recovered essentially unchanged after precipitation by immune serum, by uranyl nitrate, by basic lead acetate, or by safranine. 3. Marked chemical differences are shown to exist between the specific substances of Type II and Type III pneumococcus, although both react as polysaccharides. 4. The weight of evidence is considered to be in favor of the view that the specific substances of Pneumococcus Types II and III are actually polysaccharide derivatives. 5. The immunological significance of the foregoing view is discussed.

Heidelberger, Michael; Avery, Oswald T.

1924-01-01

247

Investigation of Soluble Salts on Kentucky Bridges.  

National Technical Information Service (NTIS)

Invisible soluble salts present on steel highway structures can act to promote corrosion even after maintenance painting. Soluble salts include chloride, nitrate and sulfate ions. Soluble salts found on bridge decks and roadways are the result of usage of...

S. Palle R. Younce T. Hopwood

2003-01-01

248

Activin receptor-like kinase 7 mediates high glucose-induced H9c2 cardiomyoblast apoptosis through activation of Smad2/3.  

PubMed

Cardiomyocyte apoptosis is an important pathological change of diabetic cardiomyopathy. How the elevated glucose levels cause cell apoptosis remains unknown. The aim of our study was to investigate whether activin receptor-like kinase 7 (ALK7)-Smad2/3 signaling pathway plays an important role in high glucose-induced cardiomyocyte apoptosis. H9c2 cardiomyoblasts and neonatal rat cardiomyocytes were treated with 33mmol/l glucose. The expression of ALK7, Smad2 and Smad3 were inhibited by small interfering RNA respectively. The level of ALK7, total Smad2/3, phosphorylated Smad2/3, B-cell lymphoma-2 (Bcl-2) and cleaved Caspase3 were evaluated using western blot. The apoptosis rate was detected by flow cytometer. High glucose treatment caused the apoptosis of H9c2 cardiomyocyte and the inhibition of Smad2 or Smad3 attenuated this apoptosis. ALK7 existed in both H9c2 cardiomyoblasts and neonatal rat cardiomyocytes and high ambient glucose upregulated its expression. The increased expression level of cleaved Caspase3 and apoptosis rate and decreased expression of Bcl-2 were reversed after ALK7 was inhibited. The expression of phosphorylated Smad2/3 also decreased after the knockdown of ALK7. Our findings suggest that ALK7 mediates high ambient glucose-induced H9c2 cardiomyoblasts apoptosis through the activation of Smad2/3. PMID:23830891

Liu, Lin; Ding, Wen-yuan; Zhao, Jing; Wang, Zhi-hao; Zhong, Ming; Zhang, Wei; Chen, Yu-guo; Zhang, Yun; Li, Li; Tang, Meng-xiong

2013-07-02

249

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

250

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

251

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

252

Thorium oxalate solubility and morphology  

Microsoft Academic Search

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 (HâCâOâ)\\/(HNOâ)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

P. R. Jr. Monson; R. Hall

1981-01-01

253

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

254

Three novel mutations in the activin receptor-like kinase 1 (ALK-1) gene in hereditary hemorrhagic telangiectasia type 2 in Brazilian patients  

Microsoft Academic Search

Hereditary hemorrhagic telangiectasia (HHT) or Osler–Rendu–Weber disease is a systemic fibrovascular dysplasia with an autosomal\\u000a dominant inheritance pattern. Mutations in two genes, endoglin and ALK-1, are known to cause HHT, both of which mediate signaling by transforming growth factor ? ligands in vascular endothelial\\u000a cells. Ten patients were analyzed. Diagnosis of HHT was carried out by means of family history,

A. M. Assis; F. F. Costa; V. R. Arruda; J. M. Annichino-Bizzacchi; C. S. Bertuzzo

2007-01-01

255

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

256

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene  

PubMed Central

Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin ? C (INHBC), part of the transforming growth factor ? pathway regulating myostatin – a negative regulator of muscle mass – signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ?2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength.

Windelinckx, An; De Mars, Gunther; Huygens, Wim; Peeters, Maarten W; Vincent, Barbara; Wijmenga, Cisca; Lambrechts, Diether; Delecluse, Christophe; Roth, Stephen M; Metter, E Jeffrey; Ferrucci, Luigi; Aerssens, Jeroen; Vlietinck, Robert; Beunen, Gaston P; Thomis, Martine A

2011-01-01

257

Comprehensive fine mapping of chr12q12-14 and follow-up replication identify activin receptor 1B (ACVR1B) as a muscle strength gene.  

PubMed

Muscle strength is important in functional activities of daily living and the prevention of common pathologies. We describe the two-staged fine mapping of a previously identified linkage peak for knee strength on chr12q12-14. First, 209 tagSNPs in/around 74 prioritized genes were genotyped in 500 Caucasian brothers from the Leuven Genes for Muscular Strength study (LGfMS). Combined linkage and family-based association analyses identified activin receptor 1B (ACVR1B) and inhibin ? C (INHBC), part of the transforming growth factor ? pathway regulating myostatin - a negative regulator of muscle mass - signaling, for follow-up. Second, 33 SNPs, selected in these genes based on their likelihood to functionally affect gene expression/function, were genotyped in an extended sample of 536 LGfMS siblings. Strong associations between ACVR1B genotypes and knee muscle strength (P-values up to 0.00002) were present. Of particular interest was the association with rs2854464, located in a putative miR-24-binding site, as miR-24 was implicated in the inhibition of skeletal muscle differentiation. Rs2854464 AA individuals were ?2% stronger than G-allele carriers. The strength increasing effect of the A-allele was also observed in an independent replication sample (n=266) selected from the Baltimore Longitudinal Study of Aging and a Flemish Policy Research Centre Sport, Physical Activity and Health study. However, no genotype-related difference in ACVR1B mRNA expression in quadriceps muscle was observed. In conclusion, we applied a two-stage fine mapping approach, and are the first to identify and partially replicate genetic variants in the ACVR1B gene that account for genetic variation in human muscle strength. PMID:21063444

Windelinckx, An; De Mars, Gunther; Huygens, Wim; Peeters, Maarten W; Vincent, Barbara; Wijmenga, Cisca; Lambrechts, Diether; Delecluse, Christophe; Roth, Stephen M; Metter, E Jeffrey; Ferrucci, Luigi; Aerssens, Jeroen; Vlietinck, Robert; Beunen, Gaston P; Thomis, Martine A

2010-11-10

258

Strategies to address low drug solubility in discovery and development.  

PubMed

Drugs with low water solubility are predisposed to low and variable oral bioavailability and, therefore, to variability in clinical response. Despite significant efforts to "design in" acceptable developability properties (including aqueous solubility) during lead optimization, approximately 40% of currently marketed compounds and most current drug development candidates remain poorly water-soluble. The fact that so many drug candidates of this type are advanced into development and clinical assessment is testament to an increasingly sophisticated understanding of the approaches that can be taken to promote apparent solubility in the gastrointestinal tract and to support drug exposure after oral administration. Here we provide a detailed commentary on the major challenges to the progression of a poorly water-soluble lead or development candidate and review the approaches and strategies that can be taken to facilitate compound progression. In particular, we address the fundamental principles that underpin the use of strategies, including pH adjustment and salt-form selection, polymorphs, cocrystals, cosolvents, surfactants, cyclodextrins, particle size reduction, amorphous solid dispersions, and lipid-based formulations. In each case, the theoretical basis for utility is described along with a detailed review of recent advances in the field. The article provides an integrated and contemporary discussion of current approaches to solubility and dissolution enhancement but has been deliberately structured as a series of stand-alone sections to allow also directed access to a specific technology (e.g., solid dispersions, lipid-based formulations, or salt forms) where required. PMID:23383426

Williams, Hywel D; Trevaskis, Natalie L; Charman, Susan A; Shanker, Ravi M; Charman, William N; Pouton, Colin W; Porter, Christopher J H

2013-01-01

259

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

260

Preparation and important functional properties of water-soluble chitosan produced through Maillard reaction  

Microsoft Academic Search

The objective of this research was to improve the solubility of chitosan at neutral or basic pH using the Maillard-type reaction method. To prepare the water-soluble chitosans, various chitosans and saccharides were used under various operating conditions. Biological and physicochemical properties of the chitosan-saccharide derivatives were investigated as well. Results indicated that the solubility of modified chitosan is significantly greater

Ying-Chien Chung; Cheng-Lang Kuo; Chiing-Chang Chen

2005-01-01

261

[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

262

An unexpected structural relationship between integral membrane phosphatases and soluble haloperoxidases.  

PubMed Central

The mechanism of a membrane-bound enzyme important in phospholipid signaling, type 2 phosphatidic acid phosphatase, is suggested by sequence motifs shared with a soluble vanadium-dependent chloroperoxidase of known structure. These regions are also conserved in other soluble globular and membrane-associated proteins, including bacterial acid phosphatases, mammalian glucose-6-phosphatases, and the Drosophila developmental protein Wunen. This implies that a similar arrangement of catalytic residues specifies the active site within both soluble and membrane spanning domains.

Neuwald, A. F.

1997-01-01

263

Solubility Limits on Radionuclide Dissolution.  

National Technical Information Service (NTIS)

This paper examines the effects of solubility in limiting dissolution rates of a number of important radionuclides from spent fuel and high-level waste. Two simple dissolution models were used for calculations that would be characteristics of a Yucca Moun...

J. F. Kerrisk

1984-01-01

264

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

265

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

266

Water-soluble conductive polymers  

Microsoft Academic Search

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

Aldissi

1990-01-01

267

Water-soluble conductive polymers  

Microsoft Academic Search

This patent describes 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

Aldissi

1990-01-01

268

Water-soluble conductive polymers  

Microsoft Academic Search

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

Aldissi

1989-01-01

269

Water-soluble conductive polymers  

Microsoft Academic Search

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

Aldissi

1988-01-01

270

Water-Soluble Conductive Polymers.  

National Technical Information Service (NTIS)

The patent relates to 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 ...

M. Aldissi

1988-01-01

271

The Activin signaling pathway promotes differentiation of dI3 interneurons in the spinal neural tube  

Microsoft Academic Search

The generation of the appropriate types and numbers of mature neurons during the development of the spinal cord requires the careful coordination of patterning, proliferation, and differentiation. In the dorsal neural tube, this coordination is achieved by the combined action of multiple ligands of both the Wnt and TGF-? families, and their effectors, such as the bHLH proteins. TGF-? signaling

John Timmer; Catherine Chesnutt; Lee Niswander

2005-01-01

272

Improved Water-Soluble Polymers for Enhanced Recovery of Oil  

Microsoft Academic Search

Two principal types of polymers have been used extensively for enhanced recovery of crude oil: partially hydrolyzed polyacrylamide (HPAM) and xanthan gum. Because of its lower cost, HPAM is being used in a majority of the field projects when water-soluble polymers are applied. However, HPAM does lose viscosity in brines, particularly when divalent ions are present, and is susceptible to

F. D. Martin; M. J. Hatch; J. S. Shepitka; J. S. Ward

1983-01-01

273

The orphan receptor ALK7 and the Activin receptor ALK4 mediate signaling by Nodal proteins during vertebrate development  

Microsoft Academic Search

Nodal proteins have crucial roles in mesendoderm formation and left-right patterning during vertebrate development. The molecular mechanisms of signal transduction by Nodal and related ligands, however, are not fully understood. In this paper, we present biochemical and functional evidence that the orphan type I serine\\/threonine kinase receptor ALK7 acts as a receptor for mouse Nodal and Xenopus Nodal-related 1 (Xnr1).

Eva Reissmann; Henrik Jörnvall; Andries Blokzijl; Olov Andersson; Chenbei Chang; Gabriella Minchiotti; M. Graziella Persico; Carlos F. Ibáñez; Ali H. Brivanlou

2010-01-01

274

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

275

WATER-SOLUBLE ORGANIC MATTER IN SOIL UNDER CHINESE FIR AND MASSON PINE FOREST  

Microsoft Academic Search

In order to understand the behavior of water soluble organic matter (WSOM) in soil under different types of forest, soil samples from twenty sites were sampled and analyzed for each forest in the area of Huzhou, China. Each sample was extracted with both cool water (25°C) and hot water (100°C). Without exception, hot water soluble organic carbon (HWSOC) was more

Qiufang Xu; Zhengqian Ye; Jianming Xu; Peikun Jiang

2002-01-01

276

Water-soluble components of four fuel oils: Chemical characterization and effects on growth of microalgae  

Microsoft Academic Search

Approximately 50% of the compounds in the water solubles from 4 fuel oils have been identified via gas chromatography and mass spectrometry. In addition to the well-described types of compounds (naphthalenes, benzenes) expected in water-soluble extracts we have found phenols, anilines, and indoles. Of these classes of compounds methyl, dimethyl, and trimethyl derivatives are present in relatively high concentrations. The

K. Winters; R. O'Donnell; J. C. Batterton; C. Van Baalen

1976-01-01

277

Protection from Fas-Mediated Apoptosis by a Soluble Form of the Fas Molecule  

Microsoft Academic Search

Fas is an apoptosis-signaling receptor molecule on the surface of a number of cell types. Molecular cloning and nucleotide sequence analysis revealed a human Fas messenger RNA variant capable of encoding a soluble Fas molecule lacking the transmembrane domain because of the deletion of an exon encoding this region. The expression of soluble Fas was confirmed by flow cytometry and

Jianhua Cheng; Tong Zhou; Changdan Liu; John P. Shapiro; Matthew J. Brauer; Michael C. Kiefer; Philip J. Barr; John D. Mountz

1994-01-01

278

Soluble monomeric IgG1 Fc.  

