Lactoferrin from Camelus dromedarius Inhibits Nuclear Transcription Factor-kappa B Activation, Cyclooxygenase-2 Expression and Prostaglandin E2 Production in Stimulated Human Chondrocytes.

PubMed

Rasheed, Naila; Alghasham, Abdullah; Rasheed, Zafar

2016-01-01

Osteoarthritis (OA) is a progressive joint disorder, which remains the leading cause of chronic disability in aged people. Nuclear factor-kappa B (NF)-κB is a major cellular event in OA and its activation by interleukin-1β (IL-1β) plays a critical role in cartilage breakdown in these patients. In this study, we examined the effect of lactoferrin on NF-κB activation, cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production in stimulated human articular chondrocytes. Human chondrocytes were derived from OA articular cartilage and treated with camel lactoferrin and then stimulated with IL-1β. Gene expression was determined by TaqMan assays and protein expression was studied by Western immunoblotting. NF-κB activity and PGE2 levels were determined by ELISA based assays. NF-κB activity was also determined by treatment of chondrocytes with NF-κB specific inhibitor Bay 11-7082. Lactoferrin inhibited IL-1β-induced activation and nuclear translocation of NF-κB p65 in human OA chondrocytes. Lactoferrin also inhibited mRNA/protein expression of COX-2 and production of PGE2. Moreover, Bay 11-7082 also inhibited IL-1β-induced expression of COX-2 and production of PGE2. The inhibitory effect of lactoferrin on the IL-1β induced expression of COX-2 or production of PGE2 was mediated at least in part via suppression of NF-κB activation. Our data determine camel lactoferrin as a novel inhibitor of IL-1β-induced activation of NF-κB signaling events and production of cartilage-degrading molecule PGE2 via inhibition of COX-2 expressions. These results may have important implications for the development of novel therapeutic strategies for the prevention/treatment of OA and other degenerative/inflammatory diseases. Lactoferrin shows anti-arthritic activity in IL-1β stimulated primary human chondrocytes.Lactoferrin inhibits IL-1β-induced NF-κB activation.Lactoferrin inhibits production of cartilage degrading PGE2 via inhibition of COX-2 expression. Abbreviations Used: OA: Osteoarthritis IL-1β: Interleukin-1 beta NF-κB: Nuclear factor-kappa B COX-2: cyclooxygenase-2 PGE2: prostaglandin E2.

Identification of anti-proliferative kinase inhibitors as potential therapeutic agents to treat canine osteosarcoma.

PubMed

Mauchle, Ulrike; Selvarajah, Gayathri T; Mol, Jan A; Kirpensteijn, Jolle; Verheije, Monique H

2015-08-01

Osteosarcoma is the most common primary bone tumour in dogs but various forms of therapy have not significantly improved clinical outcomes. As dysregulation of kinase activity is often present in tumours, kinases represent attractive molecular targets for cancer therapy. The purpose of this study was to identify novel compounds targeting kinases with the potential to induce cell death in a panel of canine osteosarcoma cell lines. The ability of 80 well-characterized kinase inhibitor compounds to inhibit the proliferation of four canine osteosarcoma cell lines was investigated in vitro. For those compounds with activity, the mechanism of action and capability to potentiate the activity of doxorubicin was further evaluated. The screening showed 22 different kinase inhibitors that induced significant anti-proliferative effects across the four canine osteosarcoma cell lines investigated. Four of these compounds (RO 31-8220, 5-iodotubercidin, BAY 11-7082 and an erbstatin analog) showed significant cell growth inhibitory effects across all cell lines in association with variable induction of apoptosis. RO 31-8220 and 5-iodotubercidin showed the highest ability to potentiate the effects of doxorubicin on cell viability. In conclusion, the present study identified several potent kinase inhibitors targeting the PKC, CK1, PKA, ErbB2, mTOR and NF-κB pathways, which may warrant further investigations for the treatment of osteosarcoma in dogs. Copyright © 2014 Elsevier Ltd. All rights reserved.

The Role of IKKβ in Venezuelan Equine Encephalitis Virus Infection

PubMed Central

Amaya, Moushimi; Voss, Kelsey; Sampey, Gavin; Senina, Svetlana; de la Fuente, Cynthia; Mueller, Claudius; Calvert, Valerie; Kehn-Hall, Kylene; Carpenter, Calvin; Kashanchi, Fatah; Bailey, Charles; Mogelsvang, Soren; Petricoin, Emanuel; Narayanan, Aarthi

2014-01-01

Venezuelan equine encephalitis virus (VEEV) belongs to the genus Alphavirus, family Togaviridae. VEEV infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the NF-κB cascade in the in vivo pathology. Initial studies indicated that at early time points of VEEV infection, the NF-κB complex was activated in cells infected with the TC-83 strain of VEEV. One upstream kinase that contributes to the phosphorylation of p65 is the IKKβ component of the IKK complex. Our previous studies with Rift valley fever virus, which exhibited early activation of the NF-κB cascade in infected cells, had indicated that the IKKβ component underwent macromolecular reorganization to form a novel low molecular weight form unique to infected cells. This prompted us to investigate if the IKK complex undergoes a comparable macromolecular reorganization in VEEV infection. Size-fractionated VEEV infected cell extracts indicated a macromolecular reorganization of IKKβ in VEEV infected cells that resulted in formation of lower molecular weight complexes. Well-documented inhibitors of IKKβ function, BAY-11-7082, BAY-11-7085 and IKK2 compound IV, were employed to determine whether IKKβ function was required for the production of infectious progeny virus. A decrease in infectious viral particles and viral RNA copies was observed with inhibitor treatment in the attenuated and virulent strains of VEEV infection. In order to further validate the requirement of IKKβ for VEEV replication, we over-expressed IKKβ in cells and observed an increase in viral titers. In contrast, studies carried out using IKKβ−/− cells demonstrated a decrease in VEEV replication. In vivo studies demonstrated that inhibitor treatment of TC-83 infected mice increased their survival. Finally, proteomics studies have revealed that IKKβ may interact with the viral protein nsP3. In conclusion, our studies have revealed that the host IKKβ protein may be critically involved in VEEV replication. PMID:24586253

Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages

PubMed Central

Kim, Seung-Jae; Cha, Ji-Young; Kang, Hye Suk; Lee, Jae-Ho; Lee, Ji Yoon; Park, Jae-Hyung; Bae, Jae-Hoon; Song, Dae-Kyu; Im, Seung-Soon

2016-01-01

Corosolic acid (CA), a triterpenoid compound isolated from Lagerstroemia speciosa L. (Banaba) leaves, exerts anti-inflammatory effects by regulating phosphorylation of interleukin receptor- associated kinase (IRAK)-2 via the NF-κB cascade. However, the protective effect of CA against endotoxic shock has not been reported. LPS (200 ng/mL, 30 min) induced phosphorylation of IRAK-1 and treatment with CA (10 μM) significantly attenuated this effect. In addition, CA also reduced protein levels of NLRP3 and ASC which are the main components of the inflammasome in BMDMs. LPS-induced inflammasome assembly through activation of IRAK-1 was down-regulated by CA challenge. Treatment with Bay11-7082, an inhibitor of IκB-α, had no effect on CA-mediated inhibition of IRAK-1 activation, indicating that CA-mediated attenuation of IRAK-1 phosphorylation was independent of NF-κB signaling. These results demonstrate that CA ameliorates acute inflammation in mouse BMDMs and CA may be useful as a pharmacological agent to prevent acute inflammation. [BMB Reports 2016; 49(5): 276-281] PMID:26615974

An essential role for the Id1/PI3K/Akt/NFkB/survivin signalling pathway in promoting the proliferation of endothelial progenitor cells in vitro.

PubMed

Li, Wei; Wang, Hang; Kuang, Chun-Yan; Zhu, Jin-Kun; Yu, Yang; Qin, Zhe-Xue; Liu, Jie; Huang, Lan

2012-04-01

The enhancement of re-endothelialisation is a critical therapeutic option for repairing injured blood vessels. Endothelial progenitor cells (EPCs) are the major source of cells that participate in endothelium repair and contribute to re-endothelialisation by reducing neointima formation after vascular injury. The over-expression of the inhibitor of differentiation or DNA binding 1 (Id1) significantly improved EPC proliferation. This study aimed to investigate the effects of Id1 on the phosphatidylinositol-3-kinase (PI3K)/Akt/nuclear factor kappa B (NFκB)/survivin signalling pathway and its significance in promoting EPC proliferation in vitro. Spleen-derived EPCs were cultured as previously described. Id1 was presented at low levels in EPCs, and was rapidly up-regulated by stimulation with vascular endothelial growth factor. We demonstrated that transient transfection of Id1 into EPCs activated the PI3K/Akt/NFκB/survivin signalling pathway and promoted EPC proliferation. The proliferation of EPCs was extensively inhibited by silencing of endogenous Id1, and knockdown of Id1 expression led to suppression of PI3K/Akt/NFκB/survivin signalling pathway in EPCs. In addition, blockade by the PI3K-specific inhibitor LY294002, Akt inhibitor, the NFκB inhibitor BAY 11-7082, the survivin inhibitor Curcumin, or the survivin inhibitor YM155 reduced the effects of Id1 transfection. These results suggest that the Id1/PI3K/Akt/NFκB/survivin signalling pathway plays a critical role in EPC proliferation. The Id1/PI3K/Akt/NFκB/survivin signalling pathway may represent a novel therapeutic target in the prevention of restenosis after vascular injury.

Pioglitazone inhibits advanced glycation end product-induced matrix metalloproteinases and apoptosis by suppressing the activation of MAPK and NF-κB.

PubMed

Zhang, Hai-Bin; Zhang, Ying; Chen, Cheng; Li, Yu-Qing; Ma, Chi; Wang, Zhao-Jun

2016-10-01

Apoptosis and degeneration coming mainly from chondrocytes are important mechanisms in the onset and progression of osteoarthritis. Specifically, advanced glycation end products (AGEs) play an important role in the pathogenesis of osteoarthritis. Pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist has a protective effect on cartilage. This study aims to evaluate the effect of pioglitazone on AGEs-induced chondrocyte apoptosis and degeneration and their underlying mechanism. The in vitro study shows that AGEs induce cleavage of caspase-3 and PARP, up-regulate MMP-13 expression, enhance chondrocyte apoptosis and down-regulate PPARγ expression in human primary chondrocytes, which is reversed by pioglitazone. Furthermore, AGEs activate phosphorylation of Erk, JNK, and p38, and pioglitazone reverses AGEs-induced phosphorylation of Erk and p38. AGEs-induced degradation of IκBα and translocation of nuclear NF-κB p65 is reversed by pioglitazone. Pretreatment of chondrocytes with SB202190 (p38 inhibitor), SP600125 (JNK inhibitor) and BAY-11-7082 (NF-κB inhibitor) inhibit AGEs-induced apoptosis and degeneration. In vivo experiments suggest that pioglitazone reverses AGEs-induced cartilage degeneration and apoptosis in a mouse model, as demonstrated by HE and Safranin O staining, immunohistochemical analyses of Type II collagen (Col II), metalloproteinases (MMPs) and caspase-3. These findings suggest that pioglitazone, a PPARγ agonist, inhibits AGEs-induced chondrocytes apoptosis and degeneration via suppressing the activation of MAPK and NF-κB.

RhoA/ROCK pathway mediates leptin-induced uPA expression to promote cell invasion in ovarian cancer cells.

PubMed

Ghasemi, Ahmad; Hashemy, Seyed Isaac; Aghaei, Mahmoud; Panjehpour, Mojtaba

2017-04-01

Previous studies have shown that leptin, an adipocyte-secreted hormone, stimulates ovarian cancer invasion. Here, we investigated the contribution of uPA in leptin-induced ovarian cancer cell invasion. The cell invasion and migration experiments were carried out using matrigel invasion and wound healing assays in ovarian cancer cell lines (OVCAR3, SKOV3and CaoV-3). The mechanism underlying the invasive effect of leptin was examined using cell transfection with Ob-Rb siRNA, pre-treatment with a specific inhibitor of RhoA and ROCK, RhoA activation assay, OB-Rb, Rock and upA protein expression. Our results show that leptin induced ovarian cancer cell invasion via up-regulating upA in a time and dose-dependent manner, which was attenuated using knockdown of OB-Rb by siRNA. Moreover, pre-incubation with C3 (inhibitor of RhoA) and Y-27632 (inhibitor of ROCK) effectively attenuated leptin-induced upA expression and inhibited invasive ability of ovarian cancer cells. We also found that pretreatment with inhibitors of PI3K/AKT (LY294002), JAK/STAT (AG490) and NF-kB (BAY 11-7082) significantly reduced leptin-induced upA expression. Collectively, our findings demonstrate that OB-Rb, RhoA/ROCK, PI3K/AKT, JAK/STAT pathways and NF-kB activation are involved in leptin-induced upA expression. These results may provide a new mechanism that facilitates leptin-induced ovarian cancer invasion. Copyright © 2017 Elsevier Inc. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saji, Chiaki; Higashi, Chizuka; Niinaka, Yasufumi

Highlights: Black-Right-Pointing-Pointer Constitutive NF-{kappa}B signaling is essential for the survival and growth of PEL cells. Black-Right-Pointing-Pointer NF-{kappa}B signaling is upregulated by the proteasome-dependent degradation of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress NF-{kappa}B signaling and induce apoptosis in PEL cells through stabilization of I{kappa}B{alpha}. Black-Right-Pointing-Pointer Proteasome inhibitors suppress viral replication in PEL cells during lytic KSHV infection. -- Abstract: Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi's sarcoma-associated herpesvirus (KSHV). This study provides evidence that proteasomal activity is required for both survival of PEL cells stably harboring the KSHV genome and viral replication of KSHV. We evaluated the cytotoxicmore » effects of proteasome inhibitors on PEL cells. The proteasome inhibitors MG132, lactacystin, and proteasome inhibitor I dramatically inhibited cell proliferation and induced apoptosis of PEL cells through the accumulation of p21 and p27. Furthermore, proteasome inhibitors induced the stabilization of NF-{kappa}B inhibitory molecule (I{kappa}B{alpha}) and suppressed the transcriptional activity of NF-{kappa}B in PEL cells. The NF-{kappa}B specific inhibitor BAY11-7082 also induced apoptosis in PEL cells. The constitutive activation of NF-{kappa}B signaling is essential for the survival and growth of B cell lymphoma cells, including PEL cells. NF-{kappa}B signaling is upregulated by proteasome-dependent degradation of I{kappa}B{alpha}. The suppression of NF-{kappa}B signaling by proteasome inhibitors may contribute to the induction of apoptosis in PEL cells. In addition, proteasome activity is required for KSHV replication in KSHV latently infected PEL cells. MG132 reduced the production of progeny virus from PEL cells at low concentrations, which do not affect PEL cell growth. These findings suggest that proteasome inhibitors may represent a novel strategy for the treatment of KSHV infection and KSHV-associated lymphomas.« less

[Mechanism of TNF-α in bone defect of chronic apical periodontitis].

PubMed

Yu, Ya-Qiong; Qu, Liu; Qiu, Li-Hong; Guo, Jia-Jie; Ma, Nan; Zhu, Li

2016-08-01

To investigate the effect of lipopolysaccharides(LPS) extracted from Porphyromonas endodontalis(P.e) on the expression of tumor necrosis factor-α(TNF-α) mRNA in MC3T3-E1 cells and the role of NF-κB signaling on the expression of macrophage colony stimulating factor (M-CSF) induced by TNF-α in MC3T3-El cells． METHODS: MC3T3-E1 cells were treated with different concentrations of P.e-LPS(0-50 mg/L) and 10 mg/L P.e-LPS for different time (0-24 h). The expression of TNF-α mRNA was detected by reverse transcription polymerase chain reaction(RT-PCR). MC3T3-E1 cells were treated with different concentrations of TNF-α(0-10 ng/L) for 6 h. The expression of M-CSF mRNA and protein was detected by RT-PCR and enzyme-linked immunoadsordent assay(ELISA).The expression of M-CSF protein was also detected in 10 ng/L TNF-α treated MC3T3-E1 cells after pretreated with BAY 11-7082 for 1 h, a special NF-κB inhibitor . Statistical analysis was performed using Multi-way ANOVA and Dunnett t test with SPSS 13.0 software package. The level of TNF-α mRNA increased significantly after treatment with different concentrations of P.e-LPS(0-50 mg/L)，which indicated that P.e-LPS induced osteoblasts to express TNF-α mRNA in dose dependent manners. Maximal induction of TNF-α mRNA expression was seen in the MC3T3-E1 cells treated with 10 mg/L P.e-LPS for 6 h. After 6 h, the expression of TNF-α mRNA decreased gradually .The expression of M-CSF mRNA and protein was increased in a does- dependent manner by different concentrations of TNF-α treatment（0-10 ng/L）. The expression of M-CSF protein increased from (37±2) ng/L(control group) to (301±8) ng/L(10 ng/L group).The protein of M-CSF decreased significantly after pretreatment with 10 μmol/L BAY 11-7082 for 1 h, and the expression of M-CSF proteins was reduced from (253±14) ng/L to (154±2) ng/L .BAY group had no significant difference from the control group. The expression of TNF-α mRNA was increased by P. endodontalis LPS treatment in osteoblast. TNF-α may induce the expression of M-CSF in MC3T3-E1 cells through the signaling of NF-κB. It suggests that TNF-α affect osteoblasts through autocrine way for bone destruction in chronic apical periodontitis induced by P.e-LPS.

Neuronal injury-induced expression and release of apolipoprotein E in mixed neuron/glia co-cultures: nuclear factor kappaB inhibitors reduce basal and lesion-induced secretion of apolipoprotein E.

PubMed

Petegnief, V; Saura, J; de Gregorio-Rocasolano, N; Paul, S M

2001-01-01

In order to better delineate the intracellular signaling pathways underlying glial apolipoprotein E (apoE) expression and release, we have characterized an in vitro model of induction of glial apoE production induced by neuronal death. Exposure of mixed fetal cortical neuron/glia co-cultures to the neurotoxin N-methyl-D-aspartate results in increased apoE expression and release in a time- and concentration-dependent manner. Increased expression of apoE messenger RNA precedes the increase in intracellular apoE, followed by accumulation of the holoprotein in the culture medium. Neuronal injury induced by N-methyl-D-aspartate is accompanied by a reactive astrogliosis as measured by an increase in glial fibrillary acidic protein messenger RNA and protein at 48 and 72h post-lesion, respectively. A similar microgliosis was observed using the microglial marker ED-1. Neuronal injury-induced glial apoE secretion is attenuated by the nuclear factor kappaB inhibitors, aspirin, Bay 11-7082 and MG-132, suggesting that this transcription factor is involved in both constitutive and induced glial apoE expression. The present data show that up-regulation of apoE is an early event in the glial activation triggered by neurodegeneration in vitro and that activation of nuclear factor kappaB directly or indirectly mediates the increase in apoE expression.

TNF-α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent β-catenin activation.

PubMed

Wang, Haibo; Han, Xiaokun; Wittchen, Erika S; Hartnett, M Elizabeth

2016-01-01

Inflammation, oxidative stress, and angiogenesis have been proposed to interact in age-related macular degeneration. It has been postulated that external stimuli that cause oxidative stress can increase production of vascular endothelial growth factor (VEGF) in retinal pigment epithelial (RPE) cells. In this study, we tested the hypothesis that the inflammatory cytokine, tumor necrosis factor alpha (TNF-α), contributed to choroidal neovascularization (CNV) by upregulating VEGF in RPE through intracellular reactive oxygen species (ROS)-dependent signaling and sought to understand the mechanisms involved. In a murine laser-induced CNV model, 7 days after laser treatment and intravitreal neutralizing mouse TNF-α antibody or isotype immunoglobulin G (IgG) control, the following measurements were made: 1) TNF-α protein and VEGF protein in RPE/choroids with western blot, 2) CNV volume in RPE/choroidal flatmounts, and 3) semiquantification of oxidized phospholipids stained with E06 antibody within CNV with immunohistochemistry (IHC). In cultured human RPE cells treated with TNF-α or PBS control, 1) ROS generation was measured using the 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence assay, and 2) NOX4 protein and VEGF protein or mRNA were measured with western blot or quantitative real-time PCR in cells pretreated with apocynin or nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, VAS 2870, or transfected with p22phox siRNA, and each was compared to its appropriate control. Western blots of phosphorylated p65 (p-p65), total p65 and β-actin, and quantitative real-time PCR of VEGF mRNA were measured in human RPE cells treated with TNF-α and pretreatment with the nuclear factor kappa B inhibitor, Bay 11-7082 or control. Western blots of β-catenin, VEGF, and p22phox and coimmunoprecipitation of β-catenin and T-cell transcriptional factor were performed in human RPE cells treated with TNF-α following pretreatment with β-catenin transcriptional inhibitors, XAV939 or JW67, or transfection with p22phox siRNA and compared to appropriate controls. Compared to the non-lasered control, TNF-α and VEGF protein were increased in the RPE/choroids in a murine laser-induced CNV model (p<0.05). An intravitreal neutralizing antibody to mouse TNF-α reduced CNV volume, and VEGF protein in the RPE/choroids (p<0.01) and oxidized phospholipids within CNV compared to IgG control (p<0.05). In cultured RPE cells and compared to controls, TNF-α induced ROS generation and increased activation of NOX4, an isoform of NADPH oxidase; both were prevented by pretreatment with the apocynin or VAS2870 or knockdown of p22phox, a subunit of NADPH oxidase. TNF-α treatment increased VEGF expression (p<0.001) and the formation of a transcriptional complex of β-catenin and T-cell transcriptional factor; both were prevented by pretreatment with apocynin or knockdown of p22phox. Inhibition of β-catenin by XAV939, but not the nuclear factor kappa B inhibitor, Bay 11-7082, prevented TNF-α-induced VEGF upregulation. Our results support the thinking that TNF-α contributes to CNV by upregulating VEGF production in RPE cells through ROS-dependent activation of β-catenin signaling. These results provide mechanisms of crosstalk between inflammatory mediator, TNF-α, and ROS in RPE cells.

Astragalus polysaccharides inhibits PCV2 replication by inhibiting oxidative stress and blocking NF-κB pathway.

PubMed

Xue, Hongxia; Gan, Fang; Zhang, Zheqian; Hu, Junfa; Chen, Xingxiang; Huang, Kehe

2015-11-01

Porcine circovirus type 2 (PCV2) is the primary causative agent of porcine circovirus-associated disease (PCVAD). Astragalus polysaccharide (APS), as one kind of biological macromolecule extracted from Astragalus, has antiviral activities. This study was undertaken to explore the effect of APS on PCV2 replication in vitro and the underlying mechanisms. Our results showed that adding APS before PCV2 infection decreased significantly PCV2 DNA copies, the number of infected cells, MDA level, ROS level and NF-κB activation in PK15 cells and increased significantly GSH contents and SOD activity compared to control without APS. Oxidative stress induced by BSO could eliminate the effect of PCV2 replication inhibition by APS. LPS, as a NF-κB activator, could attenuate the effect of PCV2 replication inhibition by APS. BAY 11-7082, as a NF-κB inhibitor, could increase the effect of PCV2 replication inhibition by APS. In conclusion, APS inhibits PCV2 replication by decreasing oxidative stress and the activation of NF-κB signaling pathway, which suggests that APS might be employed for the prevention of PCV2 infection. Copyright © 2015 Elsevier B.V. All rights reserved.

[Effects of Porphyromonas endodontalis lipopolysaccharides on the expression of matrix metalloproteinase-9 in mouse osteoblasts].

PubMed

Li, X L; Yu, Y Q; Qiu, L H; Yang, D; Wang, X M; Yu, J T

2017-08-09

Objective: To evaluate the effects of lipopolysaccharides (LPS) extracted from Porphyromonas endodontalis (Pe) on the expression of matrix metalloproteinase-9 (MMP-9) mRNA and protein as well as enzyme activity in MC3T3-E1 cells and the role of nuclear factor-κB (NF-κB) in the process, so as to investigate the expression of MMP-9 dependent signaling pathways in mouse osteoblasts induced by Pe LPS. Methods: The experiment was conducted in 3 sessions: MC3T3-E1 cells were treated with various concentrations of Pe LPS (0-20 mg/L) and 10 mg/L Pe LPS for different time intervals (0-48 h). The expression of MMP-9 mRNA and protein were detected by real-time reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), while the enzyme activity was detected by gelatin zymography method. The expression of MMP-9 mRNA was also detected in 10 mg/L Pe LPS treated MC3T3-El cells after pretreated with specific NF-κB inhibitor BAY 11-7082 for l h. Statistical analysis was performed using one-way ANOVA and Dunnett t test with SPSS 13.0 software package. Results: The levels of MMP-9 mRNA and protein increased significantly after the treatment with various concentrations of Pe LPS (0-20 mg/L), which indicated that Pe LPS induced osteoblasts to express MMP-9 in dose dependent manners. The expression of MMP-9 protein increased from (5 395±362) ng/L (blank control group) to (12 684±375) ng/L (20 mg/L group). Maximal induction of MMP-9 mRNA expression was found in the MC3T3-E1 cells treated with 10 mg/L Pe LPS for 24 h. The expression of MMP-9 mRNA in the 20 mg/L group was about 7 times than that in the blank control group. After 24 h, the expression of MMP-9 mRNA decreased. Maximal expression of MMP-9 protein was found in the MC3T3-E1 cells treated with 10 mg/L Pe LPS for 48 h ([35 055±2 346] ng/L) showing the highest enzyme activity. The mRNA of MMP-9 decreased significantly after pretreatment with 10 µmol/L BAY 11-7082 for 1 h. Conclusions: Pe LPS might induce the expression of MMP-9 in MC3T3-E1 cells through the signaling of NF-κB.

Jaceosidin, a natural flavone, promotes angiogenesis via activation of VEGFR2/FAK/PI3K/AKT/NF-κB signaling pathways in endothelial cells.

PubMed

Lee, Tae Hoon; Jung, Hana; Park, Keun Hyung; Bang, Myun Ho; Baek, Nam-In; Kim, Jiyoung

2014-10-01

Angiogenesis, the growth of new blood vessels from pre-existing vasculature, plays an important role in physiological and pathological processes such as embryonic development wound healing and revascularization of tissues after exposure to ischemia. We investigated the effects of jaceosidin, a main constituent of medicinal herbs of the genus Artemisia, on angiogenesis and signaling pathways in endothelial cells. Jaceosidin stimulated proliferation, migration and tubulogenesis of ECs as well as ex vivo sprouting from aorta rings, which are phenomena typical of angiogenesis. Jaceosidin activated vascular endothelial growth factor receptor 2 (VEGFR2, FLk-1/KDR) and angiogenic signaling molecules such as focal adhesion kinase, phosphatidylinositol 3-kinase, and its downstream target, the serine-threonine kinase AKTWe also demonstrated that jaceosidin activated the NF-κB-driven expression of a luciferase reporter gene and NF-κB binding to DNA. Jaceosidin-induced proliferation and migration of human umbilical vascular endothelial cells were strongly inhibited by the phosphatidylinositol 3-kinase inhibitor LY294002 and NF-κB inhibitor BAY11-7082, indicating that the PI3K/AKT/NF-κB signaling pathway is involved in jaceosidin-induced angiogenesis. Our results suggest that jaceosidin stimulates angiogenesis by activating the VEGFR2/FAK/PI3K/AKT/NF-κB signaling pathway and that it may be useful in developing angiogenic agents to promote the growth of collateral blood vessels in ischemic tissues. © 2014 by the Society for Experimental Biology and Medicine.

Id-1 activation of PI3K/Akt/NFkappaB signaling pathway and its significance in promoting survival of esophageal cancer cells.

PubMed

Li, Bin; Cheung, Pak Yan; Wang, Xianghong; Tsao, Sai Wah; Ling, Ming Tat; Wong, Yong Chuan; Cheung, Annie L M

2007-11-01

Inhibitor of differentiation or DNA binding (Id-1) is a helix-loop-helix protein that is over-expressed in many types of cancer including esophageal cancer. This study aims to investigate its effects on the phosphatidylinositol-3-kinase (PI3K)/Akt/ nuclear factor kappa B (NFkappaB) signaling pathway and the significance in protecting esophageal cancer cells against apoptosis. We found elevated expression of phosphorylated forms of Akt, glycogen synthase kinase 3beta and inhibitor of kappa B, as well as increased nuclear translocation of NFkappaB subunit p65 and NFkappaB DNA-binding activity, in esophageal cancer cells with stable ectopic Id-1 expression. Transient transfection of Id-1 into HEK293 cells confirmed activation of PI3K/Akt/NFkappaB signaling and the effects were counteracted by the PI3K inhibitor LY294002. Treatment with tumor necrosis factor-alpha (TNF-alpha) elicited a significantly weaker apoptotic response, following a marked and sustained activation of Akt and NFkappaB in the Id-1-over-expressing cells, compared with the vector control. The effects of Id-1 on the PI3K/Akt/NFkappaB signaling pathway and apoptosis were reversed in esophageal cancer cells transfected with siRNA against Id-1. In addition, inhibition of PI3K or NFkappaB signaling using the PI3K inhibitor LY294002 or the NFkappaB inhibitor Bay11-7082 increased the sensitivity of Id-1-over-expressing esophageal cancer cells to TNF-alpha-induced apoptosis. Our results provide the first evidence that Id-1 induces the activation of PI3K/Akt/NFkappaB signaling pathway, and protects esophageal cancer cells from TNF-alpha-induced apoptosis in vitro. Inactivation of Id-1 may provide us with a novel strategy to improve the treatment and survival of patients with esophageal cancer.

Molecular events involved in the increased expression of matrix metalloproteinase-9 by T lymphocytes of mammary tumor-bearing mice.

PubMed

Owen, Jennifer L; Torroella-Kouri, Marta; Iragavarapu-Charyulu, Vijaya

2008-01-01

Matrix metalloproteinases (MMPs) are a family of extracellular proteinases whose contributions to cancer progression have been studied because of their matrix-degrading abilities and elevated expression in advanced stage tumors. Recent findings suggest a role for MMPs during the multiple stages of tumor progression including establishment and growth, migration, invasion, metastasis, and angiogenesis. MMP-9 regulation at the molecular level can be studied by measuring the effect(s) of a variety of physiological and pharmacological agents on cells. Multiple signaling molecules such as protein kinase C, pertussis toxin-sensitive guanine nucleotide-binding protein G, and protein tyrosine kinases are known to mediate the secretion of MMPs in cell lines. We previously reported an upregulation of MMP-9 in T cells of mammary tumor-bearing mice. In this study, pharmacologic inhibitors were used to dissect the signaling pathways involved in the upregulation of MMP-9 in the splenic T cells of normal and mammary tumor-bearing mice. Staurosporine, a protein kinase inhibitor, stimulated MMP-9 secretion by normal T lymphocytes, while the constitutively high levels of MMP-9 produced by tumor bearers' T cells were decreased by Genistein, a specific tyrosine kinase inhibitor, and Rottlerin, a PKC inhibitor. Using a NF-kappaB specific probe to the murine MMP-9 promoter, electromobility shift assays of nuclear proteins from normal and tumor bearers' splenic T cells revealed a pattern of higher intensity bands from the tumor bearers' nuclear extracts, indicating a greater amount of these transcription factors bound to the recognition motif. When mammary tumor bearers' T cells were cultured with the NF-kappaB inhibitors, N-p-Tosyl-L-lysine chloromethyl ketone hydrochloride and Bay 11-7082, there was a subsequent decreased production of MMP-9. These results suggest that the tumor burden may be activating various signaling pathways within splenic T lymphocytes to upregulate MMP-9 expression.

Nuclear factor-κB modulates osteogenesis of periodontal ligament stem cells through competition with β-catenin signaling in inflammatory microenvironments

PubMed Central

Chen, X; Hu, C; Wang, G; Li, L; Kong, X; Ding, Y; Jin, Y

2013-01-01

Inflammation can influence multipotency and self-renewal of mesenchymal stem cells (MSCs), resulting in their awakened bone-regeneration ability. Human periodontal ligament tissue-derived MSCs (PDLSCs) have been isolated, and their differentiation potential was found to be defective due to β-catenin signaling indirectly regulated by inflammatory microenvironments. Nuclear factor-κB (NF-κB) is well studied in inflammation by many different groups. The role of NF-κB needs to be studied in PDLSCs, although genetic evidences have recently shown that NF-κB inhibits osteoblastic bone formation in mice. However, the mechanism as to how inflammation leads to the modulation of β-catenin and NF-κB signaling remains unclear. In this study, we investigated β-catenin and NF-κB signaling through regulation of glycogen synthase kinase 3β activity (GSK-3β, which modulates β-catenin and NF-κB signaling) using a specific inhibitor LiCl and a phosphatidylinositol 3-kinase (PI3K) inhibitor LY 294002. We identified that NF-κB signaling might be more important for the regulation of osteogenesis in PDLSCs from periodontitis compared with β-catenin. BAY 11-7082 (an inhibitor of NF-κB) could inhibit phosphorylation of p65 and partly rescue the differentiation potential of PDLSCs in inflammation. Our data indicate that NF-κB has a central role in regulating osteogenic differentiation of PDLSCs in inflammatory microenvironments. Given the molecular mechanisms of NF-κB in osteogenic differentiation governed by inflammation, it can be said that NF-κB helps in improving stem cell-mediated inflammatory bone disease therapy. PMID:23449446

Hyperuricemia Causes Pancreatic β-Cell Death and Dysfunction through NF-κB Signaling Pathway

PubMed Central

Jia, Lu; Xing, Jing; Ding, Ying; Shen, Yachen; Shi, Xuhui; Ren, Wei; Wan, Meng; Guo, Jianjin; Zheng, Shujing; Liu, Yun; Liang, Xiubin; Su, Dongming

2013-01-01

Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid–treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid–treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11–7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis. PMID:24205181

Pertussis Toxin Exploits Host Cell Signaling Pathways Induced by Meningitis-Causing E. coli K1-RS218 and Enhances Adherence of Monocytic THP-1 Cells to Human Cerebral Endothelial Cells.

PubMed

Starost, Laura Julia; Karassek, Sascha; Sano, Yasuteru; Kanda, Takashi; Kim, Kwang Sik; Dobrindt, Ulrich; Rüter, Christian; Schmidt, Marcus Alexander

2016-10-13

Pertussis toxin (PTx), the major virulence factor of the whooping cough-causing bacterial pathogen Bordetella pertussis , permeabilizes the blood-brain barrier (BBB) in vitro and in vivo. Breaking barriers might promote translocation of meningitis-causing bacteria across the BBB, thereby facilitating infection. PTx activates several host cell signaling pathways exploited by the neonatal meningitis-causing Escherichia coli K1-RS218 for invasion and translocation across the BBB. Here, we investigated whether PTx and E. coli K1-RS218 exert similar effects on MAPK p38, NF-κB activation and transcription of downstream targets in human cerebral endothelial TY10 cells using qRT-PCR, Western blotting, and ELISA in combination with specific inhibitors. PTx and E. coli K1-RS218 activate MAPK p38, but only E. coli K1-RS218 activates the NF-κB pathway. mRNA and protein levels of p38 and NF-κB downstream targets including IL-6, IL-8, CxCL-1, CxCL-2 and ICAM-1 were increased. The p38 specific inhibitor SB203590 blocked PTx-enhanced activity, whereas E. coli K1-RS218's effects were inhibited by the NF-κB inhibitor Bay 11-7082. Further, we found that PTx enhances the adherence of human monocytic THP-1 cells to human cerebral endothelial TY10 cells, thereby contributing to enhanced translocation. These modulations of host cell signaling pathways by PTx and meningitis-causing E. coli support their contributions to pathogen and monocytic THP-1 cells translocation across the BBB.

Pertussis Toxin Exploits Host Cell Signaling Pathways Induced by Meningitis-Causing E. coli K1-RS218 and Enhances Adherence of Monocytic THP-1 Cells to Human Cerebral Endothelial Cells

PubMed Central

Starost, Laura Julia; Karassek, Sascha; Sano, Yasuteru; Kanda, Takashi; Kim, Kwang Sik; Dobrindt, Ulrich; Rüter, Christian; Schmidt, Marcus Alexander

2016-01-01

Pertussis toxin (PTx), the major virulence factor of the whooping cough-causing bacterial pathogen Bordetella pertussis, permeabilizes the blood–brain barrier (BBB) in vitro and in vivo. Breaking barriers might promote translocation of meningitis-causing bacteria across the BBB, thereby facilitating infection. PTx activates several host cell signaling pathways exploited by the neonatal meningitis-causing Escherichia coli K1-RS218 for invasion and translocation across the BBB. Here, we investigated whether PTx and E. coli K1-RS218 exert similar effects on MAPK p38, NF-κB activation and transcription of downstream targets in human cerebral endothelial TY10 cells using qRT-PCR, Western blotting, and ELISA in combination with specific inhibitors. PTx and E. coli K1-RS218 activate MAPK p38, but only E. coli K1-RS218 activates the NF-κB pathway. mRNA and protein levels of p38 and NF-κB downstream targets including IL-6, IL-8, CxCL-1, CxCL-2 and ICAM-1 were increased. The p38 specific inhibitor SB203590 blocked PTx-enhanced activity, whereas E. coli K1-RS218’s effects were inhibited by the NF-κB inhibitor Bay 11-7082. Further, we found that PTx enhances the adherence of human monocytic THP-1 cells to human cerebral endothelial TY10 cells, thereby contributing to enhanced translocation. These modulations of host cell signaling pathways by PTx and meningitis-causing E. coli support their contributions to pathogen and monocytic THP-1 cells translocation across the BBB. PMID:27754355

Cardiac-specific overexpression of catalase prevents diabetes-induced pathological changes by inhibiting NF-κB signaling activation in the heart.

PubMed

Cong, Weitao; Ruan, Dandan; Xuan, Yuanhu; Niu, Chao; Tao, Youli; Wang, Yang; Zhan, Kungao; Cai, Lu; Jin, Litai; Tan, Yi

2015-12-01

Catalase is an antioxidant enzyme that specifically catabolizes hydrogen peroxide (H2O2). Overexpression of catalase via a heart-specific promoter (CAT-TG) was reported to reduce diabetes-induced accumulation of reactive oxygen species (ROS) and further prevent diabetes-induced pathological abnormalities, including cardiac structural derangement and left ventricular abnormity in mice. However, the mechanism by which catalase overexpression protects heart function remains unclear. This study found that activation of a ROS-dependent NF-κB signaling pathway was downregulated in hearts of diabetic mice overexpressing catalase. In addition, catalase overexpression inhibited the significant increase in nitration levels of key enzymes involved in energy metabolism, including α-oxoglutarate dehydrogenase E1 component (α-KGD) and ATP synthase α and β subunits (ATP-α and ATP-β). To assess the effects of the NF-κB pathway activation on heart function, Bay11-7082, an inhibitor of the NF-κB signaling pathway, was injected into diabetic mice, protecting mice against the development of cardiac damage and increased nitrative modifications of key enzymes involved in energy metabolism. In conclusion, these findings demonstrated that catalase protects mouse hearts against diabetic cardiomyopathy, partially by suppressing NF-κB-dependent inflammatory responses and associated protein nitration. Copyright © 2015 Elsevier Ltd. All rights reserved.

Poly(I:C) Induces Human Lung Endothelial Barrier Dysfunction by Disrupting Tight Junction Expression of Claudin-5

DOE PAGES

Huang, Li -Yun; Stuart, Christine; Takeda, Kazuyo; ...

2016-08-09

Viral infections are often accompanied by pulmonary microvascular leakage and vascular endothelial dysfunction via mechanisms that are not completely defined. Here, we investigated the effect of the Toll-like receptor 3 (TLR3) ligand polyinosinic-polycytidylic acid [Poly(I:C)], a synthetic analog of viral double-stranded RNA (dsRNA) commonly used to simulate viral infections, on the barrier function and tight junction integrity of primary human lung microvascular endothelial cells. Poly(I:C) stimulated IL-6, IL-8, TNFα, and IFNβ production in conjunction with the activation of NF-κB and IRF3 confirming the Poly(I:C)-responsiveness of these cells. Poly(I:C) increased endothelialmonolayer permeability with a corresponding dose- and time-dependent decrease in themore » expression of claudin-5, a transmembrane tight junction protein and reduction of CLDN5 mRNA levels. Immunofluorescence experiments revealed disappearance of membrane-associated claudin-5 and co-localization of cytoplasmic claudin-5 with lysosomal-associated membrane protein 1. Chloroquine and Bay11-7082, inhibitors of TLR3 and NF-κB signaling, respectively, protected against the loss of claudin-5. Altogether, these findings provide new insight on how dsRNA-activated signaling pathways may disrupt vascular endothelial function and contribute to vascular leakage pathologies.« less

[Effect of lipopolysaccharides from Porphyromonas endodontalis on the expression of interleukin-34 in mouse osteoblasts].

PubMed

Yu, Ya-Qiong; Guo, Jia-Jie; Qiu, Li-Hong; Li, Xiao-Lin; Yang, Di; Guo, Yan

2017-02-01

To investigate the effects of lipopolysaccharides (LPS) extracted from Porphyromonas endodontalis (P.e) on the expression of interleukin-34 (IL-34) mRNA in MC3T3-E1 cells and the role of p38MAPK, ERK1/2, NF-κB and SIRT1 in the process. MC3T3-E1 cells were treated with different concentrations of P.e-LPS(0-50 mg/L) and 20 mg/L P.e-LPS for different time (0-24 h). The expression of IL-34 mRNA was detected by real-time reverse transcription-polymerase chain reaction (real time RT-PCR). MC3T3-E1 cells were pretreated with inhibitor of NF-κB(BAY 11-7082),inhibitor of p38MAPK (SB203580), inhibitor of ERK1/2 (PD98059), agonist of sirtuin1 (SIRT1) [resveratrol (RES)] and inhibitor of SIRT1 (EX-527) for 1 h, and then were treated with 20 mg/L P.e-LPS. The expression of IL-34 mRNA was detected by real time RT-PCR. Statistical analysis was performed using one-way ANOVA and Dunnett t test with SPSS 13.0 software package. The level of IL-34 mRNA increased significantly after treatment with different concentrations of P.e-LPS(0-50 mg/L)，which indicated that P.e-LPS induced osteoblasts to express IL-34 mRNA in a dose-dependent manner. Maximal induction of IL-34 mRNA expression was observed in MC3T3-E1 cells treated with 20 mg/L P.e-LPS for 24 h.At 48 h, the expression of IL-34 mRNA decreased gradually. The mRNA of IL-34 decreased significantly after pretreatment with 10 μmol/L BAY-117082, SB203580 and PD98059 for 1 h. P.e-LPS-induced IL-34 upregulation was attenuated by pretreatment with RES, but increased by EX-527. These results suggest that P.e-LPS may mediate IL-34 mRNA expression in MC3T3-E1 cells. This process is dependent, at least in part, on p38MAPK, ERK1/2, NF-κB and SIRT1 signaling pathways.

Indoxyl Sulfate Promotes Macrophage IL-1β Production by Activating Aryl Hydrocarbon Receptor/NF-κ/MAPK Cascades, but the NLRP3 inflammasome Was Not Activated

PubMed Central

Wakamatsu, Takuya; Yamamoto, Suguru; Ito, Toru; Sato, Yoko; Matsuo, Koji; Takahashi, Yoshimitsu; Kaneko, Yoshikatsu; Goto, Shin; Kazama, Junichiro James; Gejyo, Fumitake; Narita, Ichiei

2018-01-01

In chronic kidney disease (CKD) patients, accumulation of uremic toxins is associated with cardiovascular risk and mortality. One of the hallmarks of kidney disease-related cardiovascular disease is intravascular macrophage inflammation, but the mechanism of the reaction with these toxins is not completely understood. Macrophages differentiated from THP-1 cells were exposed to indoxyl sulfate (IS), a representative uremic toxin, and changes in inflammatory cytokine production and intracellular signaling molecules including interleukin (IL)-1, aryl hydrocarbon receptor (AhR), nuclear factor (NF)-κ, and mitogen-activated protein kinase (MAPK) cascades as well as the NLRP3 inflammasome were quantified by real-time PCR, Western blot analysis, and enzyme-linked immunosorbent assay. IS induced macrophage pro-IL-1β mRNA expression, although mature IL-1 was only slightly increased. IS increased AhR and the AhR-related mRNA expression; this change was suppressed by administration of proteasome inhibitor. IS promoted phosphorylation of NF-κB p65 and MAPK enzymes; the reaction and IL-1 expression were inhibited by BAY11-7082, an inhibitor of NF-κB. In contrast, IS decreased NLRP3 and did not change ASC, pro-caspase 1, or caspase-1 activation. IS-inducing inflammation in macrophages results from accelerating AhR-NF-κB/MAPK cascades, but the NLRP3 inflammasome was not activated. These reactions may restrict mature IL-1β production, which may explain sustained chronic inflammation in CKD patients. PMID:29543732

Forskolin Inhibits Lipopolysaccharide-Induced Modulation of MCP-1 and GPR120 in 3T3-L1 Adipocytes through an Inhibition of NFκB

PubMed Central

Chiadak, Jeanne Durendale; Arsenijevic, Tatjana; Verstrepen, Kevin; Gregoire, Françoise; Bolaky, Nargis; Delforge, Valérie; Flamand, Véronique

2016-01-01

In an obese state, Toll-like receptor-4 (TLR-4) upregulates proinflammatory adipokines secretion including monocyte chemotactic protein-1 (MCP-1) in adipose tissue. In contrast, G-protein coupled receptor 120 (GPR120) mediates antiobesity effects. The aim of this study was to determine the signaling pathway by which Forskolin (FK), a cyclic adenosine monophosphate- (cAMP-) promoting agent causing positive changes in body composition in overweight and obese adult men, affects MCP-1 and GPR120 expression during an inflammatory response induced by lipopolysaccharide (LPS) in adipocytes, such as in an obese state. 3T3-L1 cells differentiated into adipocytes (DC) were stimulated with LPS in the absence or presence of FK and inhibitors of TLR-4 and inhibitor of kappa B (IκBα). In DC, LPS increased MCP-1, TLR-4, and nuclear factor-κB1 (NFκB1) mRNA levels, whereas it decreased GPR120 mRNA levels. In DC, FK inhibited the LPS-induced increase in MCP-1, TLR-4, and NFκB1 mRNA levels and the LPS-induced decrease in GPR120 mRNA. BAY11-7082 and CLI-095 abolished these LPS-induced effects. In conclusion, FK inhibits LPS-induced increase in MCP-1 mRNA levels and decrease in GPR120 mRNA levels in adipocytes and may be a potential treatment for inflammation in obesity. Furthermore, TLR-4-induced activation of NFκB may be involved in the LPS-induced regulation of these genes. PMID:27881903

Forskolin Inhibits Lipopolysaccharide-Induced Modulation of MCP-1 and GPR120 in 3T3-L1 Adipocytes through an Inhibition of NFκB.

PubMed

Chiadak, Jeanne Durendale; Arsenijevic, Tatjana; Verstrepen, Kevin; Gregoire, Françoise; Bolaky, Nargis; Delforge, Valérie; Flamand, Véronique; Perret, Jason; Delporte, Christine

2016-01-01

In an obese state, Toll-like receptor-4 (TLR-4) upregulates proinflammatory adipokines secretion including monocyte chemotactic protein-1 (MCP-1) in adipose tissue. In contrast, G-protein coupled receptor 120 (GPR120) mediates antiobesity effects. The aim of this study was to determine the signaling pathway by which Forskolin (FK), a cyclic adenosine monophosphate- (cAMP-) promoting agent causing positive changes in body composition in overweight and obese adult men, affects MCP-1 and GPR120 expression during an inflammatory response induced by lipopolysaccharide (LPS) in adipocytes, such as in an obese state. 3T3-L1 cells differentiated into adipocytes (DC) were stimulated with LPS in the absence or presence of FK and inhibitors of TLR-4 and inhibitor of kappa B (I κ B α ). In DC, LPS increased MCP-1, TLR-4, and nuclear factor- κ B1 (NF κ B1) mRNA levels, whereas it decreased GPR120 mRNA levels. In DC, FK inhibited the LPS-induced increase in MCP-1, TLR-4, and NF κ B1 mRNA levels and the LPS-induced decrease in GPR120 mRNA. BAY11-7082 and CLI-095 abolished these LPS-induced effects. In conclusion, FK inhibits LPS-induced increase in MCP-1 mRNA levels and decrease in GPR120 mRNA levels in adipocytes and may be a potential treatment for inflammation in obesity. Furthermore, TLR-4-induced activation of NF κ B may be involved in the LPS-induced regulation of these genes.

Interleukin-1beta and interleukin-6 disturb the antioxidant enzyme system in bovine chondrocytes: a possible explanation for oxidative stress generation.

PubMed

Mathy-Hartert, M; Hogge, L; Sanchez, C; Deby-Dupont, G; Crielaard, J M; Henrotin, Y

2008-07-01

Beside matrix metalloproteinases, reactive oxygen species (ROS) are the main biochemical factors of cartilage degradation. To prevent ROS toxicity, chondrocytes possess a well-coordinated enzymatic antioxidant system formed principally by superoxide dismutases (SODs), catalase (CAT) and glutathione peroxidase (GPX). This work was designed to assess the effects of interleukin (IL)-1beta and IL-6 on the enzymatic activity and gene expression of SODs, CAT and GPX in bovine chondrocytes. Bovine chondrocytes were cultured in monolayer for 4-96 h in the absence or in the presence of IL-1beta (0.018-1.8ng/ml) or IL-6 (10-100 ng/ml). To study signal transduction pathway, inhibitors of mitogen-activated protein kinases (MAPK) (PD98059, SB203580 and SP600125) (5-20 microM) and nuclear factor (NF)-kappaB inhibitors [BAY11-7082 (1-10 microM) and MG132 (0.1-10 microM)] were used. SODs, CAT and GPX enzymatic activities were evaluated in cellular extract by using colorimetric enzymatic assays. Mn SODs, Cu/Zn SOD, extracellular SOD (EC SOD), CAT and GPX gene expressions were quantified by real-time and quantitative polymerase chain reaction (PCR). Mn SOD and GPX activities were dose and time-dependently increased by IL-1beta. In parallel, IL-1beta markedly enhanced Mn SOD and GPX gene expressions, but decreased Cu/Zn SOD, EC SOD and CAT gene expressions. Induction of SOD enzymatic activity and Mn SOD mRNA expression were inhibited by NF-kappaB inhibitors but not by MAPK inhibitors. IL-6 effects were similar but weaker than those of IL-1beta. In conclusion, IL-1beta, and to a lesser extend IL-6, dysregulates enzymatic antioxidant defenses in chondrocyte. These changes could lead to a transient accumulation of H(2)O(2) in mitochondria, and consequently to mitochondria damage. These changes contribute to explain the mitochondrial dysfunction observed in osteoarthritis chondrocytes.

Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis.

PubMed

Chang, Ling-Chu; Chiang, Shih-Kai; Chen, Shuen-Ei; Yu, Yung-Luen; Chou, Ruey-Hwang; Chang, Wei-Chao

2018-03-01

Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IκBα inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-κB-independent manner. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol-containing agents, as well as iron chelation, rescued BAY-induced cell death. BAY upregulated a variety of Nrf2 target genes related to redox regulation, particularly heme oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. SLC7A11 inhibition by erastin, sulfasalazine, or shRNA interference sensitizes BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell viability. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. BAY causes compartmentalization of HO-1 into the nucleus and mitochondrion, and followed mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this study, we first discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 pathway and HO-1 is a key mediator by responding to the cellular redox status. Copyright © 2017 Elsevier B.V. All rights reserved.

Transfection of influenza A virus nuclear export protein induces the expression of tumor necrosis factor alpha.

PubMed

Lara-Sampablo, Alejandra; Flores-Alonso, Juan Carlos; De Jesús-Ortega, Nereyda; Santos-López, Gerardo; Vallejo-Ruiz, Verónica; Rosas-Murrieta, Nora; Reyes-Carmona, Sandra; Herrera-Camacho, Irma; Reyes-Leyva, Julio

2014-06-24

Influenza A virus genomic segments eight codes for non-structural 1 (NS1) protein that is involved in evasion of innate antiviral response, and nuclear export protein (NEP) that participates in the export of viral ribonucleoprotein (RNP) complexes, transcription and replication. Tumor necrosis factor alpha (TNF-α) is highly expressed during influenza virus infections and is considered an anti-infective cytokine. NS1 and NEP proteins were overexpressed and their role on TNF-α expression was evaluated. Both TNF-α mRNA and protein increased in cells transfected with NEP but not with NS1. We further investigate if NS1 or NEP regulates the activity of TNF-α promoter. In the presence of NEP the activity of TNF-α promoter increased significantly compared with the control (83.5±2.9 vs. 30.9±2.8, respectively; p=0.001). This effect decreased 15-fold when the TNF-α promoter distal region was deleted, suggesting the involvement of mitogen-activated protein kinases (MAPK) and NF-kB response elements. This was corroborated by testing the effect produced on TNF-α promoter by the treatment with Raf/MEK/ERK (U0126), NF-kB (Bay-11-7082) and PI3K (Ly294-002) cell signaling inhibitors. Treatment with U0126 and Bay-117082 reduced the activity of TNF-α promoter mediated by NEP (41.5±3.2, 70% inhibition; and 80.6±7.4, 35% inhibition, respectively) compared to mock-treated control. The results suggest a new role for NEP protein that participates in the transcriptional regulation of human TNF-α expression. Copyright © 2014 Elsevier B.V. All rights reserved.

Acemannan increases NF-κB/DNA binding and IL-6/-8 expression by selectively binding Toll-like receptor-5 in human gingival fibroblasts.

PubMed

Thunyakitpisal, Pasutha; Ruangpornvisuti, Vithaya; Kengkwasing, Pattrawadee; Chokboribal, Jaroenporn; Sangvanich, Polkit

2017-04-01

Acemannan, an acetylated polymannose from Aloe vera, has immunomodulatory effects. We investigated whether acemannan induces IL-6 and -8 expression and NF-κB/DNA binding in human gingival fibroblasts. IL-6 and -8 expression levels were assessed via RT-PCR and ELISA. The NF-κB p50/p65-DNA binding was determined. The structures of acemannan mono-pentamers and Toll-like receptor 5 (TLR5) were simulated. The binding energies between acemannan and TLR5 were identified. We found that acemannan significantly stimulated IL-6/-8 expression at both the mRNA and protein level and significantly increased p50/DNA binding. Preincubation with an anti-TLR5 neutralizing antibody abolished acemannan-induced IL-6/-8 expression and p50/DNA binding, and co-incubation of acemannan with Bay11-7082, a specific NF- κB inhibitor, abolished IL-6/-8 expression. The computer modeling indicated that monomeric/dimeric single stranded acemannan molecules interacted with the TLR5 flagellin recognition sites with a high binding affinity. We conclude that acemannan induces IL-6/-8 expression, and p50/DNA binding in gingival fibroblasts, at least partly, via a TLR5/NF-κB-dependent signaling pathway. Furthermore, acemannan selectively binds with TLR5 ectodomain flagellin recognition sites. Copyright © 2017 Elsevier Ltd. All rights reserved.

Changes in mitochondrial DNA alter expression of nuclear encoded genes associated with tumorigenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jandova, Jana; Janda, Jaroslav; Sligh, James E, E-mail: jsligh@azcc.arizona.edu

We previously reported the presence of a mtDNA mutation hotspot in UV-induced premalignant and malignant skin tumors in hairless mice. We have modeled this change (9821insA) in murine cybrid cells and demonstrated that this alteration in mtDNA associated with mtBALB haplotype can alter the biochemical characteristics of cybrids and subsequently can contribute to significant changes in their behavioral capabilities. This study shows that changes in mtDNA can produce differences in expression levels of specific nuclear-encoded genes, which are capable of triggering the phenotypes such as seen in malignant cells. From a potential list of differentially expressed genes discovered by microarraymore » analysis, we selected MMP-9 and Col1a1 for further studies. Real-time PCR confirmed up-regulation of MMP-9 and down-regulation of Col1a1 in cybrids harboring the mtDNA associated with the skin tumors. These cybrids also showed significantly increased migration and invasion abilities compared to wild type. The non-specific MMP inhibitor, GM6001, was able to inhibit migratory and invasive abilities of the 9821insA cybrids confirming a critical role of MMPs in cellular motility. Nuclear factor-{kappa}B (NF-{kappa}B) is a key transcription factor for production of MMPs. An inhibitor of NF-{kappa}B activation, Bay 11-7082, was able to inhibit the expression of MMP-9 and ultimately decrease migration and invasion of mutant cybrids containing 9821insA. These studies confirm a role of NF-{kappa}B in the regulation of MMP-9 expression and through this regulation modulates the migratory and invasive capabilities of cybrids with mutant mtDNA. Enhanced migration and invasion abilities caused by up-regulated MMP-9 may contribute to the tumorigenic phenotypic characteristics of mutant cybrids. -- Highlights: Black-Right-Pointing-Pointer Cybrids are useful models to study the role of mtDNA changes in cancer development. Black-Right-Pointing-Pointer mtDNA changes affect the expression of nuclear genes associated with tumorigenesis. Black-Right-Pointing-Pointer MMP-9 is up-regulated and Col1a1 is down-regulated in mutant cybrids. Black-Right-Pointing-Pointer GM6001 reduced the enhanced motility of mutant cybrids caused by up-regulated MMP-9. Black-Right-Pointing-Pointer The MMP-9 expression and invasiveness of mutant cybrids were reduced by Bay 11-7802.« less

TRIM29 Overexpression Promotes Proliferation and Survival of Bladder Cancer Cells through NF-κB Signaling.

PubMed

Tan, Shu-Tao; Liu, Sheng-Ye; Wu, Bin

2016-10-01

TRIM29 overexpression has been reported in several human malignancies and showed correlation with cancer cell malignancy. The aim of the current study is to examine its clinical significance and biological roles in human bladder cancer tissues and cell lines. A total of 102 cases of bladder cancer tissues were examined for TRIM29 expression by immunohistochemistry. siRNA and plasmid transfection were performed in 5637 and BIU-87 cell lines. Cell Counting Kit-8, flow cytometry, western blot, and real-time polymerase chain reaction were performed to examine its biological roles and mechanism in bladder cancer cells. We found that TRIM29 overexpression showed correlation with invading depth (p=0.0087). Knockdown of TRIM29 expression in bladder cancer cell line 5637 inhibited cell growth rate and cell cycle transition while its overexpression in BIU-87 cells accelerated cell proliferation and cell cycle progression. TRIM29 overexpression also inhibited cell apoptosis induced by cisplatin. In addition, we demonstrated that TRIM29 depletion decreased while its overexpression led to upregulated expression of cyclin D1, cyclin E, and Bcl-2. We also showed that TRIM29 knockdown inhibited protein kinase C (PKC) and nuclear factor κB (NF-κB) signaling while its overexpression stimulated the PKC and NF-κB pathways. BAY 11-7082 (NF-κB inhibitor) partly attenuated the effect of TRIM29 on expression of cyclin and Bcl-2. Treatment with PKC inhibitor staurosporine resulted in ameliorated TRIM29 induced activation of NF-κB. The current study demonstrated that TRIM29 upregulates cyclin and Bcl family proteins level to facilitate malignant cell growth and inhibit drug-induced apoptosis in bladder cancer, possibly through PKC-NF-κB signaling pathways.

From the Cover: Activation of NF-κB-Autophagy Axis by 2-Hydroxyethyl Methacrylate Commits Dental Mesenchymal Cells to Apoptosis.

PubMed

Yu, Jing-Jing; Zhu, Ling-Xin; Zhang, Jie; Liu, Shan; Lv, Feng-Yuan; Cheng, Xue; Liu, Guo-Jing; Peng, Bin

2017-05-01

2-hydroxyethyl methacrylate (HEMA) is the major resin monomer that is released from incomplete polymerized dental restorative and adhesive biomaterials during dental therapy. Autophagy and apoptosis are biologically connected and the relationship between autophagy and apoptosis is complex under various circumstances. This study aimed to determine whether autophagy is activated by HEMA and further explore the function of autophagy during the HEMA-induced apoptosis of dental mesenchymal cells (DMCs). We exposed DMCs to different concentrations of HEMA. Cell viability showed a time- and concentration-dependent decrease when exposed to HEMA. We showed that HEMA exposure increased autophagic vacuoles and the expression of autophagic biomarkers (Beclin1, Atg5 and LC3). Pre-incubated with autophagy inhibitors (3-methyladenine and chloroquine) significantly prevented HEMA-induced apoptosis. Interestingly, HEMA initiated nuclear factor-κB (NF-κB) expression and nuclear translocation, whereas the NF-κB inhibitor (Bay 11-7082) markedly suppressed HEMA-induced autophagic activation and apoptosis. As is consistent with the in vitro results, HEMA treatment resulted in dental pulp tissue toxicity and activation of typical autophagic vacuoles in the tooth slice organ culture model ex vivo. In summary, we demonstrated that NF-κB signaling functioned upstream of HEMA-inducecd autophagy in DMCs and that the activation of NF-κB-autophagy axis was responsible for HEMA-induced apoptosis. Our findings provide novel insights into the mechanisms of resin monomer-mediated dental pulp damage during dental treatment, highlighting the activation of NF-κB-autophagy axis as an important mechanism of HEMA-mediated apoptosis. © The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Omentin inhibits TNF-{alpha}-induced expression of adhesion molecules in endothelial cells via ERK/NF-{kappa}B pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhong, Xia, E-mail: zhongxia1977@126.com; Li, Xiaonan; Liu, Fuli

2012-08-24

Highlights: Black-Right-Pointing-Pointer Omentin inhibited TNF-{alpha}-induced adhesion of THP-1 cells to HUVECs. Black-Right-Pointing-Pointer Omentin reduces expression of ICAM-1 and VCAM-1 induced by TNF-{alpha} in HUVECs. Black-Right-Pointing-Pointer Omentin inhibits TNF-{alpha}-induced ERK and NF-{kappa}B activation in HUVECs. Black-Right-Pointing-Pointer Omentin supreeses TNF-{alpha}-induced expression of ICAM-1 and VCAM-1 via ERK/NF-{kappa}B pathway. -- Abstract: In the present study, we investigated whether omentin affected the expression of intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in tumor necrosis factor-{alpha} (TNF-{alpha}) induced human umbilical vein endothelial cells (HUVECs). Our data showed that omentin decreased TNF-{alpha}-induced expression of ICAM-1 and VCAM-1 in HUVECs. In addition, omentin inhibitedmore » TNF-{alpha}-induced adhesion of THP-1 cells to HUVECs. Further, we found that omentin inhibited TNF-{alpha}-activated signal pathway of nuclear factor-{kappa}B (NF-{kappa}B) by preventing NF-{kappa}B inhibitory protein (I{kappa}B{alpha}) degradation and NF-{kappa}B/DNA binding activity. Omentin pretreatment significantly inhibited TNF-{alpha}-induced ERK activity and ERK phosphorylation in HUVECs. Pretreatment with PD98059 suppressed TNF-{alpha}-induced NF-{kappa}B activity. Omentin, NF-kB inhibitor (BAY11-7082) and ERK inhibitor (PD98059) reduced the up-regulation of ICAM-1 and VCAM-1 induced by TNF-{alpha}. These results suggest that omentin may inhibit TNF-{alpha}-induced expression of adhesion molecules in endothelial cells via blocking ERK/NF-{kappa}B pathway.« less

Quantitative Analysis of NF-κB Transactivation Specificity Using a Yeast-Based Functional Assay

PubMed Central

Sharma, Vasundhara; Jordan, Jennifer J.; Ciribilli, Yari; Resnick, Michael A.; Bisio, Alessandra; Inga, Alberto

2015-01-01

The NF-κB transcription factor family plays a central role in innate immunity and inflammation processes and is frequently dysregulated in cancer. We developed an NF-κB functional assay in yeast to investigate the following issues: transactivation specificity of NF-κB proteins acting as homodimers or heterodimers; correlation between transactivation capacity and in vitro DNA binding measurements; impact of co-expressed interacting proteins or of small molecule inhibitors on NF-κB-dependent transactivation. Full-length p65 and p50 cDNAs were cloned into centromeric expression vectors under inducible GAL1 promoter in order to vary their expression levels. Since p50 lacks a transactivation domain (TAD), a chimeric construct containing the TAD derived from p65 was also generated (p50TAD) to address its binding and transactivation potential. The p50TAD and p65 had distinct transactivation specificities towards seventeen different κB response elements (κB-REs) where single nucleotide changes could greatly impact transactivation. For four κB-REs, results in yeast were predictive of transactivation potential measured in the human MCF7 cell lines treated with the NF-κB activator TNFα. Transactivation results in yeast correlated only partially with in vitro measured DNA binding affinities, suggesting that features other than strength of interaction with naked DNA affect transactivation, although factors such as chromatin context are kept constant in our isogenic yeast assay. The small molecules BAY11-7082 and ethyl-pyruvate as well as expressed IkBα protein acted as NF-κB inhibitors in yeast, more strongly towards p65. Thus, the yeast-based system can recapitulate NF-κB features found in human cells, thereby providing opportunities to address various NF-κB functions, interactions and chemical modulators. PMID:26147604

Bioluminescence methodology for the detection of protein-protein interactions within the voltage-gated sodium channel macromolecular complex.

PubMed

Shavkunov, Alexander; Panova, Neli; Prasai, Anesh; Veselenak, Ron; Bourne, Nigel; Stoilova-McPhie, Svetla; Laezza, Fernanda

2012-04-01

Protein-protein interactions are critical molecular determinants of ion channel function and emerging targets for pharmacological interventions. Yet, current methodologies for the rapid detection of ion channel macromolecular complexes are still lacking. In this study we have adapted a split-luciferase complementation assay (LCA) for detecting the assembly of the voltage-gated Na+ (Nav) channel C-tail and the intracellular fibroblast growth factor 14 (FGF14), a functionally relevant component of the Nav channelosome that controls gating and targeting of Nav channels through direct interaction with the channel C-tail. In the LCA, two complementary N-terminus and C-terminus fragments of the firefly luciferase were fused, respectively, to a chimera of the CD4 transmembrane segment and the C-tail of Nav1.6 channel (CD4-Nav1.6-NLuc) or FGF14 (CLuc-FGF14). Co-expression of CLuc-FGF14 and CD4-Nav1.6-NLuc in live cells led to a robust assembly of the FGF14:Nav1.6 C-tail complex, which was attenuated by introducing single-point mutations at the predicted FGF14:Nav channel interface. To evaluate the dynamic regulation of the FGF14:Nav1.6 C-tail complex by signaling pathways, we investigated the effect of kinase inhibitors on the complex formation. Through a platform of counter screenings, we show that the p38/MAPK inhibitor, PD169316, and the IκB kinase inhibitor, BAY 11-7082, reduce the FGF14:Nav1.6 C-tail complementation, highlighting a potential role of the p38MAPK and the IκB/NFκB pathways in controlling neuronal excitability through protein-protein interactions. We envision the methodology presented here as a new valuable tool to allow functional evaluations of protein-channel complexes toward probe development and drug discovery targeting ion channels implicated in human disorders.

Indoxyl sulfate enhances IL-1β-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway.

PubMed

Shen, Wen-Ching; Liang, Chan-Jung; Huang, Tao-Ming; Liu, Chen-Wei; Wang, Shu-Huei; Young, Guang-Huar; Tsai, Jaw-Shiun; Tseng, Ying-Chin; Peng, Yu-Sen; Wu, Vin-Cent; Chen, Yuh-Lien

2016-11-01

Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1β were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1β expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1β-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1β-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-κB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1β-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-κB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1β-treated HUVECs was inhibited by Bay11-7082, a NF-κB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.

Involvement of interleukin-23 induced by Porphyromonas endodontalis lipopolysaccharide in osteoclastogenesis

PubMed Central

Ma, Nan; Yang, Di; Okamura, Hirohiko; Teramachi, Jumpei; Hasegawa, Tomokazu; Qiu, Lihong; Haneji, Tatsuji

2017-01-01

Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin-23 (IL-23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL-23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL-23 in periodontal ligament (PDL) cells. Reverse transcription- quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL-23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL-23 in the SH-9 human PDL cell line. BAY11-7082, a nuclear factor κB inhibitor, suppressed P. endodontalis LPS-induced IL-23 expression in SH-9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS-treated SH-9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL-23-knockdown SH-9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL-23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process. PMID:28000855

GEN-27, a Newly Synthetic Isoflavonoid, Inhibits the Proliferation of Colon Cancer Cells in Inflammation Microenvironment by Suppressing NF-κB Pathway

PubMed Central

Wang, Yajing; Lu, Ping; Zhang, Weifeng; Du, Qianming; Tang, Jingjing; Wang, Hong; Lu, Jinrong; Hu, Rong

2016-01-01

Nonresolving inflammation is one of the consistent features of the tumor microenvironment in the intestine and plays a critical role in the initiation and development of colon cancer. Here we reported the inhibitory effects of GEN-27, a new derivative of genistein, on the inflammation-related colon cancer cell proliferation and delineated the mechanism of its action. The results indicated that GEN-27 inhibited the proliferation of human colon tumor HCT116 cells stimulated by culture supernatants of LPS-induced human monocytes THP-1 cells and significantly decreased LPS-induced secretion of proinflammatory cytokines interleukin-6 and interleukin-1β in THP-1 cells. The HCT116 cell proliferation elicited by THP-1-conditioned medium could be blocked by the interleukin-1 receptor antagonist (IL-1RA). Further mechanistic study revealed that GEN-27 remarkably inhibited the nuclear translocation of NF-κB and phosphorylation of IκB and IKKα/β in both HCT116 and THP-1 cells. In addition, GEN-27 markedly suppressed the HCT116 cell proliferation stimulated by IL-1β treatment, which was dependent on the inhibition of NF-κB/p65 nuclear localization, as verified by p65 overexpression and BAY 11-7082, an NF-κB inhibitor. Taken together, our findings established that GEN-27 modulated NF-κB signaling pathway involved in inflammation-induced cancer cells proliferation and therefore could be a potential chemopreventive agent against inflammation-associated colon cancer. PMID:27057094

Protective effect of Disporum sessile D.Don extract against UVB-induced photoaging via suppressing MMP-1 expression and collagen degradation in human skin cells.

PubMed

Mohamed, Mohamed Antar Aziz; Jung, Mira; Lee, Sang Min; Lee, Tae Hoon; Kim, Jiyoung

2014-04-05

In the present study, we report that Disporum sessile D.Don herbal extract (DDE) possesses anti-skin photoaging effect through inhibition of MMP-1 mRNA and protein expression levels and increase collagen production in UVB-irradiated human dermal fibroblast cells (NHDF). To delineate the molecular mechanism by which DDE inhibited MMP-1 expression, immortal human keratinocytes cells (HaCaT) have been used. We have found that DDE inhibited UVB-induced MMP-1 mRNA and protein expression levels in HaCaT cells through inhibition of UVB-induced activation of NF-κB in HaCaT cells. Inhibitors of NF-κB (Bay11-7082), and mitogen-activated protein kinases such as extracellular regulated kinase (PD98059), c-Jun N-terminal kinase (SP600125), and p38 (SB203580) suppressed expression of MMP-1, and phosphorylation of these signaling molecules were attenuated by DDE. DDE also inhibited phosphorylation of IKKα and IκBα, and reduced nuclear translocation of NF-κB. Our results also demonstrated that DDE inhibited NF-κB driven expression of luciferase reporter gene and the DNA binding of NF-κB to its cognate binding site in UV-irradiated cells. Therefore, these results strongly suggest that DDE can be utilized as a potential agent for prevention and treatment of skin photoaging. Copyright © 2014 Elsevier B.V. All rights reserved.

