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

PubMed

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)

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

PubMed

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 useful co-therapy in combination with intermittent PTH or beta-adrenergic agonists for bone loss in conditions such as osteoporosis. However, the potential use of such a co-therapy would depend on it not adversely affecting bone formation or other organ systems.

The Security Email Based on Smart Card

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

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

PubMed

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.

Proliferation marker pKi-67 affects the cell cycle in a self-regulated manner.

PubMed

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

2002-01-01

The proliferation marker pKi-67 is commonly used in research and pathology to detect proliferating cells. In a previous work, we found the protein to be associated with regulators of the cell cycle, controlling S-phase progression, as well as entry into and exit from mitosis. Here we investigate whether pKi-67 has a regulative effect on the cell cycle itself. For that purpose we cloned four fragments of pKi-67, together representing nearly the whole protein, and an N-terminal pKi-67 antisense oligonucleotide into a tetracycline inducible gene expression system. The sense fragments were C-terminally modified by addition of either a nuclear localization sequence (NLS) or a STOP codon to address the impact of their intracellular distribution. FACS based cell cycle analysis revealed that expression of nearly all pKi-67 domains and the antisense oligonucleotide led to a decreased amount of cells in S-phase and an increased number of cells in G(2)/M- and G(1)-phase. Subsequent analysis of the endogenous pKi-67 mRNA and protein levels revealed that the constructs with the most significant impact on the cell cycle were able to silence pKi-67 transcription as well. We conclude from the data that pKi-67 influences progression of S-phase and mitosis in a self-regulated manner and, therefore, effects the cell cycle checkpoints within both phases. Furthermore, we found pKi-67 mediates an anti-apoptotic effect on the cell and we verified that this marker, although it is a potential ribosomal catalyst, is not expressed in differentiated tissues with a high transcriptional activity. Copyright 2002 Wiley-Liss, Inc.

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

PubMed

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.

Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.

PubMed

Solorzano, C C; Baker, C H; Tsan, R; Traxler, P; Cohen, P; Buchdunger, E; Killion, J J; Fidler, I J

2001-08-01

We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.

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

NASA Astrophysics Data System (ADS)

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.

Expression of the proliferation marker Ki-67 during early mouse development.

PubMed

Winking, H; Gerdes, J; Traut, W

2004-01-01

In somatic tissues, the mouse Ki-67 protein (pKi-67) is expressed in proliferating cells only. Depending on the stage of the cell cycle, pKi-67 is associated with different nuclear domains: with euchromatin as part of the perichromosomal layer, with centromeric heterochromatin, and with the nucleolus. In gametes, sex-specific expression is evident. Mature MII oocytes contain pKi-67, whereas pKi-67 is not detectable in mature sperm. We investigated the re-establishment of the cell cycle-dependent distribution of pKi-67 during early mouse development. After fertilization, male and female pronuclei exhibited very little or no pKi-67, while polar bodies were pKi-67 positive. Towards the end of the first cell cycle, prophase chromosomes of male and female pronuclei simultaneously got decorated with pKi-67. In 2-cell embryos, the distribution pattern changed, presumably depending on the progress of development of the embryo, from a distribution all over the nucleus to a preferential location in the nucleolus precursor bodies (NPBs). From the 4-cell stage onwards, pKi-67 showed the regular nuclear relocations known from somatic tissues: during mitosis the protein was found covering the chromosome arms as a constituent of the perichromosomal layer, in early G1 it was distributed in the whole nucleus, and for the rest of the cell cycle it was associated with NPBs or with the nucleolus. Copyright 2004 S. Karger AG, Basel

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

PubMed

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.

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

PubMed

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.

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

PubMed

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.

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).

PubMed

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.

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

PubMed

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.

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

PubMed

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.

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

PubMed

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 system and the rest of the body.

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

PubMed

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.

Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells.

PubMed

Bullwinkel, Jörn; Baron-Lühr, Bettina; Lüdemann, Anja; Wohlenberg, Claudia; Gerdes, Johannes; Scholzen, Thomas

2006-03-01

The nuclear Ki-67 protein (pKi-67) has previously been shown to be exclusively expressed in proliferating cells. As a result, antibodies against this protein are widely used as prognostic tools in cancer diagnostics. Here we show, that despite the strong downregulation of pKi-67 expression in non-proliferating cells, the protein can nevertheless be detected at sites linked to ribosomal RNA (rRNA) synthesis. Although this finding does not argue against the use of pKi-67 as a proliferation marker, it has wide ranging implications for the elucidation of pKi-67 function. Employing the novel antibody TuBB-9, we could further demonstrate that also in proliferating cells, a fraction of pKi-67 is found at sites linked to the rRNA transcription machinery during interphase and mitosis. Moreover, chromatin immunoprecipitation (ChIP) assays provided evidence for a physical association of pKi-67 with chromatin of the promoter and transcribed region of the rRNA gene cluster. These data strongly suggest a role for pKi-67 in the early steps of rRNA synthesis. Copyright 2005 Wiley-Liss, Inc.

Chromatin preferences of the perichromosomal layer constituent pKi-67.

PubMed

Traut, Walther; Endl, Elmar; Garagna, Silvia; Scholzen, Thomas; Schwinger, Eberhard; Gerdes, Johannes; Winking, Heinz

2002-01-01

The proliferation-associated nuclear protein pKi-67 relocates from the nucleolus to the chromosome surface during the G2/M transition of the cell cycle and contributes to the formation of the 'perichromosomal layer'. We investigated the in-vivo binding preferences of pKi-67 for various chromatin blocks of the mitotic chromosomes from the human and two mouse species, Mus musculus and M. caroli. All chromosomes were decorated with pKi-67 but displayed a gap of pKi-67 decoration in the centromere and NOR regions. pKi-67 distribution in a rearranged mouse chromosome showed that the formation of the centromeric gap was controlled by the specific chromatin in that region. While most chromatin served as a substrate for direct or indirect binding of pKi-67, we identified three types of chromatin that bound less or no pKi-67. These were: (1) the centromeric heterochromatin defined by the alpha satellite DNA in the human, by the mouse minor satellite in M. musculus and the 60- and 79-bp satellites in M. caroli; (2) the pericentromeric heterochromatin in M. musculus defined by the mouse major satellite, and (3) NORs in the human and in M. musculus defined by rDNA repeats. In contrast, the conspicuous blocks of pericentromeric heterochromatin in human chromosomes 1, 9 and 16 containing the 5-bp satellite showed intense pKi-67 decoration. The centromeric gap may have a biological significance for the proper attachment of the chromosomes to the mitotic spindle. In this context, our results suggest a new role for centromeric heterochromatin: the control of the centromeric gap in the perichromosomal layer.

Proliferation marker pKi-67 occurs in different isoforms with various cellular effects.

PubMed

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

2004-04-15

The Ki-67 antigen, pKi-67, is a commonly used proliferation marker in research and pathology. It has been recognized that the protein exists in two different splice variants that differ in one exon. In the current work, we present three new splice variants of human pKi-67 consisting of two naturally occurring isoforms and one atypical version. Additionally, data is presented indicating that alternative splicing of the pKi-67 N-terminus is common in tumor cell lines. Analyzing 93 tissues mainly consisting of brain tumor specimens, we found evidence that long and short isoform can be expressed independently of each other. Induction of mitosis in human peripheral blood mononuclear cells revealed that short pKi-67 appears earlier in the cell cycle than the long isoform and reaches its expression maximum when transcription of the latter sets in. Finally, transfection of mammalian culture cells with exon 7 (specific for the long pKi-67 isoform and not present in the short isoform) in a tetracycline regulated expression system decreased the rate of cell proliferation without affecting the cell cycle. In summary, we present evidence that the pKi-67 N-terminus is differentially spliced resulting in at least five different isoforms with different functions. Copyright 2004 Wiley-Liss, Inc.

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

PubMed

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 mitotic cell cycle but at late diplotene of prophase I in meiosis, suggesting physiological similarity of these stages.

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

PubMed

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 strains tested with minimal cytotoxicity to human endothelial cells and astrocytes, two key cell types for ZIKV infection. Furthermore, we show that PKI inhibits ZIKV negative-sense RNA synthesis and viral protein translation. This study has identified a potent inhibitor of ZIKV infection which could be further explored for future therapeutic application. Copyright © 2018 American Society for Microbiology.

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

PubMed

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.

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

PubMed

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.

PKiKP amplitude observations and structure of the inner core boundary

NASA Astrophysics Data System (ADS)

Krasnoshchekov, D.; Adushkin, V.; Ovtchinnikov, V.

2003-04-01

We present PKiKP amplitude observations at distances from 5.6 to 90 degrees that evidence substantial lateral variability of reflecting conditions on the inner core boundary. Unlike other PKiKP studies, that frequently use array data, detection of PKiKP phase in the work was accomplished on single vertical component. We have carefully investigated short-period digital vertical channels of 9 stations in Central Asia that recorded 43 Underground Nuclear Explosions carried out at Nevada, Lop-Nor, Novaya Zemlya and Semipalatinsk Test Sites in 1968 - 1994, and found numerous convincing examples of PKiKP waveforms. The amplitude data set varies in the range from 1 to 62 nm with predominant period of less than 1 s. Using known seismic source parameters we compared the expected PKiKP amplitudes and travel times to the experimental ones. The observed travel times are generally agreed with PREM within 1 s scatter, though amplitudes aren't. In addition, the whole stack of experimental amplitudes may hardly be simultaneously agreed with any regular model of the inner core boundary either sharp or with transition. Thorough analysis of the data set indicates, that detection of PKiKP and its amplitude is basically pre-defined by actual physical conditions at reflection point on the surface of the inner core which may vary substantially due to boundary processes of freezing and chemical (structural) convection.

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

PubMed

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.

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

PubMed

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.

Deficient Gene Expression in Protein Kinase Inhibitor α Null Mutant Mice

PubMed Central

Gangolli, Esha A.; Belyamani, Mouna; Muchinsky, Sara; Narula, Anita; Burton, Kimberly A.; McKnight, G. Stanley; Uhler, Michael D.; Idzerda, Rejean L.

2000-01-01

Protein kinase inhibitor (PKI) is a potent endogenous inhibitor of the cyclic AMP (cAMP)-dependent protein kinase (PKA). It functions by binding the free catalytic (C) subunit with a high affinity and is also known to export nuclear C subunit to the cytoplasm. The significance of these actions with respect to PKI's physiological role is not well understood. To address this, we have generated by homologous recombination mutant mice that are deficient in PKIα, one of the three isoforms of PKI. The mice completely lack PKI activity in skeletal muscle and, surprisingly, show decreased basal and isoproterenol-induced gene expression in muscle. Further examination revealed reduced levels of the phosphorylated (active) form of the transcription factor CREB (cAMP response element binding protein) in the knockouts. This phenomenon stems, at least in part, from lower basal PKA activity levels in the mutants, arising from a compensatory increase in the level of the RIα subunit of PKA. The deficit in gene induction, however, is not easily explained by current models of PKI function and suggests that PKI may play an as yet undescribed role in PKA signaling. PMID:10779334

Secure Remote Access Issues in a Control Center Environment

NASA Technical Reports Server (NTRS)

Pitts, Lee; McNair, Ann R. (Technical Monitor)

2002-01-01

The ISS finally reached an operational state and exists for local and remote users. Onboard payload systems are managed by the Huntsville Operations Support Center (HOSC). Users access HOSC systems by internet protocols in support of daily operations, preflight simulation, and test. In support of this diverse user community, a modem security architecture has been implemented. The architecture has evolved over time from an isolated but open system to a system which supports local and remote access to the ISS over broad geographic regions. This has been accomplished through the use of an evolved security strategy, PKI, and custom design. Through this paper, descriptions of the migration process and the lessons learned are presented. This will include product decision criteria, rationale, and the use of commodity products in the end architecture. This paper will also stress the need for interoperability of various products and the effects of seemingly insignificant details.

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

PubMed

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

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.

PubMed

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.

Security on Cloud Revocation Authority using Identity Based Encryption

NASA Astrophysics Data System (ADS)

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.

32-channel single photon counting module for ultrasensitive detection of DNA sequences

NASA Astrophysics Data System (ADS)

Gudkov, Georgiy; Dhulla, Vinit; Borodin, Anatoly; Gavrilov, Dmitri; Stepukhovich, Andrey; Tsupryk, Andrey; Gorbovitski, Boris; Gorfinkel, Vera

2006-10-01

We continue our work on the design and implementation of multi-channel single photon detection systems for highly sensitive detection of ultra-weak fluorescence signals, for high-performance, multi-lane DNA sequencing instruments. A fiberized, 32-channel single photon detection (SPD) module based on single photon avalanche diode (SPAD), model C30902S-DTC, from Perkin Elmer Optoelectronics (PKI) has been designed and implemented. Unavailability of high performance, large area SPAD arrays and our desire to design high performance photon counting systems drives us to use individual diodes. Slight modifications in our quenching circuit has doubled the linear range of our system from 1MHz to 2MHz, which is the upper limit for these devices and the maximum saturation count rate has increased to 14 MHz. The detector module comprises of a single board computer PC-104 that enables data visualization, recording, processing, and transfer. Very low dark count (300-1000 counts/s), robust, efficient, simple data collection and processing, ease of connectivity to any other application demanding similar requirements and similar performance results to the best commercially available single photon counting module (SPCM from PKI) are some of the features of this system.

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

PubMed

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.

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

PubMed

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.

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

PubMed

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.

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

PubMed

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.

Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice.

PubMed

Kim, Sun-Jin; Uehara, Hisanori; Karashima, Takashi; Shepherd, David L; Killion, Jerald J; Fidler, Isaiah J

2003-03-01

We determined whether blockade of the epidermal growth factor receptor (EGF-R) signaling pathway by oral administration of the EGF-R tyrosine kinase inhibitor (PKI 166) alone or in combination with injectable Taxol inhibits the growth of PC-3MM2 human prostate cancer cells in the bone of nude mice. Male nude mice implanted with PC-3MM2 cells in the tibia were treated with oral administrations of PKI 166 or PKI 166 plus injectable Taxol beginning 3 days after implantation. The incidence and size of bone tumors and destruction of bone were determined by digitalized radiography. Expression of epidermal growth factor (EGF), EGF-R, and activated EGF-R in tumor cells and tumor-associated endothelial cells was determined by immunohistochemistry. Oral administration of PKI 166 or PKI 166 plus injectable Taxol reduced the incidence and size of bone tumors and destruction of bone. Immunohistochemical analysis revealed that PC-3MM2 cells growing adjacent to the bone expressed high levels of EGF and activated EGF-R, whereas tumor cells in the adjacent musculature did not. Moreover, endothelial cells within the bone tumor lesions, but not in uninvolved bone or tumors in the muscle, expressed high levels of activated EGF-R. Treatment with PKI 166 and more so with PKI 166 plus Taxol significantly inhibited phosphorylation of EGF-R on tumor and endothelial cells and induced significant apoptosis and endothelial cells within tumor lesions. These data indicate that endothelial cells exposed to EGF produced by tumor cells express activated EGF-R and that targeting EGF-R can produce significant therapeutic effects against prostate cancer bone metastasis.

Leishmania major: effect of protein kinase A and phosphodiesterase activity on infectivity and proliferation of promastigotes.

PubMed

Malki-Feldman, Laura; Jaffe, Charles L

2009-09-01

Effect of modulators on protein kinase A (PKA) activity, promastigote growth and their ability to infect peritoneal macrophages was monitored. PKA inhibitors reduced [Protein Kinase Inhibitor (PKI) - 56%; H89 - 54.5%] kemptide phosphorylation by Leishmania major promastigote lysates, while activators increased phosphorylation (8-CPT-cAMP - 88%; Sp-cAMPS-AM - 152%). Activation was specifically inhibited by PKI. Phosphodiesterase inhibitors also increased kemptide phosphorylation (dipyridamole - 171%; rolipram - 106%; and 3-isobutyl-1-methyl-xanthine - 154%). Parasite proliferation was significantly retarded (200 nM H89; 100 microM myristoylated-PKI) or completely inhibited (500 nM H89) by culturing with PKA inhibitors. Incubation with dipyridamole or Sp-cAMPS-AM also inhibited proliferation. Brief treatment (2h) with either H89, myristoylated-PKI, dipyridamole or Sp-cAMPS-AM reduced initial macrophage infection at days 1 and 2 (>40%) and on day 3 (>78% only for 100 microM myr-PKI). Characterization of leishmanial cAMP mediated signal transduction pathways will serve as the basis for the new drug design.

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

PubMed

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.

Network Computing Infrastructure to Share Tools and Data in Global Nuclear Energy Partnership

NASA Astrophysics Data System (ADS)

Kim, Guehee; Suzuki, Yoshio; Teshima, Naoya

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.

Targeted light-inactivation of the Ki-67 protein using theranostic liposomes leads to death of proliferating cells

NASA Astrophysics Data System (ADS)

Rahmanzadeh, Ramtin; Rai, Prakash; Gerdes, Johannes; Hasan, Tayyaba

2010-02-01

Nanomedicine is beginning to impact the treatment of several diseases and current research efforts include development of integrated nano-constructs (theranostics) which serve as probes for imaging and therapy in addition to delivering macromolecules intracellularly. In cancer, there is a vital unmet need for effective alternative treatments with high specificity and low systemic toxicity. This can be achieved by targeting key molecular markers associated with cancer cells with reduced effective drug doses. Here, we show an innovative proof-of-principle approach for efficient killing of proliferating ovarian cancer cells by inactivating a protein associated with cell proliferation namely, the nuclear Ki-67 protein (pKi-67), using nanotechnology-based photodynamic therapy (PDT). Antibodies against pKi-67 are widely used as prognostic tools for tumor diagnosis. In this work, anti pKi-67 antibodies were first conjugated to fluorescein isothiocyanate (FITC) and then encapsulated inside liposomes. After incubation of OVCAR-5 ovarian cancer cells with these liposomes, confocal microscopy confirmed the localization of the antibodies to the nucleoli of the cells. Irradiation with a 488 nm laser led to a significant loss of cell viability. The specificity of this approach for pKi-67 positive cells was demonstrated in confluent human lung fibroblasts (MRC-5) where only a small population of cells stain positive for pKi-67 and only minimal cell death was observed. Taken together, our findings suggest that pKi-67 targeted with nano-platform is an attractive therapeutic target in cancer therapy.

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

PubMed

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.

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

PubMed

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.

Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice.

PubMed

Weber, Kristy L; Doucet, Michele; Price, Janet E; Baker, Cheryl; Kim, Sun Jin; Fidler, Isaiah J

2003-06-01

Renal cell carcinoma (RCC) frequently produces metastases to the musculoskeletal system that are a major source of morbidity in the form of pain, immobilization, fractures, neurological compromise, and a decreased ability to perform activities of daily living. Patients with metastatic RCC therefore have a dismal prognosis because there is no effective adjuvant treatment for this disease. Because the epidermal growth factor receptor (EGF-R) signaling cascade is important in the growth and metastasis of RCC, its blockade has been hypothesized to inhibit tumor growth and hence prevent resultant bone destruction. We determined whether blockade of EGF-R by the tyrosine kinase inhibitor PKI 166 inhibited the growth of RCC in bone. We use a novel cell line, RBM1-IT4, established from a human RCC bone metastasis. Protein and mRNA expression of the ligands and receptors was assessed by Western and Northern blots. The stimulation of RBM1-IT4 cells with epidermal growth factor or transforming growth factor alpha resulted in increased cellular proliferation and tyrosine kinase autophosphorylation. PKI 166 prevented these effects. First, RBM1-IT4 cells were implanted into the tibia of nude mice, where they established lytic, progressively growing lesions, after which the mice were treated with PKI 166 alone or in combination with paclitaxel (Taxol). Immunohistochemical analysis revealed that tumor cells and tumor-associated endothelial cells in control mice expressed activated EGF-R. Treatment of mice with PKI 166 alone or in combination with Taxol produced a significant decrease in the incidence and size of bone lesions as compared with the results in control or Taxol-treated mice (P < 0.001). Treatment with PKI 166 also decreased the expression of phosphorylated EGF-R by tumor cells and tumor-associated endothelial cells, and this was even more pronounced with PKI 166 plus Taxol treatment. The PKI 166 plus Taxol combination produced apoptosis of tumor cells and tumor-associated endothelial cells. Tumor cell proliferation, shown by proliferating cell nuclear antigen positivity, was decreased in all treatment groups. In addition, the integrity of the bone was maintained in mice treated with PKI 166 or PKI 166 plus Taxol, whereas massive bone destruction was seen in control and Taxol-treated mice. These results suggest that blockade of EGF-R signaling inhibits growth of RCC in the bone by its effect on tumor cells and tumor-associated endothelial cells.

Interaction of ABC multidrug transporters with anticancer protein kinase inhibitors: substrates and/or inhibitors?

PubMed

Hegedus, Csilla; Ozvegy-Laczka, Csilla; Szakács, Gergely; Sarkadi, Balázs

2009-05-01

Protein kinase inhibitors (PKI) are becoming key agents in modern cancer chemotherapy, and combination of PKIs with classical chemotherapeutic drugs may help to overcome currently untreatable metastatic cancers. Since chemotherapy resistance is a recurrent problem, mechanisms of resistance should be clarified in order to help further drug development. Here we suggest that in addition to PKI resistance based on altered target structures, the active removal of these therapeutic agents by the MDR-ABC transporters should also be considered as a major cause of clinical resistance. We discuss the occurring systemic and cellular mechanisms, which may hamper PKI efficiency, and document the role of selected MDR-ABC transporters in these phenomena through their interactions with these anticancer agents. Moreover, we suggest that PKI interactions with ABC transporters may modulate overall drug metabolism, including the fate of diverse, chemically or target-wise unrelated drugs. These effects are based on multiple forms of MDR-ABC transporter interaction with PKIs, as these compounds may be both substrates and/or inhibitors of an ABC transporter. We propose that these interactions should be carefully considered in clinical application, and a combined MDR-ABC transporter and PKI effect may bring a major advantage in future drug development.

PKI: The DoD’s Critical Supporting Infrastructure for Information Assurance

DTIC Science & Technology

2009-12-01

Allen Hamilton,AF PKI SPO,4241 E Piedras Dr STE 210,San Antonio,TX,78228 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY...4241 E Piedras DR STE 210 San Antonio,TX 78228 Phone: (210) 925-9129 Fax: (210) 925-2644 E-mail: susan.chandler.3.ctr@ us.af.mil Jerrod Loyless is a...Professional. General Dynamics C4 Systems AF PKI SPO 4241 E Piedras DR STE 210 San Antonio,TX 78228 Phone: (210) 925-2073 Fax: (210) 925-2644 E-mail

Fine Structure of the Outermost Solid Core from Analysis of PKiKP Coda Waves

NASA Astrophysics Data System (ADS)

Krasnoshchekov, D.; Kaazik, P.; Ovtchinnikov, V.

2006-05-01

Near surface heterogeneities in the Earth's inner core have recently been confirmed to exist, and pods of partial melt or variations in seismic anisotropy either due to orientation of iron crystals or changes in strength were indicated as possible sources for such peculiarities. In the same time, analysis of the phase reflected from the inner core boundary (PKiKP) predicts complex character of the reflecting discontinuity in the form of local thin transition layers resulting in mosaic structure of the Earth's inner core's surface. Precritical PKiKP waveforms and coda waves provide necessary seismological constraints to investigate fine structure of the upper part of the Earth's inner core and its boundary, and rank high among researches that detected the described specifics of the solid core. PKiKP coda studies have to do with weak amplitudes and subtle effects, which frequently requires using a reference core related seismic phase and array data processing, as well as eliminating max number of factors biasing the resulting estimates (for example, source related inaccuracies typical for earthquake analysis). In this work we report new observations of PKiKP coda waves detected on records of a group of Underground Nuclear Explosions (UNEs) carried out in USSR and recorded at distances from 6 to 95 degrees by stations of the world seismological network. Our dataset benefits from using accurate ground truth information on source parameters (locations, origin times, depths, etc.), requires no accounting for different source radiation patterns and contains records corresponding to the whole range of precritical reflection including so called transparent zone where amplitudes of direct PKiKP phase are negligible. The processed dataset incorporates records of the array of sources consisted of the same magnitude explosions closely carried out at Semipalatinsk Test Site and recorded by stations located in Eurasia, Africa and North America. We detect PKiKP coda waves on records of all stations that registered this array. The performed frequency-wavenumber analysis and stacking of the array data reveal both scattering mechanism tracked in the form of slight dependence of PKiKP coda's frequency content on epicentral distance, and reflective mechanism evidenced by detection of distinct arrivals of waves reflected from isotropic or anisotropic discontinuities below the inner core boundary. We infer, that PKiKP coda is built by both volumetric scattering and reverberations on reflectors in the upper portion of the inner core. We also find no significant evidence for the presence of a constant depth global isotropic reflector all through 300 km below the ICB and attribute different types of the observed PKiKP coda patterns to variability in properties of the outermost portion of the Earth's inner core either due to its anisotropy or local specifics. The research described was made possible in part by contribution from grant RUG1-2675-MO-05 of the US Civilian Research & Development Foundation for the Independent States of the Former Soviet Union (CRDF) and the President Grant MK-1600.2005.5.

JPRS Report, East Asia, Southeast Asia.

DTIC Science & Technology

1988-08-31

Defends Foreign Aid, Loans 2 Regional Governments Instructed To Trace PKI Remnants 2 Biographic Items on Military, Government Leaders 3 Brig...DAP Leader Briefs Auckland’s Malaysian Students on National Issues 17 Minister Sees Lessening of School Requirements, Discrimination Against Chinese...Vietnamese Refugees Economic Migrants !!.."!"!"""""" 21 Opinion Leaders Debate Over Petition to King !.!"""""."."!."."!."!"!""! 22 Columnist

Safety profile of protein kinase inhibitors in rheumatoid arthritis: systematic review and meta-analysis.

PubMed

Salgado, Eva; Maneiro, Jose R; Carmona, Loreto; Gomez-Reino, Juan J

2014-05-01

To summarise the adverse events (AE) reported in patients with rheumatoid arthritis (RA) treated with protein kinase inhibitors (PKi), and identify family and molecule-related AEs. Systematic review of the PKi used in clinical trials (CTs) in RA. Medline, Embase, Cochrane Library, Web of Knowledge, and international abstracts of congress were reviewed, (up to 31 October 2012). Search was limited to interventional studies of PKi used in CTs in RA, written in English, and reporting frequencies of AE. Diseases with similar comorbidity burden also were included. Frequency of AE, serious AE (SAE), death and discontinuation due to  AEs (DCAE) were recorded. Risk of bias was assessed. Meta-analysis was carried using pooled relative risk (RR) with 95% CI as effect measure. The search produced 4410 hits. Forty-one articles reporting data on 21 PKi of the Janus kinase (JAK), SYK, p38 and cKit families were selected for detailed analysis. In patients treated with p38 inhibitors, RR for dizziness was 2.36 (1.20 to 4.63), and in patients treated with c-Kit inhibitors, RR for oedema was 3.43 (1.58 to 7.42). In patients treated with the JAK inhibitor tofacitinib, RR for hypercholesterolaemia was 1.70 (1.10 to 2.63) that was dose related. In patients treated with the Syk inhibitor fostamatinib, pooled RR for hypertransaminasaemia, hypertension, diarrhoea and neutropenia were 2.93 (1.02 to 8.43), 2.80 (1.58 to 5.99), 5.20 (3.19 to 8.49) and 9.24 (2.22 to 38.42), respectively. Serious infections and malignancies were not significantly more frequent in PKi-treated patients than in comparator groups. Event rates of serious infections and malignancies with PKi are not different from biologics. In addition, PKi have a unique safety profile related to target and off-target inhibition of kinases, at times dose related.

Blockade of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling for therapy of metastatic human pancreatic cancer.

PubMed

Baker, Cheryl H; Solorzano, Carmen C; Fidler, Isaiah J

2002-04-01

We determined whether concurrent blockage of vascular endothelial growth factor (VEGF) receptor and epidermal growth factor (EGF) receptor signaling by two novel tyrosine kinase inhibitors, PTK 787 and PKI 166, respectively, can inhibit angiogenesis and, hence, the growth and metastasis of human pancreatic carcinoma in nude mice. Highly metastatic human pancreatic carcinoma L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice began receiving oral doses of PTK 787 and PKI 166 three times weekly. Some groups of mice also received i.p. injections of gemcitabine twice a week. The mice were necropsied when the control mice became moribund. Treatment with PTK 787 and PKI 166, with gemcitabine alone, or with the combination of PTK 787, PKI 166, and gemcitabine produced 69, 50, and 97% reduction in the volume of pancreatic tumors, respectively. Administration of protein tyrosine kinase inhibitors and gemcitabine also significantly decreased the incidence of lymph node and liver metastasis. The therapeutic efficacy directly correlated with a decrease in circulating proangiogenic molecules (VEGF, interleukin-8), a decrease in microvessel density, a decrease in proliferating cell nuclear antigen staining, and an increase in apoptosis of tumor cells and endothelial cells. Therapies produced by combining gemcitabine with either PKI 166 or PTK 787 were similar to those produced by combining gemcitabine with both PKI 166 and PTK 787. These results suggest that blockade of either epidermal growth factor receptor or VEGF receptor signaling combined with chemotherapy provides an effective approach to the therapy of pancreatic cancer.

Insights into factorless translational initiation by the tRNA-like pseudoknot domain of a viral IRES.

PubMed

Au, Hilda H T; Jan, Eric

2012-01-01

The intergenic region internal ribosome entry site (IGR IRES) of the Dicistroviridae family adopts an overlapping triple pseudoknot structure to directly recruit the 80S ribosome in the absence of initiation factors. The pseudoknot I (PKI) domain of the IRES mimics a tRNA-like codon:anticodon interaction in the ribosomal P site to direct translation initiation from a non-AUG initiation codon in the A site. In this study, we have performed a comprehensive mutational analysis of this region to delineate the molecular parameters that drive IRES translation. We demonstrate that IRES-mediated translation can initiate at an alternate adjacent and overlapping start site, provided that basepairing interactions within PKI remain intact. Consistent with this, IGR IRES translation tolerates increases in the variable loop region that connects the anticodon- and codon-like elements within the PKI domain, as IRES activity remains relatively robust up to a 4-nucleotide insertion in this region. Finally, elements from an authentic tRNA anticodon stem-loop can functionally supplant corresponding regions within PKI. These results verify the importance of the codon:anticodon interaction of the PKI domain and further define the specific elements within the tRNA-like domain that contribute to optimal initiator Met-tRNA(i)-independent IRES translation.

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

PubMed

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.

Insights into Factorless Translational Initiation by the tRNA-Like Pseudoknot Domain of a Viral IRES

PubMed Central

Au, Hilda H. T.; Jan, Eric

2012-01-01

The intergenic region internal ribosome entry site (IGR IRES) of the Dicistroviridae family adopts an overlapping triple pseudoknot structure to directly recruit the 80S ribosome in the absence of initiation factors. The pseudoknot I (PKI) domain of the IRES mimics a tRNA-like codon:anticodon interaction in the ribosomal P site to direct translation initiation from a non-AUG initiation codon in the A site. In this study, we have performed a comprehensive mutational analysis of this region to delineate the molecular parameters that drive IRES translation. We demonstrate that IRES-mediated translation can initiate at an alternate adjacent and overlapping start site, provided that basepairing interactions within PKI remain intact. Consistent with this, IGR IRES translation tolerates increases in the variable loop region that connects the anticodon- and codon-like elements within the PKI domain, as IRES activity remains relatively robust up to a 4-nucleotide insertion in this region. Finally, elements from an authentic tRNA anticodon stem-loop can functionally supplant corresponding regions within PKI. These results verify the importance of the codon:anticodon interaction of the PKI domain and further define the specific elements within the tRNA-like domain that contribute to optimal initiator Met-tRNAi-independent IRES translation. PMID:23236506

Imaging the 'mosaic' structure of ICB by pre-critical PcP-PKiKP phases

NASA Astrophysics Data System (ADS)

Shen, Z.; Ai, Y.; He, Y.; Jiang, M.

2013-12-01

Slowly growing in highly homogeneous liquid outer core, earth inner core has been thought lacking of significant heterogeneous structure. However, seismic observations of recent decades have demonstrated hierarchical heterogeneous structure as hemispherical longitudinal dichotomy superimposed by coda-generating scattering heterogeneities with diameters of tens of kilometers, indicating complicity of inner core crystallizing environment and related dynamic process. Furthermore, as boundary of phase transform and energy-material exchange, ICB has been unveiled as patchy mosaic-like surface, based on high variety of global pre-critical PcP-PKiKP amplitude ratios. From dense arrays deployed across East and South China in the year 2005~2011 and 13 earthquakes of west Pacific subduction zone, we have collected over 150 clear pre-critical PcP-PKiKP waveforms of epicenter distance range between 14~35°, providing an ideal sampling to detect possible ICB regional variation of the East Asia area. The amplitude observation exhibits good geographical coherency which is characterized as region of high density contrast (>1.0g/cm3) located beneath East China demarcated by the low (around or lower than 0.6g/cm3) on the periphery, except the southeastward stretching. This contrasting depicts vividly the claimed 'mosaic' ICB and bridges the gap between hemispherical (~1000km order) and scatter-inducing (~10km order or less) scales of heterogeneity. On the other hand, travel time residues of PcP-PKiKP in our study reveal a complex pattern north of ~18°N perturbed strongly by shallow (crust and mantle) anomalies and remarkable delay of PKiKP in the south, implicating effects of undetected ULVZ below Celebes Sea. This research is supported by the National Natural Science Foundation of China (NSFC, grant 90914011, 41125015). Distribution of PcP-PKiKP relative amplitude ratio

(124)I-iodopyridopyrimidinone for PET of Abl kinase-expressing tumors in vivo.

PubMed

Doubrovin, Mikhail; Kochetkova, Tatiana; Santos, Elmer; Veach, Darren R; Smith-Jones, Peter; Pillarsetty, Nagavarakishore; Balatoni, Julius; Bornmann, William; Gelovani, Juri; Larson, Steven M

2010-01-01

Because of the recent development of an iodopyridopyrimidinone Abl protein kinase inhibitor (PKI), (124)I-SKI-212230 ((124)I-SKI230), we investigated the feasibility of a PET-based molecular imaging method for the direct visualization of Abl kinase expression and PKI treatment. In vitro pharmacokinetic properties, including specific and nonspecific binding of (124)I-SKI230 to its Abl kinase target and interaction with other PKIs, were assessed in cell-free medium and chronic myelogenous leukemia (CML) cells overexpressing BCR-Abl (K562), in comparison with BT-474 cells that are low in Abl expression. In a xenograft tumor model, we assessed the in vivo pharmacokinetics of (124)I-SKI230 using PET and postmortem tissue sampling. We also tested a paradigm of (124)I-SKI230 PET after treatment of the animal with a dose of Abl-specific PKI for the monitoring of the tumor response. In vitro studies confirmed that SKI230 binds to Abl kinase with nanomolar affinity, that selective uptake occurs in cell lines known to express Abl kinase, that RNAi knock-down supports specificity of cellular uptake due to Abl kinase, and that imatinib, an archetype Abl PKI, completely displaces SKI230. With SKI230, we obtained successful in vivo PET of Abl-expressing human tumors in a nude rat. We were also able to demonstrate evidence of substrate inhibition of in vivo radiotracer uptake in the xenograft tumor after treatment of the animal as a model of PKI treatment monitoring. These results support the hypothesis that molecular imaging using PET will be useful for the study of in vivo pharmacodynamics of Abl PKI molecular therapy in humans.

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

PubMed Central

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

2017-01-01

Background 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. Aim 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. Methods 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). Results 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. Conclusion PI3K/mTOR dual targeting is a promising new therapeutic approach in neuroendocrine tumor disease that should be evaluated in further clinical trials. PMID:27513674

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

PubMed

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.

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

PubMed Central

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

2015-01-01

Background 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). Materials and methods 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. Results 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 < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with 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 < 0.001; n = 12) and 67% by 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). Conclusions LCSC (CD133+, CD44+, CD24+) were able to develop very aggressive tumors with low cell concentrations at 4 to 6 wk. Cells CD133+, CD44+, CD24+ 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. PMID:23769634

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

PubMed

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 < 0.001). Interestingly, HuH7 cells were more sensitive to sorafenib than LCSC or PLC cells. Additionally, combination therapy with 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 < 0.001; n = 12) and 67% by 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.

Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.

PubMed

Beavers, David L; Wang, Wei; Ather, Sameer; Voigt, Niels; Garbino, Alejandro; Dixit, Sayali S; Landstrom, Andrew P; Li, Na; Wang, Qiongling; Olivotto, Iacopo; Dobrev, Dobromir; Ackerman, Michael J; Wehrens, Xander H T

2013-11-19

This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF). JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca(2+) handling and modulation of ryanodine receptor Ca(2+) channels (RyR2). Whereas defective RyR2-mediated Ca(2+) release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias. Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudoknock-in (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation. PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF than wild type (WT)-PKI mice, whereas A399S-PKI mice expressing a hypertrophic cardiomyopathy-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca(2+) release events. These changes were attributed to reduced binding of E169K-JPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca(2+) spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients and an increased frequency of spontaneous Ca(2+) release events. Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2/RyR2 ratios can promote SR Ca(2+) leak and atrial arrhythmias, representing a potential novel therapeutic target for AF. Copyright © 2013. Published by Elsevier Inc.

Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization

PubMed Central

Voigt, Niels; Garbino, Alejandro; Dixit, Sayali S.; Landstrom, Andrew P.; Li, Na; Wang, Qiongling; Olivotto, Iacopo; Dobrev, Dobromir; Ackerman, Michael J.; Wehrens, Xander H.T.

2013-01-01

Objectives To study the role of junctophilin 2 (JPH2) in atrial fibrillation (AF). Background JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca2+ handling and modulation of ryanodine receptor Ca2+ channels (RyR2). Whereas defective RyR2-mediated Ca2+ release contributes to the pathogenesis of AF, nothing is known about the potential role of JPH2 in atrial arrhythmias. Methods Screening 203 unrelated hypertrophic cardiomyopathy patients uncovered a novel JPH2 missense mutation (E169K) in 2 patients with juvenile-onset paroxysmal AF (pAF). Pseudo-knockin (PKI) mouse models were generated to determine the molecular defects underlying the development of AF caused by this JPH2 mutation. Results PKI mice expressing E169K mutant JPH2 exhibited a higher incidence of inducible AF compared with wildtype (WT)-PKI mice, while A399S-PKI mice expressing a HCM-linked JPH2 mutation not associated with atrial arrhythmias were not significantly different from WT-PKI. E169K-PKI but not A399A-PKI atrial cardiomyocytes showed an increased incidence of abnormal SR Ca2+ release events. These changes were attributed to reduced binding of E169KJPH2 to RyR2. Atrial JPH2 levels in WT-JPH2 transgenic, nontransgenic, and JPH2 knockdown mice correlated negatively with the incidence of pacing-induced AF. Ca2+ spark frequency in atrial myocytes and the open probability of single RyR2 channels from JPH2 knockdown mice was significantly reduced by a small JPH2-mimicking oligopeptide. Moreover, patients with pAF had reduced atrial JPH2 levels per RyR2 channel compared to sinus rhythm patients, and an increased frequency of spontaneous Ca2+ release events. Conclusions Our data suggest a novel mechanism by which reduced JPH2-mediated stabilization of RyR2 due to loss-of-function mutation or reduced JPH2:RyR2 ratios can promote SR Ca2+ leak and atrial arrhythmias, representing a potential novel therapeutic target for AF. PMID:23973696

AliEn—ALICE environment on the GRID

NASA Astrophysics Data System (ADS)

Saiz, P.; Aphecetche, L.; Bunčić, P.; Piskač, R.; Revsbech, J.-E.; Šego, V.; Alice Collaboration

2003-04-01

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.

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

PubMed

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.

The design and delivery of a PKA inhibitory polypeptide to treat SCA1.

PubMed

Hearst, Scoty M; Shao, Qingmei; Lopez, Mariper; Raucher, Drazen; Vig, Parminder J S

2014-10-01

Spinocerebellar ataxia-1 (SCA1) is a neurodegenerative disease that primarily targets Purkinje cells (PCs) of the cerebellum. The exact mechanism of PC degeneration is unknown, however, it is widely believed that mutant ataxin-1 becomes toxic because of the phosphorylation of its serine 776 (S776) residue by cAMP-dependent protein kinase A (PKA). Therefore, to directly modulate mutant ATXN1 S776 phosphorylation and aggregation, we designed a therapeutic polypeptide to inhibit PKA. This polypeptide comprised of a thermally responsive elastin-like peptide (ELP) carrier, which increases peptide half-life, a PKA inhibitory peptide (PKI), and a cell-penetrating peptide (Synb1). We observed that our therapeutic polypeptide, Synb1-ELP-PKI, inhibited PKA activity at concentrations similar to the PKI peptide. Additionally, Synb1-ELP-PKI significantly suppressed mutant ATXN1 S776 phosphorylation and intranuclear inclusion formation in cell culture. Further, Synb1-ELP-PKI treatment improved SCA1 PC morphology in cerebellar slice cultures. Furthermore, the Synb1-ELP peptide carrier crossed the blood-brain barrier and localized to the cerebellum via the i.p. or intranasal route. Here, we show the intranasal delivery of ELP-based peptides to the brain as a novel delivery strategy. We also demonstrate that our therapeutic polypeptide has a great potential to target the neurotoxic S776 phosphorylation pathway in the SCA1 disease. © 2014 International Society for Neurochemistry.

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

PubMed

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.

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

ERIC Educational Resources Information Center

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…

Relationship of D'' structure with the velocity variations near the inner-core boundary

NASA Astrophysics Data System (ADS)

Luo, Sheng-Nian; Ni, Sidao; Helmberger, Don

2002-06-01

Variations in regional differential times between PKiKP (i) and PKIKP (I) have been attributed to hemispheric P-velocity variations of about 1% in the upper 100 km of the inner core (referred to as HIC). The top of the inner core appears relatively fast beneath Asia where D'' is also fast. An alternative interpretation could be the lateral variation in P velocity at the lowermost outer core (HOC) producing the same differential times. To resolve this issue, we introduce the diffracted PKP phase near the B caustic (Bdiff) in the range of 139-145° epicenter distances, and the corresponding differential times between Bdiff and PKiKP and PKIKP as observed on broadband arrays. Due to the long-wavelength nature of Bdiff, we scaled the S-wave tomography model with k values (k ≡ dlnVs/dlnVp) to obtain large-scale P-wave velocity structure in the lower mantle as proposed by earlier studies. Waveform synthetics of Bdiff constructed with small k's predict complex waveforms not commonly observed, confirming the validity of large scaling factor k. With P-velocity in lower mantle constrained at large scale, the extra travel-time constraint imposed by Bdiff helps to resolve the HOC-HIC issue. Our preliminary results suggest k > 2 for the lowermost mantle and support HIC hypothesis. An important implication is that there appears to be a relationship of D'' velocity structures with the structures near the inner core boundary via core dynamics.

Inner core boundary topography explored with reflected and diffracted P waves

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

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

PubMed

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.

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

PubMed

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 studying drug-protein interactions and thus help in designing the novel drugs with higher potency. Copyright © 2015 Elsevier Inc. All rights reserved.

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

NASA Astrophysics Data System (ADS)

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 the observed temporal changes of the inner core phases are caused by temporal changes of inner core surface. The temporal changes of inner core surface are found to occur in some localized regions within a short time scale (years to months), a phenomenon that should provide important clues to a potentially fundamental change of our understanding of core dynamics.

