Chromophore-assisted light inactivation of pKi-67 leads to inhibition of ribosomal RNA synthesis.

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Rahmanzadeh, R; Hüttmann, G; Gerdes, J; Scholzen, T

2007-06-01

Expression of the nuclear Ki-67 protein (pKi-67) is strongly associated with cell proliferation. For this reason, antibodies against this protein are widely used as prognostic tools for the assessment of cell proliferation in biopsies from cancer patients. Despite this broad application in histopathology, functional evidence for the physiological role of pKi-67 is still missing. Recently, we proposed a function of pKi-67 in the early steps of ribosomal RNA (rRNA) synthesis. Here, we have examined the involvement of pKi-67 in this process by photochemical inhibition using chromophore-assisted light inactivation (CALI). Anti-pKi-67 antibodies were labelled with the fluorochrome fluorescein 5(6)-isothiocyanate and were irradiated after binding to their target protein. Performing CALI in vitro on cell lysates led to specific cross-linking of pKi-67. Moreover, the upstream binding factor (UBF) necessary for rRNA transcription was also partly subjected to cross-link formation, indicating a close spatial proximity of UBF and pKi-67. CALI in living cells, using micro-injected antibody, caused a striking relocalization of UBF from foci within the nucleoli to spots located at the nucleolar rim or within the nucleoplasm. pKi-67-CALI resulted in dramatic inhibition of RNA polymerase I-dependent nucleolar rRNA synthesis, whereas RNA polymerase II-dependent nucleoplasmic RNA synthesis remained almost unaltered. Our data presented here argue for a crucial role of pKi-67 in RNA polymerase I-dependent nucleolar rRNA synthesis.

Three-dimensional organization of pKi-67: a comparative fluorescence and electron tomography study using FluoroNanogold.

Science.gov (United States)

Cheutin, Thierry; O'Donohue, Marie-Françoise; Beorchia, Adrien; Klein, Christophe; Kaplan, Hervé; Ploton, Dominique

2003-11-01

The monoclonal antibody (MAb) Ki-67 is routinely used in clinical studies to estimate the growth fraction of tumors. However, the role of pKi-67, the protein detected by the Ki-67 MAb, remains elusive, although some biochemical data strongly suggest that it might organize chromatin. To better understand the functional organization of pKi-67, we studied its three-dimensional distribution in interphase cells by confocal microscopy and electron tomography. FluoroNanogold, a single probe combining a dense marker with a fluorescent dye, was used to investigate pKi-67 organization at the optical and ultrastructural levels. Observation by confocal microscopy followed by 3D reconstruction showed that pKi-67 forms a shell around the nucleoli. Double labeling experiments revealed that pKi-67 co-localizes with perinucleolar heterochromatin. Electron microscopy studies confirmed this close association and demonstrated that pKi-67 is located neither in the fibrillar nor in the granular components of the nucleolus. Finally, spatial analyses by electron tomography showed that pKi-67 forms cords 250-300 nm in diameter, which are themselves composed of 30-50-nm-thick fibers. These detailed comparative in situ analyses strongly suggest the involvement of pKi-67 in the higher-order organization of perinucleolar chromatin.

Suppression of cell division by pKi-67 antisense-RNA and recombinant protein.

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Duchrow, M; Schmidt, M H; Zingler, M; Anemüller, S; Bruch, H P; Broll, R

2001-01-01

The human antigen defined by the monoclonal antibody Ki-67 (pKi-67) is a human nuclear protein strongly associated with cell proliferation and found in all tissues studied. It is widely used as a marker of proliferating cells, yet its function is unknown. To investigate its function we suppressed pKi-67 expression by antisense RNA and overexpressed a partial structure of pKi-67 in HeLa cells. A BrdU-incorporation assay showed a significant decrease in DNA synthesis after antisense inhibition. Cell cycle analysis indicated a higher proportion of cells in G1 phase and a lower proportion of cells in S phase while the number of G(2)/M phase cells remained constant. Overexpression of a recombinant protein encoding three of the repetitive elements from exon 13 of pKi-67 had a similar effect to that obtained by antisense inhibition. The similarity of the effect of expressing 'Ki-67 repeats' and pKi-67 antisense RNA could be explained by a negative effect on the folding of the endogenous protein in the endoplasmatic reticulum. Furthermore excessive self-association of pKi-67 via the repeat structure could inhibit its nuclear transport, preventing it from getting to its presumptive site of action. We conclude that the Ki-67 protein has an important role in the regulation of the cell cycle, which is mediated in part by its repetitive elements. Copyright 2001 S. Karger AG, Basel

Public Key Infrastructure (PKI) Interoperability: A Security Services Approach to Support Transfer of Trust

National Research Council Canada - National Science Library

Hansen, Anthony

1999-01-01

.... This thesis defines interoperability as the capacity to support trust through retention of security services across PKI domains at a defined level of assurance and examines the elements of PKI...

The PKI in West Timor and Nusa Tenggara Timur 1965 and beyond

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Steven Farram

2010-12-01

Full Text Available This paper examines the aftermath in West Timor and elsewhere in the province of Nusa Tenggara Timur (NTT, of the 30 September 1965 ‘coup’ in Jakarta that resulted in the banning of the Indonesian Communist Party (PKI and the large-scale killing of its members and associates. An assessment is given of PKI strength in NTT in 1965, along with an analysis of the killings, including the numbers killed, who carried out the killings, who was targeted, and the fate of those captured, but not killed. Consideration is also given to the ongoing effects in NTT of accusations of PKI membership.

Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.

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Mallon, Robert; Feldberg, Larry R; Lucas, Judy; Chaudhary, Inder; Dehnhardt, Christoph; Santos, Efren Delos; Chen, Zecheng; dos Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Venkatesan, Aranapakam; Hollander, Irwin

2011-05-15

The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor). Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587. ©2011 AACR.

A cGMP kinase mutant with increased sensitivity to the protein kinase inhibitor peptide PKI(5-24).

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Ruth, P; Kamm, S; Nau, U; Pfeifer, A; Hofmann, F

1996-01-01

Synthetic peptides corresponding to the active domain of the heat-stable inhibitor protein PKI are very potent inhibitors of cAMP-dependent protein kinase, but are extremely weak inhibitors of cGMP-dependent protein kinase. In this study, we tried to confer PKI sensitivity to cGMP kinase by site-directed mutagenesis. The molecular requirements for high affinity inhibition by PKI were deduced from the crystal structure of the cAMP kinase/PKI complex. A prominent site of interaction are residues Tyr235 and Phe239 in the catalytic subunit, which from a sandwich-like structure with Phe10 of the PKI(5-24) peptide. To increase the sensitivity for PKI, the cGMP kinase codons at the corresponding sites, Ser555 and Ser559, were changed to Tyr and Phe. The mutant cGMP kinase was stimulated half maximally by cGMP at 3-fold higher concentrations (240 nM) than the wild type (77 nM). Wild type and mutant cGMP kinase did not differ significantly in their Km and Vmax for three different substrate peptides. The PKI(5-24) peptide inhibited phosphotransferase activity of the mutant cGMP kinase with higher potency than that of wild type, with Ki values of 42 +/- .3 microM and 160 +/- .7 microM, respectively. The increased affinity of the mutant cGMP kinase was specific for the PKI(5-24) peptide. Mutation of the essential Phe10 in the PKI(5-24) sequence to an Ala yielded a peptide that inhibited mutant and wild type cGMP kinase with similar potency, with Ki values of 160 +/- 11 and 169 +/- 27 microM, respectively. These results suggest that the mutations Ser555Tyr and Ser559Phe are required, but not sufficient, for high affinity inhibition of cGMP kinase by PKI.

Pengembangan Game Edukatif G30S/PKI Berbasis Android

Directory of Open Access Journals (Sweden)

Annisa Hedlina Hendraputri

2014-11-01

Full Text Available Gaya hidup masyarakat zaman sekarang tak pernah lepas dari kemajuan teknologi. Masyarakat menengah keatas, baik dari anak-anak hingga orang dewasa, hampir tidak ada yang tidak meggunakan perangkat mobile seperti handphone atau tablet. Namun sayangnya masyarakat zaman sekarang cenderung apatis dengan kondisi sekitarnya, bahkan tidak mengenal sejarah negaranya. Penelitian ini dilakukan untuk mendekatkan kembali anak-anak dengan sejarah terutama peristiwa G30S/PKI melalui game perangkat seluler berbasis Android. Penelitian ini dilakukan dengan menerapkan tahap pengembangan MDLC (Multimedia Development Life Cycle mulai dari tahap penentuan konsep sampai dengan sidtribusi. Sebagai sumber yang relevan, cerita sejarah diambil langsung dari Monumen Pancasila Sakti di Lubang Buaya, Jakarta Timur, sebagai salah satu tempat bersejarah yang erat kaitannya dengan peristiwa G30S/PKI. Hasil dari penelitian ini berupa suatu aplikasi permainan yang menceritakan peristiwa sejarah G30S/PKI yang dikemas menjadi aplikasi perangkat seluler dengan sistem operasi Android. Penelitian ini diharapkan mampu menarik minat anak-anak khususnya usia 9 sampai dengan 12 tahun untuk mempelajari dan mencintai sejarah Indonesia.

Binding-dependent disorder-order transition in PKI alpha: a fluorescence anisotropy study.

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Hauer, J A; Taylor, S S; Johnson, D A

1999-05-25

The conformational flexibility of peptidyl ligands may be an essential element of many peptide-macromolecular interactions. Consequently, the alpha-carbonyl backbone flexibility of the 8 kDa protein kinase inhibitor (PKI alpha) peptide of cAMP-dependent protein kinase (cAPK) free in solution and bound to cAPK was assessed by time-resolved fluorescence anisotropy. Specifically, three full-length, single-site PKI alpha mutants (V3C, S28C, and S59C) were prepared, and fluorescein iodoacetamide (FI) was selectively conjugated to the side chains of each substituted cysteine. The time-resolved anisotropy decay profiles of the labeled mutants were well fit to a model-free nonassociative biexponential equation. Free in solution, the three labeled proteins had very similar anisotropy decays arising primarily from local alpha-carbonyl backbone movements. Only a small fraction of the anisotropy decay was associated with slower, whole-body tumbling, confirming that PKI alpha is highly disordered at all three locations. Complexation of the mutants with the catalytic (C) subunit of cAPK decreased the rate of whole-body tumbling for all three mutants. The effects on the rapid decay processes, however, were dependent upon the site of conjugation. The anisotropy decay profiles of both FI-V3C- and FI-S28C-PKI alpha were associated with significantly reduced contributions from the fast decay processes, while that of FI-S59C-PKI alpha was largely unaffected by binding to the C-subunit. The results suggest that the cAPK-binding domain of PKI alpha extends from the its N-terminus to residues beyond Ser28 but does not include the segment around Ser59, which is still part of a highly flexible domain when bound to the C-subunit.

Tissue-specific expression and regulation by 1,25(OH)2D3 of chick protein kinase inhibitor (PKI) mRNA.

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Marchetto, G S; Henry, H L

1997-02-01

The heat-stable protein kinase inhibitor (PKI) protein is a specific and potent competitive inhibitor of the catalytic subunit of cAMP-dependent protein kinase (PKA). Previously, it has been shown that vitamin D status affects chick kidney PKI activity: a 5- to 10-fold increase in PKI activity was observed in kidneys of chronically vitamin D-deficient chicks and treatment with 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) in cultured kidney cells resulted in a 95% decrease in PKI activity. The authors have recently cloned the cDNA for chick kidney PKI and have used the coding sequence to study the regulation of PKI mRNA. Northern analysis showed the expression of two PKI messages, which are 2.7 and 3.3 kb in size. These mRNAs are expressed in brain, muscle, testis, and kidney, but not in pancreas, liver, or intestine. PKI mRNA steady-state levels are downregulated by 47% in kidneys from vitamin D-replete chicks as compared to vitamin D-deficient chicks. PKI mRNA levels in brain, muscle, and testis are not affected by vitamin D status. Treatment of primary chick kidney cultures treated with 10(-7) M 1,25(OH)2D3 for 24h resulted in a 20-30% decrease in PKI mRNA. 1,25(OH)2D3 treatment does not affect the stability of PKI mRNA as determined by treatment of cell cultures with actinomycin D. This study shows that 1,25(OH)2D3 directly and tissue-specifically downregulates PKI mRNA in the chick kidney.

Endogenous PKI gamma limits the duration of the anti-apoptotic effects of PTH and beta-adrenergic agonists in osteoblasts.

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Chen, Xin; Song, In-Hwan; Dennis, James E; Greenfield, Edward M

2007-05-01

PKI gamma knockdown substantially extended the anti-apoptotic effects of PTH and beta-adrenergic agonists, whereas PKI gamma overexpression decreased these effects. Therefore, inhibition of PKI gamma activity may provide a useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. PTH has both catabolic and anabolic effects on bone, which are primarily caused by cAMP/protein kinase A (PKA) signaling and regulation of gene expression. We previously showed that protein kinase inhibitor-gamma (PKI gamma) is required for efficient termination of cAMP/PKA signaling and gene expression after stimulation with PTH or beta-adrenergic agonists. Inhibition of osteoblast apoptosis is thought to be an important, but transient, mechanism partly responsible for the anabolic effects of intermittent PTH. Therefore, we hypothesized that endogenous PKI gamma also terminates the anti-apoptotic effect of PTH. PKI gamma knockdown by antisense transfection or siRNA was used to examine the ability of endogenous PKI gamma to modulate the anti-apoptotic effects of PTH and beta-adrenergic agonists in ROS 17/2.8 cells. Knockdown of PKI gamma substantially extended the anti-apoptotic effects of PTH, whether apoptosis was induced by etoposide or dexamethasone. In contrast, overexpression of PKI gamma decreased the anti-apoptotic effect of PTH pretreatment. This study is also the first demonstration that beta-adrenergic agonists mimic the anti-apoptotic effects of PTH in osteoblasts. Moreover, PKI gamma knockdown also substantially extended this anti-apoptotic effect of beta-adrenergic agonists. Taken together, these results show that endogenous PKI gamma limits the duration of the anti-apoptotic effects of cAMP/PKA signaling in osteoblasts. Because significant individual variability exists in the anabolic responses to PTH therapy in current clinical treatment of osteoporosis, inhibition of PKI gamma activity may provide a

Association of pKi-67 with satellite DNA of the human genome in early G1 cells.

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Bridger, J M; Kill, I R; Lichter, P

1998-01-01

pKi-67 is a nucleolar antigen that provides a specific marker for proliferating cells. It has been shown previously that pKi-67's distribution varies in a cell cycle-dependent manner: it coats all chromosomes during mitosis, accumulates in nuclear foci during G1 phase (type I distribution) and localizes within nucleoli in late G1 S and G2 phase (type II distribution). Although no function has as yet been ascribed to pKi-67, it has been found associated with centromeres in G1. In the present study the distribution pattern of pKi-67 during G1 in human dermal fibroblasts (HDFs) was analysed in more detail. Synchronization experiments show that in very early G1 cells pKi-67 coincides with virtually all satellite regions analysed, i.e. with centromeric (alpha-satellite), telomeric (minisatellite) and heterochromatic blocks (satellite III) on chromosomes 1 and Y (type Ia distribution). In contrast, later in the G1 phase, a smaller fraction of satellite DNA regions are found collocalized with pKi-67 foci (type Ib distribution). When all pKi-67 becomes localized within nucleoli, even fewer satellite regions remain associated with the pKi-67 staining. However, all centromeric and short arm regions of the acrocentric chromosomes, which are in very close proximity to or even contain the rRNA genes, are collocalized with anti-pKi-67 staining throughout the remaining interphase of the cell cycle. Thus, our data demonstrate that during post-mitotic reformation and nucleogenesis there is a progressive decline in the fraction of specific satellite regions of DNA that remain associated with pKi-67. This may be relevant to nucleolar reformation following mitosis.

High-level mRNA quantification of proliferation marker pKi-67 is correlated with favorable prognosis in colorectal carcinoma.

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Ihmann, Thomas; Liu, Jian; Schwabe, Wolfgang; Häusler, Peter; Behnke, Detlev; Bruch, Hans-Peter; Broll, Rainer; Windhövel, Ute; Duchrow, Michael

2004-12-01

The present study retrospectively examines the expression of pKi-67 mRNA and protein in colorectal carcinoma and their correlation to the outcome of patients. Immunohistochemistry and quantitative RT-PCR were used to analyze the expression of pKi-67 in 43 archival specimens of patients with curatively resected primary colorectal carcinoma, who were not treated with neo-adjuvant therapy. We determined a median pKi-67 (MIB-1) labeling index of 31.3% (range 10.3-66.4%), and a mean mRNA level of 0.1769 (DeltaC(T): range 0.01-0.69); indices and levels did not correlate. High pKi-67 mRNA DeltaC(T) values were associated with a significantly favorable prognosis, while pKi-67 labeling indices were not correlated to prognostic outcome. A multivariate analysis of clinical and biological factors indicated that tumor stage (UICC) and pKi-67 mRNA expression level were independent prognostic factors. Quantitatively determined pKi-67 mRNA can be a good and new prognostic indicator for primary resected colorectal carcinoma.

Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor.

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Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Soloveva, Veronica; Venkatesan, Aranapakam; Dehnhardt, Christoph; Delos Santos, Efren; Chen, Zecheng; Dos Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Gibbons, Jay

2010-04-01

PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR; IC(50) versus PI3K-alpha = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non-small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm(3) to 129 mm(3) and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR.

Protein kinase inhibitor peptide (PKI): a family of endogenous neuropeptides that modulate neuronal cAMP-dependent protein kinase function.

Science.gov (United States)

Dalton, George D; Dewey, William L

2006-02-01

Signal transduction cascades involving cAMP-dependent protein kinase are highly conserved among a wide variety of organisms. Given the universal nature of this enzyme it is not surprising that cAMP-dependent protein kinase plays a critical role in numerous cellular processes. This is particularly evident in the nervous system where cAMP-dependent protein kinase is involved in neurotransmitter release, gene transcription, and synaptic plasticity. Protein kinase inhibitor peptide (PKI) is an endogenous thermostable peptide that modulates cAMP-dependent protein kinase function. PKI contains two distinct functional domains within its amino acid sequence that allow it to: (1) potently and specifically inhibit the activity of the free catalytic subunit of cAMP-dependent protein kinase and (2) export the free catalytic subunit of cAMP-dependent protein kinase from the nucleus. Three distinct PKI isoforms (PKIalpha, PKIbeta, PKIgamma) have been identified and each isoform is expressed in the brain. PKI modulates neuronal synaptic activity, while PKI also is involved in morphogenesis and symmetrical left-right axis formation. In addition, PKI also plays a role in regulating gene expression induced by cAMP-dependent protein kinase. Future studies should identify novel physiological functions for endogenous PKI both in the nervous system and throughout the body. Most interesting will be the determination whether functional differences exist between individual PKI isoforms which is an intriguing possibility since these isoforms exhibit: (1) cell-type specific tissue expression patterns, (2) different potencies for the inhibition of cAMP-dependent protein kinase activity, and (3) expression patterns that are hormonally, developmentally and cell-cycle regulated. Finally, synthetic peptide analogs of endogenous PKI will continue to be invaluable tools that are used to elucidate the role of cAMP-dependent protein kinase in a variety of cellular processes throughout the nervous

Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values.

Science.gov (United States)

Meltzer, H Y; Matsubara, S; Lee, J C

1989-10-01

The pKi values of 13 reference typical and 7 reference atypical antipsychotic drugs (APDs) for rat striatal dopamine D-1 and D-2 receptor binding sites and cortical serotonin (5-HT2) receptor binding sites were determined. The atypical antipsychotics had significantly lower pKi values for the D-2 but not 5-HT2 binding sites. There was a trend for a lower pKi value for the D-1 binding site for the atypical APD. The 5-HT2 and D-1 pKi values were correlated for the typical APD whereas the 5-HT2 and D-2 pKi values were correlated for the atypical APD. A stepwise discriminant function analysis to determine the independent contribution of each pKi value for a given binding site to the classification as a typical or atypical APD entered the D-2 pKi value first, followed by the 5-HT2 pKi value. The D-1 pKi value was not entered. A discriminant function analysis correctly classified 19 of 20 of these compounds plus 14 of 17 additional test compounds as typical or atypical APD for an overall correct classification rate of 89.2%. The major contributors to the discriminant function were the D-2 and 5-HT2 pKi values. A cluster analysis based only on the 5-HT2/D2 ratio grouped 15 of 17 atypical + one typical APD in one cluster and 19 of 20 typical + two atypical APDs in a second cluster, for an overall correct classification rate of 91.9%. When the stepwise discriminant function was repeated for all 37 compounds, only the D-2 and 5-HT2 pKi values were entered into the discriminant function.(ABSTRACT TRUNCATED AT 250 WORDS)

Suppression of Zika Virus Infection and Replication in Endothelial Cells and Astrocytes by PKA Inhibitor PKI 14-22.

Science.gov (United States)

Cheng, Fan; Ramos da Silva, Suzane; Huang, I-Chueh; Jung, Jae U; Gao, Shou-Jiang

2018-02-15

The recent outbreak of Zika virus (ZIKV), a reemerging flavivirus, and its associated neurological disorders, such as Guillain-Barré (GB) syndrome and microcephaly, have generated an urgent need to develop effective ZIKV vaccines and therapeutic agents. Here, we used human endothelial cells and astrocytes, both of which represent key cell types for ZIKV infection, to identify potential inhibitors of ZIKV replication. Because several pathways, including the AMP-activated protein kinase (AMPK), protein kinase A (PKA), and mitogen-activated protein kinase (MAPK) signaling pathways, have been reported to play important roles in flavivirus replication, we tested inhibitors and agonists of these pathways for their effects on ZIKV replication. We identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. PKI effectively suppressed the replication of ZIKV from both the African and Asian/American lineages with a high efficiency and minimal cytotoxicity. While ZIKV infection does not induce PKA activation, endogenous PKA activity is essential for supporting ZIKV replication. Interestingly, in addition to PKA, PKI also inhibited another unknown target(s) to block ZIKV replication. PKI inhibited ZIKV replication at the postentry stage by preferentially affecting negative-sense RNA synthesis as well as viral protein translation. Together, these results have identified a potential inhibitor of ZIKV replication which could be further explored for future therapeutic application. IMPORTANCE There is an urgent need to develop effective vaccines and therapeutic agents against Zika virus (ZIKV) infection, a reemerging flavivirus associated with neurological disorders, including Guillain-Barré (GB) syndrome and microcephaly. By screening for inhibitors of several cellular pathways, we have identified the PKA inhibitor PKI 14-22 (PKI) to be a potent inhibitor of ZIKV replication. We show that PKI effectively suppresses the replication of all ZIKV

Modelling of P-waves velocity function from the PKiKP and PKIKP phases; Modelizacion de la funcion velocidad para las ondas P a partir de las fases PKiKP y PKIKP

Energy Technology Data Exchange (ETDEWEB)

Ramirez-Nicolas, M.

2011-07-01

The structure of the Earth is characterized by a number of regions which have different physical properties. For their study one uses models such PREM or IASPEI91. These models describe the internal structure of the Earth providing us the theoretical values of the velocity of the waves that pass through each of these regions. In this paper we focus on the waves that cross the inner core (PKIKP), and the reflected waves on the surface of the inner core (PKiKP). The aim of this study is to identify the PKiKP and PKIKP phases in a seismogram and compare them with the theoretical values obtained from the models. Another objective of this work is to propose an expression for the propagation velocity of seismic waves at the discontinuity between the outer and inner core from the minimization of waste of time (time difference between the arrival of the wave PKIKP and PKiKP). For this study we have selected two earthquakes, one occurred in Colombia, 04/26/1999 (Mw 5.9) and the other in Peru-Ecuador 16/11/2007 (Mw = 6.8). We have analyzed only the seismograms from stations with epicentral distances between 130 degree centigrade and 140 degree centigrade, because of the interference phenomena between the PKIKP and the PKiKP for epicentral distances less than 130 degree centigrade. (Author) 14 refs.

THE PKI-FDR UPRISING OF 1948 AND US POLICY REGARDING THE DUTCH-INDONESIAN DISPUTE

Directory of Open Access Journals (Sweden)

Richard Mason

2009-01-01

Full Text Available This paper contends that the abortive PKI-FDR uprising in Indonesia during the last quarter of 1948 marked an important turning point in the American policy toward the Indonesian struggle for independence against the Dutch. Before 1948, American policy toward Southeast Asia was almost exclusively dictated by the imperatives of European considerations, hence was pro-Dutch. The outbreak of the PKI-FDR not only raised the scepter of Communism in Indonesia but also underscored the belief Indonesian nationalism had to be settled in a just and practical way as a precondition to fight communism. In the final analysis, however, it cannot be said that the PKI-FDR revolt was ultimately responsible for the American decision to support the Indonesians. When threat of sanction was finally instituted against the Dutch, it was again European considerations which dictate the move.

The proliferation marker pKi-67 organizes the nucleolus during the cell cycle depending on Ran and cyclin B.

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Schmidt, Mirko H H; Broll, Rainer; Bruch, Hans-Peter; Bögler, Oliver; Duchrow, Michael

2003-01-01

The proliferation marker pKi-67 ('Ki-67 antigen') is commonly used in clinical and research pathology to detect proliferating cells, as it is only expressed during cell-cycle progression. Despite the fact that this antigen has been known for nearly two decades, there is still no adequate understanding of its function. This study has therefore identified proteins that interact with pKi-67, using a yeast two-hybrid system. A mammalian two-hybrid system and immunoprecipitation studies were used to verify these interactions. Among other cell-cycle regulatory proteins, two binding partners associated with the small GTPase Ran were identified. In addition, DNA-structural and nucleolus-associated proteins binding to pKi-67 were found. Moreover, it was demonstrated that the N-terminal domain of pKi-67 is capable of self-binding to its own repeat region encoded by exon 13. Since RanBP, a protein involved in the transport of macromolecules over the nuclear lamina, was found to be a binding partner, a possible effect of pKi-67 on the localization of cell-cycle regulatory proteins was proposed. To test this hypothesis, a tetracycline-responsive gene expression system was used to induce the pKi-67 fragments previously used for the two-hybrid screens in HeLa cells. Subsequent immunostaining revealed the translocation of cyclin B1 from cytoplasm to nucleoli in response to this expression. It is suggested that pKi-67 is a Ran-associated protein with a role in the disintegration and reformation of the nucleolus and thereby in entry into and exit from the M-phase. Copyright 2002 John Wiley & Sons, Ltd.

pKI values of prazosin and idazoxan for receptors stimulated by neuronally released transmitter in the epididymal portion of rat isolated vas deferens.

Science.gov (United States)

Mackay, D; Kengatharan, M

1994-01-01

1. A new method has been used to measure pKI values of prazosin and idazoxan against neuronally-released transmitter in the epididymal portion of the rat isolated vas deferens. The most reproducible results were obtained with a prolonged antagonist equilibration time (1 h). 2. Under these conditions the pKI of prazosin was practically unaffected by addition of alpha, beta-methylene-adenosine-5'-triphosphate (10 microM) to desensitize purinoceptors. Addition of desmethylimipramine (DMI) (0.3 microM) produced a small, but statistically non-significant, reduction. 3. The same method has been used to measure the pKI of prazosin against exogenous noradrenaline. In the latter case addition of DMI (0.3 microM) and corticosterone (30 microM) together produced a statistically significant reduction in the apparent pKI of prazosin. 4. The new method for estimating pKI values shows that DMI itself acts either pseudo-irreversibly or non-competitively and may be reducing the apparent pKI of prazosin. 5. The pKI values obtained for prazosin and idazoxan against neuronally-released transmitter are in good agreement with those obtained by other workers for the actions of these drugs on alpha-adrenoceptors.

PKI-587 and sorafenib targeting PI3K/AKT/mTOR and Ras/Raf/MAPK pathways synergistically inhibit HCC cell proliferation.

Science.gov (United States)

Gedaly, Roberto; Angulo, Paul; Hundley, Jonathan; Daily, Michael F; Chen, Changguo; Evers, B Mark

2012-08-01

Deregulated Ras/Raf/MAPK and PI3K/AKT/mTOR signaling pathways are found in hepatocellular carcinoma (HCC). This study aimed to test the inhibitory effects of PKI-587 and sorafenib as single agents or in combination on HCC (Huh7 cell line) proliferation. (3)H-thymidine incorporation and MTT assay were used to assess Huh7 cell proliferation. Phosphorylation of the key enzymes in the Ras/Raf/MAPK and PI3K/AKT/mTOR pathways was detected by Western blot. We found that PKI-587 is a more potent PI3K/mTOR inhibitor than PI-103. Combination of PKI-587 and sorafenib was a more effective inhibitor of Huh7 proliferation than the combination of PI-103 and sorafenib. Combination of PKI-587 and sorafenib synergistically inhibited epidermal growth factor (EGF)-stimulated Huh7 proliferation compared with monodrug therapy. EGF increased phosphorylation of Ras/Raf downstream signaling proteins MEK and ERK; EGF-stimulated activation was inhibited by sorafenib. However, sorafenib, as a single agent, increased AKT (Ser473) phosphorylation. EGF-stimulated AKT (ser473) activation was inhibited by PKI-587. PKI-587 is a potent inhibitor of AKT (Ser473), mTOR (Ser2448), and S6K (Thr389) phosphorylation; in contrast, rapamycin stimulated mTOR complex 2 substrate AKT(Ser473) phosphorylation although it inhibited mTOR complex 1 substrate S6K phosphorylation. PKI-587, as a single agent, stimulated MEK and ERK phosphorylation. However, when PKI-587 and sorafenib were used in combination, they inhibited all the tested kinases in the Ras/Raf /MAPK and PI3K/AKT/mTOR pathways. The combination of PKI-587 and sorafenib has the advantage over monodrug therapy on inhibition of HCC cell proliferation by blocking both PI3K/AKT/mTOR and Ras/Raf/MAPK signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.

The proliferation marker pKi-67 becomes masked to MIB-1 staining after expression of its tandem repeats.

Science.gov (United States)

Schmidt, Mirko H H; Broll, Rainer; Bruch, Hans-Peter; Duchrow, Michael

2002-11-01

The Ki-67 antigen, pKi-67, is one of the most commonly used markers of proliferating cells. The protein can only be detected in dividing cells (G(1)-, S-, G(2)-, and M-phase) but not in quiescent cells (G(0)). The standard antibody to detect pKi-67 is MIB-1, which detects the so-called 'Ki-67 motif' FKELF in 9 of the protein's 16 tandem repeats. To investigate the function of these repeats we expressed three of them in an inducible gene expression system in HeLa cells. Surprisingly, addition of a nuclear localization sequence led to a complete absence of signal in the nuclei of MIB-1-stained cells. At the same time antibodies directed against different epitopes of pKi-67 did not fail to detect the protein. We conclude that the overexpression of the 'Ki-67 motif', which is present in the repeats, can lead to inability of MIB-1 to detect its antigen as demonstrated in adenocarcinoma tissue samples. Thereafter, in order to prevent the underestimation of Ki-67 proliferation indices in MIB-1-labeled preparations, additional antibodies (for example, MIB-21) should be used. Additionally, we could show in a mammalian two-hybrid assay that recombinant pKi-67 repeats are capable of self-associating with endogenous pKi-67. Speculating that the tandem repeats are intimately involved in its protein-protein interactions, this offers new insights in how access to these repeats is regulated by pKi-67 itself.

Impact of coalition interoperability on PKI

Science.gov (United States)

Krall, Edward J.

2003-07-01

This paper examines methods for providing PKI interoperability among units of a coalition of armed forces drawn from different nations. The area in question is tactical identity management, for the purposes of confidentiality, integrity and non-repudiation in such a dynamic coalition. The interoperating applications under consideration range from email and other forms of store-and-forward messaging to TLS and IPSEC-protected real-time communications. Six interoperability architectures are examined with advantages and disadvantages of each described in the paper.

Soluciones PKI basadas en Cryptlib

OpenAIRE

Plaza Espí, Daniel

2008-01-01

El objetivo de este proyecto es realizar un estudio sobre el funcionamiento y la construcción de una infraestructura de clave pública, en adelante PKI1. Para ello se llevarán a cabo dos tareas: 1. Análisis y estudio de los estándares y protocolos más actuales y avanzados que permitan el establecimiento de PKIs jerárquicas siguiendo el esquema de identidades X509v3. 2. Desarrollo software de un conjunto de herramientas que implementen los estándares estudiados y permitan la construcción de dic...

Role of regulatory subunits and protein kinase inhibitor (PKI) in determining nuclear localization and activity of the catalytic subunit of protein kinase A.

Science.gov (United States)

Wiley, J C; Wailes, L A; Idzerda, R L; McKnight, G S

1999-03-05

Regulation of protein kinase A by subcellular localization may be critical to target catalytic subunits to specific substrates. We employed epitope-tagged catalytic subunit to correlate subcellular localization and gene-inducing activity in the presence of regulatory subunit or protein kinase inhibitor (PKI). Transiently expressed catalytic subunit distributed throughout the cell and induced gene expression. Co-expression of regulatory subunit or PKI blocked gene induction and prevented nuclear accumulation. A mutant PKI lacking the nuclear export signal blocked gene induction but not nuclear accumulation, demonstrating that nuclear export is not essential to inhibit gene induction. When the catalytic subunit was targeted to the nucleus with a nuclear localization signal, it was not sequestered in the cytoplasm by regulatory subunit, although its activity was completely inhibited. PKI redistributed the nuclear catalytic subunit to the cytoplasm and blocked gene induction, demonstrating that the nuclear export signal of PKI can override a strong nuclear localization signal. With increasing PKI, the export process appeared to saturate, resulting in the return of catalytic subunit to the nucleus. These results demonstrate that both the regulatory subunit and PKI are able to completely inhibit the gene-inducing activity of the catalytic subunit even when the catalytic subunit is forced to concentrate in the nuclear compartment.

PKI-587 and sorafenib alone and in combination on inhibition of liver cancer stem cell proliferation.

Science.gov (United States)

Gedaly, Roberto; Galuppo, Roberto; Musgrave, Yolanda; Angulo, Paul; Hundley, Jonathan; Shah, Malay; Daily, Michael F; Chen, Changguo; Cohen, Donald A; Spear, Brett T; Evers, B Mark

2013-11-01

Deregulated Ras/Raf/mitogen-activated protein kinase and PI3 K/AKT/mTOR signaling pathways are significant in hepatocellular carcinoma proliferation (HCC). In this study we evaluated differences in the antiproliferative effect of dual PI3 K/Akt/mTOR and Ras/Raf/mitogen-activated protein kinase inhibition of non liver cancer stem cell lines (PLC and HuH7) and liver cancer stem cell (LCSC) lines (CD133, CD44, CD24, and aldehyde dehydrogenase 1-positive cells). Flow cytometry was performed on the resulting tumors to identify the LCSC markers CD133, CD44, CD24, and aldehyde dehydrogenase 1. Methylthiazol tetrazolium assay was used to assess cellular proliferation. Finally, a Western blot assay was used to evaluate for inhibition of specific enzymes in these two signaling pathways. Using flow cytometry, we found that LCSC contain 64.4% CD133 + cells, 83.2% CD44 + cells, and 96.4% CD24 + cells. PKI-587 and sorafenib caused inhibiton of LCSC and HCC cell proliferation. PLC cells were more sensitive to PKI-587 than LCSC or Huh7 (P PKI-587 and sorafenib caused significantly more inhibition than monotherapy in HuH7, PLC, and LCSC. Using the methylthiazol tetrazolium assay, we found that the LCSC proliferation was inhibited with sorafenib monotherapy 39% at 5 μM (P PKI-587 at 0.1 μM (P = 0.002, n = 12) compared with control. The combination of PKI-587 and sorafenib, however, synergistically inhibited LCSC proliferation by 86% (P = 0.002; n = 12). LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+, which demonstrated at least moderate resistance to therapy in vitro. The combination of PKI-587 and sorafenib was better than either drug alone at inhibiting of LCSC and on HCC cell proliferation. Copyright © 2013 Elsevier Inc. All rights reserved.

The pkI gene encoding pyruvate kinase I links to the luxZ gene which enhances bioluminescence of the lux operon from Photobacterium leiognathi.

Science.gov (United States)

Lin, J W; Lu, H C; Chen, H Y; Weng, S F

1997-10-09

Partial 3'-end nucleotide sequence of the pkI gene (GenBank accession No. AF019143) from Photobacterium leiognathi ATCC 25521 has been determined, and the encoded pyruvate kinase I is deduced. Pyruvate kinase I is the key enzyme of glycolysis, which converts phosphoenol pyruvate to pyruvate. Alignment and comparison of pyruvate kinase Is from P. leiognathi, E. coli and Salmonella typhimurium show that they are homologous. Nucleotide sequence reveals that the pkI gene is linked to the luxZ gene that enhances bioluminescence of the lux operon from P. leiognathi. The gene order of the pkI and luxZ genes is-pk1-ter-->-R&R"-luxZ-ter"-->, whereas ter is transcriptional terminator for the pkI and related genes, and R&R" is the regulatory region and ter" is transcriptional terminator for the luxZ gene. It clearly elicits that the pkI gene and luxZ gene are divided to two operons. Functional analysis confirms that the potential hairpin loop omega T is the transcriptional terminator for the pkI and related genes. It infers that the pkI and related genes are simply linked to the luxZ gene in P. leiognathi genome.

PKI 166 induced redox signalling and apoptosis through activation of p53, MAP kinase and caspase pathway in epidermoid carcinoma.

Science.gov (United States)

Das, Subhasis; Dey, Kaushik Kumar; Bharti, Rashmi; MaitiChoudhury, Sujata; Maiti, Sukumar; Mandal, Mahitosh

2012-01-01

Cellular redox changes have emerged as a pivotal and proximal event in cancer. PKI 166 is used to determine the effects of redox sensitive inhibition of EGFR, metastasis and apoptosis in epidermoid carcinoma. Cytotoxicity study of PKI 166 (IC50 1.0 microM) treated A431 cells were performed by MTT assay for 48 and 72 hrs. Morphological analysis of PKI 166 treated A431 cells for 48 hrs. revealed the cell shrinkage, loss of filopodia and lamellipodia by phase contrast and SEM images in dose dependent manner. It has cytotoxic effects through inhibiting cellular proliferation, leads to the induction of apoptosis, as increased fraction of sub-G1 phase of the cell cycle, chromatin condensation and DNA ladder. It inhibited cyclin-D1 and cyclin-E expression and induced p53, p21 expression in dose dependent manner. Consequently, an imbalance of Bax/Bcl-2 ratio triggered caspase cascade and subsequent cleavage of PARP, thereby shifting the balance in favour of apoptosis. PKI 166 treatment actively stimulated reactive oxygen species (ROS) and mitochondrial membrane depolarization. It inhibited some metastatic properties of A431 cells supressing colony formation by soft agar assay and inhibition of MMP 9 activity by gelatin zymography and western blot analysis. PKI 166 inhibited growth factor induced phosphorylation of EGFR, Akt, MAPK, JNK and colony formation in A431 cells. Thus the inhibition of proliferation was associated with redox regulation of the caspase cascade, EGFR, Akt/PI3K, MAPK/ ERK and JNK pathway. On the other hand, increased antioxidant activity leads to decreased ROS generation inhibit the anti-proliferative and apoptotic properties of PKI 166 in A431 cells. These observations indicated PKI 166 induced redox signalling dependent inhibition of cell proliferation, metastatic properties and induction of apoptotic potential in epidermoid carcinoma.

Epidermal growth factor receptor inhibitor PKI-166 governs cardiovascular protection without beneficial effects on the kidney in hypertensive 5/6 nephrectomized rats.

Science.gov (United States)

Ulu, Nadir; Mulder, Gemma M; Vavrinec, Peter; Landheer, Sjoerd W; Duman-Dalkilic, Basak; Gurdal, Hakan; Goris, Maaike; Duin, Marry; van Dokkum, Richard P E; Buikema, Hendrik; van Goor, Harry; Henning, Robert H

2013-06-01

Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

PKI development in Estonia : issues of concern / Ksenia Melnikova, Karlis Kreslins

Index Scriptorium Estoniae

Melnikova, Ksenia

2001-01-01

Kaanel ajak. ilmumisaeg Winter 2001/2002. Probleemidest avaliku võtme infrastruktuuri arendamisel (public key infrastructure - PKI) Eestis. Puudus on kompetentsetest spetsialistidest, informatsiooni vähesuse tõttu pole olnud laiemat arutelu rahastamise teemal, probleemiks on erinevate süsteemide ühildamine

PKI development in Estonia : issues of concern / Ksenia Melnikova, Karlis Kreslins

Index Scriptorium Estoniae

Melnikova, Ksenia

2002-01-01

Kaanel ajak. ilmumisaeg 2001/2002. Probleemidest avaliku võtme infrastruktuuri arendamisel (public key infrastructure - PKI) Eestis. Puudus on kompetentsetest spetsialistidest, informatsiooni vähesuse tõttu pole olnud laiemat arutelu rahastamise teemal, probleemiks on erinevate süsteemide ühildamine

In vivo dynamics and kinetics of pKi-67: transition from a mobile to an immobile form at the onset of anaphase.

Science.gov (United States)

Saiwaki, Takuya; Kotera, Ippei; Sasaki, Mitsuho; Takagi, Masatoshi; Yoneda, Yoshihiro

2005-08-01

A cell proliferation marker protein, pKi-67, distributes to the chromosome periphery during mitosis and nucleolar heterochromatin in the interphase. We report here on the structural domains of pKi-67 that are required for its correct distribution. While both the LR domain and the conserved domain were involved in localization to the nucleolar heterochromatin, both the LR domain and the Ki-67 repeat domain were required for its distribution to the mitotic chromosome periphery. Using in vivo time-lapse microscopy, GFP-pKi-67 was dynamically tracked from the mitotic chromosome periphery to reforming nucleoli via prenucleolar bodies (PNBs). The signals in PNBs then moved towards and fused into the reforming nucleoli with a thin string-like fluorescence during early G1 phase. An analysis of the in vivo kinetics of pKi-67 using photobleaching indicated that the association of pKi-67 with chromatin was progressively altered from "loose" to "tight" after the onset of anaphase. These findings indicate that pKi-67 dynamically alters the nature of the interaction with chromatin structure during the cell cycle, which is closely related to the reformation process of the interphase nucleolar chromatin.

In vivo dynamics and kinetics of pKi-67: Transition from a mobile to an immobile form at the onset of anaphase

International Nuclear Information System (INIS)

Saiwaki, Takuya; Kotera, Ippei; Sasaki, Mitsuho; Takagi, Masatoshi; Yoneda, Yoshihiro

2005-01-01

A cell proliferation marker protein, pKi-67, distributes to the chromosome periphery during mitosis and nucleolar heterochromatin in the interphase. We report here on the structural domains of pKi-67 that are required for its correct distribution. While both the LR domain and the conserved domain were involved in localization to the nucleolar heterochromatin, both the LR domain and the Ki-67 repeat domain were required for its distribution to the mitotic chromosome periphery. Using in vivo time-lapse microscopy, GFP-pKi-67 was dynamically tracked from the mitotic chromosome periphery to reforming nucleoli via prenucleolar bodies (PNBs). The signals in PNBs then moved towards and fused into the reforming nucleoli with a thin string-like fluorescence during early G1 phase. An analysis of the in vivo kinetics of pKi-67 using photobleaching indicated that the association of pKi-67 with chromatin was progressively altered from 'loose' to 'tight' after the onset of anaphase. These findings indicate that pKi-67 dynamically alters the nature of the interaction with chromatin structure during the cell cycle, which is closely related to the reformation process of the interphase nucleolar chromatin

Two worlds, one smart card : An integrated solution for physical access and logical security using PKI on a single smart card

NARCIS (Netherlands)

Hoepman, J.H.; Kleinhuis, G.

2007-01-01

We present a use case of the introduction of a large scale Public Key Infrastructure (PKI) environment in an incumbent telecommunications company in The Netherlands. The main characteristics of the case are the integration of an existing physical access facility with a PKI environment for logical

Effective intracellular inhibition of the cAMP-dependent protein kinase by microinjection of a modified form of the specific inhibitor peptide PKi in living fibroblasts.

Science.gov (United States)

Fernandez, A; Mery, J; Vandromme, M; Basset, M; Cavadore, J C; Lamb, N J

1991-08-01

In order to obtain a peptide retaining its biological activity following microinjection into living cells, we have modified a synthetic peptide [PKi(m)(6-24)], derived from the specific inhibitor protein of the cAMP-dependent protein kinase (A-kinase) in two ways: (1) substitution of the arginine at position 18 for a D-arginine; (2) blockade of the side chain on the C-terminal aspartic acid by a cyclohexyl ester group. In an in vitro assay, PKi(m) has retained a specific inhibitory activity against A-kinase as assessed against six other kinases, with similar efficiency to that of the unmodified PKi(5-24) peptide. Microinjection of PKi(m) into living fibroblasts reveals its capacity to prevent the changes in cell morphology and cytoskeleton induced by drugs which activate endogenous A-kinase, whereas the original PKi peptide failed to do so. This inhibition of A-kinase in vivo by PKi(m) lasts between 4 and 6 h after injection. In light of its effective half-life, this modified peptide opens a route for the use of biologically active peptides in vivo, an approach which has been hampered until now by the exceedingly short half-life of peptides inside living cells. By providing a direct means of inhibiting A-kinase activity for sufficiently long periods to observe effects on cellular functions in living cells, PKi(m) represents a powerful tool in studying the potential role of cAMP-dependent phosphorylation in vivo.

Cytotoxic effect of the Her-2/Her-1 inhibitor PKI-166 on renal cancer cells expressing the connexin 32 gene.

Science.gov (United States)

Fujimoto, Eriko; Yano, Tomohiro; Sato, Hiromi; Hagiwara, Kiyokazu; Yamasaki, Hiroshi; Shirai, Sumiko; Fukumoto, Keiko; Hagiwara, Hiromi; Negishi, Etsuko; Ueno, Koichi

2005-02-01

We have reported that connexin (Cx) 32 acts as a tumor suppressor gene in renal cancer cells partly due to Her-2 inactivation. Here, we determined if a Her-2/Her-1 inhibitor (PKI-166) can enhance the tumor-suppressive effect of Cx32 in Caki-2 cells from human renal cell carcinoma. The expression of Cx32 in Caki-2 cells was required for PKI-166-induced cytotoxic effect at lower doses. The cyctotoxicity was dependent on the occurrence of apoptosis and partly mediated by Cx32-driven gap junction intercellular communications. These results suggest that PKI-166 further supports the tumor-suppressive effect of the Cx32 gene in renal cancer cells through the induction of apoptosis.

Installation, Configuration and Operational Testing of a PKI Certificate Server and Its Supporting Services

National Research Council Canada - National Science Library

Ambers, Vanessa

2004-01-01

Public key infrastructure (PKI) was created to provide the basic services of confidentiality, authenticity, integrity and non-repudiation for sensitive information that may traverse public (un-trusted) networks...

PKI, Gamma Radiation Reactor Shielding Calculation by Point-Kernel Method

International Nuclear Information System (INIS)

Li Chunhuai; Zhang Liwu; Zhang Yuqin; Zhang Chuanxu; Niu Xihua

1990-01-01

1 - Description of program or function: This code calculates radiation shielding problem of gamma-ray in geometric space. 2 - Method of solution: PKI uses a point kernel integration technique, describes radiation shielding geometric space by using geometric space configuration method and coordinate conversion, and makes use of calculation result of reactor primary shielding and flow regularity in loop system for coolant

The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL).

Science.gov (United States)

Gazi, Mohiuddin; Moharram, Sausan A; Marhäll, Alissa; Kazi, Julhash U

2017-04-28

Although significant improvements have been made in the treatment of acute lymphoblastic leukemia (ALL), there is a substantial subset of high-risk T-cell ALL (T-ALL) patients with relatively poor prognosis. Like in other leukemia types, alterations of the PI3K/mTOR pathway are predominant in ALL which is also responsible for treatment failure and relapse. In this study, we show that relapsed T-ALL patients display an enrichment of the PI3K/mTOR pathway. Using a panel of inhibitors targeting multiple components of the PI3K/mTOR pathway, we observed that the dual-specific PI3K/mTOR inhibitor PKI-587 was the most selective inhibitor for T-ALL cells dependent on the PI3K/mTOR pathway. Furthermore, we observed that PKI-587 blocked proliferation and colony formation of T-ALL cell lines. Additionally, PKI-587 selectively abrogated PI3K/mTOR signaling without affecting MAPK signaling both in in vitro and in vivo. Inhibition of the PI3K/mTOR pathway using PKI-587 delayed tumor progression, reduced tumor load and enhanced the survival rate in immune-deficient mouse xenograft models without inducing weight loss in the inhibitor treated mice. This preclinical study shows beneficial effects of PKI-587 on T-ALL that warrants further investigation in the clinical setting. Copyright © 2017 Elsevier B.V. All rights reserved.

NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.

Science.gov (United States)

Güttler, Thomas; Madl, Tobias; Neumann, Piotr; Deichsel, Danilo; Corsini, Lorenzo; Monecke, Thomas; Ficner, Ralf; Sattler, Michael; Görlich, Dirk

2010-11-01

Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Φ) residues, yet CRM1 recognizes them with the same rigid set of five Φ pockets. The different Φ spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an α-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Φ pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly.

Authentication in Virtual Organizations: A Reputation Based PKI Interconnection Model

Science.gov (United States)

Wazan, Ahmad Samer; Laborde, Romain; Barrere, Francois; Benzekri, Abdelmalek

Authentication mechanism constitutes a central part of the virtual organization work. The PKI technology is used to provide the authentication in each organization involved in the virtual organization. Different trust models are proposed to interconnect the different PKIs in order to propagate the trust between them. While the existing trust models contain many drawbacks, we propose a new trust model based on the reputation of PKIs.

Approach for Business Case Analysis of Using PKI on Smart Cards for Governmentwide Applications

National Research Council Canada - National Science Library

2001-01-01

Booz Allen & Hamilton, under contract to the General Services Administration, was tasked to document a business case approach that can be utilized by Federal agencies considering an investment in Public Key Infrastructure (PKI...

Inhibition of mTOR's Catalytic Site by PKI-587 Is a Promising Therapeutic Option for Gastroenteropancreatic Neuroendocrine Tumor Disease.

Science.gov (United States)

Freitag, Helma; Christen, Friederike; Lewens, Florentine; Grass, Irina; Briest, Franziska; Iwaszkiewicz, Sara; Siegmund, Britta; Grabowski, Patricia

2017-01-01

The characteristic clinical heterogeneity and mostly slow-growing behavior of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) cause problems in finding appropriate treatments. Thus, the current therapy options are not satisfactory. PKI-587 is a highly potent, novel dual inhibitor of PI3K and mTORC1/C2. We assessed the effects of PKI-587 in different GEP-NEN tumor models, including the poorly differentiated cell line LCC-18, and compared them with those of the established mTORC1 inhibitor everolimus. We treated BON, QGP-1, KRJ-I, and LCC-18 cell lines with increasing concentrations of the inhibitor PKI-587, and compared the results with those of everolimus and DMSO. We assessed the impact of the treatments on viability (WST-1 assay), on apoptotic processes (caspase 3/7 assay, JC-1), and on cell cycle regulation (flow cytometry). We determined alterations in signaling mediators by phosphor-specific Western blot analysis and conducted multiplexed gene expression analysis (nCounter® technology). In all cell lines, PKI-587 dose-dependently inhibited proliferation, whereas everolimus was less effective. Treatment with PKI-587 led to cell cycle arrest and induction of apoptosis and successfully suppressed activity of the direct mTORC1 target 4E-BP1, a crucial factor for tumor genesis only partially inhibited by everolimus. Gene expression analyses revealed relevant changes of RAS, MAPK, STAT, and PI3K pathway genes after treatment. Treatment-dependent and cell line-characteristic effects on AKT/Rb/E2F signaling regarding cell cycle control and apoptosis are extensively discussed in this paper. PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials. © 2016 The Author(s) Published by S. Karger AG, Basel.