The epigenetic effect of glucosamine and a nuclear factor-kappa B (NF-kB) inhibitor on primary human chondrocytes - Implications for osteoarthritis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Imagawa, Kei, E-mail: k.Imagawa@soton.ac.uk; Tohoku University School of Medicine, Sendai; Andres, MC de

Research highlights: {yields} Glucosamine and a NF-kB inhibitor reduce inflammation in OA. {yields} Cytokine induced demethylation of CpG site in IL1{beta} promoter prevented by glucosamine. {yields} Glucosamine and NF-kB inhibitor have epigenetic effects on human chondrocytes. -- Abstract: Objective: Idiopathic osteoarthritis is the most common form of osteoarthritis (OA) world-wide and remains the leading cause of disability and the associated socio-economic burden in an increasing aging population. Traditionally, OA has been viewed as a degenerative joint disease characterized by progressive destruction of the articular cartilage and changes in the subchondral bone culminating in joint failure. However, the etiology of OAmore » is multifactorial involving genetic, mechanical and environmental factors. Treatment modalities include analgesia, joint injection with steroids or hyaluronic acid, oral supplements including glucosamine and chondroitin sulfate, as well as physiotherapy. Thus, there is significant interest in the discovery of disease modifying agents. One such agent, glucosamine (GlcN) is commonly prescribed even though the therapeutic efficacy and mechanism of action remain controversial. Inflammatory cytokines, including IL-1{beta}, and proteinases such as MMP-13 have been implicated in the pathogenesis and progression of OA together with an associated CpG demethylation in their promoters. We have investigated the potential of GlcN to modulate NF-kB activity and cytokine-induced abnormal gene expression in articular chondrocytes and, critically, whether this is associated with an epigenetic process. Method: Human chondrocytes were isolated from the articular cartilage of femoral heads, obtained with ethical permission, following fractured neck of femur surgery. Chondrocytes were cultured for 5 weeks in six separate groups; (i) control culture, (ii) cultured with a mixture of 2.5 ng/ml IL-1{beta} and 2.5 ng/ml oncostatin M (OSM), (iii) cultured with 2 mM N-acetyl GlcN (Sigma-Aldrich), (iv) cultured with a mixture of 2.5 ng/ml IL-1{beta}, 2.5 ng/ml OSM and 2 mM GlcN, (v) cultured with 1.0 {mu}M BAY 11-7082 (BAY; NF-kB inhibitor: Calbiochem, Darmstadt, Germany) and, (vi) cultured with a mixture of 2.5 ng/ml IL-1{beta}, 2.5 ng/ml OSM and 1.0 {mu}M BAY. The levels of IL1B and MMP13 mRNA were examined using qRT-PCR. The percentage DNA methylation in the CpG sites of the IL1{beta} and MMP13 proximal promoter were quantified by pyrosequencing. Result:IL1{beta} expression was enhanced over 580-fold in articular chondrocytes treated with IL-1{beta} and OSM. GlcN dramatically ameliorated the cytokine-induced expression by 4-fold. BAY alone increased IL1{beta} expression by 3-fold. In the presence of BAY, IL-1{beta} induced IL1B mRNA levels were decreased by 6-fold. The observed average percentage methylation of the -256 CpG site in the IL1{beta} promoter was 65% in control cultures and decreased to 36% in the presence of IL-1{beta}/OSM. GlcN and BAY alone had a negligible effect on the methylation status of the IL1B promoter. The cytokine-induced loss of methylation status in the IL1B promoter was ameliorated by both GlcN and BAY to 44% and 53%, respectively. IL-1{beta}/OSM treatment increased MMP13 mRNA levels independently of either GlcN or BAY and no change in the methylation status of the MMP13 promoter was observed. Conclusion: We demonstrate for the first time that GlcN and BAY can prevent cytokine-induced demethylation of a specific CpG site in the IL1{beta} promoter and this was associated with decreased expression of IL1{beta}. These studies provide a potential mechanism of action for OA disease modifying agents via NF-kB and, critically, demonstrate the need for further studies to elucidate the role that NF-kB may play in DNA demethylation in human chondrocytes.« less

Subneurotoxic copper(II)-induced NF-κB-dependent microglial activation is associated with mitochondrial ROS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hu, Zhuqin; Yu, Fengxiang; Gong, Ping

2014-04-15

Microglia-mediated neuroinflammation and the associated neuronal damage play critical roles in the pathogenesis of neurodegenerative disorders. Evidence shows an elevated concentration of extracellular copper(II) in the brains of these disorders, which may contribute to neuronal death through direct neurotoxicity. Here we explored whether extracellular copper(II) triggers microglial activation. Primary rat microglia and murine microglial cell line BV-2 cells were cultured and treated with copper(II). The content of tumor necrosis factor-α (TNF-α) and nitric oxide in the medium was determined. Extracellular hydrogen peroxide was quantified by a fluorometric assay with Amplex Red. Mitochondrial superoxide was measured by MitoSOX oxidation. At subneurotoxicmore » concentrations, copper(II) treatment induced a dose- and time-dependent release of TNF-α and nitric oxide from microglial cells, and caused an indirect, microglia-mediated neurotoxicity that was blocked by inhibition of TNF-α and nitric oxide production. Copper(II)-initiated microglial activation was accompanied with reduced IkB-α expression as well as phosphorylation and translocation of nuclear factor-κB (NF-κB) p65 and was blocked by NF-κB inhibitors (BAY11-7082 and SC-514). Moreover, copper(II) treatment evoked a rapid release of hydrogen peroxide from microglial cells, an effect that was not affected by NADPH oxidase inhibitors. N-acetyl-cysteine, a scavenger of reactive oxygen species (ROS), abrogated copper(II)-elicited microglial release of TNF-α and nitric oxide and subsequent neurotoxicity. Importantly, mitochondrial production of superoxide, paralleled to extracellular release of hydrogen peroxide, was induced after copper(II) stimulation. Our findings suggest that extracellular copper(II) at subneurotoxic concentrations could trigger NF-κB-dependent microglial activation and subsequent neurotoxicity. NADPH oxidase-independent, mitochondria-derived ROS may be involved in this activation. - Highlights: • Subneurotoxic copper(II) triggers NF-κB-dependent microglial activation. • This activation leads to hippocampal neuronal death. • This activation may involve mitochondria-derived reactive oxygen species.« less

The role of cPLA2 in Methylglyoxal-induced cell apoptosis of HUVECs

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yuan, Jie; Zhu, Chao; Hong, Yali

2017-05-15

Methylglyoxal (MGO), a highly reactive dicarbonyl compound, is mainly formed as a byproduct of glycolysis. Elevated MGO level is known to induce apoptosis of vascular endothelial cells, which is implicated with progression of atherosclerosis and diabetic complications. However, the underlying mechanisms have not been exhaustively investigated yet. Here, we further characterized the mechanisms how MGO induced apoptosis in human umbilical vein endothelial cells (HUVECs). Our data revealed that cytosolic phospholipase A2 (cPLA2) played an important role in MGO-induced cell apoptosis. It was found that MGO could increase both the activity and expression of cPLA2. Inhibition of cPLA2 by Pyrrophenone (PYR)more » or siRNA significantly attenuated the MGO-induced apoptosis. Additionally, MGO time-dependently decreased the phosphorylation of nuclear factor κB (NF-κB). Pretreatment of the cells with NF-κB inhibitor, BAY11-7082, further increased MGO-induced apoptosis of HUVECs, indicating that NF-κB played a survival role in this MGO-induced apoptosis. Furthermore, in the presence of si-cPLA2 or PYR, MGO no longer decreased NF-κB phosphorylation. Beyond that, the antioxidant N-acetyl cysteine (NAC) could reverse the changes of both cPLA2 and NF-κB caused by MGO. p38, the upstream of cPLA2, was also significantly phosphorylated by MGO. However, p38 inhibitor failed to reverse the apoptosis induced by MGO. This study gives an important insight into the downstream signaling mechanisms of MGO, cPLA2-NF-κB, in endothelial apoptosis. - Highlights: • cPLA2 participated in MGO-induced HUVECs apoptosis. • Inhibition of NF-κB was involved in MGO-cPLA2-mediated cell apoptosis. • Antioxidant NAC attenuated MGO-induced cPLA2 activation and cell apoptosis.« less

Involvement of interleukin‑23 induced by Porphyromonas endodontalis lipopolysaccharide in osteoclastogenesis.

PubMed

Ma, Nan; Yang, Di; Okamura, Hirohiko; Teramachi, Jumpei; Hasegawa, Tomokazu; Qiu, Lihong; Haneji, Tatsuji

2017-02-01

Periapical lesions are characterized by the destruction of periapical bone, and occur as a result of local inflammatory responses to root canal infection by microorganisms including Porphyromonas endodontalis (P. endodontalis). P. endodontalis and its primary virulence factor, lipopolysaccharide (LPS), are associated with the development of periapical lesions and alveolar bone loss. Interleukin‑23 (IL‑23) is critical in the initiation and progression of periodontal disease via effects on peripheral bone metabolism. The present study investigated the expression of IL‑23 in tissue where a periapical lesion was present, and the effect of P. endodontalis LPS on the expression of IL‑23 in periodontal ligament (PDL) cells. Reverse transcription‑ quantitative polymerase chain reaction and immunohistochemistry revealed increased levels of IL‑23 expression in tissue with periapical lesions compared with healthy PDL tissue. Treatment with P. endodontalis LPS increased the expression of IL‑23 in the SH‑9 human PDL cell line. BAY11‑7082, a nuclear factor κB inhibitor, suppressed P. endodontalis LPS‑induced IL‑23 expression in SH‑9 cells. Treatment of RAW264.7 cells with conditioned medium from P. endodontalis LPS‑treated SH‑9 cells promoted osteoclastogenesis. By contrast, RAW264.7 cells treated with conditioned medium from IL‑23‑knockdown SH‑9 cells underwent reduced levels of osteoclastogenesis. The results of the present study indicated that the expression of IL‑23 in PDL cells induced by P. endodontalis LPS treatment may be involved in the progression of periapical lesions via stimulation of the osteoclastogenesis process.

Silymarin induces cyclin D1 proteasomal degradation via its phosphorylation of threonine-286 in human colorectal cancer cells.

PubMed

Eo, Hyun Ji; Park, Gwang Hun; Song, Hun Min; Lee, Jin Wook; Kim, Mi Kyoung; Lee, Man Hyo; Lee, Jeong Rak; Koo, Jin Suk; Jeong, Jin Boo

2015-01-01

Silymarin from milk thistle (Silybum marianum) plant has been reported to show anti-cancer, anti-inflammatory, antioxidant and hepatoprotective effects. For anti-cancer activity, silymarin is known to regulate cell cycle progression through cyclin D1 downregulation. However, the mechanism of silymarin-mediated cyclin D1 downregulation still remains unanswered. The current study was performed to elucidate the molecular mechanism of cyclin D1 downregulation by silymarin in human colorectal cancer cells. The treatment of silymarin suppressed the cell proliferation in HCT116 and SW480 cells and decreased cellular accumulation of exogenously-induced cyclin D1 protein. However, silymarin did not change the level of cyclin D1 mRNA. Inhibition of proteasomal degradation by MG132 attenuated silymarin-mediated cyclin D1 downregulation and the half-life of cyclin D1 was decreased in the cells treated with silymarin. In addition, silymarin increased phosphorylation of cyclin D1 at threonine-286 and a point mutation of threonine-286 to alanine attenuated silymarin-mediated cyclin D1 downregulation. Inhibition of NF-κB by a selective inhibitor, BAY 11-7082 suppressed cyclin D1 phosphorylation and downregulation by silymarin. From these results, we suggest that silymarin-mediated cyclin D1 downregulation may result from proteasomal degradation through its threonine-286 phosphorylation via NF-κB activation. The current study provides new mechanistic link between silymarin, cyclin D1 downregulation and cell growth in human colorectal cancer cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Ethanol increases matrix metalloproteinase-12 expression via NADPH oxidase-dependent ROS production in macrophages

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Mi Jin; Nepal, Saroj; Lee, Eung-Seok

2013-11-15

Matrix metalloproteinase-12 (MMP-12), an enzyme responsible for degradation of extracellular matrix, plays an important role in the progression of various diseases, including inflammation and fibrosis. Although most of those are pathogenic conditions induced by ethanol ingestion, the effect of ethanol on MMP-12 has not been explored. In the present study, we investigated the effect of ethanol on MMP-12 expression and its potential mechanisms in macrophages. Here, we demonstrated that ethanol treatment increased MMP-12 expression in primary murine peritoneal macrophages and RAW 264.7 macrophages at both mRNA and protein levels. Ethanol treatment also significantly increased the activity of nicotinamide adenine dinucleotidemore » (NADPH) oxidase and the expression of NADPH oxidase-2 (Nox2). Pretreatment with an anti-oxidant (N-acetyl cysteine) or a selective inhibitor of NADPH oxidase (diphenyleneiodonium chloride (DPI)) prevented ethanol-induced MMP-12 expression. Furthermore, knockdown of Nox2 by small interfering RNA (siRNA) prevented ethanol-induced ROS production and MMP-12 expression in RAW 264.7 macrophages, indicating a critical role for Nox2 in ethanol-induced intracellular ROS production and MMP-12 expression in macrophages. We also showed that ethanol-induced Nox2 expression was suppressed by transient transfection with dominant negative IκB-α plasmid or pretreatment with Bay 11-7082, a selective inhibitor of NF-κB, in RAW 264.7 macrophages. In addition, ethanol-induced Nox2 expression was also attenuated by treatment with a selective inhibitor of p38 MAPK, suggesting involvement of p38 MAPK/NF-κB pathway in ethanol-induced Nox2 expression. Taken together, these results demonstrate that ethanol treatment elicited increase in MMP-12 expression via increase in ROS production derived from Nox2 in macrophages. - Highlights: • Ethanol increases ROS production through up-regulation of Nox2 in macrophages. • Enhanced oxidative stress contributes to ethanol-induced MMP-12 expression. • p38 MAPK/NF-κB signaling pathway modulates ethanol-induced Nox2 expression.« less

45 CFR 708.2 - Policy.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 3 2010-10-01 2010-10-01 false Policy. 708.2 Section 708.2 Public Welfare Regulations Relating to Public Welfare (Continued) COMMISSION ON CIVIL RIGHTS COLLECTION BY SALARY OFFSET FROM INDEBTED CURRENT AND FORMER EMPLOYEES § 708.2 Policy. It is the policy of the Commission to apply the...

45 CFR 708.2 - Policy.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 45 Public Welfare 3 2014-10-01 2014-10-01 false Policy. 708.2 Section 708.2 Public Welfare Regulations Relating to Public Welfare (Continued) COMMISSION ON CIVIL RIGHTS COLLECTION BY SALARY OFFSET FROM INDEBTED CURRENT AND FORMER EMPLOYEES § 708.2 Policy. It is the policy of the Commission to apply the...

27 CFR 70.82 - Payment on notice and demand.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 2 2010-04-01 2010-04-01 false Payment on notice and demand. 70.82 Section 70.82 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Collection of Excise and Special (Occupational) Tax Notice and Demand § 70.82 Payment on notice and demand...

Cleome rutidosperma and Euphorbia thymifolia Suppress Inflammatory Response via Upregulation of Phase II Enzymes and Modulation of NF-κB and JNK Activation in LPS-Stimulated BV2 Microglia

PubMed Central

Ding, Hsiou-Yu; Wu, Pei-Shan; Wu, Ming-Jiuan

2016-01-01

Cleome rutidosperma DC. and Euphorbia thymifolia L. are herbal medicines used in traditional Indian and Chinese medicine to treat various illnesses. Reports document that they have antioxidant and anti-inflammatory activities; nonetheless, the molecular mechanisms involved in their anti-inflammatory actions have not yet been elucidated. The anti-neuroinflammatory activities and underlying mechanisms of ethanol extracts of Cleome rutidosperma (CR) and Euphorbia thymifolia (ET) were studied using lipopolysaccharide (LPS)-stimulated microglial cell line BV2. The morphology changes and production of pro-inflammatory mediators were assayed. Gene expression of inflammatory genes such as inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, and CC chemokine ligand (CCL)-2, as well as phase II enzymes such as heme oxygenase (HO)-1, the modifier subunit of glutamate cysteine ligase (GCLM) and NAD(P)H quinone dehydrogenase 1 (NQO1), were further investigated using reverse transcription quantitative-PCR (RT-Q-PCR) and Western blotting. The effects of CR and ET on mitogen activated protein kinases (MAPKs) and nuclear factor (NF)-κB signaling pathways were examined using Western blotting and specific inhibitors. CR and ET suppressed BV2 activation, down-regulated iNOS and COX-2 expression and inhibited nitric oxide (NO) overproduction without affecting cell viability. They reduced LPS-mediated tumor necrosis factor (TNF) and IL-6 production, attenuated IL-1β and CCL2 expression, but upregulated HO-1, GCLM and NQO1 expression. They also inhibited p65 NF-κB phosphorylation and modulated Jun-N terminal kinase (JNK) activation in BV2 cells. SP600125, the JNK inhibitor, significantly augmented the anti-IL-6 activity of ET. NF-κB inhibitor, Bay 11-7082, enhanced the anti-IL-6 effects of both CR and ET. Znpp, a competitive inhibitor of HO-1, attenuated the anti-NO effects of CR and ET. Our results show that CR and ET exhibit anti-neuroinflammatory activities by inhibiting pro-inflammatory mediator expression and production, upregulating HO-1, GCLM and NQO1, blocking NF-κB and modulating JNK signaling pathways. They may offer therapeutic potential for suppressing overactivated microglia and alleviating neurodegeneration. PMID:27618898

22 CFR 708.2 - Open meeting policy.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 22 Foreign Relations 2 2014-04-01 2014-04-01 false Open meeting policy. 708.2 Section 708.2... § 708.2 Open meeting policy. (a) It is the policy of the Corporation to provide the public with the... responsibilities. In order to effect this policy, every meeting of the Board of Directors shall be open to public...

The role of NF-κB signaling pathway in polyhexamethylene guanidine phosphate induced inflammatory response in mouse macrophage RAW264.7 cells.

PubMed

Kim, Ha Ryong; Shin, Da Young; Chung, Kyu Hyuck

2015-03-04

Polyhexamethylene guanidine (PHMG) phosphate is a competitive disinfectant with strong antibacterial activity. However, epidemiologists revealed that inhaled PHMG-phosphate may increase the risk of pulmonary fibrosis associated with inflammation, resulting in the deaths of many people, including infants and pregnant women. In addition, in vitro and in vivo studies reported the inflammatory effects of PHMG-phosphate. Therefore, the aim of the present study was to clarify the inflammatory effects and its mechanism induced by PHMG-phosphate in murine RAW264.7 macrophages. Cell viability, inflammatory cytokine secretion, nuclear factor kappa B (NF-κB) activation, and reactive oxygen species (ROS) generation were investigated in macrophages exposed to PHMG-phosphate. PHMG-phosphate induced dose-dependent cytotoxicity, with LC50 values of 11.15-0.99mg/ml at 6 and 24h, respectively. PHMG-phosphate induced pro-inflammatory cytokines including IL-1β, IL-6, and IL-8. In particular, IL-8 expression was completely inhibited by the NF-κB inhibitor BAY11-7082. In addition, PHMG-phosphate decreased IκB-α protein expression and increased NF-κB-mediated luciferase activity, which was diminished by N-acetyl-l-cystein. However, abundant amounts of ROS were generated in the presence of PHMG-phosphate at high concentrations with a cytotoxic effect. Our results demonstrated that PHMG-phosphate triggered the activation of NF-κB signaling pathway by modulating the degradation of IκB-α. Furthermore, the NF-κB signaling pathway plays a critical role in the inflammatory responses induced by PHMG-phosphate. We assumed that ROS generated by PHMG-phosphate were associated with inflammatory responses as secondary mechanism. In conclusion, we suggest that PHMG-phosphate induces inflammatory responses via NF-κB signaling pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Protective effects of anisodamine on cigarette smoke extract-induced airway smooth muscle cell proliferation and tracheal contractility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu, Guang-Ni; Yang, Kai; Xu, Zu-Peng

2012-07-01

Anisodamine, an antagonist of muscarinic acetylcholine receptors (mAChRs), has been used therapeutically to improve smooth muscle function, including microvascular, intestinal and airway spasms. Our previous studies have revealed that airway hyper-reactivity could be prevented by anisodamine. However, whether anisodamine prevents smoking-induced airway smooth muscle (ASM) cell proliferation remained unclear. In this study, a primary culture of rat ASM cells was used to evaluate an ASM phenotype through the ability of the cells to proliferate and express contractile proteins in response to cigarette smoke extract (CSE) and intervention of anisodamine. Our results showed that CSE resulted in an increase in cyclinmore » D1 expression concomitant with the G0/G1-to-S phase transition, and high expression of M2 and M3. Functional studies showed that tracheal hyper-contractility accompanied contractile marker α-SMA high-expression. These changes, which occur only after CSE stimulation, were prevented and reversed by anisodamine, and CSE-induced cyclin D1 expression was significantly inhibited by anisodamine and the specific inhibitor U0126, BAY11-7082 and LY294002. Thus, we concluded that the protective and reversal effects and mechanism of anisodamine on CSE-induced events might involve, at least partially, the ERK, Akt and NF-κB signaling pathways associated with cyclin D1 via mAChRs. Our study validated that anisodamine intervention on ASM cells may contribute to anti-remodeling properties other than bronchodilation. -- Highlights: ► CSE induces tracheal cell proliferation, hyper-contractility and α-SMA expression. ► Anisodamine reverses CSE-induced tracheal hyper-contractility and cell proliferation. ► ERK, PI3K, and NF-κB pathways and cyclin D1 contribute to the reversal effect.« less

Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes.

PubMed

Antoniellis Silveira, Angélica Aparecida; Dominical, Venina Marcela; Morelli Vital, Daiana; Alves Ferreira, Wilson; Trindade Maranhão Costa, Fabio; Werneck, Claudio C; Ferreira Costa, Fernando; Conran, Nicola

2018-05-01

Neutrophil adhesion to the vasculature in response to potent inflammatory stimuli, such as TNF-α (TNF), can contribute to atheroprogression amongst other pathophysiological mechanisms. Previous studies have shown that simvastatin, a statin with known pleiotropic anti-inflammatory properties, can partially abrogate the effects of TNF-induced neutrophil adhesion, in association with the modulation of β 2 -integrin expression. We aimed to further characterize the effects of this statin on neutrophil and leukocyte adhesive mechanisms in vitro and in vivo. A microfluidic assay confirmed the ability of simvastatin to inhibit TNF-induced human neutrophil adhesion to fibronectin ligand under conditions of shear stress, while intravital imaging microscopy demonstrated an abrogation of leukocyte recruitment by simvastatin in the microvasculature of mice that had received a TNF stimulus. This inhibition of neutrophil adhesion was accompanied by the inhibition of TNF-induced RhoA activity in human neutrophils, and alterations in cell morphology and β 2 -integrin activity. Additionally, TNF augmented the activity of the p50 NFκB subunit in human neutrophils and TNF-induced neutrophil adhesion and β 2 -integrin activity could be abolished using pharmacological inhibitors of NFκB translocation, BAY11-7082 and SC514. Accordingly, the TNF-induced elevation of neutrophil p50 activity was abolished by simvastatin. In conclusion, our data provide further evidence of the ability of simvastatin to inhibit neutrophil adhesive interactions in response to inflammatory stimuli, both in vivo and in vitro. Simvastatin appears to inhibit neutrophil adhesion by interfering in TNF-induced cytoskeletal rearrangements, in association with the inhibition of Rho A activity, NFκB translocation and, consequently, β 2 -integrin activity. Copyright © 2018 Elsevier B.V. All rights reserved.

Immunotoxicity of ochratoxin A and aflatoxin B1 in combination is associated with the nuclear factor kappa B signaling pathway in 3D4/21 cells.

PubMed

Hou, Lili; Gan, Fang; Zhou, Xuan; Zhou, Yajiao; Qian, Gang; Liu, Zixuan; Huang, Kehe

2018-05-01

The co-contamination of cereals, grains, crops, and animal feeds by mycotoxins is a universal problem. Humans and animals are exposed to several mycotoxins simultaneously as evidenced by extensive studies on this topic. Yet, most studies have addressed the effects of mycotoxins individually. Aflatoxin B1 and ochratoxin A can induce immunotoxicity. However, it remains unclear whether a combination of these mycotoxins aggravates immunotoxicity and the potential mechanism underlying this effect. In this study, we used the cell line 3D4/21, swine alveolus macrophages and innate immune cell. The results showed that the percentage of cell inhibition, annexin V/PI-positive rates, and the expression of pro-inflammatory cytokines (tumor necrosis factor alpha and interleukin-6) significantly increased and the release of lactate dehydrogenase and phagocytotic index were significantly decreased at different concentrations of aflatoxin B1 and ochratoxin A combination when compared with control. The combination of aflatoxin B1 and ochratoxin A significantly decreased the production of GSH and increased reactive oxygen species level. However, N-acetylcysteine suppressed the oxidative stress and alleviated the immunotoxicity induced by the combination. The combination of aflatoxin B1 and ochratoxin A markedly enhanced the degradation of IκBa, the phosphorylation of nuclear factor kappa B (p65), and the translocation of activated nuclear factor kappa B (NF-κB) into the nuclei as demonstrated by western blotting and confocal laser scanning microscopy. These effects could be reversed by BAY 11-7082, a specific inhibitor of NF-κB. Taken together, a combination of aflatoxin B1 and ochratoxin A could aggravate immunotoxicity by activating the NF-κB signaling pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

Aldosterone Target NGAL (Neutrophil Gelatinase-Associated Lipocalin) Is Involved in Cardiac Remodeling After Myocardial Infarction Through NFκB Pathway.

PubMed

Martínez-Martínez, Ernesto; Buonafine, Mathieu; Boukhalfa, Ines; Ibarrola, Jaime; Fernández-Celis, Amaya; Kolkhof, Peter; Rossignol, Patrick; Girerd, Nicolas; Mulder, Paul; López-Andrés, Natalia; Ouvrard-Pascaud, Antoine; Jaisser, Frédéric

2017-12-01

Myocardial infarction (MI) is accompanied by cardiac fibrosis, which contributes to cardiac dysfunction. Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with left ventricular (LV) dysfunction after MI. We herein investigated the role of the MR target NGAL (neutrophil gelatinase-associated lipocalin) in post-MI cardiac damages. Both higher baseline NGAL and a greater increase in serum NGAL levels during follow-up were significantly associated with lower 6-month LV ejection fraction recovery in a cohort of 119 post-MI patients, as assessed by cardiac magnetic resonance imaging. NGAL protein levels increased in the LV at 7 days post-MI in wild-type mice with MI. This effect was prevented by treatment with the nonsteroidal MR antagonist finerenone (1 mg/kg per day). NGAL knockout mice with MI had lower LV interstitial fibrosis and inflammation, better LV contractility and compliance, and greater stroke volume and cardiac output than wild-type mice with MI at 3 months post-MI. Aldosterone (10 -8 mol/L) increased NGAL expression in cultured human cardiac fibroblasts. Cells treated with aldosterone or NGAL (500 ng/mL) showed increased production of collagen type I. The effects of aldosterone were abolished by finerenone (10 -6 mol/L) or NGAL knockdown. This NGAL-mediated activity relied on NFκB (nuclear factor-κB) activation, confirmed by the use of the NFκB-specific inhibitor BAY11-7082, which prevented the effect of both aldosterone and NGAL on collagen type I production. In conclusion, NGAL, a downstream MR activation target, is a key mediator of post-MI cardiac damage. NGAL may be a potential therapeutic target in cardiovascular pathological situations in which MR is involved. © 2017 American Heart Association, Inc.

CARMA3 is overexpressed in colon cancer and regulates NF-{kappa}B activity and cyclin D1 expression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Miao, Zhifeng; Zhao, Tingting; Wang, Zhenning

2012-09-07

Highlights: Black-Right-Pointing-Pointer CARMA3 expression is elevated in colon cancers. Black-Right-Pointing-Pointer CARMA3 promotes proliferation and cell cycle progression in colon cancer cells. Black-Right-Pointing-Pointer CARMA3 upregulates cyclinD1 through NF-{kappa}B activation. -- Abstract: CARMA3 was recently reported to be overexpressed in cancers and associated with the malignant behavior of cancer cells. However, the expression of CARMA3 and its biological roles in colon cancer have not been reported. In the present study, we analyzed the expression pattern of CARMA3 in colon cancer tissues and found that CARMA3 was overexpressed in 30.8% of colon cancer specimens. There was a significant association between CARMA3 overexpression andmore » TNM stage (p = 0.0383), lymph node metastasis (p = 0.0091) and Ki67 proliferation index (p = 0.0035). Furthermore, knockdown of CARMA3 expression in HT29 and HCT116 cells with high endogenous expression decreased cell proliferation and cell cycle progression while overexpression of CARMA3 in LoVo cell line promoted cell proliferation and facilitated cell cycle transition. Further analysis showed that CARMA3 knockdown downregulated and its overexpression upregulated cyclin D1 expression and phospho-Rb levels. In addition, we found that CARMA3 depletion inhibited p-I{kappa}B levels and NF-{kappa}B activity and its overexpression increased p-I{kappa}B expression and NF-{kappa}B activity. NF-{kappa}B inhibitor BAY 11-7082 reversed the role of CARMA3 on cyclin D1 upregulation. In conclusion, our study found that CARMA3 is overexpressed in colon cancers and contributes to malignant cell growth by facilitating cell cycle progression through NF-{kappa}B mediated upregulation of cyclin D1.« less

Regulation of TRAIL-Medicated Apoptosis in Prostate Cancer by Overexpression of XIAP

DTIC Science & Technology

2006-01-01

induced resistance to TRAIL apoptosis. We used the nitric oxide donor DETANONOate and the NF-κB inhibitior Bay 11-7085 to inhibit NF-κB activity...treatment with chemical inhibitors such as Bay 11-7085 and DHMEQ, the nitric oxide donor DETANONOate and also following treatment with chemotherapeutic...resistance to TRAIL-induced apoptosis by various means: A) We demonstrate that treatment with the NO donor DETANONOate inhibits YY1 expression and DNA

Oridonin stabilizes retinoic acid receptor alpha through ROS-activated NF-κB signaling.

PubMed

Cao, Yang; Wei, Wei; Zhang, Nan; Yu, Qing; Xu, Wen-Bin; Yu, Wen-Jun; Chen, Guo-Qiang; Wu, Ying-Li; Yan, Hua

2015-04-10

Retinoic acid receptor alpha (RARα) plays an essential role in the regulation of many biological processes, such as hematopoietic cell differentiation, while abnormal RARα function contributes to the pathogenesis of certain diseases including cancers, especially acute promyelocytic leukemia (APL). Recently, oridonin, a natural diterpenoid isolated from Rabdosia rubescens, was demonstrated to regulate RARα by increasing its protein level. However, the underlying molecular mechanism for this action has not been fully elucidated. In the APL cell line, NB4, the effect of oridonin on RARα protein was analyzed by western blot and real-time quantitative RT-PCR analyses. Flow cytometry was performed to detect intracellular levels of reactive oxygen species (ROS). The association between nuclear factor-kappa B (NF-κB) signaling and the effect of oridonin was assessed using specific inhibitors, shRNA gene knockdown, and immunofluorescence assays. In addition, primary leukemia cells were treated with oridonin and analyzed by western blot in this study. RARα possesses transcriptional activity in the presence of its ligand, all-trans retinoic acid (ATRA). Oridonin remarkably stabilized the RARα protein, which retained transcriptional activity. Oridonin also moderately increased intracellular ROS levels, while pretreatment with the ROS scavenger, N-acetyl-l-cysteine (NAC), dramatically abrogated RARα stabilization by oridonin. More intriguingly, direct exposure to low concentrations of H2O2 also increased RARα protein but not mRNA levels, suggesting a role for ROS in oridonin stabilization of RARα protein. Further investigations showed that NAC antagonized oridonin-induced activation of NF-κB signaling, while the NF-κB signaling inhibitor, Bay 11-7082, effectively blocked the oridonin increase in RARα protein levels. In line with this, over-expression of IκΒα (A32/36), a super-repressor form of IκΒα, or NF-κB-p65 knockdown inhibited oridonin or H2O2-induced RARα stability. Finally, tumor necrosis factor alpha (TNFα), a classical activator of NF-κB signaling, modulated the stability of RARα protein. Oridonin stabilizes RARα protein by increasing cellular ROS levels, which causes activation of the NF-κB signaling pathway.

The flow dependency of Tie2 expression in endotoxemia.

PubMed

Kurniati, Neng F; Jongman, Rianne M; vom Hagen, Franziska; Spokes, Katherine C; Moser, Jill; Regan, Erzsébet Ravasz; Krenning, Guido; Moonen, Jan-Renier A J; Harmsen, Martin C; Struys, Michel M R F; Hammes, Hans-Peter; Zijlstra, Jan G; Aird, William C; Heeringa, Peter; Molema, Grietje; van Meurs, Matijs

2013-07-01

Tie2 is predominantly expressed by endothelial cells and is involved in vascular integrity control during sepsis. Changes in Tie2 expression during sepsis development may contribute to microvascular dysfunction. Understanding the kinetics and molecular basis of these changes may assist in the development of therapeutic intervention to counteract microvascular dysfunction. To investigate the molecular mechanisms underlying the changes in Tie2 expression upon lipopolysaccharide (LPS) challenge. Studies were performed in LPS and pro-inflammatory cytokine challenged mice as well as in mice subjected to hemorrhagic shock, primary endothelial cells were used for in vitro experiments in static and flow conditions. Eight hours after LPS challenge, Tie2 mRNA loss was observed in all major organs, while loss of Tie2 protein was predominantly observed in lungs and kidneys, in the capillaries. A similar loss could be induced by secondary cytokines TNF-α and IL-1β. Ang2 protein administration did not affect Tie2 protein expression nor was Tie2 protein rescued in LPS-challenged Ang2-deficient mice, excluding a major role for Ang2 in Tie2 down regulation. In vitro, endothelial loss of Tie2 was observed upon lowering of shear stress, not upon LPS and TNF-α stimulation, suggesting that inflammation related haemodynamic changes play a major role in loss of Tie2 in vivo, as also hemorrhagic shock induced Tie2 mRNA loss. In vitro, this loss was partially counteracted by pre-incubation with a pharmacologically NF-кB inhibitor (BAY11-7082), an effect further substantiated in vivo by pre-treatment of mice with the NF-кB inhibitor prior to the inflammatory challenge. Microvascular bed specific loss of Tie2 mRNA and protein in vivo upon LPS, TNFα, IL-1β challenge, as well as in response to hemorrhagic shock, is likely an indirect effect caused by a change in endothelial shear stress. This loss of Tie2 mRNA, but not Tie2 protein, induced by TNFα exposure was shown to be controlled by NF-кB signaling. Drugs aiming at restoring vascular integrity in sepsis could focus on preventing the Tie2 loss.

Nobiletin, a citrus flavonoid, activates vasodilator-stimulated phosphoprotein in human platelets through non-cyclic nucleotide-related mechanisms.

PubMed

Jayakumar, Thanasekaran; Lin, Kao-Chang; Lu, Wan-Jung; Lin, Chia-Ying; Pitchairaj, Geraldine; Li, Jiun-Yi; Sheu, Joen-Rong

2017-01-01

Nobiletin, a bioactive polymethoxylated flavone, has been described to possess a diversity of biological effects through its antioxidant and anti-inflammatory properties. Vasodilator-stimulated phosphoprotein (VASP) is a common substrate for cyclic AMP and cyclic GMP-regulated protein kinases [i.e., cyclic AMP-dependent protein kinase (PKA; also known as protein kinase A) and cyclic GMP-dependent protein kinase (PKG; also known as protein kinase G)] and it has been shown to be directly phosphorylated by protein kinase C (PKC). In the present study, we demonstrate that VASP is phosphorylated by nobiletin in human platelets via a non-cyclic nucleotide-related mechanism. This was confirmed by the use of inhibitors of adenylate cyclase (SQ22536) and guanylate cyclase [1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)], since they prevented VASP phosphorylation induced by nobiletin. Furthormore, this event was also not affected by specific inhibitors of PKA (H-89), PKG (KT5823) and PKC (Ro318220), representing cyclic nucleotide-dependent pathways upon nobiletin-induced VASP phosphorylation. Similarly, inhibitors of p38 mitogen-activated protein kinase (MAPK; SB203580), extracellular signal-regulated kinase 2 (ERK2; PD98059), c-Jun N-terminal kinase 1 (JNK1; SP600125), Akt (LY294002) and nuclear factor-κB (NF-κB; Bay11-7082) did not affect nobiletin‑induced VASP phosphorylation. Moreover, electron spin resonance, dichlorofluorescein fluorescence and western blotting techniques revealed that nobiletin did not affect hydroxyl radicals (OH•), intracellular reactive oxygen species (ROS) and on protein carbonylation, respectively. Furthermore, the nobiletin‑induced VASP phosphorylation was surprisingly reversed by the intracellular antioxidant, N-acetylcysteine (NAC), but not by the inhibitor of NADPH oxidase, diphenyleneiodonium chloride (DPI). It was surprising to observe the differential effects of nobiletin and NAC on VASP phosphorylation in human platelets, since they both have been reported to have antioxidant properties. The likely explanation for this discrepancy is that NAC may bind to allosteric sites on the receptor different from those that nobiletin binds to in human platelets. Taken together, our findings suggest that nobiletin induces VASP phosphorylation in human platelets through non-cyclic nucleotide-related mechanisms. Nevertheless, the exact mechanisms responsible for these effects need to be further confirmed in future studies.

Anticancer activity of Astragalus polysaccharide in human non-small cell lung cancer cells.

PubMed

Wu, Chao-Yan; Ke, Yuan; Zeng, Yi-Fei; Zhang, Ying-Wen; Yu, Hai-Jun

2017-01-01

We have reported that Chinese herbs Astragalus polysaccharide (APS) can inhibit nuclear factor kappaB (NF-κB) activity during the development of diabetic nephropathy in mice. NF-κB plays important roles in genesis, growth, development and metastasis of cancer. NF-κB is also involved in the development of treatment resistance in tumors. Here we investigated the antitumor activity of APS in human non-small cell lung cells (A549 and NCI-H358) and the related mechanisms of action. The dose-effect and time-effect of antitumor of APS were determined in human lung cancer cell line A549 and NCI-H358. The inhibition effect of APS on the P65 mRNA and protein was detected by reverse transcriptase-PCR (RT-PCR) and Western blot in A549 cells respectively. The inhibition effect of APS on the p50, CyclinD1 and Bcl-xL protein was detected by Western blot in A549 cells respectively. The effect of APS on NF-κB transcription activity was measured with NF-κB luciferase detection. Finally, the nude mice A549 xenograft was introduced to confirm the antitumor activity of APS in vivo. Cell viability detection results indicated that APS can inhibit the proliferation of human lung cancer cell line A549 and NCI-H358 in the concentration of 20 and 40 mg/mL. NF-κB activator Phorbol 12-myristate13-acetate (PMA) can attenuate the antitumor activity of APS in both cell lines, but NF-κB inhibitor BAY 11-7082 (Bay) can enhance the effect of APS in both cell lines. In vivo APS can delay the growth of A549 xenograft in BALB/C nude mice. APS can down-regulate the expression of P65 mRNA and protein of A549 cells and decrease the expression of p50, CyclinD1 and Bcl-xL protein. The luciferase detection showed that the APS could reduce the P65 transcription activity in A549 cells. PMA can partially alleviate the inhibition activity of P65 transcription activity of APS in A549 cells, and Bay can enhance the down-regulation of the P65 transcription activity induced by APS in A549 cells. APS has a significant antitumor activity in human lung cancer cells A549 and NCI-H358. NF-κB inhibition may mediate the antitumor effect.

TNFalpha-induced and berberine-antagonized tight junction barrier impairment via tyrosine kinase, Akt and NFkappaB signaling.

PubMed

Amasheh, Maren; Fromm, Anja; Krug, Susanne M; Amasheh, Salah; Andres, Susanne; Zeitz, Martin; Fromm, Michael; Schulzke, Jörg-Dieter

2010-12-01

TNFα-mediated tight junction defects contribute to diarrhea in inflammatory bowel diseases (IBDs). In our study, the signaling pathways of the TNFα effect on barrier- or pore-forming claudins were analyzed in HT-29/B6 human colon monolayers. Berberine, a herbal therapeutic agent that has been recently established as a therapy for diabetes and hypercholesterinemia, was able to completely antagonize the TNFα-mediated barrier defects in the cell model and in rat colon. Ussing chamber experiments and two-path impedance spectroscopy revealed a decrease of paracellular resistance after TNFα to 11±4%, whereas transcellular resistance was unchanged. The permeability of the paracellular marker fluorescein was increased fourfold. Berberine alone had no effect while it fully prevented the TNFα-induced barrier defects. This effect on resistance was confirmed in rat colon. TNFα removed claudin-1 from the tight junction and increased claudin-2 expression. Berberine prevented TNFα-induced claudin-1 disassembly and upregulation of claudin-2. The effects of berberine were mimicked by genistein plus BAY11-7082, indicating that they are mediated via tyrosine kinase, pAkt and NFκB pathways. In conclusion, the anti-diarrheal effect of berberine is explained by a novel mechanism, suggesting a therapeutic approach against barrier breakdown in intestinal inflammation.

22 CFR 708.2 - Open meeting policy.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 22 Foreign Relations 2 2012-04-01 2009-04-01 true Open meeting policy. 708.2 Section 708.2 Foreign... Open meeting policy. (a) It is the policy of the Corporation to provide the public with the fullest... responsibilities. In order to effect this policy, every meeting of the Board of Directors shall be open to public...

22 CFR 708.2 - Open meeting policy.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 22 Foreign Relations 2 2010-04-01 2010-04-01 true Open meeting policy. 708.2 Section 708.2 Foreign... Open meeting policy. (a) It is the policy of the Corporation to provide the public with the fullest... responsibilities. In order to effect this policy, every meeting of the Board of Directors shall be open to public...

22 CFR 708.2 - Open meeting policy.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 22 Foreign Relations 2 2011-04-01 2009-04-01 true Open meeting policy. 708.2 Section 708.2 Foreign... Open meeting policy. (a) It is the policy of the Corporation to provide the public with the fullest... responsibilities. In order to effect this policy, every meeting of the Board of Directors shall be open to public...

22 CFR 708.2 - Open meeting policy.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 22 Foreign Relations 2 2013-04-01 2009-04-01 true Open meeting policy. 708.2 Section 708.2 Foreign... Open meeting policy. (a) It is the policy of the Corporation to provide the public with the fullest... responsibilities. In order to effect this policy, every meeting of the Board of Directors shall be open to public...

Target Residence Time-Guided Optimization on TTK Kinase Results in Inhibitors with Potent Anti-Proliferative Activity.

PubMed

Uitdehaag, Joost C M; de Man, Jos; Willemsen-Seegers, Nicole; Prinsen, Martine B W; Libouban, Marion A A; Sterrenburg, Jan Gerard; de Wit, Joeri J P; de Vetter, Judith R F; de Roos, Jeroen A D M; Buijsman, Rogier C; Zaman, Guido J R

2017-07-07

The protein kinase threonine tyrosine kinase (TTK; also known as Mps1) is a critical component of the spindle assembly checkpoint and a promising drug target for the treatment of aggressive cancers, such as triple negative breast cancer. While the first TTK inhibitors have entered clinical trials, little is known about how the inhibition of TTK with small-molecule compounds affects cellular activity. We studied the selective TTK inhibitor NTRC 0066-0, which was developed in our own laboratory, together with 11 TTK inhibitors developed by other companies, including Mps-BAY2b, BAY 1161909, BAY 1217389 (Bayer), TC-Mps1-12 (Shionogi), and MPI-0479605 (Myrexis). Parallel testing shows that the cellular activity of these TTK inhibitors correlates with their binding affinity to TTK and, more strongly, with target residence time. TTK inhibitors are therefore an example where target residence time determines activity in in vitro cellular assays. X-ray structures and thermal stability experiments reveal that the most potent compounds induce a shift of the glycine-rich loop as a result of binding to the catalytic lysine at position 553. This "lysine trap" disrupts the catalytic machinery. Based on these insights, we developed TTK inhibitors, based on a (5,6-dihydro)pyrimido[4,5-e]indolizine scaffold, with longer target residence times, which further exploit an allosteric pocket surrounding Lys553. Their binding mode is new for kinase inhibitors and can be classified as hybrid Type I/Type III. These inhibitors have very potent anti-proliferative activity that rivals classic cytotoxic therapy. Our findings will open up new avenues for more applications for TTK inhibitors in cancer treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endothelial Activation by Platelets from Sickle Cell Anemia Patients

PubMed Central

Proença-Ferreira, Renata; Brugnerotto, Ana Flávia; Garrido, Vanessa Tonin; Dominical, Venina Marcela; Vital, Daiana Morelli; Ribeiro, Marilene de Fátima Reis; dos Santos, Melissa Ercolin; Traina, Fabíola; Olalla-Saad, Sara T.; Costa, Fernando Ferreira; Conran, Nicola

2014-01-01

Sickle cell anemia (SCA) is associated with a hypercoagulable state. Increased platelet activation is reported in SCA and SCA platelets may present augmented adhesion to the vascular endothelium, potentially contributing to the vaso-occlusive process. We sought to observe the effects of platelets (PLTs) from healthy control (CON) individuals and SCA individuals on endothelial activation, in vitro. Human umbilical vein endothelial cells (HUVEC) were cultured, in the presence, or not, of washed PLTs from CON or steady-state SCA individuals. Supernatants were reserved for cytokine quantification, and endothelial adhesion molecules (EAM) were analyzed by flow cytometry; gene expressions of ICAM1 and genes of the NF-κB pathway were analyzed by qPCR. SCA PLTs were found to be more inflammatory, displaying increased adhesive properties, an increased production of IL-1β and a tendency towards elevated expressions of P-selectin and activated αIIbβ3. Following culture in the presence of SCA PLTs, HUVEC presented significant augmentations in the expressions of the EAM, ICAM-1 and E-selectin, as well as increased IL-8 production and increased ICAM1 and NFKB1 (encodes p50 subunit of NF-κB) gene expressions. Interestingly, transwell inserts abolished the effects of SCA PLTs on EAM expression. Furthermore, an inhibitor of the NF-κB pathway, BAY 11-7082, also prevented the induction of EAM expression on the HUVEC surface by SCA PLTs. In conclusion, we find further evidence to indicate that platelets circulate in an activated state in sickle cell disease and are capable of stimulating endothelial cell activation. This effect appears to be mediated by direct contact, or even adhesion, between the platelets and endothelial cells and via NFκB-dependent signaling. As such, activated platelets in SCD may contribute to endothelial activation and, therefore, to the vaso-occlusive process. Results provide further evidence to support the use of anti-platelet approaches in association with other therapies for SCD. PMID:24551209

Interleukin-6 upregulates paraoxonase 1 gene expression via an AKT/NF-κB-dependent pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Chi-Chih; Hsueh, Chi-Mei; Chen, Chiu-Yuan

2013-07-19

Highlights: •IL-6 could induce PON1 gene expression. •IL-6 increased NF-κB protein expression and NF-κB-p50 and -p65 subunits nuclear translocation. •IL-6-induced PON1 up-regulation was through an AKT/NF-κB pathway. -- Abstract: The aim of this study is to investigate the relationship between paraoxonase 1 (PON1) and atherosclerosis-related inflammation. In this study, human hepatoma HepG2 cell line was used as a hepatocyte model to examine the effects of the pro-inflammatory cytokines on PON1 expression. The results showed that IL-6, but not TNF-α and IL-1β, significantly increased both the function and protein level of PON1; data from real-time RT-PCR analysis revealed that the IL-6-inducedmore » PON1 expression occurred at the transcriptional level. Increase of IκB kinase activity and IκB phosphorylation, and reduction of IκB protein level were also observed in IL-6-treated HepG2 cells compared with untreated culture. This event was accompanied by increase of NF-κB-p50 and -p65 nuclear translocation. Moreover, treatment with IL-6 augmented the DNA binding activity of NF-κB. Furthermore, pharmacological inhibition of NF-κB activation by PDTC and BAY 11-7082, markedly suppressed the IL-6-mediated PON1 expression. In addition, IL-6 increased the levels of phosphorylated protein kinase B (PKB, AKT). An AKT inhibitor LY294002 effectively suppressed IKK/IκB/NF-κB signaling and PON1 gene expression induced by IL-6. Our findings demonstrate that IL-6 upregulates PON1 gene expression through an AKT/NF-κB signaling axis in human hepatocyte-derived HepG2 cell line.« less

Follistatin-like protein 1 induction of matrix metalloproteinase 1, 3 and 13 gene expression in rheumatoid arthritis synoviocytes requires MAPK, JAK/STAT3 and NF-κB pathways.

PubMed

Ni, Su; Li, Chenkai; Xu, Nanwei; Liu, Xi; Wang, Wei; Chen, Wenyang; Wang, Yuji; van Wijnen, Andre J

2018-06-22

Elevated levels of follistatin-like protein 1 (FSTL1) have been found both in mouse models for human rheumatoid arthritis (RA) and collagen-induced arthritis (CIA). In this study, we elucidated the potential mechanisms by which FSTL1 contributes to the pathogenesis of RA. Fibroblast-like synoviocytes (FLSs) were established from synovial tissues of RA patients and stimulated with human recombinant FSTL1. Protein and mRNA expression levels of select matrix metalloproteinases (i.e., MMP1, MMP3, MMP13) in FLS were measured by, respectively, real-time RT-qPCR and ELISA. Activation of MAPK and other pathways that affect MMPs were evaluated by Western blotting. We also compared concentrations of MMPs in plasma in RA patients versus healthy controls (HC). Expression levels of MMP1, MMP3, and MMP13 were clearly stimulated by FSTL1 in vitro. FSTL1 activated the inflammation-related NF-κB signaling pathway, as well as all three mitogen-activated protein kinase (MAPK) pathways and the JAK/STAT3 pathway. Moreover, select chemical inhibitors that target p38 (SB203580), Erk1/2 (SP600125), JNK (SCH772984), STAT3 (AG490), and NF-κB (BAY 11-7082) significantly attenuated MMP expression. Inhibition of Toll-like receptor 4 by compound TAK-242 significantly abolished those effects of FSTL1. Importantly, elevated plasma concentrations of MMP3 were found to correlate with plasma FSTL1 levels in RA patients. These findings suggest that FSTL1 accelerates RA progression by activating MAPK, JAK/STAT3, and NF-κB pathways to enhance secretion of different MMPs and this enhancement is via TLR4. Targeting FSTL1 may provide a promising pharmacological drug therapy to ameliorate RA symptoms and perhaps reverse disease progression. © 2018 Wiley Periodicals, Inc.

Astragaloside IV attenuates inflammatory cytokines by inhibiting TLR4/NF-кB signaling pathway in isoproterenol-induced myocardial hypertrophy.

PubMed

Yang, Juan; Wang, Hong-Xin; Zhang, Ying-Jie; Yang, Yu-Hong; Lu, Mei-Li; Zhang, Jing; Li, Sheng-Tao; Zhang, Su-Ping; Li, Guang

2013-10-25

Astragaloside IV(As IV) is one of the main effective components isolated from the traditional Chinese medical herb Astragalus membranaceus. The protective effect of Astragalus membranaceus on myocardial hypertrophy has been extensively proved. To test the hypothesis that Astragaloside IV can ameliorate the myocardial hypertrophy and inflammatory effect induced by β-adrenergic hyperactivity, we carried out in vivo and in vitro experiments. In in vivo study, the isoproterenol(Iso) (5mg.kg -1 .d -1 ) was used as a model of myocardial hypertrophy by intraperitoneal injection. SD rats were randomly assigned to following six groups: A:the control；B: Iso group；C: Iso plus As IV 20mg.kg -1 .d -1 ；D: Iso plus As IV 40mg.kg -1 .d -1 ；E: Iso plus As IV 80mg.kg -1 .d -1 ；F: Iso plus Propranolol 40mg.kg -1 .d -1 . In in vitro study, cultured neonatal rat cardiomyocytes were pretreated with As IV(3, 10, 30μmol.L -1 ), Propranolol(2μmol.L -1 ) and BAY11-7082(5μmol.L -1 ) for 30minutes, and then incubated with Iso(10μmol.L -1 ) for 48 hours. For the rats in each group, the heart mass index (HMI) and the left ventricular mass index (LVMI) were measured. To measure the transverse diameter of left ventricular myocardial cells (TDM), the hematoxylin-eosin (HE) staining method was applied. In addition, the volume and the total protein content of cardiomyocytes were measured, the mRNA expression of ANP and TLR4 were quantified by RT-PCR, the protein expression of TLR4, IκBα and p65 were quantified by Western blot, and the level of TNF-α and IL-6 were measured by ELISA. In vivo: Comparing the Iso group to the control, the HMI, LVMI, TDM were significantly increased; the protein expression of TLR4 and p65 were increased, while the IκBα were decreased; the expression of ANP, TLR4 mRNA, and TNF-α, IL-6 in serum were significantly increased. These changes could be partly prevented by As IV and Pro. In vitro: the over-expression of the cell size, total protein content could remarkably down-regulated by As IV and Pro, and the results of RT-PCR, Western blot and ELISA were similar to those of in vivo. The results of these studies indicate that Astragaloside IV has good protective effect on myocardial hypertrophy induced by isoproterenol. More specifically, the cardioprotection is related to inhibiting the TLR4/NF-кB signaling pathway and the attenuating inflammatory effect. Astragaloside IV (PubChem CID:122690); BAY 11-7082 (PubChem CID:5353431); Propranolol (PubChem CID:62882); Isoproterenol (PubChem CID: 5806). © 2013 The Authors. Published by Elsevier Ireland Ltd All rights reserved.

Trichomonas vaginalis induces IL-1β production in a human prostate epithelial cell line by activating the NLRP3 inflammasome via reactive oxygen species and potassium ion efflux.

PubMed

Gu, Na-Yeong; Kim, Jung-Hyun; Han, Ik-Hwan; Im, Su-Jeong; Seo, Min-Young; Chung, Yong-Hoon; Ryu, Jae-Sook

2016-07-01

Trichomonas vaginalis is a sexually transmitted protozoan parasite that causes vaginitis in women, and urethritis and prostatitis in men. IL-1β is synthesized as immature pro-IL-1β, which is cleaved by activated caspase-1. Caspase-1 is, in turn, activated by a multi-protein complex known as an inflammasome. In this study, we investigated the inflammatory response of a prostate epithelial cell line (RWPE-1) to T. vaginalis and, specifically, the capacity of T. vaginalis to activate the NLRP3 inflammasome. RWPE-1 cells were stimulated by live T. vaginalis, and subsequent expression of pro-IL-1β, IL-1β, NLRP3, ASC and caspase-1 was determined by real-time PCR and Western blotting. IL-1β and caspase-1 production was also measured by ELISA. To evaluate the effects of NLRP3 and caspase-1 on IL-1β production, the activated RWPE-1 cells were transfected with small interfering RNAs to silence the NLRP3 and caspase-1 genes. Activation of the NLRP3 inflammasome was observed by fluorescence microscopy. Intracellular reactive oxygen species (ROS) were evaluated by spectrofluorometry. When RWPE-1 cells were stimulated with live T. vaginalis, the mRNA and protein expression of IL-1β, NLRP3, ASC, and caspase-1 increased. Moreover, silencing of NLRP3 and caspase-1 attenuated T. vaginalis-induced IL-1β secretion. The NADPH oxidase inhibitor DPI and high extracellular potassium ion suppressed the production of IL-1β, caspase-1, and the expression of NLRP3 and ASC proteins. The specific NF-κB inhibitor, Bay 11-7082, inhibited IL-1β production, and also inhibited the production of caspase-1, ASC and NLRP3 proteins. T. vaginalis induces the formation of the NLRP3 inflammasome in human prostate epithelial cells via ROS and potassium ion efflux, and this results in IL-1β production. This is the first evidence for activation of the NLRP3 inflammasome in the inflammatory response by prostate epithelial cells infected with T. vaginalis. Prostate 76:885-896, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mesenchymal stem cells promote the sustained expression of CD69 on activated T lymphocytes: roles of canonical and non-canonical NF-κB signalling

PubMed Central

Saldanha-Araujo, Felipe; Haddad, Rodrigo; de Farias, Kelen C R Malmegrim; Souza, Alessandra de Paula Alves; Palma, Patrícia V; Araujo, Amélia G; Orellana, Maristela D; Voltarelli, Julio C; Covas, Dimas T; Zago, Marco A; Panepucci, Rodrigo A

2012-01-01

Abstract Mesenchymal stem cells (MSCs) are known to induce the conversion of activated T cells into regulatory T cells in vitro. The marker CD69 is a target of canonical nuclear factor kappa-B (NF-κB) signalling and is transiently expressed upon activation; however, stable CD69 expression defines cells with immunoregulatory properties. Given its enormous therapeutic potential, we explored the molecular mechanisms underlying the induction of regulatory cells by MSCs. Peripheral blood CD3+ T cells were activated and cultured in the presence or absence of MSCs. CD4+ cell mRNA expression was then characterized by microarray analysis. The drug BAY11-7082 (BAY) and a siRNA against v-rel reticuloendotheliosis viral oncogene homolog B (RELB) were used to explore the differential roles of canonical and non-canonical NF-κB signalling, respectively. Flow cytometry and real-time PCR were used for analyses. Genes with immunoregulatory functions, CD69 and non-canonical NF-κB subunits (RELB and NFKB2) were all expressed at higher levels in lymphocytes co-cultured with MSCs. The frequency of CD69+ cells among lymphocytes cultured alone progressively decreased after activation. In contrast, the frequency of CD69+ cells increased significantly following activation in lymphocytes co-cultured with MSCs. Inhibition of canonical NF-κB signalling by BAY immediately following activation blocked the induction of CD69; however, inhibition of canonical NF-κB signalling on the third day further induced the expression of CD69. Furthermore, late expression of CD69 was inhibited by RELB siRNA. These results indicate that the canonical NF-κB pathway controls the early expression of CD69 after activation; however, in an immunoregulatory context, late and sustained CD69 expression is promoted by the non-canonical pathway and is inhibited by canonical NF-κB signalling. PMID:21777379

TRUST trial: BAY 86-6150 use in haemophilia with inhibitors and assessment for immunogenicity.

PubMed

Mahlangu, J; Paz, P; Hardtke, M; Aswad, F; Schroeder, J

2016-11-01

The most serious and challenging complication of haemophilia treatment is development of inhibitors to replacement factors VIII or IX. Innovative therapies currently being explored for patients with haemophilia and inhibitors include BAY 86-6150, a modified recombinant activated factor VII (FVIIa). Immunogenicity remains a substantial barrier in this endeavour. To present safety and efficacy results of the BAY 86-6150 study in patients with inhibitors and report detailed analysis of epitope mapping in a patient who developed anti-BAY 86-6150 antibodies. Patients aged 12-62 years with moderate or severe haemophilia A or B were eligible for the phase 3 TRUST trial if they had a history of high-titre inhibitors. Four escalating doses of BAY 86-6150 (6.5, 20, 50, 90 μg kg -1 ) were planned with ≥10 patients per dose level. Bleeding episodes were treated with BAY 86-6150. Development of anti-BAY 86-6150 antibodies was considered a serious adverse event. TRUST was discontinued after one patient in the 6.5-μg kg -1 cohort developed anti-BAY 86-6150 neutralizing antibodies following three exposures. The anti-BAY 86-6150 antibodies cross-reacted with and neutralized wild-type FVIIa (WT-FVIIa). Post hoc epitope mapping using peripheral blood mononuclear cells from the responding patient found that none of the 14 peptides unique to BAY 86-6150 were recognized by the patient's T cells, but strong responses were detected against 2 WT-FVIIa peptides. In the single patient with haemophilia A who developed anti-BAY 86-6150 antibodies, results of T-cell epitope mapping indicated BAY 86-6150 was no more immunogenic than WT-FVIIa. © 2016 The Authors. Haemophilia Published by John Wiley & Sons Ltd.

Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity.

PubMed

Wengner, Antje M; Siemeister, Gerhard; Koppitz, Marcus; Schulze, Volker; Kosemund, Dirk; Klar, Ulrich; Stoeckigt, Detlef; Neuhaus, Roland; Lienau, Philip; Bader, Benjamin; Prechtl, Stefan; Raschke, Marian; Frisk, Anna-Lena; von Ahsen, Oliver; Michels, Martin; Kreft, Bertolt; von Nussbaum, Franz; Brands, Michael; Mumberg, Dominik; Ziegelbauer, Karl

2016-04-01

Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the structure and functional characterization of two novel selective Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both Mps1 inhibitors abrogated nocodazole-induced SAC activity and induced premature exit from mitosis ("mitotic breakthrough"), resulting in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC50 nmol/L range). In vivo, BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combined with paclitaxel, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest by the weakening of SAC activity. As a result, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models, including those showing acquired or intrinsic paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy. These preclinical findings validate the innovative concept of SAC abrogation for cancer therapy and justify clinical proof-of-concept studies evaluating the Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs to enhance their efficacy and potentially overcome resistance. Mol Cancer Ther; 15(4); 583-92. ©2016 AACR. ©2016 American Association for Cancer Research.

The effect of acarbose and miglitol (BAY-M-1099) on postprandial glucose levels following ingestion of various sources of starch by nondiabetic and streptozotocin-induced diabetic rats.

PubMed

Madar, Z

1989-12-01

The effect of two alpha-glucosidase inhibitors, acarbose (BAY-G-5421) and miglitol (BAY-M-1099), on postprandial glucose levels following intubation of corn, rice, spaghetti and potato (0.5 g/100 g body wt) was evaluated in nondiabetic and diabetic rats. The peak plasma glucose level and total incremental glucose were significantly decreased following ingestion of each starch source when acarbose (8 mg/100 g body wt) or BAY-M-1099 (2 mg/100 g body wt) were simultaneously intubated. The effect of both inhibitors was more pronounced in diabetic rats than in nondiabetic rats, and their effect on digestion was in a substrate-specific manner. Potato starch digestion was inhibited 58 +/- 11% by BAY-M-1099, and by acarbose, 38 +/- 9%. Rice starch digestion was inhibited by 65 +/- 2% by acarbose, and by BAY-M-1099, only 30 +/- 9%. Both drugs had a similar inhibitory effect when corn or spaghetti was ingested. BAY-M-1099 appears to be more potent than acarbose on both a weight-per-weight basis and on a molar basis. When corn or rice was used, only 2 mg of BAY-M-1099 was required to achieve a similar inhibitory effect to that of 8 mg of acarbose (9.7 X 10(-3) M) vs. 12.2 X 10(-3) M). Since both drugs blunted to varying degrees the rise in glucose level following starch ingestion, they may be a useful adjuvant in the treatment of diabetic subjects. Simultaneous use of both drugs in therapeutic treatment should be seriously considered.

10 CFR 70.82 - Suspension and operation in war or national emergency.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 2 2010-01-01 2010-01-01 false Suspension and operation in war or national emergency. 70... NUCLEAR MATERIAL Modification and Revocation of Licenses § 70.82 Suspension and operation in war or national emergency. Whenever Congress declares that a state of war or national emergency exists, the...

Multicenter phase I trial of the mitogen-activated protein kinase 1/2 inhibitor BAY 86-9766 in patients with advanced cancer.

PubMed

Weekes, Colin D; Von Hoff, Daniel D; Adjei, Alex A; Leffingwell, Diane P; Eckhardt, S Gail; Gore, Lia; Lewis, Karl D; Weiss, Glen J; Ramanathan, Ramesh K; Dy, Grace K; Ma, Wen W; Sheedy, Beth; Iverson, Cory; Miner, Jeffrey N; Shen, Zancong; Yeh, Li-Tain; Dubowy, Ronald L; Jeffers, Michael; Rajagopalan, Prabhu; Clendeninn, Neil J

2013-03-01

To evaluate the safety, pharmacokinetics, and pharmacodynamics of BAY 86-9766, a selective, potent, orally available, small-molecule allosteric inhibitor of mitogen-activated protein kinase 1/2 in patients with advanced solid tumors. BAY 86-9766 was administered orally daily in 28-day courses, with doses escalated to establish the maximum-tolerated dose (MTD). An expanded cohort was evaluated at the MTD. Pharmacokinetic and pharmacodynamic parameters were assessed, with extracellular signal-regulated kinase (ERK) phosphorylation evaluated in paired biopsies from a subset of the expanded MTD cohort. Tumor specimens were evaluated for mutations in select genes. Sixty-nine patients were enrolled, including 20 patients at the MTD. The MTD was 100 mg given once-daily or in two divided doses. BAY 86-9766 was well-tolerated. The most common treatment-related toxicities were acneiform rash and gastrointestinal toxicity. BAY 86-9766 was well-absorbed after oral administration (plasma half-life ~12 hours), and displayed dose proportional pharmacokinetics throughout the tested dose range. Continuous daily dosing resulted in moderate accumulation at most dose levels. BAY 86-9766 suppressed ERK phosphorylation in biopsied tissue and tetradecanoylphorbol acetate-stimulated peripheral blood leukocytes. Of 53 evaluable patients, one patient with colorectal cancer achieved a partial response and 11 patients had stable disease for 4 or more courses. An ocular melanoma specimen harbored a GNAQ-activating mutation and exhibited reduced ERK phosphorylation in response to therapy. This phase I study showed that BAY 86-9766 was well-tolerated, with good oral absorption, dose proportional pharmacokinetics, target inhibition at the MTD, and some evidence of clinical benefit across a range of tumor types. ©2012 AACR.

Acrylamide-induced oxidative stress and inflammatory response are alleviated by N-acetylcysteine in PC12 cells: Involvement of the crosstalk between Nrf2 and NF-κB pathways regulated by MAPKs.

PubMed

Pan, Xiaoqi; Wu, Xu; Yan, Dandan; Peng, Cheng; Rao, Chaolong; Yan, Hong

2018-05-15

Acrylamide (ACR) is a classic neurotoxin in animals and humans. However, the mechanism underlying ACR neurotoxicity remains controversial, and effective prevention and treatment measures against this condition are scarce. This study focused on clarifying the crosstalk between the involved signaling pathways in ACR-induced oxidative stress and inflammatory response and investigating the protective effect of antioxidant N-acetylcysteine (NAC) against ACR in PC12 cells. Results revealed that ACR exposure led to oxidative stress characterized by significant increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels and glutathione (GSH) consumption. Inflammatory response was observed based on the dose-dependently increased levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). NAC attenuated ACR-induced enhancement of MDA and ROS levels and TNF-α generation. In addition, ACR activated nuclear transcription factor E2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB) signaling pathways. Knockdown of Nrf2 by siRNA significantly blocked the increased NF-κB p65 protein expression in ACR-treated PC12 cells. Down-regulation of NF-κB by specific inhibitor BAY11-7082 similarly reduced ACR-induced increase in Nrf2 protein expression. NAC treatment increased Nrf2 expression and suppressed NF-κB p65 expression to ameliorate oxidative stress and inflammatory response caused by ACR. Further results showed that mitogen-activated protein kinases (MAPKs) pathway was activated prior to the activation of Nrf2 and NF-κB pathways. Inhibition of MAPKs blocked Nrf2 and NF-κB pathways. Collectively, ACR activated Nrf2 and NF-κB pathways which were regulated by MAPKs. A crosstalk between Nrf2 and NF-κB pathways existed in ACR-induced cell damage. NAC protected against oxidative damage and inflammatory response induced by ACR by activating Nrf2 and inhibiting NF-κB pathways in PC12 cells. Copyright © 2018 Elsevier B.V. All rights reserved.

Nitrative DNA damage induced by multi-walled carbon nanotube via endocytosis in human lung epithelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Guo, Feiye, E-mail: zhizi0269@doc.medic.mie-u.ac.jp; Ma, Ning, E-mail: maning@suzuka-u.ac.jp; Horibe, Yoshiteru, E-mail: violinteru@yahoo.co.jp

Carbon nanotube (CNT) has a promising usage in the field of material science for industrial purposes because of its unique physicochemical property. However, intraperitoneal administration of CNT was reported to cause mesothelioma in experimental animals. Chronic inflammation may contribute to carcinogenesis induced by fibrous materials. 8-Nitroguanine is a mutagenic DNA lesion formed during inflammation and may play a role in CNT-induced carcinogenesis. In this study, we examined 8-nitroguanine formation in A549 human lung alveolar epithelial cells treated with multi-walled CNT (MWCNT) by fluorescent immunocytochemistry. Both MWCNTs with diameter of 20–30 nm (CNT20) and 40–70 nm (CNT40) significantly induced 8-nitroguanine formationmore » at 5 and 10 μg/ml (p < 0.05), which persisted for 24 h, although there was no significant difference in DNA-damaging abilities of these MWCNTs. MWCNTs significantly induced the expression of inducible nitric oxide synthase (iNOS) for 24 h (p < 0.05). MWCNTs also significantly increased the level of nitrite, a hydrolysis product of oxidized NO, in the culture supernatant at 4 and 8 h (p < 0.05). MWCNT-induced 8-nitroguanine formation and iNOS expression were largely suppressed by inhibitors of iNOS (1400 W), nuclear factor-κB (Bay11-7082), actin polymerization (cytochalasin D), caveolae-mediated endocytosis (methyl-β-cyclodextrin, MBCD) and clathrin-mediated endocytosis (monodansylcadaverine, MDC). Electron microscopy revealed that MWCNT was mainly located in vesicular structures in the cytoplasm, and its cellular internalization was reduced by MBCD and MDC. These results suggest that MWCNT is internalized into cells via clathrin- and caveolae-mediated endocytosis, leading to inflammatory reactions including iNOS expression and resulting nitrative DNA damage, which may contribute to carcinogenesis. Highlights: ►Multi-walled carbon nanotube (MWCNT) caused DNA damage in A549 cells. ►MWCNT formed 8-nitroguanine, a DNA lesion associated with inflammatory response. ►MWCNT was internalized into cells via caveolin- and clathrin-mediated endocytosis. ►8-Nitroguanine formation and iNOS expression involved these types of endocytosis. ►Internalized MWCNT plays a key role in inflammatory response and DNA damage.« less

A PROFILE ANALYSIS OF RAMAN-SCATTERED O VI BANDS AT 6825 Å AND 7082 Å IN SANDULEAK’S STAR

DOE Office of Scientific and Technical Information (OSTI.GOV)

Heo, Jeong-Eun; Lee, Hee-Won; Angeloni, Rodolfo

2016-12-20

We present a detailed modeling of the two broad bands observed at 6825 and 7082 Å in Sanduleak’s star, a controversial object in the Large Magellanic Cloud. These bands are known to originate from Raman scattering of O vi  λ λ 1032 and 1038 photons with atomic hydrogen and are only observed in bona fide symbiotic stars. Our high-resolution spectrum obtained with the Magellan Inamori Kyocera Echelle spectrograph at the Magellan-Clay Telescope reveals, quite surprisingly, that the profiles of the two bands look very different: while the Raman 6825 Å band shows a single broad profile with a redward extendedmore » bump, the Raman 7082 Å band exhibits a distinct triple-peak profile. Our model suggests that the O vi emission nebula can be decomposed into a red, blue, and central emission region from an accretion disk, a bipolar outflow, and a further compact, optically thick region. We also perform Monte Carlo simulations with the aim of fitting the observed flux ratio F (6825)/ F (7082) ∼ 4.5, which indicates that the neutral region in Sanduleak’s star is characterized by the column density N{sub Hi} ∼ 1 × 10{sup 23} cm{sup −2}.« less

Cyclic GMP-mediated memory enhancement in the object recognition test by inhibitors of phosphodiesterase-2 in mice.

PubMed

Lueptow, Lindsay M; Zhan, Chang-Guo; O'Donnell, James M

2016-02-01

Cyclic nucleotide phosphodiesterase-2 (PDE2) is a potential therapeutic target for the treatment of cognitive dysfunction. Using the object recognition test (ORT), this study assessed the effects of two PDE2 inhibitors, Bay 60-7550 and ND7001, on learning and memory, and examined underlying mechanisms. To assess the role of PDE2 inhibition on phases of memory, Bay 60-7550 (3 mg/kg) was administered: 30 min prior to training; 0, 1, or 3 h after training; or 30 min prior to recall testing. To assess cyclic nucleotide involvement in PDE2 inhibitor-enhanced memory consolidation, either the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg; intraperitoneal (IP)), soluble guanylyl cyclase inhibitor 1H-[-1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ; 20 mg/kg; IP), protein kinase G inhibitor KT5823 (2.5 μg; intracerebroventricular (ICV)), or protein kinase A inhibitor H89 (1 μg; ICV) was administered 30 min prior to the PDE2 inhibitor Bay 60-7550 (3 mg/kg) or ND7001 (3 mg/kg). Changes in the phosphorylation of 3'5'-cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) at Ser-133 and vasodilator-stimulated phosphoprotein (VASP) at Ser-239 were determined to confirm activation of cAMP and 3'5'-cyclic guanosine monophosphate (cGMP) signaling. Bay 60-7550 (3 mg/kg) enhanced memory of mice in the ORT when given 30 min prior to training, immediately after training, or 30 min prior to recall. Inhibitors of the cGMP pathway blocked the memory-enhancing effects of both Bay 60-7550 (3 mg/kg) and ND7001 (3 mg/kg) on early consolidation processes. Bay 60-7550 (3 mg/kg) enhanced phosphorylation of CREB and VASP, both targets of cGMP-dependent protein kinase (PKG). These results confirm a potential of PDE2, or components of its signaling pathway, as a therapeutic target for drug discovery focused on restoring memory function.

Human trabecular meshwork cell volume decrease by NO-independent soluble guanylate cyclase activators YC-1 and BAY-58-2667 involves the BKCa ion channel.

PubMed

Dismuke, William M; Sharif, Najam A; Ellis, Dorette Z

2009-07-01

There is a correlation between cell volume changes and changes in the rate of aqueous humor outflow; agents that decrease trabecular meshwork (TM) cell volume increase the rate of aqueous humor outflow. This study investigated the effects of the nitric oxide (NO)-independent activators of soluble guanylate cyclase (sGC), YC-1, and BAY-58-2667 on TM cell volume and the signal transduction pathways and ion channel involved. Cell volume was measured with the use of calcein AM fluorescent dye, detected by confocal microscopy. Inhibitors and activators of sGC, 3',5'-cyclic guanosine monophosphate (cGMP), protein kinase G (PKG), and the BK(Ca) channel were used to characterize their involvement in the YC-1- and BAY-58-2667-induced regulation of TM cell volume. cGMP was assayed by an enzyme immunoassay. YC-1 (10 nM-200 microM) and BAY-58-2667 (10 nM-100 microM) each elicited a biphasic effect on TM cell volume. YC-1 (1 microM) increased TM cell volume, but higher concentrations decreased TM cell volume. Similarly, BAY-58-2667 (100 nM) increased TM cell volume, but higher concentrations decreased cell volume. The YC-1-induced cell volume decrease was mimicked by 8-Br-cGMP and abolished by the sGC inhibitor ODQ, the PKG inhibitor (RP)-8-Br-PET-cGMP-S, and the BK(Ca) channel inhibitor IBTX. The BAY-58-2667-induced cell volume decrease was mimicked by 8-Br-cGMP and was abolished by the PKG inhibitor and the BK(Ca) channel inhibitor. Unlike the YC-1 response, ODQ potentiated the BAY-58-2667-induced decreases in cell volume. These data suggest that the NO-independent decrease in TM cell volume is mediated by the sGC/cGMP/PKG pathway and involves K(+) efflux.