CrossTalk: The Journal of Defense Software Engineering. Volume 22, Number 7, Nov/Dec 2009

DTIC Science & Technology

2009-12-01

an MBA, and is a Certified Corporate Trainer. Booz Allen Hamilton AF PKI SPO 4241 E Piedras DR STE 210 San Antonio,TX 78228 Phone: (210) 925-9129...Certified Secure Software Lifecycle Professional, and a Project Management Professional. General Dynamics C4 Systems AF PKI SPO 4241 E Piedras DR STE 210

Podocyte hypertrophy precedes apoptosis under experimental diabetic conditions.

PubMed

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.

The kinase inhibitors sunitinib and sorafenib differentially affect NK cell antitumor reactivity in vitro.

PubMed

Krusch, Matthias; Salih, Julia; Schlicke, Manuela; Baessler, Tina; Kampa, Kerstin Maria; Mayer, Frank; Salih, Helmut Rainer

2009-12-15

Sunitinib and Sorafenib are protein kinase inhibitors (PKI) approved for treatment of patients with advanced renal cell cancer (RCC). However, long-term remissions of advanced RCC have only been observed after IL-2 treatment, which underlines the importance of antitumor immune responses in RCC patients. Because PKI, besides affecting tumor cells, also may inhibit signaling in immune effector cells, we determined how Sunitinib and Sorafenib influence antitumor immunity. We found that cytotoxicity and cytokine production of resting and IL-2-activated PBMC are inhibited by pharmacological concentrations of Sorafenib but not Sunitinib. Analysis of granule-mobilization within PBMC revealed that this was due to impaired reactivity of NK cells, which substantially contribute to antitumor immunity by directly killing target cells and shaping adaptive immune responses by secreting cytokines like IFN-gamma. Analyses with resting and IL-2-activated NK cells revealed that both PKI concentration dependently inhibit cytotoxicity and IFN-gamma production of NK cells in response to tumor targets. This was due to impaired PI3K and ERK phosphorylation which directly controls NK cell reactivity. However, while Sorafenib inhibited NK cell effector functions and signaling at levels achieved upon recommended dosing, pharmacological concentrations of Sunitinib had no effect, and this was observed upon stimulation of NK cell reactivity by tumor target cells and upon IL-2 treatment. In light of the important role of NK cells in antitumor immunity, and because multiple approaches presently aim to combine PKI treatment with immunotherapeutic strategies, our data demonstrate that choice and dosing of the most suitable PKI in cancer treatment requires careful consideration.

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

ERIC Educational Resources Information Center

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…

TERENA eScience PKI

NASA Astrophysics Data System (ADS)

Sova, Milan

Several National Research and Education Networks associated in TERENA have joined their efforts to build a shared PKI able to serve potentially millions of users from their constituency. The TCS eScience Personal CA takes advantage of national identity federations to facilitate user identity vetting and enrollment procedures. The system uses identity management systems (IdMS) at participating institutions to perform the functions of registration authorities. The certificate enrollment application acts as a SAML Service Provider relying on information provided by IdMS performing as SAML Identity Providers (IdP). When applying for a personal certificate, users authenticate at their home IdP using credentials they normally use to access local services. The IdP controls the certificate issuance process by releasing SAML attributes specifying the user's eligibility for the service and the information to be included in the certificate such as the user's name and email address. The TCS eScience Personal CA is part of the TERENA Certificate Service that uses a commercial PKI provider. Outsourcing the actual CA machinery to a specialized company results in professional-level services such as CRL and OCSP management. The paper describes the legal, organizational and technical aspects of the TCS eScience PKI.

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.

PubMed

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 encoding PKI(1-31) inhibit the expression that is stimulated by the addition of cAMP analogs in both cell lines; basal expression, however, is inhibited by PKI(1-31) only in the JEG-3 cell line and not in the CV-1 cells. These observations indicate that, in JEG-3 cells, PKI(1-31) is a specific inhibitor of kinase A-mediated gene transcription, but it does not modify kinase C-directed transcription.(ABSTRACT TRUNCATED AT 400 WORDS)

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

NASA Astrophysics Data System (ADS)

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.

An eCK-Secure Authenticated Key Exchange Protocol without Random Oracles

NASA Astrophysics Data System (ADS)

Moriyama, Daisuke; Okamoto, Tatsuaki

This paper presents a (PKI-based) two-pass authenticated key exchange (AKE) protocol that is secure in the extended Canetti-Krawczyk (eCK) security model. The security of the proposed protocol is proven without random oracles (under three assumptions), and relies on no implementation techniques such as a trick by LaMacchia, Lauter and Mityagin (so-called the NAXOS trick). Since an AKE protocol that is eCK-secure under a NAXOS-like implementation trick will be no more eCK-secure if some realistic information leakage occurs through side-channel attacks, it has been an important open problem how to realize an eCK-secure AKE protocol without using the NAXOS tricks (and without random oracles).

Authentication in Virtual Organizations: A Reputation Based PKI Interconnection Model

NASA Astrophysics Data System (ADS)

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.

Virtual-optical information security system based on public key infrastructure

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

MEN16132, a novel potent and selective nonpeptide antagonist for the human bradykinin B2 receptor. In vitro pharmacology and molecular characterization.

PubMed

Cucchi, Paola; Meini, Stefania; Bressan, Alessandro; Catalani, Claudio; Bellucci, Francesca; Santicioli, Paolo; Lecci, Alessandro; Faiella, Angela; Rotondaro, Luigi; Giuliani, Sandro; Giolitti, Alessandro; Quartara, Laura; Maggi, Carlo Alberto

2005-12-28

The pharmacological characterization of the novel nonpeptide antagonist for the B2 receptor, namely MEN16132 (4-(S)-Amino-5-(4-{4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl}piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride) is presented. The affinity of MEN16132 for the bradykinin B2 receptor has been investigated by means of competition studies at [3H]bradykinin binding to membranes prepared from Chinese Hamster Ovary (CHO) cells expressing the human bradykinin B2 receptor (pKi 10.5), human lung fibroblasts (pKi 10.5), guinea pig airways (pKi 10.0), guinea pig ileum longitudinal smooth muscle (pKi 10.2), or guinea pig cultured colonic myocytes (pKi 10.3). In all assays MEN16132 was as potent as the peptide antagonist Icatibant, and from 3- to 100-fold more potent than the reference nonpeptide antagonists FR173657 or LF16-0687. The selectivity for the bradykinin B2 receptor was checked at the human bradykinin B1 receptor (pKi<5), and at a panel of 26 different receptors and channels. The antagonist potency was measured in functional assays, i.e., in blocking the bradykinin induced inositolphosphates (IP) accumulation at the human (CHO: pKB 10.3) and guinea pig (colonic myocytes: pKB 10.3) B2 receptor, or in antagonizing the bradykinin induced contractile responses in human (detrusor smooth muscle: pKB 9.9) and guinea pig (ileum longitudinal smooth muscle: pKB 10.1) tissues. In both functional assay types MEN16132 exerted a different antagonist pattern, i.e., surmountable at the human and insurmountable at the guinea pig bradykinin B2 receptors. Moreover, the receptor determinants important for the high affinity interaction of MEN16132 with the human bradykinin B2 receptor were investigated by means of radioligand binding studies performed at 24 point-mutated receptors. The results obtained revealed that residues in transmembrane segment 2 (W86A), 3 (I110A), 6 (W256A), and 7 (Y295A, Y295F but not much Y295W), were crucial for the high affinity of MEN16132. In conclusion, MEN16132 is a new, potent, and selective nonpeptide bradykinin B2 receptor antagonist.

Impact of coalition interoperability on PKI

NASA Astrophysics Data System (ADS)

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.

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

PubMed Central

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

2017-01-01

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. PMID:28855336

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

PubMed

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.

Assumptions, Trust, and Names in Computer Security Protocols

DTIC Science & Technology

2011-06-01

sharing her banking credentials with a criminal, which is clearly bad . But PKI proto- cols like this one can be used in other, less risky ways. Suppose...Figure 4.5. This is similar to a failure of PKI-based protocols in which the authority signs a bad certificate. But the interesting thing is how the... Zoo Figure 4.6: Using AdultVerify. The run is as follows: 1. As the first step in Diffie-Hellman Key Exchange, Alice picks and sends the

State of the Art in Trust and Reputation Models in P2P networks

NASA Astrophysics Data System (ADS)

Mármol, Félix Gómez; Pérez, Gregorio Martínez

Ensuring security in a distributed environment such as P2P networks is a critical issue nowadays. Nevertheless, it is in those kind of scenarios in which entities can enter or leave the community whenever they want, where traditional mboxsecurity schemes can not always be applied. Specifically, the use of a PKI (Public Key Infrastructure) may be unacceptable within highly distributed systems. Therefore, modeling concepts like trust and reputation may result very helpful and useful when trying to gain a certain level of security and confidence among inter-operating entities. Thus, this chapter presents a review of some of the most representative trust and reputation models for P2P networks, discussing their main characteristics and also their weaknesses and deficiencies. Open issues and challenges associated with them will be also covered.

Framework Design of Unified Cross-Authentication Based on the Fourth Platform Integrated Payment

NASA Astrophysics Data System (ADS)

Yong, Xu; Yujin, He

The essay advances a unified authentication based on the fourth integrated payment platform. The research aims at improving the compatibility of the authentication in electronic business and providing a reference for the establishment of credit system by seeking a way to carry out a standard unified authentication on a integrated payment platform. The essay introduces the concept of the forth integrated payment platform and finally put forward the whole structure and different components. The main issue of the essay is about the design of the credit system of the fourth integrated payment platform and the PKI/CA structure design.

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

PubMed Central

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

2014-01-01

Background: 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. Methods: 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. Results: 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. Conclusions: 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. PMID:24823695

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

PubMed

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.

Approach to spatial information security based on digital certificate

NASA Astrophysics Data System (ADS)

Cong, Shengri; Zhang, Kai; Chen, Baowen

2005-11-01

With the development of the online applications of geographic information systems (GIS) and the spatial information services, the spatial information security becomes more important. This work introduced digital certificates and authorization schemes into GIS to protect the crucial spatial information combining the techniques of the role-based access control (RBAC), the public key infrastructure (PKI) and the privilege management infrastructure (PMI). We investigated the spatial information granularity suited for sensitivity marking and digital certificate model that fits the need of GIS security based on the semantics analysis of spatial information. It implements a secure, flexible, fine-grained data access based on public technologies in GIS in the world.

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

NASA Astrophysics Data System (ADS)

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 and Q structure, obtained from modeling the PKiKP-PKIKP observations, explain the PKPbc-PKIKP observations well.

Anomalously strong observations of PKiKP/PcP amplitude ratios on a global scale

NASA Astrophysics Data System (ADS)

Waszek, Lauren; Deuss, Arwen

2015-07-01

The inner core boundary marks the phase transition between the solid inner core and the fluid outer core. As the site of inner core solidification, the boundary provides insight into the processes generating the seismic structures of the inner core. In particular, it may hold the key to understanding the previously observed hemispherical asymmetry in inner core seismic velocity, anisotropy, and attenuation. Here we use a large PKiKP-PcP amplitude ratio and travel time residual data set to investigate velocity and density contrast properties near the inner core boundary. Although hemispherical structure at the boundary has been proposed by previous inner core studies, we find no evidence for hemispheres in the amplitude ratios or travel time residuals. In addition, we find that the amplitude ratios are much larger than can be explained by variations in density contrast at the inner core boundary or core-mantle boundary. This indicates that PKiKP is primarily observed when it is anomalously large, due to focusing along its raypath. Using data in which PKiKP is not detected above the noise level, we calculate an upper estimate for the inner core boundary (ICB) density contrast of 1.2 kg m-3. The travel time residuals display large regional variations, which differ on long and short length scales. These regions may be explained by large-scale velocity variations in the F layer just above the inner core boundary, and/or small-scale topography of varying magnitude on the ICB, which also causes the large amplitudes. Such differences could arise from localized freezing and melting of the inner core.

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

NASA Astrophysics Data System (ADS)

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.

Inner core structure behind the PKP core phase triplication

NASA Astrophysics Data System (ADS)

Blom, Nienke A.; Deuss, Arwen; Paulssen, Hanneke; Waszek, Lauren

2015-06-01

The structure of the Earth's inner core is not well known between depths of ˜100-200 km beneath the inner core boundary. This is a result of the PKP core phase triplication and the existence of strong precursors to PKP phases, which hinder the measurement of inner core compressional PKIKP waves at epicentral distances between roughly 143 and 148°. Consequently, interpretation of the detailed structure of deeper regions also remains difficult. To overcome these issues we stack seismograms in slowness and time, separating the PKP and PKIKP phases which arrive simultaneously but with different slowness. We apply this method to study the inner core's Western hemisphere beneath South and Central America using paths travelling in the quasi-polar direction between 140 and 150° epicentral distance, which enables us to measure PKiKP-PKIKP differential traveltimes up to greater epicentral distance than has previously been done. The resulting PKiKP-PKIKP differential traveltime residuals increase with epicentral distance, which indicates a marked increase in seismic velocity for polar paths at depths greater than 100 km compared to reference model AK135. Assuming a homogeneous outer core, these findings can be explained by either (i) inner core heterogeneity due to an increase in isotropic velocity or (ii) increase in anisotropy over the studied depth range. Although this study only samples a small region of the inner core and the current data cannot distinguish between the two alternatives, we prefer the latter interpretation in the light of previous work.

Secure and Authenticated Data Communication in Wireless Sensor Networks.

PubMed

Alfandi, Omar; Bochem, Arne; Kellner, Ansgar; Göge, Christian; Hogrefe, Dieter

2015-08-10

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.

Secure and Authenticated Data Communication in Wireless Sensor Networks

PubMed Central

Alfandi, Omar; Bochem, Arne; Kellner, Ansgar; Göge, Christian; Hogrefe, Dieter

2015-01-01

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. PMID:26266413

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

PubMed

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-receptor with pKi>8. In general, the ergotalkaloids of Argyreia nervosa seem to prefer serotonin and dopamine receptors (pKi>7). However, with exception of ergometrine/ergometrinine only for 5-HT3A, and histamine H2 and H4 no affinities were predicted. Compared to LSD, LSA exhibited lower binding affinities in the in vitro binding assays for all tested receptor subtypes. However, with a pKi of 7.99, 7.56, and 7.21 a clear affinity for 5-HT1A, 5-HT2, and α2 could be demonstrated. For DA receptor subtypes and the α1-receptor the pKi ranged from 6.05 to 6.85. Since the psychedelic activity of LSA in the recent human study was weak and although LSA from Argyreia nervosa is often considered as natural exchange for LSD, LSA should not be regarded as LSD-like psychedelic drug. However, vegetative side effects and psychotropic effects may be triggered by serotonin or dopamine receptor subtypes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Temporal changes of the inner core from waveform doublets

NASA Astrophysics Data System (ADS)

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.

Ki-67 as a molecular target for therapy in an in vitro three-dimensional model for ovarian cancer.

PubMed

Rahmanzadeh, Ramtin; Rai, Prakash; Celli, Jonathan P; Rizvi, Imran; Baron-Lühr, Bettina; Gerdes, Johannes; Hasan, Tayyaba

2010-11-15

Targeting molecular markers and pathways implicated in cancer cell growth is a promising avenue for developing effective therapies. Although the Ki-67 protein (pKi-67) is a key marker associated with aggressively proliferating cancer cells and poor prognosis, its full potential as a therapeutic target has never before been successfully shown. In this regard, its nuclear localization presents a major hurdle because of the need for intracellular and intranuclear delivery of targeting and therapeutic moieties. Using a liposomally encapsulated construct, we show for the first time the specific delivery of a Ki-67-directed antibody and subsequent light-triggered death in the human ovarian cancer cell line OVCAR-5. Photoimmunoconjugate-encapsulating liposomes (PICEL) were constructed from anti-pKi-67 antibodies conjugated to fluorescein 5(6)-isothiocyanate, as a photoactivatable agent, followed by encapsulation in noncationic liposomes. Nucleolar localization of the PICELs was confirmed by confocal imaging. Photodynamic activation with PICELs specifically killed pKi-67-positive cancer cells both in monolayer and in three-dimensional (3D) cultures of OVCAR-5 cells, with the antibody TuBB-9 targeting a physiologically active form of pKi-67 but not with MIB-1, directed to a different epitope. This is the first demonstration of (a) the exploitation of Ki-67 as a molecular target for therapy and (b) specific delivery of an antibody to the nucleolus in monolayer cancer cells and in an in vitro 3D model system. In view of the ubiquity of pKi-67 in proliferating cells in cancer and the specificity of targeting in 3D multicellular acini, these findings are promising and the approach merits further investigation. Copyright © 2010 AACR.

Ki-67 as a molecular target for therapy in an in vitro 3D model for ovarian cancer

PubMed Central

Rahmanzadeh, Ramtin; Rai, Prakash; Celli, Jonathan P.; Rizvi, Imran; Baron-Lühr, Bettina; Gerdes, Johannes; Hasan, Tayyaba

2010-01-01

Targeting molecular markers and pathways implicated in cancer cell growth is a promising avenue for developing effective therapies. Although the Ki-67 protein (pKi-67) is a key marker associated with aggressively proliferating cancer cells and poor prognosis, its full potential as a therapeutic target has never before been successfully demonstrated. In this regard, its nuclear localization presents a major hurdle because of the need for intracellular and intranuclear delivery of targeting and therapeutic moieties. Using a liposomally encapsulated construct, we demonstrate for the first time, the specific delivery of a Ki-67 directed antibody and subsequent light-triggered death in a human ovarian cancer cell line OVCAR-5. Photoimmunoconjugate encapsulating liposomes (PICELs) were constructed from anti-pKi-67 antibodies conjugated to fluorescein isothiocyanate, as a photoactivatable agent followed by encapsulation in non-cationic liposomes. Nucleolar localization of the PICELs was confirmed by confocal imaging. Photodynamic activation with PICELs specifically killed pKi-67 positive cancer cells both in monolayer and in 3D cultures of OVCAR-5 cells with the antibody TuBB-9 targeting a physiologically active form of pKi-67 but not with MIB-1, directed to a different epitope. This is the first demonstration of: - 1. the exploitation of Ki-67 as a molecular target for therapy and - 2. specific delivery of an antibody to the nucleolus in monolayer cancer cells and in an in vitro 3D model system. In view of the ubiquity of pKi-67 in proliferating cells in cancer and the specificity of targeting in 3D multicellular acini, these findings are promising and the approach merits further investigation. PMID:21045152

A Global Study of Inner Core Boundary Topography and its Temporal Variations

NASA Astrophysics Data System (ADS)

Ibourichene, A.; Romanowicz, B. A.

2015-12-01

The inner core boundary (ICB) separates the solid inner core from the surrounding liquid outer core. Its detailed properties, such as its shape, the density jump across it or its topography are key for understanding the dynamics of the core and, ultimately, the generation and sustained character of the Earth's magnetic field. The determination of the ICB topography and its variation with time could also enhance our understanding of the inner core growth and its past history.Seismology makes use of two phases to study the shallow inner core : the PKiKP, reflected at the ICB and the PKIKP, refracted into the inner core. The PKiKP/PKIKP amplitude ratio and the travel time residual of these phases characterize the vicinity of the ICB and may help constrain ICB topography. Different studies propose various wavelengths for this topography: from hundreds of meters to tens of kilometers. Several parameters can affect PKiKP/PKIKP amplitude ratios and the corresponding differential travel time, such as the quality factor of the shallow inner core, the density jump at the ICB, the geometry of the ray paths or even the reflection coefficient at the ICB. We present a global map of PKiKP/PKIKP amplitude ratios and differential travel times filtered in different pass-bands, with regional densification based, in particular, on the relatively short wavelength sampling afforded by large aperture broadband arrays, such as USArray, and discuss their spatial variability and interpretation in terms of ICB topography, as appropriate.We also have assembled a catalog of high quality doublets which provide a reference for the stability of the measurements, and point to possible time variability of the topography.

Interoperable PKI Data Distribution in Computational Grids

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

Pala, Massimiliano; Cholia, Shreyas; Rea, Scott A.

One of the most successful working examples of virtual organizations, computational grids need authentication mechanisms that inter-operate across domain boundaries. Public Key Infrastructures(PKIs) provide sufficient flexibility to allow resource managers to securely grant access to their systems in such distributed environments. However, as PKIs grow and services are added to enhance both security and usability, users and applications must struggle to discover available resources-particularly when the Certification Authority (CA) is alien to the relying party. This article presents how to overcome these limitations of the current grid authentication model by integrating the PKI Resource Query Protocol (PRQP) into the Gridmore » Security Infrastructure (GSI).« less

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.

PubMed

Yu, Xuan; Zhang, Qiao; Zhao, Yan; Schwarz, Benjamin J; Stallone, John N; Heaps, Cristine L; Han, Guichun

2017-01-01

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.

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

PubMed Central

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

2016-01-01

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. PMID:27438149

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.

PubMed

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.

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

PubMed

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.

Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway.

PubMed

Rajagopal, Senthilkumar; Kumar, Divya P; Mahavadi, Sunila; Bhattacharya, Sayak; Zhou, Ruizhe; Corvera, Carlos U; Bunnett, Nigel W; Grider, John R; Murthy, Karnam S

2013-03-01

The present study characterized the TGR5 expression and the signaling pathways coupled to this receptor that mediates the relaxation of gastric smooth muscle. TGR5 was detected in gastric muscle cells by RT-PCR and Western blotting. Treatment of cells with the TGR5-selective ligand oleanolic acid (OA) activated Gαs, but not Gαq, Gαi1, Gαi2, or Gαi3, and increased cAMP levels. OA did not elicit contraction, but caused relaxation of carbachol-induced contraction of gastric muscle cells from wild-type mice, but not tgr5(-/-) mice. OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2'-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA inhibitor, myristoylated PKI, and by the expression of phosphorylation-deficient mutant RhoA (S188A). Both OA and Epac ligand stimulated Ras-related protein 1 (Rap1) and inhibited carbachol (CCh)-induced Rho kinase activity. Expression of RhoA (S188A) or PKI partly reversed the inhibition of Rho kinase activity by OA but had no effect on inhibition by Epac ligand. However, suppression of Rap1 with siRNA blocked the inhibition of Rho kinase by Epac ligand, and partly reversed the inhibition by OA; the residual inhibition was blocked by PKI. Muscle relaxation in response to OA, but not Epac ligand, was partly reversed by PKI. We conclude that activation of TGR5 causes relaxation of gastric smooth muscle and the relaxation is mediated through inhibition of RhoA/Rho kinase pathway via both cAMP/Epac-dependent stimulation of Rap1 and cAMP/PKA-dependent phosphorylation of RhoA at Ser(188). TGR5 receptor activation on smooth muscle reveals a novel mechanism for the regulation of gut motility by bile acids.

Activation of G protein-coupled bile acid receptor, TGR5, induces smooth muscle relaxation via both Epac- and PKA-mediated inhibition of RhoA/Rho kinase pathway

PubMed Central

Rajagopal, Senthilkumar; Kumar, Divya P.; Mahavadi, Sunila; Bhattacharya, Sayak; Zhou, Ruizhe; Corvera, Carlos U.; Bunnett, Nigel W.; Grider, John R.

2013-01-01

The present study characterized the TGR5 expression and the signaling pathways coupled to this receptor that mediates the relaxation of gastric smooth muscle. TGR5 was detected in gastric muscle cells by RT-PCR and Western blotting. Treatment of cells with the TGR5-selective ligand oleanolic acid (OA) activated Gαs, but not Gαq, Gαi1, Gαi2, or Gαi3, and increased cAMP levels. OA did not elicit contraction, but caused relaxation of carbachol-induced contraction of gastric muscle cells from wild-type mice, but not tgr5−/− mice. OA, but not a selective exchange protein activated by cAMP (Epac) ligand (8-pCPT-2′-O-Me-cAMP), caused phosphorylation of RhoA and the phosphorylation was blocked by the PKA inhibitor, myristoylated PKI, and by the expression of phosphorylation-deficient mutant RhoA (S188A). Both OA and Epac ligand stimulated Ras-related protein 1 (Rap1) and inhibited carbachol (CCh)-induced Rho kinase activity. Expression of RhoA (S188A) or PKI partly reversed the inhibition of Rho kinase activity by OA but had no effect on inhibition by Epac ligand. However, suppression of Rap1 with siRNA blocked the inhibition of Rho kinase by Epac ligand, and partly reversed the inhibition by OA; the residual inhibition was blocked by PKI. Muscle relaxation in response to OA, but not Epac ligand, was partly reversed by PKI. We conclude that activation of TGR5 causes relaxation of gastric smooth muscle and the relaxation is mediated through inhibition of RhoA/Rho kinase pathway via both cAMP/Epac-dependent stimulation of Rap1 and cAMP/PKA-dependent phosphorylation of RhoA at Ser188. TGR5 receptor activation on smooth muscle reveals a novel mechanism for the regulation of gut motility by bile acids. PMID:23275618

Electronic Voting Protocol Using Identity-Based Cryptography.

PubMed

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.

Electronic Voting Protocol Using Identity-Based Cryptography

PubMed Central

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. PMID:26090515

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

PubMed

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.

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.

PubMed

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.

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

PubMed

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.

Imaging the local crustal structure of the European Eastern Alps through teleseismic reflections from the Earth's inner core recorded during an active source experiment

NASA Astrophysics Data System (ADS)

Behm, M.

2016-12-01

The ALP2002 experiment was a large 3D active seismic experiment to reveal the crustal structure of the Eastern Alps and their neighboring tectonic provinces in Central Europe. The deployment comprised 993 autonomous Reftek Texan recorders equipped with vertical component geophones. The average station spacing was 4.5 km, and the recording instruments were distributed along 14 interlocking profiles with a total line length of 4313 km. During 5 days, 40 explosions in boreholes were fired and recorded within pre-programmed time windows. The limited memory capacity of the recorders allowed for just a few additional backup time windows. Despite the short total recording time of only 17.5 hours within 5 days, one of these backup time windows comprises the registration of the reflection from the earth's inner core (PKiKP phase) originating from an earthquake 130 km offshore Papa New Guinea. This magnitude 5.7 teleseimic event occurred in a depth of 33 km and its epicentral distance to the deployment area is 121.5°. Although the 1C geophones with a natural frequency of 4.5 Hz are not designed to capture the complete characteristics of low-frequency earthquake waveforms, the high-frequency part of the PKiKP wavelet is clearly recorded on all 993 stations. Thus the dataset represents a unique opportunity to study regional and local crustal structures from the analysis of teleseismic events, in particular since the results from the active source data provide calibration and validation. Arrival time analysis is facilitated by the sub-vertical emergence angle of the PKiKP phase. Time corrections for the near surface (< 10 km depth) and the upper mantle structure (50 - 400 km depth) are obtained from previously established seismic 3D models and allow focusing the interpretation on the lower crust and crust-mantle transition. Further, a recently developed blind deconvolution approach is applied to the data for imaging the crustal structure from surface reflections of the PKiKP phase.

75 FR 81249 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2010-12-27

...: By name, Social Security Number (SSN), and/or date of birth. Safeguards: System login is accomplished by DoD Common Access Card (CAC). Public Key Infrastructure (PKI) network login is required and allows...

Expecting the Unexpected: Towards Robust Credential Infrastructure

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

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

NASA Astrophysics Data System (ADS)

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.

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.

PubMed

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.

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

PubMed Central

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

HIV-1-associated PKA acts as a cofactor for genome reverse transcription

PubMed Central

2013-01-01

Background Host cell proteins, including cellular kinases, are embarked into intact HIV-1 particles. We have previously shown that the Cα catalytic subunit of cAMP-dependent protein kinase is packaged within HIV-1 virions as an enzymatically active form able to phosphorylate a synthetic substrate in vitro (Cartier et al. J. Biol. Chem. 278:35211 (2003)). The present study was conceived to investigate the contribution of HIV-1-associated PKA to the retroviral life cycle. Results NL4.3 viruses were produced from cells cultured in the presence of PKA inhibitors H89 (H89-NL4.3) or Myr-PKI (PKI-NL4.3) and analyzed for viral replication. Despite being mature and normally assembled, and containing expected levels of genomic RNA and RT enzymatic activity, such viruses showed poor infectivity. Indeed, infection generated reduced amounts of strong-strop minus strand DNA, while incoming RNA levels in target cells were unaffected. Decreased cDNA synthesis was also evidenced in intact H89-NL4.3 and PKI-NL4.3 cell free particles using endogenous reverse transcription (ERT) experiments. Moreover, similar defects were reproduced when wild type NL4.3 particles preincubated with PKA inhibitors were subjected to ERT reactions. Conclusions Altogether, our results indicate that HIV-1-associated PKA is required for early reverse transcription of the retroviral genome both in cell free intact viruses and in target cells. Accordingly, virus-associated PKA behaves as a cofactor of an intraviral process required for optimal reverse transcription and for early post-entry events. PMID:24344931

Secure Payload Access to the International Space Station

NASA Technical Reports Server (NTRS)

Pitts, R. Lee; Reid, Chris

2002-01-01

The ISS finally reached an operational state and exists for local and remote users. Onboard payload systems are managed by the Huntsville Operations Support Center (HOSC). Users access HOSC systems by internet protocols in support of daily operations, preflight simulation, and test. In support of this diverse user community, a modem security architecture has been implemented. The architecture has evolved over time from an isolated but open system to a system which supports local and remote access to the ISS over broad geographic regions. This has been accomplished through the use of an evolved security strategy, PKI, and custom design. Through this paper, descriptions of the migration process and the lessons learned are presented. This will include product decision criteria, rationale, and the use of commodity products in the end architecture. This paper will also stress the need for interoperability of various products and the effects of seemingly insignificant details.

Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling.

PubMed

Namkoong, Seung; Kim, Chun-Ki; Cho, Young-Lai; Kim, Ji-Hee; Lee, Hansoo; Ha, Kwon-Soo; Choe, Jongseon; Kim, Pyeung-Hyeun; Won, Moo-Ho; Kwon, Young-Geun; Shim, Eun Bo; Kim, Young-Myeong

2009-06-01

Forskolin, a potent activator of adenylyl cyclases, has been implicated in modulating angiogenesis, but the underlying mechanism has not been clearly elucidated. We investigated the signal mechanism by which forskolin regulates angiogenesis. Forskolin stimulated angiogenesis of human endothelial cells and in vivo neovascularization, which was accompanied by phosphorylation of CREB, ERK, Akt, and endothelial nitric oxide synthase (eNOS) as well as NO production and VEGF expression. Forskolin-induced CREB phosphorylation, VEGF promoter activity, and VEGF expression were blocked by the PKA inhibitor PKI.Moreover, phosphorylation of ERK by forskolin was inhibited by the MEK inhibitor PD98059, but not PKI. The forskolin-induced Akt/eNOS/NO pathway was completely inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, but not significantly suppressed by PKI. These inhibitors and a NOS inhibitor partially inhibited forskolin-induced angiogenesis. The exchange protein directly activated by cAMP (Epac) activator, 8CPT-2Me-cAMP, promoted the Akt/eNOS/NO pathway and ERK phosphorylation,but did not induce CREB phosphorylation and VEGF expression. The angiogenic effect of the Epac activator was diminished by the inhibition of PI3K and MEK, but not by the PKA inhibitor. Small interfering RNA-mediated knockdown of Epac1 suppressed forskolin-induced angiogenesis and phosphorylation of ERK, Akt, and eNOS, but not CREB phosphorylation and VEGF expression. These results suggest that forskolin stimulates angiogenesis through coordinated cross-talk between two distinct pathways, PKA-dependent VEGF expression and Epac-dependent ERKactivation and PI3K/Akt/eNOS/NO signaling.

Measuring pKa of activation and pKi of inactivation for influenza hemagglutinin from kinetics of membrane fusion of virions and of HA expressing cells.

PubMed

Mittal, Aditya; Shangguan, Tong; Bentz, Joe

2002-11-01

The data for the pH dependence of lipid mixing between influenza virus (A/PR/8/34 strain) and fluorescently labeled liposomes containing gangliosides has been analyzed using a comprehensive mass action kinetic model for hemaglutinin (HA)-mediated fusion. Quantitative results obtained about the architecture of HA-mediated membrane fusion site from this analysis are in agreement with the previously reported results from analyses of data for HA-expressing cells fusing with various target membranes. Of the eight or more HAs forming a fusogenic aggregate, only two have to undergo the "essential" conformational change needed to initiate fusion. The mass action kinetic model has been extended to allow the analysis of the pKa for HA activation and pKi for HA inactivation. Inactivation and activation of HA following protonation were investigated for various experimental systems involving different strains of HA (A/PR/8/34, X:31, A/Japan). We find that the pKa for the final protonation site on each monomer of the trimer molecule is 5.6 to 5.7, irrespective of the strain. We also find that the pKi for the PR/8 strain is 4.8 to 4.9. The inactivation rate constants for HA, measured from experiments done with PR/8 virions fusing with liposomes and X:31 HA-expressing cells fusing with red blood cells, were both found to be of the order of 10(-4) s(-1). This number appears to be the minimal rate for HA's essential conformational change at low HA surface density. At high HA surface densities, we find evidence for cooperativity in the conformational change, as suggested by other studies.

Complex inner core boundary from frequency characteristics of the reflection coefficients of PKiKP waves observed by Hi-net

NASA Astrophysics Data System (ADS)

Tanaka, Satoru; Tkalčić, Hrvoje

2015-12-01

Frequency-dependent reflection coefficients of P waves at the inner core boundary (ICB) are estimated from the spectral ratios of PKiKP and PcP waves observed by the high-sensitivity seismograph network (Hi-net) in Japan. The corresponding PKiKP reflection locations at the ICB are distributed beneath the western Pacific. At frequencies where noise levels are sufficiently low, spectra of reflection coefficients show four distinct sets of characteristics: a flat spectrum, a spectrum with a significant spectral hole at approximately 1 or 3 Hz, a spectrum with a strong peak at approximately 2 or 3 Hz, and a spectrum containing both a sharp peak and a significant hole. The variety in observed spectra suggests complex lateral variations in ICB properties. To explain the measured differences in frequency characteristics of ICB reflection coefficients, we conduct 2D finite difference simulations of seismic wavefields near the ICB. The models tested in our simulations include a liquid layer and a solid layer above the ICB, as well as sinusoidal and spike-shaped ICB topography with varying heights and scale lengths. We find that the existence of a layer above the ICB can be excluded as a possible explanation for the observed spectra. Furthermore, we find that an ICB topographic model with wavelengths and heights of several kilometers is too extreme to explain our measurements. However, restricting the ICB topography to wavelengths and heights of 1.0-1.5 km can explain the observed frequency-related phenomena. The existence of laterally varying topography may be a sign of lateral variations in inner core solidification.

Measuring pKa of activation and pKi of inactivation for influenza hemagglutinin from kinetics of membrane fusion of virions and of HA expressing cells.

PubMed Central

Mittal, Aditya; Shangguan, Tong; Bentz, Joe

2002-01-01

The data for the pH dependence of lipid mixing between influenza virus (A/PR/8/34 strain) and fluorescently labeled liposomes containing gangliosides has been analyzed using a comprehensive mass action kinetic model for hemaglutinin (HA)-mediated fusion. Quantitative results obtained about the architecture of HA-mediated membrane fusion site from this analysis are in agreement with the previously reported results from analyses of data for HA-expressing cells fusing with various target membranes. Of the eight or more HAs forming a fusogenic aggregate, only two have to undergo the "essential" conformational change needed to initiate fusion. The mass action kinetic model has been extended to allow the analysis of the pKa for HA activation and pKi for HA inactivation. Inactivation and activation of HA following protonation were investigated for various experimental systems involving different strains of HA (A/PR/8/34, X:31, A/Japan). We find that the pKa for the final protonation site on each monomer of the trimer molecule is 5.6 to 5.7, irrespective of the strain. We also find that the pKi for the PR/8 strain is 4.8 to 4.9. The inactivation rate constants for HA, measured from experiments done with PR/8 virions fusing with liposomes and X:31 HA-expressing cells fusing with red blood cells, were both found to be of the order of 10(-4) s(-1). This number appears to be the minimal rate for HA's essential conformational change at low HA surface density. At high HA surface densities, we find evidence for cooperativity in the conformational change, as suggested by other studies. PMID:12414698

J-PAKE: Authenticated Key Exchange without PKI

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

Myristoylated peptides potentiate the funny current (If) in sinoatrial myocytes

PubMed Central

Liao, Zhandi; St Clair, Joshua R; Larson, Eric D

2011-01-01

The funny current, If, in sinoatrial myocytes is thought to contribute to the sympathetic fight-or-flight increase in heart rate. If is produced by hyperpolarization-activated cyclic nucleotide sensitive-4 (HCN4) channels, and it is widely believed that sympathetic regulation of If occurs via direct binding of cAMP to HCN4, independent of phosphorylation. However, we have recently shown that Protein Kinase A (PKA) activity is required for sympathetic regulation of If, and that PKA can directly phosphorylate HCN4.1 In the present study, we examined the effects of a myristoylated PKA inhibitory peptide (myr-PKI) on If in mouse sinoatrial myocytes. We found that myr-PKI and another myristoylated peptide potently and specifically potentiated If via a mechanism that did not involve PKA inhibition and that was independent of the peptide sequence, Protein Kinase C or phosphatidylinositol-4,5-bisphosphate. The off-target activation of If by myristoylated peptides limits their usefulness for studies of pacemaker mechanisms in sinoatrial myocytes. PMID:21150293

K-Anonymous Multi-party Secret Handshakes

NASA Astrophysics Data System (ADS)

Xu, Shouhuai; Yung, Moti

Anonymity-protection techniques are crucial for various commercial and financial transactions, where participants are worried about their privacy. On the other hand, authentication methods are also crucial for such interactions. Secret handshake is a relatively recent mechanism that facilitates privacy-preserving mutual authentication between communicating peers. In recent years, researchers have proposed a set of secret handshake schemes based on different assumptions about the credentials used: from one-time credentials to the more general PKI-like credentials. In this paper, we concentrate on k-anonymous secret handshake schemes based on PKI-like infrastructures. More specifically, we deal with the k-anonymous m-party (m > 2) secret handshake problem, which is significantly more involved than its two-party counterpart due to the following: When an honest user hand-shakes with m - 1 parties, it must be assured that these parties are distinct; otherwise, under the mask of anonymity a dishonest participant may clone itself in a single handshake session (i.e., assuming multiple personalities).

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

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

Amaryan, M; Pal, Bilas

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 tomore » 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.« less

Personal Knowledge Integrators

ERIC Educational Resources Information Center

White, David C.

2013-01-01

This paper discusses, in the context of personal learning environments, the need for Personal Knowledge Integrators--PKI's or Knowers. It first illustrates and establishes the need for Knowers with usage scenarios and people's requirements. It then describes the elements required to make a Knower which can exchange information with other Knowers,…

Seismic structures in the inner and outer core constrained by the PKP observations near the caustic distance range

NASA Astrophysics Data System (ADS)

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

2002-05-01

We have extensively collected PKP waveforms around the PKP caustic distance range (141o - 147o) recorded in several dense regional arrays and the Global Seismic Network covering from 1990 to 2000. PKP observations at this distance range (141o - 147o) are usually purposely avoided in travel time analyses, because of the interference of various PKP branches. The observations there, however, will be extremely useful for constraining the seismic structures at both the top of the inner core and the bottom of the outer core. Moreover, because PKIKP phases sample a depth range of 100 km - 170 km below the inner-core boundary at this distant range, their observations fill the sampling depth gap between the PKiKP-PKIKP observations at the smaller distances and the PKPbc-PKIKP phases at the larger distances. Before the PKP caustics (141o - 145o), the diffracted PKP phases near the B caustics (PKPBdiff) and PKiKP phases are discernible in the long-period seismograms, and their differential travel times and waveforms could be used to constrain seismic structures at the bottom of the outer core and/or at the base of the mantle. The observed long-period PKiKP-PKPBdiff waveforms exhibit a hemispheric difference between those sampling the "eastern" and "western" hemispheres, with those sampling the "western" hemisphere showing larger time separations between the two phases. These observations can be explained by models with P velocity gradients of 0.0806 (km/s)/ 200 km for the "western" hemisphere and 0.114 (km/s)/200 km for the "eastern" hemisphere at the bottom of the outer core. Alternatively, these observations can also be explained by models with different velocity structures at the bottom 200 km of the mantle with P velocity variations in an order of 3 percent with respect to PREM. Broadband PKP observations after the PKP caustics (145o - 147o), on the other hand, provide high-quality constraints on the seismic structures at both the top of the inner core and the bottom of the outer core, as PKPbc phases can be used as excellent reference phases. We explore seismic models in both the bottom of the outer core and the top of the inner core, which can consistently explain the seismic observations at the caustic distance range (141o - 147o) and the PKiKP-PKIKP observations at the closer distances (Niu and Wen, Nature, 410, 1081-1084, 2001, Wen and Niu, JGR, submitted).

76 FR 48807 - Public Key Infrastructure (PKI) Certificate Action Form

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-09

...) Certificate Action Form ACTION: Proposed collection; comment request. SUMMARY: The United States Patent and... Certificate Action Form (PTO-2042), which is used by the public to request a new digital certificate, the... applicant. The Certificate Action Form has an accompanying subscriber agreement to ensure that customers...

End-to-End Service Oriented Architectures (SOA) Security Project

DTIC Science & Technology

2012-02-01

ActivClientforCommonAccessCards/ [CAC3] http://koji.fedoraproject.org/ koji /packageinfo?packageID=5 [CAC4] https://help.ubuntu.com/community...Ubuntu10.4-LTS-32.html [CAC8] http://dodpki.c3pki.chamb.disa.mil/rootca.html [CAC9] http://koji.fedoraproject.org/ koji /packageinfo?packageID=5 [CAC10

cAMP-dependent protein kinase (PKA) complexes probed by complementary differential scanning fluorimetry and ion mobility–mass spectrometry

PubMed Central

Byrne, Dominic P.; Vonderach, Matthias; Ferries, Samantha; Brownridge, Philip J.; Eyers, Claire E.; Eyers, Patrick A.

2016-01-01

cAMP-dependent protein kinase (PKA) is an archetypal biological signaling module and a model for understanding the regulation of protein kinases. In the present study, we combine biochemistry with differential scanning fluorimetry (DSF) and ion mobility–mass spectrometry (IM–MS) to evaluate effects of phosphorylation and structure on the ligand binding, dynamics and stability of components of heteromeric PKA protein complexes in vitro. We uncover dynamic, conformationally distinct populations of the PKA catalytic subunit with distinct structural stability and susceptibility to the physiological protein inhibitor PKI. Native MS of reconstituted PKA R2C2 holoenzymes reveals variable subunit stoichiometry and holoenzyme ablation by PKI binding. Finally, we find that although a ‘kinase-dead’ PKA catalytic domain cannot bind to ATP in solution, it interacts with several prominent chemical kinase inhibitors. These data demonstrate the combined power of IM–MS and DSF to probe PKA dynamics and regulation, techniques that can be employed to evaluate other protein-ligand complexes, with broad implications for cellular signaling. PMID:27444646

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

PubMed

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.

Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505).