Public Key Infrastructure (PKI) Interoperability: A Security Services Approach to Support Transfer of Trust

National Research Council Canada - National Science Library

Hansen, Anthony

1999-01-01

Public key infrastructure (PKI) technology is at a primitive stage characterized by deployment of PKIs that are engineered to support the provision of security services within individual enterprises, and are not able to support...

Failure points in the PKI architecture / Точки отказа в PKI архитектуре / Tačke otkaza u PKI arhitekturi

Directory of Open Access Journals (Sweden)

Radomir I. Prodanović

2017-07-01

Full Text Available Over the last 20 years, the PKI architecture has found its vast application, especially in the fields which require the establishment of a security infrastructure. Given that the purpose of this architecture is to be used for achieving higher security standards, its smooth operation has to be one of the main requirements for its implementation. Its complexity is mirrored in the numerous implementations that the PKI has had so far. For all the reasons mentioned above, it is of great importance to consider potential failure points of such a structure. Due to the complexity of these structures, this paper will present only a basic review of such stress points, without providing details on specific applications and types of implementations. The significance of failure points will be explained by examining the common features of the PKI architectures and the occurrence of failure points in these structures, and where possible, an overview of suggestions for preventing such failures will be provided. / За последних двадцать лет, архитектура PKI стала широко применяться, особенно в областях, требующих создания инфраструктуры безопасности. Учитывая, что цель создания такой архитектуры заключается в обеспечении безопасности систем, главными задачами при внедрении архитектуры PKI являются бесперебойная работа и взаимодействие с другими компонентами комплектной структуры. Из вышеизложенного следует, что прогноз потенциальных точек отказа представляет собой исключительно важный фактор. В связи с ограничением объема �

A PKA survival pathway inhibited by DPT-PKI, a new specific cell permeable PKA inhibitor, is induced by T. annulata in parasitized B-lymphocytes.

Science.gov (United States)

Guergnon, Julien; Dessauge, Frederic; Traincard, François; Cayla, Xavier; Rebollo, Angelita; Bost, Pierre Etienne; Langsley, Gordon; Garcia, Alphonse

2006-08-01

T. annulata, an intracellular pathogenic parasite of the Aplicomplexa protozoan family infects bovine B-lymphocytes and macrophages. Parasitized cells that become transformed survive and proliferate independently of exogenous growth factors. In the present study, we used the isogenic non parasitized BL3 and parasitized TBL3 B cell lines, as a model to evaluate the contribution of two-major PI3-K- and PKA-dependent anti-apoptotic pathways in the survival of T. annulata parasitized B lymphocytes. We found that T. annulata increases PKA activity, induces over-expression of the catalytic subunit and down-regulates the pro-survival phosphorylation state of Akt/PKB. Consistent with a role of PKA activation in survival, two pharmacological inhibitors H89 and KT5720 ablate PKA-dependent survival of parasitized cells. To specifically inhibit PKA pro-survival pathways we linked the DPTsh1 peptide shuttle sequence to PKI(5-24) and we generated DPT-PKI, a cell permeable PKI. DPT-PKI specifically inhibited PKA activity in bovine cell extracts and, as expected, also inhibited the PKA-dependent survival of T. annulata parasitized TBL3 cells. Thus, parasite-dependent constitutive activation of PKA in TBL3 cells generates an anti-apoptotic pathway that can protect T. annulata-infected B cells from apoptosis. These results also indicate that DPT-PKI could be a powerful tool to inhibit PKA pathways in other cell types.

Dual PI3K/mTOR inhibitors, GSK2126458 and PKI-587, suppress tumor progression and increase radiosensitivity in nasopharyngeal carcinoma.

Science.gov (United States)

Liu, Tongxin; Sun, Quanquan; Li, Qi; Yang, Hua; Zhang, Yuqin; Wang, Rong; Lin, Xiaoshan; Xiao, Dong; Yuan, Yawei; Chen, Longhua; Wang, Wei

2015-02-01

Although combined chemoradiotherapy has provided considerable improvements for nasopharyngeal carcinoma (NPC), recurrence and metastasis are still frequent. The PI3K/Akt/mTOR pathway plays a critical role in tumor formation and tumor cell survival after radiation-induced DNA damage. In the present study, we evaluated whether inhibition of PI3K/mTOR by two novel dual inhibitors, GSK2126458 and PKI-587, could suppress tumor progression and sensitize NPC cells to radiation. Four NPC cell lines (CNE-1, CNE-2, 5-8F, and 6-10B) were used to analyze the effects of GSK216458 and PKI-587 on cell proliferation, migration, invasion, clonogenic survival, amount of residual γ-H2AX foci, cell cycle, and apoptosis after radiation. A 5-8F xenograft model was used to evaluate the in vivo effects of the two compounds in combination with ionizing radiation (IR). Both GSK216458 and PKI-587 effectively inhibited cell proliferation and motility in NPC cells and suppressed phosphorylation of Akt, mTOR, S6, and 4EBP1 proteins in a concentration- and time-dependent manner. Moreover, both compounds sensitized NPC cells to IR by increasing DNA damage, enhancing G2-M cell-cycle delay, and inducing apoptosis. In vivo, the combination of IR with GSK2126458 or PKI-587 significantly inhibited tumor growth. Antitumor effect was correlated with induction of apoptosis and suppression of the phosphorylation of mTOR, Akt, and 4EBP1. These new findings suggest the usefulness of PI3K/mTOR dual inhibition for antitumor and radiosensitizing. The combination of IR with a dual PI3K/mTOR inhibitor, GSK2126458 or PKI-587, might be a promising therapeutic strategy for NPC. ©2014 American Association for Cancer Research.

Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts.

Science.gov (United States)

Mellinghoff, Ingo K; Tran, Chris; Sawyers, Charles L

2002-09-15

Experiments with human prostate cancer cell lines have shown that forced overexpression of the ErbB2-receptor tyrosine kinase (RTK) promotes androgen-independent growth and increases androgen receptor-transcriptional activity in a ligand-independent fashion. To investigate the relationship between ErbB-RTK signaling and androgen in genetically unmanipulated human prostate cancer, we performed biochemical and biological studies with the dual ErbB1/ErbB2 RTK inhibitor PKI-166 using human prostate cancer xenograft models with isogenic sublines reflecting the transition from androgen-dependent to androgen-independent growth. In the presence of low androgen concentrations, PKI-166 showed profound growth-inhibitory effects on tumor growth, which could be partially reversed by androgen add-back. At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI-166 to retard tumor growth. The level of extracellular signal-regulated kinase activation correlated with the response to PKI-166 treatment, whereas the expression levels of ErbB1 and ErbB2 did not. These results suggest that ErbB1/ErbB2 RTKs play an important role in the biology of androgen-independent prostate cancer and provide a rationale for clinical evaluation of inhibitors targeted to this pathway.

PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.

Science.gov (United States)

Venkatesan, Aranapakam M; Chen, Zecheng; dos Santos, Osvaldo; Dehnhardt, Christoph; Santos, Efren Delos; Ayral-Kaloustian, Semiramis; Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Yu, Ker; Chaudhary, Inder; Mansour, Tarek S

2010-10-01

A series of mono-morpholino 1,3,5-triazine derivatives (8a-8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed. Copyright © 2010. Published by Elsevier Ltd.

A PKI Approach for Deploying Modern Secure Distributed E-Learning and M-Learning Environments

Science.gov (United States)

Kambourakis, Georgios; Kontoni, Denise-Penelope N.; Rouskas, Angelos; Gritzalis, Stefanos

2007-01-01

While public key cryptography is continuously evolving and its installed base is growing significantly, recent research works examine its potential use in e-learning or m-learning environments. Public key infrastructure (PKI) and attribute certificates (ACs) can provide the appropriate framework to effectively support authentication and…

76 FR 126 - Requirement for Commercial Users To Use Commercial Public Key Information (PKI) Certificate

Science.gov (United States)

2011-01-03

... DEPARTMENT OF DEFENSE Department of the Army Requirement for Commercial Users To Use Commercial..., SDDC will require all commercial accounts accessing transportation systems and applications to use a commercial PKI certificate or Transportation Workers Identification Credential (TWIC). This requirement will...

Activity report for feasibility study on PKI authentication method with IC card in authentication system sub group of J-PARC information system group

International Nuclear Information System (INIS)

Teshima, Naoya; Aoyagi, Tetsuo; Nakajima, Norihiro; Hashimoto, Kiyoharu; Manabe, Atsushi; Yuasa, Fukuko

2009-06-01

The Authentication System Sub Group of J-PARC Information System Group completed the mapping of the several authentication methods in terms of the level of security. Of the methods, the PKI authentication method with IC card provides the Super High Security Level and will be adopted as the authentication method of several J-PARC Information Systems. We study the feasibility of this method with following four examples; (1) 'The EAP-TLS wireless LAN authentication method'. (2) 'The Web-SSL client authentication method in SSL-VPN connection'. (3) 'The PKI authentication method with a certificate issued by NAREGI-CA software stored in IC card.' (4) 'The PKI authentication method with Dual interface FeliCa card'. In each example, we confirmed the feasibility of the method in a practical way. In this report we present the details of the study. (author)

A structural insight into the inhibitory mechanism of an orally active PI3K/mTOR dual inhibitor, PKI-179 using computational approaches.

Science.gov (United States)

Mohd Rehan

2015-11-01

The PI3K/AKT/mTOR signaling pathway has been identified as an important target for cancer therapy. Attempts are increasingly made to design the inhibitors against the key proteins of this pathway for anti-cancer therapy. The PI3K/mTOR dual inhibitors have proved more effective than the inhibitors against only single protein targets. Recently discovered PKI-179, an orally effective compound, is one such dual inhibitor targeting both PI3K and mTOR. This anti-cancer compound is efficacious both in vitro and in vivo. However, the binding mechanisms and the molecular interactions of PKI-179 with PI3K and mTOR are not yet available. The current study investigated the exact binding mode and the molecular interactions of PKI-179 with PI3Kγ and mTOR using molecular docking and (un)binding simulation analyses. The study identified PKI-179 interacting residues of both the proteins and their importance in binding was ranked by the loss in accessible surface area, number of molecular interactions of the residue, and consistent appearance of the residue in (un)binding simulation analysis. The key residues involved in binding of PKI-179 were Ala-805 in PI3Kγ and Ile-2163 in mTOR as they have lost maximum accessible surface area due to binding. In addition, the residues which played a role in binding of the drug but were away from the catalytic site were also identified using (un)binding simulation analyses. Finally, comparison of the interacting residues in the respective catalytic sites was done for the difference in the binding of the drug to the two proteins. Thus, the pairs of the residues falling at the similar location with respect to the docked drug were identified. The striking similarity in the interacting residues of the catalytic site explains the concomitant inhibition of both proteins by a number of inhibitors. In conclusion, the docking and (un)binding simulation analyses of dual inhibitor PKI-179 with PI3K and mTOR will provide a suitable multi-target model for

pKI values of prazosin and idazoxan for receptors stimulated by neuronally released transmitter in the epididymal portion of rat isolated vas deferens.

OpenAIRE

Mackay, D.; Kengatharan, M.

1994-01-01

1. A new method has been used to measure pKI values of prazosin and idazoxan against neuronally-released transmitter in the epididymal portion of the rat isolated vas deferens. The most reproducible results were obtained with a prolonged antagonist equilibration time (1 h). 2. Under these conditions the pKI of prazosin was practically unaffected by addition of alpha, beta-methylene-adenosine-5'-triphosphate (10 microM) to desensitize purinoceptors. Addition of desmethylimipramine (DMI) (0.3 m...

Alterations in brain Protein Kinase A activity and reversal of morphine tolerance by two fragments of native Protein Kinase A inhibitor peptide (PKI).

Science.gov (United States)

Dalton, George D; Smith, Forrest L; Smith, Paul A; Dewey, William L

2005-04-01

Two peptide fragments of native Protein Kinase A inhibitor (PKI), PKI-(6-22)-amide and PKI-(Myr-14-22)-amide, significantly reversed low-level morphine antinociceptive tolerance in mice. The inhibition of Protein Kinase A (PKA) activity by both peptide fragments was then measured in specific brain regions (thalamus, periaqueductal gray (PAG), and medulla) and in lumbar spinal cord (LSC), which in previous studies have been shown to play a role in morphine-induced analgesia. In drug naive animals, cytosolic PKA activity was greater than particulate PKA activity in each region, while cytosolic and particulate PKA activities were greater in thalamus and PAG compared to medulla and LSC. The addition of both peptides to homogenates from each region completely abolished cytosolic and particulate PKA activities in vitro. Following injection into the lateral ventricle of the brain of drug naive mice and morphine-tolerant mice, both peptides inhibited PKA activity in the cytosolic, but not the particulate fraction of LSC. In addition, cytosolic and particulate PKA activities were inhibited by both peptides in thalamus. These results demonstrate that the inhibition of PKA reverses morphine tolerance. Moreover, the inhibition of PKA activity in specific brain regions and LSC from morphine-tolerant mice by PKI analogs administered i.c.v. is evidence that PKA plays a role in morphine tolerance.

Modeling of frequency agile devices: development of PKI neuromodeling library based on hierarchical network structure

Science.gov (United States)

Sanchez, P.; Hinojosa, J.; Ruiz, R.

2005-06-01

Recently, neuromodeling methods of microwave devices have been developed. These methods are suitable for the model generation of novel devices. They allow fast and accurate simulations and optimizations. However, the development of libraries makes these methods to be a formidable task, since they require massive input-output data provided by an electromagnetic simulator or measurements and repeated artificial neural network (ANN) training. This paper presents a strategy reducing the cost of library development with the advantages of the neuromodeling methods: high accuracy, large range of geometrical and material parameters and reduced CPU time. The library models are developed from a set of base prior knowledge input (PKI) models, which take into account the characteristics common to all the models in the library, and high-level ANNs which give the library model outputs from base PKI models. This technique is illustrated for a microwave multiconductor tunable phase shifter using anisotropic substrates. Closed-form relationships have been developed and are presented in this paper. The results show good agreement with the expected ones.

Synthesis, characterization and inhibitory activities of (4-N3[3,5-3H]Phe10)PKI(6-22)amide and its precursors: photoaffinity labeling peptides for the active site of cyclic AMP-dependent protein kinase.

Science.gov (United States)

Katz, B M; Lundquist, L J; Walsh, D A; Glass, D B

1989-06-01

PKI(6-22)amide is a 17 residue peptide corresponding to the active portion of the heat-stable inhibitor of cAMP-dependent protein kinase. The peptide is a potent (Ki = 1.6 nM), competitive inhibitor of the enzyme. The photoreactive peptide analog (4-azidophenylalanine10)PKI(6-22)amide was synthesized in both its non-radiolabeled and tritiated forms by chemical modification of precursor peptides that were prepared by stepwise solid-phase synthesis. (4-Amino[3,5-3H]phenylalanine10)PKI(6-22)amide, the precursor for the radiolabeled arylazide peptide, was obtained by catalytic reduction of the corresponding peptide containing the 3,5-diiodo-4-aminophenylalanine residue at position 10. The purified PKI peptides were analyzed by HPLC, amino acid analysis, and u.v. spectra. In the dark, (4-azidophenylalanine10)PKI(6-22)amide inhibited the catalytic subunit of cAMP-dependent protein kinase with a Ki value of 2.8 nM. The photoreactivity of the arylazide peptide was demonstrated by time-dependent u.v. spectral changes on exposure to light. Photolysis of the catalytic subunit (4-azido[3,5-3H]phenylalanine10)PKI(6-22)amide complex resulted in specific covalent labeling of the enzyme. The data indicate that this peptide is a useful photoaffinity labeling reagent for the active site of the protein kinase.

Using PKiKP coda to study heterogeneity in the top layer of the inner core's western hemisphere

Science.gov (United States)

Wu, Wenbo; Irving, Jessica C. E.

2017-05-01

Significant lateral and depth variations of the inner core's properties, such as the large-scale hemispherical pattern, have been confirmed by a variety of seismological observations. However it is still unclear which dynamic processes in the core are responsible for these variations. Small-scale volumetric heterogeneity has been detected in the top layer of the inner core by PKiKP coda observations. Studies of these small-scale heterogeneities can provide critical information, such as the degree of alignment of iron crystals, the presence of possible partial melt and the grain size of iron crystals, all of which can be used to constrain the dynamic processes of the inner core. However, most previous observations sampled the inner core beneath the Pacific Ocean and Asia, often in the inner core's 'eastern hemisphere'. We use seismic stations in the North America, including the Earthscope Transportable Array, to look at PKiKP and its coda waves. We find 21 events with clear signals. In agreement with previous studies, inner core scattering (ICS), resulting in clear PKiKP coda, is found at epicentral distances of 60°-95°. However, the ICS we observe in these 21 western hemisphere events is weaker than previously reported for the eastern hemisphere. Comparing our observations with numerical simulations, we conclude that this relatively weak ICS indicates small-scale heterogeneity in at least the top layer of the inner core beneath Central America. Combining our clear observations with previous studies suggests either a hemispherical difference, or a regional variation, of small-scale heterogeneity in the inner core.

J-PAKE: Authenticated Key Exchange without PKI

Science.gov (United States)

Hao, Feng; Ryan, Peter

Password Authenticated Key Exchange (PAKE) is one of the important topics in cryptography. It aims to address a practical security problem: how to establish secure communication between two parties solely based on a shared password without requiring a Public Key Infrastructure (PKI). After more than a decade of extensive research in this field, there have been several PAKE protocols available. The EKE and SPEKE schemes are perhaps the two most notable examples. Both techniques are however patented. In this paper, we review these techniques in detail and summarize various theoretical and practical weaknesses. In addition, we present a new PAKE solution called J-PAKE. Our strategy is to depend on well-established primitives such as the Zero-Knowledge Proof (ZKP). So far, almost all of the past solutions have avoided using ZKP for the concern on efficiency. We demonstrate how to effectively integrate the ZKP into the protocol design and meanwhile achieve good efficiency. Our protocol has comparable computational efficiency to the EKE and SPEKE schemes with clear advantages on security.

Higher Education Partners with the Federal Government for PKI: Both Communities Bring Substantial Expertise and Investment to the Solutions.

Science.gov (United States)

PKI for Networked Higher Education Working Group.

2000-01-01

One barrier to Web-based education is lack of an effective system to identify and authorize involved participants, content, and institutions. PKI (public-key infrastructure) is an emerging technology that can certify the correct identity of each person and communication in Web-based learning. A June 2000 National Science Foundation workshop…

Design and implementation of a secure workflow system based on PKI/PMI

Science.gov (United States)

Yan, Kai; Jiang, Chao-hui

2013-03-01

As the traditional workflow system in privilege management has the following weaknesses: low privilege management efficiency, overburdened for administrator, lack of trust authority etc. A secure workflow model based on PKI/PMI is proposed after studying security requirements of the workflow systems in-depth. This model can achieve static and dynamic authorization after verifying user's ID through PKC and validating user's privilege information by using AC in workflow system. Practice shows that this system can meet the security requirements of WfMS. Moreover, it can not only improve system security, but also ensures integrity, confidentiality, availability and non-repudiation of the data in the system.

The dual PI3K/mTOR inhibitor PKI-587 enhances sensitivity to cetuximab in EGFR-resistant human head and neck cancer models.

Science.gov (United States)

D'Amato, V; Rosa, R; D'Amato, C; Formisano, L; Marciano, R; Nappi, L; Raimondo, L; Di Mauro, C; Servetto, A; Fusciello, C; Veneziani, B M; De Placido, S; Bianco, R

2014-06-10

Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance. Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo. Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival. Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.

Public Key Infrastructure (PKI) Increment 2 Root Cause Analysis (RCA) for Performance Assessments and Root Cause Analyses (PARCA)

Science.gov (United States)

2015-05-01

DoD PKI enables secure encryption , authentication of network transactions, data integrity, and non-repudiation to a broad range of government- and...Identity Verification (PIV) Authentication Certificates.  Implement Rivest, Shamir, and Adelman ( RSA ) 2048 when viable and transition to Secure Hash...facilitate missions through digital signing, encryption , and web-server authentication. However, reliability of the tokens was unacceptable, with

Application of PKI in health care--needs, ambitions, prospects.

Science.gov (United States)

Suselj, Marjan; Marcun, Tomaz; Trcek, Denis; Kandus, Gorazd

2003-01-01

Through continual development and considerable investment over the past years, Slovenia has established an information infrastructure providing efficient data links between all the health care actors. This includes furnishing all the citizens and health workers with microprocessor cards--health insurance card and health professional card. These tools have significantly simplified different procedures in the health care and brought services closer to insured persons. The know-how and experiences gathered to day have given rise to vivid discussions of further development steps: introduction of new contents on the infrastructure in place and technological upgrading, in particular progressive incorporation of the PKI concept and thereby integration of card and network solutions to provide an efficient and secure communication environment. This paper outlines key perspectives of the future developments in this segment. With the volume of health care data communications through internet growing steeply, and with the paramount importance of patient--doctor trust and confidence, security tools and solutions in the health care are a critical need.

Workshop on Pion-Kaon Interactions (PKI2018) Mini-Proceedings

Energy Technology Data Exchange (ETDEWEB)

Amaryan, M; Pal, Bilas

2018-02-14

This volume is a short summary of talks given at the PKI2018 Workshop organized to discuss current status and future prospects of pi -K interactions. The precise data on pi K interaction will have a strong impact on strange meson spectroscopy and form factors that are important ingredients in the Dalitz plot analysis of a decays of heavy mesons as well as precision measurement of Vus matrix element and therefore on a test of unitarity in the first raw of the CKM matrix. The workshop has combined the efforts of experimentalists, Lattice QCD, and phenomenology communities. Experimental data relevant to the topic of the workshop were presented from the broad range of different collaborations like CLAS, GlueX, COMPASS, BaBar, BELLE, BESIII, VEPP-2000, and LHCb. One of the main goals of this workshop was to outline a need for a new high intensity and high precision secondary KL beam facility at JLab produced with the 12 GeV electron beam of CEBAF accelerator.

Bias-dependent hybrid PKI empirical-neural model of microwave FETs

Science.gov (United States)

Marinković, Zlatica; Pronić-Rančić, Olivera; Marković, Vera

2011-10-01

Empirical models of microwave transistors based on an equivalent circuit are valid for only one bias point. Bias-dependent analysis requires repeated extractions of the model parameters for each bias point. In order to make model bias-dependent, a new hybrid empirical-neural model of microwave field-effect transistors is proposed in this article. The model is a combination of an equivalent circuit model including noise developed for one bias point and two prior knowledge input artificial neural networks (PKI ANNs) aimed at introducing bias dependency of scattering (S) and noise parameters, respectively. The prior knowledge of the proposed ANNs involves the values of the S- and noise parameters obtained by the empirical model. The proposed hybrid model is valid in the whole range of bias conditions. Moreover, the proposed model provides better accuracy than the empirical model, which is illustrated by an appropriate modelling example of a pseudomorphic high-electron mobility transistor device.

Plasmids encoding PKI(1-31), a specific inhibitor of cAMP-stimulated gene expression, inhibit the basal transcriptional activity of some but not all cAMP-regulated DNA response elements in JEG-3 cells.

Science.gov (United States)

Grove, J R; Deutsch, P J; Price, D J; Habener, J F; Avruch, J

1989-11-25

Plasmids that encode a bioactive amino-terminal fragment of the heat-stable inhibitor of the cAMP-dependent protein kinase, PKI(1-31), were employed to characterize the role of this protein kinase in the control of transcriptional activity mediated by three DNA regulatory elements in the JEG-3 human placental cell line. The 5'-flanking sequence of the human collagenase gene contains the heptameric sequence, 5'-TGAGTCA-3', previously identified as a "phorbol ester" response element. Reporter genes containing either the intact 1.2-kilobase 5'-flanking sequence from the human collagenase gene or just the 7-base pair (bp) response element, when coupled to an enhancerless promoter, each exhibit both cAMP and phorbol ester-stimulated expression in JEG-3 cells. Cotransfection of either construct with plasmids encoding PKI(1-31) inhibits cAMP-stimulated but not basal- or phorbol ester-stimulated expression. Pretreatment of cells with phorbol ester for 1 or 2 days abrogates completely the response to rechallenge with phorbol ester but does not alter the basal expression of either construct; cAMP-stimulated expression, while modestly inhibited, remains vigorous. The 5'-flanking sequence of the human chorionic gonadotropin-alpha subunit (HCG alpha) gene has two copies of the sequence, 5'-TGACGTCA-3', contained in directly adjacent identical 18-bp segments, previously identified as a cAMP-response element. Reporter genes containing either the intact 1.5 kilobase of 5'-flanking sequence from the HCG alpha gene, or just the 36-bp tandem repeat cAMP response element, when coupled to an enhancerless promoter, both exhibit a vigorous cAMP stimulation of expression but no response to phorbol ester in JEG-3 cells. Cotransfection with plasmids encoding PKI(1-31) inhibits both basal and cAMP-stimulated expression in a parallel fashion. The 5'-flanking sequence of the human enkephalin gene mediates cAMP-stimulated expression of reporter genes in both JEG-3 and CV-1 cells. Plasmids

Increased expression of protein kinase A inhibitor alpha (PKI-alpha) and decreased PKA-regulated genes in chronic intermittent alcohol exposure.

Science.gov (United States)

Repunte-Canonigo, Vez; Lutjens, Robert; van der Stap, Lena D; Sanna, Pietro Paolo

2007-03-23

Intermittent models of alcohol exposure that mimic human patterns of alcohol consumption produce profound physiological and biochemical changes and induce rapid increases in alcohol self-administration. We used high-density oligonucleotide microarrays to investigate gene expression changes during chronic intermittent alcohol exposure in three brain regions that receive mesocorticolimbic dopaminergic projections and that are believed to be involved in alcohol's reinforcing actions: the medial prefrontal cortex, the nucleus accumbens and the amygdala. An independent replication of the experiment was used for RT-PCR validation of the microarray results. The protein kinase A inhibitor alpha (PKI-alpha, Pkia), a member of the endogenous PKI family implicated in reducing nuclear PKA activity, was found to be increased in all three regions tested. Conversely, we observed a downregulation of the expression of several PKA-regulated transcripts in one or more of the brain regions studied, including the activity and neurotransmitter-regulated early gene (Ania) - 1, -3, -7, -8, the transcription factors Egr1 and NGFI-B (Nr4a1) and the neuropeptide NPY. Reduced expression of PKA-regulated genes in mesocorticolimbic projection areas may have motivational significance in the rapid increase in alcohol self-administration induced by intermittent alcohol exposure.

Model for PKI interoperability in Serbia / Модель доверия и архетектура PKI в Республике Сербия / Model za PKI interoperabilnost u Republici Srbiji

Directory of Open Access Journals (Sweden)

Radomir I. Prodanović

2017-04-01

Full Text Available The increasing use of electronic services that use electronic certificates and the increasing implementation of public key infrastructures require their interconnection and interoperability. In this paper, the authors analyze the models for interoperability between various PKI domains and their possible application in achieving interoperability of the public key infrastructures in the Republic of Serbia. The implementation of the interoperability of the existing models is discussed from the following aspects: scalability, processing of certification paths, implementing policies, the points of failure and the possibilities of re-establishing trust. We proposed a conceptual model based on the Bridge Certification Authority trust model. This model can provide the establishment of the interoperability of both the existing and new national PKI domains, their interconnection as well as their connection with foreign PKI domains. The model was extended with the Validation Authority that provides more efficient processing of the certification path. / Применение электронного сервиса, использующего цифровые сертификаты увеличивается с каждым днем, увеличивается также и количество внедренных инфраструктур открытых ключей, в связи с чем появилось необходимость в их объединении и взаимодействии. В данной статье представлены результаты проведенного анализа модели взаимодействия между различными доменами инфраструктуры открытых ключей и возможность их применения в осуществлении взаимодействия инфраструктур открытых ключей в Республике �

Authentication Architecture for Region-Wide e-Health System with Smartcards and a PKI

Science.gov (United States)

Zúquete, André; Gomes, Helder; Cunha, João Paulo Silva

This paper describes the design and implementation of an e-Health authentication architecture using smartcards and a PKI. This architecture was developed to authenticate e-Health Professionals accessing the RTS (Rede Telemática da Saúde), a regional platform for sharing clinical data among a set of affiliated health institutions. The architecture had to accommodate specific RTS requirements, namely the security of Professionals' credentials, the mobility of Professionals, and the scalability to accommodate new health institutions. The adopted solution uses short-lived certificates and cross-certification agreements between RTS and e-Health institutions for authenticating Professionals accessing the RTS. These certificates carry as well the Professional's role at their home institution for role-based authorization. Trust agreements between e-Health institutions and RTS are necessary in order to make the certificates recognized by the RTS. As a proof of concept, a prototype was implemented with Windows technology. The presented authentication architecture is intended to be applied to other medical telematic systems.

Kolonizatsija Palestinõ prepjatstvujet miru / Jimmy Carter

Index Scriptorium Estoniae

Carter, Jimmy

2006-01-01

Iisraeli poliitika vastuolulisus, Palestiina koloniseerimine takistab rahulepingu sõlmimist, olenemata sellest, kes Palestiina riiki parajasti juhib. USA ekspresident Jimmy Carteri hinnang protsessidele regioonis

PKI-based secure mobile access to electronic health services and data.

Science.gov (United States)

Kambourakis, G; Maglogiannis, I; Rouskas, A

2005-01-01

Recent research works examine the potential employment of public-key cryptography schemes in e-health environments. In such systems, where a Public Key Infrastructure (PKI) is established beforehand, Attribute Certificates (ACs) and public key enabled protocols like TLS, can provide the appropriate mechanisms to effectively support authentication, authorization and confidentiality services. In other words, mutual trust and secure communications between all the stakeholders, namely physicians, patients and e-health service providers, can be successfully established and maintained. Furthermore, as the recently introduced mobile devices with access to computer-based patient record systems are expanding, the need of physicians and nurses to interact increasingly with such systems arises. Considering public key infrastructure requirements for mobile online health networks, this paper discusses the potential use of Attribute Certificates (ACs) in an anticipated trust model. Typical trust interactions among doctors, patients and e-health providers are presented, indicating that resourceful security mechanisms and trust control can be obtained and implemented. The application of attribute certificates to support medical mobile service provision along with the utilization of the de-facto TLS protocol to offer competent confidentiality and authorization services is also presented and evaluated through experimentation, using both the 802.11 WLAN and General Packet Radio Service (GPRS) networks.

Grain operator miffed at port administration

Index Scriptorium Estoniae

2006-01-01

Ventspils Grain Terminal saatis president Vaira Vike-Freibergale ja mitmetele ministritele kirja sõnumiga, et Ventspilsi Vabasadama (Ventspils Free Port) administratsiooni tegevus takistab terminali äritegevust

Tallinna sadama tax-free poed tegutsevad seaduseaugus : Illar Hallaste kaitseb maksuvaba kaupluse huve / Toomas Raag, Urmas Seaver, Mart Luik

Index Scriptorium Estoniae

Raag, Toomas, 1983-

1998-01-01

Reisisadama tollikontrolli tsoonis olevad tax-free kauplused on riigiametnike hinnangul vastuolus kehtiva tolliseadusega, kuid poodide kinnipanemist takistab valitsuse varasem maksuvabasid kauplusi lubav määrus

Establishment and antitumor effects of dasatinib and PKI-587 in BD-138T, a patient-derived muscle invasive bladder cancer preclinical platform with concomitant EGFR amplification and PTEN deletion.

Science.gov (United States)

Chang, Nakho; Lee, Hye Won; Lim, Joung Eun; Jeong, Da Eun; Song, Hye Jin; Kim, Sudong; Nam, Do-Hyun; Sung, Hyun Hwan; Jeong, Byong Chang; Seo, Seong Il; Jeon, Seong Soo; Lee, Hyun Moo; Choi, Han-Yong; Jeon, Hwang Gyun

2016-08-09

Muscle-invasive bladder cancer (MIBC) consists of a heterogeneous group of tumors with a high rate of metastasis and mortality. To facilitate the in-depth investigation and validation of tailored strategies for MIBC treatment, we have developed an integrated approach using advanced high-throughput drug screening and a clinically relevant patient-derived preclinical platform. We isolated patient-derived tumor cells (PDCs) from a rare MIBC case (BD-138T) that harbors concomitant epidermal growth factor receptor (EGFR) amplification and phosphatase and tensin homolog (PTEN) deletion. High-throughput in vitro drug screening demonstrated that dasatinib, a SRC inhibitor, and PKI-587, a dual PI3K/mTOR inhibitor, exhibited targeted anti-proliferative and pro-apoptotic effects against BD-138T PDCs. Using established patient-derived xenograft models that successfully retain the genomic and molecular characteristics of the parental tumor, we confirmed that these anti-tumor responses occurred through the inhibition of SRC and PI3K/AKT/mTOR signaling pathways. Taken together, these experimental results demonstrate that dasatinib and PKI-587 might serve as promising anticancer drug candidates for treating MIBC with combined EGFR gene amplification and PTEN deletion.

Scientific Grid activities and PKI deployment in the Cybermedia Center, Osaka University.

Science.gov (United States)

Akiyama, Toyokazu; Teranishi, Yuuichi; Nozaki, Kazunori; Kato, Seiichi; Shimojo, Shinji; Peltier, Steven T; Lin, Abel; Molina, Tomas; Yang, George; Lee, David; Ellisman, Mark; Naito, Sei; Koike, Atsushi; Matsumoto, Shuichi; Yoshida, Kiyokazu; Mori, Hirotaro

2005-10-01

The Cybermedia Center (CMC), Osaka University, is a research institution that offers knowledge and technology resources obtained from advanced researches in the areas of large-scale computation, information and communication, multimedia content and education. Currently, CMC is involved in Japanese national Grid projects such as JGN II (Japan Gigabit Network), NAREGI and BioGrid. Not limited to Japan, CMC also actively takes part in international activities such as PRAGMA. In these projects and international collaborations, CMC has developed a Grid system that allows scientists to perform their analysis by remote-controlling the world's largest ultra-high voltage electron microscope located in Osaka University. In another undertaking, CMC has assumed a leadership role in BioGrid by sharing its experiences and knowledge on the system development for the area of biology. In this paper, we will give an overview of the BioGrid project and introduce the progress of the Telescience unit, which collaborates with the Telescience Project led by the National Center for Microscopy and Imaging Research (NCMIR). Furthermore, CMC collaborates with seven Computing Centers in Japan, NAREGI and National Institute of Informatics to deploy PKI base authentication infrastructure. The current status of this project and future collaboration with Grid Projects will be delineated in this paper.

Cell-cycle-dependent three-dimensional redistribution of nuclear proteins, P 120, pKi-67, and SC 35 splicing factor, in the presence of the topoisomerase I inhibitor camptothecin.

Science.gov (United States)

Elias, Emmanuel; Lalun, Nathalie; Lorenzato, Marianne; Blache, Laurent; Chelidze, Pavel; O'Donohue, Marie-Françoise; Ploton, Dominique; Bobichon, Hélène

2003-11-15

Topoisomerase I (Topo I) is mostly known for its role in DNA relaxation, which is required for duplication and transcription. Topo I acts as a protein kinase mainly directed to the mRNA splicing factor SC35. Camptothecin is one of the specific Topo I inhibitors and is effective on the two functions of the enzyme. In this study we demonstrated that treatment of KB cells with camptothecin for only 30 min induced the 3D reorganization and redistribution of three proteins involved in the nucleus machinery, P 120, pKi-67, and SC 35, and this occurred in a cell cycle-dependent manner. Our data were obtained from confocal microscopic studies after immunolabeling, 3D reconstruction, and measurement of the nuclear components volumes. In the presence of camptothecin, P 120, which occupied the nucleolar volume, lost its reticulation and pKi-67 was redistributed within the nucleoplasm and even into the cytoplasm. Finally, for SC 35 the fusion of its dots into bigger volumes was observed specifically during the G1 phase. Variations of volumes were also observed for the nucleolus and for the nucleus. These results pointed out that, depending on the cell cycle phase, Topo I functions were selective toward the three different proteins.

Identification of cellular targets involved in cardiac failure caused by PKI in oncology: an approach combining pharmacovigilance and pharmacodynamics.

Science.gov (United States)

Patras de Campaigno, Emilie; Bondon-Guitton, Emmanuelle; Laurent, Guy; Montastruc, Francois; Montastruc, Jean-Louis; Lapeyre-Mestre, Maryse; Despas, Fabien

2017-07-01

The aims of the present study were to evaluate the risk of cardiac failure (CF) associated with 15 anticancer protein kinase inhibitors (PKIs) through a case/noncase analysis and to identify which PK(s) and pathways are involved in PKI-induced CF. In order to evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the World Health Organization safety report database (VigiBase®). We realised a literature review to identify 21 protein kinases (PKs) that were possibly involved in CF caused by PKIs. Pearson correlation coefficients (r) between aRORs and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely to be involved in PKI-induced CF. A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase® for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib. Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively. Significant values for correlation coefficients between the product of dissociation constant (pKd) and aROR were observed for two non-receptor protein kinases: ABL1 (non-phosphorylated and phosphorylated forms) and ABL2 protein kinases, with values of r = 0.83 (P = 0.0001), r = 0.75 (P = 0.0014) and r = 0.78 (P = 0.0006), respectively. We observed a higher disproportionality for CF with dasatinib, imatinib, bosutinib, sunitinib and nilotinib than with other PKIs. In addition, the study highlighted the role of ABL tyrosine kinases in CF caused by anticancer PKIs. © 2017 The British

Parlamendiliikmete immuniteedi põhimõtte rakendamine kriminaalmenetluses [Võrguteavik] / Kätlin-Chris Kruusmaa

Index Scriptorium Estoniae

Kruusmaa, Kätlin-Chris

2017-01-01

Analüüsitakse põhiseaduse §-st 76 tulenevat saadikupuutumatuse põhimõtet, püütakse anda vastus küsimusele, kuidas see regulatsioon mõjutab/takistab korruptsiooni- ja teiste latentsete kuritegude uurimist

Logistikas on andmevahetus ülitähtis / Erik Sakkov

Index Scriptorium Estoniae

Sakkov, Erik, 1967-

2004-01-01

Tallinna Sadama turundusdirektor selgitab, miks Tallinna sadam on huvitatud elektroonilise infovahetussüsteemi EDI väljatöötamisest ja mis takistab sadama kommuuni ettevõtete vahel edastatava kaubaga seotud info elektroonilise edastamise arengut

Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402.

Science.gov (United States)

Dehnhardt, Christoph M; Venkatesan, Aranapakam M; Delos Santos, Efren; Chen, Zecheng; Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Brooijmans, Natasja; Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Chaudhary, Inder; Yu, Ker; Gibbons, Jay; Abraham, Robert; Mansour, Tarek S

2010-01-28

Herein we describe the identification and lead optimization of triazolopyrimidines as a novel class of potent dual PI3K/mTOR inhibitors, resulting in the discovery of 3 (PKI-402). Compound 3 exhibits good physical properties and PK parameters, low nanomolar potency against PI3Kalpha and mTOR, and excellent inhibition of cell proliferation in several human cancer cell lines. Furthermore, in vitro and in vivo biomarker studies demonstrated the ability of 3 to shut down the PI3K/Akt pathway and induce apoptosis in cancer cells. In addition, 3 showed excellent in vivo efficacy in various human cancer xenografts, validating suppression of PI3K/mTOR signaling as a potential anticancer therapy.

Kruuda, Vichmann ja Kilp kavandavad Rocca al Maresse tervisemetropoli / Raigo Neudorf

Index Scriptorium Estoniae

Neudorf, Raigo

2007-01-01

Rocca al Mare Suurhalli uued omanikud Aare Kilp, Marcel Vichmann ja Oliver Kruuda plaanivad suurhalli lähedusse rajada suure ja uuelaadse vabaaja- ja spordikeskuse. Vt. samas: Kasumisse jõudmist takistab laenukoorem; Külastajate arv kasvab

IT-teenuste edukas sisseostmine : kas kontrollida või teha koostööd / Adriaan Kik, Aigar Koov

Index Scriptorium Estoniae

Kik, Adriaan

2008-01-01

Ettevõtete suurim väljakutse on kogenud IT- töötajate nappus ja oma ressursi tõhus kasutamine, IT-teenuste turul takistab sisseostmist teenusepakkujate piiratud hulk. Vt. samas: Eesti ja maailm: IT-teenuste sisseostmine

Sume superbiam! / Linnar Priimägi

Index Scriptorium Estoniae

Priimägi, Linnar, 1954-

2008-01-01

Vabadussõja keskne mälestusmärk Tallinna Reaalkooli (autor Ferdi Sannamees) ees on emotsionaalses mälus niivõrd tugevasti seotud noorusega, et just see sisetunne takistab paljusid omaks võtmast uue monumendi ideed

Stereoselective synthesis of an active metabolite of the potent PI3 kinase inhibitor PKI-179.

Science.gov (United States)

Chen, Zecheng; Venkatesan, Aranapakam M; Dos Santos, Osvaldo; Delos Santos, Efren; Dehnhardt, Christoph M; Ayral-Kaloustian, Semiramis; Ashcroft, Joseph; McDonald, Leonard A; Mansour, Tarek S

2010-03-05

The synthesis and stereochemical determination of 1-(4-(4-((1R,5R,6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (2), an active metabolite of the potent PI3 kinase inhibitor PKI-179 (1), is described. Stereospecific hydroboration of the double bond of 2,5-dihydro-1H-pyrrole 8 gave the 2,3-trans alcohol 9 exclusively. The configuration of the 3-hydroxyl group in 9 was inverted by an oxidation and stereoselective reduction sequence to give the corresponding 2,3-cis isomer 23. Both exo (21) and endo (27) isomers of the metabolite 2 were prepared via a practical synthetic route from 9 and 23, respectively, and the stereochemistry of 2 was determined to be endo. The endo isomer (27) was separated into two enantiomers 28 and 29 by chiral HPLC. Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2.

Piltsõnumid - uus massiteenus mobiilside turul? / Andrus Hiiepuu

Index Scriptorium Estoniae

Hiiepuu, Andrus, 1966-

2003-01-01

Autor analüüsib erinevaid teenuseid mobiilside turul ning tunnistab, et edu on neist saavutanud vaid kõne ja lühisõnumid. MMS teenuse levikut takistab vastava toetusega telefonide saadavus ja nende hind. Lisa: MMS (Multimedia Messaging Service)

Innovatsioon sünnib Eestis nõukogude pärandist / Per Högselius

Index Scriptorium Estoniae

Högselius, Per

2005-01-01

Selle asemelt et diskuteerida, mis takistab innovatsiooni, tuleks uurida edulugusid. Autor, Lundi ülikooli CIRCLE keskuse õppedirektor selgitab oma uurimistöö põhjal, millistel tingimustel on sündinud edukad uuendused Eesti info- ja arvutitehnikasektoris, märkides muu hulgas nõukogude pärandi tähtsust

Verine vihakolle Balkanil jahtus aastatega argiidülliks / Peeter Kuimet

Index Scriptorium Estoniae

Kuimet, Peeter

2007-01-01

Ilmunud ka: Postimees : na russkom jazõke 4. juuli lk. 4-5. Lõpeb Eesti kaitseväe pikim välismissioon Bosnia-Hertsegoviinas, mis kestis üksteist aastat. Vt. samas: Politseireform takistab Bosnia liikumist Euroopasse; Praeguseks lahenenud Bosnia konflikt sai alguse 1992. aastal ja põhines rahvustevahelisel vaenul

Vananemise taga võib olla kahepalgeline geen / Tiit Kändler

Index Scriptorium Estoniae

Kändler, Tiit, 1948-

2012-01-01

Kui pärssida valku nimega TOR rapamütsiiniga, pikeneb pärmide ja loomade eluiga. Ka kaloripiirang aeglustab vananemist, mõjudes samale valgule. TOR on oluline valk kasvavas organismis. Jätkuv aktiivsus küpses eas takistab raku tegutsemist, kahjustab kudesid, mõjutab vananemist ja haiguste teket

An assessment of PKI and networked electronic patient record system: lessons learned from real patient data exchange at the platform of OCHIS (Osaka Community Healthcare Information System).

Science.gov (United States)

Takeda, Hiroshi; Matsumura, Yasushi; Kuwata, Shigeki; Nakano, Hirohiko; Shanmai, Ji; Qiyan, Zhang; Yufen, Chen; Kusuoka, Hideo; Matsuoka, Masaki

2004-03-31

To enhance medical cooperation between the hospitals and clinics around Osaka local area, the healthcare network system, named Osaka Community Healthcare Information System (OCHIS), was established with support of a supplementary budget from the Japanese government in fiscal year 2002. Although the system has been based on healthcare public key infrastructure (PKI), there remain security issues to be solved technically and operationally. An experimental study was conducted to elucidate the central and the local function in terms of a registration authority and a time stamp authority in contract with the Japanese Medical Information Systems Organization (MEDIS) in 2003. This paper describes the experimental design and the results of the study concerning message security.

Erivajadustega laps / Inga Mutso

Index Scriptorium Estoniae

Mutso, Inga, 1959-

2002-01-01

Sept. 2000 - märts 2001 viidi Tartu Õppekeskuse, TPÜ täiendkoolituse osakonna ja Geomeedia Erakooli eripedagoogikaalastel täiendusõppe kursustel osalenud pedagoogide seas läbi ankeetküsitlus. Uuringus selgus, et erivajadustega õpilaste integreerimist tavakooli takistab vajaliku väljaõppe saanud pedagoogide puudumine ja koolide mittevalmisolek

Public key infrastructure building trusted applications and web services

CERN Document Server

Vacca, John R

2004-01-01

OVERVIEW OF PKI TECHNOLOGYPublic Key Infrastructures (PKIs): What Are They?Type of Certificate Authorities (CAS) ServicesPKI StandardsTypes of Vendor and Third-Party CA SystemsProtecting Private KeysCA System AttacksStolen Private Keys: What Can Be Done?Certificate Practice StatementsPKI ReadinessANALYZING AND DESIGNING PUBLIC KEY INFRASTRUCTURESPKI Design IssuesCost Justification and ConsiderationPKI Standards Design IssuesPKI Architectural Design ConsiderationsIMPLEMENTING PKIRequirementsImplementation ScheduleImplementation CostsPKI PerformanceMANAGING PKIRequesting a CertificateObtaining a

Practical Implementation of Various Public Key Infrastructure Models

Directory of Open Access Journals (Sweden)

Dmitriy Anatolievich Melnikov

2016-03-01

Full Text Available The paper proposes a short comparative analysis of the contemporary models of public key infrastructure (PKI and the issues of the PKI models real implementation. The Russian model of PKI is presented. Differences between the North American and West Europe models of PKI and Russian model of PKI are described. The problems of creation and main directions of further development and improvement of the Russian PKI and its integration into the global trust environment are defined.

Rapsist diislikütus : kallis ja tõrjutud / Heiki Raudla

Index Scriptorium Estoniae

Raudla, Heiki, 1975-

2008-01-01

Paldiski Lõunasadamas avatud Biodiesel Paldiski AS tehas loodab tulevikus täisvõimsuse juures toota 100 000 tonni biodiislikütust aastas, praegu eksporditakse kogu toodang peamiselt Lääne-Euroopasse ja Skandinaaviasse. Eesti tarbijale biodiislikütuse tootmist takistab peamiselt tooraine kõrge hind ning vähene nõudlus. Küsimusele vastavad Kai Realo ja Indrek Kaju

Birma takistab välisabi jagamist / Hendrik Vosman

Index Scriptorium Estoniae

Vosman, Hendrik

2008-01-01

Birma sõjaväediktatuur võtab küll tsüklon Nargise põhjustatud looduskatastroofi tõttu välisabi vastu, kuid keelab abiandjatel seda hädalistele kohale viia. Lisa: Ohvrite arv. Vt. samas: Referendum toimus katastroofist hoolimata

Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.

Science.gov (United States)

Venkatesan, Aranapakam M; Dehnhardt, Christoph M; Delos Santos, Efren; Chen, Zecheng; Dos Santos, Osvaldo; Ayral-Kaloustian, Semiramis; Khafizova, Gulnaz; Brooijmans, Natasja; Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Yu, Ker; Gibbons, James; Abraham, Robert T; Chaudhary, Inder; Mansour, Tarek S

2010-03-25

The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.

Investigations into the binding affinities of different human 5-HT4 receptor splice variants.

Science.gov (United States)

Irving, Helen R; Tochon-Danguy, Nathalie; Chinkwo, Kenneth A; Li, Jian G; Grabbe, Carmen; Shapiro, Marina; Pouton, Colin W; Coupar, Ian M

2010-01-01

This study examined whether the drug-receptor-binding sites of 5 selected human 5-HT(4) receptor splice variants [h5-HT4(a), h5-HT4(b), h5-HT4(c), h5-HT4(d) and h5-HT4(g)] display preferential affinities towards agonists. The agonists selected on the basis of chemical diversity and clinical relevance were: 5-HT4 benzamides, renzapride, zacopride and prucalopride; the benzimidazolones, DAU 6236 and BIMU 1; the aromatic ketone, RS67333, and the indole carbazimidamide tegaserod. The rank order of affinities ranging across the splice variants was: tegaserod (pKi: 7.38-7.91) > or = Y-36912 (pKi: 7.03-7.85) = BIMU 1 (pKi: 6.92-7.78) > or = DAU 6236 (pKi: 6.79-7.99) > or = 5-HT (pKi: 5.82-7.29) > or = 5-MeOT (pKi: 5.64-6.83) > or = renzapride (pKi: 4.85-5.56). We obtained affinity values for the 5-HT4(b), (d) and (g) variants for RS67333 (pKi: 7:48-8.29), prucalopride (pKi: 6.86-7.37) and zacopride (pKi: 5.88-7.0). These results indicate that the ligands interact with the same conserved site in each splice variant. Some splice variants have a higher affinity for certain agonists and the direction of selectivity followed a common trend of lowest affinity at the (d) variant. However, this trend was not evident in functional experiments. Our findings suggest that it may be possible to design splice variant selective ligands, which may be of relevance for experimental drugs but may be difficult to develop clinically. 2010 S. Karger AG, Basel.

75 FR 47812 - Privacy Act of 1974; Report of a New System of Records

Science.gov (United States)

2010-08-09

... do not require certificates for using encryption with a Public Key Infrastructure (PKI), to whom HHS... Infrastructure (PKI) credentials, Personal Identification Numbers (PINs) and passwords. Access to individuals... and adjudication will be two- factor protected using PKI and PIN; each person granted access to the...

The temporal and spatial distribution of the proliferation associated Ki-67 protein during female and male meiosis.