PubMed

Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small size and other unique properties. However, compared with full-size antibodies, these antibody fragments lack the ability to bind the neonatal Fc receptor (FcRn) and have reduced half-lives. Fc engineered to bind antigens but preserve interactions with FcRn and Fc fused with monomeric proteins currently are being developed as candidate therapeutics with prolonged half-lives; in these and other cases, Fc is a dimer of two CH2-CH3 chains. To further reduce the size of Fc but preserve FcRn binding, we generated three human soluble monomeric IgG1 Fcs (mFcs) by using a combination of structure-based rational protein design combined with multiple screening strategies. These mFcs were highly soluble and retained binding to human FcRn comparable with that of Fc. These results provide direct experimental evidence that efficient binding to human FcRn does not require human Fc dimerization. The newly identified mFcs are promising for the development of mFc fusion proteins and for novel types of mFc-based therapeutic antibodies of small size and long half-lives. PMID:22518843

Ying, Tianlei; Chen, Weizao; Gong, Rui; Feng, Yang; Dimitrov, Dimiter S

2012-04-19

279

Soluble Monomeric IgG1 Fc*  

PubMed Central

Antibody fragments are emerging as promising biopharmaceuticals because of their relatively small size and other unique properties. However, compared with full-size antibodies, these antibody fragments lack the ability to bind the neonatal Fc receptor (FcRn) and have reduced half-lives. Fc engineered to bind antigens but preserve interactions with FcRn and Fc fused with monomeric proteins currently are being developed as candidate therapeutics with prolonged half-lives; in these and other cases, Fc is a dimer of two CH2-CH3 chains. To further reduce the size of Fc but preserve FcRn binding, we generated three human soluble monomeric IgG1 Fcs (mFcs) by using a combination of structure-based rational protein design combined with multiple screening strategies. These mFcs were highly soluble and retained binding to human FcRn comparable with that of Fc. These results provide direct experimental evidence that efficient binding to human FcRn does not require human Fc dimerization. The newly identified mFcs are promising for the development of mFc fusion proteins and for novel types of mFc-based therapeutic antibodies of small size and long half-lives.

Ying, Tianlei; Chen, Weizao; Gong, Rui; Feng, Yang; Dimitrov, Dimiter S.

2012-01-01

280

New, Water Soluble, Antineoplastic Derivatives of Taxol.  

National Technical Information Service (NTIS)

The invention is related to new, water soluble derivatives of taxol with antineoplastic activity. More particularly, the invention is related to 2'-0-acyl derivatives of taxol with improved water solubility while retaining antineoplasic property of the pa...

R. D. Haugwitz L. Zalkow J. Glinski M. Suffness H. M. Deutsch

1988-01-01

281

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

282

Improved solubility of replication factor C (RFC) Walker A mutants  

PubMed Central

Protein insolubility often poses a significant problem during purification protocols and in enzyme assays, especially for eukaryotic proteins expressed in a recombinant bacterial system. The limited solubility of replication factor C (RFC), the clamp loader complex from Saccharomyces cerevisiae, has been previously documented. We found that mutant forms of RFC harboring a single point mutation in the Walker A motif were even less soluble than the wild-type complex. The addition of maltose at 0.75 M to the storage and assay buffers greatly increases protein solubility and prevents the complex from falling apart. Our analysis of the clamp loading reaction is dependent on fluorescence-based assays, which are environmentally sensitive. Using wt RFC as a control, we show that the addition of maltose to the reaction buffers does not affect fluorophore responses in the assays or the enzyme activity, indicating that maltose can be used as a buffer additive for further downstream analysis of these mutants.

Marzahn, Melissa R.; Bloom, Linda B.

2013-01-01

283

Diameter-dependent solubility of single-walled carbon nanotubes.  

PubMed

We study the solubility and dispersibility of as-produced and purified HiPco single-walled carbon nanotubes (SWNTs). Variation in specific operating conditions of the HiPco process are found to lead to significant differences in the respective SWNT solubilities in oleum and surfactant suspensions. The diameter distributions of SWNTs dispersed in surfactant solutions are batch-dependent, as evidenced by luminescence and Raman spectroscopies, but are identical for metallic and semiconducting SWNTs within a batch. We thus find that small diameter SWNTs disperse at higher concentration in aqueous surfactants and dissolve at higher concentration in oleum than do large-diameter SWNTs. These results highlight the importance of controlling SWNT synthesis methods in order to optimize processes dependent on solubility, including macroscopic processing such as fiber spinning, material reinforcement, and films production, as well as for fundamental research in type selective chemistry, optoelectronics, and nanophotonics. PMID:20521799

Duque, Juan G; Parra-Vasquez, A Nicholas G; Behabtu, Natnael; Green, Micah J; Higginbotham, Amanda L; Price, B Katherine; Leonard, Ashley D; Schmidt, Howard K; Lounis, Brahim; Tour, James M; Doorn, Stephen K; Cognet, Laurent; Pasquali, Matteo

2010-06-22

284

Solubilization of poorly water-soluble drugs using solid dispersions.  

PubMed

Many new drugs have been discovered in pharmaceutical industry and exposed their surprised potential therapeutic effects. Unfortunately, these drugs possess low absorption and bioavailability since their solubility limitation in water. Solid dispersion (SD) is the current technique gaining so many attractions from scientists due to its effect on improving solubility and dissolution rate of poorly water-soluble drugs. A number of patents including the most recent inventions have been undertaken in this review to address various respects of this strategy in solubilization of poorly watersoluble drugs including type of carriers, preparation methods and view of technologies used to detect SD properties and mechanisms with the aim to accomplish a SD not only effective on enhanced bioavailability but also overcome difficulties associated with stability and production. Future prospects are as well discussed with an only hope that many developments and researches in this field will be successfully reached and contributed to commercial use for treatment as much as possible. PMID:23244679

Tran, Thao T-D; Tran, Phuong H-L; Khanh, Tran N; Van, Toi V; Lee, Beom-Jin

2013-08-01

285

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

286

A "SOLUBLE SPECIFIC SUBSTANCE" DERIVED FROM GUM ARABIC  

PubMed Central

1. By partial acid hydrolysis a specific carbohydrate may be isolated from gum arabic (gum acacia). This carbohydrate is comparable in its precipitating activity for Type II (and Type III) antipneumococcus serum with the bacterial soluble specific substances themselves. 2. On hydrolysis this fraction yields galactose and two or more complex sugar acids, one of which appears to be a disaccharide add comparable with those isolated from the specific polysaccharides of the Type III pneumococcus and the Type A Friedländer bacillus. 3. The significance of these findings is discussed.

Heidelberger, Michael; Avery, Oswald T.; Goebel, Walther F.

1929-01-01

287

Solubility of ocular therapeutic agents in self-emulsifying oils. I. Self-emulsifying oils for ocular drug delivery: solubility of indomethacin, aciclovir and hydrocortisone.  

PubMed

Self-emulsifying drug delivery systems (SEDDS) were prepared by dissolving Cremophor EL, Tween 20, Tween 80 and Span 80 (1% or 5%) in oils (Miglyol 812 or castor oil). Solubilities of three ophthalmic drugs, namely aciclovir, hydrocortisone and indomethacin were determined in these systems. In addition, the effect of a small amount of water (0.5% and 2%) on solubilization properties of the systems was estimated. Of the three substances, indomethacin showed the best solubility in Miglyol while aciclovir was practically insoluble in this oil. The surfactants usually increased drug solubility in the oily phase. Only Tween 20 was found to decrease the solubility of aciclovir and hydrocortisone in Miglyol. Addition of a small amount of water to the oil/surfactant system increased solubility of hydrocortisone, but not of indomethacin. The results of the current study may be utilized to design a suitable composition of SEDDS and allow continuation of research on this type of drug carriers. PMID:20050536

Czajkowska-Ko?nik, Anna; Sznitowska, Ma?gorzata

288

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

289

Intermolecular Relationship between Neutral-salt-soluble and Acid-soluble Collagen  

Microsoft Academic Search

SOLUBLE collagen can be extracted from collagenous material with neutral salt solutions and weak acids. These extracts display many similar physical and chemical characteristics, but differ significantly with respect to their solubility. Neutral-salt-soluble collagen has been shown to be the precursor collagen1,2, with acid-soluble collagen being the more mature fibre-forming protein3. The relationship between these soluble collagens which is usually

R. J. Davidson; D. R. Cooper

1968-01-01

290

An Empirical Correlation for the Solubility of Paraffin Waxes in Base Oils  

Microsoft Academic Search

ABSTRACf. An empirical correlation was developed for the prediction of solubility of three types of paraffin waxes in various base oils. The correla­ tion was developed using the superposition approach and was proposed as

MALIK ALAHMAD; TARIQ F. AL-FARISS; MOHAMAD E. ABASHAR; HISHAM M. ETIOUNEY

291

Soluble fiber dextrin enhances the satiating power of beverages.  

PubMed

This study compared the effects of four types of fiber on satiety and energy intakes at the next meal using a standard double-blinded preload study design. Study participants (14 men and 22 women) each took part in 6 study sessions. Study preloads were a combination of a solid snack and a liquid beverage (energy range 0.78-0.83 MJ) containing four different types of fiber: soluble fiber dextrin (12 g), soluble corn fiber (11.8 g), polydextrose (11.8 g), and resistant starch (11.2g). All four fibers were compared to two control conditions of equal volume: an isoenergetic, low-fiber preload and a lower-energy, low-fiber preload. All preloads were presented twice for a total of 0.35-1.65 MJ and 1-24 g fiber. Satiety ratings were collected for 20 min intervals for 220 min during the morning testing session. A test meal was served at 1200 h and plate waste measured. The five higher-energy preloads led to higher fullness and lower hunger ratings compared to the low-energy control but were not significantly different from each other. Relative to the isoenergetic control, only soluble fiber dextrin significantly suppressed energy intakes (p=0.023). Supplementing beverages with soluble fiber dextrin affects short term energy intake and may have implications for weight control. PMID:21056069

Monsivais, Pablo; Carter, Brett E; Christiansen, Matthew; Perrigue, Martine M; Drewnowski, Adam

2010-11-04

292

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

293

Genotoxicity of poorly soluble particles.  

PubMed

Poorly soluble particles such as TiO2, carbon black, and diesel exhaust particles have been evaluated for their genotoxicity using both in vitro and in vivo assays, since inhalation of these compounds by rats at high concentrations has been found to lead to tumor formation. Two principle modes of genotoxic action can be considered for particles, referred to as primary and secondary genotoxicity. Primary genotoxicity is defined as genetic damage elicited by particles in the absence of pulmonary inflammation, whereas secondary genotoxicity implies a pathway of genetic damage resulting from the oxidative DNA attack by reactive oxygen/nitrogen species (ROS/RNS), generated during particle-elicited inflammation. Conceptually, primary genotoxicity might operate via various mechanisms, such as the actions of ROS (e.g., as generated from reactive particle surfaces), or DNA-adduct formation by reactive metabolites of particle-associated organic compounds (e.g., polycyclic aromatic hydrocarbons). Currently available literature data, however, merely indicate that the tumorigenesis of poorly soluble particles involves a mechanism of secondary genotoxicity. However, further research is urgently required, since (1) causality between pulmonary inflammation and genotoxicity has not yet been established, and (2) effects of inflammation on fundamental DNA damage responses that orchestrate mutagenesis and carcinogenic outcome,that is, cell cycle arrest, DNA repair, proliferation, and apoptosis, are currently poorly understood. PMID:17886067

Schins, Roel P F; Knaapen, Ad M

2007-01-01

294

A Soluble C1b Protein and Its Regulation of Soluble Type 7 Adenylyl Cyclase †  

Microsoft Academic Search

Adenylyl cyclase (AC) is a prototypical cell-signaling molecule expressed in virtually all organisms from bacteria to man. While C1b, a poorly conserved region within mammalian AC, has been implicated in numerous isoform-specific regulatory properties, no one has purified the C1b region as a functional protein to homogeneity in order to study its role in enzyme function. We hypothesize that C1b

Jeff A. Beeler; Shui-Zhong Yan; Sergei Bykov; Adrian Murza; Sanford Asher; Wei-Jen Tang

2004-01-01

295

A novel validated enzyme-linked immunosorbent assay to quantify soluble hemojuvelin in mouse serum  

PubMed Central

Hemojuvelin is a critical regulator of hepcidin expression and can be cleaved by proteases to form soluble hemojuvelin. Soluble hemojuvelin has been recently identified in human serum but the presence and quantity of soluble hemojuvelin in mouse serum is unknown. We developed a two-site enzyme-linked immunosorbent assay using a monoclonal anti-hemojuvelin as the capture antibody and a biotinylated polyclonal anti-hemojuvelin as the detection antibody to quantify the levels of soluble hemojuvelin in mouse serum. We validated this assay using cell-conditioned media and serum from Hemojuvelin-null and Bone morphogenetic protein 6-null mice. We also used this validated assay to measure serum soluble hemojuvelin concentrations in mice receiving an acute low iron or high iron treatment. This two-site enzyme-linked immunosorbent assay was highly specific for mouse hemojuvelin, with a lower limit of detection at 13.2-26.8 ng/mL of soluble hemojuvelin in mouse serum. The median serum soluble hemojuvelin concentration in wild-type C57BL/6J mice was 57.9±22 ng/mL, which is 4- to 20-fold less than that reported in healthy human volunteers. After acute low iron diet treatment in these mice, serum soluble hemojuvelin levels were increased and correlated with lowered serum iron levels and decreased hepatic hepcidin expression. An acute high iron diet in wild-type mice or chronically iron-overloaded Bone morphogenetic protein 6-null mice did not significantly lower serum soluble hemojuvelin concentrations. Here we report reliable quantitation of mouse serum soluble hemojuvelin using a novel and validated enzyme-linked immunosorbent assay. This assay may provide a useful tool to elucidate the source and physiological role of serum soluble hemojuvelin in hepcidin regulation and iron metabolism using well-established mouse models of iron-related disorders.

Chen, Wenjie; Sun, Chia Chi; Chen, Shanzhuo; Meynard, Delphine; Babitt, Jodie L.; Lin, Herbert Y.

2013-01-01

296

Spectroscopic and Solubility Characteristics of Oxidized Soots  

Microsoft Academic Search

Spectroscopic and solubility studies of reaction products of soot (black carbon) with O3, NO2\\/N2O4, and SO2 have revealed a relationship between reactivity and product solubility and structure. A remarkably high solubility of ozonated n-hexane soot has its origin in the formation of anhydride and lactone surface structures and their subsequent hydrolysis to carboxylic acid species. Calculations indicate that the rate

A. R. Chughtai; J. A. Jassim; J. H. Peterson; D. H. Stedman; D. M. Smith

1991-01-01

297

Solubility of triacylglycerols in supercritical carbon dioxide  

Microsoft Academic Search

The solubility of refined corn and sunflower seed oils, babassu (Attalea funifera) and ucuuba (Virola sebifera) fats in supercritical carbon dioxide (SC-CO2) were measured in a temperature range from 40 to 80°C and pressure between 200 and 350bar. Under working conditions, the values of solubility showed retrograde behavior. Experimental SC-CO2 solubility data were collected from the literature for the following

B. M. C. Soares; F. M. C. Gamarra; L. C. Paviani; L. A. G. Gonçalves; F. A. Cabral

2007-01-01

298

[Solubility enhancement with extrusion technology].  