PubMed

Dietis, N; McDonald, J; Molinari, S; Calo, G; Guerrini, R; Rowbotham, D J; Lambert, D G

2012-02-01

While producing good-quality analgesia, µ-opioid (MOP) receptor activation produces a number of side-effects including tolerance. Simultaneous blockade of δ-opioid (DOP) receptors has been shown to reduce tolerance to morphine. Here, we characterize a prototype bifunctional opioid H-Dmt-Tic-Gly-NH-Bzl (UFP-505). We measured receptor binding affinity in Chinese hamster ovary (CHO) cells expressing recombinant human MOP, DOP, k-opioid (KOP), nociceptin/orphanin (NOP) receptors. For activation, we measured the binding of GTPγ(35)S to membranes from CHO(hMOP), CHO(hDOP), rat cerebrocortex, and rat spinal cord. In addition, we assessed 'end organ' responses in the guinea pig ileum and mouse vas deferens. UFP-505 bound to CHO(hMOP) and CHO(hDOP) with (binding affinity) pK(i) values of 7.79 and 9.82, respectively. There was a weak interaction at KOP and NOP (pK(i) 6.29 and 5.86). At CHO(hMOP), UFP-505 stimulated GTPγ(35)S binding with potency (pEC(50)) of 6.37 and in CHO(hDOP) reversed the effects of a DOP agonist with affinity (pK(b)) of 9.81 (in agreement with pK(i) at DOP). UFP-505 also stimulated GTPγ(35)S binding in rat cerebrocortex and spinal cord with pEC(50) values of 6.11-6.53. In the guinea pig ileum (MOP-rich preparation), UFP-505 inhibited contractility with pEC(50) of 7.50 and in the vas deferens (DOP-rich preparation) reversed the effects of a DOP agonist with an affinity (pA(2)) of 9.15. We have shown in a range of preparations and assays that UFP-505 behaves as a potent MOP agonist and DOP antagonist; a MOP/DOP bifunctional opioid. Further studies in dual expression systems and whole animals with this prototype are warranted.

Extending key sharing: how to generate a key tightly coupled to a network security policy

NASA Astrophysics Data System (ADS)

Kazantzidis, Matheos

2006-04-01

Current state of the art security policy technologies, besides the small scale limitation and largely manual nature of accompanied management methods, are lacking a) in real-timeliness of policy implementation and b) vulnerabilities and inflexibility stemming from the centralized policy decision making; even if, for example, a policy description or access control database is distributed, the actual decision is often a centralized action and forms a system single point of failure. In this paper we are presenting a new fundamental concept that allows implement a security policy by a systematic and efficient key distribution procedure. Specifically, we extend the polynomial Shamir key splitting. According to this, a global key is split into n parts, any k of which can re-construct the original key. In this paper we present a method that instead of having "any k parts" be able to re-construct the original key, the latter can only be reconstructed if keys are combined as any access control policy describes. This leads into an easily deployable key generation procedure that results a single key per entity that "knows" its role in the specific access control policy from which it was derived. The system is considered efficient as it may be used to avoid expensive PKI operations or pairwise key distributions as well as provides superior security due to its distributed nature, the fact that the key is tightly coupled to the policy, and that policy change may be implemented easier and faster.

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

Federal Register 2010, 2011, 2012, 2013, 2014

2011-01-03

..., SDDC will require all commercial accounts accessing transportation systems and applications to use a...: Department of Defense Instruction number 8520.2, 1 April 2004, 4.4 Joint Task Force-Global Network Operations..._8520.2.pdf ). Randy Moore, CAPT, USN, Division Chief, G6, Information Management/CIO. [FR Doc. 2010...

Distributed generation of shared RSA keys in mobile ad hoc networks

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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.

Certificate Revocation Using Fine Grained Certificate Space Partitioning

NASA Astrophysics Data System (ADS)

Goyal, Vipul

A new certificate revocation system is presented. The basic idea is to divide the certificate space into several partitions, the number of partitions being dependent on the PKI environment. Each partition contains the status of a set of certificates. A partition may either expire or be renewed at the end of a time slot. This is done efficiently using hash chains.

Improved security monitoring method for network bordary

NASA Astrophysics Data System (ADS)

Gao, Liting; Wang, Lixia; Wang, Zhenyan; Qi, Aihua

2013-03-01

This paper proposes a network bordary security monitoring system based on PKI. The design uses multiple safe technologies, analysis deeply the association between network data flow and system log, it can detect the intrusion activities and position invasion source accurately in time. The experiment result shows that it can reduce the rate of false alarm or missing alarm of the security incident effectively.

Cardiotoxic and Cardioprotective Features of Chronic β-adrenergic Signaling

PubMed Central

Zhang, Xiaoying; Szeto, Christopher; Gao, Erhe; Tang, Mingxin; Jin, Jianguo; Fu, Qin; Makarewich, Catherine; Ai, Xiaojie; Li, Ying; Tang, Allen; Wang, Jenny; Gao, Hui; Wang, Fang; Ge, Xinyi Joy; Kunapuli, Satya P.; Zhou, Lin; Zeng, Chunyu; Xiang, Kevin Yang; Chen, Xiongwen

2012-01-01

Rationale In the failing heart, persistent β-adrenergic receptor (βAR) activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA-independent activation of calcium/calmodulin-dependent kinase II (CaMKII). β-Adrenergic signaling pathways are also capable of activating cardioprotective mechanisms. Objective This study used a novel PKA inhibitor peptide (PKI) to inhibit PKA activity to test the hypothesis that βAR signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways. Methods and Results In PKI transgenic mice, chronic isoproterenol (ISO) failed to induce cardiac hypertrophy, fibrosis, myocyte apoptosis and depressed cardiac function. In cultured adult feline ventricular myocytes (AFVMs), PKA inhibition protected myocytes from death induced by β1-AR agonists by preventing cytosolic and SR Ca2+ overload and CaMKII activation. PKA inhibition revealed a cardioprotective role of β-adrenergic signaling via cAMP/EPAC /Rap1/Rac/ERK pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction (MI) that was superior to β-blocker therapy. Conclusion These results suggest that selective block of PKA could be a novel heart failure therapy. PMID:23104882

Three Types of Earth's Inner Core Boundary

NASA Astrophysics Data System (ADS)

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 transmission security framework for email-based telemedicine.

PubMed

Caffery, Liam J; Smith, Anthony C

2010-01-01

Encryption is used to convert an email message to an unreadable format thereby securing patient privacy during the transmission of the message across the Internet. Two available means of encryption are: public key infrastructure (PKI) used in conjunction with ordinary email and secure hypertext transfer protocol (HTTPS) used by secure web-mail applications. Both of these approaches have advantages and disadvantages in terms of viability, cost, usability and compliance. The aim of this study was develop an instrument to identify the most appropriate means of encrypting email communication for telemedicine. A multi-method approach was used to construct the instrument. Technical assessment and existing bodies of knowledge regarding the utility of PKI were analyzed, along with survey results from users of Queensland Health's Child and Youth Mental Health Service secure web-mail service. The resultant decision support model identified that the following conditions affect the choice of encryption technology: correspondent's risk perception, correspondent's identification to the security afforded by encryption, email-client used by correspondents, the tolerance to human error and the availability of technical resources. A decision support model is presented as a flow chart to identify the most appropriate encryption for a specific email-based telemedicine service.

Ensemble cryo-EM uncovers inchworm-like translocation of a viral IRES through the ribosome

PubMed Central

Abeyrathne, Priyanka D; Koh, Cha San; Grant, Timothy; Grigorieff, Nikolaus; Korostelev, Andrei A

2016-01-01

Internal ribosome entry sites (IRESs) mediate cap-independent translation of viral mRNAs. Using electron cryo-microscopy of a single specimen, we present five ribosome structures formed with the Taura syndrome virus IRES and translocase eEF2•GTP bound with sordarin. The structures suggest a trajectory of IRES translocation, required for translation initiation, and provide an unprecedented view of eEF2 dynamics. The IRES rearranges from extended to bent to extended conformations. This inchworm-like movement is coupled with ribosomal inter-subunit rotation and 40S head swivel. eEF2, attached to the 60S subunit, slides along the rotating 40S subunit to enter the A site. Its diphthamide-bearing tip at domain IV separates the tRNA-mRNA-like pseudoknot I (PKI) of the IRES from the decoding center. This unlocks 40S domains, facilitating head swivel and biasing IRES translocation via hitherto-elusive intermediates with PKI captured between the A and P sites. The structures suggest missing links in our understanding of tRNA translocation. DOI: http://dx.doi.org/10.7554/eLife.14874.001 PMID:27159452

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

PubMed

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.

The pharmacology of GR203040, a novel, potent and selective non-peptide tachykinin NK1 receptor antagonist.

PubMed Central

Beattie, D. T.; Beresford, I. J.; Connor, H. E.; Marshall, F. H.; Hawcock, A. B.; Hagan, R. M.; Bowers, J.; Birch, P. J.; Ward, P.

1995-01-01

1. The in vitro and in vivo pharmacology of GR203040 ((2S, 3S)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), a novel, highly potent and selective non-peptide tachykinin NK1 receptor antagonist, was investigated in the present study. 2. GR203040 potently inhibited [3H]-substance P binding to human NK1 receptors expressed in Chinese hamster ovary (CHO) and U373 MG astrocytoma cells, and NK1 receptors in ferret and gerbil cortex (pKi values of 10.3, 10.5, 10.1 and 10.1 respectively). GR203040 had lower affinity at rat NK1 receptors (pKi = 8.6) and little affinity for human NK2 receptors (pKi < 5.0) in CHO cells and NK3 receptors in guinea-pig cortex (pKi < 6.0). With the exception of the histamine H1 receptor (pIC50 = 7.5). GR203040 had little affinity (pIC50 < 6.0) at all non-NK1 receptors and ion channels examined. Furthermore, GR203040 produced only weak inhibition of Na+ currents in SH-SY5Y neuroblastoma and superior cervical ganglion cells (pIC50 values < 4.0). GR203040 produced only weak antagonism of Ca(2+)-evoked contractions of rat isolated portal vein (pKn = 4.1). The enantiomer of GR203040, GR205608 (2R, 3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin-3-y l)-amine), had 10,000 fold lower affinity at the human NK1 receptor expressed in CHO cells (pKi = 6.3). 3. In gerbil ex vivo binding experiments, GR203040 produced a dose-dependent inhibition of the binding of [3H]-substance P to cerebral cortical membranes (ED50 = 15 micrograms kg-1 s.c. and 0.42 mg kg-1 p.o.). At 10 micrograms kg-1 s.c., the inhibition of [3H]-substance P binding was maintained for > 6 h. In the rat, GR203040 was less potent (ED50 = 15.4 mg kg-1 s.c.) probably reflecting, at least in part, its lower affinity at the rat NK1 receptor. 4. In guinea-pig isolated ileum and dog isolated middle cerebral and basilar arteries, GR203040 produced a rightward displacement of the concentration-effect curves to substance P methyl ester (SPOMe) with suppression of the maximum agonist response (apparent pKB values of 11.9, 11.2 and 11.1 respectively). 5. In anaesthetized rabbits, GR203040 antagonized reductions in carotid arterial vascular resistance evoked by SPOMe, injected via the lingual artery (DR10 (i.e. the dose producing a dose-ratio of 10) = 1.1 micrograms kg-1, i.v.). At a dose 20 fold greater than its DR10 value (i.e. 22 micrograms kg-1, i.v.), significant antagonism was evident more than 2 h after GR203040 administration. 6. In anaesthetized rats, GR203040 (3 and 10 mg kg-1, i.v.) produced a dose-dependent inhibition of plasma protein extravasation in dura mater, conjunctiva, eyelid and lip in response to electrical stimulation of the trigeminal ganglion. 7. It is concluded that GR203040 is one of the most potent and selective NK1 receptor antagonists yet described, and as such, has considerable potential as a pharmacological tool to characterize the physiological and pathological roles of substance P and NK1 receptors. GR203040 may also have potential as a novel therapeutic agent for the treatment of conditions such as migraine, emesis and pain. PMID:8719789

Pharmacological characterization of the bradykinin B2 receptor: inter-species variability and dissociation between binding and functional responses

PubMed Central

Paquet, J -L; Luccarini, J -M; Fouchet, C; Defrêne, E; Loillier, B; Robert, C; Bélichard, P; Cremers, B; Pruneau, D

1999-01-01

The present study addresses the differences in binding profiles and functional properties of the human and rat bradykinin (BK) B2 receptor using various kinin receptor peptide derivatives as well as the non-peptide receptor antagonists WIN 64338 (phosphonium, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2-naphtalenyl)1-oxopropyl]amino]-phenyl]-methyl]tributyl, chloride, monohydro-chloride), and FR173657 (E)-3-(6-acetamido-3-pyridyl)-N-[-N-[2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]-phenyl]N-methylamino carbonyl methyl] acrylamide. [3H]-BK bound with a similar affinity to membranes of Chinese hamster ovary cells (CHO-K1) expressing the cloned human (hB2-CHO) or rat (rB2-CHO) B2 receptor, human embryonic intestine cells (INT407) expressing the native B2 receptor, human umbilical vein (HUV) and rat uterus (RU). WIN 64338 and FR173657 bound with a 3.8–6.6 fold and 7.0–16.3 fold higher affinity the rat than the human B2 receptor, respectively. The affinity values of BK derivatives as well as non-peptide antagonists were reduced by 6–23 fold in physiological HBSS compared to low ionic strength TES binding buffer. BK (0.01–3000 nM) increased inositol triphosphates (IP3) levels in hB2-CHO, rB2-CHO and INT407 cells. The B2 receptor antagonist, Hoe 140 (D-Arg0-[ Hyp3, Thi5, D-Tic7, Oic8]-BK) at 10−7 M, significantly shifted to the right the IP3 response curves to BK giving apparent pKB values of 8.56, 9.79 and 8.84 for hB2-CHO, rB2-CHO and INT407 cells, respectively. In human isolated umbilical vein, Hoe 140, D-Arg0-[Hyp3, D-Phe7, Leu8]-BK and NPC 567 had a lower potency in functional assays (pKB 8.18, 5.77 and 5.60, respectively) than expected from their affinity in binding studies (pKi 10.52, 8.64 and 8.27, respectively). FR173657 behaved as a high affinity ligand with pKi values of 8.59 and 9.81 and potent competitive antagonist with pKB values of 7.80 and 8.17 in HUV and RU, respectively. FR173657 bound with a similar affinity the cloned and native bradykinin B2 receptor in human (pKi of 8.66 and 8.59, respectively) and in rat (pKi 9.67 and 9.81, respectively). In conclusion, we suggest that the binding buffer composition has to be taken into account when screening new compounds and that inter-species differences should be considered when setting up animal models with the aim of developing bradykinin B2 receptor antagonists as therapeutic agents. PMID:10204994

Object Signing in Bamboo

DTIC Science & Technology

2000-03-01

Dynamics. Numerous smaller companies have entered the market in just the past year offering similar PKI security solutions in an effort to take advantage...web of social , legal and business interactions that, in some cases, have taken generations to mature. We use common instruments to establish trust...types of digital certificates on the market today. However, with the recent development of object signing tools, some of the later browsers are incapable

Defense Message System Way Ahead: Conclusions and Recommendations from the Industry Advisory Panel

DTIC Science & Technology

2000-03-01

access terminals • Increasing requirement for authentication and data security for conducting business • Mergers and acquisitions in Internet space...market, used to carry PKI certificates for all types of security services including access control, confidentiality, integrity, and non-repudiation...Wireless access widespread § Unified messaging pervasive § Security /privacy dependent on service provider Long-term § Highly reliable systems

Efficient Transmission of DoD PKI Certificates in Tactical Networks

DTIC Science & Technology

2010-01-01

011 the COlll- mand line. To extract individual fields from cert ifica tes, we used the X.509 subset of the C API included with OpenSSL (vl.O.0-bcta2...www.disa.mil/nces. [17J NSA Suite Il Cryptogt"aphy. http://vvv . nsa.gov/ial programs/suiteb_cryptography/index.shtml. [18J OpenSSL : The Open Source toolk

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

PubMed

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 Pharmacological Society.

Seismic Structure in the Vicinity of the Inner Core Boundary beneath northeastern Asia

NASA Astrophysics Data System (ADS)

Ibourichene, A. S.; Romanowicz, B. A.

2016-12-01

The inner core boundary (ICB) separates the solid inner core from the liquid outer core. The crystallization of iron occurring at this limit induces the expulsion of lighter elements such as H, O, S, Si into the outer core, generating chemically-driven convection, which provides power for the geodynamo. Both the F layer, right above the ICB, and the uppermost inner core, are affected by this process so that their properties provide important constraints for a better understanding of core dynamics and, ultimately, the generation and sustained character of the earth's magnetic field. In this study, we investigate the evolution of model parameters (P-velocity, density and quality factor) with depth in the vicinity of the ICB. For this purpose, we combine observations of two body wave phases sensitive to this region: the PKP(DF) phase refracted in the inner core and the PKiKP reflected on the ICB. Variations in the PKP(DF)/PKiKP amplitude ratio and PKP(DF)-PKiKP differential travel times can be related to structure around the ICB. We use waveform data from earthquakes located in Sumatra and recorded by the dense USArray seismic network, which allows us to sample ICB structure beneath northeastern Asia. Observed waveforms are compared to synthetics computed using the DSM method (e.g., Geller et Takeuchi, 1995) in model AK135 (e.g., Montagner & Kennett, 1996) in order to measure amplitude and travel time anomalies. Previous studies (e.g., Tanaka, 1997 ; Cao and Romanowicz, 2004, Yu and Wen, 2006; Waszek and Deuss, 2011) have observed an hemispherical pattern in the vicinity of the ICB exhibiting a faster and more attenuated eastern hemisphere compared to the western hemisphere. The region studied is located in the eastern hemisphere. We find that, on average, travel time anomalies are consistent with previous studies of the eastern hemisphere, however, amplitude ratios are not. We conduct a parameter search for the 1D model that best fits our data. We also consider fluctuations around this best fitting average model and quantify the statistical properties of the short wavelength fluctuations.

Federated Ground Station Network Model and Interface Specification

DTIC Science & Technology

2014-12-01

interface definition language JSON JavaScript Object Notation LEO low Earth orbit LNA low-noise amplifier MC3 Mobile CubeSat Command and Control...Naval Research Laboratory OQPSK offset quadrature phase-shift keying xviii P2P peer-to-peer PKI public key infrastructure REST Representational...enhanced our work being performed on the Mobile CubeSat Command and Control (MC3) ground station network. You also provided crucial guidance from

Public Key Infrastructure Increment 2 (PKI Inc 2)

DTIC Science & Technology

2016-03-01

DoD - Department of Defense DoDAF - DoD Architecture Framework FD - Full Deployment FDD - Full Deployment Decision FY - Fiscal Year IA...experienced due to a delay in achieving the FDD . The Critical Change Report was provided to Congress on July 11, 2014. Firm, Fixed-Price Feasibility...to a delay in achieving the FDD . To support the Critical Change Report, the NSA Cost Estimating organization prepared a cost estimate that was

Information Sharing for Medical Triage Tasking During Mass Casualty/Humanitarian Operations

DTIC Science & Technology

2009-12-01

military patrol units or surreptitious " cloak and dagger " fact gathering missions to gain photographic/video graphic data for dissemination to the...fractured command and control organization and retarded deployment of resources. Tragedies such as Hurricane Katrina in 2005, the September 11 attacks of...with PKI certificates and HMAC protection from replay attacks and UDP flooding [17]. 3. Triage Graphical User Interface (GUI) Currently the GUI for

Ascl1-induced neuronal differentiation of P19 cells requires expression of a specific inhibitor protein of cAMP-dependent protein kinase

PubMed Central

Huang, Holly S.; Turner, David L.; Thompson, Robert C.; Uhler, Michael D.

2011-01-01

cAMP-dependent protein kinase (PKA) plays a critical role in nervous system development by modulating sonic hedgehog and bone morphogenetic protein signaling. In the current studies, P19 embryonic carcinoma cells were neuronally differentiated by expression of the proneural basic helix-loop-helix transcription factor Ascl1. After expression of Ascl1, but prior to expression of neuronal markers such as microtubule associated protein 2 and neuronal β-tubulin, P19 cells demonstrated a large, transient increase in both mRNA and protein for the endogenous protein kinase inhibitor (PKI)β. PKIβ-targeted shRNA constructs both reduced the levels of PKIβ expression and blocked the neuronal differentiation of P19 cells. This inhibition of differentiation was rescued by transfection of a shRNA-resistant expression vector for the PKIβ protein, and this rescue required the PKA-specific inhibitory sequence of the PKIβprotein. PKIβ played a very specific role in the Ascl1-mediated differentiation process since other PKI isoforms were unable to rescue the deficit conferred by shRNA-mediated knockdown of PKIβ. Our results define a novel requirement for PKIβ and its inhibition of PKA during neuronal differentiation of P19 cells. PMID:21623794

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

PubMed

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.

[Role of caveolin-1 in pulmonary microvascular endothelial cells injury induced by lipopolysaccharide in rat].

PubMed

You, Qing-hai; Zhang, Dan; Sun, Geng-yun; Yue, Yang; Xu, Xiu-juan

2013-12-01

To investigate the role of caveolin-1 (Cav-1) in the modulation of rat pulmonary microvascular endothelial cells (RPMVEC) injury induced by lipopolysaccharide (LPS). Cultured RPMVEC were randomly divided into time-dependent injury group induced by LPS and intervention group in which cells were pretreated by protein kinase A inhibitor (PKI). In the time-dependent injury group, monolayers of cells were constructed to determine permeability changes after 10 μg/mL LPS challenge for 0, 1, 3, 6, 12 and 24 hours with the method of Evans blue-labeled albumin flux across the monolayer (Pd). Western blotting was used to determine the Cav-1 expression after LPS stimulation and the phosphorylation-Cav-1 (p-Cav-1) expression after LPS challenge for 0, 10, 30, 60, 90, 120 minutes. In the intervention group, after pre-treatment with 10 μmol/L PKI for 30 minutes, RPMVECs were challenged with 10 μg/mL LPS, and the expression of p-Cav-1 was determined 30 minutes after LPS challenge, the permeability and the Cav-1 protein expression were assessed by Pd and Western blotting, respectively. Non-stimulation group and single PKI simulation group served as controls. Western blotting revealed that the expression of Cav-1 protein was elevated at 1 hour (2.97 ± 0.07), peaking at 3 hours (3.77 ± 0.37), then it lowered gradually, but it was still higher at 24 hours (1.45 ± 0.18) when compared with 0 hour group (1.12±0.08) with significant differences (F=178.047, P=0.000). After RPMVEC monolayers were challenged by LPS for different periods (0, 1, 3, 6, 12 and 24 hours), there were significant increases in a time-dependent manner in Cav-1 expression in the permeability as measured by Pd [(99.67 ± 4.32)%, (118.17 ± 2.32)%, (159.00 ± 2.61)%, (141.17 ± 2.64)%, (120.17 ± 2.79)% and (108.83 ± 2.04)%, F=345.869, P=0.000] which was similar to the changes in Cav-1 expression. LPS also increased Cav-1 phosphorylation in a time-dependent manner occurring at 10 minutes (2.41 ± 0.11), peaking at 30 minutes (2.83 ± 0.10), and then it decreased gradually, finally returned to basal levels (1.03±0.04) at 120 minutes (1.04 ± 0.04) after LPS treatment with significant difference (F=519.417, P=0.000). When PKI was pre-treated with RPMVEC the expression of Cav-1 was significantly increased (5.07 ± 0.22 vs. 3.81 ± 0.23, P<0.01), and p-Cav-1 (3.93 ± 0.23 vs. 2.77±0.10, P<0.01), and RPMVEC monolayers permeability was enhanced [(184.17 ± 5.49)% vs. (151.50 ± 3.08)%, P<0.01] after being challenged. Up-regulated expression of Cav-1 and phosphorylation-Cav-1 that may be modulated by protein kinase A signal pathway plays an important role in RPMVEC permeability injury as induced by LPS.

Simultaneous Time, Wavelength and Intensity Measurement of Optical Memory Subsystems

DTIC Science & Technology

1998-07-01

SIMULTANEOUS TIME, WAVELENGTH AND INTENSITY MEASUREMENT PE - 61102F OF OPTICAL MEMORY SUBSYSTEMS PR - 2300 6. AUTHOR( S ) TA - 06 WU -03 Joseph Osman and...Rebecca Bussjager 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER AFRL/SNDP25 letnic AFRL-SN-RS-TR- 1998...12025 Electronic Pky Rome, NY 13441-4515 9. SPONSORING/MONITORING AGENCY NAME( S ) AND ADDRESS(ES) 10. SPONSORING/MONITORING AGENCY REPORT NUMBER

Domain Name Server Security (DNSSEC) Protocol Deployment

DTIC Science & Technology

2014-10-01

all the time. For mobile devices, end-system validation is much more difficult due to the state of their networks, many of which do not allow...way to distribute keying information than the current public-key infrastructure (PKI) allows. In addition, it will take work to convince CDNs and...Control Protocol (TCP) or even DNS over Secure Sockets Layer (SSL). One of the important outcomes of our work is the realization that that a " mobile

Unified Communications: Simplifying DoD Communication Methods

DTIC Science & Technology

2013-04-18

private key to encrypt the hash. The encrypted hash, together with some other information, such as the hashing algorithm , is known as a digital...virtual private network (VPN). The use of a VPN would allow users to access corporate data while encrypting traffic.35 Another layer of protection would...sign and encrypt emails as well as controlling access to restricted sites. PKI uses a combination of public and private keys for encryption and

Finland's strategy and implementation of citizens' access to health information.

PubMed

Ruotsalainen, Pekka; Iivari, Anna-Kaisa; Doupi, Persephone

2008-01-01

The strategy for utilizing information technology in the field of social welfare and health care in Finland was published in 1996. It was redefined in the year 2006. This updated strategy defined basic principles how digitized EHRs should be stored, accessed, disclosed and archived. The strategy together with new legislation opened the right to patients and citizens to access their own EHRs, ePrescriptions and audit-logs via the Internet. A national WEB-service platform forms the base for both public and private eHealth applications. National identification and PKI-services cover health professionals, patients and entities. Citizen's consent management is provided at national level. The access to personal health information is managed using rules derived from legislation. The roll-out of the national health information infrastructure with citizen access to personal health information should by law be finalized before the end of 2011. The implementation of the NHII is demanding, but the real challenge is to clearly understand what the impacts of citizen access to personal health information are and to what direction this kind of services should be developed. At the present state, the Finnish EHR-archive contains only information created by a health professional. Citizens' eHealth services can not be limited to the use of regulated EHR data and ePrescriptions. For health promotion, proactive prevention and health prediction more comprehensive information is needed. Therefore the next step is to develop legislation and to build a trusted environment for the use and access of heterogeneous health and welfare information.

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

NASA Astrophysics Data System (ADS)

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.

MEN15596, a novel nonpeptide tachykinin NK2 receptor antagonist.

PubMed

Cialdai, Cecilia; Tramontana, Manuela; Patacchini, Riccardo; Lecci, Alessandro; Catalani, Claudio; Catalioto, Rose-Marie; Meini, Stefania; Valenti, Claudio; Altamura, Maria; Giuliani, Sandro; Maggi, Carlo Alberto

2006-11-07

The pharmacological profile of MEN15596 or (6-methyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1-(tetrahydropyran-4-ylmethyl)-piperidin-4-ylmethyl]-carbamoyl}-ethylcarbamoyl)-cyclopentyl]-amide), a novel potent and selective tachykinin NK2 receptor antagonist endowed with oral activity, is described. At the human recombinant tachykinin NK2 receptor, MEN15596 showed subnanomolar affinity (pKi 10.1) and potently antagonized (pKB 9.1) the neurokinin A-induced intracellular calcium release. MEN15596 selectivity for the tachykinin NK2 receptor was assessed by binding studies at the recombinant tachykinin NK1 (pKi 6.1) and NK3 (pKi 6.4) receptors, and at a number of 34 molecular targets including receptors, transporters and ion channels. In isolated smooth muscle preparations MEN15596 showed a marked species selectivity at the tachykinin NK2 receptor with the highest antagonist potency in guinea-pig colon, human and pig bladder (pKB 9.3, 9.2 and 8.8, respectively) whereas it was three orders of magnitude less potent in the rat and mouse urinary bladder (pKB 6.3 and 5.8, respectively). In agreement with binding experiments, MEN15596 showed low potency in blocking selective NK1 or NK3 receptor agonist-induced contractions of guinea-pig ileum preparations (pA2

Design and Development of a Web-Based DOD PKI Common Access Card (CAC) Instruction Tool

DTIC Science & Technology

2004-03-01

institute internal training programs…to help educate the appropriate personnel” (p. 269). This section indicates the need for training when...of “digital certificates” that provide for the integrity and authenticity of the user to public key value binding. • Though public keys can be...known as a digest) is a unique, fixed- length mathematical value that is determined by the content of the message and the ‘hashing’ algorithm used

Prototype Military Message Form (P772) and Mail List Agent (MLA) for National MMHS

DTIC Science & Technology

2006-12-01

Bakanliklar Ankara TURKEY murat.ucuncu@tr.net A. Betul SASIOGLU National Research Institute of Electronics and Cryptology ( TUBITAK – UEKAE) PK.74...Electronics and Cryptology ( TUBITAK – UEKAE) was used in the system. 3. THE PROTOTYPE NATIONAL MAMF ARCHITECTURE The new national military message...System” [2] ACP 123, "Common Messaging Strategy and Procedures” [3] MA3 ASYA, “PKI Software Developed by Turkish TUBITAK UEKAE” [4] ITU-T X.500

Synthesis and biological evaluation of a series of aminoalkyl-tetralones and tetralols as dual dopamine/serotonin ligands.

PubMed

Carro, Laura; Torrado, María; Raviña, Enrique; Masaguer, Christian F; Lage, Sonia; Brea, José; Loza, María I

2014-01-01

A series of novel α-tetralone and α-tetralol derivatives was synthesized, and their binding affinities for 5-HT(2A) and D₂ receptors, the most important targets implicated in the anti-schizophrenia drug action, were evaluated to elucidate how substitutions in the aromatic ring of the pharmacophore affect to the affinity or selectivity for these receptors. The replacement of the H-7 in the tetrahydronaphthalene system by an amino group resulted in privileged 5-HT(2A) affinity of the 6-fluorobenzo[d]isoxazol derivative 36 and the alcohol 25 both showing a pK(i) value for 5-HT(2A) higher than 8.3 and good binding affinities for D₂ receptor leading to a Meltzer's ratio characteristic of an atypical antipsychotic profile. Additionally, a small collection of 3-aminomethyltetralone derivatives was prepared and examined here for their affinities and selectivities as 5-HT(2A)/D₂ dual ligands. Compound 11 shows the best profile with good pKi values for 5-HT(2A) and D₂ receptors leading to a Meltzer's ratio characteristic of a typical antipsychotic behaviour. These three compounds behaved as competitive antagonists of both 5-HT(2A) and D₂ receptors, and might be promising pharmacological tools for the investigation of the dual function of the 5HT(2A)-D₂ ligands. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

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

NASA Technical Reports Server (NTRS)

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.

Identification of protein–protein interfaces by decreased amide proton solvent accessibility

PubMed Central

Mandell, Jeffrey G.; Falick, Arnold M.; Komives, Elizabeth A.

1998-01-01

Matrix-assisted laser desorption ionization–time-of-flight mass spectrometry was used to identify peptic fragments from protein complexes that retained deuterium under hydrogen exchange conditions due to decreased solvent accessibility at the interface of the complex. Short deuteration times allowed preferential labeling of rapidly exchanging surface amides so that primarily solvent accessibility changes and not conformational changes were detected. A single mass spectrum of the peptic digest mixture was analyzed to determine the deuterium content of all proteolytic fragments of the protein. The protein–protein interface was reliably indicated by those peptides that retained more deuterons in the complex compared with control experiments in which only one protein was present. The method was used to identify the kinase inhibitor [PKI(5–24)] and ATP-binding sites in the cyclic-AMP-dependent protein kinase. Three overlapping peptides identified the ATP-binding site, three overlapping peptides identified the glycine-rich loop, and two peptides identified the PKI(5–24)-binding site. A complex of unknown structure also was analyzed, human α-thrombin bound to an 83-aa fragment of human thrombomodulin [TMEGF(4–5)]. Five peptides from thrombin showed significantly decreased solvent accessibility in the complex. Three peptides identified the anion-binding exosite I, confirming ligand competition experiments. Two peptides identified a new region of thrombin near the active site providing a potential mechanism of how thrombomodulin alters thrombin substrate specificity. PMID:9843953

Global shape mimicry of tRNA within a viral internal ribosome entry site mediates translational reading frame selection

PubMed Central

Au, Hilda H.; Cornilescu, Gabriel; Mouzakis, Kathryn D.; Ren, Qian; Burke, Jordan E.; Lee, Seonghoon; Butcher, Samuel E.; Jan, Eric

2015-01-01

The dicistrovirus intergenic region internal ribosome entry site (IRES) adopts a triple-pseudoknotted RNA structure and occupies the core ribosomal E, P, and A sites to directly recruit the ribosome and initiate translation at a non-AUG codon. A subset of dicistrovirus IRESs directs translation in the 0 and +1 frames to produce the viral structural proteins and a +1 overlapping open reading frame called ORFx, respectively. Here we show that specific mutations of two unpaired adenosines located at the core of the three-helical junction of the honey bee dicistrovirus Israeli acute paralysis virus (IAPV) IRES PKI domain can uncouple 0 and +1 frame translation, suggesting that the structure adopts distinct conformations that contribute to 0 or +1 frame translation. Using a reconstituted translation system, we show that ribosomes assembled on mutant IRESs that direct exclusive 0 or +1 frame translation lack reading frame fidelity. Finally, a nuclear magnetic resonance/small-angle X-ray scattering hybrid approach reveals that the PKI domain of the IAPV IRES adopts an RNA structure that resembles a complete tRNA. The tRNA shape-mimicry enables the viral IRES to gain access to the ribosome tRNA-binding sites and form intermolecular contacts with the ribosome that are necessary for initiating IRES translation in a specific reading frame. PMID:26554019

Research in DRM architecture based on watermarking and PKI

NASA Astrophysics Data System (ADS)

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.

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

DTIC Science & Technology

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

PKPass

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

Adamson, Ryan M.

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.

Methodology issues in implementation science.

PubMed

Newhouse, Robin; Bobay, Kathleen; Dykes, Patricia C; Stevens, Kathleen R; Titler, Marita

2013-04-01

Putting evidence into practice at the point of care delivery requires an understanding of implementation strategies that work, in what context and how. To identify methodological issues in implementation science using 4 studies as cases and make recommendations for further methods development. Four cases are presented and methodological issues identified. For each issue raised, evidence on the state of the science is described. Issues in implementation science identified include diverse conceptual frameworks, potential weaknesses in pragmatic study designs, and the paucity of standard concepts and measurement. Recommendations to advance methods in implementation include developing a core set of implementation concepts and metrics, generating standards for implementation methods including pragmatic trials, mixed methods designs, complex interventions and measurement, and endorsing reporting standards for implementation studies.

Digital telephony analysis model and issues

NASA Astrophysics Data System (ADS)

Keuthan, Lynn M.

1995-09-01

Experts in the fields of digital telephony and communications security have stated the need for an analytical tool for evaluating complex issues. Some important policy issues discussed by experts recently include implementing digital wire-taps, implementation of the 'Clipper Chip', required registration of encryption/decryption keys, and export control of cryptographic equipment. Associated with the implementation of these policies are direct costs resulting from implementation, indirect cost benefits from implementation, and indirect costs resulting from the risks of implementation or factors reducing cost benefits. Presented herein is a model for analyzing digital telephony policies and systems and their associated direct costs and indirect benefit and risk factors. In order to present the structure of the model, issues of national importance and business-related issues are discussed. The various factors impacting the implementation of the associated communications systems and communications security are summarized, and various implementation tradeoffs are compared based on economic benefits/impact. The importance of the issues addressed herein, as well as other digital telephony issues, has greatly increased with the enormous increases in communication system connectivity due to the advance of the National Information Infrastructure.

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

PubMed Central

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

Heparin binding epidermal growth factor in renal ischaemia/reperfusion injury.

PubMed

Mulder, Gemma M; Nijboer, Willemijn N; Seelen, Marc A; Sandovici, Maria; Bos, Eelke M; Melenhorst, Wynand B W H; Trzpis, Monika; Kloosterhuis, Niels J; Visser, Lydia; Henning, Rob H; Leuvenink, Henri G D; Ploeg, Rutger J; Sunnarborg, Susan W; van Goor, Harry

2010-06-01

The epidermal growth factor (EGF) receptor and its ligands are crucially involved in the renal response to ischaemia. We studied the heparin binding-epidermal growth factor (HB-EGF), a major ligand for the EGF receptor, in experimental and human ischaemia/reperfusion injury (IRI). HB-EGF mRNA and protein expression was studied in rat kidneys and cultured human tubular (HK-2) cells that were subjected to IRI and in human donor kidneys during transplantation. The effect of EGF receptor inhibition was investigated in vivo and in vitro. Furthermore, urinary HB-EGF protein excretion was studied after renal transplantation. Finally, HB-EGF KO and WT mice were subjected to IRI to study the role of HB-EGF in renal injury. HB-EGF mRNA was significantly up-regulated in the early phase of IRI in rats, cells, and human donor biopsies. Treatment with PKI-166 reduces macrophage accumulation and interstitial alpha-SMA in the early phase of IRI in rats. In vitro, PKI-166 causes a marked reduction in HB-EGF-induced cellular proliferation. Urinary HB-EGF is increased after transplantation compared with control urines from healthy subjects. HB-EGF KO mice subjected to IRI revealed significantly less morphological damage after IRI, compared with WT mice. We conclude that IRI results in early induction of HB-EGF mRNA and protein in vivo and in vitro. Absence of HB-EGF and inhibition of the EGF receptor in the early phase of IRI has protective effects, suggesting a modulating role for HB-EGF.

Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates

PubMed Central

Pasquinelli, Amy E.; Powers, Maureen A.; Lund, Elsebet; Forbes, Douglass; Dahlberg, James E.

1997-01-01

Leucine-rich nuclear export signals (NESs) are recognized by the NES receptor exportin 1 and are central to the export of multiple shuttling proteins and RNAs. The export of messenger RNA in vertebrates was, however, thought to occur by a different pathway, because inhibition by injection of a synthetic Rev NES conjugate could not be demonstrated. Here we find that peptide conjugates composed of the NES of either protein kinase A inhibitor protein (PKI) or the HIV-1 Rev protein, when coupled to human serum albumin, are potent inhibitors of mRNA and small nuclear RNA export. These results provide direct evidence that mRNA export in vertebrates depends on interactions between an NES and its cognate NES receptors. PKI NES conjugates are significantly more efficient at inhibiting RNA export than are REV NES conjugates, indicating that different NESs may have different abilities to promote protein and RNA export. Surprisingly, an expected control conjugate containing the mutant Rev NES sequence M10 strongly inhibited the export of intronless dihydrofolate reductase mRNA. Nuclear injection of NES peptide conjugates led to mislocalization to the nucleus of 10–20% of the cytoplasmic Ran GTPase-binding protein (RanBP1) indicating that RanBP1 shuttles between the nucleus and the cytoplasm via an NES pathway. These results demonstrate that in vertebrates the export of mRNA, like that of small nuclear RNA, 5S rRNA, and transport factors such as RanBP1, employs NES-mediated molecular machinery. PMID:9405623

Authentication of digital video evidence

NASA Astrophysics Data System (ADS)

Beser, Nicholas D.; Duerr, Thomas E.; Staisiunas, Gregory P.

2003-11-01

In response to a requirement from the United States Postal Inspection Service, the Technical Support Working Group tasked The Johns Hopkins University Applied Physics Laboratory (JHU/APL) to develop a technique tha will ensure the authenticity, or integrity, of digital video (DV). Verifiable integrity is needed if DV evidence is to withstand a challenge to its admissibility in court on the grounds that it can be easily edited. Specifically, the verification technique must detect additions, deletions, or modifications to DV and satisfy the two-part criteria pertaining to scientific evidence as articulated in Daubert et al. v. Merrell Dow Pharmaceuticals Inc., 43 F3d (9th Circuit, 1995). JHU/APL has developed a prototype digital video authenticator (DVA) that generates digital signatures based on public key cryptography at the frame level of the DV. Signature generation and recording is accomplished at the same time as DV is recorded by the camcorder. Throughput supports the consumer-grade camcorder data rate of 25 Mbps. The DVA software is implemented on a commercial laptop computer, which is connected to a commercial digital camcorder via the IEEE-1394 serial interface. A security token provides agent identification and the interface to the public key infrastructure (PKI) that is needed for management of the public keys central to DV integrity verification.

Software Acquisition in the Age of Cyber Warfare

DTIC Science & Technology

2011-05-01

s c h o o l o f S Y S T E M S a n d L O G I S T I C S education service research Software Acquisition in the Age of Cyber Warfare Maj...DATE MAY 2011 2. REPORT TYPE 3. DATES COVERED 00-00-2011 to 00-00-2011 4. TITLE AND SUBTITLE Software Acquisition in the Age of Cyber Warfare 5a...AFIT Cyber 200/300 Courses Cyber Warfare IDE Program 34 Special Emphasis On… Enterprise Integration (Active Directory, PKI) Security

Report of the Defense Science Board Summer Study Task Force on Defense Manufacturing Enterprise Strategy

DTIC Science & Technology

1993-09-01

mapped against the desired results. "What To Do" Recomendations PrawnProe Based on reviw of 28 prior sh"(Sa Pki gffs f’orce reconmendafins a’: Q𔃺 Oak...sponsored by the UndAr Secretary of Defense (Acquisition). Mr. Edwin L. Big•ers and Mr. Gordon K . England will serve as Co-Chairmen. ARPA will provide the...sectors, and identify key pilot programs where acquisition and management reforms can be applied. C-8 "What To Do" Rcu-manedadow 1.%% k ~r Tedduce

Securing Wireless Local Area Networks with GoC PKI

DTIC Science & Technology

2007-10-01

de réseau privé virtuel (RPV) sans fil sur un banc d’essai dans le laboratoire des Opérations d’information de réseau (OIR) pour des ...locaux sans fil (WLAN) dans les réseaux d’entreprise du gouvernement. Dans ce rapport, on présente les résultats de travaux complémentaires qui tirent...mutuelle, l’autorisation, la protection et l’intégrité des données, ainsi que la gestion et la diffusion des politiques sur les

AFRRI (Armed Forces Radiobiology Research Institute) Reports, January- March 1986

DTIC Science & Technology

1986-03-01

cells , calculated from —50 to —40 mV, wap 101 nS4:0-12 (mean+ 8.E. of mean, n = 22 ). 480 E. K. GAL UN AND P. A. SHEEH Y Effect of adherence on zero...and Hagan, M. Effect of radiation on the regulation of sodium-dependent glucose transport in LLC-PKi epithelial cell line: Possible model for...epithelial cells . SR86-9: Mullin, M. J., and Hunt, W. A. Actions of ethanol on voltage-sensitive sodium channels: Effects on neurotoxin-stimulated

Matrix-specific protein kinase A signaling regulates p21 activated kinase activation by flow in endothelial cells

PubMed Central

Funk, Steven Daniel; Yurdagul, Arif; Green, Jonette M.; Jhaveri, Krishna A.; Schwartz, Martin Alexander; Orr, A. Wayne

2010-01-01

Rationale Atherosclerosis is initiated by blood flow patterns that activate inflammatory pathways in endothelial cells. Activation of inflammatory signaling by fluid shear stress is highly dependent on the composition of the subendothelial extracellular matrix. The basement membrane proteins laminin and collagen found in normal vessels suppress flow-induced p21 activated kinase (PAK) and NF-κB activation. By contrast, the provisional matrix proteins fibronectin and fibrinogen found in wounded or inflamed vessels support flow-induced PAK and NF-κB activation. PAK mediates both flow-induced permeability and matrix-specific activation of NF-κB. Objective To elucidate the mechanisms regulating matrix-specific PAK activation. Methods and Results We now show that matrix composition does not affect the upstream pathway by which flow activates PAK (integrin activation, Rac). Instead basement membrane proteins enhance flow-induced protein kinase A (PKA) activation, which suppresses PAK. Inhibiting PKA restored flow-induced PAK and NF-κB activation in cells on basement membrane proteins, whereas stimulating PKA inhibited flow-induced activation of inflammatory signaling in cells on fibronectin. PKA suppressed inflammatory signaling through PAK inhibition. Activating PKA by injection of the PGI2 analog iloprost reduced PAK activation and inflammatory gene expression at sites of disturbed flow in vivo, whereas inhibiting PKA by PKI injection enhanced PAK activation and inflammatory gene expression. Inhibiting PAK prevented the enhancement of inflammatory gene expression by PKI. Conclusions Basement membrane proteins inhibit inflammatory signaling in endothelial cells via PKA-dependent inhibition of PAK. PMID:20224042

Instrumentation issues in implementation science.