Science.gov (United States)

Traut, Walther; Endl, Elmar; Scholzen, Thomas; Gerdes, Johannes; Winking, Heinz

2002-09-01

We used immunolocalization in tissue sections and cytogenetic preparations of female and male gonads to study the distribution of the proliferation marker pKi-67 during meiotic cell cycles of the house mouse, Mus musculus. During male meiosis, pKi-67 was continuously present in nuclei of all stages from the spermatogonium through spermatocytes I and II up to the earliest spermatid stage (early round spermatids) when it appeared to fade out. It was not detected in later spermatid stages or sperm. During female meiosis, pKi-67 was present in prophase I oocytes of fetal ovaries. It was absent in oocytes from newborn mice and most oocytes of primordial follicles from adults. The Ki-67 protein reappeared in oocytes of growing follicles and was continuously present up to metaphase II. Thus, pKi-67 was present in all stages of cell growth and cell division while it was absent from resting oocytes and during the main stages of spermiocytogenesis. Progression through the meiotic cell cycle was associated with extensive intranuclear relocation of pKi-67. In the zygotene and pachytene stages, most of the pKi-67 colocalized with centromeric (centric and pericentric) heterochromatin and adjacent nucleoli; the heterochromatic XY body in male pachytene, however, was free of pKi-67. At early diplotene, pKi-67 was mainly associated with nucleoli. At late diplotene, diakinesis, metaphase I and metaphase II of meiosis, pKi-67 preferentially bound to the perichromosomal layer and was almost absent from the heterochromatic centromeric regions of the chromosomes. After the second division of male meiosis, the protein reappeared at the centromeric heterochromatin and an adjacent region in the earliest spermatid stage and then faded out. The general patterns of pKi-67 distribution were comparable to those in mitotic cell cycles. With respect to the timing, it is interesting to note that relocation from the nucleolus to the perichromosomal layer takes place at the G2/M-phase transition in

The binding of [3H]AF-DX 384 to rat ileal smooth muscle muscarinic receptors

International Nuclear Information System (INIS)

Entzeroth, M.; Mayer, N.

1991-01-01

The tritiated cardioselective muscarinic antagonist AF-DX 384 (5,11-dihydro-11-[2-[-(8-dipropylamino)methyl]-1-piperidinyl-ethyl-amino-carbonyl]-6H-pyrido [2,3-b] [1,4]benzodiazepin-6-one) was used to label muscarinic receptors in the rat ileum. Saturation binding to membrane suspensions revealed a high affinity binding site with a Kd of 9.2 nM. The maximal number of binding sites labeled in this tissue (Bmax) is 237 fmol/mg protein. The association and dissociation kinetics were well represented by single exponential reactions, and the dissociation constant obtained from the ratio of rate constants was in agreement with that derived from saturation experiments. Specific binding was inhibited by muscarinic antagonists with a rank order of potencies of atropine (pKi: 8.80) greater than 4-DAMP (pKi: 8.23) = AF-DX 384 (pKi: 8.20) greater than AF-DX 116 (pKi: 7.09) = hexahydro-sila-difenidol (pKi: 6.97) greater than pirenzepine (pKi: 6.49) and is consistent with the interaction of [3H]AF-DX 384 with muscarinic receptors of the M2 subtype. It can be concluded that [3H]AF-DX 384 can be used to selectively label M2 muscarinic receptors in heterogeneous receptor populations

77 FR 2515 - Privacy Act of 1974; System of Records

Science.gov (United States)

2012-01-18

... software uses Primary Key Infrastructure (PKI)/Common Access Card (CAC) authentication to lock out... Infrastructure (PKI)/Common Access Card (CAC) authentication to lock out unauthorized access. System software...

77 FR 94 - Privacy Act of 1974; System of Records

Science.gov (United States)

2012-01-03

... software uses Primary Key Infrastructure (PKI)/Common Access Card (CAC) authentication to lock out... Infrastructure (PKI)/Common Access Card (CAC) authentication to lock out unauthorized access. System software...

CAC on a MAC: Setting up a DOD Common Access Card Reader on the Macintosh OS X Operating System

National Research Council Canada - National Science Library

Hopfner, Phil

2006-01-01

.... The CAC readers in conjunction with the user's Smart Card enables access to DoD PKI-enabled websites and allows the user to send signed and encrypted email utilizing the DoD Public Key Infrastructure (PKI...

Implementació d'un esquema criptogràfic per gestionar remotament de forma segura els historials mèdics dels pacients

OpenAIRE

Garcia Mesas, Vicent

2009-01-01

Implementació d'un esquema criptogràfic basat en PKI (Public Key Infrastructure) per a gestionar d'una manera segura dins una xarxa de comunicacions els historials mèdics dels pacients. Implementación de un esquema criptográfico basado en PKI (Public Key Infrastructure) para gestionar de una manera segura dentro de una red de comunicaciones los historiales médicos de los pacientes. Implementation of a cryptographic scheme based on PKI (Public Key Infrastructure) to securely manage the m...

Crystal structure of a polyhistidine-tagged recombinant catalytic subunit of cAMP-dependent protein kinase complexed with the peptide inhibitor PKI(5-24) and adenosine.

Science.gov (United States)

Narayana, N; Cox, S; Shaltiel, S; Taylor, S S; Xuong, N

1997-04-15

The crystal structure of the hexahistidine-tagged mouse recombinant catalytic subunit (H6-rC) of cAMP-dependent protein kinase (cAPK), complexed with a 20-residue peptide inhibitor from the heat-stable protein kinase inhibitor PKI(5-24) and adenosine, was determined at 2.2 A resolution. Novel crystallization conditions were required to grow the ternary complex crystals. The structure was refined to a final crystallographic R-factor of 18.2% with good stereochemical parameters. The "active" enzyme adopts a "closed" conformation as found in rC:PKI(5-24) [Knighton et al. (1991a,b) Science 253, 407-414, 414-420] and packs in a similar manner with the peptide providing a major contact surface. This structure clearly defines the subsites of the unique nucleotide binding site found in the protein kinase family. The adenosine occupies a mostly hydrophobic pocket at the base of the cleft between the two lobes and is completely buried. The missing triphosphate moiety of ATP is filled with a water molecule (Wtr 415) which replaces the gamma-phosphate of ATP. The glycine-rich loop between beta1 and beta2 helps to anchor the phosphates while the ribose ring is buried beneath beta-strand 2. Another ordered water molecule (Wtr 375) is pentacoordinated with polar atoms from adenosine, Leu 49 in beta-strand 1, Glu 127 in the linker strand between the two lobes, Tyr 330, and a third water molecule, Wtr 359. The conserved nucleotide fold can be defined as a lid comprised of beta-strand 1, the glycine-rich loop, and beta-strand 2. The adenine ring is buried beneath beta-strand 1 and the linker strand (120-127) that joins the small and large lobes. The C-terminal tail containing Tyr 330, a segment that lies outside the conserved core, covers this fold and anchors it in a closed conformation. The main-chain atoms of the flexible glycine-rich loop (residues 50-55) in the ATP binding domain have a mean B-factor of 41.4 A2. This loop is quite mobile, in striking contrast to the other

KETIKA KEBIJAKAN ORDE LAMA MEMASUKI DOMAIN PENDIDIKAN: PENYIAPAN DAN KINERJA GURU SEKOLAH DASAR DI INDONESIA

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Umasih Umasih

2014-01-01

Full Text Available This article reveals how the educational policy in Indonesia during The Old Order. The domination of government (Soekarno as expressed in the domination theory by Antonio Gramsci which a politic is a commander and it can dominate whole Indonesia society life including an educational aspect. Furthermore, Soekarno as an individual manivesto has given a space for PKI because of their closeness. When the Minister, Prijono, issued a decision concerning about Pancawardhana Educational System, The Institution of National Education which is affiliated by PKI giving a formulation of Pancacinta. An education in the political manifesto obliges teachers enter into a practical politics life, teachers have to be revolutionary . It means that the learning practice is given toward students through indoctrination.  No less than 2000 teachers in the East java and the Cental Java finally became PKI members, then about  580 teachers of elementary school from the West Java. Even PKI has succeeded to divide the organization of teacher’s membership into The Cental Vak PGRI and  non Vak Central PGRI. Keywords : The Old Order, The Pacawardhana Educational System, the performance of elementary teachers.  Artikel ini mengungkapkan bagaimana kebijakan pendidikan Indonesia pada masa Orde Lama. Dominasi pemerintah (Soekarno seperti diungkapkan dalam teori  dominasi oleh ntonio Gramsci di mana politik adalah panglima dan dapat mendominasi segala kehidupan masyarakat Indonesia termasuk dalam bidang pendidikan. Tidak hanya itu, Presiden Soekarno sebagai manivesto perseorangan  juga  telah  memberi ruang gerak pada PKI karena kedekatan hubungannya dengan Presiden Soekarno.  Ketika Menteri Prijono mengeluarkan keputusan tentang Sistem Pendidikan Pancawardhana, Lembaga Pendidikan Nasional yang berafiliasi dengan PKI memberi rumusan tentang Pancacinta. Pendidikan dalam alam manipol mengharuskan guru terjun dalam kehidupan politik praktis, guru harus revolusioner yang

Toekomstvaste fysieke toegangsystemen : Public Key Infrastructure als oplossing voor fysiek toegangbeheer

NARCIS (Netherlands)

Kleinhuis, G.; Olk, J.G.E.

2011-01-01

Voor fysieke toegangssystemen wordt veelal gebruik gemaakt van toegangspassen met een contactlose chip. Soms zijn deze passen ook nog voorzien van een PKI (Public Key Infrastructure) contactchip voor toegang tot ICT en/of het plaatsen van een digitale handtekening. Ook voor fysieke toegang bied PKI

The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites

Directory of Open Access Journals (Sweden)

Elena K. Schneider

2018-03-01

Full Text Available Ivacaftor–lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators. The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1 and ivacaftorcarboxylate (iva-M6 with neurotransmitter receptors were investigated in radioligand binding assays. Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin 5-HT2C receptor (pKi=6.06±0.03, β3-adrenergic receptor (pKi=5.71±0.07, δ-opioid receptor (pKi=5.59±0.06 and the dopamine transporter (pKi=5.50±0.20; iva-M1 displayed significant affinity to the 5-HT2C receptor (pKi=5.81±0.04 and the muscarinic M3 receptor (pKi=5.70±0.10; iva-M6 displayed significant affinity to the 5-HT2A receptor (pKi=7.33±0.05. The in vivo central nervous system activity of ivacaftor (40 mg·kg−1 intraperitoneally for 21 days was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s, similarly to fluoxetine (33.8±11.0 s, and increased climbing/swimming activity (181.5±9.2 s. In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versus fluoxetine 57.9±9.5 and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor–lumacaftor resulted in significant improvements in quality of life (including anxiety in all five domains of the AweScoreCF questionnaire (p=0.092–0.096. Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.

The construction of a public key infrastructure for healthcare information networks in Japan.

Science.gov (United States)

Sakamoto, N

2001-01-01

The digital signature is a key technology in the forthcoming Internet society for electronic healthcare as well as for electronic commerce. Efficient exchanges of authorized information with a digital signature in healthcare information networks require a construction of a public key infrastructure (PKI). In order to introduce a PKI to healthcare information networks in Japan, we proposed a development of a user authentication system based on a PKI for user management, user authentication and privilege management of healthcare information systems. In this paper, we describe the design of the user authentication system and its implementation. The user authentication system provides a certification authority service and a privilege management service while it is comprised of a user authentication client and user authentication serves. It is designed on a basis of an X.509 PKI and is implemented with using OpenSSL and OpenLDAP. It was incorporated into the financial information management system for the national university hospitals and has been successfully working for about one year. The hospitals plan to use it as a user authentication method for their whole healthcare information systems. One implementation of the system is free to the national university hospitals with permission of the Japanese Ministry of Education, Culture, Sports, Science and Technology. Another implementation is open to the other healthcare institutes by support of the Medical Information System Development Center (MEDIS-DC). We are moving forward to a nation-wide construction of a PKI for healthcare information networks based on it.

Thermal Injury in Human Subjects Due to 94-GHz Radio Frequency Radiation Exposures

Science.gov (United States)

2016-02-24

1161902612 Digitally signed by JOHNSON.LELAND.R.1161902612 DN: c=US, o=U.S. Government, ou=DoD, ou= PKI , ou=USAF, cn=JOHNSON.LELAND.R.1161902612 Date...2016.03.07 15:07:11 -06󈧄’ POLHAMUS.GARR ETT.D.1175839484 Digitally signed by POLHAMUS.GARRETT.D.1175839484 DN: c=US, o=U.S. Government, ou=DoD, ou= PKI

LIMA CERPEN PROPAGANDA LEKRA (1950—1965

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I Wayan Artika

2017-11-01

Full Text Available Penelitian ini bertujuan mengungkap muatan, karakter, dan tujuan ditulisnya cerpen propaganda; serta mengkaji hubungan sastra dan politik semasa Lekra (1950—1965.  Masalah penelitian adalah muatan, tujuan, karakter cerpen propaganda serta hubungan sastra dan politik.  Metode untuk memecahkan masalah dan mencapai tujuan penelitian, menggunakan metode deskriptif kualitatif. Hasil penelitian membuktikan, cerpen propaganda sarat muatan marxisme dan agenda perjuangan PKI. Tujuan cerpen propaganda adalah memengaruhi massa rakyat agar mendukung perjuangan PKI.  Karakter cerpen propaganda dibedakan menjadi karakter umum (yaitu aktual, menyerang lawan, memengaruhi pembaca dan karakter yang tampak pada struktur karya (bertema komunisme; tidak mementingkan alur; cerita berupa pandangan ideologis-politik pengarang; setting Revolusi Indonesia; pelaku cerita; rakyat tertindas, kader partai progresif, partisipan, simpatisan, dan militan PKI; dan bahasa mudah dimengerti. Dari hasil penelitian dapat disimpulkan, cerpen propaganda menunjukkan hubungan erat antara sastra, ideologi, dan politik. Hubungan sastra dan politik menunjukkan bahwa cerpen-cerpen tersebut merupakan alat propaganda PKI sesuai dengan Mukadimah 1950 dan 1959, Konsepsi Kebudayaan Rakyat, dan prinsip 1-5-1. Dalam hubungan tersebut, sastra berada di bawah politik dan kebenaran ideologi lebih tinggi daripada nilai sastra.

Identification of Toxoplasma gondii cAMP dependent protein kinase and its role in the tachyzoite growth.

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Hitomi Kurokawa

Full Text Available cAMP-dependent protein kinase (PKA has been implicated in the asexual stage of the Toxoplasma gondii life cycle through assaying the effect of a PKA-specific inhibitor on its growth rate. Since inhibition of the host cell PKA cannot be ruled out, a more precise evaluation of the role of PKA, as well as characterization of the kinase itself, is necessary.The inhibitory effects of two PKA inhibitors, H89, an ATP-competitive chemical inhibitor, and PKI, a substrate-competitive mammalian natural peptide inhibitor, were estimated. In the in vitro kinase assay, the inhibitory effect of PKI on a recombinant T. gondii PKA catalytic subunit (TgPKA-C was weaker compared to that on mammalian PKA-C. In a tachyzoite growth assay, PKI had little effect on the growth of tachyzoites, whereas H89 strongly inhibited it. Moreover, T. gondii PKA regulatory subunit (TgPKA-R-overexpressing tachyzoites showed a significant growth defect.Our data suggest that PKA plays an important role in the growth of tachyzoites, and the inhibitory effect of substrate-competitive inhibitor PKI on T. gondii PKA was low compared to that of the ATP competitive inhibitor H89.

Inner core boundary topography explored with reflected and diffracted P waves

Science.gov (United States)

deSilva, Susini; Cormier, Vernon F.; Zheng, Yingcai

2018-03-01

The existence of topography of the inner core boundary (ICB) can affect the amplitude, phase, and coda of body waves incident on the inner core. By applying pseudospectral and boundary element methods to synthesize compressional waves interacting with the ICB, these effects are predicted and compared with waveform observations in pre-critical, critical, post-critical, and diffraction ranges of the PKiKP wave reflected from the ICB. These data sample overlapping regions of the inner core beneath the circum-Pacific belt and the Eurasian, North American, and Australian continents, but exclude large areas beneath the Pacific and Indian Oceans and the poles. In the pre-critical range, PKiKP waveforms require an upper bound of 2 km at 1-20 km wavelength for any ICB topography. Higher topography sharply reduces PKiKP amplitude and produces time-extended coda not observed in PKiKP waveforms. The existence of topography of this scale smooths over minima and zeros in the pre-critical ICB reflection coefficient predicted from standard earth models. In the range surrounding critical incidence (108-130 °), this upper bound of topography does not strongly affect the amplitude and waveform behavior of PKIKP + PKiKP at 1.5 Hz, which is relatively insensitive to 10-20 km wavelength topography height approaching 5 km. These data, however, have a strong overlap in the regions of the ICB sampled by pre-critical PKiKP that require a 2 km upper bound to topography height. In the diffracted range (>152°), topography as high as 5 km attenuates the peak amplitudes of PKIKP and PKPCdiff by similar amounts, leaving the PKPCdiff/PKIKP amplitude ratio unchanged from that predicted by a smooth ICB. The observed decay of PKPCdiff into the inner core shadow and the PKIKP-PKPCdiff differential travel time are consistent with a flattening of the outer core P velocity gradient near the ICB and iron enrichment at the bottom of the outer core.

A Non-imaging High Throughput Approach to Chemical Library Screening at the Unmodified Adenosine-A3 Receptor in Living Cells

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Maria Augusta Arruda

2017-12-01

Full Text Available Recent advances in fluorescent ligand technology have enabled the study of G protein-coupled receptors in their native environment without the need for genetic modification such as addition of N-terminal fluorescent or bioluminescent tags. Here, we have used a non-imaging plate reader (PHERAstar FS to monitor the binding of fluorescent ligands to the human adenosine-A3 receptor (A3AR; CA200645 and AV039, stably expressed in CHO-K1 cells. To verify that this method was suitable for the study of other GPCRs, assays at the human adenosine-A1 receptor, and β1 and β2 adrenoceptors (β1AR and β2AR; BODIPY-TMR-CGP-12177 were also carried out. Affinity values determined for the binding of the fluorescent ligands CA200645 and AV039 to A3AR for a range of classical adenosine receptor antagonists were consistent with A3AR pharmacology and correlated well (R2 = 0.94 with equivalent data obtained using a confocal imaging plate reader (ImageXpress Ultra. The binding of BODIPY-TMR-CGP-12177 to the β1AR was potently inhibited by low concentrations of the β1-selective antagonist CGP 20712A (pKi 9.68 but not by the β2-selective antagonist ICI 118551(pKi 7.40. Furthermore, in experiments conducted in CHO K1 cells expressing the β2AR this affinity order was reversed with ICI 118551 showing the highest affinity (pKi 8.73 and CGP20712A (pKi 5.68 the lowest affinity. To determine whether the faster data acquisition of the non-imaging plate reader (~3 min per 96-well plate was suitable for high throughput screening (HTS, we screened the LOPAC library for inhibitors of the binding of CA200645 to the A3AR. From the initial 1,263 compounds evaluated, 67 hits (defined as those that inhibited the total binding of 25 nM CA200645 by ≥40% were identified. All compounds within the library that had medium to high affinity for the A3AR (pKi ≥6 were successfully identified. We found three novel compounds in the library that displayed unexpected sub-micromolar affinity

Interoperability for electronic ID

OpenAIRE

Zygadlo, Zuzanna

2009-01-01

Electronic Business, including eBanking, eCommerce and eGovernmental services, is today based on a large variety of security solutions, comprising electronic IDs provided by a broad community of Public Key Infrastructure (PKI) vendors. Significant differences in implementations of those solutions introduce a problem of lack of interoperability in electronic business, which have not yet been resolved by standardization and interoperability initiatives based on existing PKI trust models. It i...

Huvirühmade võitlus takistab Venemaal WTO-ga liitumist / Margit Aedla

Index Scriptorium Estoniae

Aedla, Margit, 1970-

2003-01-01

Venemaa valitsus plaanib lõpetada liitumisläbirääkimised Maailma Kaubandusorganisatsiooniga(WTO) tuleva aasta jooksul, kuid majandussektor ei soovi loobuda suurtest impordibarjääridest ega sisse lasta tegijaid väljastpoolt

Podocyte hypertrophy precedes apoptosis under experimental diabetic conditions.

Science.gov (United States)

Lee, Sun Ha; Moon, Sung Jin; Paeng, Jisun; Kang, Hye-Young; Nam, Bo Young; Kim, Seonghun; Kim, Chan Ho; Lee, Mi Jung; Oh, Hyung Jung; Park, Jung Tak; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

2015-08-01

Podocyte hypertrophy and apoptosis are two hallmarks of diabetic glomeruli, but the sequence in which these processes occur remains a matter of debate. Here we investigated the effects of inhibiting hypertrophy on apoptosis, and vice versa, in both podocytes and glomeruli, under diabetic conditions. Hypertrophy and apoptosis were inhibited using an epidermal growth factor receptor inhibitor (PKI 166) and a pan-caspase inhibitor (zAsp-DCB), respectively. We observed significant increases in the protein expression of p27, p21, phospho-eukaryotic elongation factor 4E-binding protein 1, and phospho-p70 S6 ribosomal protein kinase, in both cultured podocytes exposed to high-glucose (HG) medium, and streptozotocin-induced diabetes mellitus (DM) rat glomeruli. These increases were significantly inhibited by PKI 166, but not by zAsp-DCB. In addition, the amount of protein per cell, the relative cell size, and the glomerular volume were all significantly increased under diabetic conditions, and these changes were also blocked by treatment with PKI 166, but not zAsp-DCB. Increased protein expression of cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, together with increased Bax/Bcl-2 ratios, were also observed in HG-stimulated podocytes and DM glomeruli. Treatment with either zAsp-DCB or PKI 166 resulted in a significant attenuation of these effects. Both PKI 166 and zAsp-DCB also inhibited the increase in number of apoptotic cells, as assessed by Hoechst 33342 staining and TUNEL assay. Under diabetic conditions, inhibition of podocyte hypertrophy results in attenuated apoptosis, whereas blocking apoptosis has no effect on podocyte hypertrophy, suggesting that podocyte hypertrophy precedes apoptosis.

Designing towards the Unknown: Engaging with Material and Aesthetic Uncertainty

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Danielle Wilde

2017-12-01

Full Text Available New materials with new capabilities demand new ways of approaching design. Destabilising existing methods is crucial to develop new methods. Yet, radical destabilisation—where outcomes remain unknown long enough that new discoveries become possible—is not easy in technology design where complex interdisciplinary teams with time and resource constraints need to deliver concrete outcomes on schedule. The Poetic Kinaesthetic Interface project (PKI engages with this problematic directly. In PKI we use unfolding processes—informed by participatory, speculative and critical design—in emergent actions, to design towards unknown outcomes, using unknown materials. The impossibility of this task is proving as useful as it is disruptive. At its most potent, it is destabilising expectations, aesthetics and processes. Keeping the researchers, collaborators and participants in a state of unknowing, is opening the research potential to far-ranging possibilities. In this article we unpack the motivations driving the PKI project. We present our mixed-methodology, which entangles textile crafts, design interactions and materiality to shape an embodied enquiry. Our research outcomes are procedural and methodological. PKI brings together diverse human, non-human, known and unknown actors to discover where the emergent assemblages might lead. Our approach is re-invigorating—as it demands re-envisioning of—the design process.

Information security system based on virtual-optics imaging methodology and public key infrastructure

Science.gov (United States)

Peng, Xiang; Zhang, Peng; Cai, Lilong

In this paper, we present a virtual-optical based information security system model with the aid of public-key-infrastructure (PKI) techniques. The proposed model employs a hybrid architecture in which our previously published encryption algorithm based on virtual-optics imaging methodology (VOIM) can be used to encipher and decipher data while an asymmetric algorithm, for example RSA, is applied for enciphering and deciphering the session key(s). For an asymmetric system, given an encryption key, it is computationally infeasible to determine the decryption key and vice versa. The whole information security model is run under the framework of PKI, which is on basis of public-key cryptography and digital signatures. This PKI-based VOIM security approach has additional features like confidentiality, authentication, and integrity for the purpose of data encryption under the environment of network.

Securing Cloud - The Quantum Way

OpenAIRE

Pandya, Marmik

2015-01-01

Confidentiality, Integrity, and Availability are basic goals of security architecture. To ensure CIA, many authentication scheme has been introduced in several years. Currently deployment of Public Key Infrastructure (PKI) is a most significant solution. PKI involving exchange key using certificates via a public channel to a authenticate users in the cloud infrastructure. It is exposed to widespread security threats such as eavesdropping, the man in the middle attack, masquerade et al. Quantu...

Differential expression of mRNAs for protein kinase inhibitor isoforms in mouse brain.

OpenAIRE

Seasholtz, A F; Gamm, D M; Ballestero, R P; Scarpetta, M A; Uhler, M D

1995-01-01

Many neurotransmitters are known to regulate neuronal cell function by means of activation of cAMP-dependent protein kinase (PKA) and phosphorylation of neuronal substrate proteins, including transcription factors and ion channels. Here, we have characterized the gene expression of two isoforms of a protein kinase inhibitor (PKI) specific for PKA in mouse brain by RNase protection and in situ hybridization histochemistry. The studies demonstrate that the PKI alpha isoform is abundant in many ...

CAC on a MAC: setting up a DOD Common Access Card reader on the Macintosh OS X operating system

OpenAIRE

Hopfner, Phil

2006-01-01

The Naval Postgraduate School, along with many other Department of Defense (DOD) organizations, utilizes the ActivCard USB Common Access Card (CAC) readers. The CAC readers in conjunction with the user's Smart Card enables access to DOD PKI-enabled websites and allows the user to send signed and encrypted email utilizing the DOD Public Key Infrastructure (PKI). Microsoft Windows systems utilize the ActivCard Gold middleware software to enable CAC reader functionality. This software packag...

The PKI collector

Science.gov (United States)

Rice, M. P.

1982-07-01

The design and manufacturing of a solar thermal collector is discussed. The collector has three primary subsystems: concentrator, receiver/fluid loop, and controls. Identical curved reflective columns are utilized in a faceted Fresnel design to support 864 one foot square flat inexpensive second-surface, silvered glass mirrors. The columns are ganged together and rotated through their centers of gravity to provide elevation tracking. The concentrator is supported by a lightweight spaceframe structure which distributes all wind and gravity loads to the base supports. The base of the structure is a track which rotates on wheels mounted on concrete piers. A parallel tube steel heat exchanger is mounted at the concentrator focal area in a well insulated, galvanized steel housing. Two rows of vertical close-packed, staggered tubes connect a mud header and a steam header. Automatic two axis tracking and operational control is provided with a microprocessor based package. Concentrator-mounted shadowbands are the basis for active tracking. A software program provides azimuthal tracking during cloudy periods.

Virtual-optical information security system based on public key infrastructure

Science.gov (United States)

Peng, Xiang; Zhang, Peng; Cai, Lilong; Niu, Hanben

2005-01-01

A virtual-optical based encryption model with the aid of public key infrastructure (PKI) is presented in this paper. The proposed model employs a hybrid architecture in which our previously published encryption method based on virtual-optics scheme (VOS) can be used to encipher and decipher data while an asymmetric algorithm, for example RSA, is applied for enciphering and deciphering the session key(s). The whole information security model is run under the framework of international standard ITU-T X.509 PKI, which is on basis of public-key cryptography and digital signatures. This PKI-based VOS security approach has additional features like confidentiality, authentication, and integrity for the purpose of data encryption under the environment of network. Numerical experiments prove the effectiveness of the method. The security of proposed model is briefly analyzed by examining some possible attacks from the viewpoint of a cryptanalysis.

Binding mechanism and dynamic conformational change of C subunit of PKA with different pathways.

Science.gov (United States)

Chu, Wen-Ting; Chu, Xiakun; Wang, Jin

2017-09-19

The catalytic subunit of PKA (PKAc) exhibits three major conformational states (open, intermediate, and closed) during the biocatalysis process. Both ATP and substrate/inhibitor can effectively induce the conformational changes of PKAc from open to closed states. Aiming to explore the mechanism of this allosteric regulation, we developed a coarse-grained model and analyzed the dynamics of conformational changes of PKAc during binding by performing molecular dynamics simulations for apo PKAc, binary PKAc (PKAc with ATP, PKAc with PKI), and ternary PKAc (PKAc with ATP and PKI). Our results suggest a mixed binding mechanism of induced fit and conformational selection, with the induced fit dominant. The ligands can drive the movements of Gly-rich loop as well as some regions distal to the active site in PKAc and stabilize them at complex state. In addition, there are two parallel pathways (pathway with PKAc-ATP as an intermediate and pathway PKAc-PKI as an intermediate) during the transition from open to closed states. By molecular dynamics simulations and rate constant analyses, we find that the pathway through PKAc-ATP intermediate is the main binding route from open to closed state because of the fact that the bound PKI will hamper ATP from successful binding and significantly increase the barrier for the second binding subprocess. These findings will provide fundamental insights of the mechanisms of PKAc conformational change upon binding.

Inhibition of ErbB2 by receptor tyrosine kinase inhibitors causes myofibrillar structural damage without cell death in adult rat cardiomyocytes

International Nuclear Information System (INIS)

Pentassuglia, Laura; Graf, Michael; Lane, Heidi; Kuramochi, Yukio; Cote, Gregory; Timolati, Francesco; Sawyer, Douglas B.; Zuppinger, Christian; Suter, Thomas M.

2009-01-01

Inhibition of ErbB2 (HER2) with monoclonal antibodies, an effective therapy in some forms of breast cancer, is associated with cardiotoxicity, the pathophysiology of which is poorly understood. Recent data suggest, that dual inhibition of ErbB1 (EGFR) and ErbB2 signaling is more efficient in cancer therapy, however, cardiac safety of this therapeutic approach is unknown. We therefore tested an ErbB1-(CGP059326) and an ErbB1/ErbB2-(PKI166) tyrosine kinase inhibitor in an in-vitro system of adult rat ventricular cardiomyocytes and assessed their effects on 1. cell viability, 2. myofibrillar structure, 3. contractile function, and 4. MAPK- and Akt-signaling alone or in combination with Doxorubicin. Neither CGP nor PKI induced cardiomyocyte necrosis or apoptosis. PKI but not CGP caused myofibrillar structural damage that was additive to that induced by Doxorubicin at clinically relevant doses. These changes were associated with an inhibition of excitation-contraction coupling. PKI but not CGP decreased p-Erk1/2, suggesting a role for this MAP-kinase signaling pathway in the maintenance of myofibrils. These data indicate that the ErbB2 signaling pathway is critical for the maintenance of myofibrillar structure and function. Clinical studies using ErbB2-targeted inhibitors for the treatment of cancer should be designed to include careful monitoring for cardiac dysfunction.

Důvěryhodná proxy v SSL/TLS spojení

OpenAIRE

Smolík, Jiří

2017-01-01

The problem of SSL/TLS interception ("trusted proxy in SSL/TLS connection") has been known for years and many implementations exist. However, all of them share a single technical solution which is based solely on the PKI authentication mechanism and suffers from multiple serious disadvantages. Most importantly, it is not compatible with several aspects or future trends of SSL/TLS and PKI, there's almost no space for improvement and its real use may spawn legal issues. After we analyze technic...

MENYAKSIKAN KEKERASAN POLITIK DALAM NOVEL ‘AZRA JAKARTA

Directory of Open Access Journals (Sweden)

Taufiq Ahmad Dardiri

2015-03-01

Full Text Available This article has successfully aroused the violence of human’s right (HAM by communists in the era of ironical HAM afterwards. Such a violence happens in the form of political force in the course of stricking, imprisoning, torturing, and kill- ing. Of those motives above, the forces can actually be traced back to its roots, marxis ideology. According to Galtung, it is an ideology as the cause of such vio- lence. He exemplifies with the case that most people have done killing for the sake of ideology. This novel presents an episode significant for the Indonesian historical background, G30S/PKI. The Indonesian Communist Party (PKI force aimed to internalize its ideology in a country, has a great deal of its victims in the nation. Their violence is far from humanity principles. This case is illustrated by an author by presenting symbolic Moslem characters as the victims of PKI violence.   Key words: violence, symbolic characters, protagonis, dan konstelasi sejarah.

Extended N-Arylsulfonylindoles as 5-HT6 Receptor Antagonists: Design, Synthesis & Biological Evaluation

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Gonzalo Vera

2016-08-01

Full Text Available Based on a known pharmacophore model for 5-HT6 receptor antagonists, a series of novel extended derivatives of the N-arylsulfonyindole scaffold were designed and identified as a new class of 5-HT6 receptor modulators. Eight of the compounds exhibited moderate to high binding affinities and displayed antagonist profile in 5-HT6 receptor functional assays. Compounds 2-(4-(2-methoxyphenylpiperazin-1-yl-1-(1-tosyl-1H-indol-3-ylethanol (4b, 1-(1-(4-iodophenylsulfonyl-1H-indol-3-yl-2-(4-(2-methoxyphenylpiperazin-1-ylethanol (4g and 2-(4-(2-methoxyphenylpiperazin-1-yl-1-(1-(naphthalen-1-ylsulfonyl-1H-indol-3-ylethanol (4j showed the best binding affinity (4b pKi = 7.87; 4g pKi = 7.73; 4j pKi = 7.83. Additionally, compound 4j was identified as a highly potent antagonist (IC50 = 32 nM in calcium mobilisation functional assay.

Authenticated Blind Issuing of Symmetric Keys for Mobile Access Control System without Trusted Parties

Directory of Open Access Journals (Sweden)

Shin-Yan Chiou

2013-01-01

Full Text Available Mobile authentication can be used to verify a mobile user’s identity. Normally this is accomplished through the use of logon passwords, but this can raise the secret-key agreement problem between entities. This issue can be resolved by using a public-key cryptosystem, but mobile devices have limited computation ability and battery capacity and a PKI is needed. In this paper, we propose an efficient, non-PKI, authenticated, and blind issued symmetric key protocol for mobile access control systems. An easy-to-deploy authentication and authenticated key agreement system is designed such that empowered mobile devices can directly authorize other mobile devices to exchange keys with the server upon authentication using a non-PKI system without trusted parties. Empowered mobile users do not know the key value of the other mobile devices, preventing users from impersonating other individuals. Also, for security considerations, this system can revoke specific keys or keys issued by a specific user. The scheme is secure, efficient, and feasible and can be implemented in existing environments.

PKI als veilig communicatiemiddel

NARCIS (Netherlands)

Spek, J. van der; Veugen, P.J.M.

2002-01-01

Het belang van betrouwbare elektronische communicatie neemt hand over hand toe. Niet alleen in de context van gesloten oplossingen in bedrijfsleven of overheid, maar in toenemende mate ook in open omgevingen tussen partijen die niet van tevoren contractueel met elkaar zijn verbonden. Belangrijke

Argyreia nervosa (Burm. f.): receptor profiling of lysergic acid amide and other potential psychedelic LSD-like compounds by computational and binding assay approaches.

Science.gov (United States)

Paulke, Alexander; Kremer, Christian; Wunder, Cora; Achenbach, Janosch; Djahanschiri, Bardya; Elias, Anderson; Schwed, J Stefan; Hübner, Harald; Gmeiner, Peter; Proschak, Ewgenij; Toennes, Stefan W; Stark, Holger

2013-07-09

The convolvulacea Argyreia nervosa (Burm. f.) is well known as an important medical plant in the traditional Ayurvedic system of medicine and it is used in numerous diseases (e.g. nervousness, bronchitis, tuberculosis, arthritis, and diabetes). Additionally, in the Indian state of Assam and in other regions Argyreia nervosa is part of the traditional tribal medicine (e.g. the Santali people, the Lodhas, and others). In the western hemisphere, Argyreia nervosa has been brought in attention as so called "legal high". In this context, the seeds are used as source of the psychoactive ergotalkaloid lysergic acid amide (LSA), which is considered as the main active ingredient. As the chemical structure of LSA is very similar to that of lysergic acid diethylamide (LSD), the seeds of Argyreia nervosa (Burm. f.) are often considered as natural substitute of LSD. In the present study, LSA and LSD have been compared concerning their potential pharmacological profiles based on the receptor binding affinities since our recent human study with four volunteers on p.o. application of Argyreia nervosa seeds has led to some ambiguous effects. In an initial step computer-aided in silico prediction models on receptor binding were employed to screen for serotonin, norepinephrine, dopamine, muscarine, and histamine receptor subtypes as potential targets for LSA. In addition, this screening was extended to accompany ergotalkaloids of Argyreia nervosa (Burm. f.). In a verification step, selected LSA screening results were confirmed by in vitro binding assays with some extensions to LSD. In the in silico model LSA exhibited the highest affinity with a pKi of about 8.0 at α1A, and α1B. Clear affinity with pKi>7 was predicted for 5-HT1A, 5-HT1B, 5-HT1D, 5-HT6, 5-HT7, and D2. From these receptors the 5-HT1D subtype exhibited the highest pKi with 7.98 in the prediction model. From the other ergotalkaloids, agroclavine and festuclavine also seemed to be highly affine to the 5-HT1D

Seismic velocity and attenuation structures at the top 400 km of the inner core

Science.gov (United States)

Yu, W.; Wen, L.; Niu, F.

2002-12-01

Recent seismic studies reveal an ``east-west" hemispherical difference in seismic velocity and attenuation in the top of the inner core [Niu and Wen, 2001, Wen and Niu, 2002]. The PKiKP-PKIKP observations they used only allowed them to constrain the seismic structure in the top 80 km of the inner core. The question now arises as such to what depth this hemispherical difference persists. To answer this question, we combine the PKiKP-PKIKP dataset and the PKPbc-PKIKP observations at the distance range of 147o-160o to study seismic velocity and attenuation structures in the top 400 km of the inner core along the ``equatorial paths" (the paths whose ray angles > 35o from the polar direction). We select PKPbc-PKIKP waveforms from recordings in the Global Seismic Network (GSN) and several dense regional seismic arrays. We choose recordings for events from 1990 to 2000 with simple source time functions, so only those of intermediate and deep earthquakes are used. The observed PKPbc-PKIKP differential travel times and PKIKP/PKPbc amplitude ratios exhibit an ``east-west" hemispherical difference. The PKPbc-PKIKP travel time residuals are about 0.7 second larger for those sampling the ``eastern" hemisphere than those sampling the ``western" hemisphere. The PKIKP/PKPbc amplitude ratios are generally smaller for those sampling the ``eastern" hemisphere. We construct two seismic velocity and attenuation models, with one for each ``hemisphere", by iteratively modeling the observed PKiKP-PKIKP waveforms, the PKPbc-PKIKP differential travel times and the PKIKP/PKPbc amplitude ratios. For the ``eastern" hemisphere, the observations indicate that the E1 velocity gradient and Q structure, inferred from the PKiKP-PKIKP observations sampling the top 80 km of the inner core, extend at least to 230 km inside the inner core. A change of velocity gradient and Q value is required in the deeper portion of the inner core. For the ``western" hemisphere, on the other hand, W2 velocity gradient

Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA.

Directory of Open Access Journals (Sweden)

Xuan Yu

Full Text Available Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM, or ESI-09 (20 μM, or CE3F4 (100 μM, all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM; while concurrent administration of BFA and PKI (5 μM, a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM, induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1 was up regulated by G-1 (1 μM treatment of porcine coronary artery smooth muscle cells (CASMCs. Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP was elevated by G-1 (1 μM treatment, but not by 007 (50 μM; and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.

Temporal changes of the inner core from waveform doublets

Science.gov (United States)

Yang, Y.; Song, X.

2017-12-01

Temporal changes of the Earth's inner core have been detected from earthquake waveform doublets (repeating sources with similar waveforms at the same station). Using doublets from events up to the present in the South Sandwich Island (SSI) region recorded by the station COLA (Alaska), we confirmed systematic temporal variations in the travel time of the inner-core-refracted phase (PKIKP, the DF branch). The DF phase arrives increasingly earlier than outer core phases (BC and AB) by rate of approximately 0.07 s per decade since 1970s. If we assume that the temporal change is caused by a shift of the lateral gradient from the inner core rotation as in previous studies, we estimate the rotation rate of 0.2-0.4 degree per year. We also analyzed the topography of the inner core boundary (ICB) using SSI waveform doublets recorded by seismic stations in Eurasia and North America with reflected phase (PKiKP) and refracted phases. There are clear temporal changes in the waveforms of doublets for PKiKP under Africa and Central America. In addition, for doublets recorded by three nearby stations (AAK, AML, and UCH), we observed systematic change in the relative travel time of PKiKP and PKIKP. The temporal change of the (PKiKP - PKIKP) differential time is always negative for the event pairs if both events are before 2007, while it fluctuates to positive if the later event occurs after 2007. The rapid temporal changes in space and time may indicate localized processes (e.g., freezing and melting) of the ICB in the recent decades under Africa. We are exploring 4D models consistent with the temporal changes.

User-Centric Key Entropy: Study of Biometric Key Derivation Subject to Spoofing Attacks

Directory of Open Access Journals (Sweden)

Lavinia Mihaela Dinca

2017-02-01

Full Text Available Biometric data can be used as input for PKI key pair generation. The concept of not saving the private key is very appealing, but the implementation of such a system shouldn’t be rushed because it might prove less secure then current PKI infrastructure. One biometric characteristic can be easily spoofed, so it was believed that multi-modal biometrics would offer more security, because spoofing two or more biometrics would be very hard. This notion, of increased security of multi-modal biometric systems, was disproved for authentication and matching, studies showing that not only multi-modal biometric systems are not more secure, but they introduce additional vulnerabilities. This paper is a study on the implications of spoofing biometric data for retrieving the derived key. We demonstrate that spoofed biometrics can yield the same key, which in turn will lead an attacker to obtain the private key. A practical implementation is proposed using fingerprint and iris as biometrics and the fuzzy extractor for biometric key extraction. Our experiments show what happens when the biometric data is spoofed for both uni-modal systems and multi-modal. In case of multi-modal system tests were performed when spoofing one biometric or both. We provide detailed analysis of every scenario in regard to successful tests and overall key entropy. Our paper defines a biometric PKI scenario and an in depth security analysis for it. The analysis can be viewed as a blueprint for implementations of future similar systems, because it highlights the main security vulnerabilities for bioPKI. The analysis is not constrained to the biometric part of the system, but covers CA security, sensor security, communication interception, RSA encryption vulnerabilities regarding key entropy, and much more.

The Future Internet: A World of Secret Shares

Directory of Open Access Journals (Sweden)

William J. Buchanan

2015-11-01

Full Text Available The Public Key Infrastructure (PKI is crumbling, partially due to the lack of a strong understanding of how encryption actually works, but also due to weaknesses in its implementation. This paper outlines an Internet storage technique using secret sharing methods which could be used to overcome the problems inherent with PKI, while supporting new types of architectures incorporating such things as automated failover and break-glass data recovery. The paper outlines a novel architecture: SECRET, which supports a robust cloud-based infrastructure with in-built privacy and failover. In order to understand the performance overhead of SECRET, the paper outlines a range of experiments that investigate the overhead of this and other secret share methods.

Sigma-2 receptor ligands QSAR model dataset

Directory of Open Access Journals (Sweden)

Antonio Rescifina

2017-08-01

Full Text Available The data have been obtained from the Sigma-2 Receptor Selective Ligands Database (S2RSLDB and refined according to the QSAR requirements. These data provide information about a set of 548 Sigma-2 (σ2 receptor ligands selective over Sigma-1 (σ1 receptor. The development of the QSAR model has been undertaken with the use of CORAL software using SMILES, molecular graphs and hybrid descriptors (SMILES and graph together. Data here reported include the regression for σ2 receptor pKi QSAR models. The QSAR model was also employed to predict the σ2 receptor pKi values of the FDA approved drugs that are herewith included.

75 FR 69645 - Privacy Act of 1974; System of Records

Science.gov (United States)

2010-11-15

... Smart Credential Number (FASC-N), login name, legacy login name, and persona username; object class..., Encryption CN, distinguished name, PKI login identity, e-mail encryption certificate, and other certificate...

75 FR 69644 - Privacy Act of 1974; System of Records

Science.gov (United States)

2010-11-15

... Security Number), Federal Agency Smart Credential Number (FASC-N), login name, legacy login name, and..., Encryption CN, distinguished name, PKI login identity, e-mail encryption certificate, and other certificate...

The Security Email Based on Smart Card

Science.gov (United States)

Lina, Zhang; Jiang, Meng Hai.

Email has become one of the most important communication tools in modern internet society, and its security is an important issue that can't be ignored. The security requirements of Email can be summarized as confidentiality, integrity, authentication and non-repudiation. Recently many researches on IBE (identify based encrypt) have been carried out to solve these security problems. However, because of IBE's fatal flaws and great advantages of PKI (Public Key Infrastructure), PKI is found to be still irreplaceable especially in the applications based on smart card. In this paper, a construction of security Email is presented, then the design of relatively cryptography algorithms and the configuration of certificates are elaborated, and finally the security for the proposed system is discussed.

Comparison of Certification Authority Roles in Windows Server 2003 and Windows Server 2008

Directory of Open Access Journals (Sweden)

A. I. Luchnik

2011-03-01

Full Text Available An analysis of Certification Authority components of Microsoft server operating systems was conducted. Based on the results main directions of development of certification authorities and PKI were highlighted.

Digitaalallkirja seadus saab sisu / Aare Reivart

Index Scriptorium Estoniae

Reivart, Aare, 1968-

2000-01-01

Sideoperaatorid ja pangad hakkavad välja töötama ühtset avalikku võtme infrastruktuuri (PKI), mis võimaldab telefoni ja interneti vahendusel kasutada mitmesuguseid teenuseid kiiresti ja turvaliselt

Evidence of the immunomodulatory role of dual PI3K/mTOR inhibitors in transplantation: an experimental study in mice.

Science.gov (United States)

Vilchez, Valery; Turcios, Lilia; Butterfield, David A; Mitov, Mihail I; Coquillard, Cristin L; Brandon, Ja Anthony; Cornea, Virgilius; Gedaly, Roberto; Marti, Francesc

2017-10-01

The PI3K/mTOR signaling cascade is fundamental in T-cell activation and fate decisions. We showed the distinct regulation of PI3K/mTOR in regulatory and effector T-cells and proposed the potential therapeutic benefit of targeting this pathway to control the balance between effector and regulatory T-cell activities. Substantial adverse effects in long-term clinical usage of rapamycin suggest the use of alternative treatments in restraining effector T-cell function in transplant patients. We hypothesize that dual PI3K/mTOR inhibitors may represent an immunosuppressant alternative. Here we show that dual PI3K/mTOR PI-103 and PKI-587 inhibitors interfered IL-2-dependent responses in T-cells. However, in contrast to the inhibitory effects in non-Treg T-cell proliferation and effector functions, dual inhibitors increased the differentiation, preferential expansion, and suppressor activity of iTregs. Rapamycin, PI-103, and PKI-587 targeted different signaling events and induced different metabolic patterns in primary T-cells. Similar to rapamycin, in vivo administration of PI-103 and PKI-587 controlled effectively the immunological response against allogeneic skin graft. These results characterize specific regulatory mechanisms of dual PI3K/mTOR inhibitors in T-cells and support their potential as a novel therapeutic option in transplantation. © 2017 Steunstichting ESOT.

Sadhana | Indian Academy of Sciences

Indian Academy of Sciences (India)

transactions ... e-Commerce; security; trust management; access control; PKI. ... The challenge is to see how in such a scenario trust can indeed be generated. ... present a comparative analysis of various approaches of trust management in practice ...

Security, Fraud Detection

Indian Academy of Sciences (India)

First page Back Continue Last page Overview Graphics. Secure. Secure. Server – Intruder prevention/detection; Network – Encryption, PKI; Client - Secure. Fraud detection based on audit trails. Automatic alerts like credit-card alerts based on suspicious patterns.

UJAS 21.pmd

African Journals Online (AJOL)

Prof. Adipala Ekwamu

presence of aflatoxins in food samples and their linkage to ... protein maize) lines. Inoculation .... 37 had significant GCA effects for high. PKI. ..... favorable conditions and grain injury, such as by ear .... Diallel analysis of fusarium head blight.

Development and validation of an interactive efficient dose rates distribution calculation program ARShield for visualization of radiation field in nuclear power plants

International Nuclear Information System (INIS)

He, Shuxiang; Zhang, Han; Wang, Mengqi; Zang, Qiyong; Zhang, Jingyu; Chen, Yixue

2017-01-01

Point kernel integration (PKI) method is widely used in the visualization of radiation field in engineering applications because of the features of quickly dealing with large-scale complicated geometry space problems. But the traditional PKI programs have a lot of restrictions, such as complicated modeling, complicated source setting, 3D fine mesh results statistics and large-scale computing efficiency. To break the traditional restrictions for visualization of radiation field, ARShield was developed successfully. The results show that ARShield can deal with complicated plant radiation shielding problems for visualization of radiation field. Compared with SuperMC and QAD, it can be seen that the program is reliable and efficient. Also, ARShield can meet the demands of calculation speediness and interactive operations of modeling and displaying 3D geometries on a graphical user interface, avoiding error modeling in calculation and visualization. (authors)

Authorization policy in a PKI environment

Energy Technology Data Exchange (ETDEWEB)

Thompson, Mary R.; Mudumbai, Srilekha S.; Essiari, Abdelilah; Chin, Willie

2002-04-10

The major emphasis of Public Key Infrastructure has been to provide a cryptographically secure means of authenticating identities. While there are a number of proposed standards for authorization structures and protocols based on X.509 or other key-based identities, none have been widely adopted. As part of an effort to use X.509 identities to provide authorization in highly distributed environments, we have developed and deployed an authorization service based on X.509 identified users and access policy contained in certificates signed by X.509 identified stakeholders. The major goal of this system, called Akenti, is to produce a usable authorization system for an environment consisting of distributed resources used by geographically and administratively distributed users.

Authorization policy in a PKI environment

International Nuclear Information System (INIS)

Thompson, Mary R.; Mudumbai, Srilekha S.; Essiari, Abdelilah; Chin, Willie

2002-01-01

The major emphasis of Public Key Infrastructure has been to provide a cryptographically secure means of authenticating identities. While there are a number of proposed standards for authorization structures and protocols based on X.509 or other key-based identities, none have been widely adopted. As part of an effort to use X.509 identities to provide authorization in highly distributed environments, we have developed and deployed an authorization service based on X.509 identified users and access policy contained in certificates signed by X.509 identified stakeholders. The major goal of this system, called Akenti, is to produce a usable authorization system for an environment consisting of distributed resources used by geographically and administratively distributed users

Temporal Change of Seismic Earth's Inner Core Phases: Inner Core Differential Rotation Or Temporal Change of Inner Core Surface?

Science.gov (United States)

Yao, J.; Tian, D.; Sun, L.; Wen, L.

2017-12-01

Since Song and Richards [1996] first reported seismic evidence for temporal change of PKIKP wave (a compressional wave refracted in the inner core) and proposed inner core differential rotation as its explanation, it has generated enormous interests in the scientific community and the public, and has motivated many studies on the implications of the inner core differential rotation. However, since Wen [2006] reported seismic evidence for temporal change of PKiKP wave (a compressional wave reflected from the inner core boundary) that requires temporal change of inner core surface, both interpretations for the temporal change of inner core phases have existed, i.e., inner core rotation and temporal change of inner core surface. In this study, we discuss the issue of the interpretation of the observed temporal changes of those inner core phases and conclude that inner core differential rotation is not only not required but also in contradiction with three lines of seismic evidence from global repeating earthquakes. Firstly, inner core differential rotation provides an implausible explanation for a disappearing inner core scatterer between a doublet in South Sandwich Islands (SSI), which is located to be beneath northern Brazil based on PKIKP and PKiKP coda waves of the earlier event of the doublet. Secondly, temporal change of PKIKP and its coda waves among a cluster in SSI is inconsistent with the interpretation of inner core differential rotation, with one set of the data requiring inner core rotation and the other requiring non-rotation. Thirdly, it's not reasonable to invoke inner core differential rotation to explain travel time change of PKiKP waves in a very small time scale (several months), which is observed for repeating earthquakes in Middle America subduction zone. On the other hand, temporal change of inner core surface could provide a consistent explanation for all the observed temporal changes of PKIKP and PKiKP and their coda waves. We conclude that

Audited credential delegation: a usable security solution for the virtual physiological human toolkit

Science.gov (United States)

Haidar, Ali N.; Zasada, Stefan J.; Coveney, Peter V.; Abdallah, Ali E.; Beckles, Bruce; Jones, Mike A. S.