PubMed

The transformation of the stable crystalline form can enhance the bioavailability of poorly water soluble drugs. The molecular dispersion, or solid solution, can be formed by various methods. The thermodynamic and kinetic properties of such compounds are very similar to the amorphous state. Twin-screw melt-extrusion, with controlled pressure, heat and shear stress, is a powerful way for separating the molecules of the active ingredient from each other and distributing them in the matrix homogenously. The extrudate can be processed onward immediately after a required cooling phase. The dependence of the possible effect of extrusion on the process parameters was investigated by Raman-microscopy and X-ray powder diffraction in course of the preparation of solid solution of spironolactone. PMID:20169868

Patyi, Gergo; Marosi, György; Antal, István; Bódis, Attila

2009-01-01

299

Gas solubility in hydrophobic confinement.  

PubMed

Measured forces between apolar surfaces in water have often been found to be sensitive to exposure to atmospheric gases despite low gas solubilities in bulk water. This raises questions as to how significant gas adsorption is in hydrophobic confinement, whether it is conducive to water depletion at such surfaces, and ultimately if it can facilitate the liquid-to-gas phase transition in the confinement. Open Ensemble molecular simulations have been used here to determine saturated concentrations of atmospheric gases in water-filled apolar confinements as a function of pore width at varied gas fugacities. For paraffin-like confinements of widths barely exceeding the mechanical instability threshold (spinodal) of the liquid-to-vapor transition of confined water (aqueous film thickness between three and four molecular diameters), mean gas concentrations in the pore were found to exceed the bulk values by a factor of approximately 30 or approximately 15 in cases of N2 and CO2, respectively. At ambient conditions, this does not result in visible changes in the water density profile next to the surfaces. Whereas the barrier to capillary evaporation has been found to decrease in the presence of dissolved gas (Leung, K.; Luzar, A.; and Bratko, D. Phys. Rev. Lett. 2003, 90, 065502), gas concentrations much higher than those observed at normal atmospheric conditions would be needed to produce noticeable changes in the kinetics of capillary evaporation. In simulations, dissolved gas concentrations corresponding to fugacities above approximately 40 bar for N2, or approximately 2 bar for CO2, were required to trigger expulsion of water from a hydrocarbon slit as narrow as 1.4 nm. For nanosized pore widths corresponding to the mechanical instability threshold or above, no significant coupling between adsorption layers at opposing confinement walls was observed. This finding explains the approximately linear increase in gas solubility with inverse confinement width and the apparent validity of Henry's law in the pores over a broad fugacity range. PMID:16853936

Luzar, Alenka; Bratko, Dusan

2005-12-01

300

Preparation and characterisation of water-soluble phytosterol nanodispersions  

Microsoft Academic Search

The purpose of this study was to prepare and characterise water-soluble phytosterol nanodispersions for food formulation. The effects of several factors were examined: four different types of organic phases (hexane, isopropyl alcohol, ethanol and acetone), the organic to aqueous phase ratio and conventional homogenisation vs. high-pressure homogenisation. We demonstrated the feasibility of phytosterol nanodispersions production using an emulsification–evaporation technique. The

Wai-Fun Leong; Oi-Ming Lai; Kamariah Long; Yaakob B. Che Man; Misni Misran; Chin-Ping Tan

2011-01-01

301

Membrane filtration studies of inversely soluble model metalworking fluids  

SciTech Connect

Model metalworking fluids, characterized by phase separation of functional components at elevated temperatures, were studied. Results of membrane filtration experiments with three oils of differing chemical nature confirm the feasibility of specific removal of finely dispersed contaminant oils without the simultaneous loss of active components from adequately formulated fluids. Prerequisites are that membrane materials and pore sizes be suitably chosen and that operating temperatures be kept below the cloud point of the least soluble component. The most suitable filter in the present study was a hydrophilic regenerated cellulose membrane with a NMWL of 100,000 dalton. Complete oil removal was attained if membrane pore sizes did not exceed 0.1 {micro}m. It was also found that intrinsically water-soluble boundary lubricants of the polyglycol ether type are retained by membranes in the presence of PPG-1800, which serves as a precipitation promoter above the cloud point. This is of considerable practical importance since it offers the possibility of designing water-soluble boundary lubrication and extreme pressure additives which are activated by the presence of an inversely soluble component above its cloud point. The latter compound also acts as the principal hydrodynamic lubricant of the present model formulations. The usefulness of a new analytical tool for the rapid acquisition and imaging of data pertinent to changes in molecular aggregation and phase conditions was demonstrated.

Misra, S.K.; Skoeld, R.O. [Chalmers Univ. of Technology, Gothenburg (Sweden)

1999-01-01

302

Engineered solubility tag for solution NMR of proteins.  

PubMed

The low solubility of many proteins hinders large scale expression and purification as well as biophysical measurements. Here, we devised a general strategy to solubilize a protein by conjugating it at a solvent-exposed position to a 6 kDa protein that was re-engineered to be highly soluble. We applied this method to the CARD domain of Apoptosis-associated speck-like protein containing a CARD (ASC), which represents one member of a class of proteins that are notoriously prone to aggregation. Attachment of the tag to a cysteine residue, introduced by site-directed mutagenesis at its self-association interface, improved the solubility of the ASC CARD over 50-fold under physiological conditions. Although it is not possible to use nuclear magnetic resonance (NMR) to obtain a high quality 2D correlation spectrum of the wild type domain under physiological conditions, we demonstrate that NMR relaxation parameters of the solubilized variant are sufficiently improved to facilitate virtually any demanding measurement. The method shown here represents a straightforward approach for dramatically increasing protein solubility, enabled by ease of labeling as well as flexibility in tag placement with minimal perturbation to the target. © 2013 The Protein Society. PMID:23963792

Ruschak, Amy M; Rose, Justine D; Coughlin, Michael P; Religa, Tomasz L

2013-09-20

303

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

304

Filtrates & Residues: An Experiment on the Molar Solubility and Solubility Product of Barium Nitrate.  

ERIC Educational Resources Information Center

|Provides a two hour experiment using direct gravimetric methods to determine solubility constants. Provides methodology and sample results. Discusses the effect of the common ion on the solubility constant. (MVL)|

Wruck, Betty; Reinstein, Jesse

1989-01-01

305

IUPAC-NIST Solubility Data Series. 97. Solubility of Higher Acetylenes and Triple Bonded Derivatives  

NASA Astrophysics Data System (ADS)

Solubility of Ethyne in Liquids was published in 2001 as Vol. 76 of the IUPAC-NIST Solubility Data Series. The current work extends the coverage to the solubility in liquids of higher gaseous and liquid acetylenes and to derivatives that contain a triple carbon-carbon bond. Predictive methods for estimating solubilities in water are summarised and usually give values to within an order of magnitude. The literature has been surveyed to the end of 2010.

Fogg, Peter G. T.

2013-03-01

306

Amorphous solid dispersion enhances permeation of poorly soluble ABT-102: true supersaturation vs. apparent solubility enhancement.  

PubMed

Amorphous solid dispersions (ASDs) represent a promising formulation approach for poorly soluble drugs. We explored the formulation-related impact of ASDs on permeation rate, apparent solubility and molecular solubility of the poorly soluble drug ABT-102. The influence of fasted state simulated intestinal fluid (FaSSIF) as dispersion medium was also studied. ASDs were prepared by hot-melt extrusion. Permeation rate was assessed by the Caco-2 transwell assay. Cell viability and barrier integrity were assured by AlamarBlue©, TEER and permeability of the hydrophilic marker carboxyfluorescein. Apparent solubility and molecular solubility were evaluated by using centrifugation and inverse dialysis, respectively. The in vitro permeation rate of ABT-102 from aqueous dispersions of the ASD was found 4 times faster than that from the dispersions of the crystals, while apparent solubility and molecular solubility of ABT-102 were increased. Yet, a further increase in apparent solubility due to micellar solubilization as observed when dispersing the ASD in FaSSIF, did not affect molecular solubility or permeation rate. Overall, a good correlation between permeation rate and molecular solubility but not apparent solubility was seen. PMID:22951865

Frank, Kerstin J; Rosenblatt, Karin M; Westedt, Ulrich; Hölig, Peter; Rosenberg, Jörg; Mägerlein, Markus; Fricker, Gert; Brandl, Martin

2012-08-20

307

Solubility of metals in fusible melts  

Microsoft Academic Search

We propose a method for the analysis of solubility of metals in fusible melts and evaluate the solubility of Fe, Cr, Ni, Co, Ti, Nb, Mo, V, Cu, Pt, Au, Pd, and Ag in melts of Bi, Pb, Na, Al, and Sn in the approximation of ideal solutions. We also present thermodynamic parameters of dissolution of metals and demonstrate the

M. I. Pashechko; Kh. B. Vasyliv

1996-01-01

308

Further water solubility determinations of insecticidal compounds  

SciTech Connect

The aqueous solubility of 39 insecticidal and related compounds was determined at 20 +/- 1.5 degrees C, using a previously described shaking and centrifugation method. Fenamiphos, fenthion and methidathion produced values substantially less than those reported in the literature whereas, aminocarb, diazinon, dicapthon, pirimiphos-ethyl and pirimiphos-methyl gave solubilities substantially greater than reported literature values.

Bowman, B.T.; Sans, W.W.

1983-01-01

309

Determination of ozone solubility in polymeric materials  

Microsoft Academic Search

The transport of a gas or vapour through a dense, nonporous membrane can be described in terms of a solution-diffusion mechanism, which states that the permeability is determined by its diffusivity and solubility. The solubility of many different molecules in many different polymers has been measured and can be found in the literature. However, very little information can be found

Maarten Dingemans; Jo Dewulf; Wouter Van Hecke; Herman Van Langenhove

2008-01-01

310

The solubility of ozone in various solvents  

Microsoft Academic Search

1.A method was developed for the determination of the solubility of ozone, based on spectrophoto-metric measurement of its concentration at the exit from the vessel with the solvent.2.The solubility of ozone was measured at various concentrations and temperatures for a number of the compounds most frequently used in the investigation of reactions in which ozone participates.

S. D. Razumovskii; G. E. Zaikov

1971-01-01

311

Solubility of the elements in chromium  

Microsoft Academic Search

Summary l.An examination of the solubilities of elements in chromium reveals regularities that are analogous to those that characterize the solubility of elements in other metals, such as iron, nickel, and copper.2.The formation or nonformation of solid solutions of elements in chromium is determined by the relative similarity or dissimilarity of the chemical properties of the elements, as revealed by

L. L. Kornilov

1953-01-01

312

[The solubility of drugs in lipoid vehicles].  

PubMed

A method for determination of drug substances solubility in lipophilic solvents is presented. The solubility was determined in lipophilic suppository bases meltings, in pharmaceutical lipoids as Oleum Ricini, Oleum Arachidis, Cera perliquida, Paraffinum perliquidum and in chemically defined lipoids as n-hexadecane, 1-hexadecane, cetylic alcohol, palmitic acid, cetylpalmitate. Consequences from chemical constitution of substances for solubility are discussed, also consequences from chemical constitution and dielectric constants of lipoidic solvents for their solution behavior. For the substances investigated, the apparent partition coefficients in the two-phase systems lipoid/phosphate buffer pH 7,4 and n-octanol/phosphate buffer pH 7,4 were determined, also the solubility in phosphate buffer. The results show, that connections between partition coefficients and solubility in lipophilic or aqueous phases do not exist. On the other hand, an indirect proportionality between water solubility and lipoid solubility also does not exist. In consequence, interpretations of drug release from lipophilic systems have to be proceeded from exact knowledge of partition behavior and solubilities in both the lipophilic and aqueous phase. PMID:8265709

Pflegel, P; Klaus, T; Schöbel, H; Gruno, M

1993-10-01

313

Soluble quantum map with continuous spectrum  

Microsoft Academic Search

We present a soluble model of an atomic system driven by a train of delta-function impulses. The atomic Hamiltonian describes an atom with one bound state and one continuum representing an autoionizing resonance. The model is soluble or requires very simple numerics. The results depend strongly on the shape of the resonance. Population trapping is discovered for a Gaussian-shaped continuum.

Kazimierz Rzaewski; Jan Mostowski

1987-01-01

314

Solubility Rules: Three Suggestions for Improved Understanding  

Microsoft Academic Search

This article examines the precipitation and solubility of ionic compounds in water from seven general chemistry textbooks and the CRC Handbook of Chemistry and Physics. Many general chemistry textbooks have errors or omissions in their rules for predicting solubility that the author highlights and attempts to correct. In addition, it is proposed that the following changes be made to the

Bob Blake

2003-01-01

315

Solubility of aceclofenac in polyamidoamine dendrimer solutions  

PubMed Central

In the present study we investigated the effect of polyamidoamine (PAMAM) dendrimers on the aqueous solubility of aceclofenac. The aqueous solubility of aceclofenac was measured in the presence of dendrimers in distilled water. The effect of variables, such as pH condition, concentration, temperature and generation (molecule size) of dendrimer, has been investigated. Results showed that the solubility of aceclofenac in the dendrimer solutions was proportional to dendrimer concentration. The order in which the dendrimers increased the solubility at a constant pH condition was G3 > G0. The influence of dendrimer solution pH on the solubility enhancement of aceclofenac suggests that it involves an electrostatic interaction between the carboxyl group of the aceclofenac molecule and the amine groups of the dendrimer molecule. The solubility of aceclofenac was inversely proportional to the temperature of dendrimer solution.Different generation (G0 and G3) PAMAM dendrimers have the potential to significantly enhance the solubility of poor water-soluble drugs.