PubMed

Martinez, Ruben G; Lewis, Cara C; Weiner, Bryan J

2014-09-04

Like many new fields, implementation science has become vulnerable to instrumentation issues that potentially threaten the strength of the developing knowledge base. For instance, many implementation studies report findings based on instruments that do not have established psychometric properties. This article aims to review six pressing instrumentation issues, discuss the impact of these issues on the field, and provide practical recommendations. This debate centers on the impact of the following instrumentation issues: use of frameworks, theories, and models; role of psychometric properties; use of 'home-grown' and adapted instruments; choosing the most appropriate evaluation method and approach; practicality; and need for decision-making tools. Practical recommendations include: use of consensus definitions for key implementation constructs; reporting standards (e.g., regarding psychometrics, instrument adaptation); when to use multiple forms of observation and mixed methods; and accessing instrument repositories and decision aid tools. This debate provides an overview of six key instrumentation issues and offers several courses of action to limit the impact of these issues on the field. With careful attention to these issues, the field of implementation science can potentially move forward at the rapid pace that is respectfully demanded by community stakeholders.

In and across bureaucracy: structural and administrative issues for the tobacco endgame.

PubMed

Isett, Kimberley R

2013-05-01

This article assesses the structural choices for the proposed tobacco endgame strategies. I focus on the issues associated with particular structural choices for the location of the implementation. Specifically, I discuss issues related to implementation of the endgame within a specific single agency, and issues related to a more widespread, broad implementation involving several agencies. Where appropriate, I provide examples of how the dynamics discussed would apply to particular endgame strategies. Issues related to design, administration, authority and finances are raised.

In and across bureaucracy: structural and administrative issues for the tobacco endgame

PubMed Central

Isett, Kimberley R

2013-01-01

This article assesses the structural choices for the proposed tobacco endgame strategies. I focus on the issues associated with particular structural choices for the location of the implementation. Specifically, I discuss issues related to implementation of the endgame within a specific single agency, and issues related to a more widespread, broad implementation involving several agencies. Where appropriate, I provide examples of how the dynamics discussed would apply to particular endgame strategies. Issues related to design, administration, authority and finances are raised. PMID:23591514

Network-based reading system for lung cancer screening CT

NASA Astrophysics Data System (ADS)

Fujino, Yuichi; Fujimura, Kaori; Nomura, Shin-ichiro; Kawashima, Harumi; Tsuchikawa, Megumu; Matsumoto, Toru; Nagao, Kei-ichi; Uruma, Takahiro; Yamamoto, Shinji; Takizawa, Hotaka; Kuroda, Chikazumi; Nakayama, Tomio

2006-03-01

This research aims to support chest computed tomography (CT) medical checkups to decrease the death rate by lung cancer. We have developed a remote cooperative reading system for lung cancer screening over the Internet, a secure transmission function, and a cooperative reading environment. It is called the Network-based Reading System. A telemedicine system involves many issues, such as network costs and data security if we use it over the Internet, which is an open network. In Japan, broadband access is widespread and its cost is the lowest in the world. We developed our system considering human machine interface and security. It consists of data entry terminals, a database server, a computer aided diagnosis (CAD) system, and some reading terminals. It uses a secure Digital Imaging and Communication in Medicine (DICOM) encrypting method and Public Key Infrastructure (PKI) based secure DICOM image data distribution. We carried out an experimental trial over the Japan Gigabit Network (JGN), which is the testbed for the Japanese next-generation network, and conducted verification experiments of secure screening image distribution, some kinds of data addition, and remote cooperative reading. We found that network bandwidth of about 1.5 Mbps enabled distribution of screening images and cooperative reading and that the encryption and image distribution methods we proposed were applicable to the encryption and distribution of general DICOM images via the Internet.

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

PubMed

Atkinson, Peter J; Bromidge, Steven M; Duxon, Mark S; Gaster, Laramie M; Hadley, Michael S; Hammond, Beverley; Johnson, Christopher N; Middlemiss, Derek N; North, Stephanie E; Price, Gary W; Rami, Harshad K; Riley, Graham J; Scott, Claire M; Shaw, Tracey E; Starr, Kathryn R; Stemp, Geoffrey; Thewlis, Kevin M; Thomas, David R; Thompson, Mervyn; Vong, Antonio K K; Watson, Jeannette M

2005-02-01

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.

MICROSPED Information Bulletin, Issues 1-10, 1984. Microcomputers in the Schools--Implementation in Special Education.

ERIC Educational Resources Information Center

Hanley, Tom V., Ed.; And Others

1984-01-01

Ten information bulletins on the implementation of microcomputers in special education are presented. Topics covered include the following: (1) implementation issues (including a description of a study assessing microcomputer applications in 12 local school districts' special education programs); (2) implementation strategies (which focuses on…

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

PubMed

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.

PubMed

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.

In silico optimization of pharmacokinetic properties and receptor binding affinity simultaneously: a 'parallel progression approach to drug design' applied to β-blockers.

PubMed

Advani, Poonam; Joseph, Blessy; Ambre, Premlata; Pissurlenkar, Raghuvir; Khedkar, Vijay; Iyer, Krishna; Gabhe, Satish; Iyer, Radhakrishnan P; Coutinho, Evans

2016-01-01

The present work exploits the potential of in silico approaches for minimizing attrition of leads in the later stages of drug development. We propose a theoretical approach, wherein 'parallel' information is generated to simultaneously optimize the pharmacokinetics (PK) and pharmacodynamics (PD) of lead candidates. β-blockers, though in use for many years, have suboptimal PKs; hence are an ideal test series for the 'parallel progression approach'. This approach utilizes molecular modeling tools viz. hologram quantitative structure activity relationships, homology modeling, docking, predictive metabolism, and toxicity models. Validated models have been developed for PK parameters such as volume of distribution (log Vd) and clearance (log Cl), which together influence the half-life (t1/2) of a drug. Simultaneously, models for PD in terms of inhibition constant pKi have been developed. Thus, PK and PD properties of β-blockers were concurrently analyzed and after iterative cycling, modifications were proposed that lead to compounds with optimized PK and PD. We report some of the resultant re-engineered β-blockers with improved half-lives and pKi values comparable with marketed β-blockers. These were further analyzed by the docking studies to evaluate their binding poses. Finally, metabolic and toxicological assessment of these molecules was done through in silico methods. The strategy proposed herein has potential universal applicability, and can be used in any drug discovery scenario; provided that the data used is consistent in terms of experimental conditions, endpoints, and methods employed. Thus the 'parallel progression approach' helps to simultaneously fine-tune various properties of the drug and would be an invaluable tool during the drug development process.

Public key infrastructure for DOE security research

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

Aiken, R.; Foster, I.; Johnston, W.E.

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-keymore » 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.« less

Studies on molecular properties prediction and histamine H3 receptor affinities of novel ligands with uracil-based motifs.

PubMed

Lipani, Luca; Odadzic, Dalibor; Weizel, Lilia; Schwed, Johannes-Stephan; Sadek, Bassem; Stark, Holger

2014-10-30

The histamine H3 receptor (H3R) plays a role in cognitive and memory processes and is involved in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. Therefore, several hH3R antagonists/inverse agonists entered clinical phases for a broad spectrum of mainly centrally occurring diseases. However, many other promising candidates failed due to their pharmacokinetic profile, mostly because of their strong lipophilicity accompanied with low solubility. Analysis of previous potential H3R selective antagonists/inverse agonists, e.g. pitolisant, revealed promising results concerning physicochemical properties and drug-likeness. Herein, a series of new hH3R ligands 8-20 consisting of piperidin-1-yl or piperidin-1-yl-propoxyphenyl coupled to different uracil, thymine, and 5,6-dimethyluracil related moieties, were synthesized, evaluated on their binding properties at the hH3R and the estimation of different physicochemical and drug-likeness properties. Due to the coupling to various positions at pyrimidine-2,4-(1H,3H)-dione, affinity at hH3Rs and drug-likeness parameters have been improved. For instance, compound 9 showed in addition to high affinity at the hH3R (pKi (hH3R) = 8.14) clog S, clog P, LE, LipE, and drug-likeness score values of -4.36, 3.47, 0.34, 4.63, and 1.54, respectively. Also, the methyl substituted analog 17 (pKi (hH3R) = 8.15) revealed LE, LipE and drug-likeness score values of -3.29, 2.47, 0.49, 5.52, and 1.76, respectively. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Measuring the seismic velocity in the top 15 km of Earth's inner core

NASA Astrophysics Data System (ADS)

Godwin, Harriet; Waszek, Lauren; Deuss, Arwen

2018-01-01

We present seismic observations of the uppermost layer of the inner core. This was formed most recently, thus its seismic features are related to current solidification processes. Previous studies have only constrained the east-west hemispherical seismic velocity structure in the Earth's inner core at depths greater than 15 km below the inner core boundary. The properties of shallower structure have not yet been determined, because the seismic waves PKIKP and PKiKP used for differential travel time analysis arrive close together and start to interfere. Here, we present a method to make differential travel time measurements for waves that turn in the top 15 km of the inner core, and measure the corresponding seismic velocity anomalies. We achieve this by generating synthetic seismograms to model the overlapping signals of the inner core phase PKIKP and the inner core boundary phase PKiKP. We then use a waveform comparison to attribute different parts of the signal to each phase. By measuring the same parts of the signal in both observed and synthetic data, we are able to calculate differential travel time residuals. We apply our method to data with ray paths which traverse the Pacific hemisphere boundary. We generate a velocity model for this region, finding lower velocity for deeper, more easterly ray paths. Forward modelling suggests that this region contains either a high velocity upper layer, or variation in the location of the hemisphere boundary with depth and/or latitude. Our study presents the first direct seismic observation of the uppermost 15 km of the inner core, opening new possibilities for further investigating the inner core boundary region.

Phosphodiesterase 4 regulates the migration of B16-F10 melanoma cells.

PubMed

Watanabe, Yoshihiro; Murata, Taku; Shimizu, Kasumi; Morita, Hiroshi; Inui, Madoka; Tagawa, Toshiro

2012-08-01

Phosphodiesterases (PDEs) are important regulators of signal transduction processes. Eleven PDE gene families (PDE1-11) have been identified and several PDE isoforms are selectively expressed in various cell types. PDE4 family members specifically hydrolyze cyclic AMP (cAMP). Four genes (PDE4A-D) are known to encode PDE4 enzymes, with additional diversity generated by the use of alternative mRNA splicing and the use of different promoters. While PDE4 selective inhibitors show therapeutic potential for treating major diseases such as asthma and chronic obstructive pulmonary disease, little is known concerning the role of PDE4 in malignant melanoma. In this study, we examined the role of PDE4 in mouse B16-F10 melanoma cells. In these cells, PDE4 activity was found to be ∼60% of total PDE activity. RT-PCR detected only PDE4B and PDE4D mRNA. Cell growth was inhibited by the cAMP analog, 8-bromo-cAMP, but not by the specific PDE4 inhibitors, rolipram and denbufylline, which increased intracellular cAMP concentrations. Finally, migration of the B16-F10 cells was inhibited by the PDE4 inhibitors and 8-bromo-cAMP, while migration was increased by a protein kinase A (PKA) inhibitor, PKI(14-22), and was not affected by 8-pCPT-2'-O-Me-cAMP, which is an analog of exchange protein activated by cAMP (Epac). The inhibitory effect of rolipram on migration was reversed by PKI(14-22). Based on these results, PDE4 appears to play an important role in the migration of B16-F10 cells, and therefore may be a novel target for the treatment of malignant melanoma.

Selective blockade by nicergoline of vascular responses elicited by stimulation of alpha 1A-adrenoceptor subtype in the rat.

PubMed

Alvarez-Guerra, M; Bertholom, N; Garay, R P

1999-01-01

The alpha 1-adrenergic blocking activity of nicergoline was re-examined in rats, with a particular emphasis on alpha 1-adrenoceptor subtypes. In pithed rats, nicergoline and prazosin infused at a single small dose (0.5 microgram/kg/min i.v.) produced a substantial and identical shift to the right of the control dose pressor response curve to the specific alpha 1-agonist cirazoline (ED50 = 4.0 +/- 0.1, 4.0 +/- 0.1 and 0.9 +/- 0.01 microgram/kg i.v. for nicergoline, prazosin and vehicle respectively). In the isolated perfused mesenteric vascular bed, nicergoline strongly inhibited the pressor responses elicited by cirazoline, with approximately 40-fold higher potency (pA2 = 11.1 +/- 0.3) than prazosin (pA2 = 9.5 +/- 0.3). Conversely, nicergoline was 20-fold less potent than prazosin to antagonize the contractile effects of cirazoline in isolated endothelium-denuded aorta (pA2 = 8.6 +/- 0.2 and 9.9 +/- 0.2 for nicergoline and prazosin respectively). Pretreatment of mesenteric vascular beds with chloroethylclonidine did not significantly modify nicergoline antagonistic potency (pA2 = 10.6 +/- 0.2). Nicergoline displaced [3H]-prazosin bound to rat forebrain membranes pretreated with chloroethylclonidine (pKi = 9.9 +/- 0.2) at concentrations 60-fold lower than in rat liver membranes (pKi = 8.1 +/- 0.2). Finally, of the nicergoline metabolites studied, lumilysergol acted as a modest alpha 1 antagonist (bromonicotinic acid was devoid of alpha 1 antagonist activity). In conclusion, nicergoline is a potent and selective alpha 1A-adrenoceptor subtype antagonist, an alpha 1-adrenoceptor subtype which is mainly represented in resistance arteries.

Implementation of a Point-of-Care Radiologist-Technologist Communication Tool in a Quality Assurance Program.

PubMed

Ong, Leonard; Elnajjar, Pierre; Nyman, C Gregory; Mair, Thomas; Juluru, Krishna

2017-07-01

We implemented an Image Quality Reporting and Tracking Solution (IQuaRTS), directly linked from the PACS, to improve communication between radiologists and technologists. IQuaRTS launched in May 2015. We compared MRI issues filed in the period before IQuaRTS implementation (May-September 2014) using a manual system with MRI issues filed in the IQuaRTS period (May-September 2015). The unpaired t test was used for analysis. For assessment of overall results in the IQuaRTS period alone, all issues filed across all modalities were included. Summary statistics and charts were generated using Excel and Tableau. For MRI issues, the number of issues filed during the IQuaRTS period was 498 (2.5% of overall MRI examination volume) compared with 78 issues filed during the period before IQuaRTS implementation (0.4% of total examination volume) (p = 0.0001), representing a 625% relative increase. Tickets that documented excellent work were 8%. Other issues included images not pushed to PACS (20%), film library issues (19%), and documentation or labeling (8%). Of the issues filed, 55% were MRI-related and 25% were CT-related. The issues were stratified across six sites within our institution. Staff requiring additional training could be readily identified, and 80% of the issues were resolved within 72 hours. IQuaRTS is a cost-effective online issue reporting tool that enables robust data collection and analytics to be incorporated into quality improvement programs. One limitation of the system is that it must be implemented in an environment where staff are receptive to quality improvement.

Translating Research to Practice: Overcoming Barriers to Implementing Effective Off-Campus Party Intervention. Issues in Prevention

ERIC Educational Resources Information Center

Higher Education Center for Alcohol, Drug Abuse, and Violence Prevention, 2012

2012-01-01

This issue of "Issues in Prevention" focuses on overcoming barriers in implementing effective off-campus party intervention. This issue contains the following articles: (1) Confronting the Problems Associated With Off-Campus Parties With Evidence-Based Strategies (John D. Clapp); (2) Overview of Research on Effective Off-Campus Party…

12 CFR 1204.1 - Why did FHFA issue this part?

Code of Federal Regulations, 2010 CFR

2010-01-01

... 12 Banks and Banking 7 2010-01-01 2010-01-01 false Why did FHFA issue this part? 1204.1 Section 1204.1 Banks and Banking FEDERAL HOUSING FINANCE AGENCY ORGANIZATION AND OPERATIONS PRIVACY ACT IMPLEMENTATION § 1204.1 Why did FHFA issue this part? FHFA issued this part to: (a) Implement the Privacy Act of...

Long-Term Holding Capacity of Statically Loaded Anchors in Cohesive Soils

DTIC Science & Technology

1979-01-01

Kos .,es. Hanoiver NH A.RMY~ I-N( IVIN’NLEI)-S. HunmsIlle AL: Finded-Sr. Huintsville. Al. ARMY L.N( \\%AAURWAY S EXP SIA ILihrar%. Vicksburg NIS ARNMY 1...8217CHNOIOG6Y long Beach. C’A(%\\ agnert P()RT11I.ANI) CLNI ENT ASSOC. SKO KIE. 11. )C0REL.Yt: Skokie It. (Rsch & Ic\\ Ilab. lib.) 57 Pki SCON CORP IO~ SON...Sa~ brook CTI R.Q. PALNMER Kaitua. HI ENERGY R&I ADI)N H. Sko \\% ho. %Aashington. DC( -1..’%. NI ERNIEI. %%ashingion D)C \\kNI lAI.BOT Orange CA 58

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

PubMed

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.

Distributed intrusion detection system based on grid security model

NASA Astrophysics Data System (ADS)

Su, Jie; Liu, Yahui

2008-03-01

Grid computing has developed rapidly with the development of network technology and it can solve the problem of large-scale complex computing by sharing large-scale computing resource. In grid environment, we can realize a distributed and load balance intrusion detection system. This paper first discusses the security mechanism in grid computing and the function of PKI/CA in the grid security system, then gives the application of grid computing character in the distributed intrusion detection system (IDS) based on Artificial Immune System. Finally, it gives a distributed intrusion detection system based on grid security system that can reduce the processing delay and assure the detection rates.

Efficient Authorization of Rich Presence Using Secure and Composed Web Services

NASA Astrophysics Data System (ADS)

Li, Li; Chou, Wu

This paper presents an extended Role-Based Access Control (RBAC) model for efficient authorization of rich presence using secure web services composed with an abstract presence data model. Following the information symmetry principle, the standard RBAC model is extended to support context sensitive social relations and cascaded authority. In conjunction with the extended RBAC model, we introduce an extensible presence architecture prototype using WS-Security and WS-Eventing to secure rich presence information exchanges based on PKI certificates. Applications and performance measurements of our presence system are presented to show that the proposed RBAC framework for presence and collaboration is well suited for real-time communication and collaboration.

Symmetric Key Services Markup Language (SKSML)

NASA Astrophysics Data System (ADS)

Noor, Arshad

Symmetric Key Services Markup Language (SKSML) is the eXtensible Markup Language (XML) being standardized by the OASIS Enterprise Key Management Infrastructure Technical Committee for requesting and receiving symmetric encryption cryptographic keys within a Symmetric Key Management System (SKMS). This protocol is designed to be used between clients and servers within an Enterprise Key Management Infrastructure (EKMI) to secure data, independent of the application and platform. Building on many security standards such as XML Signature, XML Encryption, Web Services Security and PKI, SKSML provides standards-based capability to allow any application to use symmetric encryption keys, while maintaining centralized control. This article describes the SKSML protocol and its capabilities.

System Issues Related to Implementing on the Internet

NASA Technical Reports Server (NTRS)

Mackey, William; Bagg, Thomas C., III

1999-01-01

Implementing capabilities on the World Wide Web should never be taken lightly. A good systems engineer is able to examine such implementations from all points of view, including political, legal, security, access, technical deployment, and quality. The evacuation discussed in this paper was conducted to ensure that the National Aeronautics and Space Administration (NASA) was proceeding in a correct direction by implementing RECALL a Lessons Learned System on the Web and, subsequently, did so successfully. The systems approach extended well beyond technical implementation to several issue that are not often addressed by an implementation team. The resulting evaluation increased the team's sensitivity to such issues and, in fact, the authors believe that the evaluation provided as much benefit as the system itself.

Issues Management Process Course # 38401

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

Binion, Ula Marie

The purpose of this training it to advise Issues Management Coordinators (IMCs) on the revised Contractor Assurance System (CAS) Issues Management (IM) process. Terminal Objectives: Understand the Laboratory’s IM process; Understand your role in the Laboratory’s IM process. Learning Objectives: Describe the IM process within the context of the CAS; Describe the importance of implementing an institutional IM process at LANL; Describe the process flow for the Laboratory’s IM process; Apply the definition of an issue; Use available resources to determine initial screening risk levels for issues; Describe the required major process steps for each risk level; Describe the personnelmore » responsibilities for IM process implementation; Access available resources to support IM process implementation.« less

Design of a Blended Learning Environment: Considerations and Implementation Issues

ERIC Educational Resources Information Center

Gedik, Nuray; Kiraz, Ercan; Ozden, M. Yasar

2013-01-01

This study identified critical issues in the design of a blended learning environment by examining basic design considerations and implementation issues. Following a design-based research approach with the phenomenological tradition of qualitative research, the study investigated instructor experiences relating to the design, development, and…

Master's Program Module "Environmental Issues--Decision Making Experience" as Precondition for Implementation of Education for Sustainable Development for Professional Training of Teachers

ERIC Educational Resources Information Center

Vinokurova, Natalia Fedorovna; Martilova, Natalia Viktorovna; Krivdina, Irina Yurievna; Badin, Mikhail Mikhailovich; Efimova, Olga Evgenyevna

2016-01-01

The article discusses current issues related to the implementation of the UNESCO roadmap implementing Global action programme on education for sustainable development. In the context of increasing the professional level of pedagogical workers is a priority area in the implementation of education for sustainable development. Therefore, we believe…

Characterization of NK1 and NK2 tachykinin receptors in guinea-pig and rat bronchopulmonary and vascular systems.

PubMed Central

Floch, A.; Fardin, V.; Cavero, I.

1994-01-01

1. NK1 and NK2 tachykinin receptors were characterized in guinea-pig and rat bronchopulmonary systems and in the vasculature of the rat by use of radioligand binding and/or functional studies. 2. The radioligands for NK1 and NK2 receptors ([3H]-SP and [3H]-pNKA, respectively) did not label tachykinin receptors in homogenates of rat lungs or bronchi. In contrast, in the guinea-pig, [3H]-SP bound with high affinity to these tissues (KD = 0.23 +/- 0.08 nM and 0.34 +/- 0.05 nM, for lungs and bronchi, respectively). The total number of binding sites was 4.6 fold greater in bronchus (Bmax = 135 +/- 27 fmol mg-1 protein) than in lung homogenates (Bmax = 29.3 +/- 0.1 fmol mg-1 protein). Furthermore, this binding was markedly displaced by CP-96,345 (pKi = 9.5 +/- 0.1) and RP 67580 (pKi = 7.6 +/- 0.1), antagonists of NK1 receptors, slightly displaced by SR 48968 (pKi = 6.6 +/- 0.1), but not affected by actinomycin D or L-659,877, antagonists of NK2 receptors. Specific binding of [3H]-pNKA, detected in guinea-pig bronchi (KD = 5.2 +/- 0.1 nM, and Bmax = 203 +/- 19 fmol mg-1 protein) but not in lungs, was similarly (40 to 53%) displaced by RP 67580 (1 microM), CP-96,345 (10 and 100 nM) or SR 48968 (10 and 100 nM). The displacement approximately doubled (87 to 91%) when SR 48968 (10 nM) was combined with either RP 67580 (1 microM) or CP-96,345 (10 nM), but not when RP 67580 was combined with CP-96,345. 3. In urethane-anaesthetized guinea-pigs, i.v. injections of the NK1 receptor agonists SP, [Pro9]-SP, [Sar9,Met(O2)11]-SP and septide, as well as the NK2 receptor agonists NKA and [Lys5,MeLeu9,NLeu10]-NKA(4-10) (0.1-10 micrograms kg-1, i.v.), dose-dependently increased lung inflation pressure. The most potent of these peptides were septide and [Lys5, MeLeu9,NLeu10]-NKA(4-10) (EC50 = 0.38 +/- 0.07 and 0.07 +/- 0.02 microgram kg-1, respectively). Interestingly, septide was 130 fold less potent than SP in displacing [3H]-SP from its binding sites in the guinea-pig lung, whereas it was 14 fold more potent than SP as a bronchoconstrictor. RP 67580 (0.3-5 mg kg-1, i.v.) and CP-96,345 (0.01-3 mg kg-1, i.v.) dose-dependently reduced the bronchoconstriction produced by the NK1 receptor agonists.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:7517328

x509-free access to WLCG resources

NASA Astrophysics Data System (ADS)

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.

Making Strategic Planning Work: Experiences from a Private University. AIR 1986 Annual Forum Paper.

ERIC Educational Resources Information Center

Chan, Susy S.

Issues in implementating strategic planning in higher education management are considered, along with successful strategies and problem areas in implementing an integrated planning and budgeting process at DePaul University, a comprehensive Catholic university. Key implementation issues are as follows: (1) maintaining an organizational balance…

GEMSS: privacy and security for a medical Grid.

PubMed

Middleton, S E; Herveg, J A M; Crazzolara, F; Marvin, D; Poullet, Y

2005-01-01

The GEMSS project is developing a secure Grid infrastructure through which six medical simulations services can be invoked. We examine the legal and security framework within which GEMSS operates. We provide a legal qualification to the operations performed upon patient data, in view of EU directive 95/46, when using medical applications on the GEMSS Grid. We identify appropriate measures to ensure security and describe the legal rationale behind our choice of security technology. Our legal analysis demonstrates there must be an identified controller (typically a hospital) of patient data. The controller must then choose a processor (in this context a Grid service provider) that provides sufficient guarantees with respect to the security of their technical and organizational data processing procedures. These guarantees must ensure a level of security appropriate to the risks, with due regard to the state of the art and the cost of their implementation. Our security solutions are based on a public key infrastructure (PKI), transport level security and end-to-end security mechanisms in line with the web service (WS Security, WS Trust and SecureConversation) security specifications. The GEMSS infrastructure ensures a degree of protection of patient data that is appropriate for the health care sector, and is in line with the European directives. We hope that GEMSS will become synonymous with high security data processing, providing a framework by which GEMSS service providers can provide the security guarantees required by hospitals with regard to the processing of patient data.

Key Policy Issues in the Implementation of User Choice. Working Paper No. 8.

ERIC Educational Resources Information Center

Smith, Joy Selby; Smith, Chris Selby; Ferrier, Fran

This working paper examines key policy issues in the implementation of Australia's User Choice policy regarding allocating public funds for vocational education and training (VET). Part 1 explains the process used to obtain stakeholders regarding the User Choice policy, the administrative arrangements required to support it, and issues that must…

Challenges Faced by Teachers Implementing Socio-Scientific Issues as Core Elements in Their Classroom Practices

ERIC Educational Resources Information Center

Bossér, Ulrika; Lundin, Mattias; Lindahl, Mats; Linder, Cedric

2015-01-01

Teachers may face considerable challenges when implementing socio-scientific issues (SSI) in their classroom practices, such as incorporating student-centred teaching practices and exploring knowledge and values in the context of socioscientific issues. This year-long study explores teachers' reflections on the process of developing their…

Human Resource Development Issues in the Implementation of the Western China Development Strategy

ERIC Educational Resources Information Center

Xiao, Mingzheng

2007-01-01

This paper systematically illustrates the value and role of human resource development in the implementation of the Western China development strategy. It analyzes in details some current human resource issues constraining the implementation of the Western China development strategy and those on the sustainable development process of economic…

A Framework for Identifying Implementation Issues Affecting Extension Human Sciences Programming

ERIC Educational Resources Information Center

Abell, Ellen; Cummings, Rebekah; Duke, Adrienne M.; Marshall, Jennifer Wells

2015-01-01

Extension programs based on identified needs, relevant theory, and solid research too often fail to realize their objectives. Program implementation is acknowledged to contribute to program effectiveness, yet systematic attention has not been paid to the array of implementation issues that can complicate achieving program goals. We developed the…

In-situ medical simulation for pre-implementation testing of clinical service in a regional hospital in Hong Kong.

PubMed

Chen, P P; Tsui, N Tk; Fung, A Sw; Chiu, A Hf; Wong, W Cw; Leong, H T; Lee, P Sf; Lau, J Yw

2017-08-01

The implementation of a new clinical service is associated with anxiety and challenges that may prevent smooth and safe execution of the service. Unexpected issues may not be apparent until the actual clinical service commences. We present a novel approach to test the new clinical setting before actual implementation of our endovascular aortic repair service. In-situ simulation at the new clinical location would enable identification of potential process and system issues prior to implementation of the service. After preliminary planning, a simulation test utilising a case scenario with actual simulation of the entire care process was carried out to identify any logistic, equipment, settings or clinical workflow issues, and to trial a contingency plan for a surgical complication. All patient care including anaesthetic, surgical, and nursing procedures and processes were simulated and tested. Overall, 17 vital process and system issues were identified during the simulation as potential clinical concerns. They included difficult patient positioning, draping pattern, unsatisfactory equipment setup, inadequate critical surgical instruments, blood products logistics, and inadequate nursing support during crisis. In-situ simulation provides an innovative method to identify critical deficiencies and unexpected issues before implementation of a new clinical service. Life-threatening and serious practical issues can be identified and corrected before formal service commences. This article describes our experience with the use of simulation in pre-implementation testing of a clinical process or service. We found the method useful and would recommend it to others.

Recent Developments: PKI Square Dish for the Soleras Project

NASA Technical Reports Server (NTRS)

Rogers, W. E.

1984-01-01

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.

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

NASA Astrophysics Data System (ADS)

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.

Scalable Authenticated Tree Based Group Key Exchange for Ad-Hoc Groups

NASA Astrophysics Data System (ADS)

Desmedt, Yvo; Lange, Tanja; Burmester, Mike

Task-specific groups are often formed in an ad-hoc manner within large corporate structures, such as companies. Take the following typical scenario: A director decides to set up a task force group for some specific project. An order is passed down the hierarchy where it finally reaches a manager who selects some employees to form the group. The members should communicate in a secure way and for efficiency, a symmetric encryption system is chosen. To establish a joint secret key for the group, a group key exchange (GKE) protocol is used. We show how to use an existing Public Key Infrastructure (PKI) to achieve authenticated GKE by modifying the protocol and particularly by including signatures.

Recent developments: PKI square dish for the Soleras Project

NASA Astrophysics Data System (ADS)

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.

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

NASA Technical Reports Server (NTRS)

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

1982-01-01

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.

Measuring Fidelity of Implementation--Methodological and Conceptual Issues and Challenges. CRESST Report 811

ERIC Educational Resources Information Center

Osmundson, Ellen; Herman, Joan; Ringstaff, Cathy; Dai, Yunyun; Timms, Mike

2012-01-01

A central challenge in efficacy studies centers on the issue of "fidelity of implementation," that is, the extent to which participants use the curriculum specified by curriculum developers. In this study, we describe and discuss a "fidelity of implementation" model using multiple methods and instruments to compare two versions of a science…

77 FR 44441 - Swap Transaction Compliance and Implementation Schedule: Clearing Requirement Under Section 2(h...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-30

... implementing Title VII, the Commission should focus first on systemic risk issues and then issues relating to... implementation of the Clearing Requirement will serve to reduce systemic risk by mitigating counterparty credit... non-financial end-users because they do not pose systemic risk, and, therefore, should be given the...

Moving from Good Ideas in Educational Systems Change to Sustainable Program Implementation: Coming to Terms with Some of the Realities

ERIC Educational Resources Information Center

Noell, George H.; Gansle, Kristin A.

2009-01-01

Proponents of systemic changes in education commonly encounter ethical, theoretical, and pragmatic challenges in moving from possibility to implementation of their vision of change. Although ethical and theoretical issues are critically important to a successful change initiative, pragmatic issues relevant to assuring program implementation have…

Architectural Optimization of Digital Libraries

NASA Technical Reports Server (NTRS)

Biser, Aileen O.

1998-01-01

This work investigates performance and scaling issues relevant to large scale distributed digital libraries. Presently, performance and scaling studies focus on specific implementations of production or prototype digital libraries. Although useful information is gained to aid these designers and other researchers with insights to performance and scaling issues, the broader issues relevant to very large scale distributed libraries are not addressed. Specifically, no current studies look at the extreme or worst case possibilities in digital library implementations. A survey of digital library research issues is presented. Scaling and performance issues are mentioned frequently in the digital library literature but are generally not the focus of much of the current research. In this thesis a model for a Generic Distributed Digital Library (GDDL) and nine cases of typical user activities are defined. This model is used to facilitate some basic analysis of scaling issues. Specifically, the calculation of Internet traffic generated for different configurations of the study parameters and an estimate of the future bandwidth needed for a large scale distributed digital library implementation. This analysis demonstrates the potential impact a future distributed digital library implementation would have on the Internet traffic load and raises questions concerning the architecture decisions being made for future distributed digital library designs.

Characterization of SB-271046: A potent, selective and orally active 5-HT6 receptor antagonist

PubMed Central

Routledge, Carol; Bromidge, Steven M; Moss, Stephen F; Price, Gary W; Hirst, Warren; Newman, Helen; Riley, Graham; Gager, Tracey; Stean, Tania; Upton, Neil; Clarke, Stephen E; Brown, Anthony M; Middlemiss, Derek N

2000-01-01

SB-271046, potently displaced [3H]-LSD and [125I]-SB-258585 from human 5-HT6 receptors recombinantly expressed in HeLa cells in vitro (pKi 8.92 and 9.09 respectively). SB-271046 also displaced [125I]-SB-258585 from human caudate putamen and rat and pig striatum membranes (pKi 8.81, 9.02 and 8.55 respectively). SB-271046 was over 200 fold selective for the 5-HT6 receptor vs 55 other receptors, binding sites and ion channels. In functional studies on human 5-HT6 receptors SB-271046 competitively antagonized 5-HT-induced stimulation of adenylyl cyclase activity with a pA2 of 8.71. SB-271046 produced an increase in seizure threshold over a wide-dose range in the rat maximal electroshock seizure threshold (MEST) test, with a minimum effective dose of ⩽0.1 mg kg−1 p.o. and maximum effect at 4 h post-dose. The level of anticonvulsant activity achieved correlated well with the blood concentrations of SB-271046 (EC50 of 0.16 μM) and brain concentrations of 0.01–0.04 μM at Cmax. These data, together with the observed anticonvulsant activity of other selective 5-HT6 receptor antagonists, SB-258510 (10 mg kg−1, 2–6 h pre-test) and Ro 04-6790 (1–30 mg kg−1, 1 h pre-test), in the rat MEST test, suggest that the anticonvulsant properties of SB-271046 are likely to be mediated by 5-HT6 receptors. Overall, these studies demonstrate that SB-271046 is a potent and selective 5-HT6 receptor antagonist and is orally active in the rat MEST test. SB-271046 represents a valuable tool for evaluating the in vivo central function of 5-HT6 receptors. PMID:10928964

Inhibition of vascular smooth muscle growth via signaling crosstalk between AMP-activated protein kinase and cAMP-dependent protein kinase

PubMed Central

Stone, Joshua D.; Narine, Avinash; Tulis, David A.

2012-01-01

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 remain 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 (VSMC), 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 VSMC migration. Collectively, these results show that AMPK is capable of reducing VSM growth in both anti-proliferative and anti-migratory fashion. 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. PMID:23112775

Dynamic mitochondrial–nuclear redistribution of the immunophilin FKBP51 is regulated by the PKA signaling pathway to control gene expression during adipocyte differentiation

PubMed Central

Toneatto, Judith; Guber, Sergio; Charó, Nancy L.; Susperreguy, Sebastián; Schwartz, Jessica; Galigniana, Mario D.; Piwien-Pilipuk, Graciela

2013-01-01

Summary Glucocorticoids play an important role in adipogenesis through the glucocorticoid receptor (GR) that forms a heterocomplex with Hsp90•Hsp70 and one high molecular weight immunophilin, either FKBP51 or FKBP52. When 3T3-L1 preadipocytes are induced to differentiate, FKBP51 expression progressively increases, whereas FKBP52 decreases, and Hsp90, Hsp70, p23 and Cyp40 remain unchanged. Interestingly, FKBP51 rapidly translocates from mitochondria to the nucleus where it is retained upon its interaction with chromatin and the nuclear matrix. FKBP51 nuclear localization is transient, and after 48 hours it cycles back to mitochondria. Importantly, this dynamic FKBP51 mitochondrial–nuclear shuttling depends on PKA signaling, because its inhibition by PKI or knockdown of PKA-cα by siRNA, prevented FKBP51 nuclear translocation induced by IBMX. In addition, the electrophoretic pattern of migration of FKBP51 is altered by treatment of cells with PKI or knockdown of PKA-cα, suggesting that FKBP51 is a PKA substrate. In preadipocytes, FKBP51 colocalizes with PKA-cα in mitochondria. When adipogenesis is triggered, PKA-cα also moves to the nucleus colocalizing with FKBP51 mainly in the nuclear lamina. Moreover, FKBP51 and GR interaction increases when preadipocytes are induced to differentiate. GR transcriptional capacity is reduced when cells are incubated in the presence of IBMX, forskolin or dibutyryl-cAMP, compounds that induced FKBP51 nuclear translocation, but not by a specific activator of EPAC. FKBP51 knockdown facilitates adipogenesis, whereas ectopic expression of FKBP51 blocks adipogenesis. These findings indicate that the dynamic mitochondrial–nuclear shuttling of FKBP51 regulated by PKA may be key in fine-tuning the transcriptional control of GR target genes required for the acquisition of adipocyte phenotype. PMID:24101724

Reconsideration of F-layer seismic model in the south polar region

NASA Astrophysics Data System (ADS)

Ohtaki, T.; Kaneshima, S.

2017-12-01

Previously, we analyzed the seismic structure near the inner core boundary beneath Antarctica (Ohtaki et al., 2012). In the study, we determined the velocity of the lowermost outer core (F-layer) using amplitude ratio observations between the inner-core phase (PKIKP) and the inner-core grazing/diffracted phase (PKPbc/c-diff). Because the observations are not so sensitive to the F-layer structure, a constant velocity is assumed in the layer to simplify the model. The obtained model (SPR) has a flat velocity zone with a 75 km thick on the inner core boundary. With this F-layer structure and using travel times of these phases as well as the phase that reflects at the boundary, we determined the seismic structure of the inner core in the south polar region. However, a constant velocity layer is unrealistic, although it is reasonable assumption.Recently, we determined F-layer velocity structures more accurately using the combined observations of PKiKP-PKPbc differential travel times and of PKPbc/c-diff dispersion (Ohtaki et al., 2015, 2016). The former observation is sensitive to average velocity in the F-layer; the latter to velocity gradient in the layer. By analyzing these two observations together, we can determine the detailed velocity structure in the F-layer. The surveyed areas are beneath the Northeast Pacific and Australia. The seismic velocity models obtained are quite different between the two regions. Thus our results require laterally heterogeneous F-layer, and show that F-layer is more complicated than we ever imagined.Then there is one question; which structure is that of the south polar region close to? Unfortunately, the seismic waveforms that we analyzed in the previous study may not have quality high enough to analyze the PKiKP-PKPbc or PKPbc dispersion. However, it would be meaningful to reanalyze the amplitude data and reconsider the F-layer velocity there. And we also estimate how large slope of velocity can be acceptable for the F-layer velocity structure in this region.

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

NASA Astrophysics Data System (ADS)

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.

Information technology and hospice palliative care: social, cultural, ethical and technical implications in a rural setting.

PubMed

Kuziemsky, Craig; Jewers, Heather; Appleby, Brenda; Foshay, Neil; Maccaull, Wendy; Miller, Keith; Macdonald, Madonna

2012-01-01

There is a need to better understand the specific settings in which health information technology (HIT) is used and implemented. Factors that will determine the successful implementation of HIT are context-specific and often reside not at the technical level but rather at the process and people level. This paper provides the results of a needs assessment for HIT to support hospice palliative care (HPC) delivery in rural settings. Roundtable discussions using the nominal group technique were done to identify priority issues regarding HIT usage to support rural HPC delivery. Qualitative content analysis was then used to identify sociotechnical themes from the roundtable data. Twenty priority issues were identified at the roundtable session. Content analysis grouped the priority issues into one central theme and five supporting themes to form a sociotechnical framework for patient-centered care in rural settings. There are several sociotechnical themes and associated issues that need to be considered prior to implementing HIT in rural HPC settings. Proactive evaluation of these issues can enhance HIT implementation and also help to make ethical aspects of HIT design more explicit.

Health-Based Capitation Risk Adjustment in Minnesota Public Health Care Programs

PubMed Central

Gifford, Gregory A.; Edwards, Kevan R.; Knutson, David J.

2004-01-01

This article documents the history and implementation of health-based capitation risk adjustment in Minnesota public health care programs, and identifies key implementation issues. Capitation payments in these programs are risk adjusted using an historical, health plan risk score, based on concurrent risk assessment. Phased implementation of capitation risk adjustment for these programs began January 1, 2000. Minnesota's experience with capitation risk adjustment suggests that: (1) implementation can accelerate encounter data submission, (2) administrative decisions made during implementation can create issues that impact payment model performance, and (3) changes in diagnosis data management during implementation may require changes to the payment model. PMID:25372356

Preparing for national implementation of an evidence-based, effective HIV prevention program among bahamian sixth-grade students.

PubMed

Knowles, Valerie; Wang, Bo; Deveaux, Lynette; Lunn, Sonja; Rolle, Glenda; Jones, Giavana; Harris, Carole; Kaljee, Linda; Li, Xiaoming; Koci, Veronica; Chen, Xinguang; Marshall, Sharon; Stanton, Bonita

2012-01-01

Using data from the preparatory phase prior to national implementation of an effective HIV prevention program (Focus on Youth in the Caribbean; FOYC) in all Bahamian government sixth-grade classes, we describe (1) actual FOYC implementation, (2) factors that influenced implementation, and (3) the relationship of implementation with intervention outcome. Six elementary schools (with 17 grade six classrooms) were selected to participate in the preparatory phase. The 17 teachers were invited to attend a training workshop, coordinate administration of questionnaires to the students, teach the 10 sessions of FOYC and complete self-assessment checklists. A total of 395 students submitted baseline and 311 students submitted year-end questionnaires. Thirteen teachers initiated FOYC; five completed all 10 sessions. Implementation of FOYC was not related to teacher FOYC workshop experience but did cluster by school. There were significant positive correlations between improved student knowledge of HIV/AIDS, protective health skills, perceived parental monitoring and reduced risk behaviours with the number of FOYC sessions delivered. Implementation was impeded by logistics issues, structural issues with the measures, and comfort-level issues, most of which can be addressed for national implementation. Degree of FOYC implementation is correlated with positive student outcomes.

Issues in Planning and Implementing National Literacy Programmes.

ERIC Educational Resources Information Center

Carron, G., Ed.; Bordia, A., Ed.

The following papers were produced by participants and resource persons on specific issues of planning, management and implementation of literacy and post-literacy strategies: "People's Participation and Mobilization: Characteristics of the Literacy Campaigns in China" (Yanwei); "Strategies for Mobilization and Participation of…

Modeling, Simulation and Analysis of Public Key Infrastructure

NASA Technical Reports Server (NTRS)

Liu, Yuan-Kwei; Tuey, Richard; Ma, Paul (Technical Monitor)

1998-01-01

Security is an essential part of network communication. The advances in cryptography have provided solutions to many of the network security requirements. Public Key Infrastructure (PKI) is the foundation of the cryptography applications. The main objective of this research is to design a model to simulate a reliable, scalable, manageable, and high-performance public key infrastructure. We build a model to simulate the NASA public key infrastructure by using SimProcess and MatLab Software. The simulation is from top level all the way down to the computation needed for encryption, decryption, digital signature, and secure web server. The application of secure web server could be utilized in wireless communications. The results of the simulation are analyzed and confirmed by using queueing theory.