2011-01-01

We present applications of audited credential delegation (ACD), a usable security solution for authentication, authorization and auditing in distributed virtual physiological human (VPH) project environments that removes the use of digital certificates from end-users' experience. Current security solutions are based on public key infrastructure (PKI). While PKI offers strong security for VPH projects, it suffers from serious usability shortcomings in terms of end-user acquisition and management of credentials which deter scientists from exploiting distributed VPH environments. By contrast, ACD supports the use of local credentials. Currently, a local ACD username–password combination can be used to access grid-based resources while Shibboleth support is underway. Moreover, ACD provides seamless and secure access to shared patient data, tools and infrastructure, thus supporting the provision of personalized medicine for patients, scientists and clinicians participating in e-health projects from a local to the widest international scale. PMID:22670214

Basis for the implementation of digital signature in Argentine's health environment

International Nuclear Information System (INIS)

Escobar, P P; Formica, M

2007-01-01

The growth of telemedical applications and electronic transactions in health environments is paced by the constant technology evolution. This implies a big cultural change in traditional medicine and in hospital information systems' users which arrival is delayed, basically, by the lack of solid laws and a well defined role-based infrastructure. The use of digital signature as a mean of identification, authentication, confidentiality and non-repudiation is the most suitable tool for assuring the electronic transactions and patient's data protection. The implementation of a Public Key Infrastructure (PKI) in health environment allows for authentication, encryption and use of digital signature for assuring confidentiality and control of the movement of sensitive information. This work defines the minimum technological, legal and procedural basis for a successful PKI implementation and establishes the roles for the different actors in the chain of confidence in the public health environment of Argentine

Audited credential delegation: a usable security solution for the virtual physiological human toolkit.

Science.gov (United States)

Haidar, Ali N; Zasada, Stefan J; Coveney, Peter V; Abdallah, Ali E; Beckles, Bruce; Jones, Mike A S

2011-06-06

We present applications of audited credential delegation (ACD), a usable security solution for authentication, authorization and auditing in distributed virtual physiological human (VPH) project environments that removes the use of digital certificates from end-users' experience. Current security solutions are based on public key infrastructure (PKI). While PKI offers strong security for VPH projects, it suffers from serious usability shortcomings in terms of end-user acquisition and management of credentials which deter scientists from exploiting distributed VPH environments. By contrast, ACD supports the use of local credentials. Currently, a local ACD username-password combination can be used to access grid-based resources while Shibboleth support is underway. Moreover, ACD provides seamless and secure access to shared patient data, tools and infrastructure, thus supporting the provision of personalized medicine for patients, scientists and clinicians participating in e-health projects from a local to the widest international scale.

Menertawakan Fobia Komunis di Era Reproduksi Digital

Directory of Open Access Journals (Sweden)

Triyono Lukmantoro

2017-04-01

Full Text Available Abstract. In May-June 2016 issue of the rise of the Indonesian Communist Party (PKI and the latent danger of communism appeared again. Excessive fear of PKI and communism continues propagated. That is what is referred to as a communist phobia. But, the issue is considered sensitive that it gave birth to criticism. The phenomenon is the presence of a number of memes comics whose contents laugh hammer and sickle symbol and three communist iconic figures, namely D.N. Aidit, Tan Malaka, and Mao Zedong. Meme comics containing parody to show incongruities that can only happen to the era of digital reproduction. The idea of meme comics can be traced to the thought Walter Benjamin about the works of art in the age of mechanical reproduction. In that era, aura was declining. The crisis and the disappearance of aura increasingly occurs to the time of digital reproduction.

Cardiovascular safety of tyrosine kinase inhibitors: Putting their “QT-phobia” in perspective

Directory of Open Access Journals (Sweden)

Rashmi Shah

2016-10-01

Full Text Available Many potentially valuable drugs, including protein kinase inhibitors (PKI, risk being dropped from further development, without exploration of their clinical benefits, if early studies show these drugs to inhibit hERG channel and therefore, to have a potential for prolonging ventricular repolarisation (QT interval. This QT-phobia results from a perceived possibility of the clinical risks of QT-related ventricular proarrhythmia, further aggravated by uncertainties surrounding the regulatory evaluation of the risk and either approvability or restrictive labelling of the drug concerned. In reality, QT interval prolongation per se is only an imperfect surrogate of the proarrhythmia risk which is much smaller than perceived and compared to their other cardiovascular and non-cardiovascular risks. PKI-induced clinical hepatotoxicity, also evaluated on the basis of surrogate markers (serum transaminases and bilirubin is another risk that far exceeds any risk arising from PKI-induced QT interval prolongation. This review of the currently approved 28 PKIs places the QT-phobia surrounding the development of PKIs in its perspective by juxta-positioning their potential to induce ventricular dysfunction, arterial thrombotic events and hepatotoxicity. Available evidence suggests that hERG channel may prove to be a valuable therapeutic target in oncology. Therefore, the development, approval and labelling of such vital oncology drugs requires careful assessment of their benefits and their risk/benefit generally, without being overtly consumed by their potential QT-liability, in terms of their more direct consequences on clinically relevant endpoints of morbidity, mortality and quality of life.

GERAKAN 30 SEPTEMBER 1965 DALAM PERSPEKTIF FILSAFAT SEJARAH MARXISME

Directory of Open Access Journals (Sweden)

Harsa Permata

2016-08-01

Full Text Available The Thirtieth of September Movement 1965 (G30S 1965, is a movement which is very influential in the history of Indonesian society until today. After G30S 1965, freedom of ideology began to be restricted in Indonesia. In addition, the slaughter of millions of human beings, with the reason to eradicate communism, began to take place after G30S 1965. A restriction on freedom of ideology is also touching the academic life. Based on TAP MPRS No.. XXV/1966, the study of Marxism-Leninism ideology is limited. This resulted in the lack of alternative and scientific thought in the academic world in Indonesia. The Thirtieth of September Movement 1965 (G30S 1965, is the manifestation of class contradictions in the Indonesian capitalist society. G30S 1965, emphasize the class contradictions in Indonesian society. Social classes in Indonesian society is a military bourgeoisie represented by the TNI (Indonesian Armed Forces, the proletariat, as represented by the PKI (Indonesian Communist Party. President Sukarno, was the one who stand in the middle of the contradiction between the army and the PKI. And then, G30S 1965, used as an excuse by Suharto and the army to stage a creeping coup against President Sukarno and slaughtered millions of cadres and sympathizers of the PKI. After the G30S 1965, the New Order regime of Suharto opened the door wide open for international capitalism to exploit the natural resources of Indonesia. Suharto's New Order regime improves Indonesian capitalism.

Een beetje wetenschap is gevaarlijk!

NARCIS (Netherlands)

Kirschner, Paul A.

2011-01-01

Kirschner, P. A. (2011, September). Een beetje wetenschap is gevaarlijk! [A little science is dangerous!]. COTimes, 3, 3. Available at http://portal.ou.nl/nl/web/pki/blog/-/blogs/1542243;jsessionid=290D80B8809693F8CC64CB1DB79EDD80

Multiple isoforms of the human pentraxin serum amyloid P component

DEFF Research Database (Denmark)

Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH

1995-01-01

major and several minor subpopulations of SAP. IEF of all SAP isolates showed a previously unreported degree of heterogeneity with six isoelectric forms (pKi range 5.5-6.1) and with minor interindividual differences in respect of isoelectric points. Total enzymatic deglycosylation of SAP reduced...

MD5 Considered Harmful Today - Creating A Rogue CA Certificate

NARCIS (Netherlands)

P. Stevens; A.K. Lenstra (Arjen); not CWI et al

2008-01-01

htmlabstractPresented at the 25th Chaos Communication Congress in Berlin on December 30, 2008. We have identified a vulnerability in the Internet Public Key Infrastructure (PKI) used to issue digital certificates for secure websites. As a proof of concept we executed a practical attack scenario

Combined molecular and biochemical approach identifies Aspergillus japonicus and Aspergillus aculeatus as two species

DEFF Research Database (Denmark)

Parenicova, L.; Skouboe, P.; Frisvad, Jens Christian

2001-01-01

of the internal transcribed spacers (ITS1 and ITS2) and the 5.8S rRNA gene could not be used to distinguish between A. japonicus and A. aculeatus but did show that these two taxa are more closely related to each other than to other species of black aspergilli. Aspergillus niger pyruvate kinase (pkiA) and pectin...... variation when they were probed with the pelA gene. The secondary-metabolite profiles supported division of the isolates into the two species and differed from those of other black aspergilli. The strains classified as A. japonicus produced indole alkaloids and a polar metabolite, while the A. aculeatus...... lyase A (pelA) and Agaricus bisporus 28S rRNA genes, which were used as probes in the RFLP analysis, revealed clear polymorphism between these two taxa. The A. niger pkiA and pelA probes placed six strains in an A. japonicus group and 12 isolates in an A. aculeatus group, which exhibited intraspecific...

PEMBELAHAN IDEOLOGI, KONTESTASI PEMILU, DAN PERSEPSI ANCAMAN KEAMANAN NASIONAL: SPEKTRUM POLITIK INDONESIA PASCA 2014?

Directory of Open Access Journals (Sweden)

Ari Ganjar Herdiansah

2017-06-01

Full Text Available Keamanan geopolitik dan sentimen keagamaan menjadi isu politik yang mencuat di Indonesia pasca 2014. Semenjak Joko Widodo menjadi presiden, isu kedekatannya dengan China seringkali dikemas sebagai citra yang negatif terhadap pemerintahannya. Di sisi lain, menguatnya pengaruh China di Asia Tenggara turut mempengaruhi perubahan peta ekonomi politik di Indonesia. Investasi dan dana pinjaman dari China meningkat tajam yang diiringi kompensasi proyek infrastruktur yang diberikan kepada China. Akan tetapi, memori kolektif masyarakat Indonesia terkait identiknya China dan komunisme menyulut kekhawatiran bangkitnya Partai Komunis Indonesia (PKI di Indonesia. Secara kebetulan, persaingan Gubernur Jakarta 2017 yang diikuti oleh Basuki Tjahaya Purnama, petahana kuat berlatar etnik China yang diusung oleh partai pemerintah (PDIP, menjadi momentum yang membangkitkan komponen Islamis yang sudah menaruh curiga terhadap kebangkitan PKI. Artikel ini menelaah bagaimana faktor menguatnya pengaruh China dan kedigdayaan politik PDIP membentuk pusaran konflik aliran antara nasionalis kiri dengan kanan Islamis yang membawa kerawanan keamanan di Indonesia pada level lebih tinggi.

78 FR 17386 - Privacy Act of 1974; System of Records

Science.gov (United States)

2013-03-21

... System name: Historical Airman Promotion Master Test File (MTF) (June 11, 1997, 62 FR 31793). Changes... of Senior Airman (E-4) to Senior Master Sergeant (E-8).'' Categories of records in the system: Delete... Infrastructure (PKI)/ Common Access Card (CAC) authentication to lock out unauthorized access. Access to the...

Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway

DEFF Research Database (Denmark)

Thams, Peter; Anwar, Mohammad R; Capito, Kirsten

2005-01-01

pancreatic islets was determined by radioimmunoassay. RESULTS: In islets cultured at 5.5 mmol/l glucose, and then perifused in physiological Krebs-Ringer medium, the PKA inhibitors, H89 (10 micromol/l) and PKI 6-22 amide (30 micromol/l) did not inhibit glucose (16.7 mmol/l)-induced insulin secretion...

Telemedicine in Remote Areas of Algeria | IDRC - International ...

International Development Research Centre (IDRC) Digital Library (Canada)

With respect to security, the research team will test a new method of encryption combining biomeasurement and the utilization of public key infrastructure (PKI) to ensure the confidentiality of patient data. To do so, they will use an internal intranet (CDTA) certification thereby avoiding the need for expensive international ...

GSM-PKI solution enabling secure mobile communications.

Science.gov (United States)

Jelekäinen, Pekka

2004-03-31

Because of its wide distribution and ease of use, the mobile phone, as a reliable personal communications channel, offers an excellent basis for the provision of reliable electronic communications services. In Finland, ca. 75% of the citizens have a mobile phone and, at present and most likely also in the future, it is the most widely spread service channel allowing reliable electronic communications. Despite the restricted functions of the mobile phone, the citizens can use the phone also as a communications medium. In 2001, the Finns sent over 1 billion SMS messages. In Finland, TeliaSonera Finland Oyi and the Population Register Centre (PRC) have closed a co-operation agreement with the aim of creating a mobile phone service for the electronic identification of a person. The co-operation launched is a significant development project from the perspective of the citizens. As a result, the consumers will have a new alternative for reliable electronic communications and commerce in data networks in addition to the electronic identification card. In the future, it will be possible to use the services of both public administration and the private sector by means of a mobile phone more reliably than before, without a physical visit, e.g. to a health centre or to another provider of healthcare services. The possibility of identification and signature by a mobile phone allows an easier provision of versatile services irrespective of time and place, because, in addition to voice, text message, and WAP functions, the service can be utilised also in communications services through the Internet, in which case, the mobile phone acts like a card reader. From the perspective of reliable personal mobile communications, the healthcare sector is one of the most significant and challenging application areas.

Implementing SSL/TLS using cryptography and PKI

CERN Document Server

Davies, Joshua

2011-01-01

Hands-on, practical guide to implementing SSL and TLS protocols for Internet security If you are a network professional who knows C programming, this practical book is for you.  Focused on how to implement Secure Socket Layer (SSL) and Transport Layer Security (TLS), this book guides you through all necessary steps, whether or not you have a working knowledge of cryptography. The book covers SSLv2, TLS 1.0, and TLS 1.2, including implementations of the relevant cryptographic protocols, secure hashing, certificate parsing, certificate generation, and more.  Coverage includes: Underst

A Survey of Public Key Infrastructure-Based Security for Mobile Communication Systems

Directory of Open Access Journals (Sweden)

Mohammed Ramadan

2016-08-01

Full Text Available Mobile communication security techniques are employed to guard the communication between the network entities. Mobile communication cellular systems have become one of the most important communication systems in recent times and are used by millions of people around the world. Since the 1990s, considerable efforts have been taken to improve both the communication and security features of the mobile communications systems. However, these improvements divide the mobile communications field into different generations according to the communication and security techniques such as A3, A5 and A8 algorithms for 2G-GSM cellular system, 3G-authentication and key agreement (AKA, evolved packet system-authentication and key agreement (EPS-AKA, and long term evolution-authentication and key agreement (LTE-AKA algorithms for 3rd generation partnership project (3GPP systems. Furthermore, these generations have many vulnerabilities, and huge security work is involved to solve such problems. Some of them are in the field of the public key cryptography (PKC which requires a high computational cost and more network flexibility to be achieved. As such, the public key infrastructure (PKI is more compatible with the modern generations due to the superior communications features. This paper surveys the latest proposed works on the security of GSM, CDMA, and LTE cellular systems using PKI. Firstly, we present the security issues for each generation of mobile communication systems, then we study and analyze the latest proposed schemes and give some comparisons. Finally, we introduce some new directions for the future scope. This paper classifies the mobile communication security schemes according to the techniques used for each cellular system and covers some of the PKI-based security techniques such as authentication, key agreement, and privacy preserving.

Universally Composable Multiparty Computation with Partially Isolated Parties

DEFF Research Database (Denmark)

Damgård, Ivan Bjerre; Nielsen, Jesper Buus; Wichs, Daniel

2009-01-01

global setup such as a common reference string (CRS) or a public key infrastructure (PKI). The recent work of Katz shows that we may instead rely on physical assumptions, and in particular tamper-proof hardware tokens. In this paper, we consider a similar but strictly weaker physical assumption. We...

Security Concerns in Accessing Naval e-Learning with Personal Mobile Devices

Science.gov (United States)

2014-12-01

associated with its use alone. When biometric data is compromised it is not like a compromised password or a lost/stolen CAC; it cannot just be changed or... replaced . Therefore, DOD requires it to be combined with another form of authentication such as a password or PIN IAW DOD-approved PKI policy. 32...26 a. Password ..................................................................................26

Lp Lp Lp-mixed intersection bodies and star duality

Indian Academy of Sciences (India)

pKi. For I. ◦. pK0 simply write I. ◦. pK. Lemma 2.1. If K,L ∈ ϕn, 0 ≤ i < n, 0 ≤ j

Certificateless short sequential and broadcast multisignature schemes using elliptic curve bilinear pairings

Directory of Open Access Journals (Sweden)

SK Hafizul Islam

2014-01-01

Full Text Available Several certificateless short signature and multisignature schemes based on traditional public key infrastructure (PKI or identity-based cryptosystem (IBC have been proposed in the literature; however, no certificateless short sequential (or serial multisignature (CL-SSMS or short broadcast (or parallel multisignature (CL-SBMS schemes have been proposed. In this paper, we propose two such new CL-SSMS and CL-SBMS schemes based on elliptic curve bilinear pairing. Like any certificateless public key cryptosystem (CL-PKC, the proposed schemes are free from the public key certificate management burden and the private key escrow problem as found in PKI- and IBC-based cryptosystems, respectively. In addition, the requirements of the expected security level and the fixed length signature with constant verification time have been achieved in our schemes. The schemes are communication efficient as the length of the multisignature is equivalent to a single elliptic curve point and thus become the shortest possible multisignature scheme. The proposed schemes are then suitable for communication systems having resource constrained devices such as PDAs, mobile phones, RFID chips, and sensors where the communication bandwidth, battery life, computing power and storage space are limited.

"Flexible Ligand Docking Studies of Matrix Metalloproteinase Inhibitors Using Lamarckian Genetic Algorithm "

Directory of Open Access Journals (Sweden)

lOrkideh Ghorban Dadrass

2004-06-01

Full Text Available As important therapeutic drug targets, matrix metalloproteinases (MMPs have recently attracted great interest in the search for potent and selective inhibitors using computer-aided molecular modelling and docking techniques. Availability of more than 60 X-ray crystal structures or NMR solution structures related to MMPs in Protein Data Bank (PDB of which more than half of them are in complex with various MMP inhibitors (MMPIs, provides a great opportunity for docking studies. In this study AutoDock 3.0.5 along with its LGA algorithm were used for automated flexible ligand docking of 32 MMPI-MMP complexes and docking accuracy and reliability of the estimated inhibition constants were evaluated. Twenty-six out of 32 docks had RMSD less than 3.0 Å which is considered as well-docked, however, for the most of the cases (15 out of 27, predicted pKi values were considerably overestimated in comparison to experimental values. To improve pKi prediction regarding MMPI-MMP complexes, inclusion of at least one such a complex in calibration of empirical free energy function in the next release of AutoDock is highly recommended.

The Initial Purging Policies after the 1965 Incident at Lubang Buaya

Directory of Open Access Journals (Sweden)

Yosef Djakababa

2013-01-01

Full Text Available After the Lubang Buaya incident on 1 October 1965 in which six top Indonesian Army generals and a lieutenant were killed, the Army began to implement a nationwide purging campaign with the assistance of civilian anti-communist groups. Thousands of PKI members, supporters and pro-Sukarno groups/individuals immediately became the target of this purge. For organisational purposes, several purging policies were released and then strictly enforced. The official purging policies that are highlighted in this paper are a series of initial directives that were released within days of the generals’ executions. They do not explicitly translate into orders to kill, but are more of a guideline to help anti-communist officials classify and contain communists and other PKI followers. This article attempts to show how these initial directives evolved and also discusses competing purge policies from non-military sources. The co-existence and overlapping nature of the various directives indicate that a power struggle existed between the anti-communist group led by General Soeharto and the presidium of the Dwikora Cabinet who were loyal to President Soekarno.

Secure Programming Cookbook for C and C++ Recipes for Cryptography, Authentication, Input Validation & More

CERN Document Server

Viega, John

2009-01-01

Secure Programming Cookbook for C and C++ is an important new resource for developers serious about writing secure code for Unix® (including Linux®) and Windows® environments. This essential code companion covers a wide range of topics, including safe initialization, access control, input validation, symmetric and public key cryptography, cryptographic hashes and MACs, authentication and key exchange, PKI, random numbers, and anti-tampering.

Development and Implementation of the DHAPP Military eHealth Information Network System

Science.gov (United States)

2016-03-01

between databases Vista LifeSciences EMP Security PKI, AES encryption Section 4: User Training Ease-of-use screen design Vista LifeSciences EMP...role-based access control, and encryption for data in transit from user device to and from the local military’s medical database. Role-based access...board Lean process management Data Quality Assessment procedures DHAPP adoption framework ACM, Association for Computing Machinery; AES , Advanced

Security infrastructures: towards the INDECT system security

OpenAIRE

Stoianov, Nikolai; Urueña, Manuel; Niemiec, Marcin; Machník, Petr; Maestro, Gema

2012-01-01

This paper provides an overview of the security infrastructures being deployed inside the INDECT project. These security infrastructures can be organized in five main areas: Public Key Infrastructure, Communication security, Cryptography security, Application security and Access control, based on certificates and smartcards. This paper presents the new ideas and deployed testbeds for these five areas. In particular, it explains the hierarchical architecture of the INDECT PKI...

Analysis and Verification of a Key Agreement Protocol over Cloud Computing Using Scyther Tool

OpenAIRE

Hazem A Elbaz

2015-01-01

The mostly cloud computing authentication mechanisms use public key infrastructure (PKI). Hierarchical Identity Based Cryptography (HIBC) has several advantages that sound well align with the demands of cloud computing. The main objectives of cloud computing authentication protocols are security and efficiency. In this paper, we clarify Hierarchical Identity Based Authentication Key Agreement (HIB-AKA) protocol, providing lightweight key management approach for cloud computing users. Then, we...

PDE4 and mAKAPβ are nodal organizers of β2-ARs nuclear PKA signaling in cardiac myocytes.

Science.gov (United States)

Bedioune, Ibrahim; Lefebvre, Florence; Lechêne, Patrick; Varin, Audrey; Domergue, Valérie; Kapiloff, Michael S; Fischmeister, Rodolphe; Vandecasteele, Grégoire

2018-05-03

β1- and β2-adrenergic receptors (β-ARs) produce different acute contractile effects on the heart partly because they impact on different cytosolic pools of cAMP-dependent protein kinase (PKA). They also exert different effects on gene expression but the underlying mechanisms remain unknown. The aim of this study was to understand the mechanisms by which β1- and β2-ARs regulate nuclear PKA activity in cardiomyocytes. We used cytoplasmic and nuclear targeted biosensors to examine cAMP signals and PKA activity in adult rat ventricular myocytes upon selective β1- or β2-ARs stimulation. Both β1- and β2-AR stimulation increased cAMP and activated PKA in the cytoplasm. While the two receptors also increased cAMP in the nucleus, only β1-ARs increased nuclear PKA activity and up-regulated the PKA target gene and pro-apoptotic factor, inducible cAMP element repressor (ICER). Inhibition of PDE4, but not Gi, PDE3, GRK2 nor caveolae disruption disclosed nuclear PKA activation and ICER induction by β2-ARs. Both nuclear and cytoplasmic PKI prevented nuclear PKA activation and ICER induction by β1-ARs, indicating that PKA activation outside the nucleus is required for subsequent nuclear PKA activation and ICER mRNA expression. Cytoplasmic PKI also blocked ICER induction by β2-AR stimulation (with concomitant PDE4 inhibition). However, in this case nuclear PKI decreased ICER up-regulation by only 30%, indicating that other mechanisms are involved. Down-regulation of mAKAPβ partially inhibited nuclear PKA activation upon β1-AR stimulation, and drastically decreased nuclear PKA activation upon β2-AR stimulation in the presence of PDE4 inhibition. β1- and β2-ARs differentially regulate nuclear PKA activity and ICER expression in cardiomyocytes. PDE4 insulates a mAKAPβ-targeted PKA pool at the nuclear envelope that prevents nuclear PKA activation upon β2-AR stimulation.

Upregulation of [125I] CGP42112 binding in the rat brainstem following nodose ganglionectomy

International Nuclear Information System (INIS)

Roulston, C.L.; Lawrence, A.J.; Jarrott, B.; Widdop, R.E.

1999-01-01

Full text: [ 125 I] CGP42112 is a specific ligand which has been used to demonstrate the presence of angiotensin AT 2 receptors in peripheral and brain tissue, although [ 125 I] CGP42112 also binds to a non-angiotensin II (Ang II) site. In the present study we have examined [ 125 I] CGP42112 binding in the brainstem following nodose ganglionectomy using autoradiography. Male spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats underwent unilateral nodose ganglionectomy or sham operation (anaesthetised with methohexitone, 60mg/kg ip). Following a 14 day recovery period, animals were killed and slide mounted brainstem sections (14μm) were prepared and incubated in the presence of either [ 125 I] (Sar 1 Ile 8 )Ang II (0.5nM), [ 125 I] CGP42112 (0.3nM) or [ 3 H] PKI11195 (3nM, a marker for activated microglia). Following incubation, slides were apposed to film for 10 days. Specific binding was determined in adjacent sections by co-incubations with either the AT 1 receptor antagonist losartan, the AT 2 receptor antagonist PD 123319, Ang II or PKI11195 (all at 10μM). In the ganglionectomised groups, there were significant reductions in [ 125 I] (Sar 1 Ile 8 )Ang II binding on the denervated side of the nucleus of the solitary tract (NTS) by 30 ± 2 % (n=5, P 125 I] CGP42112 binding in the NTS revealed an AT 2 receptor component which was displaceable by PD 123319 and Ang II (∼60%), and a non-Ang II component (∼40%). Nodose ganglionectomy increased the density of [ 125 I] CGP42112 binding on the denervated side of the NTS by 55 ± 3 % (n=5, P 125 I] CGP42112 binding in the NTS of the ganglionectomised groups was comprised of a greater non-Ang II component than in the sham group, since only ∼30% was displaced by PD123319 and Ang II. [ 125 I] CGP42112 also revealed high binding density in the dorsal motor nucleus and the nucleus ambiguus on the denervated side in both SHR and WKY rats. This binding was absent in shams and was only ∼30-40% displaceable

Plataforma smart building

OpenAIRE

Cidrera Lopez, Alain

2013-01-01

The overall project is a system (hardware + software) that allows monitoring and control in a building / office different security systems, energy, communications, home automation, PKI's overall business that will increase all the efficiency of the building and the business and ensure the continuity of it. My participation in this Project will mainly focus on the development of hardware components, monitoring and control system (home automation, energy, safety control elements ...) and softwa...

Blockchain-based Public Key Infrastructure for Inter-Domain Secure Routing

OpenAIRE

de la Rocha Gómez-Arevalillo , Alfonso; Papadimitratos , Panos

2017-01-01

International audience; A gamut of secure inter-domain routing protocols has been proposed in the literature. They use traditional PGP-like and centralized Public Key Infrastructures for trust management. In this paper, we propose our alternative approach for managing security associations, Secure Blockchain Trust Management (SBTM), a trust management system that instantiates a blockchain-based PKI for the operation of securerouting protocols. A main motivation for SBTM is to facilitate gradu...

The density jump at the inner core boundary using underground nuclear explosion records

International Nuclear Information System (INIS)

Krasnoshchekov, D.N.; Ovchinnikov, V.M.

2001-01-01

This paper presents the estimation of the minimum jump value using experimental wave forms reflected from the boundary between the Earth core and mantle (PcP) and the one between the inner and outer core (PKiKP) at a distance of 6 deg. Digital seismic records of underground nuclear tests conducted at the Semipalatinsk test site in 70s by Zerenda-Vostochny-Chkalovo seismic array have been used. (author)

Vascular and molecular pharmacology of the metabolically stable CGRP analogue, SAX

DEFF Research Database (Denmark)

Sheykhzade, Majid; Abdolalizadeh, Bahareh; Koole, Cassandra

2018-01-01

receptors (CLR and RAMP1) were expressed in the artery. In rat cerebral membranes, binding affinities (pKi) of SAX and CGRP were 8.3 ± 0.19 and 9.3 ± 0.14. In human subcutaneous artery, SAX and CGRP induced vasodilation (pEC50 8.8 ± 0.18 and 9.5 ± 0.13), while pEC50s for cAMP production by human recombinant...

Intrusion Detection: Generics and State-of-the-Art (la Detection de l’intrusion: Modeles generiques et etat de l’art)

Science.gov (United States)

2002-01-01

person operating on a host, e.g. identified by a login account; Systems: hardware, operating system; Network services (e.g. PKI, DNS); Applications...mobile-agent technology combined with network topology features. The Emerald environment is a distributed, scalable tool suite, for network surveillance...RAID ’99, Computer Networks, volume 34, number 4, 2000. 21. Source: http://www.sdl.sri.com/ emerald /project.html, 6-11-2000. 22. Lippmann

Three Types of Earth's Inner Core Boundary

Science.gov (United States)

Tian, D.; Wen, L.

2017-12-01

The Earth's inner core boundary (ICB) is the site where the liquid outer core solidifies and the solid inner core grows. Thus, the fine-scale structure of the ICB is important for our understanding of the thermo-compositional state of the Earth's core. In this study, we collect a large set of seismic records with high-quality pre-critical PKiKP and PcP phase pairs, recorded by two dense seismic arrays, Hi-net in Japan and USArray in US. This dataset samples the ICB regions beneath East Asia, Mexico and the Bering Sea. We use differential travel times, amplitude ratios and waveform differences between PKiKP and PcP phases to constrain fine-scale structure of the ICB. The sampled ICB can be grouped into three types based on their seismic characteristics: (1) a simple ICB with a flat and sharp boundary, (2) a bumpy ICB with topographic height changes of 10 km, and (3) a localized mushy ICB with laterally varying thicknesses of 4-8 km. The laterally varying fine-scale structure of the ICB indicates existence of complex small-scale forces at the surface and a laterally varying solidification process of the inner core due to lateral variation of thermo-compositional condition near the ICB.

A multicopy phr-plasmid increases the ultraviolet resistance of a recA strain of Escherichia coli

International Nuclear Information System (INIS)

Yamamoto, K.; Satake, M.; Shinagawa, H.

1984-01-01

It has been previously reported that the ultraviolet sensitivity of recA strains of Escherichia coli in the dark is suppressed by a plasmid pKY1 which carries the phr gene, suggesting that this is due to a novel effect of photoreactivating enzyme (PRE) of E. coli in the dark. In this work, it is observed that an increase of UV-resistance by pKY1 in the dark is not apparent in strains with a mutation in either uvrA, uvrB, uvrC, lexA, recBC or recF. The sensitivity of recA lexA and recA recBC multiple mutants to UV is suppressed by the plasmid but that of recA uvrA, recA uvrB and recA uvrC is not. Host-cell reactivation of UV-irradiated lambda phage is slightly more efficient in the recA/pKY1 strain compared with the parental recA strain. On the other hand, the recA and recA/pKY1 strains do not differ significantly in the following properties: Hfr recombination, induction of lambda by UV, and mutagenesis. It is suggested that dark repair of PRE is correlated with its capacity of excision repair. (Auth.)

Vehicle Authentication via Monolithically Certified Public Key and Attributes

OpenAIRE

Dolev, Shlomi; Krzywiecki, Łukasz; Panwar, Nisha; Segal, Michael

2015-01-01

Vehicular networks are used to coordinate actions among vehicles in traffic by the use of wireless transceivers (pairs of transmitters and receivers). Unfortunately, the wireless communication among vehicles is vulnerable to security threats that may lead to very serious safety hazards. In this work, we propose a viable solution for coping with Man-in-the-Middle attacks. Conventionally, Public Key Infrastructure (PKI) is utilized for a secure communication with the pre-certified public key. H...

Employing a secure Virtual Private Network (VPN) infrastructure as a global command and control gateway to dynamically connect and disconnect diverse forces on a task-force-by-task-force basis

OpenAIRE

Kilcrease, Patrick N.

2009-01-01

Approved for public release, distribution unlimited GHOSTNet is a secure and anonymous Virtual Private Network (VPN) service. Coupling Ethernet tunneling and proxy services to provide users safe and anonymous Internet access, GHOSTNet utilizes TLS (SSL) protocol with AES-256 encryption to secure the network along with PKI certificates and HMAC protection from replay attacks and UDP flooding. This thesis will be a system level test and evaluation of the GHOSTNet infrastructure. The primary...

Common Criteria for Information Technology Security Evaluation: Department of Defense Public Key Infrastructure and Key Management Infrastructure Token Protection Profile (Medium Robustness)

Science.gov (United States)

2002-03-22

may be derived from detailed inspection of the IC itself or from illicit appropriation of design information. Counterfeit smart cards can be mass...Infrastructure (PKI) as the Internet to securely and privately exchange data and money through the use of a public and a private cryptographic key pair...interference devices (SQDIS), electrical testing, and electron beam testing. • Other attacks, such as UV or X-rays or high temperatures, could cause erasure

A Survey of Research in Supervisory Control and Data Acquisition (SCADA)

Science.gov (United States)

2014-09-01

RISC ) platforms running some version of UNIX.4 Around the turn of the millennium work began on applying Web technologies to SCADA systems.5–8 Lately...the 2 trend has been to move from the UNIX/ RISC system to commodity hardware and Microsoft solutions although there is some Linux,1 to move from...Control Center MTU Master Terminal Unit OS operating system PKI Public Key Infrastructure PLC Programmable Logic Controller RISC Reduced Instruction

Public Key Infrastructure (PKI) enhanced file transfer over secure ...

African Journals Online (AJOL)

user

arises from the problem of rendezvous, and solved by asserting that in any pair of communicating applications, one side must start execution and wait (indefinitely) for the other side to connect. Applications that initiate communication is called clients, and a server is one that wait for incoming communication request from ...

Research in DRM architecture based on watermarking and PKI

Science.gov (United States)

Liu, Ligang; Chen, Xiaosu; Xiao, Dao-ju; Yi, Miao

2005-02-01

Analyze the virtue and disadvantage of the present digital copyright protecting system, design a kind of security protocol model of digital copyright protection, which equilibrium consider the digital media"s use validity, integrality, security of transmission, and trade equity, make a detailed formalize description to the protocol model, analyze the relationship of the entities involved in the digital work copyright protection. The analysis of the security and capability of the protocol model shows that the model is good at security and practicability.

Recent developments: PKI square dish for the Soleras Project

Science.gov (United States)

Rogers, W. E.

1984-03-01

The Square Dish solar collectors are subjected to rigorous design attention regarding corrosion at the site, and certification of the collector structure. The microprocessor controls and tracking mechanisms are improved in the areas of fail safe operations, durability, and low parasitic power requirements. Prototype testing demonstrates performance efficiency of approximately 72% at 730 F outlet temperature. Studies are conducted that include developing formal engineering design studies, developing formal engineering design drawing and fabrication details, establishing subcontracts for fabrication of major components, and developing a rigorous quality control system. The improved design is more cost effective to product and the extensive manuals developed for assembly and operation/maintenance result in faster field assembly and ease of operation.

Securing Wireless Local Area Networks with GoC PKI

Science.gov (United States)

2007-10-01

profit de la technologie d’infrastructure à clé publique (ICP) du Gouvernement du Canada (GC) pour une authentification forte des utilisateurs...environnements protégés du GC lorsqu’il fonctionne en mode entreprise et qu’il est combiné à des certificats délivrés par l’ICP du GC et à une...on the WPA2 secured wireless link. The VPN gateway carries out VPN authentication with the same user certificates used to perform WLAN authentication

Security Issues of the Digital Certificates within Public Key Infrastructures

Directory of Open Access Journals (Sweden)

2009-01-01

Full Text Available The paper presents the basic byte level interpretation of an X.509 v3 digital certificate according to ASN.1 DER/BER encoding. The reasons for byte level analysis are various and important. For instance, a research paper has mentioned how a PKI security may be violated by MD5 collision over information from the certificates. In order to develop further studies on the topic a serious knowledge about certificate structure is necessary.

x509-free access to WLCG resources

OpenAIRE

Short, H; Manzi, A; De Notaris, V; Keeble, O; Kiryanov, A; Mikkonen, H; Tedesco, P; Wartel, R

2017-01-01

Access to WLCG resources is authenticated using an x509 and PKI infrastructure. Even though HEP users have always been exposed to certificates directly, the development of modern Web Applications by the LHC experiments calls for simplified authentication processes keeping the underlying software unmodified. In this work we will show a solution with the goal of providing access to WLCG resources using the user’s home organisations credentials, without the need for user-acquired x509 certificat...

AliEn - ALICE environment on the GRID

International Nuclear Information System (INIS)

Saiz, P.; Aphecetche, L.; Buncic, P.; Piskac, R.; Revsbech, J.-E.; Sego, V.

2003-01-01

AliEn (http://alien.cern.ch) (ALICE Environment) is a Grid framework built on top of the latest Internet standards for information exchange and authentication (SOAP, PKI) and common Open Source components. AliEn provides a virtual file catalogue that allows transparent access to distributed datasets and a number of collaborating Web services which implement the authentication, job execution, file transport, performance monitor and event logging. In the paper we will present the architecture and components of the system

AliEn - ALICE environment on the GRID

CERN Document Server

Saiz, P; Buncic, P; Piskac, R; Revsbech, J E; Sego, V

2003-01-01

AliEn (http://alien.cern.ch) (ALICE Environment) is a Grid framework built on top of the latest Internet standards for information exchange and authentication (SOAP, PKI) and common Open Source components. AliEn provides a virtual file catalogue that allows transparent access to distributed datasets and a number of collaborating Web services which implement the authentication, job execution, file transport, performance monitor and event logging. In the paper we will present the architecture and components of the system.

Modulation of cyclic amp-dependent protein kinase isozyme expression associated with activation of a macrophage cell line

International Nuclear Information System (INIS)

Justement, L.B.; Aldrich, W.A.; Wenger, G.D.; O'Dorisio, M.S.; Zwilling, B.S.

1986-01-01

The RAW 264.7 macrophage (MO) cell line was used to study cAMPdPK isozymes during activation by lymphokine (LK) and lipopolysaccharide (LPS). Untreated cells were found to have two isozymes of cAMPdPK in their cytosol. PKI and PKII were differentiated based on the M/sub r/ of their regulatory subunits (RI, 45,500; and RII, 52,000, respectively) as determined by photoactivated incorporation of the cAMP analog 8-N 3 -[ 32 P]cAMP. Loss of the RI subunit of PKI occurred in association with activation of the cell line by suboptimal concentrations of LK and LPS. No modulation of the RII subunit of PKII was observed under these conditions. The addition of a suboptimal concentration of LPS after LK or a high dose of LPS alone was required for acquisition of cytolytic activity and loss of RI. The antitumor activity of the RAW 264.7 cell line was transiently expressed after activation. Cells no longer exhibited tumoricidal activity 48 hr after the removal of activating agents. It was observed that the loss of cytolytic function was accompanied by the reexpression of RI in the cytosol. This study provides evidence that modulation of cAMPdPK isozymes occurs during activation, suggesting a potential mechanism for controlling the effects of cAMP on the MO

ACTH-induced caveolin-1 tyrosine phosphorylation is related to podosome assembly in Y1 adrenal cells

International Nuclear Information System (INIS)

Colonna, Cecilia; Podesta, Ernesto J.

2005-01-01

Y1 adrenocortical cells respond to ACTH with a characteristic rounding-up that facilitates cAMP signaling, critical for transport of cholesterol to the mitochondria and increase in steroid secretion. We here demonstrate that caveolin-1 participates in coupling activation of protein kinase A (PKA) to the control of cell shape. ACTH/8-Br-cAMP induced reorganization of caveolin-1-positive structures in correlation with the cellular rounding-up. Concomitant with this change, there was an increase in the phosphorylation of caveolin-1 (Tyr-14) localized at focal adhesions (FA) with reorganization of FA to rounded, ringlike structures. Colocalization with phalloidin showed that phosphocaveolin is present at the edge of actin filaments and that after ACTH stimulation F-actin dots at the cell periphery become surrounded by phosphocaveolin-1. These observations along with electron microscopy studies revealed these structures as podosomes. Podosome assembly was dependent on both PKA and tyrosine kinase activities because their formation was impaired after treatment with specific inhibitors [myristoylated PKI (mPKI) or PP2, respectively] previous to ACTH/8-Br-cAMP stimulation. These results show for the first time that ACTH induces caveolin-1 phosphorylation and podosome assembly in Y1 cells and support the view that the morphological and functional responses to PKA activation in steroidogenic cells are related to cytoskeleton dynamics

Security on Cloud Revocation Authority using Identity Based Encryption

Science.gov (United States)

Rajaprabha, M. N.

2017-11-01

As due to the era of cloud computing most of the people are saving there documents, files and other things on cloud spaces. Due to this security over the cloud is also important because all the confidential things are there on the cloud. So to overcome private key infrastructure (PKI) issues some revocable Identity Based Encryption (IBE) techniques are introduced which eliminates the demand of PKI. The technique introduced is key update cloud service provider which is having two issues in it and they are computation and communication cost is high and second one is scalability issue. So to overcome this problem we come along with the system in which the Cloud Revocation Authority (CRA) is there for the security which will only hold the secret key for each user. And the secret key was send with the help of advanced encryption standard security. The key is encrypted and send to the CRA for giving the authentication to the person who wants to share the data or files or for the communication purpose. Through that key only the other user will able to access that file and if the user apply some invalid key on the particular file than the information of that user and file is send to the administrator and administrator is having rights to block that person of black list that person to use the system services.

Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-ylmethyl]piperazines: Novel Antagonists for the Histamine H3 and H4 Receptors with Anti-inflammatory Potential

Directory of Open Access Journals (Sweden)

Michelle F. Corrêa

2017-11-01

Full Text Available The histamine receptors (HRs are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson’s, and Alzheimer’s diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-ylmethyl]piperazine (LINS01 series molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pKi 6.40, while the chlorinated compound LINS01007 has moderate affinity for H4R (pKi 6.06. In addition, BRET assays to assess the functional activity of Gi1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.

A DNA-Inspired Encryption Methodology for Secure, Mobile Ad Hoc Networks

Science.gov (United States)

Shaw, Harry

2012-01-01

Users are pushing for greater physical mobility with their network and Internet access. Mobile ad hoc networks (MANET) can provide an efficient mobile network architecture, but security is a key concern. A figure summarizes differences in the state of network security for MANET and fixed networks. MANETs require the ability to distinguish trusted peers, and tolerate the ingress/egress of nodes on an unscheduled basis. Because the networks by their very nature are mobile and self-organizing, use of a Public Key Infra structure (PKI), X.509 certificates, RSA, and nonce ex changes becomes problematic if the ideal of MANET is to be achieved. Molecular biology models such as DNA evolution can provide a basis for a proprietary security architecture that achieves high degrees of diffusion and confusion, and resistance to cryptanalysis. A proprietary encryption mechanism was developed that uses the principles of DNA replication and steganography (hidden word cryptography) for confidentiality and authentication. The foundation of the approach includes organization of coded words and messages using base pairs organized into genes, an expandable genome consisting of DNA-based chromosome keys, and a DNA-based message encoding, replication, and evolution and fitness. In evolutionary computing, a fitness algorithm determines whether candidate solutions, in this case encrypted messages, are sufficiently encrypted to be transmitted. The technology provides a mechanism for confidential electronic traffic over a MANET without a PKI for authenticating users.

Beyond the Hype: On Using Blockchains in Trust Management for Authentication

OpenAIRE

Alexopoulos, Nikolaos; Daubert, Jörg; Mühlhäuser, Max; Habib, Sheikh Mahbub

2017-01-01

Trust Management (TM) systems for authentication are vital to the security of online interactions, which are ubiquitous in our everyday lives. Various systems, like the Web PKI (X.509) and PGP's Web of Trust are used to manage trust in this setting. In recent years, blockchain technology has been introduced as a panacea to our security problems, including that of authentication, without sufficient reasoning, as to its merits.In this work, we investigate the merits of using open distributed le...

Method of Anti-Virus Protection Based on (n, t Threshold Proxy Signature with an Arbitrator

Directory of Open Access Journals (Sweden)

E. A. Tolyupa

2014-01-01

Full Text Available The article suggests the method of anti-virus protection of mobile devices based on the usage of proxy digital signatures and an (n;t-threshold proxy signature scheme with an arbitrator. The unique feature of the suggested method is in the absence of necessity to install anti-virus software in a mobile device. It will be enough only to have the software verifying digital signatures and the Internet. The method is used on the base of public keys infrastructure /PKI/, thus minimizing implementation expenses.

Wireless technology infrastructures for authentication of patients: PKI that rings.

Science.gov (United States)

Sax, Ulrich; Kohane, Isaac; Mandl, Kenneth D

2005-01-01

As the public interest in consumer-driven electronic health care applications rises, so do concerns about the privacy and security of these applications. Achieving a balance between providing the necessary security while promoting user acceptance is a major obstacle in large-scale deployment of applications such as personal health records (PHRs). Robust and reliable forms of authentication are needed for PHRs, as the record will often contain sensitive and protected health information, including the patient's own annotations. Since the health care industry per se is unlikely to succeed at single-handedly developing and deploying a large scale, national authentication infrastructure, it makes sense to leverage existing hardware, software, and networks. This report proposes a new model for authentication of users to health care information applications, leveraging wireless mobile devices. Cell phones are widely distributed, have high user acceptance, and offer advanced security protocols. The authors propose harnessing this technology for the strong authentication of individuals by creating a registration authority and an authentication service, and examine the problems and promise of such a system.

Two decades of temporal change of Earth's inner core boundary

Science.gov (United States)

Yao, Jiayuan; Sun, Li; Wen, Lianxing

2015-09-01

We report two decades of changing behavior of the Earth's inner core boundary (ICB), which provides the simplest explanation for the observed temporal change of the compressional seismic waves that are reflected from the ICB (PKiKP) and refracted in the inner core (PKIKP), from earthquake doublets occurring in South Sandwich Islands between 1993 and 2013. In the early period (before 2003), the ICB is enlarged beneath the western coast of Gabon, Republic of Congo, and southwest Tanzania in the reflected points of the PKiKP observed at seismic stations OBN, AAK, and ARU, while it experiences little change beneath Zimbabwe or/and Kenya, and beneath west Angola or/and north Central African Republic, in the PKIKP entry or/and exit points of AAK and ARU observations, respectively. In the later period (after 1998), the ICB regions beneath the western coast of Gabon, Republic of Congo, and southwest Tanzania either shrink or remain unchanged, and the temporal change migrates to beneath Zimbabwe or/and Kenya, and beneath west Angola or/and north Central African Republic, with a decrease of inner core surface by 5.59 km between 1998 and 2009 beneath Zimbabwe or Kenya and by 1.73 km beneath west Angola or north Central African Republic between 1998 and 2013. These results indicate that ICB temporal change occurs in localized regions and is episodic, rapidly migrating, and alternately enlarged and shrunk.

Trust Management for Public Key Infrastructures: Implementing the X.509 Trust Broker

Directory of Open Access Journals (Sweden)

Ahmad Samer Wazan

2017-01-01

Full Text Available A Public Key Infrastructure (PKI is considered one of the most important techniques used to propagate trust in authentication over the Internet. This technology is based on a trust model defined by the original X.509 (1988 standard and is composed of three entities: the certification authority (CA, the certificate holder (or subject, and the Relying Party (RP. The CA plays the role of a trusted third party between the certificate holder and the RP. In many use cases, this trust model has worked successfully. However, we argue that the application of this model on the Internet implies that web users need to depend on almost anyone in the world in order to use PKI technology. Thus, we believe that the current TLS system is not fit for purpose and must be revisited as a whole. In response, the latest draft edition of X.509 has proposed a new trust model by adding new entity called the Trust Broker (TB. In this paper, we present an implementation approach that a Trust Broker could follow in order to give RPs trust information about a CA by assessing the quality of its issued certificates. This is related to the quality of the CA’s policies and procedures and its commitment to them. Finally, we present our Trust Broker implementation that demonstrates how RPs can make informed decisions about certificate holders in the context of the global web, without requiring large processing resources themselves.

Novel radiosensitizers for locally advanced epithelial tumors: inhibition of the PI3K/Akt survival pathway in tumor cells and in tumor-associated endothelial cells as a novel treatment strategy?

International Nuclear Information System (INIS)

Riesterer, Oliver; Tenzer, Angela; Zingg, Daniel; Hofstetter, Barbara; Vuong, Van; Pruschy, Martin; Bodis, Stephan

2004-01-01

In locally advanced epithelial malignancies, local control can be achieved with high doses of radiotherapy (RT). Concurrent chemoradiotherapy can improve tumor control in selected solid epithelial adult tumors; however, treatment-related toxicity is of major concern and the therapeutic window often small. Therefore, novel pharmacologic radiosensitizers with a tumor-specific molecular target and a broad therapeutic window are attractive. Because of clonal heterogeneity and the high mutation rate of these tumors, combined treatment with single molecular target radiosensitizers and RT are unlikely to improve sustained local tumor control substantially. Therefore, radiosensitizers modulating entire tumor cell survival pathways in epithelial tumors are of potential clinical use. We discuss the preclinical efficacy and the mechanism of three different, potential radiosensitizers targeting the PTEN/PI3K/Akt survival pathway. These compounds were initially thought to act as single-target agents against growth factor receptors (PKI 166 and PTK 787) or protein kinase C isoforms (PKC 412). We describe an additional target for these compounds. PKI 166 (an epidermal growth factor [EGF] receptor inhibitor) and PKC 412, target the PTEN/PI3K/Akt pathway mainly in tumor cells, and PTK 787 (a vascular endothelial growth factor [VEGF] receptor inhibitor) in endothelial cells. Even for these broader range molecular radiosensitizers, the benefit could be restricted to human epithelial tumor cell clones with a distinct molecular profile. Therefore, these potential radiosensitizers have to be carefully tested in specific model systems before introduction in early clinical trials

Interaction of selected vasodilating beta-blockers with adrenergic receptors in human cardiovascular tissues

International Nuclear Information System (INIS)

Monopoli, A.; Forlani, A.; Bevilacqua, M.; Vago, T.; Norbiato, G.; Bertora, P.; Biglioli, P.; Alamanni, F.; Ongini, E.

1989-01-01

beta- And alpha 1-adrenoceptor antagonist properties of bufuralol, carvedilol, celiprolol, dilevalol, labetalol, and pindolol were investigated in human myocardium and mammary artery using binding techniques and functional studies. In myocardial membranes, beta-adrenoceptor antagonists showed monophasic competition isotherms for [125I]pindolol binding with high affinity (Ki from 1-100 nM), except for celiprolol which displayed a biphasic competition isotherm (pKi = 6.4 +/- 0.06 for beta 1- and 4.8 +/- 0.07 for beta 2-adrenoceptors). Drug interactions with alpha 1-adrenoceptors were evaluated in human mammary artery by [3H]prazosin binding and by measuring contractile responses to norepinephrine (NE). Labetalol and carvedilol showed a moderate affinity for alpha 1-adrenoceptors (pKi = 6.2 +/- 0.01 and 6.1 +/- 0.06, respectively), and inhibited NE-induced contractions (pA2 = 6.93 +/- 0.23 and 8.64 +/- 0.24, respectively). Dilevalol, bufuralol, and pindolol displayed weak effect both in binding (Ki in micromolar range) and functional experiments (pA2 = 5.98, 5.54, and 6.23, respectively). Celiprolol did not show antagonist properties up to 100 microM in functional studies, but displayed a slight affinity for alpha 1-adrenoceptors in binding studies. The data indicate that the vasodilating activity of these beta-adrenoceptor antagonists is caused in some instances by an alpha 1-adrenoceptor antagonism (labetalol, carvedilol), whereas for the others alternative mechanisms should be considered

Hedgehog-PKA signaling and gnrh3 regulate the development of zebrafish gnrh3 neurons.