Patel, Jaydeep; Garala, Kevin; Basu, Biswajit; Raval, Mihir; Dharamsi, Abhay

2011-01-01

316

Solubility of Neon in Liquid Alkali Metals  

Microsoft Academic Search

We have previously [1] reviewed the published experimental data on the solubility of inert gases in molten alkali metals. The critical analysis carried out in that review paper revealed that the earlier investigations mainly involved the measurements of the solubility of helium and argon in liquid lithium and sodium, while other “inert gas?alkali metal melt” systems were studied either incompletely

E. E. Shpil'rain; S. N. Skovorod'ko; A. G. Mozgovoi

2002-01-01

317

Prodrug strategies to overcome poor water solubility  

Microsoft Academic Search

Drug design in recent years has attempted to explore new chemical spaces resulting in more complex, larger molecular weight molecules, often with limited water solubility. To deliver molecules with these properties, pharmaceutical scientists have explored many different techniques. An older but time-tested strategy is the design of bioreversible, more water-soluble derivatives of the problematic molecule, or prodrugs. This review explores

Valentino J. Stella; Kwame W. Nti-Addae

2007-01-01

318

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

319

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)

1989-01-01

320

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

321

In vitro solubility assays in drug discovery.  

PubMed

The solubility of a compound depends on its structure and solution conditions. Structure determines the lipophilicity, hydrogen bonding, molecular volume, crystal energy and ionizability, which determine solubility. Solution conditions are affected by pH, co-solvents, additives, ionic strength, time and temperature. Many drug discovery experiments are conducted under "kinetic" solubility conditions. In drug discovery, solubility has a major impact on bioassays, formulation for in vivo dosing, and intestinal absorption. A good goal for the solubility of drug discovery compounds is >60 ug/mL. Equilibrium solubility assays can be conducted in moderate throughput, by incubating excess solid with buffer and agitating for several days, prior to filtration and HPLC quantitation. Kinetic solubility assays are performed in high throughput with shorter incubation times and high throughput analyses using plate readers. The most frequently used of these are the nephelometric assay and direct UV assay, which begin by adding a small volume of DMSO stock solution of each test compound to buffer. In nephelometry, this solution is serially diluted across a microtitre plate and undissolved particles are detected via light scattering. In direct UV, undissolved particles are separated by filtration, after which the dissolved material is quantitated using UV absorption. Equilibrium solubility is useful for preformulation. Kinetic solubility is useful for rapid compound assessment, guiding optimization via structure modification, and diagnosing bioassays. It is often useful to customize solubility experiments using conditions that answer specific research questions of drug discovery teams, such as compound selection and vehicle development for pharmacology and PK studies. PMID:18991584

Kerns, Edward H; Di, Li; Carter, Guy T

2008-11-01

322

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

323

Effect of sugars on the solubility of hydrophobic solutes in water  

Microsoft Academic Search

It was found that the cosolvent effect of sugars on the solubilities of n-octanol, n-heptanol, and sodium dodecyl sulfate monomer in water depended on a set of factors that included molecular weight and concentration ofthe sugars, the kind of monosaccharides, the type of glycosidic linkages involved, and the temperature. All hexoses examined, D-glucose, D-galactose, and D-mannose, caused solubility depression of

Masanobu Janado; Toshiro Nishida

1981-01-01

324

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

325

Solubility of the diarrheic shellfish toxin okadaic acid in supercritical CO 2  

Microsoft Academic Search

The solubility of okadaic acid (OA) in supercritical CO2 was measured using a flow-type apparatus with sequential sampling during dynamic nonrecirculating experiments at saturation\\u000a conditions. Methanol and water were used as solvent modifiers of CO2. Collected OA was measured by high-performance liquid chromatography with fluorimetric detection after derivatization with\\u000a 1-bromoacetylpyrene to obtain the labeled ester of the toxin. Solubility results

J. C. González; M. R. Vieytes; J. M. Vieites; L. M. Botana

2001-01-01

326

Quantification of soluble HLA class I gene products by an enzyme linked immunosorbent assay  

Microsoft Academic Search

A simplified enzyme linked immunosorbent assay utilizing an HLA class I frameworkspecific monoclonal antibody and a polyclonal enzyme linked beta-2 microglobulin specific antiserum has been established for the quantitative measurement of soluble HLA class I molecules. A total of 219 unrelated healthy individuals and 137 members of 28 families typed for HLA were analyzed for their non-membrane bound, i.e. soluble

Ilias Doxiadis; Ulrike Westhoff; Hans Grosse-Wilde

1989-01-01

327

Gadolinium Solubility in Peralkaline Borosilicate Glasses  

SciTech Connect

Lanthanide-containing glasses, commonly used for optical and laser applications, are also important in the vitrification of actinide-bearing radioactive wastes. In order to study the effect of glass composition on the solubility of gadolinium, 25 peralkaline (Na/Al >1) borosilicate glasses were studied. Above Gd solubility, liquid-liquid phase separation was found in the glasses with Na/B less than 0.5; and in the glasses with Na/B more than 0.5, crystallization was found. For the samples from which liquid-liquid phase separation was observed, Gd solubility was mostly decided by the concentration of excess Na (e.g. Na-Al). Increasing excess Na will increase Gd solubility. For the samples from which crystallization was observed, Gd solubility was decided by the concentration of B, Si, and Al. Increasing B and Si will increase Gd solubility, but increasing Al will decrease Gd solubility. The solution mechanism of Gd in peralkaline borosilicate glasses is also discussed.

Li, Liyu; Li, Hong; Qian, Maoxu; Strachan, Denis M.

2001-05-03

328

Dengue and soluble mediators of the innate immune system.  

PubMed

Huge emphasis has been placed on the role of the adaptive immune system in dengue pathogenesis. Yet there is increasing evidence for the importance of the innate immune system in regulating dengue infection and possibly influencing the disease. This review focuses on the interplay between the innate immune system and dengue and highlights the role of soluble immunological mediators. Type I and type II interferons of the innate immune system demonstrate non-overlapping roles in dengue infection. Furthermore, while some IFN responses to dengue are protective, others may exert disease-related effects on the host. But aside from interferons, a number of cytokines have also been implicated in dengue pathogenesis. Our expanding knowledge of cytokines indicates that these soluble mediators act upon a complicated network of events to provoke the disease. This cytokine storm is generally attributed to massive T cell activation as an outcome of secondary infection. However, there is reason to believe that innate immune response-derived cytokines also have contributory effects, especially in the context of severe cases of primary dengue infection. Another less popular but interesting perspective on dengue pathogenesis is the effect of mosquito feeding on host immune responses and viral infection. Various studies have shown that soluble factors from vector saliva have the capacity to alter immune reactions and thereby influence pathogen transmission and establishment. Hence, modulation of the innate immune system at various levels of infection is a critical component of dengue disease. In the absence of an approved drug or vaccine for dengue, soluble mediators of the innate immune system could be a strategic foothold for developing anti-viral therapeutics and improving clinical management. PMID:22500137

Espada-Murao, Lyre Anni; Morita, Kouichi

2011-09-13

329

Solubility-Excipient Classification Gradient Maps  

Microsoft Academic Search

Abstract  This study assessed the effect of excipients (sodium taurocholate, 2-hydroxypropyl-?-cyclodextrin, potassium chloride, propylene\\u000a glycol, 1-methyl-2-pyrrolidone, and polyethylene glycol 400) on the apparent intrinsic solubility properties of eight sparingly\\u000a soluble drugs (four bases, two neutrals, and two acids): astemizole, butacaine, clotrimazole, dipyridamole, griseofulvin,\\u000a progesterone, glibenclamide, and mefenemic acid. Over 1,200 UV-based solubility measurements (pH 3–10) were made with a high-throughput\\u000a instrument. New

Alex Avdeef; Stefanie Bendels; Oksana Tsinman; Konstantin Tsinman; Manfred Kansy

2007-01-01

330

Oxygen solubility and permeability of carbohydrates.  

PubMed

The saturated oxygen concentration in a series of aqueous solutions of sorbitol (up to 35% w/w) and maltitol (up to 50% w/w) was measured using colorimetric reagent vials based on Rhodazine D. The results indicate that the solubility of oxygen in low-water carbohydrates is considerably lower than its solubility in pure water. It was concluded that the low-oxygen solubility is a major factor contributing to the barrier properties of low-water content carbohydrates used in the encapsulation of flavours, lipids, peptides and other oxidisable species. PMID:15882849

Whitcombe, Michael J; Parker, Roger; Ring, Stephen G

2005-06-13

331

CAPSULATION OF PNEUMOCOCCUS WITH SOLUBLE CELL WALL-LIKE POLYSACCHARIDE  

PubMed Central

Methods are described for the separation of the C or cell wall polysaccharide from the Cs or soluble C-like capsular polysaccharide of Cs pneumococcal strains. Immunologic analysis has shown that both the C and Cs polysaccharides of a variety of pneumococcal strains are heterogeneous and that the dissimilarities appear to reside in the mucopeptide portion of the molecule or in the region of its attachment to the teichoic acid moiety of the molecule rather than in the teichoic acid fraction. Differences of the type described have been observed in the C polysaccharides of wild-type capsulated strains of several types, in those of independently isolated noncapsulated variants derived from a single strain of a given capsular type, and in the C and Cs polysaccharides of spontaneous mutant or transformed strains of pneumococci producing capsules of Cs polysaccharide.

Schiffman, Gerald; Bornstein, Donald L.; Austrian, Robert

1971-01-01

332

Solubility prediction of satranidazole in propylene glycol-water mixtures using extended hildebrand solubility approach.  

PubMed

Extended Hildebrand solubility approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various propylene glycol-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility equation employs term interaction energy (W) to replace the geometric mean (?(1)?(2)), where ?(1) and ?(2) are the cohesive energy densities for the solvent and solute, respectively. The new equation 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 mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in propylene glycol-water mixtures. The expression yields an error in mole fraction solubility of ~3.74%, a value approximating that of the experimentally determined solubility. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design. PMID:23112403

Rathi, P B

2011-11-01

333

Isolation, Screening and Characterization of Soluble Exopolymer-Producing Bacteria For Enhanced Oil Recovery  

Microsoft Academic Search

Various types of bacteria isolated from samples of water-oil and palm oil mill effluents (POME) were screened for soluble exopolymers which has potential use in microbial enhanced oil recovery (MEOR) applications. The samples were collected from several Malaysian oil reservoirs and Sedenak palm oil mill. Based on the chemical analyses of the water-oil samples, 6 types of media (HAA, HAG,

Munirah Tharek; Zaharah Ibrahim; S. Hasila Hamzah; Noraha Markum; Aslizah Mohd Aris; Fareh Nunizawati Daud; Adibah Yahya; Liew Chong Wai; Nozieana Khairuddin; Rosli Illias; Mohamad Ismail Omar; Khor Siak Foo; Ezrin Johanna Elias

334

Converting to water-soluble organic varnishes makes environmental, economic, and processing sense  

Microsoft Academic Search

Types of water-based varnishes and their properties are described. They include inorganic solutions, inorganic dispersions, organic emulsions, organic dispersions, and organic solutions. The performance of these varnishes is examined. The three major types of organic water-soluble resins used as electrical insulating varnishes, namely alkyds, polyesters, and epoxies, are discussed, and guidelines for their use are given. It is shown that

G. E. Bucek

1988-01-01

335

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

336

Acid soluble, pepsin resistant platelet aggregating material  

SciTech Connect

Disclosed is an acid soluble, pepsin resistant, platelet aggregating material isolated from equine arterial tissue by extraction with dilute aqueous acid. The method of isolation and use to control bleeding are described. 4 figs.

Schneider, M.D.

1982-08-31

337

Solubilities of small molecules in liquid krypton  

SciTech Connect

Solubilities of MoF/sub 6/, CO/sub 2/, CH/sub 2/O, HN/sub 3/, and CH/sub 3/OH in liquid krypton have been measured over temperature intervals between 118 and 165 K. The solubilities at 140 K vary from approx. = 0.1 mol/L for CO/sub 2/ to approx. = 2 x 10/sup -4/ mol/L for HN/sub 3/. Relative solubilities of CCl/sub 4/ and SO/sub 2/ in liquid krypton have also been determined. The solubilities are compared with the Hildebrand-Preston-Prausnitz formalism of regular solution theory. Methanol is found to dissolve in liquid krypton as dimers or higher aggregates. Integrated cross sections have been measured for a few absorption features of the dissolved compounds.

Beattie, W.H.; Maier, W.B. II.; Freund, S.M.; Holland, R.F.

1982-01-01

338

Advanced, soluble hydroliquefaction and hydrotreating catalysts  

SciTech Connect

The purpose of the present program is to develop soluble analogs of surface confined catalysts that can be impregnated directly into the coal structure at low temperatures. This approach should avoid problems related to surface area dependence, a two phase (surface-liquid) reaction system and, mass transport limitations. Heteropolyanions (HPAs) offer the opportunity to develop soluble forms of surface confined catalysts. HPAs are multi-functional catalysts that could be used to promote both hydroliquefaction and hydrotreating. In theory, these functions could be employed sequentially or simultaneously and could permit exceptional control of liquefaction reactions and reaction conditions. Thus, the current research program involves efforts to evaluate HPAs as soluble liquefaction nd hydrotreating catalysts, with the goal of developing soluble analogs of surface confined catalysts.

Laine, R.M (Michigan Univ., Ann Arbor, MI (United States). Dept. of Materials Science and Engineering); Stoebe, T. (Washington Univ., Seattle, WA (United States). Dept. of Materials Science and Engineering)

1991-09-09

339

ANALYSIS OF WATER-SOLUBLE ORGANICS  

EPA Science Inventory

The report gives results of several analytical procedures for separating and detecting non-extractable water-soluble organic material, including low molecular weight acids, alcohols, ketones, and other categories of compounds. (There are many ways to analyze hydrophobic extractab...