A Monte Carlo Study of Flux Ratios of Raman Scattered O VI Features at 6825 and 7082 Å in Symbiotic Stars

NASA Astrophysics Data System (ADS)

Lee, Young-Min; Lee, Dae-Sub; Chang, Seok-Jun; Heo, Jeong-Eun; Lee, Hee-Won; Hwang, Narae; Park, Byeong-Gon; Lee, Ho-Gyu

2016-12-01

Symbiotic stars are regarded as wide binary systems consisting of a hot white dwarf and a mass losing giant. They exhibit unique spectral features at 6825 and 7082 Å, which are formed via Raman scattering of O VI λλ 1032 and 1038 with atomic hydrogen. We adopt a Monte Carlo technique to generate the same number of O VI λ1032 and λ1038 line photons and compute the flux ratio F(6825)/F(7082) of these Raman scattered O VI features formed in neutral regions with a simple geometric shape as a function of H I column density N H I . In cylindrical and spherical neutral regions with the O VI source embedded inside, the flux ratio F(6825)/F(7082) shows an overall decrease from 3 to 1 as N H I increases in the range {10}22{--24} {{cm}}-2. In cases of slab geometry and other geometries with the O VI source outside the H I region, Rayleigh escape operates to lower the flux ratio considerably. For moderate values of {N}{{H}{{I}}}˜ {10}23 {{cm}}-2 the flux ratio behaves in a complicated way to exhibit a broad bump with a peak value of 3.5 in the case of a sphere geometry. We find that the ratio of Raman conversion efficiencies of O VI λλ 1032, 1038 ranges from 0.8 to 3.5. Our high resolution spectra of “D” type HM Sge and “S” type AG Dra obtained with the Canada-France-Hawaii Telescope show that the flux ratio F(6825)/F(7082) of AG Dra is significantly smaller than that of HM Sge, implying that “S” type symbiotics are characterized by higher N H I than “D” type symbiotics.

Sulforaphane rescues amyloid-β peptide-mediated decrease in MerTK expression through its anti-inflammatory effect in human THP-1 macrophages.

PubMed

Jhang, Kyoung A; Park, Jin-Sun; Kim, Hee-Sun; Chong, Young Hae

2018-03-12

Mer tyrosine kinase (MerTK) activity necessary for amyloid-stimulated phagocytosis strongly implicates that MerTK dysregulation might contribute to chronic inflammation implicated in Alzheimer's disease (AD) pathology. However, the precise mechanism involved in the regulation of MerTK expression by amyloid-β (Aβ) in proinflammatory environment has not yet been ascertained. The objective of this study was to determine the underlying mechanism involved in Aβ-mediated decrease in MerTK expression through Aβ-mediated regulation of MerTK expression and its modulation by sulforaphane in human THP-1 macrophages challenged with Aβ1-42. We used protein preparation, Ca 2+ influx fluorescence imaging, nuclear fractionation, Western blotting techniques, and small interfering RNA (siRNA) knockdown to perform our study. Aβ1-42 elicited a marked decrease in MerTK expression along with increased intracellular Ca 2+ level and induction of proinflammatory cytokines such as IL-1β and TNF-α. Ionomycin A and thapsigargin also increased intracellular Ca 2+ levels and production of IL-1β and TNF-α, mimicking the effect of Aβ1-42. In contrast, the Aβ1-42-evoked responses were attenuated by depletion of Ca 2+ with ethylene glycol tetraacetic acid. Furthermore, recombinant IL-1β or TNF-α elicited a decrease in MerTK expression. However, immunodepletion of IL-1β or TNF-α with neutralizing antibodies significantly inhibited Aβ1-42-mediated downregulation of MerTK expression. Notably, sulforaphane treatment potently inhibited Aβ1-42-induced intracellular Ca 2+ level and rescued the decrease in MerTK expression by blocking nuclear factor-κB (NF-κB) nuclear translocation, thereby decreasing IL-1β and TNF-α production upon Aβ1-42 stimulation. Such adverse effects of sulforaphane were replicated by BAY 11-7082, a NF-κB inhibitor. Moreover, sulforaphane's anti-inflammatory effects on Aβ1-42-induced production of IL-1β and TNF-α were significantly diminished by siRNA-mediated knockdown of MerTK, confirming a critical role of MerTK in suppressing Aβ1-42-induced innate immune response. These findings implicate that targeting of MerTK with phytochemical sulforaphane as a mechanism for preventing Aβ1-42-induced neuroinflammation has potential to be applied in AD therapeutics.

3,4,5-Tricaffeoylquinic acid inhibits tumor necrosis factor-α-stimulated production of inflammatory mediators in keratinocytes via suppression of Akt- and NF-κB-pathways.

PubMed

Lee, Chung Soo; Lee, Seon Ae; Kim, Yun Jeong; Seo, Seong Jun; Lee, Min Won

2011-11-01

Keratinocytes may play an important role in the pathogenesis of skin disease in atopic dermatitis. Caffeoyl derivatives are demonstrated to have anti-inflammatory and anti-oxidant effects. However, the effect of 3,4,5-tricaffeoylquinic acid prepared from Aconium koreanum on the pro-inflammatory cytokine-stimulated keratinocyte responses remains uncertain. In human keratinocytes, we investigated the effect of 3,4,5-tricaffeoylquinic acid on the tumor necrosis factor (TNF)-α-stimulated production of inflammatory mediators in relation to the nuclear factor (NF)-κB and cell signaling Akt, which regulates the transcription genes involved in immune and inflammatory responses. 3,4,5-Tricaffeoylquinic acid inhibited the TNF-α-stimulated production of cytokines (IL-1β and IL-8) and chemokine (CCL17 and CCL27) in keratinocytes. Bay 11-7085 (an inhibitor of NF-κB activation) and Akt inhibitor attenuated the TNF-α-induced formation of inflammatory mediators. 3,4,5-Tricaffeoylquinic acid, Bay 11-7085, Akt inhibitor and N-acetylcysteine inhibited the TNF-α-induced activation of NF-κB, activation of Akt, and formation of reactive oxygen and nitrogen species. The results show that 3,4,5-tricaffeoylquinic acid seems to attenuate the TNF-α-stimulated inflammatory mediator production in keratinocytes by suppressing the activation of Akt and NF-κB pathways which may be mediated by reactive oxygen species. The findings suggest that 3,4,5-tricaffeoylquinic acid may exert an inhibitory effect against the pro-inflammatory mediator-induced skin disease. Copyright © 2011 Elsevier B.V. All rights reserved.

19 CFR 7.11 - Guantanamo Bay Naval Station.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 19 Customs Duties 1 2010-04-01 2010-04-01 false Guantanamo Bay Naval Station. 7.11 Section 7.11... TREASURY CUSTOMS RELATIONS WITH INSULAR POSSESSIONS AND GUANTANAMO BAY NAVAL STATION § 7.11 Guantanamo Bay Naval Station. Articles of foreign origin may enter the area (both land and water) of the Guantanamo Bay...

19 CFR 7.11 - Guantanamo Bay Naval Station.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 19 Customs Duties 1 2011-04-01 2011-04-01 false Guantanamo Bay Naval Station. 7.11 Section 7.11... TREASURY CUSTOMS RELATIONS WITH INSULAR POSSESSIONS AND GUANTANAMO BAY NAVAL STATION § 7.11 Guantanamo Bay Naval Station. Articles of foreign origin may enter the area (both land and water) of the Guantanamo Bay...

Safety and efficacy of BAY 81-8973 for surgery in previously treated patients with haemophilia A: results of the LEOPOLD clinical trial programme.

PubMed

Oldenburg, J; Windyga, J; Hampton, K; Lalezari, S; Tseneklidou-Stoeter, D; Beckmann, H; Maas Enriquez, M

2016-05-01

BAY 81-8973 is a recombinant factor VIII (rFVIII) with the same amino acid sequence as Bayer's sucrose-formulated rFVIII (rFVIII-FS) but manufactured with certain more advanced technologies. To describe surgery outcomes with BAY 81-8973 in the LEOPOLD trials. Male patients with severe haemophilia A and no inhibitors aged 12-65 years with ≥150 exposure days (EDs) to FVIII (LEOPOLD I and II), or aged ≤12 years with ≥50 EDs to FVIII (LEOPOLD Kids), received BAY 81-8973 based on dosing recommendations for rFVIII-FS according to surgical requirements. Haemostasis-related complications, investigator/surgeon assessment of haemostasis, blood loss, need for transfusion and use of BAY 81-8973 were determined. In LEOPOLD I and II, 11 patients (mean age, 35.3 years) underwent 13 major surgeries. In LEOPOLD Kids, one patient (aged 6 years) underwent one major surgery. Thirty-two adult and paediatric patients underwent 46 minor surgeries. Haemostasis was rated good or excellent in all major and minor surgeries. Blood loss during surgery did not exceed expected amounts; blood transfusions were required in three of the 14 major surgeries. For major surgeries in LEOPOLD I and II, patients received a presurgical 50-IU kg(-1) dose of BAY 81-8973; median nominal dose on day of surgery was 7000 IU (107.5 IU kg(-1) ). Total BAY 81-8973 dose was 2500 IU (108.7 IU kg(-1) ) on the day of the only major surgery in LEOPOLD Kids. No haemostasis-related complications were reported. Haemostatic control with BAY 81-8973 during all surgeries in the LEOPOLD trials was good or excellent, with no haemostasis-related complications. © 2016 John Wiley & Sons Ltd.

Characterization of novel MPS1 inhibitors with preclinical anticancer activity.

PubMed

Jemaà, M; Galluzzi, L; Kepp, O; Senovilla, L; Brands, M; Boemer, U; Koppitz, M; Lienau, P; Prechtl, S; Schulze, V; Siemeister, G; Wengner, A M; Mumberg, D; Ziegelbauer, K; Abrieu, A; Castedo, M; Vitale, I; Kroemer, G

2013-11-01

Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2-[(2-cyanophenyl)amino][1,2,4]triazolo[1,5-a]pyridin-6-yl}phenyl)-2-phenylacetamide (Mps-BAY1) (a triazolopyridine), N-cyclopropyl-4-{8-[(2-methylpropyl)amino]-6-(quinolin-5-yl)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2a) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals.

Probing the catalytic functions of Bub1 kinase using the small molecule inhibitors BAY-320 and BAY-524

PubMed Central

Baron, Anna P; von Schubert, Conrad; Cubizolles, Fabien; Siemeister, Gerhard; Hitchcock, Marion; Mengel, Anne; Schröder, Jens; Fernández-Montalván, Amaury; von Nussbaum, Franz; Mumberg, Dominik; Nigg, Erich A

2016-01-01

The kinase Bub1 functions in the spindle assembly checkpoint (SAC) and in chromosome congression, but the role of its catalytic activity remains controversial. Here, we use two novel Bub1 inhibitors, BAY-320 and BAY-524, to demonstrate potent Bub1 kinase inhibition both in vitro and in intact cells. Then, we compared the cellular phenotypes of Bub1 kinase inhibition in HeLa and RPE1 cells with those of protein depletion, indicative of catalytic or scaffolding functions, respectively. Bub1 inhibition affected chromosome association of Shugoshin and the chromosomal passenger complex (CPC), without abolishing global Aurora B function. Consequently, inhibition of Bub1 kinase impaired chromosome arm resolution but exerted only minor effects on mitotic progression or SAC function. Importantly, BAY-320 and BAY-524 treatment sensitized cells to low doses of Paclitaxel, impairing both chromosome segregation and cell proliferation. These findings are relevant to our understanding of Bub1 kinase function and the prospects of targeting Bub1 for therapeutic applications. DOI: http://dx.doi.org/10.7554/eLife.12187.001 PMID:26885717

Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma.

PubMed

Narita, Tomoko; Ishida, Takashi; Ito, Asahi; Masaki, Ayako; Kinoshita, Shiori; Suzuki, Susumu; Takino, Hisashi; Yoshida, Takashi; Ri, Masaki; Kusumoto, Shigeru; Komatsu, Hirokazu; Imada, Kazunori; Tanaka, Yuetsu; Takaori-Kondo, Akifumi; Inagaki, Hiroshi; Scholz, Arne; Lienau, Philip; Kuroda, Taruho; Ueda, Ryuzo; Iida, Shinsuke

2017-08-31

Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/P-TEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. We evaluated the therapeutic potential of BAY 1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY 1143572 decreased c-Myc and Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n = 11), and CD4 + cells from healthy volunteers (n = 5) were 0.535, 0.30, and 0.36 μM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572-treated ATL-bearing mice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n = 7 for both). Collectively, this study indicates that BAY 1143572 showed strong potential as a novel treatment of ATL. © 2017 by The American Society of Hematology.

Safety and efficacy of BAY 94-9027, a prolonged-half-life factor VIII.

PubMed

Reding, M T; Ng, H J; Poulsen, L H; Eyster, M E; Pabinger, I; Shin, H-J; Walsch, R; Lederman, M; Wang, M; Hardtke, M; Michaels, L A

2017-03-01

Essentials Recombinant factor VIII BAY 94-9027 conjugates in a site-specific manner with polyethylene glycol. BAY 94-9027 was given to patients with severe hemophilia A as prophylaxis and to treat bleeds. BAY 94-9027 prevented bleeds at dose intervals up to every 7 days and effectively treated bleeds. BAY 94-9027 treatment was mainly well tolerated and no patient developed factor VIII inhibitors. Click to hear Dr Tiede's perspective on half-life extended factor VIII for the treatment of hemophilia A SUMMARY: Background BAY 94-9027 is a B-domain-deleted prolonged-half-life recombinant factor VIII (FVIII) that conjugates in a site-specific manner with polyethylene glycol. Objective Assess efficacy and safety of BAY 94-9027 for prophylaxis and treatment of bleeds in patients with severe hemophilia A. Patients/methods In this multinational, phase 2/3, partially randomized, open-label trial, men aged 12-65 years with FVIII < 1% and ≥ 150 exposure days to FVIII received BAY 94-9027 for 36 weeks on demand or prophylactically at intervals determined following a 10-week run-in period on 25 IU kg -1 body weight two times per week. Patients with > 1 bleed during the run-in subsequently received 30-40 IU kg -1 two times per week; patients with ≤ 1 bleed were eligible for randomization to every-5-days (45-60 IU kg -1 ) or every-7-days (60 IU kg -1 ) prophylaxis (1 : 1) for 26 additional weeks until randomization arms were filled. Patients who were eligible but not randomized continued twice-weekly prophylaxis. The primary efficacy outcome was annualized bleeding rate (ABR). Results The intent-to-treat population included 132 patients (prophylaxis, n = 112; on demand, n = 20). Median ABR (quartile [Q1; Q3]) for patients treated two times per week who were not eligible for randomization (n = 13) improved after dose increase (17.4 [14.3; 26.0] to 4.1 [2.0; 10.6]). Median ABR for patients randomized to every-5-days treatment (n = 43) was 1.9 (0; 4.2), similar to patients eligible for randomization but who continued treatment two times per week (n = 11). Median ABR for 32/43 patients (74%) who continued every-7-days prophylaxis until study end was 0.96 (0.0; 4.3). Six hundred and thirty-six of 702 bleeds (90.6%) were controlled with ≤ 2 infusions. No patient developed a FVIII inhibitor. Conclusions BAY 94-9027 prevented bleeding across three individually tailored dose regimens and was effective for treatment of bleeds. © 2016 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

IL-1β upregulates Muc5ac expression via NF-κB-induced HIF-1α in asthma.

PubMed

Wu, Shouzhen; Li, Hailong; Yu, Lijuan; Wang, Ning; Li, Xu; Chen, Wei

2017-12-01

The manifest and important feature in respiratory diseases, including asthma and COPD (chronic obstructive pulmonary disease), is the increased numbers and hypersecretion of goblet cells and overexpression of mucins, especially Muc5ac. Many proinflammatory cytokines play important roles in goblet cell metaplasia and overproduction of Muc5ac. However, the effect of IL-1β on Muc5ac expression in asthma remains unknown. Here, we detected the correlation between IL-1β and Muc5ac in asthma patients and further explored the mechanism of IL-1β-induced Muc5ac overexpression. Our results showed that Muc5ac and IL-1β were up-regulated in 41 patients with asthma and that Muc5ac overexpression was related with IL-1β in asthma (R 2 =0.668, p≪0.001). Furthermore, the correlation between IL-1β and Muc5ac is higher in severe group than that in moderate group. In vitro experiments with normal human bronchial epithelial cells (NHBECs) showed that IL-1β up-regulated Muc5ac expression in NHBEC in a time- and dosage-dependent manner. Hypoxia-induced HIF-1α was responsible for Muc5ac expression mediated by IL-1β. Knocking down HIF-1α by siRNA decreased Muc5ac expression under hypoxia even in IL-1β-treated NHBEC cells. Luciferase reporter assay showed that HIF-1α enhanced Muc5ac promoter activity in HEK293T cells. HIF-1α could specifically bind to the promoter of Muc5ac by EMSA. The correlation among IL-1β, HIF-1α and Muc5ac was observed in patients with asthma. Mechanically, NF-κB activation was essential to IL-1β-induced HIF-1α upregulation via the canonical pathway of NF-κB. The level of nuclear p65, a subunit of NF-κB, was obviously increased in NHBEC cells under IL-1β treatment. IL-1β did not change either HIF-1α or Muc5ac expression when inhibiting NF-κB signaling with Bay11-7082, an inhibitor of NF-κB. Collectively, we concluded that IL-1β up-regulated Muc5ac expression via NF-κB-induced HIF-1α in asthma and provided a potential therapeutic target for asthma. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

TRIB3 mediates the expression of Wnt5a and activation of nuclear factor-κB in Porphyromonas endodontalis lipopolysaccharide-treated osteoblasts.

PubMed

Yu, Y; Qiu, L; Guo, J; Yang, D; Qu, L; Yu, J; Zhan, F; Xue, M; Zhong, M

2015-08-01

Porphyromonas endodontalis lipopolysaccharide (LPS) is considered to be correlated with the progression of bone resorption in periodontal and periapical diseases. Wnt5a has recently been implicated in inflammatory processes, but its role is unclear as a P. endodontalis LPS-induced mediator in osteoblasts. Tribbles homolog 3 (TRIB3) encodes a pseudokinase and has been linked to inflammation in certain situations. Here, we found that P. endodontalis LPS induced Wnt5a expression in a dose- and time-dependent manner and it also upregulated translocation, phosphorylation and transcriptional activity of nuclear factor-κB (NF-κB) in MC3T3-E1 cells. Bay 11-7082 blocked the translocation of NF-κB and Wnt5a expression induced by P. endodontalis LPS. Chromatin immunoprecipitation assay further established that induction of Wnt5a by P. endodontalis LPS was mediated through the NF-κB p65 subunit. Additionally, P. endodontalis LPS increased expression of TRIB3 in osteoblasts after 10 h simulated time. Overexpression of TRIB3 enhanced NF-κB phosphorylation and Wnt5a induction, whereas knockdown of TRIB3 inhibited NF-κB phosphorylation and Wnt5a expression in P. endodontalis LPS-stimulated osteoblasts. These results suggest that P. endodontalis LPS has the ability to promote the expression of Wnt5a in mouse osteoblasts, and this induction is mainly mediated by NF-κB pathway. TRIB3 seems to modulate the sustained expression of Wnt5a in osteoblasts stimulated by P. endodontalis LPS, as well as regulating NF-κB phosphorylation. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

33 CFR 165.T11-630 - Safety zone; Giants Enterprises Fireworks Display, San Francisco Bay, San Francisco, CA.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Francisco Bay, San Francisco, CA. (a) Location. This temporary safety zone is established in the navigable waters of the San Francisco Bay near Pier 48 in San Francisco, CA as depicted in National Oceanic and... Fireworks Display, San Francisco Bay, San Francisco, CA. 165.T11-630 Section 165.T11-630 Navigation and...

Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766) in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma12

PubMed Central

Schmieder, Roberta; Puehler, Florian; Neuhaus, Roland; Kissel, Maria; Adjei, Alex A; Miner, Jeffrey N; Mumberg, Dominik; Ziegelbauer, Karl; Scholz, Arne

2013-01-01

OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC. PMID:24204195

A comparative study of sildenafil, NCX-911 and BAY41-2272 on the anococcygeus muscle of diabetic rats.

PubMed

Kalsi, Jasjit S; Ralph, David J; Madge, David J; Kell, Phil D; Cellek, Selim

2004-12-01

We compared the effects of a nitric oxide (NO)-releasing sildenafil (NCX-911), NO-independent soluble guanylate cyclase activator (BAY41-2272) and sildenafil on the anococcygeus muscle from streptozotocin-induced 16-weeks diabetic rats. NCX-911, BAY41-2272 and sildenafil reduced the phenylephrine-induced tone in the control group (EC50=1088.8+/-165.0, 151.6+/-9.3 and 827.1+/-167.3 nM, respectively). The potencies of NCX-911 and BAY41-2272 were not altered, but that of sildenafil was significantly reduced in the diabetic group. EC50 values for NCX-911, BAY41-2272 and sildenafil in the diabetic group were 1765.9+/-303.5, 209.7+/-27.3 and 2842.2+/-640.3 nM, respectively (P<0.05 for sildenafil). Nitrergic relaxation responses were significantly decreased in the diabetic group. The remaining nitrergic relaxation responses were potentiated by BAY41-2272 but not by sildenafil or NCX-911. These results confirm that endogenous NO derived from nitrergic nerves is significantly decreased in diabetes, and suggest that NO-releasing PDE5 inhibitors and NO-independent soluble guanylate cyclase activators could be more useful than PDE5 inhibitors in the treatment of ED in long-term diabetes.

33 CFR 165.T11-405 - Safety zone; Sea World Fireworks; Mission Bay, San Diego, CA.

Code of Federal Regulations, 2011 CFR

2011-07-01

... 33 Navigation and Navigable Waters 2 2011-07-01 2011-07-01 false Safety zone; Sea World Fireworks; Mission Bay, San Diego, CA. 165.T11-405 Section 165.T11-405 Navigation and Navigable Waters COAST GUARD... § 165.T11-405 Safety zone; Sea World Fireworks; Mission Bay, San Diego, CA. (a) Location. The safety...

Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling.

PubMed

Masood, Anbrin; Huang, Ying; Hajjhussein, Hassan; Xiao, Lan; Li, Hao; Wang, Wei; Hamza, Adel; Zhan, Chang-Guo; O'Donnell, James M

2009-11-01

Phosphodiesterase (PDE)-2 is a component of the nitric-oxide synthase (NOS)/guanylyl cyclase signaling pathway in the brain. Given recent evidence that pharmacologically induced changes in NO-cGMP signaling can affect anxiety-related behaviors, the effects of the PDE2 inhibitors (2-(3,4-dimethoxybenzyl)-7-det-5-methylimidazo-[5,1-f][1,2,4]triazin-4(3H)-one) (Bay 60-7550) and 3-(8-methoxy-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)benzamide (ND7001), as well as modulators of NO, were assessed on cGMP signaling in neurons and on the behavior of mice in the elevated plus-maze, hole-board, and open-field tests, well established procedures for the evaluation of anxiolytics. Bay 60-7550 (1 microM) and ND7001 (10 microM) increased basal and N-methyl-d-aspartate- or detanonoate-stimulated cGMP in primary cultures of rat cerebral cortical neurons; Bay 60-7550, but not ND7001, also increased cAMP. Increased cGMP signaling, either by administration of the PDE2 inhibitors Bay 60-7550 (0.5, 1, and 3 mg/kg) or ND7001 (1 mg/kg), or the NO donor detanonoate (0.5 mg/kg), antagonized the anxiogenic effects of restraint stress on behavior in the three tests. These drugs also produced anxiolytic effects on behavior in nonstressed mice in the elevated plus-maze and hole-board tests; these effects were antagonized by the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (20 mg/kg). By contrast, the NOS inhibitor N(omega)-nitro-l-arginine methyl ester (50 mg/kg), which reduces cGMP signaling, produced anxiogenic effects similar to restraint stress. Overall, the present behavioral and neurochemical data suggest that PDE2 may be a novel pharmacological target for the development of drugs for the treatment of anxiety disorders.

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II).

PubMed

Kavakli, K; Yang, R; Rusen, L; Beckmann, H; Tseneklidou-Stoeter, D; Maas Enriquez, M

2015-03-01

BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. To demonstrate superiority of prophylaxis vs. on demand therapy with BAY 81-8973 in patients with severe hemophilia A. In this multinational,randomized, open-label crossover study (LEOPOLD II;ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20-30 IU kg(-1)), 3-times-weekly prophylaxis (30-40 IU kg(-1)), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs)and immunogenicity were also assessed. Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, ANOVA). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0;3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. Twice weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated.

Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia.

PubMed

Mahlangu, J N; Coetzee, M J; Laffan, M; Windyga, J; Yee, T T; Schroeder, J; Haaning, J; Siegel, J E; Lemm, G

2012-05-01

BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. The study included non-bleeding men (18-65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg(-1) [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5-7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26-237 nm thrombin from 6.5 to 90 μg kg(-1)). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg(-1)), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. © 2012 International Society on Thrombosis and Haemostasis.

Superior efficacy of helicase-primase inhibitor BAY 57-1293 for herpes infection and latency in the guinea pig model of human genital herpes disease.

PubMed

Baumeister, Judith; Fischer, Ruediger; Eckenberg, Peter; Henninger, Kerstin; Ruebsamen-Waigmann, Helga; Kleymann, Gerald

2007-01-01

The efficacy of BAY 57-1293, a novel non-nucleosidic inhibitor of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), bovine herpesvirus and pseudorabies virus, was studied in the guinea pig model of genital herpes in comparison with the licensed drug valaciclovir (Valtrex). Early therapy with BAY 57-1293 almost completely suppressed the symptoms of acute HSV-2 infection, and reduced virus shedding and viral load in the sacral dorsal root ganglia by up to three orders of magnitude, resulting in decreased latency and a greatly diminished frequency of subsequent recurrent episodes. In contrast, valaciclovir showed only moderate effects in this set of experiments. When treatment was initiated late during the course of disease after symptoms were apparent, that is, a setting closer to most clinical situations, the efficacy of therapy with BAY 57-1293 was even more pronounced. Compared with valaciclovir, BAY 57-1293 halved the time necessary for complete healing. Moreover, the onset of action was fast, so that only very few animals developed new lesions after treatment commenced. Finally, in a study addressing the treatment of recurrent disease in animals whose primary infection had remained untreated BAY 57-1293 was efficient in suppressing the episodes. In summary, superior potency and efficacy of BAY 57-1293 over standard treatment with valaciclovir was demonstrated in relevant animal models of human genital herpes disease in terms of abrogating an HSV infection, reducing latency and the frequency of subsequent recurrences. Furthermore, BAY 57-1293 shortens the time to healing even if initiation of therapy is delayed.

NADPH oxidase/ROS-dependent PYK2 activation is involved in TNF-α-induced matrix metalloproteinase-9 expression in rat heart-derived H9c2 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Chuen-Mao, E-mail: chuenmao@mail.cgu.edu.tw; Heart Failure Center, Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; Lee, I-Ta

TNF-α plays a mediator role in the pathogenesis of chronic heart failure contributing to cardiac remodeling and peripheral vascular disturbances. The implication of TNF-α in inflammatory responses has been shown to be mediated through up-regulation of matrix metalloproteinase-9 (MMP-9). However, the detailed mechanisms of TNF-α-induced MMP-9 expression in rat embryonic-heart derived H9c2 cells are largely not defined. We demonstrated that in H9c2 cells, TNF-α induced MMP-9 mRNA and protein expression associated with an increase in the secretion of pro-MMP-9. TNF-α-mediated responses were attenuated by pretreatment with the inhibitor of ROS (N-acetyl-L-cysteine, NAC), NADPH oxidase [apocynin (APO) or diphenyleneiodonium chloride (DPI)],more » MEK1/2 (U0126), p38 MAPK (SB202190), JNK1/2 (SP600125), NF-κB (Bay11-7082), or PYK2 (PF-431396) and transfection with siRNA of TNFR1, p47{sup phox}, p42, p38, JNK1, p65, or PYK2. Moreover, TNF-α markedly induced NADPH oxidase-derived ROS generation in these cells. TNF-α-enhanced p42/p44 MAPK, p38 MAPK, JNK1/2, and NF-κB (p65) phosphorylation and in vivo binding of p65 to the MMP-9 promoter were inhibited by U0126, SB202190, SP600125, NAC, DPI, or APO. In addition, TNF-α-mediated PYK2 phosphorylation was inhibited by NAC, DPI, or APO. PYK2 inhibition could reduce TNF-α-stimulated MAPKs and NF-κB activation. Thus, in H9c2 cells, we are the first to show that TNF-α-induced MMP-9 expression is mediated through a TNFR1/NADPH oxidase/ROS/PYK2/MAPKs/NF-κB cascade. We demonstrated that NADPH oxidase-derived ROS generation is involved in TNF-α-induced PYK2 activation in these cells. Understanding the regulation of MMP-9 expression and NADPH oxidase activation by TNF-α on H9c2 cells may provide potential therapeutic targets of chronic heart failure. - Highlights: • TNF-α induces MMP-9 secretion and expression via a TNFR1-dependent pathway. • TNF-α induces ROS/PYK2-dependent MMP-9 expression in H9c2 cells. • TNF-α induces MMP-9 expression via a NADPH oxidase/ROS-dependent NF-κB signaling. • TNF-α activates MAPK phosphorylation through NADPH oxidase/ROS generation.« less

Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes

PubMed Central

2010-01-01

Background Brain edema leading to high intracranial pressure is a lethal complication of acute liver failure (ALF), which is believed to be cytotoxic due to swelling of astrocytes. In addition to the traditional view that elevated levels of blood and brain ammonia are involved in the mechanism of brain edema in ALF, emerging evidence suggests that inflammatory cytokines also contribute to this process. We earlier reported that treatment of astrocyte cultures with a pathophysiological concentration of ammonia (5 mM NH4Cl) resulted in the activation of nuclear factor-kappaB (NF-κB) and that inhibition of such activation diminished astrocyte swelling, suggesting a key role of NF-κB in the mechanism of ammonia-induced astrocyte swelling. Since cytokines are also well-known to activate NF-κB, this study examined for additive/synergistic effects of ammonia and cytokines in the activation of NF-κB and their role in astrocyte swelling. Methods Primary cultures of astrocytes were treated with ammonia and cytokines (TNF-α, IL-1, IL-6, IFN-γ, each at 10 ng/ml), individually or in combination, and cell volume was determined by the [3H]-O-methylglucose equilibration method. The effect of ammonia and cytokines on the activation of NF-κB was determined by immunoblots. Results Cell swelling was increased by ammonia (43%) and by cytokines (37%) at 24 h. Simultaneous co-treatment with cytokines and ammonia showed no additional swelling. By contrast, cultures pretreated with ammonia for 24 h and then exposed to cytokines for an additional 24 h, showed a marked increase in astrocyte swelling (129%). Treatment of cultures with ammonia or cytokines alone also activated NF-κB (80-130%), while co-treatment had no additive effect. However, in cultures pre-treated with ammonia for 24 h, cytokines induced a marked activation of NF-κB (428%). BAY 11-7082, an inhibitor of NF-κB, completely blocked the astrocyte swelling in cultures pre-treated with ammonia and followed by the addition of a mixture of cytokines. Conclusion Our results indicate that ammonia and a mixture of cytokines each cause astrocyte swelling but when these agents are added simultaneously, no additive effects were found. On the other hand, when cells were initially treated with ammonia and 24 h later given a mixture of cytokines, a marked potentiation in cell swelling and NF-κB activation occurred. These data suggest that the potentiation in cell swelling is a consequence of the initial activation of NF-κB by ammonia. These findings provide a likely mechanism for the exacerbation of brain edema in patients with ALF in the setting of sepsis/inflammation. PMID:20942959

50 CFR 217.11 - Specified activity and specified geographical region.

Code of Federal Regulations, 2013 CFR

2013-10-01

... geographical region. 217.11 Section 217.11 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL... Coastal Commercial Fireworks Displays at Monterey Bay National Marine Sanctuary, CA § 217.11 Specified activity and specified geographical region. (a) Regulations in this subpart apply only to the Monterey Bay...

50 CFR 217.11 - Specified activity and specified geographical region.

Code of Federal Regulations, 2014 CFR

2014-10-01

... geographical region. 217.11 Section 217.11 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL... Coastal Commercial Fireworks Displays at Monterey Bay National Marine Sanctuary, CA § 217.11 Specified activity and specified geographical region. (a) Regulations in this subpart apply only to the Monterey Bay...

50 CFR 217.11 - Specified activity and specified geographical region.

Code of Federal Regulations, 2012 CFR

2012-10-01

... geographical region. 217.11 Section 217.11 Wildlife and Fisheries NATIONAL MARINE FISHERIES SERVICE, NATIONAL... Coastal Commercial Fireworks Displays at Monterey Bay National Marine Sanctuary, CA § 217.11 Specified activity and specified geographical region. (a) Regulations in this subpart apply only to the Monterey Bay...

77 FR 14276 - Regulated Navigation Area; Little Bay Bridge Construction, Little Bay, Portsmouth, NH

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

...-AA11 Regulated Navigation Area; Little Bay Bridge Construction, Little Bay, Portsmouth, NH AGENCY... under and surrounding the Little Bay and General Sullivan Bridges in order to facilitate construction of the Little Bay Bridge between Newington, NH and Dover, NH. This temporary interim rule is necessary to...

Metabolic changes associated with metformin potentiates Bcl-2 inhibitor, Venetoclax, and CDK9 inhibitor, BAY1143572 and reduces viability of lymphoma cells.

PubMed

Chukkapalli, Vineela; Gordon, Leo I; Venugopal, Parameswaran; Borgia, Jeffrey A; Karmali, Reem

2018-04-20

Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines. We demonstrated that metformin as a single agent, especially at high concentrations produced significant reductions in viability and proliferation only in Daudi and SUDHL-4 cell lines with associated alterations in mitochondrial oxidative and glycolytic metabolism. As bcl-2 proteins, cyclin dependent kinases (CDK) and phosphoinositol-3- kinase (PI3K) also influence mitochondrial physiology and metabolism with clear relevance to the pathogenesis of lymphoma, we investigated the potentiating effects of metformin when combined with novel agents Venetoclax (bcl-2 inhibitor), BAY-1143572 (CDK9 inhibitor) and Idelalisib (p110δ- PI3K inhibitor). Co-treating KPUM-UH1 and SUDHL-4 cells with 10 mM of metformin resulted in 1.4 fold and 8.8 fold decreases, respectively, in IC-50 values of Venetoclax. By contrast, 3-fold and 10 fold reduction in IC-50 values of BAY-1143572 in Daudi and Jeko-1 cells respectively was seen in the presence of 10 mM of metformin. No change in IC-50 value for Idelalisib was observed across cell lines. These data suggest that although metformin is not a potent single agent, targeting cancer metabolism with similar but more effective drugs in novel combination with either bcl-2 or CDK9 inhibitors warrants further exploration.

10 CFR 708.2 - What are the definitions of terms used in this part?

Code of Federal Regulations, 2010 CFR

2010-01-01

... calendar day. Discovery means a process used to enable the parties to learn about each other's evidence... DOE. Mediation means an informal, confidential process in which a neutral third person assists the...

75 FR 36292 - Safety Zone; Bay Swim III, Presque Isle Bay, Erie, PA

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-25

... of Presque Isle Bay, Lake Erie, near Erie, Pennsylvania between 9 a.m. to 11 a.m. on June 26, 2010.... The safety zone will encompass specified waters of Presque Isle Bay, Erie, Pennsylvania starting at...-AA00 Safety Zone; Bay Swim III, Presque Isle Bay, Erie, PA AGENCY: Coast Guard, DHS. ACTION: Temporary...

33 CFR 165.T11-534 - Safety zone; Bay Bridge construction, San Francisco Bay, San Francisco, CA.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Francisco, CA. (a) Location. This temporary safety zone is established in the navigable waters of the San... construction, San Francisco Bay, San Francisco, CA. 165.T11-534 Section 165.T11-534 Navigation and Navigable... within a box connected by the following points: 37°49′06″ N, 122°21′17″ W; 37°49′01″ N, 122°21′12″ W; 37...

Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free recombinant factor VIII product: results from a randomized trial (LEOPOLD II)

PubMed Central

Kavakli, K; Yang, R; Rusen, L; Beckmann, H; Tseneklidou-Stoeter, D; Maas Enriquez, M

2015-01-01

Background BAY 81-8973 is a new full-length human recombinant factor VIII product manufactured with technologies to improve consistency in glycosylation and expression to optimize clinical performance. Objectives To demonstrate superiority of prophylaxis vs. on-demand therapy with BAY 81-8973 in patients with severe hemophilia A. Patients/Methods In this multinational, randomized, open-label crossover study (LEOPOLD II; ClinicalTrials.gov identifier: NCT01233258), males aged 12–65 years with severe hemophilia A were randomized to twice-weekly prophylaxis (20–30 IU kg−1), 3-times-weekly prophylaxis (30–40 IU kg−1), or on-demand treatment with BAY 81-8973. Potency labeling for BAY 81-8973 was based on the chromogenic substrate assay or adjusted to the one-stage assay. Primary efficacy endpoint was annualized number of all bleeds (ABR). Adverse events (AEs) and immunogenicity were also assessed. Results Eighty patients (on demand, n = 21; twice-weekly prophylaxis, n = 28; 3-times-weekly prophylaxis, n = 31) were treated and analyzed. Mean ± SD ABR was significantly lower with prophylaxis (twice-weekly, 5.7 ± 7.2; 3-times-weekly, 4.3 ± 6.5; combined, 4.9 ± 6.8) vs. on-demand treatment (57.7 ± 24.6; P < 0.0001, anova). Median ABR was reduced by 97% with prophylaxis (twice-weekly, 4.0; 3-times-weekly, 2.0; combined, 2.0) vs. on-demand treatment (60.0). Median ABR was higher with twice-weekly vs. 3-times-weekly prophylaxis during the first 6-month treatment period (4.1 vs. 2.0) but was comparable in the second 6-month period (1.1 vs. 2.0). Few patients reported treatment-related AEs (4%); no treatment-related serious AEs or inhibitors were reported. Conclusions Twice-weekly or 3-times-weekly prophylaxis with BAY 81-8973 reduced median ABR by 97% compared with on-demand therapy, confirming the superiority of prophylaxis. Treatment with BAY 81-8973 was well tolerated. PMID:25546368

76 FR 55796 - Safety Zone; TriRock Triathlon, San Diego Bay, San Diego, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-09

...-AA00 Safety Zone; TriRock Triathlon, San Diego Bay, San Diego, CA AGENCY: Coast Guard, DHS. ACTION.... Basis and Purpose Competitor Group is sponsoring the TriRock Triathlon, consisting of 2000 swimmers.... 165.T11-431 to read as follows: Sec. 165.T11-431 Safety Zone; TriRock Triathlon, San Diego Bay, San...

Creation of a Novel Class of Potent and Selective MutT Homologue 1 (MTH1) Inhibitors Using Fragment-Based Screening and Structure-Based Drug Design.

PubMed

Rahm, Fredrik; Viklund, Jenny; Trésaugues, Lionel; Ellermann, Manuel; Giese, Anja; Ericsson, Ulrika; Forsblom, Rickard; Ginman, Tobias; Günther, Judith; Hallberg, Kenth; Lindström, Johan; Persson, Lars Boukharta; Silvander, Camilla; Talagas, Antoine; Díaz-Sáez, Laura; Fedorov, Oleg; Huber, Kilian V M; Panagakou, Ioanna; Siejka, Paulina; Gorjánácz, Mátyás; Bauser, Marcus; Andersson, Martin

2018-03-22

Recent literature has both suggested and questioned MTH1 as a novel cancer target. BAY-707 was just published as a target validation small molecule probe for assessing the effects of pharmacological inhibition of MTH1 on tumor cell survival, both in vitro and in vivo. (1) In this report, we describe the medicinal chemistry program creating BAY-707, where fragment-based methods were used to develop a series of highly potent and selective MTH1 inhibitors. Using structure-based drug design and rational medicinal chemistry approaches, the potency was increased over 10,000 times from the fragment starting point while maintaining high ligand efficiency and drug-like properties.

Inhibition of the transcription factor c-Jun by the MAPK family, and not the NF-κB pathway, suggests that peanut extract has anti-inflammatory properties.

PubMed

Catalán, Úrsula; Fernández-Castillejo, Sara; Anglès, Neus; Morelló, Jose Ramón; Yebras, Martí; Solà, Rosa

2012-10-01

Tumor necrosis factor-α (TNF-α) is involved in inflammatory responses in atherosclerosis. We propose an in vitro cellular assay to evaluate the anti-inflammatory mechanisms of potential modifiers such as food extracts. In the current model we assessed an anti-inflammatory effect of polyphenol-rich peanut extract in lipopolysaccharide (LPS)-induced THP-1 monocytes. THP-1 monocytes were incubated with peanut extract (5, 25, 50 and 100 μg/mL) consisting of 39% flavonols, 37% flavanols and 24% phenolic acid (or BAY 11-7082 (5 μM) as experiment control) for 1 h and then stimulated with LPS (500 ng/mL) for 4 h. Cytotoxicity was measured as lactate dehydrogenase (LDH) activity release. NF-κB and MAPK family were determined by TransAm kit while TNF-α mRNA levels and its mRNA stability by RT-PCR. Intra- and extracellular TNF-α protein was measured by ELISA, and TNF-α converting enzyme (TACE) activity by a fluorimetric assay. Peanut extract inhibited the maximal LPS-induced extracellular TNF-α protein secretion by 18%, 29% and 47% at 25, 50 and 100 μg/mL, respectively (P<0.05). LPS stimulation revealed that 85% of TNF-α was released extracellularly while 15% remained intracellular. Peanut extract did not modify NF-κB but, instead, reduced c-Jun transcription factor activity (P<0.05), decreased TNF-α mRNA (albeit non-significantly) and had no effect on mRNA stability and TACE activity. Polyphenol-rich peanut extract reduces extracellular TNF-α protein by inhibiting c-Jun transcription factor from MAPK family, suggesting an anti-inflammatory effect. The proposed THP-1 monocyte model could be used to assess food extract impact (site and size effects) on the inflammation pathway. Copyright © 2012 Elsevier Ltd. All rights reserved.

OM85-BV Induced the Productions of IL-1β, IL-6, and TNF-α via TLR4- and TLR2-Mediated ERK1/2/NF-κB Pathway in RAW264.7 Cells

PubMed Central

Luan, Hong; Zhang, Qian; Wang, Le; Wang, Chuanxiao; Zhang, Miao; Xu, Xiaoli; Zhou, Huan; Li, Xing'ai; Xu, Qing; He, Fan

2014-01-01

Broncho-Vaxom (OM85-BV) is an extract mixture from 8 strains of Gram+ and Gram− bacteria and plays an important role in anti-infection immune response by regulating macrophage activity and cytokine productions. However, the mechanism by which OM85-BV enhances the cytokine expression is still obscure. In this study, we evaluated the effects of OM85-BV on the productions of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) in RAW264.7 murine macrophages. Exposure of RAW264.7 cells to 100 μg/mL OM85-BV upregulated the expression of IL-1β, IL-6, and TNF-α at the mRNA and protein levels in a time- and dose-dependent manner. In addition, OM85-BV induced extracellular signal-regulated kinase (ERK) 1/2 and nuclear factor-kappa B (NF-κB) phosphorylation. Pretreatment with U0126 or Bay11-7082, respectively, could decrease IL-1β, IL-6, and TNF-α productions induced by OM85-BV. Application of Toll-like receptor (TLR) 4 or TLR2 small-interfering RNA (siRNA) into RAW264.7 cells could inhibit the productions of cytokines and ERK1/2 and NF-κB phosphorylation induced by OM85-BV. Consistent with this, downregulating either myeloid differentiation factor 88 (MyD88) or TRIF-related adaptor molecule (TRAM) gene with MyD88-siRNA or TRAM-siRNA separately could reduce the productions of cytokines and ERK1/2 and NF-κB phosphorylation induced by OM85-BV. Our study demonstrated that the productions of IL-1β, IL-6, and TNF-α induced by OM85-BV in RAW264.7 cells were through TLR4 and TLR2 signaling pathway-mediated activation of ERK1/2 and NF-κB. PMID:24605772

Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells.

PubMed

Koh, Yung-Hua; Moochhala, Shabbir; Bhatia, Madhav

2012-07-01

Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25-30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10(-6) M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Activation of neurokinin-1 receptors up-regulates substance P and neurokinin-1 receptor expression in murine pancreatic acinar cells

PubMed Central

Koh, Yung-Hua; Moochhala, Shabbir; Bhatia, Madhav

2012-01-01

Abstract Acute pancreatitis (AP) has been associated with an up-regulation of substance P (SP) and neurokinin-1 receptor (NK1R) in the pancreas. Increased SP-NK1R interaction was suggested to be pro-inflammatory during AP. Previously, we showed that caerulein treatment increased SP/NK1R expression in mouse pancreatic acinar cells, but the effect of SP treatment was not evaluated. Pancreatic acinar cells were obtained from pancreas of male swiss mice (25–30 g). We measured mRNA expression of preprotachykinin-A (PPTA) and NK1R following treatment of SP (10−6M). SP treatment increased PPTA and NK1R expression in isolated pancreatic acinar cells, which was abolished by pretreatment of a selective NK1R antagonist, CP96,345. SP also time dependently increased protein expression of NK1R. Treatment of cells with a specific NK1R agonist, GR73,632, up-regulated SP protein levels in the cells. Using previously established concentrations, pre-treatment of pancreatic acinar cells with Gö6976 (10 nM), rottlerin (5 μM), PD98059 (30 μM), SP600125 (30 μM) or Bay11-7082 (30 μM) significantly inhibited up-regulation of SP and NK1R. These observations suggested that the PKC-ERK/JNK-NF-κB pathway is necessary for the modulation of expression levels. In comparison, pre-treatment of CP96,345 reversed gene expression in SP-induced cells, but not in caerulein-treated cells. Overall, the findings in this study suggested a possible auto-regulatory mechanism of SP/NK1R expression in mouse pancreatic acinar cells, via activation of NK1R. Elevated SP levels during AP might increase the occurrence of a positive feedback loop that contributes to abnormally high expression of SP and NK1R. PMID:22040127

The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice.

PubMed

Liddie, Shervin; Anderson, Karen L; Paz, Andres; Itzhak, Yossef

2012-10-01

Several phosphodiesterase inhibitors (PDEis) improve cognition, suggesting that an increase in brain cAMP and cGMP facilitates learning and memory. Since extinction of drug-seeking behavior requires associative learning, consolidation and formation of new memory, the present study investigated the efficacy of three different PDEis in the extinction of cocaine-induced conditioned place preference (CPP) in B6129S mice. Mice were conditioned by escalating doses of cocaine which was resistant to extinction by free exploration. Immediately following each extinction session mice received (a) saline/vehicle, (b) rolipram (PDE4 inhibitor), (c) BAY-73-6691 (PDE9 inhibitor) or (d) papaverine (PDE10A inhibitor). Mice that received saline/vehicle during extinction training showed no reduction in CPP for >10 days. BAY-73-6691 (a) dose-dependently increased cGMP in hippocampus and amygdala, (b) significantly facilitated extinction and (c) diminished the reinstatement of cocaine CPP. Rolipram, which selectively increased brain cAMP levels, and papaverine which caused increases in both cAMP and cGMP levels, had no significant effect on the extinction of cocaine CPP. The results suggest that increase in hippocampal and amygdalar cGMP levels via blockade of PDE9 has a prominent role in the consolidation of extinction learning.

Differential effects of tumor necrosis factor-α on matrix metalloproteinase-2 expression in human myometrial and uterine leiomyoma smooth muscle cells.

PubMed

Wang, Yuebing; Feng, Guowei; Wang, Jiyuan; Zhou, Yu; Liu, Yixin; Shi, Yiquan; Zhu, Yingjun; Lin, Wanjun; Xu, Yang; Li, Zongjin

2015-01-01

Does tumor necrosis factor-α (TNF-α) differentially regulate matrix metalloproteinase-2 (MMP-2) expression in leiomyomas compared with normal myometrium? TNF-α up-regulates MMP-2 expression and stimulates cell migration through the activation of extracellular signal-regulated kinase (ERK) signaling pathway in leiomyoma smooth muscle cells (SMCs), but not in normal myometrial SMCs. Uterine leiomyoma, the benign smooth muscle cell tumor, is the single most common indication for hysterectomy. High expression of MMPs or TNF-α has been reported in uterine leiomyomas; however, the molecular mechanism underlying these observations remains unknown. Samples were obtained between 2009 and 2013 from 12 women of reproductive age at the proliferative phase of the menstrual cycle by hysterectomy. Leiomyomas and matched normal myometrium from each woman were analyzed in vitro. Western blot, RT-qPCR and a wound-healing assay were used to investigate the effects of TNF-α on MMP-2 expression and intracellular signal transduction in cultured SMCs from leiomyomas and matched myometrium. Western blot and RT-qPCR analyses using tissues from clinical patients showed that the levels of MMP-2 protein (P = 0.008) and mRNA (P = 0.009) were significantly higher in uterine leiomyomas compared with their matched myometrium. Treatment with TNF-α significantly up-regulated the protein (P = 0.039) and mRNA (P = 0.037) levels of MMP-2 in cultured leiomyoma SMCs but not in matched myometrial SMCs. The extracellular signal-regulated kinase (ERK) and nuclear factor-kappa B (NF-κB) pathways were activated by TNF-α in leiomyoma SMCs. Specific inhibitors of the ERK or NF-κB pathway (PD98059 or Bay11-7082) suppressed TNF-α-induced MMP-2 expression in leiomyoma SMCs. The wound-healing assay revealed that TNF-α promoted the migration of cultured leiomyoma SMCs (P = 0.036); however, PD98059 compromised the cell migration triggered by TNF-α. This study is descriptive and although we observed clear differential regulation of MMP-2 by TNF-α at mRNA and protein levels in leiomyoma, future studies are needed to identify why the difference in TNF-α response exists between human leiomyoma tissue and normal myometrium. Including some of the experiments such as transfection studies for TNF-α and MMP-2 promoter mapping could have added more insight as to why this difference exists. In addition, further studies in vivo are needed to verify the results obtained from primary cultured SMCs. Considering the positive effect of TNF-α on leiomyoma SMC migration, strategies targeting TNF-α, in parallel with the production of more specific inhibitors of MMPs, may provide alternative therapeutic approaches for the treatment of leiomyoma. This work was partially supported by grants from the Program for New Century Excellent Talents in University (NCET-12-0282), National Natural Science Foundation of China (81371620) and Tianjin Natural Science Foundation (12JCZDJC24900). The authors have no conflicts of interest to declare. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Discovery and SAR of Novel 2,3‐Dihydroimidazo[1,2‐c]quinazoline PI3K Inhibitors: Identification of Copanlisib (BAY 80‐6946)

PubMed Central

Hentemann, Martin F.; Rowley, R. Bruce; Bull, Cathy O.; Jenkins, Susan; Bullion, Ann M.; Johnson, Jeffrey; Redman, Anikó; Robbins, Arthur H.; Esler, William; Fracasso, R. Paul; Garrison, Timothy; Hamilton, Mark; Michels, Martin; Wood, Jill E.; Wilkie, Dean P.; Xiao, Hong; Levy, Joan; Stasik, Enrico; Liu, Ningshu; Schaefer, Martina; Brands, Michael

2016-01-01

Abstract The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3‐dihydroimidazo[1,2‐c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure–activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80‐6946) as a clinical candidate for the treatment of solid and hematological tumors are described. PMID:27310202

Effect of increasing photon irradiance on the growth of Vallisneria americana in the tidal Potomac River

USGS Publications Warehouse

Carter, V.; Rybicki, N.B.; Turtora, M.

1996-01-01

Following declines in submersed macrophyte populations in tidal ecosystems, revegetation of areas devoid of macrophytes may be sudden and rapid or may not occur for years. Declines of submersed macrophyte populations in the Chesapeake Bay and the tidal Potomac River have been attributed to insufficient light in the water column; however, the role of light in promoting revegetation has never been unequivocally documented. Photon irradiance was artificially increased for Vallisneria americana transplants in two unvegetated embayments in the otherwise vegetated freshwater tidal Potomac River: Pohick Bay and Belmont Bay. Pohick Bay had high nutrient concentrations and frequent algal blooms. Belmont Bay was broader and shallower than Pohick Bay with turbidity resulting from wind- driven resuspension of sediment. The total number of plants of V. americana in the lighted cages was 7.5 times higher than that in the unlighted cages at Pohick Bay and 11 times higher than that in the unlighted control cages in Belmont Bay. The biomass in the lighted cages was 11-fold higher in Belmont Bay and 38-fold higher in Pohick Bay than that in the control cages. Plants were less numerous and more robust in lighted cages in Pohick Bay than in Belmont Bay.

Temporal variations of Cu in Jiaozhou Bay 1982-1986

NASA Astrophysics Data System (ADS)

Yang, Dongfang; Zhu, Sixi; Wang, Zhikang; Su, Chunhua; Wang, Qiang

2017-12-01

This paper analyzed the temporal variations of Cu in Jiaozhou Bay during 1982-1986. Results showed that Cu contents in study years were 0.15-5.31 μg L-1, 0.77-20.60 μg L-1, 0.11-4.00 μg L-1, 0.10-0.43 μg L-1 and 0.18-0.77 μg L-1, respectively. The Cu pollution level in this bay was moderate during 1982-1983, yet for temporal variations Cu contents in surface waters were showing decreasing trend. Cu contents in spring, summer and autumn were 0.11-20.60 μg L-1, 0.10-4.86 μg L-1 and 0.11-3.56 μg L-1, respectively. This bay was moderate pollution in spring in 1982-1983, while in other seasons in study years was still slight. These indicated that the temporal variations of Cu pollution in this bay should be taken in to account in decision-making of pollution control practice.

33 CFR 165.T11-560 - Safety Zone; Sea World San Diego Fireworks 2013 Season, Mission Bay; San Diego, CA.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 33 Navigation and Navigable Waters 2 2013-07-01 2013-07-01 false Safety Zone; Sea World San Diego Fireworks 2013 Season, Mission Bay; San Diego, CA. 165.T11-560 Section 165.T11-560 Navigation and Navigable... Eleventh Coast Guard District § 165.T11-560 Safety Zone; Sea World San Diego Fireworks 2013 Season, Mission...

Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Helbig, Linda; Department of Radiation Oncology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden; Koi, Lydia

2014-01-01

Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluatedmore » 150 days after irradiation, and the dose to control 50% of tumors (TCD{sub 50}) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD{sub 50}, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD{sub 50}. Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of radiation response. Whether this mechanism contributes to the improved outcome of fractionated chemoradiation therapy warrants further investigation.« less

78 FR 59902 - Regulated Navigation Area; Special Buzzards Bay Vessel Regulation, Buzzards Bay, MA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-09-30

... DEPARTMENT OF HOMELAND SECURITY Coast Guard 33 CFR Part 165 [Docket No. USCG-2011-0322] RIN 1625-AA11 Regulated Navigation Area; Special Buzzards Bay Vessel Regulation, Buzzards Bay, MA AGENCY: Coast Guard, DHS. ACTION: Notice of extension of comment period. SUMMARY: The Coast Guard is extending the...

76 FR 13611 - Bay Gas Storage, LLC; Notice of Filing

Federal Register 2010, 2011, 2012, 2013, 2014

2011-03-14

... DEPARTMENT OF ENERGY Federal Energy Regulatory Commission [Docket No. PR11-91-000] Bay Gas Storage, LLC; Notice of Filing Take notice that on February 28, 2011, Bay Gas Storage, LLC (Bay Gas) filed pursuant to Section 12.2.4 of its Statement of Operating Conditions to revise its Company Use Percentage as...

Pb’s high sedimentation inside the bay mouth of Jiaozhou Bay

NASA Astrophysics Data System (ADS)

Yang, Dongfang; Miao, Zhenqing; Huang, Xinmin; Wei, Linzhen; Feng, Ming

2017-12-01

Sedimentation is one of the key environmental behaviors of pollutants in the ocean. This paper analyzed the seasonal and temporal variations of Pb’s sedimentation process in Jiaozhou Bay in 1987. Results showed that Pb contents in bottom waters in Jiaozhou Bay in May, July and November 1987 were 1.87-2.60 μg L-1, 15.11-19.68 μg L-1 and 11.08-15.18 μg L-1, and the pollution levels of Pb in May, July and November 1987 were slight, heavy and heavy, respectively. In May 1987, there was low sedimentation process in waters in the outside of the bay mouth, yet were high sedimentation process in waters in the middle and inside of the bay mouth. In July and November 1987, there was low sedimentation process in waters in the outside of the bay mouth, yet were high sedimentation process in waters in the inside of the bay mouth. The seasonal-temporal variation of sedimentation processes of Pb were determined by the variations of sources input and the vertical water’s effect.

Age-Related Intraindividual Performance Variability with Practice

ERIC Educational Resources Information Center

Miller, Suzanne Bonneau; Odell, Katharine H.

2007-01-01

Fluctuations in cognitive task performance in older individuals have been reported. To examine intraindividual variability as a function of practice, 34 younger and 34 older female participants, aged 20-30 years and 70-82 years, respectively, performed a reading span task 16 times over four sessions. Each individual's recall accuracy was analyzed…

Do the physiotherapy results make us happy in a case with ‘happy puppet’ (Angelman) syndrome?

PubMed Central

Kara, Ozgun Kaya; Mutlu, Akmer; Gunel, Mintaze Kerem; Haliloglu, Goknur

2010-01-01

This study aimed to investigate the benefits of physiotherapy programme in a patient with Angelman syndrome (AS) during a follow-up of 3 years. Assessments included: disability level with gross motor function classification systems, gross motor function with gross motor function measurement (GMFM), balance with Berg Balance Scale, motor performance with gross motor performance measurement (GMPM) and tonus assessment with Modified Ashworth Scale. Physiotherapy programme was performed during 36 months, 3 days per week by physical therapist according to Neurodevelopmental Treatment approach. During the 36 months, GMFM increased from 11.46% to 70.82% and GMPM increased from 1.25% to 70.25%. This case report is the first study about the effectiveness of physiotherapy with medium-term follow-up in a child with AS. Physiotherapy results make us happy in this particular patient with ‘happy puppet’ syndrome. PMID:22802472

33 CFR 165.T11-304 - Safety zone; Sea World Summer Nights Fireworks; Mission Bay, San Diego, California.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 33 Navigation and Navigable Waters 2 2010-07-01 2010-07-01 false Safety zone; Sea World Summer Nights Fireworks; Mission Bay, San Diego, California. 165.T11-304 Section 165.T11-304 Navigation and Navigable Waters COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) PORTS AND WATERWAYS SAFETY REGULATED NAVIGATION AREAS AND LIMITED ACCESS AREA...

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Selective anti-herpesvirus agents.

PubMed

De Clercq, Erik

2013-01-23

This review article focuses on the anti-herpesvirus agents effective against herpes simplex virus, varicella-zoster virus and cytomegalovirus, which have either been licensed for clinical use (idoxuridine, trifluridine, brivudin, acyclovir, valaciclovir, valganciclovir, famciclovir and foscarnet) or are under clinical development (CMX001 [the hexadecyloxypropyl prodrug of cidofovir], the helicase-primase inhibitor BAY 57-1293 [now referred to as AIC316], FV-100 [the valine ester of Cf 1743] and the terminase inhibitor letermovir [AIC246]).

Underwater views of STS-11 crewman Robert L. Stewart during EVA training

NASA Technical Reports Server (NTRS)

1983-01-01

Underwater views of STS-11 crewman Robert L. Stewart during extravehicular activity (EVA) training in the cargo bay in the weightless environment training facility (WETF) in bldg 27. Stewart busies himself with donning and doffing of the manned maneuvering unit (MMU) in a mockup of the Shuttle's cargo bay.

75 FR 34362 - Safety Zone; Festivals & Fireworks Celebration, East Moran Bay, Lake Huron, St. Ignace, MI

Federal Register 2010, 2011, 2012, 2013, 2014

2010-06-17

...-AA00 Safety Zone; Festivals & Fireworks Celebration, East Moran Bay, Lake Huron, St. Ignace, MI AGENCY... safety zone on East Moran Bay, Lake Huron, St. Ignace, MI. This zone is intended to restrict vessels from... portion of East Moran Bay, Lake Huron, St. Ignace, MI between 9 p.m. and 11 p.m. on June 26, July 10, July...

Inhibition of NF-kappa B pathway leads to deregulation of epithelial-mesenchymal transition and neural invasion in pancreatic cancer.

PubMed

Nomura, Alice; Majumder, Kaustav; Giri, Bhuwan; Dauer, Patricia; Dudeja, Vikas; Roy, Sabita; Banerjee, Sulagna; Saluja, Ashok K

2016-12-01

NF-κB has an essential role in the initiation and progression of pancreatic cancer and specifically mediates the induction of epithelial-mesenchymal transition and invasiveness. In this study, we demonstrate the importance of activated NF-κB signaling in EMT induction, lymphovascular metastasis, and neural invasion. Modulation of NF-κB activity was accomplished through the specific NF-κB inhibitor (BAY 11-7085), triptolide, and Minnelide treatment, as well as overexpression of IKBα repressor and IKK activator plasmids. In the classical lymphovascular metastatic cascade, inhibition of NF-κB decreased the expression of several EMT transcription factors (SNAI1, SNAI2, and ZEB1) and mesenchymal markers (VIM and CDH2) and decreased in vitro invasion, which was rescued by IKK activation. This was further demonstrated in vivo via BAY 11-7085 treatment in a orthotopic model of pancreatic cancer. In vivo NF-κB inhibition decreased tumor volume; decreased tumor EMT gene expression, while restoring cell-cell junctions; and decreasing overall metastasis. Furthermore, we demonstrate the importance of active NF-κB signaling in neural invasion. Triptolide treatment inhibits Nerve Growth Factor (NGF) mediated, neural-tumor co-culture in vitro invasion, and dorsal root ganglia (DRG) neural outgrowth through a disruption in tumor-neural cross talk. In vivo, Minnelide treatment decreased neurotrophin expression, nerve density, and sciatic nerve invasion. Taken together, this study demonstrates the importance of NF-κB signaling in the progression of pancreatic cancer through the modulation of EMT induction, lymphovascular invasion, and neural invasion.

Quercetin inhibits glucose transport by binding to an exofacial site on GLUT1.

PubMed

Hamilton, Kathryn E; Rekman, Janelle F; Gunnink, Leesha K; Busscher, Brianna M; Scott, Jordan L; Tidball, Andrew M; Stehouwer, Nathan R; Johnecheck, Grace N; Looyenga, Brendan D; Louters, Larry L

2018-05-29

Quercetin, a common dietary flavone, is a competitive inhibitor of glucose uptake and is also thought to be transported into cells by GLUT1. In this study, we confirm that quercetin is a competitive inhibitor of GLUT1 and also demonstrate that newly synthesized compounds, WZB-117 and BAY-876 are robust inhibitors of GLUT1 in L929 cells. To measure quercetin interaction with L929 cells, we develop a new fluorescent assay using flow cytometry. The binding of quercetin and its inhibitory effects on 2-deoxyglucose (2DG) uptake showed nearly identical dose dependent effects, with both having maximum effects between 50 and 100 μM and similar half maximum effects at 8.9 and 8.5 μM respectively. The interaction of quercetin was rapid with t 1/2 of 54 s and the onset and loss of its inhibitory effects on 2DG uptake were equally fast. This suggests that either quercetin is simply binding to surface GLUT1 or its transport in and out of the cell reaches equilibrium very quickly. If quercetin is transported, the co-incubation of quercetin with other glucose inhibitors should block quercetin uptake. However, we observed that WZB-117, an exofacial binding inhibitor of GLUT1 reduced quercetin interaction, while cytochalasin B, an endofacial binding inhibitor, enhanced quercetin interaction, and BAY-876 had no effect on quercetin interaction. Taken together, these data are more consistent with quercetin simply binding to GLUT1, but not actually being transported into L929 cells via the glucose channel in GLUT1. Copyright © 2018. Published by Elsevier B.V.

50 CFR 85.11 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., their connecting waters, harbors, roadsteads, and estuary-type areas such as bays, shallows, and marshes... sea water, including sounds, bays, lagoons, bayous, ponds, and estuaries. Coastal zone. Coastal zone...

50 CFR 85.11 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., their connecting waters, harbors, roadsteads, and estuary-type areas such as bays, shallows, and marshes... sea water, including sounds, bays, lagoons, bayous, ponds, and estuaries. Coastal zone. Coastal zone...

40 CFR 63.7082 - What parts of my plant does this subpart cover?

Code of Federal Regulations, 2010 CFR

2010-07-01

... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants for Lime Manufacturing Plants... applies to each existing or new lime kiln(s) and their associated cooler(s), and processed stone handling (PSH) operations system(s) located at an LMP that is a major source. (b) A new lime kiln is a lime kiln...

10 CFR 708.2 - What are the definitions of terms used in this part?

Code of Federal Regulations, 2014 CFR

2014-01-01

... type of contract with DOE to perform work directly related to activities at DOE-owned or -leased..., but only with respect to work related to activities at DOE-owned or -leased facilities. Day means a calendar day. Discovery means a process used to enable the parties to learn about each other's evidence...

10 CFR 708.2 - What are the definitions of terms used in this part?

Code of Federal Regulations, 2012 CFR

2012-01-01

... type of contract with DOE to perform work directly related to activities at DOE-owned or -leased..., but only with respect to work related to activities at DOE-owned or -leased facilities. Day means a calendar day. Discovery means a process used to enable the parties to learn about each other's evidence...

10 CFR 708.2 - What are the definitions of terms used in this part?

Code of Federal Regulations, 2011 CFR

2011-01-01

... type of contract with DOE to perform work directly related to activities at DOE-owned or -leased..., but only with respect to work related to activities at DOE-owned or -leased facilities. Day means a calendar day. Discovery means a process used to enable the parties to learn about each other's evidence...

10 CFR 708.2 - What are the definitions of terms used in this part?

Code of Federal Regulations, 2013 CFR

2013-01-01

... type of contract with DOE to perform work directly related to activities at DOE-owned or -leased..., but only with respect to work related to activities at DOE-owned or -leased facilities. Day means a calendar day. Discovery means a process used to enable the parties to learn about each other's evidence...

16 CFR 801.40 - Formation of joint venture or other corporations.

Code of Federal Regulations, 2013 CFR

2013-01-01

... in assets and each to make additional contributions of $21 million in each of the next three years..., 1983; 52 FR 7082, Mar. 6, 1987; 66 FR 8690, Feb. 1, 2001; 70 FR 4992, Jan. 31, 2005] ... 16 Commercial Practices 1 2013-01-01 2013-01-01 false Formation of joint venture or other...

16 CFR 801.40 - Formation of joint venture or other corporations.

Code of Federal Regulations, 2010 CFR

2010-01-01

... in assets and each to make additional contributions of $21 million in each of the next three years..., 1983; 52 FR 7082, Mar. 6, 1987; 66 FR 8690, Feb. 1, 2001; 70 FR 4992, Jan. 31, 2005] ... 16 Commercial Practices 1 2010-01-01 2010-01-01 false Formation of joint venture or other...

16 CFR 801.40 - Formation of joint venture or other corporations.

Code of Federal Regulations, 2012 CFR

2012-01-01

... in assets and each to make additional contributions of $21 million in each of the next three years..., 1983; 52 FR 7082, Mar. 6, 1987; 66 FR 8690, Feb. 1, 2001; 70 FR 4992, Jan. 31, 2005] ... 16 Commercial Practices 1 2012-01-01 2012-01-01 false Formation of joint venture or other...

16 CFR 801.40 - Formation of joint venture or other corporations.

Code of Federal Regulations, 2011 CFR

2011-01-01

... in assets and each to make additional contributions of $21 million in each of the next three years..., 1983; 52 FR 7082, Mar. 6, 1987; 66 FR 8690, Feb. 1, 2001; 70 FR 4992, Jan. 31, 2005] ... 16 Commercial Practices 1 2011-01-01 2011-01-01 false Formation of joint venture or other...

16 CFR 801.40 - Formation of joint venture or other corporations.

Code of Federal Regulations, 2014 CFR

2014-01-01

... in assets and each to make additional contributions of $21 million in each of the next three years..., 1983; 52 FR 7082, Mar. 6, 1987; 66 FR 8690, Feb. 1, 2001; 70 FR 4992, Jan. 31, 2005] ... 16 Commercial Practices 1 2014-01-01 2014-01-01 false Formation of joint venture or other...

50 CFR 85.11 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-10-01

... Great lakes, their connecting waters, harbors, roadsteads, and estuary-type areas such as bays, shallows... percentage of sea water, including sounds, bays, lagoons, bayous, ponds, and estuaries. Coastal zone. Coastal...

The non-nucleoside antiviral, BAY 38-4766, protects against cytomegalovirus (CMV) disease and mortality in immunocompromised guinea pigs

PubMed Central

Schleiss, Mark R.; Bernstein, David I.; McVoy, Michael A.; Stroup, Greg; Bravo, Fernando; Creasy, Blaine; McGregor, Alistair; Henninger, Kristin; Hallenberger, Sabine

2008-01-01

New antiviral drugs are needed for the treatment of cytomegalovirus (CMV) infections, particularly in immunocompromised patients. These studies evaluated the in vitro and in vivo activity of the non-nucleosidic CMV inhibitor, BAY 38-4766, against guinea pig cytomegalovirus (GPCMV). Plaque reduction assays indicated that BAY 38-4766 was active against GPCMV, with an IC50 of 0.5 μM. Yield reduction assays demonstrated an ED90 and ED99 of 0.4 and 0.6 μM, respectively, of BAY 38-4766 against GPCMV. Guinea pigs tolerated oral administration of 50 mg/kg/day of BAY 38-4766 without evidence of biochemical or hematologic toxicity. Plasma concentrations of BAY 38-4766 were high following oral dosing, with a mean peak level at 1-h post-dose of 26.7 mg/ml (n = 6; range, 17.8-35.4). Treatment with BAY 38-4766 reduced both viremia and DNAemia, as determined by a real-time PCR assay, following GPCMV infection of cyclophosphamide-immunosuppressed strain 2 guinea pigs (p < 0.05, Mann-Whitney test). BAY 38-4766 also reduced mortality following lethal GPCMV challenge in immunosuppressed Hartley guinea pigs, from 83% (20/24) in placebo-treated guinea pigs, to 17% (4/24) in BAY 38-4766-treated animals (p < 0.0001, Fisher’s exact test). Mortality differences were accompanied by reduction in DNAemia in Hartley guinea pigs. Based upon its favorable safety, pharmacokinetic, and therapeutic profiles, BAY 38-4766 warrants further investigation in the GPCMV model. PMID:15652969

77 FR 62437 - Regulated Navigation Area; Columbus Day Weekend, Biscayne Bay, Miami, FL

Federal Register 2010, 2011, 2012, 2013, 2014

2012-10-15

...-AA11 Regulated Navigation Area; Columbus Day Weekend, Biscayne Bay, Miami, FL AGENCY: Coast Guard, DHS. ACTION: Final rule. SUMMARY: The Coast Guard is amending the Columbus Day weekend regulated navigation area on Biscayne Bay in Miami, Florida. The amended regulated navigation area alters the boundaries of...

N-acetyl cysteine inhibits lipopolysaccharide-mediated induction of interleukin-6 synthesis in MC3T3-E1 cells through the NF-kB signaling pathway.

PubMed

Guo, Ling; Zhang, Hui; Li, Wangyang; Zhan, Danting; Wang, Min

2018-06-06

Interleukin-6 (IL-6) is a potent stimulator of osteoclastic activity. Lipopolysaccharide (LPS) has been shown to regulate the expression of potent inflammatory factors, including TNF-α and IL-6. Currently, effective therapeutic treatments for bacteria-caused bone destruction are limited. N-acetyl cysteine (NAC) is an antioxidant small molecule that possibly modulates osteoblastic differentiation. However, whether NAC can affect the LPS-mediated reduction of IL-6 synthesis in MC3T3-E1 cells is still unknown. The aim of this study was to investigate the role of NAC in the LPS -mediated reduction of IL-6 synthesis by MC3T3-E1 cells and to explore the underlying molecular mechanisms. In addition, we aimed to determine the involvement of the NF-kB pathway in any changes in IL-6 expression observed in response to LPS and NAC. MC3T3-E1 cells (ATCC, CRL-2593) were cultured in α-minimum essential medium. Cells were stimulated using NAC or LPS at various concentrations. Cell proliferation was observed at multiple time points using a cell counting kit 8 (CCK-8). IL-6 mRNA expression and protein synthesis were determined using quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay analyses. NF-kB mRNA expression and protein synthesis was determined using qPCR and Western blots analyses. The results demonstrate that LPS induced IL-6 and NF-kB mRNA expression and protein synthesis in the cultured MC3T3-E1 cells. However, these effects were abolished following pre-treatment with NAC. Pretreatment with NAC (1 mmol/l) or BAY11-7082 (10 μmol/l) both significantly inhibited the NF-kB activity induced by LPS. NAC inhibits the LPS-mediated induction of IL-6 synthesis in MC3T3-E1 cells through the NF-kB pathway. Copyright © 2018 Elsevier Ltd. All rights reserved.