Directory of Open Access Journals (Sweden)

Ming-Wei Kuo

Full Text Available GnRH neurons secrete GnRH that controls the development of the reproduction system. Despite many studies, the signals controlling the development of GnRH neurons from its progenitors have not been fully established. To understand the development of GnRH neurons, we examined the development of gnrh3-expressing cells using a transgenic zebrafish line that expresses green fluorescent protein (GFP and LacZ driven by the gnrh3 promoter. GFP and LacZ expression recapitulated that of gnrh3 in the olfactory region, olfactory bulb and telencephalon. Depletion of gnrh3 by morpholinos led to a reduction of GFP- and gnrh3-expressing cells, while over-expression of gnrh3 mRNA increased the number of these cells. This result indicates a positive feed-forward regulation of gnrh3 cells by gnrh3. The gnrh3 cells were absent in embryos that lack Hedgehog signaling, but their numbers were increased in embryos overexpressing shhb. We manipulated the amounts of kinase that antagonizes the Hedgehog signaling pathway, protein kinase A (PKA, by treating embryos with PKA activator forskolin or by injecting mRNAs encoding its constitutively active catalytic subunit (PKA* and dominant negative regulatory subunit (PKI into zebrafish embryos. PKA* misexpression or forskolin treatment decreased GFP cell numbers, while PKI misexpression led to ectopic production of GFP cells. Our data indicate that the Hedgehog-PKA pathway participates in the development of gnrh3-expressing neurons during embryogenesis.

What we know about Oslo meteorite from cosmogenic isotope analysis

Science.gov (United States)

Tymiński, Z.; Stolarz, M.; Kubalczak, T.; Zaręba, P.; Burski, M.; Bilet, M.; Miśta, E.; Tymińska, K.; Kołakowska, E.; Burakowska, A.; Żołądek, P.; Olech, A.; Wiśniewski, M.; Listkowska, A.; Saganowski, P.

2015-10-01

The fragments of an asteroid that had crashed over Norway were found in a few locations in Oslo at the beginning of March 2012. Later on some pieces of meteorite from the most South area were collected by the Meteoritical Section members of Comet and Meteor Workshop (PKiM) with the help of local meteoritical authorities. One meteorite fragment of 32g was used to measure cosmogenic radionuclides using non-destructive high-resolution gamma spectrometry technique. Five radioisotopes such as Al-26, Na-22, Mn-54, Co-57 and Co-60 were detected

PKPass

Energy Technology Data Exchange (ETDEWEB)

2017-06-30

Password management solutions exist, but few are designed for enterprise systems administrators sharing oncall rotations. Due to the Multi-Factor Level of Assurance 4 effort, DOE is now distributing PIV cards with cryptographically signed certificate and private key pairs to administrators and other security-significant users. We utilize this public key infrastructure (PKI) to encrypt passwords for other recipients in a secure way. This is cross platform (works on OSX and Linux systems), and has already been adopted internally by the NCCS systems administration staff to replace their old password book system.

Design of Thymidine Analogues Targeting Thymidilate Kinase of Mycobacterium tuberculosis

Directory of Open Access Journals (Sweden)

Luc Calvin Owono Owono

2013-01-01

Full Text Available We design here new nanomolar antituberculotics, inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt, by means of structure-based molecular design. 3D models of TMPKmt-inhibitor complexes have been prepared from the crystal structure of TMPKmt cocrystallized with the natural substrate deoxythymidine monophosphate (dTMP (1GSI for a training set of 15 thymidine analogues (TMDs with known activity to prepare a QSAR model of interaction establishing a correlation between the free energy of complexation and the biological activity. Subsequent validation of the predictability of the model has been performed with a 3D QSAR pharmacophore generation. The structural information derived from the model served to design new subnanomolar thymidine analogues. From molecular modeling investigations, the agreement between free energy of complexation (ΔΔGcom and Ki values explains 94% of the TMPKmt inhibition (pKi=-0.2924ΔΔGcom+3.234;R2=0.94 by variation of the computed ΔΔGcom and 92% for the pharmacophore (PH4 model (pKi=1.0206×pKipred-0.0832,  R2=0.92. The analysis of contributions from active site residues suggested substitution at the 5-position of pyrimidine ring and various groups at the 5′-position of the ribose. The best inhibitor reached a predicted Ki of 0.155 nM. The computational approach through the combined use of molecular modeling and PH4 pharmacophore is helpful in targeted drug design, providing valuable information for the synthesis and prediction of activity of novel antituberculotic agents.

DAT/SERT Selectivity of Flexible GBR 12909 Analogs Modeled Using 3D-QSAR Methods

Science.gov (United States)

Gilbert, Kathleen M.; Boos, Terrence L.; Dersch, Christina M.; Greiner, Elisabeth; Jacobson, Arthur E.; Lewis, David; Matecka, Dorota; Prisinzano, Thomas E.; Zhang, Ying; Rothman, Richard B.; Rice, Kenner C.; Venanzi, Carol A.

2007-01-01

The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pKi (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q2 = 0.508, standard error of prediction = 0.601, two components, r2 = 0.685, standard error of estimate = 0.481, F value = 39, percent steric contribution = 65, and percent electrostatic contribution = 35. A CoMFA contour map identified areas of the molecule that affect pKi (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules. PMID:17127069

The 1965 coup and reformasi 1998: two critical moments in Indonesia-Malaysia relations during and after the Cold War.

Science.gov (United States)

Maksum, Ali; Bustami, Reevany

2014-01-01

This article discusses the significant impact of the two crucial moments in Indonesia namely, the 1965 coup and reformasi (reformation) in May 1998 and the impact towards the Indonesia-Malaysia relationship. History had demonstrated that both events were followed by some changes in the bilateral relationship. The 1965 coup for instance resulted the fall of Sukarno and the collapse of PKI, while reformasi brought the fall of Suharto and the collapse of New Order. However, it was undeniable that the demands of international situation especially during and after the Cold War were significant factor in driving of those events.

Ein PKI-basiertes Protokoll für sichere und praktikable Onlinewahlen

Directory of Open Access Journals (Sweden)

Lucie Langer

2010-04-01

Full Text Available Wir stellen ein Protokoll für Onlinewahlen vor, welches auf dem Schema von Ohkubo et al. [13] basiert. Besonders an diesem Protokoll ist, dass der Auszähler nicht vertrauenswürdig sein muss. Der geheime Schlüssel des Auszählers wird am Ende der Wahl veröffentlicht und ermöglicht so die universelle Verifizierbarkeit der Stimmauszählung. Wir diskutieren die Sicherheit des Protokolls angesichts der allgemein anerkannten Sicherheitsanforderungen für elektronische Wahlschemata.

PKI solar thermal plant evaluation at Capitol Concrete Products, Topeka, Kansas

Science.gov (United States)

Hauger, J. S.; Borton, D. N.

1982-07-01

A system feasibility test to determine the technical and operational feasibility of using a solar collector to provide industrial process heat is discussed. The test is of a solar collector system in an industrial test bed plant at Capitol Concrete Products in Topeka, Kansas, with an experiment control at Sandia National Laboratories, Albuquerque. Plant evaluation will occur during a year-long period of industrial utilization. It will include performance testing, operability testing, and system failure analysis. Performance data will be recorded by a data acquisition system. User, community, and environmental inputs will be recorded in logs, journals, and files. Plant installation, start-up, and evaluation, are anticipated for late November, 1981.

On Cryptographic Information Security in Cloud Infrastructures: PKI and IBE Methods

Directory of Open Access Journals (Sweden)

Konstantin Grigorevich Kogos

2014-05-01

Full Text Available The application of cryptographic security methods in cloud infrastructure information security is analyzed. The cryptographic problems in cloudy infrastructures are chosen; the appropriate protocols are investigated; the appropriate mathematical problems are examined.

Increased sensitivity to ionizing radiation by targeting the homologous recombination pathway in glioma initiating cells.

Science.gov (United States)

Lim, Yi Chieh; Roberts, Tara L; Day, Bryan W; Stringer, Brett W; Kozlov, Sergei; Fazry, Shazrul; Bruce, Zara C; Ensbey, Kathleen S; Walker, David G; Boyd, Andrew W; Lavin, Martin F

2014-12-01

Glioblastoma is deemed the most malignant form of brain tumour, particularly due to its resistance to conventional treatments. A small surviving group of aberrant stem cells termed glioma initiation cells (GICs) that escape surgical debulking are suggested to be the cause of this resistance. Relatively quiescent in nature, GICs are capable of driving tumour recurrence and undergo lineage differentiation. Most importantly, these GICs are resistant to radiotherapy, suggesting that radioresistance contribute to their survival. In a previous study, we demonstrated that GICs had a restricted double strand break (DSB) repair pathway involving predominantly homologous recombination (HR) associated with a lack of functional G1/S checkpoint arrest. This unusual behaviour led to less efficient non-homologous end joining (NHEJ) repair and overall slower DNA DSB repair kinetics. To determine whether specific targeting of the HR pathway with small molecule inhibitors could increase GIC radiosensitivity, we used the Ataxia-telangiectasia mutated inhibitor (ATMi) to ablate HR and the DNA-dependent protein kinase inhibitor (DNA-PKi) to inhibit NHEJ. Pre-treatment with ATMi prior to ionizing radiation (IR) exposure prevented HR-mediated DNA DSB repair as measured by Rad51 foci accumulation. Increased cell death in vitro and improved in vivo animal survival could be observed with combined ATMi and IR treatment. Conversely, DNA-PKi treatment had minimal impact on GICs ability to resolve DNA DSB after IR with only partial reduction in cell survival, confirming the major role of HR. These results provide a mechanistic insight into the predominant form of DNA DSB repair in GICs, which when targeted may be a potential translational approach to increase patient survival. Copyright © 2014. Published by Elsevier B.V.

Novel, customizable scoring functions, parameterized using N-PLS, for structure-based drug discovery.

Science.gov (United States)

Catana, Cornel; Stouten, Pieter F W

2007-01-01

The ability to accurately predict biological affinity on the basis of in silico docking to a protein target remains a challenging goal in the CADD arena. Typically, "standard" scoring functions have been employed that use the calculated docking result and a set of empirical parameters to calculate a predicted binding affinity. To improve on this, we are exploring novel strategies for rapidly developing and tuning "customized" scoring functions tailored to a specific need. In the present work, three such customized scoring functions were developed using a set of 129 high-resolution protein-ligand crystal structures with measured Ki values. The functions were parametrized using N-PLS (N-way partial least squares), a multivariate technique well-known in the 3D quantitative structure-activity relationship field. A modest correlation between observed and calculated pKi values using a standard scoring function (r2 = 0.5) could be improved to 0.8 when a customized scoring function was applied. To mimic a more realistic scenario, a second scoring function was developed, not based on crystal structures but exclusively on several binding poses generated with the Flo+ docking program. Finally, a validation study was conducted by generating a third scoring function with 99 randomly selected complexes from the 129 as a training set and predicting pKi values for a test set that comprised the remaining 30 complexes. Training and test set r2 values were 0.77 and 0.78, respectively. These results indicate that, even without direct structural information, predictive customized scoring functions can be developed using N-PLS, and this approach holds significant potential as a general procedure for predicting binding affinity on the basis of in silico docking.

Incitement to Genocide against a Political Group: The Anti-Communist Killings in Indonesia

Directory of Open Access Journals (Sweden)

Annie Elizabeth Pohlman

2014-08-01

Full Text Available Genocide and mass atrocities can be seen as the culminative result of extreme social exclusion. Two of the critical steps on the path to genocidal persecution are the isolation and exclusion of a particular group and the mobilisation and incitement of perpetrators. This paper examines the case of the 1965-1966 massacres in Indonesia in light of these two incipient stages of genocide. First, I discuss the Indonesian killings of 1965-1966 by situating them within the conceptual and legal understandings of genocide and argue that those persecuted belonged predominantly to a defined political group, that is, members and associates of the Indonesian Communist Party (PKI. I argue that the exclusion of political groups from the legal definition of genocide given in the UN Convention on Genocide is unsupportable when examined both within the context that it was created and the greater conceptual understandings of genocide studies. To support this argument, I then outline the political situation in Indonesia prior to the 1 October 1965 coup and explain how the country went through a process of political pillarisation, effectively creating the conditions for the creation and then eradication of the Left in Indonesia. In the final part of the paper, I examine how these killings were incited. I argue that hate propaganda was used against the PKI and its supporters by the main perpetrators of the massacres, the Indonesian military, to incite a popular, genocidal campaign. As a result of this hate-propaganda campaign, Leftists in Indonesia experienced extreme forms of dehumanisation and social death which, in turn, facilitated their eradication.

Public key infrastructure for DOE security research

Energy Technology Data Exchange (ETDEWEB)

Aiken, R.; Foster, I.; Johnston, W.E. [and others

1997-06-01

This document summarizes the Department of Energy`s Second Joint Energy Research/Defence Programs Security Research Workshop. The workshop, built on the results of the first Joint Workshop which reviewed security requirements represented in a range of mission-critical ER and DP applications, discussed commonalties and differences in ER/DP requirements and approaches, and identified an integrated common set of security research priorities. One significant conclusion of the first workshop was that progress in a broad spectrum of DOE-relevant security problems and applications could best be addressed through public-key cryptography based systems, and therefore depended upon the existence of a robust, broadly deployed public-key infrastructure. Hence, public-key infrastructure ({open_quotes}PKI{close_quotes}) was adopted as a primary focus for the second workshop. The Second Joint Workshop covered a range of DOE security research and deployment efforts, as well as summaries of the state of the art in various areas relating to public-key technologies. Key findings were that a broad range of DOE applications can benefit from security architectures and technologies built on a robust, flexible, widely deployed public-key infrastructure; that there exists a collection of specific requirements for missing or undeveloped PKI functionality, together with a preliminary assessment of how these requirements can be met; that, while commercial developments can be expected to provide many relevant security technologies, there are important capabilities that commercial developments will not address, due to the unique scale, performance, diversity, distributed nature, and sensitivity of DOE applications; that DOE should encourage and support research activities intended to increase understanding of security technology requirements, and to develop critical components not forthcoming from other sources in a timely manner.

Multiple isoforms of the human pentraxin serum amyloid P component

DEFF Research Database (Denmark)

Sørensen, Inge Juul; Andersen, Ove; Nielsen, EH

1995-01-01

Human serum amyloid P component (SAP) isolated from 20 healthy individuals was analyzed by anion exchange chromatography and isoelectric focusing (IEF) in order to investigate the existence of multiple forms of SAP and interindividual structural differences. Anion exchange chromatography showed one...... major and several minor subpopulations of SAP. IEF of all SAP isolates showed a previously unreported degree of heterogeneity with six isoelectric forms (pKi range 5.5-6.1) and with minor interindividual differences in respect of isoelectric points. Total enzymatic deglycosylation of SAP reduced...... the number of bands in IEF to two indicating the existence of two types of polypeptide chains....

Trust and its ramification for the DoD public key infrastructure (PKI)

OpenAIRE

Pedersen, Carl M.

2001-01-01

Approved for public release; distribution is unlimited Researchers have used a wide variety of trust definitions, leading to a plethora of meanings of the concept. But what does the word trust' mean? While most scholars provide their own definition of trust, they are dissatisfied regarding their own lack of consensus about what trust is. Trust is a cognitive function and modeling trust is an attempt to emulate the way a human assesses trust. Models of trust have been developed in an attemp...

PKI Layer Cake: New Collision Attacks against the Global X.509 Infrastructure

Science.gov (United States)

Kaminsky, Dan; Patterson, Meredith L.; Sassaman, Len

Research unveiled in December of 2008 [15] showed how MD5's long-known flaws could be actively exploited to attack the real-worldCertification Authority infrastructure. In this paper, we demonstrate two new classes of collision, which will be somewhat trickier to address than previous attacks against X.509: the applicability of MD2 preimage attacks against the primary root certificate for Verisign, and the difficulty of validating X.509 Names contained within PKCS#10 Certificate Requests.We also draw particular attention to two possibly unrecognized vectors for implementation flaws that have been problematic in the past: the ASN.1 BER decoder required to parsePKCS#10, and the potential for SQL injection fromtext contained within its requests. Finally, we explore why the implications of these attacks are broader than some have realized - first, because Client Authentication is sometimes tied to X.509, and second, because Extended Validation certificates were only intended to stop phishing attacks from names similar to trusted brands. As per the work of Adam Barth and Collin Jackson [4], EV does not prevent an attacker who can synthesize or acquire a "low assurance" certificate for a given name from acquiring the "green bar" EV experience.

Towards Trustable Digital Evidence with PKIDEV: PKI Based Digital Evidence Verification Model

Science.gov (United States)

Uzunay, Yusuf; Incebacak, Davut; Bicakci, Kemal

How to Capture and Preserve Digital Evidence Securely? For the investigation and prosecution of criminal activities that involve computers, digital evidence collected in the crime scene has a vital importance. On one side, it is a very challenging task for forensics professionals to collect them without any loss or damage. On the other, there is the second problem of providing the integrity and authenticity in order to achieve legal acceptance in a court of law. By conceiving digital evidence simply as one instance of digital data, it is evident that modern cryptography offers elegant solutions for this second problem. However, to our knowledge, there is not any previous work proposing a systematic model having a holistic view to address all the related security problems in this particular case of digital evidence verification. In this paper, we present PKIDEV (Public Key Infrastructure based Digital Evidence Verification model) as an integrated solution to provide security for the process of capturing and preserving digital evidence. PKIDEV employs, inter alia, cryptographic techniques like digital signatures and secure time-stamping as well as latest technologies such as GPS and EDGE. In our study, we also identify the problems public-key cryptography brings when it is applied to the verification of digital evidence.

AUTHENTICATION ALGORITHM FOR PARTICIPANTS OF INFORMATION INTEROPERABILITY IN PROCESS OF OPERATING SYSTEM REMOTE LOADING ON THIN CLIENT

Directory of Open Access Journals (Sweden)

Y. A. Gatchin

2016-05-01

Full Text Available Subject of Research.This paper presents solution of authentication problem for all components of information interoperabilityin process of operation system network loading on thin client from terminal server. System Definition. In the proposed solution operation system integrity check is made by hardware-software module, including USB-token with protected memory for secure storage of cryptographic keys and loader. The key requirement for the solution is mutual authentication of four participants: terminal server, thin client, token and user. We have created two algorithms for the problem solution. The first of the designed algorithms compares the encrypted one-time password (random number with the reference value stored in the memory of the token and updates this number in case of successful authentication. The second algorithm uses the public and private keys of the token and the server. As a result of cryptographic transformation, participants are authenticated and the secure channel is formed between the token, thin client and terminal server. Main Results. Additional research was carried out to find out if the designed algorithms meet the necessary requirements. Criteria used included applicability in a multi-access terminal system architecture, potential threats evaluation and overall system security. According to analysis results, it is recommended to use the algorithm based on PKI due to its high scalability and usability. High level of data security is proved as a result of asymmetric cryptography application with the guarantee that participants' private keys are never sent in the authentication process. Practical Relevance. The designed PKI-based algorithm allows solving the problem with the use of cryptographic algorithms according to state standard even in its absence on asymmetric cryptography. Thus, it can be applied in the State Information Systems with increased requirements to information security.

TINDAKAN NEGARA TERKAIT PERISTIWA G30S: STUDI MAKNA GADAMERIAN PADA PESELAMAT

Directory of Open Access Journals (Sweden)

Hamdan Tri Atmaja

2012-07-01

Full Text Available This study aims to gain knowledge of a deep understanding of the state action related to the G30S event. The research method used was a qualitative research approach initiated by Gadamer's hermeneutics. The results showed that state action against survivors were to arrest, investigate, and imprison them to the island of Buru (for men survivors and Plantungan (for women survivors. The G30S event, by survivors, was interpreted as a story of the assassination of the generals by Indonesian Communist Party (PKI, as well as the form of a political conspiracy for Sukarno’s power within ideological background. Investigation and arrest were interpreted by them as an act of unwarranted, political scapegoat, and a form of abuse against them. While prison life, for survivors, was as a form of forced labor, punishment to stigmatize and isolate women Keywords: State Action, the G30S event, Meaning, and Survivor.   Tulisan ini mendeskripsikan secara mendalam tindakan negara terkait peristiwa G30S. Metode penelitian yang digunakan adalah penelitian kualitatif dengan pendekatan hermeneutika yang digagas Gadamer. Hasil penelitian menunjukkan tindakan negara terhadap peselamat adalah melakukan penangkapan, pemeriksaan, dan penahanan serta memenjarakan mereka ke pulau Buru (untuk peselamat laki-laki dan Plantungan (untuk peselamat perempuan. Peristiwa G30S oleh peselamat dimaknai sebagai kisah pembunuhan para jendral oleh PKI, bentuk konspirasi politik memperebutkan kekuasaan Soekarno dengan latar belakang ideologi. Pemeriksaan dan penangkapan dimaknai peselamat sebagai tindakan tidak beralasan, politik kambing hitam, dan sebagai bentuk kesewenang-wenangan terhadap peselamat. Kehidupan penjara dimaknai peselamat sebagai bentuk kerja paksa, hukuman dengan menstigmatisasi dan mengisolasi kaum perempuan. Kata kunci: Tindakan Negara, Peristiwa G30S, Makna, dan  Peselamat.      

Key exchange using biometric identity based encryption for sharing encrypted data in cloud environment

Science.gov (United States)

Hassan, Waleed K.; Al-Assam, Hisham

2017-05-01

The main problem associated with using symmetric/ asymmetric keys is how to securely store and exchange the keys between the parties over open networks particularly in the open environment such as cloud computing. Public Key Infrastructure (PKI) have been providing a practical solution for session key exchange for loads of web services. The key limitation of PKI solution is not only the need for a trusted third partly (e.g. certificate authority) but also the absent link between data owner and the encryption keys. The latter is arguably more important where accessing data needs to be linked with identify of the owner. Currently available key exchange protocols depend on using trusted couriers or secure channels, which can be subject to man-in-the-middle attack and various other attacks. This paper proposes a new protocol for Key Exchange using Biometric Identity Based Encryption (KE-BIBE) that enables parties to securely exchange cryptographic keys even an adversary is monitoring the communication channel between the parties. The proposed protocol combines biometrics with IBE in order to provide a secure way to access symmetric keys based on the identity of the users in unsecure environment. In the KE-BIOBE protocol, the message is first encrypted by the data owner using a traditional symmetric key before migrating it to a cloud storage. The symmetric key is then encrypted using public biometrics of the users selected by data owner to decrypt the message based on Fuzzy Identity-Based Encryption. Only the selected users will be able to decrypt the message by providing a fresh sample of their biometric data. The paper argues that the proposed solution eliminates the needs for a key distribution centre in traditional cryptography. It will also give data owner the power of finegrained sharing of encrypted data by control who can access their data.

Inhibition of Vascular Smooth Muscle Growth via Signaling Crosstalk between AMP-Activated Protein Kinase and cAMP-Dependent Protein Kinase

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Joshua Daniel Stone

2012-10-01

Full Text Available Abnormal vascular smooth muscle (VSM growth is central in the pathophysiology of vascular disease yet fully effective therapies to curb this growth are lacking. Recent findings from our lab and others support growth control of VSM by adenosine monophosphate (AMP-based approaches including the metabolic sensor AMP-activated protein kinase (AMPK and cAMP-dependent protein kinase (PKA. Molecular crosstalk between AMPK and PKA has been previously suggested, yet the extent to which this occurs and its biological significance in VSM remains unclear. Considering their common AMP backbone and similar signaling characteristics, we hypothesized that crosstalk exists between AMPK and PKA in the regulation of VSM growth. Using rat primary VSM cells, the AMPK agonist AICAR increased AMPK activity and phosphorylation of the catalytic Thr172 site on AMPK. Interestingly, AICAR also phosphorylated a suspected PKA-inhibitory Ser485 site on AMPK, and these cumulative events were reversed by the PKA inhibitor PKI suggesting possible PKA-mediated regulation of AMPK. AICAR also increased PKA activity in a reversible fashion. The cAMP stimulator forskolin increased PKA activity and completely ameliorated Ser/Thr protein phosphatase-2C activity, suggesting a potential mechanism of AMPK modulation by PKA since inhibition of PKA by PKI reduced AMPK activity. Functionally, AMPK inhibited serum-stimulated cell cycle progression and cellular proliferation; however, PKA failed to do so. Moreover, AMPK and PKA reduced PDGF-β-stimulated VSM cell migration. Collectively, these results show that AMPK is capable of reducing VSM growth in both anti-proliferative and anti-migratory fashions. Furthermore, these data suggest that AMPK may be modulated by PKA and that positive feedback may exist between these two systems. These findings reveal a discrete nexus between AMPK and PKA in VSM and provide basis for metabolically-directed targets in reducing pathologic VSM growth.

Secure and Authenticated Data Communication in Wireless Sensor Networks

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Omar Alfandi

2015-08-01

Full Text Available Securing communications in wireless sensor networks is increasingly important as the diversity of applications increases. However, even today, it is equally important for the measures employed to be energy efficient. For this reason, this publication analyzes the suitability of various cryptographic primitives for use in WSNs according to various criteria and, finally, describes a modular, PKI-based framework for confidential, authenticated, secure communications in which most suitable primitives can be employed. Due to the limited capabilities of common WSN motes, criteria for the selection of primitives are security, power efficiency and memory requirements. The implementation of the framework and the singular components have been tested and benchmarked in our testbed of IRISmotes.

Synthesis and pharmacological evaluation of several N-(2-nitrophenylpiperazine derivatives

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DEANA ANDRIC

2007-05-01

Full Text Available Six newly synthesized heterocyclic (2-nitrophenylpiperazines, with a specific structure of the heteroaryl group, whichmimics the catechol moiety of dopamine (benzimidazoles and substituted benzimidazoles, were evaluated for their binding affinity to rat dopamine (DA, serotonin (5-HT and α1 receptors. All compounds with a benzimidazole group had a 5-HT2A/D2 receptors binding ratio characteristic for atypical neuroleptics (>1, pKi values. Compound 7c, 4-bromo-6-{2-[4-(2-nitrophenylpiperazin-1-yl]ethyl}-1H-benzimidazole, expressed higher affinities for all receptor classes than clozapine. Also, it exhibited the best characteristic for atypical neuroleptics and presents a compound with the best profile for further in vivo investigations.

Verification testing of the PKI collector at Sandia National Laboratories, Albuquerque, New Mexico

Science.gov (United States)

Hauger, J. S.; Pond, S. L.

1982-07-01

Verification testing of a solar collector was undertaken prior to its operation as part of an industrial process heat plant at Capitol Concrete Products in Topeka, Kansas. Testing was performed at a control plant installed at Sandia National Laboratory, Albuquerque, New Mexico (SNLA). Early results show that plant performance is even better than anticipated and far in excess of test criteria. Overall plant efficiencies of 65 to 80 percent were typical during hours of good insolation. A number of flaws and imperfections were detected during operability testing, the most important being a problem in elevation drive alignment due to a manufacturing error. All problems were corrected as they occurred and the plant, with over 40 hours of operation, is currently continuing operability testing in a wholly-automatic mode.

The ‘Gestapu’ events of 1965 in Indonesia: New evidence from Russian and German archives

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Ragna Boden

2008-12-01

Full Text Available One of the unsolved riddles of Indonesian history in the twentieth century is the so-called Gestapu affair and its aftermath. For the murder of six army generals on the night of 30 September 1965 the Indonesian communists and President Soekarno were widely held responsible. Indonesian leftists – real and alleged – were persecuted; hundreds of thousands were killed. The longterm consequences affected Indonesian domestic as well as foreign policy: the changeover in government resulted in 30 years of rule by Soeharto; the Partai Komunis Indonesia (PKI, Indonesian Communist Party and leftist organizations were banned; relations with China were severed, those with the Union of Soviet Socialist Republics (USSR were reduced; and ties with Washington and the Western world intensified.

Electrochemical study in molten sodium fluoroborate at 4200C

International Nuclear Information System (INIS)

Wagner, J.F.

1983-06-01

By analysing the behavior of the electrochemical system Cu (I)/Cu it was possible to study the acid-base properties of molten sodium fluoroborate. The anion of the solvent BF 4 - is shown to undergo a strong dissociation according to the equilibrium BF 4 - BF 3 (g) + F - , the Ki constant at 420 0 C being evaluated at 1.58 x 10 -2 mol kg -1 atm. The acidity variations of sodium fluoroborate at this temperature are limited to about two pF units (pKi=1.8). A potentiometric study of the copper, silver and nickel systems showed that the corresponding metallic cations are little complexed by fluoride ions in spite of the strong dissociation of the solvent [fr

Thermal behavior of La2O3/Nio composite prepared by sol-gel method

International Nuclear Information System (INIS)

Sakallioglu, M.

2005-01-01

The La 2 O 3 /NiO composite was prepared by sol-gel method by using transition metal oxides (La 2 O 3 /NiO). The variation of specific heat capacity Cp with temperature for La2O3/NiO composite was investigated by DSC. The heat capacity curve was taken with a heating rate of 20 degrees/min between 0-100 degrees. The variation of specific heat capacity was found by PKI Muse Standard Analysis Program. The thermal stability of the La 2 O 3 /NiO composite was investigated by thermogravimetric analysis (TG) in air atmosphere at a heating rate of 20 degrees/min. The weight loss of La 2 O 3 /NiO composite was determined by the variation of temperature

Iga gümnasist saab õiguse õppida ettevõtluse põhitõdesid : ettevõtlusõpet takistab Eestis ärikogukonna passiivsus / Caroline Jenner, Hendrik Hindov ; intervjueerinud Laura Raus

Index Scriptorium Estoniae

Jenner, Caroline

2011-01-01

Intervjuu rahvusvahelise ettevõtlusorganisatsioonide koostöövõrgustiku Junior Achievement - Young Enterprise Europe juhi Caroline Jenner'i ja ettevõtja Hendrik Hindoviga ettevõtlus- ja majandusõppest gümnaasiumis

The 1965 Indonesian Killing Discourse by Generation 2000 Writers

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Diah Ariani Arimbi

2011-06-01

Full Text Available The fall of Soeharto’s authority in 1998 has indeed impacted numerous sides of Indonesian life: political, social and cultural. The shifting of authoritative government to the state of “reformation” and “democratization” has forced the nation to redefine its authority to its members. This paper aims to look at these public responses which are narrated in contemporary Indonesian fiction. Although fiction may be seen as imaginative production, discursive ideologies can be examined clearly. By examining thematic significant of the narratives about G30S/PKI and the killings aftermath in the literary writings published in post 1998 by contemporary Indonesia writers, who are known as the Generation 2000 writers (who were mostly born in 1970s at least five years after the 1965 incident: also known as the millennials, this paper will attempt to answer whether or not this generation presents shift and creates its own notions of the incident. Abstrak: Jatuhnya kekuasaan Soeharto pada tahun 1998 berdampak pada berbagai sisi kehidupan di Indonesia: politik, sosial, dan budaya. Pergeseran dari pemerintahan yang dulunya otoritatif menjadi pemerintahan yang sarat dengan "reformasi" dan "demokratisasi" telah memaksa negara untuk mendefinisikan kembali wewenangnya kepada para anggotanya. Makalah ini bertujuan untuk melihat respons publik yang diceritakan dalam fiksi Indonesia kontemporer. Walaupun fiksi dapat dipandang sebagai produk imajinatif, ideologi diskursif dapat dilihat dengan je-las. Dengan memeriksa tema-tema yang secara signifikan dimunculkan dari narasi tentang G30S/PKI dan tragedi pembunuhan sesudahnya dalam tulisan-tulisan sastra yang diterbitkan pasca tahun 1998 oleh penulis Indonesia kontemporer, yang dikenal sebagai penulis Generasi 2000 (penulis yang kebanyakan lahir di tahun 1970-an setidaknya 5 tahun setelah 1965 kejadian: juga dikenal sebagai millenials, makalah ini berusaha menjawab apakah generasi baru mengalami pergeseran dalam

Electronic signature for medical documents--integration and evaluation of a public key infrastructure in hospitals.

Science.gov (United States)

Brandner, R; van der Haak, M; Hartmann, M; Haux, R; Schmücker, P

2002-01-01

Our objectives were to determine the user-oriented and legal requirements for a Public Key Infrastructure (PKI) for electronic signatures for medical documents, and to translate these requirements into a general model for a signature system. A prototype of this model was then implemented and evaluated in clinical routine use. Analyses of documents, processes, interviews, observations, and of the available literature supplied the foundations for the development of the signature system model. Eight participants of the Department of Dermatology of the Heidelberg University Medical Center evaluated the implemented prototype from December 2000 to January 2001, during the course of an intervention study. By means of questionnaires, interviews, observations and database analyses, the usefulness and user acceptance of the electronic signature and its integration into electronic discharge letters were established. Since the major part of medical documents generated in a hospital are signature-relevant, they will require electronic signatures in the future. A PKI must meet the multitude of responsibilities and security needs required in a hospital. Also, the signature functionality must be integrated directly into the workflow surrounding document creation. A developed signature model, fulfilling user-oriented and legal requirements, was implemented using hard and software components that conform to the German Signature Law. It was integrated into the existing hospital information system of the Heidelberg University Medical Center. At the end of the intervention study, the average acceptance scores achieved were mean = 3.90; SD = 0.42 on a scale of 1 (very negative attitude) to 5 (very positive attitude) for the electronic signature procedure. Acceptance of the integration into computer-supported discharge letter writing reached mean = 3.91; SD = 0.47. On average, the discharge letters were completed 7.18 days earlier. The electronic signature is indispensable for the

Evolution of RAINSTORM

International Nuclear Information System (INIS)

Morgan, K.; Brunhuber, C.

2015-01-01

The IAEA began using remote monitoring in 1997 as a means of optimizing inspection efforts while simultaneously improving the timeliness of safeguards information. Use of remote monitoring has gradually expanded over the last 15+ years. To manage the complexity of this vast network of diverse instruments, in 2012 the IAEA Department of Safeguards initiated an effort to define a set of requirements for Real-time And INtegrated STream-Oriented Remote Monitoring (RAINSTORM). In 2013, 'Remote Monitoring Requirements for the Development of IAEA Safeguards Equipment' was published, which defines the data interface and data security requirements for all new remote-monitoring capable safeguards instruments. The data interface requirements centre on the Hypertext Transfer Protocol (HTTP) [RFC 2616]. HTTP is an extremely simple, yet ubiquitous protocol (used many billions of times per day). HTTP also boasts a feature set that is well-suited to remote monitoring, e.g., range retrieval and on-the-wire compression. Several sample software implementations are available with a BSD 3-Clause Licence. The data security requirements centre on public-key infrastructure (PKI) and the publickey cryptography standards (PKCS). PKI provides far superior encryption/authentication security than pre-shared keys. The Agency has selected a Universal Instrument (cryptography) Token (UIT) that will provide greater private key protection and allow instruments to offload the CPU-intensive private-key operations. An ultralight platform-independent software driver and a sample software implementation are available with a BSD 3-Clause Licence. Currently there are several instruments under development or in field testing that are 'RAINSTORM compliant', including the Remote Monitoring Sealing Array (RMSA from Canberra/SNL), On-Line Enrichment Monitor (OLEM from ORNL/LANL), Laser Mapping for Containment Verification (LMCV from ISPRA) and Next Generation Adam Module (NGAM from Bot

Electronic Voting Protocol Using Identity-Based Cryptography

Directory of Open Access Journals (Sweden)

Gina Gallegos-Garcia

2015-01-01

Full Text Available Electronic voting protocols proposed to date meet their properties based on Public Key Cryptography (PKC, which offers high flexibility through key agreement protocols and authentication mechanisms. However, when PKC is used, it is necessary to implement Certification Authority (CA to provide certificates which bind public keys to entities and enable verification of such public key bindings. Consequently, the components of the protocol increase notably. An alternative is to use Identity-Based Encryption (IBE. With this kind of cryptography, it is possible to have all the benefits offered by PKC, without neither the need of certificates nor all the core components of a Public Key Infrastructure (PKI. Considering the aforementioned, in this paper we propose an electronic voting protocol, which meets the privacy and robustness properties by using bilinear maps.

Certificateless Public Auditing Protocol with Constant Verification Time

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Dongmin Kim

2017-01-01

Full Text Available To provide the integrity of outsourced data in the cloud storage services, many public auditing schemes which allow a user to check the integrity of the outsourced data have been proposed. Since most of the schemes are constructed on Public Key Infrastructure (PKI, they suffer from several concerns like management of certificates. To resolve the problems, certificateless public auditing schemes also have been studied in recent years. In this paper, we propose a certificateless public auditing scheme which has the constant-time verification algorithm. Therefore, our scheme is more efficient than previous certificateless public auditing schemes. To prove the security of our certificateless public auditing scheme, we first define three formal security models and prove the security of our scheme under the three security models.

Distributed Trust Management for Validating SLA Choreographies

Science.gov (United States)

Haq, Irfan Ul; Alnemr, Rehab; Paschke, Adrian; Schikuta, Erich; Boley, Harold; Meinel, Christoph

For business workflow automation in a service-enriched environment such as a grid or a cloud, services scattered across heterogeneous Virtual Organizations (VOs) can be aggregated in a producer-consumer manner, building hierarchical structures of added value. In order to preserve the supply chain, the Service Level Agreements (SLAs) corresponding to the underlying choreography of services should also be incrementally aggregated. This cross-VO hierarchical SLA aggregation requires validation, for which a distributed trust system becomes a prerequisite. Elaborating our previous work on rule-based SLA validation, we propose a hybrid distributed trust model. This new model is based on Public Key Infrastructure (PKI) and reputation-based trust systems. It helps preventing SLA violations by identifying violation-prone services at service selection stage and actively contributes in breach management at the time of penalty enforcement.

Electronic Voting Protocol Using Identity-Based Cryptography.

Science.gov (United States)

Gallegos-Garcia, Gina; Tapia-Recillas, Horacio

2015-01-01

Electronic voting protocols proposed to date meet their properties based on Public Key Cryptography (PKC), which offers high flexibility through key agreement protocols and authentication mechanisms. However, when PKC is used, it is necessary to implement Certification Authority (CA) to provide certificates which bind public keys to entities and enable verification of such public key bindings. Consequently, the components of the protocol increase notably. An alternative is to use Identity-Based Encryption (IBE). With this kind of cryptography, it is possible to have all the benefits offered by PKC, without neither the need of certificates nor all the core components of a Public Key Infrastructure (PKI). Considering the aforementioned, in this paper we propose an electronic voting protocol, which meets the privacy and robustness properties by using bilinear maps.

Designing towards the unknown

DEFF Research Database (Denmark)

Wilde, Danielle; Underwood, Jenny

2018-01-01

the research potential to far-ranging possibilities. In this article we unpack the motivations driving the PKI project. We present our mixed-methodology, which entangles textile crafts, design interactions and materiality to shape an embodied enquiry. Our research outcomes are procedural and methodological......New materials with new capabilities demand new ways of approaching design. Destabilising existing methods is crucial to develop new methods. Yet, radical destabilisation—where outcomes remain unknown long enough that new discoveries become possible—is not easy in technology design where complex......, to design towards unknown outcomes, using unknown materials. The impossibility of this task is proving as useful as it is disruptive. At its most potent, it is destabilising expectations, aesthetics and processes. Keeping the researchers, collaborators and participants in a state of unknowing, is opening...

The strategy for the development of information society in Serbia by 2020: Information security and critical infrastructure

Directory of Open Access Journals (Sweden)

Danijela D. Protić

2012-10-01

Full Text Available The development of technology has changed the world economy and induced new political trends. The European Union (EU and many non-EU member states apply the strategies of information society development that raise the level of information security (IS. The Serbian Government (Government has adopted the Strategy for Information Society in Serbia by 2020 (Strategy, and pointed to the challenges for the development of a modern Serbian information society. This paper presents an overview of the open-ended questions about IS, critical infrastructures and protection of critical infrastructures. Based on publicly available data, some critical national infrastructures are listed. As a possible solution to the problem of IS, the Public Key Infrastructure (PKI-based Information security integrated information system (ISIIS is presented. The ISIIS provides modularity and interoperability of critical infrastructures both in Serbia and neighboring countries.

Šalies ūkio konkurencinio pranašumo didinimo problemos ir galimybės: darbo produktyvumo atvejis

Directory of Open Access Journals (Sweden)

Alma Mačiulytė-Šniukienė

2011-07-01

Full Text Available Straipsnyje atskleista nacionalinio konkurencingumo samprata, nustatyta darbo produktyvumo įtaka „Pasaulio ekonomikos forumo“ skaičiuojamam Pasaulio konkurencingumo indeksui (PKI. Aptarti teoriniai darbo produktyvumo klausimai, nustatyti veiksniai, galintys nulemti darbo produktyvumo pokyčius. Taip pat atlikta Lietuvos darbo produktyvumo pokyčių 2000–2009 m. analizė, nustatytos darbo produktyvumo sumažėjimo 2009 m. priežastys. Ištirta išlaidų moksliniams tyrimams ir technologijų plėtrai (MTTP, darbo užmokesčio, tiesioginių užsienio investicijų, materialaus ir nematerialaus kapitalo įtaka darbo produktyvumui. Prieita prie išvados, kad vienas iš būdų kelti Lietuvos darbo produktyvumą, o drauge ir konkurencingumą – didinti investicijas į MTTP verslo sektorių.Straipsnis lietuvių kalba

Developing Access Control Model of Web OLAP over Trusted and Collaborative Data Warehouses

Science.gov (United States)

Fugkeaw, Somchart; Mitrpanont, Jarernsri L.; Manpanpanich, Piyawit; Juntapremjitt, Sekpon

This paper proposes the design and development of Role- based Access Control (RBAC) model for the Single Sign-On (SSO) Web-OLAP query spanning over multiple data warehouses (DWs). The model is based on PKI Authentication and Privilege Management Infrastructure (PMI); it presents a binding model of RBAC authorization based on dimension privilege specified in attribute certificate (AC) and user identification. Particularly, the way of attribute mapping between DW user authentication and privilege of dimensional access is illustrated. In our approach, we apply the multi-agent system to automate flexible and effective management of user authentication, role delegation as well as system accountability. Finally, the paper culminates in the prototype system A-COLD (Access Control of web-OLAP over multiple DWs) that incorporates the OLAP features and authentication and authorization enforcement in the multi-user and multi-data warehouse environment.

Study on Strengthening Plan of Safety Network CCTV Monitoring by Steganography and User Authentication

Directory of Open Access Journals (Sweden)

Jung-oh Park

2015-01-01

Full Text Available Recently, as the utilization of CCTV (closed circuit television is emerging as an issue, the studies on CCTV are receiving much attention. Accordingly, due to the development of CCTV, CCTV has IP addresses and is connected to network; it is exposed to many threats on the existing web environment. In this paper, steganography is utilized to confirm the Data Masquerading and Data Modification and, in addition, to strengthen the security; the user information is protected based on PKI (public key infrastructure, SN (serial number, and R value (random number attributed at the time of login and the user authentication protocol to block nonauthorized access of malicious user in network CCTV environment was proposed. This paper should be appropriate for utilization of user infringement-related CCTV where user information protection-related technology is not applied for CCTV in the future.

A dual-specificity isoform of the protein kinase inhibitor PKI produced by alternate gene splicing.

Science.gov (United States)

Kumar, Priyadarsini; Walsh, Donal A

2002-03-15

We have previously shown that the protein kinase inhibitor beta (PKIbeta) form of the cAMP-dependent protein kinase inhibitor exists in multiple isoforms, some of which are specific inhibitors of the cAMP-dependent protein kinase, whereas others also inhibit the cGMP-dependent enzyme [Kumar, Van Patten and Walsh (1997), J. Biol. Chem. 272, 20011-20020]. We have now demonstrated that the switch from a cAMP-dependent protein kinase (PKA)-specific inhibitor to one with dual specificity arises as a consequence of alternate gene splicing. We have confirmed using bacterially produced pure protein that a single inhibitor species has dual specificity for both PKA and cGMP-dependent protein kinase (PKG), inhibiting each with very high and closely similar inhibitory potencies. The gene splicing converted a protein with 70 amino acids into one of 109 amino acids, and did not change the inhibitory potency to PKA, but changed it from a protein that had no detectable PKG inhibitory activity to one that now inhibited PKG in the nanomolar range.

Infraestructura de Clau Pública (PKI) per a la gestió d'historials mèdics

OpenAIRE

Lerch Hostalot, Daniel

2008-01-01

L'objectiu d'aquest projecte, emmarcat en l'àrea de la Seguretat Informàtica, és implementar un esquema criptogràfic, que garanteixi els requisits de seguretat d'un sistema de gestió d'historials mèdics, a través d'una xarxa de comunicacions. El objetivo de este proyecto, enmarcado en el área de la Seguridad Informática, es implementar un esquema criptográfico, que garantice los requisitos de seguridad de un sistema de gestión de historiales médicos, a través de una red de comunicac...

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines

International Nuclear Information System (INIS)

Ooko, Edna; Alsalim, Tahseen; Saeed, Bahjat; Saeed, Mohamed E.M.; Kadioglu, Onat; Abbo, Hanna S.; Titinchi, Salam J.J.; Efferth, Thomas

2016-01-01

Background: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methods: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC 50 values and binding energies. Results: The compounds displayed IC 50 values between 0.7 ± 0.03 and 20.2 ± 0.25 μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from − 9.00 ± 0.10 to − 6.20 ± 0.02 kcal/mol and pKi values from 0.24 ± 0.04 to 29.17 ± 0.88 μM. At the ATP-binding site of P-gp, lowest binding energies ranged from − 9.78 ± 0.17 to − 6.79 ± 0.01 kcal/mol and pKi values from 0.07 ± 0.02 to 0.03 ± 0.03 μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF–CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R = 0.797 and R = 0.794 for training and test sets). Conclusion: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR. - Highlights: • Novel derivatives of curcumin in reversing multidrug

Modulation of P-glycoprotein activity by novel synthetic curcumin derivatives in sensitive and multidrug-resistant T-cell acute lymphoblastic leukemia cell lines

Energy Technology Data Exchange (ETDEWEB)

Ooko, Edna [Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany); Alsalim, Tahseen; Saeed, Bahjat [Department of Chemistry, College of Education for Pure Sciences, University of Basrah, P.O. Box 49 Basrah, Al Basrah (Iraq); Saeed, Mohamed E.M.; Kadioglu, Onat [Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany); Abbo, Hanna S. [Department of Chemistry, University of the Western Cape, P/B X17, Bellville, 7535 Cape Town (South Africa); Titinchi, Salam J.J., E-mail: stitinchi@uwc.ac.za [Department of Chemistry, University of the Western Cape, P/B X17, Bellville, 7535 Cape Town (South Africa); Efferth, Thomas, E-mail: efferth@uni-mainz.de [Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz (Germany)

2016-08-15

Background: Multidrug resistance (MDR) and drug transporter P-glycoprotein (P-gp) represent major obstacles in cancer chemotherapy. We investigated 19 synthetic curcumin derivatives in drug-sensitive acute lymphoblastic CCRF–CEM leukemia cells and their multidrug-resistant P-gp-overexpressing subline, CEM/ADR5000. Material and methods: Cytotoxicity was tested by resazurin assays. Doxorubicin uptake was assessed by flow cytometry. Binding modes of compounds to P-gp were analyzed by molecular docking. Chemical features responsible for bioactivity were studied by quantitative structure activity relationship (QSAR) analyses. A 7-descriptor QSAR model was correlated with doxorubicin uptake values, IC{sub 50} values and binding energies. Results: The compounds displayed IC{sub 50} values between 0.7 ± 0.03 and 20.2 ± 0.25 μM. CEM/ADR5000 cells exhibited cross-resistance to 10 compounds, collateral sensitivity to three compounds and regular sensitivity to the remaining six curcumins. Molecular docking studies at the intra-channel transmembrane domain of human P-gp resulted in lowest binding energies ranging from − 9.00 ± 0.10 to − 6.20 ± 0.02 kcal/mol and pKi values from 0.24 ± 0.04 to 29.17 ± 0.88 μM. At the ATP-binding site of P-gp, lowest binding energies ranged from − 9.78 ± 0.17 to − 6.79 ± 0.01 kcal/mol and pKi values from 0.07 ± 0.02 to 0.03 ± 0.03 μM. CEM/ADR5000 cells accumulated approximately 4-fold less doxorubicin than CCRF–CEM cells. The control P-gp inhibitor, verapamil, partially increased doxorubicin uptake in CEM/ADR5000 cells. Six curcumins increased doxorubicin uptake in resistant cells or even exceeded uptake levels compared to sensitive one. QSAR yielded good activity prediction (R = 0.797 and R = 0.794 for training and test sets). Conclusion: Selected derivatives may serve to guide future design of novel P-gp inhibitors and collateral sensitive drugs to combat MDR. - Highlights: • Novel derivatives of curcumin in reversing

Pharmacological profile of DA-6886, a novel 5-HT4 receptor agonist to accelerate colonic motor activity in mice.

Science.gov (United States)

Lee, Min Jung; Cho, Kang Hun; Park, Hyun Min; Sung, Hyun Jung; Choi, Sunghak; Im, Weonbin

2014-07-15

DA-6886, the gastrointestinal prokinetic benzamide derivative is a novel 5-HT4 receptor agonist being developed for the treatment of constipation-predominant irritable bowel syndrome (IBS-C). The purpose of this study was to characterize in vitro and in vivo pharmacological profile of DA-6886. We used various receptor binding assay, cAMP accumulation assay, organ bath experiment and colonic transit assay in normal and chemically constipated mice. DA-6886 exhibited high affinity and selectivity to human 5-HT4 receptor splice variants, with mean pKi of 7.1, 7.5, 7.9 for the human 5-HT4a, 5-HT4b and 5-HT4d, respectively. By contrast, DA-6886 did not show significant affinity for several receptors including dopamine D2 receptor, other 5-HT receptors except for 5-HT2B receptor (pKi value of 6.2). The affinity for 5-HT4 receptor was translated into functional agonist activity in Cos-7 cells expressing 5-HT4 receptor splice variants. Furthermore, DA-6886 induced relaxation of the rat oesophagus preparation (pEC50 value of 7.4) in a 5-HT4 receptor antagonist-sensitive manner. The evaluation of DA-6886 in CHO cells expressing hERG channels revealed that it inhibited hERG channel current with an pIC50 value of 4.3, indicating that the compound was 1000-fold more selective for the 5-HT4 receptor over hERG channels. In the normal ICR mice, oral administration of DA-6886 (0.4 and 2mg/kg) resulted in marked stimulation of colonic transit. Furthermore, in the loperamide-induced constipation mouse model, 2mg/kg of DA-6886 significantly improved the delay of colonic transit, similar to 10mg/kg of tegaserod. Taken together, DA-6886 is a highly potent and selective 5-HT4 receptor agonist to accelerate colonic transit in mice, which might be therapeutic agent having a favorable safety profile in the treatment of gastrointestinal motor disorders such as IBS-C and chronic constipation. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterisation of the Novel Mixed Mu-NOP Peptide Ligand Dermorphin-N/OFQ (DeNo.