Architecture for networked electronic patient record systems.

PubMed

Takeda, H; Matsumura, Y; Kuwata, S; Nakano, H; Sakamoto, N; Yamamoto, R

2000-11-01

There have been two major approaches to the development of networked electronic patient record (EPR) architecture. One uses object-oriented methodologies for constructing the model, which include the GEHR project, Synapses, HL7 RIM and so on. The second approach uses document-oriented methodologies, as applied in examples of HL7 PRA. It is practically beneficial to take the advantages of both approaches and to add solution technologies for network security such as PKI. In recognition of the similarity with electronic commerce, a certificate authority as a trusted third party will be organised for establishing networked EPR system. This paper describes a Japanese functional model that has been developed, and proposes a document-object-oriented architecture, which is-compared with other existing models.

Making grandma's data secure: a security architecture for home telemedicine.

PubMed Central

Starren, J.; Sengupta, S.; Hripcsak, G.; Ring, G.; Klerer, R.; Shea, S.

2001-01-01

Home telemedicine presents special challenges for data security and privacy. Experience in the Informatics for Diabetes Education And Telemedicine (IDEATel) project has demonstrated that data security is not a one-size-fits-all problem. The IDEATel users include elderly patients in their homes, nurse case managers, physicians, and researchers. The project supports multiple computer systems that require a variety of user interactions, including: data entry, data review, patient education, videoconferencing, and electronic monitoring. To meet these various needs, a number of different of security solutions were utilized, including: UserID/Password, PKI certificates, time-based tokens, IP filtering, VPNs, symmetric and asymmetric encryption schemes, firewalls and dedicated connections. These were combined in different ways to meet the needs of each user groups. PMID:11825267

A 20 MHz CMOS reorder buffer for a superscalar microprocessor

NASA Technical Reports Server (NTRS)

Lenell, John; Wallace, Steve; Bagherzadeh, Nader

1992-01-01

Superscalar processors can achieve increased performance by issuing instructions out-of-order from the original sequential instruction stream. Implementing an out-of-order instruction issue policy requires a hardware mechanism to prevent incorrectly executed instructions from updating register values. A reorder buffer can be used to allow a superscalar processor to issue instructions out-of-order and maintain program correctness. This paper describes the design and implementation of a 20MHz CMOS reorder buffer for superscalar processors. The reorder buffer is designed to accept and retire two instructions per cycle. A full-custom layout in 1.2 micron has been implemented, measuring 1.1058 mm by 1.3542 mm.

'Virtual' central business office: how UMMS improved revenue cycle performance.

PubMed

Henciak, Bill; Fontaine, Christine; Fields, Keith; Parks, Stacy

2010-06-01

Based on its experience with implementing a virtual central business office, UMMS recommends the following steps to ensure the success of such an initiative: Define the process flow for the organization's day-today revenue cycle operations prior to implementation. Then select best practices and milestones for managing accounts. Identify any possible technology issues that could arise during implementation prior to go live. Hold a midproject debriefing with staff. Develop an organizational chart that details who is responsible for handling issues that arise during implementation and afterward.

GASB's New Financial Reporting Model: Implementation Project for School Districts.

ERIC Educational Resources Information Center

Bean, David; Glick, Paul

1999-01-01

In June 1999, the Governmental Accounting Standards Board (GASB) issued its statement on the structure of the basic financial reporting model for state and local governments. Explains the new financial reporting model and reviews the implementation issues that school districts will need to address. (MLF)

Filling the healthcare IT gap by 2015.

PubMed

Bigalke, John T

2009-06-01

Healthcare organizations have been slow to adopt health IT. However, the government stimulus package and impending fines for hospitals that have not implemented HIT by 2015 will motivate adoption. Issues confronting healthcare executives include selection of vendors, command of privacy and security issues, and implementation of industry standards.

Comprehensive Metric Education Project: Implementing Metrics at a District Level Administrative Guide.

ERIC Educational Resources Information Center

Borelli, Michael L.

This document details the administrative issues associated with guiding a school district through its metrication efforts. Issues regarding staff development, curriculum development, and the acquisition of instructional resources are considered. Alternative solutions are offered. Finally, an overall implementation strategy is discussed with…

Implementing programs for chronic illness management: the case of hypertension services.

PubMed

Christianson, J B; Pietz, L; Taylor, R; Woolley, A; Knutson, D J

1997-11-01

This article describes the process by which HealthSystem Minnesota (a vertically integrated health care organization), functioning in a competitive managed care environment, has been implementing a hypertension services program. The program involves a team approach to care, with emphasis on patient participation in treatment; decentralized care delivery by nurse coordinators at primary care practice sites; ongoing training and education for patients and providers; and the continuous monitoring and evaluation of patient outcomes and satisfaction. JOB-LEVEL ISSUES: A variety of issues, such as the role and responsibilities of the nurse coordinator, became evident as the program moved towards operational status at four primary care practice sites, which prolonged the implementation period. PROCESS-LEVEL ISSUES: Issues relating to work process changes were more complicated to resolve and required, in some cases, changes in the proposed model. The most significant process-level issues related to educating physicians about the program to secure their participation and support. ORGANIZATION-LEVEL ISSUES: Such issues, which were the most difficult for program implementors to anticipate and resolve, included an organizational culture that emphasized decision making autonomy at primary practice sites. In part, the difficulty encountered in resolving organization-level issues reflected the implementors' lack of awareness of the strength or complexity of the environmental pressures facing the organization, as well as a lack of sensitivity to nuances relating to organizational culture. Two groups of hypertensive patients--at the implementation and comparison sites--will be compared with respect to satisfaction with care, clinical outcomes, and costs. Expansion of the model to patients with other chronic conditions is under consideration.

Implementation Issues in Federal Reform Efforts in Education: The United States and Australia.

ERIC Educational Resources Information Center

Porter, Paige

Multiple data sources are used in this study of educational change in the United States and Australia. The author considers political issues that may affect the implementation of educational reform efforts at the federal level, such as homogeneity versus heterogeneity, centralization versus decentralization, constitutional responsibility for…

From EDI to Internet Commerce: The BHP Steel Experience.

ERIC Educational Resources Information Center

Chan, Caroline; Swatman, Paula M. C.

2000-01-01

Discusses the issue of business-to-business electronic commerce implementation and the factors affecting it. Discusses electronic data interchange technology, describes the results of a case study of BHP Steel (Australia), and considers paradigm shifts in implementation issues related to electronic commerce that occur over time. (Author/LRW)

Administrative Issues in Planning a Library End User Searching Program. ERIC Digest.

ERIC Educational Resources Information Center

Machovec, George S.

This digest presents a reprint of an article which examines management principles that should be considered when implementing library end user searching programs. A brief discussion of specific implementation issues includes needs assessment, hardware, software, training, budgeting, what systems to offer, publicity and marketing, policies and…

Extending Engineering Design Graphics Laboratories to Have a CAD/CAM Component: Implementation Issues.

ERIC Educational Resources Information Center

Juricic, Davor; Barr, Ronald E.

1996-01-01

Reports on a project that extended the Engineering Design Graphics curriculum to include instruction and laboratory experience in computer-aided design, analysis, and manufacturing (CAD/CAM). Discusses issues in project implementation, including introduction of finite element analysis to lower-division students, feasibility of classroom prototype…

Issues Emerging from First-Year PDS Implementation.

ERIC Educational Resources Information Center

Castle, Sharon; Groth, Lois; Shaklee, Beverly

This paper focuses on a revised Professional Development School (PDS) program and what participant groups perceived to be key issues during the first year of implementation. It addresses the role of PDSs in improving the quality of beginning teachers within a non-supportive state policy environment. The George Mason University Elementary program…

75 FR 39443 - Implementation of OMB Guidance on Drug-Free Workplace Requirements

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-09

... (DOE) is removing its regulation implementing the Governmentwide common rule on drug-free workplace... drug legislation on November 18, 1988. Federal agencies issued an interim final common rule to... Governmentwide common rule on nonprocurement suspension and debarment. The agencies issued a final common rule...

Implementation of Service-Learning in Business Education: Issues and Challenges

ERIC Educational Resources Information Center

Poon, Patrick; Chan, Tsang Sing; Zhou, Lianxi

2011-01-01

This paper examines the issues and challenges in the implementation of service-learning in undergraduate business education. It also provides an assessment of the students' learning efficacy and outcomes over time through the service-learning participation. Service-learning is a pedagogical approach that integrates academic learning and community…

Commentary: The Tyranny of Time and the Reality Principle

ERIC Educational Resources Information Center

Gersten, Russell

2016-01-01

Each of the five articles in this special issue gets "into the weeds" in terms of studying actual classroom or school implementation of evidence-based or promising practices. Virtually all confront the issue of logistics and establishing an infrastructure for ensuring adequate implementation. In general, those studies that ask teachers…

Web Services Security - Implementation and Evaluation Issues

NASA Astrophysics Data System (ADS)

Pimenidis, Elias; Georgiadis, Christos K.; Bako, Peter; Zorkadis, Vassilis

Web services development is a key theme in the utilization the commercial exploitation of the semantic web. Paramount to the development and offering of such services is the issue of security features and they way these are applied in instituting trust amongst participants and recipients of the service. Implementing such security features is a major challenge to developers as they need to balance these with performance and interoperability requirements. Being able to evaluate the level of security offered is a desirable feature for any prospective participant. The authors attempt to address the issues of security requirements and evaluation criteria, while they discuss the challenges of security implementation through a simple web service application case.

Primary Prevention Programs at the Elementary Level: Issues of Treatment Integrity, Systematic Screening, and Reinforcement

ERIC Educational Resources Information Center

Lane, Kathleen Lynne; Kalberg, Jemma Robertson; Bruhn, Allison Leigh; Mahoney, Michelle E.; Driscoll, Steven A.

2008-01-01

This study examined issues of treatment integrity, systematic screenings, and access to reinforcement relative to school-wide positive behavior support programs (SW-PBS) implemented in two rural elementary schools during the first year of program implementation. Results suggested that treatment fidelity, as measured by self-report and direct…

Social Justice: A Long-Term Challenge for Counseling Psychology

ERIC Educational Resources Information Center

Ivey, Allen E.; Collins, Noah M.

2003-01-01

Counseling psychology has a long history of interest and commitment to social justice and multicultural issues. This article discusses some of that history and, in addition, speaks to specifics of implementing a liberation psychology frame of reference into clinical practice along with the issues of implementation and challenges faced by those of…

Non-Formal Education Implementations in Turkey: Issues and Latest Challenges

ERIC Educational Resources Information Center

Bilir, Mehmet

2007-01-01

The aim of this article is to analyse the latest implementations and issues raised in Turkish non-formal education from a historical perspective in Turkey. The high population rate and lack of adequate educational opportunities for adults and migration from rural areas to urban areas caused many educational, social and cultural problems in…

Gender Issues in the Implementation of Social Studies Curriculum in Nigerian Universities

ERIC Educational Resources Information Center

Mezieobi, Dan I.; Oyeoku, E. K.; Ezegbe, B. N.; Igbo, Janeth

2012-01-01

The study investigated gender issues in the implementation of social studies curriculum in Nigerian universities. The subjects for the study comprised of all the 200 final-year sandwich social studies students of University of Port-Harcourt in the 2009 contact session. Five research questions guided the study. Researchers developed questionnaire…

Information Retrieval System Design Issues in a Microcomputer-Based Relational DBMS Environment.

ERIC Educational Resources Information Center

Wolfram, Dietmar

1992-01-01

Outlines the file structure requirements for a microcomputer-based information retrieval system using FoxPro, a relational database management system (DBMS). Issues relating to the design and implementation of such systems are discussed, and two possible designs are examined in terms of space economy and practicality of implementation. (15…

76 FR 76609 - Implementation of Office of Management and Budget Guidance on Drug-Free Workplace Requirements

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-08

... removing its regulation implementing the Governmentwide common rule on drug-free workplace requirements for....) as a part of omnibus drug legislation. Federal agencies issued an interim final common rule to... Governmentwide common rule on nonprocurement suspension and debarment. The agencies issued a final common rule...

A Framework for Institutional Adoption and Implementation of Blended Learning in Higher Education

ERIC Educational Resources Information Center

Graham, Charles R.; Woodfield, Wendy; Harrison, J. Buckley

2013-01-01

There has been rapid growth in blended learning implementation and research focused on course-level issues such as improved learning outcomes, but very limited research focused on institutional policy and adoption issues. More institutional-level blended learning research is needed to guide institutions of higher education in strategically…

Introduction to the Special Issue: Challenges and Solutions to Implementing Effective Reading Intervention in Schools.

PubMed

Foorman, Barbara

2016-12-01

This special issue focuses on challenges and solutions to implementing effective reading intervention in schools in the United States. Researchers often develop interventions that prove effective in efficacy studies but then show no impact when implemented at scale in public school settings. The authors of the intervention studies presented here describe a number of common implementation problems stemming from research in primary grades, middle grades, and high schools. Solutions to these implementation problems include establishing researcher-practitioner partnerships to address the systems-level challenges, suggestions for how to obtain buy-in from teachers, and recommendations for reforming preservice and in-service teacher education. © 2016 Wiley Periodicals, Inc.

San Antonio I Software Workshop Proceedings. DoD Software for the 1990s, Held in San Antonio, Texas on 28 January - 1 February 1991

DTIC Science & Technology

1991-12-01

management and engineering issues common to the military-industrial complex, - to learn from past experience, - to understand future software...prospective policy documents. - :Prepare a draft issue paper and presentation for the DAE. These items should address the key implementation issues with...respect to MCCR software metrics and establish a clear need for DAE support. Long Term Actions ( past 12-18 mcnths) ... Draft final implementation

Implementation Issues for Departure Planning Systems

NASA Technical Reports Server (NTRS)

Hansman, R. John; Feron, Eric; Clarke, John-Paul; Odoni, Amedeo

1999-01-01

The objective of the proposed effort is to investigate issues associated with the design and implementation of decision aiding tools to assist in improving the departure process at congested airports. This effort follows a preliminary investigation of potential Departure Planning approaches and strategies, which identified potential benefits in departure efficiency, and also in reducing the environmental impact of aircraft in the departure queue. The preliminary study bas based, in large part, on observations and analysis of departure processes at Boston, Logan airport. The objective of this follow-on effort is to address key implementation issues and to expand the observational base to include airports with different constraints and traffic demand. Specifically, the objectives of this research are to: (1) Expand the observational base to include airports with different underlying operational dynamics. (2) Develop prototype decision aiding algorithms/approaches and assess potential benefits. and (3) Investigate Human Machine Integration (HMI) issues associated with decision aids in tower environments.

Qualitative and mixed methods research in dissemination and implementation science: introduction to the special issue.

PubMed

Southam-Gerow, Michael A; Dorsey, Shannon

2014-01-01

This special issue provides examples of how qualitative and mixed methods research approaches can be used in dissemination and implementation science. In this introductory article, we provide a brief rationale for why and how qualitative and mixed methods approaches can be useful in moving the field forward. Specifically, we provide a brief primer on common qualitative methods, including a review of guidelines provided by the National Institutes of Health. Next, we introduce the six articles in the issue. The first of the articles by Palinkas represents a more thorough and authoritative discussion related to qualitative methods, using the other five articles in the issue (and other published works) as examples. The remaining five articles are empirical and/or descriptive articles of recently completed or ongoing qualitative or mixed methods studies related to dissemination and implementation of evidence-based practices for children and adolescents.

System Wide Information Management (SWIM)

NASA Technical Reports Server (NTRS)

Hritz, Mike; McGowan, Shirley; Ramos, Cal

2004-01-01

This viewgraph presentation lists questions regarding the implementation of System Wide Information Management (SWIM). Some of the questions concern policy issues and strategies, technology issues and strategies, or transition issues and strategies.

Implementation Issues of Virtual Desktop Infrastructure and Its Case Study for a Physician's Round at Seoul National University Bundang Hospital.

PubMed

Yoo, Sooyoung; Kim, Seok; Kim, Taegi; Kim, Jon Soo; Baek, Rong-Min; Suh, Chang Suk; Chung, Chin Youb; Hwang, Hee

2012-12-01

The cloud computing-based virtual desktop infrastructure (VDI) allows access to computing environments with no limitations in terms of time or place such that it can permit the rapid establishment of a mobile hospital environment. The objective of this study was to investigate the empirical issues to be considered when establishing a virtual mobile environment using VDI technology in a hospital setting and to examine the utility of the technology with an Apple iPad during a physician's rounds as a case study. Empirical implementation issues were derived from a 910-bed tertiary national university hospital that recently launched a VDI system. During the physicians' rounds, we surveyed patient satisfaction levels with the VDI-based mobile consultation service with the iPad and the relationship between these levels of satisfaction and hospital revisits, hospital recommendations, and the hospital brand image. Thirty-five inpatients (including their next-of-kin) and seven physicians participated in the survey. Implementation issues pertaining to the VDI system arose with regard to the highly availability system architecture, wireless network infrastructure, and screen resolution of the system. Other issues were related to privacy and security, mobile device management, and user education. When the system was used in rounds, patients and their next-of-kin expressed high satisfaction levels, and a positive relationship was noted as regards patients' decisions to revisit the hospital and whether the use of the VDI system improved the brand image of the hospital. Mobile hospital environments have the potential to benefit both physicians and patients. The issues related to the implementation of VDI system discussed here should be examined in advance for its successful adoption and implementation.

Implementation Issues of Virtual Desktop Infrastructure and Its Case Study for a Physician's Round at Seoul National University Bundang Hospital

PubMed Central

Yoo, Sooyoung; Kim, Seok; Kim, Taegi; Kim, Jon Soo; Baek, Rong-Min; Suh, Chang Suk; Chung, Chin Youb

2012-01-01

Objectives The cloud computing-based virtual desktop infrastructure (VDI) allows access to computing environments with no limitations in terms of time or place such that it can permit the rapid establishment of a mobile hospital environment. The objective of this study was to investigate the empirical issues to be considered when establishing a virtual mobile environment using VDI technology in a hospital setting and to examine the utility of the technology with an Apple iPad during a physician's rounds as a case study. Methods Empirical implementation issues were derived from a 910-bed tertiary national university hospital that recently launched a VDI system. During the physicians' rounds, we surveyed patient satisfaction levels with the VDI-based mobile consultation service with the iPad and the relationship between these levels of satisfaction and hospital revisits, hospital recommendations, and the hospital brand image. Thirty-five inpatients (including their next-of-kin) and seven physicians participated in the survey. Results Implementation issues pertaining to the VDI system arose with regard to the highly availability system architecture, wireless network infrastructure, and screen resolution of the system. Other issues were related to privacy and security, mobile device management, and user education. When the system was used in rounds, patients and their next-of-kin expressed high satisfaction levels, and a positive relationship was noted as regards patients' decisions to revisit the hospital and whether the use of the VDI system improved the brand image of the hospital. Conclusions Mobile hospital environments have the potential to benefit both physicians and patients. The issues related to the implementation of VDI system discussed here should be examined in advance for its successful adoption and implementation. PMID:23346476

Reflections on organizational issues in developing, implementing, and maintaining state Web-based data query systems.

PubMed

Love, Denise; Shah, Gulzar H

2006-01-01

Emerging technologies, such as Web-based data query systems (WDQSs), provide opportunities for state and local agencies to systematically organize and disseminate data to broad audiences and streamline the data distribution process. Despite the progress in WDQSs' implementation, led by agencies considered the "early adopters," there are still agencies left behind. This article explores the organizational issues and barriers to development of WDQSs in public health agencies and highlights factors facilitating the implementation of WDQSs.

Issues to consider before implementing digital breast tomosynthesis into a breast imaging practice.

PubMed

Hardesty, Lara A

2015-03-01

OBJECTIVE. The purpose of this article is to discuss issues surrounding the implementation of digital breast tomosynthesis (DBT) into a clinical breast imaging practice and assist radiologists, technologists, and administrators who are considering the addition of this new technology to their practices. CONCLUSION. When appropriate attention is given to image acquisition, interpretation, storage, technologist and radiologist training, patient selection, billing, radiation dose, and marketing, implementation of DBT into a breast imaging practice can be successful.

Usability and feasibility of a tablet-based Decision-Support and Integrated Record-keeping (DESIRE) tool in the nurse management of hypertension in rural western Kenya.

PubMed

Vedanthan, Rajesh; Blank, Evan; Tuikong, Nelly; Kamano, Jemima; Misoi, Lawrence; Tulienge, Deborah; Hutchinson, Claire; Ascheim, Deborah D; Kimaiyo, Sylvester; Fuster, Valentin; Were, Martin C

2015-03-01

Mobile health (mHealth) applications have recently proliferated, especially in low- and middle-income countries, complementing task-redistribution strategies with clinical decision support. Relatively few studies address usability and feasibility issues that may impact success or failure of implementation, and few have been conducted for non-communicable diseases such as hypertension. To conduct iterative usability and feasibility testing of a tablet-based Decision Support and Integrated Record-keeping (DESIRE) tool, a technology intended to assist rural clinicians taking care of hypertension patients at the community level in a resource-limited setting in western Kenya. Usability testing consisted of "think aloud" exercises and "mock patient encounters" with five nurses, as well as one focus group discussion. Feasibility testing consisted of semi-structured interviews of five nurses and two members of the implementation team, and one focus group discussion with nurses. Content analysis was performed using both deductive codes and significant inductive codes. Critical incidents were identified and ranked according to severity. A cause-of-error analysis was used to develop corresponding design change suggestions. Fifty-seven critical incidents were identified in usability testing, 21 of which were unique. The cause-of-error analysis yielded 23 design change suggestions. Feasibility themes included barriers to implementation along both human and technical axes, facilitators to implementation, provider issues, patient issues and feature requests. This participatory, iterative human-centered design process revealed previously unaddressed usability and feasibility issues affecting the implementation of the DESIRE tool in western Kenya. In addition to well-known technical issues, we highlight the importance of human factors that can impact implementation of mHealth interventions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Usability and Feasibility of a Tablet-Based Decision-Support and Integrated Record-Keeping (DESIRE) Tool in the Nurse Management of Hypertension in Rural Western Kenya

PubMed Central

Vedanthan, Rajesh; Blank, Evan; Tuikong, Nelly; Kamano, Jemima; Misoi, Lawrence; Tulienge, Deborah; Hutchinson, Claire; Ascheim, Deborah D.; Kimaiyo, Sylvester; Fuster, Valentin; Were, Martin C.

2015-01-01

Background Mobile health (mHealth) applications have recently proliferated, especially in low- and middle-income countries, complementing task-redistribution strategies with clinical decision support. Relatively few studies address usability and feasibility issues that may impact success or failure of implementation, and few have been conducted for non-communicable diseases such as hypertension. Objective To conduct iterative usability and feasibility testing of a tablet-based Decision Support and Integrated Record-keeping (DESIRE) tool, a technology intended to assist rural clinicians taking care of hypertension patients at the community level in a resource-limited setting in western Kenya. Methods Usability testing consisted of “think aloud” exercises and “mock patient encounters” with five nurses, as well as one focus group discussion. Feasibility testing consisted of semi-structured interviews of five nurses and two members of the implementation team, and one focus group discussion with nurses. Content analysis was performed using both deductive codes and significant inductive codes. Critical incidents were identified and ranked according to severity. A cause-of-error analysis was used to develop corresponding design change suggestions. Results Fifty-seven critical incidents were identified in usability testing, 21 of which were unique. The cause-of-error analysis yielded 23 design change suggestions. Feasibility themes included barriers to implementation along both human and technical axes, facilitators to implementation, provider issues, patient issues and feature requests. Conclusions This participatory, iterative human-centered design process revealed previously unaddressed usability and feasibility issues affecting the implementation of the DESIRE tool in western Kenya. In addition to well-known technical issues, we highlight the importance of human factors that can impact implementation of mHealth interventions. PMID:25612791

Distributed Trust Management for Validating SLA Choreographies

NASA Astrophysics Data System (ADS)

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.

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

NASA Technical Reports Server (NTRS)

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

1982-01-01

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.

Partially Key Distribution with Public Key Cryptosystem Based on Error Control Codes

NASA Astrophysics Data System (ADS)

Tavallaei, Saeed Ebadi; Falahati, Abolfazl

Due to the low level of security in public key cryptosystems based on number theory, fundamental difficulties such as "key escrow" in Public Key Infrastructure (PKI) and a secure channel in ID-based cryptography, a new key distribution cryptosystem based on Error Control Codes (ECC) is proposed . This idea is done by some modification on McEliece cryptosystem. The security of ECC cryptosystem obtains from the NP-Completeness of block codes decoding. The capability of generating public keys with variable lengths which is suitable for different applications will be provided by using ECC. It seems that usage of these cryptosystems because of decreasing in the security of cryptosystems based on number theory and increasing the lengths of their keys would be unavoidable in future.

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

NASA Astrophysics Data System (ADS)

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.

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

PubMed

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 conserved loops that converge at the active site cleft. The catalytic loop (residues 166-171) and the Mg2+ positioning loop (residues 184-186) are a stable part of the large lobe and have low B-factors in all structures solved to date. The stability of the glycine-rich loop is highly dependent on the ligands that occupy the active site cleft with maximum stability achieved in the ternary complex containing Mg x ATP and the peptide inhibitor. In this ternary complex the gamma-phosphate is secured between both lobes by hydrogen bonds to the backbone amide of Ser 53 in the glycine-rich loop and the amino group of Lys 168 in the catalytic loop. In the adenosine ternary complex the water molecule replacing the gamma-phosphate hydrogen bonds between Lys 168 and Asp 166 and makes no contact with the small lobe. This glycine-rich loop is thus the most mobile component of the active site cleft, with the tip of the loop being highly sensitive to what occupies the gamma-subsite.

Ethical issues in the development and implementation of nutrition-related public health policies and interventions: A scoping review.

PubMed

Hurlimann, Thierry; Peña-Rosas, Juan Pablo; Saxena, Abha; Zamora, Gerardo; Godard, Béatrice

2017-01-01

The limited integration of ethics in nutrition-related public health policies and interventions is one major concern for those who have the task of implementing them. Ethical challenges that are overlooked during the development of such interventions could raise serious ethical issues during their implementation and even after. As a result, these decision makers need technical support and ethical guidance for adaptation of interventions to local (cultural, social, economic, etc.) contexts. The goal of this scoping review is to delineate and "map" the range of ethical issues in nutrition-related public health interventions, as well as the range of the various fields in which they may arise. A scoping review of empirical research and conceptual literature was conducted following the framework of Arksey and O'Malley. Searches using PubMed with Medical Subject Headings (MeSH) categories and Advanced Search Builder as well as in the Global Health Library were performed. The final sample consists of 169 publications. The ethics of public health prevention or treatment of obesity and non-communicable diseases is the most explicitly and frequently discussed subject. In comparison, ethical issues raised by public health interventions in the fields of undernutrition, breastfeeding, vitamin/mineral supplementation and food fortification, food security, food sustainability and food safety are addressed in a lower proportion of the sample. The results illustrate the various natures, types, and scopes of existing public health nutrition-related interventions, and the various ethical issues that may be raised by these interventions, in addition to the numerous and different contexts in which they may be implemented. The ethical issues faced in the development and implementation of nutrition-related public health interventions are varied and cannot be equated with, nor generalized about, when dealing with specific activities in this field. More importantly, these ethical issues cannot be managed without a careful consideration for the complexity of contexts in which nutrition-related interventions are expected to be implemented. These interventions engage a variety of actors with diverse perspectives and interests. We discuss these challenges and also comment on the importance of considering ethical impacts in the monitoring and evaluation of such interventions. General ethical frameworks or recommendations-although useful-cannot be expected to provide policy makers, implementators and other public health personnel with sufficient practical ethical guidance as they cannot consider and anticipate the particularities of all specific nutrition-related public health interventions and the complexity of the contexts in which they are implemented. Further research is needed in order to develop more targeted ethical frameworks.

Practical Issues in Developing a Culturally Tailored Physical Activity Promotion Program for Chinese and Korean American Midlife Women: A Pilot Study

PubMed Central

Chee, Wonshik; Kim, Sangmi; Chu, Tsung-Lan; Ji, Xiaopeng; Zhang, Jingwen; Chee, Eunice; Im, Eun-Ok

2016-01-01

Background With advances in computer technologies, Web-based interventions are widely accepted and welcomed by health care providers and researchers. Although the benefits of Web-based interventions on physical activity promotion have been documented, the programs have rarely targeted Asian Americans, including Asian American midlife women. Subsequently, culturally competent Web-based physical activity programs for Asian Americans may be necessary. Objective The purpose of our study was to explore practical issues in developing and implementing a culturally competent Web-based physical activity promotion program for 2 groups of Asian American women—Chinese American and Korean American midlife women—and to provide implications for future research. Methods While conducting the study, the research team members wrote individual memos on issues and their inferences on plausible reasons for the issues. The team had group discussions each week and kept the minutes of the discussions. Then, the memos and minutes were analyzed using a content analysis method. Results We identified practical issues in 4 major idea categories: (1) bilingual translators’ language orientations, (2) cultural sensitivity requirement, (3) low response rate, interest, and retention, and (4) issues in implementation logistics. Conclusions Based on the issues, we make several suggestions for the use of bilingual translators, motivational strategies, and implementation logistics. PMID:27872035

Implementation Issues of a Standards-Based Teacher Evaluation System: Perceptions of Campus Administrators

ERIC Educational Resources Information Center

Nixon, Lisa

2013-01-01

The purpose of this mixed methods study was to determine the key implementation issues of a standards-based teacher evaluation system as perceived by campus administrators. The 80 campus administrators that participated in this study were from six public school districts located in southeastern Texas that serve students in grades Kindergarten…

Issues and Prospects of Effetive Implementation of New Secondary School Curriculum in Nigeria

ERIC Educational Resources Information Center

Ahmadi, Ali A.; Lukman, Ajibola A.

2015-01-01

This paper digs into the issues surrounding effective implementation of new secondary school curriculum in Nigeria. This is based on the feeling that 21st century education is characterized with a dramatic technological revolution. The paper therefore portrays education in the 21st century as a total departure from the factory-model education of…

A Case Study of Issues of Strategy Implementation in Internationalization of Higher Education

ERIC Educational Resources Information Center

Jiang, Nan; Carpenter, Victoria

2013-01-01

Purpose: The purpose of this research is to identify and critically evaluate key issues faced by an institution in the quest to implement higher education internationalization. Design/methodology/approach: A qualitative research is conducted in a post-1992 UK university. A total of 20 interviewees from three key departments participated in this…

Ethics of Implementing Electronic Health Records in Developing Countries: Points to Consider

PubMed Central

Were, Martin C.; Meslin, Eric M.

2011-01-01

Electronic Health Record systems (EHRs) are increasingly being used in many developing countries, several of which have moved beyond isolated pilot projects to active large-scale implementation as part of their national health strategies. Despite growing enthusiasm for adopting EHRs in resource poor settings, almost no attention has been paid to the ethical issues that might arise. In this article we argue that these ethical issues should be addressed now if EHRs are to be appropriately implemented in these settings. We take a systematic approach guided by a widely accepted ethical framework currently in use for developing countries to first describe the ethical issues, and then propose a set of ‘Points to Consider’ to guide further thinking and decision-making. PMID:22195214

Detecting and addressing adolescent issues and concerns: evaluating the efficacy of a primary care previsit questionnaire.

PubMed

Lewin, Warren; Knäuper, Bärbel; Roseman, Michelle; Adler, Perry; Malus, Michael

2009-07-01

To assess the efficacy of a previsit questionnaire (PVQ), implemented without formal training, that was designed to screen for biomedical and psychosocial health issues and concerns among adolescent patients in a hospital-based primary care clinic, and to examine the subsequent action taken for health issues and concerns identified with the PVQ. Retrospective review of adolescent medical charts, using a pre-post design. An outpatient primary care clinic located in an urban teaching hospital in Montreal, Que. A total of 210 adolescent patients aged 13 to 19 who visited the clinic between 2000 and 2004. The type (medical vs psychosocial) and number of issues detected and actions taken by physicians in one-to-one consultations with adolescent patients 2 years before (2000-2002) and 2 years after (2002-2004) PVQ implementation, as noted in the patients' medical charts. In total, 105 charts were reviewed for each group. An increase in the number of psychosocial issues was detected following the introduction of the PVQ. An increase in the frequency of action taken for psychosocial concerns and a decrease in the frequency of medical action taken by physicians were found after PVQ implementation. More notations related to psychosocial concerns were also found in the adolescents' charts after introduction of the PVQ. A PVQ is an effective strategy to improve adolescent screening for psychosocial issues and concerns. Implementing such a questionnaire requires no training and can therefore be easily incorporated into clinical practice.

Soil Vapor Extraction Implementation Experiences

EPA Pesticide Factsheets

This issue paper identifies issues and summarizes experiences with soil vapor extraction (SVE) as a remedy for volatile organic compounds (VOCs) in soils. The issues presented here reflect discussions with over 30 Remedial Project Managers (RPMs)...

A diffusion of innovations model of physician order entry.

PubMed

Ash, J S; Lyman, J; Carpenter, J; Fournier, L

2001-01-01

To interpret the results of a cross-site study of physician order entry (POE) in hospitals using a diffusion of innovations theory framework. Qualitative study using observation, focus groups, and interviews. Data were analyzed by an interdisciplinary team of researchers using a grounded approach to identify themes. Themes were then interpreted using classical Diffusion of Innovations (DOI) theory as described by Rogers [1]. Four high level themes were identified: organizational issues; clinical and professional issues; technology implementation issues; and issues related to the organization of information and knowledge. Further analysis using the DOI framework indicated that POE is an especially complex information technology innovation when one considers communication, time, and social system issues in addition to attributes of the innovation itself. Implementation strategies for POE should be designed to account for its complex nature. The ideal would be a system that is both customizable and integrated with other parts of the information system, is implemented with maximum involvement of users and high levels of support, and is surrounded by an atmosphere of trust and collaboration.

A complex adaptive systems perspective of health information technology implementation.

PubMed

Keshavjee, Karim; Kuziemsky, Craig; Vassanji, Karim; Ghany, Ahmad

2013-01-01

Implementing health information technology (HIT) is a challenge because of the complexity and multiple interactions that define HIT implementation. Much of the research on HIT implementation is descriptive in nature and has focused on distinct processes such as order entry or decision support. These studies fail to take into account the underlying complexity of the processes, people and settings that are typical of HIT implementations. Complex adaptive systems (CAS) is a promising field that could elucidate the complexity and non-linear interacting issues that are typical in HIT implementation. Initially we sought new models that would enable us to better understand the complex nature of HIT implementation, to proactively identify problem issues that could be a precursor to unintended consequences and to develop new models and new approaches to successful HIT implementations. Our investigation demonstrates that CAS does not provide prediction, but forces us to rethink our HIT implementation paradigms and question what we think we know. CAS provides new ways to conceptualize HIT implementation and suggests new approaches to increasing HIT implementation successes.

78 FR 35117 - Orphan Drug Regulations

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-12

...The Food and Drug Administration (FDA) is issuing final regulations amending the 1992 Orphan Drug Regulations issued to implement the Orphan Drug Act. These amendments are intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since those regulations were issued.

Campus and Community Coalitions. Issues in Prevention

ERIC Educational Resources Information Center

Higher Education Center for Alcohol, Drug Abuse, and Violence Prevention, 2012

2012-01-01

This issue of "Issues in Prevention" focuses on campus and community coalitions. This issue contains the following articles: (1) Campus and Community Coalitions: Implementing Environmental Prevention Strategies (John D. Clapp); (2) Campus Brief: University of Rhode Island; (3) International Town & Gown Association; (4) Q&A With…

Interagency Collaborative Team Model for Capacity Building to Scale-Up Evidence-Based Practice

PubMed Central

Hurlburt, Michael; Aarons, Gregory A; Fettes, Danielle; Willging, Cathleen; Gunderson, Lara; Chaffin, Mark J

2015-01-01

Background System-wide scale up of evidence-based practice (EBP) is a complex process. Yet, few strategic approaches exist to support EBP implementation and sustainment across a service system. Building on the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework, we developed and are testing the Interagency Collaborative Team (ICT) process model to implement an evidence-based child neglect intervention (i.e., SafeCare®) within a large children’s service system. The ICT model emphasizes the role of local agency collaborations in creating structural supports for successful implementation. Methods We describe the ICT model and present preliminary qualitative results from use of the implementation model in one large scale EBP implementation. Qualitative interviews were conducted to assess challenges in building system, organization, and home visitor collaboration and capacity to implement the EBP. Data collection and analysis centered on EBP implementation issues, as well as the experiences of home visitors under the ICT model. Results Six notable issues relating to implementation process emerged from participant interviews, including: (a) initial commitment and collaboration among stakeholders, (b) leadership, (c) communication, (d) practice fit with local context, (e) ongoing negotiation and problem solving, and (f) early successes. These issues highlight strengths and areas for development in the ICT model. Conclusions Use of the ICT model led to sustained and widespread use of SafeCare in one large county. Although some aspects of the implementation model may benefit from enhancement, qualitative findings suggest that the ICT process generates strong structural supports for implementation and creates conditions in which tensions between EBP structure and local contextual variations can be resolved in ways that support the expansion and maintenance of an EBP while preserving potential for public health benefit. PMID:27512239

Interagency Collaborative Team Model for Capacity Building to Scale-Up Evidence-Based Practice.

PubMed

Hurlburt, Michael; Aarons, Gregory A; Fettes, Danielle; Willging, Cathleen; Gunderson, Lara; Chaffin, Mark J

2014-04-01

System-wide scale up of evidence-based practice (EBP) is a complex process. Yet, few strategic approaches exist to support EBP implementation and sustainment across a service system. Building on the Exploration, Preparation, Implementation, and Sustainment (EPIS) implementation framework, we developed and are testing the Interagency Collaborative Team (ICT) process model to implement an evidence-based child neglect intervention (i.e., SafeCare®) within a large children's service system. The ICT model emphasizes the role of local agency collaborations in creating structural supports for successful implementation. We describe the ICT model and present preliminary qualitative results from use of the implementation model in one large scale EBP implementation. Qualitative interviews were conducted to assess challenges in building system, organization, and home visitor collaboration and capacity to implement the EBP. Data collection and analysis centered on EBP implementation issues, as well as the experiences of home visitors under the ICT model. Six notable issues relating to implementation process emerged from participant interviews, including: (a) initial commitment and collaboration among stakeholders, (b) leadership, (c) communication, (d) practice fit with local context, (e) ongoing negotiation and problem solving, and (f) early successes. These issues highlight strengths and areas for development in the ICT model. Use of the ICT model led to sustained and widespread use of SafeCare in one large county. Although some aspects of the implementation model may benefit from enhancement, qualitative findings suggest that the ICT process generates strong structural supports for implementation and creates conditions in which tensions between EBP structure and local contextual variations can be resolved in ways that support the expansion and maintenance of an EBP while preserving potential for public health benefit.

Institutional and policy issues in adopting advanced public transportation systems technology

DOT National Transportation Integrated Search

1995-09-01

This project, Institutional and Policy Issues in Adopting Advanced Public Transportation Systems Technologies, aimed to study critical mass transportation issues associated with the implementation of intelligent transportation systems (ITS) in the no...

Inner Core Anisotropy in Attenuation

NASA Astrophysics Data System (ADS)

Yu, W.; Wen, L.

2004-12-01

It is now well established that the compressional velocity in the Earth's inner core varies in both direction and geographic location. The compressional waves travel faster along the polar directions than along the equatorial directions. Such polar-equatorial difference is interpreted as a result of inner core anisotropy in velocity (with a magnitude of about 3%) and such anisotropy appears to be stronger in the ``western hemisphere" (180oW -40oE) than in the ``eastern hemisphere" (40oE-180oE). Along the equatorial paths, the compressional velocity also exhibits a hemispheric pattern with the eastern hemisphere being about 1% higher than the western hemisphere. Possible explanations for the causes of the velocity in anisotropy and the hemispheric difference in velocity along the equatorial paths include different geometric inclusions of melt or different alignments of iron crystals which are known to be anisotropic in velocities. Here, we report an observation of ubiquitous correlation between small (large) amplitude and fast (slow) travel time of the PKIKP waves sampling the top 300 km of the inner core. We study this correlation by jointly analyzing the differential travel times and amplitude ratios of the PKiKP-PKIKP and the PKPbc-PKIKP phases recorded by the Global Seismographic Network (1990-2001), various regional seismic networks (BANJO, BLSP, FREESIA, GEOFON, GEOSCOPE, Kazakhstan, Kyrgyz, MEDNET, and OHP), and several PASSCAL Networks deployed in Alaska and Antarctica (XE: 1999-2001, XF: 1995-1996, and YI: 1998-1999). Our dataset consists of 310 PKiKP-PKIKP and 240 PKPbc-PKIKP phases, selected from a total of more than 16,000 observations. PKIKP waves exhibit relatively smaller amplitudes for those sampling the eastern hemisphere along the equatorial paths and even smaller amplitudes for those sampling the polar paths in the western hemisphere. One simple explanation for the velocity-attenuation relation is that the inner core is anisotropic in attenuation and the direction of high attenuation correlates with that of high P velocity. Different anisotropic behaviors in velocity and attenuation can be best explained by different alignments of iron crystals under the hypothesis that iron crystals are anisotropic in both velocity and attenuation and their axes of high P velocity correspond to those of high attenuation.

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

PubMed

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.

Study of Issues Related to the Implementation of Computer Technology in Schools. Final Report, July, 1981. Technical Report No. 2.

ERIC Educational Resources Information Center

Sheingold, Karen; And Others

This study examined ways in which microcomputers are used in schools and the complex issues that surround their implementation. Three fictional geographically distinct school districts with a diversity of microcomputer applications at both the elementary and secondary levels were studied: Salerno, a large southern city; Granite, a midwestern city;…

75 FR 50845 - Privacy Act of 1974: Implementation of Exemptions; Department of Homeland Security/ALL-027 The...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-08-18

... Policy, Department of Homeland Security, Washington, DC 20528. For privacy issues please contact: Mary...;Prices of new books are listed in the first FEDERAL REGISTER issue of each #0;week. #0; #0; #0; #0;#0...] Privacy Act of 1974: Implementation of Exemptions; Department of Homeland Security/ALL--027 The History of...

75 FR 67909 - Privacy Act of 1974: Implementation of Exemptions; Department of Homeland Security Office of the...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-04

... facsimile (202) 254-4299. For privacy issues please contact: Mary Ellen Callahan (703-235-0780), Chief...;Prices of new books are listed in the first FEDERAL REGISTER issue of each #0;week. #0; #0; #0; #0;#0...] Privacy Act of 1974: Implementation of Exemptions; Department of Homeland Security Office of the Inspector...

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

NASA Astrophysics Data System (ADS)

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 Retrievals, Data Mining, Web Image Mining, & Applications, Defining Spectrum Rights and Open Spectrum Solutions, E-Comerce, Ubiquitous, RFID, Applications, Fingerprint/Hand/Biometrics Recognitions and Technologies, Foundations of High-performance Computing, IC-card Security, OTP, and Key Management Issues, IDS/Firewall, Anti-Spam mail, Anti-virus issues, Mobile Computing for E-Commerce, Network Security Applications, Neural Networks and Biomedical Simulations, Quality of Services and Communication Protocols, Quantum Computing, Coding, and Error Controls, Satellite and Optical Communication Systems, Theory of Parallel Processing and Distributed Computing, Virtual Visions, 3-D Object Retrievals, & Virtual Simulations, Wireless Access Security, etc. The success of ICCSCM 2017 is reflected in the received papers from authors around the world from several countries which allows a highly multinational and multicultural idea and experience exchange. The accepted papers of ICCSCM 2017 are published in this Book. Please check http://www.iccscm.com for further news. A conference such as ICCSCM 2017 can only become successful using a team effort, so herewith we want to thank the International Technical Committee and the Reviewers for their efforts in the review process as well as their valuable advices. We are thankful to all those who contributed to the success of ICCSCM 2017. The Secretary

Performance issues for domain-oriented time-driven distributed simulations

NASA Technical Reports Server (NTRS)

Nicol, David M.