Recent results of Daya Bay reactor neutrino experiment

NASA Astrophysics Data System (ADS)

Leitner, R.; Daya Bay Collaboration

2017-04-01

The Daya Bay reactor neutrino experiment has been designed to precisely measure the least known neutrino mixing angle θ13. In March 2012, Daya Bay collaboration announced [Daya Bay Collaboration (F. P. An et al.), Observation of electron-antineutrino disappearance at Daya Bay, Phys. Rev. Lett. 108 (2012) 171803] the observation of non-zero value of sin2 ⁡ 2θ13. Because of large statistics of detected antineutrinos and excellent performance of the experiment, Daya Bay continuously improves the precision of world best measurement of sin2 ⁡ 2θ13. In addition it provides results on neutrino mass splitting Δ mee2 competitive with measurements of other experiments, results on precise measurement of reactor fluxes and on limits of the existence of hypothetical fourth neutrino. In this paper, we report the results available by the time of the 6th Capri workshop: the measurement of oscillation parameters sin2 ⁡ (2θ13) = 0.084 ± 0.005 and | Δmee2 | = (2.42 ± 0.11) ×10-3eV2 [Daya Bay Collaboration (F. P. An et al.), New Measurement of Antineutrino Oscillation with the Full Detector Configuration at Daya Bay, Phys. Rev. Lett. 115 (2015) no. 11, 111802], searches for sterile neutrinos [Daya Bay Collaboration (F. P. An et al.) Search for a Light Sterile Neutrino at Daya Bay, Phys. Rev. Lett. 113 (2014) 141802] and precise measurement of reactor neutrino flux [Daya Bay Collaboration (F. P. An et al.), Measurement of the Reactor Anti-neutrino Flux and Spectrum at Daya Bay, Phys. Rev. Lett. 116 (2016) no. 6, 061801]. These are based on 621 days of measurement, most of the data has been taken in full detector configuration. More precise results [Daya Bay Collaboration (F. P. An et al.), Measurement of electron antineutrino oscillation based on 1230 days of operation of the Daya Bay experiment, arxiv:arXiv:1610.04802] with 1230 days of operation have been presented few weeks later at the Neutrino 2016 conference.

Prevalence, incidence, indication, and choice of antidepressants in patients with and without chronic kidney disease: a matched cohort study in UK Clinical Practice Research Datalink.

PubMed

Iwagami, Masao; Tomlinson, Laurie A; Mansfield, Kathryn E; McDonald, Helen I; Smeeth, Liam; Nitsch, Dorothea

2017-07-01

People with chronic kidney disease (CKD) have an increased prevalence of depression, anxiety, and neuropathic pain. We examined prevalence, incidence, indication for, and choice of antidepressants among patients with and without CKD. Using the UK Clinical Practice Research Datalink, we identified patients with CKD (two measurements of estimated glomerular filtration rate < 60 mL/min/1.73m 2 for ≥3 months) between April 2004 and March 2014. We compared those with CKD to a general population cohort without CKD (matched on age, sex, general practice, and calendar time [index date]). We identified any antidepressant prescribing in the six months prior to index date (prevalence), the first prescription after index date among non-prevalent users (incidence), and recorded diagnoses (indication). We compared antidepressant choice between patients with and without CKD among patients with a diagnosis of depression. There were 242 349 matched patients (median age 76 [interquartile range 70-82], male 39.3%) with and without CKD. Prevalence of antidepressant prescribing was 16.3 and 11.9%, and incidence was 57.2 and 42.4/1000 person-years, in patients with and without CKD, respectively. After adjusting for confounders, CKD remained associated with higher prevalence and incidence of antidepressant prescription. Regardless of CKD status, selective serotonin reuptake inhibitors were predominantly prescribed for depression or anxiety, while tricyclic antidepressants were prescribed for neuropathic pain or other reasons. Antidepressant choice was similar in depressed patients with and without CKD. The rate of antidepressant prescribing was nearly one and a half times higher among people with CKD than in the general population. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

40 CFR 63.7082 - What parts of my plant does this subpart cover?

Code of Federal Regulations, 2012 CFR

2012-07-01

... (PSH) operations system(s) located at an LMP that is a major source. (b) A new lime kiln is a lime kiln... reconstruction. (c) A new PSH operations system is the equipment in paragraph (g) of this section, for which....7081 at the time you began construction or reconstruction. (d) A lime kiln or PSH operations system is...

40 CFR 63.7082 - What parts of my plant does this subpart cover?

Code of Federal Regulations, 2011 CFR

2011-07-01

... (PSH) operations system(s) located at an LMP that is a major source. (b) A new lime kiln is a lime kiln... reconstruction. (c) A new PSH operations system is the equipment in paragraph (g) of this section, for which....7081 at the time you began construction or reconstruction. (d) A lime kiln or PSH operations system is...

40 CFR 63.7082 - What parts of my plant does this subpart cover?

Code of Federal Regulations, 2013 CFR

2013-07-01

... (PSH) operations system(s) located at an LMP that is a major source. (b) A new lime kiln is a lime kiln... reconstruction. (c) A new PSH operations system is the equipment in paragraph (g) of this section, for which....7081 at the time you began construction or reconstruction. (d) A lime kiln or PSH operations system is...

40 CFR 63.7082 - What parts of my plant does this subpart cover?

Code of Federal Regulations, 2014 CFR

2014-07-01

... (PSH) operations system(s) located at an LMP that is a major source. (b) A new lime kiln is a lime kiln... reconstruction. (c) A new PSH operations system is the equipment in paragraph (g) of this section, for which....7081 at the time you began construction or reconstruction. (d) A lime kiln or PSH operations system is...

Support vector inductive logic programming outperforms the naive Bayes classifier and inductive logic programming for the classification of bioactive chemical compounds.

PubMed

Cannon, Edward O; Amini, Ata; Bender, Andreas; Sternberg, Michael J E; Muggleton, Stephen H; Glen, Robert C; Mitchell, John B O

2007-05-01

We investigate the classification performance of circular fingerprints in combination with the Naive Bayes Classifier (MP2D), Inductive Logic Programming (ILP) and Support Vector Inductive Logic Programming (SVILP) on a standard molecular benchmark dataset comprising 11 activity classes and about 102,000 structures. The Naive Bayes Classifier treats features independently while ILP combines structural fragments, and then creates new features with higher predictive power. SVILP is a very recently presented method which adds a support vector machine after common ILP procedures. The performance of the methods is evaluated via a number of statistical measures, namely recall, specificity, precision, F-measure, Matthews Correlation Coefficient, area under the Receiver Operating Characteristic (ROC) curve and enrichment factor (EF). According to the F-measure, which takes both recall and precision into account, SVILP is for seven out of the 11 classes the superior method. The results show that the Bayes Classifier gives the best recall performance for eight of the 11 targets, but has a much lower precision, specificity and F-measure. The SVILP model on the other hand has the highest recall for only three of the 11 classes, but generally far superior specificity and precision. To evaluate the statistical significance of the SVILP superiority, we employ McNemar's test which shows that SVILP performs significantly (p < 5%) better than both other methods for six out of 11 activity classes, while being superior with less significance for three of the remaining classes. While previously the Bayes Classifier was shown to perform very well in molecular classification studies, these results suggest that SVILP is able to extract additional knowledge from the data, thus improving classification results further.

Src-dependent EGFR transactivation regulates lung inflammation via downstream signaling involving ERK1/2, PI3Kδ/Akt and NFκB induction in a murine asthma model.

PubMed

El-Hashim, Ahmed Z; Khajah, Maitham A; Renno, Waleed M; Babyson, Rhema S; Uddin, Mohib; Benter, Ibrahim F; Ezeamuzie, Charles; Akhtar, Saghir

2017-08-30

The molecular mechanisms underlying asthma pathogenesis are poorly characterized. In this study, we investigated (1) whether Src mediates epidermal growth factor receptor (EGFR) transactivation; (2) if ERK1/2, PI3Kδ/Akt and NF-κB are signaling effectors downstream of Src/EGFR activation; and (3) if upstream inhibition of Src/EGFR is more effective in downregulating the allergic inflammation than selective inhibition of downstream signaling pathways. Allergic inflammation resulted in increased phosphorylation of EGFR, Akt, ERK1/2 and IκB in the lung tissues from ovalbumin (OVA)-challenged BALB/c mice. Treatment with inhibitors of Src (SU6656) or EGFR (AG1478) reduced EGFR phosphorylation and downstream signaling which resulted in the inhibition of the OVA-induced inflammatory cell influx in bronchoalveolar lavage fluid (BALF), perivascular and peribronchial inflammation, fibrosis, goblet cell hyper/metaplasia and airway hyper-responsiveness. Treatment with pathway-selective inhibitors for ERK1/2 (PD89059) and PI3Kδ/Akt (IC-87114) respectively, or an inhibitor of NF-κB (BAY11-7085) also reduced the OVA-induced asthmatic phenotype but to a lesser extent compared to Src/EGFR inhibition. Thus, Src via EGFR transactivation and subsequent downstream activation of multiple pathways regulates the allergic airway inflammatory response. Furthermore, a broader upstream inhibition of Src/EGFR offers an attractive therapeutic alternative in the treatment of asthma relative to selectively targeting the individual downstream signaling effectors.

50 CFR Figure 21 to Part 679 - Nunivak Island, Etolin Strait, and Kuskokwim Bay Habitat Conservation Area

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 11 2011-10-01 2011-10-01 false Nunivak Island, Etolin Strait, and Kuskokwim Bay Habitat Conservation Area 21 Figure 21 to Part 679 Wildlife and Fisheries FISHERY CONSERVATION..., Etolin Strait, and Kuskokwim Bay Habitat Conservation Area ER25JY08.012 [73 FR 43372, July 25, 2008] ...

50 CFR Table 44 to Part 679 - Nunivak Island, Etolin Strait, and Kuskokwim Bay Habitat Conservation Area

Code of Federal Regulations, 2011 CFR

2011-10-01

... 50 Wildlife and Fisheries 11 2011-10-01 2011-10-01 false Nunivak Island, Etolin Strait, and Kuskokwim Bay Habitat Conservation Area 44 Table 44 to Part 679 Wildlife and Fisheries FISHERY CONSERVATION..., Etolin Strait, and Kuskokwim Bay Habitat Conservation Area Longitude Latitude 1651.54W 6045.54N* 1627.01W...

77 FR 54811 - Safety Zone; TriRock San Diego, San Diego Bay, San Diego, CA

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-06

... 1625-AA00 Safety Zone; TriRock San Diego, San Diego Bay, San Diego, CA AGENCY: Coast Guard, DHS. ACTION... sponsoring the TriRock Triathlon, consisting of 2000 swimmers swimming a predetermined course. The sponsor... to read as follows: Sec. 165.T11-516 Safety Zone; TriRock Triathlon; San Diego Bay, San Diego, CA. (a...

Exploring the environmental effects of shale gas development in the Chesapeake Bay watershed

Treesearch

Scientific and Technical Committee [STAC] Chesapeake Bay Program

2013-01-01

On April 11-12, 2012, the Chesapeake Bay Program's Scientific and Technical Advisory Committee (STAC) convened an expert workshop to investigate the environmental effects of shale gas development in the Chesapeake Bay Watershed. The purpose of this workshop was to engage scientists from across the nation in a review of the state-of-the-science regarding shale gas...

76 FR 68101 - Safety Zone; Art Gallery Party St. Pete 2011 Fireworks Display, Tampa Bay, St. Petersburg, FL

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-03

...-AA00 Safety Zone; Art Gallery Party St. Pete 2011 Fireworks Display, Tampa Bay, St. Petersburg, FL... temporary safety zone on the waters of Tampa Bay in the vicinity of Spa Beach in St. Petersburg, Florida during the Art Gallery Party St. Pete 2011 Fireworks Display on Friday, November 11, 2011. The safety...

76 FR 23189 - Safety Zone; Pensacola Bay; Pensacola, FL

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-26

...-AA00 Safety Zone; Pensacola Bay; Pensacola, FL AGENCY: Coast Guard, DHS. ACTION: Temporary final rule. SUMMARY: The Coast Guard is establishing a temporary safety zone for a portion of Pensacola Bay including...[deg]17'20.31'' W, 30[deg]20'41.51'' N 087[deg]15'01.15'' W, and 30[deg]20'11.76'' N 087[deg]15'01.18...

11. Photocopy of drawing dated November 25, 1957, SECTIONS & ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

11. Photocopy of drawing dated November 25, 1957, SECTIONS & METHODS OF REPAIR, REHABILITATION OF 29TH ST. PIER, GOWANUS BAY. City of New York Department of Marine and Aviation, Contract 2994, Drawing 1. (On file, City of New York Department of Ports and Trade). - South Brooklyn Freight Terminal, 29th Street Pier, Opposite end of Twenty-ninth Street on upper New York Bay, Brooklyn, Kings County, NY

Biological Testing of Solid Phase and Suspended Phase Dredged Material from Commencement Bay, Tacoma, Washington

DTIC Science & Technology

1983-04-01

BAY, TACOMA, WASHINGTON PREPARED BY: FISHERIES RESEARCH INSTITUTE University of Washington DTIC C. A ELECTE JUL11 1985 DISTRIBUTIONSTATEMENT A...Nakatani 9. PERFORMING ORGANIZATION NAME AND ADDRESS 10. PROGRAM ELEMENT. PROJECT, TASK Fisheries Research Institute AREA & WORK UNIT NUMBERS School of... Fisheries WH-10 University of Washington Seattle, Washington 98195 11. CONTROLLING OFFICE NAME AND ADDRESS 12. REPORT DATE US Army Corps of Engineers

Severe Weather Guide - Mediterranean Ports. 9. Villefranche

DTIC Science & Technology

1988-03-01

NSTL, MS 39529-5000 10 SOURCE QF CUNDING NUMBERS PROGRAM ELEMENT NO PROJECT NO TASK NO. WORK UNIT ACCESSION NO DN656794 11 TITLE...AUGUSTA BAY, ITALY 5 CAGLIARI, ITALY 6 LA MADDALENA, ITALY 7 MARSEILLE, FRANCE 8 TOULON, FRANCE 9 VILLEFRANCHE, FRANCE 10 MALAGA, SPAIN 11 NICE... FRANCE 12 CANNES, FRANCE 13 MONACO 14 ASHDOD, ISRAEL 15 HAIFA, ISRAEL BARCELONA, SPAIN PALMA, SPAIN IBIZA, SPAIN POLLENSA BAY, SPAIN VALENCIA

Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: involvement of antioxidant and anti-apoptotic mechanisms.

PubMed

Ding, Lianshu; Zhang, Chong; Masood, Anbrin; Li, Jianxin; Sun, Jiao; Nadeem, Ahmed; Zhang, Han-Ting; O' Donnell, James M; Xu, Ying

2014-07-15

Stress occurs in everyday life, but the relationship between stress and the onset or development of depression/anxiety remains unknown. Increasing evidence suggests that the impairment of antioxidant defense and the neuronal cell death are important in the process of emotional disorders. Chronic stress impairs the homeostasis of antioxidants/oxidation, which results in the aberrant stimulation of the cell cycle proteins where cGMP-PKG signaling is thought to have an inhibitory role. Phosphodiesterase 2 (PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala, which may play important roles in the treatment of depression and anxiety. To address the possible effects of PDE2 inhibitors on depression-/anxiety-like behaviors and the underlying mechanisms, Bay 60-7550 (0.75, 1.5 and 3 mg/kg, i.p.) was administered 30 min before chronic stress. The results suggested that Bay 60-7550 not only restored the behavioral changes but also regulated Cu/Zn superoxide dismutase (SOD) levels differentially in hippocampus and amygdala, which were increased in the hippocampus while decreased in the amygdala. It was also significant that Bay 60-7550 regulated the abnormalities of pro- and anti-apoptotic components, such as Bax, Caspase 3 and Bcl-2, and the indicator of PKG signaling characterized by pVASP(ser239), in these two brain regions. The results suggested that Bay 60-7550 is able to alleviate oxidative stress and mediate part of the apoptotic machinery in neuronal cells possibly through SOD-cGMP/PKG-anti-apoptosis signaling and that inhibition of PDE2 may represent a novel therapeutic target for psychiatric disorders, such as depression and anxiety. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of differential disaccharide excretion in urine for non-invasive investigation of altered intestinal disaccharidase activity caused by alpha-glucosidase inhibition, primary hypolactasia, and coeliac disease.

PubMed Central

Bjarnason, I; Batt, R; Catt, S; Macpherson, A; Maxton, D; Menzies, I S

1996-01-01

BACKGROUND/AIM: The reliability of a quantitative method for the non-invasive assessment of intestinal disaccharide hydrolysis was assessed. METHODS: Differential excretion of intact disaccharide, expressed as ratios of lactulose to appropriate hydrolysable disaccharides in urine collected following combined ingestion, has been investigated in healthy volunteers with drug induced alpha-glucosidase inhibition, in subjects with primary hypolactasia, and patients with coeliac disease. RESULTS: Oral administration of the alpha-glucosidase inhibitor 'Acarbose' (BAY g 5421, 200 mg) together with sucrose and lactulose increased the urinary sucrose/lactulose excretion ratios (% dose/10 h) fivefold. The effect was quantitatively reproducible, a higher dose of 'Acarbose' (500 mg) increasing the excretion ratio to about 1.0 indicating complete inhibition of intestinal sucrase activity. The suitability of the method for measuring differences in dose/response and duration of action was assessed by comparing three different alpha-glucosidase inhibitors (BAY g 5421, BAY m 1099, and BAY o 1248) and found to be satisfactory. Subjects with primary adult hypolactasia had urine lactose/lactulose excretion ratios raised to values indicating reduced rather than complete absence of lactase activity whereas sucrose/lactulose ratios were not significantly affected. 'Whole' intestinal disaccharidase activity assessed by this method demonstrated impairment of lactase, sucrase, and isomaltase in eight, one, and seven, respectively, of 20 patients with coeliac disease. By contrast in vitro assay of jejunal biopsy tissue indicated pan-disaccharidase deficiency in all but five of these patients. This shows the importance of distinguishing between 'local' and 'whole' intestinal performance. CONCLUSIONS: Differential urinary excretion of ingested disaccharides provides a reliable, quantitative, and non-invasive technique for assessing profiles of intestinal disaccharidase activity. PMID:8949640

76 FR 34867 - Safety Zones; Annual Fireworks Events in the Captain of the Port Detroit Zone

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-15

....941(a)(30) Bay-Rama Fishfly Festival Fireworks, New Baltimore, MI This safety zone will be enforced...) Bay City Fireworks Festival, Bay City, MI This safety zone will be enforced daily from 9:30 p.m. to 11...:45 p.m. to 10:45 p.m. on July 3, 2011. Section 165.941(a)(43) Lexington Independence Festival...

33 CFR 165.T01-0084 - Regulated Navigation Area; Little Bay Bridge Construction, Little Bay, Portsmouth, NH.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Construction, Little Bay, Portsmouth, NH. (a) Location. The following area is a Regulated Navigation Area (RNA... regulations contained in 33 CFR 165.10, 165.11, and 165.13 apply within the RNA. In addition, the following... vessels must proceed through the area with caution and operate in such a manner as to produce no wake. (4...

33 CFR 165.T01-0084 - Regulated Navigation Area; Little Bay Bridge Construction, Little Bay, Portsmouth, NH.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Construction, Little Bay, Portsmouth, NH. (a) Location. The following area is a Regulated Navigation Area (RNA... regulations contained in 33 CFR 165.10, 165.11, and 165.13 apply within the RNA. In addition, the following... vessels must proceed through the area with caution and operate in such a manner as to produce no wake. (4...

Earth observations of Hudson Bay, Canada taken from OV-105 during STS-99

NASA Image and Video Library

2000-03-14

STS099-706-090 (11-22 February 2000) ---One of the astronauts aboard the Space Shuttle Endeavour for the STS-99 mission recorded this 70mm image of Hannah Bay, in the southern part of St. James Bay. The river is the Harricanaw River. Numerous shorelines around Hudson and St. James Bays are distinctive in winter because of snow cover. According to NASA scientists, shorelines were created when the overlying glaciers retreated and the land underneath rebounded causing the Hudson and St. James Bay waters to retreat northward. These ridges are 100 to 200 meters in width and heights can reach up to 7 meters. The land along St. James Bay consists mainly of tidal flats and salt marshes.

Reconnaissance Report Section 107, Weeks Bay, Baldwin County, Alabama

DTIC Science & Technology

1990-08-01

Goals and Objectives 6 Management 7 Plan Formulation 7 Economic Analysis 7 Channel Design 9 Dredging Cost Computations 11 Cost-Benefit Analysis 11...Aerial Photography of Study Area 2 Channel Location and Reaches 3 LIST OF APPENDICES Title Appendix Pertinent Correspondence A Economic Analysis B... community situated on the north side of the Magnolia River approximately a mile and a half from the bay, the River Bluff subdivision, and the community of

Evaluation of P1'-diversified phosphinic peptides leads to the development of highly selective inhibitors of MMP-11.

PubMed

Matziari, Magdalini; Beau, Fabrice; Cuniasse, Philippe; Dive, Vincent; Yiotakis, Athanasios

2004-01-15

Phosphinic peptides were previously reported to be potent inhibitors of several matrixins (MMPs). To identify more selective inhibitors of MMP-11, a matrixin overexpressed in breast cancer, a series of phosphinic pseudopeptides bearing a variety of P(1)'-side chains has been synthesized, by parallel diversification of a phosphinic template. The potencies of these compounds were evaluated against a set of seven MMPs (MMP-2, MMP-7, MMP-8, MMP-9, MMP-11, MMP-13, and MMP-14). The chemical strategy applied led to the identification of several phosphinic inhibitors displaying high selectivity toward MMP-11. One of the most selective inhibitors of MMP-11 in this series, compound 22, exhibits a K(i) value of 0.23 microM toward MMP-11, while its potency toward the other MMPs tested is 2 orders of magnitude lower. This remarkable selectivity may rely on interactions of the P(1)'-side chain atoms of these inhibitors with residues located at the entrance of the S(1)'-cavity of MMP-11. The design of inhibitors able to interact with residues located at the entrance of MMPs' S(1)'-cavity might represent an alternative strategy to identify selective inhibitors that will fully differentiate one MMP among the others.

2009 Spawning cisco investigations in the Canadian waters of Lake Superior

USGS Publications Warehouse

Yule, Daniel L.; Cholwek, Gary A.; Evrard, Lori M.; E. Berglund,; K.I. Cullis,

2010-01-01

We sampled with acoustics (AC) and midwater trawls (MT) to determine cisco abundance in Lake Superior’s Thunder and Black bays during 8-14 November, 2009. Total abundance of spawning-size (≥ 250 mm total length) ciscoes was estimated at 6.25 million in Thunder Bay and 1.12 million in Black Bay. Exploitation fractions of market-size (≥ age 6) females from Thunder and Black bays for 2009 were estimated at 7.1% and 11.3%, respectively; below the recommended maximum annual harvest of 15% recently adopted by Lake Superior fisheries managers. Given Thunder Bay spawner densities are on a downward trajectory, and recruitment since the 2003 year-class has been low, it is likely the exploitation fractions will increase in the future. After 2010, the Ontario Ministry of Natural Resources (OMNR) will carry on the AC program as a management activity. It is likely suspended experimental gill net (GN) samples will be used to ground truth future AC samples. In 2009, we characterized the length and age structure of Thunder Bay ciscoes using both MT samples and GN samples. Females represented 49% of the MT catch, but only 39% in GN samples. Catching a smaller proportion of females in GN samples resulted in a lower female population estimate and a higher estimated exploitation fraction (10.4%) compared to MT samples (7.1%). Experimental gill net effort was limited to 10-11.8 m water column depths where midwater trawl samples also caught roughly 40% females. Ciscoes ≥ age 17 (≥ 1992 year class) were common in Black Bay, but rare in Thunder Bay suggesting: 1) the stocks may be distinct; and 2) total mortality of ciscoes returning to spawn in Black Bay in recent years has been lower than ciscoes returning to Thunder Bay. Our mid-November 2009 effort to assess the Black Bay stock by sampling outside of the 3 bay in the lake proper was deemed successful, but this should be confirmed by sampling the Black Bay region during both mid- and late-November 2010.

Variations in sediment texture on the northern Monterey Bay National Marine Sanctuary continental shelf

USGS Publications Warehouse

Edwards, B.D.

2002-01-01

The storm-protected continental shelf of Monterey Bay, part of the Monterey Bay National Marine Sanctuary, north-central California, is subject to abundant, episodic sediment input from fluvial sources. North of Monterey Bay, conditions of reduced sediment supply combined with the exposed nature of the shelf provide an effective laboratory for studying the contrasting effects of storm- versus fluvial-dominated conditions on modern sedimentation. Textural analyses performed on surface sediment samples collected from more than 380 box cores and MultiCores??? document the existence of a clearly defined mud belt occupying the mid-shelf throughout the region. Inshore sands combined with these mid-shelf muds represent deposits from modern sedimentation processes. In Monterey Bay, where episodic fluvial input from winter storms dominates sedimentation, the mid-shelf mud belt extends across the shelf to the shelf break. North of Monterey Bay, where sediment loads are reduced and both oceanographic and storm processes dominate, the mid-shelf mud belt is bordered by relict sediments occupying the outer shelf. In the study area, mass accumulation rates established by radiochemical studies support the contention that storm-induced along-shelf processes result in northward transport of sediment within the mud belt. The continuity of transport, however, is interrupted by topographic highs which are barriers or inhibitors to sediment transport created by wrench-style tectonics associated with the San Andreas fault system.

Interior oblique view of bathroom (converted to handicap) at ground ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Interior oblique view of bathroom (converted to handicap) at ground floor of building 11, from hall doorway, looking northeast - North Beach Place, 531 Bay Street, 650 Francisco Street, 531 Bay Street, 650 Francisco Street, San Francisco, San Francisco County, CA

Danshen attenuates osteoarthritis-related cartilage degeneration through inhibition of NF-κB signaling pathway in vivo and in vitro.

PubMed

Xu, Xilin; Lv, Hang; Li, Xiaodong; Su, Hui; Zhang, Xiaofeng; Yang, Jun

2017-12-01

Danshen (Salvia miltiorrhiza) is a traditional Chinese medicine herb that can alleviate the symptoms of osteoarthritis (OA) (Söder et al. 2006) in animals. However, the underlying mechanisms remain poorly understood and require further investigation. In this study, rabbits with experimentally induced OA were given an intra-articular injection of danshen (0.7 mL/day) for 5 weeks. In addition to attenuating the cartilage degeneration of OA in the rabbits, danshen decreased the expression and activity of matrix metalloproteinase 9 (MMP-9) and MMP-13, and increased the expression of their natural inhibitors: tissue inhibitor of matrix metalloproteinase 1 (TIMP-1) and TIMP-2. Apoptosis in osteoarthritic cartilage tissues was attenuated by danshen, accompanied with increased expression of B cell lymphoma 2 (Bcl-2) and decreased levels of Bcl-2-associated X protein (Bax). Further, danshen inhibited the nuclear accumulation of nuclear factor kappa-B (NF-κB) p65 in osteoarthritic cartilage. The therapeutic effects of danshen in vivo were comparable to that of sodium hyaluronate, which is a drug used clinically for the treatment OA. In vitro, sodium nitroprusside (SNP) was used to stimulate apoptosis in primary rabbit chondrocytes. We found that the SNP-induced apoptosis was mitigated by danshen. BAY11-7028, an inhibitor of the NF-κB pathway, augmented danshen's anti-apoptotic effects in cells exposed to SNP. When these results are considered together, they indicate that danshen alleviates the cartilage injury in rabbit OA through inhibition of the NF-κB signaling pathway.

Pharmacokinetic properties of BAY 81-8973, a full-length recombinant factor VIII.

PubMed

Shah, A; Delesen, H; Garger, S; Lalezari, S

2015-11-01

BAY 81-8973 is a full-length recombinant factor VIII (FVIII) with the same primary amino acid sequence as sucrose-formulated recombinant FVIII (rFVIII-FS) but is produced with advanced manufacturing technologies. To analyse the pharmacokinetics (PK) of BAY 81-8973 after single and multiple dosing across different age and ethnic groups in the LEOPOLD clinical trial programme. The LEOPOLD trials enrolled patients with severe haemophilia A aged 12-65 years (LEOPOLD I and II) or ≤12 years (LEOPOLD Kids) with ≥150 (LEOPOLD I and II) or ≥50 (LEOPOLD Kids) exposure days to any FVIII product and no history of FVIII inhibitors. PK were assessed using chromogenic and one-stage assays (only chromogenic assay for LEOPOLD Kids) after a single 50-IU kg(-1) dose of BAY 81-8973 and, in a subset of patients in LEOPOLD I, after repeated dosing. Pharmacokinetic analyses were also performed based on age (18 to 65, 12 to <18, 6 to <12 and <6 years) and ethnicity (Asian and non-Asian). Pharmacokinetic assessments in the LEOPOLD I trial showed non-inferiority of BAY 81-8973 vs. rFVIII-FS. The PK of BAY 81-8973 were comparable after single and multiple dosing. Age-based analysis in the three trials showed that plasma concentrations were slightly lower for children, but similar for adolescents compared with adults. Pharmacokinetic results were similar in the different ethnic groups. Results of the LEOPOLD trials show that the BAY 81-8973 pharmacokinetic profile is non-inferior to rFVIII-FS. Similar BAY 81-8973 pharmacokinetic values were observed following single and repeated dosing and across ethnic groups. © 2015 John Wiley & Sons Ltd.

Comparison of land-based sources with ambient estuarine concentrations of total dissolved nitrogen in Jiaozhou Bay (China)

NASA Astrophysics Data System (ADS)

Lu, Dongliang; Yang, Nannan; Liang, Shengkang; Li, Keqiang; Wang, Xiulin

2016-10-01

Seasonal, land-sea synchronous surveys were conducted from 2012 to 2013 to characterize the relationship between the composition of land-based total dissolved nitrogen (TDN) and the concentration of dissolved inorganic nitrogen (DIN) in Jiaozhou Bay (JZB). A total of 11 freshwater riverine sampling sites were selected at the river mouths and at waste water outfalls around JZB, while a total 23 Bay stations were established in JZB. Among them, 11 Bay stations were located near the 11 outfalls. Each land-sea sampling was conducted synchronously during a semi-tidal cycle. The contribution of NO3sbnd N, NO2sbnd N, NH4sbnd N, and dissolved organic nitrogen (DON) to TDN in land-based freshwater were similar to those in JZB seawater, while the contribution of the sum of NO3sbnd N and NO2sbnd N to TDN and the contribution of DON to TDN were about 3.2 and 4.1 times higher than the contribution of NH4sbnd N to TDN, respectively. These results showed that inputs of all land-based forms of nitrogen impact the DIN in seawater. Spatial distributions of DIN and DON, showing a gradual decrease from inner bay to the mouth of the bay, were negatively correlated with S in different seasons. In summer and winter, the ratio of DIN to DON in seawater (Rs) gradually decreased from the inner bay to the center of the bay, and the ratio of land-based DIN to DON (RL) was less than RS, indicating net transformation from land-based DON into marine DIN. However, in spring and autumn, the distribution of Rs was opposite to that in summer and winter, and RL was greater than RS, indicating net conversion from land-based DIN into marine DON. Throughout the whole year, net land-based DON was transformed into marine DIN. We provided direct evidence that the variation in DIN concentration in JZB was affected both by land-based TDN inputs and by their hydrodynamic transport and biogeochemical transformation processes.

A comparison of two nitrification inhibitors used to measure nitrification rates in estuarine sediments

USGS Publications Warehouse

Caffrey, J.M.; Miller, L.G.

1995-01-01

Nitrification rates were measured using intact sediment cores from South San Francisco Bay and two different nitrification inhibitors: acetylene and methyl fluoride. Sediment oxygen consumption and ammonium and nitrate fluxes were also measured in these cores. Four experiments were conducted in the spring, and one in the fall of 1993. There was no significant difference in nitrification rates measured using the two inhibitors, which suggests that methyl fluoride can be used as an effective inhibitor of nitrification. Nitrification was positively correlated with sediment oxygen consumption and numbers of macrofauna. This suggests that bioturbation by macrofauna is an important control of nitrification rates. Irrigation by the tube-dwelling polychaete, Asychis elongata, which dominates the benthic biomass at this location, appears particularly important. Ammonium fluxes out of the sediment were greatest about one week after the spring bloom, while nitrification peaked about one month later.

Comparison of a homology model and the crystallographic structure of human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in a structure-based identification of inhibitors

NASA Astrophysics Data System (ADS)

Miguet, Laurence; Zhang, Ziding; Barbier, Maryse; Grigorov, Martin G.

2006-02-01

Human 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes the interconversion of cortisone into active cortisol. 11βHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11βHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11βHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11βHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114'000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11βHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.

Interior oblique view of laundry room (converted from original offices) ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Interior oblique view of laundry room (converted from original offices) in ground floor of Building 11, from southeast corner of room, looking northwest - North Beach Place, 531 Bay Street, 650 Francisco Street, 531 Bay Street, 650 Francisco Street, San Francisco, San Francisco County, CA

San Francisco Bay Area Endangered Species Litigation - Center for Biological Diversity v. EPA

EPA Pesticide Factsheets

EPA and the Center for Biological Diversity have agreed to a revised settlement agreement that amends a 2010 court order for effects determinations on 11 endangered or threatened (listed) species in the San Francisco Bay area. Find out about the new order.

Lake Erie Water Level Study. Appendix F. Environmental Effects.

DTIC Science & Technology

1981-07-01

were reevaluated with weight being placed on the most recent data. The wetland area in Pennsylvania was limited to that area on and around Presque Isle ...and East Harbor, Sandusky Bay, Northeast Yacht Club, Mentor Harbor, Presque Isle Bay, Port Dover, and Sturgeon Creek. In Lake Ontario the regulation...valued at close to 4 million dollars (Melski 1973), and the winter ice fishery was valued at 1.1 million dollars. Presque Isle Bay (which is on the

Phase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia A.

PubMed

Coyle, T E; Reding, M T; Lin, J C; Michaels, L A; Shah, A; Powell, J

2014-04-01

BAY 94-9027 is a B-domain-deleted recombinant factor VIII (rFVIII) with site-specific attachment of poly(ethylene glycol) that has shown an extended half-life in animal models of hemophilia. To assess the pharmacokinetics and safety of BAY 94-9027 after single and repeated administration in subjects with severe hemophilia A. This 8-week, prospective, multicenter, open-label, phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1%, ≥ 150 days of exposure to FVIII, and no history of FVIII inhibitors. After a ≥ 3-day washout, subjects received a single dose of sucrose-formulated rFVIII (rFVIII-FS) (cohort 1 [n = 7], 25 IU kg−1; cohort 2 [n = 7], 50 IU kg−1) for a 48-h pharmacokinetic (PK) study. After another ≥ 3-day washout, cohort 1 received twice-weekly BAY 94-9027 at 25 IU kg−1 (16 doses), and cohort 2 received once-weekly BAY 94-9027 at 60 IU kg−1 (nine doses). A 168-h PK study was performed after the first and last BAY 94-9027 doses. BAY 94-9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS, with a half-life of ~ 19 h (vs. ~ 13.0 h for rFVIII-FS). BAY 94-9027 was well tolerated, and no immunogenicity was observed. This phase I study demonstrates that BAY 94-9027 has an extended half-life in subjects with hemophilia A and, after multiple dosing, was well tolerated with no immunogenicity during the 8-week trial. A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia.

Phytoplankton composition and microcystin concentrations in open and closed bays of Lake Victoria, Tanzania

PubMed Central

Mbonde, Athanasio S.; Sitoki, Lewis; Kurmayer, Rainer

2017-01-01

This study was carried out in order to investigate the spatial variation of algal toxin (microcystin) concentrations along the shoreline of Lake Victoria. A total of 16 nearshore stations differing in connectivity to the main lake basin were categorized as either closed bays (ratio of bay area to bay opening < 1) or open bays (ratio ≥ 1) and sampled during November and December 2009. Water samples were analyzed for total phosphorus (TP), chlorophyll a, phytoplankton community composition and concentrations of microcystin (MC). Open and closed bays were significantly different for phytoplankton abundance and composition: Average phytoplankton biovolume was higher for closed bays (45 mm3 L-1 ± 11 SE) than open bays (5 ± 2 mm3 L-1). Cyanobacterial biovolume (mainly Microcystis spp., Anabaena spp. and Planktolyngbya spp.) also was significantly higher in closed bays (82 ± 9% of total biovolume) than in open bays (44 ± 5%). In contrast, diatom biovolume was lower in closed bays (7 ± 1%) than in open bays (36 ± 6%). MCs were found only among sites from closed bays and concentrations ranged from 0.4 to 13 μg L-1 MC-LR equiv. and coincided with high abundance of Microcystis spp. It is concluded that the level of water exchange from individual bays to the main basin is an important factor influencing eutrophication and microcystin production in nearshore habitats of Lake Victoria. PMID:28077928

Hydrodynamics and Eutrophication Model Study of Indian River and Rehoboth Bay, Delaware

DTIC Science & Technology

1994-05-01

Station, Vicksburg, MS. V Chapter I: Introduction The Study System Indian River and Rehoboth Bay (Figure 1-1) are two water bodies that form part of the...and mass trans- port throughout the system . Objectives The primary objective of this study is to provide a hydrodynamic/ water quality model packge of...portion opens out into Indian River Bay (Figure 3-1). The cooling water diversion was included in the hydrodynamic model. Flow through the power plant, at

Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors.

PubMed

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Joerg; Hartmann, Rolf W; Schuster, Daniela

2017-01-01

Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing's syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8 - 10 ), one selective CYP11B1 inhibitor (Compound 11 , IC 50 = 2.5 μM), and one selective CYP11B2 inhibitor (compound 12 , IC 50 = 1.1 μM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models.

Pharmacophore modeling and in silico / in vitro screening for human cytochrome P450 11B1 & cytochrome P450 11B2 inhibitors

NASA Astrophysics Data System (ADS)

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Joerg; Hartmann, Rolf W.; Schuster, Daniela

2017-12-01

Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing’s syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8-10), one selective CYP11B1 inhibitor (Compound 11, IC50 = 2.5 µM), and one selective CYP11B2 inhibitor (compound 12, IC50 = 1.1 µM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models.

Toll-like receptors participate in Naegleria fowleri recognition.

PubMed

Martínez-Castillo, Moisés; Santos-Argumedo, Leopoldo; Galván-Moroyoqui, José Manuel; Serrano-Luna, Jesús; Shibayama, Mineko

2018-01-01

Naegleria fowleri is a protozoan that invades the central nervous system and causes primary amoebic meningoencephalitis. It has been reported that N. fowleri induces an important inflammatory response during the infection. In the present study, we evaluated the roles of Toll-like receptors in the recognition of N. fowleri trophozoites by human mucoepithelial cells, analyzing the expression and production of innate immune response mediators. After amoebic interactions with NCI-H292 cells, the expression and production levels of IL-8, TNF-α, IL-1β, and human beta defensin-2 were evaluated by RT-PCR, ELISA, immunofluorescence, and dot blot assays, respectively. To determine whether the canonical signaling pathways were engaged, we used different inhibitors, namely, IMG-2005 for MyD88 and BAY 11-7085 for the nuclear factor NFkB. Our results showed that the expression and production of the pro-inflammatory cytokines and beta defensin-2 were induced by N. fowleri mainly through the canonical TLR4 pathway in a time-dependent manner.

11β-Hydoxylase Inhibitors Protect Against Seizures in Mice by Increasing Endogenous Neurosteroid Synthesis

PubMed Central

Kaminski, Rafal M.; Rogawski, Michael A.

2011-01-01

Steroid 11β-hydroxylase (CYP11B1; EC 1.14.15.4) is a mitochondrial enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone. Inhibitors of CYP11B1, such as metyrapone and etomidate, reduce glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the GABAA receptor modulating neurosteroid allotetrahydrodeoxycorticosterone (THDOC). Because THDOC is a potent anticonvulsant, it is plausible that CYP11B1 inhibitors could protect against seizures. Here we demonstrate that metyrapone affords dose-dependent protection against 6-Hz seizures 30 min after injection (ED50, 191 mg/kg), but is markedly more potent at 6 h (ED50, 30 mg/kg). Similarly, etomidate is also protective at 30 min and 6 h (ED50 values, 4.5 and 1.7 mg/kg). Finasteride, an inhibitor of neurosteroid synthesis, attenuated the anticonvulsant effects of both CYP11B1 inhibitors at 6 h, but not 30 min following their injection. Plasma THDOC levels measured by liquid chromatography-mass spectrometry were markedly increased 6 h after injection of both CYP11B1 inhibitors and this increase was attenuated by finasteride pretreatment. We conclude that inhibition of CYP11B1 causes delayed seizure protection due to slow build-up of neurosteroids. Early seizure protection is independent of neurosteroids. PMID:21458468

Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results from the LEOPOLD I trial.

PubMed

Saxena, K; Lalezari, S; Oldenburg, J; Tseneklidou-Stoeter, D; Beckmann, H; Yoon, M; Maas Enriquez, M

2016-09-01

BAY 81-8973 (Kovaltry(®) ) is a full-length, unmodified recombinant human factor VIII (FVIII) with the same amino acid sequence as sucrose-formulated recombinant FVIII and is produced using additional advanced manufacturing technologies. To demonstrate efficacy and safety of BAY 81-8973 for treatment of bleeds and as prophylaxis based on two different potency assignments. In LEOPOLD I (ClinicalTrials.gov identifier, NCT01029340), males aged 12-65 years with severe haemophilia A and ≥150 exposure days received BAY 81-8973 20-50 IU kg(-1) two or three times per week for 12 months. Potency was based on chromogenic substrate assay per European Pharmacopoeia and label adjusted to mimic one-stage assay potency. Patients were randomized for potency sequence and crossed over potency groups after 6 months, followed by an optional 12-month extension. Primary efficacy endpoint was annualized bleeding rate (ABR). Patients also received BAY 81-8973 during major surgeries. Sixty-two patients received BAY 81-8973 prophylaxis and were included in the analysis. Median ABR was 1.0 (quartile 1, 0; quartile 3, 5.1) without clinically relevant differences between potency periods. Median ABR was similar for twice-weekly vs. three times-weekly dosing (1.0 vs. 2.0). Haemostasis was maintained during 12 major surgeries. Treatment-related adverse event (AE) incidence was ≤7% overall; no patient developed inhibitors. One patient with risk factors for cardiovascular disease developed a myocardial infarction. BAY 81-8973 was efficacious in preventing and treating bleeding episodes, irrespective of the potency assignment method, with few treatment-related AEs. Caution should be used when treating older patients with cardiovascular risk factors. © 2016 Bayer. Haemophilia Published by John Wiley & Sons Ltd.

Analysis of the Japanese subgroup in LEOPOLD II: a phase 2/3 study of BAY 81-8973, a new recombinant factor VIII product.

PubMed

Fujii, Teruhisa; Hanabusa, Hideji; Shima, Midori; Morinaga, Takeshi; Fukutake, Katsuyuki

2017-03-01

BAY 81-8973, a new full length recombinant FVIII product, has been developed for prophylaxis and on-demand therapy in patients with hemophilia A. LEOPOLD II was a phase 2/3 study comparing prophylaxis versus on-demand treatment with BAY 81-8973. The analysis herein evaluated the clinical profile in Japanese subjects enrolled in LEOPOLD II. The LEOPOLD II was an open-label randomized crossover study. Our analysis evaluated the efficacy using the annualized bleeding rate, safety, and pharmacokinetics in Japanese subjects with severe hemophilia A enrolled in LEOPOLD II. The median annualized bleeding rate was 59.9/year in the on-demand group and 1.9/year in the prophylaxis group for Japanese subjects. There were no study drug-related adverse events in the Japanese subjects. None of the subjects developed FVIII inhibitors. There were no apparent clinical differences in efficacy, safety, and pharmacokinetics between the Japanese and the non-Japanese subjects. Data for the Japanese subjects showed annualized bleeding rates to be remarkably lower in the prophylaxis group compared to the on-demand group and that BAY 81-8973 exhibited a good safety profile and tolerability. These results were similar for the non-Japanese subjects. The results support adoption of BAY 81-8973 for treatment of Japanese subjects with severe hemophilia A.

Identifying sources of nitrogen to Hanalei Bay, Kauai, utilizing the nitrogen isotope signature of macroalgae

USGS Publications Warehouse

Derse, E.; Knee, K.L.; Wankel, Scott D.; Kendall, C.; Berg, C.J.; Paytan, A.

2007-01-01

Sewage effluent, storm runoff, discharge from polluted rivers, and inputs of groundwater have all been suggested as potential sources of land derived nutrients into Hanalei Bay, Kauai. We determined the nitrogen isotopic signatures (??15N) of different nitrate sources to Hanalei Bay along with the isotopic signature recorded by 11 species of macroalgal collected in the Bay. The macroalgae integrate the isotopic signatures of the nitrate sources over time, thus these data along with the nitrate to dissolved inorganic phosphate molar ratios (N:P) of the macroalgae were used to determine the major nitrate source to the bay ecosystem and which of the macro-nutrients is limiting algae growth, respectively. Relatively low ??15N values (average -0.5???) were observed in all algae collected throughout the Bay; implicating fertilizer, rather than domestic sewage, as an important external source of nitrogen to the coastal water around Hanalei. The N:P ratio in the algae compared to the ratio in the Bay waters imply that the Hanalei Bay coastal ecosystem is nitrogen limited and thus, increased nitrogen input may potentially impactthis coastal ecosystem and specifically the coral reefs in the Bay. Identifying the major source of nutrient loading to the Bay is important for risk assessment and potential remediation plans. ?? 2007 American Chemical Society.

Views of the payload bay of OV-105 taken during the STS-99 mission

NASA Image and Video Library

2000-03-30

STS099-315-031 (11-22 February 2000) --- The Space Shuttle Endeavour orbits Earth with its lengthy SRTM mast at work (out of frame). Part of the SRTM payload is silhouetted in the cargo bay. Airglow effect of Earth's atmosphere makes for interesting light and color display.

DISTRIBUTION AND COMPOSITION OF DISSOLVED AND PARTICULATE ORGANIC CARBON IN NORTHERN SAN FRANCISCO BAY DURING LOW FRESHWATER FLOW CONDITIONS

EPA Science Inventory

The distribution of dissolved and particulate organic matter was studied in northern San Francisco Bay on seven dates during declining flow conditions from April to October 1996. Measurements were made at 3 to 11 stations (usually 8) along the salinity gradient from the Sacrament...

Reducing Nutrients and Nutrient Impacts Priority Issue Team - St. Louis Bay Project: Implementing Nutrients PIT Action Step 1.1

NASA Technical Reports Server (NTRS)

Mason, Ted

2011-01-01

The NASA Applied Science & Technology Project Office at Stennis Space Center(SSC) used satellites, in-situ measurements and computational modeling to study relationships between water quality in St. Louis Bay, Mississippi and the watershed characteristics of the Jourdan and Wolf rivers from 2000-2010.

Contemporaneous Ultraviolet and Optical Observations of Direct and Raman-scattered O VI Lines in Symbiotic Stars

NASA Astrophysics Data System (ADS)

Birriel, Jennifer J.; Espey, Brian R.; Schulte-Ladbeck, Regina E.

2000-12-01

Symbiotic stars are binary systems consisting of a hot star, typically a white dwarf, and a cool giant companion. The wind from the cool star is ionized by the radiation from the hot star, resulting in the characteristic combination of sharp nebular emission lines and stellar molecular absorption bands in the optical spectrum. Most of the emission lines are readily identifiable with common ions. However, two strong, broad emission lines at 6825 and 7082 Å defied identification with known atoms and ions. In 1989 Schmid made the case that these long unidentified emission lines resulted from the Raman scattering of the O VI resonance photons at 1032, 1038 Å by neutral hydrogen. We present contemporaneous far-UV and optical observations of direct and Raman-scattered O VI lines for nine symbiotic stars obtained with the Hopkins Ultraviolet Telescope (Astro-2) and various ground-based optical telescopes. The O VI emission lines are present in every instance in which the λλ6825, 7082 lines are present, in support of the Schmid Raman-scattering model. We calculate the scattering efficiencies and discuss the results in terms of the Raman-scattering model. Additionally, we measure the flux of the Fe II fluorescence line at 1776 Å, which is excited by the O VI line at 1032 Å, and calculate the first estimates of the conversion efficiencies for this process.

Pharmacophore Modeling and in Silico/in Vitro Screening for Human Cytochrome P450 11B1 and Cytochrome P450 11B2 Inhibitors

PubMed Central

Akram, Muhammad; Waratchareeyakul, Watcharee; Haupenthal, Joerg; Hartmann, Rolf W.; Schuster, Daniela

2017-01-01

Cortisol synthase (CYP11B1) is the main enzyme for the endogenous synthesis of cortisol and its inhibition is a potential way for the treatment of diseases associated with increased cortisol levels, such as Cushing's syndrome, metabolic diseases, and delayed wound healing. Aldosterone synthase (CYP11B2) is the key enzyme for aldosterone biosynthesis and its inhibition is a promising approach for the treatment of congestive heart failure, cardiac fibrosis, and certain forms of hypertension. Both CYP11B1 and CYP11B2 are structurally very similar and expressed in the adrenal cortex. To facilitate the identification of novel inhibitors of these enzymes, ligand-based pharmacophore models of CYP11B1 and CYP11B2 inhibition were developed. A virtual screening of the SPECS database was performed with our pharmacophore queries. Biological evaluation of the selected hits lead to the discovery of three potent novel inhibitors of both CYP11B1 and CYP11B2 in the submicromolar range (compounds 8–10), one selective CYP11B1 inhibitor (Compound 11, IC50 = 2.5 μM), and one selective CYP11B2 inhibitor (compound 12, IC50 = 1.1 μM), respectively. The overall success rate of this prospective virtual screening experiment is 20.8% indicating good predictive power of the pharmacophore models. PMID:29312923

Recent advances in the study of 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2)Inhibitors.

PubMed

Zhou, Chunchun; Ye, Fan; Wu, He; Ye, Hui; Chen, Quanxu

2017-06-01

11β-Hydroxysteroid dehydrogenase (11β-HSD), which interconverts hormonally active cortisol and inactive cortisone in multiple human tissues, has two distinct isoforms named 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) and 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2). 11β-HSD2 is an NAD + -dependent oxidase which lowers cortisol by converting it to cortisone while 11β-HSD1 mainly catalyzes the reduction which converts cortisone into cortisol. Selective inhibition of 11β-HSD2 is generally detrimental to health because the accumulation of cortisol can cause metabolic symptoms such as apparent mineralocorticoid excess (AME), fetal developmental defects and lower testosterone levels in males. There has been some advances on the study of 11β-HSD2 inhibitors and we think it necessary to make a summary of the characteristics and inhibiting properties of latest 11β-HSD2 inhibitors. As another review on 11β-HSD2 inhibitors has been issued on 2011 (see review (Ma et al., 2011)), this mini-review concerns advances during the last 5 years. Copyright © 2017 Elsevier B.V. All rights reserved.

Late Quaternary uplift along the North America-Caribbean plate boundary: Evidence from the sea level record of Guantanamo Bay, Cuba

NASA Astrophysics Data System (ADS)

Muhs, Daniel R.; Schweig, Eugene S.; Simmons, Kathleen R.; Halley, Robert B.

2017-12-01

The tectonic setting of the North America-Caribbean plate boundary has been studied intensively, but some aspects are still poorly understood, particularly along the Oriente fault zone. Guantanamo Bay, southern Cuba, is considered to be on a coastline that is under a transpressive tectonic regime along this zone, and is hypothesized to have a low uplift rate. We tested this by studying emergent reef terrace deposits around the bay. Reef elevations in the protected, inner part of the bay are ∼11-12 m and outer-coast, wave-cut benches are as high as ∼14 m. Uranium-series analyses of corals yield ages ranging from ∼133 ka to ∼119 ka, correlating this reef to the peak of the last interglacial period, marine isotope stage (MIS) 5.5. Assuming a span of possible paleo-sea levels at the time of the last interglacial period yields long-term tectonic uplift rates of 0.02-0.11 m/ka, supporting the hypothesis that the tectonic uplift rate is low. Nevertheless, on the eastern and southern coasts of Cuba, east and west of Guantanamo Bay, there are flights of multiple marine terraces, at higher elevations, that could record a higher rate of uplift, implying that Guantanamo Bay may be anomalous. Southern Cuba is considered to have experienced a measurable but modest effect from glacial isostatic adjustment (GIA) processes. Thus, with a low uplift rate, Guantanamo Bay should show no evidence of emergent marine terraces dating to the ∼100 ka (MIS 5.3) or ∼80 ka (MIS 5.1) sea stands and results of the present study support this.

Late Quaternary uplift along the North America-Caribbean plate boundary: Evidence from the sea level record of Guantanamo Bay, Cuba

USGS Publications Warehouse

Muhs, Daniel; Schweig, Eugene S.; Simmons, Kathleen; Halley, Robert B.

2017-01-01

The tectonic setting of the North America-Caribbean plate boundary has been studied intensively, but some aspects are still poorly understood, particularly along the Oriente fault zone. Guantanamo Bay, southern Cuba, is considered to be on a coastline that is under a transpressive tectonic regime along this zone, and is hypothesized to have a low uplift rate. We tested this by studying emergent reef terrace deposits around the bay. Reef elevations in the protected, inner part of the bay are ∼11–12 m and outer-coast, wave-cut benches are as high as ∼14 m. Uranium-series analyses of corals yield ages ranging from ∼133 ka to ∼119 ka, correlating this reef to the peak of the last interglacial period, marine isotope stage (MIS) 5.5. Assuming a span of possible paleo-sea levels at the time of the last interglacial period yields long-term tectonic uplift rates of 0.02–0.11 m/ka, supporting the hypothesis that the tectonic uplift rate is low. Nevertheless, on the eastern and southern coasts of Cuba, east and west of Guantanamo Bay, there are flights of multiple marine terraces, at higher elevations, that could record a higher rate of uplift, implying that Guantanamo Bay may be anomalous. Southern Cuba is considered to have experienced a measurable but modest effect from glacial isostatic adjustment (GIA) processes. Thus, with a low uplift rate, Guantanamo Bay should show no evidence of emergent marine terraces dating to the ∼100 ka (MIS 5.3) or ∼80 ka (MIS 5.1) sea stands and results of the present study support this.

A covalent G-site inhibitor for glutathione S-transferase Pi (GSTP1-1).

PubMed

Shishido, Yuko; Tomoike, Fumiaki; Kimura, Yasuaki; Kuwata, Keiko; Yano, Takato; Fukui, Kenji; Fujikawa, Haruka; Sekido, Yoshitaka; Murakami-Tonami, Yuko; Kameda, Tomoshi; Shuto, Satoshi; Abe, Hiroshi

2017-10-10

We herein report the first covalent G-site-binding inhibitor for GST, GS-ESF (1), which irreversibly inhibited the GSTP 1-1 function. LC-MS/MS and X-ray structure analyses of the covalently linked GST-inhibitor complex suggested that 1 reacted with Tyr108 of GSTP 1-1 . The mechanism of covalent bond formation was discussed based on MD simulation results.

Canopies of Blue: The American Airborne Experience in the Pacific in the Second World War as a Case Study in Operational Art and Multi-role Flexibility

DTIC Science & Technology

2008-03-25

capture of Bougainville.25 Since both ends of the island contained Japanese strongholds, the central Empress August Bay region on the western side of...tactics, I MAC withdrew the raiders at a cost of 11 dead and 14 wounded.29 The Empress Augusta Bay invasion was now in full swing and the...Japanese positions in the north that held the potential to damage efforts at Empress Augusta Bay. Japanese heavy bombers focused their efforts on

South San Francisco Bay, California

USGS Publications Warehouse

Dartnell, Peter; Gibbons, Helen

2007-01-01

View eastward. Elevations in mapped area color coded: purple (approx 15 m below sea level) to red-orange (approx 90 m above sea level). South San Francisco Bay is very shallow, with a mean water depth of 2.7 m (8.9 ft). Trapezoidal depression near San Mateo Bridge is where sediment has been extracted for use in cement production and as bay fill. Land from USGS digital orthophotographs (DOQs) overlaid on USGS digital elevation models (DEMs). Distance across bottom of image approx 11 km (7 mi); vertical exaggeration 1.5X.

Metasomatism-induced magnesium isotope fractionation in ultramafic rocks: Evidence from the Franciscan Complex, California

NASA Astrophysics Data System (ADS)

Li, W. Y.; Teng, F. Z.; Xiao, Y.

2016-12-01

To investigate the behaviour of Mg isotopes during metasomatic reactions between peridotites and infiltrating fluids along the slab-mantle interface, we analyzed Mg isotopic compositions of a set of well-characterized samples from the ultramafic blocks in the Franciscan Complex of California [1]. The Group 1 and Group 2 samples that were defined by the initial serpentinization and complete serpentinization of peridotites at temperatures of 450-500 ºC, respectively [1], have δ26Mg values (from -0.26 to -0.14‰) clustered around the mantle value. This suggests that Mg isotope fractionation during serpentinization by slab-derived fluids, if any, is small. By contrast, the Group 3 samples that were defined by the replacement of serpentine by talc [1], are enriched in heavy Mg isotopes (δ26Mg of -0.13 to -0.01‰). This may reflect the loss of light Mg isotopes into fluids during the dehydration reaction that produced talc from serpentine, which is consistent with previous observations that secondary clay minerals preferentially incorporate heavy Mg isotopes during water-rock interactions [2, 3]. The Group 4 samples that were defined by the further replacement of talc by tremolite [1], however, have light Mg isotopic compositions (δ26Mg of -0.50 to -0.41‰). Such a shift towards light Mg isotopic compositions likely results from metasomatism by fluids that derived from isotopically light carbonates, which is supported by the remarkably higher CaO content of Group 4 samples (from 6.9 to 9.2 wt%) than Group 3 ones (from 1.1 to 1.4 wt%). Collectively, significant Mg isotopic variations occur during metasomatism of peridotites in the mantle wedge, which would potentially lead to heterogeneous Mg isotopic compositions in arc lavas [4]. Therefore, Mg isotopes can be used as a powerful tracer of crust-mantle interaction at subduction zones. [1] King et al. (2003) Geol. Soc. Am. Bull. 115, 1097-1109. [2] Teng et al. (2010) Earth Planet. Sci. Lett. 300, 63-71. [3] Wimpenny et al. (2014) Geochim. Cosmochim. Acta 128, 178-194. [4] Teng et al. (2016) Proc. Natl. Acad. Sci. 113, 7082-7087. et al. (2016) Proc. Natl. Acad. Sci. 113, 7082-7087.

Views of Endeavour's payload bay and an Earth limb taken during STS-99

NASA Image and Video Library

2000-02-12

STS099-703-082 (11-22 February 2000) --- Part of the Space Shuttle Endeavour's aft cargo bay, its vertical stabilizer and orbital maneuvering system (OMS) pods are seen in this 70mm frame. Part of Earth's horizon, with an expanse of heavy cloud cover over land and water, is at bottom of frame.

78 FR 14644 - Airworthiness Directives; The Boeing Company Airplanes

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-07

... within the ECS bay, which in combination with flammable fuel vapors, could result in a center wing fuel... ECS bay, but allows installation of clamp P/N TA0930034-11 at the same clamp position. Delta Air Lines (Delta) requested that we ensure that paragraph (h) of the NPRM, only applies to those airplanes subject...

Orbiter Docking System/Spacelab-Mir Module in Atlantis

NASA Technical Reports Server (NTRS)

1995-01-01

The STS-71 mission payload is in its final flight configuration after integration into the payload bay of the Space Shuttle orbiter Atlantis and prior to payload bay door closing and rollover of the spaceplane from Orbiter Processing Facility Bay 3 to the Vehicle Assembly Building. In the foreground is the Orbiter Docking System (ODS) that is topped with the red Russian- built Androgynous Peripheral Docking System (APDS). During the 11-day mission, the APDS will lock together with a similar system on the Russian Mir Space Station so that the two spacecraft can remain docked together for four days. The ODS features an airlock that will provide access to and from both the Mir and orbiter for the U.S. and Russian flight crews. A Spacelab transfer tunnel runs from the ODS to the Spacelab-Mir module, where joint U.S. medical experiments will be conducted during the 11-day spaceflight.

Occurrence and distribution of organochlorine compounds in sediment and livers of striped bass (Morone saxatilis) from the San Francisco Bay-Delta Estuary

USGS Publications Warehouse

Pereira, W.E.; Hostettler, F.D.; Cashman, J.R.; Nishioka, R.S.

1994-01-01

A preliminary assessment was made in 1992 of chlorinated organic compounds in sediments and in livers of striped bass from the San Francisco Bay-Delta Estuary. Samples of sediment and striped bass livers contained DDT (ethane, 1,1,1-trichloro-2,2-bis (p-chlorophenyl)-) and its degradation products, DDD (ethane, 1,1-dichloro-2,2-bis(p-chlorophenyl)-) and DDE (ethylene, 1,1-dichloro-2,2-bis (p-chlorophenyl)-); PCBs (polychlorinated biphenyls); alpha and gamma chlordane, and cis and trans nonachlor. In addition, the livers of striped bass contained small concentrations of DCPA (dimethyl tetrachloroterephthalate), a pre-emergent herbicide. Agricultural run-off from the Sacramento and San Joaquin Rivers, as well as atmospheric deposition, are probably responsible for a low chronic background of DDT in sediments throughout San Francisco Bay. Larger concentrations of DDT in sediment near Richmond in the Central Bay, and Coyote Creek in the South Bay may be derived from point sources. Ratios of pentachloro isomers of PCBs to hexachloro isomers in the South Bay sediments were different from those in the Central and North Bay, suggesting either differences in microbial activity in the sediments or different source inputs of PCBs. Concentrations of alpha chlordane in livers of striped bass were greater than those of gamma chlordane, which suggests a greater environmental stability and persistence of alpha chlordane. Trans nonachlor, a minor component of technical chlorodane, was present in greater concentrations than alpha and gamma chlordane and cis nonachlor. Trans nonachlor is more resistant to metabolism than alpha and gamma chlordane and cis nonachlor, and serves as an environmentally stable marker compound of chlordane contamination in the estuary. Chlorinated organic compounds have bioaccumulated in the livers of striped bass. These compounds may contribute to the decline of the striped bass in San Francisco Bay-Delta Estuary.

Nitrobenzoxadiazole-based GSTP1-1 inhibitors containing the full peptidyl moiety of (pseudo)glutathione.

PubMed

Luisi, Grazia; Mollica, Adriano; Carradori, Simone; Lenoci, Alessia; De Luca, Anastasia; Caccuri, Anna Maria

2016-12-01

The inhibition of glutathione S-transferase P1-1 (GSTP1-1) is a sound strategy to overcome drug resistance in oncology practice. The nitrobenzoxadiazolyl (NBD) S-conjugate of glutathione and the corresponding γ-oxa-glutamyl isostere (compounds 1 and 5, respectively) have been disclosed as GST inhibitors. The rationale of their design is discussed in juxtaposition to non-peptide NBD thioethers. Synthesis of derivatives 1 and 5 and in vitro evaluation on human GSTP1-1 and M2-2 are reported. Conjugates 1 and 5 were found to be low micromolar inhibitors of both isoforms. Furthermore, they display a threefold reduction in selectivity for GSTM2-2 over the P1-1 isozyme in comparison with the potent non-peptide inhibitor nitrobenzoxadiazolyl-thiohexanol (NBDHEX). Spectroscopic data are congruent with the formation of a stable sigma-complex between GSH and the inhibitors in the protein active site. Conjugate 5 is suitable for in vivo modulation of GST activity in cancer treatment.

Homology modeling, docking studies and molecular dynamic simulations using graphical processing unit architecture to probe the type-11 phosphodiesterase catalytic site: a computational approach for the rational design of selective inhibitors.

PubMed

Cichero, Elena; D'Ursi, Pasqualina; Moscatelli, Marco; Bruno, Olga; Orro, Alessandro; Rotolo, Chiara; Milanesi, Luciano; Fossa, Paola

2013-12-01

Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross-react with PDE11. Accordingly, many non-selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2-d]pyrimidin-4(3H)-one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X-ray structures, we found interesting to gain a better understanding of the enzyme-inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors. © 2013 John Wiley & Sons A/S.

Research on Fire-Resistant Diesel Fuel Flammability Mitigation Mechanisms

DTIC Science & Technology

1982-12-01

Naegeli U.S. Army Fuels and Lubricants Research Laboratory Southwest Research Institute San Antonio, Texas Under Contract to U.S. Army Mobility Equipment...David Naegeli DAAK70-80-C-0001 DAAK70-82-C-0001 9. PERFORMING ORGANIZATION NAME AND ADDRESSES 10. PROGRAM ELEMENT, PROJECT. TASK U.S. Army Fuels and...water-containing diesel fuel blends. 43 VI. LIST OF REFERENCES 1. Weatherford, W.D., Jr., Fodor, G.E., Naegeli , D.W., Wright, B.R., Owens, E.C., and

Assessment for water quality by artificial neural network in Daya Bay, South China Sea.

PubMed

Wu, Mei-Lin; Wang, You-Shao; Gu, Ji-Dong

2015-10-01

In this study, artificial neural network such as a self-organizing map (SOM) was used to assess for the effects caused by climate change and human activities on the water quality in Daya Bay, South China Sea. SOM has identified the anthropogenic effects and seasonal characters of water quality. SOM grouped the four seasons as four groups (winter, spring, summer and autumn). The Southeast Asian monsoons, northeasterly from October to the next April and southwesterly from May to September have also an important influence on the water quality in Daya Bay. Spatial pattern is mainly related to anthropogenic activities and hydrodynamics conditions. In spatial characteristics, the water quality in Daya Bay was divided into two groups by chemometrics. The monitoring stations (S3, S8, S10 and S11) were in these area (Dapeng Ao, Aotou Harbor) and northeast parts of Daya Bay, which are areas of human activity. The thermal pollution has been observed near water body in Daya Bay Nuclear Power Plant (S5). The rest of the monitoring sites were in the south, central and eastern parts of Daya Bay, which are areas that experience water exchanges from South China Sea. The results of this study may provide information on the spatial and temporal patterns in Daya Bay. Further research will be carry out more research concerning functional changes in the bay ecology with respect to changes in climatic factor, human activities and bay morphology in Daya Bay.

Synergistic effects of BAY 60-4552 and vardenafil on relaxation of corpus cavernosum tissue of patients with erectile dysfunction and clinical phosphodiesterase type 5 inhibitor failure.

PubMed

Albersen, Maarten; Linsen, Loes; Tinel, Hanna; Sandner, Peter; Van Renterghem, Koenraad

2013-05-01

Overall efficacy rates of phosphodiesterase type 5 inhibitors (PDE5-i) for erectile dysfunction (ED) are 60-70%. PDE5-i treatment failures currently have to resort to invasive treatment options for restoration of erectile function. AIMS.: To assess changes in the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/protein kinase (PKG) pathway in human corpus cavernosum (HCC) of PDE5-i nonresponders compared with healthy controls. To evaluate the effects of BAY 60-4552, a stimulator of soluble guanylate cyclase (sGC), and vardenafil on relaxation of HCC strips from PDE5-i nonresponders. mRNA expression, morphological localization of the NO/cGMP/PKG pathway, and relaxant capacity of both compounds alone or combined. Analysis of variance, t-test or Mann-Whitney test based upon number of groups and normality of data. HCC tissues were harvested after consent from individuals undergoing penile prosthesis implantation (patients) and potent patients undergoing transurethral surgery (healthy controls, needle biopsy). HCC tissues of patients were compared with those of healthy controls for the expression of mRNA coding for PDE5A, eNOS, PKGα1, PKG2, sGCα1, sGCα2, sGCβ1, sGCβ2, α-smooth muscle actin (aSMA) and β-actin by quantitative polymerase chain reaction (qPCR). The respective proteins were localized using immunofluorescence. Tissue strips of patients were precontracted with phenylepinephrine followed by incubation with 1 μM of either vardenafil or BAY 60-4552, or both simultaneously. The main targets in the NO/cGMP/sGC pathway were downregulated in PDE5-i nonresponders. The pathway was morphologically located to HCC smooth muscle, of which the overall content was preserved in ED patients based on aSMA expression. BAY 60-4552 and vardenafil have synergistic effects on relaxation of HCC of PDE5-i nonresponders. The main limitation is the small amount of control tissue precluding functional testing on these samples. Despite downregulation of the NO/cGMP/PKG pathway, combining BAY 60-4552 with vardenafil significantly enhanced relaxation HCC strips of PDE5-i nonresponders. © 2013 International Society for Sexual Medicine.

Geochemical and geo-statistical assessment of selected heavy metals in the surface sediments of the Gorgan Bay, Iran.

PubMed

Bastami, Kazem Darvish; Bagheri, Hossein; Haghparast, Sarah; Soltani, Farzaneh; Hamzehpoor, Ali; Bastami, Mousa Darvish

2012-12-01

We investigated heavy metal concentrations of zinc (Zn), copper (Cu), chromium (Cr), and lead (Pb), their spatial distribution and enrichment factor index in surface sediments of the Gorgan Bay. Sediment Quality Guidelines were also applied to assess adverse biological effects of these metals. Heavy metals were determined by inductively coupled plasma-mass spectroscopy (ICP-MS). The results indicated mean concentrations (ppm) of heavy metals were (mean±S.D.) Pb: 11.5±4.88, Cu: 18±8.83, Zn: 42±22.15 and Cr: 32±15.19. Based on Enrichment index, the Gorgan Bay is a low-enriched to non-enriched bay. Heavy metal contents were lower than the standard limits of PEL, ERL, and ERM that reveal no threatening influence of the metals in the Bay. Copyright © 2012 Elsevier Ltd. All rights reserved.

Cav1.2 channel current block by the PKA inhibitor H-89 in rat tail artery myocytes via a PKA-independent mechanism: Electrophysiological, functional, and molecular docking studies.

PubMed

Fusi, Fabio; Trezza, Alfonso; Spiga, Ottavia; Sgaragli, Giampietro; Bova, Sergio

2017-09-15

To characterize the role of cAMP-dependent protein kinase (PKA) in regulating vascular Ca 2+ current through Ca v 1.2 channels [I Ca1.2 ], we have documented a marked capacity of the isoquinoline H-89, widely used as a PKA inhibitor, to reduce current amplitude. We hypothesized that the I Ca1.2 inhibitory activity of H-89 was mediated by mechanisms unrelated to PKA inhibition. To support this, an in-depth analysis of H-89 vascular effects on both I Ca1.2 and contractility was undertaken by performing whole-cell patch-clamp recordings and functional experiments in rat tail main artery single myocytes and rings, respectively. H-89 inhibited I Ca1.2 with a pIC 50 (M) value of about 5.5, even under conditions where PKA activity was either abolished by both the PKA antagonists KT5720 and protein kinase inhibitor fragment 6-22 amide or enhanced by the PKA stimulators 6-Bnz-cAMP and 8-Br-cAMP. Inhibition of I Ca1.2 by H-89 appeared almost irreversible upon washout, was charge carrier- and voltage-dependent, and antagonised by the Ca v 1.2 channel agonist (S)-(-)-Bay K 8644. H-89 did not alter both potency and efficacy of verapamil, did not affect current kinetics or voltage-dependent activation, while shifting to the left the 50% voltage of inactivation in a concentration-dependent manner. H-89 docked at the α 1C subunit in a pocket region close to that of (S)-(-)-Bay K 8644 docking, forming a hydrogen bond with the same, key amino acid residue Tyr-1489. Finally, both high K + - and (S)-(-)-Bay K 8644-induced contractions of rings were fully reverted by H-89. In conclusion, these results indicate that H-89 inhibited vascular I Ca1.2 and, consequently, the contractile function through a PKA-independent mechanism. Therefore, caution is recommended when interpreting experiments where H-89 is used to inhibit vascular smooth muscle PKA. Copyright © 2017 Elsevier Inc. All rights reserved.

75 FR 50700 - Quarterly Listings; Safety Zones, Security Zones, Special Local Regulations, and Drawbridge...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-17

... Morgan City--07-012 New Iberia, LO Safety Zones (Parts 147 and 10/2/2007 165). COTP Morgan City--07-014... Iberia, LO Safety Zones (Parts 147 and 10/11/2007 165). COTP San Francisco Bay 06-013 Carquinez Strait...-0043 Savannah, GA Security zones (Part 165)..... 1/24/2008 USCG-2008-0050 Atchafalaya Bay, LO...