340

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

341

Solubility of hydrogen in worked steel  

Microsoft Academic Search

Conclusions 1.Hydrogen solubility increases with an increase in the degree of deformation. This effect develops more strongly with cold working than with hot working, which is connected with the presence of a larger number of structural defects and absence of recrystallization in cold-worked steel.2.Optimum hydrogen distribution and an increase in its solubility in hot-worked steel is achieved after exposure at

A. A. Astaf'ev; V. G. Dubinskaya; N. D. Eremenko

1987-01-01

342

Soluble graphene through edge-selective functionalization  

Microsoft Academic Search

Thermally expanded graphite was functionalized with 4-bromophenyl addends using the in situ diazonium formation procedure, and after mild sonication treatment in N,N?-dimethylformamide, thin graphene layers were exfoliated from the bulk graphite. These chemically-assisted exfoliated graphene\\u000a (CEG) sheets had higher solubility than pristine graphene without any stabilizer additive. More than 70% of these soluble\\u000a flakes had less than 5 layers. Energy

Zhengzong Sun; Shin-ichiro Kohama; Zengxing Zhang; Jay R. Lomeda; James M. Tour

2010-01-01

343

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

344

The Water-Soluble Cytochromes of Cyanobacteria  

Microsoft Academic Search

\\u000a The water-soluble cytochromes of cyanobacteria were first characterized in a biochemical sense in 1963. Three distinct cytochromes—cytochrome\\u000a c554, cytochrome c552 and cytochrome c550 were named by the location of their absorption peak near the red end of the visible\\u000a spectrum. These cytochromes were similar in size, heme coenzyme and redox behavior compared to the soluble cytochrome c found\\u000a in eukaryotic

Kwok Ki Ho; Cheryl A. Kerfeld; David W. Krogmann

345

MTA Solubility: A Long Term Study  

Microsoft Academic Search

The purposes of this long-term study was to assess the amount of soluble material released by Mineral Trioxide Aggregate to a water medium, to determine if the solubility differences between specimens of various water\\/powder ratio, as demonstrated in a previous study, would be maintained over time, and to measure the pH of the water that was in contact with the

Marcela Fridland; Rafael Rosado

2005-01-01

346

The solubility of waxes in chloronitroalkanes  

Microsoft Academic Search

1.The solubilities of waxes having different melting points and of dewaxed diesel fuels and oils in chloro-nitroalkanes, in acetone, and in methylethylketone have been investigated.2.The solubilities of wax hydrocarbons in chloronitroalkanes increases with a reduction in the melting point of the wax and with a reduction in the temperature of dissolution process.3.As the number of carbon atoms in the chloronitroalkanes

S. V. Bondarev; L. M. Kozlov

1968-01-01

347

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

348

Water-soluble polymers and utilization thereof  

Microsoft Academic Search

Water-soluble polymers that thicken reversibly in aqueous solution on alteration of the degree of alkalinity are manufactured by treating an aqueous suspension of protein with the enzymes elaborated extracellularly by a species of the genus Pseudomonas. The water-soluble polymers resulting therefrom are biodegradable. They are useful for stabilizing emulsions, as flow-control agents in water base paint, and as antiredeposition agents

Leavitt

1976-01-01

349

Comparative solubility and acute toxicity to Daphnia magna of coal liquids, shale oil and petroleum  

SciTech Connect

Evaluating toxicity of complex organic mixtures to aquatic biota involves generating and characterizing water-soluble fractions (WSF) of test materials. Depending on the mixture, WSFs may contain several biologically active compound classes including phenolics, aromatic and saturate hydrocarbons, aromatic amines, sulfur heterocycles and others. Although some components (e.g. phenolics) may predominate, each contributes to overall toxicity. We studied the relationships among solubility, chemical composition and acute toxicity of several fossil-derived materials. These included coal liquids with different boiling ranges, coal liquids produced by different technological processes and under different process conditions, coal liquids derived from different source coals, a shale oil and, crude and refined petroleum. Results indicated that concentrations of water-soluble components varied with component solubility and chemical composition of parent material, provided that mixing conditions were similar. Acute toxicity to Daphnia magna reflected solubility of chemical components and, in most cases, could be predicted from concentrations of total carbon in solution. Coal liquids were generally more soluble in water than shale oil and petroleum materials and, thus, posed a greater potential toxic hazard to aquatic biota. Lower boiling range coal liquids were most soluble, and thus, posed the greatest acute hazard in water. Coal type had little influence on acute toxicity of coal liquid WSFs to D. magna. 20 references, 1 figure, 1 table.

Gray, R.H.; Dauble, D.D.; Scott, A.J.; Thomas, B.L.

1984-10-01

350

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

351

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

352

Soluble levels of cytosolic tubulin regulate ciliary length control  

PubMed Central

The primary cilium is an evolutionarily conserved dynamic organelle important for regulating numerous signaling pathways, and, as such, mutations disrupting ciliogenesis result in a variety of developmental abnormalities and postnatal disorders. The length of the cilium is regulated by the cell through largely unknown mechanisms. Normal cilia length is important, as either shortened or elongated cilia have been associated with disease and developmental defects. Here we explore the importance of cytoskeletal dynamics in regulating cilia length. Using pharmacological approaches in different cell types, we demonstrate that actin depolymerization or stabilization and protein kinase A activation result in a rapid elongation of the primary cilium. The effects of pharmacological agents on cilia length are associated with a subsequent increase in soluble tubulin levels and can be impaired by depletion of soluble tubulin with taxol. In addition, subtle nocodazole treatment was able to induce ciliogenesis under conditions in which cilia are not normally formed and also increases cilia length on cells that have already established cilia. Together these data indicate that cilia length can be regulated through changes in either the actin or microtubule network and implicate a possible role for soluble tubulin levels in cilia length control.

Sharma, Neeraj; Kosan, Zachary A.; Stallworth, Jannese E.; Berbari, Nicolas F.; Yoder, Bradley K.

2011-01-01

353

Identification of a haem domain in human soluble adenylate cyclase  

PubMed Central

The second messengers cAMP and cGMP mediate a multitude of physiological processes. In mammals, these cyclic nucleotides are formed by related Class III nucleotidyl cyclases, and both ACs (adenylate cyclases) and GCs (guanylate cyclases) comprise transmembrane receptors as well as soluble isoforms. Whereas sGC (soluble GC) has a well-characterized regulatory HD (haem domain) that acts as a receptor for the activator NO (nitric oxide), very little is known about the regulatory domains of the ubiquitous signalling enzyme sAC (soluble AC). In the present study, we identify a unique type of HD as a regulatory domain in sAC. The sAC-HD (sAC haem domain) forms a larger oligomer and binds, non-covalently, one haem cofactor per monomer. Spectral analyses and mutagenesis reveal a 6-fold co-ordinated haem iron atom, probably with non-typical axial ligands, which can bind both NO and CO (carbon monoxide). Splice variants of sAC comprising this domain are expressed in testis and skeletal muscle, and the HD displays an activating effect on the sAC catalytic core. Our results reveal a novel mechanism for regulation of cAMP signalling and suggest a need for reanalysis of previous studies on mechanisms of haem ligand effects on cyclic nucleotide signalling, particularly in testis and skeletal muscle.

Middelhaufe, Sabine; Leipelt, Martina; Levin, Lonny R.; Buck, Jochen; Steegborn, Clemens

2012-01-01

354

Polymorphisms in human soluble epoxide hydrolase.  

PubMed

Human soluble epoxide hydrolase (hsEH) metabolizes a variety of epoxides to the corresponding vicinal diols. Arachidonic and linoleic acid epoxides are thought to be endogenous substrates for hsEH. Enzyme activity in humans shows high interindividual variation (e.g., 500-fold in liver) suggesting the existence of regulatory and/or structural gene polymorphisms. We resequenced each of the 19 exons of the hsEH gene (EPHX2) from 72 persons representing black, Asian, and white populations. A variety of polymorphisms was found, six of which result in amino acid substitutions. Amino acid variants were localized on the crystal structure of the mouse sEH, resulting in the prediction that at least two of these (Arg287Gln and Arg103Cys) might significantly affect enzyme function. The six variants of the hsEH cDNA corresponding to each single polymorphism and one corresponding to a double polymorphism were then constructed by site-directed mutagenesis and expressed in insect cells. As predicted, Arg287Gln and the double mutant Arg287Gln/Arg103Cys showed decreased enzyme activity using trans-stilbene oxide, trans-diphenylpropene oxide, and 14,15-epoxyeicosatrienoic acid as substrates. Lys55Arg and Cys154Tyr mutants had elevated activity for all three substrates. Detailed kinetic studies revealed that the double mutant Arg287Gln/Arg103Cys showed significant differences in Km and Vmax. In addition, stability studies showed that the double mutant was less stable than wild-type protein when incubated at 37 degrees C. These results suggest that at least six hsEH variants exist in the human population and that at least four of these may influence hsEH-mediated metabolism of exogenous and endogenous epoxide substrates in vivo. PMID:12869654

Przybyla-Zawislak, Beata D; Srivastava, Punit K; Vazquez-Matias, Johana; Mohrenweiser, Harvey W; Maxwell, Joseph E; Hammock, Bruce D; Bradbury, J Alyce; Enayetallah, Ahmed E; Zeldin, Darryl C; Grant, David F

2003-08-01

355

Calibrative approaches to protein solubility modeling of a mutant series using physicochemical descriptors  

PubMed Central

A set of physicochemical properties describing a protein of known structure is employed for a calibrative approach to protein solubility. Common hydrodynamic and electrophoretic properties routinely measured in the bio-analytical laboratory such as zeta potential, dipole moment, the second osmotic virial coefficient are first estimated in silico as a function a pH and solution ionic strength starting with the protein crystal structure. The utility of these descriptors in understanding the solubility of a series of ribonuclease Sa mutants is investigated. A simple two parameter model was trained using solubility data of the wild type protein measured at a restricted number of solution pHs. Solubility estimates of the mutants demonstrate that zeta potential and dipole moment may be used to rationalize solubility trends over a wide pH range. Additionally a calibrative model based on the protein’s second osmotic virial coefficient, B22 was developed. A modified DVLO type potential along with a simplified representation of the protein allowed for efficient computation of the second viral coefficient. The standard error of prediction for both models was on the order of 0.3 log S units. These results are very encouraging and demonstrate that these models may be trained with a small number of samples and employed extrapolatively for estimating mutant solubilities.

Labute, P.

2010-01-01

356

Solubility enhancement of desloratadine by solid dispersion in poloxamers.  

PubMed

The present study investigates the possibility of using poloxamers as solubility and dissolution rate enhancing agents of the poorly water soluble drug substance desloratadine that can be used for the preparation of immediate release tablet formulation. Two commercially available poloxamer grades (poloxamer P 188 and poloxamer P 407) were selected, and solid dispersions (SDs) containing different weight ratio of poloxamers and desloratadine were prepared by a low temperature melting method. All SDs were subjected to basic physicochemical characterization by thermal and vibrational spectroscopy methods in order to evaluate the efficiency of poloxamers as solubility enhancers. Immediate release tablets were prepared by direct compression of powdered solid dispersions according to a General Factorial Design, in order to evaluate the statistical significance of two formulation (X(1) - type of poloxamer in SD and X(2) - poloxamer ratio in SD) and one process variable (X(3) - compression force) on the drug dissolution rate. It was found that desloratadine in SDs existed in the amorphous state, and that can be largely responsible for the enhanced intrinsic solubility, which was more pronounced in SDs containing poloxamer 188. Statistical analysis of the factorial design revealed that both investigated formulation variables exert a significant effect on the drug dissolution rate. Increased poloxamer ratio in SDs resulted in increased drug dissolution rate, with poloxamer 188 contributing to a faster dissolution rate than poloxamer 407, in accordance with the results of intrinsic dissolution tests. Moreover, there is a significant interaction between poloxamer ratio in SD and compression force. Higher poloxamer ratio in SDs and higher compression force results in a significant decrease of the drug dissolution rate, which can be attributed to the lower porosity of the tablets and more pronounced bonding between poloxamer particles. PMID:22772487

Kolašinac, Nemanja; Kachrimanis, Kyriakos; Homšek, Irena; Gruji?, Branka; Ðuri?, Zorica; Ibri?, Svetlana

2012-07-06

357

Preparation and properties of hybrids of organo-soluble polyimide and montmorillonite with various chemical surface modification methods  

Microsoft Academic Search

Montmorillonite (MMT)\\/Organo-soluble polyimide (PI) hybrids were prepared using a monomer solution intercalation polymerization method. The organo-soluble polyimide was based on pyromellitic dianhydride and 4,4?-diamino-3,3?-dimethyldiphenylmethane. The MMT was organo-modified with three types of intercalation agents: amino acids, primary aliphatic amines and quaternary ammonium salt. The dispersion behavior of MMT in organic solvents and polyimide depends on the type of the functional

Yong Yang; Zi-kang Zhu; Jie Yin; Xin-yu Wang; Zong-eng Qi

1999-01-01

358

Solubility advantage from amorphous etoricoxib solid dispersions.  

PubMed

Abstract Objective: This study aimed to evaluate kinetic solubility advantage of amorphous etoricoxib solid dispersions prepared with three water soluble polymers and correlate it with solid state and supersaturated drug solution stabilization potential of these polymers. Methods: Amorphous solid dispersions (ASDs) of etoricoxib were prepared with polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP) and hydroxyethyl cellulose (HEC) at 70:30w/w ratio and characterized for glass transition temperature (T(g)), miscibility and intermolecular interactions. Kinetic solubility profiles of amorphous etoricoxib and its ASDs were determined in water at 37 °C. Solid-state stability was assessed by enthalpy relaxation studies at a common degree of undercooling of around 19.0 °C at 0% RH. Recrystallization behavior of supersaturated drug solution was evaluated in the absence and presence of pre-dissolved polymer at 37 °C. Results: Amorphous etoricoxib exhibited rapid solid-to-solid transition to yield a solubility advantage of merely 1.5-fold in water. Among the ASDs, etoricoxib-PVP dispersion exhibited maximal "peak" (2-fold) and "plateau" (1.8-fold) solubility enhancement, while etoricoxib-PVA dispersion could only sustain the "peak" solubility achieved by amorphous etoricoxib. In contrast, etoricoxib-HEC dispersion displayed no solubility advantage. The rank order for solid state and supersaturated solution stabilization followed a similar trend of amorphous etoricoxib?

Dani, Prateek; Puri, Vibha; Bansal, A K

2013-01-10

359

Solubility of pllutonium in alkaline salt solutions  

SciTech Connect

Plutonium solubility data from several studies have been evaluated. For each data set, a predictive model has been developed where appropriate. In addition, a statistical model and corresponding prediction intervals for plutonium solubility as a quadratic function of the hydroxide concentration have been developed. Because of the wide range of solution compositions, the solubility of plutonium can vary by as much as three orders of magnitude for any given hydroxide concentration and still remain within the prediction interval. Any nuclear safety assessments that depend on the maximum amount of plutonium dissolved in alkaline salt solutions should use concentrations at least as great as the upper prediction limits developed in this study. To increase the confidence in the prediction model, it is recommended that additional solubility tests be conducted at low hydroxide concentrations and with all of the other solution components involved. To validate the model for application to actual waste solutions, it is recommended that the plutonium solubilities in actual waste solutions be determined and compared to the values predicted by the quadratic model.