1987-01-01

It has long been recognized that simulations form an interesting and important class of computations that may benefit from distributed or parallel processing. Since the point of parallel processing is improved performance, the recent proliferation of multiprocessors requires that we consider the performance issues that naturally arise when attempting to implement a distributed simulation. Three such issues are: (1) the problem of mapping the simulation onto the architecture, (2) the possibilities for performing redundant computation in order to reduce communication, and (3) the avoidance of deadlock due to distributed contention for message-buffer space. These issues are discussed in the context of a battlefield simulation implemented on a medium-scale multiprocessor message-passing architecture.

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

Not Available

This report contains papers on the following topics: NREN Security Issues: Policies and Technologies; Layer Wars: Protect the Internet with Network Layer Security; Electronic Commission Management; Workflow 2000 - Electronic Document Authorization in Practice; Security Issues of a UNIX PEM Implementation; Implementing Privacy Enhanced Mail on VMS; Distributed Public Key Certificate Management; Protecting the Integrity of Privacy-enhanced Electronic Mail; Practical Authorization in Large Heterogeneous Distributed Systems; Security Issues in the Truffles File System; Issues surrounding the use of Cryptographic Algorithms and Smart Card Applications; Smart Card Augmentation of Kerberos; and An Overview of the Advanced Smart Card Access Control System.more » Selected papers were processed separately for inclusion in the Energy Science and Technology Database.« less

Ethical issues in the development and implementation of nutrition-related public health policies and interventions: A scoping review

PubMed Central

Peña-Rosas, Juan Pablo; Saxena, Abha; Zamora, Gerardo

2017-01-01

Background The limited integration of ethics in nutrition-related public health policies and interventions is one major concern for those who have the task of implementing them. Ethical challenges that are overlooked during the development of such interventions could raise serious ethical issues during their implementation and even after. As a result, these decision makers need technical support and ethical guidance for adaptation of interventions to local (cultural, social, economic, etc.) contexts. Aim The goal of this scoping review is to delineate and “map” the range of ethical issues in nutrition-related public health interventions, as well as the range of the various fields in which they may arise. Methods A scoping review of empirical research and conceptual literature was conducted following the framework of Arksey and O’Malley. Searches using PubMed with Medical Subject Headings (MeSH) categories and Advanced Search Builder as well as in the Global Health Library were performed. The final sample consists of 169 publications. Results The ethics of public health prevention or treatment of obesity and non-communicable diseases is the most explicitly and frequently discussed subject. In comparison, ethical issues raised by public health interventions in the fields of undernutrition, breastfeeding, vitamin/mineral supplementation and food fortification, food security, food sustainability and food safety are addressed in a lower proportion of the sample. The results illustrate the various natures, types, and scopes of existing public health nutrition-related interventions, and the various ethical issues that may be raised by these interventions, in addition to the numerous and different contexts in which they may be implemented. Discussion The ethical issues faced in the development and implementation of nutrition-related public health interventions are varied and cannot be equated with, nor generalized about, when dealing with specific activities in this field. More importantly, these ethical issues cannot be managed without a careful consideration for the complexity of contexts in which nutrition-related interventions are expected to be implemented. These interventions engage a variety of actors with diverse perspectives and interests. We discuss these challenges and also comment on the importance of considering ethical impacts in the monitoring and evaluation of such interventions. Conclusion General ethical frameworks or recommendations–although useful–cannot be expected to provide policy makers, implementators and other public health personnel with sufficient practical ethical guidance as they cannot consider and anticipate the particularities of all specific nutrition-related public health interventions and the complexity of the contexts in which they are implemented. Further research is needed in order to develop more targeted ethical frameworks. PMID:29073186

Implementation science approaches for integrating eHealth research into practice and policy.

PubMed

Glasgow, Russell E; Phillips, Siobhan M; Sanchez, Michael A

2014-07-01

To summarize key issues in the eHealth field from an implementation science perspective and to highlight illustrative processes, examples and key directions to help more rapidly integrate research, policy and practice. We present background on implementation science models and emerging principles; discuss implications for eHealth research; provide examples of practical designs, measures and exemplar studies that address key implementation science issues; and make recommendations for ways to more rapidly develop and test eHealth interventions as well as future research, policy and practice. The pace of eHealth research has generally not kept up with technological advances, and many of our designs, methods and funding mechanisms are incapable of providing the types of rapid and relevant information needed. Although there has been substantial eHealth research conducted with positive short-term results, several key implementation and dissemination issues such as representativeness, cost, unintended consequences, impact on health inequities, and sustainability have not been addressed or reported. Examples of studies in several of these areas are summarized to demonstrate this is possible. eHealth research that is intended to translate into policy and practice should be more contextual, report more on setting factors, employ more responsive and pragmatic designs and report results more transparently on issues important to potential adopting patients, clinicians and organizational decision makers. We outline an alternative development and assessment model, summarize implementation science findings that can help focus attention, and call for different types of more rapid and relevant research and funding mechanisms. Published by Elsevier Ireland Ltd.

Issues in Implementing a Structured Problem-Based Learning Strategy in a Volcano Unit: A Case Study

ERIC Educational Resources Information Center

Lee, Hyunju; Bae, Sungah

2008-01-01

The purpose of this study was to understand how an 8th grade science class used a structured problem-based learning (PBL) strategy to study volcanoes and to discuss some of the issues that science teachers might encounter when designing and implementing the PBL strategy. This study took place at Collins Middle School, which is located in a…

Privacy-Driven Design of Learning Analytics Applications: Exploring the Design Space of Solutions for Data Sharing and Interoperability

ERIC Educational Resources Information Center

Hoel, Tore; Chen, Weiqin

2016-01-01

Studies have shown that issues of privacy, control of data, and trust are essential to implementation of learning analytics systems. If these issues are not addressed appropriately, systems will tend to collapse due to a legitimacy crisis, or they will not be implemented in the first place due to resistance from learners, their parents, or their…

An intervention to help community-based organizations implement an evidence-based HIV prevention intervention: the Mpowerment Project technology exchange system.

PubMed

Kegeles, Susan M; Rebchook, Gregory; Pollack, Lance; Huebner, David; Tebbetts, Scott; Hamiga, John; Sweeney, David; Zovod, Benjamin

2012-03-01

Considerable resources have been spent developing and rigorously testing HIV prevention intervention models, but such models do not impact the AIDS pandemic unless they are implemented effectively by community-based organizations (CBOs) and health departments. The Mpowerment Project (MP) is being implemented by CBOs around the U.S. It is a multilevel, evidence-based HIV prevention program for young gay/bisexual men that targets individual, interpersonal, social, and structural issues by using empowerment and community mobilization methods. This paper discusses the development of an intervention to help CBOs implement the MP called the Mpowerment Project Technology Exchange System (MPTES); CBOs' uptake, utilization and perceptions of the MPTES components; and issues that arose during technical assistance. The seven-component MPTES was provided to 49 CBOs implementing the MP that were followed longitudinally for up to two years. Except for the widely used program manual, other program materials were used early in implementing the MP and then their use declined. In contrast, once technical assistance was proactively provided, its usage remained constant over time, as did requests for technical assistance. CBOs expressed substantial positive feedback about the MPTES, but felt that it needs more focus on diversity issues, describing real world implementation approaches, and providing guidance on how to adapt the MP to diverse populations.

International and domestic regulator issues facing the Canadian MSAT system

NASA Technical Reports Server (NTRS)

Bahman, Azarbar; Langlois, Jacques R.; Frank, Christopher J.

1988-01-01

International and domestic regulatory issues which affect the implementation of a mobile satellite system (MSAT) over North America are addressed. WARC-MOB-87, MSAT frequency co-ordination, frequency sharing and key Canadian domestic issues are discussed.

Implementation of Socioscientific Issues Instruction to Fostering Students’ Decision Making Based Gender on Environmental Pollution

NASA Astrophysics Data System (ADS)

Rizal, H. P.; Siahaan, P.; Yuliani, G.

2017-02-01

The purpose of this study was to investigate the implementation socioscientific issues (SSI) instruction to examine students’ decision making based gender. Selection of environmental problem based on the consideration this issue has potential to evaluate from various scientific disciplines and may initiate to make decision. The participant was students grade VII in South Sulawesi. Pre experiment method was utilized in study with one group pre-test and post-test design. The instrument used in this study comprised of open-ended question, observation sheets for group discussion, sheet for interview and observation sheet of implementation instruction in class. The result indicated that instruction has been implemented successfully. It was found that pre-test and post-test was fostered with N-gain for male and female in medium category. Based on independent t test was found there was no difference improvement of decision making between male and female students. The group showed there was no difference between male group and female group, but a significant difference was noted in mix group. Students and teacher give positive response to the implementation of instruction. It is concluded that science instruction based SSI can be implemented to foster male and female decision making by forming group discussion.

Bacterial cellulose production by Gluconacetobacter sp. PKY5 in a rotary biofilm contactor.

PubMed

Kim, Yong-Jun; Kim, Jin-Nam; Wee, Young-Jung; Park, Don-Hee; Ryu, Hwa-Won

2007-04-01

A rotary biofilm contactor (RBC) inoculated with Gluconacetobacter sp. RKY5 was used as a bioreactor for improved bacterial cellulose production. The optimal number of disk for bacterial cellulose production was found to be eight, at which bacterial cellulose and cell concentrations were 5.52 and 4.98 g/L. When the aeration rate was maintained at 1.25 vvm, bacterial cellulose and cell concentrations were maximized (5.67 and 5.25 g/L, respectively). The optimal rotation speed of impeller in RBC was 15 rpm. When the culture pH in RBC was not controlled during fermentation, the maximal amount of bacterial cellulose (5.53 g/L) and cells (4.91 g/L) was obtained. Under the optimized culture conditions, bacterial cellulose and cell concentrations in RBC reached to 6.17 and 5.58 g/L, respectively.

Synthesis and conformational study of 3,4-carbocyclic bridged indole melatonin and serotonin analogues.

PubMed

Bedini, Annalida; Di Giacomo, Barbara; Gatti, Giuseppe; Spadoni, Gilberto

2005-08-01

Tetrahydrobenz[cd]indole, has been usually assumed to be a rigid scaffold of arylethylamines of pharmaceutical interest, such as melatonin and serotonin. A series of molecules containing this scaffold has been synthesized and their conformation in solution has been determined by 1H NMR. The values of the coupling constants show that the carbocycle fused with the indole ring is a mixture of the two conformers with substituent in equatorial or axial orientation. The molar fraction of the conformers appears to be sensibly affected by the bulkiness of the C-2 indole substituent. A pseudo-axial orientation of the C-3 alkylamido side chain is important for melatonin ligands to access the binding site and exhibit potent in vitro affinity, as illustrated for melatonin ligand 1 (pK(i)=9.32).

25 CFR 275.4 - Implementing regulations.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 25 Indians 1 2011-04-01 2011-04-01 false Implementing regulations. 275.4 Section 275.4 Indians... ACT PROGRAM STAFFING § 275.4 Implementing regulations. Regulations to implement section 105 of the Act will be issued by the Civil Service Commission. The regulations will cover the situations described in...

25 CFR 275.4 - Implementing regulations.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Implementing regulations. 275.4 Section 275.4 Indians... ACT PROGRAM STAFFING § 275.4 Implementing regulations. Regulations to implement section 105 of the Act will be issued by the Civil Service Commission. The regulations will cover the situations described in...

Implementing and Sustaining School Improvement. The Informed Educator Series

ERIC Educational Resources Information Center

Protheroe, Nancy

2011-01-01

This "Informed Educator" examines research-proven strategies for implementing and sustaining school improvement by looking at the key elements of the process, enabling conditions for improvement, issues of school culture, and implementation. It also looks at school turnarounds and how to sustain school improvement once reforms are implemented.

Going digital: a checklist in preparing for hospital-wide electronic medical record implementation and digital transformation.

PubMed

Scott, Ian A; Sullivan, Clair; Staib, Andrew

2018-05-24

Objective In an era of rapid digitisation of Australian hospitals, practical guidance is needed in how to successfully implement electronic medical records (EMRs) as both a technical innovation and a major transformative change in clinical care. The aim of the present study was to develop a checklist that clearly and comprehensively defines the steps that best prepare hospitals for EMR implementation and digital transformation. Methods The checklist was developed using a formal methodological framework comprised of: literature reviews of relevant issues; an interactive workshop involving a multidisciplinary group of digital leads from Queensland hospitals; a draft document based on literature and workshop proceedings; and a review and feedback from senior clinical leads. Results The final checklist comprised 19 questions, 13 related to EMR implementation and six to digital transformation. Questions related to the former included organisational considerations (leadership, governance, change leaders, implementation plan), technical considerations (vendor choice, information technology and project management teams, system and hardware alignment with clinician workflows, interoperability with legacy systems) and training (user training, post-go-live contingency plans, roll-out sequence, staff support at point of care). Questions related to digital transformation included cultural considerations (clinically focused vision statement and communication strategy, readiness for change surveys), management of digital disruption syndromes and plans for further improvement in patient care (post-go-live optimisation of digital system, quality and benefit evaluation, ongoing digital innovation). Conclusion This evidence-based, field-tested checklist provides guidance to hospitals planning EMR implementation and separates readiness for EMR from readiness for digital transformation. What is known about the topic? Many hospitals throughout Australia have implemented, or are planning to implement, hospital wide electronic medical records (EMRs) with varying degrees of functionality. Few hospitals have implemented a complete end-to-end digital system with the ability to bring about major transformation in clinical care. Although the many challenges in implementing EMRs have been well documented, they have not been incorporated into an evidence-based, field-tested checklist that can practically assist hospitals in preparing for EMR implementation as both a technical innovation and a vehicle for major digital transformation of care. What does this paper add? This paper outlines a 19-question checklist that was developed using a formal methodological framework comprising literature review of relevant issues, proceedings from an interactive workshop involving a multidisciplinary group of digital leads from hospitals throughout Queensland, including three hospitals undertaking EMR implementation and one hospital with complete end-to-end EMR, and review of a draft checklist by senior clinical leads within a statewide digital healthcare improvement network. The checklist distinguishes between issues pertaining to EMR as a technical innovation and EMR as a vehicle for digital transformation of patient care. What are the implications for practitioners? Successful implementation of a hospital-wide EMR requires senior managers, clinical leads, information technology teams and project management teams to fully address key operational and strategic issues. Using an issues checklist may help prevent any one issue being inadvertently overlooked or underemphasised in the planning and implementation stages, and ensure the EMR is fully adopted and optimally used by clinician users in an ongoing digital transformation of care.

Strategies for teaching object-oriented concepts with Java

NASA Astrophysics Data System (ADS)

Sicilia, Miguel-Ángel

2006-03-01

A considerable amount of experiences in teaching object-oriented concepts using the Java language have been reported to date, some of which describe language pitfalls and concrete learning difficulties. In this paper, a number of additional issues that have been experienced as difficult for students to master, along with approaches intended to overcome them, are addressed. Concretely, practical issues regarding associations, interfaces, genericity and exceptions are described. These issues suggest that more emphasis is required on presenting Java programs as derivations of conceptual models, in order to guarantee that a thorough design of the object structure actually precedes implementation issues. In addition, common student misunderstandings about the uses of interfaces and exceptions point to the necessity of introducing both specific design philosophies and also a clear distinction between design-for-reuse and more specific implementation issues.

Parallelizing alternating direction implicit solver on GPUs

USDA-ARS?s Scientific Manuscript database

We present a parallel Alternating Direction Implicit (ADI) solver on GPUs. Our implementation significantly improves existing implementations in two aspects. First, we address the scalability issue of existing Parallel Cyclic Reduction (PCR) implementations by eliminating their hardware resource con...

Ethical Issues in Live-Donor Reimbursement Program.

PubMed

Voo, T C; Koh, S; Campbell, A V

2016-04-01

Reimbursement of expenses and costs incurred by live organ donation is permitted in many countries to encourage donation and to protect the welfare of live donors. Potential ethical issues may arise with reimbursement programs and their implementation, which vary across countries. This paper discusses some ethical issues with live donor reimbursement to stimulate discussion on how to ethically enhance its implementation to improve outcomes for both donors and recipients. In addition, we will consider whether reimbursement should be supplemented with compensation for nonfinancial losses, such as pain and suffering, to encourage live donation. Copyright © 2016 Elsevier Inc. All rights reserved.

PURPA 210 avoided cost rates: Economic and implementation issues

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

Devine, M.D.; Chartock, M.A.; Gunn, E.M.

The purpose of Section 210 of the Public Utilities Regulatory Policies Act (PURPA) was to promote the utilization of waste and renewable fuels and cogeneration processes for increasing electric power supplies. It represents a radical change in policy by allowing financially unregulated parties to generate power in ''qualifying facilities'' and by requiring utilities to purchase this power at the utilities' marginal (or ''avoided'') cost. PURPA 210 has clearly had a major impact as measured by the actual and proposed number of new qualifying facilities; however, implementation has been difficult due to the adversarial nature of the process for negotiating ormore » setting the avoided cost rates. This paper reviews the pertinent PURPA rules and regulations, analyzes the status of current avoided cost rates that have been established, and discusses implementation issues and options for resolving those issues.« less

Issues in the digital implementation of control compensators. Ph.D. Thesis

NASA Technical Reports Server (NTRS)

Moroney, P.

1979-01-01

Techniques developed for the finite-precision implementation of digital filters were used, adapted, and extended for digital feedback compensators, with particular emphasis on steady state, linear-quadratic-Gaussian compensators. Topics covered include: (1) the linear-quadratic-Gaussian problem; (2) compensator structures; (3) architectural issues: serialism, parallelism, and pipelining; (4) finite wordlength effects: quantization noise, quantizing the coefficients, and limit cycles; and (5) the optimization of structures.

Strategies to Build Readiness in Community Mobilization Efforts for Implementation in a Multi-Year Teen Pregnancy Prevention Initiative.

PubMed

Bhuiya, Nazmim; House, L Duane; Desmarais, Jeffrey; Fletcher, Erica; Conlin, Maeve; Perez-McAdoo, Sarah; Waggett, Jessica; Tendulkar, Shalini A

2017-03-01

This paper describes an assessment of community readiness to implement a community-wide teen pregnancy prevention initiative, Youth First, and presents strategies used to enhance this readiness as informed by the assessment. Twenty-five community stakeholder interviews were conducted to assess four domains of readiness: (1) attitudes, perception, and knowledge of teen pregnancy; (2) perceived level of readiness; (3) resources, existing and current efforts; and (4) leadership. Interview transcripts were coded and analyzed to identify key themes. Stakeholders acknowledged teen pregnancy as an issue but lacked contextual information. They also perceived the community as ready to address the issue and recognized some organizations already championing efforts. However, many key players were not involved, and ongoing data collection to assess teen pregnancy and prevention efforts was limited. Though many stakeholders were ready to engage in teen pregnancy prevention efforts, they required additional information and training to appropriately address the issue. In response to the assessment findings, several strategies were applied to address readiness and build Youth First partners' capacity to implement the community-wide initiative. Thus, to successfully implement community-wide prevention efforts, it is valuable to assess the level of community readiness to address health issues. Copyright © 2016 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

IPAS Implementation Handbook

ERIC Educational Resources Information Center

Brooks, D. Christopher

2014-01-01

While the use of analytics to promote student success is gaining in popularity, basic questions about what IPAS is and the issues institutions face during implementation and integration. The "IPAS Implementation Handbook" catalogs the experiences, observations, and practical advice from 19 institutions engaged in IPAS implementation…

Programme Implementation in Social and Emotional Learning: Basic Issues and Research Findings

ERIC Educational Resources Information Center

Durlak, Joseph A.

2016-01-01

This paper discusses the fundamental importance of achieving quality implementation when assessing the impact of social and emotional learning interventions. Recent findings in implementation science are reviewed that include a definition of implementation, its relation to programme outcomes, current research on the factors that affect…

Practical Issues in Developing a Culturally Tailored Physical Activity Promotion Program for Chinese and Korean American Midlife Women: A Pilot Study.

PubMed

Chee, Wonshik; Kim, Sangmi; Chu, Tsung-Lan; Tsai, Hsiu-Min; Ji, Xiaopeng; Zhang, Jingwen; Chee, Eunice; Im, Eun-Ok

2016-11-21

With advances in computer technologies, Web-based interventions are widely accepted and welcomed by health care providers and researchers. Although the benefits of Web-based interventions on physical activity promotion have been documented, the programs have rarely targeted Asian Americans, including Asian American midlife women. Subsequently, culturally competent Web-based physical activity programs for Asian Americans may be necessary. The purpose of our study was to explore practical issues in developing and implementing a culturally competent Web-based physical activity promotion program for 2 groups of Asian American women-Chinese American and Korean American midlife women-and to provide implications for future research. While conducting the study, the research team members wrote individual memos on issues and their inferences on plausible reasons for the issues. The team had group discussions each week and kept the minutes of the discussions. Then, the memos and minutes were analyzed using a content analysis method. We identified practical issues in 4 major idea categories: (1) bilingual translators' language orientations, (2) cultural sensitivity requirement, (3) low response rate, interest, and retention, and (4) issues in implementation logistics. Based on the issues, we make several suggestions for the use of bilingual translators, motivational strategies, and implementation logistics. ©Wonshik Chee, Sangmi Kim, Tsung-Lan Chu, Hsiu-Min Tsai, Xiaopeng Ji, Jingwen Zhang, Eunice Chee, Eun-Ok Im. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 21.11.2016.

Ethical issues with colorectal cancer screening-a systematic review.

PubMed

Hofmann, Bjørn

2017-06-01

Colorectal cancer (CRC) screening is widely recommended and implemented. However, sometimes CRC screening is not implemented despite good evidence, and some types of CRC screening are implemented despite lack of evidence. The objective of this article is to expose and elucidate relevant ethical issues in the literature on CRC screening that are important for open and transparent deliberation on CRC screening. An axiological question-based method is used for exposing and elucidating ethical issues relevant in HTA. A literature search in MEDLINE, Embase, PsycINFO, PubMed Bioethics subset, ISI Web of Knowledge, Bioethics Literature Database (BELIT), Ethics in Medicine (ETHMED), SIBIL Base dati di bioetica, LEWI Bibliographic Database on Ethics in the Sciences and Humanities, and EUROETHICS identified 870 references of which 114 were found relevant according to title and abstract. The content of the included papers were subject to ethical analysis to highlight the ethical issues, concerns, and arguments. A wide range of important ethical issues were identified. The main benefits are reduced relative CRC mortality rate, and potentially incidence rate, but there is no evidence of reduced absolute mortality rate. Potential harms are bleeding, perforation, false test results, overdetection, overdiagnosis, overtreatment (including unnecessary removal of polyps), and (rarely) death. Other important issues are related to autonomy and informed choice equity, justice, medicalization, and expanding disease. A series of important ethical issues have been identified and need to be addressed in open and transparent deliberation on CRC screening. © 2016 John Wiley & Sons, Ltd.

Experiences of Agency for Healthcare Research and Quality-funded projects that implemented practices for safer patient care.

PubMed

Taylor, Stephanie L; Ridgely, M Susan; Greenberg, Michael D; Sorbero, Melony E S; Teleki, Stephanie S; Damberg, Cheryl L; Farley, Donna O

2009-04-01

To synthesize lessons learned from the experiences of Agency for Healthcare Research and Quality-funded patient safety projects in implementing safe practices. Self-reported data from individual and group interviews with Original, Challenge, and Partnerships in Implementing Patient Safety (PIPS) grantees, from 2003 to 2006. Interviews with three grantee groups (n=60 total) implementing safe practice projects, with comparisons on factors influencing project implementation and sustainability. Semi-structured protocols contained open-ended questions on lessons learned and more structured questions on factors associated with project implementation and sustainability. The grantees shared common experiences, frequently identifying lessons learned regarding structural components needing to be in place before implementation, components of the implementation process, components of interventions' results needed for sustainability, changes in timelines or activities, unanticipated issues, and staff acceptance/adoption. Also, fewer Original grants had many of the factors related project to implementation/sustainability than the PIPS or Challenge grantees had. Although much of what was reported seemed like common sense, surprisingly few projects actually planned for or expected many of the barriers or facilitators they experienced during their project implementation. Others implementing practice improvements likely will share the experiences and issues identified by these implementation projects and can learn from their lessons.

7 CFR 7.36 - Implementation.

Code of Federal Regulations, 2010 CFR

2010-01-01

... part, the Deputy Administrator, State and County Operations, or the Deputy Administrator, Management, ASCS, is authorized to issue the instructions and procedures referred to herein which implement the...

Issues and Answers about Section 504.

ERIC Educational Resources Information Center

American School and University, 1979

1979-01-01

The first of several installments that address the complex issues and questions related to implementation of the requirement that persons should have equal educational opportunity despite handicap. (Author)

Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice.

PubMed

Cohen, Stacey A; Laurino, Mercy; Bowen, Deborah J; Upton, Melissa P; Pritchard, Colin; Hisama, Fuki; Jarvik, Gail; Fichera, Alessandro; Sjoding, Britta; Bennett, Robin L; Naylor, Lorraine; Jacobson, Angela; Burke, Wylie; Grady, William M

2016-02-01

Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center. A multidisciplinary team developed the new process design. Issues in 5 themes were noted: timing, funding, second-opinion patients, result processing, and the role of genetics providers. A committee approach was used to examine each issue for process-improvement development. The issues related to testing were addressed individually for the successful implementation of UTS at the institutional level. In the conventional-care period, 9 of 30 cases (30%) received Lynch syndrome screening, and 4 cases were referred to medical genetics. During the 6 months following the implementation of UTS, 32 of 44 patients (73%) received Lynch syndrome screening. The 13 unscreened patients all had identified reasons for nonscreening (eg, financial limitations). Ten patients were referred to medical genetics, which identified no new cases of Lynch syndrome, but a low-risk adenomatous polyposis coli (APC) variant was detected in 1 individual. The implementation of effective Lynch syndrome UTS can feasibly alter practice at the institutional level. This experience with the assessment and management of issues relevant to the successful implementation of a new clinical care paradigm based on emerging technology has implications for the uptake of advances across molecular oncology into clinical practice, and this is highly relevant in the current era of rapidly evolving genomic technology. © 2015 American Cancer Society.

Organizational issues in the implementation and adoption of health information technology innovations: an interpretative review.

PubMed

Cresswell, Kathrin; Sheikh, Aziz

2013-05-01

Implementations of health information technologies are notoriously difficult, which is due to a range of inter-related technical, social and organizational factors that need to be considered. In the light of an apparent lack of empirically based integrated accounts surrounding these issues, this interpretative review aims to provide an overview and extract potentially generalizable findings across settings. We conducted a systematic search and critique of the empirical literature published between 1997 and 2010. In doing so, we searched a range of medical databases to identify review papers that related to the implementation and adoption of eHealth applications in organizational settings. We qualitatively synthesized this literature extracting data relating to technologies, contexts, stakeholders, and their inter-relationships. From a total body of 121 systematic reviews, we identified 13 systematic reviews encompassing organizational issues surrounding health information technology implementations. By and large, the evidence indicates that there are a range of technical, social and organizational considerations that need to be deliberated when attempting to ensure that technological innovations are useful for both individuals and organizational processes. However, these dimensions are inter-related, requiring a careful balancing act of strategic implementation decisions in order to ensure that unintended consequences resulting from technology introduction do not pose a threat to patients. Organizational issues surrounding technology implementations in healthcare settings are crucially important, but have as yet not received adequate research attention. This may in part be due to the subjective nature of factors, but also due to a lack of coordinated efforts toward more theoretically-informed work. Our findings may be used as the basis for the development of best practice guidelines in this area. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

75 FR 74045 - Guidance on Planning, Implementing, Maintaining, and Enforcing Institutional Controls at...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-30

..., Implementing, Maintaining, and Enforcing Institutional Controls at Contaminated Sites AGENCY: Environmental... stakeholder input regarding the issues addressed in the EPA interim final guidance, titled Institutional Controls: A Guide to Planning, Implementing, Maintaining, and Enforcing Institutional Controls at...

Strategic environmental noise mapping: methodological issues concerning the implementation of the EU Environmental Noise Directive and their policy implications.

PubMed

Murphy, E; King, E A

2010-04-01

This paper explores methodological issues and policy implications concerning the implementation of the EU Environmental Noise Directive (END) across Member States. Methodologically, the paper focuses on two key thematic issues relevant to the Directive: (1) calculation methods and (2) mapping methods. For (1), the paper focuses, in particular, on how differing calculation methods influence noise prediction results as well as the value of the EU noise indicator L(den) and its associated implications for comparability of noise data across EU states. With regard to (2), emphasis is placed on identifying the issues affecting strategic noise mapping, estimating population exposure, noise action planning and dissemination of noise mapping results to the general public. The implication of these issues for future environmental noise policy is also examined. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Experimentation and evaluation of advanced integrated system concepts

NASA Astrophysics Data System (ADS)

Ross, M.; Garrigus, K.; Gottschalck, J.; Rinearson, L.; Longee, E.

1980-09-01

This final report examines the implementation of a time-phased test bed for experimentation and evaluation of advanced system concepts relative to the future Defense Switched Network (DSN). After identifying issues pertinent to the DSN, a set of experiments which address these issues are developed. Experiments are ordered based on their immediacy and relative importance to DSN development. The set of experiments thus defined allows requirements for a time phased implementation of a test bed to be identified, and several generic test bed architectures which meet these requirements are examined. Specific architecture implementations are costed and cost/schedule profiles are generated as a function of experimental capability. The final recommended system consists of two separate test beds: a circuit switch test bed, configured around an off-the-shelf commercial switch, and directed toward the examination of nearer term and transitional issues raised by the evolving DSN; and a packet/hybrid test bed, featuring a discrete buildup of new hardware and software modules, and directed toward examination of the more advanced integrated voice and data telecommunications issues and concepts.

Ada 9X Project Report: Ada 9X Revision Issues. Release 1

DTIC Science & Technology

1990-04-01

interrupts in Ada. Users are using specialized run-time executives which promote semaphores , monitors , etc ., as well as interrupt support, are using...The focus here is on two specific problems: 1. lack of time-out on operations . 2. no efficient way to program a shared-variable monitor for the... operation . 43 !Issue implementation [3 - Remote Operations for Real-Time Systems ] The real-time implementation standards should define various remote

Employee Involvement. Issues for Agencies To Consider in Designing and Implementing Programs. Report to the Ranking Minority Member, Subcommittee on Federal Services, Post Office, and Civil Service, Committee on Governmental Affairs, U.S. Senate.

ERIC Educational Resources Information Center

General Accounting Office, Washington, DC. General Government Div.

An investigation identified issues that are important for federal agencies to consider in designing and implementing employee involvement programs. Employee involvement programs in the private sector and in the federal government were studied. The use of seven involvement practices was examined: suggestion systems, survey feedback, quality…

Feasibility study of shared-ride auto transit. Final report

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

Kocur, G.; Zaelke, D.; Neumann, L.

1977-09-01

The report examines the feasibility of the implementation of shared-ride auto transit (SRAT), which is an innovative approach for increasing auto occupancy in rural and urban areas. The report focuses on operational concepts, potential usage, legal and regulatory issues, and institutional issues. Formulation of the SRAT concept was motivated by several concerns, such as: (1) energy conservation; (2) transit service to areas unable to economically justify conventional transit services, and to travel disadvantaged groups; (3) transit service replacement to achieve greater efficiency and to reduce transit deficits; (4) provision of inexpensive transit service; and (5) the increase of safety andmore » reliability of hitchhiking. Four case study sites (Boulder, Colorado; Boston, Massachusetts; Portland, Oregon; and Tidewater, Virginia), were used to identify the specific institutional issues likely to impact SRAT implementation for that site, and to identify the opportunities for designing, implementing and operating SRAT in a variety of institutional settings.« less

Pharmaceutical information systems and possible implementations of informed consent -- developing an heuristic.

PubMed

Ploug, Thomas; Holm, Søren

2012-11-16

Denmark has implemented a comprehensive, nationwide pharmaceutical information system, and this system has been evaluated by the Danish Council of Ethics. The system can be seen as an exemplar of a comprehensive health information system for clinical use. The paper analyses 1) how informed consent can be implemented in the system and how different implementations create different impacts on autonomy and control of information, and 2) arguments directed towards justifying not seeking informed consent in this context. Based on the analysis a heuristic is provided which enables a ranking and estimation of the impact on autonomy and control of information of different options for consent to entry of data into the system and use of data from the system.The danger of routinisation of consent is identified.The Danish pharmaceutical information system raises issues in relation to autonomy and control of information, issues that will also occur in relation to other similar comprehensive health information systems. Some of these issues are well understood and their impact can be judged using the heuristic which is provided. More research is, however needed in relation to routinisation of consent.

7 CFR 622.5 - Guidelines.

Code of Federal Regulations, 2010 CFR

2010-01-01

... NEPA (40 CFR parts 1500-1508) issued by the Council on Environmental Quality, and in Economic and Environmental Principles and Guidelines for Water and Related Land Resources Implementation Studies issued by...

Information Issues and Contexts that Impair Team Based Communication Workflow: A Palliative Sedation Case Study.

PubMed

Cornett, Alex; Kuziemsky, Craig

2015-01-01

Implementing team based workflows can be complex because of the scope of providers involved and the extent of information exchange and communication that needs to occur. While a workflow may represent the ideal structure of communication that needs to occur, information issues and contextual factors may impact how the workflow is implemented in practice. Understanding these issues will help us better design systems to support team based workflows. In this paper we use a case study of palliative sedation therapy (PST) to model a PST workflow and then use it to identify purposes of communication, information issues and contextual factors that impact them. We then suggest how our findings could inform health information technology (HIT) design to support team based communication workflows.

Distributed numerical controllers

NASA Astrophysics Data System (ADS)

Orban, Peter E.

2001-12-01

While the basic principles of Numerical Controllers (NC) have not changed much during the years, the implementation of NCs' has changed tremendously. NC equipment has evolved from yesterday's hard-wired specialty control apparatus to today's graphics intensive, networked, increasingly PC based open systems, controlling a wide variety of industrial equipment with positioning needs. One of the newest trends in NC technology is the distributed implementation of the controllers. Distributed implementation promises to offer robustness, lower implementation costs, and a scalable architecture. Historically partitioning has been done along the hierarchical levels, moving individual modules into self contained units. The paper discusses various NC architectures, the underlying technology for distributed implementation, and relevant design issues. First the functional requirements of individual NC modules are analyzed. Module functionality, cycle times, and data requirements are examined. Next the infrastructure for distributed node implementation is reviewed. Various communication protocols and distributed real-time operating system issues are investigated and compared. Finally, a different, vertical system partitioning, offering true scalability and reconfigurability is presented.

48 CFR 47.403 - Guidelines for implementation of the Fly America Act.

Code of Federal Regulations, 2014 CFR

2014-10-01

... implementation of the Fly America Act. 47.403 Section 47.403 Federal Acquisition Regulations System FEDERAL... Guidelines for implementation of the Fly America Act. This section 47.403 is based on the Guidelines for Implementation of the Fly America Act (case number B-138942), issued by the Comptroller General of the United...

48 CFR 47.403 - Guidelines for implementation of the Fly America Act.

Code of Federal Regulations, 2011 CFR

2011-10-01

... implementation of the Fly America Act. 47.403 Section 47.403 Federal Acquisition Regulations System FEDERAL... Guidelines for implementation of the Fly America Act. This section 47.403 is based on the Guidelines for Implementation of the Fly America Act (case number B-138942), issued by the Comptroller General of the United...

48 CFR 47.403 - Guidelines for implementation of the Fly America Act.

Code of Federal Regulations, 2012 CFR

2012-10-01

... implementation of the Fly America Act. 47.403 Section 47.403 Federal Acquisition Regulations System FEDERAL... Guidelines for implementation of the Fly America Act. This section 47.403 is based on the Guidelines for Implementation of the Fly America Act (case number B-138942), issued by the Comptroller General of the United...

48 CFR 47.403 - Guidelines for implementation of the Fly America Act.

Code of Federal Regulations, 2013 CFR

2013-10-01

... implementation of the Fly America Act. 47.403 Section 47.403 Federal Acquisition Regulations System FEDERAL... Guidelines for implementation of the Fly America Act. This section 47.403 is based on the Guidelines for Implementation of the Fly America Act (case number B-138942), issued by the Comptroller General of the United...

Understanding and avoiding potential problems in implementing automation

NASA Astrophysics Data System (ADS)

Rouse, W. B.; Morris, N. M.

1985-11-01

Technology-driven efforts to implement automation often encounter problems due to lack of acceptance or begrudging acceptance by the personnel involved. It is argued in this paper that the level of automation perceived by an individual heavily influences whether or not the automation is accepted by that individual. The factors that appear to affect perceived level of automation are discussed. Issues considered include the impact of automation on the system and the individual, correlates of acceptance, problems and risks of automation, and factors influencing alienation. Based on an understanding of these issues, a set of eight guidelines is proposed as a possible means of avoiding problems in implementing automation.

Understanding and avoiding potential problems in implementing automation

NASA Technical Reports Server (NTRS)

Rouse, W. B.; Morris, N. M.

1985-01-01

Technology-driven efforts to implement automation often encounter problems due to lack of acceptance or begrudging acceptance by the personnel involved. It is argued in this paper that the level of automation perceived by an individual heavily influences whether or not the automation is accepted by that individual. The factors that appear to affect perceived level of automation are discussed. Issues considered include the impact of automation on the system and the individual, correlates of acceptance, problems and risks of automation, and factors influencing alienation. Based on an understanding of these issues, a set of eight guidelines is proposed as a possible means of avoiding problems in implementing automation.

The Efficacy of Psychophysiological Measures for Implementing Adaptive Technology

NASA Technical Reports Server (NTRS)

Scerbo, Mark W.; Freeman, Frederick G.; Mikulka, Peter J.; Parasuraman, Raja; DiNocero, Francesco; Prinzel, Lawrence J., III

2001-01-01

Adaptive automation refers to technology that can change its mode of operation dynamically. Further, both the technology and the operator can initiate changes in the level or mode of automation. The present paper reviews research on adaptive technology. It is divided into three primary sections. In the first section, issues surrounding the development and implementation of adaptive automation are presented. Because physiological-based measures show much promise for implementing adaptive automation, the second section is devoted to examining candidate indices. In the final section, those techniques that show the greatest promise for adaptive automation as well as issues that still need to be resolved are discussed.

Issues in providing a reliable multicast facility

NASA Technical Reports Server (NTRS)

Dempsey, Bert J.; Strayer, W. Timothy; Weaver, Alfred C.

1990-01-01

Issues involved in point-to-multipoint communication are presented and the literature for proposed solutions and approaches surveyed. Particular attention is focused on the ideas and implementations that align with the requirements of the environment of interest. The attributes of multicast receiver groups that might lead to useful classifications, what the functionality of a management scheme should be, and how the group management module can be implemented are examined. The services that multicasting facilities can offer are presented, followed by mechanisms within the communications protocol that implements these services. The metrics of interest when evaluating a reliable multicast facility are identified and applied to four transport layer protocols that incorporate reliable multicast.

A Teacher Professional Development Model for Teaching Socioscientific Issues

ERIC Educational Resources Information Center

Carson, Katherine; Dawson, Vaille

2016-01-01

This paper describes the development and implementation of a three-pillared model for teaching socioscientific issues: teacher professional development; curriculum resources; and classroom support. A professional development program and curriculum resource based on the socioscientific issue of climate change was trialled with 75 Western Australian…

32 CFR 199.1 - General provisions.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., management control and coordination as required for CHAMPUS, and to develop, issue, and maintain regulations..., to consult with the Secretary of Defense or a designee and to approve and issue joint regulations... an issue joint regulations implementing 10 U.S.C., chapter 55. (iv) Office of CHAMPUS (OCHAMPUS). By...

32 CFR 199.1 - General provisions.

Code of Federal Regulations, 2012 CFR

2012-07-01

..., management control and coordination as required for CHAMPUS, and to develop, issue, and maintain regulations..., to consult with the Secretary of Defense or a designee and to approve and issue joint regulations... an issue joint regulations implementing 10 U.S.C., chapter 55. (iv) Office of CHAMPUS (OCHAMPUS). By...

32 CFR 199.1 - General provisions.

Code of Federal Regulations, 2013 CFR

2013-07-01

..., management control and coordination as required for CHAMPUS, and to develop, issue, and maintain regulations..., to consult with the Secretary of Defense or a designee and to approve and issue joint regulations... an issue joint regulations implementing 10 U.S.C., chapter 55. (iv) Office of CHAMPUS (OCHAMPUS). By...

Planning for the Global Earth Observation System of Systems (GEOSS)

USGS Publications Warehouse

Christian, E.

2005-01-01

The Group on Earth Observations was established to promote comprehensive, coordinated, and sustained Earth observations. Its mandate is to implement the Global Earth Observation System of Systems (GEOSS) in accord with the GEOSS 10-Year Implementation Plan and Reference Document. During the months over which the GEOSS Implementation Plan was developed, many issues surfaced and were addressed. This article discusses several of the more interesting or challenging of those issues-e.g. fitting in with existing organizations and securing stable funding - some of which have yet to be resolved fully as of this writing. Despite the relatively short period over which the Implementation Plan had to be developed, there is a good chance that the work undertaken will be influential for decades to come. ?? 2005 Elsevier Ltd. All rights reserved.

Development of an existential support training program for healthcare professionals.

PubMed

Henoch, Ingela; Strang, Susann; Browall, Maria; Danielson, Ella; Melin-Johansson, Christina

2015-12-01

Our aim was to describe the developmental process of a training program for nurses to communicate existential issues with severely ill patients. The Medical Research Council (MRC) framework for the development and evaluation of complex interventions was used to develop a training program for nurses to communicate about existential issues with their patients. The steps in the framework were employed to describe the development of the training intervention, and the development, feasibility and piloting, evaluation, and implementation phases. The development and feasibility phases are described in the Methods section. The evaluation and implementation phases are described in the Results section. In the evaluation phase, the effectiveness of the intervention was shown as nurses' confidence in communication increased after training. The understanding of the change process was considered to be that the nurses could describe their way of communicating in terms of prerequisites, process, and content. Some efforts have been made to implement the training intervention, but these require further elaboration. Existential and spiritual issues are very important to severely ill patients, and healthcare professionals need to be attentive to such questions. It is important that professionals be properly prepared when patients need this communication. An evidence-based training intervention could provide such preparation. Healthcare staff were able to identify situations where existential issues were apparent, and they reported that their confidence in communication about existential issues increased after attending a short-term training program that included reflection. In order to design a program that should be permanently implemented, more knowledge is needed of patients' perceptions of the quality of the healthcare staff's existential support.

Critical Issues in Language and Education Planning in Twenty First Century in South Africa

ERIC Educational Resources Information Center

Brook Napier, Diane

2011-01-01

Language and education planning issues and democratic policy implementation in the post-apartheid era in South Africa encompass a range of language-related issues and dilemmas that have counterparts in many countries, within the emerging global education system. The issues in South Africa were and continue to be shaped by the historical legacy of…

Implementation of the NCSS Guidelines for Teaching Science-Related Social Issues: Exemplar Lessons.

ERIC Educational Resources Information Center

Otto, Robert A., Ed.