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Mark F Bird

Full Text Available Opioid receptors are currently classified as Mu (μ, Delta (δ, Kappa (κ plus the opioid related nociceptin/orphanin FQ (N/OFQ peptide receptor (NOP. Despite compelling evidence for interactions and benefits of targeting more than one receptor type in producing analgesia, clinical ligands are Mu agonists. In this study we have designed a Mu-NOP agonist named DeNo. The Mu agonist component is provided by dermorphin, a peptide isolated from the skin of Phyllomedusa frogs and the NOP component by the endogenous agonist N/OFQ.We have assessed receptor binding profile of DeNo and compared with dermorphin and N/OFQ. In a series of functional screens we have assessed the ability to (i increase Ca2+ in cells coexpressing recombinant receptors and a the chimeric protein Gαqi5, (ii stimulate the binding of GTPγ[35S], (iii inhibit cAMP formation, (iv activate MAPKinase, (v stimulate receptor-G protein and arrestin interaction using BRET, (vi electrically stimulated guinea pig ileum (gpI assay and (vii ability to produce analgesia via the intrathecal route in rats.DeNo bound to Mu (pKi; 9.55 and NOP (pKi; 10.22 and with reasonable selectivity. This translated to increased Ca2+ in Gαqi5 expressing cells (pEC50 Mu 7.17; NOP 9.69, increased binding of GTPγ[35S] (pEC50 Mu 7.70; NOP 9.50 and receptor-G protein interaction in BRET (pEC50 Mu 8.01; NOP 9.02. cAMP formation was inhibited and arrestin was activated (pEC50 Mu 6.36; NOP 8.19. For MAPK DeNo activated p38 and ERK1/2 at Mu but only ERK1/2 at NOP. In the gpI DeNO inhibited electrically-evoked contractions (pEC50 8.63 that was sensitive to both Mu and NOP antagonists. DeNo was antinociceptive in rats.Collectively these data validate the strategy used to create a novel bivalent Mu-NOP peptide agonist by combining dermorphin (Mu and N/OFQ (NOP. This molecule behaves essentially as the parent compounds in vitro. In the antonocicoeptive assays employed in this study DeNo displays only weak antinociceptive

A survey and taxonomy of distributed certificate authorities in mobile ad hoc networks

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Jabbehdari Sam

2011-01-01

Full Text Available Abstract Certificate authorities (CAs are the main components of PKI that enable us for providing basic security services in wired networks and Internet. But, we cannot use centralized CAs, in mobile ad hoc networks (MANETs. So, many efforts have been made to adapt CA to the special characteristics of MANETs and new concepts such as distributed CAs (DCAs have been proposed that distribute the functionality of CA between MANET nodes. In this article, we study various proposed DCA schemes for MANET and then classify these schemes according to their internal structures and techniques. Finally, we propose the characteristics of an ideal DCA system that can be used to verify the completeness of any DCA scheme. This classification and taxonomy identify the weakness and constraints of each scheme, and are very important for designing more secure, scalable, and high performance DCA systems for MANETs and other networks.

Expecting the Unexpected: Towards Robust Credential Infrastructure

Science.gov (United States)

Xu, Shouhuai; Yung, Moti

Cryptographic credential infrastructures, such as Public key infrastructure (PKI), allow the building of trust relationships in electronic society and electronic commerce. At the center of credential infrastructures is the methodology of digital signatures. However, methods that assure that credentials and signed messages possess trustworthiness and longevity are not well understood, nor are they adequately addressed in both literature and practice. We believe that, as a basic engineering principle, these properties have to be built into the credential infrastructure rather than be treated as an after-thought since they are crucial to the long term success of this notion. In this paper we present a step in the direction of dealing with these issues. Specifically, we present the basic engineering reasoning as well as a model that helps understand (somewhat formally) the trustworthiness and longevity of digital signatures, and then we give basic mechanisms that help improve these notions.

ESnet authentication services and trust federations

Energy Technology Data Exchange (ETDEWEB)

Muruganantham, Dhivakaran; Helm, Mike; Genovese, Tony [ESnet, Energy Sciences Network, 1 Cyclotron Road, MS 50A-3111 Berkeley, California 94720 (United States)

2005-01-01

ESnet provides authentication services and trust federation support for SciDAC projects, collaboratories, and other distributed computing applications. The ESnet ATF team operates the DOEGrids Certificate Authority, available to all DOE Office of Science programs, plus several custom CAs, including one for the National Fusion Collaboratory and one for NERSC. The secure hardware and software environment developed to support CAs is suitable for supporting additional custom authentication and authorization applications that your program might require. Seamless, secure interoperation across organizational and international boundaries is vital to collaborative science. We are fostering the development of international PKI federations by founding the TAGPMA, the American regional PMA, and the worldwide IGTF Policy Management Authority (PMA), as well as participating in European and Asian regional PMAs. We are investigating and prototyping distributed authentication technology that will allow us to support the 'roaming scientist' (distributed wireless via eduroam), as well as more secure authentication methods (one-time password tokens)

ESnet authentication services and trust federations

International Nuclear Information System (INIS)

Muruganantham, Dhivakaran; Helm, Mike; Genovese, Tony

2005-01-01

ESnet provides authentication services and trust federation support for SciDAC projects, collaboratories, and other distributed computing applications. The ESnet ATF team operates the DOEGrids Certificate Authority, available to all DOE Office of Science programs, plus several custom CAs, including one for the National Fusion Collaboratory and one for NERSC. The secure hardware and software environment developed to support CAs is suitable for supporting additional custom authentication and authorization applications that your program might require. Seamless, secure interoperation across organizational and international boundaries is vital to collaborative science. We are fostering the development of international PKI federations by founding the TAGPMA, the American regional PMA, and the worldwide IGTF Policy Management Authority (PMA), as well as participating in European and Asian regional PMAs. We are investigating and prototyping distributed authentication technology that will allow us to support the 'roaming scientist' (distributed wireless via eduroam), as well as more secure authentication methods (one-time password tokens)

FROM CONTROVERSY TO TOLERANCE: Dynamics of the Development of Istiqomah Mosque in Front of a Church in Ungaran Central Java Indonesia

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Muh Saerozi

2017-12-01

Full Text Available This study aims to reveal the dynamic of the development of a mosque in front of a church: the case study of Istiqomah Mosque of Ungaran. The dynamics of the development is seen from some factors that encouraged the establishment of the mosque, the phenomenon of controversy, the problem solution, and the development of tolerance model. The study uses a historical-qualitative approach. The primary data are gathered from interviews, documentation, and observation. The purposes of building the mosque were to balance the national development, to prevent the influence of the Partai Komunis Indonesia (PKI, Indonesian Communist Party, and to create a symbol of tolerance. Controversy occurred in the process of construction because some political and religious elites considered the mosque as political Islam. The controversy waned after the New Order’s elites supported the construction of the mosque. The implementation of a moderate Islamic principles influenced the mosque in building tolerance to the Kristus Raja church in front of it.

Novel chalcone-based fluorescent human histamine H3 receptor ligands as pharmacological tools

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Holger eStark

2012-03-01

Full Text Available Novel fluorescent chalcone-based ligands at human histamine H3 receptors (hH3R have been designed, synthesized and characterized. Compounds described are non-imidazole analogues of ciproxifan with a tetralone motif. Tetralones as chemical precursors and related fluorescent chalcones exhibit affinities at hH3R in the same concentration range like that of the reference antagonist ciproxifan (hH3R pKi value of 7.2. Fluorescence characterization of our novel ligands shows emission maxima about 570 nm for yellow fluorescent chalcones and ≥600 nm for the red fluorescent derivatives. Interferences to cellular autofluorescence could be excluded. All synthesized chalcone compounds could be taken to visualize hH3R proteins in stably transfected HEK-293 cells using confocal laser scanning fluorescence microscopy. These novel fluorescent ligands possess high potential to be used as pharmacological tools for hH3R visualization in different tissues.

A Secure and Robust Object-Based Video Authentication System

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He Dajun

2004-01-01

Full Text Available An object-based video authentication system, which combines watermarking, error correction coding (ECC, and digital signature techniques, is presented for protecting the authenticity between video objects and their associated backgrounds. In this system, a set of angular radial transformation (ART coefficients is selected as the feature to represent the video object and the background, respectively. ECC and cryptographic hashing are applied to those selected coefficients to generate the robust authentication watermark. This content-based, semifragile watermark is then embedded into the objects frame by frame before MPEG4 coding. In watermark embedding and extraction, groups of discrete Fourier transform (DFT coefficients are randomly selected, and their energy relationships are employed to hide and extract the watermark. The experimental results demonstrate that our system is robust to MPEG4 compression, object segmentation errors, and some common object-based video processing such as object translation, rotation, and scaling while securely preventing malicious object modifications. The proposed solution can be further incorporated into public key infrastructure (PKI.

Strong Authentication Protocol based on Java Crypto Chip as a Secure Element

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Majid Mumtaz

2016-10-01

Full Text Available Smart electronic devices and gadgets and their applications are becoming more and more popular. Most of those devices and their applications handle personal, financial, medical and other sensitive data that require security and privacy protection. In this paper we describe one aspect of such protection – user authentication protocol based on the use of X.509 certificates. The system uses Public Key Infrastructure (PKI, challenge/response protocol, mobile proxy servers, and Java cards with crypto capabilities used as a Secure Element. Innovative design of the protocol, its implementation, and evaluation results are described. In addition to end-user authentication, the described solution also supports the use of X.509 certificates for additional security services – confidentiality, integrity, and non-repudiation of transactions and data in an open network environment. The system uses Application Programming Interfaces (APIs to access Java cards functions and credentials that can be used as add-ons to enhance any mobile application with security features and services.

Design of the XML Security System for Electronic Commerce Application

Institute of Scientific and Technical Information of China (English)

无

2003-01-01

The invocation of World Wide Web (www) first triggered mass adoption of the Internet for public access to digital information exchanges across the globe. To get a big market on the Web, a special security infrastructure would need to be put into place transforming the wild-and-woolly Internet into a network with end-to-end protections. XML (extensible Markup Language) is widely accepted as powerful data representation standard for electronic documents, so a security mechanism for XML documents must be provided in the first place to secure electronic commerce over Internet. In this paper the authors design and implement a secure framework that provides XML signature function, XML Element-wise Encryption function, smart card based crypto API library and Public Key Infrastructure (PKI) security functions to achieve confidentiality, integrity, message authentication, and/or signer authentication services for XML documents and existing non-XML documents that are exchanged by Internet for E-commerce application.

The ABCs of LDAP how to install, run, and administer LDAP services

CERN Document Server

Voglmaier, Reinhard E

2004-01-01

Until now, it has been difficult to find the right source of information on LDAP and directory server implementations: books on the subject are overly product-specific, and a search on the Web results in information overload. The ABCs of LDAP: How to Install, Run, and Administer LDAP Services strikes the right balance, providing a synopsis of LDAP fundamentals without getting wrapped up in one particular implementation.This book is for network and systems administrators who want to begin using LDAP more extensively. It delivers the theoretical background needed to understand how these servers work, resulting in clear, concise examples of implementations in both commercial and OpenLDAP environments.The text is structured so that each chapter can stand on its own, with brief descriptions of terms supplemented by references to more detailed explanations in other chapters. You also benefit from a concise overview of how to design a directory, preparing you to execute directory deployments for email, PKI, DNS, NIS...

Anomalous top layer in the inner core beneath the eastern hemisphere

Science.gov (United States)

Yu, W.; Wen, L.; Niu, F.

2003-12-01

Recent studies reported hemispheric variations in seismic velocity and attenuation in the top of the inner core. It, however, remains unclear how the inner core hemisphericity extends deep in the inner core. Here, we analyze PKPbc-PKIKP and PKiKP-PKIKP waveforms collected from the Global Seismographic Network (GSN), regional recordings from the German Regional Seismic Network (GRSN) and Graefenberg (GRF) sampling along the equatorial path (the ray path whose ray angle is larger than 35o from the Earth's rotation axis). The observed global and regional PKPbc-PKIKP differential traveltimes and PKIKP/PKPbc amplitude ratios suggest a simple W2 model (Wen/Niu:2002) in the western hemisphere with a constant velocity gradient of 0.049(km/sec)/100km and a Q value of 600 in the top 400 km of the inner core. In the eastern hemisphere, the data require a change of velocity gradient and Q value at about 235 km below the inner core boundary (ICB). Based on forward modeling, we construct radial velocity and attenuation models in the eastern hemisphere which can explain both the PKiKP-PKIKP and PKPbc-PKIKP observations. The inner core in the eastern hemisphere has a flat velocity gradient extending to about 235 km below the ICB. We test two solutions for the velocity models in the deeper portion of the inner core, with one having a first-order discontinuity at 235 km below the ICB with a velocity jump of 0.07(km/sec) followed by the PREM gradient, and the other having a gradual velocity transition with 0.1(km/sec)/100km gradient extended from 235 km to 375 km below the ICB followed by the PREM gradient. The observed traveltimes exclude the sharp discontinuity velocity model, as it predicts a kink in differential traveltimes at distance of 151o-152o which is not observed in the global and regional datasets. The observed PKIKP/PKPbc amplitude ratios can be best explained by a step function of attenuation with a Q value of 250 at the top 300 km and a Q value of 600 at 300-400 km

The Density Jump at the Inner Core Boundary in the Eastern and Western Hemispheres

Science.gov (United States)

Krasnoshchekov, D. N.; Ovtchinnikov, V. M.

2018-02-01

The results of analysis of more than 1300 new PKiKP/PcP amplitude ratios measured in Southeast Asia and South America at the epicentral distances of 3.2°-35.2° are presented. The density jump in the Eastern Hemisphere of the Earth's inner core (IC) is 0.3 g/cm3, and it is 0.9 g/cm3 in the Western one. Taking the large discrepancy in the obtained estimates into consideration, maintenance of such large lateral variations in the mosaic properties of the IC reflecting surface requires considerable variations in the thermodynamic parameters (mostly temperature) of the inner-outer core transition. However, if the observed asymmetry in the density jump distribution is of a global character, the data presented support the translation model of the IC dynamics. This model implies IC crystallization in the Western Hemisphere and melting in the Eastern one, not vice versa, as suggested by another geodynamic model based on thermochemical convection in the outer core and the thermal balance of the core-mantle system.

Efficient Certification Path Discovery for MANET

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Kambourakis Georgios

2010-01-01

Full Text Available A Mobile Ad Hoc Network (MANET is characterized by the lack of any infrastructure, absence of any kind of centralized administration, frequent mobility of nodes, network partitioning, and wireless connections. These properties make traditional wireline security solutions not straightforwardly applicable in MANETs, and of course, constitute the establishment of a Public Key Infrastructure (PKI in such networks a cumbersome task. After surveying related work, we propose a novel public key management scheme using the well-known web-of-trust or trust graph model. Our scheme is based on a binary tree formation of the network's nodes. The binary tree structure is proved very effective for building certificate chains between communicating nodes that are multihops away and the cumbersome problem of certificate chain discovery is avoided. We compare our scheme with related work and show that it presents several advantages, especially when a fair balancing between security and performance is desirable. Simulations of the proposed scheme under different scenarios demonstrate that it is effective in terms of tree formation, join and leave occurrences, and certificate chain establishment.

Structure-activity relationships studies on weakly basic N-arylsulfonylindoles with an antagonistic profile in the 5-HT6 receptor

Science.gov (United States)

Mella, Jaime; Villegas, Francisco; Morales-Verdejo, César; Lagos, Carlos F.; Recabarren-Gajardo, Gonzalo

2017-07-01

We recently reported a series of 39 weakly basic N-arylsulfonylindoles as novel 5-HT6 antagonists. Eight of the compounds exhibited moderate to high binding affinities, with 2-(4-(2-Methoxyphenyl)piperazin-1-yl)-1-(1-tosyl-1H-indol-3-yl)ethanol 16 showing the highest binding affinity (pKi = 7.87). Given these encouraging results and as a continuation of our research, we performed an extensive step-by-step search for the best 3D-QSAR model that allows us to rationally propose novel molecules with improved 5-HT6 affinity based on our previously reported series. A comparative molecular similarity indices analysis (CoMSIA) model built on a docking-based alignment was developed, wherein steric, electrostatic, hydrophobic and hydrogen bond properties are correlated with biological activity. The model was validated internally and externally (q2 = 0.721; r2pred = 0.938), and identified the sulfonyl and hydroxyl groups and the piperazine ring among the main regions of the molecules that can be modified to create new 5-HT6 antagonists.

The Role of Digital Certificates in EGoverning. The Case of the Romanian Regulation and Surveillance Authority

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Andra Marin

2012-08-01

Full Text Available The implementation of electronic governance related projects implies user authentication,accounts activation and personal data verification. Certain public services, particularly thoseinvolving financial transactions or statements, require a high security level. The use of the PKI technology and, consequently, of digital signatures, constitutes the most viable solution, meeting the required security standards, protecting, on the one hand, the signatory’s identity, and, on the other hand, the integrity of the transmitted message. Due to the use of the digital certificate, the development of online public services is now possible, especially since it meets the requirements of security standards, but also because it is highly trusted by users. This article intends to analyze the impact of the digital certificate on the improvement of communication between state authorities, including specific transactional relations, and also to consider its influence on security improvement of dataflow. The study demonstrates that the digital certificate is closely connected to the information society, directly determining the dynamics of the development of new applications that provide a better interface between the state and its citizens.

Pharmacological evaluation of halogenated and non-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles as D(2) and 5-HT(2A) receptor ligands.

Science.gov (United States)

Tomić, Mirko; Vasković, Djurdjica; Tovilović, Gordana; Andrić, Deana; Penjišević, Jelena; Kostić-Rajačić, Sladjana

2011-05-01

Five groups of previously synthesized and initially screened non-substituted and 4-halogenated arylpiperazin-1-yl-ethyl-benzimidazoles were estimated for their in-vitro binding affinities at the rat D(2) , 5-HT(2A) , and α(1) -adrenergic receptors. Among all these compounds, 2-methoxyphenyl and 2-chlorophenyl piperazines demonstrate the highest affinities for the tested receptors. The effects of 4-halogenation of benzimidazoles reveal that substitution with bromine may greatly increase the affinity of the compounds for the studied receptors, while the effect of substitution with chlorine is less remarkable. Most of the tested components show 5-HT(2A)/D(2) pK(i) binding ratios slightly above or less than 1, while only 4-chloro-6-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-1H-benzimidazole expresses an appropriate higher binding ratio (1.14), which was indicated for atypical neuroleptics. This compound exhibits a non-cataleptic action in rats and prevents d-amphetamine-induced hyperlocomotion in mice, which suggest its atypical antipsychotic potency. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents.

Science.gov (United States)

Brocco, Mauricette; Dekeyne, Anne; Mannoury la Cour, Clotilde; Touzard, Manuelle; Girardon, Sylvie; Veiga, Sylvie; de Nanteuil, Guillaume; deJong, Trynke R; Olivier, Berend; Millan, Mark J

2008-10-01

This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.

PENGARUH KONFIGURASI POLITIK PEMERINTAH TERHADAP PRODUK HUKUM

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Solikhul Hadi

2015-11-01

Full Text Available Konfigurasi politik tertentu akan menghasilkan karakter produk hukum tertentu. Pada periode 1945-1959, konfigurasi politik yang ditunjukkan di era ini adalah konfigurasi politik demokratis. Kehidupan politik ditandai sebagai demokrasi liberal. Konfigurasi ini muncul bahwa politik memainkan peran yang sangat dominan dalam proses perumusan kebijakan melalui negara hukum (parlemen. Dalam era demokrasi terpimpin (1959-1966, konfigurasi politik yang ditampilkan adalah konfigurasi otoriter. Partai politik, kecuali Partai Komunis Indonesia (PKI, tidak memiliki peran politik yang signifikan dalam periode ini. Secara umum, produk hukum yang dihasilkan di era ini adalah hukum konservatif. Pada periode 1966 - 1993, awal Orde Baru adalah demokrasi. Namun, Orde Baru ini akhirnya membentuk konfigurasi otoriter. Eksekutif sangat dominan, press atau media dikontrol, legislatif ditandai sebagai lembaga yang lemah karena telah ditanamkan di tangan eksekutif melalui Golongan Karya (Golkar dan Angkatan Bersenjata Republik Indonesia (ABRI. Dengan demikian, produk hukum yang dihasilkan adalah karakter konservatif. Di era reformasi, hukum yang langsung diubah, terutama hukum publik yang berkaitan dengan distribusi kekuasaan (hukum konstitusi. Berbagai undang-undang produk politik Orde Baru langsung diubah dengan membongkar pada asumsi-asumsi serta hilangnya kekerasan politik. Kata Kunci: Konfigurasi, Politik, Produk, Hukum. THE INFLUENCE OF GOVERNMENTS POLITICAL CONFIGURATION TO THE PRODUCT OF LAW. Certain political configuration will produce the character of certain law products. In the period 1945-1959, the political configuration shown in this era was a democratic political configuration. Political life was characterized as a liberal democracy. This configuration appeared that parties played a very dominant role in the process of policy formulation through the constitutional state (parliament. In the era of guided democracy (1959- 1966, the political configuration

Distributed generation of shared RSA keys in mobile ad hoc networks

Science.gov (United States)

Liu, Yi-Liang; Huang, Qin; Shen, Ying

2005-12-01

Mobile Ad Hoc Networks is a totally new concept in which mobile nodes are able to communicate together over wireless links in an independent manner, independent of fixed physical infrastructure and centralized administrative infrastructure. However, the nature of Ad Hoc Networks makes them very vulnerable to security threats. Generation and distribution of shared keys for CA (Certification Authority) is challenging for security solution based on distributed PKI(Public-Key Infrastructure)/CA. The solutions that have been proposed in the literature and some related issues are discussed in this paper. The solution of a distributed generation of shared threshold RSA keys for CA is proposed in the present paper. During the process of creating an RSA private key share, every CA node only has its own private security. Distributed arithmetic is used to create the CA's private share locally, and that the requirement of centralized management institution is eliminated. Based on fully considering the Mobile Ad Hoc network's characteristic of self-organization, it avoids the security hidden trouble that comes by holding an all private security share of CA, with which the security and robustness of system is enhanced.

A semi-automatic calibration method for seismic arrays applied to an Alaskan array

Science.gov (United States)

Lindquist, K. G.; Tibuleac, I. M.; Hansen, R. A.

2001-12-01

Well-calibrated, small (less than 22 km) aperture seismic arrays are of great importance for event location and characterization. We have implemented the crosscorrelation method of Tibuleac and Herrin (Seis. Res. Lett. 1997) as a semi-automatic procedure, applicable to any seismic array. With this we are able to process thousands of phases with several days of computer time on a Sun Blade 1000 workstation. Complicated geology beneath elements and elevation differences amonst the array stations made station corrections necessary. 328 core phases (including PcP, PKiKP, PKP, PKKP) were used in order to determine the static corrections. To demonstrate this application and method, we have analyzed P and PcP arrivals at the ILAR array (Eielson, Alaska) between years 1995-2000. The arrivals were picked by PIDC, for events (mb>4.0) well located by the USGS. We calculated backazimuth and horizontal velocity residuals for all events. We observed large backazimuth residuals for regional and near-regional phases. We are discussing the possibility of a dipping Moho (strike E-W, dip N) beneath the array versus other local structure that would produce the residuals.

DI BAWAH TEKANAN KAPITALISME PERKEBUNAN: PERTUMBUHAN DAN RADIKALISASI SAREKAT RA’JAT TEGAL 1923-1926

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Wijanarto Wijanarto

2016-12-01

Full Text Available This article examines on the radicalization growth of Sarekat Ra’jat (SR in several factors as its key influence. The one factor interrelated on radicalization was the existence of sugar industry in Tegal. It views on linkages between the sugar industry with the development of SR and its influence indicators of radicalization. This condition was part of the communist partij’s expansion. The development of SR shows suprisingly number of members. SR Tegal reached 5327 peoples as their members. The total membership evenly came from all areas, especially close to the sugar industry in Pangkah, Pagongan, Kemanglen, Adiwerna and Balapoelang. It was the main reason to make the Dutch government to striccht oversight the administrative and appled legal sanctions. The SR resistance was took-placed at Karangcegak in 1926, effected the undiscipline and sporadic resistance of the members. It made the Dutch government easy to suppress and acted tough. The trial rebellion conducted by SR in Karangcecek, but it was failed. However it was not effect the eagerness to re-against  PKI in November 1926. The revolutionary in Tegal option was chosed as result.

BECSI: Bandwidth Efficient Certificate Status Information Distribution Mechanism for VANETs

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Carlos Gañán

2013-01-01

Full Text Available Certificate revocation is a challenging task, especiallyin mobile network environments such as vehicular ad Hoc networks (VANETs.According to the IEEE 1609.2 security standard for VANETs, public keyinfrastructure (PKI will provide this functionality by means of certificate revocation lists (CRLs.When a certificate authority (CAneeds to revoke a certificate, itglobally distributes CRLs.Transmitting these lists pose a problem as they require high update frequencies and a lot of bandwidth. In this article, we propose BECSI, aBandwidth Efficient Certificate Status Informationmechanism to efficiently distributecertificate status information (CSI in VANETs.By means of Merkle hash trees (MHT, BECSI allowsto retrieve authenticated CSI not onlyfrom the infrastructure but also from vehicles actingas mobile repositories.Since these MHTs are significantly smaller than the CRLs, BECSIreduces the load on the CSI repositories and improves the response time for the vehicles.Additionally, BECSI improves the freshness of the CSIby combining the use of delta-CRLs with MHTs.Thus, vehicles that have cached the most current CRLcan download delta-CRLs to have a complete list of revoked certificates.Once a vehicle has the whole list of revoked certificates, it can act as mobile repository.

Chemical mechanism of D-amino acid oxidase from Rhodotorula gracilis: pH dependence of kinetic parameters.

Science.gov (United States)

Ramón, F; Castillón, M; De La Mata, I; Acebal, C

1998-01-01

The variation of kinetic parameters of d-amino acid oxidase from Rhodotorula gracilis with pH was used to gain information about the chemical mechanism of the oxidation of D-amino acids catalysed by this flavoenzyme. d-Alanine was the substrate used. The pH dependence of Vmax and Vmax/Km for alanine as substrate showed that a group with a pK value of 6.26-7.95 (pK1) must be unprotonated and a group with a pK of 10.8-9.90 (pK2) must be protonated for activity. The lower pK value corresponded to a group on the enzyme involved in catalysis and whose protonation state was not important for binding. The higher pK value was assumed to be the amino group of the substrate. Profiles of pKi for D-aspartate as competitive inhibitor showed that binding is prevented when a group on the enzyme with a pK value of 8.4 becomes unprotonated; this basic group was not detected in Vmax/Km profiles suggesting its involvement in binding of the beta-carboxylic group of the inhibitor. PMID:9461524

A Survey on HTTPS Implementation by Android Apps: Issues and Countermeasures

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Xuetao Wei

2017-07-01

Full Text Available As more and more sensitive data is transferred from mobile applications across unsecured channels, it seems imperative that transport layer encryption should be used in any non-trivial instance. Yet, research indicates that many Android developers do not use HTTPS or violate rules which protect user data from man-in-the-middle attacks. This paper seeks to find a root cause of the disparities between theoretical HTTPS usage and in-the-wild implementation of the protocol by looking into Android applications, online resources, and papers published by HTTPS and Android security researchers. From these resources, we extract a set of barrier categories that exist in the path of proper TLS use. These barriers not only include improper developer practices, but also server misconfiguration, lacking documentation, flaws in libraries, the fundamentally complex TLS PKI system, and a lack of consumer understanding of the importance of HTTPS. Following this discussion, we compile a set of potential solutions and patches to better secure Android HTTPS and the TLS/SSL protocol in general. We conclude our survey with gaps in current understanding of the environment and suggestions for further research.

A comprehensive Software Copy Protection and Digital Rights Management platform

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Ayman Mohammad Bahaa-Eldin

2014-09-01

Full Text Available This article proposes a Powerful and Flexible System for Software Copy Protection (SCP and Digital Rights Management (DRM based on Public Key Infrastructure (PKI standards. Software protection is achieved through a multi-phase methodology with both static and dynamic processing of the executable file. The system defeats most of the attacks and cracking techniques and makes sure that the protected software is never in a flat form, with a suitable portion of it always being encrypted during execution. A novel performance-tuning algorithm is proposed to lower the overhead of the protection process to its minimum depending on the software dynamic execution behavior. All system calls to access resources and objects such as files, and input/output devices are intercepted and encapsulated with secure rights management code to enforce the required license model. The system can be integrated with hardware authentication techniques (like dongles, and to Internet based activation and DRM servers over the cloud. The system is flexible to apply any model of licensing including state-based license such as expiration dates and number of trials. The usage of a standard markup language (XrML to describe the license makes it easier to apply new licensing operations like re-sale and content rental.

Pemerintahan Provinsi Lampung 1945-1964

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Arizka Waranegara

2014-06-01

Full Text Available This is a library research about political elite contestation in Lampung from 1945 until 1964, at that time there are three major ideology, first is Islam, second is Nationalism and third is Communism. In the old orde era, the elite politics competition in the national level describe the same thing with the local level. If in the national level there are three major ideology, in Lampung also three ideology had played important role, the Party Communist (PKI, Indonesian Nationalsit Party (PNI and Masyumi (Islamic Faction. In the first political stage after Independence of Indonesia. In 1964, there was a first Lampung’s Governor Election, at that time R.A Zulkifli Warganegara had appointed to be Lampung first Governor, but because of the political intervention his position was replaced by Koesno Danopoyo which was fully supported by Communist Party. This is a decsriptive qualitative research, the main data comes from indepth interview and documentation. The results shown that there is basic difference between Lampung’s political elite contestation in the old orde era and reformation era. In the old orde era the competition based on ideology but in the reformation era the competition based on purely political interest.Keywords: contestation, political elite and election

Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1.

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Ronald A Merrill

2011-04-01

Full Text Available Mitochondrial shape is determined by fission and fusion reactions catalyzed by large GTPases of the dynamin family, mutation of which can cause neurological dysfunction. While fission-inducing protein phosphatases have been identified, the identity of opposing kinase signaling complexes has remained elusive. We report here that in both neurons and non-neuronal cells, cAMP elevation and expression of an outer-mitochondrial membrane (OMM targeted form of the protein kinase A (PKA catalytic subunit reshapes mitochondria into an interconnected network. Conversely, OMM-targeting of the PKA inhibitor PKI promotes mitochondrial fragmentation upstream of neuronal death. RNAi and overexpression approaches identify mitochondria-localized A kinase anchoring protein 1 (AKAP1 as a neuroprotective and mitochondria-stabilizing factor in vitro and in vivo. According to epistasis studies with phosphorylation site-mutant dynamin-related protein 1 (Drp1, inhibition of the mitochondrial fission enzyme through a conserved PKA site is the principal mechanism by which cAMP and PKA/AKAP1 promote both mitochondrial elongation and neuronal survival. Phenocopied by a mutation that slows GTP hydrolysis, Drp1 phosphorylation inhibits the disassembly step of its catalytic cycle, accumulating large, slowly recycling Drp1 oligomers at the OMM. Unopposed fusion then promotes formation of a mitochondrial reticulum, which protects neurons from diverse insults.

In vivo evaluation of [123I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide: a potential sigma receptor ligand for SPECT studies

International Nuclear Information System (INIS)

Staelens, Ludovicus; Oltenfreiter, Ruth; Dumont, Filip; Waterhouse, Rikki N.; Vandenbulcke, Katia; Blanckaert, Peter; Dierckx, Rudi A.; Slegers, Guido

2005-01-01

In this study, in vivo evaluation in mice and rabbits of [ 123 I]-4-iodo-N-(4-(4-(2-methoxyphenyl)-piperazin-1-yl)butyl)-benzamide ([ 123 I]-BPB), a potential radioligand for visualisation of the sigma receptor by single photon emission computed tomography (SPECT), is reported. The compound possesses appropriate lipophilicity (log P=2.2) and binds sigma-1 and sigma-2 receptors (pKi=6.51 and 6.79, respectively). In mice, this new radioiodinated tracer exhibited high brain uptake (4.99% ID/g tissue at 10 min postinjection) and saturable binding (3.06% ID/g tissue at 10 min postinjection) as determined by pretreatment with unlabeled [ 123 I]-BPB. A metabolite study demonstrated no (less than 5%) labeled metabolites in the brain. In rabbits, regional brain distribution was investigated and the tracer displayed high, homogeneous central nervous system uptake. Selectivity was assessed by competition experiments with known sigma ligands. Metabolite analysis showed no (less than 8%) labeled metabolites in the rabbit brain. In conclusion, our findings indicate that [ 123 I]-BPB is not a suitable tracer for visualisation of D 3 receptors while its potential for sigma receptor imaging is severely hampered by its affinity for dopamine receptors

Aqueous Molecular Dynamics Simulations of the M. tuberculosis Enoyl-ACP Reductase-NADH System and Its Complex with a Substrate Mimic or Diphenyl Ethers Inhibitors

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Camilo Henrique da Silva Lima

2015-10-01

Full Text Available Molecular dynamics (MD simulations of 12 aqueous systems of the NADH-dependent enoyl-ACP reductase from Mycobacterium tuberculosis (InhA were carried out for up to 20–40 ns using the GROMACS 4.5 package. Simulations of the holoenzyme, holoenzyme-substrate, and 10 holoenzyme-inhibitor complexes were conducted in order to gain more insight about the secondary structure motifs of the InhA substrate-binding pocket. We monitored the lifetime of the main intermolecular interactions: hydrogen bonds and hydrophobic contacts. Our MD simulations demonstrate the importance of evaluating the conformational changes that occur close to the active site of the enzyme-cofactor complex before and after binding of the ligand and the influence of the water molecules. Moreover, the protein-inhibitor total steric (ELJ and electrostatic (EC interaction energies, related to Gly96 and Tyr158, are able to explain 80% of the biological response variance according to the best linear equation, pKi = 7.772 − 0.1885 × Gly96 + 0.0517 × Tyr158 (R2 = 0.80; n = 10, where interactions with Gly96, mainly electrostatic, increase the biological response, while those with Tyr158 decrease. These results will help to understand the structure-activity relationships and to design new and more potent anti-TB drugs.

Complex Conjugated certificateless-based signcryption with differential integrated factor for secured message communication in mobile network.

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Sumithra Alagarsamy

Full Text Available Certificateless-based signcryption overcomes inherent shortcomings in traditional Public Key Infrastructure (PKI and Key Escrow problem. It imparts efficient methods to design PKIs with public verifiability and cipher text authenticity with minimum dependency. As a classic primitive in public key cryptography, signcryption performs validity of cipher text without decryption by combining authentication, confidentiality, public verifiability and cipher text authenticity much more efficiently than the traditional approach. In this paper, we first define a security model for certificateless-based signcryption called, Complex Conjugate Differential Integrated Factor (CC-DIF scheme by introducing complex conjugates through introduction of the security parameter and improving secured message distribution rate. However, both partial private key and secret value changes with respect to time. To overcome this weakness, a new certificateless-based signcryption scheme is proposed by setting the private key through Differential (Diff Equation using an Integration Factor (DiffEIF, minimizing computational cost and communication overhead. The scheme is therefore said to be proven secure (i.e. improving the secured message distributing rate against certificateless access control and signcryption-based scheme. In addition, compared with the three other existing schemes, the CC-DIF scheme has the least computational cost and communication overhead for secured message communication in mobile network.

Complex Conjugated certificateless-based signcryption with differential integrated factor for secured message communication in mobile network.

Science.gov (United States)

Alagarsamy, Sumithra; Rajagopalan, S P

2017-01-01

Certificateless-based signcryption overcomes inherent shortcomings in traditional Public Key Infrastructure (PKI) and Key Escrow problem. It imparts efficient methods to design PKIs with public verifiability and cipher text authenticity with minimum dependency. As a classic primitive in public key cryptography, signcryption performs validity of cipher text without decryption by combining authentication, confidentiality, public verifiability and cipher text authenticity much more efficiently than the traditional approach. In this paper, we first define a security model for certificateless-based signcryption called, Complex Conjugate Differential Integrated Factor (CC-DIF) scheme by introducing complex conjugates through introduction of the security parameter and improving secured message distribution rate. However, both partial private key and secret value changes with respect to time. To overcome this weakness, a new certificateless-based signcryption scheme is proposed by setting the private key through Differential (Diff) Equation using an Integration Factor (DiffEIF), minimizing computational cost and communication overhead. The scheme is therefore said to be proven secure (i.e. improving the secured message distributing rate) against certificateless access control and signcryption-based scheme. In addition, compared with the three other existing schemes, the CC-DIF scheme has the least computational cost and communication overhead for secured message communication in mobile network.

Encriptación en la comunicación de información electrónica. Una propuesta didáctica

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Sánchez García, Juan Francisco

2004-01-01

Full Text Available Cada vez es mayor la cantidad de información que circula por la Red, de ahí la creciente necesidad de contar con mecanismos que proporcionen seguridad en las transmisiones, fundamentalmente las que involucran transacciones económicas, comunicaciones que es preciso proteger para garantizar la integridad e inviolabilidad de su confidencialidad; para ello se recurre al encriptado de mensajes y al uso de funciones HASH y claves asimétricas (PKI, estas últimas basadas en complejos algoritmos matemáticos (como el RSA. Aunque existe software específico para ello, nuestra propuesta va encaminada a la realización de un programa informático al efecto, elaborado con una herramienta versátil y asequible como es la hoja de cálculo, que con una finalidad fundamentalmente didáctica, permita visualizar la acción sobre un mensaje dado, de una encriptación, de las funciones HASH, así como de la generación y utilización, de las dobles claves pública y privada del emisor y el receptor, permitiendo de esta forma una mejor comprensión de la metodología y del funcionamiento real de estos sistemas

An Internet of Things Based Multi-Level Privacy-Preserving Access Control for Smart Living

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Usama Salama

2018-05-01

Full Text Available The presence of the Internet of Things (IoT in healthcare through the use of mobile medical applications and wearable devices allows patients to capture their healthcare data and enables healthcare professionals to be up-to-date with a patient’s status. Ambient Assisted Living (AAL, which is considered as one of the major applications of IoT, is a home environment augmented with embedded ambient sensors to help improve an individual’s quality of life. This domain faces major challenges in providing safety and security when accessing sensitive health data. This paper presents an access control framework for AAL which considers multi-level access and privacy preservation. We focus on two major points: (1 how to use the data collected from ambient sensors and biometric sensors to perform the high-level task of activity recognition; and (2 how to secure the collected private healthcare data via effective access control. We achieve multi-level access control by extending Public Key Infrastructure (PKI for secure authentication and utilizing Attribute-Based Access Control (ABAC for authorization. The proposed access control system regulates access to healthcare data by defining policy attributes over healthcare professional groups and data classes classifications. We provide guidelines to classify the data classes and healthcare professional groups and describe security policies to control access to the data classes.

Gate crashing arbuscular mycorrhizas: in vivo imaging shows the extensive colonization of both symbionts by Trichoderma atroviride.

Science.gov (United States)

Lace, Beatrice; Genre, Andrea; Woo, Sheridan; Faccio, Antonella; Lorito, Matteo; Bonfante, Paola

2015-02-01

Plant growth-promoting fungi include strains of Trichoderma species that are used in biocontrol, and arbuscular mycorrhizal (AM) fungi, that enhance plant nutrition and stress resistance. The concurrent interaction of plants with these two groups of fungi affects crop performance but has only been occasionally studied so far. Using in vivo imaging of green fluorescent protein-tagged lines, we investigated the cellular interactions occurring between Trichoderma atroviride PKI1, Medicago truncatula and two Gigaspora species under in vitro culture conditions. Trichoderma atroviride did not activate symbiotic-like responses in the plant cells, such as nuclear calcium spiking or cytoplasmic aggregations at hyphal contact sites. Furthermore, T. atroviride parasitized G. gigantea and G. margarita hyphae through localized wall breaking and degradation - although this was not associated with significant chitin lysis nor the upregulation of two major chitinase genes. Trichoderma atroviride colonized broad areas of the root epidermis, in association with localized cell death. The infection of both symbionts was also observed when T. atroviride was applied to a pre-established AM symbiosis. We conclude that - although this triple interaction is known to improve plant growth in agricultural environments - in vitro culture demonstrate a particularly aggressive mycoparasitic and plant-colonizing behaviour of a biocontrol strain of Trichoderma. © 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.

Impact of kinase activating and inactivating patient mutations on binary PKA interactions.

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Röck, Ruth; Mayrhofer, Johanna E; Bachmann, Verena; Stefan, Eduard

2015-01-01

The second messenger molecule cAMP links extracellular signals to intracellular responses. The main cellular cAMP effector is the compartmentalized protein kinase A (PKA). Upon receptor initiated cAMP-mobilization, PKA regulatory subunits (R) bind cAMP thereby triggering dissociation and activation of bound PKA catalytic subunits (PKAc). Mutations in PKAc or RIa subunits manipulate PKA dynamics and activities which contribute to specific disease patterns. Mutations activating cAMP/PKA signaling contribute to carcinogenesis or hormone excess, while inactivating mutations cause hormone deficiency or resistance. Here we extended the application spectrum of a Protein-fragment Complementation Assay based on the Renilla Luciferase to determine binary protein:protein interactions (PPIs) of the PKA network. We compared time- and dose-dependent influences of cAMP-elevation on mutually exclusive PPIs of PKAc with the phosphotransferase inhibiting RIIb and RIa subunits and the protein kinase inhibitor peptide (PKI). We analyzed PKA dynamics following integration of patient mutations into PKAc and RIa. We observed that oncogenic modifications of PKAc(L206R) and RIa(Δ184-236) as well as rare disease mutations in RIa(R368X) affect complex formation of PKA and its responsiveness to cAMP elevation. With the cell-based PKA PPI reporter platform we precisely quantified the mechanistic details how inhibitory PKA interactions and defined patient mutations contribute to PKA functions.

The relation between xyr1 overexpression in Trichoderma harzianum and sugarcane bagasse saccharification performance.

Science.gov (United States)

da Silva Delabona, Priscila; Rodrigues, Gisele Nunes; Zubieta, Mariane Paludetti; Ramoni, Jonas; Codima, Carla Aloia; Lima, Deise Juliana; Farinas, Cristiane Sanchez; da Cruz Pradella, José Geraldo; Seiboth, Bernhard

2017-03-20

This work investigates the influence of the positive regulator XYR1 of Trichoderma harzianum on the production of cellulolytic enzymes, using sugarcane bagasse as carbon source. Constitutive expression of xyr1 was achieved under the control of the strong Trichoderma reesei pki1 promoter. Five clones with xyr1 overexpression achieved higher xyr1 expression and greater enzymatic productivity when cultivated under submerged fermentation, hence validating the genetic construction for T. harzianum. Clone 5 presented a relative expression of xyr1 26-fold higher than the parent strain and exhibited 66, 37, and 36% higher values for filter paper activity, xylanase activity, and β-glucosidase activity, respectively, during cultivation in a stirred-tank bioreactor. The overexpression of xyr1 in T. harzianum resulted in an enzymatic complex with significantly improved performance in sugarcane bagasse saccharification, with an enhancement of 25% in the first 24h. Our results also show that constitutive overexpression of xyr1 leads to the induction of several important players in biomass degradation at early (24h) and also late (48h) timepoints of inoculation. However, we also observed that the carbon catabolite repressor CRE1 was upregulated in xyr1 overexpression mutants. These findings demonstrate the feasibility of improving cellulase production by modifying regulator expression and suggest an attractive approach for increasing total cellulase productivity in T. harzianum. Copyright © 2017 Elsevier B.V. All rights reserved.

The Interplay between Cyclic AMP, MAPK, and NF-κB Pathways in Response to Proinflammatory Signals in Microglia

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Mousumi Ghosh

2015-01-01

Full Text Available Cyclic AMP is an important intracellular regulator of microglial cell homeostasis and its negative perturbation through proinflammatory signaling results in microglial cell activation. Though cytokines, TNF-α and IL-1β, decrease intracellular cyclic AMP, the mechanism by which this occurs is poorly understood. The current study examined which signaling pathways are responsible for decreasing cyclic AMP in microglia following TNF-α stimulation and sought to identify the role cyclic AMP plays in regulating these pathways. In EOC2 microglia, TNF-α produced a dramatic reduction in cyclic AMP and increased cyclic AMP-dependent PDE activity that could be antagonized by Rolipram, myristoylated-PKI, PD98059, or JSH-23, implicating a role for PDE4, PKA, MEK, and NF-κB in this regulation. Following TNF-α there were significant increases in iNOS and COX-2 immunoreactivity, phosphorylated ERK1/2 and NF-κB-p65, IκB degradation, and NF-κB p65 nuclear translocation, which were reduced in the presence of high levels of cyclic AMP, indicating that reductions in cyclic AMP during cytokine stimulation are important for removing its inhibitory action on NF-κB activation and subsequent proinflammatory gene expression. Further elucidation of the signaling crosstalk involved in decreasing cyclic AMP in response to inflammatory signals may provide novel therapeutic targets for modulating microglial cell activation during neurological injury and disease.

Network computing infrastructure to share tools and data in global nuclear energy partnership

International Nuclear Information System (INIS)

Kim, Guehee; Suzuki, Yoshio; Teshima, Naoya

2010-01-01

CCSE/JAEA (Center for Computational Science and e-Systems/Japan Atomic Energy Agency) integrated a prototype system of a network computing infrastructure for sharing tools and data to support the U.S. and Japan collaboration in GNEP (Global Nuclear Energy Partnership). We focused on three technical issues to apply our information process infrastructure, which are accessibility, security, and usability. In designing the prototype system, we integrated and improved both network and Web technologies. For the accessibility issue, we adopted SSL-VPN (Security Socket Layer - Virtual Private Network) technology for the access beyond firewalls. For the security issue, we developed an authentication gateway based on the PKI (Public Key Infrastructure) authentication mechanism to strengthen the security. Also, we set fine access control policy to shared tools and data and used shared key based encryption method to protect tools and data against leakage to third parties. For the usability issue, we chose Web browsers as user interface and developed Web application to provide functions to support sharing tools and data. By using WebDAV (Web-based Distributed Authoring and Versioning) function, users can manipulate shared tools and data through the Windows-like folder environment. We implemented the prototype system in Grid infrastructure for atomic energy research: AEGIS (Atomic Energy Grid Infrastructure) developed by CCSE/JAEA. The prototype system was applied for the trial use in the first period of GNEP. (author)

Simple group password-based authenticated key agreements for the integrated EPR information system.

Science.gov (United States)

Lee, Tian-Fu; Chang, I-Pin; Wang, Ching-Cheng

2013-04-01

The security and privacy are important issues for electronic patient records (EPRs). The goal of EPRs is sharing the patients' medical histories such as the diagnosis records, reports and diagnosis image files among hospitals by the Internet. So the security issue for the integrated EPR information system is essential. That is, to ensure the information during transmission through by the Internet is secure and private. The group password-based authenticated key agreement (GPAKE) allows a group of users like doctors, nurses and patients to establish a common session key by using password authentication. Then the group of users can securely communicate by using this session key. Many approaches about GAPKE employ the public key infrastructure (PKI) in order to have higher security. However, it not only increases users' overheads and requires keeping an extra equipment for storing long-term secret keys, but also requires maintaining the public key system. This investigation presents a simple group password-based authenticated key agreement (SGPAKE) protocol for the integrated EPR information system. The proposed SGPAKE protocol does not require using the server or users' public keys. Each user only remembers his weak password shared with a trusted server, and then can obtain a common session key. Then all users can securely communicate by using this session key. The proposed SGPAKE protocol not only provides users with convince, but also has higher security.

[Advenella kashmirensis subsp. methylica PK1, a facultative methylotroph from carex rhizosphere].

Science.gov (United States)

Poroshina, M N; Doronina, N V; Kaparullina, E N; Trotsenko, Iu A

2015-01-01

A strain (PK1) of facultative methylobacteria growing on methanol as a carbon and energy source was isolated from carex rhizosphere (Pamukkale National Park, Turkey). The cells were nonmotile gram-negative rods propagating by binary fission. The organism was a strict anaerobe, oxidase- and catalase-positive. Optimal growth occurred at 29°C, pH 8.0-8.5, and 0.5% NaCl; no growth occurred at 2% NaCl. The organism used the ribulose bisphosphate pathway of C1 assimilation. Predominant fatty acids were 11-octodecenoic (18:1ω7) and cis-hexadecenoic (16:1ω7c). Phosphatidylethanolamine and diphosphatidylglycerol were the dominant phospholipids. Q8 was the main ubiquinone. DNA G+C content was 55.4 mol % (mp). Sequencing of the 16S rRNA gene revealed that strain PK1 belonged to the genus Advenella with 98.8 and 99.2% similarity to the type strains A. incenata CCUG 45225T and A. kashmirensis WT001T, respectively. DNA-DNA homology of strain PK1 and A. kashmirensis WT001T was 70%. While MALDI analysis confirmed their close clusterization, RAPD analysis revealed the differences between strain PKI and other Advenella strains. Based on its geno- and phenotypic properties, the isolate PK1 was classified as A. kashmirensis subsp. methylica PK1 (VKM-B 2850 = DSM 27514), the first known methylotroph of the genus Advenella.

Stargate GTM: Bridging Descriptor and Activity Spaces.

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Gaspar, Héléna A; Baskin, Igor I; Marcou, Gilles; Horvath, Dragos; Varnek, Alexandre

2015-11-23

Predicting the activity profile of a molecule or discovering structures possessing a specific activity profile are two important goals in chemoinformatics, which could be achieved by bridging activity and molecular descriptor spaces. In this paper, we introduce the "Stargate" version of the Generative Topographic Mapping approach (S-GTM) in which two different multidimensional spaces (e.g., structural descriptor space and activity space) are linked through a common 2D latent space. In the S-GTM algorithm, the manifolds are trained simultaneously in two initial spaces using the probabilities in the 2D latent space calculated as a weighted geometric mean of probability distributions in both spaces. S-GTM has the following interesting features: (1) activities are involved during the training procedure; therefore, the method is supervised, unlike conventional GTM; (2) using molecular descriptors of a given compound as input, the model predicts a whole activity profile, and (3) using an activity profile as input, areas populated by relevant chemical structures can be detected. To assess the performance of S-GTM prediction models, a descriptor space (ISIDA descriptors) of a set of 1325 GPCR ligands was related to a B-dimensional (B = 1 or 8) activity space corresponding to pKi values for eight different targets. S-GTM outperforms conventional GTM for individual activities and performs similarly to the Lasso multitask learning algorithm, although it is still slightly less accurate than the Random Forest method.

Seguridad en entornos de seguridad virtual

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Hernán Santiso

2016-12-01

Full Text Available En los últimos tiempos se han estado incorporando diferentes tecnologías de información y comunicaciones (TICs a los ámbitos de educación virtual, hasta el punto de convertirse en herramientas esenciales para el apoyo de los procesos de enseñanza y aprendizaje. Como consecuencia de este fenómeno, estos entornos se encuentran expuestos a nuevos riesgos tecnológicos que si no son identificados y mitigados de manera apropiada, pueden afectar la seguridad de las plataformas educativas. El objetivo del proyecto fue el de definir un marco de gestión de riesgo informático para entornos de educación virtual que permita garantizar la protección de la información utilizada en los procesos educativos a través de Internet. Para ello se realizó un relevamiento de los principales riesgos de seguridad asociados a las plataformas virtuales, y una vez hecho esto se definieron un conjunto de controles asociados a dichos riesgos que conformaron el marco de gestión propuesto. Por último se desarrollaron modelos técnicos para la aplicación efectiva de tecnologías de seguridad en plataformas de educación virtual, como UTM (Gestión de Amenazas Unificada para seguridad de los protocolos de red y PKI (Infraestructura de Clave Pública para mejorar los mecanismos de autenticación a las plataformas.