Hobbs, D.T.; Edwards, T.B.

1993-02-26

360

Hydrophobic Ion Pairing: Altering the Solubility Properties of Biomolecules  

Microsoft Academic Search

The high aqueous solubility of ionic compounds can be attributed to the ease of solvation of the counter ions. Replacement of the counter ions with ionic detergents dramatically alters the solubility properties of the molecule. Not only does the aqueous solubility drop precipitously, but the solubility in organic phases increases as well. Consequently, the partition coefficient changes by orders of

Jeffrey D. Meyer; Mark C. Manning

1998-01-01

361

Partially soluble organics as cloud condensation nuclei: Role of trace soluble and surface active species  

Microsoft Academic Search

The ability of partially soluble organic species to act as cloud condensation nuclei (CCN) has been studied. A Köhler model incorporating solute solubility and droplet surface tension describes the behavior of solid adipic and succinic acid particles, whereas solid azelaic acid activates much more efficiently that predicted. In addition, it was shown that trace levels of either sulfate or surface

K. Broekhuizen; P. Pradeep Kumar; J. P. D. Abbatt

2004-01-01

362

Improvement in solubility of poor water-soluble drugs by solid dispersion.  

PubMed

This article is intended to combine recent literature on solid dispersion technology for solubility enhancement with special emphasis on mechanism responsible for the same by solid dispersion, various preparation methods, and evaluation parameters. Solubility behavior is the most challenging aspect for various new chemical entities as 60% of the new potential products possess solubility problems. This is the biggest reason for new drug molecules not reaching to the market or not reaches to full potential. There are various techniques to enhance the drug solubility such as particle size reduction, nanosuspension, use of surfactants, salt formation, solid dispersion, etc. From this article it may be concluded that solid dispersion is an important approach for improvement of bioavailability of poor water-soluble drugs. PMID:23071955

Sareen, Swati; Mathew, George; Joseph, Lincy

2012-01-01

363

Soluble and membrane-anchored forms of the human lFN-a\\/?3 receptor  

Microsoft Academic Search

The recently cloned ligand binding compo- nent of the type I human interferon-a\\/n receptor (IFN- a\\/DR) and its soluble analogue (p4O) were characterized. p40 is a potent inhibitor of type I IFNs and antibodies directed against p40 completely block the activity of type I IFNs in human cells. These antibodies immunoprecipi. tate cellular 102-kDa (major) and 5 1-kDa (minor) forms

Daniela Novick; Batya Cohen; Natan Tal; Menachem Rubinstein

364

Spectroscopic and solubility characteristics of oxidized soots  

SciTech Connect

Spectroscopic and solubility studies of reaction products of soot (black carbon) with O{sub 3}, NO{sub 2}/N{sub 2}O{sub 4}, and SO{sub 2} have revealed a relationship between reactivity and product solubility and structure. A remarkably high solubility of ozonated n-hexane soot has its origin in the formation of anhydride and lactone surface structures and their subsequent hydrolysis to carboxylic acid species. Calculations indicate that the rate of surface carboxylation of 0.1-{mu}m diameter spheroidal soot particles, in the presence of 50 ppbv ozone at ambient temperature, is such that solubilization may occur within a 30-minute time frame. Measurements on ambient air aerosol samples in metropolitan Denver are consistent with these observations and demonstrate the high reactivity of soot with ozone even at very low levels in natural systems.

Chughtai, A.R.; Jassim, J.A.; Peterson, J.H.; Stedman, D.H.; Smith, D.M. (Univ. of Denver, CO (United States))

1991-01-01

365

Solubilities of molybdenum in liquid tin  

SciTech Connect

During the course of studies directed toward the better understanding of the high-temperature metallurgical processes for the recovery of valuable metals, e.g., palladium, rhodium, ruthenium, and molybdenum, from spent nuclear fuel generated at nuclear reactors, it became necessary to know the solubilities of molybdenum in liquid tin at temperatures between 1,473 and 1,723 K. To the best of the authors` knowledge, such data are from allen only, where molybdenum solubilities are expressed by weight pct [pct Mo]. At the temperatures of the authors` interest, i.e., 1,473 to 1,723 K, Allen`s values for [pct Mo] are relatively insensitive to temperature and might not be accurate. In the present study, a conventional sampling technique was applied for the determinations of the molybdenum solubilities in liquid tin: attention was focused on temperatures between 1,473 and 1,723 K.

Kawabata, Ryo; Iwase, Masanori [Kyoto Univ. (Japan). Dept. of Energy Science and Engineering; Myochin, Munetaka [Power Reactor and Nuclear Fuel Development Corp., Ibaraki (Japan). Nuclear Fuel Technology Development Div.

1995-06-01

366

AN-107 entrained solids - Solubility versus temperature  

SciTech Connect

This report describes the results of a test conducted by Battelle to assess the solubility of the solids entrained in the diluted AN-107 low-activity waste (LAW) sample. BNFL requested Battelle to dilute the AN-107 sample using sodium hydroxide and de-ionized water to mimic expected plant operating conditions. BNFL further requested Battelle to assess the solubility of the solids present in the diluted AN-107 sample versus temperature conditions of 30, 40, and 50 C. BNFL requested these tests to assess the composition of the LAW supernatant and solids versus expected plant-operating conditions.

GJ Lumetta; RC Lettau

2000-03-31

367

Soluble polyimides with specific dielectric behavior  

NASA Astrophysics Data System (ADS)

The present necessity to use heat resistant materials in electronics justifies scientific activity on different heterocyclic polymers, especially for their application as dielectric films, interlayers dielectric or passication coatings. For this purpose it is interesting to use heterocyclic materials fully cyclized and soluble for spin coating and casting processes. Two new soluble polyimides have been synthetized by introduction of diphenylfluorene groups in the imide chain. We discuss in this paper the synthesis and the mechanical, thermal and dielectrical properties of these polymers. This study shows that it is possible to control the processing and the electrical properties of thermostable polymers polymers by a suitable choice of the chain structure.

Boiteux, G.; Oraison, J. M.; Seytre, G.; Rabilloud, G.; Sillion, B.

368

Nitrogen solubility in upper mantle minerals  

NASA Astrophysics Data System (ADS)

Nitrogen solubility in the upper mantle minerals forsterite, diopside, enstatite and pyrope has been quantified by SIMS measurements of nitrogen-saturated, synthetic samples. The crystals were grown in a 15N–H–O fluid buffered by Ni–NiO, Co–CoO, and Fe–FeO, at 1000–1300?°C and 15–35 kbar in a piston cylinder apparatus. Nitrogen solubility in minerals is significantly affected by temperature, pressure, mineral composition and, in particular, by oxygen fugacity. Nitrogen in all crystals buffered by Ni–NiO or Co–CoO is below detection limit or at most a few ?g/g at very high pressures. Concentrations of 5–24 ?g/g nitrogen have been quantified in diopside, enstatite and pyrope buffered by Fe–FeO at 1100?°C/15 kbar. Very high nitrogen solubility up to 100 ?g/g is observed at the Fe–FeO buffer in enstatite at high-temperature or in Al-bearing enstatite and diopside. The nitrogen solubility in forsterite at the Fe–FeO buffer also clearly increases with temperature and pressure; a maximum solubility of 10 ppm is obtained at 1300?°C/35 kbar. The strong enhancement of nitrogen solubility under reducing conditions may be related to nitrogen dissolution as either NH+4 or as N3? directly replacing O2?. Both mechanisms require some charge compensation, consistent with the enhancement of nitrogen solubility with Al content in enstatite. Our results demonstrate that the reduced lower part of the upper mantle has a large nitrogen storage capacity, and may store ˜20–50 times more nitrogen than the present atmosphere. Therefore, some 'missing' nitrogen may still be retained in the Earth's deep, reduced mantle. The calculated nitrogen partition coefficients between upper mantle minerals and silicate melt reveal that an oxidized mantle source would lose almost its entire nitrogen during partial melting, whereas under reducing conditions a considerable fraction of nitrogen could be retained in the residual solids. The high nitrogen solubility in upper mantle minerals at reducing conditions also suggests that solidification of the magma ocean on the early Earth should have retained significant nitrogen, yielding higher N/Ar and N/C ratios in the young upper mantle as compared to the young atmosphere.

Li, Yuan; Wiedenbeck, Michael; Shcheka, Svyatoslav; Keppler, Hans

2013-09-01

369

Solubilities of krypton and xenon in dichlorodifluoromethane  

SciTech Connect

The solubility behavior of krypton and xenon in dichlorodifluoromethane was investigated for the Consolidated Fuel Reprocessing Program (CFRP) in support of the fluorocarbon absorption process. The solubility data derived from solute radioisotopes had uncertainties of approx. 0.1%. Values for Henry's law constants were initially determined under equilibrium conditions at infinite solute dilution. Based on these results, the study was extended to finite solute concentrations. Nonidealities in the two binary systems were expressed as gas phase fugacity coefficients for each solute at 10/sup 0/ intervals over the range -30 to +50/sup 0/C. 22 references, 4 figures, 2 tables.

Shaffer, J.H.; Shockley, W.E.; Greene, C.W.

1984-07-01

370

Optimization of single-walled carbon nanotube solubility by noncovalent PEGylation using experimental design methods.  

PubMed

In this study, noncovalent functionalization of single-walled carbon nanotubes (SWCNTs) with phospholipid-polyethylene glycols (Pl-PEGs) was performed to improve the solubility of SWCNTs in aqueous solution. Two kinds of PEG derivatives, ie, Pl-PEG 2000 and Pl-PEG 5000, were used for the PEGylation process. An experimental design technique (D-optimal design and second-order polynomial equations) was applied to investigate the effect of variables on PEGylation and the solubility of SWCNTs. The type of PEG derivative was selected as a qualitative parameter, and the PEG/SWCNT weight ratio and sonication time were applied as quantitative variables for the experimental design. Optimization was performed for two responses, aqueous solubility and loading efficiency. The grafting of PEG to the carbon nanostructure was determined by thermogravimetric analysis, Raman spectroscopy, and scanning electron microscopy. Aqueous solubility and loading efficiency were determined by ultraviolet-visible spectrophotometry and measurement of free amine groups, respectively. Results showed that Pl-PEGs were grafted onto SWCNTs. Aqueous solubility of 0.84 mg/mL and loading efficiency of nearly 98% were achieved for the prepared Pl-PEG 5000-SWCNT conjugates. Evaluation of functionalized SWCNTs showed that our noncovalent functionalization protocol could considerably increase aqueous solubility, which is an essential criterion in the design of a carbon nanotube-based drug delivery system and its biodistribution. PMID:21556348

Hadidi, Naghmeh; Kobarfard, Farzad; Nafissi-Varcheh, Nastaran; Aboofazeli, Reza

2011-04-08

371

Empirical evaluation of lung solubilities of airborne contamination at Harwell facilities.  

PubMed

Lung solubility is the key parameter in determining intakes and doses from inhalation of airborne contamination. However, information on lung solubility can be difficult to acquire, particularly for the historical exposures that are of relevance to lifetime-dose reconstruction. In this study, an empirical approach has been made in which over 200 dose assessments, mainly for Pu and Am, from the period 1986 to 2005 were re-evaluated and the solubility mix required for the best fit to the data was determined. The average of these solubility mixtures for any building or facility can be used as the default solubility for retrospective dose assessments for that facility. Results are presented for a radiochemistry facility, a materials development facility and a waste-storage/handling building at Harwell. The latter two areas are characterised by aerosols that are predominantly insoluble (type S), whereas the radiochemistry facility has a heterogeneous mixture of insoluble and soluble aerosols. The implications of these results for dose reconstruction are discussed in the paper. PMID:21123242

Bull, R K; Wilson, G

2010-11-30

372

Characterization of the conglomerate form of acetyl-DL-leucine by thermal analysis and solubility measurements  

NASA Astrophysics Data System (ADS)

Starting from a mixture of enantiomers in solution, crystallization can generate different types of crystals. In order to determine which type of crystal is obtained in the case of acetyl leucine, an active pharmaceutical ingredient (API), analytical methods have been used to partially elucidate the binary and ternary phase diagrams of the system composed of the two enantiomers and water.The melting temperature phase diagram of this compound has been obtained by using differential scanning calorimetry (DSC) analyzes. The results show that it is characteristic of a conglomerate. This mode of crystallization has also been confirmed by X-ray powder diffraction analysis.Solubility measurements of enantiomerical mixtures in water enabled the determination of the ternary diagram of solubility. The empiric Meyerhoffer double solubility rule has been modified, due to the characterization of interactions between enantiomers.

Estime, N.; Pena, R.; Teychené, S.; Autret, J. M.; Biscans, B.

2012-03-01

373

Solid dispersions of itraconazole for inhalation with enhanced dissolution, solubility and dispersion properties.  