This document contains the Guidelines for Teaching Science-Related Social Issues adopted in 1982 by the National Council for the Social Studies and 10 examplar lessons each keyed to particular guidelines and drawing upon contemporary issues. The premise upon which the guidelines are based is that science is a social issue and that the examination…

Supports and Concerns for Teacher Professional Growth During the Implementation of a Science Curriculum Innovation

NASA Astrophysics Data System (ADS)

Peers, Cheryl (Shelley) E.; Diezmann, Carmel M.; Watters, James J.

2003-02-01

Internationally, considerable reform in science education is occurring which promotes constructivist philosophies and advocates constructivist-inspired pedagogical strategies that are new to many teachers. This paper reports on the supporting factors necessary for teacher professional growth and the issues of concern that were evident during one primary teacher''s successful implementation of a unit of work based on a draft of a new state-wide science syllabus which proposes such approaches. One researcher (CEP) provided guidance during the writing and implementation of the unit through professional development workshops complemented by ongoing collegial support. The analysis of the teacher''s practice reveals that professional growth required a willingness of the teacher to engage with change and modify his professional practice. The support factors for teacher growth consisted of an appropriate program of professional development, teacher understanding of the elements of the curriculum innovation, and successful experiences in implementing new approaches. In contrast, the issues of concern were: the adequacy of support for planning including the time required to understand the innovation and make changes to teaching practice; science equipment; teacher knowledge; classroom management strategies; and ways to cope with change. Understanding of these support factors and issues of concern is vital for the successful implementation of science curriculum innovations.

Photochemical Phenomenology Model for the New Millennium

NASA Technical Reports Server (NTRS)

Bishop, James; Evans, J. Scott

2001-01-01

The "Photochemical Phenomenology Model for the New Millennium" project tackles the issue of reengineering and extension of validated physics-based modeling capabilities ("legacy" computer codes) to application-oriented software for use in science and science-support activities. While the design and architecture layouts are in terms of general particle distributions involved in scattering, impact, and reactive interactions, initial Photochemical Phenomenology Modeling Tool (PPMT) implementations are aimed at construction and evaluation of photochemical transport models with rapid execution for use in remote sensing data analysis activities in distributed systems. Current focus is on the Composite Infrared Spectrometer (CIRS) data acquired during the CASSINI flyby of Jupiter. Overall, the project has stayed on the development track outlined in the Year 1 annual report and most Year 2 goals have been met. The issues that have required the most attention are: implementation of the core photochemistry algorithms; implementation of a functional Java Graphical User Interface; completion of a functional CORBA Component Model framework; and assessment of performance issues. Specific accomplishments and the difficulties encountered are summarized in this report. Work to be carried out in the next year center on: completion of testing of the initial operational implementation; its application to analysis of the CASSINI/CIRS Jovian flyby data; extension of the PPMT to incorporate additional phenomenology algorithms; and delivery of a mature operational implementation.

Accuracy and time requirements of a bar-code inventory system for medical supplies.

PubMed

Hanson, L B; Weinswig, M H; De Muth, J E

1988-02-01

The effects of implementing a bar-code system for issuing medical supplies to nursing units at a university teaching hospital were evaluated. Data on the time required to issue medical supplies to three nursing units at a 480-bed, tertiary-care teaching hospital were collected (1) before the bar-code system was implemented (i.e., when the manual system was in use), (2) one month after implementation, and (3) four months after implementation. At the same times, the accuracy of the central supply perpetual inventory was monitored using 15 selected items. One-way analysis of variance tests were done to determine any significant differences between the bar-code and manual systems. Using the bar-code system took longer than using the manual system because of a significant difference in the time required for order entry into the computer. Multiple-use requirements of the central supply computer system made entering bar-code data a much slower process. There was, however, a significant improvement in the accuracy of the perpetual inventory. Using the bar-code system for issuing medical supplies to the nursing units takes longer than using the manual system. However, the accuracy of the perpetual inventory was significantly improved with the implementation of the bar-code system.

Evaluation of physical activity interventions in youth via the Reach, Efficacy/Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework: A systematic review of randomised and non-randomised trials.

PubMed

McGoey, Tara; Root, Zach; Bruner, Mark W; Law, Barbi

2015-07-01

An identified limitation of existing reviews of physical activity interventions in school-aged youth is the lack of reporting on issues related to the translatability of the research into health promotion practice. This review used the Reach, Efficacy/Effectiveness, Adoption, Implementation and Maintenance framework to determine the extent to which intervention studies promoting physical activity in youth report on factors that inform generalizability across settings and populations. A systematic search for controlled interventions conducted within the last ten years identified 50 studies that met the selection criteria. Based on Reach, Efficacy/Effectiveness, Adoption, Implementation and Maintenance criteria, most of these studies focused on statistically significant findings and internal validity rather than on issues of external validity. Due to this lack of information, it is difficult to determine whether or not reportedly successful interventions are feasible and sustainable in an uncontrolled, real-world setting. Areas requiring further research include costs associated with recruitment and implementation, adoption rate, and representativeness of participants and settings. This review adds data to support recommendations that interventions promoting physical activity in youth should include assessment of adoption and implementation issues. Copyright © 2015 Elsevier Inc. All rights reserved.

Strategy development for the implementation of telenursing in Korea.

PubMed

Yun, Eun Kyoung; Park, Hyeoun-Ae

2007-01-01

This study aimed to evaluate the feasibility of telenursing, to analyze the issues that should be considered for the development of telenursing in the future, and to provide efficient strategies for the implementation of telenursing in Korea. The authors used the Delphi survey method and a strengths, weaknesses, opportunities, and threats analysis. A total of 30 experts and specialists in the field of nursing informatics and telemedicine contributed to a three-round Delphi survey. The results of the study suggest that telenursing can potentially be implemented in Korea. However, to implement telenursing in Korea, it is necessary to identify telenursing specialties, to construct an infrastructure within which telenursing can function, to develop a business model, and to integrate strategies with government plans to develop the e-health industry. The issues that emerged as important requirements for the successful introduction of telenursing were classified as systematic, economic, societal, or technical. Issues such as driving force, target market, and expense sharing were examined in detail from both ideal and realistic points of view. The results of this study will enable health professionals to appreciate the feasibility of implementing telenursing in Korea. In addition, the study suggests that telenursing could be used efficiently in a variety of environments as a practical strategy to improve healthcare in Korea.

Isoform-specific PKA dynamics revealed by dye-triggered aggregation and DAKAP1alpha-mediated localization in living cells.

PubMed

Martin, Brent R; Deerinck, Thomas J; Ellisman, Mark H; Taylor, Susan S; Tsien, Roger Y

2007-09-01

The tetracysteine sequence YRECCPGCCMWR fused to the N terminus of green fluorescent protein (GFP) self-aggregates upon biarsenical labeling in living cells or in vitro. Such dye-triggered aggregates form temperature-dependent morphologies and are dispersed by photobleaching. Fusion of the biarsenical aggregating GFP to the regulatory (R) or catalytic (C) subunit of PKA traps intact holoenzyme in compact fluorescent puncta upon biarsenical labeling. Contrary to the classical model of PKA activation, elevated cAMP does not allow RIalpha and Calpha to diffuse far apart unless the pseudosubstrate inhibitor PKI or locally concentrated substrate is coexpressed. However, RIIalpha releases Calpha upon elevated cAMP alone, dependent on autophosphorylation of the RIIalpha inhibitory domain. DAKAP1alpha overexpression induced R and C outer mitochondrial colocalization and showed similar regulation. Overall, effective separation of type I PKA is substrate dependent, whereas type II PKA dissociation relies on autophosphorylation.

A novel expression system for intracellular production and purification of recombinant affinity-tagged proteins in Aspergillus niger.

PubMed

Roth, Andreas H F J; Dersch, Petra

2010-03-01

A set of different integrative expression vectors for the intracellular production of recombinant proteins with or without affinity tag in Aspergillus niger was developed. Target genes can be expressed under the control of the highly efficient, constitutive pkiA promoter or the novel sucrose-inducible promoter of the beta-fructofuranosidase (sucA) gene of A. niger in the presence or absence of alternative carbon sources. All expression plasmids contain an identical multiple cloning sequence that allows parallel construction of N- or C-terminally His6- and StrepII-tagged versions of the target proteins. Production of two heterologous model proteins, the green fluorescence protein and the Thermobifida fusca hydrolase, proved the functionality of the vector system. Efficient production and easy detection of the target proteins as well as their fast purification by a one-step affinity chromatography, using the His6- or StrepII-tag sequence, was demonstrated.

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

NASA Astrophysics Data System (ADS)

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.

Kinetics of acrylodan-labelled cAMP-dependent protein kinase catalytic subunit denaturation.

PubMed

Kivi, Rait; Loog, Mart; Jemth, Per; Järv, Jaak

2013-10-01

Fluorescence spectroscopy was used to study denaturation of cAMP-dependent protein kinase catalytic subunit labeled with an acrylodan moiety. The dye was covalently bound to a cystein residue introduced into the enzyme by replacement of arginine in position 326 in the native sequence, located near the enzyme active center. This labeling had no effect on catalytic activity of the enzyme, but provided possibility to monitor changes in protein structure through measuring the fluorescence spectrum of the dye, which is sensitive to changes in its environment. This method was used to monitor denaturation of the protein kinase catalytic subunit and study the kinetics of this process as well as influence of specific ligands on stability of the protein. Stabilization of the enzyme structure was observed in the presence of adenosine triphosphate, peptide substrate RRYSV and inhibitor peptide PKI[5-24].

ESnet authentication services and trust federations

NASA Astrophysics Data System (ADS)

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).

Regional Variations in the Earth's upper inner core

NASA Astrophysics Data System (ADS)

Stroujkova, A.; Cormier, V. F.

2003-12-01

Strong regional variations in seismic velocity and attenuation have been observed in the uppermost layer of the inner core. Different studies suggest hemispherical differences within this transitional layer, with eastern hemisphere faster than the western (e.g. Garcia, 2002; Wen and Niu, 2002). The scale and the depth dependence of the heterogeneities are still in debate. In order to systematically study smaller scale heterogeneities we selected a data set of PKIKP and PKiKP phases with epicentral distances between 120\\deg and 140\\deg. The upper layer of the inner core was divided into `bins' and the seismograms were gathered into these bins according to the ray turning points. After correcting for source, site and propagation effects we stacked traces with close epicentral distance within each bin to improve signal-to-noise ratio. Finally we performed full 3D modeling of the obtained waveforms.

Report: EPA Has Not Fully Implemented a National Emergency Response Equipment Tracking System

EPA Pesticide Factsheets

Report #11-P-0616, September 13, 2011. Although EPA spent $2.8 million as of October 2010 to develop and implement an EMP emergency equipment tracking module, EPA has not fully implemented the module, and the module suffers from operational issues.

Issues and Answers about Section 504: Part 2.

ERIC Educational Resources Information Center

American School and University, 1979

1979-01-01

The second of several installments that address the complex issues and questions related to the implementation of the requirement that persons should have equal educational opportunity despite handicaps. (Author/MLF)

Contemporary Issues in Science. Implementation Manual.

ERIC Educational Resources Information Center

Staten Island Continuum of Education, NY.

Contemporary Issues in Science Program (CIIS) is designed to provide teachers and students with the necessary tools and strategies for bringing contemporary scientific issues into the classroom. Provided in this document are discussions of the three major elements in the program, support elements, and major activities. Major elements include the…

Job-Sharing: A Survey of the Literature and a Plan for Academic Libraries.

ERIC Educational Resources Information Center

Bobay, Julie

1988-01-01

Discusses the social context of job sharing, reported benefits and disadvantages, and general issues that affect the successful implementation of job sharing programs. Issues specifically affecting job sharing in academic libraries are outlined, and methods for dealing with these issues are suggested. (15 references) (CLB)

The Distance Education Evolution: Issues and Case Studies

ERIC Educational Resources Information Center

Monolescu, Dominique; Schifter, Catherine; Greenwood, Linda

2004-01-01

"The Distance Education Evolution: Case Studies" addresses issues regarding the development and design of online courses, and the implementation and evaluation of an online learning program. Several chapters include design strategies for online courses that range from the specific to the universal. Many authors address pedagogical issues from both…

Science Teachers Taking their First Steps toward Teaching Socioscientific Issues through Collaborative Action Research

NASA Astrophysics Data System (ADS)

Lee, Hyunju; Yang, Jung-eun

2017-06-01

This study presents two science teachers, Catherine and Jennifer, who took their first steps toward teaching socioscientific issues through collaborative action research. The teachers participated in the collaborative action research project because they wanted to address socioscientific issues but had limited experience in teaching them. The research questions included what kinds of challenges the teachers encountered when implementing socioscientific issues and to what extent they resolved the challenging issues as participating in collaborative action research. The primary data source consisted of audiotapes of regular group meetings containing information on the process of constructing and implementing lesson plans and reflecting on their teaching of socioscientific issues. We also collected classroom videotapes of the teachers' instruction and audiotapes of students' small group discussions and their worksheets. The findings indicated that when addressing socioscientific issues in the classes, the teachers encountered several challenging issues. We categorized them into four: (1) restructuring classroom dynamics and culture, (2) scaffolding students' engagement in socioscientific issues, (3) dealing with values, and (4) finding their niche in schools. However, this study showed that collaborative action research could be a framework for helping the teachers to overcome such challenges and have successful experiences of teaching socioscientific issues. These experiences became good motivation, to gradually develop their understanding of teaching socioscientific issues and instructional strategies for integrating the knowledge and skills that they had accumulated over the years.

Issues for Universities Working with K-12 Institutions Implementing Prepackaged Pre-Engineering Curricula Such as Project Lead the Way

ERIC Educational Resources Information Center

Reid, Kenneth J.; Feldhaus, Charles R.

2007-01-01

The implementation of pre-engineering, standard curricula in K-12 schools is growing at a rapid pace. One such curriculum model, Project Lead the Way, consists of six standardized courses requiring significant training for teachers, specified laboratory equipment, standard topics, exams, etc. Schools implementing Project Lead the Way implement an…

Pharmacist Staffing, Technology Use, and Implementation of Medication Safety Practices in Rural Hospitals

ERIC Educational Resources Information Center

Casey, Michelle M.; Moscovice, Ira S.; Davidson, Gestur

2006-01-01

Context: Medication safety is clearly an important quality issue for rural hospitals. However, rural hospitals face special challenges implementing medication safety practices in terms of their staffing and financial and technical resources. Purpose: This study assessed the capacity of small rural hospitals to implement medication safety…

78 FR 5860 - Eighth Meeting: RTCA Next Gen Advisory Committee (NAC)

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-28

...] Preliminary report to identify and mitigate barriers to implementing PBN. Issues associated with Implementing RNAV/RNP [cir] An open discussion by the Committee of Non-technical barriers of PBN procedures... NextGen. Cat Ex 2 Task Group [cir] Preliminary report on the recommendation for implementing new...

75 FR 67450 - Pipeline Safety: Control Room Management Implementation Workshop

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-02

... PHMSA-2010-0294] Pipeline Safety: Control Room Management Implementation Workshop AGENCY: Pipeline and...) on the implementation of pipeline control room management. The workshop is intended to foster an understanding of the Control Room Management Rule issued by PHMSA on December 3, 2009, and is open to the public...

Implementation Challenges for a Constructivist Physical Education Curriculum

ERIC Educational Resources Information Center

Zhu, Xihe; Ennis, Catherine D.; Chen, Ang

2011-01-01

Background: Curriculum fidelity describes the extent to which a curriculum is implemented faithfully as planned. Curriculum fidelity issues may arise when teachers implement the curriculum inconsistently due to differences in philosophy, barriers in the setting, or other local concerns. Purpose: The study examined challenges that a teacher faced…

Controversial Issues within Biology: Enriching Biology Teaching.

ERIC Educational Resources Information Center

Van Rooy, Wilhelmina

2000-01-01

Describes the development and implementation of a senior high school biology lesson concerned with organ transplantation. Discusses the teacher's rationale and techniques for using controversial issues in science teaching. (Contains 18 references.) (Author/WRM)

An interagency space nuclear propulsion safety policy for SEI - Issues and discussion

NASA Technical Reports Server (NTRS)

Marshall, A. C.; Sawyer, J. C., Jr.

1991-01-01

An interagency Nuclear Safety Policy Working Group (NSPWG) was chartered to recommend nuclear safety policy, requirements, and guidelines for the Space Exploration Initiative nuclear propulsion program to facilitate the implementation of mission planning and conceptual design studies. The NSPWG developed a top level policy to provide the guiding principles for the development and implementation of the nuclear propulsion safety program and the development of Safety Functional Requirements. In addition, the NSPWG reviewed safety issues for nuclear propulsion and recommended top level safety requirements and guidelines to address these issues. Safety topics include reactor start-up, inadvertent criticality, radiological release and exposure, disposal, entry, safeguards, risk/reliability, operational safety, ground testing, and other considerations. In this paper the emphasis is placed on the safety policy and the issues and considerations that are addressed by the NSPWG recommendations.

Secure environment for real-time tele-collaboration on virtual simulation of radiation treatment planning.

PubMed

Ntasis, Efthymios; Maniatis, Theofanis A; Nikita, Konstantina S

2003-01-01

A secure framework is described for real-time tele-collaboration on Virtual Simulation procedure of Radiation Treatment Planning. An integrated approach is followed clustering the security issues faced by the system into organizational issues, security issues over the LAN and security issues over the LAN-to-LAN connection. The design and the implementation of the security services are performed according to the identified security requirements, along with the need for real time communication between the collaborating health care professionals. A detailed description of the implementation is given, presenting a solution, which can directly be tailored to other tele-collaboration services in the field of health care. The pilot study of the proposed security components proves the feasibility of the secure environment, and the consistency with the high performance demands of the application.

Technology and Policy Challenges in the Adoption and Operation of Health Information Exchange Systems.

PubMed

Ji, Hyerim; Yoo, Sooyoung; Heo, Eun-Young; Hwang, Hee; Kim, Jeong-Whun

2017-10-01

This study aimed to identify problems and issues that arise with the implementation of online health information exchange (HIE) systems in a medical environment and to identify solutions to facilitate the successful operation of future HIE systems in primary care clinics and hospitals. In this study, the issues that arose during the establishment and operation of an HIE system in a hospital were identified so that they could be addressed to enable the successful establishment and operation of a standard-based HIE system. After the issues were identified, they were reviewed and categorized by a group of experts that included medical information system experts, doctors, medical information standard experts, and HIE researchers. Then, solutions for the identified problems were derived based on the system development, operation, and improvement carried out during this work. Twenty-one issues were identified during the implementation and operation of an online HIE system. These issues were then divided into four categories: system architecture and standards, documents and data items, consent of HIE, and usability. We offer technical and policy recommendations for various stakeholders based on the experiences of operating and improving the online HIE system in the medical field. The issues and solutions identified in this study regarding the implementation and operate of an online HIE system can provide valuable insight for planners to enable them to successfully design and operate such systems at a national level in the future. In addition, policy support from governments is needed.

Impact and desirability of taxing unmined coal interests in the same manner as other real property

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

Vasek, S.J. Jr.

1986-01-01

A brief summary of Kentucky's property taxes and the historical development of the state's unmined minerals taxes leads into a discussion of the implementation issues now being tested in the courts, such as valuation, the effects of the Broad Form Deed Act, and the impact on farms and minerals other than coal. An assessment of the economic impact of the tax on taxpayers and on state revenues concludes that prior scholarly attempts to estimate economic impact have erred because they failed to consider the implementation issues. These issues involve value choices about who should bear the economic burden and whenmore » that burden should take place.« less

Implementing the chemical weapons convention: The nuts and bolts of compliance

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

Tanzman, E.A.

This paper is a presentation prepared for the American Bar Association in which the author discusses the issue of rights to privacy in the United States in the face of implementing the Chemical Weapons Convention inspections. The author points out that there are no clear precedents in law which deal with all the issues which will result from international inspections for verification which are required by the treaty. In particular as inspections tread on the issue of personal rights or private property there is a fairly ill defined legal area which needs to be developed to allow such inspections inmore » the face of constitutional guarantees.« less

75 FR 68911 - Regulations Under the Genetic Information Nondiscrimination Act of 2008

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-09

...The Equal Employment Opportunity Commission (``EEOC'' or ``Commission'') is issuing a final rule to implement Title II of the Genetic Information Nondiscrimination Act of 2008 (``GINA''). Congress enacted Title II of GINA to protect job applicants, current and former employees, labor union members, and apprentices and trainees from discrimination based on their genetic information. Title II of GINA requires the EEOC to issue implementing regulations. The Commission issued a proposed rule in the Federal Register on March 2, 2009, for a sixty-day notice and comment period that ended on May 1, 2009. After consideration of the public comments, the Commission has revised portions of both the final rule and the preamble.

Building a COTS archive for satellite data

NASA Technical Reports Server (NTRS)

Singer, Ken; Terril, Dave; Kelly, Jack; Nichols, Cathy

1994-01-01

The goal of the NOAA/NESDIS Active Archive was to provide a method of access to an online archive of satellite data. The archive had to manage and store the data, let users interrogate the archive, and allow users to retrieve data from the archive. Practical issues of the system design such as implementation time, cost and operational support were examined in addition to the technical issues. There was a fixed window of opportunity to create an operational system, along with budget and staffing constraints. Therefore, the technical solution had to be designed and implemented subject to constraint imposed by the practical issues. The NOAA/NESDIS Active Archive came online in July of 1994, meeting all of its original objectives.

Implementing the Equal Access Act and State Constitutional Provisions.

ERIC Educational Resources Information Center

Bjorklun, Eugene C.

1992-01-01

Examines the issue of whether implementation of the Equal Access Act would violate the constitutions of some states that require a stricter separation of church and state than the federal Constitution. (MLF)

Context awareness and sensitivity in SEA implementation

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

Hilding-Rydevik, Tuija; Bjarnadottir, Holmfridur

2007-10-15

The Impact Assessment research community repeatedly asserts that the implementation of Strategic Environmental Assessment (SEA) should take the issue of context into consideration. The primary aim of this paper then is to attempt to give substance to the concept of 'context' in relation to the implementation of SEA. The second aim is to discuss the relevance of context consciousness and sensitivity in relation to one of the main aims given to SEA implementation i.e. to contribute to the 'integration' of environmental perspectives in planning processes. Context must be defined in relation to a certain question. In this paper the questionmore » in focus is the assumption that SEA implementation will contribute to integration of environmental issues in planning processes. Research results relating to the use of environmental tools, like for example SEA, and experiences of integration efforts, strongly indicate that the use of a single tool like SEA is not enough to achieve this integration. The current 'context free' normative and procedural assumptions concerning the aim of SEA implementation and 'best practice' in term of SEA can be criticised on the same grounds as normative and procedural planning theories, as being context free. The assumptions behind the current formulations of the aim and best practice of SEA need to be revisited. A firm empirical and theoretical knowledge and discussion is needed, especially in relation to the issue of context and integration. This paper provides a starting point in this direction.« less

Ada issues in implementing ART-Ada

NASA Technical Reports Server (NTRS)

Lee, S. Daniel

1990-01-01

Due to the Ada mandate of a number of government agencies, interest in deploying expert systems such as Ada has increased. Recently, several Ada-based expert system tools have been developed. According to a recent benchmark report, these tools do not perform as well as similar tools written in C. While poorly implemented Ada compilers contribute to the poor benchmark result, some fundamental problems of the Ada language itself have been uncovered. Here, the authors describe Ada language issues encountered during the deployment of ART-Ada, an expert system tool for Ada deployment. ART-Ada is being used to implement several prototype expert systems for the Space Station Freedom and the U.S. Air Force.

Environmental concept for engineering software on MIMD computers

NASA Technical Reports Server (NTRS)

Lopez, L. A.; Valimohamed, K.

1989-01-01

The issues related to developing an environment in which engineering systems can be implemented on MIMD machines are discussed. The problem is presented in terms of implementing the finite element method under such an environment. However, neither the concepts nor the prototype implementation environment are limited to this application. The topics discussed include: the ability to schedule and synchronize tasks efficiently; granularity of tasks; load balancing; and the use of a high level language to specify parallel constructs, manage data, and achieve portability. The objective of developing a virtual machine concept which incorporates solutions to the above issues leads to a design that can be mapped onto loosely coupled, tightly coupled, and hybrid systems.

Pre-implementation guidelines for infectious disease point-of-care testing in medical institutions.

PubMed

van der Eijk, Annemiek A; Tintu, Andrei N; Hays, John P

2017-01-01

Infectious disease point-of-care test (ID-POCT) devices are becoming widely available, and in this respect, international quality standards and guidelines are available for consultation once ID-POCT has been implemented into medical institutions. However, specific guidelines for consultation during the initial pre-implementation decision-making process are currently lacking. Further, there exist pre-implementation issues specific to ID-POCT. Here we present pre-implementation guidelines for consultation when considering the implementation of ID-POCT in medical institutions.

Minimum Standards for Tribal Child Care Centers.

ERIC Educational Resources Information Center

Administration on Children, Youth, and Families (DHHS), Washington, DC. Child Care Bureau.

These minimum standards for tribal child care centers are being issued as guidance. An interim period of at least 1 year will allow tribal agencies to identify implementation issues, ensure that the standards reflect tribal needs, and guarantee that the standards provide adequate protection for children. The standards will be issued as regulations…

Educational Policy Issues for the 1990s: Balancing Equity and Excellence in Implementing the Reform Agenda.

ERIC Educational Resources Information Center

Marcoulides, George A.; Heck, Ronald H.

1990-01-01

Discusses problems with reform issues that focus specifically on changing the system of educational policymaking to achieve excellence but lack safeguards against compromising equality of educational opportunity in the public school system. Explores the conflicting political views of reform policy, which include economic issues and democratic…

76 FR 78929 - Establishing Timeframes for Implementation of Product Safety Labeling Changes; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-20

... labeling; (2) supply chain issues; and, (3) other issues. FDA may use the information received to develop...? B. Supply Chain Issues 3. What are the supply chain factors (including storage, shipping, and... the optimal point in the supply chain (e.g., newly manufactured product, newly shipped product) and...

Issues and Concerns Faced by Undergraduate Language Student Teachers during Teaching Practicum Experiences

ERIC Educational Resources Information Center

Ali, Mohd Sofi; Othman, Abdul Jalil; Karim, Abdul Faruk Abdul

2014-01-01

This study examined specific issues and concerns faced by Bachelor of Education student teachers majoring in Language and Literature during their 12-week teaching practicum experience. Specifically, three main areas of concerns were examined. They were: (1) specific issues and concerns related to the implementation of teaching practicum faced by…

Teacher Compensation: Performance Pay and Other Issues. The Informed Educator Series

ERIC Educational Resources Information Center

Protheroe, Nancy

2011-01-01

This "Informed Educator" examines the issue of performance pay for teachers. Research looking for a possible link between performance pay and student learning is examined, and implementation issues are addressed. Finally, the need to broaden the discussion of performance pay to a more comprehensive review that explicitly connects the structure of…

A Cross-site Qualitative Study of Physician Order Entry

PubMed Central

Ash, Joan S.; Gorman, Paul N.; Lavelle, Mary; Payne, Thomas H.; Massaro, Thomas A.; Frantz, Gerri L.; Lyman, Jason A.

2003-01-01

Objective: To describe the perceptions of diverse professionals involved in computerized physician order entry (POE) at sites where POE has been successfully implemented and to identify differences between teaching and nonteaching hospitals. Design: A multidisciplinary team used observation, focus groups, and interviews with clinical, administrative, and information technology staff to gather data at three sites. Field notes and transcripts were coded using an inductive approach to identify patterns and themes in the data. Measurements: Patterns and themes concerning perceptions of POE were identified. Results: Four high-level themes were identified: (1) organizational issues such as collaboration, pride, culture, power, politics, and control; (2) clinical and professional issues involving adaptation to local practices, preferences, and policies; (3) technical/implementation issues, including usability, time, training and support; and (4) issues related to the organization of information and knowledge, such as system rigidity and integration. Relevant differences between teaching and nonteaching hospitals include extent of collaboration, staff longevity, and organizational missions. Conclusion: An organizational culture characterized by collaboration and trust and an ongoing process that includes active clinician engagement in adaptation of the technology were important elements in successful implementation of physician order entry at the institutions that we studied. PMID:12595408

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

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

Ooko, Edna

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 0.7more » ± 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 resistance (MDR) • Biological and Insilco assays to assess effect on P-glycoprotein (P-gp) • Curcumin synthetic derivatives as possible lead compound against multidrug resistant cancer.« less

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

PubMed Central

Bird, Mark F.; Malfacini, Davide; Vezzi, Vanessa; Molinari, Paola; Micheli, Laura; Mannelli, Lorenzo Di Cesare; Ghelardini, Carla; Guerrini, Remo; Calò, Girolamo; Lambert, David G.

2016-01-01

Introduction 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. Methods 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. Results 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. Conclusion 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 properties. PMID:27272042

Anomalous top layer in the inner core beneath the eastern hemisphere

NASA Astrophysics Data System (ADS)

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 below the ICB. The top portion of the inner core in the eastern hemisphere is anomalous compared to the rest of the inner core, in having a flat velocity gradient, higher velocities and higher attenuation.

Development of a theory-informed implementation intervention to improve the triage, treatment and transfer of stroke patients in emergency departments using the Theoretical Domains Framework (TDF): the T3 Trial.

PubMed

Craig, Louise E; Taylor, Natalie; Grimley, Rohan; Cadilhac, Dominique A; McInnes, Elizabeth; Phillips, Rosemary; Dale, Simeon; O'Connor, Denise; Levi, Chris; Fitzgerald, Mark; Considine, Julie; Grimshaw, Jeremy M; Gerraty, Richard; Cheung, N Wah; Ward, Jeanette; Middleton, Sandy

2017-07-17

Theoretical frameworks and models based on behaviour change theories are increasingly used in the development of implementation interventions. Development of an implementation intervention is often based on the available evidence base and practical issues, i.e. feasibility and acceptability. The aim of this study was to describe the development of an implementation intervention for the T 3 Trial (Triage, Treatment and Transfer of patients with stroke in emergency departments (EDs)) using theory to recommend behaviour change techniques (BCTs) and drawing on the research evidence base and practical issues of feasibility and acceptability. A stepped method for developing complex interventions based on theory, evidence and practical issues was adapted using the following steps: (1) Who needs to do what, differently? (2) Using a theoretical framework, which barriers and enablers need to be addressed? (3) Which intervention components (behaviour change techniques and mode(s) of delivery) could overcome the modifiable barriers and enhance the enablers? A researcher panel was convened to review the list of BCTs recommended for use and to identify the most feasible and acceptable techniques to adopt. Seventy-six barriers were reported by hospital staff who attended the workshops (step 1: thirteen TDF domains likely to influence the implementation of the T 3 Trial clinical intervention were identified by the researchers; step 2: the researcher panellists then selected one third of the BCTs recommended for use as appropriate for the clinical context of the ED and, using the enabler workshop data, devised enabling strategies for each of the selected BCTs; and step 3: the final implementation intervention consisted of 27 BCTs). The TDF was successfully applied in all steps of developing an implementation intervention for the T 3 Trial clinical intervention. The use of researcher panel opinion was an essential part of the BCT selection process to incorporate both research evidence and expert judgment. It is recommended that this stepped approach (theory, evidence and practical issues of feasibility and acceptability) is used to develop highly reportable implementation interventions. The classifying of BCTs using recognised implementation intervention components will facilitate generalisability and sharing across different conditions and clinical settings.

33 CFR 230.12 - Notice of intent and scoping.

Code of Federal Regulations, 2011 CFR

2011-07-01

..., DEPARTMENT OF DEFENSE PROCEDURES FOR IMPLEMENTING NEPA § 230.12 Notice of intent and scoping. As soon as... issues to be analyzed in depth. Public concerns on issues, studies needed, alternatives to be examined...

Pharmaceutical information systems and possible implementations of informed consent - developing an heuristic

PubMed Central

2012-01-01

Background Denmark has implemented a comprehensive, nationwide pharmaceutical information system, and this system has been evaluated by the Danish Council of Ethics. The system can be seen as an exemplar of a comprehensive health information system for clinical use. Analysis The paper analyses 1) how informed consent can be implemented in the system and how different implementations create different impacts on autonomy and control of information, and 2) arguments directed towards justifying not seeking informed consent in this context. Results and Conclusion Based on the analysis a heuristic is provided which enables a ranking and estimation of the impact on autonomy and control of information of different options for consent to entry of data into the system and use of data from the system. The danger of routinisation of consent is identified. The Danish pharmaceutical information system raises issues in relation to autonomy and control of information, issues that will also occur in relation to other similar comprehensive health information systems. Some of these issues are well understood and their impact can be judged using the heuristic which is provided. More research is, however needed in relation to routinisation of consent. PMID:23157854

Non-compliance with the International Code of Marketing of Breast Milk Substitutes is not confined to the infant formula industry.

PubMed

Forsyth, Stewart

2013-06-01

Infant feeding policy and practice continues to be a contentious area of global health care. The infant formula industry is widely considered to be the bête noire with frequent claims that they adopt marketing and sales practices that are not compliant with the WHO Code. However, failure to resolve these issues over three decades suggests that there may be wider systemic failings. Review of published papers, commentaries and reports relating to the implementation and governance of the WHO Code with specific reference to issues of non-compliance. The analysis set out in this paper indicates that there are systemic failings at all levels of the implementation and monitoring process including the failure of WHO to successfully 'urge' governments to implement the Code in its entirety; a lack of political will by Member States to implement and monitor the Code and a lack of formal and transparent governance structures. Non-compliance with the WHO Code is not confined to the infant formula industry and several actions are identified, including the need to address issues of partnership working and the establishment of governance systems that are robust, independent and transparent.

Smart-Glasses: Exposing and Elucidating the Ethical Issues.

PubMed

Hofmann, Bjørn; Haustein, Dušan; Landeweerd, Laurens

2017-06-01

The objective of this study is to provide an overview over the ethical issues relevant to the assessment, implementation, and use of smart-glasses. The purpose of the overview is to facilitate deliberation, decision making, and the formation of knowledge and norms for this emerging technology. An axiological question-based method for human cognitive enhancement including an extensive literature search on smart-glasses is used to identify relevant ethical issues. The search is supplemented with relevant ethical issues identified in the literature on human cognitive enhancement (in general) and in the study of the technical aspects of smart-glasses. Identified papers were subject to traditional content analysis: 739 references were identified of which 247 were regarded as relevant for full text examinations, and 155 were included in the study. A wide variety of ethical issues with smart-glasses have been identified, such as issues related to privacy, safety, justice, change in human agency, accountability, responsibility, social interaction, power and ideology. Smart-glasses are envisioned to change individual human identity and behavior as well as social interaction. Taking these issues into account appears to be relevant when developing, deliberating, deciding on, implementing, and using smart-glasses.

Philosophies of Policy Development and Implementation in Technical and Vocational Education. Report on UNESCO/UNEVOC Regional Expert Group Meeting (Auckland, New Zealand, April 2-9, 1995).

ERIC Educational Resources Information Center

Auckland Inst. of Tech. (New Zealand).

This report begins with an outline of key issues in policy development and implementation in technical and vocational education (TVE). It sets forth the bases of policy development and implementation, the purpose of TVE, contextual factors that affect policy development and implementation. The following values significant in policy determination…

Galactic cosmic ray simulation at the NASA Space Radiation Laboratory

PubMed Central

Norbury, John W.; Schimmerling, Walter; Slaba, Tony C.; Azzam, Edouard I.; Badavi, Francis F.; Baiocco, Giorgio; Benton, Eric; Bindi, Veronica; Blakely, Eleanor A.; Blattnig, Steve R.; Boothman, David A.; Borak, Thomas B.; Britten, Richard A.; Curtis, Stan; Dingfelder, Michael; Durante, Marco; Dynan, William S.; Eisch, Amelia J.; Elgart, S. Robin; Goodhead, Dudley T.; Guida, Peter M.; Heilbronn, Lawrence H.; Hellweg, Christine E.; Huff, Janice L.; Kronenberg, Amy; La Tessa, Chiara; Lowenstein, Derek I.; Miller, Jack; Morita, Takashi; Narici, Livio; Nelson, Gregory A.; Norman, Ryan B.; Ottolenghi, Andrea; Patel, Zarana S.; Reitz, Guenther; Rusek, Adam; Schreurs, Ann-Sofie; Scott-Carnell, Lisa A.; Semones, Edward; Shay, Jerry W.; Shurshakov, Vyacheslav A.; Sihver, Lembit; Simonsen, Lisa C.; Story, Michael D.; Turker, Mitchell S.; Uchihori, Yukio; Williams, Jacqueline; Zeitlin, Cary J.

2017-01-01

Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation. PMID:26948012

Galactic cosmic ray simulation at the NASA Space Radiation Laboratory.

PubMed

Norbury, John W; Schimmerling, Walter; Slaba, Tony C; Azzam, Edouard I; Badavi, Francis F; Baiocco, Giorgio; Benton, Eric; Bindi, Veronica; Blakely, Eleanor A; Blattnig, Steve R; Boothman, David A; Borak, Thomas B; Britten, Richard A; Curtis, Stan; Dingfelder, Michael; Durante, Marco; Dynan, William S; Eisch, Amelia J; Robin Elgart, S; Goodhead, Dudley T; Guida, Peter M; Heilbronn, Lawrence H; Hellweg, Christine E; Huff, Janice L; Kronenberg, Amy; La Tessa, Chiara; Lowenstein, Derek I; Miller, Jack; Morita, Takashi; Narici, Livio; Nelson, Gregory A; Norman, Ryan B; Ottolenghi, Andrea; Patel, Zarana S; Reitz, Guenther; Rusek, Adam; Schreurs, Ann-Sofie; Scott-Carnell, Lisa A; Semones, Edward; Shay, Jerry W; Shurshakov, Vyacheslav A; Sihver, Lembit; Simonsen, Lisa C; Story, Michael D; Turker, Mitchell S; Uchihori, Yukio; Williams, Jacqueline; Zeitlin, Cary J

2016-02-01

Most accelerator-based space radiation experiments have been performed with single ion beams at fixed energies. However, the space radiation environment consists of a wide variety of ion species with a continuous range of energies. Due to recent developments in beam switching technology implemented at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), it is now possible to rapidly switch ion species and energies, allowing for the possibility to more realistically simulate the actual radiation environment found in space. The present paper discusses a variety of issues related to implementation of galactic cosmic ray (GCR) simulation at NSRL, especially for experiments in radiobiology. Advantages and disadvantages of different approaches to developing a GCR simulator are presented. In addition, issues common to both GCR simulation and single beam experiments are compared to issues unique to GCR simulation studies. A set of conclusions is presented as well as a discussion of the technical implementation of GCR simulation. Published by Elsevier Ltd.

Implementation of Mamdani Fuzzy Method in Employee Promotion System

NASA Astrophysics Data System (ADS)

Zulfikar, W. B.; Jumadi; Prasetyo, P. K.; Ramdhani, M. A.

2018-01-01

Nowadays, employees are big assets to an institution. Every employee has a different educational background, degree, work skill, attitude and ethic that affect the performance. An institution including government institution implements a promotion system in order to improve the performance of the employees. Pangandaran Tourism, Industry, Trade, and SME Department is one of government agency that implements a promotion system to discover employees who deserve to get promotion. However, there are some practical deficiencies in the promotion system, one of which is the subjectivity issue. This work proposed a classification model that could minimize the subjectivity issue in employee promotion system. This paper reported a classification employee based on their eligibility for promotion. The degree of membership was decided using Mamdani Fuzzy based on determinant factors of the performance of employees. In the evaluation phase, this model had an accuracy of 91.4%. It goes to show that this model may minimize the subjectivity issue in the promotion system, especially at Pangandaran Tourism, Industry, Trade, and SME Department.

Advancing Perspectives of Sustainability and Large-Scale Implementation of Design Teams in Ghana's Polytechnics: Issues and Opportunities

ERIC Educational Resources Information Center

Bakah, Marie Afua Baah; Voogt, Joke M.; Pieters, Jules M.

2012-01-01

Polytechnic staff perspectives are sought on the sustainability and large-scale implementation of design teams (DT), as a means for collaborative curriculum design and teacher professional development in Ghana's polytechnics, months after implementation. Data indicates that teachers still collaborate in DTs for curriculum design and professional…

Charting New Territory: Early Implementation of the Workforce Investment Act. Field Report Series.

ERIC Educational Resources Information Center

Buck, Maria L.

This report highlights issues for policymakers and provides guidance to states and localities implementing the Workforce Investment Act of 1998 (WIA) by describing the successes and struggles of five cities implementing the new legislation. It presents WIA's basic framework and discusses its impact on these four major audiences: employment and…

Service Learning for At-Risk Student Populations: The Contextual Dynamism of Implementation

ERIC Educational Resources Information Center

Akin, Jacob T.; Vesely, Randall S.

2016-01-01

The central purpose of this article is to explore research, issues, and perspectives on the implementation of service learning programs to improve student achievement in at-risk student populations. The implementation of service learning programs takes place within multiple contexts and across several terrains. The complexities of implementing…

Teachers' Reflections on Cooperative Learning: Issues of Implementation

ERIC Educational Resources Information Center

Gillies, Robyn M.; Boyle, Michael

2010-01-01

Cooperative learning (CL) is a well documented pedagogical practice that promotes academic achievement and socialization, yet many teachers struggle with implementing it in their classes. This study reports on the perceptions of 10, middle-year teachers who implemented cooperative learning in a unit of work across two school terms. Data from the…

Pay-for-Performance in Education: An Issue Brief for Business Leaders.

ERIC Educational Resources Information Center

National Alliance of Business, Inc., Washington, DC.

Implementing pay-for-performance salary structures has been used successfully in business and can result in benefits for educational systems when implemented along with other compensation reforms. Business leaders can help in the implementation of teacher pay-for-performance systems in the following ways: (1) ensure that pay-for-performance plans…

A Review of the Change Literature with Implications for ISSOE Dissemination. Second Printing.

ERIC Educational Resources Information Center

Beuke, Vernon; Farrar, Steven

The state of the art in the implementation of education innovation is assessed in three parts: (1) the identification of promising theories, important issues, and proven implementation strategies with emphasis on practical implications; (2) a review of research directly related to the development and implementation of new occupational education…

Issues of Implementation of Early Childhood Education and Support Programs.

ERIC Educational Resources Information Center

Prinsen, Bert

This document comprises three papers related to the implementation of early childhood education, health care, and support programs. The first paper is a brief reflection on the nature of implementation, based on the contributions of Boudewijn Bekkers. The second is a proceedings chapter by Marian Hanrahan titled "Community Based Innovative…

78 FR 16679 - Center for Drug Evaluation and Research Medical Policy Council; Request for Comments

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-18

... Council to ensure better coordination of medical policy development and implementation within CDER and... and implementation. II. Range of Medical Policy Issues To Be Considered FDA envisions a variety of... to other products; or Strategies for implementation of a new policy. III. Establishment of a Docket...

20 CFR 1010.220 - How are recipients required to implement priority of service?

Code of Federal Regulations, 2010 CFR

2010-04-01

... COVERED PERSONS Understanding Priority of Service § 1010.220 How are recipients required to implement...) memoranda of understanding or other service provision agreements, issued or executed by qualified job...

Barriers to Effective Implementation of Programs for the Prevention of Workplace Violence in Hospitals.

PubMed

Blando, James; Ridenour, Marilyn; Hartley, Daniel; Casteel, Carri

2015-01-01

Effective workplace violence (WPV) prevention programs are essential, yet challenging to implement in healthcare. The aim of this study was to identify major barriers to implementation of effective violence prevention programs. After reviewing the related literature, the authors describe their research methods and analysis and report the following seven themes as major barriers to effective implementation of workplace violence programs: a lack of action despite reporting; varying perceptions of violence; bullying; profit-driven management models; lack of management accountability; a focus on customer service; and weak social service and law enforcement approaches to mentally ill patients. The authors discuss their findings in light of previous studies and experiences and offer suggestions for decreasing WPV in healthcare settings. They conclude that although many of these challenges to effective implementation of workplace violence programs are both within the program itself and relate to broader industry and societal issues, creative innovations can address these issues and improve WPV prevention programs.