33 CFR 165.704 - Safety Zone; Tampa Bay, Florida.

Code of Federal Regulations, 2010 CFR

2010-07-01

..., Florida. (a) A floating safety zone is established consisting of an area 1000 yards fore and aft of a... ending at Gadsden Point Cut Lighted Buoys “3” and “4”. The safety zone starts again at Gadsden Point Cut... the marked channel at Tampa Bay Cut “K” buoy “11K” enroute to Rattlesnake, Tampa, FL, the floating...

A lead discovery strategy driven by a comprehensive analysis of proteases in the peptide substrate space

PubMed Central

Sukuru, Sai Chetan K; Nigsch, Florian; Quancard, Jean; Renatus, Martin; Chopra, Rajiv; Brooijmans, Natasja; Mikhailov, Dmitri; Deng, Zhan; Cornett, Allen; Jenkins, Jeremy L; Hommel, Ulrich; Davies, John W; Glick, Meir

2010-01-01

We present here a comprehensive analysis of proteases in the peptide substrate space and demonstrate its applicability for lead discovery. Aligned octapeptide substrates of 498 proteases taken from the MEROPS peptidase database were used for the in silico analysis. A multiple-category naïve Bayes model, trained on the two-dimensional chemical features of the substrates, was able to classify the substrates of 365 (73%) proteases and elucidate statistically significant chemical features for each of their specific substrate positions. The positional awareness of the method allows us to identify the most similar substrate positions between proteases. Our analysis reveals that proteases from different families, based on the traditional classification (aspartic, cysteine, serine, and metallo), could have substrates that differ at the cleavage site (P1–P1′) but are similar away from it. Caspase-3 (cysteine protease) and granzyme B (serine protease) are previously known examples of cross-family neighbors identified by this method. To assess whether peptide substrate similarity between unrelated proteases could reliably translate into the discovery of low molecular weight synthetic inhibitors, a lead discovery strategy was tested on two other cross-family neighbors—namely cathepsin L2 and matrix metallo proteinase 9, and calpain 1 and pepsin A. For both these pairs, a naïve Bayes classifier model trained on inhibitors of one protease could successfully enrich those of its neighbor from a different family and vice versa, indicating that this approach could be prospectively applied to lead discovery for a novel protease target with no known synthetic inhibitors. PMID:20799349

BAY 41-2272, a soluble guanylate cyclase stimulator, relaxes isolated human ureter in a standardized in vitro model.

PubMed

Miyaoka, Ricardo; Mendes, Camila; Schenka, André; Gonzalez, Paulo Gabriel; de Nucci, Gilberto; Antunes, Edson; Monga, Manoj; Levi D'Ancona, Carlos Arturo; Mónica, Fabíola Zakia

2014-01-01

To characterize the relaxation induced by BAY 41-2272 in human ureteral segments. Ureter specimens (n = 17) from multiple organ human deceased donors (mean age 40 ± 3.2 years, male/female ratio 2:1) were used to characterize the relaxing response of BAY 41-2272. Immunohistochemical analysis for endothelial and neuronal nitric oxide synthase, guanylate cyclase stimulator (sGC) and type 5 phosphodiesterase was also performed. The potency values were determined as the negative log of the molar to produce 50% of the maximal relaxation in potassium chloride-precontracted specimens. The unpaired Student t test was used for the comparisons. Immunohistochemistry revealed the presence of endothelial nitric oxide synthase in vessel endothelia and neuronal nitric oxide synthase in urothelium and nerve structures. sGC was expressed in the smooth muscle and urothelium layer, and type 5 phosphodiesterase was present in the smooth muscle only. BAY 41-2272 (0.001-100 μM) relaxed the isolated ureter in a concentration dependent manner, with a potency and maximal relaxation value of 5.82 ± 0.14 and 84% ± 5%, respectively. The addition of nitric oxide synthase and sGC inhibitors reduced the maximal relaxation values by 21% and 45%, respectively. However, the presence of sildenafil (100 nM) significantly potentiated (6.47 ± 0.10, P <.05) this response. Neither glibenclamide or tetraethylammonium nor ureteral urothelium removal influenced the relaxation response by BAY 41-2272. BAY 41-2272 relaxes the human isolated ureter in a concentration-dependent manner, mainly by activating the sGC enzyme in smooth muscle cells rather than in the urothelium, although a cyclic guanosine monophosphate-independent mechanism might have a role. The potassium channels do not seem to be involved. Copyright © 2014 Elsevier Inc. All rights reserved.

The sGC activator inhibits the proliferation and migration, promotes the apoptosis of human pulmonary arterial smooth muscle cells via the up regulation of plasminogen activator inhibitor-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Shuai; Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, 8 Gongti South Rd, Beijing; Zou, Lihui

Background: Different types of pulmonary hypertension (PH) share the same process of pulmonary vascular remodeling, the molecular mechanism of which is not entirely clarified by far. The abnormal biological behaviors of pulmonary arterial smooth muscle cells (PASMCs) play an important role in this process. Objectives: We investigated the regulation of plasminogen activator inhibitor-2 (PAI-2) by the sGC activator, and explored the effect of PAI-2 on PASMCs proliferation, apoptosis and migration. Methods: After the transfection with PAI-2 overexpression vector and specific siRNAs or treatment with BAY 41-2272 (an activator of sGC), the mRNA and protein levels of PAI-2 in cultured humanmore » PASMCs were detected, and the proliferation, apoptosis and migration of PASMCs were investigated. Results: BAY 41-2272 up regulated the endogenous PAI-2 in PASMCs, on the mRNA and protein level. In PAI-2 overexpression group, the proliferation and migration of PASMCs were inhibited significantly, and the apoptosis of PASMCs was increased. In contrast, PAI-2 knockdown with siRNA increased PASMCs proliferation and migration, inhibited the apoptosis. Conclusions: PAI-2 overexpression inhibits the proliferation and migration and promotes the apoptosis of human PASMCs. Therefore, sGC activator might alleviate or reverse vascular remodeling in PH through the up-regulation of PAI-2. - Highlights: • sGC activator BAY41-2272 up regulated PAI-2 in PASMCs, on the mRNA and protein level. • PAI-2 overexpression inhibits the proliferation and migration of human PASMCs. • PAI-2 overexpression promotes the apoptosis of human PASMCs. • sGC activator might alleviate the vascular remodeling in pulmonary hypertension.« less

ROSA Transfer (for SpaceX CRS-11)

NASA Image and Video Library

2017-04-12

Inside the Space Station Processing Facility high bay at NASA's Kennedy Space Center in Florida, the Roll-Out Solar Array, or ROSA, is being prepared for transfer out of the high bay. ROSA will be delivered to the International Space Station aboard the SpaceX Dragon cargo carrier on the company’s 11th commercial resupply services mission to the space station. ROSA is a new type of solar panel that rolls open in space and is more compact than current rigid panel designs. The ROSA investigation will test deployment and retraction, shape changes when the Earth blocks the sun, and other physical challenges to determine the array's strength and durability.

Effects of Inundation by the 14th November, 2016 Kaikōura Tsunami on Banks Peninsula, Canterbury, New Zealand

NASA Astrophysics Data System (ADS)

Lane, Emily M.; Borrero, Jose; Whittaker, Colin N.; Bind, Jo; Chagué-Goff, Catherine; Goff, James; Goring, Derek; Hoyle, Jo; Mueller, Christof; Power, William L.; Reid, Catherine M.; Williams, James H.; Williams, Shaun P.

2017-05-01

At 12:02:56 a.m. Monday, November 14 2016 NZDT (11:02:56 a.m., November 13 2016 UTC) a magnitude 7.8 earthquake struck near Kaikōura on the north-eastern coast of the South Island of New Zealand. This earthquake caused a tsunami along New Zealand's east coast that was recorded on a number of sea level gauges. Outside of the Kaikōura region, north facing bays along Banks Peninsula were most affected by the tsunami. Of these, Little Pigeon Bay experienced extensive inundation and an unoccupied cottage was destroyed by the wave run-up. We report on the inundation extent and (inferred) flow directions at Little Pigeon Bay, including a study on temporal changes in the field evidence of this inundation. Preliminary modelling results indicate that the waves may have excited resonance in the bay. We also present results from inundation surveys of nearby, north-facing bays on Banks Peninsula. The excitation of resonance in Little Pigeon Bay provides an explanation for the more severe inundation and damage there in comparison to these nearby bays.

Detection of dechallenge in spontaneous reporting systems: a comparison of Bayes methods.

PubMed

Banu, A Bazila; Alias Balamurugan, S Appavu; Thirumalaikolundusubramanian, Ponniah

2014-01-01

Dechallenge is a response observed for the reduction or disappearance of adverse drug reactions (ADR) on withdrawal of a drug from a patient. Currently available algorithms to detect dechallenge have limitations. Hence, there is a need to compare available new methods. To detect dechallenge in Spontaneous Reporting Systems, data-mining algorithms like Naive Bayes and Improved Naive Bayes were applied for comparing the performance of the algorithms in terms of accuracy and error. Analyzing the factors of dechallenge like outcome and disease category will help medical practitioners and pharmaceutical industries to determine the reasons for dechallenge in order to take essential steps toward drug safety. Adverse drug reactions of the year 2011 and 2012 were downloaded from the United States Food and Drug Administration's database. The outcome of classification algorithms showed that Improved Naive Bayes algorithm outperformed Naive Bayes with accuracy of 90.11% and error of 9.8% in detecting the dechallenge. Detecting dechallenge for unknown samples are essential for proper prescription. To overcome the issues exposed by Naive Bayes algorithm, Improved Naive Bayes algorithm can be used to detect dechallenge in terms of higher accuracy and minimal error.

8. CAR FLOAT AND TUG DOCKED AT BRIDGE NO. 11 ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

8. CAR FLOAT AND TUG DOCKED AT BRIDGE NO. 11 FROM BRIDGE NO. 9 APRON. LOOKING SOUTHEAST. - Greenville Yard, Transfer Bridge System, Port of New York/New Jersey, Upper New York Bay, Jersey City, Hudson County, NJ

Distribution, Source, and Ecological Risk Assessment of Polycyclic Aromatic Hydrocarbons in Surface Sediment of Liaodong Bay, Northeast China

NASA Astrophysics Data System (ADS)

Xu, Shuang; Tao, Ping; Li, Yuxia; Guo, Qi; Zhang, Yan; Wang, Man; Jia, Hongliang; Shao, Mihua

2018-01-01

Sixteen polycyclic aromatic hydrocarbons (PAHs) were determined in surface sediments from Liaodong Bay, northeast China. The concentration levels of total PAHs (Σ16PAHs) in sediment were 11.0˜249.6 ng·g-1 dry weight (dw), with a mean value of 89.9 ng·g-1 dry weight (dw). From the point of the spatial distribution, high PAHs levels were found in the western areas of Liaodong Bay. In the paper, sources of PAHs were investigated by diagnostic ratios, which indicated that pyrogenic sources were the main sources of PAHs in the sediment of Liaodong Bay. Therefore, selected PAH levels in sediments were compared with Sediments Quality Guidelines (ERM-ERL indexes) for evaluation probable toxic effects on marine organism.

Chesapeake Bay, New England

NASA Image and Video Library

1994-09-30

STS068-234-044 (30 September-11 October 1994) --- From the wetlands in Maryland to the nation's capital and onto Baltimore, this 70mm photograph from the Space Shuttle Endeavour shows some details of the historic Chesapeake Bay and Potomac River area. With the rather low altitude of Endeavour at 115 nautical miles, features as small as Kennedy Memorial Stadium and Andrews Air Force Base are clearly seen.

San Juan Bay Estuary watershed urban forest inventory

Treesearch

Thomas J. Brandeis; Francisco J. Escobedo; Christina L. Staudhammer; David J. Nowak; Wayne C. Zipperer

2014-01-01

We present information on the urban forests and land uses within the watershed of Puerto Rico’s 21 658-ha San Juan Bay Estuary based on urban forest inventories undertaken in 2001 and 2011. We found 2548 ha of mangrove and subtropical moist secondary forests covering 11.8 percent of the total watershed area in 2011. Red, black, and white mangroves (Rhizophora...

Maximization of beta-galactosidase production: a simultaneous investigation of agitation and aeration effects.

PubMed

Alves, Fernanda Germano; Filho, Francisco Maugeri; de Medeiros Burkert, Janaína Fernandes; Kalil, Susana Juliano

2010-03-01

In this work, the agitation and aeration effects in the maximization of the beta-galactosidase production from Kluyveromyces marxianus CCT 7082 were investigated simultaneously, in relation to the volumetric enzyme activity and the productivity, as well as the analysis of the lactose consumption and production of glucose, and galactose of this process. Agitation and aeration effects were studied in a 2 L batch stirred reactor. A central composite design (2(2) trials plus three central points) was carried out. Agitation speed varied from 200 to 500 rpm and aeration rate from 0.5 to 1.5 vvm. It has been shown in this study that the volumetric enzyme production was strongly influenced by mixing conditions, while aeration was shown to be less significant. Linear models for activity and productivity due to agitation and aeration were obtained. The favorable condition was 500 rpm and 1.5 vvm, which lead to the best production of 17 U mL(-1) for enzymatic activity, 1.2 U mL(-1) h(-1) for productivity in 14 h of process, a cellular concentration of 11 mg mL(-1), and a 167.2 h(-1) volumetric oxygen transfer coefficient.

Albino mutation rates in red mangroves (Rhizophora mangle L.) as a bioassay of contamination history in Tampa Bay, Florida, USA

USGS Publications Warehouse

Proffitt, C.E.; Travis, S.E.

2005-01-01

We assessed the sensitivity of a viviparous estuarine tree species, Rhizophora mangle, to historic sublethal mutagenic stress across a fine spatial scale by comparing the frequency of trees producing albino propagules in historically contaminated (n=4) and uncontaminated (n=11) forests in Tampa Bay, Florida, USA. Data from uncontaminated forests were used to provide estimates of background mutation rates. We also determined whether other fitness parameters were negatively correlated with mutagenic stress (e.g., degree of outcrossing and numbers of reproducing trees km-1). Contaminated sites in Tampa Bay had significantly higher frequencies of trees that were heterozygous for albinism per 1000 total reproducing trees (FHT) than uncontaminated forests (mean ?? SE: 11.4 ?? 4.3 vs 4.3 ?? 0.73, P 25 yrs of subsequent recruitment and tree replacement may have allowed an initial elevation in the FHT to decay. Patterns of FHT were not explained by distance from the bay mouth or the degree of urbanization. However, there was a significant positive relationship between tree size and FHT (r=0.83, P<0.018), which suggests that forests with older or larger trees provide a more lasting record of cumulative mutagenic stress. No other fitness parameters correlated with FHT. There was a difference in FHT between two latitudes, as determined by comparing Tampa Bay with literature values for Puerto Rico. The sensitivity of this bioassay for the effects of mutagens will facilitate future monitoring of contamination events and comparisons of bay-wide recovery in future decades. Development of a database of FHT values for a range of subtropical and tropical estuaries is underway that will provide a baseline against which to compare mutational consequences of global change. ?? 2005, The Society of Wetland Scientists.

Seasonal and spatial variations of water quality and trophic status in Daya Bay, South China Sea.

PubMed

Wu, Mei-Lin; Wang, You-Shao; Wang, Yu-Tu; Sun, Fu-Lin; Sun, Cui-Ci; Cheng, Hao; Dong, Jun-De

2016-11-15

Coastal water quality and trophic status are subject to intensive environmental stress induced by human activities and climate change. Quarterly cruises were conducted to identify environmental characteristics in Daya Bay in 2013. Water quality is spatially and temporally dynamic in the bay. Cluster analysis (CA) groups 12 monitoring stations into two clusters. Cluster I consists of stations (S1, S2, S4-S7, S9, and S12) located in the central, eastern, and southern parts of the bay, representing less polluted regions. Cluster II includes stations (S3, S8, S10, and S11) located in the western and northern parts of the bay, indicating the highly polluted regions receiving a high amount of wastewater and freshwater discharge. Principal component analysis (PCA) identified that water quality experience seasonal change (summer, winter, and spring-autumn seasons) because of two monsoons in the study area. Eutrophication in the bay is graded as high by Assessment of Estuarine Trophic Status (ASSETS). Copyright © 2016 Elsevier Ltd. All rights reserved.

33 CFR 165.1107 - San Diego Bay, California.

Code of Federal Regulations, 2010 CFR

2010-07-01

...)(1). [CGD11-90-07, 56 FR 14645, Apr. 11, 1991; 56 FR 40360, Aug. 14, 1991, as amended by USCG-1998-3799, 63 FR 35533, June 30, 1998. Redesignated by USCG-2001-9286, 66 FR 33642, June 25, 2001] ...

33 CFR 165.1107 - San Diego Bay, California.

Code of Federal Regulations, 2011 CFR

2011-07-01

...)(1). [CGD11-90-07, 56 FR 14645, Apr. 11, 1991; 56 FR 40360, Aug. 14, 1991, as amended by USCG-1998-3799, 63 FR 35533, June 30, 1998. Redesignated by USCG-2001-9286, 66 FR 33642, June 25, 2001] ...

Earth Observations taken by Expedition 38 crewmember

NASA Image and Video Library

2014-02-21

ISS038-E-57806 (21 Feb. 2014) --- One of the Expedition 38 crew members aboard the International Space Station photographed this image of the Gulf of Mexico's Intracoastal Waterway in southern Texas. Represented in the photo are 18 kilometers (11.2 miles) of the overall 4800 kilometers-long (3000 miles) barge channel that lies on the protected inshore of the coastal islands of the southern and eastern USA, including coastal Texas. The small city of Port Aransas lies on a barrier island fully 18 kilometers (11.2 miles) seaward of the mainland and its sister city, Aransas Pass (lower left). This image shows parts of the waterway that are artificial, as in the straight sector leading into Corpus Christi Bay. Corpus Christi lies outside the lower margin of the image. Other sectors of the waterway are natural bays such as Aransas Bay. Jetties protect the inlet into the Gulf of Mexico (top right). Inlets at many points cut through the barrier islands to give shipping access to the Gulf of Mexico and the Atlantic Ocean.

76 FR 61040 - Standard Instrument Approach Procedures, and Takeoff Minimums and Obstacle Departure Procedures...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-10-03

.../South 1/1141 9/8/11 VOR/DME RNAV OR GPS RWY 35, Amdt 3 Padre Island Intl. 20-Oct-11 TX Brownsville......... Brownsville/South 1/1142 9/8/11 VOR OR TACAN OR GPS A, Amdt 1A Padre Island Intl. 20-Oct-11 TX Brownsville......... Brownsville/South 1/1143 9/8/11 LOC BC RWY 31L, Amdt 11B Padre Island Intl. 20-Oct-11 AL Bay Minette...

Structure based design of 11β-HSD1 inhibitors.

PubMed

Singh, Suresh; Tice, Colin

2010-11-01

Controlling elevated tissue-specific levels of cortisol may provide a novel therapeutic approach for treating metabolic syndrome. This concept has spurred large scale medicinal chemistry efforts in the pharmaceutical industry for the design of 11β-HSD1 inhibitors. High resolution X-ray crystal structures of inhibitors in complex with the enzyme have facilitated the structure-based design of diverse classes of molecules. A summary of binding modes, trends in structure-activity relationships, and the pharmacodynamic data of inhibitors from each class is presented.

Synthesis and biological evaluation of kresoxim-methyl analogues as novel inhibitors of hypoxia-inducible factor (HIF)-1 accumulation in cancer cells.

PubMed

Lee, Sanghyuck; Kwon, Oh Seok; Lee, Chang-Soo; Won, Misun; Ban, Hyun Seung; Ra, Choon Sup

2017-07-01

We designed and synthesized strobilurin analogues as hypoxia-inducible factor (HIF) inhibitors based on the molecular structure of kresoxim-methyl. Biological evaluation in human colorectal cancer HCT116 cells showed that most of the synthesized kresoxim-methyl analogues possessed moderate to potent inhibitory activity against hypoxia-induced HIF-1 transcriptional activation. Three candidates, compounds 11b, 11c, and 11d were identified as potent inhibitors against HIF-1 activation with IC 50 values of 0.60-0.94µM. Under hypoxic condition, compounds 11b, 11c, and 11d increased the intracellular oxygen contents, thereby attenuating the hypoxia-induced accumulation of HIF-1α protein. Copyright © 2017 Elsevier Ltd. All rights reserved.

STS-98 payload U.S. Lab Destiny is moved into Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- The U.S. Lab Destiny is ready to move into the orbiter'''s payload bay from the Payload Changeout Room. The PCR is the enclosed, environmentally controlled portion of the rotating service structure that supports payload delivery at the launch pad and vertical installation in the orbiter payload bay. Destiny, a key element in the construction of the International Space Station is designed for space science experiments and already has five system racks installed inside. STS-98 is the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

STS-98 payload U.S. Lab Destiny is moved into Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Technicians in the Payload Changeout Room oversee the transfer of the U.S. Lab Destiny to the orbiter'''s payload bay. The PCR is the enclosed, environmentally controlled portion of the rotating service structure that supports payload delivery at the launch pad and vertical installation in the orbiter payload bay. Destiny, a key element in the construction of the International Space Station is designed for space science experiments and already has five system racks installed inside. STS-98 is the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

Deep Borehole Instrumentation Along San Francisco Bay Bridges - 2001

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hutchings, L.; Kasameyer, P.; Long, L.

2001-05-01

This is a progress report on the Bay Bridges downhole network. Between 2 and 8 instruments have been spaced along the Dumbarton, San Mateo, Bay, and San Rafael bridges in San Francisco Bay, California. The instruments will provide multiple use data that is important to geotechnical, structural engineering, and seismological studies. The holes are between 100 and 1000 ft deep and were drilled by Caltrans. There are twenty-one sensor packages at fifteen sites. The downhole instrument package contains a three component HS-1 seismometer and three orthogonal Wilcox 731 accelerometers, and is capable of recording a micro g from local Mmore » = 1.0 earthquakes to 0.5 g strong ground motion form large Bay Area earthquakes. This report list earthquakes and stations where recordings were obtained during the period February 29, 2000 to November 11, 2000. Also, preliminary results on noise analysis for up and down hole recordings at Yerba Buena Island is presented.« less

Investigation of Spatial and Temporal Trends in Water Quality in Daya Bay, South China Sea

PubMed Central

Wu, Mei-Lin; Wang, You-Shao; Dong, Jun-De; Sun, Cui-Ci; Wang, Yu-Tu; Sun, Fu-Lin; Cheng, Hao

2011-01-01

The objective is to identify the spatial and temporal variability of the hydrochemical quality of the water column in a subtropical coastal system, Daya Bay, China. Water samples were collected in four seasons at 12 monitoring sites. The Southeast Asian monsoons, northeasterly from October to the next April and southwesterly from May to September have also an important influence on water quality in Daya Bay. In the spatial pattern, two groups have been identified, with the help of multidimensional scaling analysis and cluster analysis. Cluster I consisted of the sites S3, S8, S10 and S11 in the west and north coastal parts of Daya Bay. Cluster I is mainly related to anthropogenic activities such as fish-farming. Cluster II consisted of the rest of the stations in the center, east and south parts of Daya Bay. Cluster II is mainly related to seawater exchange from South China Sea. PMID:21776234

Separation or Unification for Taiwan: An Economic Comparison.

DTIC Science & Technology

1996-09-01

Table 11-9. Average Size of Taiwan’s FDI in SE Asia (Cumulative through 1993) Host Country $M per Project Indonesia 13.50 Vietnam 13.09 Malaysia ...leaders. By April 1996, Taiwan had signed investment protection agreements with Indonesia, Malaysia , the Philippines, Singapore, and Vietnam and...and Surabaya, Indonesia; Penang, Malaysia ; Laos; and Subic Bay, the Philippines. See Chen Hurng-yu (1994), 128. The first stage of the Subic Bay

33 CFR 334.110 - Delaware Bay off Cape Henlopen, Del.; naval restricted area.

Code of Federal Regulations, 2010 CFR

2010-07-01

....110 Delaware Bay off Cape Henlopen, Del.; naval restricted area. (a) The area. Beginning at a point on...′11″; thence to latitude 38°49′16″, longitude 74°59′35″; thence to a point on the shore at latitude 38°46′09″; thence northwesterly and southwesterly along the shore at Cape Henlopen to the point of...

Earth Observations taken by the Expedition 11 crew

NASA Image and Video Library

2005-05-28

ISS011-E-07471 (28 May 2005) --- Sept-Îles, Gulf of St Lawrence, Quebec, Canada is featured in this image photographed by an Expedition 11 crewmember on the International Space Station (ISS). Seven Island Bay (left side of the image) is one of the largest (8–10 kilometers across) and best protected bays on Quebec’s north shore of the Gulf of St. Lawrence. Because this is both a deep water port and ice-free year round, Sept-Îles is one of Quebec’s busiest ports. Locally produced materials (iron ore, alumina) comprise the bulk of port traffic, but Sept-Îles also acts as a trans-shipment point for goods moving to Europe, the Far East and South America. The small city of Sept-Îles (~30,000 people) appears in the center of the view; Pointe Noir is opposite the city in the lower left corner. The industrial park lies top left and the angled runways of the airport appear east of the city. Five (of the bay’s seven) islands appear at the bottom of the view. Wind and swells produce patterns on the water. Ships can be seen in the bay and a ship wake appears between the two left islands at the bottom of the view.

Effect of distal Sacramento-San Joaquin Delta outflow on suspended-sediment flux in Lower South San Francisco Bay

NASA Astrophysics Data System (ADS)

Livsey, D. N.; Downing-Kunz, M.; Schoellhamer, D. H.; Shellenbarger, G.; Wright, S. A.

2016-12-01

Tidal marshes are an important component of estuarine ecosystems. Within the San Francisco Bay Estuary (SFB) tidal marshes play an important role in food web dynamics, are home to an array of endemic mammals, birds, and fishes, filter pollutants, and dampen coastal flooding. With 80% of SFB tidal marshes lost to human development, numerous restoration efforts are underway. The largest tidal marsh restoration project in SFB, the South Bay Salt Pond Restoration Project, is underway in Lower South San Francisco Bay to restore 60,000 ha of this critical habitat; however, rising sea levels, could jeopardize these gains without concomitant vertical accretion rates of the marsh surface via organic matter accumulation and sediment deposition. Recent work in Lower South Bay using continuously collected data from water years (WY) 2009-11 indicates that the direction of net springtime residual sediment flux is related to the amount of springtime Sacramento-San Joaquin Delta (Delta) outflow. Large outflow freshens the Central Bay, causing a density gradient and inverse gravitational circulation that flushes Lower South Bay. In this study we extend the sediment budget for Lower South Bay from WY 2011 to present using 15-minute turbidity and velocity data paired with Acoustic Doppler Current Profiler cross-sectional measurements and in situ suspended-sediment concentration samples to: 1) further examine the mechanisms controlling net springtime residual sediment flux, and 2) further test the hypothesis that Delta outflow controls the direction of net sediment flux for Lower South Bay.

(/sup 11/C)clorgyline and (/sup 11/C)-L-deprenyl and their use in measuring functional monoamine oxidase activity in the brain using positron emission tomography

DOEpatents

Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

1986-04-17

This invention involves a new strategy for imaging the activity of the enzyme monoamine oxidase in the living body by using /sup 11/C-labeled enzyme inhibitors which bind irreversibly to an enzyme as a result of catalysis. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

Impact of human activities on subaqueous topographic change in Lingding Bay of the Pearl River estuary, China, during 1955–2013

PubMed Central

Wu, Z. Y.; Saito, Yoshiki; Zhao, D. N.; Zhou, J. Q.; Cao, Z. Y.; Li, S. J.; Shang, J. H.; Liang, Y. Y.

2016-01-01

Estuaries have been sites of intensive human activities during the past century. Tracing the evolution of subaqueous topography in estuaries on a decadal timescale enables us to understand the effects of human activities on estuaries. Bathymetric data from 1955 to 2010 show that land reclamation decreased the subaqueous area of Lingding Bay, in the Pearl River estuary, by ~170 km2 and decreased its water volume by 615 × 106 m3, representing a net decrease of 11.2 × 106 m3 per year and indicating the deposition of approximately 14.5 Mt/yr of sediment in Lingding Bay during that period. Whereas Lingding Bay was mainly governed by natural processes with slight net deposition before 1980, subsequent dredging and large port engineering projects changed the subaqueous topography of the bay by shallowing its shoals and deepening its troughs. Between 2012 and 2013, continuous dredging and a surge of sand excavation resulted in local changes in water depth of ± 5 m/yr, far exceeding the magnitude of natural topographic evolution in Lingding Bay. Reclamation, dredging, and navigation-channel projects removed 8.4 Mt/yr of sediment from Lingding Bay, representing 29% of the sediment input to the bay, and these activities have increased recently. PMID:27886227

Differential regulation of eotaxin-1/CCL11 and eotaxin-3/CCL26 production by the TNF-alpha and IL-4 stimulated human lung fibroblast.

PubMed

Rokudai, Akiko; Terui, Yasuhito; Kuniyoshi, Ryoko; Mishima, Yuji; Mishima, Yuko; Aizu-Yokota, Eriko; Sonoda, Yoshiko; Kasahara, Tadashi; Hatake, Kiyohiko

2006-06-01

Allergic asthma and allergic dermatitis are chronic inflammatory diseases and are characterized by an accumulation of eosinophils at sites of inflammation. Eotaxin-1/CCL11 and eotaxin-3/CCL26 are members of the CC chemokine family, which are known to be potent chemoattractants for eosinophils. We observed that a human lung fibroblast, HFL-1 produces eotaxin-1 and -3 in response to TNF-alpha plus IL-4 stimulation, accompanied with NF-kappaB and STAT6 activation. We explored which signaling pathways are operative in the production of eotaxin-1 and -3 using several inhibitors. Eotaxin-1/CCL11 production was inhibited by a p38 mitogen-activated protein kinase (MAPK) inhibitor, SB203580, but not by the MEK (MAPK/ERK kinase) inhibitors, PD98059 and U0126. In contrast, eotaxin-3/CCL26 production was inhibited similarly by PD98059 as well as U0126 and SB203580. In addition, two proteasome inhibitors, N-acetyl-leucyl-leucyl-norleucinal (ALLN) and bortezomib with significant inhibitory activity on NF-kappaB activation, inhibited eotaxin-1/CCL11 production with IC50 8 microM for ALLN and IC50 16 nM for bortezomib. In contrast, eotaxin-3/CCL26 production was not inhibited significantly up to 10 microM of ALLN (IC50 16 microM) and up to 10 nM of bortezomib (IC50 11 nM), giving inhibition of eotaxin-3/CCL26 less sensitive than eotaxin-1/CCL11 production by the proteasome inhibitors. Synergistic inhibition was observed among lower doses of SB203580 and proteasome inhibitors, particularly in the eotaxin-1/CCL11 production. No such prominent synergism was found on the eotaxin-3/CCL26 production. The suppression of eotaxin family production by these inhibitors may be efficacious against allergic diseases.

Discovery of novel quinazoline-2,4(1H,3H)-dione derivatives as potent PARP-2 selective inhibitors.

PubMed

Zhao, Hailong; Ji, Ming; Cui, Guonan; Zhou, Jie; Lai, Fangfang; Chen, Xiaoguang; Xu, Bailing

2017-08-01

The PARP-2 selective inhibitor is important for clarifying specific roles of PARP-2 in the pathophysiological process and developing desired drugs with reduced off-target side effects. In this work, a series of novel quinazoline-2,4(1H,3H)-dione derivatives was designed and synthesized to explore isoform selective PARP inhibitors. As a result, compound 11a (PARP-1 IC 50 =467nM, PARP-2 IC 50 =11.5nM, selectivity PARP-1/PARP-2=40.6) was disclosed as the most selective PARP-2 inhibitor with high potency to date. The binding features of compound 11a within PARP-1 and PARP-2 were investigated respectively to provide useful insights for the further construction of new isoform selective inhibitors of PARP-1 and PARP-2 by using CDOCKER program. Copyright © 2017 Elsevier Ltd. All rights reserved.

Endopeptidase-24.11 is the integral membrane peptidase initiating degradation of somatostatin in the hippocampus.

PubMed

Barnes, K; Doherty, S; Turner, A J

1995-04-01

The membrane metalloenzyme endopeptidase-24.11 has been localized by immunocytochemistry in the porcine hippocampus in the stratum oriens and stratum radiatum. Endopeptidase-24.11 was found to be approximately 10-fold more abundant in a striatal than a hippocampal membrane preparation. Both somatostatin-28 and somatostatin-14 were metabolized by endopeptidase-24.11, but the kinetics of hydrolysis markedly favoured the smaller form of the neuropeptide. After phase separation with Triton X-114 of striatal and hippocampal membrane preparations, and by using selective inhibitors, the major (> 80%) somatostatin-metabolizing activity was found to partition into the detergent-rich phase and was attributable predominantly to endopeptidase-24.11. The residual activity observed in the presence of the selective endopeptidase-24.11 inhibitor phosphoramidon was blocked by Pro-Ile or N-[1-(RS)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, inhibitors of endopeptidase-24.16 and endopeptidase-24.15, respectively. However, Pro-Ile, at comparable concentrations, was shown to inhibit endopeptidase-24.11, challenging the validity of its use as a selective inhibitor of endopeptidase-24.16. The immunocytochemical and Triton X-114 phase-separation data implicate endopeptidase-24.11, rather than endopeptidase-24.16 or endopeptidase-24.15, as the major physiological somatostatin-degrading neuropeptidase in the striatum and hippocampus.

Combining inhibitor tolerance and D-xylose fermentation in industrial Saccharomyces cerevisiae for efficient lignocellulose-based bioethanol production.

PubMed

Demeke, Mekonnen M; Dumortier, Françoise; Li, Yingying; Broeckx, Tom; Foulquié-Moreno, María R; Thevelein, Johan M

2013-08-26

In addition to efficient pentose utilization, high inhibitor tolerance is a key trait required in any organism used for economically viable industrial bioethanol production with lignocellulose biomass. Although recent work has succeeded in establishing efficient xylose fermentation in robust industrial Saccharomyces cerevisiae strains, the resulting strains still lacked sufficient inhibitor tolerance for efficient sugar fermentation in lignocellulose hydrolysates. The aim of the present work was to combine high xylose fermentation activity and high inhibitor tolerance in a single industrial yeast strain. We have screened 580 yeast strains for high inhibitor tolerance using undetoxified acid-pretreated spruce hydrolysate and identified a triploid industrial baker's yeast strain as having the highest inhibitor tolerance. From this strain, a mating competent diploid segregant with even higher inhibitor tolerance was obtained. It was crossed with the recently developed D-xylose fermenting diploid industrial strain GS1.11-26, with the Ethanol Red genetic background. Screening of 819 diploid segregants from the tetraploid hybrid resulted in two strains, GSF335 and GSF767, combining high inhibitor tolerance and efficient xylose fermentation. In a parallel approach, meiotic recombination of GS1.11-26 with a haploid segregant of Ethanol Red and screening of 104 segregants resulted in a similar inhibitor tolerant diploid strain, GSE16. The three superior strains exhibited significantly improved tolerance to inhibitors in spruce hydrolysate, higher glucose consumption rates, higher aerobic growth rates and higher maximal ethanol accumulation capacity in very-high gravity fermentation, compared to GS1.11-26. In complex medium, the D-xylose utilization rate by the three superior strains ranged from 0.36 to 0.67 g/g DW/h, which was lower than that of GS1.11-26 (1.10 g/g DW/h). On the other hand, in batch fermentation of undetoxified acid-pretreated spruce hydrolysate, the three superior strains showed comparable D-xylose utilization rates as GS1.11-26, probably because of their higher inhibitor tolerance. They produced up to 23% more ethanol compared to Ethanol Red. We have successfully constructed three superior industrial S. cerevisiae strains that combine efficient D-xylose utilization with high inhibitor tolerance. Since the background strain Ethanol Red has a proven record of successful industrial application, the three new superior strains have strong potential for direct application in industrial bioethanol production.

Combining inhibitor tolerance and D-xylose fermentation in industrial Saccharomyces cerevisiae for efficient lignocellulose-based bioethanol production

PubMed Central

2013-01-01

Background In addition to efficient pentose utilization, high inhibitor tolerance is a key trait required in any organism used for economically viable industrial bioethanol production with lignocellulose biomass. Although recent work has succeeded in establishing efficient xylose fermentation in robust industrial Saccharomyces cerevisiae strains, the resulting strains still lacked sufficient inhibitor tolerance for efficient sugar fermentation in lignocellulose hydrolysates. The aim of the present work was to combine high xylose fermentation activity and high inhibitor tolerance in a single industrial yeast strain. Results We have screened 580 yeast strains for high inhibitor tolerance using undetoxified acid-pretreated spruce hydrolysate and identified a triploid industrial baker’s yeast strain as having the highest inhibitor tolerance. From this strain, a mating competent diploid segregant with even higher inhibitor tolerance was obtained. It was crossed with the recently developed D-xylose fermenting diploid industrial strain GS1.11-26, with the Ethanol Red genetic background. Screening of 819 diploid segregants from the tetraploid hybrid resulted in two strains, GSF335 and GSF767, combining high inhibitor tolerance and efficient xylose fermentation. In a parallel approach, meiotic recombination of GS1.11-26 with a haploid segregant of Ethanol Red and screening of 104 segregants resulted in a similar inhibitor tolerant diploid strain, GSE16. The three superior strains exhibited significantly improved tolerance to inhibitors in spruce hydrolysate, higher glucose consumption rates, higher aerobic growth rates and higher maximal ethanol accumulation capacity in very-high gravity fermentation, compared to GS1.11-26. In complex medium, the D-xylose utilization rate by the three superior strains ranged from 0.36 to 0.67 g/g DW/h, which was lower than that of GS1.11-26 (1.10 g/g DW/h). On the other hand, in batch fermentation of undetoxified acid-pretreated spruce hydrolysate, the three superior strains showed comparable D-xylose utilization rates as GS1.11-26, probably because of their higher inhibitor tolerance. They produced up to 23% more ethanol compared to Ethanol Red. Conclusions We have successfully constructed three superior industrial S. cerevisiae strains that combine efficient D-xylose utilization with high inhibitor tolerance. Since the background strain Ethanol Red has a proven record of successful industrial application, the three new superior strains have strong potential for direct application in industrial bioethanol production. PMID:23971950

Environmental quality in sediments of Cadiz and Algeciras Bays based on a weight of evidence approach (southern Spanish coast).

PubMed

Usero, José Antonio; Rosado, Daniel; Usero, José; Morillo, José

2016-09-15

This research applies an integrated sediment quality assessment method using a weight of evidence approach to Cadiz and Algeciras Bays (southern Spain). The method is composed of several analyses (particle size profile, aqua regia extractable metals, acid labile metals, total organic carbon, toxicity bioassay with Photobacterium phosphoreum and macrobenthic community alteration). The proposed method provides a single result, the environmental degradation index (EDI). EDI defined samples as low degraded (outer areas of both bays) and moderately degraded (Inner Bay of Cadiz Bay, the surroundings of Algeciras port and the northern part of Algeciras Bay). These samples showed the highest concentration of aqua regia extractable metals, which exceeded effects range-low (ERL) for Zn (51-176mg/l), Cu (11-54mg/l), As (4.3-9.5mg/l), Hg (0.17-0.28mg/l), Ni (23-82mg/l), and. Cr (37-134mg/l). They also exceeded some quality criteria for total organic carbon (4.0-6.5%) and toxicity (120-240TU/g) and showed poor results for macrobenthic community. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sea snakes rarely venture far from home

PubMed Central

Lukoschek, Vimoksalehi; Shine, Richard

2012-01-01

The extent to which populations are connected by dispersal influences all aspects of their biology and informs the spatial scale of optimal conservation strategies. Obtaining direct estimates of dispersal is challenging, particularly in marine systems, with studies typically relying on indirect approaches to evaluate connectivity. To overcome this challenge, we combine information from an eight-year mark-recapture study with high-resolution genetic data to demonstrate extremely low dispersal and restricted gene flow at small spatial scales for a large, potentially mobile marine vertebrate, the turtleheaded sea snake (Emydocephalus annulatus). Our mark-recapture study indicated that adjacent bays in New Caledonia (<1.15 km apart) contain virtually separate sea snake populations. Sea snakes could easily swim between bays but rarely do so. Of 817 recaptures of marked snakes, only two snakes had moved between bays. We genotyped 136 snakes for 11 polymorphic microsatellite loci and found statistically significant genetic divergence between the two bays (FST= 0.008, P < 0.01). Bayesian clustering analyses detected low mixed ancestry within bays and genetic relatedness coefficients were higher, on average, within than between bays. Our results indicate that turtleheaded sea snakes rarely venture far from home, which has strong implications for their ecology, evolution, and conservation. PMID:22833788

Sea snakes rarely venture far from home.

PubMed

Lukoschek, Vimoksalehi; Shine, Richard

2012-06-01

The extent to which populations are connected by dispersal influences all aspects of their biology and informs the spatial scale of optimal conservation strategies. Obtaining direct estimates of dispersal is challenging, particularly in marine systems, with studies typically relying on indirect approaches to evaluate connectivity. To overcome this challenge, we combine information from an eight-year mark-recapture study with high-resolution genetic data to demonstrate extremely low dispersal and restricted gene flow at small spatial scales for a large, potentially mobile marine vertebrate, the turtleheaded sea snake (Emydocephalus annulatus). Our mark-recapture study indicated that adjacent bays in New Caledonia (<1.15 km apart) contain virtually separate sea snake populations. Sea snakes could easily swim between bays but rarely do so. Of 817 recaptures of marked snakes, only two snakes had moved between bays. We genotyped 136 snakes for 11 polymorphic microsatellite loci and found statistically significant genetic divergence between the two bays (F(ST)= 0.008, P < 0.01). Bayesian clustering analyses detected low mixed ancestry within bays and genetic relatedness coefficients were higher, on average, within than between bays. Our results indicate that turtleheaded sea snakes rarely venture far from home, which has strong implications for their ecology, evolution, and conservation.

In silico prediction of ROCK II inhibitors by different classification approaches.

PubMed

Cai, Chuipu; Wu, Qihui; Luo, Yunxia; Ma, Huili; Shen, Jiangang; Zhang, Yongbin; Yang, Lei; Chen, Yunbo; Wen, Zehuai; Wang, Qi

2017-11-01

ROCK II is an important pharmacological target linked to central nervous system disorders such as Alzheimer's disease. The purpose of this research is to generate ROCK II inhibitor prediction models by machine learning approaches. Firstly, four sets of descriptors were calculated with MOE 2010 and PaDEL-Descriptor, and optimized by F-score and linear forward selection methods. In addition, four classification algorithms were used to initially build 16 classifiers with k-nearest neighbors [Formula: see text], naïve Bayes, Random forest, and support vector machine. Furthermore, three sets of structural fingerprint descriptors were introduced to enhance the predictive capacity of classifiers, which were assessed with fivefold cross-validation, test set validation and external test set validation. The best two models, MFK + MACCS and MLR + SubFP, have both MCC values of 0.925 for external test set. After that, a privileged substructure analysis was performed to reveal common chemical features of ROCK II inhibitors. Finally, binding modes were analyzed to identify relationships between molecular descriptors and activity, while main interactions were revealed by comparing the docking interaction of the most potent and the weakest ROCK II inhibitors. To the best of our knowledge, this is the first report on ROCK II inhibitors utilizing machine learning approaches that provides a new method for discovering novel ROCK II inhibitors.

Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes.

PubMed

Hamilton, Bradford S; Himmelsbach, Frank; Nar, Herbert; Schuler-Metz, Annette; Krosky, Paula; Guo, Joan; Guo, Rong; Meng, Shi; Zhao, Yi; Lala, Deepak S; Zhuang, Linghang; Claremon, David A; McGeehan, Gerard M

2015-01-05

To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585. Copyright © 2014 Elsevier B.V. All rights reserved.

Angiotensin-Converting Enzyme Inhibitor Use and Major Cardiovascular Outcomes in Type 2 Diabetes Mellitus Treated With the Dipeptidyl Peptidase 4 Inhibitor Alogliptin.

PubMed

White, William B; Wilson, Craig A; Bakris, George L; Bergenstal, Richard M; Cannon, Christopher P; Cushman, William C; Heller, Simon K; Mehta, Cyrus R; Nissen, Steven E; Zannad, Faiez; Kupfer, Stuart

2016-09-01

Activation of the sympathetic nervous system when there is dipeptidyl peptidase 4 inhibition in the presence of high-dose angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin versus Standard of Care) trial according to ACE inhibitor use. Patients with type 2 diabetes mellitus and a recent acute coronary syndrome were randomly assigned to receive the dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing antihyperglycemic and cardiovascular prophylactic therapies. Risks of adjudicated cardiovascular death, nonfatal myocardial infarction and stroke, and hospitalized heart failure were analyzed using a Cox proportional hazards model in patients according to ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an ACE inhibitor (1681 on alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke were comparable for alogliptin and placebo with ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and heart failure in patients on ACE inhibitor occurred in 6.8% of patients on alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of ACE inhibitor. Cardiovascular outcomes were similar for alogliptin and placebo in patients with type 2 diabetes mellitus and coronary disease treated with ACE inhibitors. © 2016 American Heart Association, Inc.

33 CFR 117.559 - Isle of Wight (Sinepuxent) Bay.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 4, the draw need not open from 10 p.m. until 11 p.m. to accommodate the annual July 4th fireworks... not open from 10 p.m. until 11 p.m. on July 5th to accommodate the annual July 4th fireworks show...

Mono-carbonyl curcumin analogues as 11β-hydroxysteroid dehydrogenase 1 inhibitors.

PubMed

Lin, Han; Hu, Guo-Xin; Guo, Jingjing; Ge, Yufei; Liang, Guang; Lian, Qing-Quan; Chu, Yanhui; Yuan, Xiaohuan; Huang, Ping; Ge, Ren-Shan

2013-08-01

A series of structurally novel mono-carbonyl curcumin analogues have been synthesized and biologically evaluated to test their inhibitory potencies and the structure-activity relationship (SAR) on human and rat 11β-hydroxysteroid dehydrogenase isoform (11β-HSD1) activities. 11β-HSD1 selective inhibitors have been discovered and compound A10 is discovered as a very potent with an IC50 value of 97 nM without inhibiting 11β-HSD2. Copyright © 2013 Elsevier Ltd. All rights reserved.

Short Term Sediment Exchange Between Marshes and Bays Using Beryllium-7 as a Tracer, Fourleague Bay, Louisiana.

NASA Astrophysics Data System (ADS)

Restreppo, G. A.; Bentley, S. J.; Xu, K.; Wang, J.

2016-12-01

Modern delta models focus on the availability and exchange of coarse sediment as one of the major factors of deltaic growth or decay. Fine-grained sediment exchange within a river's delta is relatively poorly understood, as is the impact that this exchange has on land building and land loss. To better understand the dynamics of fine grain sediment exchange between river mouth, adjacent bays, and marshland, sediment cores from Fourleague Bay, LA, were collected and analyzed for 7Be, a naturally occurring radioisotope that serves as a marker for recently deposited sediment. Time-series push cores were collected every two months at ten sites, five located across a longitudinal transect in the middle bay and five located along adjacent marshes, from May 2015 to May 2016. All sites fall within 11 to 28 km of the Atchafalaya Delta, along a gradient extending towards the open ocean. Cores were extruded in 2 cm intervals, dried, ground, and analyzed via gamma spectrometry for the presence of 7Be. Inventories of 7Be were then calculated and used to determine bimonthly sedimentation rates over the course twelve months. Sediment deposition on the bay floor and marsh surface were then compared to Atchafalaya River discharge, wind speed and direction, and wave action. Preliminary results indicate patterns of initial fluvial sediment transfer from river to bay floor, then bay floor to marsh surface, with decreasing fluvial influence towards the open ocean. Sediment transport from bay to marsh appears to be coupled with meteorological forcing that induces bay-floor sediment resuspension and the flooding of marsh surfaces. This indirect mechanism of fluvial sediment supply to wetland surfaces may extend the region of influence for sediment delivery from man-made river-sediment diversions.

Should air medical patients be transferred on helipad or trauma bay?

PubMed

Lehrfeld, David; Gemignani, Robert; Shiroff, Adam; Kuhlmann, Sarah; Ohman-Strickland, Pamela; Merlin, Mark A

2013-01-01

Helicopter emergency medical services (HEMS) are widely used in regional trauma care and present unique challenges in the patient handoff process. In particular, the practice of patient handoff on the landing zone versus the trauma bay does not exist in ground emergency medical services. We hypothesized that patients handed off on the landing zone versus the trauma bay would have different patient characteristics and outcomes. A retrospective review identified 305 HEMS trauma patients received at our level 1 trauma center over a 3-year period. Patients were sorted on the basis of the handoff location, (landing zone vs. trauma bay) and assessed for predictors of injury severity including the Revised Trauma Score, the Injury Severity Score, the Trauma and Injury Severity Score, and other outcomes, primarily mortality. Of the 305 patients, 235 (77%) were handed off in the bay, and 70 (23%) were not. Regarding the characteristics of patients who were handed off in the bay, they were more likely to have hypotension (100% vs. 73%), have a lower O(2) saturation level (97.9 vs. 99.4), and a lower Glasgow Coma Scale at the scene (10.9 vs. 13.9.). When controlling for injury severity, the odds of survival for patients who were handed off in the bay were 11.06 times the odds for patients who were not handed off in the bay. In this limited study, we found that HEMS did identify the sickest patients and brought them to the trauma bay. Despite their greater injury severity, the patients handed off in the bay fared better than those handed off on the landing zone. Copyright © 2013 Air Medical Journal Associates. Published by Elsevier Inc. All rights reserved.

Spawning habitat unsuitability: an impediment to cisco rehabilitation in Lake Michigan?

USGS Publications Warehouse

Madenjian, Charles P.; Rutherford, Edward S.; Blouin, Marc A.; Sederberg, Bryan J.; Elliott, Jeff R.

2011-01-01

The cisco Coregonus artedi was one of the most important native prey fishes in Lake Michigan and in the other four Laurentian Great Lakes. Most of the cisco spawning in Lake Michigan was believed to have occurred in Green Bay. The cisco population in Lake Michigan collapsed during the 1950s, and the collapse was attributed in part to habitat degradation within Green Bay. Winter water quality surveys of lower Green Bay during the 1950s and 1960s indicated that the bottom dissolved oxygen (DO) concentration was less than 2 mg/L throughout much of the lower bay, and most cisco eggs would not successfully hatch at such low DO concentrations. To determine present-day spawning habitat suitability in lower Green Bay, we compared cisco egg survival in lower Green Bay with survival at a reference site (St. Marys River, Michigan–Ontario) during 2009. We also conducted winter water quality surveys in lower Green Bay and the St. Marys River during 2009 and 2010. Cisco egg survival in lower Green Bay averaged 65.3%, which was remarkably similar to and not significantly different from the mean at the St. Marys River site (64.0%). Moreover, the lowest bottom DO concentrations recorded during the winter surveys were 11.2 mg/L in lower Green Bay and 12.7 mg/L in the St. Marys River. These relatively high DO concentrations would not be expected to have any negative effect on cisco egg survival. We conclude that winter water quality conditions in lower Green Bay were suitable for successful hatching of cisco eggs and that water quality during the egg incubation period did not represent an impediment to cisco rehabilitation in Lake Michigan. Our approach to determining spawning habitat suitability for coregonids would be applicable to other aquatic systems.

Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2.

PubMed

Eggert, Erik; Hillig, Roman C; Koehr, Silke; Stöckigt, Detlef; Weiske, Jörg; Barak, Naomi; Mowat, Jeffrey; Brumby, Thomas; Christ, Clara D; Ter Laak, Antonius; Lang, Tina; Fernandez-Montalvan, Amaury E; Badock, Volker; Weinmann, Hilmar; Hartung, Ingo V; Barsyte-Lovejoy, Dalia; Szewczyk, Magdalena; Kennedy, Steven; Li, Fengling; Vedadi, Masoud; Brown, Peter J; Santhakumar, Vijayaratnam; Arrowsmith, Cheryl H; Stellfeld, Timo; Stresemann, Carlo

2016-05-26

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.

STS-98 payload U.S. Lab Destiny is moved into Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Workers in the Payload Changeout Room check the movement of the U.S. Lab Destiny, which is being transferred to the orbiter'''s payload bay. The PCR is the enclosed, environmentally controlled portion of the rotating service structure that supports payload delivery at the launch pad and vertical installation in the orbiter payload bay. Destiny, a key element in the construction of the International Space Station is designed for space science experiments and already has five system racks installed inside. STS-98 is the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

Survival of insects in the wheel bays of a Boeing 747B aircraft on flights between tropical and temperate airports

PubMed Central

Russell, R. C.

1987-01-01

Mosquitos (Culex quinquefasciatus), house flies (Musca domestica), and flour beetles (Tribolium confusum) located in cages within the wheel bays of a Boeing 747B aircraft, survived travel on the following normal commercial routes: Sydney—Melbourne; Melbourne—Singapore; Singapore—Bangkok; Bangkok—Singapore; and Singapore—Melbourne. Survival of all three species was high, averaging 84% for mosquitos and higher for flies (93%) and beetles (>99%). Although external temperatures were -42 °C to -54 °C for aircraft cruising at 10 700-11 900 m, minimum temperatures within the wheel bays ranged from +8 °C to +25 °C. PMID:3501345

San Francisco, San Pablo Bay Area

NASA Image and Video Library

1994-09-30

STS068-244-022 (30 September-11 October 1994) --- (San Francisco, San Pablo Bay Area) Photographed through the Space Shuttle Endeavour's flight deck windows, the heavily populated bay area is featured in this 70mm frame. The relatively low altitude of Endeavour's orbit (115 nautical miles) and the use of a 250mm lens on the Hasselblad camera allowed for capturing detail in features such as the Berkeley Marina (frame center). The region's topography is well depicted with the lowland areas heavily populated and the hills much more sparsely covered. The Oakland Hills in the right lower center appear to be re-vegetated after a devastating fire. The Golden Gate Recreation Area in the upper left also shows heavy vegetation. The three bridges across the main part of the bay and their connecting roads are prominent. Cultural features such as Golden Gate Park and the Presidio contrast with the gray of the city.

Sand waves at the mouth of San Francisco Bay, California

USGS Publications Warehouse

Barnard, Patrick L.; Hanes, Daniel M.; Kvitek, Rikk G.; Iampietro, Pat J.

2006-01-01

A multibeam bathymetric survey that produced unprecedented high resolution images of the mouth of San Francisco Bay was conducted in 2004 and 2005. The survey, performed over forty-four days by the Seafloor Mapping Lab at California State University, Monterey Bay, consisted of 1,138 track lines, 1.1 billion soundings, and covered an area of 154 km2 (60 mi2). The goals of this survey were to analyze sediment transport pathways at the mouth of San Francisco Bay and to calculate bathymetric change since the last survey was completed in 1956. The survey showed that significant bathymetric changes have occurred over the past 50 years. It also revealed that the study area contains sand waves that are among the largest and bedform morphologies that are among the most varied in the world. This set of five sheets shows views of the sand waves on the seafloor from different perspectives along with descriptive text.

Positron emitter labeled enzyme inhibitors

DOEpatents

Fowler, Joanna S.; MacGregor, Robert R.; Wolf, Alfred P.; Langstrom, Bengt

1990-01-01

This invention involves a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography.

Impact of Bay-Breeze Circulations on Surface Air Quality and Boundary Layer Export

NASA Technical Reports Server (NTRS)

Loughner, Christopher P.; Tzortziou, Maria; Follette-Cook, Melanie; Pickering, Kenneth E.; Goldberg, Daniel; Satam, Chinmay; Weinheimer, Andrew; Crawford, James H.; Knapp, David J.; Montzka, Denise D.;

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- STS-98 Mission Specialist Marsha Ivins (center, pointing) checks out the U.S. Lab Destiny in the payload bay of the orbiter Atlantis. The crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. Destiny, a key element in the construction of the International Space Station, is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

NICER Transfer (for SpaceX CRS-11)

NASA Image and Video Library

2017-04-12

Inside the Space Station Processing Facility high bay at NASA's Kennedy Space Center in Florida, the Neutron star Interior Composition Explorer, or NICER, payload is secured inside a protective container and loaded onto a truck outside the high bay. NICER will be delivered to the International Space Station aboard the SpaceX Dragon cargo carrier on the company’s 11th commercial resupply services mission to the space station. NICER will study neutron stars through soft X-ray timing. NICER will enable rotation-resolved spectroscopy of the thermal and non-thermal emissions of neutron stars in the soft X-ray band with unprecedented sensitivity, probing interior structure, the origins of dynamic phenomena and the mechanisms that underlie the most powerful cosmic particle accelerators known.

78 FR 64971 - Endangered and Threatened Species; Permits Issued

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-30

.../8/13 2/7/16 EAST BAY ZOOLOGICAL SOCIETY 85448A 4/5/13 4/4/16 SHANAHAN, SETH A 231424 4/5/13 4/4/16.../13 4/4/17 HAGAR ENVIRONMENTAL SCIENCE 089980 4/12/13 4/11/17 OBERHOFF, DWAYNE N 180579 4/12/13 4/11...

Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor

DTIC Science & Technology

2012-07-01

Award Number: W81XWH-11-1-0270 TITLE: Enhancement of Radiation Therapy in Prostate Cancer by DNA-PKcs Inhibitor PRINCIPAL INVESTIGATOR...TITLE AND SUBTITLE Enhancement of Radiation Therapy in Prostate Cancer by 5a. CONTRACT NUMBER DNA-PKcs Inhibitor 5b. GRANT NUMBER W81XWH-11-1-0270...the treatment of localized prostate cancer . However, a proportion of locally advanced cancers develop radiation resistance and recur after therapy

Examination of Chesapeake Bay Observing System for Local Environmental Data for Coast Guard Operations

DTIC Science & Technology

2004-12-01

U.S. Coast Guard Research and Development Center 1082 Shennecossett Road, Groton, CT 06340-6048 Report No. CG-D-04-05 Examination of Chesapeake Bay...Director "United States Coast Guard Research & Development Center 1082 Shennecossett Road r Groton, CT 06340-6048 ii Technical Report Documentation Page...and Mary Research & Development Center 11. Contract or Grant No. Route 1208, Greate Road 1082 Shennecossett Road DTCG32-03-C-R0006 Gloucester Point, VA

HST, flyaround of the telescope after deployment on this second servicing mission

NASA Image and Video Library

1997-02-19

STS082-746-071 (11-21 Feb. 1997) --- This nearly-vertical view, photographed from the Space Shuttle Discovery, shows the Hubble Space Telescope (HST) over Shark Bay. Shallowest parts of the bay appear light blue. In this view of Australia's arid west, sets of sand dunes are clearly visible on Peron Peninsula (lower center) from southwest to northeast (bottom left to top right), blown by the prevailing wind. Hartog Island lies bottom right.

Monterey Bay Aquarium Volunteer Guide Scheduling Analysis

DTIC Science & Technology

2014-12-01

wetlands/aviary 1 24 splash zone—rocky shore, coral reef kingdom 8 play your part 25 sandy seafloor 9 wetlands/aviary 2 26 octopus/deep reef 10...greeter (main entry) 27 coastal stream/ waves and tides (rocky shore) 11 marine mammal cart 28 enchanted kelp forest 12 today on the bay 1 29...sea otter exhibit 13 kelp touch pool 4 30 boiler/ cannery row exhibit 14 touch pool 3 31 shale reef /wharf 15 tentacles 32 jellies experience 16

A bill to redesignate the Department of Veterans Affairs Healthcare System located at 10000 Bay Pines Boulevard in Bay Pines, Florida, as the "C.W. Bill Young Department of Veterans Affairs Medical Center".

THOMAS, 113th Congress

Sen. Nelson, Bill [D-FL

2013-10-28

Senate - 10/30/2013 Committee on Veterans' Affairs. Hearings held. Hearings printed: S.Hrg. 113-280. (All Actions) Notes: For further action, see H.R.3302, which became Public Law 113-49 on 11/13/2013. Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in previously treated children with severe haemophilia A: results of the LEOPOLD Kids Trial.

PubMed

Ljung, R; Kenet, G; Mancuso, M E; Kaleva, V; Rusen, L; Tseneklidou-Stoeter, D; Michaels, L A; Shah, A; Hong, W; Maas Enriquez, M

2016-05-01

BAY 81-8973, a full-length, unmodified, recombinant factor VIII (FVIII) in development for treatment of haemophilia A, has the same primary amino acid sequence as Bayer's sucrose-formulated recombinant FVIII but is produced with more advanced manufacturing technologies. To demonstrate safety and efficacy of BAY 81-8973 for prophylaxis and treatment of bleeds in previously treated children. In this phase III, multicentre, open-label, nonrandomized study, boys aged ≤12 years with severe haemophilia A and ≥50 exposure days (EDs) to FVIII products received prophylaxis with BAY 81-8973 25-50 IU kg(-1) ≥2 times weekly for ≥50 EDs. The efficacy endpoint was annualized number of total bleeds. Adverse events (AEs) and immunogenicity were assessed. Fifty-one patients were treated (age: <6 years, n = 25; 6-<12 years, n = 26) with a 2× per week (43%) or >2× per week (57%) regimen at study start. Median [quartile 1; quartile 3 (Q1; Q3)] annualized number of bleeds for the combined age groups was 1.90 (0; 6.02) for total bleeds, 0 (0; 2.01) for joint bleeds and 0 (0; 0) for spontaneous bleeds. Median (Q1; Q3) annualized number of total bleeds within 48 h of previous prophylaxis infusion was 1.88 (0; 3.97) for children aged <6 years and 0 (0; 1.96) for children aged 6-<12 years. No drug-related serious AEs or inhibitors were reported. Prophylaxis with BAY 81-8973 using individualized prophylaxis regimens of 2× per week, 3× per week and every-other-day infusions was efficacious in prevention and treatment of bleeds in children with severe haemophilia A. Treatment with BAY 81-8973 was well tolerated. © 2015 John Wiley & Sons Ltd.

The helicase-primase inhibitor BAY 57-1293 reduces the Alzheimer's disease-related molecules induced by herpes simplex virus type 1.

PubMed

Wozniak, M A; Frost, A L; Itzhaki, R F

2013-09-01

Herpes simplex virus type 1 (HSV1) infection of cultured cells causes the formation of β-amyloid (Aβ) and abnormal tau (P-tau). These molecules comprise the main components of the abnormal protein deposits, amyloid plaques and neurofibrillary tangles, respectively, in Alzheimer's disease (AD) brains, and they have been implicated in disease development. The formation of P-tau, but not of Aβ, depends on viral DNA replication, but nonetheless, three antiviral agents that inhibit HSV1 DNA replication, including acyclovir (ACV), were found to reduce greatly the level of Aβ as well as P-tau, the former probably through prevention of viral spread. Previous studies showed that HSV1 DNA is present and is active in the brain of many elderly people, including AD patients, and that in combination with the type 4 allele of the apolipoprotein E gene, it is likely to play a role in the disease, perhaps via Aβ and P-tau production. With the aim of finding the most suitable antiviral for inhibiting Aβ and P-tau formation as well as HSV1 DNA replication, for future use in a clinical trial for treating AD, we compared the efficacy of ACV with that of another antiviral, BAY 57-1293, which acts by a different mechanism from ACV. We found that BAY 57-1293 is more efficient than ACV not only in inhibiting HSV1 replication, confirming previous studies, but also in decreasing Aβ and P-tau formation. Also, the cell clusters that are formed during infection are reduced in size much more efficiently by BAY 57-1293 than by ACV. These data suggest that BAY 57-1293 would be a more effective agent than ACV for treating AD. Copyright © 2013 Elsevier B.V. All rights reserved.

Preferential glutathione conjugation of a reverse diol epoxide compared to a bay region diol epoxide of phenanthrene in human hepatocytes: relevance to molecular epidemiology studies of glutathione-s-transferase polymorphisms and cancer.

PubMed

Hecht, Stephen S; Berg, Jeannette Zinggeler; Hochalter, J Bradley

2009-03-16

Bay region diol epoxides are recognized ultimate carcinogens of polycyclic aromatic hydrocarbons (PAH), and in vitro studies have demonstrated that they can be detoxified by conjugation with glutathione, leading to the widely investigated hypothesis that individuals with low activity forms of glutathione-S-transferases are at higher risk of PAH induced cancer, a hypothesis that has found at most weak support in molecular epidemiology studies. A weakness in this hypothesis was that the mercapturic acids resulting from the conjugation of PAH bay region diol epoxides had never been identified in human urine. We recently analyzed smokers' urine for mercapturic acids derived from phenanthrene, the simplest PAH with a bay region. The only phenanthrene diol epoxide-derived mercapturic acid in smokers' urine was produced from the reverse diol epoxide, anti-phenanthrene-3,4-diol-1,2-epoxide (11), not the bay region diol epoxide, anti-phenanthrene-1,2-diol-3,4-epoxide (10), which does not support the hypothesis noted above. In this study, we extended these results by examining the conjugation of phenanthrene metabolites with glutathione in human hepatocytes. We identified the mercapturic acid N-acetyl-S-(r-4,t-2,3-trihydroxy-1,2,3,4-tetrahydro-c-1-phenanthryl)-L-cysteine (14a), (0.33-35.9 pmol/mL at 10 microM 8, 24 h incubation, N = 10) in all incubations with phenanthrene-3,4-diol (8) and the corresponding diol epoxide 11, but no mercapturic acids were detected in incubations with phenanthrene-1,2-diol (7), and only trace amounts were observed in incubations with the corresponding bay region diol epoxide 10. Taken together with our previous results, these studies clearly demonstrate that glutathione conjugation of a reverse diol epoxide of phenanthrene is favored over conjugation of a bay region diol epoxide. Since reverse diol epoxides of PAH are generally weakly or nonmutagenic/carcinogenic, these results, if generalizable to other PAH, do not support the widely held assumption that glutathione-S-transferases are important in the detoxification of PAH in humans.

[Benthic flora and reproduction of Batophora spp. algae (Chlorophyta: Dasycladaceae) in a polluted coastal lagoon (Chetumal Bay, Mexico)].

PubMed

Quan-Young, L I; Jiménez-Flores, S G; Espinoza-Avalos, J

2006-06-01

The benthic flora, and the vegetative and reproductive characters of the algae Batophora oerstedii and B. occidentalis (Chlorophyta) were recorded from five sites of Chetumal Bay, Quintana Roo, Mexico. A sewage gradient has been reported along those sites. Plants were sampled in May and October 1999, which corresponded to dry and rainy seasons, respectively. Forty taxa were found, 11 are new records for the Chetumal Bay, and 6 are new records for the Mexican Caribbean. Enteromorpha species were present in sites known as rich in organic matter (both from anthropogenic and natural sources). Batophora spp. is the dominant algae in all Chetumal Bay. However, it was absent next to sewage outfalls. The morphological characters of B. oerstedii and B. occidentalis did not change significantly along the sites reported as polluted. The length and width of gametophores, as well as the diameter of the gametangia were clearly different for both species. Different reproductive strategies may help B. oerstedii and B. occidentalis to closely coexist in the Chetumal Bay.

Foraminiferal assemblages in Biscayne Bay, Florida, USA: Responses to urban and agricultural influence in a subtropical estuary

USGS Publications Warehouse

Carnahan, E.A.; Hoare, A.M.; Hallock, P.; Lidz, B.H.; Reich, C.D.

2009-01-01

This study assessed foraminiferal assemblages in Biscayne Bay, Florida, a heavily utilized estuary, interpreting changes over the past 65 years and providing a baseline for future comparisons. Analyses of foraminiferal data at the genus level revealed three distinct biotopes. The assemblage from the northern bay was characterized by stress-tolerant taxa, especially Ammonia, present in low abundances (???2.0 ?? 103 foraminifers/gram) though relatively high diversity (???19 genera/sample). The southwestern margin of the bay was dominated by Ammonia and Quinqueloculina, an assemblage characterized by the lowest diversities (???12 genera/sample) and highest abundances (???1.1 ?? 104 foraminifers/gram), influenced by both reduced salinity and elevated organic-carbon concentrations. A diverse assemblage of smaller miliolids and rotaliids (???26 genera/sample) characterized the open-bay assemblage, which also had a significant component (???10%) of taxa that host algal endosymbionts. In the past 65 years, populations of symbiont-bearing taxa, which are indicators of normal-marine conditions, have decreased while stress-tolerant taxa, especially Ammonia spp., have increased in predominance. ?? 2009 Elsevier Ltd.

Radionuclides as tracer for submarine groundwater discharge (SGD) research at Dapeng Bay in Southern Taiwan

NASA Astrophysics Data System (ADS)

Huang, Jun-Chen; Su, Chih-Chieh

2017-04-01

Conventionally, river is the most important source for delivering nutrients, such as nitrogen, phosphorus and silicon, and trace elements into the ocean. The issues of land-sea interaction by rivers have been long-tern concerned and studied, on contrary, the pathway and impact through submarine groundwater discharge (SGD) is still unclear and the relevant researches need to be strengthened. The research site, Dapeng Bay, is located at Pingtung County in Southern Taiwan. Dapeng Bay is an bag-shape lagoon with a sand spit serving as the single outlet of the bay. The longshore currents transport sediments which delivered by Donggang and Linbian Rivers deposited at the nearshore and eventually form the semi-enclosed shallow bay. In the Dapeng Bay, there is no river poured into the lagoon and the main sources of freshwater are rainwater, domestic wastewater and fish ponds etc. The tidal driven water exchange between lagoon and ocean is through the sand spit outlet. The purpose of this study is to evaluate the weighting and seasonal change between SGD and riverine input in the Dapeng Bay. The radium isotopes, 223Ra (11.4d), 224Ra (3.7d), 226Ra (1600y), 228Ra (5.7y), were used as tracers for assessing SGD and riverine inputs. Samples were collected by using MnO2-coated fibers for radium isotopes adsorption.

Novel 11β-hydroxysteroid dehydrogenase 1 inhibitors reduce cortisol levels in keratinocytes and improve dermal collagen content in human ex vivo skin after exposure to cortisone and UV.

PubMed

Boudon, Stéphanie M; Vuorinen, Anna; Geotti-Bianchini, Piero; Wandeler, Eliane; Kratschmar, Denise V; Heidl, Marc; Campiche, Remo; Jackson, Eileen; Odermatt, Alex

2017-01-01

Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

Colored dissolved organic matter in Tampa Bay, Florida

USGS Publications Warehouse

Chen, Z.; Hu, C.; Conmy, R.N.; Muller-Karger, F.; Swarzenski, P.

2007-01-01

Absorption and fluorescence of colored dissolved organic matter (CDOM) and concentrations of dissolved organic carbon (DOC), chlorophyll and total suspended solids in Tampa Bay and its adjacent rivers were examined in June and October of 2004. Except in Old Tampa Bay (OTB), the spatial distribution of CDOM showed a conservative relationship with salinity in June, 2004 (aCDOM(400) = − 0.19 × salinity + 6.78, R2 = 0.98, n = 17, salinity range = 1.1–32.5) with little variations in absorption spectral slope and fluorescence efficiency. This indicates that CDOM distribution was dominated by mixing. In October, 2004, CDOM distribution was nonconservative with an average absorption coefficient (aCDOM(400), ∼ 7.76 m-1) about seven times higher than that in June (∼ 1.11 m-1). The nonconservative behavior was caused largely by CDOM removal at intermediate salinities (e.g., aCDOM(400) removal > 15% at salinity ∼ 13.0), which likely resulted from photobleaching due to stronger stratification. The spatial and seasonal distributions of CDOM in Tampa Bay showed that the two largest rivers, the Alafia River (AR) and Hillsborough River (HR) were dominant CDOM sources to most of the bay. In OTB, however, CDOM showed distinctive differences: lower absorption coefficient, higher absorption spectral slopes, and lower ratios of CDOM absorption to DOC and higher fluorescence efficiency. These differences may have stemmed from (1) changes in CDOM composition by more intensive photobleaching due to the longer residence time of water mass in OTB; (2) other sources of CDOM than the HR/AR inputs, such as local creeks, streams, groundwater, and/or bottom re-suspension. Average CDOM absorption in Tampa Bay at 443 nm, aCDOM(443), was about five times higher in June and about ten times higher in October than phytoplankton pigment absorption, aph(443), indicating that blue light attenuation in the water column was dominated by CDOM rather than by phytoplankton absorption throughout the year.

Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene-fusion: A Long Response to mammalian target of rapamycin (mTOR) Inhibitors.

PubMed

Rua Fernández, Oliver R; Escala Cornejo, Roberto; Navarro Martín, Miguel; García Muñoz, María; Antunez Plaza, Patricia; García Dominguez, Aracely Rocío; Cruz Hernández, Juan J

2018-04-24

To demonstrate that patients with Xp11.2/TFE3 gene-fusion translocation renal cell carcinoma (RCC), despite having an aggressive course in young adults, could have valid treatment options such as mammalian target of rapamycin (mTOR) inhibitors with good outcomes. Furthermore, to explain possible mechanisms of action of mTOR inhibitors in this type of RCC. We report a case of a 44-year-old man who has been treated with everolimus for a Xp11.2 translocation/TFE3 gene-fusion RCC after 2 previous failed treatments with tyrosine kinase inhibitor. During the follow-up, we evaluated type and duration of response with everolimus. The patient obtained a long-lasting response of disease of 25 months with everolimus without any symptom. We believe that mTOR inhibitors could be a good line option treatment to consider for this type of patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Fuel Property Effects on Diesel Engine and Gas Turbine Combustor Performance.