PubMed

The purpose of this study was to produce a dry powder for inhalation (DPI) of a poorly soluble active ingredient (itraconazole: ITZ) that would present an improved dissolution rate and enhanced solubility with good aerosolization properties. Solid dispersions of amorphous ITZ, mannitol and, when applicable, D-?-tocopherol polyethylene glycol 1000 succinate (TPGS) were produced by spray-drying hydro-alcoholic solutions in which all agents were dissolved. These dry formulations were characterized in terms of their aerosol performances and their dissolution, solubility and physical properties. Modulate differential scanning calorimetry and X-ray powder diffraction analyses showed that ITZ recovered from the different spray-dried solutions was in an amorphous state and that mannitol was crystalline. The inlet drying temperature and, indirectly, the outlet temperature selected during the spray-drying were critical parameters. The outlet temperature should be below the ITZ glass transition temperature to avoid severe particle agglomeration. The formation of a solid dispersion between amorphous ITZ and mannitol allowed the dry powder to be produced with an improved dissolution rate, greater saturation solubility than bulk ITZ and good aerosol properties. The use of a polymeric surfactant (such as TPGS) was beneficial in terms of dissolution rate acceleration and solubility enhancement, but it also reduced aerosol performance. For example, significant dissolution rate acceleration (f(2)<50) and greater saturation solubility were obtained when introducing 1% (w/w) TPGS (mean dissolution time dropped from 50.4 min to 36.9 min and saturation solubility increased from 20 ± 3 ng/ml to 46 ± 2 ng/ml). However, the fine particle fraction dropped from 47 ± 2% to 37.2 ± 0.4%. This study showed that mannitol solid dispersions may provide an effective formulation type for producing DPIs of poorly soluble active ingredients, as exemplified by ITZ. PMID:22414388

Duret, Christophe; Wauthoz, Nathalie; Sebti, Thami; Vanderbist, Francis; Amighi, Karim

2012-03-10

374

Physicochemical investigation of the effects of water-soluble polymers on vinpocetine complexation with ?-cyclodextrin and its sulfobutyl ether derivative in solution and solid state  

Microsoft Academic Search

The studies reported in this work aimed to elucidate the inclusion complex formation of vinpocetine (VP), a poorly water-soluble base type drug, with ?-cyclodextrin (?CD) and its sulfobutyl ether derivative (sulfobutyl ether ?-cyclodextrin (SBE?CD)), with or without water-soluble polymers (PVP and HPMC), by thoroughly investigating their interactions in solution and solid state. Phase solubility studies were carried out to evaluate

Laura S. S Ribeiro; Domingos C Ferreira; Francisco J. B Veiga

2003-01-01

375

Solubility of Solids in Dense Gases.  

National Technical Information Service (NTIS)

The thermodynamics of solid-dense gas equilibria is discussed, and two techniques are described for calculating the solubility of a solid component in a gas at high pressure. The first one is based on the recent empirical equation of state of Redlich whic...

J. M. Prausnitz

1965-01-01

376

Water-soluble polymers and compositions thereof  

DOEpatents

Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polyvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

Smith, Barbara F. (Los Alamos, NM); Robison, Thomas W. (Los Alamos, NM); Gohdes, Joel W. (Los Alamos, NM)

1999-01-01

377

Water-soluble polymers and compositions thereof  

DOEpatents

Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

Smith, Barbara F. (Los Alamos, NM); Robison, Thomas W. (Los Alamos, NM); Gohdes, Joel W. (Los Alamos, NM)

2002-01-01

378

Water-soluble polymers and compositions thereof  

DOEpatents

Water-soluble polymers including functionalization from the group of amino groups, carboxylic acid groups, phosphonic acid groups, phosphonic ester groups, acylpyrazolone groups, hydroxamic acid groups, aza crown ether groups, oxy crown ethers groups, guanidinium groups, amide groups, ester groups, aminodicarboxylic groups, permethylated polyvinylpyridine groups, permethylated amine groups, mercaptosuccinic acid groups, alkyl thiol groups, and N-alkylthiourea groups are disclosed.

Smith, B.F.; Robison, T.W.; Gohdes, J.W.

1999-04-06

379

Steam Solubilities for Combustion Turbine Steam Cooling  

Microsoft Academic Search

Steam cooling of combustion turbine parts provides significant advantages over air cooling. Steam potentially carries dissolved salts that can deposit on the cooled parts and cause corrosion. By maintaining the salt concentration below its solubility limit in the steam, deposition of salts may be avoided. A literature survey reveals that only sodium chloride and silica have adequate data for reasonable

J. C. Bellows; A. H. Harvey

1999-01-01

380

UV Disinfection of Soluble Oil Metalworking Fluids  

Microsoft Academic Search

The efficacy of a new high-intensity germicidal ultraviolet (UV) lamp for disinfection of opaque metalworking fluids (MWF) was investigated under laboratory conditions. Three dilutions of “soluble oil” MWF and water controls in a circulating system were inoculated with suspensions of Pseudomonas fluorescens to an initial concentration of about 10 colony forming units (CFU) per milliliter and irradiated with a submerged

David L. Johnson; Margaret L. Phillips

2002-01-01

381

Thermodynamic models for asphaltene solubility and precipitation  

Microsoft Academic Search

A number of different models that have been applied to modeling of asphaltene precipitation and estimating asphaltene solubility in various systems are critically reviewed. Particular attention is paid to the basic assumptions and the performance of the models as compared to the present knowledge of composition and phase equilibrium of asphaltenes. In all models a number of parameters are tuned

Simon I. Andersen; James G. Speight

1999-01-01

382

Treatment of wood ash containing soluble chromate  

Microsoft Academic Search

The “TA Siedlungsabfall” issued in Germany in May 1993 will entail severe problems concerning the disposal of wood ash. One particular problem is associated with the occurrence of soluble chromium compounds in the leachates of wood ash. During combustion of wood, wood residues or waste wood, Cr-III which is generally found in wood is partly oxidized to Cr-VI. Under the

K. Pohlandt-Schwandt

1999-01-01

383

Solubilities of five triglycerides in aqueous ethanol  

Microsoft Academic Search

The solubilities of trilaurin, trimyristin, tripalmitin, tristearin, and triolein in 90, 95.4, 98, and 100% ethanol between\\u000a 40C and 90C were determined. The data were compared with data calculated by the ideal solution law.

Lionel K. Arnold; R. Basu Roy Choudhury; Alberto Guzman

1963-01-01

384

Evaluating soluble toxicants in contaminated soils  

Microsoft Academic Search

Complex mixtures of water soluble materials from contaminated soils can move into groundwater and surface water by leaching, percolation, and runoff. We evaluated the potential toxicity of leachable materials from seven soils. Five soil samples were obtained at designated toxic or hazardous waste sites, and two additional soils samples were obtained from a coal storage area and from an agricultural

J. R. Pratt; P. V. McCormick; K. W. Pontasch; J. Cairns

1988-01-01

385

Golden rule for buttressing vulnerable soluble proteins.  

PubMed

Local weaknesses in the structure of soluble proteins have received little attention. The structure may be inherently weak at sites where hydration of the protein backbone is locally hampered by formation of an intramolecular hydrogen bond which in turn is not fully stabilized through burial within a hydrophobic environment. The result is insufficient compensation for the thermodynamic cost of dehydrating the backbone polar groups. This work shows that these structural deficiencies, the unburied backbone hydrogen bonds, are compensated in natural proteins by disulfide bonds that are needed to maintain the structural integrity. Examination of all PDB-reported soluble structures reveals that, after suitable normalization, the number of disulfide bonds, X, correlates tightly with the number of unburied backbone hydrogen bonds, Y, beyond the baseline level Y = 20, revealing a simple balance relation: Y = 5X + 20. This equation introduces a 1:5 ratio associated with the buttressing of soluble proteins with structural deficiencies. The results are justified on thermodynamic grounds and have implications for biomolecular engineering as they introduce two constants of universal applicability determining the architecture of soluble proteins. PMID:20364868

Fernández, Ariel; Berry, R Stephen

2010-05-01

386

SOLUBILITY OF URANYL SALTS IN ORGANIC ESTERS  

Microsoft Academic Search

The relations of solubility for uranyl acetate, uranyl nitrate, and ; uranyl sulfate were investigated in dioctyl phthalate, dibutyl phthalate, dibutyl ; phosphate, and tributyl phosphate. For all the three uranyl salts, dibutyl ; phosphate proved to be the best solvent. Tributyl phosphate is an excellent ; solvent for uranyl nitrate, while it is only a mediocre solvent for the

Szilagyi

1960-01-01

387

Soluble arsenic removal at water treatment plants  

SciTech Connect

Arsenic profiles were obtained from full-scale conventional treatment (coagulation, Fe-Mn oxidation, or softening) plants, facilitating testing of theories regarding arsenic removal. Soluble As(V) removal efficiency was controlled primarily by pH during coagulation, be Fe{sup +2} oxidation and Fe(OH){sub 3} precipitation during Fe-Mn oxidation, and by Mg(OH){sub 2} formation during softening. Insignificant soluble As(V) removal occurred during calcite precipitation at softening plants or during Mn{sup +2} oxidation-precipitation at Fe-Mn oxidation plants. The extent of soluble As(V) removal during coagulation and softening treatments was lower than expected. Somewhat surprisingly, during coagulation As(V) removal efficiencies were limited by particulate aluminum formation and removal, because much of the added coagulant was not removed by 0.45-{mu}m-pore-size filters. At one utility, reducing the coagulation pH from 7.4 to 6.8 (at constant alum dose) improved removal of particulate aluminum, thereby enhancing soluble As(V) removal during treatment.

McNeill, L.S.; Edwards, M. [Univ. of Colorado, Boulder, CO (United States). Dept. of Civil Engineering

1995-04-01

388

Advanced soluble hydroliquefaction and hydrotreating catalysts  

SciTech Connect

The purpose of the present program is to develop soluble analogs of surface confined catalysts that can be impregnated directly into the coal structure at low temperatures. This approach should avoid problems related to surface area dependence, a two phase (surface- liquid) reaction system and, mass transport limitations.

Laine, R.M. (Michigan Univ., Ann Arbor, MI (United States). Dept. of Materials Science and Engineering); Stoebe, T. (Washington Univ., Seattle, WA (United States). Dept. of Materials Science and Engineering)

1992-01-31

389

Advanced soluble hydroliquefaction and hydrotreating catalysts  

SciTech Connect

The purpose of the present program is to develop soluble analogs of surface confined catalysts that can be impregnated directly into the coal structure at low temperatures. This approach should avoid problems related to surface area dependence, a two phase (surface-liquid) reaction system and, mass transport limitations.

Laine, R.M. (Michigan Univ., Ann Arbor, MI (United States). Dept. of Materials Science and Engineering); Stoebe, T. (Washington Univ., Seattle, WA (United States). Dept. of Materials Science and Engineering)

1991-11-22

390

Hemopoietic Effects of Intravenous Soluble Glucan Administration.  

National Technical Information Service (NTIS)

A soluble form of the reticuloendothelial- and immune modulating agent glucan (glucan-F) has been evaluated for its effects on hemopoiesis. A single 5.0 mg intravenous injection of glucan-F into C3H/HeN mice increased peripheral white blood cellularity, b...

M. L. Patchen T. J. MacVittie

1986-01-01

391

Fluosilicate solubilities affect HF acid compositions  

SciTech Connect

The purpose of this work was to determine the solubilities of sodium and potassium fluosilicate over a broad range of HCl concentrations, ionic strengths, and temperatures. These data were required for determining optimum or safe HCl/HF treating-fluid compositions for acidizing sandstone formations containing feldspars. Solubilities of sodium and potassium fluosilicate were determined over a temperature range of 150 to 300 F. Analysis of the solubility data indicated that the solids formed were not simply Na[sub 2]SiF[sub 6] and K[sub 2]SiF[sub 6]. Regression analyses indicated that the sodium salt could best be described as NaHSiF[sub 6] [center dot] 0.52HCl. Regression analyses indicated that the potassium salt could best be described as KHSiF[sub 6] [center dot] 0.41 KCl. The solubility data were then included in a HF-spending simulator to determine regions where possible precipitation of the fluosilicates could occur. Optimum HCl/HF concentrations were then determined for specific mineral and temperature conditions.

Gdanski, R.D. (Halliburton Services Research Center, Duncan, OK (United States). Stimulation Research and Engineering Dept.)

1994-11-01

392

Solubility of Uranium Hexafluoride in Perfluoroethers.  

National Technical Information Service (NTIS)

The polyperfluoroethers are compatible with uranium hexafluoride (UF sub 6 ) and are suitable for use in diffusion pumps and in mechanical vacuum pumps which rely on oil as both the lubricant and the seal. The UF sub 6 is soluble in all fluids with which ...

E. J. Barber

1984-01-01

393

Development of male urogenital epithelia elicited by soluble mesenchymal factors.  

PubMed

Androgen-dependent development of male secondary sexual glands is mediated by paracrine mesenchymal-epithelial interactions that regulate a complex array of biological events such as epithelial morphogenesis, growth, and cytodifferentiation. It is not known whether the action of mesenchyme on epithelial development in the male genital tract requires cell-cell contact or whether soluble, diffusible mediators are involved. To examine paracrine effects of urogenital sinus mesenchyme (UGM) on epithelial development, conditioned media (CM) from embryonic mouse UGM of normal (wild-type) and androgen-insensitive Tfm (testicular feminization) mice were tested for growth and morphogenetic effects on heterotypic tissue recombinants composed of rat or mouse bladder mesenchyme plus neonatal mouse seminal vesicle epithelium (BLM+SVE) or rat or mouse bladder mesenchyme plus neonatal mouse bulbourethral gland epithelium (BLM+BUG-E). Addition of a concentrate of CM from wild-type UGM grown in the presence of dihydrotestosterone (DHT) induced epithelial growth and complex epithelial morphogenesis in BLM+SVE recombinants, whereas CM from DHT-treated Tfm UGM or a saline control were without effect. CM from wild-type UGM elicited similar trophic effects in BLM+BUG-E recombinants, but in addition induced precocious mucous epithelial differentiation in BLM+BUG-E recombinants. These results suggest that the normally androgen-dependent epithelial growth and branching morphogenesis in developing male urogenital organs is elicited by soluble mesenchymal factors. Two-dimensional gel electrophoresis of proteins synthesized and secreted by wild-type UGM revealed several androgen-dependent proteins with molecular weights of approximately 30 kDa that are absent in CM of Tfm UGM either in the presence or absence of DHT.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7559156

Shima, H; Tsuji, M; Elfman, F; Cunha, G R

394

Solubilities of significant compounds in HLW tank supernate solutions - FY 1996 progress report  

SciTech Connect

The solubilities of two sodium salts of organic acids that are thought to exist in high-level waste at the Hanford Site were measured in tank supernate simulant solutions during FY1996 This solubility information will be used to determine if these organic salts could exist in solid phases (saltcake or sludges) in the waste where they might react violently with the nitrate or nitrite salts present in the tanks. Solubilities of sodium butyrate and trisodium N-(2-hydroxyethyl)ethylenediaminetriacetate were measured in simulated waste supernate solutions at 25 {degrees}C, 30 {degrees}C, 40 {degrees}C, and 50 {degrees}C. The organic compounds were selected because they are expected to exist in relatively high concentrations in the tanks. Two types of tank supernate simulants were used - a 4.O M sodium nitrate - 0.97 M sodium nitrite solution with sodium hydroxide concentrations ranging from O.00003 M to 2.O M and a 2.O M sodium nitrite solution saturated with crystalline sodium nitrate with sodium hydroxide concentrations ranging from 0.1 M to 2. 0 M. The solubilities of sodium butyrate and trisodium N-(2-hydroxyethyl)ethylene- diaminetriacetate in both types of HLW tank supernate solutions were high over the temperature and sodium hydroxide concentration ranges expected in the tanks. The solubilities of these compounds are similar (in terms of total organic carbon) to sodium glycolate, succinate, caproate, dibutylphosphate, citrate, formate, ethylenediaminetetraacetate, and nitrilotriacetate which were measured previously. High solubilities will prevent solid sodium salts of these organic acids from precipitating from tank supernate solutions. The total organic carbon concentrations (TOC) of actual tank supernates are generaly much lower than the TOC ranges for the simulated supernate solutions saturated (at the solubility limit) with the organic salts. This is true even if all the dissolved carbon in a given tank supernate is due to only one of these eight soluble compounds (an unlikely situation). Solubilities of all the organic salts decrease with increasing sodium hydoxide and sodium nitrate concentration because of the common ion effect of Na{sup +}. Increasing temperatures has little effect on the solubilities of sodium butyrate and trisodium N-(2-hydroxyethyl)ethylenediaminetriacetate.