TRANSFORMATION OF LUDRUK PERFORMANCES: FROM POLITICAL INVOLVEMENT AND STATE HEGEMONY TO CREATIVE SURVIVAL STRATEGY

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Ikwan Setiawan

2014-06-01

Full Text Available This article discusses the transformation of ludruk performances, from Soekarno to Reformation era. In discussing the problem, we apply a cultural studies perspective. From our analysis, there are three findings related to the discursive transformation of ludruk stories. Firstly, in the era of Soekarno, many ludruk groups joined Lembaga Kebudayaan Rakyat (Lekra/Institute of People’s Culture, which had many ideological similarities with Partai Komunis Indonesia (PKI/ Indonesian Communist Party. Consequently, ludruk groups performed some provocative stories that exposed the problems of lower-class people and criticized Islamic religious beliefs. Secondly, after the bloody 1965 tragedy, the regional military apparatuses controlled ludruk groups and their performances, including the stories. In this era, ludruk stories supported the New Order regime’s national development programs and raised people’s consensus on the significance of militarism through popular stories about people’s resistance to colonizers. Thirdly, in the Reformation era, some ludruk groups make newer, interesting stories about many complicated social problems in contemporary society. Finally, we conclude that this mode of transformation through creating newer, social problem-based stories that intertwine with historical conditions has deep historical roots in ludruk performances. In addition, during the Reformation period in whichmarket capitalism becomes a dominant ideology and practice, such newer stories and breakthroughs of staging may become a suitable creative survival strategy for ludruk groups in the midst of techno-cultural popularity as the dominant taste and orientation in societies.

VIHARA DI TENGAH-TENGAH SERIBU PURA (STUDI KASUS TENTANG KONVERSI AGAMA DARI AGAMA HINDU KE AGAMA BUDHA DI DESA ALASANGKER, KECAMATAN BULELENG, KABUPATEN BULELENG-BALI

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Ketut Sedana Arta

2014-05-01

Full Text Available Tujuan penelitian ini adalah (1 Untuk mengetahui latar belakang adanya anggota masyarakat di Desa Alasangker yang beralih agama dari agama Hindu ke Agama Budha; (2 Untuk mengetahui proses konversi agama dan perkembangan Agama Budha di Desa Alasangker dari awal masuknya sampai sekarang; (3 Untuk mengetahui implikasi konversi agama terhadap keluarga dan desa pakraman Penelitian ini secara metodologis menggunakan pendekatan kualitatif, teknik penentuan informan dengan purposive sampling dan informan terus dikembangkan dengan teknik snowball. Dalam pengumpulan data peneliti menggunakan: (1 Wawancara mendalam dengan membuat pedoman wawancara; (2 Observasi partisipasi. (3 Studi dokumen. Hasil penelitian ini menunjukkan bahwa latar belakang konversi agama di Desa Alasangker disebabkan oleh faktor Interen:1 untuk memperbaiki citra diri, hal ini disebabkan masyarakat yang berkonversi agama pada zaman Orde Lama adalah anggota PKI dan Partindo, sehingga segala aktivitasnya dicurigai oleh masyarakat desa. 2 Kurangnya pemahaman terhadap ajaran agama Hindu, yang disebabkan sumber ajaran agama hanya berasal dari lontar dan buku-buku agama Hindu sulit didapatkan di awal tahun 1970-an ditambah pihak PHDI kurang mengadakan pembinaan ke desa-desa tentang agama Hindu. 3 Faktor kemiskinan, kepapaan disebabkan mereka kehilangan orang tua maupun saudara yang menjadi tulang punggung keluarga. Sedangkan faktor eksternal adalah adanya pengaruh ajaran tokoh-tokoh agama Budha yang mempunyai keahlian dan kharisma, kemiripan ajaran agama Hindu dan Budha seperti ajaran hukum karma, punarbawa, dan tujuan akhir agama hidup manusia, kemudahan-kemudahan yang diberikan dari lembaga agama Budha,  seperti pemberian buku-buku secara gratis.

The testis-specific Cα2 subunit of PKA is kinetically indistinguishable from the common Cα1 subunit of PKA

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Herberg Friedrich W

2011-08-01

Full Text Available Abstract Background The two variants of the α-form of the catalytic (C subunit of protein kinase A (PKA, designated Cα1 and Cα2, are encoded by the PRKACA gene. Whereas Cα1 is ubiquitous, Cα2 expression is restricted to the sperm cell. Cα1 and Cα2 are encoded with different N-terminal domains. In Cα1 but not Cα2 the N-terminal end introduces three sites for posttranslational modifications which include myristylation at Gly1, Asp-specific deamidation at Asn2 and autophosphorylation at Ser10. Previous reports have implicated specific biological features correlating with these modifications on Cα1. Since Cα2 is not modified in the same way as Cα1 we tested if they have distinct biochemical activities that may be reflected in different biological properties. Results We show that Cα2 interacts with the two major forms of the regulatory subunit (R of PKA, RI and RII, to form cAMP-sensitive PKAI and PKAII holoenzymes both in vitro and in vivo as is also the case with Cα1. Moreover, using Surface Plasmon Resonance (SPR, we show that the interaction patterns of the physiological inhibitors RI, RII and PKI were comparable for Cα2 and Cα1. This is also the case for their potency to inhibit catalytic activities of Cα2 and Cα1. Conclusion We conclude that the regulatory complexes formed with either Cα1 or Cα2, respectively, are indistinguishable.

x509-free access to WLCG resources

Science.gov (United States)

Short, H.; Manzi, A.; De Notaris, V.; Keeble, O.; Kiryanov, A.; Mikkonen, H.; Tedesco, P.; Wartel, R.

2017-10-01

Access to WLCG resources is authenticated using an x509 and PKI infrastructure. Even though HEP users have always been exposed to certificates directly, the development of modern Web Applications by the LHC experiments calls for simplified authentication processes keeping the underlying software unmodified. In this work we will show a solution with the goal of providing access to WLCG resources using the user’s home organisations credentials, without the need for user-acquired x509 certificates. In particular, we focus on identity providers within eduGAIN, which interconnects research and education organisations worldwide, and enables the trustworthy exchange of identity-related information. eduGAIN has been integrated at CERN in the SSO infrastructure so that users can authenticate without the need of a CERN account. This solution achieves x509-free access to Grid resources with the help of two services: STS and an online CA. The STS (Security Token Service) allows credential translation from the SAML2 format used by Identity Federations to the VOMS-enabled x509 used by most of the Grid. The IOTA CA (Identifier-Only Trust Assurance Certification Authority) is responsible for the automatic issuing of short-lived x509 certificates. The IOTA CA deployed at CERN has been accepted by EUGridPMA as the CERN LCG IOTA CA, included in the IGTF trust anchor distribution and installed by the sites in WLCG. We will also describe the first pilot projects which are integrating the solution.

Design of IP Camera Access Control Protocol by Utilizing Hierarchical Group Key

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Jungho Kang

2015-08-01

Full Text Available Unlike CCTV, security video surveillance devices, which we have generally known about, IP cameras which are connected to a network either with or without wire, provide monitoring services through a built-in web-server. Due to the fact that IP cameras can use a network such as the Internet, multiple IP cameras can be installed at a long distance and each IP camera can utilize the function of a web server individually. Even though IP cameras have this kind of advantage, it has difficulties in access control management and weakness in user certification, too. Particularly, because the market of IP cameras did not begin to be realized a long while ago, systems which are systematized from the perspective of security have not been built up yet. Additionally, it contains severe weaknesses in terms of access authority to the IP camera web server, certification of users, and certification of IP cameras which are newly installed within a network, etc. This research grouped IP cameras hierarchically to manage them systematically, and provided access control and data confidentiality between groups by utilizing group keys. In addition, IP cameras and users are certified by using PKI-based certification, and weak points of security such as confidentiality and integrity, etc., are improved by encrypting passwords. Thus, this research presents specific protocols of the entire process and proved through experiments that this method can be actually applied.

Ethanol extract of the seed of Zizyphus jujuba var. spinosa potentiates hippocampal synaptic transmission through mitogen-activated protein kinase, adenylyl cyclase, and protein kinase A pathways.

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Jo, So Yeon; Jung, In Ho; Yi, Jee Hyun; Choi, Tae Joon; Lee, Seungheon; Jung, Ji Wook; Yun, Jeanho; Lee, Young Choon; Ryu, Jong Hoon; Kim, Dong Hyun

2017-03-22

As the seed of Zizyphus jujuba var. spinosa (Bunge) Hu ex H.F. Chow (Rhamnaceae) has been used to sleep disturbances in traditional Chinese and Korean medicine, many previous studies have focused on its sedative effect. Recently, we reported the neuroprotective effect of the effect of Z. jujuba var. spinosa. However, its effects on synaptic function have not yet been studied. In this project, we examined the action of ethanol extract of the seed of Z. jujuba var. spinosa (DHP1401) on synaptic transmission in the hippocampus. To investigate the effects of DHP1401, field recordings were conducted using hippocampal slices (400µm). Object recognition test was introduced to examine whether DHP1401 affect normal recognition memory. DHP1401 (50μg/ml) induced a significant increase in synaptic activity in Shaffer collateral pathway in a concentration-dependent manner. This increase of synaptic responses was blocked by NBQX, a broad spectrum α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, but not IEM-1460, a Ca 2+ -permeable AMPAR blocker. Moreover, U0126, a mitogen-activated protein kinase inhibitor, SQ22536, an adenylyl cyclase inhibitor, and PKI, a protein kinase A inhibitor, blocked DHP1401-induced increase in synaptic transmission. Finally, DHP1401 facilitated object recognition memory. These results suggest that DHP1401 increase synaptic transmission through increase of synaptic AMPAR transmission via MAPK, AC and PAK. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Specific labelling of serotonin 5-HT(1B) receptors in rat frontal cortex with the novel, phenylpiperazine derivative, [3H]GR125,743. A pharmacological characterization.

Science.gov (United States)

Millan, M J; Newman-Tancredi, A; Lochon, S; Touzard, M; Aubry, S; Audinot, V

2002-04-01

Although several tritiated agonists have been used for radiolabelling serotonin (5-hydroxytryptamine, 5-HT)(1B) receptors in rats, data with a selective, radiolabelled antagonist have not been presented. Inasmuch as [3H]GR125,743 specifically labels cloned, human and native guinea pig 5-HT(1B) receptors and has been employed for characterization of cerebral 5-HT(1B) receptor in the latter species [Eur. J. Pharmacol. 327 (1997) 247.], the present study evaluated its utility for characterization of native, cerebral 5-HT(1B) sites in the rat. In homogenates of frontal cortex, [3H]GR125,743 (0.8 nM) showed rapid association (t(1/2)=3.4 min), >90% specific binding and high affinity (K(d)=0.6 nM) for a homogeneous population of receptors with a density (B(max)) of 160 fmol/mg protein. In competition binding studies, affinities were determined for 15 chemically diverse 5-HT(1B) agonists, including 2-[5-[3-(4-methylsulphonylamino)benzyl-1,2,4-oxadiazol-5-yl]-1H-indole-3-yl]ethylamine (L694,247; pK(i), 10.4), 5-carboxamidotryptamine (5-CT; 9.7), 3-[3-(2-dimethylamino-ethyl)-1H-indol-6-yl]-N-(4-methoxybenzyl)acrylamide (GR46,611; 9.6), 5-methoxy-3-(1,2,5,6-tetrahydro-4-pyridinyl)-1H-indole (RU24,969; 9.5), dihydroergotamine (DHE; 8.6), 5-H-pyrrolo[3,2-b]pyridin-5-one,1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl (CP93,129; 8.4), anpirtoline (7.9), sumatriptan (7.4), 1-[2-(3-fluorophenyl)ethyl]-4-[3-[5-(1,2,4-triazol-4-yl)-1H-indol-3-yl]propyl]piperazine (L775,606; 6.4) and (minus sign)-1(S)-[2-[4-(4-methoxyphenyl)piperazin-1-yl]ethyl]-N-methyl-3,4-dihydro-1H-2-benzopyran-6-carboxamide (PNU109,291; <5.0). Similarly, affinities were established for 13 chemically diverse antagonists, including N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-3-methyl-4-(4-pyridyl)benzamide (GR125,743; pK(i), 9.1), (-)cyanopindolol (9.0), (-)-tertatolol (8.2), N-(4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiozol-3-yl)biphenyl-4-carboxamide (GR127,935; 8.2), N-[3

PKA catalytic subunit compartmentation regulates contractile and hypertrophic responses to β-adrenergic signaling

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Yang, Jason H.; Polanowska-Grabowska, Renata K.; Smith, Jeffrey S.; Shields, Charles W.; Saucerman, Jeffrey J.

2014-01-01

β-adrenergic signaling is spatiotemporally heterogeneous in the cardiac myocyte, conferring exquisite control to sympathetic stimulation. Such heterogeneity drives the formation of protein kinase A (PKA) signaling microdomains, which regulate Ca2+ handling and contractility. Here, we test the hypothesis that the nucleus independently comprises a PKA signaling microdomain regulating myocyte hypertrophy. Spatially-targeted FRET reporters for PKA activity identified slower PKA activation and lower isoproterenol sensitivity in the nucleus (t50 = 10.60±0.68 min; EC50 = 89.00 nmol/L) than in the cytosol (t50 = 3.71±0.25 min; EC50 = 1.22 nmol/L). These differences were not explained by cAMP or AKAP-based compartmentation. A computational model of cytosolic and nuclear PKA activity was developed and predicted that differences in nuclear PKA dynamics and magnitude are regulated by slow PKA catalytic subunit diffusion, while differences in isoproterenol sensitivity are regulated by nuclear expression of protein kinase inhibitor (PKI). These were validated by FRET and immunofluorescence. The model also predicted differential phosphorylation of PKA substrates regulating cell contractility and hypertrophy. Ca2+ and cell hypertrophy measurements validated these predictions and identified higher isoproterenol sensitivity for contractile enhancements (EC50 = 1.84 nmol/L) over cell hypertrophy (EC50 = 85.88 nmol/L). Over-expression of spatially targeted PKA catalytic subunit to the cytosol or nucleus enhanced contractile and hypertrophic responses, respectively. We conclude that restricted PKA catalytic subunit diffusion is an important PKA compartmentation mechanism and the nucleus comprises a novel PKA signaling microdomain, insulating hypertrophic from contractile β-adrenergic signaling responses. PMID:24225179

Problem Teologis Ideologi Komunisme

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Muhamad Yakub Mubaro

2017-05-01

Full Text Available It is known that the communism had affected the history of this world. This ideology had succeeded influencing a third of the world in less than one century after Karl Marx’s death and it had caused some revolutionary movements at some countries of the world. It is interesting to say that even what Marx had predicted about the history of human being in the future was not surely proven, but his ideas have been affecting people. But, the communism has serious problems related to the theological matter for sure. It could make people becoming atheist. Moreover, it could create the people hate their religion, but they could become religion’s antagonists. Marx’s hatred toward religions was expressed by the words: “Religion is the opium of the masses”. Then Lenin, another figure of the communism, did a discrimination to religious people, as well as, Joseph Stalin and Mao Zedong who prohibited all kinds of religious activities during their lifetime. Long time ago, thousands of Indonesian Moslems were becoming victims of a communist party in Indonesia (PKI. Nowadays, the communism doctrine begins to appear and affect some youths of Indonesia. Perhaps, it does because they have been frustrated and being disappointed by the socio-political condition which is controlled by modern capitalists. But, they have to be aware that the communism is not a solution. In fact, it is surely dangerous. It could ruin religions’ concepts. Hence, this article would try to explain some theological problems of the communism ideology.

Book Reviews

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J. Noorduyn

1982-10-01

Full Text Available - C. van Dijk, M.C. Ricklefs, A history of modern Indonesia. C. 1300 to the present, London and Basingstoke, The MacMillan Press Ltd., 1981. xii + 335 pp. MacMillan Asian Histories Series. - L.A. Hoedemaker, S.C. Graaf van Randwijck, Handelen en denken in dienst der zending (Oestgeest 1897-1942, 2 delen, Den Haag Boekencentrum, 1981. - G.J. Knaap, Hubert Jacobs SJ, Documenta Malucensia II (1577-1606, annotated by Hubert Jacobs SJ, Monumenta Missionum Societatis Iesu volumen XXXIX, Missiones Orientalis, Rome, Jesuit Historical Institute; 1980, XXXI + 65* + 794 blz. - David S. Moyer, H. Sutherland, The making of a bureaucratic elite; The colonial transformation of the Javanese Priyayi, Asian studies association of Australia, Southeast Asia publication series no. 2, Heinemann educational books (Asia, Singapore, Kuala Lumpur, Hong Kong, 1979, xx + 182 pp. - S.A. Niessen, Garrett Solyom, The world of the Javanese Keris, 1978, East-West Centre, Honolulu, Hawaii., Bronwen Solyom (eds. - S.A. Niessen, Anne Leonard, Patterns of Paradise; The styles and significance of bark cloth around the world, 1980, Field museum of natural history., John Terrell (eds. - S.A. Niessen, Kirk Endicott, Batek Negrito Religion, 1979, Oxford Clarendon Press. - J. Noorduyn, Olivier Carré, L’Islam et l’état dans le monde d’aujourd’hui, Paris, Presses Universitaires de France, 1982. 270 p. - H.A. Poeze, Joop Morriën, Indonesië los van Holland. De CPN en de PKI in hun strijd tegen het Nederlands kolonialisme, Pegasus Amsterdam, 1982, 272 pp.

Linear Interaction Energy Based Prediction of Cytochrome P450 1A2 Binding Affinities with Reliability Estimation.

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Luigi Capoferri

Full Text Available Prediction of human Cytochrome P450 (CYP binding affinities of small ligands, i.e., substrates and inhibitors, represents an important task for predicting drug-drug interactions. A quantitative assessment of the ligand binding affinity towards different CYPs can provide an estimate of inhibitory activity or an indication of isoforms prone to interact with the substrate of inhibitors. However, the accuracy of global quantitative models for CYP substrate binding or inhibition based on traditional molecular descriptors can be limited, because of the lack of information on the structure and flexibility of the catalytic site of CYPs. Here we describe the application of a method that combines protein-ligand docking, Molecular Dynamics (MD simulations and Linear Interaction Energy (LIE theory, to allow for quantitative CYP affinity prediction. Using this combined approach, a LIE model for human CYP 1A2 was developed and evaluated, based on a structurally diverse dataset for which the estimated experimental uncertainty was 3.3 kJ mol-1. For the computed CYP 1A2 binding affinities, the model showed a root mean square error (RMSE of 4.1 kJ mol-1 and a standard error in prediction (SDEP in cross-validation of 4.3 kJ mol-1. A novel approach that includes information on both structural ligand description and protein-ligand interaction was developed for estimating the reliability of predictions, and was able to identify compounds from an external test set with a SDEP for the predicted affinities of 4.6 kJ mol-1 (corresponding to 0.8 pKi units.

Performance Evaluation of Public Key Based Authentication in Future Mobile Communication Systems

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Kambourakis Georgios

2004-01-01

Full Text Available While mobile hosts are evolving into full-IP enabled devices, there is a greater demand to provide a more flexible, reconfigurable, and scalable security mechanism in mobile communication systems beyond 3G (B3G. Work has already begun on such an “all-IP” end-to-end solution, commonly referred to as 4G systems. Fully fledged integration between heterogeneous networks, such as 2.5G, UMTS, WLAN, Bluetooth, and the Internet, demands fully compatible, time-tested, and reliable mechanisms to depend on. SSL protocol has proved its effectiveness in the wired Internet and it will probably be the most promising candidate for future wireless environments. In this paper, we discuss existing problems related to authentication and key agreement (AKA procedures, such as compromised authentication vectors attacks, as they appear in current 2/2.5G/3G mobile communication systems, and propose how SSL, combined with public key infrastructure (PKI elements, can be used to overcome these vulnerabilities. In this B3G environment, we perceive authentication as a service, which has to be performed at the higher protocol layers irrespective of the underlying network technology. Furthermore, we analyze the effectiveness of such a solution, based on measurements of a “prototype” implementation. Performance measurements indicate that SSL-based authentication can be possible in terms of service time in future wireless systems, while it can simultaneously provide both the necessary flexibility to network operators and a high level of confidence to end users.

Crystal structure of the Xpo1p nuclear export complex bound to the SxFG/PxFG repeats of the nucleoporin Nup42p.

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Koyama, Masako; Hirano, Hidemi; Shirai, Natsuki; Matsuura, Yoshiyuki

2017-10-01

Xpo1p (yeast CRM1) is the major nuclear export receptor that carries a plethora of proteins and ribonucleoproteins from the nucleus to cytoplasm. The passage of the Xpo1p nuclear export complex through nuclear pore complexes (NPCs) is facilitated by interactions with nucleoporins (Nups) containing extensive repeats of phenylalanine-glycine (so-called FG repeats), although the precise role of each Nup in the nuclear export reaction remains incompletely understood. Here we report structural and biochemical characterization of the interactions between the Xpo1p nuclear export complex and the FG repeats of Nup42p, a nucleoporin localized at the cytoplasmic face of yeast NPCs and has characteristic SxFG/PxFG sequence repeat motif. The crystal structure of Xpo1p-PKI-Nup42p-Gsp1p-GTP complex identified three binding sites for the SxFG/PxFG repeats on HEAT repeats 14-20 of Xpo1p. Mutational analyses of Nup42p showed that the conserved serines and prolines in the SxFG/PxFG repeats contribute to Xpo1p-Nup42p binding. Our structural and biochemical data suggest that SxFG/PxFG-Nups such as Nup42p and Nup159p at the cytoplasmic face of NPCs provide high-affinity docking sites for the Xpo1p nuclear export complex in the terminal stage of NPC passage and that subsequent disassembly of the nuclear export complex facilitates recycling of free Xpo1p back to the nucleus. © 2017 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.

[The dynamic mitochondria-nuclear redistribution of FKBP51 during the process of adipocyte differentiation is regulated by PKA].

Science.gov (United States)

Toneatto, Judith; Charó, Nancy L; Susperreguy, Sebastián; Piwien-Pilipuk, Graciela

2013-01-01

Glucocorticoids play an important role in adipogenesis via the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90-Hsp70 and a high molecular weight immunophilin FKBP51 or FKBP52. We have found that FKBP51 level of expression progressively increases, FKBP52 decreases, whereas Hsp90, Hsp70, and p23 remain unchanged when 3T3-L1 preadipocytes differentiate. Interestingly, FKBP51 translocates from mitochondria to the nucleus at the onset of adipogenesis. FKBP51 transiently concentrates in the nuclear lamina, at a time that this nuclear compartment undergoes its reorganization. FKBP51 nuclear localization is transient, after 48 h it cycles back to mitochondria. We found that the dynamic FKBP51 mitochondrial-nuclear shuttling is regulated by glucocorticoids and mainly on cAMP-PKA signaling since PKA inhibition by myristoilated-PKI, abrogated FKBP51 nuclear translocation induced by 3-isobutyl-1-methylxanthine (IBMX). It has been reported that PKA interacts with GR in a ligand dependent manner potentiating its transcriptional capacity. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutyryl-cAMP, compounds that induced nuclear translocation of FKBP51, therefore PKA may exert a dual role in the control of GR. In summary, the presence of FKBP51 in the nucleus may be critical for GR transcriptional control, and possibly for the control of other transcription factors that are not members of the nuclear receptor family but are regulated by PKA signaling pathway, when transcription has to be strictly controlled to succeed in the acquisition of the adipocyte phenotype.

Enhancing the Earth System Grid Authentication Infrastructure through Single Sign-On and Autoprovisioning

Energy Technology Data Exchange (ETDEWEB)

Siebenlist, Frank [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bernholdt, David E. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Williams, Dean N. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

2009-01-01

Climate scientists face an overarching need to efficiently access and manipulate climate model data. Increasingly, researchers must assemble and analyze large datasets that are archived in different formats on disparate platforms and must extract portions of datasets to compute statistical or diagnostic metrics in place. The need for a common virtual environment in which to access both climate model datasets and analysis tools is therefore keenly felt. The software infrastructure to support such an environment must not only provide ready access to climate data but must also facilitate the use of visualization software, diagnostic algorithms, and related resources. To this end, the Earth System Grid Center for Enabling Technologies (ESG-CET) was established in 2006 by the Scientific Discovery through Advanced Computing program of the U.S. Department of Energy through the Office of Advanced Scientific Computing Research and the Office Biological and Environmental Research within the Office of Science. ESG-CET is working to advance climate science by developing computational resources for accessing and managing model data that are physically located in distributed multiplatform archives. In this paper, we discuss recent development and implementation efforts by the Earth System Grid (ESG) concerning its security infrastructure. ESG's requirements are to make user logon as easy as possible and to facilitate the integration of security services and Grid components for both developers and system administrators. To meet that goal, we leverage existing primary authentication mechanisms, deploy a 'lightweight' but secure OpenID WebSSO, deploy a 'lightweight' X.509-PKI, and use autoprovisioning to ease the burden of security configuration management. We are close to completing the associated development and deployment.

AliEn - GRID application for ALICE Collaboration

International Nuclear Information System (INIS)

Zgura, Ion-Sorin

2003-01-01

AliEn (ALICE Environment) is a GRID framework built on top of the latest Internet standards for information exchange and authentication (SOAP, PKI) and common Open Source components. AliEn provides a virtual file catalogue that allows transparent access to distributed data-sets and a number of collaborating Web services which implement the authentication, job execution, file transport, performance monitor and event logging.The ALICE experiment has developed AliEn as an implementation of distributed computing infrastructure needed to simulate, reconstruct and analyze data from the experiment. The sites that belong to the ALICE Virtual Organisation can be seen and used as a single entity - any available node executes jobs and access to logical and datasets is transparent to the user. In developing AliEn common standards and solutions in the form of Open Source components were used. Only 1% (25k physical lines of code in Perl) is native AliEn code while 99% of the code has been imported in form of Open Sources packages and Perl modules. Currently ALICE is using the system for distributed production of Monte Carlo data at over 30 sites on four continents. During the last twelve months more than 30,000 jobs have been successfully run under AliEn control worldwide, totalling 25 CPU years and producing 20 TB of data. The user interface is compatible to EU DataGrid at the level of authentication and job description language. In perspective AliEn will be interfaced to the mainstream Grid infrastructure in HEP and it will remain to serve as interface between ALICE Offline framework and external Grid infrastructure. (authors)

Modulation of the TGF-β1-induced epithelial to mesenchymal transition (EMT) mediated by P1 and P2 purine receptors in MDCK cells.

Science.gov (United States)

Zuccarini, Mariachiara; Giuliani, Patricia; Buccella, Silvana; Di Liberto, Valentina; Mudò, Giuseppa; Belluardo, Natale; Carluccio, Marzia; Rossini, Margherita; Condorelli, Daniele Filippo; Rathbone, Michel Piers; Caciagli, Francesco; Ciccarelli, Renata; Di Iorio, Patrizia

2017-12-01

Epithelial to mesenchymal transition (EMT) occurs during embryogenesis or under pathological conditions such as hypoxia, injury, chronic inflammation, or tissue fibrosis. In renal tubular epithelial cells (MDCK), TGF-β1 induces EMT by reducing or increasing epithelial or mesenchymal marker expression, respectively. In this study, we confirmed that the cAMP analogues, 8-CPT-cAMP or N6-Ph-cAMP, inhibited the TGF-β1-driven overexpression of the mesenchymal markers ZEB-1, Slug, Fibronectin, and α-SMA. Furthermore, we showed that A1, A2A, P2Y1, P2Y11, and P2X7 purine receptor agonists modulated the TGF-β1-induced EMT through the involvement of PKA and/or MAPK/ERK signaling. The stimulation of A2A receptor reduced the overexpression of the EMT-related markers, mainly through the cAMP-dependent PKA pathway, as confirmed by cell pre-treatment with Myr-PKI. Both A1 and P2Y1 receptor stimulation exacerbated the TGF-β1-driven effects, which were reduced by cell pre-treatment with the MAPK inhibitor PD98059, according to the increased ERK1/2 phosphorylation upon receptor activation. The effects induced by P2Y11 receptor activation were oppositely modulated by PKA or MAPK inhibition, in line with the dual nature of the Gs- and Gq-coupled receptor. Differently, P2X7 receptor induced, per se, similar and not additive effects compared to TGF-β1, after prolonged cell exposure to BzATP. These results suggest a putative role of purine receptors as target for anti-fibrotic agents.

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 1. Synthesis and SAR of alpha,alpha-dimethylglycine sulfonamides.

Science.gov (United States)

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Berettoni, Marco; Calvani, Federico; Catrambone, Fernando; Felicetti, Patrizia; Gensini, Martina; Terracciano, Rosa; Altamura, Maria; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2006-06-15

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B(2) receptor (hB(2)R) antagonists. Here we report, in detail, how this family of compounds was designed, synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB(2)R and high in vivo potency after topical administration to the respiratory tract. The series was designed on the basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists and is characterized by the presence of an alpha,alpha-dialkyl amino acid. The first lead (17) of the series was submitted to extensive chemical work to elucidate the structural requirements to increase hB(2) receptor affinity and antagonist potency in bioassays expressing the human B(2) receptor (hB(2)R). The following structural features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino acid. The representative lead compound 68 inhibited the specific binding of [(3)H]BK to hB(2)R with a pKi of 9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems expressing the hB(2)R with a pA(2) of 9.1. Moreover, compound 68 when administered (300 nmol/kg) intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.

First-in-Human Study of PF-05212384 (PKI-587), a Small-Molecule, Intravenous, Dual Inhibitor of PI3K and mTOR in Patients with Advanced Cancer.

Science.gov (United States)

Shapiro, Geoffrey I; Bell-McGuinn, Katherine M; Molina, Julian R; Bendell, Johanna; Spicer, James; Kwak, Eunice L; Pandya, Susan S; Millham, Robert; Borzillo, Gary; Pierce, Kristen J; Han, Lixin; Houk, Brett E; Gallo, Jorge D; Alsina, Maria; Braña, Irene; Tabernero, Josep

2015-04-15

To evaluate safety (primary endpoint), tolerability, pharmacokinetics, pharmacodynamic profile, and preliminary activity of the intravenous, pan-class I isoform PI3K/mTOR inhibitor PF-05212384 in patients with advanced solid tumors. Part 1 of this open-label phase I study was designed to estimate the maximum-tolerated dose (MTD) in patients with nonselected solid tumors, using a modified continual reassessment method to guide dose escalation. Objectives of part 2 were MTD confirmation and assessment of preliminary activity in patients with selected tumor types and PI3K pathway dysregulation. Seventy-seven of the 78 enrolled patients received treatment. The MTD for PF-05212384, administered intravenously once weekly, was estimated to be 154 mg. The most common treatment-related adverse events (AE) were mucosal inflammation/stomatitis (58.4%), nausea (42.9%), hyperglycemia (26%), decreased appetite (24.7%), fatigue (24.7%), and vomiting (24.7%). The majority of patients treated at the MTD experienced only grade 1 treatment-related AEs. Grade 3 treatment-related AEs occurred in 23.8% of patients at the MTD. No treatment-related grade 4-5 AEs were reported at any dose level. Antitumor activity was noted in this heavily pretreated patient population, with two partial responses (PR) and an unconfirmed PR. Eight patients had long-lasting stable disease (>6 months). Pharmacokinetic analyses showed a biphasic concentration-time profile for PF-05212384 (half-life, 30-37 hours after multiple dosing). PF-05212384 inhibited downstream effectors of the PI3K pathway in paired tumor biopsies. These findings demonstrate the manageable safety profile and antitumor activity of the PI3K/mTOR inhibitor PF-05212384, supporting further clinical development for patients with advanced solid malignancies. ©2015 American Association for Cancer Research.

The pharmacology of TD-8954, a potent and selective 5-HT4 receptor agonist with gastrointestinal prokinetic properties

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David T Beattie

2011-05-01

Full Text Available This study evaluated the in vitro and in vivo pharmacological properties of TD-8954, a potent and selective 5-HT4 receptor agonist. TD-8954 had high affinity (pKi = 9.4 for human recombinant 5-HT4(c (h5-HT4(c receptors, and selectivity (> 2,000-fold over all other 5-HT receptors and non-5-HT receptors, ion channels, enzymes and transporters tested (n = 78. TD-8954 produced an elevation of cAMP in HEK-293 cells expressing the h5-HT4(c receptor (pEC50 = 9.3, and contracted the guinea pig colonic longitudinal muscle/myenteric plexus (LMMP preparation (pEC50 = 8.6. TD-8954 had moderate intrinsic activity (IA in the in vitro assays. In conscious guinea pigs, subcutaneous (s.c. administration of TD 8954 (0.03 - 3 mg/kg increased the colonic transit of carmine red dye, reducing the time taken for its excretion. Following intraduodenal (i.d. dosing to anesthetized rats, TD 8954 (0.03 - 10 mg/kg evoked a dose-dependent relaxation of the esophagus. Following oral administration to conscious dogs, TD 8954 (10 and 30 µg/kg produced an increase in contractility of the antrum, duodenum and jejunum. In a single ascending oral dose study in healthy human subjects, TD-8954 (0.1 - 20 mg increased bowel movement frequency and reduced the time to first stool. It is concluded that TD-8954 is a potent and selective 5-HT4 receptor agonist in vitro, with robust in vivo stimulatory activity in the gastrointestinal (GI tract of guinea pigs, rats, dogs and humans. TD-8954 may have clinical utility in patients with disorders of reduced GI motility.

Mechanistic deductions from multiple kinetic and solvent deuterium isotope effects and pH studies of pyridoxal phosphate dependent carbon-carbon lyases: escherichia coli tryptophan indole-lyase

International Nuclear Information System (INIS)

Kiick, D.M.; Phillips, R.S.

1988-01-01

Analysis of the pH dependence of the kinetic parameters and competitive inhibitor Ki values for tryptophan indole-lyase suggests two enzymic groups must be unprotonated in order to facilitate binding and catalysis of tryptophan. The V/K for tryptophan and the pKi for oxindolyl-L-alanine, a putative transition state analogue and competitive inhibitor, decrease below two pK values of 7.6 and 6.0, while the Ki for L-alanine, also a competitive inhibitor, is 3300-fold larger (20 mM) than that for oxindolyl-L-alanine and increases below a single pK of 7.6. A single pK of 7.6 is also observed in the V/K profile for the alternate substrate, S-methyl-L-cysteine. Therefore, the enzymic group with a pK of 7.6 is responsible for proton abstraction at the 2-position of tryptophan, while the enzymic group with a pK of 6.0 interacts with the indole portion of tryptophan and probably catalyzes formation of the indolenine tautomer of tryptophan (in concert with proton transfer to C-3 of indole from the group with pK 7.6) to facilitate carbon-carbon bond cleavage and elimination of indole. The pH variation of the primary deuterium isotope effects for proton abstraction at the 2-position of tryptophan (DV = 2.5 and D(V/Ktrp) = 2.8) are pH independent, while the Vmax for tryptophan or S-methyl-L-cysteine is the same and also pH independent. Thus, substrates bind only to the correctly protonated form of the enzyme. Further, tryptophan is not sticky, and the pK values observed in both V/K profiles are the correct ones

Reciprocally coupled residues crucial for protein kinase Pak2 activity calculated by statistical coupling analysis.

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Yuan-Hao Hsu

2010-03-01

Full Text Available Regulation of Pak2 activity involves at least two mechanisms: (i phosphorylation of the conserved Thr(402 in the activation loop and (ii interaction of the autoinhibitory domain (AID with the catalytic domain. We collected 482 human protein kinase sequences from the kinome database and globally mapped the evolutionary interactions of the residues in the catalytic domain with Thr(402 by sequence-based statistical coupling analysis (SCA. Perturbation of Thr(402 (34.6% suggests a communication pathway between Thr(402 in the activation loop, and Phe(387 (DeltaDeltaE(387F,402T = 2.80 in the magnesium positioning loop, Trp(427 (DeltaDeltaE(427W,402T = 3.12 in the F-helix, and Val(404 (DeltaDeltaE(404V,402T = 4.43 and Gly(405 (DeltaDeltaE(405G,402T = 2.95 in the peptide positioning loop. When compared to the cAMP-dependent protein kinase (PKA and Src, the perturbation pattern of threonine phosphorylation in the activation loop of Pak2 is similar to that of PKA, and different from the tyrosine phosphorylation pattern of Src. Reciprocal coupling analysis by SCA showed the residues perturbed by Thr(402 and the reciprocal coupling pairs formed a network centered at Trp(427 in the F-helix. Nine pairs of reciprocal coupling residues crucial for enzymatic activity and structural stabilization were identified. Pak2, PKA and Src share four pairs. Reciprocal coupling residues exposed to the solvent line up as an activation groove. This is the inhibitor (PKI binding region in PKA and the activation groove for Pak2. This indicates these evolutionary conserved residues are crucial for the catalytic activity of PKA and Pak2.

The novel non-imidazole histamine H3 receptor antagonist DL77 reduces voluntary alcohol intake and ethanol-induced conditioned place preference in mice.

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Bahi, Amine; Sadek, Bassem; Nurulain, Syed M; Łażewska, Dorota; Kieć-Kononowicz, Katarzyna

2015-11-01

It has become clear that histamine H3 receptors (H3R) have been implicated in modulating ethanol intake and preference in laboratory animals. The novel non-imidazole H3R antagonist DL77 with excellent selectivity profile shows high in-vivo potency as well as in-vitro antagonist affinity with ED50 of 2.1 ± 0.2 mg/kg and pKi=8.08, respectively. In the present study, and applying an unlimited access two-bottle choice procedure, the anti-alcohol effects of the H3R antagonist, DL77 (0, 3, 10 and 30 mg/kg; i.p.), were investigated in adult mice. In this C57BL/6 line, effects of DL77 on voluntary alcohol intake and preference, as well as on total fluid intake were evaluated. Results have shown that DL77, dose-dependently, reduced both ethanol intake and preference. These effects were very selective as both saccharin and quinine, used to control for taste sensitivity, and intakes were not affected following DL77 pre-application. More importantly, systemic administration of DL77 (10 mg/kg) during acquisition inhibited ethanol-induced conditioned-place preference (EtOH-CPP) as measured using an unbiased protocol. The anti-alcohol activity observed for DL77 was abrogated when mice were pretreated with the selective H3R agonist R-(α)-methyl-histamine (RAMH) (10 mg/kg), or with the CNS penetrant H1R antagonist pyrilamine (PYR) (10mg/kg). These results suggest that DL77 has a predominant role in two in vivo effects of ethanol. Therefore, signaling via H3R is essential for ethanol-related consumption and conditioned reward and may represent a novel therapeutic pharmacological target to tackle ethanol abuse and alcoholism. Copyright © 2015 Elsevier Inc. All rights reserved.

5D-QSAR for spirocyclic sigma1 receptor ligands by Quasar receptor surface modeling.

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Oberdorf, Christoph; Schmidt, Thomas J; Wünsch, Bernhard

2010-07-01

Based on a contiguous and structurally as well as biologically diverse set of 87 sigma(1) ligands, a 5D-QSAR study was conducted in which a quasi-atomistic receptor surface modeling approach (program package Quasar) was applied. The superposition of the ligands was performed with the tool Pharmacophore Elucidation (MOE-package), which takes all conformations of the ligands into account. This procedure led to four pharmacophoric structural elements with aromatic, hydrophobic, cationic and H-bond acceptor properties. Using the aligned structures a 3D-model of the ligand binding site of the sigma(1) receptor was obtained, whose general features are in good agreement with previous assumptions on the receptor structure, but revealed some novel insights since it represents the receptor surface in more detail. Thus, e.g., our model indicates the presence of an H-bond acceptor moiety in the binding site as counterpart to the ligands' cationic ammonium center, rather than a negatively charged carboxylate group. The presented QSAR model is statistically valid and represents the biological data of all tested compounds, including a test set of 21 ligands not used in the modeling process, with very good to excellent accuracy [q(2) (training set, n=66; leave 1/3 out) = 0.84, p(2) (test set, n=21)=0.64]. Moreover, the binding affinities of 13 further spirocyclic sigma(1) ligands were predicted with reasonable accuracy (mean deviation in pK(i) approximately 0.8). Thus, in addition to novel insights into the requirements for binding of spirocyclic piperidines to the sigma(1) receptor, the presented model can be used successfully in the rational design of new sigma(1) ligands. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

Next Generation Surveillance System (NGSS): Field Implementation & Associated Developments

International Nuclear Information System (INIS)

Hadfi, G.; John, M.; Liguori, C.; Moeslinger, M.; Murray, J.; Rocchi, S.

2015-01-01

The NGSS is the product of more than five years of development between the IAEA, other Inspectorates, Member State Support Programmes, and commercial vendors. The product of these efforts has now matured into the field implementation stage. This paper details the goals, achievements and challenges experienced during the implementation phase and associated developments of the project. NGSS procurement was subject to the IAEA's stringent procurement policies involving independent third party assessments to assure supplier reliability and competitive pricing controls. More than 1200 surveillance cameras currently installed in facilities worldwide will be replaced by NGSS within the next 4 to 5 years. Joint use procedures have been established taking advantage of the technical capabilities integrated within the design of the NGSS which allow for multiple inspectorates and States to securely and independently share and review data. Utilization of outdated facility infrastructure poses many challenges to implementation efforts; these were met with innovative technical solutions to take advantage of cost benefits allowed in its re-utilization. New partnerships were established with Member States, regulatory bodies and nuclear power plant operators for new nuclear facilities under construction, to address infrastructural requirements spanning the next half century. The utilization of the IAEA's well-established PKI infrastructure enhances data security features and usability with regard to data sharing, key management and joint use of the NGSS system data. Embedded inventory reporting capability aids electronic inventory verification of safeguards equipment, simplifying accountability, configuration control and troubleshooting of installed systems. Current developments ongoing within the project include the design of hardware and software components for use of the system in special applications (e.g., underwater and outdoor installations, mechanism to

A search for presynaptic inhibitory histamine receptors in guinea-pig tissues: Further H3 receptors but no evidence for H4 receptors.

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Petri, Doris; Schlicker, Eberhard

2016-07-01

The histamine H4 receptor is coupled to Gi/o proteins and expressed on inflammatory cells and lymphoid tissues; it was suggested that this receptor also occurs in the brain or on peripheral neurones. Since many Gi/o protein-coupled receptors, including the H3 receptor, serve as presynaptic inhibitory receptors, we studied whether the sympathetic neurones supplying four peripheral tissues and the cholinergic neurones in the hippocampus from the guinea-pig are equipped with release-modulating H4 and H3 receptors. For this purpose, we preincubated tissue pieces from the aorta, atrium, renal cortex and vas deferens with (3)H-noradrenaline and hippocampal slices with (3)H-choline and determined the electrically evoked tritium overflow. The stimulation-evoked overflow in the five superfused tissues was inhibited by the muscarinic receptor agonist oxotremorine, which served as a positive control, but not affected by the H4 receptor agonist 4-methylhistamine. The H3 receptor agonist R-α-methylhistamine inhibited noradrenaline release in the peripheral tissues without affecting acetylcholine release in the hippocampal slices. Thioperamide shifted the concentration-response curve of histamine in the aorta and the renal cortex to the right, yielding apparent pA2 values of 8.0 and 8.1, respectively, which are close to its affinity at other H3 receptors but higher by one log unit than its pKi at the H4 receptor of the guinea-pig. In conclusion, histamine H4 receptors could not be identified in five experimental models of the guinea-pig that are suited for the detection of presynaptic inhibitory receptors whereas H3 receptors could be shown in the peripheral tissues but not in the hippocampus. This article is part of the Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A): a potent and selective corticotrophin-releasing factor(1) receptor antagonist. I. Biochemical and pharmacological characterization.

Science.gov (United States)

Gully, Danielle; Geslin, Michel; Serva, Laurence; Fontaine, Evelyne; Roger, Pierre; Lair, Christine; Darre, Valerie; Marcy, Claudine; Rouby, Pierre-Eric; Simiand, Jacques; Guitard, Josette; Gout, Georgette; Steinberg, Regis; Rodier, Daniel; Griebel, Guy; Soubrie, Philippe; Pascal, Marc; Pruss, Rebecca; Scatton, Bernard; Maffrand, Jean-Pierre; Le Fur, Gerard

2002-04-01

4-(2-Chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1- (3-fluoro-4-methylphenyl)ethyl]5-methyl-N-(2-propynyl)-1,3-thiazol-2-amine hydrochloride (SSR125543A), a new 2-aminothiazole derivative, shows nanomolar affinity for human cloned or native corticotrophin-releasing factor (CRF)(1) receptors (pK(i) values of 8.73 and 9.08, respectively), and a 1000-fold selectivity for CRF(1) versus CRF(2 alpha) receptor and CRF binding protein. SSR125543A antagonizes CRF-induced stimulation of cAMP synthesis in human retinoblastoma Y 79 cells (IC(50) = 3.0 +/- 0.4 nM) and adrenocorticotropin hormone (ACTH) secretion in mouse pituitary tumor AtT-20 cells. SSR125543A is devoid of agonist activity in these models. Its brain penetration was demonstrated in rats by using an ex vivo [(125)I-Tyr(0)] ovine CRF binding assay. SSR125543A displaced radioligand binding to the CRF(1) receptor in the brain with an ID(50) of 6.5 mg/kg p.o. (duration of action >24 h). SSR125543A also inhibited the increase in plasma ACTH levels elicited in rats by i.v. CRF (4 microg/kg) injection (ID(50) = 1, 5, or 5 mg/kg i.v., i.p., and p.o., respectively); this effect lasted for more than 6 h when the drug was given orally at a dose of 30 mg/kg. SSR125543A (10 mg/kg p.o.) reduced by 73% the increase in plasma ACTH levels elicited by a 15-min restraint stress in rats. Moreover, SSR125543A (20 mg/kg i.p.) also antagonized the increase of hippocampal acetylcholine release induced by i.c.v. injection of 1 microg of CRF in rats. Finally, SSR125543A reduced forepaw treading induced by i.c.v. injection of 1 microg of CRF in gerbils (ID(50) = approximately 10 mg/kg p.o.). Altogether, these data indicate that SSR125543A is a potent, selective, and orally active CRF(1) receptor antagonist.

Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic {beta} cells

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Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Mirshahi, Faridoddin [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Grider, John R. [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Murthy, Karnam S., E-mail: skarnam@vcu.edu [Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA (United States); Sanyal, Arun J., E-mail: asanyal@mcvh-vcu.edu [Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (United States)

2012-10-26

Highlights: Black-Right-Pointing-Pointer G protein coupled receptor TGR5 is expressed in mouse and human islets. Black-Right-Pointing-Pointer TGR5 is coupled to activation of Gs and Ca{sup 2+} release via cAMP/Epac/PLC-{epsilon} pathway. Black-Right-Pointing-Pointer Activation of TGR5 by bile salts and selective ligands causes insulin secretion. Black-Right-Pointing-Pointer TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic {beta} cells. In the present study, we have identified the expression of TGR5 in pancreatic {beta} cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated G{alpha}{sub s} and caused an increase in intracellular cAMP and Ca{sup 2+}. OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective G{alpha}{sub s} inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G{sub s}/cAMP/Ca{sup 2+} pathway. 8-pCPT-2 Prime -O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic {beta} cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

Activation of transmembrane bile acid receptor TGR5 stimulates insulin secretion in pancreatic β cells

International Nuclear Information System (INIS)

Kumar, Divya P.; Rajagopal, Senthilkumar; Mahavadi, Sunila; Mirshahi, Faridoddin; Grider, John R.; Murthy, Karnam S.; Sanyal, Arun J.

2012-01-01

Highlights: ► G protein coupled receptor TGR5 is expressed in mouse and human islets. ► TGR5 is coupled to activation of Gs and Ca 2+ release via cAMP/Epac/PLC-ε pathway. ► Activation of TGR5 by bile salts and selective ligands causes insulin secretion. ► TGR5 could be a potential therapeutic target to treat diabetes. -- Abstract: Bile acids act as signaling molecules and stimulate the G protein coupled receptor, TGR5, in addition to nuclear farnesoid X receptor to regulate lipid, glucose and energy metabolism. Bile acid induced activation of TGR5 in the enteroendocrine cells promotes glucagon like peptide-1 (GLP-1) release, which has insulinotropic effect in the pancreatic β cells. In the present study, we have identified the expression of TGR5 in pancreatic β cell line MIN6 and also in mouse and human pancreatic islets. TGR5 selective ligands, oleanolic acid (OA) and INT-777 selectively activated Gα s and caused an increase in intracellular cAMP and Ca 2+ . OA and INT-777 also increased phosphoinositide (PI) hydrolysis and the increase was blocked by NF449 (a selective Gα s inhibitor) or (U73122) (PI hydrolysis inhibitor). OA, INT-777 and lithocholic acid increased insulin release in MIN6 and human islets and the increase was inhibited by treatment with NF449, (U73122) or BAPTA-AM (chelator of calcium), but not with myristoylated PKI (PKA inhibitor), suggesting that the release is dependent on G s /cAMP/Ca 2+ pathway. 8-pCPT-2′-O-Me-cAMP, a cAMP analog, which activates Epac, but not PKA also stimulated PI hydrolysis. In conclusion, our study demonstrates that the TGR5 expressed in the pancreatic β cells regulates insulin secretion and highlights the importance of ongoing therapeutic strategies targeting TGR5 in the control of glucose homeostasis.

NPOESS Field Terminal Updates

Science.gov (United States)

Heckmann, G.; Route, G.

2009-12-01

downlinks identifying differences between the direct broadcast downlinks including the variability of the LRD downlink and NPOESS management and distribution of decryption keys to approved field terminals using Public Key Infrastructure (PKI) AES standard with 256 bit encryption and elliptical curve cryptography.

Kunitz Proteinase Inhibitors Limit Water Stress Responses in White Clover (Trifolium repens L.) Plants.

Science.gov (United States)

Islam, Afsana; Leung, Susanna; Nikmatullah, Aluh; Dijkwel, Paul P; McManus, Michael T

2017-01-01

The response of plants to water deficiency or drought is a complex process, the perception of which is triggered at the molecular level before any visible morphological responses are detected. It was found that different groups of plant proteinase inhibitors (PIs) are induced and play an active role during abiotic stress conditions such as drought. Our previous work with the white clover ( Trifolium repens L.) Kunitz Proteinase Inhibitor ( Tr-KPI ) gene family showed that Tr-KPIs are differentially regulated to ontogenetic and biotic stress associated cues and that, at least some members of this gene family may be required to maintain cellular homeostasis. Altered cellular homeostasis may also affect abiotic stress responses and therefore, we aimed to understand if distinct Tr-PKI members function during drought stress. First, the expression level of three Tr-KPI genes, Tr-KPI1 , Tr-KPI2 , and Tr-KPI5 , was measured in two cultivars and one white clover ecotype with differing capacity to tolerate drought. The expression of Tr-KPI1 and Tr-KPI5 increased in response to water deficiency and this was exaggerated when the plants were treated with a previous period of water deficiency. In contrast, proline accumulation and increased expression of Tr-NCED1 , a gene encoding a protein involved in ABA biosynthesis, was delayed in plants that experienced a previous drought period. RNAi knock-down of Tr-KPI1 and Tr-KPI5 resulted in increased proline accumulation in leaf tissue of plants grown under both well-watered and water-deficit conditions. In addition, increased expression of genes involved in ethylene biosynthesis was found. The data suggests that Tr-KPIs , particularly Tr-KPI5 , have an explicit function during water limitation. The results also imply that the Tr-KPI family has different in planta proteinase targets and that the functions of this protein family are not solely restricted to one of storage proteins or in response to biotic stress.