DTIC Science & Technology

1981-11-01

REPORT AFLRL No. 149 By A.F. Montemayor D.W. Naegeli -* L.G. Dodge E.C. Owens J.N. Bowden U.S. Army Fuels and Lubricants Research Laboratory Southwest...6800-120/ 1 7 AUTHOR18) S. CONTRACT ORt GRANT NUMBER(a) A.F. Vmotemeyor E. C. Owens DMA7-8O-C-0001 D. W. Naegeli J.N. Bowden DAAK70-82-C-OOO1 L.G...Acquisition Magazine, 18-20, September-October 1980. 5. Noses, C.A. and Naegeli , D.W., "Fuel Property Effects on Combustor Performance," ASME 79-GT-178

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor.

PubMed

Zhuang, Linghang; Tice, Colin M; Xu, Zhenrong; Zhao, Wei; Cacatian, Salvacion; Ye, Yuan-Jie; Singh, Suresh B; Lindblom, Peter; McKeever, Brian M; Krosky, Paula M; Zhao, Yi; Lala, Deepak; Kruk, Barbara A; Meng, Shi; Howard, Lamont; Johnson, Judith A; Bukhtiyarov, Yuri; Panemangalore, Reshma; Guo, Joan; Guo, Rong; Himmelsbach, Frank; Hamilton, Bradford; Schuler-Metz, Annette; Schauerte, Heike; Gregg, Richard; McGeehan, Gerard M; Leftheris, Katerina; Claremon, David A

2017-07-15

A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC 50 of 4.3nM and in primary human adipose tissue with an IC 80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011. Copyright © 2017 Elsevier Ltd. All rights reserved.

Using Bayes factors for testing hypotheses about intervention effectiveness in addictions research

PubMed Central

Dienes, Zoltan; Muirhead, Colin; West, Robert

2016-01-01

Abstract Background and Aims It has been proposed that more use should be made of Bayes factors in hypothesis testing in addiction research. Bayes factors are the ratios of the likelihood of a specified hypothesis (e.g. an intervention effect within a given range) to another hypothesis (e.g. no effect). They are particularly important for differentiating lack of strong evidence for an effect and evidence for lack of an effect. This paper reviewed randomized trials reported in Addiction between January and June 2013 to assess how far Bayes factors might improve the interpretation of the data. Methods Seventy‐five effect sizes and their standard errors were extracted from 12 trials. Seventy‐three per cent (n = 55) of these were non‐significant (i.e. P > 0.05). For each non‐significant finding a Bayes factor was calculated using a population effect derived from previous research. In sensitivity analyses, a further two Bayes factors were calculated assuming clinically meaningful and plausible ranges around this population effect. Results Twenty per cent (n = 11) of the non‐significant Bayes factors were < ⅓ and 3.6% (n = 2) were > 3. The other 76.4% (n = 42) of Bayes factors were between ⅓ and 3. Of these, 26 were in the direction of there being an effect (Bayes factor > 1 and < 3); 12 tended to favour the hypothesis of no effect (Bayes factor < 1 and > ⅓); and for four there was no evidence either way (Bayes factor = 1). In sensitivity analyses, 13.3% of Bayes Factors were < ⅓ (n = 20), 62.7% (n = 94) were between ⅓ and 3 and 24.0% (n = 36) were > 3, showing good concordance with the main results. Conclusions Use of Bayes factors when analysing data from randomized trials of interventions in addiction research can provide important information that would lead to more precise conclusions than are obtained typically using currently prevailing methods. PMID:27347846

Using Bayes factors for testing hypotheses about intervention effectiveness in addictions research.

PubMed

Beard, Emma; Dienes, Zoltan; Muirhead, Colin; West, Robert

2016-12-01

It has been proposed that more use should be made of Bayes factors in hypothesis testing in addiction research. Bayes factors are the ratios of the likelihood of a specified hypothesis (e.g. an intervention effect within a given range) to another hypothesis (e.g. no effect). They are particularly important for differentiating lack of strong evidence for an effect and evidence for lack of an effect. This paper reviewed randomized trials reported in Addiction between January and June 2013 to assess how far Bayes factors might improve the interpretation of the data. Seventy-five effect sizes and their standard errors were extracted from 12 trials. Seventy-three per cent (n = 55) of these were non-significant (i.e. P > 0.05). For each non-significant finding a Bayes factor was calculated using a population effect derived from previous research. In sensitivity analyses, a further two Bayes factors were calculated assuming clinically meaningful and plausible ranges around this population effect. Twenty per cent (n = 11) of the non-significant Bayes factors were < ⅓ and 3.6% (n = 2) were > 3. The other 76.4% (n = 42) of Bayes factors were between ⅓ and 3. Of these, 26 were in the direction of there being an effect (Bayes factor > 1 and < 3); 12 tended to favour the hypothesis of no effect (Bayes factor < 1 and > ⅓); and for four there was no evidence either way (Bayes factor = 1). In sensitivity analyses, 13.3% of Bayes Factors were < ⅓ (n = 20), 62.7% (n = 94) were between ⅓ and 3 and 24.0% (n = 36) were > 3, showing good concordance with the main results. Use of Bayes factors when analysing data from randomized trials of interventions in addiction research can provide important information that would lead to more precise conclusions than are obtained typically using currently prevailing methods. © 2016 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

Late Wisconsinan-Holocene paleogeography of Delaware Bay; a large coastal plain estuary

USGS Publications Warehouse

Knebel, H.J.; Fletcher, C. H.; Kraft, J.C.

1988-01-01

Analyses of an extensive grid of seismic reflection profiles along with previously published core data and modern sedimentary environment information from surrounding coastal areas permit an outline of the paleogeography of the large Delaware Bay estuary during the last transgression of sea level. During late Wisconsinan times, the Delaware River system eroded a dendritic drainage pattern into the gravelly and muddy sands of Tertiary and younger age beneath the southern half of the lower bay area. This system included the trunk valley of the ancestral river and a large tributary valley formed by the convergence of secondary streams along the Delaware coast. The evolution of the estuary from this drainage system proceeded as follows: (1) When local relative sea level was at -50 m, the head of the tide reached the present bay-mouth area. (2) At -40 m (possibly 15,000-12,000 yrs ago), the trunk valley of the drainage system was a tidal river that extended more than 30 km up the bay, and a small contiguous inlet existed at the bay mouth. (3) At -30 m (approximately 11,000-10,000 yrs ago), the estuary comprised two narrow passages formed by the drowning of the main and tributary river valleys, and the bay-mouth inlet was 5-6 km wide. (4) At -20 m (between 8000 and 7000 yrs ago), the two passages of the estuary were joined, except for a series of small islands on top of a low intervening ridge, and the inlet channel was 11 km wide. (5) At -10 m (between 6000 and 5000 yrs ago), the estuary was nearly continuous and encompassed about 60% of the present lower bay area. Thin, coarse-grained fluvial deposits accumulated initially within the main channels of the former drainage system as base level was elevated by rising sea level. During the subsequent development of the estuary, clayey silts were deposited rapidly beneath the nontidal estuarine depocenter (turbidity maximum) as it migrated through the bay area, and organic muds accumulated in tidal wetlands that occupied the mouths of tributaries and small marginal embayments. As the fetch and tidal prism of the estuary increased, narrow barrier and headland beaches, composed of fine to coarse sands, were formed locally along the bay shorelines. In the later stages of development, sediment scour, reworking and transport became the dominant processes within the open estuary. Data from this study demonstrate the great temporal and spatial variability of sedimentary deposits within large drowned river-valley estuaries and outline a model that can be used to interpret ancient estuarine strata. ?? 1988.

Positron emitter labeled enzyme inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

This invention involves a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide inactivators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline andmore » L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography.« less

Positron emitter labeled enzyme inhibitors

DOEpatents

Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

1987-05-22

This invention involved a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide in activators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgyline and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.

Positron emitter labeled enzyme inhibitors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, J.S.; MacGregor, R.R.; Wolf, A.P.

This invention involved a new strategy for imaging and mapping enzyme activity in the living human and animal body using positron emitter-labeled suicide enzyme inactivators or inhibitors which become covalently bound to the enzyme as a result of enzymatic catalysis. Two such suicide in activators for monoamine oxidase have been labeled with carbon-11 and used to map the enzyme subtypes in the living human and animal body using PET. By using positron emission tomography to image the distribution of radioactivity produced by the body penetrating radiation emitted by carbon-11, a map of functionally active monoamine oxidase activity is obtained. Clorgylinemore » and L-deprenyl are suicide enzyme inhibitors and irreversibly inhibit monoamine oxidase. When these inhibitors are labeled with carbon-11 they provide selective probes for monoamine oxidase localization and reactivity in vivo using positron emission tomography. 2 figs.« less

Determination of broadband moment magnitude (Mwp) for August 11, 2009 Suruga-Bay earthquake (MJMA=6.5)

NASA Astrophysics Data System (ADS)

Tsuboi, S.; Hirshorn, B. F.

2009-12-01

We have determined Mwp for the August 11, 2009 Suruga-Bay earthquake (MJMA=6.5) using broadband seismograms recorded at close epicentral distance stations. We have used two broadband seismograph stations: JHJ2 (epicentral distance 1.9 degree) and FUJ (epicentral distance 0.44 degree). Because of the close epicentral distance of FUJ, the seismogram is clipped at about 10 second after the P-wave arrival. However, it was possible to use the first 10 second of this seismogram to compute Mwp. We get Mwp=6.4 for JHJ2 and 6.8 for FUJ(figure 1). After we apply Whitmore et al (2000)’s correction and average these two stations, we get Mwp=6.6 for this event. The epicentral distance of 0.44 degree for magnitude 6.5 earthquake is marginal to treat this seismogram as far-field. However, considering the aftershock distribution, the fault area seems to be limited to within the Suruga-Bay, which may confirm the fact that Mwp can be successfully computed at FUJ based on the far-field approximation. This result is significant in using Mwp from close epicentral distance seismograms to issue early tsunami warning. A large earthquake with Mw=7.5 (GCMT) occurred in Andaman Island, India, 10 minutes before this Suruga-Bay event. This made it very difficult to estimate Mwp for the Suruga-Bay event from broadband seismograms at teleseismic distances because of the large amplitude of Mw7.5 Andaman Island earthquake. In this case, it is therefore difficult to issue accurate tsunami warnings based on the teleseismic stations. We used broadband seismograms recorded by F-net operated by the National Research Institute for Earth Science and Disaster Prevention.

Spectroscopic study of trivalent praseodymium in barium yttrium fluoride

NASA Astrophysics Data System (ADS)

Bowlby, Brian Edward

1998-09-01

This work investigates the spectroscopic properties of trivalent praseodymium (Pr3+) in barium yttrium fluoride (BaY2F8). Two doping concentrations were studied: BaY2F8:Pr3+ (.3%) and BaY2F8:Pr3+ (1%). Absorption spectra were taken at 77K and 300K and these were then used to calculate the Judd-Ofelt coefficients for both samples. These coefficients were then used to calculate the theoretical lifetimes and radiative branching ratios for all manifolds. Continuous luminescence spectra and lifetime measurements were also performed, and from these, experimentally determined values for the branching ratio and lifetimes were determined. These were then compared to their theoretical counterparts. It was found that while the theory gave values that were qualitatively correct, the quantitative correlation between theory and experiment shows the complexity of the physical reality and the difficulty of synthesizing an encompassing theoretical model. Absorption spectra and continuous luminescence spectra were also used to determine the energy levels of all manifolds in both samples. A total of 59 energy levels in 11 manifolds were identified in the BaY2F8:Pr3+ (1%) sample, while 51 levels in 11 manifolds were identified in the BaY2F8:Pr3+ (.3%) sample. Finally, the effects of temperature on the line width and line position for several radiative transitions was studied. It was found that while most transitions exhibited the expected broadening and shifting towards longer wavelengths at higher temperatures (a 'red shift'), the transition from the 3P0 level to the 3H4 ground state showed a shift towards shorter wavelengths at higher temperature (a 'blue shift'). Again this highlights the complexity of the ion- host interaction.

A Global Talent Magnet: How a San Francisco/Bay Area Global Higher Education Hub Could Advance California's Comparative Advantage in Attracting International Talent and Further Build US Economic Competitiveness. Research & Occasional Paper Series: CSHE.9.11

ERIC Educational Resources Information Center

Douglass, John; Edelstein, Richard; Hoareau, Cecile

2011-01-01

During the 2009-10 academic year international students generated more than $18.8 billion in net income into the US economy. California alone had nearly 100,000 international students with an economic impact of nearly $3.0 billion. In this paper, we outline a strategy for the San Francisco/Bay Area to double the number of international students…

STS-65 Earth observation of Rio de Janeiro in Brazil taken from OV-102

NASA Image and Video Library

1994-07-23

STS065-88-001 (8-23 July 1994) --- Rio de Janeiro, a port city in Brazil with a population of 11.6 million people, can be seen to the left of Governador Island in the Bay of Guanabara. Aeroporto Galeao is visible on the left, or western half of Governador Island. Below Governador Island is the Ponte Rio Niteroi bridge which connects the cities of Rio de Janeiro and Niteroi. Several ships can be seen in the Bay of Guanabara.

Saco Bay, Maine: Sediment Budget for Late Twentieth Century to Present

DTIC Science & Technology

2016-02-01

determined that sediment flux was variable, depending on bathymetry and input wave conditions. Despite these variations in conditions, there is no obvious...DETAILS, SACO BAY, MAINE V3. Last update: 11 September 2014 Units are yd3/year. Source1 = bluffs, river influx, wind . Sink1 = wind -blown loss or...Beach05 (B05), Pine Point QSource1 1,600 Wind transport (from Kelley et al. 2005). DeltaV 1,600 Dune accumulation 1859–1991 (from Kelley et al. 2005

50 CFR 217.15 - Mitigation.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 50 Wildlife and Fisheries 10 2012-10-01 2012-10-01 false Mitigation. 217.15 Section 217.15... Monterey Bay National Marine Sanctuary, CA § 217.15 Mitigation. (a) The activity identified in § 217.11(a....11(a) of this chapter, the mitigation measures contained in the LOA issued under §§ 216.106 and 217...

50 CFR 217.15 - Mitigation.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 50 Wildlife and Fisheries 10 2014-10-01 2014-10-01 false Mitigation. 217.15 Section 217.15... Monterey Bay National Marine Sanctuary, CA § 217.15 Mitigation. (a) The activity identified in § 217.11(a....11(a) of this chapter, the mitigation measures contained in the LOA issued under §§ 216.106 and 217...

27 CFR 9.114 - Old Mission Peninsula.

Code of Federal Regulations, 2011 CFR

2011-04-01

... boundary in Grand Traverse County, Michigan, consists of all of Peninsula Township, excluding Marion and Bassett Islands. In addition, the viticultural area takes in a small portion of Traverse City Township. (1... Grand Traverse Bay at Section 1, Township 27 North, Range 11 West (T27N, R11W), approximately 500 feet...

27 CFR 9.114 - Old Mission Peninsula.

Code of Federal Regulations, 2010 CFR

2010-04-01

... boundary in Grand Traverse County, Michigan, consists of all of Peninsula Township, excluding Marion and Bassett Islands. In addition, the viticultural area takes in a small portion of Traverse City Township. (1... Grand Traverse Bay at Section 1, Township 27 North, Range 11 West (T27N, R11W), approximately 500 feet...

An analysis of anthropometric data on Iranian primary school children.

PubMed

Hafezi, R; Mirmohammadi, Sj; Mehrparvar, Ah; Akbari, H; Akbari, H

2010-01-01

Anthropometric data can be used to identify the physical dimensions of equipment, furniture, etc. The use of furniture that fails to fulfill the anthropometric data of its users has a negative impact on human health. Specific anthropometric dimensions are necessary to design school furniture. Anthropometric data have been measured in many communities especially among schoolchildren. There are different ethnic groups with probably different anthropometric data in Iran, and anthropometric data can change by time, so gathering data about anthropometric dimensions is important. This study was designed to obtain anthropometric dimensions of Iranian children (Fars ethnicity) aged 7-11 years. In a cross-sectional study in Yazd, Iran, descriptive statistics as well as key percentiles for 17 static anthropometric data of primary school students (1015 males and 1015 females), were measured and compared between boys and girls. The age of the students was between 6 and 11 years. Mean weight was between 21.56±5.33 kg and 36.63±9.45 kg in boys and between 20.79±3.48 kg and 35.88±9.40 kg in girls. Mean height was between 1187/02±53.98 mm and 1420.83± 69.39 mm in boys and between 1173.90±51.01mm and 1421.27±70.82 mm in girls. There was also some difference in other anthropometric data between two genders. Results of this study showed some differences in anthropometric data with other studies. We also observed significant gender differences in some dimensions as well.

Disruption of Annexin II /p11 Interaction Suppresses Leukemia Cell Binding, Homing and Engraftment, and Sensitizes the Leukemia Cells to Chemotherapy.

PubMed

Gopalakrishnapillai, Anilkumar; Kolb, E Anders; Dhanan, Priyanka; Mason, Robert W; Napper, Andrew; Barwe, Sonali P

2015-01-01

The bone marrow microenvironment plays an important role in acute lymphoblastic leukemia (ALL) cell proliferation, maintenance, and resistance to chemotherapy. Annexin II (ANX2) is abundantly expressed on bone marrow cells and complexes with p11 to form ANX2/p11-hetero-tetramer (ANX2T). We present evidence that p11 is upregulated in refractory ALL cell lines and patient samples. A small molecule inhibitor that disrupts ANX2/p11 interaction (ANX2T inhibitor), an anti-ANX2 antibody, and knockdown of p11, abrogated ALL cell adhesion to osteoblasts, indicating that ANX2/p11 interaction facilitates binding and retention of ALL cells in the bone marrow. Furthermore, ANX2T inhibitor increased the sensitivity of primary ALL cells co-cultured with osteoblasts to dexamethasone and vincristine induced cell death. Finally, in an orthotopic leukemia xenograft mouse model, the number of ALL cells homing to the bone marrow was reduced by 40-50% in mice injected with anti-ANX2 antibody, anti-p11 antibody or ANX2T inhibitor compared to respective controls. In a long-term engraftment assay, the percentage of ALL cells in mouse blood, bone marrow and spleen was reduced in mice treated with agents that disrupt ANX2/p11 interaction. These data show that disruption of ANX2/p11 interaction results in reduced ALL cell adhesion to osteoblasts, increased ALL cell sensitization to chemotherapy, and suppression of ALL cell homing and engraftment.

NFκB inhibitors induce cell death in glioblastomas.

PubMed

Zanotto-Filho, Alfeu; Braganhol, Elizandra; Schröder, Rafael; de Souza, Luís Henrique T; Dalmolin, Rodrigo J S; Pasquali, Matheus A Bittencourt; Gelain, Daniel Pens; Battastini, Ana Maria Oliveira; Moreira, José Cláudio Fonseca

2011-02-01

Identification of novel target pathways in glioblastoma (GBM) remains critical due to poor prognosis, inefficient therapies and recurrence associated with these tumors. In this work, we evaluated the role of nuclear-factor-kappa-B (NFκB) in the growth of GBM cells, and the potential of NFκB inhibitors as antiglioma agents. NFκB pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues, respectively. Treatment of a panel of established GBM cell lines (U138MG, U87, U373 and C6) with pharmacological NFκB inhibitors (BAY117082, parthenolide, MG132, curcumin and arsenic trioxide) and NFκB-p65 siRNA markedly decreased the viability of GBMs as compared to inhibitors of other signaling pathways such as MAPKs (ERK, JNK and p38), PKC, EGFR and PI3K/Akt. In addition, NFκB inhibitors presented a low toxicity to normal astrocytes, indicating selectivity to cancerous cells. In GBMs, mitochondrial dysfunction (membrane depolarization, bcl-xL downregulation and cytochrome c release) and arrest in the G2/M phase were observed at the early steps of NFκB inhibitors treatment. These events preceded sub-G1 detection, apoptotic body formation and caspase-3 activation. Also, NFκB was found overstimulated in cisplatin-resistant C6 cells, and treatment of GBMs with NFκB inhibitors overcame cisplatin resistance besides potentiating the effects of the chemotherapeutics, cisplatin and doxorubicin. These findings support NFκB as a potential target to cell death induction in GBMs, and that the NFκB inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy. Copyright © 2010 Elsevier Inc. All rights reserved.

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- In the payload bay of the orbiter Atlantis, STS-98 Mission Specialist Robert Curbeam works with equipment he will use in space to attach the U.S. Lab Destiny to the International Space Station. The crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. A key element in the construction of the International Space Station, Destiny is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- In the payload bay of the orbiter Atlantis, STS-98 Commander Ken Cockrell (center) and Mission Specialist Marsha Ivins (right) look over the mission payload, the U.S. Lab Destiny (in the background). The crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. A key element in the construction of the International Space Station, Destiny is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- In the payload bay of the orbiter Atlantis, STS-98 Mission Specialists Thomas Jones (left) and Robert Curbeam (right) talk about their mission, attaching the U.S. Lab Destiny (in the background) to the International Space Station. The crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. A key element in the construction of the International Space Station, Destiny is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- In the payload bay of Atlantis, two workers (background and right) watch STS-98 Robert Curbeam practice work he will do on the U.S. Lab Destiny in space. The mission payload, Destiny is a key element in the construction of the International Space Station. The lab is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. The STS-98 crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

NICER Transfer (for SpaceX CRS-11)

NASA Image and Video Library

2017-04-12

Inside the Space Station Processing Facility high bay at NASA's Kennedy Space Center in Florida, the Neutron star Interior Composition Explorer, or NICER, payload is secured inside a protective container. A technician uses a Hyster forklift to pick up the container and move it outside of the high bay. NICER will be delivered to the International Space Station aboard the SpaceX Dragon cargo carrier on the company’s 11th commercial resupply services mission to the space station. NICER will study neutron stars through soft X-ray timing. NICER will enable rotation-resolved spectroscopy of the thermal and non-thermal emissions of neutron stars in the soft X-ray band with unprecedented sensitivity, probing interior structure, the origins of dynamic phenomena and the mechanisms that underlie the most powerful cosmic particle accelerators known.

Molecular Modeling Studies of 11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors through Receptor-Based 3D-QSAR and Molecular Dynamics Simulations.

PubMed

Qian, Haiyan; Chen, Jiongjiong; Pan, Youlu; Chen, Jianzhong

2016-09-19

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a potential target for the treatment of numerous human disorders, such as diabetes, obesity, and metabolic syndrome. In this work, molecular modeling studies combining molecular docking, 3D-QSAR, MESP, MD simulations and free energy calculations were performed on pyridine amides and 1,2,4-triazolopyridines as 11β-HSD1 inhibitors to explore structure-activity relationships and structural requirement for the inhibitory activity. 3D-QSAR models, including CoMFA and CoMSIA, were developed from the conformations obtained by docking strategy. The derived pharmacophoric features were further supported by MESP and Mulliken charge analyses using density functional theory. In addition, MD simulations and free energy calculations were employed to determine the detailed binding process and to compare the binding modes of inhibitors with different bioactivities. The binding free energies calculated by MM/PBSA showed a good correlation with the experimental biological activities. Free energy analyses and per-residue energy decomposition indicated the van der Waals interaction would be the major driving force for the interactions between an inhibitor and 11β-HSD1. These unified results may provide that hydrogen bond interactions with Ser170 and Tyr183 are favorable for enhancing activity. Thr124, Ser170, Tyr177, Tyr183, Val227, and Val231 are the key amino acid residues in the binding pocket. The obtained results are expected to be valuable for the rational design of novel potent 11β-HSD1 inhibitors.

Discharge, water-quality characteristics, and nutrient loads from McKay Bay, Delaney Creek, and East Bay, Tampa, Florida, 1991-1993

USGS Publications Warehouse

Stoker, Y.E.; Levesque, V.A.; Fritz, E.M.

1996-01-01

Nutrient enrichment in Tampa Bay has caused a decline in water quality in the estuary. Efforts to reduce the nutrient loading to Tampa Bay have resulted in improvement in water quality from 1981 to 1991. However, Tampa Bay still is onsidered enriched with nutrients. Water quality in East Bay (located at the northeastern part of Hillsborough Bay, which is an embayment in Tampa Bay) is not improving at the same rate as the rest of the bay. East Bay is the center of shipping activity in Tampa Bay and the seventh largest port in the United States. One of the primary cargoes is phosphate ore and related products such as fertilizer. The potential for nutrient loading to East Bay from shipping activities is high and has not previously been measured. Nitrogen and phosphorus loads from East Bay to Hillsborough Bay were measured during selected time periods during June 1992 through May 1993; these data were used to estimate seasonal and annual loads. These loads were evaluated to determine whether the loss of fertilizer products from shipping activities resulted in increased nutrient loading to Hillsborough Bay. Discharge was measured, and water-quality samples were collected at the head of East Bay (exiting McKay Bay), and at the mouth of East Bay. Discharge and nitrogen and phosphorus concentrations for the period June 1992 through May 1993 were used to compute loads. Discharges from McKay Bay, Delaney Creek, and East Bay are highly variable because of the effect of tide. Flow patterns during discharge measurements generally were unidirectional in McKay Bay and Delaney Creek, but more complex, bidirectional patterns were observed at the mouth of East Bay. Tidally affected discharge data were digitally filtered with the Godin filter to remove the effects of tide so that residual, or net, discharge could be determined. Daily mean discharge from McKay Bay ranged from -1,900 to 2,420 cubic feet per second; from Delaney Creek, -3.8 to 162 cubic feet per second; and from East Bay, -437 to 3,780 cubic feet per second. Water quality in McKay Bay, Delaney Creek, and East Bay varies vertically, areally, and seasonally. Specific conductance and concentrations of phosphorus and ammonia nitrogen were greater near the bottom than near the surface at the head and mouth of East Bay. Concentrations of total nitrogen and ammonia plus organic nitrogen generally were greater at the head of East Bay than at the mouth, indicating that McKay Bay is the primary source of nitrogen to East Bay. Concentrations of total ammonia nitrogen, nitrite plus nitrate nitrogen, phosphorus, orthophosphorus, and suspended solids and values of turbidity and specific conductance generally were greater at the mouth of East Bay than at the head. The greatest concentrations of nitrogen and phosphorus were measured in Delaney Creek. In East Bay and McKay Bay, the greatest concentrations of nitrogen, phosphorus, and ammonia plus organic nitrogen occurred in summer, whereas turbidity, specific conductance, and concentrations of suspended solids were greater in winter. The greatest daily mean loads from McKay Bay and East Bay occurred in late June 1992 and April and May 1993 and coincided with periods of daily mean discharge greater than about 2,000 cubic feet per second. Although concentrations of nitrogen and phosphorus were greater in Delaney Creek than in McKay Bay and East Bay, loads were minimal because of minimal discharges from Delaney Creek. Monthly loads of total nitrogen ranged from about 20 tons to about 83 tons at McKay Bay; from about 1 ton to 4.2 tons at Delaney Creek; and from about 17 tons to 76 tons at the mouth of East Bay. Monthly loads of phosphorus ranged from about 11 tons to about 45 tons at McKay Bay; from about 0.62 ton to 2.6 tons at Delaney Creek; and from about 10 tons to about 45 tons at the mouth of East Bay. The results of this study indicate that nitrogen and phosphorus loads from the basin draining directly to East Bay (excluding loads from the McKa

Is there a signal of sea-level rise in Chesapeake Bay salinity?

NASA Astrophysics Data System (ADS)

Hilton, T. W.; Najjar, R. G.; Zhong, L.; Li, M.

2008-09-01

We evaluate the hypothesis that sea-level rise over the second half of the 20th century has led to detectable increases in Chesapeake Bay salinity. We exploit a simple, statistical model that predicts monthly mean salinity as a function of Susquehanna River flow in 23 segments of the main stem Chesapeake Bay. The residual (observed minus modeled) salinity exhibits statistically significant linear (p < 0.05) trends between 1949 and 2006 in 13 of the 23 segments of the bay. The salinity change estimated from the trend line over this period varies from -2.0 to 2.2, with 10 of the 13 cells showing positive changes. The mean and median salinity changes over all 23 cells are 0.47 and 0.72; over the 13 cells with significant trends they are 0.71 and 1.1. We ran a hydrodynamic model of the bay under present-day and reduced sea level conditions and found a bay-average salinity increase of about 0.5, which supports the hypothesis that the salinity residual trends have a significant component due to sea-level rise. Uncertainties remain, however, due to the spatial and temporal extent of historical salinity data and the infilling of the bay due to sedimentation. The salinity residuals also exhibit interannual variability, with peaks occurring at intervals of roughly 7 to 9 years, which are partially explained by Atlantic Shelf salinity, Potomac River flow and the meridional component of wind stress.

Probability-based estimates of site-specific copper water quality criteria for the Chesapeake Bay, USA.

PubMed

Arnold, W Ray; Warren-Hicks, William J

2007-01-01

The object of this study was to estimate site- and region-specific dissolved copper criteria for a large embayment, the Chesapeake Bay, USA. The intent is to show the utility of 2 copper saltwater quality site-specific criteria estimation models and associated region-specific criteria selection methods. The criteria estimation models and selection methods are simple, efficient, and cost-effective tools for resource managers. The methods are proposed as potential substitutes for the US Environmental Protection Agency's water effect ratio methods. Dissolved organic carbon data and the copper criteria models were used to produce probability-based estimates of site-specific copper saltwater quality criteria. Site- and date-specific criteria estimations were made for 88 sites (n = 5,296) in the Chesapeake Bay. The average and range of estimated site-specific chronic dissolved copper criteria for the Chesapeake Bay were 7.5 and 5.3 to 16.9 microg Cu/L. The average and range of estimated site-specific acute dissolved copper criteria for the Chesapeake Bay were 11.7 and 8.3 to 26.4 microg Cu/L. The results suggest that applicable national and state copper criteria can increase in much of the Chesapeake Bay and remain protective. Virginia Department of Environmental Quality copper criteria near the mouth of the Chesapeake Bay, however, need to decrease to protect species of equal or greater sensitivity to that of the marine mussel, Mytilus sp.

Microcontaminants and reproductive impairment of the Forster's tern on Green Bay, Lake Michigan,1983

USGS Publications Warehouse

Kubiak, T.J.; Harris, H.J.; Smith, L.M.; Schwartz, T.R.; Stalling, D.L.; Trick, J.A.; Sileo, L.; Docherty, D.E.; Erdman, T.C.

1989-01-01

For the 1983 nesting season, Forster's tern (Sterna forsteri) reproductive success was significantly impaired on organochlorine contaminated Green Bay, Lake Michigan compared to a relatively uncontaminated inland location at Lake Poygan, Wisconsin. Compared with tern eggs from Lake Poygan, eggs from Green Bay had significantly higher median concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), other polychlorinated dibenzo-p-dioxins (PCDDs), total polychlorinated biphenyls (PCBs), total (three congeners) non-ortho, ortho' PCBs, five individual PCB congeners known to induce aryl hydrocarbon hydroxylase (AHH) and several other organochlorine contaminants. Conversions of analytical concentrations of TCDD and PCB congeners based on relative AHH induction potencies allowed for estimation of total 2,3,7,8-TCDD equivalents. Two PCB congeners, 2,3,3′,4,4′- and 3,3′,4,4′,5-pentachlorobiphenyl (PeCB) accounted for more than 90% of the median estimated TCDD equivalents at both Green Bay and Lake Poygan. The median estimated TCDD equivalents were almost 11-fold higher in tern eggs from Green Bay than in eggs from Lake Poygan (2175 and 201 pg/g). The hatching success of Green Bay sibling eggs from nests where eggs were collected for contaminant analyses was 75% lower at Green Bay than at Lake Poygan. Hatchability of eggs taken from other nests and artificially incubated was about 50% lower for Green Bay than for Lake Poygan. Among hatchlings from laboratory incubation, those from Green Bay weighed approximately 20% less and had a mean liver weight to body weight ratio 26% greater than those from Lake Poygan. In both field and laboratory, mean minimum incubation periods were significantly longer for eggs from Green Bay compared to Lake Poygan (8.25 and 4.58 days, respectively). Mean minimum incubation time for Green Bay eggs in the field was 4.37 days longer than in the laboratory. Hatchability was greatly improved when Green Bay eggs were incubated by Lake Poygan adults in an egg-exchange experiment, but was sharply decreased in Lake Poygan eggs incubated in Green Bay nests. Nest abandonment and egg disappearance were substantial at Green Bay but nil at Lake Poygan. Thus, not only factors intrinsic to the egg, but also extrinsic factors (parental attentiveness), impaired reproductive outcome at Green Bay. The epidemiological evidence from this study strongly suggested that contaminants were a causal factor. AHH-active PCB congeners (intrinsic effects) and PCBs in general (extrinsic effects) appeared to be the only contaminants at the concentrations measured in eggs, capable of producing the effects that were observed at Green Bay.

Effect of the South Bay Ocean Outfall (SBOO) on ocean beach water quality near the USA-Mexico border.

PubMed

Gersberg, Richard; Tiedge, Jürgen; Gottstein, Dana; Altmann, Sophie; Watanabe, Kayo; Lüderitz, Volker

2008-04-01

In early 1999, primary treatment and discharge of sewage from Tijuana, Mexico (approximately 95 million liters per day) began through South Bay Ocean Outfall (SBOO) into the ocean 4.3 km offshore. In this study, statistical comparisons were made of the bacterial water quality (total and fecal coliforms and enterococci densities) of the ocean, both before and after discharge of sewage to the SBOO began, so that the effect of this ocean discharge on nearshore ocean water quality could be quantitatively assessed. The frequency of exceedence of bacterial indicator thresholds was statistically analyzed for 11 shore (surfzone) stations throughout US and Mexico using the Fisher's exact test, for the years before (1995-1998) as compared to after the SBOO discharge began (1999-2003). Only four of the 11 shoreline stations (S2, S3, S11, and S12) showed significant improvement (decreased frequency of exceedence of bacterial indicator thresholds) after SBOO discharge began.

Retro-binding thrombin active site inhibitors: identification of an orally active inhibitor of thrombin catalytic activity.

PubMed

Iwanowicz, Edwin J; Kimball, S David; Lin, James; Lau, Wan; Han, W-C; Wang, Tammy C; Roberts, Daniel G M; Schumacher, W A; Ogletree, Martin L; Seiler, Steven M

2002-11-04

A series of retro-binding inhibitors of human alpha-thrombin was prepared to elucidate structure-activity relationships (SAR) and optimize in vivo performance. Compounds 9 and 11, orally active inhibitors of thrombin catalytic activity, were identified to be efficacious in a thrombin-induced lethality model in mice.

Polychlorinated naphthalenes (PCNs) in riverine and marine sediments of the Laizhou Bay area, North China.

PubMed

Pan, Xiaohui; Tang, Jianhui; Chen, Yingjun; Li, Jun; Zhang, Gan

2011-12-01

PCN congeners were analyzed in marine and riverine sediments of the Laizhou Bay area, North China. Concentrations of PCNs ranged from 0.12 to 5.1 ng g(-)(1) dry weight (dw) with a mean value of 1.1 ng g(-)(1) dw. The levels of PCNs varied largely, with industrial group approximately ten folds higher than those of the rural in riverine sediment. A strong impact by direct discharge from local factories was suggested. Similar compositional profiles were found within groups. High resemblance of compositional profiles between industrial samples and Halowax 1014 was observed. It was indicated that PCNs in riverine sediments were mainly from release of industrial usage, with additional contributions from industrial thermal process at certain sites. In marine sediments, it was suggested that PCNs along the coast of Laizhou Bay were mainly controlled by riverine input. While in the central bay, PCN distributions were possibly impacted by combined multiple factors. Copyright © 2011 Elsevier Ltd. All rights reserved.

STS-43 MS Adamson checks OCTW experiment on OV-104's aft flight deck

NASA Image and Video Library

1991-08-11

STS043-04-038 (2-11 Aug 1991) --- Astronaut James C. Adamson, STS-43 mission specialist, checks on an experiment on Atlantis? flight deck. Part of the experiment, Optical Communications Through the Shuttle Window (OCTW), can be seen mounted in upper right. The OCTW system consists of two modules, one inside the orbiter crew cabin (as pictured here) and one in the payload bay. The crew compartment version houses an optoelectronic transmitter/receiver pair for video and digital subsystems, test circuitry and interface circuitry. The payload bay module serves as a repeater station. During operation a signal is transmitted through the shuttle window to a bundle of optical fiber cables mounted in the payload bay near an aft window. The cables carry optical signals from the crew compartment equipment to the OCTW payload bay module. The signals are returned via optical fiber cable to the aft flight deck window, retransmitted through the window, and received by the crew compartment equipment.

Distinct effects of EGFR inhibitors on epithelial- and mesenchymal-like esophageal squamous cell carcinoma cells.

PubMed

Yoshioka, Masahiro; Ohashi, Shinya; Ida, Tomomi; Nakai, Yukie; Kikuchi, Osamu; Amanuma, Yusuke; Matsubara, Junichi; Yamada, Atsushi; Miyamoto, Shin'ichi; Natsuizaka, Mitsuteru; Nakagawa, Hiroshi; Chiba, Tsutomu; Seno, Hiroshi; Muto, Manabu

2017-08-01

Epidermal growth factor receptor (EGFR) plays a pivotal role in the pathophysiology of esophageal squamous cell carcinoma (ESCC). However, the clinical effects of EGFR inhibitors on ESCC are controversial. This study sought to identify the factors determining the therapeutic efficacy of EGFR inhibitors in ESCC cells. Immortalized-human esophageal epithelial cells (EPC2-hTERT), transformed-human esophageal epithelial cells (T-Epi and T-Mes), and ESCC cells (TE-1, TE-5, TE-8, TE-11, TE-11R, and HCE4) were treated with the EGFR inhibitors erlotinib or cetuximab. Inhibitory effects on cell growth were assessed by cell counting or cell-cycle analysis. The expression levels of genes and proteins such as involucrin and cytokeratin13 (a squamous differentiation marker), E-cadherin, and vimentin were evaluated by real-time polymerase chain reaction or western blotting. To examine whether mesenchymal phenotype influenced the effects of EGFR inhibitors, we treated T-Epi cells with TGF-β1 to establish a mesenchymal phenotype (mesenchymal T-Epi cells). We then compared the effects of EGFR inhibitors on parental T-Epi cells and mesenchymal T-Epi cells. TE-8 (mesenchymal-like ESCC cells)- or TE-11R (epithelial-like ESCC cells)-derived xenograft tumors in mice were treated with cetuximab, and the antitumor effects of EGFR inhibitors were evaluated. Cells were classified as epithelial-like or mesenchymal-like phenotypes, determined by the expression levels of E-cadherin and vimentin. Both erlotinib and cetuximab reduced cell growth and the ratio of cells in cell-cycle S phase in epithelial-like but not mesenchymal-like cells. Additionally, EGFR inhibitors induced squamous cell differentiation (defined as increased expression of involucrin and cytokeratin13) in epithelial-like but not mesenchymal-like cells. We found that EGFR inhibitors did not suppress the phosphorylation of EGFR in mesenchymal-like cells, while EGFR dephosphorylation was observed after treatment with EGFR inhibitors in epithelial-like cells. Furthermore, mesenchymal T-Epi cells showed resistance to EGFR inhibitors by circumventing the dephosphorylation of EGFR signaling. Cetuximab consistently showed antitumor effects, and increased involucrin expression in TE-11R (epithelial-like)-derived xenograft tumors but not TE-8 (mesenchymal-like)-derived xenograft tumors. The factor determining the therapeutic effects of EGFR inhibitors in ESCC cells is the phenotype representing the epithelial-like or mesenchymal-like cells. Mesenchymal-like ESCC cells are resistant to EGFR inhibitors because EGFR signaling is not blocked. EGFR inhibitors show antitumor effects on epithelial-like ESCC cells accompanied by promotion of squamous cell differentiation.

Characterization of proteins in the muscle of limanda yokohamae from the masan bay, Korea

NASA Astrophysics Data System (ADS)

Kim, Soo Woon; Kim, Sam Moon; Lee, Dong Kun; Moon, Hyo Bang; Choi, Hee Gu; Kang, Chang Keun; Choe, Eun Sang

2007-06-01

Increasing industrial development in the Masan Bay area of Korea over the past decades increased the risk for the survival of marine organisms in the bay area by the deterioration of the water quality. Since living organisms have the ability to adapt contamination-associated stimuli by the alteration of gene expression, changes in proteins can be used as an important criterion for assessing the levels of environmental conditions. In this study, therefore, alterations of the expression of proteins in the muscle of Limanda yokohamae from Dukdong and Dotsum in the bay area were surveyed and characterized as compared with Haegumgang, which served as a control site. The results demonstrated that the twenty spots detected from Dukdong and Dotsum were similar to each other. Fifteen proteins were found to be predicted or undefined proteins, while five proteins were identified as heavy polypeptide 11 of myosin, apolipoprotein A-I, fibroblast growth factor 17b precursor, G protein-coupled receptor kinase 1 b and bonnie and clyde. These data suggest that local fish in the bay area have dysfunction in muscle physiology including contraction, lipid metabolism, proliferation and differentiation and nervous system.

KSC-99pp1367

NASA Image and Video Library

1999-11-29

KENNEDY SPACE CENTER, FLA. -- Orbiter Endeavour waits in the Orbiter Processing Facility bay 2 for the closing of its payload bay doors. The Ku-band antenna (upper right) is still in the open position, outside the payload bay. Endeavour is expected to roll over to the Vehicle Assembly Building in three days for mating to the external tank and solid rocket boosters in high bay 1. Space Shuttle Endeavour is targeted for launch on mission STS-99 Jan. 13, 2000 at 1:11 p.m. EST. STS-99 is the Shuttle Radar Topography Mission, an international project spearheaded by the National Imagery and Mapping Agency and NASA, with participation of the German Aerospace Center DLR. The SRTM consists of a specially modified radar system that will gather data for the most accurate and complete topographic map of the Earth's surface that has ever been assembled. SRTM will make use of radar interferometry, wherein two radar images are taken from slightly different locations. Differences between these images allow for the calculation of surface elevation, or change. The SRTM hardware will consist of one radar antenna in the shuttle payload bay and a second radar antenna attached to the end of a mast extended 60 meters (195 feet) out from the shuttle

KSC-99pp1368

NASA Image and Video Library

1999-11-01

KENNEDY SPACE CENTER, FLA. -- Orbiter Endeavour waits in the Orbiter Processing Facility bay 2 for the closing of its payload bay doors. The Ku-band antenna (upper right) is now in its closed position inside the payload bay. Endeavour is expected to roll over to the Vehicle Assembly Building in three days for mating to the external tank and solid rocket boosters in high bay 1. Space Shuttle Endeavour is targeted for launch on mission STS-99 Jan. 13, 2000 at 1:11 p.m. EST. STS-99 is the Shuttle Radar Topography Mission, an international project spearheaded by the National Imagery and Mapping Agency and NASA, with participation of the German Aerospace Center DLR. The SRTM consists of a specially modified radar system that will gather data for the most accurate and complete topographic map of the Earth's surface that has ever been assembled. SRTM will make use of radar interferometry, wherein two radar images are taken from slightly different locations. Differences between these images allow for the calculation of surface elevation, or change. The SRTM hardware will consist of one radar antenna in the shuttle payload bay and a second radar antenna attached to the end of a mast extended 60 meters (195 feet) out from the shuttle

STS-98 payload U.S. Lab Destiny is moved into Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Workers in the Payload Changeout Room begin moving the U.S. Lab Destiny to the orbiter'''s payload bay. The PCR is the enclosed, environmentally controlled portion of the rotating service structure that supports payload delivery at the launch pad and vertical installation in the orbiter payload bay. Destiny, a key element in the construction of the International Space Station, is 28 feet long and weighs 16 tons. This research and command-and- control center is the most sophisticated and versatile space laboratory ever built. It will ultimately house a total of 23 experiment racks for crew support and scientific research. STS-98 is the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

Modelling the Shallow Water Equations in Curvilinear Coordinates with Physical Application

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wingenter, Suzanne

2005-01-12

The goal of this project is to provide the capability for simulating fluid flow on complicated geometries, such as in the Bahia de Todos Santos. The Bahia de Todos Santos is a bay situated in the northwest corner of Mexico, off the coast of Ensenada and south of San Diego, California, USA. Figure 1.1 shows the Bahia de Todos Santos. It is part of an image taken from the Moderate Resolution Imaging Spectroradiometer (MODIS) sensors on the Aqua and Terra satellites in late June and early July 2003 [8]. Roughly 200 square kilometers in size, the bay also contains twomore » islands off the peninsula of Punta Banda. Characteristics of flow in this bay are driven by the moon tide (M2) and wind forcing [9].« less

Enhancement of acetylcholine-induced desensitization of guinea-pig ileal longitudinal muscle in Ca2+-free conditions.

PubMed

Horio, S; Nagare, T; Moritoki, H

1999-10-01

1. To determine the role of cellular Ca2+ in desensitization, acetylcholine(ACh)-induced desensitization was studied under Ca2+-free condition in guinea-pig ileal longitudinal muscle. 2. Pretreatment of the tissue with 10(-4) M ACh (desensitizing treatment) in normal Tyrode solution caused desensitization of the responses both to ACh and histamine. The desensitizing treatment performed in Ca2+-free solution enhanced desensitization of the responses to ACh and histamine significantly. 3. The desensitizing treatment with ACh caused suppression of the responses to high K+ (tonic component) and Bay K 8644. The desensitizing treatment performed in Ca2+-free solution potentiated the suppression of the responses to high K+ and Bay K 8644 significantly. 4. ACh-induced desensitization was enhanced significantly in the presence of a protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine(H-7, 10(-4) M) to a similar extent as desensitization obtained under Ca2+-free condition, but not in the presence of a non-specific and less potent kinase inhibitor, N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride (HA1004, 10(-4) M). 5. These results suggested that voltage-gated Ca2+ channels were involved in ACh-induced desensitization and that intracellular Ca2+, which was increased during the stimulation with ACh, inhibited desensitization through the activation of protein kinase C. This kinase could have activated or protected Ca2+ channels during the desensitization process to reduce desensitization.

Oceanographic characteristics of an impacted coastal bay: Baía de Guanabara, Rio de Janeiro, Brazil

NASA Astrophysics Data System (ADS)

Kjerfve, Björn; Ribeiro, Cesar H. A.; Dias, Gilberto T. M.; Filippo, Alessandro M.; Da Silva Quaresma, Valéria

1997-11-01

Baía de Guanabara is a 384 km 2 eutrophic coastal bay in Brazil, impacted by the polluted discharge from the Rio de Janeiro metropolitan area. The structurally controlled bay has a central channel with a depth of 30 m and a sandy bottom near the entrance, reflecting wave and tidal forcing. In contrast, the bay-averaged water depth is 5.7 m and the bottom sediments are mostly muds as a result of the Holocene transgression and rapid fluvial sedimentation, accelerated by channelization of rivers and deforestation. An extensive sand bank is located seaward of the bay entrance and a flood-oriented sand wave system indicates sand transport into the bay. The mean freshwater discharge measures 100±59 m 3 s -1 and is greatest in the rainy austral summer in December and January. Tides are mixed mainly semidiurnal with a range of 0.7 m, and peak spring tidal currents reach 0.5 m s -1 inside the bay and 1.6 m s -1 near the bay entrance. The passage of northward propagating polar fronts results in regular strong southwesterly winds and heavy wave forcing. The bay has mean salinities from 21.0 to 34.5‰ with an average of 29.5±4.8‰. The vertical salinity stratification, Δs/s, varies from 0.06 to 0.21 and is relatively weak and inversely proportional to rms tidal currents. The residual circulation is characterized by both gravitational circulation and transverse residual tidal circulation, measuring 800 and 400 m 3 s -1 respectively. The renewal time of 50% of the bay water volume is 11.4 days. Untreated sewage runoff enters the bay from the west, resulting in locally poor water quality, where the near-bottom mean dissolved oxygen measures only 3.1 mg 1 -1 and results in anoxic bottom muds. The worst water quality is indicated by average fecal coliform of 1140 counts ml -1 and excessive ammonia and phosphate loading. The average chlorophyll concentration in this region responds to the nutrient loading and exceeds 130 μg 1 -1 although 57 μg 1 -1 is the overall mean for the bay. The atomic N:P ratio measures 14 for the bay as a whole.

Study on the Coastline Change of Jiaozhou Bay Based on High Resolution Remote Sensing Image

NASA Astrophysics Data System (ADS)

Zhu, H.; Xing, B.; Ni, S.; Wei, P.

2018-05-01

In recent years, with the rapid development of the Jiaozhou Bay area of Qingdao, the influence of human activities on the coastline of Jiaozhou Bay is becoming more and more serious. Based on the high resolution remote sensing image data of 10 periods from 2001 to 2017 in the Jiaozhou Bay area, and combined with the data of on-the-spot survey and expert knowledge, this paper have completed the interpretation and extraction of coastline data of each year, and analyzed the distribution, size, rate of change, and trend of the increase and decrease of the coastal area of Jiaozhou Bay in different time periods, combined with the economic construction and the marine hydrodynamic environment of the region to analyze the reasons for the change of the coastline of Jiaozhou Bay. The results show that the increase and reduction of the coastal area of Jiaozhou Bay was mainly affected by human activities such as sea reclamation and marine aquaculture, resulting in a gradual change in the rate of increase and decrease with human development. For coastal advance part,2001-2013, the average increase rate on the coastal area of Jiaozhou Bay was 2.30 km2/a, showing a trend of rapid growth, 2013-2017 the average increase rate of 0.53 km2/a, and the growth rate slowed down. For coastal retreat part, 2001-2013, the average decrease rate was 2.58 × 10-3 km2/a. 2013-2014, the decrease rate reached a peak value of 1.11 km2/a. 2014-2017, the average decrease rate was 0.14 km2/a. The decrease rate shows a trend of increasing first and then slowing down.

Department of the Army Fiscal Year (FY) 2001 Budget Estimates. Military Construction, Army, Family Housing and Homeowners Assistance. Justification Data Submitted to Congress February 2000

DTIC Science & Technology

2000-02-01

outside oversized heavy tracked vehicle cleaning bay; a utility, equipment, and storage area. The double bays will be sized to support Family Medium...very well delay important airborne combat missions. The facility will be operated during four seasons, with most of the heavy activity accruing in the...protective security a metal clad door on the evidence depository with 24 hour lighting will be provided. 11. REQ: 607 m2 ADQT: NONE SUBSTD: 315 m2 PROJECT

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Members of the STS-98 crew, along with Scott Thurston (left), with the VITT office, check out the U.S. Lab Destiny in the payload bay of the orbiter Atlantis. Wearing white caps are Commander Ken Cockrell (center) and Mission Specialist Marsha Ivins (right). The crew is at KSC for Terminal Countdown Demonstration Test activities, which include a simulated launch countdown. Destiny, a key element in the construction of the International Space Station, is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Along with Scott Thurston (left), of the VITT office, members of the STS-98 crew Mission Specialist Robert Curbeam, Commander Ken Cockrell and Mission Specialist Marsha Ivins are in Atlantis''' payload bay to check out their mission payload, the U.S. Lab Destiny. The crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. A key element in the construction of the International Space Station, Destiny is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

STS-98 crew checks out the U.S. Lab Destiny in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- STS-98 Mission Specialist Robert Curbeam (left), Commander Ken Cockrell (center) and Mission Specialist Marsha Ivins (right) look over the U.S. Lab Destiny in the payload bay of the orbiter Atlantis. Behind Ivins is Scott Thurston, of the VITT office. The crew is at KSC for Terminal Countdown Demonstration Test activities, which also include a simulated launch countdown. A key element in the construction of the International Space Station, Destiny is a pressurized module designed to accommodate pressurized payloads. It has a capacity of 24 rack locations. Payload racks will occupy 13 locations especially designed to support experiments. The module already has five system racks installed inside. Launch of STS-98 on its 11-day mission is scheduled for Jan. 19 at 2:11 a.m. EST.

Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

PubMed

Perez, Christian; Li, Jing; Parlati, Francesco; Rouffet, Matthieu; Ma, Yuyong; Mackinnon, Andrew L; Chou, Tsui-Fen; Deshaies, Raymond J; Cohen, Seth M

2017-02-23

The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn 2+ -dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation. A fragment-based drug discovery (FBDD) approach was utilized to identify fragments with activity against Rpn11. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ, IC 50 value ∼2.5 μM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC 50 value ∼400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.

PDE4 and PDE5 regulate cyclic nucleotide contents and relaxing effects on carbachol-induced contraction in the bovine abomasum.

PubMed

Kaneda, Takeharu; Kido, Yuuki; Tajima, Tsuyoshi; Urakawa, Norimoto; Shimizu, Kazumasa

2015-01-01

The effects of various selective phosphodiesterase (PDE) inhibitors on carbachol (CCh)-induced contraction in the bovine abomasum were investigated. Various selective PDE inhibitors, vinpocetine (type 1), erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, type 2), milrinone (type 3), Ro20-1724 (type 4), vardenafil (type 5), BRL-50481 (type 7) and BAY73-6691 (type 9), inhibited CCh-induced contractions in a concentration-dependent manner. Among the PDE inhibitors, Ro20-1724 and vardenafil induced more relaxation than the other inhibitors based on the data for the IC50 or maximum relaxation. In smooth muscle of the bovine abomasum, we showed the expression of PDE4B, 4C, 4D and 5 by RT-PCR analysis. In the presence of CCh, Ro20-1724 increased the cAMP content, but not the cGMP content. By contrast, vardenafil increased the cGMP content, but not the cAMP content. These results suggest that Ro20-1724-induced relaxation was correlated with cAMP and that vardenafil-induced relaxation was correlated with cGMP in the bovine abomasum. In conclusion, PDE4 and PDE5 are the enzymes involved in regulation of the relaxation associated with cAMP and cGMP, respectively, in the bovine abomasum.

Preclinical Characterization of the Phosphodiesterase 10A PET Tracer [(11)C]MK-8193.

PubMed

Hostetler, Eric D; Fan, Hong; Joshi, Aniket D; Zeng, Zhizhen; Eng, Waisi; Gantert, Liza; Holahan, Marie; Meng, Xianjun; Miller, Patricia; O'Malley, Stacey; Purcell, Mona; Riffel, Kerry; Salinas, Cristian; Williams, Mangay; Ma, Bennett; Buist, Nicole; Smith, Sean M; Coleman, Paul J; Cox, Christopher D; Flores, Brock A; Raheem, Izzat T; Cook, Jacquelynn J; Evelhoch, Jeffrey L

2016-08-01

A positron emission tomography (PET) tracer for the enzyme phosphodiesterase 10A (PDE10A) is desirable to guide the discovery and development of PDE10A inhibitors as potential therapeutics. The preclinical characterization of the PDE10A PET tracer [(11)C]MK-8193 is described. In vitro binding studies with [(3)H]MK-8193 were conducted in rat, monkey, and human brain tissue. PET studies with [(11)C]MK-8193 were conducted in rats and rhesus monkeys at baseline and following administration of a PDE10A inhibitor. [(3)H]MK-8193 is a high-affinity, selective PDE10A radioligand in rat, monkey, and human brain tissue. In vivo, [(11)C]MK-8193 displays rapid kinetics, low test-retest variability, and a large specific signal that is displaced by a structurally diverse PDE10A inhibitor, enabling the determination of pharmacokinetic/enzyme occupancy relationships. [(11)C]MK-8193 is a useful PET tracer for the preclinical characterization of PDE10A therapeutic candidates in rat and monkey. Further evaluation of [(11)C]MK-8193 in humans is warranted.

Endocrine disruptors and other inhibitors of 11β-hydroxysteroid dehydrogenase 1 and 2: Tissue-specific consequences of enzyme inhibition.

PubMed

Vitku, Jana; Starka, Luboslav; Bicikova, Marie; Hill, Martin; Heracek, Jiri; Sosvorova, Lucie; Hampl, Richard

2016-01-01

Numerous chemicals in the environment have the ability to interact with the endocrine system. These compounds are called endocrine disruptors (EDs). Exposure to EDs represents one of the hypotheses for decreasing fertility, the increased risk of numerous cancers and obesity, metabolic syndrome and type 2 diabetes. There are various mechanisms of ED action, one of which is their interference in the action of 11β-hydroxysteroid dehydrogenase (11βHSD) that maintains a balance between active and inactive glucocorticoids on the intracellular level. This enzyme has two isoforms and is expressed in various tissues. Inhibition of 11βHSD in various tissues can have different consequences. In the case of EDs, the results of exposure are mainly adverse; on the other hand pharmaceutically developed inhibitors of 11βHSD type 1 are evaluated as an option for treating metabolic syndrome, as well as related diseases and depressive disorders. This review focuses on the effects of 11βHSD inhibitors in the testis, colon, adipose tissue, kidney, brain and placenta. Copyright © 2014 Elsevier Ltd. All rights reserved.

Hyaluronan inhibits prostaglandin E2 production via CD44 in U937 human macrophages.

PubMed

Yasuda, Tadashi

2010-03-01

Prostaglandin E(2) (PGE(2)) is one of the key mediators of inflammation in affected joints of rheumatoid arthritis (RA). Intra-articular injection of high molecular weight hyaluronan (HA) into RA knee joints relieves arthritic pain. Although HA has been shown to inhibit PGE(2) production in cytokine-stimulated synovial fibroblasts, it remains unclear how HA suppresses PGE(2) production in activated cells. Furthermore, HA effect on macrophages has rarely been investigated in spite of their contribution to RA joint pathology. This study was aimed to investigate the inhibitory mechanism of HA on lipopolysaccharide (LPS)-stimulated PGE(2) production in U937 human macrophages. Stimulation of U937 macrophages with LPS enhanced PGE(2) production in association with increased protein levels of cyclooxygenase-2 (COX-2). Pretreatment with HA of 2,700 kDa resulted in suppression of the LPS-mediated induction of COX-2, leading to a decrease in PGE(2) production. Likewise, the LPS-stimulated PGE(2) production was inhibited by the pretreatment with a specific COX2 inhibitor, NS-398, or a specific inhibitor of nuclear factor (NF)-kappaB, BAY11-7085. HA also decreased the degree of phosphorylation and nuclear translocation of NF-kappaB enhanced by LPS. Fluorescence cytochemistry demonstrated that HA bound to CD44, the principal HA receptor, on U937 macrophages. Anti-CD44 antibody reversed the inhibitory effects of HA on the LPS-mediated increase in PGE(2) production, COX-2 induction, and activation of NF-kappaB. These results indicate that HA suppresses the LPS-stimulated PGE(2) production via CD44 through down-regulation of NF-kappaB. Administration of HA into RA joints may decrease PGE(2) production by activated macrophages, which could result in improvement of arthritic pain.

78 FR 27032 - National Maritime Week Tugboat Races, Seattle, WA

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-09

... Maritime Week Tugboat Races, Seattle, WA AGENCY: Coast Guard, DHS. ACTION: Notice of enforcement of... Maritime Week Tugboat Races in Elliott Bay, WA from 12 p.m. until 4:30 p.m. on May 11, 2013. This action is... for the annual National Maritime Week Tugboat Races, Seattle, WA listed in 33 CFR 100.1306 on May 11...

Distribution, population status and trends of kittlitz's murrelet brachyramphus brevirostris in lower cook inlet and kachemak bay, Alaska

USGS Publications Warehouse

Kuletz, Kathy J.; Speckman, Suzann G.; Piatt, John F.; Labunski, E.A.

2011-01-01

Lower Cook Inlet (LCI) in south-central Alaska is unusual among the breeding areas of Kittlitz's Murrelet Brachyramphus brevirostris because of human impacts on the marine and terrestrial environments and because of the lack of tidewater glaciers. In LCI the Kittlitz's Murrelet co-exists with the more abundant Marbled Murrelet, which complicates abundance estimates because of the difficulty of species identification. We compared survey data for an area with overlapping coverage in LCI (Core area) in 1993 (June) and from 1996 to 1999 (July-early August). Within this LCI Core area, the surveys in 1996-1999 estimated ~1600 Kittlitz's Murrelets and ~17 000 Marbled Murrelets, including prorated unidentified murrelets. The Kittlitz's Murrelet population declined between 1993 and 1999 at 26% per annum (84% overall). Simultaneously, Marbled Murrelets declined by 12% per annum (56% overall), though the decline was not statistically significant. Declines were estimated conservatively because the 1993 survey was conducted in June, when both murrelet species are less abundant on the water. We also surveyed Kachemak Bay, a large embayment of LCI, during mid-summer (July) of 2005-2007 and estimated a population of 2047 Kittlitz's Murrelets (SD 1120, n = 3 years) residing primarily in the inner bay. Marbled Murrelets numbered 11 040 (SD 1306) and were found throughout the bay. On one transect set in inner Kachemak Bay, Kittlitz's Murrelet density in late summer (1-16 August) declined 7.5% per annum between 1988 and 2007 (n = 6 years), and Marbled Murrelet density increased 4.9% per annum. On two other transect sets in the inner bay, however, neither murrelet species showed a change in density between 1996 and 2007. Inner Kachemak Bay is a persistent hotspot for Kittlitz's Murrelet and may attract murrelets from LCI and beyond. We recommend monitoring murrelet populations in Kachemak Bay, although Kittlitz's Murrelets likely move between the main body of Cook Inlet and Kachemak Bay, and a complete LCI survey is needed to gauge regional population trends.

Hydrodynamic Characteristics and Salinity Patterns in Estero Bay, Lee County, Florida

USGS Publications Warehouse

Byrne, Michael J.; Gabaldon, Jessica N.

2008-01-01

Estero Bay is an estuary (about 12 miles long and 3 miles wide) on the southwestern Florida coast, with several inlets connecting the bay to the Gulf of Mexico and numerous freshwater tributaries. Continuous stage and salinity data were recorded at eight gaging stations in Estero Bay estuary from October 2001 to September 2005. Continuous water velocity data were recorded at six of these stations for the purpose of measuring discharge. In addition, turbidity data were recorded at four stations, suspended sediment concentration were measured at three stations, and wind measurements were taken at one station. Salinity surveys, within and around Estero Bay, were conducted 15 times from July 2002 to January 2004. The average daily discharge ranged from 35,000 to -34,000 ft3/s (cubic feet per second) at Big Carlos Pass, 10,800 to -11,200 ft3/s at Matanzas Pass, 2,200 to -2,900 ft3/s at Big Hickory Pass, 680 to -700 ft3/s at Mullock Creek, 330 to -370 ft3/s at Estero River, and 190 to -180 ft3/s at Imperial River. Flood tide is expressed as negative discharge and ebb flow as positive discharge. Reduced salinity at Matanzas Pass was negatively correlated (R2 = 0.48) to freshwater discharge from the Caloosahatchee River at Franklin Locks (S-79). Matanzas Pass is hydrologically linked to Hell Peckney Bay; therefore, water-quality problems associated with the Caloosahatchee River also affect Hell Peckney Bay. Rocky Bay was significantly less saline than Coconut Point and Matanzas Pass was significantly less saline than Ostego Bay, based on data from the salinity surveys. The quality-checked and edited continuous data and the salinity maps have been compiled and are stored on the U.S. Geological Survey South Florida Information Access (SOFIA) website (http://sofia.usgs.gov).

Synthesis of sterically encumbered 11β-aminoprogesterone derivatives and evaluation as 11β-hydroxysteroid dehydrogenase inhibitors and mineralocorticoid receptor antagonists.

PubMed

Pandya, Keyur; Dietrich, David; Seibert, Julia; Vederas, John C; Odermatt, Alex

2013-11-01

11β-Hydroxyprogesterone is a well-known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2. It also activates the mineralocorticoid receptor (MR). Modulation of corticosteroid action by inhibition of 11βHSDs or blocking MR is currently under consideration for treatment of electrolyte disturbances, metabolic diseases and chronic inflammatory disorders. We established conditions to synthesize sterically demanding 11β-aminoprogesterone, which following subsequent nucleophilic or reductive amination, allowed extension of the amino group to prepare amino acid derivatives. Biological testing revealed that some of the 11β-aminoprogesterone derivatives selectively inhibit 11βHSD2. Moreover, two compounds that did not significantly inhibit 11βHSDs had antagonist properties on MR. The 11β-aminoprogesterone derivatives form a basis for the further development of improved modulators of corticosteroid action. Copyright © 2013 Elsevier Ltd. All rights reserved.

Sorafenib: targeting multiple tyrosine kinases in cancer.

PubMed

Hasskarl, Jens

2014-01-01

Sorafenib (BAY 43-9006, Nexavar®) is an oral multiple tyrosine kinase inhibitor. Main targets are receptor tyrosine kinase pathways frequently deregulated in cancer such as the Raf-Ras pathway, vascular endothelial growth factor (VEGF) pathway, and FMS-like tyrosine kinase 3 (FLT3). Sorafenib was approved by the FDA in fast track for advanced renal cell cancer and hepatocellular cancer and shows good clinical activity in thyroid cancer. Multiple clinical trials are undertaken to further investigate the role of sorafenib alone or in combination for the treatment of various tumor entities.

Formestane, a steroidal aromatase inhibitor after failure of non-steroidal aromatase inhibitors (anastrozole and letrozole): is a clinical benefit still achievable?

PubMed

Carlini, P; Frassoldati, A; De Marco, S; Casali, A; Ruggeri, E M; Nardi, M; Papaldo, P; Fabi, A; Paoloni, F; Cognetti, F

2001-11-01

There are few clinical data on the sequential use of aromatase inhibitors (AI). This paper focuses on the relevance of clinical benefit CB (CR + PR + SD > or = 6 months) in postmenopausal metastatic breast cancer (MBC) patients treated with the steroidal aromatase inhibitor (SAI) formestane (FOR). who had already received non-steroidal aromatase inhibitor (nSAI): letrozole (LTZ) or anastrozole (ANZ). Twenty postmenopausal women with MBC were analysed in this retrospective two-centre study with the sequence nSAI-FOR. When receiving ANZ, 1 of 11 achieved a complete response and 9 of 11 a stable disease > or = 6 months, and receiving LTZ 1 of 9 achieved a partial response and 4 of 9 a stable disease > or = 6 months. The analysis of the entire population treated with FOR showed an overall CB of 55% (11 of 20) with a median duration of 15 months and median time to progression (TTP) of 6 months. Formestane 250 mg once bi-weekly seems to be an attractive alternative third-line hormonal therapy for the treatment of patients with MBC, previously treated with nSAI.

STS-98 payload U.S. Lab Destiny is moved into Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Technicians in the Payload Changeout Room work to secure the U.S. Lab Destiny in the orbiter'''s payload bay. The PCR is the enclosed, environmentally controlled portion of the rotating service structure that supports payload delivery at the launch pad and vertical installation in the orbiter payload bay. Destiny, a key element in the construction of the International Space Station, is 28 feet long and weighs 16 tons. This research and command-and- control center is the most sophisticated and versatile space laboratory ever built. It will ultimately house a total of 23 experiment racks for crew support and scientific research. STS-98 is the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

Assessment of estuarine water-quality indicators using MODIS medium-resolution bands: initial results from Tampa Bay, FL

USGS Publications Warehouse

Hu, Chuanmin; Chen, Zhiqiang; Clayton, Tonya D.; ,; Brock, John C.; Muller-Karger, Frank E.

2004-01-01

Using Tampa Bay, FL as an example, we explored the potential for using MODIS medium-resolution bands (250- and 500-m data at 469-, 555-, and 645-nm) for estuarine monitoring. Field surveys during 21–22 October 2003 showed that Tampa Bay has Case-II waters, in that for the salinity range of 24–32 psu, (a) chlorophyll concentration (11 to 23 mg m−3), (b) colored dissolved organic matter (CDOM) absorption coefficient at 400 nm (0.9 to 2.5 m−1), and (c) total suspended sediment concentration (TSS: 2 to 11 mg L−1) often do not co-vary. CDOM is the only constituent that showed a linear, inverse relationship with surface salinity, although the slope of the relationship changed with location within the bay. The MODIS medium-resolution bands, although designed for land use, are 4–5 times more sensitive than Landsat-7/ETM+ data and are comparable to or higher than those of CZCS. Several approaches were used to derive synoptic maps of water constituents from concurrent MODIS medium-resolution data. We found that application of various atmospheric-correction algorithms yielded no significant differences, due primarily to uncertainties in the sensor radiometric calibration and other sensor artifacts. However, where each scene could be groundtruthed, simple regressions between in situ observations of constituents and at-sensor radiances provided reasonable synoptic maps. We address the need for improvements of sensor calibration/characterization, atmospheric correction, and bio-optical algorithms to make operational and quantitative use of these medium-resolution bands.

Elevated hepatic 11β-hydroxysteroid dehydrogenase type 1 induces insulin resistance in uremia

PubMed Central

Chapagain, Ananda; Caton, Paul W.; Kieswich, Julius; Andrikopoulos, Petros; Nayuni, Nanda; Long, Jamie H.; Harwood, Steven M.; Webster, Scott P.; Raftery, Martin J.; Thiemermann, Christoph; Walker, Brian R.; Seckl, Jonathan R.; Corder, Roger; Yaqoob, Muhammad Magdi

2014-01-01

Insulin resistance and associated metabolic sequelae are common in chronic kidney disease (CKD) and are positively and independently associated with increased cardiovascular mortality. However, the pathogenesis has yet to be fully elucidated. 11β-Hydroxysteroid dehydrogenase type 1 (11βHSD1) catalyzes intracellular regeneration of active glucocorticoids, promoting insulin resistance in liver and other metabolic tissues. Using two experimental rat models of CKD (subtotal nephrectomy and adenine diet) which show early insulin resistance, we found that 11βHSD1 mRNA and protein increase in hepatic and adipose tissue, together with increased hepatic 11βHSD1 activity. This was associated with intrahepatic but not circulating glucocorticoid excess, and increased hepatic gluconeogenesis and lipogenesis. Oral administration of the 11βHSD inhibitor carbenoxolone to uremic rats for 2 wk improved glucose tolerance and insulin sensitivity, improved insulin signaling, and reduced hepatic expression of gluconeogenic and lipogenic genes. Furthermore, 11βHSD1−/− mice and rats treated with a specific 11βHSD1 inhibitor (UE2316) were protected from metabolic disturbances despite similar renal dysfunction following adenine experimental uremia. Therefore, we demonstrate that elevated hepatic 11βHSD1 is an important contributor to early insulin resistance and dyslipidemia in uremia. Specific 11βHSD1 inhibitors potentially represent a novel therapeutic approach for management of insulin resistance in patients with CKD. PMID:24569863

Ferrocene labelings as inhibitors and dual electrochemical sensors of human glutathione S-transferase P1-1.

PubMed

Martos-Maldonado, Manuel C; Quesada-Soriano, Indalecio; García-Maroto, Federico; Vargas-Berenguel, Antonio; García-Fuentes, Luís

2012-12-01

The inhibitory and sensor properties of two ferrocene conjugates, in which the ferrocene and glutathione are linked through a spacer arm of different length and chemical structure, on human Pi glutathione S-transferase, were examined by activity assays, ITC, fluorescence spectroscopy and voltammetry. Such ferrocene conjugates are strong competitive inhibitors of this enzyme with an enhanced binding affinity, the one bearing the longest spacer arm being the most potent inhibitor. Voltammetric measurements showed a strong decrease of the peak current intensity and an increase of the oxidation potential upon binding of ferrocene-glutathione conjugates to GST P1-1 showing that both conjugates can be used as dual electrochemical sensors for GST P1-1. Copyright © 2012 Elsevier Ltd. All rights reserved.

Radiocarbon chronology of the last deglaciation in the Baffin Bay reveals asynchronous melting of Arctic and Laurentide ice sheets

NASA Astrophysics Data System (ADS)

Jackson, Rebecca; Kucera, Michal; Vogt, Christoph; Wacker, Lukas

2016-04-01

The transition from the last ice age into the Holocene interglacial was characterised by rapid retreat of North American ice sheets, discharging large quantities of meltwater into the Labrador Sea. Whereas the meltwater chronology of the Laurentide Ice Sheet is well documented, the deglacial history of the American Arctic ice sheets (Inuit Ice sheet and northern Greenland Ice Sheet) draining into the Labrador Sea via the Baffin Bay is less well constrained. Here we present the first high-resolution radiocarbon-dated deglacial records from the Canadian and Greenland margins of the central Baffin Bay. Sedimentological and geochemical data confirm the presence during Termination I of two events of enhanced delivery of detrital carbonate (Baffin Bay Detrital Carbonate Events) dated to 14.2-13.7 ka BP and 12.7-11 ka BP. The events are synchronous across the Baffin Bay and their mineralogical signature indicates a common source of detrital carbonate from the Canadian Arctic, with a synchronous clastic source proximal to Greenland. The events postdate Heinrich layers and their onset is not linked to Greenland temperature change. This indicates that the deglaciation of American Arctic ice sheets and associated meltwater discharge were decoupled from the dominant North Atlantic climate mode.

Development of the beliefs about yoga scale.