Barney, G.S.

1996-09-30

395

Water-Soluble Antioxidant Potential of Melon Lines Grown in Turkey  

Microsoft Academic Search

The antioxidant potential of 42 melon (Cucumis melo) lines including six cultivars grown in Turkey was assessed by measuring total water-soluble antioxidant capacity, phenolic and vitamin C contents. The lines showed significant variability for all three antioxidant parameters with breeding lines having higher antioxidant capacity and phenolic content than some popular cultivars. Different types of melons also showed significantly different

Hatice ?elale; Hasan Ozgur S?gva; ?brahim Celik; Sami Doganlar; Anne Frary

2012-01-01

396

WATER-SOLUBLE ANTIOXIDANT POTENTIAL OF MELON LINES GROWN IN TURKEY  

Microsoft Academic Search

The antioxidant potential of 42 melon (Cucumis melo) lines including six cultivars grown in Turkey was assessed by measuring total water-soluble antioxidant capacity, phenolic and vitamin C contents. The lines showed significant variability for all three antioxidant parameters with breeding lines having higher antioxidant capacity and phenolic content than some popular cultivars. Different types of melons also showed significantly different

Hatice ?elale; Hasan Ozgur S?gva; ?brahim Celik; Sami Doganlar; Anne Frary

2011-01-01

397

Cholinergic Agonists Stimulate Secretion of Soluble Full-Length Amyloid Precursor Protein in Neuroendocrine Cells  

Microsoft Academic Search

The Abeta peptide of Alzheimer disease is derived from the proteolytic processing of the amyloid precursor proteins (APP), which are considered type I transmembrane glycoproteins. Recently, however, soluble forms of full-length APP were also detected in several systems including chromaffin granules. In this report we used antisera specific for the cytoplasmic sequence of APP to show that primary bovine chromaffin

Spiros Efthimiopoulos; Dido Vassilacopoulou; James A. Ripellino; Nikolaos Tezapsidis; Nikolaos K. Robakis

1996-01-01

398

Pyrene Excimer Formation in Micelles of Ninionic Detergents and of Water-Soluble Polymers.  

National Technical Information Service (NTIS)

Pyrene excimer formation has been investigated in two nonionic micellar systems, one composed of water-soluble copolymers of poly(ethylene oxide-propylene oxide) (E/P 0.8) and one composed of surfactants of the Triton type (alkylphenol ethoxylate). The ra...

N. J. Turro P. L. Kuo

1986-01-01

399

PEPTIZATION AND COAGULATION OF ASPHALTENES IN APOLAR MEDIA USING OIL-SOLUBLE POLYMERS  

Microsoft Academic Search

The asphaltene fraction of crude oil contains a variety of acidic and basic functional groups. During oil production and transportation, changes in temperature, pressure or oil composition can cause asphaltenes to precipitate out crude oil through the flocculation among these polar functional groups. In this study, two types of oil-soluble polymers, dodecylphenolic resin and poly (octadecene maleic anhydride), were synthesized

Chia-Lu Chang; H. Scott Fogler

1996-01-01

400

CANDIDATE GENES AFFECTING SOLUBLE CARBOHYDRATE CONCENTRATIONS AND HEALTH-ENHANCING ATTRIBUTES OF ONION  

Technology Transfer Automated Retrieval System (TEKTRAN)

Onion bulbs accumulate fructans, a type of soluble dietary fiber associated with lower rates of corectal cancers. Higher fructan concentrations in bulbs are correlated with higher pungency, longer dormancy, and greater onion-induced antiplatelet activity (OIAA). We analyzed replicated field trials...

401

Investigation of the Solubility and Diffusivity of Chromium in Gallium Arsenide.  

National Technical Information Service (NTIS)

Phase equilibria in the Ga-As-Cr system have been studied and determined between room temperature and 1300 C by differential thermal analysis and x-ray diffraction. Solubility studies of Cr in GaAs have also been performed together with three types of dif...

T. J. Magee G. R. Woolhouse D. A. Stevensen M. Deal

1984-01-01

402

Biorelevant solubility of poorly soluble drugs: rivaroxaban, furosemide, papaverine and niflumic acid.  

PubMed

In this work the biorelevant solubility of four drugs representing different acid-base property, wide range of lipohilicity and low aqueous solubility was studied. The equilibrium solubility of rivaroxaban (non-ionizable), furosemide (acid), papaverine (base) and niflumic acid (ampholyte) was determined in simulated gastric fluid (SGF pH 1.2), in simulated intestinal fluid fasted state (FaSSIF pH 6.5) and fed state (FeSSIF pH 5.0) and their corresponding blank buffers at a temperature of 37 °C using saturation shake-flask method. The concentration was measured by optimized HPLC analysis. The solubilizing effect of bile acid/lipid micelles as additive components of biorelevent media (BRM) is expressed with the solubility ratio (SR: SBRM/Sblank buffer) and the food effect was estimated from SFeSSIF/SFaSSIF coefficient. It was revealed that ionization plays primarily role in solubility of compounds which undergo ionization in BRM. The solubilizing effect in FaSSIF was marginal for the neutral compound (rivaroxaban) and for molecules are anionic at pH 6.5 (furosemide and niflumic acid). The higher concentration of solubilizing agents in FeSSIF improved the solubility of papaverine carrying positive charge and niflumic acid being partially zwitterionic at pH 5.0. PMID:23770783

Takács-Novák, Krisztina; Sz?ke, Vera; Völgyi, Gergely; Horváth, Péter; Ambrus, Rita; Szabó-Révész, Piroska

2013-05-18

403

Solubility Diagram of a Fullerenol-d-NaCl-H2O System at 25°C  

NASA Astrophysics Data System (ADS)

Solubility in a ternary fullerenol-d-NaCl-H2O system is studied at 25°C with the use of isothermal saturation. It is established that the solubility diagram is composed of two branches that are responsible for the crystallization of fullerenol-d crystallohydrate and anhydrous sodium chloride, and it contains one invariant eutonic-type point that corresponds to cosaturation by the above two solid phases. The so-called salting-out effect was observed on the branch of the crystallization of fullerenol-d, while salting in was observed on the branch of the crystallization of sodium chloride.

Semenov, K. N.; Charykov, N. A.

2012-10-01

404

Glucose and insulin responses to whole grain breakfasts varying in soluble fiber, ?-glucan  

Microsoft Academic Search

Background  A high intake of whole grains containing soluble fiber has been shown to lower glucose and insulin responses in overweight\\u000a humans and humans with type 2 diabetes.\\u000a \\u000a \\u000a \\u000a Aim of the study  We investigated the linearity of this response after consumption of 5 breakfast cereal test meals containing wheat and\\/or\\u000a barley to provide varying amounts of soluble fiber, ?-glucan (0, 2.5, 5,

Hyunsook Kim; Kim S. Stote; Kay M. Behall; Karen Spears; Bryan Vinyard; Joan M. Conway

2009-01-01

405

Properties of spores of Bacillus subtilis strains which lack the major small, acid-soluble protein  

SciTech Connect

Bacillus subtilis strains containing a deletion in the gene coding for the major small, acid-soluble, spore protein (SASP-gamma) grew and sporulated, and their spores initiated germination normally, but outgrowth of SASP-gamma- spores was significantly slower than that of wild-type spores. The absence of SASP-gamma had no effect on spore protoplast density or spore resistance to heat or radiation. Consequently, SASP-gamma has a different function in spores than do the other major small, acid-soluble proteins.

Hackett, R.H.; Setlow, P.

1988-03-01

406

Soluble oligomerization provides a beneficial fitness effect on destabilizing mutations  

PubMed Central

Mutations create the genetic diversity on which selective pressures can act, yet also create structural instability in proteins. How, then, is it possible for organisms to ameliorate mutation-induced perturbations of protein stability while maintaining biological fitness and gaining a selective advantage? Here we used site-specific chromosomal mutagenesis to introduce a selected set of mostly destabilizing mutations into folA—an essential chromosomal gene of Escherichia coli encoding dihydrofolate reductase (DHFR)—to determine how changes in protein stability, activity, and abundance affect fitness. In total, 27 E. coli strains carrying mutant DHFR were created. We found no significant correlation between protein stability and its catalytic activity nor between catalytic activity and fitness in a limited range of variation of catalytic activity observed in mutants. The stability of these mutants is strongly correlated with their intracellular abundance, suggesting that protein homeostatic machinery plays an active role in maintaining intracellular concentrations of proteins. Fitness also shows a significant correlation with intracellular abundance of soluble DHFR in cells growing at 30?°C. At 42?°C, the picture was mixed, yet remarkable: A few strains carrying mutant DHFR proteins aggregated, rendering them nonviable, but, intriguingly, the majority exhibited fitness higher than wild type. We found that mutational destabilization of DHFR proteins in E. coli is counterbalanced at 42?°C by their soluble oligomerization, thereby restoring structural stability and protecting against aggregation.

Bershtein, Shimon; Wu, Wanmeng; Shakhnovich, Eugene I.

2012-01-01

407

Preparation of soluble proteins from Escherichia coli.  

PubMed

Purification of human IL-1beta is used in this unit as an example of the preparation of soluble proteins from E. coli. Bacteria containing IL-1beta are lysed, and IL-1 beta in the resulting supernatant is purified by anion-exchange chromatography, salt precipitation and cation-exchange chromatography, and then concentrated. Finally, the IL-1 beta protein is applied to a gel-filtration column to separate it from remaining higher- and lower-molecular-weight contaminants, the purified protein is stored frozen or is lyophilized. The purification protocol described is typical for a protein that is expressed in fairly high abundance (i.e., >5% total protein) and accumulates in a soluble state. PMID:18429289

Wingfield, Paul T

2005-09-01

408

Soluble catalysts for improved Pschorr cyclizations  

SciTech Connect

Several improved catalysts for the Pschorr phenanthrene synthesis have been discovered; all are soluble substances which initiate free-radical reactions by electron donation and thereby shorten the reaction time and increase the yield. One technique with K{sub 4}Fe(CN){sub 6} in water produced phenanthrene-9-carboxylic acid (6a) in 87% yield, but its application did not extend to substituted examples where the diazonium salt is less soluble in water. A more general procedure with ferrocene in acetone produced not only 6a but also substituted examples 6b-f in yields of 88-94%. A modification which avoids the isolation of diazonium salts was developed for occasional synthetic use. 3 tabs.

Wassmundt, F.W.; Kiesman, W.F. [Univ. of Connecticut, Storrs, CT (United States)

1995-01-13

409

Oil soluble antioxidant polymetharylates for lubricants  

SciTech Connect

The evaluation of oil soluble, antioxidant bound polymethacrylates used as viscosity index improver lubricant additives, is described herein. They were synthesized by copolymerization of the antioxidant-dispersant monomer and alkyl methacrylates. Oxidative stability was determined by oxidative pressure differential scanning calorimetry, thin film oxidation uptake test and aluminum beaker oxidation text. These tests show that lubricants containing these polymers show performance advantages over commercial polymethacrylates, with additional benefits in other viscometric properties such as shear stability and Brookfield viscosity. The antioxidant monomer also serves as a dispersant moiety, thus improving the polymer disperancy. Binding the antioxidant to the polymer ensures the solubility of the antioxidant while eliminating the possibility of its volatilization in high temperature environments. The current results suggest that antioxidant-dispersant polymethacrylates have excellent potential as additives in lubricants such as automatic transmission fluids. 13 refs., 5 figs., 3 tabs.

Shirodkar, S.M.; Benfaremo, N. [Texaco Additive Company, Beacon, NY (United States); Skarlos, L. [Texaco Research and Development, Port Arthur, TX (United States)

1994-08-01

410

Lymphocyte subset, lymphocyte proliferative response, and soluble interleukin-2 receptor in anorexic patients  

Microsoft Academic Search

Background: Despite a prominent malnourished state, anorexics are unexpectedly free from infection. Several studies have shown that the cell-mediated immunity of anorexics might be well preserved, but results are conflicting.Methods: Lymphocyte subsets, lymphoproliferative response to phytohemagglutinin, and soluble interleukin-2 receptor (sIL-2R) were measured in 7 patients with anorexia nervosa restricting type (RAN), 6 with anorexia nervosa binge-eating\\/purging type (ANBP), and

Toshihiko Nagata; Nobuo Kiriike; Wataru Tobitani; Youjirou Kawarada; Hisato Matsunaga; Sakae Yamagami

1999-01-01

411

Serum levels of soluble interleukin-2 receptors in acute and chronic viral hepatitis  

Microsoft Academic Search

To analyze interleukin-2-dependent immunoregulatory function in hepatitis B virus infection and in other forms of viral hepatitis, levels of soluble interleukin-2 receptors (sIL-2R) were measured by an enzyme-linked assay in sera from patients with acute and chronic viral hepatitis of different etiology. Increased sIL-2R levels were detected in the early phase of acute hepatitis type A and type B, but

Alfredo Alberti; Liliana Chemello; Giovanna Fattovich; Patrizia Pontisso; Giampietro Semenzato; Cosimo Colletta; Fabrizio Vinante; Giovanni Pizzol