NILAI-NILAI PENDIDIKAN PADA PEMBERONTAKAN RAKYAT SUMATERA BARAT PADA AWAL TAHUN 1927

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Bain Bain

2011-10-01

Full Text Available Each incident in history contain high values that can be taken and utilized as the guidance for the next generation to be the guide for their life in the future. The history lesson will become really significant if each history teacher always invest the values of education from each kind of history material that is taught to the pupil. The West Sumatera riot revolt at the beginning of 1927 at least contain three values of education that that is good to be socialized to students, firstly, the disintegration of the West Sumatera community contain the value of the importance of the spirit of unity, secondly, authoritarianism the colonial Dutch government in undertaking his authority in West Sumatera contain the value of democracy of the importance of social, political, economic and cultural life, thirdly, tactics of Indonesian Communist Party in inciting the West Sumatera community to carry out the revolt show us the importance of the value of vigilance towards the disturbance and the threat to himself, the community, the nation.   Keywords:, values ​​education, historical events, popular uprising   Setiap kejadian dalam sejarah mengandung nilai-nilai yang tinggi untuk diambil dan memanfaatkan sebagai pedoman bagi generasi berikutnya sebagai panduan untuk hidup mereka di masa depan. Pelajaran sejarah akan menjadi benar-benar signifikan jika setiap guru sejarah selalu menanamkan nilai pendidikan dari materi sejarah yang diajarkan kepada murid. Pemberontakan rakyat di Sumatera Barat pada awal tahun 1927 setidaknya mengandung tiga nilai-nilai pendidikan yang yang baik sebagai bahan pelajaran dan internalisasi nilai murid-murid, pertama, disintegrasi masyarakat Sumatera Barat mengandung nilai pentingnya persatuan, dua, otoritarianisme pemerintah kolonial Belanda dalam melaksanakan kekuasaannya di Sumatera Barat mengandung nilai pentingnya demokrasi dalam kehidupan sosial, politik, ekonomi dan budaya, tiga, taktik PKI dalam menghasut

Lipoic acid attenuates inflammation via cAMP and protein kinase A signaling.

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Sonemany Salinthone

2010-09-01

Full Text Available Abnormal regulation of the inflammatory response is an important component of diseases such as diabetes, Alzheimer's disease and multiple sclerosis (MS. Lipoic acid (LA has been shown to have antioxidant and anti-inflammatory properties and is being pursued as a therapy for these diseases. We first reported that LA stimulates cAMP production via activation of G-protein coupled receptors and adenylyl cyclases. LA also suppressed NK cell activation and cytotoxicity. In this study we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are mediated by the cAMP/PKA signaling cascade. Additionally, we show that LA oral administration elevates cAMP levels in MS subjects.We determined the effects of LA on IL-6, IL-17 and IL-10 secretion using ELISAs. Treatment with 50 µg/ml and 100 µg/ml LA significantly reduced IL-6 levels by 19 and 34%, respectively, in T cell enriched PBMCs. IL-17 levels were also reduced by 35 and 50%, respectively. Though not significant, LA appeared to have a biphasic effect on IL-10 production. Thymidine incorporation studies showed LA inhibited T cell proliferation by 90%. T-cell activation was reduced by 50% as measured by IL-2 secretion. Western blot analysis showed that LA treatment increased phosphorylation of Lck, a downstream effector of protein kinase A. Pretreatment with a peptide inhibitor of PKA, PKI, blocked LA inhibition of IL-2 and IFN gamma production, indicating that PKA mediates these responses. Oral administration of 1200 mg LA to MS subjects resulted in increased cAMP levels in PBMCs four hours after ingestion. Average cAMP levels in 20 subjects were 43% higher than baseline.Oral administration of LA in vivo resulted in significant increases in cAMP concentration. The anti-inflammatory effects of LA are mediated in part by the cAMP/PKA signaling cascade. These novel findings enhance our understanding of the mechanisms of action of LA.

Tonic 5nM DA stabilizes neuronal output by enabling bidirectional activity-dependent regulation of the hyperpolarization activated current via PKA and calcineurin.

Science.gov (United States)

Krenz, Wulf-Dieter C; Rodgers, Edmund W; Baro, Deborah J

2015-01-01

Volume transmission results in phasic and tonic modulatory signals. The actions of tonic dopamine (DA) at type 1 DA receptors (D1Rs) are largely undefined. Here we show that tonic 5nM DA acts at D1Rs to stabilize neuronal output over minutes by enabling activity-dependent regulation of the hyperpolarization activated current (I h). In the presence but not absence of 5nM DA, I h maximal conductance (G max) was adjusted according to changes in slow wave activity in order to maintain spike timing. Our study on the lateral pyloric neuron (LP), which undergoes rhythmic oscillations in membrane potential with depolarized plateaus, demonstrated that incremental, bi-directional changes in plateau duration produced corresponding alterations in LP I hG max when preparations were superfused with saline containing 5nM DA. However, when preparations were superfused with saline alone there was no linear correlation between LP I hGmax and duty cycle. Thus, tonic nM DA modulated the capacity for activity to modulate LP I h G max; this exemplifies metamodulation (modulation of modulation). Pretreatment with the Ca2+-chelator, BAPTA, or the specific PKA inhibitor, PKI, prevented all changes in LP I h in 5nM DA. Calcineurin inhibitors blocked activity-dependent changes enabled by DA and revealed a PKA-mediated, activity-independent enhancement of LP I hG max. These data suggested that tonic 5nM DA produced two simultaneous, PKA-dependent effects: a direct increase in LP I h G max and a priming event that permitted calcineurin regulation of LP I h. The latter produced graded reductions in LP I hG max with increasing duty cycles. We also demonstrated that this metamodulation preserved the timing of LP's first spike when network output was perturbed with bath-applied 4AP. In sum, 5nM DA permits slow wave activity to provide feedback that maintains spike timing, suggesting that one function of low-level, tonic modulation is to stabilize specific features of a dynamic output.

Tonic 5nM DA stabilizes neuronal output by enabling bidirectional activity-dependent regulation of the hyperpolarization activated current via PKA and calcineurin.

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Wulf-Dieter C Krenz

Full Text Available Volume transmission results in phasic and tonic modulatory signals. The actions of tonic dopamine (DA at type 1 DA receptors (D1Rs are largely undefined. Here we show that tonic 5nM DA acts at D1Rs to stabilize neuronal output over minutes by enabling activity-dependent regulation of the hyperpolarization activated current (I h. In the presence but not absence of 5nM DA, I h maximal conductance (G max was adjusted according to changes in slow wave activity in order to maintain spike timing. Our study on the lateral pyloric neuron (LP, which undergoes rhythmic oscillations in membrane potential with depolarized plateaus, demonstrated that incremental, bi-directional changes in plateau duration produced corresponding alterations in LP I hG max when preparations were superfused with saline containing 5nM DA. However, when preparations were superfused with saline alone there was no linear correlation between LP I hGmax and duty cycle. Thus, tonic nM DA modulated the capacity for activity to modulate LP I h G max; this exemplifies metamodulation (modulation of modulation. Pretreatment with the Ca2+-chelator, BAPTA, or the specific PKA inhibitor, PKI, prevented all changes in LP I h in 5nM DA. Calcineurin inhibitors blocked activity-dependent changes enabled by DA and revealed a PKA-mediated, activity-independent enhancement of LP I hG max. These data suggested that tonic 5nM DA produced two simultaneous, PKA-dependent effects: a direct increase in LP I h G max and a priming event that permitted calcineurin regulation of LP I h. The latter produced graded reductions in LP I hG max with increasing duty cycles. We also demonstrated that this metamodulation preserved the timing of LP's first spike when network output was perturbed with bath-applied 4AP. In sum, 5nM DA permits slow wave activity to provide feedback that maintains spike timing, suggesting that one function of low-level, tonic modulation is to stabilize specific features of a dynamic output.

Security and privacy in electronic health records: a systematic literature review.

Science.gov (United States)

Fernández-Alemán, José Luis; Señor, Inmaculada Carrión; Lozoya, Pedro Ángel Oliver; Toval, Ambrosio

2013-06-01

To report the results of a systematic literature review concerning the security and privacy of electronic health record (EHR) systems. Original articles written in English found in MEDLINE, ACM Digital Library, Wiley InterScience, IEEE Digital Library, Science@Direct, MetaPress, ERIC, CINAHL and Trip Database. Only those articles dealing with the security and privacy of EHR systems. The extraction of 775 articles using a predefined search string, the outcome of which was reviewed by three authors and checked by a fourth. A total of 49 articles were selected, of which 26 used standards or regulations related to the privacy and security of EHR data. The most widely used regulations are the Health Insurance Portability and Accountability Act (HIPAA) and the European Data Protection Directive 95/46/EC. We found 23 articles that used symmetric key and/or asymmetric key schemes and 13 articles that employed the pseudo anonymity technique in EHR systems. A total of 11 articles propose the use of a digital signature scheme based on PKI (Public Key Infrastructure) and 13 articles propose a login/password (seven of them combined with a digital certificate or PIN) for authentication. The preferred access control model appears to be Role-Based Access Control (RBAC), since it is used in 27 studies. Ten of these studies discuss who should define the EHR systems' roles. Eleven studies discuss who should provide access to EHR data: patients or health entities. Sixteen of the articles reviewed indicate that it is necessary to override defined access policies in the case of an emergency. In 25 articles an audit-log of the system is produced. Only four studies mention that system users and/or health staff should be trained in security and privacy. Recent years have witnessed the design of standards and the promulgation of directives concerning security and privacy in EHR systems. However, more work should be done to adopt these regulations and to deploy secure EHR systems. Copyright

Kunitz Proteinase Inhibitors Limit Water Stress Responses in White Clover (Trifolium repens L. Plants

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Afsana Islam

2017-10-01

Full Text Available The response of plants to water deficiency or drought is a complex process, the perception of which is triggered at the molecular level before any visible morphological responses are detected. It was found that different groups of plant proteinase inhibitors (PIs are induced and play an active role during abiotic stress conditions such as drought. Our previous work with the white clover (Trifolium repens L. Kunitz Proteinase Inhibitor (Tr-KPI gene family showed that Tr-KPIs are differentially regulated to ontogenetic and biotic stress associated cues and that, at least some members of this gene family may be required to maintain cellular homeostasis. Altered cellular homeostasis may also affect abiotic stress responses and therefore, we aimed to understand if distinct Tr-PKI members function during drought stress. First, the expression level of three Tr-KPI genes, Tr-KPI1, Tr-KPI2, and Tr-KPI5, was measured in two cultivars and one white clover ecotype with differing capacity to tolerate drought. The expression of Tr-KPI1 and Tr-KPI5 increased in response to water deficiency and this was exaggerated when the plants were treated with a previous period of water deficiency. In contrast, proline accumulation and increased expression of Tr-NCED1, a gene encoding a protein involved in ABA biosynthesis, was delayed in plants that experienced a previous drought period. RNAi knock-down of Tr-KPI1 and Tr-KPI5 resulted in increased proline accumulation in leaf tissue of plants grown under both well-watered and water-deficit conditions. In addition, increased expression of genes involved in ethylene biosynthesis was found. The data suggests that Tr-KPIs, particularly Tr-KPI5, have an explicit function during water limitation. The results also imply that the Tr-KPI family has different in planta proteinase targets and that the functions of this protein family are not solely restricted to one of storage proteins or in response to biotic stress.

Circulating aldosterone induces the apical accumulation of the proton pumping V-ATPase and increases proton secretion in clear cells in the caput epididymis.

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Roy, Jeremy W; Hill, Eric; Ruan, Ye Chun; Vedovelli, Luca; Păunescu, Teodor G; Brown, Dennis; Breton, Sylvie

2013-08-15

Clear cells express the vacuolar proton-pumping H(+)-ATPase (V-ATPase) and acidify the lumen of the epididymis, a process that is essential for male fertility. The renin-angiotensin-aldosterone system (RAAS) regulates fluid and electrolyte balance in the epididymis, and a previous study showed binding of aldosterone exclusively to epididymal clear cells (Hinton BT, Keefer DA. Steroid Biochem 23: 231-233, 1985). We examined here the role of aldosterone in the regulation of V-ATPase in the epididymis. RT-PCR showed expression of the mineralocorticoid receptor [MR; nuclear receptor subfamily 3, group C member 2 (NR3C2)] and 11-β-dehydrogenase isozyme 2 (HSD11β2) mRNAs specifically in clear cells, isolated by fluorescence-activated cell sorting from B1-enhanced green fluorescent protein (EGFP) mice. Tail vein injection of adult rats with aldosterone, 1,2-dioctanoyl-sn-glycerol (DOG), or 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) induced V-ATPase apical membrane accumulation and extension of V-ATPase-labeled microvilli in clear cells in the caput epididymis but not in the cauda. V-ATPase activity was measured in EGFP-expressing clear cells using the intracellular pH (pHi)-sensing dye seminaphthorhodafluor-5F-5-(and 6)-carboxylic acid, acetoxymethyl ester acetate (SNARF-5F). Aldosterone induced a rapid increase in the rate of Na(+)- and bicarbonate-independent pHi recovery following an NH4Cl-induced acid load in clear cells isolated from the caput but not the cauda. This effect was abolished by concanamycin A, spironolactone, and chelerythrine but not myristoylated-protein kinase inhibitor (mPKI) or mifepristone. Thus aldosterone increases V-ATPase-dependent proton secretion in clear cells in the caput epididymis via MR/NR3C2 and PKC activation. This study, therefore, identifies aldosterone as an active member of the RAAS for the regulation of luminal acidification in the proximal epididymis.

Efficacy of antipsychotic agents at human 5-HT(1A) receptors determined by [3H]WAY100,635 binding affinity ratios: relationship to efficacy for G-protein activation.

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Newman-Tancredi, A; Verrièle, L; Touzard, M; Millan, M J

2001-10-05

5-HT(1A) receptors are implicated in the aetiology of schizophrenia. Herein, the influence of 15 antipsychotics on the binding of the selective 'neutral' antagonist, [3H]WAY100,635 ([3H]N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)-cyclo-hexanecarboxamide), was examined at human 5-HT(1A) receptors expressed in Chinese Hamster Ovary cells. In competition binding experiments, 5-HT displayed biphasic isotherms which were shifted to the right in the presence of the G-protein uncoupling agent, GTPgammaS (100 microM). In analogy, the isotherms of ziprasidone, quetiapine and S16924 (((R-2-[1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-pyrrolidin-3yl]-1-(4-fluoro-phenyl)-ethanone), were displaced to the right by GTPgammaS, consistent with agonist actions. Binding of several other antipsychotics, such as ocaperidone, olanzapine and risperidone, was little influenced by GTPgammaS. Isotherms of the neuroleptics, haloperidol, chlorpromazine and thioridazine were shifted to the left in the presence of GTPgammaS, suggesting inverse agonist properties. For most ligands, the magnitude of affinity changes induced by GTPgammaS (alteration in pK(i) values) correlated well with their previously determined efficacies in [35S]GTPgammaS binding studies [Eur. J. Pharmacol. 355 (1998) 245]. In contrast, the affinity of the 'atypical' antipsychotic agent, clozapine, which is a known partial agonist at 5-HT(1A) receptors, was less influenced by GTPgammaS. When the ratio of high-/low-affinity values was plotted against efficacy, hyperbolic isotherms were obtained, consistent with a modified ternary complex model which assumes that receptors can adopt active conformations in the absence of agonist. In conclusion, modulation of [3H]-WAY100,635 binding by GTPgammaS differentiated agonist vs. inverse agonist properties of antipsychotics at 5-HT(1A) receptors. These may contribute to differing profiles of antipsychotic activity.

Outstanding scientist of the year 2006: Rogel Patawaran, BS.

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Rubin, Robert A; Hazirjian, Courtney L

2006-01-01

further reports that out of 100 hospital patients, five or six will be the victim of a preventable error. He states that medication errors alone kill 7000 people each year, adding $2 billion to the overall cost of healthcare. He stresses that these 7000 needless deaths are not only unacceptable but un-American as well. During the 1990s, the pharmaceutical industry sought help from the Food and Drug Administration (FDA) to develop a standard by which a paperless system could be adopted for healthcare. In March of 1997, the FDA issued its final ruling, which established the criteria for which the FDA will recognize the transmission of authenticity within electronic data as well as establishing standards of authenticity for electronic data equivalent to the validity of signatures on paper documents and records. The FDA also recognizes the growth that can be experienced by converting healthcare technology to a paperless system, such as the expediting of patient files in a more organized manner, increasing the speed of file transfer of such documents, reducing prescription errors, enabling computer-generated data analysis and statistics, and reducing storage space. Rogel Patawaran and his colleagues also realized that electronic healthcare technology using the highest standard of data encryption to transfer data could also dramatically improve the safety of patients in our nation and the world. To answer the needs within healthcare technology, Rogel Patawaran created a system for healthcare providers using the most superior encryption methods, and in the process creating iQSolutions, Inc. Its web mail system uses the Public Key Infrastructure (PKI) format, which is the strongest known encryption format. PKI is used in combination with the Advance Encryption Standard (AES) digital encryption algorithm, which is the current algorithm used by banks and government agencies, thereby protecting the privacy and accuracy of the information. Rogel Patawaran's remarkable contributions

The GENIUS Grid Portal and robot certificates: a new tool for e-Science.

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Barbera, Roberto; Donvito, Giacinto; Falzone, Alberto; La Rocca, Giuseppe; Milanesi, Luciano; Maggi, Giorgio Pietro; Vicario, Saverio

2009-06-16

Grid technology is the computing model which allows users to share a wide pletora of distributed computational resources regardless of their geographical location. Up to now, the high security policy requested in order to access distributed computing resources has been a rather big limiting factor when trying to broaden the usage of Grids into a wide community of users. Grid security is indeed based on the Public Key Infrastructure (PKI) of X.509 certificates and the procedure to get and manage those certificates is unfortunately not straightforward. A first step to make Grids more appealing for new users has recently been achieved with the adoption of robot certificates. Robot certificates have recently been introduced to perform automated tasks on Grids on behalf of users. They are extremely useful for instance to automate grid service monitoring, data processing production, distributed data collection systems. Basically these certificates can be used to identify a person responsible for an unattended service or process acting as client and/or server. Robot certificates can be installed on a smart card and used behind a portal by everyone interested in running the related applications in a Grid environment using a user-friendly graphic interface. In this work, the GENIUS Grid Portal, powered by EnginFrame, has been extended in order to support the new authentication based on the adoption of these robot certificates. The work carried out and reported in this manuscript is particularly relevant for all users who are not familiar with personal digital certificates and the technical aspects of the Grid Security Infrastructure (GSI). The valuable benefits introduced by robot certificates in e-Science can so be extended to users belonging to several scientific domains, providing an asset in raising Grid awareness to a wide number of potential users. The adoption of Grid portals extended with robot certificates, can really contribute to creating transparent access to

La redistribución dinámica mitocondria-núcleo de la inmunofilina FKBP51 es regulada por PKA para modular la expresión de genes durante el proceso de adipogénesis

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Judith Toneatto

2013-10-01

Full Text Available Los glucocorticoides tienen un papel central en la adipogénesis, por su unión al receptor RG citoplasmático formando parte de un heterocomplejo también integrado por una inmunofilina (INM de alto peso molecular, FKBP51 o FKBP52. Durante la diferenciación adipocítica los niveles de Hsp90, Hsp70 y p23 no se modifican, mientras la expresión de FKBP52 disminuye y la de FKBP51 aumenta progresivamente. FKBP51 sufre una dinámica redistribución mitocondria-núcleo al inicio del proceso de adipogénesis, concentrándose en la lámina nuclear coincidiendo temporalmente con su reorganización. A las 48 h la INM se concentra nuevamente en las mitocondrias. Esta dinámica redistribución mitocondria-núcleo es regulada por glucocorticoides principalmente, por la vía AMPc-PKA ya que la inhibición de PKA por PKI-miristoilado bloquea la traslocación de FKBP51 a núcleo inducida por 3-isobutil-1-metilxantina (IBMX. PKA-c se asocia con RG de manera ligando-dependiente potenciando su actividad transcripcional y ésta disminuye con IBMX, forskolina o dibutiril-AMPc que inducen la traslocación a núcleo de FKBP51 y, por lo tanto, PKA podría ejercer un papel dual en la regulación de dicho factor. En síntesis, la presencia de FKBP51 en el núcleo dependiente de la activación de PKA puede ser crítica para el control de RG y posiblemente para otros factores no pertenecientes a la familia de los receptores nucleares cuya función es regulada también por dicha vía de señalización, evento que tiene lugar en una etapa del proceso de diferenciación con alto nivel de remodelamiento de cromatina, pero donde la transcripción debe estar estrictamente controlada para la adquisición del fenotipo adipocítico.

Emerging role of epidermal growth factor receptor inhibition in therapy for advanced malignancy: focus on NSCLC

International Nuclear Information System (INIS)

Langer, Corey J.

2004-01-01

Combination chemotherapy regimens have emerged as the standard approach in advanced non-small-cell lung cancer. Meta-analyses have demonstrated a 2-month increase in median survival after platinum-based therapy vs. best supportive care, and an absolute 10% improvement in the 1-year survival rate. Just as importantly, cytotoxic therapy has produced benefits in symptom control and quality of life. Newer agents, including the taxanes, vinorelbine, gemcitabine, and irinotecan, have expanded our therapeutic options in the treatment of advanced non-small-cell lung cancer. Despite their contributions, we have reached a therapeutic plateau, with response rates seldom exceeding 30-40% in cooperative group studies and 1-year survival rates stable between 30% and 40%. It is doubtful that substituting one agent for another in various combinations will lead to any further improvement in these rates. The thrust of current research has focused on targeted therapy, and epidermal growth factor receptor inhibition is one of the most promising clinical strategies. Epidermal growth factor receptor inhibitors currently under investigation include the small molecules gefitinib (Iressa, ZD1839) and erlotinib (Tarceva, OSI-774), as well as monoclonal antibodies such as cetuximab (IMC-225, Erbitux). Agents that have only begun to undergo clinical evaluation include CI-1033, an irreversible pan-erbB tyrosine kinase inhibitor, and PKI166 and GW572016, both examples of dual kinase inhibitors (inhibiting epidermal growth factor receptor and Her2). Preclinical models have demonstrated synergy for all these agents in combination with either chemotherapy or radiotherapy, leading to great enthusiasm regarding their ultimate contribution to lung cancer therapy. However, serious clinical challenges persist. These include the identification of the optimal dose(s); the proper integration of these agents into popular, established cytotoxic regimens; and the selection of the optimal setting(s) in which

Nuclear Physics Science Network Requirements Workshop, May 2008 - Final Report

Energy Technology Data Exchange (ETDEWEB)

Tierney, Ed., Brian L; Dart, Ed., Eli; Carlson, Rich; Dattoria, Vince; Ernest, Michael; Hitchcock, Daniel; Johnston, William; Kowalski, Andy; Lauret, Jerome; Maguire, Charles; Olson, Douglas; Purschke, Martin; Rai, Gulshan; Watson, Chip; Vale, Carla

2008-11-10

The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the US Department of Energy Office of Science, the single largest supporter of basic research in the physical sciences in the United States of America. In support of the Office of Science programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet to be a highly successful enabler of scientific discovery for over 20 years. In May 2008, ESnet and the Nuclear Physics (NP) Program Office of the DOE Office of Science organized a workshop to characterize the networking requirements of the science programs funded by the NP Program Office. Most of the key DOE sites for NP related work will require significant increases in network bandwidth in the 5 year time frame. This includes roughly 40 Gbps for BNL, and 20 Gbps for NERSC. Total transatlantic requirements are on the order of 40 Gbps, and transpacific requirements are on the order of 30 Gbps. Other key sites are Vanderbilt University and MIT, which will need on the order of 20 Gbps bandwidth to support data transfers for the CMS Heavy Ion program. In addition to bandwidth requirements, the workshop emphasized several points in regard to science process and collaboration. One key point is the heavy reliance on Grid tools and infrastructure (both PKI and tools such as GridFTP) by the NP community. The reliance on Grid software is expected to increase in the future. Therefore, continued development and support of Grid software is very important to the NP science community. Another key finding is that scientific productivity is greatly enhanced by easy researcher-local access to instrument data. This is driving the creation of distributed repositories for instrument data at collaborating institutions, along with a corresponding increase in demand for network-based data transfers and the tools

Book reviews

Directory of Open Access Journals (Sweden)

Redactie KITLV

2013-01-01

Full Text Available Tony Day and Maya H.T. Liem (eds, Cultures at war: The Cold War and cultural expression in Southeast Asia (Manneke Budiman Fox, Richard, Critical reflections on religion and media in contemporary Bali (Martin Ramstedt Faisal S. Hazis, Domination and contestation: Muslim bumiputera politics in Sarawak (Gerhard Hoffstaedter Liesbeth Hesselink, Healers on the colonial market: Native doctors and midwivesin the Dutch East Indies (Leo van Bergen May Ingawanij and Benjamin McKay (eds, Glimpses of freedom: Independent cinema in Southeast Asia (Katinka van Heeren Laura Jarnagin (ed., The making of the Luso-Asian world: Intricacies of engagement (Hans Hägerdal J.J.P. de Jong, Avondschot: Hoe Nederland zich terugtrok uit zijn Aziatisch imperium (William H. Frederick Eben Kirksey, Freedom in entangled worlds: West Papua and the architecture of global power (Pieter Drooglever Lev, Daniel S., No concessions: The life of Yap Thiam Hien, Indonesian human rights lawyer (Gerry van Klinken Rémy Madinier, L’Indonésie, entre démocratie musulmane et Islam intégral: Histoire du parti Masjumi (1945-1960 (Chiara Formichi Rod Nixon, Justice and governance in East Timor: Indigenous approaches and the ‘New Subsistence State’ (Hans Hägerdal Philippe M.F. Peycam, The birth of Vietnamese political journalism: Saïgon 1916-1930 (Pierre Brocheux Harry Poeze, Madiun 1948: PKI bergerak (Avsi Warman Adam Ronit Ricci, Islam translated: Literature, conversion, and the Arabic cosmopolis of South and Southeast Asia (William Cummings Sokhieng Au, Mixed medicines: Health and culture in French colonial Cambodia (Leo van Bergen Kobkua Suwannathat-Pian, Palace, political party and power: A story of the sociopolitical development of Malay Kingship (A.J. Stockwell G. Teitler, Op het koloniale oorlogspad; De strijd tegen Moslim-fundamentalisten ter Westkust van Sumatra (1817-1838, vergeleken met de Russische verovering van Tjetsjenië en Dagestan (1817-1859 (Joshua Gedacht Gerard

Distinctive G Protein-Dependent Signaling by Protease-Activated Receptor 2 (PAR2 in Smooth Muscle: Feedback Inhibition of RhoA by cAMP-Independent PKA.

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Wimolpak Sriwai

Full Text Available We examined expression of protease-activated receptors 2 (PAR2 and characterized their signaling pathways in rabbit gastric muscle cells. The PAR2 activating peptide SLIGRL (PAR2-AP stimulated Gq, G13, Gi1, PI hydrolysis, and Rho kinase activity, and inhibited cAMP formation. Stimulation of PI hydrolysis was partly inhibited in cells expressing PAR2 siRNA, Gaq or Gai minigene and in cells treated with pertussis toxin, and augmented by expression of dominant negative regulator of G protein signaling (RGS4(N88S. Stimulation of Rho kinase activity was abolished by PAR-2 or Ga13 siRNA, and by Ga13 minigene. PAR2-AP induced a biphasic contraction; initial contraction was selectively blocked by the inhibitor of PI hydrolysis (U73122 or MLC kinase (ML-9, whereas sustained contraction was selectively blocked by the Rho kinase inhibitor (Y27632. PAR2-AP induced phosphorylation of MLC20, MYPT1 but not CPI-17. PAR2-AP also caused a decrease in the association of NF-kB and PKA catalytic subunit: the effect of PAR2-AP was blocked by PAR2 siRNA or phosphorylation-deficient RhoA (RhoA(S188A. PAR2-AP-induced degradation of IkBa and activation of NF-kB were abolished by the blockade of RhoA activity by Clostridium botulinum C3 exoenzyme suggesting RhoA-dependent activation of NF-kB. PAR2-AP-stimulated Rho kinase activity was significantly augmented by the inhibitors of PKA (myristoylated PKI, IKK2 (IKKIV or NF-kB (MG132, and in cells expressing dominant negative mutants of IKK (IKK(K44A, IkBa (IkBa (S32A/S36A or RhoA(S188A, suggesting feedback inhibition of Rho kinase activity via PKA derived from NF-kB pathway. PAR2-AP induced phosphorylation of RhoA and the phosphorylation was attenuated in cells expressing phosphorylation-deficient RhoA(S188A. Our results identified signaling pathways activated by PAR2 to mediate smooth muscle contraction and a novel pathway for feedback inhibition of PAR2-stimulated RhoA. The pathway involves activation of the NF-kB to

Protonation mechanism and location of rate-determining steps for the Ascaris suum nicotinamide adenine dinucleotide-malic enzyme reaction from isotope effects and pH studies

International Nuclear Information System (INIS)

Kiick, D.M.; Harris, B.G.; Cook, P.F.

1986-01-01

The pH dependence of the kinetic parameters and the primary deuterium isotope effects with nicotinamide adenine dinucleotide (NAD) and also thionicotinamide adenine dinucleotide (thio-NAD) as the nucleotide substrates were determined in order to obtain information about the chemical mechanism and location of rate-determining steps for the Ascaris suum NAD-malic enzyme reaction. The maximum velocity with thio-NAD as the nucleotide is pH-independent from pH 4.2 to 9.6, while with NAD, V decreases below a pK of 4.8. V/K for both nucleotides decreases below a pK of 5.6 and above a pK of 8.9. Both the tartronate pKi and V/Kmalate decrease below a pK of 4.8 and above a pK of 8.9. Oxalate is competitive vs. malate above pH 7 and noncompetitive below pH 7 with NAD as the nucleotide. The oxalate Kis increases from a constant value above a pK of 4.9 to another constant value above a pK of 6.7. The oxalate Kii also increases above a pK of 4.9, and this inhibition is enhanced by NADH. In the presence of thio-NAD the inhibition by oxalate is competitive vs. malate below pH 7. For thio-NAD, both DV and D(V/K) are pH-independent and equal to 1.7. With NAD as the nucleotide, DV decreases to 1.0 below a pK of 4.9, while D(V/KNAD) and D(V/Kmalate) are pH-independent. Above pH 7 the isotope effects on V and the V/K values for NAD and malate are equal to 1.45, the pH-independent value of DV above pH 7. Results indicate that substrates bind to only the correctly protonated form of the enzyme. Two enzyme groups are necessary for binding of substrates and catalysis. Both NAD and malate are released from the Michaelis complex at equal rates which are equal to the rate of NADH release from E-NADH above pH 7. Below pH 7 NADH release becomes more rate-determining as the pH decreases until at pH 4.0 it completely limits the overall rate of the reaction

Naftopidil inhibits 5-hydroxytryptamine-induced bladder contraction in rats.

Science.gov (United States)

Sakai, Takumi; Kasahara, Ken-ichi; Tomita, Ken-ichi; Ikegaki, Ichiro; Kuriyama, Hiroshi

2013-01-30

Naftopidil is an α(1D) and α(1A) subtype-selective α(1)-adrenoceptor antagonist that has been used to treat lower urinary tract symptoms of benign prostatic hyperplasia. In this study, we investigated the effects of naftopidil on 5-hydroxytryptamine (5-HT)-induced rat bladder contraction (10(-8)-10(-4) M). Naftopidil (0.3, 1, and 3 μM) inhibited 5-HT-induced bladder contraction in a concentration-dependent manner. On the other hand, other α(1)-adrenoceptor antagonists, tamsulosin, silodosin or prazosin, did not inhibit 5-HT-induced bladder contraction. The 5-HT-induced bladder contraction was inhibited by both ketanserin and 4-(4-fluoronaphthalen-1-yl)-6-propan-2-ylpyrimidin-2-amine (RS127445), serotonin 5-HT(2A) and 5-HT(2B) receptor antagonists, respectively. In addition, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and α-methyl-5-HT, 5-HT(2A) and 5-HT(2) receptor agonists, respectively, induced bladder contraction. The 5-HT-induced bladder contraction was not inhibited by N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-N-pyridin-2-yl-cyclohexanecarboxamide (WAY-100635), [1-[2[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl-1-methyl-1H-indole-3-carboxylate (GR113808) or (R)-3-[2-[2-(4-methylpiperidin-1-yl)ethyl]pyrrolidine-1-sulphonyl]phenol (SB269970), 5-HT(1A), 5-HT(4) and 5-HT(7) receptor antagonists, respectively. Naftopidil inhibited both the 5-HT(2A) and 5-HT(2) receptor agonists-induced bladder contractions. Naftopidil binds to the human 5-HT(2A) and 5-HT(2B) receptors with pKi values of 6.55 and 7.82, respectively. These results suggest that naftopidil inhibits 5-HT-induced bladder contraction via blockade of the 5-HT(2A) and 5-HT(2B) receptors in rats. Furthermore, 5-HT-induced bladder contraction was enhanced in bladder strips obtained from bladder outlet obstructed rats, with this contraction inhibited by naftopidil. The beneficial effects of naftopidil on storage symptoms such as urinary frequency and nocturia in patients with benign

Picroside I and Picroside II from Tissue Cultures of Picrorhiza kurroa

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Ganeshkumar, Yamjala; Ramarao, Ajmera; Veeresham, Ciddi

2017-01-01

Background: Picrorhiza kurroa (PK) belongs to Scrophulariaceae family and is a representative endemic, medicinal herb, widely distributed throughout the higher altitudes of alpine Himalayas from west to east, between 3000 and 4500 m above mean sea level. Objective: The objective of the present study is to assess the production of picroside I and picroside II from tissue cultures of PK. Materials and Methods: Auxiliary shoot tips of PK were incubated in Murashige and Skoog medium supplemented with indole-3-butyric acid and kinetin phytohormones. The callus produced was collected at different time intervals and was processed for extraction of picroside I and picroside II followed by thin layer chromatography and high-performance liquid chromatography HPLC analysis. Results: The maximum growth index was found to be 5.109 ± 0.159 at 16-week-old callus culture. The estimation of picroside-I and picroside-II was carried out by (HPLC) analysis; quantity of secondary metabolite found to be 16.37 ± 0.0007 mg/g for PK-I and 6.34 ± 0.0012 mg/g for PK-II. Conclusion: This is the first attempt to produce the Picroside-I and II in large amount by the tissue culture technique. It can be observed that the method of callus culture can be used in production of secondary metabolites Picroside-I and II from PK SUMMARY Picrorhiza kurroa is a high value medicinal herb due to rich source of hepatoprotective metabolites, Picroside-I and Picroside-II. The medicinal importance of P. kurroa is due to its pharmacological properties like hepatoprotective, antioxidant (particularly in liver), antiallergic and antiasthamatic, anticancer activity particularly in liver and immunomodulatory. Shoot apices which were produced a good response was inoculated on selected medium i.e., on MS medium containing 2, 4 D (mg/l) + KN (1mg/l) for induction of callus. The initiation of callus was observed after 4weeks and it was light green and fragile Maximum growth was observed with 3% w/v of sucrose

Orthosteric Binding of ρ-Da1a, a Natural Peptide of Snake Venom Interacting Selectively with the α1A-Adrenoceptor

Science.gov (United States)

Maïga, Arhamatoulaye; Merlin, Jon; Marcon, Elodie; Rouget, Céline; Larregola, Maud; Gilquin, Bernard; Fruchart-Gaillard, Carole; Lajeunesse, Evelyne; Marchetti, Charles; Lorphelin, Alain; Bellanger, Laurent; Summers, Roger J.; Hutchinson, Dana S.; Evans, Bronwyn A.; Servent, Denis; Gilles, Nicolas

2013-01-01

ρ-Da1a is a three-finger fold toxin from green mamba venom that is highly selective for the α1A-adrenoceptor. This toxin has atypical pharmacological properties, including incomplete inhibition of 3H-prazosin or 125I-HEAT binding and insurmountable antagonist action. We aimed to clarify its mode of action at the α1A-adrenoceptor. The affinity (pKi 9.26) and selectivity of ρ-Da1a for the α1A-adrenoceptor were confirmed by comparing binding to human adrenoceptors expressed in eukaryotic cells. Equilibrium and kinetic binding experiments were used to demonstrate that ρ-Da1a, prazosin and HEAT compete at the α1A-adrenoceptor. ρ-Da1a did not affect the dissociation kinetics of 3H-prazosin or 125I-HEAT, and the IC50 of ρ-Da1a, determined by competition experiments, increased linearly with the concentration of radioligands used, while the residual binding by ρ-Da1a remained stable. The effect of ρ-Da1a on agonist-stimulated Ca2+ release was insurmountable in the presence of phenethylamine- or imidazoline-type agonists. Ten mutations in the orthosteric binding pocket of the α1A-adrenoceptor were evaluated for alterations in ρ-Da1a affinity. The D1063.32A and the S1885.42A/S1925.46A receptor mutations reduced toxin affinity moderately (6 and 7.6 times, respectively), while the F862.64A, F2886.51A and F3127.39A mutations diminished it dramatically by 18- to 93-fold. In addition, residue F862.64 was identified as a key interaction point for 125I-HEAT, as the variant F862.64A induced a 23-fold reduction in HEAT affinity. Unlike the M1 muscarinic acetylcholine receptor toxin MT7, ρ-Da1a interacts with the human α1A-adrenoceptor orthosteric pocket and shares receptor interaction points with antagonist (F862.64, F2886.51 and F3127.39) and agonist (F2886.51 and F3127.39) ligands. Its selectivity for the α1A-adrenoceptor may result, at least partly, from its interaction with the residue F862.64, which appears to be important also for HEAT binding. PMID:23935897

Imidazoquinolinone, imidazopyridine, and isoquinolindione derivatives as novel and potent inhibitors of the poly(ADP-ribose) polymerase (PARP): a comparison with standard PARP inhibitors.

Science.gov (United States)

Eltze, Tobias; Boer, Rainer; Wagner, Thomas; Weinbrenner, Steffen; McDonald, Michelle C; Thiemermann, Christoph; Bürkle, Alexander; Klein, Thomas

2008-12-01

We have identified three novel structures for inhibitors of the poly(ADP-ribose) polymerase (PARP), a nuclear enzyme activated by strand breaks in DNA and implicated in DNA repair, apoptosis, organ dysfunction or necrosis. 2-[4-(5-Methyl-1H-imidazol-4-yl)-piperidin-1-yl]-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK49187), 2-(4-pyridin-2-yl-phenyl)-4,5-dihydro-imidazo[4,5,1-i,j]quinolin-6-one (BYK236864), 6-chloro-8-hydroxy-2,3-dimethyl-imidazo-[1,2-alpha]-pyridine (BYK20370), and 4-(1-methyl-1H-pyrrol-2-ylmethylene)-4H-isoquinolin-1,3-dione (BYK204165) inhibited cell-free recombinant human PARP-1 with pIC(50) values of 8.36, 7.81, 6.40, and 7.35 (pK(i) 7.97, 7.43, 5.90, and 7.05), and murine PARP-2 with pIC(50) values of 7.50, 7.55, 5.71, and 5.38, respectively. BYK49187, BYK236864, and BYK20370 displayed no selectivity for PARP-1/2, whereas BYK204165 displayed 100-fold selectivity for PARP-1. The IC(50) values for inhibition of poly(ADP-ribose) synthesis in human lung epithelial A549 and cervical carcinoma C4I cells as well in rat cardiac myoblast H9c2 cells after PARP activation by H(2)O(2) were highly significantly correlated with those at cell-free PARP-1 (r(2) = 0.89-0.96, P < 0.001) but less with those at PARP-2 (r(2) = 0.78-0.84, P < 0.01). The infarct size caused by coronary artery occlusion and reperfusion in the anesthetized rat was reduced by 22% (P < 0.05) by treatment with BYK49187 (3 mg/kg i.v. bolus and 3 mg/kg/h i.v. during 2-h reperfusion), whereas the weaker PARP inhibitors, BYK236864 and BYK20370, were not cardioprotective. In conclusion, the imidazoquinolinone BYK49187 is a potent inhibitor of human PARP-1 activity in cell-free and cellular assays in vitro and reduces myocardial infarct size in vivo. The isoquinolindione BYK204165 was found to be 100-fold more selective for PARP-1. Thus, both compounds might be novel and valuable tools for investigating PARP-1-mediated effects.

Nuclear Physics Science Network Requirements Workshop, May 6 and 7, 2008. Final Report

International Nuclear Information System (INIS)

Tierney, Ed. Brian L; Dart, Ed. Eli; Carlson, Rich; Dattoria, Vince; Ernest, Michael; Hitchcock, Daniel; Johnston, William; Kowalski, Andy; Lauret, Jerome; Maguire, Charles; Olson, Douglas; Purschke, Martin; Rai, Gulshan; Watson, Chip; Vale, Carla

2008-01-01

The Energy Sciences Network (ESnet) is the primary provider of network connectivity for the US Department of Energy Office of Science, the single largest supporter of basic research in the physical sciences in the United States of America. In support of the Office of Science programs, ESnet regularly updates and refreshes its understanding of the networking requirements of the instruments, facilities, scientists, and science programs that it serves. This focus has helped ESnet to be a highly successful enabler of scientific discovery for over 20 years. In May 2008, ESnet and the Nuclear Physics (NP) Program Office of the DOE Office of Science organized a workshop to characterize the networking requirements of the science programs funded by the NP Program Office. Most of the key DOE sites for NP related work will require significant increases in network bandwidth in the 5 year time frame. This includes roughly 40 Gbps for BNL, and 20 Gbps for NERSC. Total transatlantic requirements are on the order of 40 Gbps, and transpacific requirements are on the order of 30 Gbps. Other key sites are Vanderbilt University and MIT, which will need on the order of 20 Gbps bandwidth to support data transfers for the CMS Heavy Ion program. In addition to bandwidth requirements, the workshop emphasized several points in regard to science process and collaboration. One key point is the heavy reliance on Grid tools and infrastructure (both PKI and tools such as GridFTP) by the NP community. The reliance on Grid software is expected to increase in the future. Therefore, continued development and support of Grid software is very important to the NP science community. Another key finding is that scientific productivity is greatly enhanced by easy researcher-local access to instrument data. This is driving the creation of distributed repositories for instrument data at collaborating institutions, along with a corresponding increase in demand for network-based data transfers and the tools

Inferences on the Physical Nature of Earth's Inner Core Boundary Region from Observations of Antipodal PKIKP and PKIIKP Waves

Science.gov (United States)

Cormier, V. F.; Attanayake, J.; Thomas, C.; Koper, K. D.; Miller, M. S.

2017-12-01

The Earth's Inner Core Boundary (ICB) is considered a uniform and sharp liquid-to-solid transition in standard Earth models such as PREM and AK135-F. By analysing seismic wave reflections emanating from the ICB, this hypothesis of a simple ICB can be tested. Observed absolute and relative amplitudes and coda of the PKiKP phase that is reflected on the topside of the ICB suggest that the ICB is neither uniform nor has a simple structure. Similarly, waves that are reflected from the underside of the ICB - PKIIKP phase - can be used to determine the physical nature of the region immediately below the ICB. Using high-frequency synthetic waveform experiments, we confirm that antipodal PKIIKP amplitudes can discriminate the state of the uppermost 10 km of the inner core: A standard liquid-to-solid ICB (high shear velocity/shear modulus discontinuity) produces a maximum PKIIKP amplitude equal to only a factor of 0.14 of the PKIKP amplitude, whereas a non-standard liquid-to-near liquid ICB (low shear velocity/shear modulus discontinuity) can produce PKIIKP amplitudes comparable to PKIKP. We searched for PKIIKP in individual and stacked array waveforms in the 170° - 180° distance range for the 2000 to 2016 time period globally to compare with our synthetic results. We attribute a lack of PKIIKP detection in the stacked array recordings due to (1) ranges closer to 170° and not 180°, where the PKIIKP signal-to-noise ratio is very poor; (2) scattered coda following PKIKP masking the PKIIKP phase; and (3) large azimuthal variations of array recordings closer to 180° preventing the formation of an accurate beam. Envelopes of individual recordings in the 178° - 180° distance range, however, clearly show energy peaks correlating with the travel time of PKIIKP phase. Our global set of PKIIKP/PKIKP energy ratio measurements vary between 0.1 and 1.1, indicating significant structural complexity immediately below the ICB. While a complex inner core anisotropy structure and ICB

Střípky dějin – brněnské pracoviště Ústavu pro etnografii a folkloristiku ČSAV v korespondenci Karla Vetterla s Jiřím Horákem

Czech Academy of Sciences Publication Activity Database

Bahenská, Marie; Jůnová Macková, Adéla

2017-01-01

Roč. 9, č. 2 (2017), s. 63-106 ISSN 1803-9448 R&D Projects: GA ČR GA15-03754S Institutional support: RVO:67985921 Keywords : Karel Vetterl * Jiří Horák * history of ethnology Subject RIV: AB - History OBOR OECD: History (history of science and technology to be 6.3, history of specific sciences to be under the respective headings)

The 6th International Conference on Computer Science and Computational Mathematics (ICCSCM 2017)

Science.gov (United States)

2017-09-01

The ICCSCM 2017 (The 6th International Conference on Computer Science and Computational Mathematics) has aimed to provide a platform to discuss computer science and mathematics related issues including Algebraic Geometry, Algebraic Topology, Approximation Theory, Calculus of Variations, Category Theory; Homological Algebra, Coding Theory, Combinatorics, Control Theory, Cryptology, Geometry, Difference and Functional Equations, Discrete Mathematics, Dynamical Systems and Ergodic Theory, Field Theory and Polynomials, Fluid Mechanics and Solid Mechanics, Fourier Analysis, Functional Analysis, Functions of a Complex Variable, Fuzzy Mathematics, Game Theory, General Algebraic Systems, Graph Theory, Group Theory and Generalizations, Image Processing, Signal Processing and Tomography, Information Fusion, Integral Equations, Lattices, Algebraic Structures, Linear and Multilinear Algebra; Matrix Theory, Mathematical Biology and Other Natural Sciences, Mathematical Economics and Financial Mathematics, Mathematical Physics, Measure Theory and Integration, Neutrosophic Mathematics, Number Theory, Numerical Analysis, Operations Research, Optimization, Operator Theory, Ordinary and Partial Differential Equations, Potential Theory, Real Functions, Rings and Algebras, Statistical Mechanics, Structure Of Matter, Topological Groups, Wavelets and Wavelet Transforms, 3G/4G Network Evolutions, Ad-Hoc, Mobile, Wireless Networks and Mobile Computing, Agent Computing & Multi-Agents Systems, All topics related Image/Signal Processing, Any topics related Computer Networks, Any topics related ISO SC-27 and SC- 17 standards, Any topics related PKI(Public Key Intrastructures), Artifial Intelligences(A.I.) & Pattern/Image Recognitions, Authentication/Authorization Issues, Biometric authentication and algorithms, CDMA/GSM Communication Protocols, Combinatorics, Graph Theory, and Analysis of Algorithms, Cryptography and Foundation of Computer Security, Data Base(D.B.) Management & Information

Effective sharing of health records, maintaining privacy: a practical schema.

Science.gov (United States)

Neame, Roderick

2013-01-01

.). For added security, as well as for trustworthiness, a method of verifying authenticity, integrity and authorship is required, which can be provided using a public key infrastructure (PKI) for cryptography (2). The second part of the solution is to give control over record access and sharing to the patient (or their identified representative), enabling them to authorise access by providing the index and access keys to their records. This can be done using a token (fe.g. smart card) or a secure online index which holds these details: this serves to relieve the formal record keeper of responsibility for external access control and privacy (internal access control and privacy can remain an institutional responsibility). The third part of the solution is to process the content of the stored records such that there is a 'plain English' copy, as well as an electronic copy which is coded and marked up using XML tags for each data element to signify 'type' (e.g. administrative, financial, operational, clinical etc.) and sub-types (e.g. diagnosis, medication, procedure, investigation result etc.). This ensures that the recipient can always read the data using a basic browser, but can readily manipulate and re-arrange the data for display and storage if they have a more sophisticated installation.

Actions of alpha2 adrenoceptor ligands at alpha2A and 5-HT1A receptors: the antagonist, atipamezole, and the agonist, dexmedetomidine, are highly selective for alpha2A adrenoceptors.

Science.gov (United States)

Newman-Tancredi, A; Nicolas, J P; Audinot, V; Gavaudan, S; Verrièle, L; Touzard, M; Chaput, C; Richard, N; Millan, M J

1998-08-01

This study examined the activity of chemically diverse alpha2 adrenoceptor ligands at recombinant human (h) and native rat (r) alpha2A adrenoceptors compared with 5-HT1A receptors. First, in competition binding experiments at h alpha2A and h5-HT1A receptors expressed in CHO cells, several compounds, including the antagonists 1-(2-pyrimidinyl)piperazine (1-PP), (+/-)-idazoxan, benalfocin (SKF 86466), yohimbine and RX 821,002, displayed preference for h alpha2A versus h5-HT1A receptors of only 1.4-, 3.6-, 4-, 10- and 11-fold, respectively (based on differences in pKi values). Clonidine, brimonidine (UK 14304), the benzopyrrolidine fluparoxan and the guanidines guanfacine and guanabenz exhibited intermediate selectivity (22- to 31-fold) for h alpha2A receptors. Only the antagonist atipamezole and the agonist dexmedetomidine (DMT) displayed high preference for alpha2 adrenoceptors (1290- and 91-fold, respectively). Second, the compounds were tested for their ability to induce h5-HT1A receptor-mediated G-protein activation, as indicated by the stimulation of [35S]GTPgammaS binding. All except atipamezole and RX 821,002 exhibited agonist activity, with potencies which correlated with their affinity for h5-HT1A receptors. Relative efficacies (Emax values) were 25-35% for guanabenz, guanfacine, WB 4101 and benalfocin, 50-65% for 1-PP, (+/-)-idazoxan and clonidine, and over 70% for fluparoxan, oxymetazoline and yohimbine (relative to 5-HT = 100%). Yohimbine-induced [35S]GTPgammaS binding was inhibited by the selective 5-HT1A receptor antagonist WAY 100,635. In contrast, RX 821,002 was the only ligand which exhibited antagonist activity at h5-HT1A receptors, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Atipamezole, which exhibited negligeable affinity for 5-HT1A receptors, was inactive. Third, the affinities for r alpha2A differed considerably from the affinities for h alpha2A receptors whereas the affinities for r5-HT1A differed much less from the affinities for h5-HT

Security Technologies for Open Networking Environments (STONE)

Energy Technology Data Exchange (ETDEWEB)

Muftic, Sead

2005-03-31

-domain scenarios is supported by a set of security engines that represent the core of the Federated Identities Management Server, which is also an extension of the Domain Security Server. The Federated Identity Management server allows users to federate their identities or terminate the federation between the service provider and the identity provider. At the service provider web site, the users are offered a list of identity providers to which they can choose to federate their identities. After users federate their identity, they can perform Single Sign-On protocol in an environment of federated domains. The group security system consists of a number of security technologies under a unified architecture, which supports creation of secure groups and execution of secure group transactions and applications in an open networking environment. The system is based on extensions of the GSAKMP standard for group key distribution and management. The Top layer is the Security Infrastructure with the Security Management and Administration System components and protocols that provide security functions common to all secure network applications The Middle layer is the Secure Group Protocols and Applications layer, consisting of the Policy and Group Key Distribution Server and Web-based (thin) Client. The Bottom layer is the supporting Middleware Security Platform, the cryptographic platform already described above. The group security system is designed to perform the functions necessary to create secure groups and enable secure group applications. Specifically, the system can manage group roles, create and disseminate a group security policy, perform authentication and authorization of users using PKI certificates and Web services security, generate group keys, and recover from compromises. In accordance with the GSAKMP standard, the group security system must perform all the required group life-cycle functions: group definition, group establishment, group maintenance, and group removal. The