PubMed

Sohl, Stephanie J; Schnur, Julie B; Daly, Leslie; Suslov, Kathryn; Montgomery, Guy H

2011-01-01

Beliefs about yoga may influence participation in yoga and outcomes of yoga interventions. There is currently no scale appropriate for assessing these beliefs in the general U.S. population. This study took the first steps in developing and validating a Beliefs About Yoga Scale (BAYS) to assess beliefs about yoga that may influence people's engagement in yoga interventions. Items were generated based on previously published research about perceptions of yoga and reviewed by experts within the psychology and yoga communities. 426 adult participants were recruited from an urban medical center to respond to these items. The mean age was 40.7 (SD=13.5) years. Participants completed the BAYS and seven additional indicators of criterion-related validity. The BAYS demonstrated internal consistency (11 items; α=0.76) and three factors emerged: expected health benefits, expected discomfort, and expected social norms. The factor structure was confirmed: x2 (41, n=213)=72.06, p<.001; RMSEA=06, p=.23. Criterion-related validity was supported by positive associations of the BAYS with past experiences and future intentions related to yoga. This initial analysis of the BAYS demonstrated that it is an adequately reliable and valid measure of beliefs about yoga with a three-factor structure. However, the scale may need to be modified based on the population to which it is applied.

KSC-99pp1369

NASA Image and Video Library

1999-11-29

KENNEDY SPACE CENTER, FLA. -- Viewed end to end, the interior of orbiter Endeavour's payload bay can be seen with its cargo (center and right) in place, before the close of its payload bay doors. The Ku-band antenna (lower right) is now in its closed position inside the payload bay. Endeavour is expected to roll over to the Vehicle Assembly Building in three days for mating to the external tank and solid rocket boosters in high bay 1. Space Shuttle Endeavour is targeted for launch on mission STS-99 Jan. 13, 2000 at 1:11 p.m. EST. STS-99 is the Shuttle Radar Topography Mission, an international project spearheaded by the National Imagery and Mapping Agency and NASA, with participation of the German Aerospace Center DLR. The SRTM consists of a specially modified radar system that will gather data for the most accurate and complete topographic map of the Earth's surface that has ever been assembled. SRTM will make use of radar interferometry, wherein two radar images are taken from slightly different locations. Differences between these images allow for the calculation of surface elevation, or change. The SRTM hardware will consist of one radar antenna in the shuttle payload bay and a second radar antenna attached to the end of a mast extended 60 meters (195 feet) out from the shuttle

A Bayesian framework based on a Gaussian mixture model and radial-basis-function Fisher discriminant analysis (BayGmmKda V1.1) for spatial prediction of floods

NASA Astrophysics Data System (ADS)

Tien Bui, Dieu; Hoang, Nhat-Duc

2017-09-01

In this study, a probabilistic model, named as BayGmmKda, is proposed for flood susceptibility assessment in a study area in central Vietnam. The new model is a Bayesian framework constructed by a combination of a Gaussian mixture model (GMM), radial-basis-function Fisher discriminant analysis (RBFDA), and a geographic information system (GIS) database. In the Bayesian framework, GMM is used for modeling the data distribution of flood-influencing factors in the GIS database, whereas RBFDA is utilized to construct a latent variable that aims at enhancing the model performance. As a result, the posterior probabilistic output of the BayGmmKda model is used as flood susceptibility index. Experiment results showed that the proposed hybrid framework is superior to other benchmark models, including the adaptive neuro-fuzzy inference system and the support vector machine. To facilitate the model implementation, a software program of BayGmmKda has been developed in MATLAB. The BayGmmKda program can accurately establish a flood susceptibility map for the study region. Accordingly, local authorities can overlay this susceptibility map onto various land-use maps for the purpose of land-use planning or management.

Water-Rock Interactions in the Peridotite Aquifer of the Oman-UAE Ophiolite: Strontium Isotopic Ratio and Geochemical Evolution of Groundwater

NASA Astrophysics Data System (ADS)

Bompard, Nicolas; Matter, Juerg; Teagle, Damon

2016-04-01

The peridotite aquifer in Wadi Tayin, Sultanate of Oman, is a perfect example of natural carbonation of ultramafic rocks. In situ mineral carbonation is considered the most safest and permanent option of CO2 Capture and Sequestration (CCS). However, the process itself is yet to be characterised and a better understanding of the mechanisms involved in natural mineral carbonation is needed before geo-engineering it. We used the 87Sr/86Sr system to follow the water-rock interactions along the groundwater flowpath in the peridotite aquifer and to determine the sources of divalent cations (Mg2+, Ca2+) required for mineral carbonation. The Sr-isotope data of groundwater show that the aquifer rocks are the main source for divalent cations (Mg2+, Ca2+ and Sr2+) and secondary carbonates are their main sink. The groundwater 87Sr/86Sr ratio evolves with its pH: from 87Sr/86Sr = 0.7087 (n=3) to 0.7082 (n=8) between pH 7 and 8, and from 0.7086 (n=6) at pH 9 to 0.07075 (n=9) at pH 11. This evolution seems to support a two-step model for the water-rock interactions in the peridotite aquifer. From pH 7 to 8, secondary Ca-carbonate precipitation buffers the pH rise resulting from peridotite serpentinisation. From pH 9 to 11, peridotite serpentinisation drives the pH to alkaline condition. The change from a Mg-rich to a Ca-rich groundwater at pH 9 seems to confirm the two-step model.

[An integrated assessment method of ecological quality status in coastal waters: taking Tong'an Bay as a case].

PubMed

Chen, Zhao-hua; Wu, Hai-yan; Chen, Ke-liang; Chen, Qing-hui; Wu, Ji-chun; Zhang, Jing-fei

2011-07-01

Based on the integrated assessment methods of ecological quality status (EcoQS) in coastal waters abroad as well as the domestic related research status, 11 indices were selected from the biotic and physicochemical elements of water and sediment to built an integrated EcoQS assessment index system, and, with the comprehensive consideration of domestic and international evaluation standards, 5 levels of EcoQS classified as "high, good, moderate, poor, and bad" were determined. Then, an integrated assessment method of EcoQS in coastal waters was established by using analytic hierarchy process (AHP) and fuzzy mathematics method, and tested by the analysis of the correlations between the EcoQS grade and the major anthropogenic disturbances and pollutant concentrations of Tong' an Bay. The EcoQS of Tong' an Bay was assessed as moderate, i.e., the Bay was moderately disturbed and in transitional to poor status. The established integrated assessment method could not only reflect the major anthropogenic environmental pressure and risk factors, but also give an early warning of the pollutants satisfied by law in the study area.

Metagenomic characterization of viral communities in Goseong Bay, Korea

NASA Astrophysics Data System (ADS)

Hwang, Jinik; Park, So Yun; Park, Mirye; Lee, Sukchan; Jo, Yeonhwa; Cho, Won Kyong; Lee, Taek-Kyun

2016-12-01

In this study, seawater samples were collected from Goseong Bay, Korea in March 2014 and viral populations were examined by metagenomics assembly. Enrichment of marine viral particles using FeCl3 followed by next-generation sequencing produced numerous sequences. De novo assembly and BLAST search showed that most of the obtained contigs were unknown sequences and only 0.74% of sequences were associated with known viruses. As a result, 138 viruses, including bacteriophages (87%), viruses infecting algae and others (13%) were identified. The identified 138 viruses were divided into 11 orders, 14 families, 34 genera, and 133 species. The dominant viruses were Pelagibacter phage HTVC010P and Roseobacter phage SIO1. The viruses infecting algae, including the Ostreococcus species, accounted for 9.4% of total identified viruses. In addition, we identified pathogenic herpes viruses infecting fishes and giant viruses infecting parasitic acanthamoeba species. This is a comprehensive study to reveal the viral populations in the Goseong Bay using metagenomics. The information associated with the marine viral community in Goseong Bay, Korea will be useful for comparative analysis in other marine viral communities.

Urban rivers as conveyors of hydrocarbons to sediments of estuarine areas: source characterization, flow rates and mass accumulation.

PubMed

Mauad, Cristiane R; Wagener, Angela de L R; Massone, Carlos G; Aniceto, Mayara da S; Lazzari, Letícia; Carreira, Renato S; Farias, Cássia de O

2015-02-15

Aliphatic (n-C12-n-C40, unresolved complex mixture, resolved peaks) and aromatic hydrocarbons (46 PAH) were investigated in suspended particulate matter (SPM) sampled over eleven months in six of the major rivers and two channels of the Guanabara Bay Basin. PAH flow rates of the most contaminated rivers, the contribution to the PAH sediment load of the receiving bay, and the main sources of hydrocarbons were determined. PAH (38) ranged from 28 ng L(-1) to 11,514 ng L(-1). Hydrocarbon typology and statistical evaluation demonstrated contribution of distinct sources in different regions and allowed quantification of these contributions. Total flow rate for the five major rivers amounts to 3 t year(-1) and responds for 30% of the total PAH annual input into the northern area of the Guanabara Bay. For the first time PAH mass deposited in the bay sediments has been estimated and shall serve as base for decision making and source abatement. Copyright © 2014 Elsevier B.V. All rights reserved.

Annual cycle of zooplankton abundance and species composition in Izmit Bay (the northeastern Marmara Sea)

NASA Astrophysics Data System (ADS)

Isinibilir, Melek; Kideys, Ahmet E.; Tarkan, Ahmet N.; Yilmaz, I. Noyan

2008-07-01

The monthly abundance, biomass and taxonomic composition of zooplankton of Izmit Bay (the northeastern Marmara Sea) were studied from October 2001 to September 2002. Most species within the zooplankton community displayed a clear pattern of succession throughout the year. Generally copepods and cladocerans were the most abundant groups, while the contribution of meroplankton increased at inner-most stations and dominated the zooplankton. Both species number ( S) and diversity ( H') were positively influenced by the increase in salinity of upper layers ( r = 0.30 and r = 0.31, p < 0.001, respectively), while chlorophyll a was negatively affected ( r = -0.36, p < 0.001). Even though Noctiluca scintillans had a significant seasonality ( F11,120 = 8.45, p < 0.001, ANOVA), abundance was not related to fluctuations in temperature and only chlorophyll a was adversely correlated ( r = -0.35, p < 0.001). In general, there are some minor differences in zooplankton assemblages of upper and lower layers. A comparison of the species composition and abundance of Izmit Bay with other Black Sea bays reveals a high similarity between them.

Comparison of sediment supply to San Francisco Bay from watersheds draining the Bay Area and the Central Valley of California

USGS Publications Warehouse

McKee, L.J.; Lewicki, M.; Schoellhamer, D.H.; Ganju, N.K.

2013-01-01

Quantifying suspended sediment loads is important for managing the world's estuaries in the context of navigation, pollutant transport, wetland restoration, and coastal erosion. To address these needs, a comprehensive analysis was completed on sediment supply to San Francisco Bay from fluvial sources. Suspended sediment, optical backscatter, velocity data near the head of the estuary, and discharge data obtained from the output of a water balance model were used to generate continuous suspended sediment concentration records and compute loads to the Bay from the large Central Valley watershed. Sediment loads from small tributary watersheds around the Bay were determined using 235 station-years of suspended sediment data from 38 watershed locations, regression analysis, and simple modeling. Over 16 years, net annual suspended sediment load to the head of the estuary from its 154,000 km2 Central Valley watershed varied from 0.13 to 2.58 (mean = 0.89) million metric t of suspended sediment, or an average yield of 11 metric t/km2/yr. Small tributaries, totaling 8145 km2, in the nine-county Bay Area discharged between 0.081 and 4.27 (mean = 1.39) million metric t with a mean yield of 212 metric t/km2/yr. The results indicate that the hundreds of urbanized and tectonically active tributaries adjacent to the Bay, which together account for just 5% of the total watershed area draining to the Bay and provide just 7% of the annual average fluvial flow, supply 61% of the suspended sediment. The small tributary loads are more variable (53-fold between years compared to 21-fold for the inland Central Valley rivers) and dominated fluvial sediment supply to the Bay during 10 out of 16 yr. If San Francisco Bay is typical of other estuaries in active tectonic or climatically variable coastal regimes, managers responsible for water quality, dredging and reusing sediment accumulating in shipping channels, or restoring wetlands in the world's estuaries may need to more carefully account for proximal small urbanized watersheds that may dominate sediment supply.

Phosphate oxygen isotope ratios as a tracer for sources and cycling of phosphate in North San Francisco Bay, California

USGS Publications Warehouse

McLaughlin, K.; Kendall, C.; Silva, S.R.; Young, M.; Paytan, A.

2006-01-01

A seasonal analysis assesing variations in the oxygen isotopic composition of dissolved inorganic phosphate (DIP) was conducted in the San Francisco Bay estuarine system, California. Isotopic fractionation of oxygen in DIP (exchange of oxygen between phosphate and environmental water) at surface water temperatures occurs only as a result of enzyme-mediated, biological reactions. Accordingly, if phospate demand is low relative to input and phosphate is not heavily cycled in the ecosystem, the oxygen isotopic composition of DIP (?? 18Op) will reflect the isotopic composition of the source of phosphate to the system. Such is the case for the North San Francisco Bay, an anthropogenically impacted estuary with high surface water phosphate concentrations. Variability in the ?? 18Op in the bay is primarily controlled by mixing of water masses with different ??18Op signatures. The ??18Op values range from 11.4??? at the Sacramento River to 20.1??? at the Golden Gate. Deviations from the two-component mixing model for the North Bay reflect additional, local sources of phosphate to the estuary that vary seasonally. Most notably, deviations from the mixing model occur at the confluence of a major river into the bay during periods of high river discharge and near wastewater treatment outlets. These data suggest that ??18Op can be an effective tool for identifying P point sources and understanding phosphate dynamics in estuarine systems. Copyright 2006 by the American Geophysical Union.

STS-114 Flight Day 11 Highlights

NASA Technical Reports Server (NTRS)

2005-01-01

Flight Day 11 begins with the STS-114 crew of Space Shuttle Discovery (Commander Eileen Collins, Pilot James Kelly, Mission Specialists Soichi Noguchi, Stephen Robinson, Andrew Thomas, Wendy Lawrence, and Charles Camarda) awaking to "Anchors Away," to signify the undocking of the Raffaello Multipurpose Logistics Module (MPLM) from the International Space Station (ISS). Canadarm 2, the Space Station Remote Manipulator System (SSRMS), retrieves the Raffaello Multipurpose Logistics Module (MPLM) from the nadir port of the Unity node of the ISS and returns it to Discovery's payload bay. The Shuttle Remote Manipulator System (SRMS) hands the Orbiter Boom Sensor System (OBSS) to its counterpart, the SSRMS, for rebearthing in the payload bay as well. The rebearthing of the OBSS is shown in detail, including centerline and split-screen views. Collins sends a message to her husband, and talks with Representative Tom DeLay (R-TX). Earth views include the Amalfi coast of Italy. The ISS control room bids farewell to the STS-114 crew and the Expedition 11 crew (Commander Sergei Krikalev and NASA ISS Science Officer and Flight Engineer John Phillips) of the ISS.

Activation of AKT1/GSK-3β/β-Catenin-TRIM11/Survivin Pathway by Novel GSK-3β Inhibitor Promotes Neuron Cell Survival: Study in Differentiated SH-SY5Y Cells in OGD Model.

PubMed

Darshit, B S; Ramanathan, M

2016-12-01

The objective of this study is to elucidate the effect of a new glycogen synthase kinase-3β (GSK-3β) inhibitor in RA differentiated SH-SY5Y cells in oxygen and glucose deprivation (OGD) model. The pathway involved in GSK-3β signaling during OGD was measured to elucidate the mechanism of action. The differentiation of SH-SY5Y into mature neuronal cells was done with retinoic acid. During differentiation, upregulation of the growth-associated protein 43 (GAP43), neurogenin1 (NGN1), neuronal differentiation 2 (NeuroD2), and tripartite motif containing 11 (TRIM11) genes were observed. Twelve hours of optimal OGD exposure resulted in the alteration of GSK-3β functions of the neuron cells. Of the five molecules selected for this study, molecule G3 showed better effect in the initial phase of the study. Hence, G3 (0.5, 1, and 5 μM) was selected for further study in the OGD model. The standard GSK-3β inhibitor, AR-A014418 (1 μM), was used for comparison. Molecules were pretreated (30 min) and cotreated during OGD exposure. GSK-3β inhibitors showed antiapoptotic activity as evidenced by reduced caspase-3 enzyme activity and increased survivin transcription, as well as improved membrane integrity, evidenced by LDH assay. The inhibitor molecules also up-regulated survival AKT1/GSK-3β/β-catenin pathway and stabilized β-catenin. Inhibition of GSK-3β maintained neuronal survival by upregulating GAP43, Ngn1, and NeuroD2 gene transcription. Further GSK-3β inhibition reduced the TRIM11 gene transcription. In conclusion, both inhibitors have been found to control apoptosis and maintain neuronal functioning and this effect might have been mediated through AKT1/GSK-3β/β-catenin-TRIM11/survivin pathway.

STS-98 U.S. Lab Destiny rests in Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- The U.S. Lab Destiny rests in the payload bay of Space Shuttle Atlantis. A key element in the construction of the International Space Station, Destiny is 28 feet long and weighs 16 tons. This research and command-and-control center is the most sophisticated and versatile space laboratory ever built. It will ultimately house a total of 23 experiment racks for crew support and scientific research. Destiny will fly on STS-98, the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

Plastic litter in sediments from the Croatian marine protected area of the natural park of Telaščica bay (Adriatic Sea).

PubMed

Blašković, Andrea; Fastelli, Paolo; Čižmek, Hrvoje; Guerranti, Cristiana; Renzi, Monia

2017-01-15

This paper reports baseline levels of litter (macro, meso and microplastics) in sediments collected from different areas of the Croatian MPA of the Natural Park of Telaščica bay (Adriatic Sea, GSA n. 17). The distribution of total abundance according to size, for all analysed locations evidences that microplastics are the dominant fraction concerning item's numbers. In all analysed samples no macroplastics were found, while microplastics are 88.71% and mesoplastics are 11.29% of the total. Copyright © 2016 Elsevier Ltd. All rights reserved.

Contents of payload bay of the STS-68 Space Shuttle Endeavour

NASA Image and Video Library

1994-09-30

STS068-267-079 (30 September-11 October 1994) --- The rear windows of the Space Shuttle Endeavour reflect sunlight in this view of part of the cargo bay, 115 nautical miles above the Earth. The Space Radar Laboratory (SRL-2) Multipurpose Experiment Support Structure (MPESS) is seen at bottom frame. Also partially seen are other experiments including other components of the primary payload. They are the antenna for the Spaceborne Imaging Radar (SIR-C), the X-band Synthetic Aperture Radar (X-SAR), the device for Measurement of Air Pollution from Satellites (MAPS) and some Getaway Special (GAS) canisters.

Contents of payload bay of the STS-68 Space Shuttle Endeavour

NASA Image and Video Library

1994-09-30

STS068-272-075 (30 September-11 October 1994) --- The darkness of space forms the backdrop for this scene of the Space Shuttle Endeavour's cargo bay, 115 nautical miles above a cloud covered Indian Ocean. The Space Radar Laboratory (SRL-2) Multipurpose Experiment Support Structure (MPESS) is seen at bottom frame. Also partially seen are other experiments including other components of the primary payload. They are the antenna for the Spaceborne Imaging Radar (SIR-C), the X-band Synthetic Aperture Radar (X-SAR), the device for Measurement of Air Pollution from Satellites (MAPS) and some Getaway Special (GAS) canisters.

KSC-07pd2825

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors are closed around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton

KSC-07pd2824

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors are nearly closed around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton

KSC-07pd2820

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, preparations are under way to close space shuttle Discovery's payload bay doors around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton

KSC-07pd2823

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors slowly enclose the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton

KSC-07pd2822

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors are partially closed around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton

KSC-07pd2821

NASA Image and Video Library

2007-10-09

KENNEDY SPACE CENTER, FLA. -- At Launch Pad 39A, space shuttle Discovery's payload bay doors begin to close around the U.S. Node 2 module, named Harmony. The name was chosen from an academic competition involving more than 2,200 U. S. students in kindergarten through high school. The module will be delivered to the International Space Station aboard Discovery on the 14-day STS-120 mission. An orbiter's payload bay door closure at the pad is a milestone signaling that the launch date is near. Discovery's launch is targeted for Oct. 23 at 11:38 a.m. EDT. Photo credit: NASA/George Shelton

Lost lake - restoration of a Carolina bay

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hanlin, H.G.; McLendon, J.P.; Wike, L.D.

1994-09-01

Carolina bays are shallow wetland depressions found only on the Atlantic Coastal Plain. Although these isolated interstream wetlands support many types of communities, they share the common features of having a sandy margin, a fluctuating water level, an elliptical shape, and a northwest to southeast orientation. Lost Lake, an 11.3 hectare Carolina bay, was ditched and drained for agricultural production before establishment of the Savannah River Site in 1950. Later it received overflow from a seepage basin containing a variety of chemicals, primarily solvents and some heavy metals. In 1990 a plan was developed for the restoration of Lost Lake,more » and restoration activities were complete by mid-1991. Lost Lake is the first known project designed for the restoration and recovery of a Carolina bay. The bay was divided into eight soil treatment zones, allowing four treatments in duplicate. Each of the eight zones was planted with eight species of native wetland plants. Recolonization of the bay by amphibians and reptiles is being evaluated by using drift fences with pitfall traps and coverboard arrays in each of the treatment zones. Additional drift fences in five upland habitats were also established. Hoop turtle traps, funnel minnow traps, and dip nets were utilized for aquatic sampling. The presence of 43 species common to the region has been documented at Lost Lake. More than one-third of these species show evidence of breeding populations being established. Three species found prior to the restoration activity and a number of species common to undisturbed Carolina bays were not encountered. Colonization by additional species is anticipated as the wetland undergoes further succession.« less

A computer model of long-term salinity in San Francisco Bay: Sensitivity to mixing and inflows

USGS Publications Warehouse

Uncles, R.J.; Peterson, D.H.

1995-01-01

A two-level model of the residual circulation and tidally-averaged salinity in San Francisco Bay has been developed in order to interpret long-term (days to decades) salinity variability in the Bay. Applications of the model to biogeochemical studies are also envisaged. The model has been used to simulate daily-averaged salinity in the upper and lower levels of a 51-segment discretization of the Bay over the 22-y period 1967–1988. Observed, monthly-averaged surface salinity data and monthly averages of the daily-simulated salinity are in reasonable agreement, both near the Golden Gate and in the upper reaches, close to the delta. Agreement is less satisfactory in the central reaches of North Bay, in the vicinity of Carquinez Strait. Comparison of daily-averaged data at Station 5 (Pittsburg, in the upper North Bay) with modeled data indicates close agreement with a correlation coefficient of 0.97 for the 4110 daily values. The model successfully simulates the marked seasonal variability in salinity as well as the effects of rapidly changing freshwater inflows. Salinity variability is driven primarily by freshwater inflow. The sensitivity of the modeled salinity to variations in the longitudinal mixing coefficients is investigated. The modeled salinity is relatively insensitive to the calibration factor for vertical mixing and relatively sensitive to the calibration factor for longitudinal mixing. The optimum value of the longitudinal calibration factor is 1.1, compared with the physically-based value of 1.0. Linear time-series analysis indicates that the observed and dynamically-modeled salinity-inflow responses are in good agreement in the lower reaches of the Bay.

mTOR inhibitors blunt the p53 response to nucleolar stress by regulating RPL11 and MDM2 levels

PubMed Central

Goudarzi, Kaveh M; Nistér, Monica; Lindström, Mikael S

2014-01-01

Mechanistic target of rapamycin (mTOR) is a master regulator of cell growth through its ability to stimulate ribosome biogenesis and mRNA translation. In contrast, the p53 tumor suppressor negatively controls cell growth and is activated by a wide range of insults to the cell. The mTOR and p53 signaling pathways are connected by a number of different mechanisms. Chemotherapeutics that inhibit ribosome biogenesis often induce nucleolar stress and activation of p53. Here we have investigated how the p53 response to nucleolar stress is affected by simultaneous mTOR inhibition in osteosarcoma and glioma cell lines. We found that inhibitors of the mTOR pathway including rapamycin, wortmannin, and caffeine blunted the p53 response to nucleolar stress induced by actinomycin D. Synthetic inhibitors of mTOR (temsirolimus, LY294.002 and PP242) also impaired actinomycin D triggered p53 stabilization and induction of p21. Ribosomal protein (RPL11) is known to be required for p53 protein stabilization following nucleolar stress. Treatment of cells with mTOR inhibitors may lead to reduced synthesis of RPL11 and thereby destabilize p53. We found that rapamycin mimicked the effect of RPL11 depletion in terms of blunting the p53 response to nucleolar stress. However, the extent to which the levels of p53 and RPL11 were reduced by rapamycin varied between cell lines. Additional mechanisms whereby rapamycin blunts the p53 response to nucleolar stress are likely to be involved. Indeed, rapamycin increased the levels of endogenous MDM2 despite inhibition of its phosphorylation at Ser-166. Our findings may have implications for the design of combinatorial cancer treatments with mTOR pathway inhibitors. PMID:25482947

Direct sGC Activation Bypasses NO Scavenging Reactions of Intravascular Free Oxy-Hemoglobin and Limits Vasoconstriction

PubMed Central

Tabima, D. Marcela; Specht, Patricia A.C.; Tejero, Jesús; Champion, Hunter C.; Kim-Shapiro, Daniel B.; Baust, Jeff; Mik, Egbert G.; Hildesheim, Mariana; Stasch, Johannes-Peter; Becker, Eva-Maria; Truebel, Hubert

2013-01-01

Abstract Aims: Hemoglobin-based oxygen carriers (HBOC) provide a potential alternative to red blood cell (RBC) transfusion. Their clinical application has been limited by adverse effects, in large part thought to be mediated by the intravascular scavenging of the vasodilator nitric oxide (NO) by cell-free plasma oxy-hemoglobin. Free hemoglobin may also cause endothelial dysfunction and platelet activation in hemolytic diseases and after transfusion of aged stored RBCs. The new soluble guanylate cyclase (sGC) stimulator Bay 41-8543 and sGC activator Bay 60-2770 directly modulate sGC, independent of NO bioavailability, providing a potential therapeutic mechanism to bypass hemoglobin-mediated NO inactivation. Results: Infusions of human hemoglobin solutions and the HBOC Oxyglobin into rats produced a severe hypertensive response, even at low plasma heme concentrations approaching 10 μM. These reactions were only observed for ferrous oxy-hemoglobin and not analogs that do not rapidly scavenge NO. Infusions of L-NG-Nitroarginine methyl ester (L-NAME), a competitive NO synthase inhibitor, after hemoglobin infusion did not produce additive vasoconstriction, suggesting that vasoconstriction is related to scavenging of vascular NO. Open-chest hemodynamic studies confirmed that hypertension occurred secondary to direct effects on increasing vascular resistance, with limited negative cardiac inotropic effects. Intravascular hemoglobin reduced the vasodilatory potency of sodium nitroprusside (SNP) and sildenafil, but had no effect on vasodilatation by direct NO-independent activation of sGC by BAY 41-8543 and BAY 60-2770. Innovation and Conclusion: These data suggest that both sGC stimulators and sGC activators could be used to restore cyclic guanosine monophosphate-dependent vasodilation in conditions where cell-free plasma hemoglobin is sufficient to inhibit endogenous NO signaling. Antioxid. Redox Signal. 19, 2232–2243. PMID:23697678

Molecular determinants of melanoma malignancy: selecting targets for improved efficacy of chemotherapy

PubMed Central

Yang, Jinming; Zaja-Milatovic, Snjezana; Thu, Yee-Mon; Lee, Francis; Smykla, Richard; Richmond, Ann

2011-01-01

The BRAFV600E mutation is common in human melano-ma. This mutation enhances IκB kinase (IKK)/nuclear factor-κB (NF-κB) and extracellular signal-regulated kinase/activator protein signaling cascades. In this study, we evaluated the efficacy of targeting either B-Raf or IKKβ in combination with the DNA alkylating agent temozolomide for treatment of advanced metastatic melanoma. Xenografts of Hs294T human metastatic melanoma cells exhibiting the BRAFV600E mutation were treated with inhibitors of IKKβ (BMS-345541), B-Raf (BAY 54–9085), and/or temozolomide. Drug response was mechanistically analyzed in vitro and in vivo. In this study, we determined that the antitumor activity of all three drugs depends on inhibition of NF-κB. BMS-345541 inhibits IKKβ-mediated phosphorylation of IκBα and thus blocks the nuclear localization of NF-κB, whereas BAY 54–9085 inhibits activation of NF-κB through a mechanism that does not involve stabilization of IκBα. Moreover, BMS-345541, but not BAY 54–9085, activates the death pathways of p53 and c-Jun-NH2-kinase, contributing to the killing of melanoma cells. Temozolomide inhibits both NF-κB and extracellular signal-regulated kinase activity, conferring effective in vivo antitumor activity. Thus, temozolomide, but not BAY 54–9085, has a synergistic in vivo antitumor effect with BMS-345541. We conclude that the efficacy of antimelanoma therapy depends on inhibition of expression of antiapoptotic genes transcriptionally regulated by NF-κB. In contrast, drug targeting of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway alone in melanoma cells is ineffective for melanoma therapy in cases where NF-κB is not also targeted. PMID:19276165

Off-label use of TNF-alpha inhibitors in a dermatological university department: retrospective evaluation of 118 patients.

PubMed

Sand, Freja Lærke; Thomsen, Simon Francis

2015-01-01

Tumor necrosis factor-alpha (TNF)-alpha inhibitors are licensed for patients with severe refractory psoriasis and psoriatic arthritis. However, TNF-alpha inhibitors have also been used off-label for various recalcitrant mucocutaneous diseases. This study aimed to evaluate the efficacy and safety of TNF-alpha inhibitors used for off-label dermatological indications. We retrospectively evaluated patient records of 118 patients treated off-label with TNF-alpha inhibitors in a dermatological university department. Patients presented with severe aphthous stomatitis/genital aphthous lesions (26), chronic urticaria (25), hidradenitis suppurativa (29), acne conglobata (11), dissecting cellulitis of the scalp (two), orofacial granulomatosis (four), sarcoidosis (four), granuloma annulare (two), granulomatous rosacea (one), granuloma faciale (one), subcorneal pustulosis (one), pyoderma gangrenosum (four), Sweet's syndrome (four), Well's syndrome (one), benign familial pemphigus (one), lichen planus (one), and folliculitis decalvans (one). A significant number of these patients went into remission during therapy with TNF-alpha inhibitors. A total of 11 patients (9%) experienced severe adverse effects during therapy. Off-label therapy with TNF-alpha inhibitors may be considered for selected patients with severe recalcitrant mucocutaneous diseases. The risk of severe adverse effects signals that a thorough benefit-risk assessment should be performed before initiating off-label treatment with TNF-alpha inhibitors for these conditions. © 2015 Wiley Periodicals, Inc.

[Application of Bayes Probability Model in Differentiation of Yin and Yang Jaundice Syndromes in Neonates].

PubMed

Mu, Chun-sun; Zhang, Ping; Kong, Chun-yan; Li, Yang-ning

2015-09-01

To study the application of Bayes probability model in differentiating yin and yang jaundice syndromes in neonates. Totally 107 jaundice neonates who admitted to hospital within 10 days after birth were assigned to two groups according to syndrome differentiation, 68 in the yang jaundice syndrome group and 39 in the yin jaundice syndrome group. Data collected for neonates were factors related to jaundice before, during and after birth. Blood routines, liver and renal functions, and myocardial enzymes were tested on the admission day or the next day. Logistic regression model and Bayes discriminating analysis were used to screen factors important for yin and yang jaundice syndrome differentiation. Finally, Bayes probability model for yin and yang jaundice syndromes was established and assessed. Factors important for yin and yang jaundice syndrome differentiation screened by Logistic regression model and Bayes discriminating analysis included mothers' age, mother with gestational diabetes mellitus (GDM), gestational age, asphyxia, or ABO hemolytic diseases, red blood cell distribution width (RDW-SD), platelet-large cell ratio (P-LCR), serum direct bilirubin (DBIL), alkaline phosphatase (ALP), cholinesterase (CHE). Bayes discriminating analysis was performed by SPSS to obtain Bayes discriminant function coefficient. Bayes discriminant function was established according to discriminant function coefficients. Yang jaundice syndrome: y1= -21. 701 +2. 589 x mother's age + 1. 037 x GDM-17. 175 x asphyxia + 13. 876 x gestational age + 6. 303 x ABO hemolytic disease + 2.116 x RDW-SD + 0. 831 x DBIL + 0. 012 x ALP + 1. 697 x LCR + 0. 001 x CHE; Yin jaundice syndrome: y2= -33. 511 + 2.991 x mother's age + 3.960 x GDM-12. 877 x asphyxia + 11. 848 x gestational age + 1. 820 x ABO hemolytic disease +2. 231 x RDW-SD +0. 999 x DBIL +0. 023 x ALP +1. 916 x LCR +0. 002 x CHE. Bayes discriminant function was hypothesis tested and got Wilks' λ =0. 393 (P =0. 000). So Bayes discriminant function was proved to be with statistical difference. To check Bayes probability model in discriminating yin and yang jaundice syndromes, coincidence rates for yin and yang jaundice syndromes were both 90% plus. Yin and yang jaundice syndromes in neonates could be accurately judged by Bayesian discriminating functions.

Development of a Hydrodynamic and Transport model of Bellingham Bay in Support of Nearshore Habitat Restoration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Taiping; Yang, Zhaoqing; Khangaonkar, Tarang

2010-04-22

In this study, a hydrodynamic model based on the unstructured-grid finite volume coastal ocean model (FVCOM) was developed for Bellingham Bay, Washington. The model simulates water surface elevation, velocity, temperature, and salinity in a three-dimensional domain that covers the entire Bellingham Bay and adjacent water bodies, including Lummi Bay, Samish Bay, Padilla Bay, and Rosario Strait. The model was developed using Pacific Northwest National Laboratory’s high-resolution Puget Sound and Northwest Straits circulation and transport model. A sub-model grid for Bellingham Bay and adjacent coastal waters was extracted from the Puget Sound model and refined in Bellingham Bay using bathymetric lightmore » detection and ranging (LIDAR) and river channel cross-section data. The model uses tides, river inflows, and meteorological inputs to predict water surface elevations, currents, salinity, and temperature. A tidal open boundary condition was specified using standard National Oceanic and Atmospheric Administration (NOAA) predictions. Temperature and salinity open boundary conditions were specified based on observed data. Meteorological forcing (wind, solar radiation, and net surface heat flux) was obtained from NOAA real observations and National Center for Environmental Prediction North American Regional Analysis outputs. The model was run in parallel with 48 cores using a time step of 2.5 seconds. It took 18 hours of cpu time to complete 26 days of simulation. The model was calibrated with oceanographic field data for the period of 6/1/2009 to 6/26/2009. These data were collected specifically for the purpose of model development and calibration. They include time series of water-surface elevation, currents, temperature, and salinity as well as temperature and salinity profiles during instrument deployment and retrieval. Comparisons between model predictions and field observations show an overall reasonable agreement in both temporal and spatial scales. Comparisons of root mean square error values for surface elevation, velocity, temperature, and salinity time series are 0.11 m, 0.10 m/s, 1.28oC, and 1.91 ppt, respectively. The model was able to reproduce the salinity and temperature stratifications inside Bellingham Bay. Wetting and drying processes in tidal flats in Bellingham Bay, Samish Bay, and Padilla Bay were also successfully simulated. Both model results and observed data indicated that water surface elevations inside Bellingham Bay are highly correlated to tides. Circulation inside the bay is weak and complex and is affected by various forcing mechanisms, including tides, winds, freshwater inflows, and other local forcing factors. The Bellingham Bay model solution was successfully linked to the NOAA oil spill trajectory simulation model “General NOAA Operational Modeling Environment (GNOME).” Overall, the Bellingham Bay model has been calibrated reasonably well and can be used to provide detailed hydrodynamic information in the bay and adjacent water bodies. While there is room for further improvement with more available data, the calibrated hydrodynamic model provides useful hydrodynamic information in Bellingham Bay and can be used to support sediment transport and water quality modeling as well as assist in the design of nearshore restoration scenarios.« less

35. DETAIL OF COMPLETE APRONTOFLOAT LOCKING MECHANISM AND RAILS ON ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

35. DETAIL OF COMPLETE APRON-TO-FLOAT LOCKING MECHANISM AND RAILS ON BRIDGE NO. 11. LOOKING NORTH. - Greenville Yard, Transfer Bridge System, Port of New York/New Jersey, Upper New York Bay, Jersey City, Hudson County, NJ

9. LOADED CAR FLOAT AND TUG IN THE PROCESS OF ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

9. LOADED CAR FLOAT AND TUG IN THE PROCESS OF DOCKING AT BRIDGE NO. 11. LOOKING EAST. - Greenville Yard, Transfer Bridge System, Port of New York/New Jersey, Upper New York Bay, Jersey City, Hudson County, NJ

Mass Transit: Actions Needed for the BART Airport Extension

DOT National Transportation Integrated Search

1996-05-31

The Bay Area Rapid Transit District (BART) intends to spend over $1.1 billion, including $750 million in federal funds, to extend mass transit service to the San Francisco International Airport. The project is controversial, encountering both widespr...

75 FR 40798 - City of Seattle; Notice of Application Ready for Environmental Analysis and Soliciting Comments...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-14

...; (10) six horseshoe-shaped transformer bays; (11) six individual three-phase, 230-kilovolt (kV...-up transformer replacements. m. Locations of the Application: A copy of the application is available...

Clinical Features and Management of Acquired Resistance to PD-1 Axis Inhibitors in 26 Patients With Advanced Non-Small Cell Lung Cancer.

PubMed

Gettinger, Scott N; Wurtz, Anna; Goldberg, Sarah B; Rimm, David; Schalper, Kurt; Kaech, Susan; Kavathas, Paula; Chiang, Anne; Lilenbaum, Rogerio; Zelterman, Daniel; Politi, Katerina; Herbst, Roy S

2018-06-01

With expanding indications for programmed death 1 (PD-1) axis inhibitors in non-small cell lung cancer (NSCLC), acquired resistance (AR) to these therapies is increasingly being encountered. We sought to characterize clinical patterns of AR to PD-1 axis inhibitors in patients with advanced NSCLC, and evaluate subsequent outcome and management strategies for such patients. Patients with NSCLC who developed AR to PD-1 axis inhibitor therapy initiated between December 2009 and February 2016 at one institution were identified and examined by clinical and radiographic features. AR was defined as progressive disease after initial response by either Response Evaluation Criteria in Solid Tumors v1.1 or immune-related response criteria. Twenty-six patients with AR to PD-1 axis inhibitor therapy were identified and evaluated. Median time to AR was 313 days; the 2-year survival rate from AR was 70% (95% confidence interval: 0.53-0.92). Twenty patients (77%) experienced AR in lymph nodes (LNs), including 11 patients with LN-only progression. Twenty-three (88%) patients had recurrence limited to one (54%) or two (35%) sites of disease. Fourteen patients (54%) continued PD-1 axis inhibitor therapy beyond progression. Three patients were re-challenged with the same PD-1 axis inhibitor after holiday from and progression off therapy, 2 again responded. Fifteen patients (58%) received local therapy to site(s) of AR, 11 continued respective PD-1 axis inhibitor after local therapy. The 2-year survival rate from AR among these 15 patients was 92% (95% confidence interval: 0.77-1). Acquired resistance to PD-1 axis inhibitors is often limited to one or two sites when local therapy and continuation of PD-1 axis inhibitor therapy can result in prolonged benefit. LN metastases appear to be particularly susceptible sites to AR. When progression of disease following response occurs after holiday from PD-1 axis inhibitor, re-challenge can again lead to tumor regression. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Wind and tidal forcing of a buoyant plume, Mobile Bay, Alabama

USGS Publications Warehouse

Stumpf, R.P.; Gelfenbaum, G.; Pennock, J.R.

1993-01-01

AVHRR satellite imagery and in situ observations were combined to study the motion of a buoyant plume at the mouth of Mobile Bay, Alabama. The plume extended up to 30 km from shore, with a thickness of about 1 m. The inner plume, which was 3-8 m thick, moved between the Bay and inner shelf in response to tidal forcing. The tidal prism could be identified through the movement of plume waters between satellite images. The plume responded rapidly to alongshore wind, with sections of the plume moving at speeds of more than 70 cm s-1, about 11% of the wind speed. The plume moved predominantly in the direction of the wind with a weak Ekman drift. The enhanced speed of the plume relative to normal surface drift is probably due to the strong stratification in the plume, which limits the transfer of momentum into the underlying ambient waters. ?? 1993.

The microgravity environment of the Space Shuttle Columbia payload bay during STS-32

NASA Technical Reports Server (NTRS)

Dunbar, Bonnie J.; Giesecke, Robert L.; Thomas, Donald A.

1991-01-01

Over 11 hours of three-axis microgravity accelerometer data were successfully measured in the payload bay of Space Shuttle Columbia as part of the Microgravity Disturbances Experiment on STS-32. These data were measured using the High Resolution Accelerometer Package and the Aerodynamic Coefficient Identification Package which were mounted on the Orbiter keel in the aft payload bay. Data were recorded during specific mission events such as Orbiter quiescent periods, crew exercise on the treadmill, and numerous Orbiter engine burns. Orbiter background levels were measured in the 10(exp -5) G range, treadmill operations in the 10(exp -3) G range, and the Orbiter engine burns in the 10(exp -2) G range. Induced acceleration levels resulting from the SYNCOM satellite deploy were in the 10 (exp -2) G range, and operations during the pre-entry Flight Control System checkout were in the 10(exp -2) to 10(exp -1) G range.

Organic carbon balance and net ecosystem metabolism in Chesapeake Bay

USGS Publications Warehouse

Kemp, W.M.; Smith, E.M.; Marvin-DiPasquale, M.; Boynton, W.R.

1997-01-01

The major fluxes of organic carbon associated with physical transport and biological metabolism were compiled, analyzed and compared for the mainstem portion of Chesapeake Bay (USA). In addition, 5 independent methods were used to calculate the annual mean net ecosystem metabolism (NEM = production - respiration) for the integrated Bay. These methods, which employed biogeochemical models, nutrient mass-balances anti summation of individual organic carbon fluxes, yielded remarkably similar estimates, with a mean NEM of +50 g C m-2 yr-1 (?? SE = 751, which is approximately 8% of the estimated annual average gross primary production. These calculations suggest a strong cross-sectional pattern in NEM throughout the Bay, wherein net heterotrophic metabolism prevails in the pelagic zones of the main channel, while net autotrophy occurs in the littoral zones which flank the deeper central area. For computational purposes, the estuary was separated into 3 regions along the land-sea gradient: (1) the oligohaline Upper Bay (11% of total area); (2) the mesohaline Mid Bay (36% of area); and (3) the polyhaline Lower Bay (53% of area). A distinct regional trend in NEM was observed along this salinity gradient, with net here(atrophy (NEM = 87 g C m-2 yr-1) in the Upper Bay, balanced metabolism in the Mid Bay and net autotrophy (NEM = +92 g C m-2 yr-1) in the Lower Bay. As a consequence of overall net autotrophy, the ratio of dissolved inorganic nitrogen (DIN) to total organic nitrogen (TON) changed from DIN:TON = 5.1 for riverine inputs to DIN:TON = 0.04 for water exported to the ocean. A striking feature of this organic C mass-balance was the relative dominance of biologically mediated metabolic fluxes compared to physical transport fluxes. The overall ratio of physical TOC inputs (1) to biotic primary production (P) was 0.08 for the whole estuary, but varied dramatically from 2.3 in the Upper Bay to 0.03 in the Mid and Lower Bay regions. Similarly, ecosystem respiration was some 6-fold higher than the sum of all physical carbon sinks. This general negative correspondence between I:P ratio and NEM, which occurred among Bay regions, was also evident in data available for organic C fluxes in other coastal ecosystems. An inverse relationship between NEM and P, postulated in a previous study, did not apply to Chesapeake Bay, and closer examination of available data revealed the importance of the loading ratio of DIN:TOC as a key control on coastal NEM. It is proposed here that the general global trend of coastal eutrophication will lead to increasing values of NEM in estuaries worldwide. The management implications of this trend are complex, involving both increased potential fisheries harvest and decreased demersal habitat.

Reactive oxygen species-generating mitochondrial DNA mutation up-regulates hypoxia-inducible factor-1alpha gene transcription via phosphatidylinositol 3-kinase-Akt/protein kinase C/histone deacetylase pathway.

PubMed

Koshikawa, Nobuko; Hayashi, Jun-Ichi; Nakagawara, Akira; Takenaga, Keizo

2009-11-27

Lewis lung carcinoma-derived high metastatic A11 cells constitutively overexpress hypoxia-inducible factor (HIF)-1alpha mRNA compared with low metastatic P29 cells. Because A11 cells exclusively possess a G13997A mutation in the mitochondrial NADH dehydrogenase subunit 6 (ND6) gene, we addressed here a causal relationship between the ND6 mutation and the activation of HIF-1alpha transcription, and we investigated the potential mechanism. Using trans-mitochondrial cybrids between A11 and P29 cells, we found that the ND6 mutation was directly involved in HIF-1alpha mRNA overexpression. Stimulation of HIF-1alpha transcription by the ND6 mutation was mediated by overproduction of reactive oxygen species (ROS) and subsequent activation of phosphatidylinositol 3-kinase (PI3K)-Akt and protein kinase C (PKC) signaling pathways. The up-regulation of HIF-1alpha transcription was abolished by mithramycin A, an Sp1 inhibitor, but luciferase reporter and chromatin immunoprecipitation assays indicated that Sp1 was necessary but not sufficient for HIF-1alpha mRNA overexpression in A11 cells. On the other hand, trichostatin A, a histone deacetylase (HDAC) inhibitor, markedly suppressed HIF-1alpha transcription in A11 cells. In accordance with this, HDAC activity was high in A11 cells but low in P29 cells and in A11 cells treated with the ROS scavenger ebselene, the PI3K inhibitor LY294002, and the PKC inhibitor Ro31-8220. These results suggest that the ROS-generating ND6 mutation increases HIF-1alpha transcription via the PI3K-Akt/PKC/HDAC pathway, leading to HIF-1alpha protein accumulation in hypoxic tumor cells.

A forward chemical genetic screen reveals an inhibitor of the Mre11–Rad50–Nbs1 complex

PubMed Central

Dupré, Aude; Boyer-Chatenet, Louise; Sattler, Rose M; Modi, Ami P; Lee, Ji-Hoon; Nicolette, Matthew L; Kopelovich, Levy; Jasin, Maria; Baer, Richard; Paull, Tanya T; Gautier, Jean

2009-01-01

The MRN (Mre11-Rad50-Nbs1)-ATM (ataxia-telangiectasia mutated) pathway is essential for sensing and signaling from DNA double-strand breaks. The MRN complex acts as a DNA damage sensor, maintains genome stability during DNA replication, promotes homology-dependent DNA repair and activates ATM. MRN is essential for cell viability, which has limited functional studies of the complex. Small-molecule inhibitors of MRN could circumvent this experimental limitation and could also be used as cellular radio- and chemosensitization compounds. Using cell-free systems that recapitulate faithfully the MRN-ATM signaling pathway, we designed a forward chemical genetic screen to identify inhibitors of the pathway, and we isolated Z-5-(4-hydroxybenzylidene)-2-imino-1,3-thiazolidin-4-one (mirin, 1) as an inhibitor of MRN. Mirin prevents MRN-dependent activation of ATM without affecting ATM protein kinase activity, and it inhibits Mre11-associated exonuclease activity. Consistent with its ability to target the MRN complex, mirin abolishes the G2/M checkpoint and homology-dependent repair in mammalian cells. PMID:18176557

Low molecular weight squash trypsin inhibitors from Sechium edule seeds.

PubMed

Laure, Hélen J; Faça, Vítor M; Izumi, Clarice; Padovan, Júlio C; Greene, Lewis J

2006-02-01

Nine chromatographic components containing trypsin inhibitor activity were isolated from Sechium edule seeds by acetone fractionation, gel filtration, affinity chromatography and RP-HPLC in an overall yield of 46% of activity and 0.05% of protein. The components obtained with highest yield of total activity and highest specific activity were sequenced by Edman degradation and their molecular masses determined by mass spectrometry. The inhibitors contained 31, 32 and 27 residues per molecule and their sequences were: SETI-IIa, EDRKCPKILMRCKRDSDCLAKCTCQESGYCG; SETI-IIb, EEDRKCPKILMRCKRDSDCLAKCTCQESGYCG and SETI-V, CPRILMKCKLDTDCFPTCTCRPSGFCG. SETI-IIa and SETI-IIb, which differed by an amino-terminal E in the IIb form, were not separable under the conditions employed. The sequences are consistent with consensus sequences obtained from 37 other inhibitors: CPriI1meCk_DSDCla_C_C_G_CG, where capital letters are invariant amino acid residues and lower case letters are the most preserved in this position. SETI-II and SETI-V form complexes with trypsin with a 1:1 stoichiometry and have dissociation constants of 5.4x10(-11)M and 1.1x10(-9)M, respectively.

Identification of compounds that modulate retinol signaling using a cell-based qHTS assay

PubMed Central

Chen, Yanling; Sakamuru, Srilatha; Huang, Ruili; Reese, David H.; Xia, Menghang

2016-01-01

In vertebrates, the retinol (vitamin A) signaling pathway (RSP) controls the biosynthesis and catabolism of all-trans retinoic acid (atRA), which regulates transcription of genes essential for embryonic development. Chemicals that interfere with the RSP to cause abnormal intracellular levels of atRA are potential developmental toxicants. To assess chemicals for the ability to interfere with retinol signaling, we have developed a cell-based RARE (Retinoic Acid Response Element) reporter gene assay to identify RSP disruptors. To validate this assay in a quantitative high-throughput screening (qHTS) platform, we screened the Library of Pharmacologically Active Compounds (LOPAC) in both agonist and antagonist modes. The screens detected known RSP agonists, demonstrating assay reliability, and also identified novel RSP agonists including kenpaullone, niclosamide, PD98059 and SU4312, and RSP antagonists including Bay 11-7085, LY294002, 3,4-Methylenedioxy-β-nitrostyrene, and topoisomerase inhibitors (camptothecin, topotecan, amsacrine hydrochloride, and idarubicin). When evaluated in the P19 pluripotent cell, these compounds were found to affect the expression of the Hoxa1 gene that is essential for embryo body patterning. These results show that the RARE assay is an effective qHTS approach for screening large compound libraries to identify chemicals that have the potential to adversely affect embryonic development through interference with retinol signaling. PMID:26820057

Anti-inflammatory effect of a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor via the stimulation of heme oxygenase-1 in LPS-activated mice and J774.1 murine macrophages.

PubMed

Park, Sung Bum; Park, Ji Seon; Jung, Won Hoon; Kim, Hee Youn; Kwak, Hyun Jung; Ahn, Jin Hee; Choi, Kyoung-Jin; Na, Yoon-Ju; Choi, Sunhwa; Dal Rhee, Sang; Kim, Ki Young

2016-08-01

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive cortisone to the active cortisol. 11β-HSD1 may be involved in the resolution of inflammation. In the present study, we investigate the anti-inflammatory effects of 2-(3-benzoyl)-4-hydroxy-1,1-dioxo-2H-1,2-benzothiazine-2-yl-1-phenylethanone (KR-66344), a selective 11β-HSD1 inhibitor, in lipopolysaccharide (LPS)-activated C57BL/6J mice and macrophages. LPS increased 11β-HSD1 activity and expression in macrophages, which was inhibited by KR-66344. In addition, KR-66344 increased survival rate in LPS treated C57BL/6J mice. HO-1 mRNA expression level was increased by KR-66344, and this effect was reversed by the HO competitive inhibitor, ZnPP, in macrophages. Moreover, ZnPP reversed the suppression of ROS formation and cell death induced by KR-66344. ZnPP also suppressed animal survival rate in LPS plus KR-66344 treated C57BL/6J mice. In the spleen of LPS-treated mice, KR-66344 prevented cell death via suppression of inflammation, followed by inhibition of ROS, iNOS and COX-2 expression. Furthermore, LPS increased NFκB-p65 and MAPK phosphorylation, and these effects were abolished by pretreatment with KR-66344. Taken together, KR-66344 protects against LPS-induced animal death and spleen injury by inhibition of inflammation via induction of HO-1 and inhibition of 11β-HSD1 activity. Thus, we concluded that the selective 11β-HSD1 inhibitor may provide a novel strategy in the prevention/treatment of inflammatory disorders in patients. Copyright © 2016 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Flood of January 1982 in the San Francisco Bay area, California

USGS Publications Warehouse

Blodgett, J.C.; Chin, E.H.

1989-01-01

A major winter storm originating over the Pacific Ocean moved through central California in early January 1982. As much as 16 inches of rain fell in Marin County and 25 inches in the mountains bordering Santa Cruz County. The storm of January 3-5, 1982 had a stable atmospheric structure, and the layer of moist maritime air was confined to altitudes between 50 and 700 ft; this phenomenon caused the rain to fall most heavily along the lower slopes of the coastal mountains. As a result of antecedent rainfall, streamflow in the San Francisco Bay area exceeded normal from the end of October to the end of December 1981. For most streams, the January 1982 flood was the largest since the flood of December 1955, but it was not significantly large in comparison with historic peak-flow data. Damages associated with the storm were substantial, but flooding from stream runoff was not the major problem. Greater than normal antecedent rainfall, together with the prolonged heavy rain, liquified the supersaturated soil cover and caused numerous slope failures and debris flows on steep, unstable slopes. The median recurrence interval of the 1982 peak for 66 streamflow-gaging stations in the San Francisco Bay area is 10 years; for the 1955 flood, the median recurrence interval for 16 stations is 11 years. Streams with highest unit peak runoff were in the Santa Cruz Mountains and North Bay subareas. Median recurrence intervals of flood volumes for durations of 1, 3, and 8 consecutive days during the January 1982 flood are 18, 11, and 8; these recurrence intervals are comparable to those of the December 1955 flood, which are 13 , 16, and 14 years. (USGS)

Sewage derive [sup 15]N in the Baltic traced in fucus

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hobbie, J.E.; Fry, B.; Larsson, U.

Himmerfjarden, a fjord-like bay on the eastern shore of the Baltic, receives treated sewage from 250,000 inhabitants. Because the inorganic N in the effluent is enriched in [sup 15]N through denitrification, nitrification, and ammonia volatilization, an analysis of the distribution of [sup 15]N in the Bay tells how far from the source the sewage nitrogen moves. The attached macroalga Fucus vesiculosus was collected in early May from rocky shore at 0-0.5 m depth and the [sup 15]N content of the tips of the fronds analyzed. This N represents uptake and storage during the previous six months and growth during Marchmore » and April. The [delta][sup 15]N was uniformly high (11-13[per thousand]) in the main body of the Bay within 15 km from the sewage source. Beyond 15 km values decreased with distance to a low of 4.6[per thousand] at 35 km, where the Bay ends and the coastal waters begin. Using the 11-13 and 4.6[per thousand] as endmembers, the percentage of sewage N making up the Fucus at any point may be calculated. The [delta][sub 15]N of particulate organic matter in the offshore Baltic waters was around 0[per thousand] and Fucus had an [delta][sup 15]N about 1.5[per thousand] higher than the POM. From this and other evidence we conclude that there is a belt of coastal water with an elevated [delta][sup 15]N lying along the east coast of the Baltic. This presumably derives from sewage and perhaps from agriculture and is potentially of use as a tracer of coastal zone/pelagic zone interactions.« less

[Temporal and spatial distribution of the crab Callinectes sapidus (Decapoda: Portunidae) in Chetumal Bay, Quintana Roo, Mexico].

PubMed

Ortiz-León, Héctor J; Jesús-Navarrete, Alberto de; Cordero, Eloy Sosa

2007-03-01

In order to determine temporal and spatial distribution patterns of Callinectes sapidus, samplings were carried out during the cold-front (January-February), dry (May-June) and rainy (August-September, 2002) climatic seasons, in 30 sampling stations of Chetumal Bay, grouped in sectors A (14 stations), B (eight stations) and C (eight stations). In each sampling station crabs were collected from two transects parallel to the coast, each with three traps, separated by 30 m. Sediments were calcareous coarse and medium sand, white or lightly gray. A total of 1 031 specimens were collected. CPEU (Capture Per Effort Unit) differed spatially and temporally. Highest CPEU was found in sector C with 1.3 ind.trap(-1), and in the rainy season with 1.1 ind.trap(-1). Population was predominantly composed of male individuals. The male:female ratio was 15:1. Males and adults (group II) CPEU was significant different between sectors and climatic seasons. Both males and adults (group II) had a greater CPEU in sector C (1.2 ind.trap-) and in the rainy season (1.1 ind.trap(-1)). Abundance of female and juvenile individuals (group I) was low during the sampling period whereas group 0 juvenile individuals were not found. A greater relative frequency between sectors and climatic seasons were observed in 130-139 mm and 140-149 mm size interval (CW). C. sapidus occurred on sandy sediments in Chetumal Bay. Pearson product moment correlations exhibited significant relationships between CPEU and temperature, salinity and dissolved oxygen. In Chetumal Bay, the spatial and temporal distribution of C. sapidus can be related to salinity, temperature, habitat quality, food availability, recruitment and reproduction events of individuals.

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, workers remove the protective cover from NASA’s MESSENGER spacecraft. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, workers remove the protective cover from NASA’s MESSENGER spacecraft. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, workers move NASA’s MESSENGER spacecraft into a high bay clean room. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, workers move NASA’s MESSENGER spacecraft into a high bay clean room. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, NASA’s MESSENGER spacecraft is revealed. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, NASA’s MESSENGER spacecraft is revealed. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

Looking north at the threading machine of the no. 1 ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

Looking north at the threading machine of the no. 1 seamless line in bay 11 of the main pipe mill building - U.S. Steel National Tube Works, Main Pipe Mill Building, Along Monongahela River, McKeesport, Allegheny County, PA

San Francisco Bay Area Endangered Species Litigation: The Complaint

EPA Pesticide Factsheets

The Center for Biological Diversity filed a lawsuit in the United States District Court for the Northern District of California alleging that EPA failed to comply with the ESA related to 47 pesticides and 11 endangered or threatened species.

Holocene depositional history of a large glaciated estuary, Penobscot Bay, Maine

USGS Publications Warehouse

Knebel, H.J.

1986-01-01

Data from seismic-reflection profiles, sidescan sonar images, and sediment samples reveal the Holocene depositional history of the large (1100 km2) glaciated Penobscot Bay estuary of coastal Maine. Previous work has shown that the late Wisconsinan ice sheet retreated from the three main passages of the bay between 12,700 and 13,500 years ago and was accompanied by a marine transgression during which ice and sea were in contact. Isostatic recovery of the crust caused the bay to emerge during the immediate postglacial period, and relative sea level fell to at least -40 m sometime between 9000 and 11,500 years ago. During lowered sea level, the ancestral Penobscot River flowed across the subaerially exposed head of the bay and debouched into Middle Passage. Organic-matter-rich mud from the river was deposited rapidly in remnant, glacially scoured depressions in the lower reaches of Middle and West Passages behind a shallow (???20 m water depth) bedrock sill across the bay mouth. East Passage was isolated from the rest of the bay system and received only small amounts of locally derived fine-grained sediments. During the Holocene transgression that accompanied the eustatic rise of sea level, the locus of sedimentation shifted to the head of the bay. Here, heterogeneous fluvial deposits filled the ancestral valley of the Penobscot River as base level rose, and the migrating surf zone created a gently dipping erosional unconformity, marked by a thin (<2 m) lag deposit of coarse sand and gravel. As sea level continued to rise, a thin (???9 m) layer of acoustically transparent muddy sediments accumulated over a shallow platform in the eastern half of the bay head. Graded sediments within this stratum began to accumulate early in the transgression, and they record both the decrease in energy conditions and the waning influence of the Penobscot River at the head of the bay. In contrast, relatively thick (up to 25 m) silty clays accumulated within a subbottom trough in the western half of the bay head. This deposit apparently developed late in the transgression after sea level had reached -20 m and after the westward transport of fine-grained sediments from the Penobscot River had been established. During and since the late Holocene transgression of sea level, waves and currents have eroded, reworked, and redistributed Holocene sediments: (1) atop the shallow margins; (2) within constricted channels; (3) around topographic highs; and (4) over the shallow bedrock sill at the bay mouth. The variable distribution, characteristics, and thickness (0 to more than 30 m) of Holocene deposits in Penobscot Bay primarily reflect: (1) the irregular glacially eroded bedrock topography beneath the bay; (2) the paleogeography of the bay during the sea-level lowstand; (3) the postglacial location of the ancestral Penobscot River; and (4) the wave and current regime during and since the Holocene sea-level transgression. ?? 1986.

High Prevalence of Gammaproteobacteria in the Sediments of Admiralty Bay and North Bransfield Basin, Northwestern Antarctic Peninsula.

PubMed

Franco, Diego C; Signori, Camila N; Duarte, Rubens T D; Nakayama, Cristina R; Campos, Lúcia S; Pellizari, Vivian H

2017-01-01

Microorganisms dominate most Antarctic marine ecosystems, in terms of biomass and taxonomic diversity, and play crucial role in ecosystem functioning due to their high metabolic plasticity. Admiralty Bay is the largest bay on King George Island (South Shetland Islands, Antarctic Peninsula) and a combination of hydro-oceanographic characteristics (bathymetry, sea ice and glacier melting, seasonal entrance of water masses, turbidity, vertical fluxes) create conditions favoring organic carbon deposition on the seafloor and microbial activities. We sampled surface sediments from 15 sites across Admiralty Bay (100-502 m total depth) and the adjacent North Bransfield Basin (693-1147 m), and used the amplicon 454-sequencing of 16S rRNA gene tags to compare the bacterial composition, diversity, and microbial community structure across environmental parameters (sediment grain size, pigments and organic nutrients) between the two areas. Marine sediments had a high abundance of heterotrophic Gammaproteobacteria (92.4% and 83.8% inside and outside the bay, respectively), followed by Alphaproteobacteria (2.5 and 5.5%), Firmicutes (1.5 and 1.6%), Bacteroidetes (1.1 and 1.7%), Deltaproteobacteria (0.8 and 2.5%) and Actinobacteria (0.7 and 1.3%). Differences in alpha-diversity and bacterial community structure were found between the two areas, reflecting the physical and chemical differences in the sediments, and the organic matter input.

Environmental management of a highly impacted, urbanized tropical estuary: rehabilitation and restoration

NASA Astrophysics Data System (ADS)

Thorhaug, A.

1980-03-01

The principles of the dynamics and interrelationships within the dominant subtropical and tropical Caribbean seagrass community have been studied previously before, during, and after impact. From these and scores of observations of damage and recovery patterns in Thalassia ecosystems, a sense of management recovery strategy has emerged. Artificial restoring of Thalassia testudinum seeds into areas cut off from stock (fruit, seeds) appeared feasible on a large scale after the Turkey Point (Biscayne Bay, Miami, Florida) restoration and test sampling throughout North Biscayne Bay. Two large-scale seeding attempts were made; after 11 months they compared favorably with Turkey Point specimens with regard to growth parameters, despite the turbidity and other persistent pollution. Thus, the possible areas in which Thalassia seed restoration can be used has increased to include estuaries of multiple impact still in various stages of recovery after physical and sewage pollution. This technique should be especially useful to “developing” nations where important nearshore fisheries nurseries based on Thalassia ecosystems have been heavily damaged and now lie barren. Man's impact on the estuary where seed restoration was attempted includes the following activities: 50% of the bay bottom directly dredged or filled (leaving much unconsolidated sediment); 50 million gallons of domestic waste dumped directly into a low flushing part of the bay for 20 years; seven major causeways transecting the bay, restricting circulation and flushing; two artificial inlets made into navigational channels; freshwater sheet flow drastically changed due to channelization by flood-control canals; urban runoff from a million people entering the bay. Most of the impacts have now abated; however, their long-term effects remain.

Impact of huge tsunami in March 2011 on seaweed bed distributions in Shizugawa Bay, Sanriku Coast, revealed by remote sensing

NASA Astrophysics Data System (ADS)

Sakamoto, Shingo X.; Sasa, Shuji; Sawayama, Shuhei; Tsujimoto, Ryo; Terauchi, Genki; Yagi, Hiroshi; Komatsu, Teruhisa

2012-10-01

Seaweed beds are very important for abalones and sea urchins as a habitat. In Sanriku Coast, these animals are target species of coastal fisheries. The huge tsunami hit Sanriku Coast facing Pacific Ocean on 11 March 2011. It is needed for fishermen to know present situation of seaweed beds and understand damages of the huge tsunami on natural environments to recover coastal fisheries. We selected Shizugawa Bay as a study site because abalone catch of Shizugawa Bay occupied the first position in Sanriku Coast. To evaluate impact of tsunami on seaweed beds, we compared high spatial resolution satellite image of Shizugawa Bay before the tsunami with that after the tsunami by remote sensing with ground surveys to know impact of the tsunami on seaweed beds. We used two multi-band imageries of commercial high-resolution satellite, Geoeye-1, which were taken on 4 November 2009 before the tsunami and on 22 February 2012 after the tsunami. Although divers observed the tsunami damaged a very small part of Eisenia bicyclis distributions on rock substrates at the bay head, it was not observed clearly by satellite image analysis. On the other hand, we found increase in seaweed beds after the tsunami from the image analysis. The tsunami broke concrete breakwaters, entrained a large amount of rocks and pebble from land to the sea, and disseminated them in the bay. Thus, hard substrates suitable for attachment of seaweeds were increased. Ground surveys revealed that seaweeds consisting of E. bicyclis, Sargassum and Laminaria species grew on these hard substrates on the sandy bottom.

Peptidases involved in the catabolism of neurotensin: inhibitor studies using superfused rat hypothalamic slices.

PubMed

McDermott, J R; Virmani, M A; Turner, J D; Kidd, A M

1986-01-01

In order to identify which peptidases are involved in the catabolism of neurotensin in the CNS, [3H-Tyr3,11]-neurotensin was superfused over rat hypothalamic slices in the presence and absence of peptidase inhibitors. The degree of degradation of the peptide was determined by reverse phase HPLC separation of 3H-labelled neurotensin from 3H-labelled products. Very little degrading activity was released from the slice into the medium during the superfusion. In the absence of inhibitors, 20 to 50% of 3H-neurotensin was degraded giving mainly 3H-Tyr along with other unidentified 3H-labelled products. Inhibitors of endopeptidase 24.11 (phosphoramidon) and proline endopeptidase (antibody) had no effect on the degradation. Captopril, an inhibitor of angiotensin converting enzyme, had a small inhibitory effect. In contrast, dynorphin(1-13), an inhibitor of a soluble, thiol dependent metallopeptidase which hydrolyses neurotensin at Arg8-Arg9, gave greater than 80% inhibition of 3H-neurotensin degradation in the slice preparation. 1,10-Phenanthroline, an inhibitor of metallopeptidases, was also an effective inhibitor. The dynorphin sequence responsible for the inhibition contains the Arg6-Arg7 bond. Other peptides (bradykinin and angiotensin) which are substrates of the soluble metallopeptidase also inhibited neurotensin breakdown by the slice. This evidence suggests that this thiol dependent metalloendopeptidase is the major neurotensin catabolizing enzyme in hypothalamic slices.

Enfuvirtide (T20)-Based Lipopeptide Is a Potent HIV-1 Cell Fusion Inhibitor: Implications for Viral Entry and Inhibition.

PubMed

Ding, Xiaohui; Zhang, Xiujuan; Chong, Huihui; Zhu, Yuanmei; Wei, Huamian; Wu, Xiyuan; He, Jinsheng; Wang, Xinquan; He, Yuxian

2017-09-15

The peptide drug enfuvirtide (T20) is the only viral fusion inhibitor used in combination therapy for HIV-1 infection, but it has relatively low antiviral activity and easily induces drug resistance. Emerging studies demonstrate that lipopeptide-based fusion inhibitors, such as LP-11 and LP-19, which mainly target the gp41 pocket site, have greatly improved antiviral potency and in vivo stability. In this study, we focused on developing a T20-based lipopeptide inhibitor that lacks pocket-binding sequence and targets a different site. First, the C-terminal tryptophan-rich motif (TRM) of T20 was verified to be essential for its target binding and inhibition; then, a novel lipopeptide, termed LP-40, was created by replacing the TRM with a fatty acid group. LP-40 showed markedly enhanced binding affinity for the target site and dramatically increased inhibitory activity on HIV-1 membrane fusion, entry, and infection. Unlike LP-11 and LP-19, which required a flexible linker between the peptide sequence and the lipid moiety, addition of a linker to LP-40 sharply reduced its potency, implying different binding modes with the extended N-terminal helices of gp41. Also, interestingly, LP-40 showed more potent activity than LP-11 in inhibiting HIV-1 Env-mediated cell-cell fusion while it was less active than LP-11 in inhibiting pseudovirus entry, and the two inhibitors displayed synergistic antiviral effects. The crystal structure of LP-40 in complex with a target peptide revealed their key binding residues and motifs. Combined, our studies have not only provided a potent HIV-1 fusion inhibitor, but also revealed new insights into the mechanisms of viral inhibition. IMPORTANCE T20 is the only membrane fusion inhibitor available for treatment of viral infection; however, T20 requires high doses and has a low genetic barrier for resistance, and its inhibitory mechanism and structural basis remain unclear. Here, we report the design of LP-40, a T20-based lipopeptide inhibitor that has greatly improved anti-HIV activity and is a more potent inhibitor of cell-cell fusion than of cell-free virus infection. The binding modes of two classes of membrane-anchoring lipopeptides (LP-40 and LP-11) verify the current fusion model in which an extended prehairpin structure bridges the viral and cellular membranes, and their complementary effects suggest a vital strategy for combination therapy of HIV-1 infection. Moreover, our understanding of the mechanism of action of T20 and its derivatives benefits from the crystal structure of LP-40. Copyright © 2017 American Society for Microbiology.

[Diversity and antimicrobial activities of cultivable bacteria isolated from Jiaozhou Bay].

PubMed

Wang, Yiting; Zhang, Chuanbo; Qi, Lin; Jia, Xiaoqiang; Lu, Wenyu

2016-12-04

Marine microorganisms have a great potential in producing biologically active secondary metabolites. In order to study the diversity and antimicrobial activity, we explored 9 sediment samples in different observation sites of Jiaozhou bay. We used YPD and Z2216E culture medium to isolate bacteria from the sediments; 16S rRNA was sequenced for classification and identification of the isolates. Then, we used Oxford cup method to detect antimicrobial activities of the isolated bacteria against 7 test strains. Lastly, we selected 16 representatives to detect secondary-metabolite biosynthesis genes:PKSI, NRPS, CYP, PhzE, dTGD by PCR specific amplification. A total of 76 bacterial strains were isolated from Jiaozhou bay; according to the 16S rRNA gene sequence analysis. These strains could be sorted into 11 genera belonging to 8 different families:Aneurinibacillus, Brevibacillus, Microbacterium, Oceanisphae, Bacillus, Marinomonas, Staphylococcus, Kocuria, Arthrobacters, Micrococcus and Pseudoalteromonas. Of them 34 strains showed antimicrobial activity against at least one of the tested strains. All 16 strains had at least one function genes, 5 strains possessed more than three function genes. Jiaozhou bay area is rich in microbial resources with potential in providing useful secondary metabolites.

Development of novel prediction model for drug-induced mitochondrial toxicity by using naïve Bayes classifier method.

PubMed

Zhang, Hui; Yu, Peng; Ren, Ji-Xia; Li, Xi-Bo; Wang, He-Li; Ding, Lan; Kong, Wei-Bao

2017-12-01

Mitochondrial dysfunction has been considered as an important contributing factor in the etiology of drug-induced organ toxicity, and even plays an important role in the pathogenesis of some diseases. The objective of this investigation was to develop a novel prediction model of drug-induced mitochondrial toxicity by using a naïve Bayes classifier. For comparison, the recursive partitioning classifier prediction model was also constructed. Among these methods, the prediction performance of naïve Bayes classifier established here showed best, which yielded average overall prediction accuracies for the internal 5-fold cross validation of the training set and external test set were 95 ± 0.6% and 81 ± 1.1%, respectively. In addition, four important molecular descriptors and some representative substructures of toxicants produced by ECFP_6 fingerprints were identified. We hope the established naïve Bayes prediction model can be employed for the mitochondrial toxicity assessment, and these obtained important information of mitochondrial toxicants can provide guidance for medicinal chemists working in drug discovery and lead optimization. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of local geology on ground motion in the San Francisco Bay region, California—A continued study

USGS Publications Warehouse

Gibbs, James F.; Borcherdt, Roger D.