Barriers to Effective Implementation of Programs for the Prevention of Workplace Violence in Hospitals.

PubMed

Blando, James; Ridenour, Marilyn; Hartley, Daniel; Casteel, Carri

2014-12-04

Effective workplace violence (WPV) prevention programs are essential, yet challenging to implement in healthcare. The aim of this study was to identify major barriers to implementation of effective violence prevention programs. After reviewing the related literature, the authors describe their research methods and analysis and report the following seven themes as major barriers to effective implementation of workplace violence programs: a lack of action despite reporting; varying perceptions of violence; bullying; profit-driven management models; lack of management accountability; a focus on customer service; and weak social service and law enforcement approaches to mentally ill patients. The authors discuss their findings in light of previous studies and experiences and offer suggestions for decreasing WPV in healthcare settings. They conclude that although many of these challenges to effective implementation of workplace violence programs are both within the program itself and relate to broader industry and societal issues, creative innovations can address these issues and improve WPV prevention programs.

Implementing a Social Knowledge Networking (SKN) system to enable meaningful use of an EHR medication reconciliation system.

PubMed

Rangachari, Pavani

2018-01-01

Despite the regulatory impetus toward meaningful use of electronic health record (EHR) Medication Reconciliation (MedRec) to prevent medication errors during care transitions, hospital adherence has lagged for one chief reason: low physician engagement, stemming from lack of consensus about which physician is responsible for managing a patient's medication list. In October 2016, Augusta University received a 2-year grant from the Agency for Healthcare Research and Quality to implement a Social Knowledge Networking (SKN) system for enabling its health system (AU Health) to progress from "limited use" of EHR MedRec technology to "meaningful use." The hypothesis is that SKN would bring together a diverse group of practitioners, to facilitate tacit knowledge exchange on issues related to EHR MedRec, which in turn is expected to increase practitioners' engagement in addressing those issues and enable meaningful use of EHR. The specific aims are to examine: 1) user-engagement in the SKN system, and 2) associations between "SKN use" and "meaningful use" of EHR. The 2-year project uses an exploratory mixed-method design and consists of three phases: 1) development; 2) SKN implementation; and 3) analysis. Phase 1, completed in May 2017, sought to identify a comprehensive set of issues related to EHR MedRec from practitioners directly involved in the MedRec process. This process facilitated development of a "Reporting Tool" on issues related to EHR MedRec, which, along with an existing "SKN/Discussion Tool," was integrated into the EHR at AU Health. Phase 2 (launched in June 2017) involves implementing the EHR-integrated SKN system over a 52-week period in inpatient and outpatient medicine units. The prospective implementation design is expected to generate context-sensitive strategies for meaningful use and successful implementation of EHR MedRec and thereby make substantial contributions to the patient safety and risk management literature. From a health care policy perspective, if the hypothesis holds, federal vendors could be encouraged to incorporate SKN features into EHR systems.

Towards Behavioral Reflexion Models

NASA Technical Reports Server (NTRS)

Ackermann, Christopher; Lindvall, Mikael; Cleaveland, Rance

2009-01-01

Software architecture has become essential in the struggle to manage today s increasingly large and complex systems. Software architecture views are created to capture important system characteristics on an abstract and, thus, comprehensible level. As the system is implemented and later maintained, it often deviates from the original design specification. Such deviations can have implication for the quality of the system, such as reliability, security, and maintainability. Software architecture compliance checking approaches, such as the reflexion model technique, have been proposed to address this issue by comparing the implementation to a model of the systems architecture design. However, architecture compliance checking approaches focus solely on structural characteristics and ignore behavioral conformance. This is especially an issue in Systems-of- Systems. Systems-of-Systems (SoS) are decompositions of large systems, into smaller systems for the sake of flexibility. Deviations of the implementation to its behavioral design often reduce the reliability of the entire SoS. An approach is needed that supports the reasoning about behavioral conformance on architecture level. In order to address this issue, we have developed an approach for comparing the implementation of a SoS to an architecture model of its behavioral design. The approach follows the idea of reflexion models and adopts it to support the compliance checking of behaviors. In this paper, we focus on sequencing properties as they play an important role in many SoS. Sequencing deviations potentially have a severe impact on the SoS correctness and qualities. The desired behavioral specification is defined in UML sequence diagram notation and behaviors are extracted from the SoS implementation. The behaviors are then mapped to the model of the desired behavior and the two are compared. Finally, a reflexion model is constructed that shows the deviations between behavioral design and implementation. This paper discusses the approach and shows how it can be applied to investigate reliability issues in SoS.

Implementing advanced nurse practitioner roles in acute care: an evaluation of organizational change.

PubMed

Cummings, Greta G; Fraser, Kim; Tarlier, Denise S

2003-03-01

Medical shortages are seen as the driving force behind the recent implementation of the advanced nurse practitioner (ANP) role in some Canadian hospitals. The authors analyzed the implementation of the ANP role in one tertiary care teaching hospital from the organizational change perspective. Despite successful implementation, issues of role definition, scope of practice boundaries, and staff reactions remain unresolved. Recommendations are discussed for implementing ANP roles in other acute care facilities.

Implementation of a documentation model comprising nursing terminologies--theoretical and methodological issues.

PubMed

von Krogh, Gunn; Nåden, Dagfinn

2008-04-01

To describe and discuss theoretical and methodological issues of implementation of a nursing services documentation model comprising NANDA nursing diagnoses, Nursing Intervention Classification and Nursing Outcome Classification terminologies. The model is developed for electronic patient record and was implemented in a psychiatric hospital on an organizational level and on five test wards in 2001-2005. The theory of Rogers guided the process of innovation, whereas the implementation procedure of McCloskey and Bulecheck combined with adult learning principals guided the test site implementation. The test wards managed in different degrees to adopt the model. Two wards succeeded fully, including a ward with high percentage of staff with interdisciplinary background. Better planning regarding the impact of the organization's innovative aptitude, the innovation strategies and the use of differentiated methods regarding the clinician's individual premises for learning nursing terminologies might have enhanced the adoption to the model. To better understand the nature of barriers and the importance of careful planning regarding the implementation of electronic patient record elements in nursing care services, focusing on nursing terminologies. Further to indicate how a theory and specific procedure can be used to guide the process of implementation throughout the different levels of management.

Personal, Electronic, Secure National Library of Medicine Hosts Health Records Conference

MedlinePlus

... Bar Home Current Issue Past Issues EHR Personal, Electronic, Secure: National Library of Medicine Hosts Health Records ... One suggestion for saving money is to implement electronic personal health records. With this in mind, the ...

Development of a novel regulatory pharmacovigilance prioritisation system: an evaluation of its performance at the UK Medicines and Healthcare products Regulatory Agency.

PubMed

Seabroke, Suzie; Wise, Lesley; Waller, Patrick

2013-10-01

The prioritisation of drug safety issues for further evaluation or regulatory action is critical to ensure that acceptable timelines and appropriate resource allocation are defined to meet public health and regulatory obligations. Our objective was to develop, pilot and implement a novel tool for prioritising pharmacovigilance issues within the Medicines and Healthcare products Regulatory Agency (MHRA). An initial system was developed empirically and then piloted over a 10-month period in the pharmacovigilance signal management meeting at the MHRA that discusses potential pharmacovigilance issues, and determines, through consensus, their priority and a timescale for action. The priority assigned by the tool was compared with the priority decided by collective judgement at the meeting. Once an acceptable level of concordance between the tool and the meeting had been achieved, the finalised tool was implemented into routine use at the MHRA, with an evaluation of its performance conducted after the first year. The Regulatory Pharmacovigilance Prioritisation System (RPPS) tool prioritises pharmacovigilance issues according to the following four broad categories, each with four inputs: strength of evidence, public health implications, agency regulatory obligations and public perceptions. A weighted scoring system links the inputs to a pre-defined number of points where if a threshold is reached then the points are awarded. The overall priority is determined by the sum of all points obtained from each of the inputs. The pilot study included a total of 73 pharmacovigilance issues during the 10-month study period, with an overall exact agreement between the RPPS priority and the collective judgement of the meeting of 60.3 %. Where exact agreement was not obtained, the RPPS generally prioritised the issues slightly higher than the meeting. Over the first year following implementation, the RPPS achieved an overall exact agreement of 82.2 %. Following the pilot study and implementation at the UK MHRA, the RPPS has provided a systematic approach to drug safety issue prioritisation that should help to reduce the subjectivity of reliance on individual judgement.

International Education Issues in Saudi Arabia's Public Education Curricula: An Analytical Study

ERIC Educational Resources Information Center

Almogbel, Ali Naser

2015-01-01

The objective of this study is to improve the situation of the general education curriculum in Saudi Arabia, in line with global aspirations in this area and a proposal to implement international education issues in general education curricula. The study was centered on answering the following questions: What is the reality of issues of…

Design and Implementation Issues in Surveying the Views of Young Children in Ethnolinguistically Diverse Developing Country Contexts

ERIC Educational Resources Information Center

Smith, Hilary A.; Haslett, Stephen J.

2016-01-01

This paper discusses issues in the development of a methodology appropriate for eliciting sound quantitative data from primary school children in the complex contexts of ethnolinguistically diverse developing countries. Although these issues often occur in field-based surveys, the large extent and compound effects of their occurrence in…

Identifying the challenges and facilitators of implementing a COPD care bundle.

PubMed

Lennox, Laura; Green, Stuart; Howe, Cathy; Musgrave, Hannah; Bell, Derek; Elkin, Sarah

2014-01-01

Care bundles have been shown to improve outcomes, reduce hospital readmissions and reduce length of hospital stay; therefore increasing the speed of uptake and delivery of care bundles should be a priority in order to deliver more timely improvements and consistent high-quality care. Previous studies have detailed the difficulties of obtaining full compliance to bundle elements but few have described the underlying reasons for this. In order to improve future implementation this paper investigates the challenges encountered by clinical teams implementing a chronic obstructive pulmonary disease (COPD) care bundle and describes actions taken to overcome these challenges. An initial retrospective documentary analysis of data from seven clinical implementation teams was undertaken to review the challenges faced by the clinical teams. Three focus groups with healthcare professionals and managers explored solutions to these challenges developed during the project. Documentary analysis identified 28 challenges which directly impacted implementation of the COPD care bundle within five themes; staffing, infrastructure, process, use of improvement methodology and patient and public involvement. Focus groups revealed that the five most significant challenges for all groups were: staff too busy, staff shortages, lack of staff engagement, added workload of the bundle and patient coding issues. The participants shared facilitating factors used to overcome issues including: shifting perceptions to improve engagement, further education sessions to increase staff participation and gaining buy-in from managers through payment frameworks. Maximising the impact of a care bundle relies on its successful and timely implementation. Teams implementing the COPD care bundle encountered challenges that were common to all teams and sites. Understanding and learning from the challenges faced by previous endeavours and identifying the facilitators to overcoming these barriers provides an opportunity to mitigate issues that waste time and resources, and ensures that training can be tailored to the anticipated challenges.

77 FR 39425 - Approval and Promulgation of Implementation Plans; Louisiana; Regional Haze State Implementation...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-03

... disapproval because of deficiencies in Louisiana's RH SIP submittal that go beyond the issues addressed in the... submittal includes several deficient provisions. The deficiencies identified in the proposal go beyond those...

Identifying impediments and solutions to sidewalk project implementation in Pennsylvania.

DOT National Transportation Integrated Search

2016-09-30

The purpose of this research project was to evaluate the implementation issues of sidewalk projects that are funded through various federal programs administrated by the Pennsylvania Department of Transportation (PennDOT). This evaluation has identif...

Integrated corridor management : implementation guide and lessons learned.

DOT National Transportation Integrated Search

2012-02-01

This implementation guide is intended for use by adopters of integrated corridor management (ICM) approaches and strategies to address congestion and travel time reliability issues within specific travel corridors. It introduces the topic of ICM and ...

Preserving the Future from the Demands of the Present

ERIC Educational Resources Information Center

Ardaiolo, Frank P.

2010-01-01

This chapter offers a case study of how one institution has implemented budget reductions. Using a narrative approach, the vice president for student life reviews the issues faced and the processes used to implement the changes.

50 CFR 600.1004 - Accepting a request for, and determinations about initiating, a financed program.

Code of Federal Regulations, 2011 CFR

2011-10-01

... design, propose, and adopt a timely and reliable implementation plan as well as propose and issue timely and reliable implementation regulations and otherwise complete the program in accordance with this...

Implementation of Audio Computer-Assisted Interviewing Software in HIV/AIDS Research

PubMed Central

Pluhar, Erika; Yeager, Katherine A.; Corkran, Carol; McCarty, Frances; Holstad, Marcia McDonnell; Denzmore-Nwagbara, Pamela; Fielder, Bridget; DiIorio, Colleen

2007-01-01

Computer assisted interviewing (CAI) has begun to play a more prominent role in HIV/AIDS prevention research. Despite the increased popularity of CAI, particularly audio computer assisted self-interviewing (ACASI), some research teams are still reluctant to implement ACASI technology due to lack of familiarity with the practical issues related to using these software packages. The purpose of this paper is to describe the implementation of one particular ACASI software package, the Questionnaire Development System™ (QDS™), in several nursing and HIV/AIDS prevention research settings. We present acceptability and satisfaction data from two large-scale public health studies in which we have used QDS with diverse populations. We also address issues related to developing and programming a questionnaire, discuss practical strategies related to planning for and implementing ACASI in the field, including selecting equipment, training staff, and collecting and transferring data, and summarize advantages and disadvantages of computer assisted research methods. PMID:17662924

Examining the Multi-level Fit between Work and Technology in a Secure Messaging Implementation.

PubMed

Ozkaynak, Mustafa; Johnson, Sharon; Shimada, Stephanie; Petrakis, Beth Ann; Tulu, Bengisu; Archambeault, Cliona; Fix, Gemmae; Schwartz, Erin; Woods, Susan

2014-01-01

Secure messaging (SM) allows patients to communicate with their providers for non-urgent health issues. Like other health information technologies, the design and implementation of SM should account for workflow to avoid suboptimal outcomes. SM may present unique workflow challenges because patients add a layer of complexity, as they are also direct users of the system. This study explores SM implementation at two Veterans Health Administration facilities. We interviewed twenty-nine members of eight primary care teams using semi-structured interviews. Questions addressed staff opinions about the integration of SM with daily practice, and team members' attitudes and experiences with SM. We describe the clinical workflow for SM, examining complexity and variability. We identified eight workflow issues directly related to efficiency and patient satisfaction, based on an exploration of the technology fit with multilevel factors. These findings inform organizational interventions that will accommodate SM implementation and lead to more patient-centered care.

Ethics and community-based participatory research: perspectives from the field.

PubMed

Bastida, Elena M; Tseng, Tung-Sung; McKeever, Corliss; Jack, Leonard

2010-01-01

Exploring the importance of ethical issues in the conduct of community-based participatory research (CBPR) continues to be an important topic for researchers and practitioners. This article uses the Beyond Sabor Project, a CBPR project implemented in the Lower Rio Grande Valley, as a case example to discuss ethical issues such as the importance of increasing community involvement in research, ensuring that communities benefit from the research, sharing leadership roles, and sensitive issues regarding data collection and sharing. Thereafter, this article concludes with a brief discussion of six principles that can inform the practice of ethical conduct when implementing CBPR studies. This article also lists additional reading resources on the importance of ethics in the conduct of CBPR.

Designing and implementing a balanced scorecard: lessons learned in nonprofit implementation.

PubMed

Gumbus, Andra; Wilson, Tom

2004-01-01

The balanced scorecard has been referred to as the management innovation of the century, and extensive articles have been written using case studies of organizations that use this performance measurement system. This article addresses the key issues of design and implementation with a step-by-step guide to how to design a balanced scorecard and lessons to avoid implementation problems in government and nonprofit settings.

The Collier Chautauqua program: A formative evaluation of the implementation of the Iowa Chautauqua model of professional development and its effectiveness in improving science teaching

NASA Astrophysics Data System (ADS)

Dass, Pradeep Maxwell

1997-11-01

A formative evaluation of the implementation of the Iowa Chautauqua model of professional development in Collier County, Florida, was conducted during 1995-97, focusing on implementation issues and teacher enhancement. Major findings are as follows: Implementation issues. (1) Development of a shared vision through collaborative interaction between teachers, school administrators, and district administrators is critical to successful program implementation. (2) When a new program is implemented on a district-wide basis, the success of implementation depends upon how well the program matches local goals and needs and how ready the district and teachers are to make changes necessary for implementing the tenets of the program. (3) Development of proper understanding of desired pedagogical approaches requires modeling of these approaches in program activities, with explicit attention drawn to the modeling. (4) Successful implementation of desired pedagogical approaches in the classroom is critically influenced by the support and continual feedback teachers receive from district administrators, building administrators, and their peers. (5) Unwavering commitment of district and school administrators is essential for encouraging more teachers to participate in the program, leading to district-wide implementation without making it mandatory. Teacher Enhancement. (1) Participants developed leadership skills in mentorship, teamwork, presenting at professional meetings, and assuming responsibility within the program. (2) Participants learned to focus more on student questions and concerns, value prior conceptions of students, and develop instructional activities accordingly. They grew in their understanding and use of the constructivist pedagogy. (3) Participants attitude toward teaching in general and science in particular improved markedly, leading to new excitement and enthusiasm toward their profession. (4) Participants became more confident about teaching science. Elementary teachers reported spending more time on science activities and integrating science topics more with other curricular areas. (5) Participants collaborated more with their peers, administrators, and local community resources in improving instructional activities, providing more meaningful learning experiences for their students. (6) Participants integrated more technological resources than they did formerly, helping students explore avenues otherwise inaccessible. This investigation reveals that teacher enhancement is closely related to changed practice, which is critically influenced by implementation issues at broader levels.

A Nationwide Study of Pharmacists' Perception of the Impact of Medicare Part D on the Pharmacist-Patient Relationship.

PubMed

Spooner, Joshua J; Spotts, Harlan; Khan, Shamima

2017-10-01

Medicare Part D was implemented in 2006, introducing change to the community pharmacy marketplace, with profound disruption to independent pharmacy operations across the United States. To understand pharmacist perceptions about Part D and their perceived obligation to address Part D issues on behalf of their beneficiaries. A nationwide, cross-sectional survey of pharmacists was conducted between April and July 2013. The 43-item online survey collected information about demographics, implications of Part D on community pharmacy and patients, and beliefs about ideal pharmacy practice. Pharmacists reported more responsibility to address prior authorization issues (55.3% strongly agree or agree) than dispensing preferred medications (43.5%) or addressing patient copayment issues (38.1%). Predictors of the perceived responsibility to assist patients varied and included practice site, pharmacist age, pharmacy prescription volume, and pharmacy financial performance. Financial concerns continue to be the most significant issue following Part D implementation. The degree to which pharmacists feel responsible for addressing patient Part D concerns is variable and dependent on a variety of factors. Pharmacists who felt a personal responsibility to address patient copayment issues reported a better pharmacy financial performance, a larger increase in prescription volume, and a better pharmacist-patient relationship since Part D implementation. Nationwide, Part D financial concerns remain significant. Pharmacists can assist patients with managing cost issues, which can help alleviate pharmacy financial concerns. Many pharmacists practicing at independent locations do not feel responsible for addressing patient cost concerns, which may inadvertently impart a negative financial effect upon their pharmacy.

Toward a sustainable biomedical research enterprise: Finding consensus and implementing recommendations

PubMed Central

Pickett, Christopher L.; Corb, Benjamin W.; Matthews, C. Robert; Sundquist, Wesley I.; Berg, Jeremy M.

2015-01-01

The US research enterprise is under significant strain due to stagnant funding, an expanding workforce, and complex regulations that increase costs and slow the pace of research. In response, a number of groups have analyzed the problems and offered recommendations for resolving these issues. However, many of these recommendations lacked follow-up implementation, allowing the damage of stagnant funding and outdated policies to persist. Here, we analyze nine reports published since the beginning of 2012 and consolidate over 250 suggestions into eight consensus recommendations made by the majority of the reports. We then propose how to implement these consensus recommendations, and we identify critical issues, such as improving workforce diversity and stakeholder interactions, on which the community has yet to achieve consensus. PMID:26195768

Developing Information Systems for Competitive Intelligence Support.

ERIC Educational Resources Information Center

Hohhof, Bonnie

1994-01-01

Discusses issues connected with developing information systems for competitive intelligence support; defines the elements of an effective competitive information system; and summarizes issues affecting system design and implementation. Highlights include intelligence information; information needs; information sources; decision making; and…

Implementing and Evaluating School-Based Primary Prevention Programs and the Importance of Differential Effects on Outcomes

ERIC Educational Resources Information Center

Hussey, David L.; Flannery, Daniel J.

2007-01-01

In 2004, Second Step (Committee for Children, 2002), a violence prevention program, was implemented in the Cleveland Heights-University Heights school district for 1,416 K through second grade students. Both process and outcome measures were used to evaluate program impact and examine issues related to the implementation and evaluation of…

autokonf - A Configuration Script Generator Implemented in Perl

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

Reus, J F

This paper discusses configuration scripts in general and the scripting language issues involved. A brief description of GNU autoconf is provided along with a contrasting overview of autokonf, a configuration script generator implemented in Perl, whose macros are implemented in Perl, generating a configuration script in Perl. It is very portable, easily extensible, and readily mastered.

Implementation Issues: A "FRIENDS for Life" Course in a Mainstream Secondary School

ERIC Educational Resources Information Center

Green, Sarah L.; Atkinson, Sarah

2016-01-01

"FRIENDS for life" is a manualised, 10 week, Cognitive Behavioural Therapy (CBT) based programme designed to be run in school and community settings. The aim of this study was to evaluate the impact of "FRIENDS for life" when implemented in a mainstream secondary school by school staff. Data regarding implementation of the…

Implementation Fidelity of MyTeachingPartner Literacy and Language Activities: Association with Preschoolers' Language and Literacy Growth

ERIC Educational Resources Information Center

Hamre, Bridget K.; Justice, Laura M.; Pianta, Robert C.; Kilday, Carolyn; Sweeney, Beverly; Downer, Jason T.; Leach, Allison

2010-01-01

There is surprisingly little empirical research examining issues of fidelity of implementation within the early childhood education literature. In the MyTeachingPartner project, 154 teachers were provided with materials to implement a supplemental classroom curriculum addressing six aspects of literacy and language development. The present study…

Never the twain shall meet? - a comparison of implementation science and policy implementation research

PubMed Central

2013-01-01

Background Many of society’s health problems require research-based knowledge acted on by healthcare practitioners together with implementation of political measures from governmental agencies. However, there has been limited knowledge exchange between implementation science and policy implementation research, which has been conducted since the early 1970s. Based on a narrative review of selective literature on implementation science and policy implementation research, the aim of this paper is to describe the characteristics of policy implementation research, analyze key similarities and differences between this field and implementation science, and discuss how knowledge assembled in policy implementation research could inform implementation science. Discussion Following a brief overview of policy implementation research, several aspects of the two fields were described and compared: the purpose and origins of the research; the characteristics of the research; the development and use of theory; determinants of change (independent variables); and the impact of implementation (dependent variables). The comparative analysis showed that there are many similarities between the two fields, yet there are also profound differences. Still, important learning may be derived from several aspects of policy implementation research, including issues related to the influence of the context of implementation and the values and norms of the implementers (the healthcare practitioners) on implementation processes. Relevant research on various associated policy topics, including The Advocacy Coalition Framework, Governance Theory, and Institutional Theory, may also contribute to improved understanding of the difficulties of implementing evidence in healthcare. Implementation science is at a relatively early stage of development, and advancement of the field would benefit from accounting for knowledge beyond the parameters of the immediate implementation science literature. Summary There are many common issues in policy implementation research and implementation science. Research in both fields deals with the challenges of translating intentions into desired changes. Important learning may be derived from several aspects of policy implementation research. PMID:23758952

Never the twain shall meet?--a comparison of implementation science and policy implementation research.

PubMed

Nilsen, Per; Ståhl, Christian; Roback, Kerstin; Cairney, Paul

2013-06-10

Many of society's health problems require research-based knowledge acted on by healthcare practitioners together with implementation of political measures from governmental agencies. However, there has been limited knowledge exchange between implementation science and policy implementation research, which has been conducted since the early 1970s. Based on a narrative review of selective literature on implementation science and policy implementation research, the aim of this paper is to describe the characteristics of policy implementation research, analyze key similarities and differences between this field and implementation science, and discuss how knowledge assembled in policy implementation research could inform implementation science. Following a brief overview of policy implementation research, several aspects of the two fields were described and compared: the purpose and origins of the research; the characteristics of the research; the development and use of theory; determinants of change (independent variables); and the impact of implementation (dependent variables). The comparative analysis showed that there are many similarities between the two fields, yet there are also profound differences. Still, important learning may be derived from several aspects of policy implementation research, including issues related to the influence of the context of implementation and the values and norms of the implementers (the healthcare practitioners) on implementation processes. Relevant research on various associated policy topics, including The Advocacy Coalition Framework, Governance Theory, and Institutional Theory, may also contribute to improved understanding of the difficulties of implementing evidence in healthcare. Implementation science is at a relatively early stage of development, and advancement of the field would benefit from accounting for knowledge beyond the parameters of the immediate implementation science literature. There are many common issues in policy implementation research and implementation science. Research in both fields deals with the challenges of translating intentions into desired changes. Important learning may be derived from several aspects of policy implementation research.

Service quality: understanding and implementing the concept in the clinical laboratory. Match service quality to consumer expectations.

PubMed

O'Connor, S J

1989-01-01

The increasingly competitive health-care marketplace has mandated that health-care managers pay careful attention to the issue of quality from the perspective of the consumer. The importance of this issue is underscored by the fact that numerous health-care institutions and associations have recently begun to recognize the urgent need to obtain a greater understanding of service quality in a health-care situation. This article suggests means to understand, identify, improve, and implement effective approaches to this vital aspect of the marketing mix.

Mode Selection Techniques in Variable Mass Flexible Body Modeling

NASA Technical Reports Server (NTRS)

Quiocho, Leslie J.; Ghosh, Tushar K.; Frenkel, David; Huynh, An

2010-01-01

In developing a flexible body spacecraft simulation for the Launch Abort System of the Orion vehicle, when a rapid mass depletion takes place, the dynamics problem with time varying eigenmodes had to be addressed. Three different techniques were implemented, with different trade-offs made between performance and fidelity. A number of technical issues had to be solved in the process. This paper covers the background of the variable mass flexibility problem, the three approaches to simulating it, and the technical issues that were solved in formulating and implementing them.

Practical lessons in remote connectivity.

PubMed Central

Kouroubali, A.; Starren, J.; Barrows, R. C.; Clayton, P. D.

1997-01-01

Community Health Information Networks (CHINs) require the ability to provide computer network connections to many remote sites. During the implementation of the Washington Heights and Inwood Community Health Management Information System (WHICHIS) at the Columbia-Presbyterian Medical Center (CPMC), a number of remote connectivity issues have been encountered. Both technical and non-technical issues were significant during the installation. We developed a work-flow model for this process which may be helpful to any health care institution attempting to provide seamless remote connectivity. This model is presented and implementation lessons are discussed. PMID:9357643

Data link communications in the National Airspace System

NASA Technical Reports Server (NTRS)

Lee, Alfred T.

1989-01-01

In the near future, conventional radio communications, currently the primary medium for the transfer of information between aircraft and ground stations, will be replaced by digital data link. This paper briefly describes this technology and summarizes what are believed to be the principal human factor issues associated with data link implementation in the airspace system. Integration of data link communications with existing systems on the flight deck and in the Air Traffic Control system is discussed with regard for both near term implementation and longer term operational issues.

28 CFR 61.1 - Background.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) PROCEDURES FOR IMPLEMENTING THE NATIONAL ENVIRONMENTAL POLICY... 102(2) of NEPA contains certain procedural requirements directed toward the attainment of such goals... regulations to implement the procedural provisions of NEPA. Accordingly, CEQ issued final NEPA regulations, 40...

28 CFR 61.1 - Background.

Code of Federal Regulations, 2012 CFR

2012-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) PROCEDURES FOR IMPLEMENTING THE NATIONAL ENVIRONMENTAL POLICY... 102(2) of NEPA contains certain procedural requirements directed toward the attainment of such goals... regulations to implement the procedural provisions of NEPA. Accordingly, CEQ issued final NEPA regulations, 40...

28 CFR 61.1 - Background.

Code of Federal Regulations, 2014 CFR

2014-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) PROCEDURES FOR IMPLEMENTING THE NATIONAL ENVIRONMENTAL POLICY... 102(2) of NEPA contains certain procedural requirements directed toward the attainment of such goals... regulations to implement the procedural provisions of NEPA. Accordingly, CEQ issued final NEPA regulations, 40...

28 CFR 61.1 - Background.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) PROCEDURES FOR IMPLEMENTING THE NATIONAL ENVIRONMENTAL POLICY... 102(2) of NEPA contains certain procedural requirements directed toward the attainment of such goals... regulations to implement the procedural provisions of NEPA. Accordingly, CEQ issued final NEPA regulations, 40...

28 CFR 61.1 - Background.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Administration DEPARTMENT OF JUSTICE (CONTINUED) PROCEDURES FOR IMPLEMENTING THE NATIONAL ENVIRONMENTAL POLICY... 102(2) of NEPA contains certain procedural requirements directed toward the attainment of such goals... regulations to implement the procedural provisions of NEPA. Accordingly, CEQ issued final NEPA regulations, 40...

Identifying impediments and solutions to sidewalk project implementation in Pennsylvania : final report.

DOT National Transportation Integrated Search

2016-09-30

The purpose of this research project was to evaluate the implementation issues of sidewalk projects that are funded through various federal programs administrated by the Pennsylvania Department of Transportation (PennDOT). This evaluation has identif...

Integrating natural and social sciences to inspire public confidence in radioactive waste policy case study - Committee on radioactive waste management

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

Usher, Sam

2007-07-01

Integrating Natural and Social Sciences to Inspire Public Confidence in Radioactive Waste Policy Case Study: Committee on Radioactive Waste Management Implementing effective long-term radioactive waste management policy is challenging, and both UK and international experience is littered with policy and programme failures. Policy must not only be underpinned by sound science and technical rationale, it must also inspire the confidence of the public and other stakeholders. However, in today's modern society, communities will not simply accept the word of scientists for setting policy based purely on technical grounds. This is particularly so in areas where there are significant social andmore » ethical issues, such as radioactive waste disposal. To develop and implement effective policy, governments, waste owners and implementing bodies must develop processes which effectively integrate both complex technical and scientific issues, with equally challenging social and ethical concerns. These integrating processes must marry often intricate technical issues with broad public and stakeholder engagement programmes, in programmes which can expect the highest levels of public scrutiny, and must invariably be delivered within challenging time and budget constraints. This paper considers a model for how such integrating processes can be delivered. The paper reviews, as a case study, how such challenges were overcome by the Committee on Radioactive Waste Management (CoRWM), which, in July 2006, made recommendations to the UK government for the establishment of a long-term radioactive waste policy. Its recommendations were underpinned by sound science, but also engendered public confidence through undertaking the largest and most significant deliberative public and stakeholder engagement programme on a complex policy issue in the UK. Effective decision-making was enabled through the integration of both proven and bespoke methodologies, including Multi-criteria Decision Analysis and Holistic assessments, coupled with an overarching deliberative approach. How this was managed and delivered to programme demonstrates how important effective integration of different issues, interests and world views can be achieved, and the paper looks forward to how the continued integration of both natural and social sciences is essential if public confidence is to be maintained through implementation stages. This paper will be particularly relevant to governments, waste owners and implementing bodies who are responsible for developing and implementing policy. (author)« less

Technology Solutions for Schools.

ERIC Educational Resources Information Center

Association of School Business Officials International, Reston, VA.

This publication is the third of three publications to assist school business officials with the challenges of improving school facilities. This report explores issues relating to technology implementation in school buildings, including cost and finance issues, space requirements, classroom configuration, equity in technology availability,…

Evaluation of design and construction issues of thin HMA overlays.

DOT National Transportation Integrated Search

2015-04-01

While the overall implementation of thin HMA overlays in Texas has been successful, some issues need to be addressed: : appropriate blending of SAC A and SAC B aggregate to ensure adequate skid resistance; best practices to achieve adequate bonding :...

ITS National Architecture -- Rural Issues Workshop

DOT National Transportation Integrated Search

1995-06-15

THE PURPOSE OF THE WORKSHOP IS TO BRING TOGETHER A DIVERSITY OF PEOPLE INTERESTED IN HOW THE NATIONAL ITS ARCHITECTURE IS ADDRESSING ISSUES THAT IMPACT IMPLEMENTATION OF ITS IN RURAL AREAS (AND TO WHAT DEGREE IT ADDRESSES THEM). : THE TWO-DAY AGEN...

Urban School Facilities: An A-Z Primer. IssueTrak: A CEFPI Brief on Educational Facility Issues

ERIC Educational Resources Information Center

DeJong, William S.

2004-01-01

This "IssueTrak" addresses the condition of urban school facilities as a matter of great urgency. Facility planners, are committed to working with urban school districts to develop and implement a systematic approach for modernizing aging urban school facilities. The next generation of school children is far too important and valuable to be forced…

The Use and Management of Infant Teachers' Time: Some Policy Issues.

ERIC Educational Resources Information Center

Campbell, R. J.; And Others

The first part of this paper reviews the literature on fundamental issues that relate to the work of teachers as the national curriculum is implemented in the United Kingdom. These issues include: (1) the work day of junior and secondary school teachers; (2) the politics and sociology of teaching; (3) the work of primary school teachers; and (4)…

Electronic medical archives: a different approach to applying re-signing mechanisms to digital signatures.

PubMed

Chen, Tzer-Long; Lin, Frank Y S

2011-08-01

Electronic medical records can be defined as a digital format of the traditionally paper-based anamneses, which contains the history of a patient such as his somewhat illness, current health problems, and his chronic treatments. An electronic anamnesis is meant to make the patient's health information more conveniently accessible and transferable between different medical institutions and also easier to be kept quite a long time. Because of such transferability and accessibility of electronic anamneses, we can use less resource than before on storing the patients' medical information. This also means that medical care providers could save more funds on record-keeping and access a patient's medical background directly since shown on the computer screen more quickly and easily. Overall, the service quality has seemingly improved greatly. However, the usage of electronic anamneses involves in some concerned issues such as its related law declaration, and the security of the patient's confidential information. Because of these concerns, a secure medical networking scheme is taking into consideration. Nowadays, the administrators at the medical institutions are facing more challenges on monitoring computers and network systems, because of dramatic advances in this field. For instance, a trusted third party is authorized to access some medical records for a certain period of time. In regard to the security purpose, all the electronic medical records are embedded with both of the public-key infrastructure (PKI) cryptography and the digital signature technique so as to ensure the records well-protected. Since the signatures will be invalid due to the revocation or time expiration, the security of records under this premise would turn into vulnerable. Hence, we propose a re-signing scheme, whose purpose is to make a going-expired digital signature been resigned in time, in keeping with the premise of not conflicting with the laws, morals, and privacy while maintaining the security of the electronic medical records.

Inner Core Structure Behind the PKP Core Phase Triplication

NASA Astrophysics Data System (ADS)

Blom, N.; Paulssen, H.; Deuss, A. F.; Waszek, L.

2015-12-01

Despite its small size, the Earth's inner core plays an important role in the Earth's dynamics. Because it is slowly growing, its structure - and the variation thereof with depth - may reveal important clues about the history of the core, its convection and the resulting geodynamo. Learning more about this structure has been a prime effort in the past decades, leading to discoveries about anisotropy, hemispheres and heterogeneity in the inner core in general. In terms of detailed structure, mainly seismic body waves have contributed to these advances. However, at depths between ~100-200 km, the seismic structure is relatively poorly known. This is a result of the PKP core phase triplication and the existence of strong precursors to PKP phases, whose simultaneous arrival hinders the measurement of inner core waves PKIKP at epicentral distances between roughly 143-148°. As a consequence, the interpretation of deeper structure also remains difficult. To overcome these issues, we stack seismograms in slowness and time, separating PKP and PKIKP phases which arrive simultaneously, but with different slowness. We apply this method to study the inner core's Western hemisphere between South and Central America using paths travelling in the quasi-polar direction between epicentral distances of 140-150°. This enables us to measure PKiKP-PKIKP differential travel times up to greater epicentral distance than has previously been done. The resulting differential travel time residuals increase with epicentral distance, indicating a marked increase in seismic velocity with depth compared to reference model AK135 for the studied polar paths. Assuming a homogeneous outer core, these findings can be explained by either (i) inner core heterogeneity due to an increase in isotropic velocity, or (ii) increase in anisotropy over the studied depth range. Our current data set cannot distinguish between the two hypotheses, but in light of previous work we prefer the latter interpretation.

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

PubMed

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.

Safety management practices in small and medium enterprises in India.

PubMed

Unnikrishnan, Seema; Iqbal, Rauf; Singh, Anju; Nimkar, Indrayani M

2015-03-01

Small and medium enterprises (SMEs) are often the main pillar of an economy. Minor accidents, ergonomics problems, old and outdated machinery, and lack of awareness have created a need for implementation of safety practices in SMEs. Implementation of healthy working conditions creates positive impacts on economic and social development. In this study, a questionnaire was developed and administered to 30 randomly chosen SMEs in and around Mumbai, Maharashtra, and other states in India to evaluate safety practices implemented in their facilities. The study also looked into the barriers and drivers for technology innovation and suggestions were also received from the respondent SMEs for best practices on safety issues. In some SMEs, risks associated with safety issues were increased whereas risks were decreased in others. Safety management practices are inadequate in most SMEs. Market competitiveness, better efficiency, less risk, and stringent laws were found to be most significant drivers; and financial constraints, lack of awareness, resistance to change, and lack of training for employees were found to be main barriers. Competition between SMEs was found to be major reason for implementation of safety practices in the SMEs. The major contribution of the study has been awareness building on safety issues in the SMEs that participated in the project.

Safety Management Practices in Small and Medium Enterprises in India

PubMed Central

Unnikrishnan, Seema; Iqbal, Rauf; Singh, Anju; Nimkar, Indrayani M.

2014-01-01

Background Small and medium enterprises (SMEs) are often the main pillar of an economy. Minor accidents, ergonomics problems, old and outdated machinery, and lack of awareness have created a need for implementation of safety practices in SMEs. Implementation of healthy working conditions creates positive impacts on economic and social development. Methods In this study, a questionnaire was developed and administered to 30 randomly chosen SMEs in and around Mumbai, Maharashtra, and other states in India to evaluate safety practices implemented in their facilities. The study also looked into the barriers and drivers for technology innovation and suggestions were also received from the respondent SMEs for best practices on safety issues. Results In some SMEs, risks associated with safety issues were increased whereas risks were decreased in others. Safety management practices are inadequate in most SMEs. Market competitiveness, better efficiency, less risk, and stringent laws were found to be most significant drivers; and financial constraints, lack of awareness, resistance to change, and lack of training for employees were found to be main barriers. Conclusion Competition between SMEs was found to be major reason for implementation of safety practices in the SMEs. The major contribution of the study has been awareness building on safety issues in the SMEs that participated in the project. PMID:25830070

Telepathology Impacts and Implementation Challenges: A Scoping Review.

PubMed

Meyer, Julien; Paré, Guy

2015-12-01

Telepathology is a particular form of telemedicine that fundamentally alters the way pathology services are delivered. Prior reviews in this area have mostly focused on 2 themes, namely technical feasibility issues and diagnosis accuracy. To synthesize the literature on telepathology implementation challenges and broader organizational and societal impacts and to propose a research agenda to guide future efforts in this domain. Two complementary databases were systematically searched: MEDLINE (PubMed) and ABI/INFORM (ProQuest). Peer-reviewed articles and conference proceedings were considered. The final sample consisted of 159 papers published between 1992 and 2013. This review highlights the diversity of telepathology networks and the importance of considering these distinctions when interpreting research findings. Various network structures are associated with different benefits. Although the dominant rationale in single-site projects is financial, larger centralized and decentralized telepathology networks are targeting a more diverse set of benefits, including extending access to pathology to a whole region, achieving substantial economies of scale in workforce and equipment, and improving quality by standardizing care. Importantly, our synthesis reveals that the nature and scale of encountered implementation challenges also varies depending on the network structure. In smaller telepathology networks, organizational concerns are less prominent, and implementers are more focused on usability issues. As the network scope widens, organizational and legal issues gain prominence.

Two-dimensional gap analysis: a tool for efficient conservation planning and biodiversity policy implementation.

PubMed

Angelstam, Per; Mikusiński, Grzegorz; Rönnbäck, Britt-Inger; Ostman, Anders; Lazdinis, Marius; Roberge, Jean-Michel; Arnberg, Wolter; Olsson, Jan

2003-12-01

The maintenance of biodiversity by securing representative and well-connected habitat networks in managed landscapes requires a wise combination of protection, management, and restoration of habitats at several scales. We suggest that the integration of natural and social sciences in the form of "Two-dimensional gap analysis" is an efficient tool for the implementation of biodiversity policies. The tool links biologically relevant "horizontal" ecological issues with "vertical" issues related to institutions and other societal issues. Using forest biodiversity as an example, we illustrate how one can combine ecological and institutional aspects of biodiversity conservation, thus facilitating environmentally sustainable regional development. In particular, we use regional gap analysis for identification of focal forest types, habitat modelling for ascertaining the functional connectivity of "green infrastructures", as tools for the horizontal gap analysis. For the vertical dimension we suggest how the social sciences can be used for assessing the success in the implementation of biodiversity policies in real landscapes by identifying institutional obstacles while implementing policies. We argue that this interdisciplinary approach could be applied in a whole range of other environments including other terrestrial biota and aquatic ecosystems where functional habitat connectivity, nonlinear response to habitat loss and a multitude of economic and social interests co-occur in the same landscape.

Ten years (1990--1999) of teacher workshops in Investigating and Evaluating Environmental Issues and Actions (IEEIA) curriculum: Teachers' implementation practices and perceptions

NASA Astrophysics Data System (ADS)

Paul, Regina J.

This study examined the success rate of IEEIA inservice training, and attempted to identify key variables that influenced successful implementation of the IEEIA curriculum. The study used both quantitative and qualitative methods to obtain in-depth data. The total sample consisted of 251 participants; 132 usable surveys were returned resulting in a 53% response rate. The quantitative phase of the study consisted of a nine-page survey. The survey was designed to determine the effectiveness of inservice teacher training for the implementation of IEEIA, teachers' implementation, and their perceptions of the effectiveness of the inservice, the impact using IEEIA had on students and themselves, and barriers that prevented complete implementation. Additional analyses examined the relationships between use of the approach with the variables of length and type of training, and support types teachers received. The second phase analyzed both comments written by the respondents on their surveys, and eight teacher interviews. The research found that teachers perceived their workshops to be between moderately to very effective in helping them develop skills related to IEEIA and for teaching them how to implement it with students. Analyses revealed that teachers who received extended training or attended multiple inservices tended to use IEEIA more than teachers who did not. However, the number of years the teachers had been using the approach had a stronger influence for addressing the action components. Over half of the teachers had used the approach. Support after the inservice was important to implementation. The component of having students conduct an actual issue investigation was addressed the most. Fewer teachers addressed the final component of action by having their students resolve the issues they investigated. However, the teachers who fully implemented IEEIA had students who were active in their communities. Teachers perceived using the approach resulted in positive impacts for students, themselves, and their communities.