1974-01-01

Measurements of ground motion generated by nuclear explosions in Nevada have been completed for 99 locations in the San Francisco Bay region, California. The seismograms, Fourier amplitude spectra, spectral amplification curves for the signal, and the Fourier amplitude spectra of the seismic noise are presented for 60 locations. Analog amplifications, based on the maximum signal amplitude, are computed for an additional 39 locations. The recordings of the nuclear explosions show marked amplitude variations which are consistently related to the local geologic conditions of the recording site. The average spectral amplifications observed for vertical and horizontal ground motions are, respectively: (1, 1) for granite, (1.5, 1.6) for the Franciscan Formation, (2.3, 2.3), for other pre-Tertiary and Tertiary rocks, (3.0, 2.7) for the Santa Clara Formation, (3.3, 4.4) for older bay sediments, and (3.7, 11.3) for younger bay mud. Spectral amplification curves define predominant ground frequencies for younger bay mud sites and for some older bay sediment sites. The predominant frequencies for most sites were not clearly defined by the amplitude spectra computed from the seismic background noise. The intensities ascribed to various sites in the San Francisco Bay region for the California earthquake of April 18, 1906, are strongly dependent on distance from the zone of surface faulting and the geological character of the ground. Considering only those sites (approximately one square city block in size) for which there is good evidence for the degree of ascribed intensity, the intensities for 917 sites on Franciscan rocks generally decrease with the logarithm of distance as Intensity = 2.69 - 1.90 log (Distance Km). For sites on other geologic units, intensity increments, derived from this empirical rela.tion, correlate strongly with the Average Horizontal Spectral Amplifications (MISA) according to the empirical relation Intensity Increment= 0.27 + 2.70 log(AHSA). Average intensity increments predicted for various geologic units are -0.3 for granite, 0.2 for Franciscan Formation, 0.6 for other pre-Tertiary, Tertiary bedrock, 0.8 for Santa Clara Formation, 1 .3 for older bay sediments, 2.4 for younger bay mud. These empirical relations, together with detailed geologic maps, delineate areas in the San Francisco Bay region of potentially high intensity from future earthquakes on either the San Andreas fault or the Hayward fault.

STS-98 payload U.S. Lab Destiny is moved into Atlantis' payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

KENNEDY SPACE CENTER, Fla. -- Workers check out the U.S. Lab Destiny after it has been installed in Atlantis''' payload bay at the pad. Destiny, a key element in the construction of the International Space Station, is 28 feet long and weighs 16 tons. This research and command-and- control center is the most sophisticated and versatile space laboratory ever built. It will ultimately house a total of 23 experiment racks for crew support and scientific research. STS-98 is the seventh construction flight to the ISS. Launch of STS-98 is scheduled for Jan. 19 at 2:11 a.m. EST.

The application of large numbers of pleasure boats to collect synoptic sea-truth for ERTS-1 overpasses

NASA Technical Reports Server (NTRS)

Klemas, V. (Principal Investigator); Davis, G.; Philpot, W.

1974-01-01

The author has identified the following significant results. In order to interpret and annotate current circulation and suspended sediment concentration maps derived from ERTS-1 digital tapes, the University of Delaware has been collecting water samples and other data from boats and helicopters. In order to increase the number of samples at the exact time of the ERTS-1 pass over Delaware Bay, pleasure craft were organized to obtain samples of the entire test site. On the ERTS-1 pass of July second, scientists were stationed at three public boat launches along the Bay to hand out sampling packets to interested boaters. The packets contained two litre sampling bottles, a map, data card, and a pen. The boaters were asked to fill the two bottles between 11 and 11:15 a.m., mark their location on the map, and fill out the data card. Forty-nine packets were handed out of which 40 were returned (82%). Only four of the 40 were not in the alloted time range. This gave 36 real time data points covering approximately 30 nautical miles. The samples are being analyzed for sediment concentration, particle size, and salinity. Participating boaters will receive a copy of an ERTS image of the Delaware Bay and a summary report of the project. Because of the success of the project, future use of pleasure boaters is being planned.

Leptin-induced IL-6 production is mediated by leptin receptor, insulin receptor substrate-1, phosphatidylinositol 3-kinase, Akt, NF-kappaB, and p300 pathway in microglia.

PubMed

Tang, Chih-Hsin; Lu, Da-Yuu; Yang, Rong-Sen; Tsai, Huei-Yann; Kao, Ming-Ching; Fu, Wen-Mei; Chen, Yuh-Fung

2007-07-15

Leptin, the adipocyte-secreted hormone that centrally regulates weight control, is known to function as an immunomodulatory regulator. We investigated the signaling pathway involved in IL-6 production caused by leptin in microglia. Microglia expressed the long (OBRl) and short (OBRs) isoforms of the leptin receptor. Leptin caused concentration- and time-dependent increases in IL-6 production. Leptin-mediated IL-6 production was attenuated by OBRl receptor antisense oligonucleotide, PI3K inhibitor (Ly294002 and wortmannin), Akt inhibitor (1L-6-hydroxymethyl-chiro-inositol-2-((R)-2-O-methyl-3-O-octadecylcarbonate)), NF-kappaB inhibitor (pyrrolidine dithiocarbamate), IkappaB protease inhibitor (L-1-tosylamido-2-phenylenylethyl chloromethyl ketone), IkappaBalpha phosphorylation inhibitor (Bay 117082), or NF-kappaB inhibitor peptide. Transfection with insulin receptor substrate (IRS)-1 small-interference RNA or the dominant-negative mutant of p85 and Akt also inhibited the potentiating action of leptin. Stimulation of microglia with leptin activated IkappaB kinase alpha/IkappaB kinase beta, IkappaBalpha phosphorylation, IkappaBalpha degradation, p65 phosphorylation at Ser(276), p65 and p50 translocation from the cytosol to the nucleus, and kappaB-luciferase activity. Leptin-mediated an increase of IkappaB kinase alpha/IkappaB kinase beta activity, kappaB-luciferase activity, and p65 and p50 binding to the NF-kappaB element was inhibited by wortmannin, Akt inhibitor, and IRS-1 small-interference RNA. The binding of p65 and p50 to the NF-kappaB elements, as well as the recruitment of p300 and the enhancement of histone H3 and H4 acetylation on the IL-6 promoter was enhanced by leptin. Our results suggest that leptin increased IL-6 production in microglia via the leptin receptor/IRS-1/PI3K/Akt/NF-kappaB and p300 signaling pathway.

Light-Dependent Sulfide Oxidation in the Anoxic Zone of the Chesapeake Bay Can Be Explained by Small Populations of Phototrophic Bacteria

PubMed Central

Bennett, Alexa J.; Hanson, Thomas E.; Luther, George W.

2015-01-01

Microbial sulfide oxidation in aquatic environments is an important ecosystem process, as sulfide is potently toxic to aerobic organisms. Sulfide oxidation in anoxic waters can prevent the efflux of sulfide to aerobic water masses, thus mitigating toxicity. The contribution of phototrophic sulfide-oxidizing bacteria to anaerobic sulfide oxidation in the Chesapeake Bay and the redox chemistry of the stratified water column were investigated in the summers of 2011 to 2014. In 2011 and 2013, phototrophic sulfide-oxidizing bacteria closely related to Prosthecochloris species of the phylum Chlorobi were cultivated from waters sampled at and below the oxic-anoxic interface, where measured light penetration was sufficient to support populations of low-light-adapted photosynthetic bacteria. In 2012, 2013, and 2014, light-dependent sulfide loss was observed in freshly collected water column samples. In these samples, extremely low light levels caused 2- to 10-fold increases in the sulfide uptake rate over the sulfide uptake rate under dark conditions. An enrichment, CB11, dominated by Prosthecochloris species, oxidized sulfide with a Ks value of 11 μM and a Vmax value of 51 μM min−1 (mg protein−1). Using these kinetic values with in situ sulfide concentrations and light fluxes, we calculated that a small population of Chlorobi similar to those in enrichment CB11 can account for the observed anaerobic light-dependent sulfide consumption activity in natural water samples. We conclude that Chlorobi play a far larger role in the Chesapeake Bay than currently appreciated. This result has potential implications for coastal anoxic waters and expanding oxygen-minimum zones as they begin to impinge on the photic zone. PMID:26296727

Inhibitors for human glutaminyl cyclase by structure based design and bioisosteric replacement.

PubMed

Buchholz, Mirko; Hamann, Antje; Aust, Susanne; Brandt, Wolfgang; Böhme, Livia; Hoffmann, Torsten; Schilling, Stephan; Demuth, Hans-Ulrich; Heiser, Ulrich

2009-11-26

The inhibition of human glutaminyl cyclase (hQC) has come into focus as a new potential approach for the treatment of Alzheimer's disease. The hallmark of this principle is the prevention of the formation of Abeta(3,11(pE)-40,42), as these Abeta-species were shown to be of elevated neurotoxicity and likely to act as a seeding core leading to an accelerated formation of Abeta-oligomers and fibrils. Starting from 1-(3-(1H-imidazol-1-yl)propyl)-3-(3,4-dimethoxyphenyl)thiourea, bioisosteric replacements led to the development of new classes of inhibitors. The optimization of the metal-binding group was achieved by homology modeling and afforded a first insight into the probable binding mode of the inhibitors in the hQC active site. The efficacy assessment of the hQC inhibitors was performed in cell culture, directly monitoring the inhibition of Abeta(3,11(pE)-40,42) formation.

Phosphoramidon potentiates mammalian tachykinin-induced biting, licking and scratching behaviour in mice.

PubMed

Sakurada, T; Tan-No, K; Yamada, T; Sakurada, S; Kisara, K

1990-12-01

The effects of peptidase inhibitors were examined upon behavioural responses including scratch, bite and lick produced by intrathecal (IT) injection of substance P (SP) and neurokinin A (NK A) in mice. Phosphoramidon (0.002-2.0 nmol), an endopeptidase-24.11 inhibitor, simultaneously injected with SP or NK A, remarkably enhanced and prolonged SP- or NK A-induced behavioural response in a dose-dependent manner. The behavioural response to SP was significantly increased by 2.0 nmol of bestatin, an aminopeptidase inhibitor, but not by 1.0 nmol. Captopril, an angiotensin-converting enzyme inhibitor, was without effect on both tachykinin-induced responses. When phosphoramidon was injected together with bestatin and captopril which have no significant effect alone, SP- or NK A-induced behavioral response was significantly increased. These data suggest that endopeptidase-24.11 may be an important enzyme responsible for terminating of SP- or NK A-induced behavioral response at the spinal cord level.

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibition Attenuates the Adverse Effects of Glucocorticoids on Dermal Papilla Cells.

PubMed

Lee, Sang Eun; Lee, Eun Young; Kang, Sang Jin; Lee, Seung Hun

2017-11-01

Glucocorticoids, stress-related hormones, inhibit hair growth. Intracellular glucocorticoid availability is regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). 11β-HSD1 was recently detected in keratinocytes and fibroblasts. However, the expression of 11β-HSD1 in human hair follicles remains unknown. We aimed to examine 11β-HSD1 expression in human dermal papilla cells (DPCs) and to investigate whether modulation of 11β-HSD1 activity can regulate the negative effects of glucocorticoids on DPCs. 11β-HSD1 expression in normal human scalp skin was examined by immunohistochemistry. 11β-HSD1 protein was detected in Western blots of human DPCs. Cultured human DPCs were treated with cortisol with or without a selective 11β-HSD1 inhibitor and subsequently stained for Ki-67 antibody. Expression levels of 11β-HSD1, Wnt5a, alkaline phosphatase (ALP), and vascular endothelial growth factor (VEGF) were analyzed by Western blotting. 11β-HSD1 was detected in dermal papilla in human scalp skin by immunohistochemistry. Human DPCs expressed 11β-HSD1 protein in vitro. Furthermore, cortisol stimulated the expression of 11β-HSD1 in DPCs. Glucocorticoids decreased cellular proliferation and the expression of Wnt5a, ALP, and VEGF in DPCs. A specific 11β-HSD1 inhibitor significantly attenuated the anti-proliferative effects of cortisol and reversed the cortisol-induced suppression of Wnt5a, ALP, and VEGF expression in DPCs. Our data demonstrated the expression of 11β-HSD1 in human DPCs and revealed that inhibition of 11β-HSD1 activity can partially prevent the negative effect of glucocorticoids on DPCs, suggesting the possible application of 11β-HSD1 inhibitors for stress-related hair loss. © Copyright: Yonsei University College of Medicine 2017

Effect of milk on somatostatin degradation in suckling rat jejunum in vivo.

PubMed

Rao, R K; Davis, T P; Williams, C; Koldovsky, O

1999-01-01

Somatostatin-14 is present in breast milk, and intact somatostatin-14 has been recovered from gastric lumen of infants. Studies have shown that somatostatin-14 is metabolized in the intestinal luminal contents in vitro, which could be prevented by the presence of breast milk. In this study, the effect of milk on stability of somatostatin-14 in suckling rat jejunum in vivo was examined. 125I-Somatostatin-14[Tyr 11] was administered to the isolated jejunal loops in anesthetized suckling rats in the absence or presence of milk, fractions of milk, or known protease-peptidase inhibitors. Structural integrity of 125I-somatostatin-14[Tyr 11] recovered from tissues at different intervals was analyzed by gel filtration and high-performance liquid chromatography. Radioactivity rapidly disappeared from the jejunal lumen with a 50% clearance achieved by 1.2 minutes. Gel filtration and high-performance liquid chromatography analyses showed that 125I-somatostatin- 14[Tyr 11] was rapidly degraded into smaller fragments. At 1 minute, jejunal luminal radioactivity was eluted in a major peak with retention time of 42.4 minutes, along with other minor peaks (retention time, 5.6, 8.0, 10.4, and 14.4 minutes); only a trace amount of intact 125I-somatostatin-14[Tyr 11] (retention time, 44.8 minutes) was present. Coadministration of rat's milk or its soluble fraction increased the level of intact 125I-somatostatin-14[Tyr 11] in the jejunal lumen and jejunal tissue. Presence of rat's milk-casein or peptidase inhibitors (bestatin, phosphoramidon, or Bowman-Birk inhibitor), however, failed to increase the level of intact 125I-somatostatin-14[Tyr 11]. These results suggest that somatostatin-14 is rapidly degraded in the jejunal lumen of suckling rats, and that milk-borne peptidase inhibitors prevent this somatostatin-14 degradation.

Low-dose aspirin, non-steroidal anti-inflammatory drugs, selective COX-2 inhibitors and breast cancer recurrence

PubMed Central

Cronin-Fenton, Deirdre P; Heide-Jørgensen, Uffe; Ahern, Thomas P; Lash, Timothy L; Christiansen, Peer; Ejlertsen, Bent; Sørensen, Henrik T

2017-01-01

Background Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and selective COX-2 inhibitors may improve outcomes in breast cancer patients. We investigated the association of aspirin, NSAIDs, and use of selective COX-2 inhibitors with breast cancer recurrence. Methods We identified incident stage I–III Danish breast cancer patients in the Danish Breast Cancer Cooperative Group registry, who were diagnosed during 1996–2008. Prescriptions for aspirin (>99% low-dose aspirin), NSAIDs, and selective COX-2 inhibitors were ascertained from the National Prescription Registry (NPR). Follow-up began on the date of breast cancer primary surgery and continued until the first of recurrence, death, emigration, or 01/01/2013. We used Cox regression models to compute hazard ratios (HR) and corresponding 95% confidence intervals (95%CI) associating prescriptions with recurrence, adjusting for confounders. Results We identified 34,188 breast cancer patients with 233,130 person-years of follow-up. Median follow-up was 7.1 years; 5,325 patients developed recurrent disease. Use of aspirin, NSAIDs, or selective COX-2 inhibitors was not associated with the rate of recurrence (HRadjusted aspirin=1.0, 95% CI=0.90, 1.1; NSAIDs=0.99, 95% CI=0.92, 1.1; selective COX-2 inhibitors=1.1, 95% CI=0.98, 1.2), relative to non-use. Pre-diagnostic use of the exposure drugs was associated with reduced recurrence rates (HRaspirin=0.92, 95%CI=0.82, 1.0; HRNSAIDs=0.86, 95%CI=0.81, 0.91; HRsCOX-2inhibitors=0.88, 95%CI=0.83, 0.95). Conclusions This prospective cohort study suggests that post-diagnostic prescriptions for aspirin, NSAIDs, and selective COX-2 inhibitors have little or no association with the rate of breast cancer recurrence. Pre-diagnostic use of the drugs was, however, associated with a reduced rate of breast cancer recurrence. PMID:27007644

Up-regulated expression of WNT5a increases inflammation and oxidative stress via PI3K/AKT/NF-κB signaling in the granulosa cells of PCOS patients.

PubMed

Zhao, Yue; Zhang, Chunmei; Huang, Ying; Yu, Yang; Li, Rong; Li, Min; Liu, Nana; Liu, Ping; Qiao, Jie

2015-01-01

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder accompanied by chronic low-grade inflammation, but the molecular mechanism remains unclear. We investigated the action of WNT5a in the development of chronic inflammation in PCOS and the related molecular signaling pathways. This was a prospective study conducted at the Division of Reproduction Center, Peking University Third Hospital. A total of 35 PCOS patients and 87 control women who reported to the clinic for the in vitro procedure and the cause of marital infertility was male azoospermia were included. Mural granulosa cells (GCs) of 35 PCOS patients and 37 controls were collected during oocyte retrieval and gene expression was analyzed. The human KGN cells and mural GCs from 50 control subjects (six to eight samples were pooled together for each experiment) were cultured in vitro. The regulation of inflammation and oxidative stress was confirmed by quantitative PCR, flow-cytometric assay, and dual-luciferase reporter assay after inflammatory stimuli or WNT5a overexpression. Relevant signaling pathways were identified using specific inhibitors. Our data demonstrate significantly elevated WNT5a expression in the mural GCs of PCOS patients compared with the controls. Lipopolysaccharide stimulation increased WNT5a expression in KGN cells and mural GCs, and BAY-117082 and pyrrolidinedithiocarbamic acid [nuclear factor-κB (NF-κB) inhibitor] treatments suppressed WNT5a mRNA below the control level. WNT5a overexpression also enhanced the expression of inflammation-related genes and increased intracellular reactive oxygen species, whereas both BAY-117082 and LY-294002 (phosphatidylinositol 3-kinase inhibitor) significantly inhibited WNT5a-induced inflammation and oxidative stress. WNT5a acts as a proinflammatory factor in human ovarian GCs. The up-regulated expression of WNT5a in PCOS increases inflammation and oxidative stress predominantly via the phosphatidylinositol 3-kinase/AKT/NF-κB signaling pathway. The proinflammatory cytokines induced might further enhance WNT5a expression via NF-κB-dependent regulation, indicating a novel regulatory system for chronic inflammation in PCOS.

Involvement of a lipoxygenase-like enzyme in abscisic Acid biosynthesis.

PubMed

Creelman, R A; Bell, E; Mullet, J E

1992-07-01

Several lines of evidence indicate that abscisic acid (ABA) is derived from 9'-cis-neoxanthin or 9'-cis-violaxanthin with xanthoxin as an intermediate. (18)O-labeling experiments show incorporation primarily into the side chain carboxyl group of ABA, suggesting that oxidative cleavage occurs at the 11, 12 (11', 12') double bond of xanthophylls. Carbon monoxide, a strong inhibitor of heme-containing P-450 monooxygenases, did not inhibit ABA accumulation, suggesting that the oxygenase catalyzing the carotenoid cleavage step did not contain heme. This observation, plus the ability of lipoxygenase to make xanthoxin from violaxanthin, suggested that a lipoxygenase-like enzyme is involved in ABA biosynthesis. To test this idea, the ability of several soybean (Glycine max L.) lipoxygenase inhibitors (5,8,11-eicosatriynoic acid, 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid, and naproxen) to inhibit stress-induced ABA accumulation in soybean cell culture and soybean seedlings was determined. All lipoxygenase inhibitors significantly inhibited ABA accumulation in response to stress. These results suggest that the in vivo oxidative cleavage reaction involved in ABA biosynthesis requires activity of a nonheme oxygenase having lipoxygenase-like properties.

Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice.

PubMed

Park, Sung Bum; Jung, Won Hoon; Kang, Nam Sook; Park, Ji Seon; Bae, Gyu Hwan; Kim, Hee Youn; Rhee, Sang Dal; Kang, Seung Kyu; Ahn, Jin Hee; Jeong, Hye Gwang; Kim, Ki Young

2013-12-05

It has been reported that the selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11β-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11β-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11β-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11β-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11β-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity. © 2013 Elsevier B.V. All rights reserved.

Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

DTIC Science & Technology

2016-12-01

no specifi c biomarkers were tested in a trial of a PARP inhibitor in patients with ovarian carcinoma with measurable disease . There is currently no... disease that was measurable with the Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST) and amenable to biopsy at trial entry. Patients...have measurable disease treated with a PARP inhibitor, thereby testing the assay as a biomarker for PARP inhibitor response. Other prospective

Effect of phoshpodiesterase 4 (PDE4) inhibibtors on eotaxin expression in humen bronchial epithelial cells.

PubMed

Paplinska, M; Chazan, R; Grubek-Jaworska, H

2011-06-01

The increasing number of eosinophils into bronchoaelvolar space is observed during noninfectious inflammatory lung diseases. Eotaxins (eotaxin-1/CCL11, eotaxin-2/CCL24, eotaxin-3/CCL26) are the strongest chemotactic agents for eosinophils. Inhibitors of phosphodiesterase 4 (PDE4), the enzyme decomposing cAMP, are anti-inflammatory agents which act through cAMP elevation and inhibit numerous steps of allergic inflammation. The effect of PDE4 inhibitors on eotaxin expression is not known in details. The aim of our study was to evaluate the influence of PDE4 inhibitors: rolipram and RO-20-1724 on expression of eotaxins in bronchial epithelial cell line BEAS-2B. Cells were preincubated with PDE4 inhibitors or dexamethasone for 1 hour and then stimulated with IL-4 or IL-13 alone or in combination with TNF-α. After 48 hours eotaxin protein level was measured by ELISA and mRNA level by real time PCR. PDE4 inhibitors decreased CCL11 and CCL26 expression only in cultures co-stimulated with TNF-α. In cultures stimulated with IL-4 and TNF-α rolipram and RO-20-1724 diminished CCL11 mRNA expression by 34 and 37%, respectively, and CCL26 by 43 and 47%. In cultures stimulated with IL-13 and TNF-α rolipram and RO-20-1724 decreased expression of both eotaxins by about 50%. These results were confirmed at the protein level. The effect of PDE4 inhibitors on eotaxin expression in BEAS-2B cells, in our experimental conditions, depends on TNF-α contribution.

54. INTERIOR OF APRON SUSPENSION STRUCTURE SHOWING APRON COUNTERWEIGHT SYSTEM ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

54. INTERIOR OF APRON SUSPENSION STRUCTURE SHOWING APRON COUNTERWEIGHT SYSTEM OF CABLES AND PULLEYS ABOVE BRIDGE NOS. 12 AND 11. LOOKING NORTH. - Greenville Yard, Transfer Bridge System, Port of New York/New Jersey, Upper New York Bay, Jersey City, Hudson County, NJ

Land and Sea: Linking Ecosystem Services with Local Concerns in Guanica Bay Watershed, Puerto Rico

EPA Pesticide Factsheets

The United States Coral Reef Task Force—comprised of leaders from EPA and 11 other federal agencies along with select States, Territories, and Commonwealths—was established in 1998 to stem loses and preserve and protect coral reef ecosystems.

High resolution FTIR spectroscopy of BaY2F8 single crystals doped with trivalent Er

NASA Astrophysics Data System (ADS)

Baraldi, A.; Capelletti, R.; Cornelli, M.; Ponzoni, A.; Ruffini, A.; Sperzagni, A.; Tonelli, M.

High resolution (0.04 cm-1) FTIR spectroscopy is applied to monoclinic Er3+-doped BaY2F8 single crystals in the wavenumber range 500-24000 cm-1 and temperature range 9-300 K to study the crystal field splitting of the fundamental 4I15/2 and of the excited 4I13/2, 4I11/2, 4I9/2, 4F9/2, 4S3/2, 2H11/2, 4F7/2, 4F5/2, and 4F3/2 states and the effects caused by increasing Er3+-concentrations (2-20% m.f.), such as inhomogeneous line-broadening and new lines due to Er3+-Er3+ interaction. In the framework of the electron-phonon interaction, the thermally induced line-broadening and -shift are detected and accounted for by the two-phonon Raman model and the vibronic replicas of a few lines are investigated.

Incidence and risk factors for inhibitor development in previously untreated severe haemophilia A patients born between 2005 and 2010.

PubMed

Vézina, C; Carcao, M; Infante-Rivard, C; Lillicrap, D; Stain, A M; Paradis, E; Teitel, J; Rivard, G E

2014-11-01

The objective of this study was to evaluate the inhibitor development (ID) in previously untreated patients (PUPs) with severe haemophilia A (FVIII ≤ 0.01 IU mL(-1) ). All Canadian Haemophilia Treatment Centres completed a questionnaire on patients born between September 2005 and August 2010 and followed for up to 7 years. Eligible patients had at least 20 exposure days (ED) or had developed an inhibitor. The odds ratio (OR) and 95% confidence intervals (95% CI) for risk factors to develop an inhibitor were estimated using unconditional logistic regression. A total of 99 haemophilia A PUPs were studied. Thirty-four (34%) developed an inhibitor (24/34 of high titre). Inhibitors developed in 25/63 (40%) patients with a high-risk mutation. ID was most frequent in Aboriginals (86%). Dose intensity (IU kg(-1)  day(-1) X number of ED) at first exposure to factor VIII (FVIII) was associated with a crude OR increase of 1.10 (95% CI: 0.99-1.23) with each increase of 100 dose-intensity units. Haemarthrosis and intracranial bleeding as the indication for first exposure to FVIII concentrate were associated with a crude OR for ID of 7.63 (95% CI: 2.14-27.17) and 5.08 (95% CI: 1.11-23.31) respectively. ID according to FVIII concentrate used was: Advate (®) 18/50 (36%), Kogenate FS(®) or Helixate FS(®) 15/36 (42%), Wilate(®) 0/11 and Xyntha(®) 1/2. In multivariate analysis, Aboriginal ethnicity (OR = 11.69; 95% CI: 1.11-122.86) and haemarthrosis (OR = 4.49; 95% CI: 1.08-18.61) were statistically significant. The cumulative incidence of ID in severe haemophilia A PUPs was 34% and varied according to ethnicity, type of bleeding at first ED, type of FVIII product and dose intensity at first exposure. © 2014 John Wiley & Sons Ltd.

United States Army, Seventh Army Field Order No. 1 (ANVIL)

DTIC Science & Technology

1944-07-29

4471- FHANCE, 1/100,000, GSGS 4249. ’ FR..fu."JCE, road maps, 1/200,000, GSGS 4238. FR.~~CE, 1/250,000, GSGS 2738. Target Area Beach panoramas . All...8217These plants are link.... ed to the thermal plants in the nor-th by a high tension. grid system of 150 and 220 kv, . b. The hydro-electric piants in...Saint-Lary Soulcm Trame zaygues ~ Sms~M’·- BIGOT ANVIL BAY OF BI~ ~: Thermal II II .§PANISH BORDE1t Type: Hydro 11 11 11 II II 11 "" "II "II tI "" II

Evaluation of Oceanic Transport Statistics By Use of Transient Tracers and Bayesian Methods

NASA Astrophysics Data System (ADS)

Trossman, D. S.; Thompson, L.; Mecking, S.; Bryan, F.; Peacock, S.

2013-12-01

Key variables that quantify the time scales over which atmospheric signals penetrate into the oceanic interior and their uncertainties are computed using Bayesian methods and transient tracers from both models and observations. First, the mean residence times, subduction rates, and formation rates of Subtropical Mode Water (STMW) and Subpolar Mode Water (SPMW) in the North Atlantic and Subantarctic Mode Water (SAMW) in the Southern Ocean are estimated by combining a model and observations of chlorofluorocarbon-11 (CFC-11) via Bayesian Model Averaging (BMA), statistical technique that weights model estimates according to how close they agree with observations. Second, a Bayesian method is presented to find two oceanic transport parameters associated with the age distribution of ocean waters, the transit-time distribution (TTD), by combining an eddying global ocean model's estimate of the TTD with hydrographic observations of CFC-11, temperature, and salinity. Uncertainties associated with objectively mapping irregularly spaced bottle data are quantified by making use of a thin-plate spline and then propagated via the two Bayesian techniques. It is found that the subduction of STMW, SPMW, and SAMW is mostly an advective process, but up to about one-third of STMW subduction likely owes to non-advective processes. Also, while the formation of STMW is mostly due to subduction, the formation of SPMW is mostly due to other processes. About half of the formation of SAMW is due to subduction and half is due to other processes. A combination of air-sea flux, acting on relatively short time scales, and turbulent mixing, acting on a wide range of time scales, is likely the dominant SPMW erosion mechanism. Air-sea flux is likely responsible for most STMW erosion, and turbulent mixing is likely responsible for most SAMW erosion. Two oceanic transport parameters, the mean age of a water parcel and the half-variance associated with the TTD, estimated using the model's tracers as data (BayesPOP) and those estimated using tracer observations as data (BayesObs) provide information about the sources of model biases, and give a more nuanced picture than can be found by comparing the simulated CFC-11 concentrations with observed CFC-11 concentrations. Using the differences between the two oceanic transport parameters from BayesObs and those from BayesPOP with and without a constant Peclet number assumption along each of the hydrographic cross-sections considered here, it is found that the model's diffusivity tensor biases lead to larger model errors than the model's mean advection time biases. However, it is also found that mean advection time biases in the model are statistically significant at the 95% level where mode water is found.

Use of Polyamine Derivatives as Selective Histone Deacetylase Inhibitors

PubMed Central

Woster, Patrick M.

2014-01-01

Histone acetylation and deacetylation, mediated by histone acetyltransferase and the 11 isoforms of histone deacetylase, play an important role in gene expression. Histone deacetylase inhibitors have found utility in the treatment of cancer by promoting the reexpression of aberrantly silenced genes that code for tumor suppressor factors. It is unclear which of the 11 histone deacetylase isoforms are important in human cancer. We have designed a series of polyaminohydroxamic acid (PAHA) and polyaminobenzamide (PABA) histone deacetylase inhibitors that exhibit selectivity among four histone deacetylase isoforms. Although all of the active inhibitors promote reexpression of tumor suppressor factors, they produce variable cellular effects ranging from stimulation of growth to cytostasis and cytotoxicity. This chapter describes the procedures used to quantify the global and isoform-specific inhibition caused by these inhibitors, and techniques used to measure cellular effects such as reexpression of tumor suppressor proteins and hyperacetylation of histones H3 and H4. Procedures are also described to examine the ability of PAHAs and PABAs to utilize the polyamine transport system and to induce overexpression of the early apoptotic factor annexin A1. PMID:21318894

The role of profilin-1 in endothelial cell injury induced by advanced glycation end products (AGEs).

PubMed

Li, Zhenyu; Zhong, Qiaoqing; Yang, Tianlun; Xie, Xiumei; Chen, Meifang

2013-10-04

Accumulation of advanced glycation end products (AGEs) in the vasculature triggers a series of morphological and functional changes contributing to endothelial hyperpermeability. The reorganisation and redistribution of the cytoskeleton regulated by profilin-1 mediates endothelial cell contraction, which results in vascular hyperpermeability. This study aimed to investigate the pivotal role of profilin-1 in the process of endothelial cell damage induced by AGEs. Human umbilical vein endothelial cells (HUVECs) were incubated with AGEs. The mRNA and protein expression of profilin-1 was determined using real-time PCR and western blotting analyses. The levels of intercellular adhesion molecule-1 (ICAM-1), nitric oxide (NO) and reactive oxygen species (ROS), as well as the activities of nuclear factor-κB (NF-κB) and protein kinase C (PKC), were detected using the appropriate kits. The levels of asymmetric dimethylarginine (ADMA) were determined using HPLC. The distribution of the cytoskeleton was visualised using immunofluorescent staining. Compared with the control, incubation of endothelial cells with AGEs (200 μg/ml) for 4 or 24 h significantly up-regulated the mRNA and protein expression of profilin-1, markedly increased the levels of ICAM-1 and ADMA and decreased the production of NO (P<0.05, P<0.01), which was significantly attenuated by pretreatment with DPI (an antioxidant), GF 109203X (PKC inhibitor) or BAY-117082 (NF-κB inhibitor). DPI (10 μmol/L) markedly decreased the elevated levels of ROS induced by AGEs (200 μg/ml, 24 h); however, GF 109203X (10 μmol/L) and BAY-117082 (5 μmol/L) exhibited no significant effect on the formation of ROS by AGEs. Immunofluorescent staining indicated that AGEs markedly increased the expression of profilin-1 in the cytoplasm and the formation of actin stress fibres, resulting in the rearrangement and redistribution of the cytoskeleton. This effect was significantly ameliorated by DPI, GF 109203X, BAY-117082 or siRNA treatment of profilin-1. Incubation with DPI and GF 109203X markedly inhibited the activation of PKC triggered by AGEs, and DPI and BAY-117082 significantly decreased the activity of NF-κB mediated by AGEs. Disruption of profilin-1 gene expression attenuated the extent of endothelial abnormalities by reducing ICAM-1 and ADMA levels and elevating NO levels (P<0.05, P<0.01), but this disruption had no effect on the activities of NF-κB and PKC (P>0.05). These findings suggested that profilin-1 might act as an ultimate and common cellular effector in the process of metabolic memory (endothelial abnormalities) mediated by AGEs via the ROS/PKC or ROS/NF-қB signalling pathways.

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study

PubMed Central

Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

2016-01-01

Background Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. Methods We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population – patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3] and 1.4 [1.1, 1.8], respectively). Increasing the number of studies by two and ten times for the multiple study scenarios (Case 2: 1.9 [0.6, 4.0] and 1.9 [1.5, 2.6]; Case 3: 2.4 [0.9, 5.0] and 2.6 [1.9, 3.5], respectively) had a similar effect. Conclusion Bayesian approach as a robust, transparent, and reproducible analytic method can be efficiently used to estimate the inhibitor rate of hemophilia A in complex clinical settings. PMID:27822129

Bayesian approach to the assessment of the population-specific risk of inhibitors in hemophilia A patients: a case study.

PubMed

Cheng, Ji; Iorio, Alfonso; Marcucci, Maura; Romanov, Vadim; Pullenayegum, Eleanor M; Marshall, John K; Thabane, Lehana

2016-01-01

Developing inhibitors is a rare event during the treatment of hemophilia A. The multifacets and uncertainty surrounding the development of inhibitors further complicate the process of estimating inhibitor rate from the limited data. Bayesian statistical modeling provides a useful tool in generating, enhancing, and exploring the evidence through incorporating all the available information. We built our Bayesian analysis using three study cases to estimate the inhibitor rates of patients with hemophilia A in three different scenarios: Case 1, a single cohort of previously treated patients (PTPs) or previously untreated patients; Case 2, a meta-analysis of PTP cohorts; and Case 3, a previously unexplored patient population - patients with baseline low-titer inhibitor or history of inhibitor development. The data used in this study were extracted from three published ADVATE (antihemophilic factor [recombinant] is a product of Baxter for treating hemophilia A) post-authorization surveillance studies. Noninformative and informative priors were applied to Bayesian standard (Case 1) or random-effects (Case 2 and Case 3) logistic models. Bayesian probabilities of satisfying three meaningful thresholds of the risk of developing a clinical significant inhibitor (10/100, 5/100 [high rates], and 1/86 [the Food and Drug Administration mandated cutoff rate in PTPs]) were calculated. The effect of discounting prior information or scaling up the study data was evaluated. Results based on noninformative priors were similar to the classical approach. Using priors from PTPs lowered the point estimate and narrowed the 95% credible intervals (Case 1: from 1.3 [0.5, 2.7] to 0.8 [0.5, 1.1]; Case 2: from 1.9 [0.6, 6.0] to 0.8 [0.5, 1.1]; Case 3: 2.3 [0.5, 6.8] to 0.7 [0.5, 1.1]). All probabilities of satisfying a threshold of 1/86 were above 0.65. Increasing the number of patients by two and ten times substantially narrowed the credible intervals for the single cohort study (1.4 [0.7, 2.3] and 1.4 [1.1, 1.8], respectively). Increasing the number of studies by two and ten times for the multiple study scenarios (Case 2: 1.9 [0.6, 4.0] and 1.9 [1.5, 2.6]; Case 3: 2.4 [0.9, 5.0] and 2.6 [1.9, 3.5], respectively) had a similar effect. Bayesian approach as a robust, transparent, and reproducible analytic method can be efficiently used to estimate the inhibitor rate of hemophilia A in complex clinical settings.

Impacts of environmental and anthropogenic stresses on macrozoobenthic communities in Jinhae Bay, Korea.

PubMed

Bae, Hanna; Lee, Jung-Ho; Song, Sung Joon; Park, Jinsoon; Kwon, Bong-Oh; Hong, Seongjin; Ryu, Jongseong; Choi, Kyungsik; Khim, Jong Seong

2017-03-01

In this study, spatiotemporal dynamics of macrofaunal assemblages and their associations with environmental conditions were examined in Jinhae Bay (10 sites), where the obvious sources of pollution including industries, oyster farms (hanging cultures), and municipal discharges has surrounded. The survey had performed over five consecutive seasons in 2013-2014. Target sedimentary variables included grain size, organic content, C/N ratio, carbon and nitrogen stable isotope ratios, and some heavy metals. Five ecological quality indices (EcoQ) were calculated from the benthic community data to evaluate ecological qualities in site-specific manner. Jinhae Bay is a shallow (depths range, 11-24 m) and typical semi-enclosed bay. The benthic environments represented mud dominated bottoms (>70%) with fairly substantial organic content levels (>2%) over all five seasons. Seasonal patterns were observed with peak abundances in the spring and distinctive macrozoobenthos species shifts in the summer. The spring bloom could be explained by drastic increases of some polychaetes, mainly Capitella sp., at certain site, particularly near the shore. The oyster farms situated in the innermost locations seem to provide organic-rich bottoms being dominated by opportunistic species and/or organic pollution indicator species, such as Lumbrineris longifolia, Capitella sp., and Paraprionospio patiens. In general, the EcoQ indicators indicated that Jinhae Bay was moderately polluted, with exceptionally poor EcoQ in a few locations during the specific season(s). Overall, adverse effects on benthic community was broadly attributable to contaminations of heavy metals and nearby aquatic farm activities in Jinhae Bay, which requires a prompt action toward ecosystem-based management practice in the given area. Copyright © 2016 Elsevier Ltd. All rights reserved.

A century of landscape disturbance and urbanization of the San Francisco Bay region affects the present-day genetic diversity of the California Ridgway’s rail (Rallus obsoletus obsoletus)

USGS Publications Warehouse

Wood, Dustin A.; Bui, Thuy-Vy D.; Overton, Cory T.; Vandergast, Amy; Casazza, Michael L.; Hull, Joshua M.; Takekawa, John Y.

2016-01-01

Fragmentation and loss of natural habitat have important consequences for wild populations and can negatively affect long-term viability and resilience to environmental change. Salt marsh obligate species, such as those that occupy the San Francisco Bay Estuary in western North America, occupy already impaired habitats as result of human development and modifications and are highly susceptible to increased habitat loss and fragmentation due to global climate change. We examined the genetic variation of the California Ridgway’s rail (Rallus obsoletus obsoletus), a state and federally endangered species that occurs within the fragmented salt marsh of the San Francisco Bay Estuary. We genotyped 107 rails across 11 microsatellite loci and a single mitochondrial gene to estimate genetic diversity and population structure among seven salt marsh fragments and assessed demographic connectivity by inferring patterns of gene flow and migration rates. We found pronounced genetic structuring among four geographically separate genetic clusters across the San Francisco Bay. Gene flow analyses supported a stepping stone model of gene flow from south-to-north. However, contemporary gene flow among the regional embayments was low. Genetic diversity among occupied salt marshes and genetic clusters were not significantly different. We detected low effective population sizes and significantly high relatedness among individuals within salt marshes. Preserving genetic diversity and connectivity throughout the San Francisco Bay may require attention to salt marsh restoration in the Central Bay where habitat is both most limited and most fragmented. Incorporating periodic genetic sampling into the management regime may help evaluate population trends and guide long-term management priorities.

Efficacy, safety and tolerability of the CCR1 antagonist BAY 86-5047 for the treatment of endometriosis-associated pelvic pain: a randomized controlled trial.

PubMed

Trummer, Dietmar; Walzer, Anja; Groettrup-Wolfers, Esther; Schmitz, Heinz

2017-06-01

Antagonism of CC chemokine receptor type 1 (CCR1) may provide a novel treatment approach for women with symptomatic endometriosis. Studies of CCR1 antagonists in these patients have not been reported. Women (n = 110; 18-45 years) with symptomatic endometriosis were randomized to BAY 86-5047 or placebo for 12 weeks. Pelvic pain was assessed using the visual analogue scale (VAS) and women recorded the intake of pain medication in a diary. The primary efficacy outcome was a composite of the absolute change in VAS score and the cumulative change in consumption of analgesics between baseline and the end of treatment. Safety assessments included adverse events, blood and urine evaluation and electrocardiography. Mean VAS scores decreased from 64.8 mm at baseline to 49.2 mm at week 12 in the BAY 86-5047 group and from 67.2 mm to 47.8 mm in the placebo group. The proportion of women using analgesics decreased from 33.9% to 11.5% or from 44.4% to 15.4% for patients who received BAY 86-5047 or placebo, respectively. There was no significant difference between the two treatment groups in terms of change in VAS scores (p = 0.45) or intake of analgesics (p = 0.82). A three-step sensitivity analysis failed to show superiority of BAY 86-5047 over placebo (p = 0.67). BAY 86-5047 was well tolerated and no significant safety concerns arose during the study. Based on these results, BAY 86-5047 is unlikely to be useful in the treatment of women with endometriosis-associated pelvic pain. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

Gene transfer agent (GTA) genes reveal diverse and dynamic Roseobacter and Rhodobacter populations in the Chesapeake Bay.

PubMed

Zhao, Yanlin; Wang, Kui; Budinoff, Charles; Buchan, Alison; Lang, Andrew; Jiao, Nianzhi; Chen, Feng

2009-03-01

Within the bacterial class Alphaproteobacteria, the order Rhodobacterales contains the Roseobacter and Rhodobacter clades. Roseobacters are abundant and play important biogeochemical roles in marine environments. Roseobacter and Rhodobacter genomes contain a conserved gene transfer agent (GTA) gene cluster, and GTA-mediated gene transfer has been observed in these groups of bacteria. In this study, we investigated the genetic diversity of these two groups in Chesapeake Bay surface waters using a specific PCR primer set targeting the conserved Rhodobacterales GTA major capsid protein gene (g5). The g5 gene was successfully amplified from 26 Rhodobacterales isolates and the bay microbial communities using this primer set. Four g5 clone libraries were constructed from microbial assemblages representing different regions and seasons of the bay and yielded diverse sequences. In total, 12 distinct g5 clusters could be identified among 158 Chesapeake Bay clones, 11 fall within the Roseobacter clade, and one falls in the Rhodobacter clade. The vast majority of the clusters (10 out of 12) lack cultivated representatives. The composition of g5 sequences varied dramatically along the bay during the wintertime, and a distinct Roseobacter population composition between winter and summer was observed. The congruence between g5 and 16S rRNA gene phylogenies indicates that g5 may serve as a useful genetic marker to investigate diversity and abundance of Roseobacter and Rhodobacter in natural environments. The presence of the g5 gene in the natural populations of Roseobacter and Rhodobacter implies that genetic exchange through GTA transduction could be an important mechanism for maintaining the metabolic flexibility of these groups of bacteria.

Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer.

PubMed

Sah, Bert-Ram; Burger, Irene A; Schibli, Roger; Friebe, Matthias; Dinkelborg, Ludger; Graham, Keith; Borkowski, Sandra; Bacher-Stier, Claudia; Valencia, Ray; Srinivasan, Ananth; Hany, Thomas F; Mu, Linjing; Wild, Peter J; Schaefer, Niklaus G

2015-03-01

The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa). Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new (18)F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with (18)F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software. Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7-4.9 mSv). BAY 864367, a novel (18)F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

The effects of different environmental factors on the biochemical composition of particulate organic matter in Gwangyang Bay, South Korea

NASA Astrophysics Data System (ADS)

Lee, Jang Han; Lee, Dabin; Kang, Jae Joong; Joo, Hui Tae; Lee, Jae Hyung; Lee, Ho Won; Ahn, So Hyun; Kang, Chang Keun; Lee, Sang Heon

2017-04-01

The biochemical composition of particulate organic matter (POM) produced through phytoplankton photosynthesis is important in determining food quality for planktonic consumers as well as the physiological conditions of phytoplankton. Major environmental factors controlling the biochemical composition were seasonally investigated in Gwangyang Bay, South Korea, which has only natural conditions (e.g., no artificial dams). Water samples for the biochemical compositions were obtained from three different light depths (100, 30, and 1 %) mainly at three sites in Gwangyang Bay from April 2012 to April 2013. Different biochemical classes (carbohydrates, CHO; proteins, PRT; and lipids, LIP) were extracted, and then the concentrations were determined by the optical density measured with a spectrophotometer. The highest and lowest PRT compositions among the three biochemical classes were found in April 2012 (58.0 %) and August 2012 (21.2 %), whereas the highest and lowest LIP compositions were found in August 2012 (49.0 %) and April 2012 (24.8 %), respectively. The CHO composition was recorded as high in January 2013 and remained above 25 % during the study period. The calorific contents of the food material (FM) ranged from 1.0 to 6.1 Kcal m-3 (annual average ± SD = 2.8 ± 1.1 Kcal m-3). Based on a Pearson's correlation coefficient analysis, a major governing factor in the biochemical composition of POM was dissolved inorganic nitrogen loading from the river input in Gwangyang Bay. In conclusion, a relatively larger amount of FM and the higher calorific contents of POM found in this study compared to other regions reflected good nutritive conditions for sustaining productive shellfish and fish populations in Gwangyang Bay. Continuous observations are needed to monitor the marine ecosystem response to potential environmental perturbations in Gwangyang Bay.

Comparison between Observed Tsunami Heights and Numerical Simulation of the 1854 Ansei-Tokai Earthquake Tsunami in Gokasho Bay, central Japan

NASA Astrophysics Data System (ADS)

Naruhashi, R.; Satake, K.; Heidarzadeh, M.; Harada, T.

2014-12-01

　Gokasho Bay is a blockade inner bay which has typical ria coasts and drowned valleys. It is located in the central Kii Peninsula and faces the Nankai Trough subduction zone. This Kumano-nada coastal area has been repeatedly striked by historical great tsunamis. For the 1854 Ansei-Tokai earthquake and its tsunami, there are comparatively many historical records including historical documents and oral traditions for tsunami behavior and damages along the coast.　Based on these records, a total of 42 tsunami heights were measured by using a laser range finder and a hand level on the basis of spot elevation given by 1/2500 topographical maps. The average inundation height of whole bay area was approximately 4 - 5 m. On the whole, in the closed-off section of the bay, large values were obtained. For example, the average value in Gokasho-ura town area was 4 m, and the maximum run-up height along the Gokasho river was 6.8 m. Particularly in Konsa, located in the most closed-off section of the bay, tsunami heights ranged between 4 - 11 m, and were higher than those in other districts. It was comparatively high along the eastern coast and eastern baymouth.　We simulate the distribution of the tsunami wave heights using numerical modeling, and compare the simulation results and above-mentioned actual historical data and results of our field survey. Based on fault models by Ando (1975), Aida (1981), and Annaka et al. (2003), the tsunami simulation was performed.　After comparing the calculated results by three fault models, the wave height based on the model by Annaka et al. (2003) was found to have better agreement with observations. Moreover, the wave height values in a closed-off section of bay and at the eastern baymouth are high consistent with our survey data.

Evaluation for the ecological quality status of coastal waters in East China Sea using fuzzy integrated assessment method.

PubMed

Wu, H Y; Chen, K L; Chen, Z H; Chen, Q H; Qiu, Y P; Wu, J C; Zhang, J F

2012-03-01

This research presented an evaluation for the ecological quality status (EcoQS) of three semi-enclosed coastal areas using fuzzy integrated assessment method (FIAM). With this method, the hierarchy structure was clarified by an index system of 11 indicators selected from biotic elements and physicochemical elements, and the weight vector of index system was calculated with Delphi-Analytic Hierarchy Process (AHP) procedure. Then, the FIAM was used to achieve an EcoQS assessment. As a result of assessment, most of the sampling stations demonstrated a clear gradient in EcoQS, ranging from high to poor status. Among the four statuses, high and good, owning a ratio of 55.9% and 26.5%, respectively, were two dominant statuses for three bays, especially for Sansha Bay and Luoyuan Bay. The assessment results were found consistent with the pressure information and parameters obtained at most stations. In addition, the sources of uncertainty in classification of EcoQS were also discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

An Empirical Bayes before-after evaluation of road safety effects of a new motorway in Norway.

PubMed

Elvik, Rune; Ulstein, Heidi; Wifstad, Kristina; Syrstad, Ragnhild S; Seeberg, Aase R; Gulbrandsen, Magnus U; Welde, Morten

2017-11-01

This paper presents an Empirical Bayes before-after evaluation of the road safety effects of a new motorway (freeway) in Østfold county, Norway. The before-period was 1996-2002. The after-period was 2009-2015. The road was rebuilt from an undivided two-lane road into a divided four-lane road. The number of killed or seriously injured road users was reduced by 75 percent, controlling for (downward) long-term trends and regression-to-the-mean (statistically significant at the 5 percent level; recorded numbers 71 before, 11 after). There were small changes in the number of injury accidents (185 before, 123 after; net effect -3%) and the number of slightly injured road users (403 before 279 after; net effect +5%). Motorways appear to mainly reduce injury severity, not the number of accidents. The paper discusses challenges in implementing the Empirical Bayes design when less than ideal data are available. Copyright © 2017 Elsevier Ltd. All rights reserved.

Temporal and spatial trends of perfluorinated compounds in juvenile loggerhead sea turtles (Caretta caretta) along the East Coast of the United States.

PubMed

O'Connell, Steven G; Arendt, Michael; Segars, Al; Kimmel, Tricia; Braun-McNeill, Joanne; Avens, Larisa; Schroeder, Barbara; Ngai, Lily; Kucklick, John R; Keller, Jennifer M

2010-07-01

Perfluorinated compounds (PFCs) are globally distributed persistent environmental contaminants. This study provides temporal trends as well as large-scale spatial trends of PFC concentrations in threatened juvenile loggerhead sea turtles near or from Florida Bay (FL Bay), Cape Canaveral (FL), Charleston (SC), Core Sound (NC), and Chesapeake Bay (MD). PFCs were extracted from 163 plasma and serum samples using solid-phase extraction and quantified with LC-MS/MS. Concentrations of six compounds significantly varied by site, with MD or FL Bay turtles having the highest concentrations. Perfluorooctane sulfonate (PFOS) was the predominant PFC at all sites (range: 0.31 ng/g to 39.0 ng/g). FL Bay turtles, compared to other sites, accumulated a unique PFC pattern with a higher proportion of perfluorocarboxylates compared to PFOS. Furthermore, this study was the first to statistically correlate wildlife PFC concentrations with human population, used as a proxy for urbanization and sources of PFCs to the environment. Positive relationships were found in which human population accounted for 75 and 81% of the variance in turtle PFOS and perfluoroundecanoate (PFUnA) concentrations (p = 0.06 and 0.04), respectively. PFOS and perfluorononanoate (PFNA) significantly decreased from 2000-2008 in SC turtles annually by 20 and 11%, respectively (p

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, workers prepare NASA’s MESSENGER spacecraft for transfer to a work stand. There employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, workers prepare NASA’s MESSENGER spacecraft for transfer to a work stand. There employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, workers begin moving NASA’s MESSENGER spacecraft into the building MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - is being taken into a high bay clean room where employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, workers begin moving NASA’s MESSENGER spacecraft into the building MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - is being taken into a high bay clean room where employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, a lift begins lowering NASA’s MESSENGER spacecraft onto the ground. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be taken into a high bay clean room and employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, a lift begins lowering NASA’s MESSENGER spacecraft onto the ground. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be taken into a high bay clean room and employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, workers get ready to remove the protective cover from NASA’s MESSENGER spacecraft. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - In the high bay clean room at the Astrotech Space Operations processing facilities near KSC, workers get ready to remove the protective cover from NASA’s MESSENGER spacecraft. Employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, workers check the moveable pallet holding NASA’s MESSENGER spacecraft. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be taken into a high bay clean room and employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

NASA Image and Video Library

2004-03-10

KENNEDY SPACE CENTER, FLA. - At the Astrotech Space Operations processing facilities near KSC, workers check the moveable pallet holding NASA’s MESSENGER spacecraft. MESSENGER - short for MErcury Surface, Space ENvironment, GEochemistry and Ranging - will be taken into a high bay clean room and employees of the Johns Hopkins University Applied Physics Laboratory, builders of the spacecraft, will perform an initial state-of-health check. Then processing for launch can begin, including checkout of the power systems, communications systems and control systems. The thermal blankets will also be attached for flight. MESSENGER will be launched May 11 on a six-year mission aboard a Boeing Delta II rocket. Liftoff is targeted for 2:26 a.m. EDT on Tuesday, May 11.

10. LOOKING DOWN ON TUG AND CAR FLOAT BEING UNLOADED ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

10. LOOKING DOWN ON TUG AND CAR FLOAT BEING UNLOADED AT BRIDGE NO. 11 SHOWING TRACK, LOCKING MECHANISMS, AND MOORING WINCH IN FOREGROUND. LOOKING EAST. - Greenville Yard, Transfer Bridge System, Port of New York/New Jersey, Upper New York Bay, Jersey City, Hudson County, NJ

3. Historic American Buildings Survey Cortlandt V. D. Hubbard, Photographer ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

3. Historic American Buildings Survey Cortlandt V. D. Hubbard, Photographer July 1966 SOUTH AND EAST (STREET) ELEVATIONS (NOTE: Chimney in gable hidden by tree at left, windows of fourth bay hidden by tree at right) - Thomas Starbuck Homestead, 11 Milk Street, Nantucket, Nantucket County, MA

2. Historic American Buildings Survey Cortlandt V. D. Hubbard, Photographer ...

Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

2. Historic American Buildings Survey Cortlandt V. D. Hubbard, Photographer July 1966 SOUTH AND EAST (STREET) ELEVATIONS (NOTE: Chimney in gable hidden by tree at left, windows of fourth bay hidden by tree at right) - Thomas Starbuck Homestead, 11 Milk Street, Nantucket, Nantucket County, MA

78 FR 62357 - Georgia Power Company; Notice of Application Accepted for Filing, Soliciting Motions To Intervene...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-21

... project, from west to east, consists of: (1) A 1,230-foot-long, 11.25-foot-high, 22-bay auxiliary.... Commission issues EA April 2014. Comments on EA May 2014. Modified terms and conditions July 2014. p. Final...

Sea otter studies in Glacier Bay National Park and Preserve: Aerial surveys, foraging observations, and intertidal clam sampling

USGS Publications Warehouse

Bodkin, James L.; Kloecker, Kimberly A.; Esslinger, George G.; Monson, Daniel H.; DeGroot, J.D.

2001-01-01

Following translocations to the outer coast of Southeast Alaska in 1965, sea otters have been expanding their range and increasing in abundance. We began conducting surveys for sea otters in Cross Sound, Icy Strait and Glacier Bay, Alaska in 1994, following initial reports of their presence in Glacier Bay in 1993. Since 1995, the number of sea otters in Glacier Bay proper has increased from about 5 to more than 500. Between 1993 and 1997 sea otters were apparently only occasional visitors to Glacier Bay, but in 1998 long-term residence was established as indicated by the presence of adult females and their dependent pups. Sea otter distribution is limited to the Lower Bay, south of Sandy Cove, and is not continuous within that area. Concentration occur in the vicinity of Sita Reef and Boulder Island and between Pt. Carolus and Rush Pt. on the west side of the Bay (Figure 1). We describe the diet of sea otters in Glacier Bay and south Icy Strait through visual observations of prey during >4,000 successful forage dives. In 2,399 successful foraging dives observed in Glacier Bay proper, diet consisted of 40% clam, 21% urchins, 18% mussel, 4% crab, 5% other and 12% unidentified. Most prey recovered by sea otters are commercially, socially, or ecological important species. Species of clam are primarily Saxidomus gigantea, Protothaca staminea, and Serripes groenlandicus. Urchins are primarily Strongylocentrotus droebachiensis while both mussles, Modiolus modiolus and Mytilus trossulus, are taken. Crabs include species of Cancer, Chinoecetes, Paralithodes, and Telmessus. Although we characterize diet at broad geographic scales, we found diet to vary between sites separated by as little as several hundred meters. Dietary variation among and within sites can reflect differences in prey availability and individual choice.We estimated species composition, density, biomass, and sizes of intertidal clams at 59 sites in Glacier Bay, 14 sites in Idaho Inlet, 12 sites in Port Althorp and 2 sites in Dundas Bay. There is no direct evidence of otter foraging at any of our clam sampling sites except at Port Althorp where sea otters have been present for >20 years and regularly forage intertidally. There is some indication of intertidal foraging in Idaho Inlet, based on reduced mean size of preferred clam species. Sea otters have been present in Idaho Inlet for at least 12 years. We sampled 48 systematically selected sites to allow inference throughout Glacier Bay intertidal areas and 12 preferred habitat intertidal sites to estimate maximum clam densities in the Bay. We also sampled 14 and 12 random sites in Idaho Inlet and Port Althorp, respectively, to provide contrast between sites with and without sea otters. Densities and biomass of intertidal clams were greater in the Lower Bay than either the East or West Arms. Mean densities (#/0.25m2) of all species of clams > 10.0 mm total length were 96.5 at preferred sites, 32.8 in the Lower Bay, 12.2 in the East Arm, 6.6 in the West Arm, 11.32 at Port Althorp and 27.1 at Idaho Inlet. Clam densities were lower in the Upper Arms of Glacier Bay, compared to the Lower Bay and were similar to densities at Port Althorp. In the Lower Bay, clam densities were nearly twice as high at preferred clam sites compared to those systematically sampled. Species of Macoma were the numerically dominant intertidal clam at most sites in Glacier Bay, while Protothaca staminea was dominant at Idaho Inlet and Port Althorp. Biomas (g/0.25m2) was higher in the Lower Bay (23.5) than either Arm (2.1 and .91) and higher at preferred sites (73.4) than systematically selected sites in Glacier Bay. Biomass estimates at Port Althorp were 5.2 and 9.7 at Idaho Inlet. Biomass estimates were dominated by species of Saxidomus, Protothaca and Mya in Glacier Bay and by Protothaca and Saxidomus at Idaho Inlet and Port Althrop. We suspect differences in density and biomass relate to habitat differences between areas within Glacier Bay

Persistent organochlorine pollutants in eggs of colonial waterbirds from Galveston Bay and East Texas, USA

USGS Publications Warehouse

Frank, D.S.; Mora, M.A.; Sericano, J.L.; Blankenship, Alan L.; Kannan, K.; Giesy, J.P.

2001-01-01

Eggs of neotropic cormorants (Phalacrocorax brasilianus), black-crowned night herons (Nycticorax nycticorax), and great egrets (Ardea alba) nesting on several locations in Galveston Bay (TX, USA) and at two control sites outside the bay were collected during April–May 1996 and analyzed for chlorinated pesticides, PCBs, polychlorinated dibenzo-p-dioxins, and polychlor-inated dibenzofurans. Additionally, concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin equivalents (TCDD-EQs) were determined by use of relative potency factors (TEQs) or the H4IIE-luc bioassay TCDD-EQs. Concentrations of 1,1,-dichloro-2,2-bis(p-chlo-rophenyl)ethylene (DDE) were greater in eggs of neotropic cormorants from Alexander Island (mean = 1,040 ng/g wet wt) in the Houston Ship Channel (Houston, TX, USA) and in those from Telfair Island (mean = 1,460 ng/g wet wt), a reference location outside the bay, than in most locations inside the bay (mean range = 119–453 ng/g wet wt). Mean PCB concentrations were greater in eggs of neotropic cormorants from Alexander Island (mean = 5,720 ng/g wet wt) than in eggs of cormorants from areas farther away from the ship channel, including two reference sites outside the bay (mean range = 404–3,140 ng/g wet wt). The TCDD was the main dioxin congener detected in eggs from all locations within Galveston Bay. Instrumental TEQs in eggs ranged from 67 pg/g wet weight at control sites to 452 pg/g wet weight at Alexander Island. Concentrations of TCDD-EQs determined in the H4IIE assay were correlated with instrumental TEQs and were greater in eggs of cormorants from islands within the bay, although these were farther away from the ship channel. Overall, concentrations of DDE, PCBs, TCDD, and TCDD-EQs were less than the threshold levels known to affect reproduction. However, some eggs contained concentrations of total PCBs or DDE greater than what would elicit adverse effects on birds. No identifiable deformities or abnormalities were detected in embryos collected from all sites.

Carbenoxolone prevents chemical eye ischemia-reperfusion-induced cell death via 11β-hydroxysteroid dehydrogenase type 1 inhibition.

PubMed

Choi, Kyoung-Jin; Na, Yoon-Ju; Park, Sung Bum; Jung, Won Hoon; Sung, Hye-Rim; Kim, Ki Young

2017-09-01

Glaucoma is one of the leading causes of preventable blindness diseases, affecting more than 2 million people in the United States. Recently, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors were found to exert preventive effects against glaucoma. Therefore, we investigated whether carbenoxolone (CBX), an 11β-HSD1 inhibitor, prevents chemical ischemia-reperfusion-induced cell death in human trabecular meshwork (HTM) cells. The present study demonstrated that CBX inhibited cell death caused by iodoacetic acid (IAA)-induced ischemia-reperfusion, and its effect was associated with the inhibition of 11β-HSD1 expression and activity. Furthermore, CBX reversed the IAA-induced structural damage on filamentous actin in HTM cells. In IAA-treated cells, the levels of 11β-HSD1 and the apoptosis-related factors Bax and FASL were increased throughout the reperfusion period, and CBX was able to attenuate the expression of 11β-HSD1 and the apoptosis-related factors. CBX also effectively suppressed IAA-induced intracellular ROS formation and cytochrome c release, which are involved in the mitochondrial apoptosis pathway. In addition, IAA-induced chemical ischemia-reperfusion stimulated TNF-α expression and NF-κB p65 phosphorylation, and these effects were attenuated by CBX. 11β-HSD1 RNAi also suppressed IAA-induced cell apoptosis via reduction of oxidative stress and inhibition of the pro-inflammatory pathway. Taken together, the present study demonstrated that the inhibition of 11β-HSD1 protected the TM against chemical ischemia-reperfusion injury, suggesting that the use of 11β-HSD1 inhibitors could be a useful strategy for glaucoma therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases

PubMed Central

von Nussbaum, Franz; Li, Volkhart M-J; Allerheiligen, Swen; Anlauf, Sonja; Bärfacker, Lars; Bechem, Martin; Delbeck, Martina; Fitzgerald, Mary F; Gerisch, Michael; Gielen-Haertwig, Heike; Haning, Helmut; Karthaus, Dagmar; Lang, Dieter; Lustig, Klemens; Meibom, Daniel; Mittendorf, Joachim; Rosentreter, Ulrich; Schäfer, Martina; Schäfer, Stefan; Schamberger, Jens; Telan, Leila A; Tersteegen, Adrian

2015-01-01

Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease–anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases. PMID:26083237

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study.

PubMed

Ewenstein, B M; Gomperts, E D; Pearson, S; O'Banion, M E

2004-09-01

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.

Raffaello Multi-Purpose Logistics Module (MPLM) in Discovery Cargo Bay

NASA Technical Reports Server (NTRS)

2005-01-01

Launched on July 26, 2005 from the Kennedy Space Center in Florida, STS-114 was classified as Logistics Flight 1. Among the Station-related activities of the mission were the delivery of new supplies and the replacement of one of the orbital outpost's Control Moment Gyroscopes (CMGs). STS-114 also carried the Raffaello Multi-Purpose Logistics Module (MPLM) and the External Stowage Platform-2. Back dropped by popcorn-like clouds, the MPLM can be seen in the cargo bay as Discovery undergoes rendezvous and docking operations. Cosmonaut Sergei K. Kriklev, Expedition 11 Commander, and John L. Phillips, NASA Space Station officer and flight engineer photographed the spacecraft from the International Space Station (ISS).

Raffaello Multi-Purpose Logistics Module (MPLM) in Discovery Cargo Bay

NASA Technical Reports Server (NTRS)

2005-01-01

Launched on July 26 2005 from the Kennedy Space Center in Florida, STS-114 was classified as Logistics Flight 1. Among the Station-related activities of the mission were the delivery of new supplies and the replacement of one of the orbital outpost's Control Moment Gyroscopes (CMGs). STS-114 also carried the Raffaello Multi-Purpose Logistics Module (MPLM) and the External Stowage Platform-2. Back dropped by popcorn-like clouds, the MPLM can be seen in the cargo bay as Discovery undergoes rendezvous and docking operations. Cosmonaut Sergei K. Kriklev, Expedition 11 Commander, and John L. Phillips, NASA Space Station officer and flight engineer photographed the spacecraft from the International Space Station (ISS).

Latest progress from the Daya Bay reactor neutrino experiment

NASA Astrophysics Data System (ADS)

Wang, Zhe; Daya Bay Collaboration

2016-05-01

Recently the Daya Bay reactor neutrino experiment has presented several new results about neutrino and reactor physics after acquiring a large data sample and after gaining a more sophisticated understanding of the experiment. In this talk I will introduce the latest progress made by the experiment including a three-flavor neutrino oscillation analysis using neutron capture on gadolinium, which gave sin2 2θ 13 = 0.084 ± 0.005 and |Δm2 ee| = (2.42 ±0.11) × 10-3 eV2, an independent θ 13 measurement using neutron capture on hydrogen, a search for a light sterile neutrino, and a measurement of the reactor antineutrino flux and spectrum.

IMAX films Destiny in Atlantis's payload bay

NASA Technical Reports Server (NTRS)

2001-01-01

In the Payload Changeout Room at Launch Pad 39A, a film crew from IMAX prepares its 3-D movie camera to film the payload bay door closure on Atlantis. Behind them is the payload, the U.S. Laboratory Destiny, which will fly on mission STS-98, the seventh construction flight to the ISS. Destiny, a key element in the construction of the International Space Station, is 28 feet long and weighs 16 tons. This research and command-and-control center is the most sophisticated and versatile space laboratory ever built. It will ultimately house a total of 23 experiment racks for crew support and scientific research. Launch of Atlantis is Feb. 7 at 6:11 p.m. EST.

Summary of oceanographic and water-quality measurements in Barnegat Bay, New Jersey, 2014–15

USGS Publications Warehouse

Suttles, Steven E.; Ganju, Neil K.; Montgomery, Ellyn T.; Dickhudt, Patrick J.; Borden, Jonathan; Brosnahan, Sandra M.; Martini, Marinna A.

2016-09-26

Scientists and technical support staff from the U.S. Geological Survey measured suspended-sediment concentrations, currents, pressure, and water temperature in two tidal creeks, Reedy Creek and Dinner Creek, in Barnegat Bay, New Jersey, from August 11, 2014, to July 10, 2015 as part of the Estuarine Physical Response to Storms project (GS2–2D). The oceanographic and water-quality data quantify suspended-sediment transport in Reedy Creek and Dinner Creek, which are part of a tidal marsh wetland complex in the Edwin B. Forsythe National Wildlife Refuge. All deployed instruments were removed between January 7, 2015, and April 14, 2015, to avoid damage by ice.

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models.

PubMed

Troiani, Teresa; Napolitano, Stefania; Martini, Giulia; Martinelli, Erika; Cardone, Claudia; Normanno, Nicola; Vitagliano, Donata; Morgillo, Floriana; Fenizia, Francesca; Lambiase, Matilde; Formisano, Luigi; Bianco, Roberto; Ciardiello, Davide; Ciardiello, Fortunato

2015-09-15

The use of cetuximab in the treatment of metastatic colorectal cancer is limited by development of resistance. We have investigated in three models of highly epidermal growth factor receptor (EGFR)-dependent colorectal cancer xenografts, the effect of maintenance therapy with different kinase inhibitors alone or in combination with cetuximab, after cytotoxic treatment induction with irinotecan plus cetuximab. SW48, LIM 1215, and GEO colorectal cancer cell lines were engrafted into nude mice and treated for 3 weeks with irinotecan and/or cetuximab. The combined treatment induced a significant reduction of tumor size. A subsequent experiment was performed in all three xenograft models in which after an induction treatment with irinotecan plus cetuximab, mice were randomly assigned to one of the following treatments: control, cetuximab, regorafenib, a selective PIK3CA inhibitor (PIK3CAi), a selective MEK inhibitor (MEKi), and/or the combination of each inhibitor with cetuximab. The cetuximab plus MEKi treatment determined the best antitumor activity with suppression of tumor growth. This effect was prolonged for 13 to 15 weeks after cessation of therapy and was accompanied by prolonged survival. Antitumor activity was accompanied by inhibition of the MAPK and MEK pathways. Moreover, in the cetuximab plus MEKi-treated SW48 xenograft group, KRAS mutations as a mechanism of acquired resistance were detected in 25% of cases compared with 75% KRAS mutations in the MEKi-treated group. A possible strategy to prevent and/or overcome resistance to anti-EGFR inhibitors in metastatic colorectal cancer is a maintenance therapy with cetuximab plus MEKi after an initial treatment with irinotecan plus cetuximab. ©2015 American Association for Cancer Research.

Combination of aptamer and drug for reversible anticoagulation in cardiopulmonary bypass.

PubMed

Gunaratne, Ruwan; Kumar, Shekhar; Frederiksen, James W; Stayrook, Steven; Lohrmann, Jens L; Perry, Kay; Bompiani, Kristin M; Chabata, Charlene V; Thalji, Nabil K; Ho, Michelle D; Arepally, Gowthami; Camire, Rodney M; Krishnaswamy, Sriram; Sullenger, Bruce A

2018-06-04

Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.

A three-dimensional construction of the active site (region 507-749) of human neutral endopeptidase (EC.3.4.24.11).

PubMed

Tiraboschi, G; Jullian, N; Thery, V; Antonczak, S; Fournie-Zaluski, M C; Roques, B P

1999-02-01

A three-dimensional model of the 507-749 region of neutral endopeptidase-24.11 (NEP; E.C.3.4.24.11) was constructed integrating the results of secondary structure predictions and sequence homologies with the bacterial endopeptidase thermolysin. Additional data were extracted from the structure of two other metalloproteases, astacin and stromelysin. The resulting model accounts for the main biological properties of NEP and has been used to describe the environment close to the zinc atom defining the catalytic site. The analysis of several thiol inhibitors, complexed in the model active site, revealed the presence of a large hydrophobic pocket at the S1' subsite level. This is supported by the nature of the constitutive amino acids. The computed energies of bound inhibitors correspond with the relative affinities of the stereoisomers of benzofused macrocycle derivatives of thiorphan. The model could be used to facilitate the design of new NEP inhibitors, as illustrated in the paper.

Early calcification of the aortic Mitroflow pericardial bioprosthesis in the elderly.

PubMed

Alvarez, Jose Rubio; Sierra, Juan; Vega, Marino; Adrio, Belen; Martinez-Comendador, Jose; Gude, Francisco; Martinez-Cereijo, Jose; Garcia, Javier

2009-11-01

We report our experience in the elderly with aortic valve replacement using the Mitroflow A12 pericardial bioprosthesis. From January 1993 to January 2006, 491 patients over the age of 70 years received an aortic Mitroflow A12 bioprosthesis implantation. Concomitant procedures included coronary artery bypass grafting in 20% of patients. All patients had routine postoperative Echo-Doppler studies at discharge, one month and a mean of 11.1 months after surgery and annually thereafter. Twenty (4%) patients underwent a second aortic valve replacement due to bioprosthetic valve dysfunction (Group 2). Calcified stenosis was the most common finding at reoperation (98%). Median time to valve reoperation was 76 months. Of patients requiring reoperation, median age at first and second implantation was 73 (70-78) and 79 (76-83) years, respectively. For all patients, freedom from structural valve dysfunction (SVD) was 95+/-3% at 5 years and 55.8+/-2% at 10 years. Bioprosthetic valve deterioration was identified in 27 patients (Group 1). Median age of these patients at first operation and at diagnosis of deterioration by echo was 75 (70-84) and 77 (70-82) years, respectively. The median interval between operation and detection of bioprosthesis valve deterioration was 46 months. Among the total patient population, freedom from bioprosthetic deterioration was 85.7+/-2% at 5 years and 33.5+/-4% at 10 years. The Mitroflow A12 pericardial bioprosthesis provides less than optimal performance in elderly patients.

Development of a potent and selective FLT3 kinase inhibitor by systematic expansion of a non-selective fragment-screening hit.

PubMed

Nakano, Hirofumi; Hasegawa, Tsukasa; Imamura, Riyo; Saito, Nae; Kojima, Hirotatsu; Okabe, Takayoshi; Nagano, Tetsuo

2016-05-01

A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information. Copyright © 2016 Elsevier Ltd. All rights reserved.

Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

PubMed

Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

2017-09-01

The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

KQED and Its Audience.

ERIC Educational Resources Information Center

McKay, Bruce

KQED is the community-supported, non-commercial public television station for the San Francisco Bay Area and Northern California. A telephone survey was conducted to determine the size, composition, and general viewing patterns of the station's audience and to ascertain what programs were or were not popular. A total of 11,538 telephone interviews…

46 CFR 12.05-11 - General provisions respecting merchant mariner's document endorsed for service as able seamen.

Code of Federal Regulations, 2012 CFR

2012-10-01

... as a rating forming part of a navigational watch (RFPNW) on a seagoing ship of 500 GT or more. (b) An... seaman—on freight vessels, 500 gross tons or less on bays or sounds, and on tugs, towboats, and barges on...